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IJCP Group of Publications
Volume 28, Number 1, June 2017
Dr Sanjiv Chopra Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor
Dr KK Aggarwal Padma Shri Awardee Group Editor-in-Chief Dr Veena Aggarwal Group Executive Editor
IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das, Dr A Ramachandran, Dr Samith A Shetty, Dr Vijay Viswanathan, Dr V Mohan, Dr V Seshiah, Dr Vijayakumar ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla, Dr JS Rajkumar Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri, Dr Jayakar Thomas Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri, Dr AV Srinivasan Oncology Dr V Shanta Orthopedics Dr J Maheshwari
Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India
FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF
5
Dilli Chalo: Enough is Enough KK Aggarwal
AMERICAN FAMILY PHYSICIAN
8
Diet and Physical Activity for Cardiovascular Disease Prevention Jeffrey B. Lanier, David C. Bury, Sean W. Richardson
DERMATOLOGY
15
Minoxidil* Alone versus Minoxidil* plus ProcapilTM* Combination in Clinical Efficacy Study Srinivas C, Nilanjana Bose
DIABETOLOGY
20
Diabetes Reversal Technique JS Rajkumar, S Akbar, JR Anirudh
ENDOCRINOLOGY
26
Primary Amenorrhea in a Young Female - Complete Androgen Insensitivity Syndrome: A Rare Cause Rajesh Rajput, Deepak Jain, Laxminarayan Yadav, Tekchand Yadav
ENT
31
Globus Hystericus Not Only Headache to Doctor But Also Lump Problem in Throat for Patient: A Study in 100 Patients Shamendra Kumar Meena
GASTROENTEROLOGY
34
A Case Report of Pancreatic Lipomatosis
N Jeeva, S Arun Kumar, Joga Veera Balaji, Deepa James
36
Nonalcoholic Fatty Liver Disease, Cardiovascular Risks and Therapeutic Approaches Pragati Kapoor, Pankaj Kumar, AK Kapoor
HEMATOLOGY
46
Pancytopenia: An Evaluation in a Tertiary Care Center Uma Ramanathan, J Thanka, Lawrence Deruze, S Sri Gayathri
INTERNAL MEDICINE
55
A Case of Leptospirosis Presenting as Multiorgan Failure AK Badrinath, K Suresh, R Raghunathan, Suresh Babu S
NEUROLOGY
58
Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions
This journal is indexed in IndMED (http://indmed.nic.in) and full-text of articles are included in medIND databases (http://mednic.in) hosted by National Informatics Centre, New Delhi.
63
Childhood Multiple Sclerosis: A Diagnostic Challenge Sakshi Singh, Jemima Bhaskar, Manish Mehta, SS Chatterjee
OBSTETRICS AND GYNECOLOGY
Comparison of Serum Anti-mullerian Hormone with Ultrasound as a Diagnostic Marker in Polycystic Ovarian Syndrome Aneesha Awasthy, Shikha Singh, Rekha Rani
OBSTETRICS AND GYNECOLOGY
Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com
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Ectopic Pregnancy Presenting as True Gestational Epilepsy Shyamal G, Vijayalakshmi, Sunil kumar N, Anudeep Reddy
OPHTHALMOLOGY
71
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To Study the Effect of Steroid Eye Drops on Intraocular Pressure After Cataract Surgery Jitender Phogat, Sumit Sachdeva, Sumeet Khanduja, CS Dhull, Himani Anchal
ORTHOPEDICS
75
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Diagnostic Dilemma and Limb Salvage Surgery of a Large Giant Cell Tumor of Fibular Head Involving Posterior Tibial Vessels: A Case Report Mantu Jain, Ritesh Runu, Santosh Kumar, Avnish Sheel, Ritika Choudhry
PEDIATRICS
Editorial Policies
80
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A Study of Sociodemographic Profile of Children with Severe Acute Malnutrition Under 5 Years of Age and Caregivers Characteristics Mudit Kumar Aggarwal, V Krishna Agarwal, S Agarwal
PSYCHIATRY
85
Illness Anxiety Disorder: A Case Report Pankhuri Aggarwal
SURGERY
87
Situs Inversus: A Preoperative Finding Not So Uncommon Venkatesh Subbiah, S Asokan, Somasundaram
MEDILAW
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Issuing a Medical Certificate: Guidelines for Medical Practitioners AROUND THE GLOBE
92
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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF
Dr KK Aggarwal
Padma Shri Awardee Group Editor-in-Chief
Dilli Chalo: Enough is Enough A Big Thank You to each one of you for making it a historical success
T
he Indian Medical Association (IMA) represents the collective consciousness of all of you. Today, we are directly connected to its 3 lakh members and indirectly to more than 12 lakh doctors in the country through Federation of Medical Associations (FOMA) and via the World Medical Association (WMA) to 112 countries. “Dilli Chalo: Enough is Enough” was successfully organized by IMA on June 6, 2017. This date was chosen as it was on June 7, 1983 that Mahatma Gandhi carried out the first act of civil disobedience. We had been working hard for this event over the last 2½ years. This was not a protest or a strike, but a satyagraha, a peaceful movement organized by the IMA to make the nation aware of the atrocities against doctors in the country. The medical profession is being strangulated from all directions. Justice is being denied to doctors even within the framework of the Constitution of India. The day began with homage to the Father of the Nation Mahatma Gandhi at 6.30 AM. The Protest March started at 8:00 AM from Rajghat and reached Indira Gandhi Indoor Stadium by 11:00 AM, where all doctors gathered to deliberate on the issues. The event had unprecedented attendance and participation of doctors from across the country, MBBS students and others associated with the profession.
All members of FOMA participated in the movement. Those not present in person joined the movement digitally over a live webcast. More than a lakh were connected to the movement. Total participation: 66,745 ÂÂ
More than 11,000 doctors marched from Rajghat to Indira Gandhi Stadium
ÂÂ
55,745 digitally present
ÂÂ
Petitions signed: 65,281
ÂÂ
Over a lakh reached through eMedinews and eMediNexus
ÂÂ
WhatsApp videos sent 172564
ÂÂ
Voice SMSs sent: 1,80,000; 32,456 answered the call; 8,634 signed their pledge
We want a central law for violence against doctors, which is occurring with increasing frequency in India and everybody, including the government remain a silent spectator. Doctors themselves are blamed as being the cause of provocation. IMA stands for accountability but no one can be allowed to take the law in their hands. Based on the recommendations of the Inter-ministerial Committee, the Central Govt. should urgently enact a ‘uniform central act against violence’ along the lines of that enacted in 19 states and make violence against doctors a non-bailable offense punishable with up to 14 years
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
5
FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF imprisonment on the lines of abatement of a murder as violence against doctors may cause death of other unattended patients. Criminal prosecution of medical negligence is not acceptable to us. Doctors are now being tried under criminal law for medical negligence. IPC Section 304-A cannot be routinely applied on doctors; it is applicable only when the negligence is ‘gross’, which can be decided only by a Board of Experts. Neither the police nor the complainant can decide if the negligence is criminal negligence or not. As per the Supreme Court Judgment in Jacob Mathew vs State of Punjab, no FIR can be filed against the doctor till a preliminary enquiry reveals a prima facie case of professional negligence. Every doctor is innocent till he/she is convicted. The media should not be allowed to disclose the names of the doctors even before they are convicted in a court of law as this may mean defamation. Criminal penal provisions have also been provided under MTP Act, PCPNDT Act, POCSO Act, HIV-AIDS Act, West Bengal Clinical Establishment Regulatory Commission Act, etc. Under many of these, a doctor can be prosecuted for even non-professional violations like not wearing an apron, not wearing a name plate, etc. The West Bengal Clinical Establishment Regulatory Commission Act has used the word ‘shall’ for imprisonment of up to 3 years for any violation of the act. About 80% of the healthcare services today are handled by private sector indicating that either the services of the government are not up to the mark or they lack adequate infrastructure. It’s the constitutional duty of the government to provide free drugs and investigations for primary and emergency care. Why should doctors face the limitations of the government? Why so many exams for medical students, so many registrations for opening a new medical establishment and so many windows for accountability? We want single window registration and single window accountability. The country is already facing a shortage of doctors, establishment and beds. We want professional autonomy - to choose patients, drugs, brands, investigations and the line of treatment. We say No to National Medical Commission (NMC). Why should the government attempt to constitute
6
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
a bureaucratic, undemocratic, non-representative, 20-member nominated body including 8 non-medical persons to oversee medical education, ethics and practice by abolishing the democratically elected federally-represented 168-member Medical Council of India (MCI). No to NEXT. Why is an MBBS graduate, who has already gone through 36 examinations in 3 dimensions to get his degree, being asked to sit for another 3-hour MCQ test to obtain his license to practice under NEXT? No to crosspathy. We oppose promotion of AYUSH to practice modern medicine. Are we not finishing the very existence of AYUSH in the country? Only doctors of modern system of medicine should be allowed to write scheduled drugs. We demand capping of compensation awarded in cases of medical negligence. When the medical profession is considered a noble profession and doctors provide subsidy in consultation to all patients, than why are compensations awarded in crores based on the patient’s income? The formula 70-age of injury × annual income + 30% 1/3 is not the right formula. Compensation has to take into consideration age of the patient and disease severity along with workman compensation formula. We demand action against quacks. No unqualified person should be allowed to prefix ‘Dr’ before their name. Medicine in the hand of quacks is like handing over a razor to a monkey. Empowerment of MBBS doctors. Today most MBBS doctors are frustrated as their services are inadequately utilized. They need to be empowered. We need more than 25,000 additional PG seats in Family Medicine. IMA should be a part of policy making. We want IMA to be a part of every policy making committee of the government Why are professional decisions about the medical profession taken without taking the medical profession into confidence? We want implementation of recommendations of the Inter-ministerial committee formed more than 2 years back, which is still in the recommendation stages. The ministries involved are Health, Consumer, Law and MCI.
FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF Our Demands ÂÂ
Stringent central act against violence.
ÂÂ
ÂÂ
Criminal prosecution of medical negligence and clerical errors is not acceptable.
Single window registration of doctors and medical establishments.
ÂÂ
Uniform final MBBS exam instead of ‘NEXT’.
ÂÂ
Uniform service conditions for doctors and faculty.
ÂÂ
Same work - Same pay - Pay parity - No to adhocism.
ÂÂ
Fair conduction of NEET exam.
ÂÂ
Capping the compensation awarded under CPA on doctors.
ÂÂ
Professional autonomy prescriptions.
in
treatment
and
ÂÂ
No to NMC: Amend IMC Act to maintain professional autonomy.
ÂÂ
ÂÂ
Amendments in PC PNDT, Central CEA, West Bengal CEA Acts.
IMA member committee.
ÂÂ
Central anti-quackery law.
No unscientific mixing of systems of medicine.
ÂÂ
ÂÂ ÂÂ
Empower MBBS graduates.
Reimbursement of emergency services for private sector.
ÂÂ
One drug - One company - One price.
25,000 Family Medicine PG seats.
ÂÂ
ÂÂ
ÂÂ
Implement Inter-ministerial recommendations in 6 weeks.
Aided hospitals and retainership in general practice.
ÂÂ
ÂÂ
Single window accountability.
Health budget of 5% of GDP for universal health coverage.
Committee
June 6, 2017 will be a memorable day in the history of IMA and will be observed as IMA Sangharsh Day from now onwards. Friends, now is the time to sustain and further strengthen the movement. Our next slogan is “Do not force us to go to a nation-wide strike”.
in
every
government
health
I would like to share here the link to my speech delivered on June 6: Video Link: https://youtu.be/ isl4AfBR17U; on website: http://module.ima-india.org/ dillichalo/live/ I salute all of you for giving me the courage in taking this event forward…
■■■■
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
7
AMERICAN FAMILY PHYSICIAN
Diet and Physical Activity for Cardiovascular Disease Prevention JEFFREY B. LANIER, DAVID C. BURY, SEAN W. RICHARDSON
ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the United States. One-third of these deaths may be preventable through healthy lifestyle choices including diet and physical activity. The Mediterranean diet is associated with reduced cardiovascular mortality, whereas the Dietary Approaches to Stop Hypertension (DASH) eating plan is associated with a reduced risk of coronary artery disease. Substituting dietary saturated fat with polyunsaturated fatty acids is associated with improved cardiovascular outcomes, although exogenous supplementation with omega-3 fatty acids does not improve cardiovascular outcomes. There is an association between increased sodium intake and cardiovascular risk, but reducing dietary sodium has not consistently shown a reduction in cardiovascular risk. Physical activity recommendations for adults are at least 150 minutes of moderate-intensity aerobic activity per week, 75 minutes of vigorous-intensity aerobic activity per week, or an equivalent combination. Increases in physical activity by any level are associated with reduced cardiovascular risk. Introducing muscle-strengthening activities at least twice per week in previously inactive adults is associated with improved cardiovascular outcomes. Inactive adults without known CVD can gradually increase activity to a moderate-intensity level without consulting a physician. The U.S. Preventive Services Task Force recommends behavioral counseling to promote healthy diet and physical activity in adults at high risk of CVD. Evidence of benefit for counseling patients at average risk is less established.
Keywords: Cardiovascular disease prevention, U.S. Preventive Services Task Force, behavioral counseling, healthy diet, physical activity
C
ardiovascular disease (CVD) is the leading cause of death in the United States.1 From 2008 to 2010, CVD accounted for 272,668 deaths annually in persons younger than 80 years. Nearly onethird of deaths from CVD are considered potentially preventable.1 The American Heart Association (AHA) has published recommendations defining ideal cardiovascular health. Recommendations for physical activity in adults are at least 150 minutes of moderateintensity aerobic activity or at least 75 minutes of vigorous-intensity aerobic activity per week.2 Ideal cardiovascular health also includes adhering to at least
four of five components of a diet consistent with the Dietary Approaches to Stop Hyper tension (DASH) 2 eating plan (Table 1). Adherence to these recommendations is low. Only 5% of adults achieve the recom mended amount of moderate-intensity physical activity when objectively measured,3 and only 18% meet the AHA goals for daily fruit and vegetable consumption.4 Additionally, nearly 35% of adults in the United States were obese cians can make an in 2011 and 2012.5 Family physi important contribution by counseling patients on the Table 1. Dietary Approaches to Stop Hypertension (DASH) Eating Plan
JEFFREY B. LANIER, MD, FAAFP, is a physician recruiter for the United States Army Recruiting Command and a staff family physician at Ireland Army Community Hospital, Fort Knox, Ky. At the time the article was written, he was the associate residency director at Martin Army Community Hospital Family Medicine Residency Program, Fort Benning, Ga. DAVID C. BURY, DO, is a staff family physician at U.S. Army Health Clinic, Camp Casey, South Korea. At the time the article was written, he was a third-year family medicine resident at Martin Army Community Hospital Family Medicine Residency Program. SEAN W. RICHARDSON, DO, is a third-year family medicine resident at Martin Army Community Hospital Family Medicine Residency Program. Source: Adapted from Am Fam Physician. 2016;93(11):919-924.
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Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
yy ≥ 4.5 cups of fruits and vegetables per day yy ≥ 2 3.5-oz servings of fish, preferably oily fish, per week yy ≥ 3 1-oz-equivalent servings of fiber-rich whole grains per day (defined as at least 1.1 g of fiber per 10 g of carbohydrate) yy < 1,500 mg of sodium per day yy < 450 calories (36 oz) of sugar-sweetened beverages per week Information from reference 2.
AMERICAN FAMILY PHYSICIAN health benefits of adhering to healthy diet and physical activity recommendations. DIET It is difficult to isolate the effects of individual nutrients on health benefits. Current research suggests the greater importance of viewing diet as a whole rather than focusing on specific nutrients.6,7 Several dietary approaches have been studied for their effects on CVD. Low-fat diets and high-fat, low-carbohydrate diets are popular and effective for weight loss, but there is insufficient evidence to recommend them for primary CVD prevention.8,9 There are several dietary strategies that have been evaluated for patient-oriented outcomes, such as cardiovascular events, cardiovascular mortality, and all-cause mortality. A summary of different dietary strategies is shown in Table 2.7,10-14
Mediterranean Diet Mediterranean diets emphasize diversity and seasonality, fruits and vegetables, whole grains, and olive oil, with moderate intake of fish, seafood, dairy, and wine.12 A 2010 meta-analysis of prospective cohort studies showed that increased adherence to a Mediterranean diet reduced cardiovascular events such as myocardial infarction (MI) and stroke, and lowered cardiovascular mortality (relative risk [RR] = 0.90; 95% confidence interval [CI], 0.87 to 0.93) and all-cause mortality (RR = 0.92; 95% CI, 0.90 to 0.94).13 A 2013 randomized controlled trial (RCT) of 7,447
patients in Spain with type 2 diabetes mellitus or three other cardiovascular risk factors showed that a Mediterranean diet was associated with a five-year reduction in a composite end point of MI, stroke, and cardiovascular mortality. The diet was supplemented with extra virgin olive oil (absolute risk reduction = 0.6%; number needed to treat = 167) or nuts (absolute risk reduction = 1%; number needed to treat = 100).14
Swedish Diet A population-based prospective cohort study of 17,216 men in Sweden evaluated diet quality as measured by adherence to the 2005 Swedish dietary guidelines, emphasizing low intake of saturated fat and sugar, and higher intake of dietary fiber, fish, and fruits and vegetables. The primary composite outcome after 16 years was cardiovascular events including MI, ischemic stroke, or death from ischemic heart disease. Participants with a high-quality diet had a lower risk of cardiovascular events (hazard ratio [HR] = 0.68; 95% CI, 0.49 to 0.73 for men; HR = 0.73; 95% CI, 0.59 to 0.91 for women).7
DASH Eating Plan The DASH eating plan emphasizes a diet with high intake of fruits and vegetables, low-fat dairy products, whole grains, poultry, fish, and nuts, and low intake of total and saturated fat and cholesterol.10 A 2013 metaanalysis of six cohort studies evaluated the association of adherence to the DASH diet and the incidence of cardiovascular outcomes. Adherence decreased the risk
Table 2. Diet and Effects on Cardiovascular Outcomes Diet
Description
Study type
Outcomes studies11
21% reduced risk of coronary artery disease and 21% reduced risk of stroke11
10% reduction in cardiovascular events and 8% reduction in mortality13
DASH eating plan
High intake of fruits and vegetables, low-fat dairy products, whole grains, poultry, fish, and nuts; low intake of total and saturated fat and cholesterol10
Meta-analysis of cohort
Mediterranean diet
Fruits and vegetables; whole grains; olive oil; moderate intake of fish, seafood, dairy, wine12
Meta-analysis of cohort studies13 Spanish randomized controlled
trial14
Reduction in cardiovascular events over 4.8 years14 Swedish diet (based on national standards)
Low intake of saturated fat and sugar; higher intake of dietary fiber, fish, and fruits and vegetables7
Swedish prospective cohort7
Reduced risk of cardiovascular events (32% in men, 27% in women)7
DASH = Dietary Approaches to Stop Hypertension. Information from references 7, and 10 through 14.
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
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AMERICAN FAMILY PHYSICIAN of coronary artery disease (RR = 0.79; 95% CI, 0.71 to 0.88) and stroke (RR = 0.81; 95% CI, 0.72 to 0.92).11
Polyunsaturated Fatty Acids There is significant debate about polyunsaturated fatty acids (PUFAs) and their role in the primary prevention of cardiovascular events. Several meta-analyses of RCTs have shown varying degrees of benefit for omega-3 fatty acids.15 Several of these analyses, however, pooled the effect of increased dietary intake and exogenous supplementation of omega-3 fatty acids. A 2012 meta-analysis of 21 prospective cohort studies involving more than 675,000 participants evaluated fish consumption and cerebrovascular disease over a mean of 15.1 years. The authors found that eating two to four servings of fish weekly was associated with a reduced risk of cerebrovascular disease (RR = 0.94; 95% CI, 0.90 to 0.98). An increase of two servings of any fish per week was associated with a 4% risk reduction of cerebrovascular disease.16 However, a 2014 RCT of more than 4,200 patients 50 to 85 years of age taking omega-3 fatty acids for macular degeneration showed that supplementation did not decrease the risk of cardiovascular events.17 A 2010 meta-analysis of eight RCTs with more than 13,000 patients evaluated an increase in total or omega-6 PUFA intake as a substitute for saturated fat intake. The primary outcome was a composite of cardiovascular events including MI, cardiovascular mortality, or sudden death. In aggregate, participants in the intervention group consumed 15% of daily calories from PUFAs vs. 5% in the control group. Increased PUFA consumption was associated with an RR of 0.81 (95% CI, 0.70 to 0.95) for the primary outcome.18 The U.S. Food and Drug Administration recommends that saturated fats account for no more than 5% to 6% of daily caloric intake.10 Evidence shows that a diet high in PUFAs is associated with a reduction in cardiovascular events, but current evidence does not conclusively support the use of omega-3 fatty acid supplements for CVD prevention.
Sodium Restriction Observational data have linked increased sodium intake in overweight patients to an increased risk of stroke, CVD mortality, and all-cause mortality.19 Increased sodium intake is associated with higher rates of stroke and CVD. Based largely on observational data, the AHA published an updated recommendation in 2012 reaffirming that dietary sodium intake should not exceed 1,500 mg per day.20 However, a 2014 Cochrane
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review of eight RCTs evaluating dietary sodium restriction in normotensive and hypertensive patients showed no effect on cardiovascular outcomes and allcause mortality.21 Current evidence suggests a J-shaped association between sodium intake and CVD, with the lowest risk occurring with consumption of 3 to 5 g of sodium per day.22 Prospective evidence currently does not support sodium restriction. PHYSICAL ACTIVITY Physical activity is routinely recommended to promote optimal cardiovascular health. Physical inactivity and a less active lifestyle have been linked to significant increases in CVD risk.23 Elimination of a sedentary life style may reduce CVD by 15% to 39% and stroke by 33%.23 A meta-analysis of prospective cohort studies estimated that reducing the time spent sitting to less than three hours per day would result in a two-year increase in average life expectancy.24 Observational studies con sistently show an association between increased physical activity and reduction of CVD. A study of 9,181 men and women 50 years and older used self-reports of physical activity to categorize participants into low, moderate, and high levels of activity.25 The primary outcome was incident or fatal CVD. When adjusted for age, sex, and other comorbid conditions, a high level of physical activity was associated with a reduction in incident CVD (HR = 0.77; 95% CI, 0.68 to 0.89) and cardiovascular mortality in patients with baseline CVD (HR = 0.77; 95% CI, 0.65 to 0.89). Additionally, high (HR = 0.68; 95% CI, 0.56 to 0.84) and moderate (HR = 0.78; 95% CI, 0.64 to 0.94) levels of physical activity were associated with a reduction in cardiovascular mortality in patients without baseline CVD.25 Objective parameters of exercise tolerance also show that increased exercise capacity is associated with lower mortality. In one observational study, 6,213 men (mean age = 59 years) were referred for treadmill stress testing and followed for a mean of 6.2 years. Among the men without CVD, there was a significantly increased risk of all-cause mortality (RR = 4.5; 95% CI, 3.0 to 6.8) for those with an exercise capacity of less than six metabolic equivalents compared with those achieving a capacity of at least 13 metabolic equivalents. Additionally, the age-adjusted RR of death incrementally increased with decreasing exercise capacity, both among otherwise healthy participants and those with CVD.26 The 2008 Physical Activity Guidelines for Americans provide recommendations for physical activity (Table 3).27 Adults healthy enough to exercise should engage in a total of 150 minutes of moderate-intensity
AMERICAN FAMILY PHYSICIAN aerobic activ ity or 75 minutes of vigorous-intensity aerobic activity per week. A systematic review of 33 studies evaluated different levels of physical activity on the risk of coronary heart disease.28 Adults who were physically active at half of the level suggested by the 2008 guidelines had reduced risks of coronary heart disease (RR = 0.86; 95% CI, 0.77 to 0.96), similar to the degree of risk reduction observed in those who met the recommended physical activity targets. Those who met the standard for additional health benefits had an additional risk reduction (RR = 0.80; 95% CI, 0.74 to 0.88).28 These data suggest that any physical activity is associated with lower cardiovascular risk, and the Table 3. 2008 Physical Activity Guidelines for Americans yy All adults should avoid inactivity. Adults who participate in any form of physical activity gain health benefits. yy For substantial health benefits, adults should engage in at least 150 minutes of moderate-intensity aerobic activity per week, 75 minutes of vigorous-intensity aerobic activity per week, or an equivalent combination. Aerobic activity should be performed in at least 10-minute bouts and preferably spread throughout the week. yy For additional health benefits, adults should engage in 300 minutes of moderate-intensity aerobic activity per week, 150 minutes of vigorous-intensity aerobic activity per week, or an equivalent combination. Additional health benefits are gained by increasing physical activity above this amount. yy Adults should perform muscle-strengthening activities that are moderate to high intensity and involve all major muscle groups at least twice per week, because these activities are associated with health benefits. Information from reference 27.
benefit increases as the amount of weekly physical activity increases. Analysis of data from the 1999 to 2004 National Health and Nutrition Examination Survey showed that the adjusted HR for all-cause mortality was 44% lower among previously insufficiently active adults who engaged in muscle-strengthening activity at least twice per week.29 The benefits of physical activity on reducing cardiovascular events and mortality have also been demonstrated in men with diabetes. A subset of 2,803 men in the Health Professionals Follow-up Study with self-reported type 2 diabetes at 30 years or older were grouped into quintiles of physical activity and followed for 14 years. Compared with those in the lowest quintile, men who performed in the second quintile of physical activity had a lower risk of fatal CVD (RR = 0.55; 95% CI, 0.32 to 0.96), and continued risk reduction was demonstrated to the highest quintile of physical activity (RR = 0.45; 95% CI, 0.24 to 0.84).30 Data on the effects of physical activity on mortality and cardiovascular events in other high-risk populations are limited. Recommendations for physical activity should be tailored to individual patients’ long-term goals. Various examples of physical activity and their associated levels of intensity are provided in Table 4.23,27 These are general associations; individual effort in each of these activi ties will determine the intensity of the activity. Inactive adults who are otherwise healthy can gradually increase their activity to moderate intensity without consulting a physician.27 Likewise, adults with a baseline regimen of regular moderate-intensity
Table 4. Intensity Levels for Various Forms of Physical Activity Activity category
Mild intensity
Moderate intensity
Vigorous intensity
Gym activities
Slow swimming
Body pump
Climbing
Tai chi
Moderate swimming
Jumping rope
Yoga or Pilates
Water aerobics
Swimming competitively
Walking < 3 mph
Ballroom dancing
Aerobic dancing
Bicycling (< 10 mph)
Bicycling (≥ 10 mph)
General gardening
Hiking uphill or with a heavy pack
Walking briskly (3 mph)
Intense gardening (continuous digging or hoeing)
Physical activities
Racewalking, jogging, or running Sporting activities
Golf
Horseback riding
Canoeing
Hunting
Leisurely canoeing
Mountain biking
Sport fishing
Tennis (doubles)
Tennis (singles)
mph = Miles per hour. Information from references 23 and 27.
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AMERICAN FAMILY PHYSICIAN activity can safely advance to vigorous-intensity activities without consultation.27 PUTTING IT TOGETHER Research on the effect of combined dietary and physical activity interventions on cardiovascular events suggests that there may be more benefit than with either intervention alone. A 2014 population-based cohort study of Swedish men 45 to 79 years of age followed for 12 years showed that the combination of high-quality diet (the highest quintile of adherence to a diet high in fruits and vegetables, legumes, nuts, reduced-fat dairy products, whole grains, and fish) and physically active lifestyle (at least 40 minutes of walking or biking per day and one hour of additional physical activity per week), when added to moderate alcohol consumption and tobacco cessation, was associated with a reduced risk of MI (RR = 0.24; 95% CI, 0.12 to 0.47) compared with those who adopted none of the healthy lifestyle behaviors.31 The U.S. Preventive Services Task Force (USPSTF) currently recommends that physicians consider initiating behavioral counseling in adults without preexisting CVD or CVD risk factors to promote adherence to a healthy diet and physical activity on an individual basis. In addition to CVD risk, they should consider other factors, such as a patient’s readiness to change, social support, and community resources that can provide support. The USPSTF did not find high-quality evidence that behavioral counseling interventions in adults at average risk of CVD reduces CVD events or mortality.32 The USPSTF is currently in the process of updating this recommendation. Benefits of counseling interventions may be more pronounced in groups at higher cardiovascular risk. A 2011 Cochrane review of 55 RCTs reporting on pooled data for multiple counseling and educational methods showed no effect on primary prevention of all-cause or cardiovascular mortality or cardiovascular events. However, all-cause mortality was reduced when including only studies recruiting patients with diabetes or hypertension (RR = 0.78) or in patients taking antihypertensives or lipid-lowering therapy at baseline (RR = 0.86).33 Specific counseling strategies promoting dietary compliance and increased physical activity were not recommended based on this review. The USPSTF found four good-quality trials involving more than 3,900 patients with cardiovascular risk factors that evaluated combined lifestyle-counseling interventions promoting healthy diet and physical
12
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
activity. None of the tri als showed a reduction in mortality or cardiovascular events. One trial that did show benefit had high baseline rates of CVD and allowed for pharmacologic therapy in patients who did not respond to counseling.34 For adults who are overweight (body mass index greater than 25 kg per m2) or obese (body mass index greater than 30 kg per m2) with CVD risk factors (e.g., hypertension, dyslipidemia, impaired glucose tolerance, metabolic syndrome), the USPSTF recommends providing intensive behavioral health counseling to promote a healthy diet and physical activity or referring patients for such services. Effective counseling strategies have involved face-toface sessions with information on diet and physical activity and behavioral change strategies, typically delivered by dietitians or health educators.35 REFERENCES 1. Yoon PW, et al; Centers for Disease Control and Prevention. Potentially preventable deaths from the five leading causes of death—United States, 2008-2010. MMWR Morb Mortal Wkly Rep. 2014;63(17):369-374. 2. Lloyd-Jones DM, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic impact goal through 2020 and beyond. Circula tion. 2010;121(4):586-613. 3. Troiano RP, et al. Physical activity in the United States measured by accelerometer. Med Sci Sports Exerc. 2008;40(1):181-188. 4. Miller RR, Sales AE, Kopjar B, Fihn SD, Bryson CL. Adherence to heart-healthy behaviors in a sample of the U.S. population. Prev Chronic Dis. 2005;2(2):A18. 5. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity among adults: United States, 2011-2012. NCHS Data Brief. 2013;(131):1-8. 6. Akesson A, et al. Low-risk diet and lifestyle habits in the primary prevention of myocardial infarction in men: a population-based prospective cohort study. J Am Coll Cardiol. 2014;64(13):1299-1306. 7. Hlebowicz J, et al. A high diet quality is associated with lower incidence of cardiovascular events in the Malmö diet and cancer cohort. PLoS One. 2013;8(8):e71095. 8. Schwingshackl L, Hoffmann G. Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis. J Acad Nutr Diet. 2013;113(12):1640-1661. 9. Bazzano LA, Hu T, Reynolds K, et al. Effects of lowcarbohydrate and low-fat diets: a randomized trial. Ann Intern Med. 2014;161(5):309-318. 10. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ ACC guideline on life style management to reduce cardiovascular risk: a report of the Ameri can College
AMERICAN FAMILY PHYSICIAN of Cardiology/American Heart Association Task Force on Practice Guidelines [published corrections appear in Circulation. 2014;129(25 suppl 2):S100-S101, and Circulation. 2015;131(4):e326]. Circulation. 2014;129(25 suppl 2): S76-S99. 11. Salehi-Abargouei A, et al. Effects of Dietary Approaches to Stop Hypertension (DASH)-style diet on fatal or nonfatal cardiovascular diseases—incidence: a systematic review and meta-analysis on observational prospective studies. Nutrition. 2013;29(4):611-618. 12. de Lorgeril M, Salen P. Mediterranean diet and n-3 fatty acids in the prevention and treatment of cardiovascular disease. J Cardiovasc Med (Hagerstown). 2007;8(suppl 1): S38-S41. 13. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr. 2010;92(5):1189-1196. 14. Estruch R, Ros E, Salas-Salvadó J, et al.; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet [published correction appears in N Engl J Med. 2014;370(9):886]. N Engl J Med. 2013;368(14):1279-1290. 15. Michas G, Micha R, Zampelas A. Dietary fats and cardiovascular disease: putting together the pieces of a complicated puzzle. Atherosclerosis. 2014;234(2):320-328. 16. Chowdhury R, Stevens S, Gorman D, et al. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ. 2012;345:e6698. 17. Bonds DE, Harrington M, Worrall BB, et al. Effect of longchain ω-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA Intern Med. 2014;174(5):763-771. 18. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and metaanalysis of randomized controlled trials. PLoS Med. 2010;7(3):e1000252.
23. Giada F, Biffi A, Agostoni P, et al.; Joint Italian Societies’ Task Force on Sports Cardiology. Exercise prescription for the prevention and treatment of cardiovascular diseases: part I. J Cardiovasc Med (Hagerstown). 2008;9(5):529-544. 24. Katzmarzyk PT, Lee IM. Sedentary behaviour and life expectancy in the USA: a cause-deleted life table analysis. BMJ Open. 2012;2(4):e000828. 25. Franco OH, de Laet C, Peeters A, Jonker J, Mackenbach J, Nusselder W. Effects of physical activity on life expectancy with cardiovascular disease. Arch Intern Med. 2005;165(20):2355-2360. 26. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exer cise capacity and mortality among men referred for exercise testing. N Engl J Med. 2002;346(11):793-801. 27. U.S. Department of Health and Human Services. 2008 physical activity guidelines for Americans. Office of Disease Prevention and Health Promotion publication no. U0036. October 2008. http://health.gov/paguidelines/pdf/ paguide.pdf. Accessed October 27, 2015. 28. Sattelmair J, Pertman J, Ding EL, Kohl HW III, Haskell W, Lee IM. Dose response between physical activity and risk of coronary heart disease: a meta-analysis. Circulation. 2011;124(7):789-795. 29. Zhao G, Li C, Ford ES, et al. Leisure-time aerobic physical activity, muscle-strengthening activity and mortality risks among US adults: the NHANES linked mortality study. Br J Sports Med. 2014;48(3):244-249. 30. Tanasescu M, Leitzmann MF, Rimm EB, Hu FB. Physical activity in relation to cardiovascular disease and total mortality among men with type 2 diabetes. Circulation. 2003;107(19):2435-2439. 31. Åkesson A, Larsson SC, Discacciati A, Wolk A. Lowrisk diet and lifestyle habits in the primary prevention of myocardial infarction in men: a populationbased prospective cohort study. J Am Coll Cardiol. 2014;64(13):1299-1306. 32. Moyer VA. Behavioral counseling interventions to promote a healthful diet and physical activity for cardiovascular disease prevention in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(5):367-371.
19. He J, et al. Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults. JAMA. 1999;282(21):2027-2034.
33. Ebrahim S, et al. Multiple risk factor interventions for primary prevention of coronary heart disease. Cochrane Database Syst Rev. 2011;(1):CD001561.
20. Whelton PK, et al. Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association sodium reduction recommendations [published correction appears in Circula tion. 2013;27(1):e263]. Circulation. 2012;126(24):2880-2889.
34. Lin JS, et al. Behavioral counseling to promote a healthy lifestyle for cardiovascular disease prevention in persons with cardiovascular risk factors: an updated systematic evidence review for the U.S. Preventive Services Task Force. Evidence synthesis no. 113. Rockville, Md.: Agency for Healthcare Research and Quality (US); August 2014. http://www.ncbi.nlm.nih.gov/books/NBK241537/. Accessed January 26, 2015.
21. Adler AJ, Taylor F, Martin N, Gottlieb S, Taylor RS, Ebrahim S. Reduced dietary salt for the prevention of cardiovascular disease. Cochrane Data base Syst Rev. 2014;(12):CD009217. 22. O’Donnell M, Mente A, Yusuf S. Sodium intake and cardiovascular health. Circ Res. 2015;116(6):1046-1057.
35. LeFevre ML. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors: U.S. Preventive Services Task Force recom mendation statement. Ann Intern Med. 2014;161(8):587-593.
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DERMATOLOGY
Minoxidil* Alone versus Minoxidil* plus ProcapilTM* Combination in Clinical Efficacy Study SRINIVAS C*, NILANJANA BOSE†
ABSTRACT This survey was conducted across various regions in India to evaluate the efficacy of the product and dermatologists’ and patients’ perspectives related to the use of Minoxidil*, either alone or in combination with ProcapilTM* for hair growth in alopecia. Survey design: The clinical experience of 175 dermatologists, with regard to the benefits and safety of Minoxidil* alone and Minoxidil* + ProcapilTM*, was documented with the help of a simple questionnaire. For analysis, survey participants were divided into the following two treatment groups: Group I Minoxidil* 5% alone, Group II Minoxidil* 5% + ProcapilTM*. Patient demographics: The majority of patients who visited the dermatologists were males (70.5%; n = 1,636) and most of them were in the age range of 25-40 years. Results: Treatment results were evident from reduction in hair fall within 4-12 weeks, with 25-50% reduction in bald area and 20-40% improvement in hair density after 4 months of therapy. There was a statistically significant difference (p < 0.0056) in the overall perception between the two treatment groups in favor of Minoxidil* 5% + ProcapilTM* therapy. Conclusion: It was concluded that Minoxidil* 5% + ProcapilTM* therapy for hair loss was found to be better than Minoxidil* stand alone therapy by both dermatologists as well as patients.
Keywords: Androgenetic alopecia, Minoxidil*, vitaminated matrikine, apigenin, oleanolic acid, survey, dermatologists
ANDROGENETIC ALOPECIA
MINOXIDIL*
Androgenetic alopecia, one of the most common chronic problems seen by dermatologists worldwide, it is characterized by progressive hair loss of scalp hair, especially the central scalp.1 It affects 30-50% of men by age 50.2 When it affects women, it leads to diffuse alopecia over the mid-frontal scalp (female pattern hair loss).3
Minoxidil*, one of the most widely recommended treatments for androgenetic alopecia,5 has been proven to increase hair growth rate, thicken the diameter of hair follicle and lengthen the anagen phase with a shortened telogen phase of the hair follicle.6 The clinical efficacy and safety of Minoxidil*, when compared with placebo have been well-demonstrated in androgenic alopecia.7,8
Typically, its severity and frequency increase with age.4 It has a significant impact on the psychological well-being of patients and often leads to distress and symptoms of depression, and so it is indeed important to tackle alopecia in its early stages.
PROCAPILTM*
*Medical Affairs Dr. Reddy’s Laboratories Ltd., Hyderabad †Senior Medical Writer BioQuest Solutions Private Limited, Bangalore Address for correspondence Dr Srinivas C Medical Affairs Dr. Reddy’s Laboratories Ltd. 7-1-27, Ameerpet, Hyderabad - 500 016, Telangana
Biopeptides are one of the latest advancements in the management of hair loss, with a high level of acceptance across the globe. ProcapilTM*, a combination of vitaminated matrikine (biotinyl-GHK), apigenin (a flavonoid from citrus) and oleanolic acid (from olive tree leaves) is a potent hair loss complex. This complex improves the anchoring of hair shaft to the hair follicle; it improves blood circulation by vasodilation and inhibits production of dihydrotestosterone by 5α-reductase. Four-month use of ProcapilTM* has been shown to increase the anagen/ telogen ratio, comparable to oral finasteride treatment. It has been found to enhance structuring by increasing concentrations of adhesion proteins (collagen IV and
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
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DERMATOLOGY laminin 5) responsible for anchorage of the hair in the dermis, to enhance maintenance of a viable root sheath and to have anti-aging activity on hair follicle keratinocytes.
Physician and Patient Perspectives
This survey was conducted across various regions in India and the collected data were evaluated for understanding the efficacy of the product and dermatologists’ and patients’ perspectives related to the use of Minoxidil*, either alone or in combination with ProcapilTM* for hair growth in alopecia.
Dermatologists reported that majority of the patients (20.87%) had stage 2 hair loss in Minoxidil* 5% + ProcapilTM* group (Fig. 1). Among males, most of the patients had stage 3 hair loss (24.26%), whereas almost 15% of the patients had stage 2, followed by stage 4 (11.77%) hair loss. Among females, most of them had stage 2 hair loss (11.27%) followed by stage 3 (5.5%) hair loss, according to Norwood Hamilton grading/ scale, before initiation of treatment.
SURVEY DESIGN The clinical experience of 175 dermatologists, with regard to the benefits and safety of Minoxidil* + ProcapilTM*, was documented with the help of a simple questionnaire. Each dermatologist was requested to share his clinical experience in treating at least 10 patients (5 patients on Minoxidil* only and 5 patients on Minoxidil* + ProcapilTM*) who were diagnosed with androgenic alopecia and were advised to use Minoxidil*, either alone or in combination with ProcapilTM*. For analysis, survey participants were divided into the following two treatment groups: ÂÂ
Group I: Minoxidil* 5%
ÂÂ
Group II: Minoxidil* 5% + ProcapilTM*.
Stages of Hair Loss in Patients Before Initiation of Treatment
Frequency of Application by Treatment Majority of the patients (41%) were prescribed Minoxidil* 5% lotion + ProcapilTM* and the patients had applied it twice-daily (Fig. 2).
Hair Fall Reduction More than half of the patients (53.25%) had first observed a reduction in hair fall in 4-12 weeks (Table 1 and Fig. 3). There was a statistically significant difference (p < 0.0049) in the observation of first reduction of hair loss between the two treatment groups in favor of Minoxidil* + ProcapilTM* therapy.
Treatment Results
RESULTS Overall, 175 dermatologists responded to this survey and shared clinical experience related to 2,321 patients.
Patient Demographics The majority of patients who visited the dermatologists were males (70.5%; n = 1,636) and most of them were in the age range of 25-40 years. 50
Minoxidil* 5%
Approximately 45% of the patients (n = 1,035) had noticed results in 2-3 months after initiation of treatment, whereas 24.17% of the patients (n = 561) had noticed results 3-4 months after initiation of treatment (Table 2 and Fig. 4). There was a statistically significant difference in the duration of treatment when noticeable results were observed between the two treatment groups (p < 0.0095) in favor of Minoxidil* + ProcapilTM* therapy. Minoxidil* 5% + ProcapilTM*
Percentage (%)
40 30 20.9
20
18.8
13.3 10 0
5.9
9.1 3.6
Type I
Type II
Type III
7.2 2.3
1.0 1.6
0.2 0.5
0.1 0.1
0.3 0.1
Type IIIV (Vertex)
Type IV
Type V
Type VI
Type VII
Other
Figure 1. Stages of hair loss in patients.
16
6.1
3.4
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
DERMATOLOGY Table 2. Noticeable Results After Initiation of Treatment
50 40.5
Percentage (%)
40 30
24.7
When was the result noticed?
Overall, N (%)
Minoxidil* 5% N (%)
Minoxidil* 5% + ProcapilTM* N (%)
<2 months
431 (18.57)
137 (9.05)
169 (11.16)
2-3 months
20 10 0 Minoxidil* 5%
Minoxidil 5% + ProcapilTM*
1,035 (44.59) 277 (18.3) 561 (24.17)
102 (6.74)
229 (15.13)
4-6 months
243 (10.47)
48 (3.17)
77 (5.09)
>6 months
29 (1.25)
2 (0.13)
7 (0.46)
N/A
22 (0.95)
7 (0.46)
7 (0.46)
Figure 2. Prescription.
Minoxidil* 5%
50
Table 1. First Observation of Hair Fall Reduction Minoxidil* 5% N (%)
Minoxidil* 5% + ProcapilTM* N (%)
<4 weeks
452 (19.47)
132 (8.72)
176 (11.62)
4-12 weeks
1236 (53.25) 314 (20.74)
542 (35.8)
12-16 weeks
520 (22.4)
98 (6.47)
201 (13.28)
>16 weeks
91 (3.92)
22 (1.45)
17 (1.12)
N/A
22 (0.95)
7 (0.46)
5 (0.33)
Minoxidil 5% + ProcapilTM*
40 Percentage (%)
Overall, N (%)
When was the reduction in hair fall first noticed?
452 (29.85)
3-4 months
29.9
30 18.3
20 10
9.1
15.1
11.2 6.7
3.2
5.1
0
0.1 0.5
<2 months 2-3 months 3-4 months 4-6 months >6 months
Figure 4. Noticing the results after treatment initiation. 50
Minoxidil* 5%
Percentage (%)
40
Minoxidil 5% + ProcapilTM*
30
10
20.7 13.3
11.6 8.7
6.5
0 <4 weeks
4-12 weeks
Overall, N (%)
Minoxidil* 5% N (%)
Minoxidil* 5% + ProcapilTM* N (%)
<25%
538 (23.18)
186 (12.29)
203 (13.41)
25-50%
1097 (47.26)
257 (16.97)
461 (30.45)
50-75%
571 (24.6)
100 (6.61)
230 (15.19)
>75%
72 (3.1)
16 (1.06)
30 (1.98)
N/A
43 (1.85)
14 (0.92)
17 (1.12)
What was the extent of reduction in the bald area?
35.8
20
Table 3. Reduction in Bald Area
12-16 weeks
1.5
1.1
>16 weeks
Figure 3. Reduction in hair fall first noticed.
Reduction in Bald Area Approximately half of the patients (47.26%) reported a 25-50% reduction in bald area, while a quarter of the patients (25%) reported a 50-75% reduction in bald area after completing 4 months of treatment (Table 3 and Fig. 5). There was a statistically significant difference in the extent of reduction in bald area between the two
treatment groups (p < 0.0001) in favor of Minoxidil* + ProcapilTM* therapy.
Improvement in Hair Density Approximately 45% of the patients (n = 1,043) reported 20-40% improvement in hair density, while 30.42% of the patients (n = 706) reported 40-60% improvement in hair density after completion of 4 months of treatment (Table 4 and Fig. 6). There was a
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
17
DERMATOLOGY
50
Minoxidil* 5%
Minoxidil 5% + ProcapilTM*
Percentage (%)
40
20 10
Further, there was a statistically significant difference in the overall response between the two treatment groups (p < 0.0026) in favor of Minoxidil* + ProcapilTM* therapy.
30.5
30
12.3
13.4
17
15.2
Hair Appearance
6.6 1.1 2.0
0 <25%
25-50%
50-75%
>75%
Figure 5. Extent of reduction in the bald area.
Table 4. Improvement in Hair Density How much was the improvement in hair density? <20%
Minoxidil* Minoxidil* 5% + 5% N (%) ProcapilTM* N (%)
Overall, N (%)
379 (16.33)
20-40%
134 (8.85)
131 (8.65)
1,043 (44.94) 261 (17.24)
451 (29.79)
40-60%
706 (30.42)
125 (8.26)
284 (18.76)
>60%
133 (5.73)
36 (2.38)
54 (3.57)
N/A
60 (2.59)
17 (1.12)
21 (1.39)
Minoxidil* 5%
50
Minoxidil 5% + ProcapilTM*
Percentage (%)
29.8
20 10
18.8
17.2 8.9 8.7
8.3
2.4 3.6
0 <20%
20-40%
40-60%
>60%
Figure 6. Improvement in hair density.
statistically significant difference in the improvement in hair density between the two treatment groups (p < 0.0001) in favor of Minoxidil* + ProcapilTM* therapy.
Overall Treatment Response More than half of the patients (53.12%) believed that their condition had ‘moderately improved’ after
18
Overall, more than half of the patients (58.12%) reported that their hair appeared ‘slightly better’, whereas 36.11% of the patients reported that their hair appeared ‘better’ after 4 months of treatment. There was no statistically significant difference in how the patient scored in hair appearance after 4 months of treatment between the two treatment groups (p = 0.8590) in favor of Minoxidil* + ProcapilTM* therapy.
Appearance of the Bald Spot More than half of the patients (58.44%) had reported their bald spot appeared to be ‘slightly better’, whereas approximately 38% of the patients had reported their bald spot appeared to be ‘better’ after completing 4 months of treatment (Table 5). There was no statistically significant difference in the appearance of the bald spot between the two treatment groups (p = 0.3755) in favor of Minoxidil* + ProcapilTM* therapy.
Overall Perception of Patients Towards Ongoing Treatment Approximately 48.08% of the patients (n = 1,116) reported that they had a ‘moderately effective’ perception towards ongoing treatment, whereas 24.47% of the patients (n = 568) had a ‘slightly effective’ perception towards ongoing treatment (Table 6). There was a statistically significant difference (p < 0.0056)
40 30
4 months of Minoxidil* therapy, while 22% reported ‘great improvement’ in their condition. However, 21.46% of the patients reported ‘slight improvement’ in their condition.
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
Table 5. Appearance of the Bald Spot Overall, N (%)
Minoxidil* 5% N (%)
Minoxidil* 5% + ProcapilTM* N (%)
854 (37.72)
186 (12.61)
340 (23.05)
Slightly better
1,323 (58.44)
345 (23.39)
539 (36.54)
Slightly worse
13 (0.57)
2 (0.14)
9 (0.61)
Unchanged
69 (3.05)
22 (1.49)
28 (1.9)
Worse
1 (0.04)
0 (0)
1 (0.07)
N/A
61 (2.63)
18 (42.85)
24 (57.14)
Appearance of the bald spot Better
DERMATOLOGY 4-12 weeks, with 25-50% reduction in bald area and 20-40% improvement in hair density after 4 months of therapy.
Table 6. Overall Perception of Patients Towards Ongoing Treatment Overall perception of patients
Overall, N (%)
Minoxidil* 5% N (%)
Minoxidil* 5% + ProcapilTM* N (%)
Made situation worse
4 (0.17)
3 (0.2)
0 (0)
Ineffective
35 (1.51)
6 (0.4)
17 (1.12)
568 (24.47)
170 (11.23)
211 (13.94)
1,116 (48.08)
264 (17.44)
472 (31.18)
541 (23.31)
118 (7.79)
221 (14.6)
57 (2.46)
12 (0.79)
20 (1.32)
Slightly effective Moderately effective Very effective N/A
*Brand
names.
REFERENCES 1. Varothai S, Bergfeld WF. Androgenetic alopecia: an evidence-based treatment update. Am J Clin Dermatol. 2014;15(3):217-30. 2. Sinclair RD. Male 2004;1(4):319-27.
androgenetic
alopecia.
JMHG.
3. Norwood OT. Incidence of female androgenetic alopecia (female pattern alopecia). Dermatol Surg. 2001;27(1):53-4. 4. Kaliyadan F, Nambiar A, Vijayaraghavan S. Androgenetic alopecia: an update. Indian J Dermatol Venereol Leprol. 2013;79(5):613-25.
in the overall perception between the two treatment groups in favor of Minoxidil* + ProcapilTM* therapy.
5. França K, Rodrigues TS, Ledon J, Savas J, Chacon A. Comprehensive overview and treatment update on hair loss. J Cosmet Dermatol Sci Appl. 2013;3(3A):1-8.
Treatment Discontinuation
6. Headington JT, Novak E. Clinical and histologic studies of male pattern hair baldness treated with topical minoxidil. Curr Ther Res Clin Exp. 1984;36:1098-106.
Of the 2,321 patients, only about 9% of the patients discontinued treatment in which 31.21% of the patients discontinued after 6 months of treatment. Resolution of the problem or condition was the main reason (61.4%) for discontinuation. CONCLUSION
7. Hasanzadeh H, Nasrollahi SA, Halavati N, Saberi M, Firooz A. Efficacy and safety of 5% minoxidil topical foam in male pattern hair loss treatment and patient satisfaction. Acta Dermatovenerol Alp Pannonica Adriat. 2016;25(3):41-4.
8. Olsen EA, Whiting D, Bergfeld W, Miller J, Hordinsky M, Wanser R, et al. A multicenter, randomized, placebocontrolled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007;57(5):767-74. ■■■■
Based on the outcomes noted in the survey, it can be concluded that Minoxidil* 5% + ProcapilTM* therapy for hair loss was found to be better than Minoxidil* stand alone by both dermatologists as well as patients. Treatment results were evident from reduction in hair fall within
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
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DIABETOLOGY
Diabetes Reversal Technique JS RAJKUMAR*, S AKBAR†, JR ANIRUDH†
ABSTRACT Apart from a case report of successful remission of diabetes through surgery, in this article, we explain the rationale for achieving remission of diabetes mellitus (DM) by surgical manipulation of the gut endocrine axis, and present the scientific evidence available thus far in support of the same. The evolution of ‘metabolic’ surgery is presented here. The reduction in mortality and comorbidity is presented. The two main theories of causation of euglycemia are discussed in detail. Most authors now believe in both the theories, and the gastric bypass and the biliary pancreatic diversion are the procedures with the highest rate of remission. Finally, in the context of reappearance of hyperglycemia, the beneficial effects of a prolonged period of normal blood sugar are discussed.
Keywords: Diabetes mellitus, remission, gastric bypass, biliary pancreatic diversion
CASE REPORT A 62-year-old male, known diabetic for the past 10 years, came to us for permanent remission of diabetes. His fasting and stimulated C-peptide levels were 2.2 IU and 6.8 IU, respectively (high levels); hence, a fit candidate for metabolic surgery. The patient’s body mass index (BMI) was 25.3, so we opted for sleeve gastrectomy + ileal transposition (SGIT), which is one of the recommended procedures for diabetic patients with lower BMI. After obtaining fitness from Diabetologist, Physician, Cardiologist and Anesthetist, patient was taken up for the procedure. A loose sleeve gastrectomy (since weight loss should be minimum) + transposition of a 270 cm ileal segment to the mid jejunum level (Fig. 1) was performed laparoscopically. Postoperatively, the patient recovery was uneventful. His diabetic control was achieved within the first month and complete remission of diabetes mellitus was seen in the third month after surgery. After follow-up, he remains euglycemic without any oral hypoglycemic agents.
*Chief Surgeon †Assistant Surgeon Lifeline Institute of Minimal Access Surgery Chennai, Tamil Nadu Address for correspondence Dr JS Rajkumar Chief Surgeon Lifeline Institute of Minimal Access Surgery Chennai - 600 010, Tamil Nadu
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Figure 1. Sleeve gastrectomy + Transposition of a 270 cm ileal segment to the mid jejunum level.
DISCUSSION Ever since the monumental article in 1955, outlining the normalization of sugar levels after gastrectomy, a causal link between gut surgery and correction of diabetes was suspected. However, it was also attributed to the weight loss suffered by gastric cancer patients or the liver metastases interfering with hepatic glycogenolysis. Subsequently, an epoch-making article appeared in the Annals of Surgery (1995), documenting long-term control for both obesity and diabetes with a gastric bypass. Authored by Walter Pories, this paper analyzed results based on 14 years of gastric bypass
DIABETOLOGY surgery and 608 patients. This was a serendipitous finding in a cohort group that had the bypass but essentially as a weight reduction (bariatric) procedure. This was the first time that a direct link between gastric bypass surgery and blood sugar normalization was established. It was then believed by most surgeons and other researchers that the loss of weight, the reduction of caloric intake and the diminished insulin resistance accounted for these effects. However, the last 20 years of research into gastrointestinal endocrine molecules has completely changed the direction of surgical logic. Based on the varied metabolic effects of these procedures, the American Bariatric Surgery Society renamed itself as the American Society of Metabolic and Bariatric Surgeons (ASMBS). Let us study the available procedures: ÂÂ
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Gastric banding: In this procedure, a silastic or polyvinyl chloride (PVC) band is inserted 2 to 3 cms below the esophagogastric junction, causing a functional obstruction of the upper gastric segment, and restriction of food intake. It is not a very effective form of bariatric surgery and seems to have very little metabolic component. Although mild reductions of plasma glucose have been documented, its effects are more due to weight loss and resetting insulin resistance than due to a hormonal effect. Therefore, there will be no more discussion about this procedure in this article. Sleeve gastrectomy: In this increasingly popular procedure, a sleeve is made of the stomach by resecting the greater curvature and three-fourths of the left part of the stomach. This results in a maximal reduction of the gastric size, and also effects some endocrine changes by reducing serum levels of ghrelin. Although this operation was initially thought to be merely restrictive, we now know that it has a prominent role in endocrine manipulation. Gastric bypass: In this operation, the stomach is divided into a tiny proximal pouch and a large segment distally, which is bypassed. The proximal jejunum is divided 50 cm from the duodenojejunal flexure and the distal limb is anastomosed to the stomach (Fig. 2). The proximal jejunum is now anastomosed to the distal jejunum 100-150 cm from the site of the GJ. This operation has been proved to be the most efficacious to restore euglycemia. Ileal transposition: The newest of the procedures, interposing a considerable length of ileum within the proximal jejunum in an isoperistaltic manner, is a technique of incretin stimulation by the pathways
Figure 2. Gastric bypass.
described in greater detail later. The advantage of this operation is its use in lower BMI individuals, between 22 and 30 BMI. When used for higher BMI patients, a sleeve gastrectomy is added and the procedure is known as sleeve gastrectomy with ileal transposition (SGIT). However, compared to the sleeve and the bypass, this is still an experimental procedure.
Bariatric and Metabolic Surgery Although the procedures described for bariatric and metabolic surgery are the same, the latter term is used specifically for lower BMI individuals undergoing surgery for control of diabetes, dyslipidemias, hypertension or any other component of the metabolic syndrome.
Pathophysiology Weight loss per se leads to reduction in blood sugar, a common finding in obese or overweight patients with diabetes in the Indian subcontinent. Almost all diabetics undergoing metabolic surgery manifest normalization of sugars within 2-3 weeks of surgery, whereas weight loss takes several weeks or months to be achieved. There are two main pathophysiological
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DIABETOLOGY theories put forth to explain the correction of diabetes in these patients. They are the foregut and the hindgut theories. Foregut Theory This theory was first propounded by Rubino et al. According to this group of workers, the mucosa of the duodenum, coming in contact with the food, releases glucagon, which accounts for immediate postprandial hyperglycemia, a consistent feature of the pre-diabetic and diabetic state. A number of studies have shown that excess glucagon, rather than insufficient insulin, is the major derangement in diabetes. Patients undergoing Roux-en-Y gastric bypass procedure (RGBP) exhibit minimal or no increase in serum level of glucagon in the postprandial phase. The ‘Rubino’ factor refers to the putative duodenal contact cell, which triggers off the glucagon release. Recent advances: Based on the Rubino hypothesis, the newest noninvasive treatment for diabetes mellitus is a loose and floppy plastic sleeve that completely coats the duodenum up to the jejunum and is introduced endoscopically. This is known as the endo gastrointestinal barrier and is said to be the treatment of choice in the future for low BMI patients with diabetes mellitus. Hindgut Theory Proponents of the hindgut theory of diabetes control after RGBP invoke a set of internal insulin like secretions known as incretins. These are released from specialized cells of the ileal mucosa (K and L cells), which release a peptide known as glucagon-like peptide-1 (GLP-1). The latter is one of the most powerful insulin agonists known to man. It increases the serum insulin by whipping the beta cells of the pancreas. It is also antiapoptotic towards the beta cells, putatively prolonging their lifespan. Indeed, there have been a few cases reported of nesidioblastosis or idiopathic hypertrophy of the beta cells, which in post bypass cases is said to be mediated by GLP-1. The other incretin that is released by the ileal cells as part of the “ileal brake mechanism” in response to early passage of semi-digested chyme into the distal reaches of the ileum, is the peptide called gastric inhibitory peptide (GIP). Peptide YY (PYY) is another peptide that is released after gastric bypass. Both GIP and PYY have antiglucagon effects, effectively tipping the balance in favor of insulin and pro-insulin molecules. Incretins are especially
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involved in the immediate postprandial glucoseinsulin synergy. It is notable that high incretin levels in the post bypass patients correlate positively with lower postprandial sugar levels. Most bariatric surgery protagonists subscribe to the combination of foregut and hindgut theories. What is beyond debate; however, is the rapid fall of blood sugars seen immediately after surgery. Figure 3 depicts the mechanism of correction of diabetes with surgery while Figure 4 shows the pathways of adiposity and satiety signals.
Time to Euglycemia Significant weight loss occurs about 4 weeks after bariatric surgery, about 8-10 kg. The common statement of physicians that improved glycemic control is a direct result of weight loss, cannot hold water as normalization of sugars takes an average of about 2-3 weeks, when the weight loss is barely 4-6 kg. This minimal loss of weight cannot account for complete euglycemia. It is now said to be a combination of two factors: ÂÂ
Incretin levels especially GLP-1.
ÂÂ
The sudden near total caloric restriction that occurs postoperatively washes out the fat from the cytoplasm of the beta cells, in which fat accumulation prevents adequate and appropriate release of insulin. This is known as lipotoxicity, and lipid washout is putatively a cause for early normalization of blood sugar.
How Effective are Metabolic Surgeries? Looking at the data of Buchwald, Schauer, Gagner and Scopinaro, several hundred thousand patients have been followed up in careful detail, and the average figures of diabetes remission (no drugs, no insulin) are 83% for gastric bypass, 67% for sleeve, and 48% for the band, in the Caucasian population. This figure approaches 95% for the biliopancreatic diversion of Scopinaro. Our own experience over the last 11 years and that of several other Indian workers indicate a much higher percentage of remission in the Indian patient. Perhaps insulin resistance, which comes down sharply after bariatric surgery is an important factor, as is the viability of beta cells in our population. C-peptide Evaluation In diabetics who are on insulin injections, the serum C-peptide represents their indigenous insulin output, as all injected insulins have only the A and B peptides. Finding a serum C-peptide of >3 ng/mL is a sign of a fairly well-functioning pancreas with sufficient reserve to be stimulated by the incretins.
DIABETOLOGY
Figure 3. Mechanism of correction of diabetes with surgery.
Figure 4. Pathways of adiposity and satiety signals.
Other Comorbidities
Impact on Lifespan
Diabetes is often one of a host of diseases like hypertension, dyslipidemia, gout and hypertension. Several studies have shown significant resolution of these other ailments, to the tune of 80-90%. Also, like with diabetes, these parameters normalize very rapidly usually within a few weeks of the bariatric surgery.
The World Health Organization (WHO) figures and the Framingham study figures indicate that an obese smoker loses about 13 years of his life, and an obese nonsmoker about 10. Definite evidence has accumulated that these operations significantly increase the lifespan of the patient. Death due to vasculopathy of the
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DIABETOLOGY coronary and cerebral vessels is especially prevented by this surgery. Also, the fluctuating insulin levels seen in poorly controlled diabetes trigger instability of the DNA, and trigger off the neoplastic process. Reversal of the diabetic state decreases the risk of cancer occurrence in this group of patients.
Small Vessel Disease Diabetic retinopathy and nephropathy occur in up to 38% of patients who have well-controlled sugars. The disease process seems more related to the duration of the diabetes. Effecting a reversal of diabetes in these patients will move them to a 0% risk group as in the nondiabetics. This is a very powerful reason for attempting reversal of diabetes through surgical procedures.
How Long Do They Last? A recent slew of articles has indicated that 5-10% of patients who undergo metabolic surgery return to the diabetic stage when followed up for 10-15 years. The medical community was quick to denounce these operations as merely temporary successes. However, careful follow-up data now indicates that even in this small percentage of patients who relapse into the hyperglycemic state, the arteriolar disease when followed up longitudinally, is much less than their nonoperated counterparts. Thus, the current understanding is that a period of euglycemia of 10-15 years is remembered by the cells with a much better vascular prognosis in this group of patients. This phenomenon is called “metabolic memory” of the cell, and is evoked to explain the overall better prognosis. CONCLUSION The last word about metabolic surgery has not been spoken, and will not be spoken for a long time. What emerges from a vast amount of data is that there definitely seems to be a role for attempting to reverse the diabetic process, and that doing so positively impacts upon the health and longevity of the individual. Until futuristic magic pills arrive upon the scene, the most efficacious treatment available right now is metabolic surgery. For the higher BMI individual (32 and above), the RGBP remains the best option. In lower BMI individuals, the ileal transposition is an attractive alternative. Definite slowing down or reversal of microangiopathy has been documented in patients undergoing these operations. Incretin release either through the foregut or hindgut theory seems to explain return to euglycemia, which
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occurs within a few weeks of the procedure. Metabolic memory of the cell gives a survival and morbidity advantage, even in the small percentage of metabolic surgery patients who return to a hyperglycemic state, thus vindicating this procedure. SUGGESTED READING 1. Conn JW, Seltzer HS. Spontaneous hypoglycemia. Am J Med. 1955;19(3):460-78. 2. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3): 339-50; discussion 350-2. 3. Rubino F, Forgione A, Cummings DE, Vix M, Gnuli D, Mingrone G, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741-9. 4. Fried M, Ribaric G, Buchwald JN, Svacina S, Dolezalova K, Scopinaro N. Metabolic surgery for the treatment of type 2 diabetes in patients with BMI <35 kg/m2: an integrative review of early studies. Obes Surg. 2010;20(6): 776-90. 5. Rubino F, Schauer PR, Kaplan LM, Cummings DE. Metabolic surgery to treat type 2 diabetes: clinical outcomes and mechanisms of action. Annu Rev Med. 2010;61:393-411. 6. Rubino F, Gagner M. Potential of surgery for curing type 2 diabetes mellitus. Ann Surg. 2002;236(5):554-9. 7. Scopinaro N, Gianetta E, Adami GF, Friedman D, Traverso E, Marinari GM, et al. Biliopancreatic diversion for obesity at eighteen years. Surgery. 1996;119(3):261-8. 8. Lundell L. Principles and results of bariatric surgery. Dig Dis. 2012;30(2):173-7. 9. Sjöström L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, et al; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351(26):2683-93. 10. Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA. 2004;292(14):1724-37. 11. Ferchak CV, Meneghini LF. Obesity, bariatric surgery and type 2 diabetes - a systematic review. Diabetes Metab Res Rev. 2004;20(6):438-45. 12. Cummings DE, Overduin J, Foster-Schubert KE. Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution. J Clin Endocrinol Metab. 2004;89(6): 2608-15. 13. Izzedine H, Coupaye M, Reach I, Deray G. Gastric bypass and resolution of proteinuria in an obese diabetic patient. Diabet Med. 2005;22(12):1761-2.
DIABETOLOGY 14. Torquati A, Wright K, Melvin W, Richards W. Effect of gastric bypass operation on Framingham and actual risk of cardiovascular events in class II to III obesity. J Am Coll Surg. 2007;204(5):776-82; discussion 782-3. 15. Schauer PR, Burguera B, Ikramuddin S, Cottam D, Gourash W, Hamad G, et al. Effect of laparoscopic Rouxen Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003;238(4):467-84; discussion 84-5. 16. Schwartz ML, Drew RL, Chazin-Caldie M. Laparoscopic Roux-en-Y gastric bypass: preoperative determinants of prolonged operative times, conversion to open gastric bypasses, and postoperative complications. Obes Surg. 2003;13(5):734-8. 17. Rubino F, Gagner M, Gentileschi P, Kini S, Fukuyama S, Feng J, et al. The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg. 2004;240(2):236-42.
gastric bypass surgery: a time course study. Obes Surg. 2005;15(4):474-81. 19. Patriti A, Facchiano E, Sanna A, Gullà N, Donini A. The enteroinsular axis and the recovery from type 2 diabetes after bariatric surgery. Obes Surg. 2004;14(6):840-8. 20. Clements RH, Gonzalez QH, Long CI, Wittert G, Laws HL. Hormonal changes after Roux-en Y gastric bypass for morbid obesity and the control of type-II diabetes mellitus. Am Surg. 2004;70(1):1-4; discussion 4-5. 21. Rosa G, Mingrone G, Manco M, Euthine V, Gniuli D, Calvani R, et al. Molecular mechanisms of diabetes reversibility after bariatric surgery. Int J Obes (Lond). 2007;31(9):1429-36. 22. Camastra S, Manco M, Mari A, Greco AV, Frascerra S, Mingrone G, et al. Beta-cell function in severely obese type 2 diabetic patients: long-term effects of bariatric surgery. Diabetes Care. 2007;30(4):1002-4.
18. Wickremesekera K, Miller G, Naotunne TD, Knowles G, 23. Available at: https://www.framinghamheartstudy.org/ Stubbs RS. Loss of insulin resistance after Roux-en-Y ■■■■
Effects of Diabetes Mellitus on Cognitive Decline in Patients with Alzheimer’s Disease: A Systematic Review A recent study published in the Canadian Journal of Diabetes analyzed the relationship between diabetes and cognitive decline in patients with Alzheimer’s disease (AD). In this study, a literature search was conducted from PubMed, Embase and Cochrane. Two out of the 10 studies which were included, demonstrated that the presence of diabetes did not influence the progression of cognitive decline in the patients with AD, while three studies suggested that a history of diabetes could not be correlated with the changes in cognitive function in patients with AD. On the contrary, 50% of the articles hinted at lesser declines in cognitive function with AD, among patients having a history of diabetes. Hence, it was concluded that the association between diabetes and cognitive decline in patients with AD was obscure. It was proposed that further clinical studies with long-term follow-ups could reveal more information in this regard.
Cardiovascular Safety of Therapies for Type 2 Diabetes A recent study published in the Expert Opinion on Drug Safety analyzed the cardiovascular (CV) effects and noncardiovascular safety issues of newer therapies for the treatment of type 2 diabetes mellitus, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose cotransporter 2 (SGLT2) inhibitors. In this study, a literature search was conducted, including 10-year data up to June 2016. The results suggested that 3 classes of antihyperglycemic therapies were rendered safe for the CV profiles of patients with type 2 diabetes. It was stated that latest trials indicated that liraglutide and empagliflozin provide CV benefits that may prove to be of clinical importance in the management of type 2 diabetes mellitus.
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ENDOCRINOLOGY
Primary Amenorrhea in a Young Female - Complete Androgen Insensitivity Syndrome: A Rare Cause RAJESH RAJPUT*, DEEPAK JAIN†, LAXMINARAYAN YADAV‡, TEKCHAND YADAV#
ABSTRACT Androgen insensitivity syndrome (AIS) is a rare X-linked recessive disorder that occurs in phenotypically normal woman with male karyotype (46,XY), with an incidence of 1:20,000-64,000 male births. Syndrome may have varied presentation from male infertility to completely normal external female genitalia. Syndrome has been linked to mutations in gene for the human androgen receptor, located at Xq11-12 leading to the insensitivity of the receptor to testosterone. We report a case of a 22-year-old girl who presented with primary amenorrhea. Further examination and investigation revealed complete female external genitalia and presence of testis internally leading to diagnosis of complete AIS. Patient underwent gonadectomy with vaginoplasty followed by hormone replacement therapy.
Keywords: Androgen insensitivity syndrome, X-linked recessive disorder, testosterone, primary amenorrhea, hormone replacement therapy
A
ndrogen insensitivity syndrome (AIS) is defined as female or ambiguous phenotype in a 46,XY male with testes as internal gonads and normal testosterone production and metabolism.1 It is an X-linked recessive disorder with an incidence of 1:20,000-64,000 male births. This genetic disorder is caused by mutation of the androgen receptor gene located on X chromosome resulting in complete loss of the androgen to bind to its receptor.2 It is generally accepted that defects in the androgen receptor gene prevent the normal development of both internal and external genital structures in 46,XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia. Precise diagnosis requires clinical, hormonal and molecular investigation and is of great importance for appropriate gender assignment and management in general. The
complexity of phenotypic presentation of AIS with genotype-phenotype variability of identical mutations complicates both the diagnostic procedure and genetic counseling of the affected families. In complete AIS patients are complete women phenotypically with breast development, normal external genitalia, vagina of varied depth, absent uterus as a result of normal anti-mullerian hormone action and sparse to complete absence of axillary and pubic hairs. Partial androgen insensitivity present as male infertility to ambiguous external genitalia. Internal gonads are testis which may be intra-abdominally, inguinal or labial. Management includes detailed psychological counseling about the sexual mentation and infertility. In view of a high incidence of gonadal malignancy associated with dysgenetic gonads; gonadectomy is advocated. CASE REPORT
*Senior Professor and Head †Assistant Professor ‡Resident Dept. of Endocrinology and Medicine VI #Senior Resident Dept. of Endocrinology Pt. BD Sharma University of Health Sciences, Rohtak, Haryana Address for correspondence Dr Deepak Jain Assistant Professor Dept. of Endocrinology and Medicine VI Pt. BD Sharma University of Health Sciences, Rohtak - 124 001, Haryana E-mail: jaindeepakdr@gmail.com
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A 22-year-old unmarried girl presented to Endocrine OPD of Post Graduate Institute of Medical Sciences with complaint of primary amenorrhea. There was no history of prior medical consultation for it in past. There was no other positive relevant medical history. On examination, her vitals were stable, height - 168 cm, weight - 95 kg, body mass index (BMI) - 33.6 kg/m2. Patient had well-developed breasts (Tanner stage 4), with sparse axillary and pubic hair as shown in Figure 1.
ENDOCRINOLOGY On local examination, external genitalia were normal, per speculum vagina 3-4 cm long with normal rugae and ending in blind pouch, cervix was not visualized. Uterus and adnexa could not be revealed on per vaginal and per rectum examination. Routine blood investigations were normal. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were 19.54 mIU/mL (1.9-12.5) and 2.24 mIU/mL (1.411.5). Serum testosterone and 5α-dihydrotestosterone (5α-DHT) levels were raised 448.03 ng/dL (14-76) and 554.32 pg/mL (24-368), respectively. Karyotype revealed normal male karyotype (46,XY). USG revealed absence of uterus and ovaries. Magnetic resonance imaging (MRI) pelvis and abdomen showed an oval
Figure 1. Well-developed breasts with sparse axillary and pubic hair.
mass on right and left posterolateral aspect of urinary bladder, which appeared to be testis with absence of uterus and ovaries. Prostate and seminal vesicles were not seen (Fig. 2). In view of elevated testosterone, 5α-testosterone and LH with 46,XY karyotype and presence of bilateral intra-abdominal testis, a diagnosis of complete AIS was made. Since patient was reared as a female, so after discussion with patient and parents, in view of risk of malignancy of intra-abdominal testis, and after explaining risk and taking proper consent gonadectomy was planned and performed. After that patient was put on hormone replacement therapy. DISCUSSION Primary amenorrhea is the failure of menses to occur by age 16 years, in the presence of normal growth and secondary sexual characteristics. If by age 13, menses has not occurred and the onset of puberty, such as breast development, is absent, a work-up for primary amenorrhea should start. The relative prevalence of primary amenorrhea includes hypergonadotropic hypogonadism (48.5% of cases), hypogonadotropic hypogonadism (27.8%) and eugonadism (pubertal delay with normal gonadotropins; 23.7%).3 Out of all, androgen insensitivity contributes 1.5% only. AIS is an X-linked disease characterized by variable defects in virilization of 46,XY individuals due to loss-of-function mutations in the androgen receptor gene. Androgens exert their effects by mediating the differentiation and development of the normal male phenotype via a single receptor protein, the androgen receptor.4 The most common causes of AIS are the point mutations in the androgen receptor gene resulting in a defective receptor protein, which is unable to bind hormone or bind to DNA.5 This alteration in the gene blocks the body’s response to androgen during fetal development and after birth. The body can respond to feminizing hormones (estrogen), but not androgen. The clinical phenotypes of AIS are variable and are classified into three main categories: complete IAS (CAIS), partial IAS (PAIS) and mild IAS (MAIS) form, the designations reflecting the severity of androgen resistance.
Figure 2. MRI pelvis and abdomen showing an oval mass on right and left posterolateral aspect of urinary bladder, which appeared to be testis with absence of uterus and ovaries. Prostate and seminal vesicles were not seen.
Individuals affected by CAIS present with normal female external genitalia with a short blind ending vagina. Subjects with CAIS are born unambiguously female and are not suspected of being abnormal until the onset of puberty, when breast development is normal but pubic and axillary hair is not developed and menses do not occur. All the above features
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ENDOCRINOLOGY were present in our case. Like in our case most of the cases are diagnosed in the post-pubertal stage due to primary amenorrhea. A recent retrospective study of 9 post-pubertal individuals with CAIS suggests that these individuals enter puberty at an age closer to that of females.6 In contrast, PAIS patients present with genital ambiguity. Such individuals with predominantly female external genitalia have mild clitoromegaly, some fusion of the labia and pubic hair at puberty, while those of predominantly male appearance of external genitalia exhibit micropenis, perineal hypospadias and cryptorchidism (also called Reifenstein syndrome).7 Because of variability of clinical manifestations and the existence of subtle or atypical forms of androgen resistance such as male infertility, the prevalence of partial forms of AIS is unknown. At puberty, elevated LH, testosterone and estradiol levels are observed, but in general, the degree of undervirilization is less as compared with individuals with CAIS. At puberty MAIS takes two phenotypic forms, both presenting with various degrees of gynecomastia, high-pitched voice, sparse sexual hair and impotence. In one form of MAIS, spermatogenesis and fertility are impaired, while in another spermatogenesis is normal or sufficient to preserve fertility.8 In patients with clinically suspecting CAIS one should do serum LH, FSH, testosterone, 5α-DHT with karyotype and ultrasonography. Laparoscopy should be done in all such patients to examine internal genital organs. Measurement of serum 17-hydroxyprogesterone and its sulfate should be done to detect testosterone biosynthetic defects.9 Successful management of patients with this condition requires counseling, gonadectomy, vaginal enlargement and estrogen replacement. Gonadectomy is best delayed until after puberty is completed as pubertal development generally proceeds more smoothly in response to endogenous hormonal production10 and the overall risk of gonadal tumor development is 3.6% and 33% at the age of 25 years and 50 years, respectively. Once the testes have been removed, estrogen needs to be taken in order to maintain feminity.
CONCLUSION Androgen insensitivity syndrome, although very rare, is extremely distressing to the concerned individual and requires expert and sympathetic handling. Patients can be helped to achieve an excellent quality-of-life as a female by a multispecialty approach including gonadectomy, surgical correction, detailed and repeated psychological counseling along with estrogen replacement. REFERENCES 1. Hensle TW. Genital anomalies. In: Gillenwater JY, Grayback JT, Howards SS (Eds.). Adult and Pediatric Urology. 3rd Edition, St. Luis: Mosby Inc.; 1996. pp. 2529-48. 2. Rajender S, Singh L, Thangaraj K. L859F mutation in androgen receptor gene results in complete loss of androgen binding to the receptor. J Androl. 2007;28(5): 772-6. 3. Reindollar RH, Tho SPT, McDonough PG. Delayed puberty: an updated study of 326 patients. Trans Gynecol Obstet Soc. 1989;8:146-62. 4. McPhaul MJ, Griffin JE. Male pseudohermaphroditism caused by mutations of the human androgen receptor. J Clin Endocrinol Metab. 1999;84(10):3435-41. 5. Nitsche EM, Hiort O. The molecular basis of androgen insensitivity. Horm Res. 2000;54(5-6):327-33. 6. Papadimitriou DT, Linglart A, Morel Y, Chaussain JL. Puberty in subjects with complete androgen insensitivity syndrome. Horm Res. 2006;65(3):126-31. 7. Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C, et al. Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf). 2006;65(5):606-10. 8. Migeon CJ, Brown TR, Lanes R, Palacios A, Amrhein JA, Schoen EJ. A clinical syndrome of mild androgen insensitivity. J Clin Endocrinol Metab. 1984;59(4):672-8. 9. Viner RM, Teoh Y, Williams DM, Patterson MN, Hughes IA. Androgen insensitivity syndrome: a survey of diagnostic procedures and management in the UK. Arch Dis Child. 1997;77(4):305-9.
10. Silverstein AM, Jones RT. Testicular feminization syndrome with pelvic seminoma. J Ultrasound Med. 1988;7(8):477-9. ■■■■
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ENT
Globus Hystericus Not Only Headache to Doctor But Also Lump Problem in Throat for Patient: A Study in 100 Patients SHAMENDRA KUMAR MEENA
ABSTRACT A sensation of lump in throat expressed by patients is real and needs a thorough investigation of upper aerodigestive tract. Gastroesophageal reflux disease/laryngopharyngeal reflux was found to be the most common cause followed by emotional instability (females) and chronic granular pharyngitis, others being sinusitis (post-nasal drip), cervical osteophytes, hypothyroidism, lingual tonsil, laryngopharyngeal malignancy, etc. Globus sensation can may an early malignant lesion sign. Hence investigations like video laryngoscopy, direct laryngoscopy, barium swallow and esophagoscopy should be done in all patients. Psychotropic drugs have an important role in the management of these patients especially, where no organic lesions were found. Globus pharyngeus is a term which denotes a symptom rather than a diagnosis. Treatment with proton pump inhibitors, antidepressants/anxiolytics, saline gargles and avoidance of cold water and certain food items, in patients with no definite cause, was found to be very effective. And this combination of treatment can be taken as an initial line of treatment until detailed evaluation and investigation results are not obtained.
Keywords: Laryngopharyngeal reflux, globus hystericus, globus pharyngeus
G
lobus sensation can have underlying physiological or anatomical causes and it is thought that it could be due to a number of potential etiologies.1 Globus sensation is a common symptom, accounting for 4-5% of new referrals to ear, nose and throat (ENT) outpatient clinics.2 The classical sign of lump in the throat sensation is described as a median or paramedian sensation of an unidentified object in the pharynx mainly at or around the cricopharyngeal level in neck region. True dysphagia and weight loss are absolutely absent. Hippocrates was the first one to have described globus sensation. (Latin word globus means lump), but accurate definition of globus was given by John Purcell in 1707. The term “Globus pharyngeus” was proposed by Malcomson3 in 1968, as it was assumed to
Medical Officer (Clinical Tutor) Dept. of ENT Government Medical College Kota, Kota, Rajasthan Address for correspondence Dr Shamendra Kumar Meena KR-21 Civil Line, Nayapura, Kota, Rajasthan - 324 001 E-mail: shamendrameena82@gmail.com
be of psychic origin. It was Pratt4 who coined the term “Globus hystericus” in 1976. Purcell postulated that it was due to contraction of strap muscles of neck pressing on thyroid cartilage and therefore globus symptoms were “not vain imaginations and groundless fancies” expressed by the patient but were real sensations actually felt by the patient. Wareing et al5 believed that this throat sensation could be caused by excessive pharyngolaryngeal tension, therefore, neck and shoulder exercises to reduce the laryngeal muscle tension general relaxation techniques, together with voice exercises and voice hygiene may be of benefit especially for those whose globus is accompanied by dysphonia. Many regarded cricopharyngeal spasm as the principal generator of the symptom, but evidence to support this is scanty. In the past decade, there has been an increasing acceptance that globus is not merely a hysterical manifestation, but is related to some underlying dysfunction of the pharyngoesophageal segment. It was postulated that the condition described as globus sensation may be no more than a variant presentation of reflux esophagitis, the basis of these symptoms being an esophageal motility disturbance consequent upon the irritant effect of gastroesophageal reflux, though
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ENT many workers disagree to this assumption. Still, etiology is unknown but appears to be multifactorial; recent study focuses on gastroesophageal reflux disease (GERD). Role of pepsin-induced laryngeal injury is an exciting concept. Multifactorial causes are hiatus hernia, maxillary sinusitis, lingual tonsillitis, dental malocclusion, cervical osteophytes, vallecular cyst, hypothyroidism; it is also found to be associated with sideropenic anemia prior to the development of Paterson-Brown Kelly syndrome. Indeed, throat clearing is the most common single symptom endorsed when direct enquiry is made of a voice clinic population.6 Now, there is a general consensus that these patients are presenting with treatable conditions and the expression globus hystericus should be discarded in favor of globus pharyngeus, a symptom rather than diagnosis. There is always a female predominance seen in many studies. Patients observe: “If I swallow something, I feel nothing, but if I swallow nothing, I feel something”. OBJECTIVE Investigations for clinical features and etiology of lump. MATERIAL AND METHODS A total of 100 patients from the OPD with complaints of lump in the throat sensation were selected for study during the period (2015-2016). All went through detailed history taking, clinical examination and investigations like diagnostic nasal endoscopy, video laryngoscopy, X-ray PNS (post-nasal drip), barium swallow and X-ray soft tissue neck - lateral view and anteroposterior view. Thyroid function tests and psychiatric evaluation were also done. Patient selection criteria was as follows:
Inclusion Criteria7 ÂÂ Age between 15-65 years of both sexes.2 ÂÂ No previous treatment taken for the same complaints. Exclusion Criteria8 ÂÂ Patients with malignancies of oropharynx, oral cavity, esophagus and stomach. ÂÂ Patients with symptoms of less than 14 days duration. Patients with definite etiology were treated as per the cause. Patients without any specific association or causes were treated with proton pump inhibitors (PPIs), antidepressants plus anxiolytics and saline gargles. All patients were followed up for 5-7 months.
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RESULTS AND OBSERVATIONS Out of hundred patients studied, 66% patients were females and 34% were males with ratio of 1.9:1. This indicates a female predominance in the study. In 91% of patients, the site of sensation was at and above the level of cricoid and in 9% it was below the cricoid level. None of the patients had any true dysphagia. The onset of symptoms was gradual in 72% and precipitating events were recollected only by 8%. Fear of cancer was a major contributing factor and was present in more than 50% of the patients. Majority of patients fell in the age group of 25-45 years (45%), followed by 46-60 years (35%). In both groups, female predominance was been observed. Emotional instability was shown by 31% patients, of which, 25% were males and 75% were females. All those patients with GERD and emotional instability had undergone gastro as well as psychiatric evaluation. Most common association found was laryngopharyngeal reflux (LPR), then emotional instability, followed by chronic granular pharyngitis; 53% patients showed symptoms related to GERD like acid regurgitation, retrosternal pain, abdominal distension and belching. Third common association was chronic granular pharyngitis, consisting of 19% of the study population, 55% of them being males and 45% females, which is almost equal. Hypothyroidism was seen in 2%, PND in 2% and cervical osteophytes in 3% as shown in the X-ray of neck - lateral view. No patient showed any esophageal web or growth. Lingual tonsil (1%) and hypopharyngeal malignancy (1%) were observed, both were females. All those patients without specific reasons were given reassurance, PPIs twice-daily, antidepressants plus anxiolytics in the night and saline gargles twice-daily. They were also advised to avoid intake of cold water and cold food items. Patients with specific reasons were treated accordingly. Follow-up for 5-7 months revealed approximately complete relief of symptoms. DISCUSSION Lump in the throat is a persistent or intermittent, nonpainful sensation of foreign body in the throat. Commonly seen in clinical practice, usually longstanding, difficult to treat and has a good tendency to recur. Due to undefined etiology, it remains difficult to establish standard investigations and treatment plans. Condition is classically considered to occur most frequently in middle-aged people but other studies have shown that both younger and older age groups
ENT are also affected. In our study, age of patients varied from 15 to 65 years. The maximum incidence was found in the age group of 31-40 years. Hippocrates considered that lump in throat sensation was a disease of menopausal woman. Now, it has been proven that both sexes are affected, but there is always a female predominance. This study also showed a female predominance of 1.9:1. The duration of symptoms of patients included in this study varied from 14 days to 5 months; average duration of history was found to be 2.5 months. This is in difference with the study by Batch,8 where average duration of symptoms was 20 months. Osteophytes in the region of C5, C6, C7 cause lump, pain on swallowing. Malcomson3 has also reported it as a positive finding in 60 out of 307 patients. In our study, only 3% patient reported cervical osteophytes. Psychological evaluation showed that majority of patients were either anxious, worried or depressed mainly due to this disease. In two different studies by Pratt et al4 and Puhakka,9 it was found that patients have higher than average score on depression and hypochondriac scales. But in this study, majority patients (76%) were having anxiety when compared to depression. The percentage of malignancy in this study was negligible i.e., only 1%. This is different from that of the study by Bradley et al, in which it was 3% and 5%, respectively.10 CONCLUSION In this study, most of the cases of lump in the throat sensation was found in the age group of 25-40 years, followed by the age group of 41-55 years. Lump in throat sensation, expressed by patients, is real and needs a full investigations of upper aerodigestive tract. LPR was found to be the most common cause followed by emotional instability (females) and chronic granular pharyngitis, others being sinusitis (PND), cervical osteophytes, hypothyroidism, lingual tonsil, laryngopharyngeal malignancy, etc. Globus sensation may be a sign an early malignant lesion.
Hence investigations like video laryngoscopy, direct laryngoscopy, barium swallow, esophagoscopy should be done in all patients. Psychotropic drugs have an important role in the management of these patients especially, where no organic lesions are found. Globus pharyngeus is a term which denotes a symptom rather than a diagnosis. Treatment with PPIs, antidepressants/ anxiolytics, saline gargles and avoidance of cold water and certain food items, in patients with no definite cause was found to be very effective. And this combination of teatment can be taken as an initial line of treatment until detailed evaluation and investigation results are not obtained. REFERENCES 1. Lee BE, Kim GH. Globus pharyngeus: a review of its etiology, diagnosis and treatment. World J Gastroenterol. 2012;18(20):2462-71. 2. Cashman EC, Donnelly MJ. The natural history of globus pharyngeus. Int J Otolaryngol. 2010;2010:159630. 3. Malcomson KG. Globus hystericus vel pharyngis (a reconnaissance of proximal vagal modalities). J Laryngol Otol. 1968;82(3):219-30. 4. Pratt LW, Tobin WH, Gallagher RA. Globus hystericus office evaluation by psychological testing with the MMPI. Laryngoscope. 1976;86(10):1540-51. 5. Wareing M, Elias A, Mitchell D. Management of globus sensation by the speech therapist. Logoped Phoniatr Vocol. 1997;22(1):39-42. 6. Wilson JA, Webb A, Carding PN, Steen IN, MacKenzie K, Deary IJ. The Voice Symptom Scale (VoiSS) and the Vocal Handicap Index (VHI): a comparison of structure and content. Clin Otolaryngol Allied Sci. 2004;29(2):169-74. 7. Ardran GM. Feeling of a lump in the throat: thoughts of a radiologist. J R Soc Med. 1982;75(4):242-4. 8. Batch AJ. Globus pharyngeus (Part I). J Laryngol Otol. 1988;102(2):152-8. 9. Puhakka H, Lehtinen V, Aalto T. Globus hystericus - a psychosomatic disease? J Laryngol Otol. 1976;90(11): 1021-6.
10. Bradley PJ, Narula A. Clinical aspects of pseudodysphagia. J Laryngol Otol. 1987;101(7):689-94. ■■■■
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GASTROENTEROLOGY
A Case Report of Pancreatic Lipomatosis N JEEVA*, S ARUN KUMAR†, JOGA VEERA BALAJI‡, DEEPA JAMES#
ABSTRACT Total fat replacement of the pancreas is rare. Focal fatty replacement is the most common degenerative lesion of pancreas. Focal fatty deposits have no major clinical significance; however, extreme fat replacement is of pathologic significance, as it is associated with marked reduction in exocrine function of pancreas, resulting in malabsorption due to pancreatic enzyme insufficiency. Here we are presenting a case with nonalcoholic fatty liver disease and pancreatic lipomatosis, which is a incidental finding for which we found that aging is the only etiological factor in this case.
Keywords: Exocrine function, malabsorption, nonalcoholic fatty liver disease, pancreatic lipomatosis
I
n pancreatic lipomatosis, there will be complete replacement of pancreas by fat usually associated with pancreatic insufficiency. It is speculated that nonalcoholic fatty liver disease begets pancreatic lipomatosis. However, in this case, pancreatic lipomatosis was associated with nonalcoholic steatohepatitis in early cirrhosis. Higher incidence of pancreatic lipomatosis had been observed in obese but in our case the patient was thin.
CASE REPORT A 75-year-old woman presented with the complaints of abdominal pain on and off, bilateral lower limb swelling, generalized fatigue since 15 days. History of loss of appetite was present. Not a known-case of hypertension, diabetes mellitus, tuberculosis, coronary artery disease. Clinical examination revealed pallor and bilateral pitting pedal edema. Body mass index (BMI): 19.2. Vital signs were within normal limits. Systemic examination
revealed no abnormality. Laboratory investigations: Hemoglobin (Hb) - 6 g/dL, peripheral smear showed microcytic hypochromic anemia. Prothrombin time (PT) - 19.1, international normalized ratio (INR) - 2.02, routine blood tests, renal function tests are normal. Lipid profile - normal. Blood sugar - normal. Echo - within normal limits. USG abdomen - chronic parenchymal liver disease. CT abdomen - diffuse parenchymal liver disease with heterogeneous fatty infiltration. Mild nodular surface with complete fatty replacement of pancreas, few perigastric collaterals and degenerative changes in spine. Liver biopsy early cirrhosis. Upper gastrointestinal endoscopy - no abnormality. Serum amylase and lipase - normal. DISCUSSION Incidence of pancreatic lipomatosis is unknown. Several predisposing factors have been suggested. These include age, obesity, diabetes mellitus, chronic pancreatitis, hereditary pancreatitis, pancreatic duct obstruction by calculus or tumor and cystic fibrosis. In normal individuals, only 10% of parenchyma is sufficient for maintenance of normal exocrine function.
*Unit Chief †Assistant Professor ‡Final Year PG #Second Year PG Unit III, Dept. of General Medicine Vinayaka Missions Medical College and Hospital, Karaikal, Puducherry Address for correspondence Dr Joga Veera Balaji Final Year PG Unit III, Dept. of General Medicine Vinayaka Missions Medical College and Hospital, Karaikal, Puducherry E-mail: jogaveerabalaji@gmail.com
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Even though the total parenchyma of pancreas was replaced by fat in our patient, she had no exocrine and endocrine deficiency symptoms. The subtypes are even pancreatic lipomatosis and uneven pancreatic lipomatosis. Uneven pancreatic lipomatosis may present as: ÂÂ
Type 1a: Preferential fatty replacement of head. Cont'd on page 50...
GASTROENTEROLOGY
Nonalcoholic Fatty Liver Disease, Cardiovascular Risks and Therapeutic Approaches PRAGATI KAPOOR*, PANKAJ KUMAR†, AK KAPOOR‡
ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a fairly common, slowly progressive liver disease having cardiovascular risks implications and meets diagnostic criteria for metabolic syndrome. NAFLD is histologically categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Although the pathogenesis of NAFLD remains unclear yet ‘two hits’ theory has been proposed for NASH, which being modified by the ‘multiple parallel hits’. A number of factors have been implicated for NAFLD development including metabolic alterations, hormones, inflammation, diet and physical activity and rare genetic conditions. Interestingly, NAFL is generally benign whereas NASH can progress to cirrhosis, liver failure and liver cancer. Liver biopsy remains the gold standard in the diagnosis of NAFLD though noninvasive measures like serum biomarkers, ultrasonography and magnetic resonance spectroscopy may be helpful. Patient with NAFLD and NASH are at increased risk of cardiovascular disease and these constitute most common cause of death. The controllable risk factors include weight, insulin resistance and metabolic syndrome. It may be emphasized that NAFLD without steatohepatitis is not an indication for treatment. The treatment strategies for NAFLD and cardiovascular disease are similar, aimed primarily at reducing insulin resistance and modifying the associated cardiometabolic risk factors. Different drug treatment approaches/modalities have been discussed.
Keywords: Nonalcoholic fatty liver disease, nonalcoholic fatty liver, nonalcoholic steatohepatitis, liver biopsy, cardiovascular disease
C
urrently nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease representing over 75% of the chronic liver disease in United States.1 The increasing incidence of NAFLD is tied to the snowballing epidemic of obesity and the subsequent metabolic alterations consequent to it. Besides, it is also one of the most common indications for liver transplantation, contributing to major financial burden and is projected as a growing public health problem worldwide. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from fatty
*Assistant Professor Dept. of Cardiothoracic Surgery Nizam Institute of Medical Sciences, Hyderabad, Andhra Pradesh †Assistant Professor ‡Professor Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh Address for correspondence Dr AK Kapoor Professor Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh E-mail: drakkapoor@rediffmail.com
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liver to steatohepatitis and cirrhosis. Currently, there is growing body of evidence suggesting that cardiovascular disease (CVD) is the leading cause of death in patients with advanced NAFLD and that NAFLD is associated with increased risk of incident CVD that is independent of risk conferred by traditional risk factors and components of metabolic syndrome.2 Moreover, patients with NAFLD, both adults and children, typically meet the diagnostic criteria for metabolic syndrome (i.e., abdominal obesity, hypertension, atherogenic dyslipidemia and dysglycemia) and therefore have multiple risk factors for CVD.3,4 Increase in morbidity and mortality from CVD are probably among the most important clinical features associated with NAFLD.2 Moreover, liver related illness is the third leading cause of death in liver patients. DEFINITION OF NAFLD The definition of NAFLD requires that: a) There is an evidence of hepatic steatosis, either by imaging or by histology and b) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption (>20 g/day for men and 10 g/day for women), use of steatogenic medication or
GASTROENTEROLOGY hereditary disorders. NAFLD is histologically further categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocytes injury (ballooning) with or without fibrosis.5 Steatosis is the presence of lipid within the cytoplasm of hepatocytes, the criteria for which is defined as either hepatic lipid levels above the 95th percentile of healthy individuals (about >55 mg/g liver), greater than 5% of liver’s weight or found in greater than 5% of hepatocytes histologically.6 Approximately 10-29% of patients with NASH will develop cirrhosis within a 10-year period.7 A key feature of NASH is the presence of inflammation and subsequent fibrosis. PREVALENCE IN GENERAL POPULATION Briefly, worldwide prevalence of NAFLD ranges from 6.3% to 33% with a median of 20% in the general population, based on a variety of assessment methods and that the estimated prevalence of NASH ranges between 3-5%.8 A very high prevalence of NAFLD can be seen in type 2 diabetes patients and patients with dyslipidemia as also in cases of excessive body mass index (BMI) and visceral obesity.5 Moreover, the prevalence of NAFLD has nearly doubled over the last 20-years.1 Prevalence of NAFLD increases with age.9 Male gender is a risk factor for fatty liver disease,8 and that prevalence of NAFLD was 31% in men and 16% in women.10 Given the increasing prevalence of the disease, adequate knowledge regarding the pathogenesis of the disease as well as its diagnosis, preventive and therapeutic approaches for the management of NAFLD is becoming important for physicians. PATHOGENESIS The liver is one of the principal regulators of lipid in the body. Fatty acids in the liver used for the synthesis of triglycerides are provided by diet, adipose tissue or de novo synthesis from excess glucose. A net retention of lipids within hepatocytes, mostly in the form of triglycerides is a prerequisite for the development of NASH. The primary metabolic abnormality leading to lipid accumulation is not well-understood. Insulin resistance represents the most reproducible factor for the development of NAFLD, and that insulin resistance and oxidative stress play a critical role in the pathogenesis of NAFLD. Although the pathogenesis of NAFLD remains unclear yet some investigators
have proposed ‘two hits’ theory in the development of NASH. While the ‘first hit’ involves insulin resistance and results in the accumulation of fat in the liver, the ‘second hit’ includes oxidative stress resulting in lipid peroxidation, hepatocellular degeneration, cell death, hepatic stellate cell activation and fibrogenesis.11,12 However, ‘two hit’ pathophysiological theory has been challenged. It has been suggested that the hepatic steatosis may represent an epiphenomenon of several distinct injurious mechanisms rather than a true ‘first hit’. For this reason, the initial ‘two hit’ theory for explaining the progression from NAFLD to NASH is now being modified by the ‘multiple parallel hits’ hypothesis.13 Hyperinsulinemia, caused by insulin resistance, results in an increased hepatic de novo lipogenesis and impaired inhibition of adipose tissue lipolysis that ultimately leads to an increased efflux of free fatty acids from adipose tissue to the liver. After initial hepatic infiltration, the liver becomes extremely vulnerable to a series of hits that may follow, leading to hepatocytes injury and finally progressing from simple steatosis to NASH and fibrosis. The multiple pathogenetic factors may include oxidative damage, dysregulated hepatocytes apoptosis, activation of the profibrogenic transforming growth factors (TGF)-β pathway, dysregulation of multiple adipokines and hepatic stellate cell activation.13 All these factors collectively act in a complicated way to enhance the development and progression of the hepatic lesions through the NAFLD spectrum.14
Genetic Conditions A number of rare genetic conditions alter processing of lipids by liver and can cause steatosis. Thus, mutations which either cause an increase in lipid synthesis/uptake or a decrease in hydrolysis/export were associated with NAFLD, for example, glycogen storage diseases, adipose triacylglycerol lipase (ATGL) defects or very low-density lipoproteins mutations.6 Since, majority of genetic mutations are rare, hence these do not explain the vast majority of the cases of NAFLD, though heritability of NAFLD has been demonstrated.
Metabolic Alterations The nuclear receptors, peroxisome proliferatoractivated receptors (PPARs) are involved in regulation of fatty acid metabolism and storage. PPAR-α increases the β-oxidation thus creates energy, as also uptake and clearance of fatty acids. Whereas PPAR-γ is involved in insulin sensitivity and triglyceride storage, PPAR-α has been implicated in development of steatosis, thus
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GASTROENTEROLOGY fibrates which are agonists at PPAR-α have been tried as treatment option. PPAR-γ too have some relation to NAFLD and thiazolidinediones are the activators of PPAR-γ.6
Gut Microbiota
Hormones
Other Factors
Insulin resistance is commonly and concurrently encountered in metabolic syndrome, obesity and/or diabetes and can be characterized as a prime factor in developing hepatic steatosis.6 However, whether the insulin resistance is caused by NAFLD or vice versa is controversial.15 Two major biochemical pathways, which insulin affects in liver and concerned with pathogenesis of fatty liver are: lipogenetic pathway which remains sensitive to effects of insulin while the gluconeogenesis pathway, which is normally inhibited by insulin become resistant. This process results in hyperglycemia, which stimulates the body to produce more insulin. This insulin hypersecretion stimulates lipogenesis as sterol regulatory element-binding protein-1c (SREBP-1c)mediated pathway maintains its response.6
There are data to suggest that hypothyroidism, hypopituitarism, hypogonadism, obstructive sleep apnea and polycystic ovary syndrome independent of obesity are important risk factors for the presence of NAFLD.5 Deficiency of choline, a micronutrient found in legumes and egg yolk probably has an association with NAFLD; however, it is unclear if choline supplementation can reverse the associated fatty liver.22
Inflammation The progression of steatosis to NASH is frequently associated with change of concentration in several inflammatory cytokines especially tumor necrosis factor (TNF)-α, which has been linked to both insulin resistance and progression to NASH.16 TNF-α mediated insulin resistance has been correlated with increased levels of SREBP-1c and hepatic steatosis.17 Besides, TNF-α levels have been correlated to increased levels of inflammation, steatosis and histological damage in patients with NASH.18 Thus, anti-TNF-α therapy may be useful in the management of NAFLD.6 Another cytokine, interleukin (IL)-6 is also increased in fatty liver disease and has been correlated to development of insulin resistance, diabetes and fatty liver.6 IL-6 on long-term is being held as a mediator of inflammation, apoptosis and liver damage/scarring.19
Diet and Physical Activity The pathogenesis of fatty liver disease has also been linked to diet and physical activity since increased caloric intake and sedentary lifestyle are associated with metabolic syndrome and insulin resistance, and consequently with NAFLD.6,20 Further, individuals with NAFLD have lower activity levels. Besides, low intake of antioxidants such as vitamin E, zinc and polyunsaturated fatty acids have also been shown to have a connection with NAFLD.21
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It has been observed that intestinal flora has a role in obesity and that modification of intestinal flora has an effect on NAFLD.
Regarding Alcohol Consumption The precise definition of significant alcohol consumption in patient with NAFLD is uncertain and inconsistent, and ranged from >1 alcoholic drink (~10 g of alcohol/ drink) per day to >40 g/day.5 SYMPTOMS Patients with NAFLD are typically asymptomatic and often diagnosed incidentally. Vague symptoms such as fatigue and abdominal discomfort may be noted. Since, there exists an association between metabolic syndrome and NAFLD, hence clinical indications of insulin resistance should raise suspicion for NAFLD. It is useful to examine risk factors for NAFLD such as increased BMI, weight and raised blood pressure. Moreover, in majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus and dyslipidemia and that presence of metabolic syndrome is a strong predictor for the presence of steatohepatitis in patients with NAFLD.23
Disease Outcomes and Prognosis The long-term outcomes include the most common cause of death in patients with NAFLD, NAFL and NASH is CVD and secondly patients with NASH (but not NAFL) have an increased liver-related mortality rate.5 Basically, NAFL is generally benign whereas NASH can progress to cirrhosis, liver failure and liver cancer.5 Prognosis depends on the severity of liver damage found on liver biopsy. Patients with pure steatosis seem to have best prognosis, whereas NASH or more advanced fibrosis are associated with worse prognosis. It is established that some patients with NAFL (simple steatosis) follow a relatively benign course whereas; in some others (NASH) the disease progresses to cirrhosis
GASTROENTEROLOGY and its complication.8 NAFLD is a slowly progressing disease, and it may either regress or stay at baseline for years and simple steatosis cases progressing to clinically significant cirrhosis is approximately 1-2%.6,24 On the other hand, NASH patients are at increased risk of developing hepatic decompensation and liver failure.25 NASH may subsequently proceed to liver cirrhosis or hepatocellular carcinoma or end-stage liver disease. Oxidative stress and lipid peroxidation are key factors in the development and progression from steatosis to more advanced stage of liver damage.
Screening Screening for NAFLD, even in higher risk individuals is not recommended owing to uncertainties surrounding diagnostic tests, treatment options, long-term benefits as well as cost-effectiveness of screening. Moreover, liver biochemistries can be within normal ranges in patients with NAFLD and NASH, and these may not be sufficiently sensitive to serve as screening tests.5 Furthermore, systematic screening of family members for NAFLD is also currently not recommended.5
Prediction Models The natural history of NAFLD is fairly dichotomous, and the diagnosis is heterogeneous and relies on a variety of assessment tools, including liver biopsy, radiological tests such as ultrasonography and blood tests such as liver enzymes.8 EVALUATING NEWLY SUSPECTED NAFLD PATIENTS It is important to exclude co-existing etiologies for chronic liver disease including hemochromatosis, autoimmune liver disease, chronic viral hepatitis and Wilson disease.23 The presence metabolic syndrome is a strong predictor for the presence of steatohepatitis in patients with NAFLD.23 Noninvasive scoring models are being used to assess fibrosis in NAFLD. The most widely acceptable and externally validated test model is the NAFLD fibrosis score, which incorporates six variables (e.g., age, BMI, aspartate transaminase/alanine transaminase [AST/ALT] ratio, hyperglycemia, platelet count and albumin).5 However, one major limitation of the scoring system is that about 25% of patients were indeterminate.
Serum Markers Mild-to-moderate elevation of serum aminotransferases (ALT, AST) is the most common and often the only laboratory abnormality found in patients with NAFLD. The AST/ALT ratio is useful in differentiating NAFLD
from alcoholic liver disease.26 Thus, raised ALT and AST levels may indicate the presence of hepatic steatosis, inflammation or fibrosis; however, their utility in the diagnosis of NASH is limited because of their low specificity, sensitivity and prognostic value.27 Therefore, other diagnostic methods are required to confirm the diagnosis of NAFLD. Serum markers such as cytokeratin-18 (CK-18) fragments are most promising in the diagnosis of NASH. CK-18 fragments are novel biomarkers for the presence of steatohepatitis in patients with NAFLD. CK-18 fragments are markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies. CK-18 levels have a sensitivity of 78%, specificity of 87%, and an area under the receiver operative curve (AUROC) of 0.82 for steatohepatitis in patients with NAFLD.5 Other serum biomarkers being used in the diagnosis of NASH include various cytokines such as IL-6, TNF-Îą and CC-chemokine ligand-2. Despite a raised IL-6 and TNF-Îą, these lack clinical utility, due to inconsistent correlation. Adiponectin which has antilipogenic and anti-inflammatory effects and is thought to be reduced in NASH also exhibited conflicting results.18,28 Acute phase reactants, C-reactive protein (CRP) and pentatrix-3 have been studied in the diagnosis of NASH, yet more extensive studies are required to prove their overall clinical utility. Hypoalbuminemia, elevated serum bilirubin and prolonged prothrombin time suggest advanced disease.26
Radiological Evaluation Ultrasonography is a cheap, fast, noninvasive method for evaluating and diagnosing steatosis and NASH. Ultrasonography has a sensitivity ranging from 60% to 94% and a specificity of 66% to 95%. Contrastenhanced ultrasonography provides increased sensitivity in finding fatty liver infiltration. Liver ultrasonography is useful in patients with increased levels of Îł-glutamyltransferase not only for the diagnosis of NAFLD but also for better cardiovascular risk stratification. Transient elastography (TE), which is used to measure liver stiffness via ultrasound noninvasively, can also be used in steatosis and NASH, and is a valuable diagnostic tool. It has a higher failure rate in individuals with higher BMI. Computed tomography (CT) without contrast is a useful tool for assessing the presence and amount of steatosis, with a sensitivity ranging from 82% to 95% and a specificity approximately 100%.
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GASTROENTEROLOGY However, the CT scans are expensive and expose patient to ionizing radiation.6 Magnetic resonance spectroscopy (MRS) is the most sensitive and specific imaging modality with both values being greater than 90% and almost 100% accuracy in detecting steatosis.29 It has the advantage that one can calculate the fraction of liver composed of fat and a fraction greater than 5.56% is considered abnormal.29 Recent studies using MR spectroscoping to assess changes in hepatic fat in response to lifestyle changes observed that the degree of hepatic fat reduction is proportional to the intensity of the lifestyle intervention and generally required a weight loss ranging 5-10%.29 However, MRS is costly and exposes patients to radiation like CT.6 It may be emphasized that serum aminotransferase levels and imaging tests such as ultrasound, CT, MR do not reliably assess steatohepatitis and fibrosis in patients with NAFLD.5
Liver Biopsy NAFLD is histologically indistinguishable from the liver damage resulting from alcohol abuse.26 Features of liver biopsy include steatosis, mixed inflammatory cell infiltration, hepatocytes ballooning and necrosis, glycogen nuclei, Mallory’s hyaline and fibrosis.26 The presence of fibrosis suggests a more advanced and severe liver injury. The pattern of fibrosis in NAFLD is a characteristic feature. Collagen is first laid down in the pericellular space around the central vein, and in the perisinusoidal region. Progressive injury in NAFLD results in portal fibrosis, central-portal and portalportal septum formation and eventually cirrhosis. Most patients with NASH will show some degree of fibrosis, whereas Mallory’s hyaline may or may not be present.26 Currently, liver biopsy remains the gold-standard for differentiating hepatic steatosis from steatohepatitis.6 In hepatic steatosis, there is presence of intracellular fat in more than 5% of hepatocytes, whereas steatohepatitis has Mallory hyaline, hepatocyte ballooning as well as the presence of polymorphonuclear leukocytes and perisinusoidal fibrosis in zone 3 of the acinus.6 However, liver biopsy is expensive, and studded with sampling error, interobserver/intraobserver variability and risk of morbidity and very rarely mortality and other major risks.6 A liver biopsy should be performed only in patients who are at increased risk to have steatohepatis and advanced fibrosis for example who have metabolic syndrome as well as a suggestive NAFLD fibrosis score.
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NAFLD AND RISK OF CVD Patients with NAFLD and NASH are at increased risk for CVD and several studies have established CVD as their most common cause of death.30 Accumulating evidences suggest that CVD dictates the outcome (or outcomes) in patients with NAFLD more frequently and to a greater extent than does the progression of liver disease.3 Hence, management of cardiovascular risk factors including dyslipidemia should be taken care of accordingly. It has been observed that cardiovascular risk is greater among patients with NASH than among those with simple steatosis. Moreover, a strong association of NAFLD with metabolic syndrome has added fuel to fire because of multiple risk factors in the development and progression of CVD.3,4 However, it is not known whether ameliorating NAFLD will ultimately prevent or slow the development and progression. Patients with NAFLD not only meet the diagnostic criteria for the metabolic syndrome (i.e., abdominal obesity, hypertension, atherogenic dyslipidemia and dysglycemia) but also have impaired flow-mediated vasodilation and increased carotid-artery intimal medial thickness - two reliable markers of subclinical atherosclerosis that are independent of obesity and other established risk factors.31 In addition, the histological severity of NASH was associated with the degree of carotid-artery intimal medial thickness, independently of classical cardiovascular risk factors, insulin resistance and metabolic syndrome components.2 In a community-based cohort of 2,088 male workers, the presence of ultrasonographically diagnosed NAFLD was independently associated with an increased prevalence of ischemic heart disease (IHD).32 Data from various studies have shown that CVD is a serious threat to patients with NASH.2 The current body of evidence suggest careful monitoring and evaluation of the risk of CVD in all patients of NAFLD. In a meta-analysis of 11 prospective studies, Fraser et al33 confirmed that an elevated serum γ-glutamyl transferase level (a marker of NAFLD and oxidative stress) was an independent, long-term predictor of incident cardiovascular events in both genders. In comparison, increased serum ALT level is less predictive of incident CVD than is an increased serum γ-glutamyl transferase level, a biomarker for NAFLD as well as oxidative stress.3,4 It was also demonstrated that NAFLD is linked to an increased risk of cardiovascular events both in patients without diabetes and in those with type 2 diabetes. Moreover, insulin resistance is a pathogenic factor in the development and progression of NAFLD and also
GASTROENTEROLOGY plays a major role in the development of metabolic syndrome and CVD. Moreover, liver inflammation plays a role in the pathogenesis of CVD and that NAFLD may also contribute to cardiovascular risk through abnormal lipoprotein metabolism, especially during the postprandial phase. PREVENTION AND MANAGEMENT Since, the leading cause of death in patients with NAFLD is CVD;30 hence, various comorbidity factors be tackled adequately. However, the prevention of NAFLD poses a difficult problem since pathogenesis of the disease is not clearly understood hence prevention and management of patients with NAFLD includes treating liver disease as well as the associated-metabolic comorbidity.6 The controllable risk factors include weight, insulin resistance and metabolic syndrome. Therefore, lifestyle changes such as diet and exercise, weight reduction are the mainstay for the prevention of NAFLD. It may be emphasized that NAFLD without steatohepatitis is not an indication for treatment though associated comorbidities in steatosis alone should be tackled, as also with steatohepatitis. Further, the hepatitis vaccines A and B may be used in patients of NAFLD and NASH to prevent further insult to already damaged liver.6
Lifestyle Modifications Diet and exercise are the two prime factors of lifestyle changes for the management of steatosis and NASH. An improvement in NAFLD activity score (NAS) as well as ALT was noted in patients who have lost 7-10% of their body weight as compared to controls.34 Diet and exercise are successful in preventing steatosis progression to NASH. The positive effect of weight loss to improve liver histology in NASH has been reported in participants who lost >9% body weight improved steatosis, necrosis and inflammation but not fibrosis, whereas individuals with >7% weight loss had significant improvement in steatosis, lobular inflammation, ballooning and NAS.34 Further, American Gastroenterology Association recommends both exercise and weight loss as a modality for NASH. Many studies indicate that lifestyle modifications may reduce aminotransferases and improve hepatic steatosis when measured either by ultrasound35,36 or MR imaging and spectroscopy.37,38 The degree of fatty infiltration usually improve with weight loss in most patients, although the degree of necroinflammation and fibrosis may worsen. Orlistat (an enteric lipase inhibitor) in conjunction with lifestyle modification have shown equivocal results.
Dietary Supplementation Antioxidants like vitamin E probably have beneficial effects in NASH, since oxidative stress is the cause of hepatocellular injury. Several studies with vitamin E has reported consistent decrease in ALT and improvement in liver histology.39 Vitamin E causes decrease in aminotransferases, improvement in steatosis, inflammation and ballooning and resolution of steatohepatitis in adults with NASH though, it has no effect on hepatic fibrosis. However, no significant histological benefits with vitamin E also have been observed.40 Vitamin E (800 IU) should be considered as first-line pharmacotherapy in nondiabetic adults with biopsy proven NASH as it improves liver histology though, vitamin E is not recommended to treat NASH in diabetic patients, NASH cirrhosis or NAFLD without biopsy.5 Furthermore, controversial data have been reported that high dose vitamin E cause an increase in all-cause mortality, but others noted no association. Besides, 400 IU/day vitamin E increased the risk of prostate cancer in relatively healthy men. Caffeine and coffee use has been correlated to decreased fibrosis, decreased progression to steatohepatitis as well as decreased incidence of the disease.41,42 Probiotics have also been shown to lower aminotransferases, total cholesterol, TNF-Îą and improve insulin resistance in NAFLD.43 Ursodeoxycholic acid, omega-3 and several other supplements have also shown beneficial effects but lack significant histological improvements. High dose niacin therapy may prevent steatohepatitis and may record a potential promising agent for NAFLD.44 Preliminary evidence supports a role for antioxidants, anticytokine agents and hepatoprotectants including bile acids; however, due to insufficient data these cannot be recommended as standard therapy for NAFLD. DRUGS USED IN THE TREATMENT OF NAFLD The treatment strategies for NAFLD and CVD are similar, aimed primarily at reducing insulin resistance and modifying the associated cardiometabolic risk factors.3,4,45 Thus, the treatment revolves round the management of associated condition as well as discontinuation of potentially hepatotoxic drugs known to produce NAFLD. Pharmacotherapy for NAFLD should probably be reserved for patients with NASH, who are at greater risk for disease progression; though owing to insufficient data definitive recommendations cannot be made for treatment of NASH. Primarily weight reduction by means of diet and exercise and treatment of individual components of metabolic syndrome are being recommended. Hence, in patients with diabetes mellitus or hyperlipidemia,
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GASTROENTEROLOGY good metabolic control is always required but rarely effective in reversing NAFLD. Inspite of this, the use of medications that improve insulin sensitivity (insulin sensitizers) for type 2 diabetes, drugs directed at rennin-angiotensin-aldosterone system to control hypertension and increase antioxidant chemical species may be of potential benefit in the treatment of patients with NASH. Besides bariatric surgery may be opted for obesity. It may be noted that rapid weight loss may worsen NASH; therefore, use of medication that can directly reduce or reverse liver damage independently of weight loss are reasonable alternatives. Briefly all patients with NASH should get early aggressive treatment aimed at their associated cardiovascular risk factors to avoid major cardiovascular events and mortality before advanced liver disease develops.
Insulin Sensitizing Agents Metformin Metformin, a insulin-sensitizing agent, is commonly being used as there is a link between insulin resistance and NAFLD. Several studies have shown that in patients with fatty liver metformin caused a decrease in ALT and an increase in insulin sensitivity.46,47 with improvement in histology in some cases.48 In a small long-term study (48-week treatment), metformin exhibited lack of efficacy in NASH patients.49 Other studies also failed to show major benefit for metformin on hepatic insulin sensitivity, aminotransferases or liver histology.49,50 A recent meta-analysis concluded that metformin plus lifestyle intervention did not improve aminotransferases or liver histology, compared with lifestyle intervention alone, independently of metformin dose or the presence of diabetes.8 In brief, metformin has no significant effect on liver histology and is not recommended as specific treatment in adults with NASH.5 Thiazolidinediones Thiazolidinediones especially pioglitazone and rosiglitazone are also insulin-sensitizing agents and are activators of PPAR-γ receptors, which appeared to be down-regulated in NAFLD models. FLIRT trial (2008) and FLIRT 2 trial (2010) showed improvement in steatosis, transaminase levels, ballooning and inflammation scores with rosiglitazone but not necroinflammation or fibrosis.51 A study has demonstrated that pioglitazone improved fibrosis in NASH.52 Thiazolidinediones increased weight and rosiglitazone may cause congestive heart failure and myocardial infarction and death. Belfort et al53 observed that pioglitazone (45 mg/day) in patients with
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NASH, who have impaired glucose tolerance or type 2 diabetes millitus, caused significant improvement in aminotransferases, steatosis, ballooning, inflammation and NAS. The pioglitazone or vitamin E for NASH study (PIVENS) in nondiabetic patients with NASH demonstrated that pioglitazone (30 mg/day) for 24 months caused histological benefits and resolution of NASH, a key secondary endpoint, which was achieved in significantly higher number of patients compared to placebo though it was associated with weight gain.54 Moreover, pioglitazone has not been associated with an increased risk of cardiovascular events, thus pioglitazone may be considered thiazolidinedione of choice as evidence suggests beneficial effects in NASH.
Fibrates Fibrates are agonist of PPAR-α. A pilot study, conducted by Miranda et al55 demonstrated that in patients with NAFLD, treatment with fenofibrate for 48 weeks in doses used to decrease triglycerides, is safe and improves metabolic syndrome, lipid profile, glucose and liver tests, though effect on liver histology are minimal, ballooning improved mildly and NAS index did not show any significant changes. This small study also demonstrated a significant decrease in ALT in patients taking fenofibrate with an improvement in hepatocellular ballooning but not in the amount of steatosis or fibrosis.55 Large studies with histopathological improvement data are still lacking. Further, a recently developed dual PPARα/-δ agonist (GFT505) demonstrated decreased hepatic and peripheral insulin sensitivity in obese patients along with decrease in ALT levels.56 Despite promising results, human data with GFT505 are not available.
Statins NAFLD is commonly associated with adverse cardiovascular manifestations. Statins are HMG-Co-A reductase inhibitors and are commonly administered as safe preventive treatment in patients with cardiovascular risk factors in patients with NAFLD.57 They are basically used for the treatment of dyslipidemia and thus exhibit cardiovascular risk reduction in patients with NAFLD. Several studies have demonstrated that statins may improve liver biochemistries and histology in patients with NASH.57 The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study in 2010 using statins demonstrated a significant reduction in liver enzymes as well as a reduction in chance of having an adverse cardiovascular event and improve cardiovascular outcomes.58 Presently, statins cannot be
GASTROENTEROLOGY advocated to be used in NASH as histopathological data are scarce and needs further research.59 Although, there is no convincing evidence that lipid-lowering agents, including statins are beneficial for patients with NASH, these can be safely prescribed in diabetes and high cardiovascular risk patients.59 Inspite of this, all patients with NASH should get early treatment of their liver disease but also for early, aggressive treatment aimed at their associated cardiovascular risk factors to avoid major cardiovascular events and mortality before advanced liver disease develops.
based on selectively burning hepatic fat. However, it is possible that burning hepatic fat with a liver specific thyromimetic may not be effective enough to achieve these goals in NASH.63 Pentoxifylline, an anti-TNF therapy, in small studies has shown improvement in aminotransferases and histopathological features.64 In another study, a plant supplement, chlorella vulgaris has been shown to decrease levels of transaminases and increase insulin sensitivity.65
Surgery
1. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, Srishord M. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9(6):524-530.e1; quiz e60.
Weight reduction is one of the prime therapeutic modality for patients with NAFLD. Bariatric surgery has shown a significant decrease in steatohepatitis and that NASH improves following bariatric surgery.60,61 Foregut bariatric surgery is a potential treatment option for NASH. Mathurin et al60 observed that compared to baseline, there was a significant improvement in the prevalence and severity of steatosis and ballooning at 1 and 5 years following bariatric surgery. A metaanalysis evaluating the effect of bariatric surgery on the liver histology in patients with NAFLD showed that steatosis, steatohepatitis and fibrosis, appear to improve or completely resolve after bariatric surgery. It is premature to consider foregut bariatric surgery as established option to specifically treat NASH.5 Liver transplantation is a life-extending therapeutic alternative and is the only option for patients with NAFLD progressing to end-stage liver disease; though NAFLD can recur after transplant or develop de novo.6
Other Potential Treatment Approaches With the growing prevalence of the disease, the potential future therapeutic options, though still in their infancy include, a mixture of high molecular weight beeswax alcohols, D-002 which has shown to improve symptoms in patients with NAFLD along with an improvement in ultrasonographic findings, insulin resistance as well as NAFLD symptoms. Obeticholic acid, a farnesoid X receptor agonist, improves insulin sensitivity and reduces markers of liver inflammation and fibrosis in patients with diabetes and NAFLD.62 Liver selective thyroid hormone receptor (THR) agonists especially thyroid hormone receptor beta-1 (THRβ-1) agonists exert beneficial effects including lowering of low-density lipoprotein cholesterol and a reduction in whole body adiposity and weight. Moreover, selective activation of hepatic THR prevents or reverses fatty liver and points to a new approach to treat NAFLD
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44. Ganji SH, Kukes GD, Lambrecht N, Kashyap ML, Kamanna VS. Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol. 2014;306(4):G320-7. 45. Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut. 2007;56(12):1760-9. 46. Razavizade M, Jamali R, Arj A, Matini SM, Moraveji A, Taherkhani E. The effect of pioglitazone and metformin on liver function tests, insulin resistance, and liver fat content in nonalcoholic Fatty liver disease: a randomized double blinded clinical trial. Hepat Mon. 2013;13(5):e9270. 47. Sofer E, Boaz M, Matas Z, Mashavi M, Shargorodsky M. Treatment with insulin sensitizer metformin improves arterial properties, metabolic parameters, and liver function in patients with nonalcoholic fatty liver disease: a randomized, placebo-controlled trial. Metabolism. 2011;60(9):1278-84.
57. Nseir W, Mahamid M. Statins in nonalcoholic fatty liver disease and steatohepatitis: updated review. Curr Atheroscler Rep. 2013;15(3):305. 58. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010;376(9756):1916-22. 59. Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2013;(12):CD008623.
48. Shyangdan D, Clar C, Ghouri N, Henderson R, Gurung T, Preiss D, et al. Insulin sensitisers in the treatment of non-alcoholic fatty liver disease: a systematic review. Health Technol Assess. 2011;15(38):1-110.
60. Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology. 2009;137(2):532-40.
49. Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853-60.
61. Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008;6(12):1396-402.
50. Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki M, et al. Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;28(2):200-8.
62. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574-82.
51. Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, et al; LIDO Study Group. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2010;51(2):445-53.
63. Kapoor P, Kumar P, Kapoor AK. Thyroid, obesity and thyromimetic compounds. IJCP. 2016;26(9):836-45.
52. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35(1):66-75.
64. Li W, Zheng L, Sheng C, Cheng X, Qing L, Qu S. Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease. Lipids Health Dis. 2011;10:49.
65. Panahi Y, Ghamarchehreh ME, Beiraghdar F, Zare R, Jalalian HR, Sahebkar A. Investigation of the effects of Chlorella vulgaris supplementation in patients with nonalcoholic fatty liver disease: a randomized clinical trial. 53. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone Hepatogastroenterology. 2012;59(119):2099-2103. ■■■■
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HEMATOLOGY
Pancytopenia: An Evaluation in a Tertiary Care Center UMA RAMANATHAN*, J THANKA†, LAWRENCE DERUZE‡, S SRI GAYATHRI‡
ABSTRACT Objective: The aim of this study was to assess the clinical picture, bone marrow morphology and etiology of pancytopenia, as causes of pancytopenia are extensive. Material and methods: This was an observational study performed retrospectively analyzing cases of pancytopenia seen during the period of 2013-2015, at the Dept. of Pathology, Sri Ramachandra University, Chennai. Inclusion criteria: Patients were included in the study if they fulfilled the following 3 criteria: low hemoglobin or red blood cell count, low white blood cell count and reduced platelet count according to age-specific reference range. Exclusion criteria: Immunocompromised status, disease or therapy related; adequate platelet count on peripheral smear and inconclusive aspirates and biopsies. Results: Pancytopenia was found in a wide age range and was more common in males. Neoplastic diseases arising from or infiltrating the bone marrow (39.5%) accounted for the most common cause of pancytopenia. Others included hypoplastic/aplastic anemia and megaloblastic anemia. Conclusion: Pancytopenia is not a disease entity by itself, but rather a clinical manifestation of a number of diseases. Work-up of patients presenting with pancytopenia with bone marrow studies and ancillary tests is essential to rule out life-threatening illnesses.
Keywords: Pancytopenia, anemia, aplastic, megaloblastic, leukemia
P
ancytopenia is a reduction in the formed elements of blood leading to anemia, leukopenia and thrombocytopenia. The clinical suspicion of pancytopenia is raised when patients present with fever, recurrent infections, pallor and bleeding diathesis. The causes of pancytopenia are extensive and vary based on age, gender, ethnicity and geographic distribution.
OBJECTIVE The aim of this study is to assess the clinical picture, bone marrow morphology and etiology of pancytopenia. MATERIAL AND METHODS The present study was an observational study for a period of 3 years from January 2013 to December 2015 at the Hematology Unit, Dept. of Pathology, Sri Ramachandra University, Chennai.
*Postgraduate †Professor and Head ‡Assistant Professor Dept. of Pathology Sri Ramachandra University, Chennai, Tamil Nadu Address for correspondence Dr Uma Ramanathan 43, Kothari Road, Nungambakkam Chennai - 600 034, Tamil Nadu E-mail: uma_89@hotmail.com
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Inclusion Criteria Patients of all ages, clinical features, age-specific laboratory parameters including hemoglobin (Hb) estimation or red blood cell (RBC) count, white blood cell (WBC) count, platelet count and peripheral smears. Patients were included in the study if they fulfilled the following 3 criteria: (i) low Hb or RBC count, (ii) low WBC count and (iv) reduced platelet count according to age-specific reference values. The normal values for various age groups is shown in Table 1. Ancillary tests for serum vitamin B12, folic acid, iron studies, lactate dehydrogenase (LDH), liver function tests, lipid profile and erythrocyte sedimentation rate (ESR) were also noted.
Exclusion Criteria Immunocompromised states, disease or therapy related. ÂÂ
Platelet counts, which were adequate on smear due to giant platelets, aggregates and microclots.
ÂÂ
Inconclusive aspirates and biopsies.
Three milliliter anticoagulated (dipotassium ethylenediaminetetraacetic acid, 5.4 mg) was collected in lavender top vacutainers. The samples were processed and analyzed in the Beckman Coulter (version LH 780) automated hematology analyzer. Peripheral smears were stained by Leishman stain for all the cases examined. This was subsequently followed up by bone marrow aspiration and biopsy performed
HEMATOLOGY Table 1. Age-specific Laboratory Parameters Age
Hb (g/L) Mean (±2SD)
1 day 2 weeks 1 month
RBC [x10^12/L] Mean (±2SD)
WBC [x10^9/L] Mean (±2SD)
Platelets [x10^9/L]
180 (40)
6 (1)
18 (8)
100-450
165 (4)
4.9 (1.3)
14 (8)
170-500
140 (25)
4.2 (1.2)
12 (7)
200-500
2 months
112 (18)
3.7 (0.6)
10 (5)
210-650
3-6 months
126 (15)
4.7 (0.6)
12 (6)
200-550
1 year
126 (15)
4.5 (0.6)
11 (5)
200-550
2-6 years
125 (15)
4.6 (0.6)
10 (5)
200-490
6-12 years
135 (20)
4.6 (0.6)
9 (4)
170-450
12-18 years (male)
14.5 (2)
4.5 (4.9)
4.5-13.5 (7.8)
150-350
12-18 years (female)
14.0 (2)
4.1 (4.6)
4.5-13.5 (7.8)
150-350
Adult male
150 (20)
5 (0.5)
4-10
150-350
Adult female
135 (15)
4.3 (0.5)
4-10
150-350
Hb = Hemoglobin; RBC = Red blood cell; WBC = White blood cell; L = Liter.
RESULTS In the current study, 119 cases being evaluated for pancytopenia in a tertiary care set up were examined; age ranged from 1 to 80 years with a mean age of 50 years. Incidence of pancytopenia in various age groups in this study is shown in Figure 1. The proportion of pancytopenia was more in males with a male (M) to female (F) ratio of 1.33:1. The incidence of the common manifestations among the patients is shown in Figure 2. Pallor and hepatosplenomegaly were among the more common signs elicited in the patients in this study. Cellularity of the bone marrow among the cases, which presented as pancytopenia in our study were compared and correlated with reference to age. Only 42.9% of the cases showed a hypocellular marrow, while the rest were normocellular (47.9%) to hypercellular (9.2%). The most common cause was neoplastic (39.5%). The distribution pattern of the various types of neoplastic lesions reported is given in Table 2. Incidence was more among men with a M:F of 2.4:1. Dysplastic
35 30 Incidence (%)
under aseptic precautions with the consent of the patients. Bone marrow aspirate smears, fixed in 95% alcohol, were stained with Leishman stain, while airdried smears were fixed with May-Grunwald-Giemsa stain. Bone marrow biopsies were decalcified, processed using Leica autoprocessor ASP 6025 and auto stained with hematoxylin and eosin (H&E) stains using Leica autostainer XL.
25
29.41
29.41 25.21
20
15.97
15 10 5 0 1-20
21-40
41-60
>61
Figure 1. Incidence of pancytopenia among various age groups in the study.
Cough (2) GI disturbances (2)
Giddiness (2) Seizures (2)
Bleeding diathesis (7)
Weight loss (3)
Fever (28) Breathlessness (11) Generalized weakness (18)
Symptoms (No. of cases)
Figure 2. Common symptoms of patients which were associated with pancytopenia in our study.
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
47
HEMATOLOGY Table 2. Distribution Pattern of Neoplastic Diseases Causing Pancytopenia in Our Study Age (years)
1-20
21-40
41-60
>61
Total
Myelodysplastic syndrome
2
4
3
4
13/47
Myeloproliferative neoplasm
-
-
2
-
2/47
Myelofibrosis
-
-
-
1
1/47
Acute myeloid leukemia
2
2
2
5
11/47
Acute lymphoblastic leukemia
7
1
-
1
9/47
Acute leukemia
5
-
2
1
8/47
Others
-
(1- Diffuse large B-cell lymphoma)
(1-Plasma cell myeloma)
-
2/47
marrows were found to be more in the age group of 21-40 years and 61 years and above. Reticulin stains and cytogenetics helped to differentiate aplastic from hypoplastic myelodysplastic syndrome in our series. Myeloproliferative neoplasms and myelofibrosis (MF) accounted for only 3 cases evaluated for pancytopenia. Twenty-nine of the 47 cases were acute leukemias. Blasts were seen in 29.6% of the peripheral smears; 41.9% cases required biopsy confirmation due to diluted aspirates. Ancillary tests such as immunohistochemistry (IHC) and flow cytometry to type specify the leukemias could not be done on 8 of the 29 cases due to logistic reasons. Plasma cell myeloma and diffuse large B-cell lymphoma infiltrating the marrow were reported in 2 cases. Hypoplastic marrows were reported in 25 cases, while 72% were confirmed to be aplastic. Comparison of the various features of aplastic anemia reported in our study is given in Table 3. Of the 9 cases of megaloblastic anemias, 3 were identified with peripheral smears showing macrovalocytes and hypersegmented neutrophils in correlation with mean corpuscular volume (MCV) and vitamin B12 levels and subsequently confirmed on aspirate. Biopsy confirmation was required in 3 due to dilute aspirates. LDH was found to be >250 IU/L in all but 3 cases and serum total bilirubin, direct bilirubin and indirect bilirubin were elevated in all cases. This finding can be attributed to ineffective erythropoiesis and intramedullary hemolysis. The marrow studies were normocellular in all the cases though the peripheral smears were suggestive of pancytopenia. Five of the 6 cases associated with an inflammatory etiology showed hemophagocytosis on bone marrow examination. The specific etiologies could be confirmed with the help of clinical, microbiological and biochemical correlation in 3 of them. Two cases were diagnosed as granulomatous inflammation possibly of tuberculosis origin, but only one showed hemophagocytosis.
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Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
Table 3. Features of Aplastic Anemia Variables
Findings
M:F
1.25:1 (Ratio)
Reticulocyte %
0.2-4% (Range)
Peripheral smear-Neutropenic leukopenia
16.6% (Incidence)
Cellularity <25%
27.8% (Incidence)
Prussian blue stain
Grade 3-4 (Incidence)
Ziehl-Neelsen stain for acid-fast bacilli were negative in both the cases. Another case was found to have malarial antigen positivity. Hemophagocytic lymphohistiocytosis (HLH) was confirmed in the last case in correlation with elevated levels of serum ferritin (>16,500 ng/mL), serum triglycerides (242 mg/dL) and serum LDH (576 IU/L) along with clinical parameters such as fever for more than 7 days and splenomegaly, with no underlying etiology. A cause could not be identified for the 2 cases showing hemophagocytosis on bone marrow examination with no significant biochemical factors. Of the cases evaluated for pancytopenia, 26.9% were unclassified as marrow studies showed nonspecific changes. Sixteen of the 32 cases had a hypocellular marrow, 3 were hypercellular and the remaining were normocellular. Erythroid hyperplasia was seen in 8 cases. DISCUSSION Pancytopenia is a finding that encompasses a broad range of etiological factors. It can primarily or secondarily involve the bone marrow. The causes can be classified based on decreased production due to congenital failure of the marrow, spaceoccupying lesions or ineffective hematopoiesis. Other causes include increased peripheral destruction or sequestration.
HEMATOLOGY The age and sex distribution of other studies in comparison to ours is given in Table 4.1-3 In a study done in Stanford University, USA, 250 aspirates were evaluated for pancytopenia among which 193 were taken from adults, while the remaining 57 were from children.4 The pattern distribution of the various causes of pancytopenia varied among different studies and is shown in Table 5.5-13 In comparison to studies that evaluated causes of pancytopenia in India, the current study showed neoplastic disease either arising from or infiltrating the marrow to be the most common cause. This is comparable to the study done by Weinzierl et al, which showed B-lymphoblastic leukemia in children and acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults to be more common.4 MDS and MF accounted for a minor component in our study, which was comparable to a study done by Pathak et al.2 A study done in India by Jayachandran et al found that 9% of the cases evaluated for pancytopenia in their study were due to malignancies.3 A study done by Jha et al showed that 97% of the acute leukemias studied presented with pancytopenia/bicytopenia, which was similar to our study. Subleukemic leukemia Table 4. Comparison of Age and Sex Distribution with Other Studies of Pancytopenia Study
Year
Mean age range (years)
M:F
Gayathri et al1
2011
42 (2-80)
1.2:1
2012
38.8 (15-30)
1:1.04
Pathak et al2 Jayachandran et
al3
Current study
2015
>14
-
2016
50 (1-80)
1.36:1
was reported in 31% of the cases in our study in comparison to Gayathri et al and Khunger et al who reported an incidence of 3.58% and 5% of subleukemic cases, respectively.1,10,14 Matsuda et al reported a case of hypoplastic chronic myeloid leukemia (CML).15 Similarly, one case of pancytopenia was found to be CML with myelofibrosis in our study. Hypoplastic anemia and megaloblastic anemia were among the more common causes in India as opposed to similar studies done in western countries.3,6,7,9,10,12 Prashanth et al attributed these findings to the nutritional status in these areas. To confound this, a study done in Zimbabwe by Savage et al with a similar socioeconomic background like our country also published similar results with megaloblastic anemia being the more prevalent disease.8 Six cases in the current study were grouped under inflammation, either due to infectious or noninfectious etiology. Hemophagocytosis was seen in all but one case. One was associated with granulomatous inflammation possibly of tuberculosis origin, while the other was associated with malarial infection. HLH was diagnosed in one case following clinical and biochemical correlation, with no underlying etiology. This observation in our study deviated from results of other studies in India, which showed more cases of inflammatory etiology to be associated with parasitic diseases like malaria, leishmaniasis and others like enteric fever.1,13 Lastly, the unclassified group comprised of cases where no specific etiology could be identified on both aspiration and biopsy. Review of literature suggests that it could be a stage of evolution into a particular disease process like aplastic anemia, MDS, refractory anemia, hypersplenism or systemic illness.4,13
Table 5. Comparison of Various Causes of Pancytopenia in Other Studies Study
Year
Country
No. of cases
Most common
International Agranulocytosis and Aplastic Anemia Study Group5
1987
Israel & Europe
319
Hypoplastic anemia
Varma and Dash6
1992
India
202
Hypoplastic anemia
Tilak and Jain7
1999
India
77
Megaloblastic
al8
1999
Zimbabwe
134
Megaloblastic anemia
Khodke et al9
2001
India
50
Megaloblastic anemia
2002
India
200
Megaloblastic anemia
2004
Pakistan
200
Megaloblastic anemia
2008
Nepal
148
Hypoplastic anemia
2011
India
134
Megaloblastic anemia
2016
India
119
Neoplastic
Savage et
Khunger et Ishtiaq et
al10
al11
Jha et al12 Prashanth B
Gandhi13
Present study
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
49
HEMATOLOGY CONCLUSION Pancytopenia is not a disease entity by itself, but rather a clinical manifestation of a number of diseases. Workup of patients presenting with pancytopenia with bone marrow studies and ancillary tests is essential to rule out early life-threatening illnesses. REFERENCES 1. Gayathri BN, Rao KS. Pancytopenia: a clinicohematological study. J Lab Physicians. 2011;3(1):15-20. 2. Pathak R, Jha A, Sayami G. Evaluation of bone marrow in patients with pancytopenia. J Pathol Nepal. 2012;2:265-71. 3. Jayachandran K, Gauri Shankar J. Aetiology of pancytopenia in a tertiary care hospital – Coimbatore, South India. J Assoc Physicians India. 2015;63: 4. Weinzierl EP, Arber DA. Bone marrow evaluation in newonset pancytopenia. Hum Pathol. 2013;44(6):1154-64. 5. International Agranulocytosis and Aplastic Anemia Study. Incidence of aplastic anemia: the relevance of diagnostic criteria. Blood. 1987;70(6):1718-21. 6. Varma N, Dash S. A reappraisal of underlying pathology in adult patients presenting with pancytopenia. Trop Geogr Med. 1992;44(4):322-7.
8. Savage DG, Allen RH, Gangaidzo IT, Levy LM, Gwanzura C, Moyo A, et al. Pancytopenia in Zimbabwe. Am J Med Sci. 1999;317(1):22-32. 9. Khodke K, Marwah S, Buxi G, Yadav RB, Chaturvedi NK. Bone marrow examination in cases of pancytopenia. J Indian Acad Clin Med. 2001;2(1&2):55-9. 10. Khunger JM, Arulselvi S, Sharma U, Ranga S, Talib VH. Pancytopenia - a clinico haematological study of 200 cases. Indian J Pathol Microbiol. 2002;45(3):375-9. 11. Ishtiaq O, Baqai HZ, Anwer F, Hussain N. Patterns of pancytopenia patients in a general medical ward and a proposed diagnostic approach. J Ayub Med Coll Abbottabad. 2004;16(1):8-13. 12. Jha A, Sayami G, Adhikari RC, Panta AD, Jha R. Bone marrow examination in cases of pancytopenia. JNMA J Nepal Med Assoc. 2008;47(169):12-7. 13. Kumar DB, Raghupathi AR. Clinicohematologic analysis of pancytopenia: study in a tertiary care centre. Basic Appl Pathol. 2012;5(1):19-21. 14. Jha A. Spectrum of hematological malignancies and peripheral cytopenias. J Nepal Health Res Counc. 2013;11(25):273-8. 15. Matsuda M, Miyazato H, Ueda S, Morita Y, Sakaguchi M, Tatsumi Y, et al. A case of hypoplastic chronic myelogenous leukemia initiating with pancytopenia. Int J Hematol. 2002;75(3):335-6.
7. Tilak V, Jain R. Pancytopenia - a clinico-hematologic analysis of 77 cases. Indian J Pathol Microbiol. 1999;42(4):399-404. ■■■■
...Cont'd from page 34 ÂÂ Type 1b: Preferential fatty replacement of head, neck and body. ÂÂ
Type 2a: Preferential fatty replacement of head and uncinate process.
ÂÂ
Type 2b: Fatty replacement of most of pancreas except peribiliary region.
The role of ultrasound in the diagnosis of pancreatic lipomatosis is very limited. However, the CT has an important role in evaluation of pancreatic disease.
50
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
SUGGESTED READING 1. Reddy OJ, Gafoor JA, Reddy GM, Prasad PO. Total pancreatic lipomatosis: A rare presentation. J NTR Univ Health Sci. 2015;4(4):272-4. 2. Anand R, Narula MK, Chaudhary V, Agrawal R. Total pancreatic lipomatosis with malabsorption syndrome. Indian J Endocrinol Metab. 2011;15(1): 51-3. 3. Prachayakul V, Aswakul P. Pancreatic steatosis: what should gastroenterologists know? JOP. J Pancreas (Online). 2015;16(3):227-31.
Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background
Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India
E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177
“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund
Who is Eligible?
“Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people.
Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment. Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background. Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program. Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country. To promote heart care research in India.
All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office.
Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License. The patient must be needy and underprivileged, to be assessed by Fund Committee. The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof. The review of applications may take 4-6 weeks. All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications. The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.
To promote and train hands-only CPR.
Activities of the Fund Financial Assistance
The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment.
Financial assistance is given to eligible non emergent heart patients. Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.
The financial assistance granted will be given directly to the treating hospital/medical center.
After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done.
Drug Subsidy
The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted). The HCFI Fund does not provide assistance for any emergent heart interventions.
Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records Identity proof with proof of residence Income proof (preferably given by SDM)
The HCFI Fund has tied up with Helpline Pharmacy in Delhi to facilitate
BPL Card (If Card holder)
patients with medicines at highly discounted rates (up to 50%) post surgery.
Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.
The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)
Free Diagnostic Facility
Free Education and Employment Facility
The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.
HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.
This machine is used to screen children and adult patients for any heart disease.
Laboratory Subsidy HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.
About Heart Care Foundation of India
Help Us to Save Lives The Foundation seeks support, donations and contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.
Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof. HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.
Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care
Donate Now... Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.
Committee Members
Chief Patron
President
Raghu Kataria
Dr KK Aggarwal
Entrepreneur
Padma Shri, Dr BC Roy National & DST National Science Communication Awardee
Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur
Advisors Mukul Rohtagi Ashok Chakradhar
Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka
This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.
Rishab Soni
HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.
http://heartcarefoundationfund.heartcarefoundation.org
INTERNAL MEDICINE
A Case of Leptospirosis Presenting as Multiorgan Failure AK BADRINATH*, K SURESH†, R RAGHUNATHAN†, SURESH BABU S‡
ABSTRACT Leptospirosis, an infection of worldwide distribution has come to international attention as a re-emerging infectious disease. It is caused by spirochetes of the genus Leptospira, which infect most of the domestic and wild animals and spread to humans by the infected urine of animals. Patients with leptospirosis may present with acute febrile illness to life-threatening multiorgan failure. Here we present a 25-year-old female with fever, jaundice and altered sensorium admitted as a case of sepsis with multiple organ dysfunction syndrome who was later diagnosed as a case of leptospirosis.
Keywords: Leptospirosis, icterus, renal failure, meningitis
CASE REPORT A 25-year-old female presented with complaints of fever for 7 days, continuous high-grade fever, no chills or rigor with generalized body pain. Patient had altered sensorium since 1 day. Patient had one episode of seizure (generalized tonic-clonic seizure [GTCS]) with frothing from mouth and post-ictal confusion a few hours prior to admission in the hospital. No history of vomiting or cough with expectoration. No history of decreased urine output or abdominal pain. Patient was not a diabetic and he had no history of pulmonary tuberculosis in the past. Patient was married, had 2 children and had no menstrual irregularities at present. On examination, patient was irritable, not obeying to oral commands, responded to pain. Patient's general physical examination revealed patient febrile 100.6°F with pallor++; icterus+ and subconjunctival hemorrhage. Pulse - 126/min and regular, blood pressure (BP) - 100/60 mmHg, cardiac examination
*Professor †Associate Professor ‡Resident Dept. of General Medicine Sri Manakula Vinayagar Medical College and Hospital, Puducherry, Tamil Nadu Address for correspondence Dr AK Badrinath No. 4, Shree Apartments, II Floor, 29 #, Avvai Nagar, Lawspet Puducherry - 605 008, Tamil Nadu E-mail: akbsts@yahoo.co.in
was normal, respiratory system - patient tachypneic, normal vesicular breathe sounds present with scattered crepitations and per abdomen - soft, hepatomegaly present. Central nervous system - patient had altered sensorium, agitated responded to pain, moved all limbs, reflexes diminished bilaterally and bilateral plantars extensor. Bilateral pupils equal and reacting to light and terminal neck rigidity present. Patient was admitted with the provisional diagnosis of meningitis with multiorgan dysfunction syndrome and evaluated. Her complete hemogram revealed anemia with hemoglobin - 9.9 g/dL, total leukocyte count - 8,400/mm3, differential count: polymorphs - 67% and lymphocytes 24% with severe thrombocytopenia platelets 24,000/mm3. She had hypoglycemia with random blood glucose of 60 mg/dL. Her renal function tests and serum electrolytes were normal. Her liver function was deranged: total bilirubin - 4.6 mg/dL, SGOT - 430 IU/L, SGPT - 190 IU/L, ALP - 190 IU/L, total protein 7.0 g/dL and albumin - 3.7 g/dL. Her urine examination showed microalbuminuria with plenty of RBCs and hemogranular casts were present suggestive of acute tubular necrosis. Arterial blood gas analysis revealed metabolic acidosis. ECG showed sinus tachycardia but was otherwise normal and chest X-ray revealed increased bronchovascular markings. Patient was started on intravenous (IV) fluids, Ryle’s tube feeding, nasal O2, antipyretics and IV antibiotics (injection ceftriaxone 1 g IV b.i.d. and injection vancomycin 1 g IV b.i.d.). Patient treatment was continued with glucose and platelet monitoring in
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
55
INTERNAL MEDICINE intensive care unit. Since, patient had altered sensorium a computed tomography (CT) brain was done and showed multiple small calcifications but was otherwise normal. A lumbar puncture was done for cerebrospinal fluid (CSF) analysis - cytology showed moderate cellularity with 240 cells predominant of neutrophils - 70% and monocytes - 20%. However, CSF protein was normal - 25 mg/dL, glucose - 55 mg/dL and lactate dehydrogenase (LDH) - 80. Dengue serology, scrub typhus and viral markers were negative. Blood, urine and CSF culture were negative and peripheral smear normal. On Day 2 of admission, her platelets decreased to 12,000/mm3 and prothrombin time prolonged and was transfused with 4 units of platelet concentrate and 2 units of fresh frozen plasma. On Day 3 of admission, we had a suspicion of leptospirosis and serum leptospirosis antibody test (IgM) was negative. A serum microagglutination test (MAT) for leptospirosis was positive - 1:160 dilution (significant >1:80 dilution). Patient continued on injection ceftriaxone 1 g IV b.i.d. and injection vancomycin 1 g IV b.i.d. for 7 days. Patient gradually improved over a period of 7 days; sensorium improved, no fever spikes, platelets returned to normal and liver function improved. After 10 days of intensive care treatment patient was discharged. Final diagnosis Leptospirosis with multiorgan failure. DISCUSSION Leptospirosis is a re-emerging infectious disease of worldwide distribution but more commonly seen in the tropical countries and outbreaks occur in the rainy season. The causative organism is Leptospira interrogans, a Gram-negative thin and motile bacteria, 6-20 Âľm in length with flagella and it includes around 250 serovars. It is the most common zoonosis and humans are accidental hosts infected from body fluids especially urine of infected animal and rodents are the most common source worldwide. Leptospirosis presents after a incubation period of 5-14 days. Often a good clinical history is needed to suspect and diagnose leptospirosis. Studies have shown that most of the patients (around 90%) present with acute febrile illness due to bacteremia (anicteric leptospirosis), which is often self-limiting. Patients typically present with fever associated with headache and muscle ache (typically calf pain) and conjunctival suffusion. Also patients may have symptoms of vomiting, diarrhea and pharyngitis. Inspite of fever being the cardinal symptom, studies have shown that about 5% of cases have no history of fever.
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Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
The second phase (immune stage) of illness occurs 1-3 days of symptom free after the initial bacteremic phase. The exact pathogenesis of this immune phase remains still unclear. This is probably due to the host immune response to the leptospiral antigens and protein. The two phases are often indistinguishable in icteric leptospirosis. Renal manifestations include oliguric acute tubular necrosis due to hypovolemia and decreased renal perfusion, direct tissue injury, presence of vasoconstrictor agents and some studies suggest rhabdomyolysis but could not prove it. Acute renal failure is associated with increased mortality. Patients present with jaundice and deranged liver function because of hepatic necrosis. Acalculous cholecystitis though rare is clinically significant. Weilâ&#x20AC;&#x2122;s syndrome, the severe form of leptospirosis, manifests with hepatic, renal and pulmonary dysfunction is associated with increased mortality. The pulmonary complications are life-threatening; these include acute respiratory distress syndrome and massive hemoptysis. Aseptic meningitis is seen in patients in anicteric immune stage and cranial nerve palsies, encephalitis and altered sensorium are uncommon and our patient had meningitis with icterus and altered sensorium. Conjunctival hemorrhage is common in immune stage and uveitis may be observed and persist for a year. The complications of leptospirosis are Weilâ&#x20AC;&#x2122;s disease, disseminated intravascular coagulation, meningoencephalitis, massive hemoptysis, acute renal failure, myocarditis, acalculous cholecystitis and pancreatitis has been observed in severe illness. Thus leptospirosis can involve most of the vital organs in the body. Diagnosis is made by rapid diagnostic kits by detecting antibodies IgM and IgG but are negative during first week of illness. Limitation of serology is that antibodies are lacking in the acute phase of the disease. In recent years, several real-time polymerase chain reaction assays have been described. Culturing the bacteria in the blood during first week of illness and in urine from Day 7 of illness is diagnostic but it takes weeks for diagnosis. The MAT represents growth of battery of serovars of 26 leptospiral groups. Detection of agglutination by dark field microscopy is definitive of diagnosis but it usually is negative in first week of illness and is done in specialized centers. Most of the antibiotics are sensitive in leptospirosis and the drugs commonly used are doxycycline, penicillins and macrolides. Some studies suggest no definite
INTERNAL MEDICINE role of antibiotics in milder form of disease. But early antibiotic treatment is found to reduce mortality in recent studies. Patients with Weil’s disease require IV antibiotics. Cefotaxime and ceftriaxone have replaced penicillin in treatment of leptospirosis. Patients with Weil’s disease should be treated in intensive care unit. Renal failure requires dialysis and other supportive care should be given. Patients should be carefully monitored for the pulmonary complications, which are life-threatening. Few studies showed that oliguria, hypotension and abnormal chest auscultations were important prognostic factors in leptospirosis. There are few case reports of patients with Weil’s disease managed successfully with plasma exchange. CONCLUSION To conclude, physicians should be aware of complicated leptospirosis. A high-degree of clinical suspicion is required to diagnose leptospirosis. If any patient presents with multiorgan dysfunction, leptospirosis should be ruled out as earlier is the diagnosis and treatment better the prognosis. SUGGESTED READING 1. Vijayachari P, Sugunan AP, Shriram AN. Leptospirosis: an emerging global public health problem. J Biosci. 2008;33(4):557-69.
Consortium. Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis. 2003;3(12):757-71. 3. Togal T, Sener A, Yucel N, Demirbilek S, Akgun FS, Aydogan M, et al. Intensive care of a Weil’s disease with multiorgan failure. J Clin Med Res. 2010;2(3):145-9. 4. Aydemir S, Ustundag Y, Borazan A, Sekitmez N, Ozdemir H. A case with jaundice, acute renal failure and thrombocytopenia: Weil’s disease. Acad Gastroenterol J. 2004;3(1):42-5. 5. Abdulkader RC. Acute renal failure in leptospirosis. Ren Fail. 1997;19(2):191-8. 6. Thammakumpee K, Silpapojakul K, Borrirak B. Leptospirosis and its pulmonary complications. Respirology. 2005;10(5):656-9. 7. Pappas MG, Ballou WR, Gray MR, Takafuji ET, Miller RN, Hockmeyer WT. Rapid serodiagnosis of leptospirosis using the IgM-specific Dot-ELISA: comparison with the microscopic agglutination test. Am J Trop Med Hyg. 1985;34(2):346-54. 8. Kee SH, Kim IS, Choi MS, Chang WH. Detection of leptospiral DNA by PCR. J Clin Microbiol. 1994;32(4): 1035-9. 9. Trivedi SV, Vasava AH, Bhatia LC, Patel TC, Patel NK, Patel NT. Plasma exchange with immunosuppression in pulmonary alveolar haemorrhage due to leptospirosis. Indian J Med Res. 2010;131:429-33.
10. Tse KC, Yip PS, Hui KM, Li FK, Yuen KY, Lai KN, et al. Potential benefit of plasma exchange in treatment of severe icteric leptospirosis complicated by acute renal 2. Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz failure. Clin Diagn Lab Immunol. 2002;9(2):482-4. MM, Lovett MA, et al; Peru-United States Leptospirosis ■■■■
Endorphins Release Induced by Social Laughter Promote Social Bonding Modulation of endogenous opioidergic activity by social laughter may be an important neurochemical mechanism reinforcing and maintaining social bonds between humans, suggests a new study reported May 23, 2017 in the Journal of Neuroscience.
Intraoperative Ketamine Does Not Decrease Delirium, may Increase Hallucinations A single subanesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experience such as hallucinations, suggest results of the multicenter, international randomized “Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study” published online May 30 in The Lancet.
Low Testosterone After Testicular Cancer Linked to Chronic Health Problems In a large study, 38% of 491 testicular cancer survivors had low testosterone levels and compared to survivors with normal testosterone levels, survivors with low testosterone were more likely to have a range of chronic health problems, including high blood pressure, diabetes, erectile dysfunction and anxiety or depression. This study is to be presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
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NEUROLOGY
Childhood Multiple Sclerosis: A Diagnostic Challenge SAKSHI SINGH*, JEMIMA BHASKAR†, MANISH MEHTA‡, SS CHATTERJEE#
ABSTRACT Neurological problems presenting in childhood are generally due to congenital lesions, head trauma or central nervous system infections. Multiple sclerosis is rarely considered as a diagnosis in a child living in the tropics but the presentation of recurrent and persistent central nervous system deficits in this child which was confirmed by associated magnetic resonance imaging findings, led us to establish this rare diagnosis.
Keywords: Multiple sclerosis, demyelination, dissemination in time and space, recurrent central nervous system deficits
M
ultiple sclerosis (MS) is a demyelinating disorder of central nervous system (CNS) with sparing of peripheral nervous system. There are many clinical episodes of neurological deficits involving the cognitive functions, cranial nerves, motor and sensory system and cerebellum. They are recurring in nature and correlate with magnetic resonance imaging (MRI) changes, which are diagnostic. MS usually occurs in temperate climate zones and are rarely seen in tropical zones.
CASE REPORT A 13-year-old female patient presented with the chief complaints of high-grade fever since 2 days with chills and rigors, irritability, irrelevant talking, weakness of both lower limbs with inability to stand without support. No history of seizures, loss of consciousness and incontinence of bowel/bladder. There was no headache or projectile vomiting. On systemic examination, patient was conscious, oriented but hyperactive, indicating an euphoric state. Right facial nerve upper motor neuron (UMN) palsy was present. Power in both lower limbs was Grade 3/5,
*3rd Year Resident †Senior Resident ‡Professor and Head #Head of the Unit Dept. of Medicine MP Shah Government Medical College, Jamnagar, Gujarat Address for correspondence Dr Jemima Bhaskar H. No. - 4041, King’s Palace, Mehulnagar, Opposite BSNL Telephone Exchange Jamnagar - 361 006, Gujarat E-mail: jemimabhaskar@yahoo.com
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tone was normal, the deep tendon reflexes were exaggerated in all limbs and plantars were extensor bilaterally. There was a subjective sense of paresthesia in right lower limb. Cerebellar signs were also present intention tremors on right side, appendicular ataxia, gait ataxia and tandem walking was not possible. Further investigations showed neutrophilic leukocytosis, peripheral smear negative for malaria, serum C-reactive protein (CRP) - 42 mg/dL; renal function tests and liver function tests were normal. Cerebrospinal fluid (CSF) was normal. Fundus was also normal. MRI brain showed multiple patchy areas of altered signal intensity white matter in subcortical and periventricular distribution, appeared confluent and involved bilateral frontal, parietal and temporal (right more than left) and bilateral occipital regions, anterior limb of right internal capsule, callososeptal interface, bilateral cerebral peduncles, pons, midbrain, superior and inferior quadrigeminal tubercles. Patient had undergone MRI brain previously for similar illness, which showed similar pattern. Patient recovered with steroids (IV methylprednisolone) under the umbrella of broad-spectrum antibiotics and fluid support. Patient had significant past history as follows: Around age of 8 years, patient presented with complaints of high-grade fever with chills for 14 days followed by generalized seizures and altered sensorium. When investigated, she was found to have neutrophilic leukocytosis with smear negative for malaria. CSF showed raised cell count with increased protein though sugar was in normal range.
NEUROLOGY Contrast-enhanced computed tomography (CECT) brain was normal but MRI brain showed T2W hyperintensity lesions in multiple areas with mild communicating hydrocephalus. Tests were also done to rule out glucose-6-phosphate dehydrogenase (G6PD), disorders of fatty acids, amino acids and cystic fibrosis. Patient was treated with steroids under antibiotic cover. Further serial MRI brain showed similar lesions in brain but spinal cord screening was unremarkable. Patient improved clinically with subsidence of fever, became more oriented, reacting adequately to vocal commands with improvement in lower limb weakness. Patient could walk without support though cerebellar signs persisted. In view of presentation of illness, with precipitation of neurological symptoms with fever and dissemination of demyelinating lesions in brain in time and space, after ruling out possibilities of other causes, we reached a conclusion that the underlying pathology should be MS. DISCUSSION Multiple sclerosis is characterized by a triad of inflammation, demyelination and gliosis of the CNS. Lesions of MS typically occur disseminated in time and space. MS is characterized by periventricular plaques. Myelin specific antibodies are present promoting demyelination. As lesions evolve, there is prominent astrocytic proliferation (gliosis). There is partial remyelination of the surviving naked axons producing shadow plaques. Many lesions, however, fail to remyelinate although oligodendrocyte precursors are present. Peripheral nervous system is spared. Due to the demyelination, conduction block occurs and the nerve impulse cannot be propagated but later redistribution of sodium channels allows conduction to occur along the naked axon. Chemical fluctuations occur due to variable conduction block. This explains clinical fluctuations that vary from hour to hour. It may appear with fever mimicking meningoencephalitis. Multiple sclerosis is threefold more common in women than men. Age of onset is 20-40 years (a little later in males than females). Onset in childhood is 0.2-0.4%. Prevalence rates are higher in high latitudes. It is uncommon in Japan, Asia, Africa and the Middle East. The onset may be abrupt or insidious. Symptoms are very varied depending upon location and severity of
lesions in the CNS. The usual symptoms and signs are weakness of the limbs, spasticity, optic neuritis, diplopia, ataxia, bladder dysfunction, cognitive dysfunction, fatigue, facial weakness and vertigo. Ancillary symptoms, such as heat sensitivity, Lhermitte’s sign are present along with trigeminal neuralgia and facial myokymia. The disease presents with 4 clinical types: ÂÂ
Relapsing remitting MS
ÂÂ
Secondary progressive MS
ÂÂ
Primary progressive MS
ÂÂ
Progressive relapsing MS.
Diagnostic criteria for MS ÂÂ
There should be objective abnormalities of CNS
ÂÂ
Predominant involvement of long tracts
ÂÂ
There should be involvement of two or more areas of CNS, clinically or by MRI
ÂÂ
Clinical pattern must consist of two or more episodes of worsening in different sites of CNS
ÂÂ
The neurologic condition cannot be attributed to another disease.
MRI has revolutionized the diagnosis and management of MS. An increase in vascular permeability is detected by leakage of gadolinium into the parenchyma. This produces a MS plaque, focal areas of hyperintensity, which remain visible indefinitely. Lesions are perpendicular to the ventricular surface corresponding to the pattern of perivenous demyelination. The lesions are multifocal within the brain, brainstem and spinal cord. There are also hypointense lesions (black holes) which are markers of irreversible demyelination and axonal loss. Evoked potential testing and CSF abnormalities help in diagnosis. CSF protein is usually normal but there is mononuclear pleocytosis and an increase in intrathecally synthesized immunoglobulin G, which is measured by oligoclonal bands. This patient had some rare features of this disease. She presented first at the age of 8, which is very rare. Another uncommon feature was that two of her attacks of MS were precipitated by fever. In some patients attacks of demyelination do occur with fever due to heat in body (Uhthoff’s phenomenon). During first episode of demyelination at the age of 8, CSF analysis showed a rise in cell count above
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NEUROLOGY 50 cells and a rise in protein content, which made the diagnosis of MS unlikely but her serial MRI showed demyelinating plaques disseminated in time and space.
viral encephalitis, it was later proved to be MS, since it fulfilled the definitive criteria of MS. Hence the presentation.
She had multiple episodes over the last 6 years and repeat CSF during another attack precipitated by fever neither showed pleocytosis or rise in protein. She fulfills all the 5 diagnostic criteria for definite MS although her presentation is unusual. Even residence in the tropics has low incidence of MS - another unusual feature.
SUGGESTED READING
CONCLUSION The diagnostic challenges made this case unique. Although she presented initially with a picture of
1. Nelson’s Textbook of Paediatrics. Book 2: 15th Edition, Chapter 552. 2. Harrison’s Principles of Internal Medicine: Volume 2: 17th Edition, Chapter 24. 3. Harrison’s Principles of Internal Medicine: Volume 2: 17th Edition, Chapter 375. 4. Adam’s Principles of Neurology. 9th Edition, Chapter 36.
5. DeJong’s The Neurologic Examination. 5th Edition, Chapter 1. ■■■■
Study Shows Variations in Transitioning from Treatment to Comfort Care Post-stroke Hospitals vary widely in how often they transition people with strokes from active treatment to comfort or hospice care within 48 hours after they get to the hospital, according to a new study published in the May 24, 2017 in the journal Neurology. People who were transitioned earliest to comfort care were more likely to have had an intracerebral or subarachnoid hemorrhage than an ischemic stroke.
Long-term Opioid Therapy Increases Risk of Adverse Events in Patients with Polyneuropathy Long-term opioid therapy, for 90 days or more, in patients with polyneuropathy is associated with increased risk of depression, opioid dependence or opioid overdose compared to those receiving shorter durations of opioid therapy, suggests a retrospective study published online May 22, 2017 in JAMA Neurology.
EMA Approves Marketing Authorization for Cenegermin for Neurotrophic Keratitis The European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorization for cenegermin (Oxervate, Dompé farmaceutici S.p.A.) for the treatment of adults with moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis.
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OBSTETRICS AND GYNECOLOGY
Comparison of Serum Anti-mullerian Hormone with Ultrasound as a Diagnostic Marker in Polycystic Ovarian Syndrome ANEESHA AWASTHY*, SHIKHA SINGH†, REKHA RANI‡
ABSTRACT Objectives: To study the sensitivity and specificity of serum anti-mullerian hormone (AMH) as a diagnostic marker in comparison with ultrasound in diagnosed cases of polycystic ovarian syndrome (PCOS). Material and methods: The study was conducted in patients attending the OPD of Dept. of Obstetrics and Gynecology of SN Medical College and Hospital, Agra. Three hundred eighty patients attending OPD with complaints of menstrual irregularities, and/or hirsutism and/or infertility were screened and 80 diagnosed cases of PCOS according to revised Rotterdam criteria (2003) were taken for study. All women included in the study underwent ultrasound for polycystic ovarian morphology (PCOM) and serum AMH levels were measured. Both of them were compared for their sensitivity and specificity in diagnosing PCOS. Study design: This study was a prospective comparative study. Results: The levels of serum AMH were found significantly high (>5 ng/mL) in 93.75% of cases compared to 75% cases being diagnosed with PCOM. Conclusion: Serum AMH is more sensitive and specific in diagnosis of PCOS as compared to ultrasound.
Keywords: Anti-mullerian hormone, polycystic ovarian syndrome, ultrasonography
P
olycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age group. The prevalence among women of fertile age group is 6-10% using National Institute of Health (NIH) criteria1 and 14-17% using the revised Rotterdam criteria.2 For many years, different combinations of clinical (irregular menstrual cycles, hirsutism), biological (elevated serum testosterone or androstenedione levels or increased luteinizing hormone/follicle-stimulating hormone [LH/FSH] ratio) and ultrasound (US) criteria have been proposed with very little international consensus.3 The aim of the study was to evaluate how anti-mullerian hormone (AMH) actually performs when used instead of polycystic ovarian morphology (PCOM) when diagnosing PCOS in the age group in which it is most prevalent (20-35 years).
*3rd Year Resident †Associate Professor ‡Assistant Professor Dept. of Obstetrics and Gynecology, SN Medical College, Agra, Uttar Pradesh Address for correspondence Dr Aneesha Awasthy D/o Dr KD Sharma H. No. 104, Rajendra Nagar, Bharatpur, Rajasthan
MATERIAL AND METHODS The study was conducted in patients attending indoor and outdoor of Dept. of Obstetrics and Gynecology, SN Medical College and Hospital, Agra and ethical clearance was taken for the same. Three hundred eighty patients attending OPD with complaints of menstrual irregularities, and/or hirsutism and/or infertility were screened and 80 diagnosed cases of PCOS according to revised Rotterdam criteria (2003) were taken for study. The criteria being at least 2 of (1) clinical and/or biochemical signs of hyperandrogenism (HA) (2) oligo and/or ovulation (3) polycystic ovaries. All women included in the study underwent ultrasound for PCOM. Ultrasound machine used was US (Medison 8000 SR) and transvaginal scan (TVS) was preferred for diagnosis. In patients in whom TVS was not possible transabdominal scan (TAS) (3.5-5 MHz) was done. PCOM was identified according to the Rotterdam European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS Consensus Workshop Group, 2003. PCOM as described below was used as diagnosing PCOS. ÂÂ
Presence of either 12 or more follicles measuring 2-9 mm in diameter
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OBSTETRICS AND GYNECOLOGY ÂÂ
An ovarian volume (OV) 10 mL in one or both ovaries.
TVS/TAS was performed by a single observer on the same day that the blood sample was obtained. Measurements were performed in real time, using the highest possible magnification to view the ovaries. Serum AMH levels were measured using an ultrasensitive Generation II enzyme-linked immunosorbent assay (ELISA) (AMHEIA, Beckman Coulter) according to the supplier’s instructions. Results were expressed in nanograms per milliliter. There are no internationally acceptable levels of serum AMH for diagnosis of PCOS. An arbitrary cutoff of 5 ng/mL was taken as positive for the diagnosis of PCOS in our study.
Statistical Analysis Results were reported as mean and standard deviation. Comparisons of means were carried out using the Student’s t-test. P-value <0.05 was considered significant. Sensitivity, specificity, positive and negative predictive values were used to evaluate the results. RESULTS AND OBSERVATIONS Eighty cases having PCOS after screening 380 women were included in the study. Forty-two percent cases belonged to age group of 20-25 years and 58% between 26-35 years (Table 1).
anovulation the mean serum AMH was found to be 7.01 ± 1.10 ng/mL; and in cases having PCOM on USG, hyperandrogenism and anovulation was 6.94 ± 0.99 ng/mL and in cases having only hyperandrogenism and anovulation but no PCOM in USG was 6.73 ± 1.39 ng/mL (Table 4). Maximum number of cases were diagnosed by two important criteria of Rotterdam that are oligo/ anovulation in 96% of cases and USG findings of PCOM, which were positive in 75% of cases while hyperandrogenism was present in 66% of patients (Table 5). Seventy-five PCOS cases in the study group Table 2. Distribution of Cases According to Menstrual Cycle Patterns Menstrual cycle abnormality
No. of cases
Percentage (%)
Amenorrhea
21
26
Oligomenorrhea
43
54
Polymenorrhea
2
2
Polymenorrhagia
2
2
Normal cycle
4
6
Hypomenorrhea
8
10
Total
80
100
Table 3. Distribution of Cases According to Serum AMH Level
Oligomenorrhea was most common complaint (54%). Amenorrhea (26%) was second most common complaint. Hypomenorrhea was found in (10%) of the cases and polymenorrhea was found in (2%) cases, polymenorrhagia was found in (2%) cases, while normal cycles were seen in (6%) of the cases (Table 2). Majority of the cases (62.5%) had serum AMH level between 5-6.4 ng/mL (Table 3).
Serum AMH (ng/mL) 3.5-4.9 5-6.4 6.5-7.9 ≥8 Total
In our study population, mean serum AMH values in cases having (PCOM) on ultrasound and hyperandrogenism was 7.11 ± 1.14 ng/mL, in those having PCOM in ultrasonography (USG) and
Table 4. Correlation of Mean Serum AMH Values in Cases According to Different Criteria Positivity of Revised Rotterdam Consensus Criteria
No. of cases Percentage (%) 5 6.25 50 62.5 20 25 5 6.25 80 100
Mean serum AMH 4.28 5.64 7.68 8.86
Positivity criteria
No. of patients
Mean serum AMH
Table 1. Distribution of Cases of PCOS According to Age
PCOM in USG + Hyperandrogenism
35
7.11 ± 1.14
Age (years)
PCOM in USG + Anovulation
39
7.01 ± 1.10
PCOM in USG + Hyperandrogenism + Anovulation
25
6.94 ± 0.99
Hyperandrogenism + Anovulation
20
6.73 ± 1.39
Cases No. of cases
Percentage (%)
20-25
34
42
26-30
20
25
31-35
26
33
Total
80
100
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Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
OBSTETRICS AND GYNECOLOGY Table 5. Distribution of Cases According to Serum AMH Levels Serum AMH (ng/mL)
No. of patients
Percentage (%)
>5
75
93.75
<5
5
6.25
Total
80
100
Table 6. Comparison of Serum AMH with PCOM (According to Different Statistical Parameters) in Diagnosing PCOS Comparative parameter Sensitivity Specificity
Serum AMH
PCOM in USG
93.75
75
84
62
PPV
0.967
0.89
NPV
0.15
0.60
PPV = Positive predictive value; NPV = Negative predictive value.
had serum AMH levels higher than cut-off (>5 ng/mL), so 75 cases out of 80 tested positive by serum AMH evaluation. While 5 PCOS cases had serum AMH level less than cut off for our study. Seventy-five percent cases, who had PCOM in USG had a mean serum AMH of 7.2 ng/mL, while 25% cases who didn’t have PCOM in USG also had high serum AMH level (6.7 ng/mL). Approximately 62.5% could be diagnosed by both PCOM in USG and serum AMH. But an additional, 21.5% cases could be diagnosed by serum AMH alone. Out of the 6.25% cases not detectable by serum AMH only 2.5% cases had PCOM in USG (Table 6). DISCUSSION This study was an attempt to study the sensitivity and specificity of serum AMH as a diagnostic marker in comparison with PCOM on ultrasound in diagnosed cases among Indian PCOS women and to find a suitable cut-off level of serum AMH. In our study, 42% of patient belonged to age group of 20-25 years and 58% between 26-35 years, thus our study was in accordance with other investigators, who also found PCOS to be common in the age group of 15-39 years, Sharquie et al (2007)4 and 18-35 years according to Vandermolen (2001).5 In our study, PCOS subjects were defined by Revised Rotterdam 2003 criteria. In our study, it was seen that mean serum AMH was higher than the cut-off for all women with different criteria positive. Twenty-five percent cases that didn’t have PCOM in USG and were diagnosed on
the basis of HA and oligo/anovulation also had a mean serum AMH value of 6.73 ± 0.39 ng/mL. In our study; in ultrasound; follicle number (FN) of size 2-5 mm were 13.6 on an average corresponding to high levels of serum AMH. In a study by Dewailly et al,6 it was 12.8. AMH level was 2- to 3-fold higher in PCOS than in controls, an increase of the same order of magnitude as the one of FN in the 2- to 5-mm range. Only the 2- to 5-mm FN remained significantly related to the AMH level. In our study, levels of serum AMH were found in 93.75% cases to be >5 ng/mL while only 6.25% had serum AMH less than the cut-off. Most of the cases (62.5%) had a serum AMH level between 5-6.4 ng/mL. This corresponds to a study by Eilertsen et al,7 where the mean serum AMH level in PCOS-R women is 44.8 pmol/L. Approximately 72.5% cases could be diagnosed by PCOM in USG who also had a serum AMH level >5 ng/mL. But 21.25% cases despite having a serum AMH level >5 ng/mL; couldn’t be detected by PCOM in USG. So, AMH has higher sensitivity in diagnosing PCOS. A study by Wiweko et al,8 also shows that PCOS cases who do not have PCOM in USG also have high serum AMH level (6.0-17.1 ng/mL). Our study shows that AMH could be used as an alternative diagnostic tool in PCOS patients. In a similar study, Pigny et al found that the specificity and sensitivity of serum AMH measurement reached 92% and 67%, respectively.9 Lin et al obtained the cut-off AMH level of 7.3 ng/mL, giving 76% specificity and 70% sensitivity to predict PCOS.10 There exists a good correlation between AMH and PCOM. Van Rooij et al, in a study of 119 patients found serum AMH levels highly correlating with the PCOM.11 Laven et al,12 in a study of PCOS women (n = 128), also found AMH levels to significantly correlate with the mean PCOM. In our study, sensitivity of serum AMH was found to be 93.75% and that of ultrasound was found to be 75% while specificity was 84% and 62%, respectively. In a similar study, Dewailly et al concluded that a serum AMH level of >4.9 ng/mL could be able to replace the finding of PCOM in PCOS.6 Eilertsen et al7 suggested a cut-off value of 4.8 ng/mL for PCOM in PCOS, with 80% sensitivity and 72% specificity, which also corresponds to our study. In a similar study, Homburg et al13 found that a serum AMH threshold of 6.72 ng/mL had an excellent (98%) specificity while using PCOM for PCOS diagnosis.
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OBSTETRICS AND GYNECOLOGY However, this excellent (98%) specificity appeared at the expense of a poor (60%) sensitivity. Casadei et al14 using ROC analysis yielded a threshold cut-off of AMH >4.64 ng/mL for diagnosis of PCOM in PCOS with 95% sensitivity and 95% specificity. These findings open the possibility of a simpler way to diagnose PCOS. According to the high prevalence of the syndrome, the high level of undiagnosed women and the long-term health risk these women face, this seems necessary. If there were an easy way to obtain hyperandrogenism as well, diagnosis could be obtained by a simple question about menstrual regularity and a blood sample. CONCLUSION Our study found serum AMH to be more sensitive and specific than PCOM in diagnosing PCOS. Obtaining good data on ovarian morphology demands a time and resource consuming ultrasound examination by a specialist with appropriate skills. There has been a lack of standardization in assessing PCOM leading to intraobserver and interobserver variations and TVS (transvaginal ultrasound) is required for better diagnosis and TVS is not feasible in unmarried women, so there is need of a serum marker for diagnosis of PCOS, which can make diagnosis easier and uniform. This study was planned to compare sensitivity and specificity of serum AMH with PCOM on ultrasound for diagnosing PCOS cases and found serum AMH to be a useful, noninvasive way of diagnosing PCOS. Larger studies with more number of cohorts need to be done to establish internationally accepted cut-off levels of serum AMH for diagnosis of PCOS. REFERENCES 1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83(9):3078-82. 2. Tehrani FR, Simbar M, Tohidi M, Hosseinpanah F, Azizi F. The prevalence of polycystic ovary syndrome in a community sample of Iranian population: Iranian PCOS prevalence study. Reprod Biol Endocrinol. 2011;9:39.
clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril. 2005;83(6):1717-23. 4. Sharquie KE, Al-Bayatti AA, Al-Ajeel AI, Al-Bahar AJ, Al-Nuaimy AA. Free testosterone, luteinizing hormone/ follicle stimulating hormone ratio and pelvic sonography in relation to skin manifestations in patients with polycystic ovary syndrome. Saudi Med J. 2007;28(7): 1039-43. 5. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75(2):310-5. 6. Dewailly D, Gronier H, Poncelet E, Robin G, Leroy M, Pigny P, et al. Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries. Hum Reprod. 2011;26(11):3123-9. 7. Eilertsen TB, Vanky E, Carlsen SM. Anti-Mullerian hormone in the diagnosis of polycystic ovary syndrome: can morphologic description be replaced? Hum Reprod. 2012;27(8):2494-502. 8. Wiweko B, Maidarti M, Priangga MD, Shafira N, Fernando D, Sumapraja K, et al. Anti-mullerian hormone as a diagnostic and prognostic tool for PCOS patients. J Assist Reprod Genet. 2014;31(10):1311-6. 9. Pigny P, Jonard S, Robert Y, Dewailly D. Serum antiMullerian hormone as a surrogate for antral follicle count for definition of the polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(3):941-5. 10. Lin YH, Chiu WC, Wu CH, Tzeng CR, Hsu CS, Hsu MI. Antimüllerian hormone and polycystic ovary syndrome. Fertil Steril. 2011;96(1):230-5. 11. van Rooij IA, Broekmans FJ, te Velde ER, Fauser BC, Bancsi LF, de Jong FH, et al. Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve. Hum Reprod. 2002;17(12):3065-71. 12. Laven JS, Mulders AG, Visser JA, Themmen AP, De Jong FH, Fauser BC. Anti-Müllerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J Clin Endocrinol Metab. 2004;89(1):318-23. 13. Homburg R, Ray A, Bhide P, Gudi A, Shah A, Timms P, et al. The relationship of serum anti-Mullerian hormone with polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study. Hum Reprod. 2013;28(4):1077-83.
14. Casadei L, Madrigale A, Puca F, Manicuti C, Emidi E, Piccione E, et al. The role of serum anti-Müllerian 3. Chang WY, Knochenhauer ES, Bartolucci AA, Azziz R. hormone (AMH) in the hormonal diagnosis of polycystic Phenotypic spectrum of polycystic ovary syndrome: ovary syndrome. Gynecol Endocrinol. 2013;29(6):545-50. ■■■■
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2017
OBSTETRICS AND GYNECOLOGY
Ectopic Pregnancy Presenting as True Gestational Epilepsy SHYAMAL G*, VIJAYALAKSHMI†, SUNIL KUMAR N‡, ANUDEEP REDDY‡
ABSTRACT Ectopic pregnancy refers to implantation of fertilized egg in a location outside of uterine cavity including fallopian tube, cervix, ovary, cornual region of uterus and abdominal cavity. It is a life-threatening condition. Though it is familiar to physicians when it presents with abdominal pain, amenorrhea, vaginal bleeding, but when it gets ruptured patients present with weakness, dizziness, near syncope and low blood pressure. Ectopic pregnancy, presenting as multiple episodes of seizures, is difficult to distinguish from other causes of seizures. Here we describe a previously normal 24-year-old female, with no previous history of seizures, who presented with 8 weeks of amenorrhea and sudden onset of seizures (true gestational epilepsy).
Keywords: Ectopic pregnancy, seizures, true gestational epilepsy
E
ctopic pregnancy refers to implantation of blastocyst anywhere else other than endometrial lining of uterus in the uterine cavity. It almost occurs 2 in every 100 pregnancies and over 95% involve oviduct. This is life- and fertility-threatening for further pregnancy. The rate of ectopic pregnancy was increased to 4-fold since 1970. The incidence of ectopic pregnancy for nonwhite is 1.5 times compared to whites. Although ectopic pregnancy is familiar to most of physicians, ectopic pregnancy presenting with atypical symptoms like new-onset seizures is very difficult to distinguish from other causes of seizures such as cerebral venous thrombosis, cerebrovascular accident, eclampsia, electrolyte disorders, neurocysticercosis, autoimmune encephalitis, anxiety, stress, hyperventilation, other structural disorders due to similar presentations. Here we describe a 24-year-old female with 2 months of amenorrhea who presented
*Professor Dept. of Medicine †Associate Professor Dept. of Obstetrics and Gynecology ‡Post Graduate Dept. of Medicine Vijayanagara Institute of Medical Sciences, Bellary, Karnataka Address for correspondence Dr Sunil Kumar N Post Graduate Dept. of Medicine Vijayanagara Institute of Medical Sciences, Bellary, Karnataka E-mail: sunil.kumar.n6@gmail.com
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to emergency in altered sensorium after 7 episodes of generalized tonic-clonic seizures (GTCS) for which she was referred from a peripheral center. CASE REPORT A 24-year-old female presented to emergency department with altered sensorium following 7 episodes of GTCS. She had history of 2 months of amenorrhea and was a primi who was not aware of her pregnancy. On examination, her pulse rate was 95/min and blood pressure was 110/80 mmHg. Patient was pale and tachypneic. Patient was conscious and in postictal confusion with no other focal neurological deficits. Systemic examination was otherwise normal. Laboratory work-up revealed: Hemoglobin - 4.5 g/dL, leukocyte count - 8,900/mm3, platelet count - 1.2 lakh/µL. Blood urea levels of 48 mg/dL and creatinine level of 1.2 mg/dL. Sodium, potassium, chloride, calcium levels were 138 mEq/L, 3.3 mEq/L, 108 mEq/L, 4.0 mEq/dL, respectively; urine albumin was negative. Vanillylmandelic acid (VMA) levels were normal. Chest X-ray and CT brain with contrast were normal. Ultrasound abdomen showed an ill-defined hypoechoic lesion in pelvic region possibly due to ruptured ectopic pregnancy, 350 cc of volume collection. A diagnosis of ectopic pregnancy was made and patient was taken for emergency laparotomy. Laparotomy revealed clots and hemoperitoneum. Ampullary end of the left fallopian tube was found ruptured (Fig. 1 a and b). The clots, measuring about 550 g,
OBSTETRICS AND GYNECOLOGY The incidence is higher in women between 35 and 44 years of age and it is counted as 27 per 1,000 reported pregnancies.4
a
b
Figure 1 a and b. Ampullary end of fallopian tube was found ruptured at emergency laparotomy.
were removed and around 1,000 mL of peritoneal fluid was drained. Hemostasis was achieved and tubes were transfixed and ligated. She was resuscitated with blood. Antiepileptic, injection phenytoin 100 mg t.i.d., was administered for 8 days. Antibiotic coverage was given and further course in hospital was uneventful. On further follow-up, she was seizure-free for a period lasting more than 6 months. DISCUSSION Ectopic pregnancy, the implantation of a fertilized ovum outside the uterine cavity, has been increasing in numbers and now accounts for 2% of all pregnancies in the United States.1 Worldwide, ectopic pregnancy remains the leading cause of maternal death in the first trimester.2 Ectopic pregnancy continues to be an important contributor to maternal mortality, morbidity and early fetal wastage in the first trimester of pregnancy.3
Distribution of cases in percentage according to predisposing factors are pelvic inflammatory disease (47.5%), infertility treatment (22.5%), previous ectopic pregnancy (25%), tubal surgery (10%), lower-segment cesarean section (12.5%) and intrauterine contraceptive device (IUCD) insertion (12.5%).5 No single clinical feature accurately indicates ectopic pregnancy. Less than half of women with ectopic pregnancy exhibit the classic triad of a history of amenorrhea, abdominal pain and irregular vaginal bleeding. And, unfortunately, these features are seen commonly in patients with both viable (50%) and nonviable (25%) intrauterine pregnancies, as well as in threatened abortion, cervical irritation, infection and trauma.6 Abdominal pain and vaginal bleeding are highly sensitive for ectopic pregnancy, but are not specific for the disorder. Pain located in the hypogastrium or iliac fossa may be mild-to-severe. Vaginal bleeding, present in 50-80% of patients with ectopic pregnancy, can be mistaken for a normal menstrual period. Pregnancyassociated symptoms of nausea and vomiting, breast tenderness and fatigue may be present. Lower abdominal and adnexal tenderness can be elicited in most women with ectopic pregnancy. Cervical motion tenderness, peritoneal signs and adnexal masses are most specific for ectopic pregnancy, but are not sensitive. An adnexal mass is palpable in less than 10% of cases; when it is detected, one-third of patients will have a contralateral ectopic pregnancy on ultrasonography. Symptoms of hemodynamic compromise (orthostasis, hypotension, shock) are becoming uncommon with earlier diagnosis of ectopic pregnancy, facilitated by improved detection methods.6 The above-mentioned clinical features make the diagnosis of ectopic pregnancy easy, but when it presents with none of above-mentioned symptoms it, like our case, makes the diagnosis difficult. True gestational epilepsy is one of cause for seizures in pregnancy. An ectopic pregnancy can present as true gestational epilepsy like in our case. It is wellknown fact that estrogens activate seizure foci and lower seizure threshold and progesterones dampen the seizure foci.7 Differential diagnosis of convulsion diagnosed for the first time during pregnancy include: eclampsia, thrombotic thrombocytopenic purpura,8 pheochromocytoma, neurofibromatosis, oxytocin infusion, water intoxication, cerebral vein thrombosis, neurocysticercosis,9 autoimmune encephalitis and
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OBSTETRICS AND GYNECOLOGY anti-NMDA (N-methyl-D-aspartate) receptor encephalitis during pregnancy.10 Other metabolic and structural causes of seizures were ruled out from relevant investigations. During pregnancy, seizures presenting first time is called true gestational epilepsy.10 In our case, she did not have any past history of epilepsy and all abovementioned and possible structural and metabolic causes were ruled out. In our patient, after removal of ectopic products of conception, there were no further episodes of seizures and at follow-up till now about 6 months, no further complications occurred. So, the convulsions could be attributed to ectopic pregnancy, which is very unusual. CONCLUSION There are many causes of seizures in pregnancy. Ectopic pregnancy, autoimmune encephalitis and neurocysticercosis have to be considered as some of the important differential diagnosis after ruling out common causes of seizures in pregnancy mentioned above. Early recognition of the disease and prompt treatment of the condition will be a lifesaving and fertility preserving measure. REFERENCES
2. Autry AM. Medical treatment of ectopic pregnancy: is there something new? Obstet Gynecol. 2013;122(4): 733-4. 3. Igberase GO, Ebeigbe PN, Igbekoyi OF, Ajufoh BI. Ectopic pregnancy: an 11-year review in a tertiary centre in the Niger Delta. Trop Doct. 2005;35(3):175-7. 4. Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy -United States, 1970-1989. MMWR CDC Surveill Summ. 1993;42(6):73-85. 5. Gupta R, Porwal S, Swarnkar M, Sharma N, Maheshwari P. Incidence, trends and risk factors for ectopic pregnancies in a tertiary care hospital of Rajasthan. JPBMS. 2012;16(7):1-3. 6. Ramakrishnan K, Scheid DC. Ectopic pregnancy: forget the "classic presentation" if you want to catch it sooner. J Fam Pract. 2006;55(5):388-95. 7. Gerard N Bamboo, Thomas P Duffy. Medical Complications During Pregnancy. 5th Edition, 411. 8. Kafali H, Harma M, Harma M. Pseudoeclampsia: convulsion diagnosed for the first time during pregnancy; eclampsia versus epileptic or psychogenic seizures. Artemis. 2004;5(1):70-2. 9. Suarez VR, Iannucci TA. Neurocysticercosis in pregnancy: a case initially diagnosed as eclampsia. Obstet Gynecol. 1999;93(5 Pt 2):816-8.
10. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. Anti-NMDA-receptor encephalitis: case series 1. Centers for Disease Control and Prevention (CDC). and analysis of the effects of antibodies. Lancet Neurol. Ectopic pregnancy - United States, 1990-1992. MMWR Morb Mortal Wkly Rep. 1995;44(3):46-8. 2008;7(12):1091-8. ■■■■
Diagnostic Performance of the Gynecology Imaging Reporting and Data System for Malignant Adnexal Masses A recent study published in the International Journal of Gynaecology Obstetrics aimed at the evaluation of the Gynecology Imaging Reporting and Data System (GI-RADS) for diagnosis of malignant adnexal masses in a Chinese population. This was a retrospective study which was conducted in patients for the evaluation of suspected adnexal masses. Patients with thick wall, solid papillary projection, solid area, central blood flow, ascites and GI-RADS classification were associated with malignancy. Masses evaluated were classified as GIRADS 2 (functional cyst); GI-RADS 3 (benign neoplasm); GI-RADS 4 (one or two morphological findings suggestive of malignancy); GI-RADS 5 (more than 3 morphological findings suggestive of malignancy). The sensitivity, specificity, false-positive rate, false-negative rate and accuracy of the GI-RADS classification were found to be 96.4%, 84.3%, 18.5%, 3.0% and 89.3%, respectively. Hence GI-RADS classification was stated as a reliable tool for the diagnosis of malignant adnexal masses.
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OPHTHALMOLOGY
To Study the Effect of Steroid Eye Drops on Intraocular Pressure After Cataract Surgery JITENDER PHOGAT*, SUMIT SACHDEVA, SUMEET KHANDUJA, CS DHULL, HIMANI ANCHAL
ABSTRACT Objective: To study the effect of steroid eye drops on intraocular pressure (IOP) after cataract surgery. Material and methods: This study was conducted in tertiary eye care center. Total of 300 eyes which underwent uncomplicated cataract surgery were studied for IOP change for up to 6 weeks after use of topical steroids and the pressures were measured with applanation tonometer. Results: After 6 weeks of steroid therapy, 18% patients had persistently raised IOP of which 1.3% still had raised IOP after 4 weeks of steroid omission. Conclusion: Topical steroid therapy after cataract surgery increases IOP in significant number of cases.
Keywords: Intraocular pressure, steroids, cataract, applanation tonometry
S
teroids are the mainstay of treatment to control inflammation after cataract surgery. Usually steroids are required for almost 6 weeks in tapering doses for effective control of inflammation and prompt recovery of visual acuity after cataract surgery. Steroids are definitely more potent than nonsteroidal anti-inflammatory drugs (NSAIDs) and hence are used as primary drug in post surgical period.
Steroids cause elevation of intraocular pressure (IOP) when given by any route including topical, periocular and systemic. Maximum rise of IOP occurs with periocular route. The degree of IOP elevation depends up on the specific drug, the dose, the frequency of administration and the individual patient.1 There are three different mechanisms of increased resistance to the outflow of aqueous humor that act synergistically to produce corticosteroid-induced ocular hypertension.2 First is structural changes of trabecular meshwork, second is mechanical obstruction of the orbicular meshwork by steroid particles and last mechanism is inhibition of phagocytes by orbicular meshwork cells. Glucocorticoids exert their effect by increased
*Assistant Professor Regional Institute of Ophthalmology Pt BD Sharma, PGIMS, Rohtak, Haryana Address for correspondence Dr Jitendar Phogat 923/A-28, Bharat Colony, Rohtak, Haryana E-mail: drjitenderphogat@gmail.com
expression of myocilin (MYOC) gene located on locus GLC1A on 1q25 chromosome.3 Glucocorticoids cause increased production of elastin, fibronectin and laminin by trabecular cells and decreased production of tissue plasminogen-activator, collagenase IV and stromelysin, ultimately causing accumulation of extracellular matrix (ECM) and increased resistance to aqueous outflow. Cross-linked actin networks form within the trabecular cells which inhibit their proliferation, migration and phagocytic activity and hence causes accumulation of cellular debris and clogging of aqueous outflow channels. MATERIAL AND METHODS The study was conducted in the Regional Institute of Ophthalmology, PGIMS, Rohtak. A total of 300 patients operated for cataract surgery were taken up for study. Patients were operated for cataract surgery by phacoemulsification and small-incision cataract surgery (SICS) technique with intraocular lens implantation. Exclusion criteria was history of glaucoma, complicated cataract, pediatric patients, pathological myopia and patients with any complication during surgery. Patients were admitted in the hospital and informed and written consent was taken before surgery. Detailed history of patient was taken including chief complaints, ocular history and systemic history. Examination was done in detail which included best corrected visual acuity with Snellenâ&#x20AC;&#x2122;s chart, slitlamp examination, fundus examination and IOP
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OPHTHALMOLOGY measurement with applanation tonometer. Patients were started preoperative topical antibiotics 3 days prior to surgery to minimize the risk of infection. Patients were operated under local and topical anesthesia with phacoemulsification and SICS technique and posterior chamber intraocular lens (PCIOL) was implanted. Patients were examined on first postoperative day including visual acuity assessment, slit-lamp examination and IOP was recorded. Patients were started on antibiotic eye drop and steroid eye drop (1% prednisolone acetate) 6 times a day for first week and 4 times a day for 5 weeks. Patients who had IOP between 25 and 30 mmHg on first postoperative day were given tablet acetazolamide thrice a day for 3 days. Patients who had IOP >30 mmHg on first postoperative day were treated with intravenous mannitol and tablet acetazolamide thrice a day for 3 days. Follow-up of all patients was done 1 week after surgery and another was done 6 weeks after surgery. Later, a follow-up was done after 4 weeks of omission of steroid eye drops and visual acuity, IOP were recorded. RESULTS Medical records of 300 patients who were operated for cataract surgery showed that 30 (10%) had a rise of IOP >25 mmHg on first operative day. On 1 week followup, only 2 patients had persistently raised IOP after above treatment. Fifty-four patients (18%) had an IOP rise of >6 mmHg from baseline, of which 9 (3%) had >15 mmHg after 6 weeks of cataract surgery. Thus, the percentage of steroid responders was 3%. At the end of 6 weeks of cataract surgery, 82% (246) of the patients had an IOP <20 mmHg (low steroid responders), 15% (45) had between 20-30 mmHg (intermediate steroid responders) and 3% (9) had IOP of >30 mmHg (high steroid responders) (Table 1). At the end of 4 weeks of omission of steroid eye drop, 2 patients out of 9 patients had persistently raised IOP. These 2 patients were treated with topical antiglaucoma drugs and none of them required any surgical treatment for glaucoma. Table 1. Classification of Steroid Responders on the Basis of Final IOP After 6 Weeks of Use of Topical Steroids (Prednisolone 0.1%) Eye Drops Type of responder Low Intermediate High
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Final IOP (mmHg)
Patient (%)
<20
246 (82)
20-30
45 (15)
>30
9 (3)
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Table 2. Rise of Intraocular Pressure Time interval after cataract surgery
Patients (%)
yy First postoperative day
30 (10)
yy First week
3 (1)
yy 6 weeks
54 (18)
yy 4 weeks after omission of steroid (10 weeks after surgery)
4 (1.3)
Table 3. Treatment Strategy Treatment protocol
Topical and systemic steroid
First-line of treatment
Discontinuation of steroids in all form if possible. Medical control of IOP for the wash off period of steroids
Second-line of treatment
Substitute with other nonsteroidal drugs or use minimal dose and duration of less potent steroid
Third-line of treatment
Medical treatment
Fourth-line of treatment
Laser or surgery
Thus, in this study of 300 patients operated for cataract surgery, 30 (10%) patients had raised IOP on first postoperative day, which may be due to intraocular inflammation or any retained viscoelastic substance or any retained cortical matter. Patients with higher IOP were treated accordingly. After first week of cataract surgery only 3 patients of higher IOP on first day had persistently raised IOP. All 300 patients were given steroid eye drops (prednisolone acetate 1%) for 6 weeks and raised IOP was observed in 54 (18%) of them. After stoppage of steroids eye drops for 4 weeks, only 4 (1.3%) of total operated patients had persistently raised IOP, which required antiglaucoma treatment (Table 2). DISCUSSION Cataract surgery is performed by removal of opaque natural lens and implantation of artificial transparent lens in eye with different techniques including newer phacoemulsification and conventional SICS. Steroids are used along with antibiotics for a prolonged postoperative time to control inflammation and for faster visual recovery. But topical steroid used also cause elevation of IOP in a significant number of patients. In most of the patients, elevated IOP is usually transient and harmless. But some patients may develop ocular complications including corneal edema, ocular discomfort and even vision threatening complications
OPHTHALMOLOGY Table 4. Patients Responding to Steroids (IOP Changes After 6 Weeks of Steroid Use) in Present and Other Study Study Armaly et al
% of pts with rise of IOP after 6 weeks of steroid
IOP change >6-15 mmHg (%)
IOP change >15 mmHg (%)
34
29
5
Becker et al
36
-
-
Beidner et al
12
10
2.5
Present study
18
15
3
requiring further intervention. The increase in IOP may be marked and is the most frequent postoperative complication requiring specific treatment.4,5 Numerous studies have evaluated the risk of increase in IOP following demographics, etiology and the most effective way to treat it in short- and long-term.6 Treatment options include different antiglaucoma medications and sometime surgical option including trabeculectomy. In most of patients, IOP increase will return to baseline with or without treatment, some patients may experience ocular pain, corneal edema and even sight-threatening complications such as progressive field loss in advanced glaucoma and retinal vascular occlusion.7 Increase in IOP following cataract surgery is transient in most of patients.8 According to a recent study, as many as 25% of patients experience IOP spike >30 mmHg, 4-6 hours after uncomplicated phacoemulsification.9,10 At 24 hours postoperatively, the incidence of IOP spikes decreased to 10% and in all cases IOP was normal (<21 mmHg) 3 weeks later. Another study found >18% of nonglaucoma patients had an IOP of >28 mmHg, 3-7 hours postoperatively, which decreased to below preoperative levels by 4 days in most patients.2 As a general rule, patients with healthy eyes can tolerate transient rise in IOP with no damage to visual function, but in patients of risk factors like pre-existing glaucoma, high myopia damage affecting visual function may occur. After cataract surgery, steroid-induced IOP elevation occurs within a few weeks of beginning of steroid therapy. After stoppage of steroids, the IOP lowers spontaneously to the baseline within few weeks without any antiglaucoma medications in majority of patients. In rare cases, only IOP remains elevated and requires treatment to lower it. In our study, 10% patients had rise of IOP on first postoperative day, which is comparable to previous studies. Retained viscoelastic, cortical matter and intraocular inflammation are reasons for elevated IOP on first postoperative day. After 1 week of follow-up only 1% of patient had raised IOP. After 6 weeks of steroid use, 18% of the patients showed rise in IOP of >6 mmHg, which is comparable to other studies.
Steroid responders (>15 mmHg) were 3%, which is similar to other studies. In the present study, steroid eye drops were given for 6 weeks and 98.7% patients had normal IOP after 4 weeks of stoppage of steroid eye drops. In a similar study by Nema et al, 100% patient had normal IOP and in another study by Espilora et al 98% patients had normal IOP. CONCLUSION Steroids are primary drugs used after cataract surgery to control inflammation, but they also increase IOP in significant number of patients. But in almost all of patients increase in IOP is transient and returns to baseline after omission of steroid therapy spontaneously without causing any damage to visual function. Risk factors for IOP fluctuations include glaucoma, high myopia or high hypermetropia, intraocular inflammation, etc. Care must be taken while prescribing topical steroids in such patients and IOP monitoring should be done regularly in such patients to prevent vision threatening persistent ocular hypertension. REFERENCES 1. Shingleton BJ, Gamell LS, Oâ&#x20AC;&#x2122;Donoghue MW, Baylus SL, King R. Long-term changes in intraocular pressure after clear corneal phacoemulsification: normal patients versus glaucoma suspect and glaucoma patients. J Cataract Refract Surg. 1999;25(7):885-90. 2. Drance SM. Glaucoma: a look beyond intraocular pressure. Am J Ophthalmol. 1997;123(6):817-9. 3. Gonzalez P, Epstein DL, BorrĂĄs T. Genes upregulated in the human trabecular meshwork in response to elevated intraocular pressure. Invest Ophthalmol Vis Sci. 2000;41(2):352-61. 4. Shields MB. The non-contact tonometer. Its value and limitations. Surv Ophthalmol. 1980;24(4):211-9. 5. Hildebrand GD, Wickremasinghe SS, Tranos PG, Harris ML, Little BC. Efficacy of anterior chamber decompression in controlling early intraocular pressure spikes after uneventful phacoemulsification. J Cataract Refract Surg. 2003;29(6):1087-92.
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OPHTHALMOLOGY 6. Tranos PG, Wickremasinghe SS, Hildebrand D, Asaria R, Mearza A, Ghazi-Nouri S, et al. Same-day versus first-day review of intraocular pressure after uneventful phacoemulsification. J Cataract Refract Surg. 2003;29(3):508-12.
8. Tranos P, Bhar G, Little B. Postoperative intraocular pressure spikes: the need to treat. Eye (Lond). 2004;18(7):673-9. 9. Ahmed II, Kranemann C, Chipman M, Malam F. Revisiting early postoperative follow-up after phacoemulsification. J Cataract Refract Surg. 2002;28(1):100-8.
7. Vannas S, Tarkkanen A. Retinal vein occlusion and glaucoma. Tonographic study of the incidence of glaucoma 10. Gokhale PA, Patterson E. Elevated IOP after cataract and of its prognostic significance. Br J Ophthalmol. 1960;44:583-9. surgery. Glaucoma Today. 2007;5(3):19-22. ■■■■
Eat a Healthy Diet to Lower Risk of Cataract A new research from UK presented May 11, 2017 at the annual meeting of the Association for Research in Vision and Ophthalmology, in Baltimore, Maryland suggests that a healthy diet is associated with a lower risk of agerelated nuclear cataract (ARNC). The difference in the gut bacteria of people who ate healthy diets have been suggested to have a protective effect against cataract.
The First Topical Ocular Cetirizine Formulation for Allergic Conjunctivitis The FDA has approved cetirizine ophthalmic solution 0.24% (Zerviate), the first topical ocular formulation of cetirizine, as treatment for ocular itching associated with allergic conjunctivitis. It is to be administered as one drop in each affected eye twice-daily, 8 hours apart.
Age-adjusted Doses of Melphalan Reduce Complications of Intra-arterial Chemotherapy A study from the UK has shown that visual and ocular motility complications of intra-arterial chemotherapy may be reduced by providing age-adjusted doses of melphalan in children with refractory retinoblastoma. The study concluded that dose rather than complications from catheterization is the most important risk factor for ocular injury. The study is reported online April 21, 2017 in the British Journal of Ophthalmology.
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ORTHOPEDICS
Diagnostic Dilemma and Limb Salvage Surgery of a Large Giant Cell Tumor of Fibular Head Involving Posterior Tibial Vessels: A Case Report MANTU JAIN*, RITESH RUNU†, SANTOSH KUMAR‡, AVNISH SHEEL#, RITIKA CHOUDHRY¥
ABSTRACT Giant cell tumor (GCT) is common in young age group and is more frequent in females than in males. The upper end of fibula is a rare site for tumors and about one-fifth of all are GCTs. Neurovasculature involvement is a rare and dreaded complication. This article highlights the associated diagnostic dilemma and management with limb-sparing surgery.
Keywords: Giant cell tumor, proximal fibula, en bloc resection, vascular repair
G
iant cell tumor (GCT) is common in young age group and females are more commonly affected than males. The fibula is a rare anatomic location where both malignant and benign lesions are encountered. Of these, the proximal fibula is the most common area to be involved followed by diaphysis and the distal fibula.1 Osteosarcoma, Ewing’s sarcoma and GCT are the most frequent tumor types to develop at this location even though metastatic lesions have also been reported. Fibular head tumors account for about 2.5% of total tumor load;2 of these, about 19% are GCTs.3 This location is pathognomonic and the tumor grows for considerable time without causing much symptoms though the adjacent peroneal nerve may be entrapped. The X-ray findings are characteristic and additional investigations like computed tomography (CT) and
*Assistant Professor Dept. of Orthopedics AIIMS, Bhubaneswar, Odisha †Associate Professor ‡Additional Professor Dept. of Orthopedics #Assistant Professor Dept. of Cardiothoracic and Vascular Surgery ¥Senior Resident Dept. of Pathology Indira Gandhi Institute of Medical Sciences, Patna, Bihar Address for correspondence Dr Mantu Jain 106, Mahadev Orchid, Cosmopolis Road, Dumduma, Bhubaneswar - 751 019, Odisha E-mail: montu_jn@yahoo.com
magnetic resonance imaging (MRI) are only needed to see the extent and involvement of soft tissues and to plan surgery. We report a case where the X-ray findings were typical of GCT but contrast MRI suggested telangiectatic osteosarcoma and created a diagnostic confusion. Intraoperative vessel involvement is rare in GCT. Eventually, the limb was salvaged after vascular reconstruction following tumor excision. Histopathologic examination proved GCT. CASE REPORT A 19-year-old female presented with swelling around the outer aspect of left knee for 6 months associated with pain while walking and restriction on squatting. There was no significant contributing history. On examination, the swelling was 6 × 4 cm in size, firm to hard inconsistency, nontender on deep palpation. The overlying skin was nonadherent, nonshiny with no associated vessel engorgement. The adjoining peroneal nerve revealed a normal function. All routine hematological investigations were normal and chest radiograph was also normal. Anteroposterior and lateral radiographs of the knee with leg were taken, which showed single epiphyseal lesion involving the fibular head with little loculations (Fig. 1a). The lesion was expansile more medial than lateral (Fig. 1b). MRI showed lesion about 52 × 50 × 54 mm size with ballooning, cortical thinning and breech at places, hypointense on T1W and isointense
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ORTHOPEDICS
Figure 1a. X-ray of the knee joint showing the tumor involving upper end of fibula. Figure 2a. MRI images of the right knee shows a large welldefined, lobulated mass (black arrows) and in proximal fibula (white arrow in B), the lesion is predominately hyperintense in STIR coronal images.
Figure 2b. T2 sagittal shows lesion is isointense to hyperintense.
Figure 1b. Chest X-ray PA view looks normal.
to hyperintense in T2W, short tau inversion recovery (STIR) and heterogeneous enhancement on post gadolinium images involving the posterior vascular bundle with most likely diagnosis of telangiectatic osteosarcoma (Fig. 2 a-d). Fine-needle aspiration cytology (FNAC) of the swelling was done and giant cells were seen. With an inconclusive preoperative diagnosis, excisional biopsy (type 1 resection) was planned after explaining the prognosis
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Figure 2c. STIR post contrast axial showing heterogeneous enhancement.
ORTHOPEDICS
Figure 2d. STIR post contrast coronal showing heterogeneous enhancement.
Figure 3a. Intraoperative picture with peroneal nerve dissection.
to the patient and her husband. With the patient in supine position, a pneumatic tourniquet was applied in the left thigh. Limb exsanguination was not done. The peroneal nerve was carefully dissected (Fig. 3a). The fibula was osteotomized distal to tumor area at the normal bone level. The tumor mass was then lifted and carefully dissected bluntly from distal to proximal. On the medial aspect, the post-tibial vessels were adherent with the capsule of tumor. Even with meticulous and slow dissection three tears were found in the posterior tibial vessels. Immediately, a saphenous vein was harvested from contralateral limb and end-toend anastomosis was performed by vascular surgeon (Fig. 3b and 3c). The lateral collateral ligament and biceps femoris tendon were sutured to adjacent tibia to prevent instability. The wound was thoroughly washed and closed in layers with drain. A postoperative slab with knee in flexion was applied. The mass was sent for biopsy. Postoperatively patient was heparinized and it was tapered off with warfarin tablets. Postoperative CT angiography was performed at 7th day, which showed continuity of flow (Fig. 4). Postoperative radiographs were taken (Fig. 5). Histopathological examination confirmed GCT (Fig. 6). Sutures were removed after 2 weeks with removal of slab. Patient was kept nonweight-bearing for 6 weeks and gradually mobilized with range of motion knee brace. The patient had full range of motions with mild weakness of foot evertors in affected limb on follow-up at 1 year.
Figure 3b. Intraoperative picture showing vessel opening held with clamps.
Figure 3c. Intraoperative picture with vascular anastomosis showing continuity.
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ORTHOPEDICS
Figure 4. CT angiography demonstrating filling of all three vessels post repair. The stenotic segment of saphenous graft can be noted very well.
Figure 6. Histopathological examination showing multinucleated giant cells dispersed in mononuclear cells.
GCT. It is a benign lesion that is locally aggressive but in rare instances has the potential for metastasis.5 Most patients present with a painless slow-growing mass around the joint with discomfort. Acute symptoms are noted when the lesion erodes the cortex irritating the periosteum or when the weakening of the bone causes pathologic fracture. Rarely, GCT presents with involvement of adjacent neurovascular bundle.6,7 1
X-rays findings are characteristic and usually a geographic, expansile lesion involves whole of the epiphyseometaphyseal area. There is a surrounding ‘egg shell’ rim of calcification indicating an intact periosteum. Internal trabeculations are seen within the tumor. In our case, this soap bubble appearance was absent.
Figure 5. Post-op X-ray showing resected fibula.
DISCUSSION Giant cell tumor (GCT) is the most common bone tumor in the young adults with female preponderance.4 The common sites are epiphyseometaphyseal areas of long bones, most often the distal femur, proximal tibia and distal radius. The proximal fibula is a rare location for 4
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The MRI findings are not so specific for particular lesion. The low to intermediate signal on T1 and intermediate to high signal on T2-weighted images can also be seen in other malignant conditions. The tumor diffusely enhanced with contrast. The MRI nicely demonstrated the local extent of the tumor and involvement of the vascular structures. The lesions displace the peroneal nerve and popliteal blood vessels. But, in our case, vasculature was involved and can be seen in capsule. There were no ‘fluid-fluid’ levels that would indicate cystic changes. Giant cells can be seen in many different situations. The key is that the cells surrounding the giant cells are all mononuclear cells, which coalesce to form the giant cells. Hence, the nuclei are dispersed in giant cells
ORTHOPEDICS unlike the Langerhan’s giant cells seen in tuberculosis and fungal infections where the nuclei are arranged around the periphery of the giant cell. Management of fibular head GCT is surgical resection. Resection of a high-grade primary bone sarcoma of the proximal fibula is a type 2 resection8 involving an en bloc extra-articular resection of the proximal fibula (sacrificing the common peroneal nerve), in contrast to a type 1 resection9 of the proximal fibula for benign aggressive, low-grade malignant tumors (sparing of the covering muscle layer and peroneal nerve). But, even with type 1 resection, the close proximity of neurovascular bundle warrants careful dissection. Whenever the vessels are sacrificed or inadvertently opened, the surgical team must be prepared for vascular repair. CONCLUSION Fibular lesions can be associated with vascular involvement in proximal area. For any surgical intervention, the relation of lesion with vessels should be determined by investigations. The GCT can present as telangiectatic type of osteosarcoma. Hence, thorough investigations should be done before surgical resection. The purpose of this article was to highlight the diagnostic dilemma associated with GCT and proper preoperative preparations and counseling to deliver the outcome.
REFERENCES 1. Bickels J, Kellar K, Malawer M. Fibular resection (Chapter 32). In: Malawer, Sugarbaker (Eds.). Musculoskeletal Cancer Surgery Treatment of Sarcomas and Allied Diseases. 2001. pp. 505-18. 2. Unni KK. Dahlin’s Bone Tumors: General Aspects and Data on 11,087 Cases. Philadelphia, PA: Lippincott-Raven; 1996. pp. 1-9. 3. Abdel MP, Papagelopoulos PJ, Morrey ME, Wenger DE, Rose PS, Sim FH. Surgical management of 121 benign proximal fibula tumors. Clin Orthop Relat Res. 2010;468(11):3056-62. 4. Reddy CR, Rao PS, Rajakumari K. Giant-cell tumors of bone in South India. J Bone Joint Surg Am. 1974;56(3):617-9. 5. Faisham WI, Zulmi W, Mutum SS, Shuaib IL. Natural history of giant cell tumour of the bone. Singapore Med J. 2003;44(7):362-5. 6. Mnif H, Koubaa M, Zrig M, Zammel N, Abid A. Peroneal nerve palsy resulting from fibular head osteochondroma. Orthopedics. 2009;32(7):528. 7. Cardelia JM, Dormans JP, Drummond DS, Davidson RS, Duhaime C, Sutton L. Proximal fibular osteochondroma with associated peroneal nerve palsy: a review of six cases. J Pediatr Orthop. 1995;15(5):574-7. 8. Malawer MM. Surgical management of aggressive and malignant tumors of the proximal fibula. Clin Orthop Relat Res. 1984;(186):172-81.
9. Capanna R, van Horn JR, Biagini R, Ruggieri P, Bettelli G, Campanacci M. Reconstruction after resection of the distal fibula for bone tumor. Acta Orthop Scand. 1986;57(4):290-4. ■■■■
AAOS Guidelines on Hip Osteoarthritis The American Academy of Orthopedic Surgeons (AAOS) has for the first time issued guidelines for hip osteoarthritis, which have been published on the Academy's website on April 5, 2017. The guidelines recommend use of physical therapy, NSAIDs, intra-articular corticosteroids for symptomatic hip osteoarthritis. But it does recommends against use of glucosamine sulfate because of lack of evidence.
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PEDIATRICS
A Study of Sociodemographic Profile of Children with Severe Acute Malnutrition Under 5 Years of Age and Caregivers Characteristics MUDIT KUMAR AGGARWAL*, V KRISHNA AGARWAL*, S AGARWAL*
ABSTRACT Objectives: This study aimed to determine anthropometry, clinical profile of children less than 5 years of age suffering from severe acute malnutrition (SAM) and caregivers sociodemographic characteristics. Material and methods: A prospective observational study was carried out including total of 48 children aged less than 5 years diagnosed as SAM. Detailed history including dietary and socioeconomic history was taken and anthropometric measurements were computed using standard instruments. Results: Of the 48 cases included in this study, 29 were marasmic, 16 were suffering from kwashiorkar and 3 were suffering from marasmic-kwashiorkar. The age ranged from 5 to 59 months with maximum children in the 12-36 months group. In this study, the most common preceding infection was acute gastroenteritis (52.1%) followed by respiratory tract infection (27.1%). Escherichia coli was the most common organism (33.3%) cultured. Mid upper arm circumference (MUAC) was found <11.5 cm in 83.3%, while weight/height ratio was <-3SD in 93.8% cases. Majority cases were delivered at home (75%) with birth order >3 in 64.6%. 70.8% were nonexclusively breast-fed and 72.9% were given animal diluted milk. Weaning was done at less than 6-month of age in 68.8% and 81.3% were bottle-fed. Also, 41.7% of children were partially immunized. Caregivers were mainly housewives (20-30 years of age) and not formally educated (52.1%); 58.3% families were nuclear and 79.2% were inhabitating rural area. Maximum cases (33.3%) belonged to upper middle class according to Kuppuswamy classification. Conclusion: Improper hygiene and feeding practices, large family size, recent infections and food fads are contributors to SAM.
Keywords: Severe acute malnutrition, sociodemographic profile, caregiver, mid upper arm circumference, less than 5-year children
T
he World Health Organization (WHO) estimates that globally nearly 20 million children less than 5 years of age suffer from severe acute malnutrition (SAM).1 A large majority of children with SAM live in South Asia and sub-Saharan Africa. The recent National Family Health Survey (NFHS)-3 of India indicated that 6.4% (roughly 8 million) of under 5 children are classified as SAM in India.2,3 Undernutrition dramatically increases case fatality rate in children suffering from common illnesses such as diarrhea and pneumonia. Estimates suggest that globally SAM contributes to about 1 million child deaths every year; one child death every 30 seconds.1 The WHO and UNICEF proposed diagnostic criteria
*Dept. of Pediatrics Guru Kripa Jagrati Hospital and Research Centre Pvt. Ltd., Allahabad, Uttar Pradesh Address for correspondence Dr Mudit Kumar Aggarwal 124/A/1, Thornhill Road, Near Public Service Commission, Allahabad, Uttar Pradesh E-mail: drmudit.aggarwal@yahoo.com
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for SAM in children aged 6-60 months are weight/ height <-3SD and/or presence of bipedal edema or mid upper arm circumference (MUAC) <115 mm (using WHO growth standards).1 MATERIAL AND METHODS A prospective observational study was conducted in Guru Kripa Jagrati Hospital, Allahabad from August 2013 to February 2015. The cases were consecutive children of either gender less than 5 years of age with SAM who presented in hospital for various complaints. A case was diagnosed to have SAM if weight/height ratio <-3 SD of WHO 2006 growth standards and/or MUAC <115 mm and/or nutritional edema of both feet. Children with congenital malformation and known chronic diseases were excluded from the study. Ethical clearance was obtained from Institutional Ethics Committee. Written consent was obtained from the next of kin. A detailed history including dietary, immunization and socioeconomic history was obtained. Thorough clinical examination including
PEDIATRICS anthropometry was done according to standardized methodology. Relevant investigation was conducted as per case. A self-developed questionnaire with 8 survey items was used to capture information on the extent of the caregiver’s awareness of the child’s nutritional status. Statistical testing was conducted with the Statistical Package for the Social Sciences (SPSS), version 17.0. Continuous variables were presented as mean + SD or median if the data was unevenly distributed. Categorical variables were expressed as frequencies and percentages. RESULTS A total of 48 cases were taken; 43.8% were female and 56.2% were male. The mean age of the cases was 22.6 Table 1. Anthropometry
months. Anthropometric measures are shown in Table 1. Twenty-four parameters including dietary practices, sociodemographic characteristics, immunization status and knowledge status of caregiver were studied (Tables 2-4). Among the dietary practices, exclusive breastfeeding appeared to be a protective factor against SAM. Diluted animal milk, bottle-feeding and early Table 2. Dietary Practices Breastfeeding Exclusive
29.2%
Nonexclusive
70.8%
Type of top feed Diluted animal milk
72.9%
Undiluted animal milk
14.6%
Formula feed
12.5%
Mode of feeding
Anthropometric measures MUAC <115 mm >115 mm Weight/Height ratio <-3SD >-3SD
83.3% 16.7% 93.8% 6.2%
Bottle-feeding
81%
Spoon-feeding
19%
Age of weaning Before 6 months
68.8%
At 6-7 months
18.8%
After 7 months
12.4%
Table 3. Sociodemographic Profile and Immunization Status Maternal education Illiterate Primary education Secondary education Higher education Paternal education Illiterate Primary education Secondary education Higher education Mother’s occupation Housewife Working women Father’s occupation Unemployed Business Service Housing Kuccha Pakka Water supply Municipal water Ground water
52.1% 8.3% 6.3% 33.3% 20.8% 37% 25% 16.7% 87.5% 12.5% 10.4% 56.3% 33.3% 60.4% 39.6%
Toilet Private Open-field Food habits Vegetarian Nonvegetarian Family size <5 members >5 members Place of delivery Home Hospital Birth order 1 2-3 >3 Immunization Partially immunized Nonimmunized Completely immunized
72.9% 27.1% 87.5% 12.5% 41.7% 58.3% 75% 25% 15% 50% 35% 41.7% 39.6% 18.8%
Family income <Rs. 6,000/month >Rs. 6,000/month Kuppuswamy classification Kuppuswamy Class I Kuppuswamy Class II Kuppuswamy Class III Kuppuswamy Class IV Kuppuswamy Class V Comorbid disease Diarrhea Acute respiratory tract infection Tuberculosis Organism cultured Escherichia coli Shigella Haemophilus influenzae Pseudomonas Mycobacterium tuberculae
60.5% 39.5% 2.08% 33.3% 14.5% 22.91% 27.08% 52.1% 27.1% 8.3% 33.3% 12.5% 22.4% 20.3% 11.5%
81.3% 18.7%
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PEDIATRICS Table 4. Sociodemography and Knowledge Status of Caregiver Marital status of caregiver Married
97.9%
Widow
2.1%
Awareness of benefits of colostrums Yes
33.3%
No
66.7%
Age groups of caregivers
15-20 y
20-30 y
30-40 y
40-50 y
>50 y
Percentage
16.6%
62.5%
16.6%
14.3%
0
Aware of reason for admission
14.5%
60.4%
15.1%
2%
0
2%
2%
2%
2%
0
Unaware of reason for admission Reason for admission Vomiting
2%
8.3%
2%
0
0
Diarrhea
6.3%
8.3%
2%
2%
0
Coughing
0
8.3%
2%
0
0
Swollen limbs
8.3%
14.5%
10.4%
2%
0
Not eating well
0
10.4%
0
0
0
0
12.5%
0
0
0
Action taken for childâ&#x20AC;&#x2122;s condition
Weight loss
10.4%
41.66%
12.5%
2%
0
No action taken for childâ&#x20AC;&#x2122;s condition
6.25%
20.5%
4.2%
2%
0
12.5%
52%
10.4%
4.1%
0
Took child to traditional Healer
2%
6.2%
2%
0
0
Tried different feeds
2%
0
2%
0
0
0
4.1%
2%
0
0
Action taken by caregiver Immediately took child to clinic
Bought medicine at the pharmacy
weaning (before 6 months) were found to be higher among children with SAM. Sociodemographic features like illiterate mother, partial or nonimmunization, low family income and large family size contributed to SAM. It was observed that 66.7% caregivers were unaware of benefits of colostrum. Maximum cases occurred in patients with caregiver of age group 20-30 years; swollen limbs and diarrhea appeared to be the most common reason for the caregiver to seek medical advice. Majority of caregivers immediately took child to clinics; still a significant proportion took child to traditional healers. DISCUSSION The parental education status was found to be possibly causally associated to SAM. This is observed in studies done in North Wollo in Ethiopia,4 other African countries,5,6 South-East Asian7-9 and Latin American countries.10 In a case-control study in Bangladesh, the maternal illiteracy was associated with a four-fold increase in the risk of SAM. It was found that maternal, rather than paternal illiteracy has a possible causal
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association with SAM, which is consistent with earlier reports.6,11-14 A larger family size has possible causal association with SAM. The effect of a large family size with overcrowding and inadequate spacing has causal association in different studies as well.4,11,15 Elizabeth in 2012 described cases of edematous SAM who did not have the typical risk factor like poverty, ignorance and illiteracy, educated caregiver-some even being graduates.16 In the present study, it was found that exclusive breastfeeding during first 6 months of life protected against SAM. Bottle-feeding was shown in the present study to have an independent possible causal association for SAM, contrary to the result of others.11,15,17 A study from Uganda observed that neither the age of weaning nor the number of meals per day affected the incidence of stunting or underweight.6 In our study, 68.8% cases were weaned off milk before 6 months, 18.8% cases were weaned in 6-7 months and 12.5% were weaned in more than 7 months.
PEDIATRICS Amsalu et al, found that late initiation of complementary diet beyond 12 months was an independent risk factor for SAM.15 On the other hand, studies from China and Kenya have shown that early introduction of complementary feeding before 6 months of age increased the risk of being underweight.18 In the present study, a significantly larger fraction of cases received weaning food which had a thin or watery consistency, rather than a semisolid one and independently influenced the risk of SAM. It is expected that the energy and protein content of diluted (thin or watery consistency) food item would be less than that of semisolid item. Kikafunda et al had observed that consumption of food with low energy density was associated with increased risk of stunting.6 The capacity of a weaning diet to prevent SAM depends on its nutritional quality as well as its volume.19 Studies on feeding practices show that the type of complementary feeding given is greatly influenced by traditional sociocultural beliefs and taboos. In most countries, including India, thin gruels like diluted milk, dilute starch-based liquid without good quality protein are favored as weaning food and semisolid and solids are introduced relatively late.16 The majority of caregivers (92%) knew why their child had been admitted to hospital. As regards the reasons caregivers mentioned for admission, 10.4% mentioned that the child was “not eating well” and "has lost weight" in 12.5%. These caregivers seemed to know that the child suffered from some degree of malnutrition. One reason for admission given by 35.2% caregivers, was that the child had “swollen limbs”. Caregivers were not aware that the swelling could be linked to malnutrition. Other reasons for admission included coughing, vomiting and diarrhea. Most of the caregivers focused on the child’s symptoms as the reason for admission. They were not aware that the primary reason for admission was malnutrition. Most caregivers 66.5% took some action to assist the child in addressing the illness, but 33.5% did nothing. These caregivers probably did not realise that the child was malnourished and why the child was referred to the hospital after a routine child welfare clinic visit. Seventy-nine percent caregivers immediately took the child to the clinic when they suspected that the child was not well. Some caregivers 10.2% took the child to a traditional healer first, and a small number of caregivers bought some medicine at a pharmacy or tried different feeds at home before they took the
child to the clinic. These findings are close to those of a study in Sri Lanka involving 1,102 children and their caregivers. Twenty-eight percent of the caregivers tried some home remedies before they took the child to the clinic, and 51% immediately took the child to the clinic.20 Most of the caregivers in this study were aware that they had to take the child to the clinic before its condition worsened. A small percentage of caregivers were still attached to traditional medicine. This poses a challenge as a child’s condition can deteriorate quickly, while the caregiver still trusted the traditional healer. CONCLUSION Improper hygiene and feeding practices, large family size, recent infections and food fads are contributors to SAM. A community based approach with more focussed attention in health policy formulation for taking appropriate preventable and therapeutic strategies is required. REFERENCES 1. World Health Organisation/UNICEF. WHO child growth standards and the identification of severe acute malnutrition in infants and children (2009). A joint statement by the World Health Organisation and the United Nation’s Children’s Fund. Available at: http://www.who. int/nutrition/publications//severemalnutrition/en/ index. html. Accessed on 26th June 2016. 2. International Institute of Population Sciences (IIPS) and Macro International. Mumbai: IIPS; National Family Health Survey of India (NFHS-3) 2005-06;1:196-7. Mumbai: IIPS/Macro International 2007. 3. Sachdev HP, Kapil U, Vir S. Consensus Statement National Consensus Workshop on Management of SAM Children through Medical Nutrition Therapy. Indian Pediatr. 2010;47(8):661-5. 4. Haidar J, Abate G, Kogi-Makau W, Sorensen P. Risk factors for child under-nutrition with a human rights edge in rural villages of North Wollo, Ethiopia. East Afr Med J. 2005;82(12):625-30. 5. Ighogboja SI. Some factors contributing to protein-energy malnutrition in the middle belt of Nigeria. East Afr Med J. 1992;69(10):566-71. 6. Kikafunda JK, Walker AF, Collett D, Tumwine JK. Risk factors for early childhood malnutrition in Uganda. Pediatrics. 1998;102(4):E45. 7. Jeyaseelan L, Lakshman M. Risk factors for malnutrition in south Indian children. J Biosoc Sci. 1997;29(1):93-100. 8. Islam MA, Rahman MM, Mahalanabis D. Maternal and socioeconomic factors and the risk of severe malnutrition in a child: a case-control study. Eur J Clin Nutr. 1994;48(6):416-24.
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PEDIATRICS 9. Henry FJ, Briend A, Fauveau V, Huttly SR, Yunus M, Chakraborty J. Risk factors for clinical marasmus: a casecontrol study of Bangladeshi children. Int J Epidemiol. 1993;22(2):278-83. 10. Sakisaka K, Wakai S, Kuroiwa C, Cuadra Flores L, Kai I, Mercedes Aragón M, et al. Nutritional status and associated factors in children aged 0-23 months in Granada, Nicaragua. Public Health. 2006;120(5):400-11. 11. Mishra K, Kumar P, Basu S, Rai K, Aneja S. Risk factors for severe acute malnutrition in children below 5 y of age in India: a case-control study. Indian J Pediatr. 2014;81(8): 762-5. 12. Wamani H, Tylleskär T, Astrøm AN, Tumwine JK, Peterson S. Mothers’ education but not fathers’ education, household assets or land ownership is the best predictor of child health inequalities in rural Uganda. Int J Equity Health. 2004;3(1):9.
14. Abuya BA, Onsomu EO, Kimani JK, Moore D. Influence of maternal education on child immunization and stunting in Kenya. Matern Child Health J. 2011;15(8):1389-99. 15. Amsalu S, Tigabu Z. Risk factors for severe acute malnutrition in children under the age of five: a casecontrol study. Ethiop J Health Dev. 2008;22(1):21-5. 16. Elizabeth KE. Changing profile of undernutrition and edematous severe acute malnutrition (ESAM). Indian Pediatr. 2012;49(10):843. 17. Ghosh S, Shah D. Nutritional problems in urban slum children. Indian Pediatr. 2004;41(7):682-96. 18. Wang X, Wang Y, Kang C. Feeding practices in 105 counties of rural China. Child Care Health Dev. 2005;31(4):417-23. 19. Sajilata G, Singhal RS, Kulkarni PR. Weaning foods: a review of the Indian experience. Food Nutr Bull. 2002;23(2):208-26.
20. 13. Huq MN, Tasnim T. Maternal education and child healthcare in Bangladesh. Matern Child Health J. 2008;12(1):43-51. ■■■■
Peiris TDR, Wijesinghe DGNG. Nutritional status of under 5 year old children and its relationship with maternal nutrition knowledge in Weeraketiya DS Division of Sri Lanka. Tropical Agricultural Research. 2010;21(4):330-9.
Genetic Testing in Pediatric Epilepsy A new article published in the Current Neurology and Neuroscience Reports summarized the advancements in pediatric epilepsy with an emphasis on genetic contributions and approaches to genetic evaluation for pediatric epilepsy. Recent advances in sequencing approaches and clinical tests for the evaluation of pediatric epilepsy have shown to provide positive diagnosis outcome rates to up to 50%. It was stated that the highest outcome of genetic testing is currently in children with infrequent severe epilepsy which is caused by genetic variation. The approach to genetic evaluation and interpretation of results mandates an understanding of the epilepsy phenotype and specific advantages and limitations of different genetic tests available.
Pediatric Concerns Due to Expanded Cannabis Use: Unintended Consequences of Legalization A recent study published in the Journal of Medical Toxicology evaluated the impact of marijuana legalization on children and adolescents. It was stated that marijuana exposure can affect pediatric patients at every stage of childhood, which included the prenatal exposures of fetuses. The benefits of cannabidiol (CBD) for the treatment of epilepsy were acknowledged. However, the need for extensive clinical trials, to determine the safety and efficacy of CBD in pediatric patients, was emphasized. Since, the availability and prevalence of marijuana use is expected to increase with its legalization for both medical and recreational purposes, adequate monitoring and research was recommended to determine its effects on the pediatric population.
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PSYCHIATRY
Illness Anxiety Disorder: A Case Report PANKHURI AGGARWAL
ABSTRACT Illness anxiety disorder is characterized by a preoccupation that normal or minor physical signs and symptoms are indicators of serious illnesses, despite of contrary medical evidence. Up to 10% of visits to primary healthcare physicians might be due to illness anxiety disorder related concerns. A case of a 25-year-old male with illness anxiety disorder with panic attacks is presented, who benefited immensely from cognitive behavioral therapy, reiterating the importance of psychotherapy in such cases.
Keywords: Illness anxiety disorder, panic attacks, psychotherapy
CASE REPORT A 25-year-old single, male came with the presenting concerns of palpitation, anxiety about possibly experiencing panic attacks and recurrent thoughts about being diagnosed with and dying from an illness since last 3-4 years. The client has approached multiple physicians in the past for complaints of backache, neck ache, irritation while urinating, stomach ache, premature ejaculation, skin disease, etc. and despite receiving negative test results from the laboratories, he either got himself retested or approached other doctors in the field. The client reports feeling physically discomforted when he hears any of his family members diagnosed with even mildest of illnesses, or when he sees an ambulance passing by. He is unable to enjoy action movies or any reality shows with highly aggressive content as he experiences severe headache and high blood pressure. The client’s second youngest sister died of jaundice when the client was 12 years old. At around the same time, he also witnessed his grandfather’s brother-inlaw struggle with an illness. The client remembers his childhood characterized by financial constraints. He was frequently hit by his father when he was young. The client also received severe physical beatings from his girlfriend’s three brothers when he was spotted
Postgradute in Applied Psychology (Specialized in Clinical Psychology) School of Human Ecology Tata Institute of Social Sciences, Mumbai, Maharashtra E-mail: pankhuri.aggarwal@gmail.com
with her outside his coaching center although no major injuries were reported. The client is currently on tablet escitalopram (10 mg), tablet alprax (0.25 mg), tablet propranolol (40 mg) and tablet olanzapine (2.5 mg). Despite the positive effect of the medicines, the client approached the psychiatrist complaining that the effects are gradually wearing off. The client was diagnosed with illness anxiety disorder (specifier care seeking type) with panic attack and was referred to the psychologist for psychotherapy. DISCUSSION Formerly referred to as hypochondriasis or health anxiety, illness anxiety disorder is characterized by preoccupation with one’s health in the absence of objective and verifiable evidence for a minimum duration of 6 months.1 Other symptoms include heightened feelings of hypervigilance about one’s or others’ health conditions, experiencing clinically significant stress in terms of impairment in personal, social and occupational functioning, etc. The genesis of the clients’ beliefs rests in their misinterpretation of physical symptoms or signs due to heightened bodily sensations. Even in cases of verifiable health conditions, the severity of the problem is minor and usually lies within normal limits. This is often followed by repeated self-examination, selfdiagnosis and unsatisfactory examination by others as these individuals are likely to doubt the test results and discard their doctors repeated assurances. In such cases, a denial to treat these clients or prescribe additional medicines for their exaggerated medical
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PSYCHIATRY concerns doesn’t help solve the dilemma. Neither does stopping of the existing consumption of medications is advised as these clients derive a sense of meaning from these medicines. These medicines give the clients a new direction and purpose in life. Even if the doctor decides not to prescribe medicines to these clients, they usually approach other doctors who they think will understand their problems better. Therefore, in such cases, clients would immensely benefit from cognitive behavioral therapy.2 Their distorted thinking patterns and irrational beliefs are brought into therapeutic limelight, and are worked upon using different psychotherapeutic tools and techniques until they become adaptive. In the present case, the client was explained the links between emotion, cognition, physical sensation and behavior. The client was further explained the plausible reasons of the emergence of his psychological disturbance. It is likely that the client had associated the aversive situations of his childhood (struggle of multiple closed ones due to various illnesses and physical beatings by father and girlfriend’s brothers) with hypervigilant health related thoughts (preoccupation) and terrifying emotions of anxiety and fear using classical conditioning.3 These behaviors were further generalized to similar situations in the outside world (passing of ambulance, watching wrestling match on television, etc.) and thus elicited the same physiological, emotional and cognitive responses from the client. His behavior of visiting doctors and getting himself tested, and consuming medicines led to a reduction in his anxiety levels and were thus reinforced through the principles of operant conditioning4 and theory of law of effect.5 He was told about the nature of anxiety using the cycle of panic, thereby helping him understand that during crisis situations, anxiety would have gradually worn off even if he did not engage in any immediate safety behaviors. Downward pyramid technique of cognition was employed to illustrate ways in which the client arrived at hasty
generalizations despite the availability of contradictory evidence. Arousal reduction technique of Jacobson’s Progressive Muscle Relaxation (JPMR) was taught to the client and practiced in each session. The client was told to include a worry period in his daily schedule, whereby he would devote 5-10 minutes thinking about all his worries. Therefore, he was told to postpone his worry thoughts from throughout the day, to the worry period of the day, freeing himself from the clutches of omnipresent anxiety. CONCLUSION A doctor’s response towards a client with illness anxiety disorder is critical. He/she should not deny the client of the only phenomena which might provide him with a sense of meaning and purpose in his life, while at the same time, the refusal to treat or prescribe medications may serve no good as the client would continue to approach different practitioners. It is advised that the client in addition to being prescribed antidepressants and selective serotonin reuptake inhibitors (SSRIs) should be referred to a clinical psychologist/counselor for psychotherapy. REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition, Arlington, VA: American Psychiatric Publishing; 2013. 2. Beck AT. Depression: Clinical, experimental, and theoretical aspects. New York: Harper and Row; 1967. Republished as: Beck AT. Depression: Causes and treatment. Philadelphia: University of Pennsylvania Press; 1970. 3. Pavlov IP. Conditioned reflexes. Oxford, UK: Oxford University Press; 1927. 4. Skinner BF. About behaviorism; 2011.
5. Thorndike EL. The elements of psychology. New York: AG Seiler; 1905. ■■■■
Study Suggests Thyroid Function Tests in Women with Refractory Rapid-cycling Bipolar Disorder New research presented at the American Psychiatric Association (APA) 2017 Annual Meeting in San Diego, California suggests that addition of levothyroxine (T4) to mood stabilizers may decrease mood episodes and reduce symptoms in women with refractory rapid-cycling bipolar disorder.
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SURGERY
Situs Inversus: A Preoperative Finding Not So Uncommon VENKATESH SUBBIAH*, S ASOKAN†, SOMASUNDARAM‡
ABSTRACT We present a case of abdominal pain presenting as obstructive paraumbilical hernia with situs inversus and appendicitis also. Situs inversus totalis, also called situs transversus or opposites, a rare condition causing mirror image of the thoracic and abdominal contents with frequency of about 1 in 10,000 among the normal population. The major organs within the abdomen and thorax are transposed through the sagittal plane. The heart is located on the right side of the thorax, the stomach and spleen on the right side of the abdomen and the liver and gallbladder on the left side.
Keywords: Situs inversus, dextrocardia, obstructive paraumbilical hernia, appendicitis
S
itus inversus totalis, also called situs transversus or opposites, is a rare condition causing mirror image of the thoracic and abdominal contents with frequency of about 1 in 10,000 among the normal population.1,2 Nearly 3-5% of the above mentioned population have congenital heart disease, while others have a structurally normal heart.3 The major organs within the abdomen and thorax are transposed through the sagittal plane. The heart is located on the right side of the thorax, the stomach and spleen on the right side of the abdomen and the liver and gallbladder on the left side. The left lung is trilobed and right lung is bilobed. The blood vessels, nerves, lymphatics and intestines are also transposed. There is usually no functional abnormality.
Patient gave history of swelling around the umbilicus for the last 2 years. Patient is premorbidly healthy. There was no previous history of hospitalization or any surgeries in the past. Her vitals were as follows: Heart rate (HR) - 102/min, blood pressure (BP) 120/80 mmHg, blood oxygen saturation (SpO2) 100% on RA, blood glucose - 98 mg/dL. Examination revealed heart sounds S1, S2 in right 5th intercostal space. Respiratory and central nervous system examination were normal. Per abdomen: A palpable mass of size 8 × 8 cm was noted in the left paraumbilical region. Abdomen had guarding rigidity. Mass was not reducible. Bowel sounds were absent. Provisional diagnosis of obstructed paraumbilical hernia was made. Preoperative investigations were done. Basic blood investigations revealed elevated total counts.
CASE REPORT
ÂÂ
X-ray-chest (Fig. 1).
ÂÂ
ECG showed right axis deviation, positive QRS complexes (upright P and T wave) in aVR, Lead I showed global negativity (inverted P, inverted T and negative QRS) (Fig. 2).
ÂÂ
U/S abdomen - Situs inversus totalis, a defect of 5 × 5 cm in the anterior abdominal wall. Contents found were omentum and tip of appendix.
ÂÂ
2D Echo - Dextrocardia with normal sized cardiac chambers and normal LV function.
ÂÂ
Human immunodeficiency virus (HIV) nonreactive; hepatitis B surface antigen (HBsAg) negative.
A 40-year-old lady presented to the OPD complaints of abdominal pain for the last 3 She had 3-4 episodes of vomiting. She also history of not passing stools and flatus for last 3
*Assistant Professor †Professor ‡Professor and Head Dept. of General Surgery Velammal Medical College and Hospital, Madurai, Tamil Nadu Address for correspondence Dr Venkatesh Subbiah Assistant Professor Dept. of General Surgery Velammal Medical College and Hospital, Madurai, Tamil Nadu E-mail: venkateshpims@gmail.com
with days. gave days.
PA view
-
showed
dextrocardia
Surgery was planned. Under spinal anesthesia, parts were prepared and draped. Pfannenstiel skin incision was made. Incision was deepened in layers
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Figure 1. X-ray-chest PA view - showing dextrocardia.
up to the rectus. Upper flap was raised just above the defect level. Defect was well-defined, structures within the defect were found to be omentum and tip of appendix. Omentum were pale with adhesions. Appendix, which was found in the defect, was inflamed. Omentectomy and appendicectomy were done. Remaining contents were reduced, anatomical repair was done. A mesh of appropriate size was anchored over the anterior abdominal wall using 2-0 prolene. Hemostasis was achieved, a romovac drain kept and the wound was closed in layers. Postoperatively, patient was treated with intravenous antibiotics, antacids and analgesics. Patient was discharged after a week in a stable condition with: ÂÂ
Oral antibiotics (cefixime)
ÂÂ
Oral analgesics (a combination of aceclofenac, paracetamol and serratiopeptidase)
ÂÂ
Antacids.
Patient was advised to come for review in OPD after 3 days. DISCUSSION The importance of situs inversus is in clinical diagnosis of medical conditions with pain on the opposite side of the commonly presenting site. It also helps in preventing surgical mishaps resulting from failure in recognizing the history with the clinical presentation and the reversed anatomy. The reversal of the organs may lead to some confusion as the clinical signs and symptoms will be on the reverse side. People with situs inversus can lead normal healthy lives, without any complications related to their medical condition. Most of them are unaware of their unusual anatomy until they seek medical
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Figure 2. ECG showing right axis deviation, positive QRS complexes.
attention for an unrelated condition. HM Blegen, in his paper on surgery in situs inversus says, “Although a busy surgeon, therefore, may expect to encounter this anomaly only once or twice in a lifetime, it is his responsibility, in order to protect these individuals and to avoid embarrassing errors, to familiarize himself with this anomaly and to consider it as a remote possibility in all cases of obscure abdominal pain.”4 In all, 144 cases of situs inversus were reviewed in which 158 surgical procedures were performed and approximately 45% cases had incorrect preoperative diagnosis, due to which 31% had an incorrect surgical incision made.4 CONCLUSION Magnetic resonance imaging, CT and ultrasound have played a major role in suspected diagnosis of situs inversus. Organ transplantation operations also may be complicated as donor organs will mostly come from situs solitus donors. In any patient, presenting with abdominal pain, situs inversus should be kept in mind as clinical signs and symptoms may be reversed. REFERENCES 1. Le Wald LT. Complete transposition of the viscera: a report of twenty-nine cases, with remark on etiology. JAMA. 1925;84:216-68. 2. Yokoyama T, Copeland NG, Jenkins NA, Montgomery CA, Elder FF, Overbeek PA. Reversal of left-right asymmetry: a situs inversus mutation. Science. 1993;260(5108):679-82. 3. Kulkarni PR, Inamdar VV. Situs inversus with dextrocardia associated with ventricular septal defect - a case report. J Anat Soc India. 2005;54(1) 4. Blegen HM. Surgery in situs inversus. Ann Surg. 1949;129(2):244-59.
MEDILAW
Issuing a Medical Certificate: Guidelines for Medical Practitioners A 30-year-old man submitted a medical certificate including fitness certificate to his office on resuming work. When the HR Manager examined the certificates, he found a discrepancy between the date that the employee had been certified as being sick, and the date of issue. The certificate had been issued for a period of 20 days and also did not have the signature of the employee. The company filed a complaint with the medical council seeking verification of the authenticity of the medical certificate issued by the doctor. Proceed
This is a complaint from the HR Dept of a company regarding a retrospective certificate issued by this doctor for a minor illness dated in the present. The signature or thumb impression of the patient on the certificate issued is missing.
The certificate issued is not in line with the guidelines for issuance of medical certificate. Hence, this is an act of professional misconduct. A warning is issued.
Lesson: A medical certificate under normal circumstances should specify the anticipated period of absence from duty necessitated because of the ailment of the patient. Due consideration should be given to the circumstances before issuing a certificate certifying a period of illness in back date particularly in relation to a patient with a minor short illness, which is not evident on the date of examination and should add supplementary remarks, where appropriate, to explain the circumstances that warranted the issuance of certificate retrospective in nature. The medical certificate should carry the signature or thumb impression of the patients. (DMC/647/2010)
to Mr Y on the same date stating that the patient was fit to resume work from 21.12.2009.
CASE SUMMARY ÂÂ
A complaint was submitted to the Delhi Medical Council by Mr X, CEO of a company A who asked the Council to examine and verify a medical certificate submitted by one of his employees, Mr Y. The certificate was issued by Dr Z.
ÂÂ
The Council examined the complaint, the written statement of Dr Z, which confirmed that the medical certificate in question was issued by him to Mr Y for the period mentioned therein, the medical certificate issued and other relevant documents. The Council also heard the doctor in person.
ÂÂ
The medical certificate was found to be issued on 17.12.2009 for a period of 52 days with effect from 31.10.2009 to 21.12.2009 for illness specified as enteric fever with peripheral neuritis with injury of the left big toe. The fitness certificate was also issued
Observations of the Delhi Medical Council ÂÂ
The Council observed that the certificate issued was not in line with the Regulation 1.3.3 of the MCI Code of Ethics Regulations, 2002; which states that:“He/She shall not omit to record the signature and/ or thumb mark, address and at least one identification mark of the patient on the medical certificates or report. The medical certificate shall be prepared in the format prescribed under the aforesaid regulation.”
ÂÂ
The certificate was issued on 17.12.2009 with effect from 31.10.2009 to 21.12.2009. Hence, it was retrospective in nature. A medical certificate should generally certify a period of absence from duty prospectively, from the date on which the patient is examined by the doctor i.e., it may
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
89
MEDILAW
ÂÂ
ÂÂ
state the anticipated period of absence from duty necessitated because of the ailment of the patient.
(v) Indicate the date the Certificate was written and signed
The certificate was issued for a period of 52 days, which is a very long duration for the illness specified in the certificate ‘‘Enteric fever with peripheral neuritis with injury (Lt) big toe’’ that too without proper investigations.
(vi) Name, signature, qualifications and registered number of the consulting registered medical practitioner
The Council issued guidelines that doctors should abide by when issuing medical certificates. (a) “Medical certificates are legal documents. Medical practitioners who deliberately issue a false, misleading or inaccurate certificate could face disciplinary action under the Indian Medical Council (Professional Conduct, Etiquette and Ethics), Regulations, 2002. Medical practitioners may also expose themselves to civil or criminal legal action. Medical practitioners can assist their patients by displaying a notice to this effect in their waiting rooms.
It is, therefore, a misnomer to state that medical certificate is “not valid for legal or Court purposes”, and should be avoided. Registered medical practitioners are legally responsible for their statements and signing a false certificate may result in a registered medical practitioner facing a charge of negligence or fraud.
(b) The certificate should be legible, written on the doctor’s letterhead and should not contain abbreviations or medical jargon. The certificate should be based on facts known to the doctor. The certificate may include information provided by the patient but any medical statements must be based upon the doctor’s own observations or must indicate the factual basis of those statements. The Certificate should only be issued in respect of an illness or injury observed by the doctor or reported by the patient and deemed to be true by the doctor. The certificate should:
When issuing a sickness certificate, doctors should consider whether or not an injured or partially incapacitated patient could return to work with altered duties.
(c) The medical certificate under normal circumstances, as a rule, should be prospective in nature i.e., it may specify the anticipated period of absence from duty necessitated because of the ailment of the patient. However, there may be medical conditions which enable the medical practitioner to certify that a period of illness occurred prior to the date of examination. Medical practitioners need to give careful consideration to the circumstances before issuing a certificate certifying a period of illness prior to the date of examination, particularly in relation to patients with a minor short illness which is not demonstrable on the day of examination and should add supplementary remarks, where appropriate, to explain the circumstances which warranted the issuances of certificate retrospective in nature. (d) It is further observed that under no circumstances, a medical certificate should certify period of absence from duty, for a duration of more than 15 days. In case, the medical condition of the patient is of such a nature that it may require further absence from duty, then in such case a fresh medical certificate may be issued. (e) Record of issuing medical certificate - Documentation should include:
(i) Indicate the date on which the examination took place
–
Patient to put signature/thumb impression on the medical certificate
(ii) Indicate the degree of incapacity of the patient as appropriate
–
Identification marks to be mentioned on medical certificate
(iii) Indicate the date on which the doctor considers the patient is likely to be able to return to work
–
That a medical certificate has been issued
(iv) Be addressed to the party requiring the certificate as evidence of illness e.g., employer, insurer, magistrate
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(vii) The nature and probable duration of the illness should also be specified. This certificate must be accompanied by a brief resume of the case giving the nature of the illness, its symptoms, causes and duration.
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
– The date/time range covered by the medical certificate –
The level of incapacity (i.e., unfit for work, light duties, etc. within scope of practice)
MEDILAW An official serially numbered certificate should be utilized. The original medical certificate is given to the patient to provide the documentary evidence for the employer. The duplicate copy will remain in the Medical Certificate book for records. The records of medical certificate are to be retained with the doctor for a period of 3 years from the date of issue.”
Judgment After examination of the facts, the Council considered it an act of professional misconduct and issued a warning to Dr Z.
Reference 1. DMC/DC/F.14/Comp.647/2010/
RELEVANT MCI REGULATIONS FOR ISSUANCE OF MEDICAL CERTIFICATES 1.3.3 A Registered medical practitioner shall maintain a Register of Medical Certificates giving full details of certificates issued. When issuing a medical certificate he/she shall always enter the identification marks of the patient and keep a copy of the certificate. He/She shall not omit to record the signature and/or thumb mark, address and at least one identification mark of the patient on the medical certificates or report. The medical certificate shall be prepared as in Appendix 2.
1.4.1 Every physician shall display the registration number accorded to him by the State Medical Council/Medical Council of India in his clinic and in all his prescriptions, certificates, money receipts given to his patients. 1.4.2 Physicians shall display as suffix to their names only recognized medical degrees or such certificates/diplomas and memberships/honors, which confer professional knowledge or recognizes any exemplary qualification/ achievements. 7.3 If he/she does not display the registration number accorded to him/her by the State Medical Council or the Medical Council of India in his clinic, prescriptions and certificates, etc. issued by him or violates the provisions of regulation 1.4.2. 7.7 Signing Professional Certificates, Reports and Other Documents: Registered medical practitioners are in certain cases bound by law to give, or may from time to time be called upon or requested to give certificates, notification, reports and other documents of similar character signed by them in their professional capacity for subsequent use in the courts or for administrative purposes etc. Such documents, among others, include the ones given at Appendix–4. Any registered practitioner who is shown to have signed or given under his name and authority any such certificate, notification, report or document of a similar character which is untrue, misleading or improper, is liable to have his name deleted from the Register. Source: MCI Code of Ethics Regulations, 2002. Appendix 2
Form of Certificate Recommended for Leave or Extension or Communication of Leave and for Fitness Signature of patient or thumb impression ___________________________________________ To be filled in by the applicant in the presence of the Government Medical Attendant, or Medical Practitioner. Identification marks: a. __________________________
b. __________________________
I, Dr. _________________________ after careful examination of the case certify hereby that __________ whose signature is given above is suffering from _________________ and I consider that a period of absence from duty of __________________ with effect from ________________ is absolutely necessary for the restoration of his health. I, Dr. _______________________ after careful examination of the case certify hereby that ___________on restoration of health is now fit to join service. Place: ________________ Date: ______________
Signature of Medical Attendant Registration No.: ______________________
(Medical Council of India/State Medical Council of ……….......................…. State) Note: The nature and probable duration of the illness should also be specified. This certificate must be accompanied by a brief resume of the case giving the nature of the illness, its symptoms, causes and duration. Source: MCI Code of Ethics Regulations, 2002.
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AROUND THE GLOBE
News and Views ‘Remember the People’ Behind the Facts and Figures, Says Outgoing WHO Director-General The outgoing chief of the United Nations health agency highlighted the relevance of the World Health Organization (WHO), and offered its decision-making body parting advice that included protecting scientific evidence, pushing for innovation and thinking of people in every decision that is taken. “Remember the people,” WHO Director-General Margaret Chan told the 70th World Health Assembly in Geneva. “Behind every number is a person who defines our common humanity and deserves our compassion, especially when suffering or premature death can be prevented.” Among other advice, Dr Chan, who steps down after two 5-year terms, urged the body to work towards realizing the “tremendous potential of vaccines. She noted that the current measles outbreak in Europe and North America would have never occurred, had immunization coverage not dropped below the necessary 95% threshold. She also stressed the importance of listening to civil society, calling it “society’s conscience” and who can “give people who suffer the most a face and a voice.” (UN, May 22, 2017)
WMA Leader Issues Warning Over Violence Against Physicians and Healthcare A warning about an increase in violence against physicians and a general disrespect for medical and health institutions in both civil and conflict situations has come from the Chair of the World Medical Association Dr Ardis Hoven.
situations. The resolution demanded an end to impunity for those responsible and respect for international law on the part of all warring parties. Dr Hoven said: “We need much more attention paid to the increasing violence in civil situations. Here, there is an urgent need for better protection. Facilities have to be secured against bringing in weapons, especially firearms and knives. Hospitals and clinics must be weapon free” And in conflict situations, health care personnel and facilities are becoming weapons of war and this must end. “We need better legal protection for medical and other health professionals as many countries already do for law-enforcement officers. Whoever attacks a nurse, physician or another health worker, regardless whether this is a verbal or physical attack, must know that he or she will be severely punished for it”. “Finally, the decreasing threshold for using violence in civil situations is a question that points directly to the social determinants of health. They must come more into our focus. We must learn what the underlying reasons are for this trend to use more violence”. (WMA, May 22, 2017)
Exposure to Secondhand Smoke Worsens Longterm QoL in Flight Attendants Early results from the Flight Attendant Lung Health Study evaluating the long-term impact of secondhand smoke exposure show that flight attendants who were exposed to secondhand smoke reported worsened quality-of-life (QoL), respiratory symptoms and abnormalities in pulmonary function pre-ban versus post-ban. These findings were presented at the American Thoracic Society (ATS) meeting in Washington.
Dr Hoven, who was addressing a Health Care in Danger side event at the 70th World Health Assembly in Geneva, said that the decreasing threshold for using violence in conflicts such as Syria and Turkey could also be observed in civil situations. Violence in health-care was occurring on a daily basis across China and India, as well as in Europe and America, where patients or relatives were trying to sort out their problems with verbal or physical abuse.
Study Links Intestinal Fungi to Worsening of Alcoholic Liver Disease
The event in Geneva, organized by the Swiss and Canadian Governments, was held to mark the first anniversary of the Security Council resolution strongly condemning attacks on medical personnel in conflict
Chronic Anabolic Steroid Use may Damage Heart, Arteries
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A new study suggested that intestinal fungi may contribute to the development of alcoholic liver disease. Researchers demonstrated that oral antifungal treatment protects mice from alcohol-related liver disease progression. The study is published May 22, 2017 in the Journal of Clinical Investigation.
Long-term anabolic-androgenic steroid use may reduce the heart’s ability to pump blood throughout the body and
AROUND THE GLOBE accelerated coronary atherosclerosis, according to new research published May 22, 2017 in the journal Circulation. The heart can recover pumping ability after anabolic steroid use stops, but the ability to relax between beats is less reversible.
CBT via Internet Reduces Depressive Symptom A meta-analysis of 14 randomized controlled trials of adults with mild-to-moderate depression presented May 20, 2017 at the American Psychiatric Association (APA) 2017 Annual Meeting in San Diego, California has shown that cognitive-behavioral therapy (CBT) delivered through the internet had a significant “medium effect” on symptom severity at end of study and a “large sustained effect” during follow-up assessment compared with no treatment.
HSG with Oil-based Contrast Improves Fertility Infertile women who underwent hysterosalpingography with oil-based contrast had 10% higher rates of ongoing pregnancy and live births compared to women who underwent the procedure with water-based contrast, according to findings from a multicenter randomized trial published online May 18, 2017 in the New England Journal of Medicine.
A New Treatment Option for Vitiligo Topical ruxolitinib may provide significant repigmentation in facial vitiligo, suggests a new study reported in the June 2017 issue of the Journal of the American Academy of Dermatology. A 23% improvement in overall Vitiligo Area Scoring Index scores was observed in all enrolled patients at Week 20 of the treatment with topical ruxolitinib1.5% cream.
A1c a Better Test Than Fasting Blood Glucose to Detect Diabetes, Says Study Findings of a study published recently in the Annals of Family Medicine show that HbA1c testing is an effective method to identify individuals with undiagnosed prediabetes and diabetes. Point-of-care tests are a timely and convenient screening method.
First Guidelines on Comorbidity Screening in Children with Psoriasis The Pediatric Dermatology Research Alliance and National Psoriasis Foundation have jointly issued the first guidelines on comorbidity screening in children with psoriasis published online May 17, 2017 in JAMA Dermatology. The guidelines recommend routine screening and identification of risk factors for associated comorbidities in cases of pediatric psoriasis.
Too Little Sleep Increases Risk of Death in People with Cluster of Heart Disease Risk Factors People with a common cluster of risk factors for heart disease and diabetes were approximately twice as likely to die of heart disease or stroke as people without the same set of risk factors if they failed to get more than 6 hours of sleep, according to a new observational study published May 17, 2017 in the Journal of the American Heart Association. This effect was particularly strong in those with elevated blood pressure or poor glucose metabolism.
FDA Approves First Cancer Treatment for any Solid Tumor with a Specific Genetic Feature The US Food and Drug Administration has granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated. Keytruda (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.
Draft of Focused Update to HER2 Testing Guideline in Breast Cancer Open to Comments Draft recommendations as part of a focused update to the American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) evidence-based guideline for human epidermal growth factor receptor 2 (HER2) testing in breast cancer are now open for public comment through June 12, 2017 online at cap.org.
Strep Throat Linked to Risk of Mental Disorders in Children A study from Denmark has found an 18% increased risk of any mental disorder in children with a streptococcal throat infection. The risk of obsessive-compulsive disorder was 51% and that of tic disorders was 35%. The study is published online May 24, 2017 in JAMA Psychiatry.
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AROUND THE GLOBE WHO List of Priority Medical Devices for Cancer Management The WHO has published a new list of priority medical devices for cancer management based on the list of clinical interventions selected from clinical guidelines on prevention, screening, diagnosis, treatment, palliative care, monitoring and end of life care. The publication “WHO list of priority medical devices for cancer management - WHO Medical device technical series” addresses medical devices that can be used for management of cancer and specifically describes medical devices for six types of cancer: breast, cervical, colorectal, leukemia, lung and prostate … (WHO)
Thrombocytosis is a Risk Marker of Cancer Results from a large, population-based study published online in the British Journal of General Practice on May 22, 2017 indicated that thrombocytosis or increased blood platelet count is a risk marker of cancer in adults. The risk of cancer increased to 18.1% for males and 10.1%) for females when a second raised platelet count was recorded within 6 months.
Study Identifies Risk Factors for Pregnancyassociated Stroke in Pre-eclampsia According to a retrospective study published online May 25, 2017 in the journal Stroke, infections present on admission, chronic hypertension, bleeding or clotting disorders increase the risk of pregnancy-associated stroke in women with pre-eclampsia.
Fitness Devices Reliably Measure Heart Rate, But Not Calories Burnt Most wrist-worn fitness devices adequately measure heart rate, but provide a poor estimation of energy expenditure, suggests a study published online May 24, 2017 in the Journal of Personalized Medicine. Devices reported the lowest error for cycling and the highest for walking. Device error was higher for males, greater body mass index (BMI), darker skin tone and walking.
FDA Approves Sarilumab for Adults with Rheumatoid Arthritis The US Food and Drug Administration (FDA) has approved sarilumab (Kevzara, Sanofi/Regeneron) for
the treatment of patients with moderate-to-severe active rheumatoid arthritis intolerant to disease-modifying antirheumatic drugs.
Patients with Vision Problems at Risk of Developing Depression New research presented May 8 at ARVO 2017, the annual meeting of the Association for Research in Vision and Ophthalmology, in Baltimore, Maryland suggests that patients with low vision or blindness, and those who smoke or have diabetes, are at increased risk of being depressed. These patients presenting to the general ophthalmology, cornea, glaucoma or retina clinics should be screened for depression.
ACOG Committee Opinion on Female Athlete Triad In a Committee Opinion, The American College of Obstetricians and Gynecologists (ACOG) states that ob-gyns should screen for the three components of this condition at comprehensive visits for preventive care in all active females: low energy availability with or without disordered eating, menstrual dysfunction and low bone density. Further evaluation should be performed if one or more components are identified. Female athlete triad is a medical condition observed in physically active girls and women.
Zika Virus Spread Undetected for Many Months: NIH Genetic analysis of samples collected as the Zika virus spread throughout the Americas after its introduction in 2013 or 2014 has shown that the virus circulated undetected for up to a year in some regions before it came to the attention of public health authorities. The research published in Nature concluded that the virus spread rapidly upon its initial introduction in Brazil, likely sometime in 2013. Later, at several points in early-to-mid 2015, the virus separated into at least three clades, or distinct genetic groups whose members share a common ancestor, in Colombia, Honduras and Puerto Rico, as well as a fourth type found in parts of the Caribbean and the continental United States… (NIH, May 24, 2017)
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Emerging role of Cardiac MRI in Ischemic and Non-ischemic Cardiomyopathy
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LIGHTER READING
DON’T BE NERVOUS This older man was on the operating table awaiting surgery and he insisted that his son, a renowned surgeon, perform the operation as he was about to receive the anesthesia he asked to speak to his son. “Yes dad, what is it?” “Don’t be nervous, son. Do your best and just remember, if it doesn’t go well and if something happens to me, your mother is going to come and live with you and your wife.” I’LL TRUST YOU THAT YOU PAID A man walks into a bar and has a couple of beers. Once he is done the bartender tells him he owes $9.00. “But I paid, don’t you remember?” says the customer. “Okay,” says the bartender, “If you said you paid, you did.” The man then goes outside and tells the first person he sees that the bartender can’t keep track of whether his customers have paid. The second man then rushes in, orders a beer and later pulls the same stunt. The barkeep replies, “If you say you paid, I’ll take your word for it.” Soon the customer goes into the street, sees an old friend, and tells him how to get free drinks. The man hurries into the bar and begins to drink high-balls when, suddenly, the bartender leans over sand says, “You know, a funny thing happened in here tonight. Two men were drinking beer, neither paid and both claimed that they did. The next guy who tries that is going to get punched right in the nose.”
“My hairline is in recession, my stomach is a victim of inflation, and both of these together are putting me into a deep depression!” I KEEP THINKING I’M GOD! Doctor, Doctor! I keep thinking I’m God! Doc: When did this start? Well first I created the sun, then the earth, then the… JOGGING SHOES Deciding to take up jogging, the middle-aged man was astounded by the wide selection of jogging shoes available at the local sports shoe store. While trying on a basic pair of jogging shoe, he noticed a minor feature and asked the clerk about it. “What’s this little pocket thing here on the side for?” “Oh, that’s to carry spare change so you can call your wife to come pick you up when you’ve jogged too far.”
Dr. Good and Dr. Bad SITUATION: An obese patient with visceral fat wanted dietary advice.
You need a high fiber diet.
Go on a low calorie, high fiber diet.
© IJCP Academy
HUMOR
Lighter Side of Medicine
“Don’t bother me with your troubles,” the final patron responds. “Just give me my change and I’ll be on my way.” A WALKING ECONOMY This guy is walking with his friend, who happens to be a psychologist. He says to this friend, “I’m a walking economy.” The friend asks, “How so?”
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LESSON: A low calorie-high fiber diet with balanced nutritive elements
has a positive effect on fasting glucose, lipid profile, hypertension and visceral obesity, in obese people with impaired glucose tolerance with a consecutive lowering of cardiometabolic risk.
Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767). Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so. The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript. Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper. Covering letter –
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The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper. Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors. Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.
Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures). –
The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.
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All pages should be numbered consecutively beginning with the title page.
Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors. Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,
name of the corresponding authors, acknowledgment of financial support and abbreviations used. – The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary. – A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included. – The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page. – A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text. Summary – The summary of not more than 200 words. It must convey the essential features of the paper. – It should not contain abbreviations, footnotes or references. Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives. Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others. – Ethical guidelines followed by the investigations should be described. Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected. – Method of selecting the sample (cases, subjects, etc. from the statistical universe). – Method of allocating the subjects into different groups. – Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques. –
Confidence intervals for the measurements should be provided wherever appropriate.
Results – These should be concise and include only the tables and figures necessary to enhance the understanding of the text.
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Discussion –
This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.
References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111.
Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat. – All photomicrographs should indicate the magnification of the print. – Special features should be indicated by arrows or letters which contrast with the background. – The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen. – Color illustrations will be accepted if they make a contribution to the understanding of the article. –
Do not use clips/staples on photographs and artwork.
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Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.
Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________
Books
5. Special requests _____________________________
Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.
6. Suggestions for reviewers (name and postal address)
Articles in Books
2.____________ 2.________________
Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.
3.____________ 3.________________
4.____________ 4.________________
Tables –
These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.
Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text. –
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The legend must include enough information to permit interpretation of the figure without reference to the text.
Indian Journal of Clinical Practice, Vol. 28, No. 1, June 2017
Indian 1.____________Foreign 1.________________
7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________
Online Submission Also e-Issue @ www.ijcpgroup.com For Editorial Correspondence
Dr KK Aggarwal
Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com
R.N.I. No. 50798/1990 Date of Publication 13th of Same Month Date of Posting 13-14 Same Month
POSTAL REGISTRATION NO. DL (S)-01/3200/2015-2017 Posted in N.D. PSO New Delhi