07 Gastroenterology by Urvi Trivedi

SECTION 7

Gastroenterology 34.

A Practical Approach to Loss of Appetite Dwijen Das, Tirthankar Roy

181

35.

Practical Approach to Blood Vomiting Jatinder K Mokta

187

36.

Indications, Contraindications & Long Term Care in Liver Transplantation Mohamed Rela

194

37.

A Practical Approach to a Person with Positive HBsAg Salimur Rahman

198

38.

Practical approach to Chronic Diarrhoea Sanjay Tandon

204

C H A P T E R

A Practical Approach to Loss of Appetite Dwijen Das, Tirthankar Roy

ABSTRACT

overgrowth.1 Long lasting anorexia usually occurs only in people with serious and chronic underlying disorder. Disorders that affect the part of brain where appetite is regulated can cause anorexia as well. In addition, the anorexia-cachexia syndrome is multifactorial and may involve chronic pain, depression or anxiety, hypogeusia and hyposmia, chronic nausea, early satiety, malfunction of the GIT and metabolic alterations.1,2 Unexplained chronic anorexia is a signal to the doctor that something is wrong. A thorough evaluation of the person’s symptoms and a complete physical examination often suggest a cause and help the physician decide which tests are needed.

Detailed clinical history and physical examination usually suffice to pinpoint the cause but in certain situationsa more aggressive approach with a battery of investigations may be needed to diagnosethe exact cause of anorexia. Detailed and extensive investigations in anorexia of shorter duration is usually unnecessary. Change in the pattern of meals served and change of eating environment can change appetite in certain cases. Therapy may be required according to the underlying disease causing anorexia.

Feeding and Satiety

Appetite is the desire to eat food, sometimes due to hunger. Decreased desire to eat is termed as anorexia. A brief period of anorexia usually accompanies almost all acute illnesses. Long lasting anorexia usually occurs only in people with serious and chronic underlying disorder. Hypothalamus plays a central role for maintaining the appetite along with different neuropeptides. Loss of appetite in acute illness is a sort of acute phase response causes of which may vary from benign viral or bacterial infection or drug induced to very serious lethal conditions like chronic liver or kidney disease, carcinoma stomach and colon.

INTRODUCTION

Our survival depends on the ability to procure food for immediate metabolic needs and to store excess energy in the form of fat to meet metabolic demands during fasting. Eating behaviour is stimulated by hunger, craving and hedonic sensations and controlled by homeostatic processes. Appetite is the desire to eat food, sometimes due to hunger. Appealing foods can stimulate appetite even when hunger is absent. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is termed as anorexia, while polyphagia (or hyperphagia) is increased eating. Dysregulation of appetite contributes to anorexia nervosa, bulimia nervosa, cachexia, overeating and binge eating. Loss of appetite implies that hunger is absent- a person with anorexia has no desire to eat. A brief period of anorexia usually accompanies almost all acute illnesses. Anorexia during disease can be beneficial or deleterious depending on the timing and duration. Temporary anorexia during acute disease may be beneficial, since restriction of intake of micro- and macronutrients will inhibit bacterial

PATHOPHYSIOLOGY

Body weight depends on the balance between intake and utilization of the calories. Weight loss is usually the result of reduced energy intake, not increased energy expenditure. Reduced energy intake arises from dieting, loss of appetite, malabsorption or malnutrition.3 Food intake is regulated not only on a meal to meal basis but also in a way that generally maintains a given set point, for example if animals are starved and then permitted to eat freely, their spontaneous food intake increases until they regain the lost weight. Similarly, during recovery from illness, food intake is increased in a catch up fashion until lost weight is regained.3

Role of the Hypothalamus3

Appetite and metabolism are regulated by an intricate network of neural and hormonal factors. Regulation of appetite depends primarily on the interaction of two areas: a lateral hypothalamus “feeding center” in the nucleus of the medial forebrain bundle at its junction with the pallidohypothalamic fibres, and the ventromedial hypothalamus “satiety centre” in the ventromedial nucleus. Stimulation of the feeding centre evokes eating behaviour in conscious individuals, and its destruction causes severe, fatal anorexia in otherwise healthy individuals. Stimulation of satiety centre causes cessation of eating, whereas lesion in this region causes hyperphagia and, if the food supply is abundant, the syndrome of hypothalamic obesity. Destruction of feeding centre with lesion of the satiety centre causes anorexia, which indicates that, the satiety centre functions by inhibiting the feeding centre. Hence, it appears that the feeding centre is chronically active and that its activity is transiently inhibited by activity in the satiety centre after ingestion of the food. Neuropeptides such as corticotrophin releasing hormone

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(CRH), α- melanocyte stimulating hormone (α-MSH), cocaine and amphetamine related transcript (CART) induce anorexia by acting centrally on satiety centres.4 One important polypeptide is Neuropeptide Y, which exerts its action through Y5 receptor in the hypothalamus resulting in increased food intake. Other polypeptides that increase food intake include Orexin-A and Orexin-B. They are synthesized in the neurons located in the lateral hypothalamus. They are also of interest because mutation in the receptor causes narcolepsy.3,4 A potentially important observation is that accumulation of malonylCoA in the tissue inhibits food intake. This substance is produced from Acetyl-CoA and is converted to fatty acids by fatty acid synthase.

Afferent Mechanisms3,5

Four main hypotheses about afferent mechanisms involved in the control of food intake are: i.

Lipostatic hypothesis: Adipose tissue produces a humoral signal that is proportionate to the amount of fat and acts on the hypothalamus to decrease food intake and increase energy output.

ii.

Gut peptide hypothesis: Postulates that food in the GIT causes the release of one or more polypeptides that act on the hypothalamus to inhibit food intake.

iii.

Glucostatichypothesis: Increase glucose utilization in the hypothalamus and produces a sensation of satiety.

iv.

Thermostatic hypothesis: Fall in body temperature below a given set point stimulates appetite and a rise above the set point inhibits appetite.

reducing glucose utilization and inhibiting the satiety centre. A variety of cytokines, including TNFα, IFNγ and Leukaemia inhibitory factor (LIF), can induce cachexia. In addition to causing anorexia, these factors may stimulate fever, depress myocardial function, modulate immune and inflammatory responses and induce a variety of specificmetabolic alterations.6 Anorexia ininfection is a part of the Acute Phase Response (APR) to it. The APR can be triggered by lipopolysaccharides, a peptidoglycan from bacterial cell walls, bacterial DNA and glycoproteins, which can trigger production of a variety of pro-inflammatory cytokines. Cytokines causes increased production of leptin from fat stores. They can also signal the central nervous system directly by specialized transport mechanisms through the blood brain barrier. Mechanism of weight loss includes decreased food intake, malabsorption, loss of calories and increased energy requirements. Hence loss of appetite (resulting in decreased food intake) is directly related to weight loss. Food intake may be influenced by a wide variety of visual, olfactory and gustatory stimuli as well as genetic, psychological and social factors.5,6

ETIOLOGY OF ANOREXIA4

•

Cancer :

Some types of cancer–including ovarian, pancreatic and stomach cancers–may cause a loss of appetite, usually by affecting a person’s metabolism.

Advanced cancer

Some cancers may cause the spleen to become larger. When a spleen grows in size, it can push on the stomach, creating a feeling of fullness.

Ascites, may create a feeling of fullness even after eating a small amount of food.

Medications, including chemotherapy, immunotherapy, and drugs called sedatives that cause feelings of calmness or sleepiness.

Radiation treatment or surgery to any part of the gastrointestinal organs, such as the stomach or intestines.

•

Endocrine and metabolic

Leptin

It is produced by adipose tissue, and it plays a central role in the long term maintenance of weight homeostasis by acting on the hypothalamus to decrease food intake and increase energy expenditure.4 Leptin suppresses expression of hypothalamic neuropeptide Y and increases the expression of α-MSH, which decreases appetite. Thus, leptin activates a series of downstream neural pathways that alter food seeking behaviour and metabolism. Leptin deficiency, which occurs in conjunction with the loss of adipose tissue, stimulates appetite.5 A physiologically active form of marijuana (cannabinoids) that are found in the body increases appetite by an action on their CB1 receptors. The cannabinoid receptor type 1, often abbreviated as CB1, is a G protein-coupled cannabinoid receptor located primarily in the central and peripheral nervous sytem. It is activated by the endocannabinoid neurotransmitter anadamide and 2-arachidonoglycerol (2-AG). The anorexiant action of leptin is antagonised by CB1 blockade. Leptin activates the enzyme phosphotidylinisitol-3-hydroxykinase in hypothalamic cells, and inhibition of this enzyme blocks the effect of leptin. The gastrointestinal peptides ghrelin, glucagon, somatostatin and cholecystokinin signal satiety and thus decrease food intake. Hypoglycemia suppresses insulin,

1. Hypothyroidism 2.

Diabetes mellitus

Adrenal insufficiency

Pheochromocytoma

•

Gastrointestinal disorders

Acid peptic disorder

Malabsorption

Obstruction

Pernicious anemia

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Loss of appetite

Long duration

Short duration (Usually benign)

H/o nausea, pain abdomen or dyspepsia

-Infection,

APD, Hepatitis, Fatty liver, Drug induced etc.

Cholecystitis, cholangitis, Appendicitis, UTI etc

Apigastric tenderness... APD

Fever with chills and jaundice.. cholangitis,

Icterus.. Hepatitis, fatty liver

Dysuria... UTI Look for signs of appendicitis, cholecystitis

H/o drug intake

CBC, Urine RE,CRP, USG abdomen, serological markers for specific infection

S. Bilirubin and fraction, ALT, viral markers, UGI endoscopy

Rule out IBS, APD, early CKD, early CLD, psychiatric disorder CBC, S. Creat, LFT, Blood sugar, CRP, USG Abdomen, UGI Endoscopy

Significant wt loss present Warning sign Maligancy, Chronic liver disease, Diabetes mellitus, CKD, HIV infection etc.

Normal physical examination

CBC, S. Creat, LFT, Blood sugar, CRP,Stool for occult blood,HIV testing, Chest imaging, USG Abdomen, UGI Endoscopy, Colonoscopy as indicated

Wait and observe for 6 months.

Treat according to etiology

To be treated accordingly

No recovery indicates evaluation

Treat accordingly

Fig. 1: Algorithmic approach to loss of appetite 5.

Pancreatic disorders

1. HIV

•

Hepatic disorders

2. Tuberculosis

Chronic liver disease

Parasitic infection

Viral hepatitis

Subacute bacterial endocarditis

Biliary disorders

•

Medications

Acute fatty liver of pregnancy

1. Amphetamine

•

Cardiac disorders

Dexmethylphenidate

Chronic ischemia

Selective serotonin reuptake inhibitors

Congestive heart failure

Topiramate

•

Respiratory disorders

Stimulants such as caffeine, nicotine and cocaine

Chronic obstructive pulmonary disease

•

Renal insufficiency

Abrupt cessation of appetite increasing drugs like corticosteroids and cannabis.

•

Rheumatologic disease

Opiates, NSAIDS.

•

Disorders of mouth and teeth

•

Age related factors

• Infections

CHAPTER 34

No Fever

Fever present

No significant wt loss

184

Physiologic changes

Decreased taste and smell

parotid enlargement, dental caries, sudden diffuse hair loss, acne, dry skin, nail dystrophy and scarring resulting from cutting, burning and other self induced trauma, bradycardia, tachycardia, hypothermia and hypotension, edema and clinical obesity.

• Neurologic 1. Stroke 2. Dementia 3. Parkinsonism

GASTROENTEROLOGY

Neuromuscular disorders

• Social 1. Isolation 2.

Economic hardship

• Psychiatric 1. Depression 2. Anxiety 3.

Anorexia Nervosa: There are two types of anorexia nervosa: anorexia nervosa binge/purge type- The individual suffering from this disorder will purge when he or she eats. This is typically a result of the overwhelming feelings of guilt the sufferer experiences in relation to eating; they compensate by vomiting, abusing laxatives or excessively exercising. In restrictive anorexia nervosa- the individual will fiercely limit the quantity of food consumed, characteristically ingesting a minimal amount that is well below their body’s caloric needs.

4. Bereavement 5. Alcoholism 6.

Smoking (heavy)

Bulimia nervosa is type of binge eating behaviour characterized by frequent episodes of binge eating associated with emotional distress and sense of loss of control. Binge eating is eating in a discrete period of time (eg 2 hours) an amount of food that is significantly larger than is typical for most people during the same defined period. This behaviour is associated with a perceived loss of control of eating during this time. Compensatory behaviours used by individuals with bulimia nervosa include self-induced vomiting, laxative abuse, excessive exercise generally experienced as being joyless and/ or compulsive, episodes of fasting or strict dieting, diuretic abuse, use of appetite suppressants, failure to use insulin in those with type I diabetes, and/or use of medications intended to speed metabolism (eg. thyroid hormone). DSM-5 diagnostic criteria require episodes of binge eating that occur at least once weekly for 3 months. Dizziness, light headedness, palpitation, dry skin, pharyngeal irritation, abdominal pain with self induced vomiting, dysphagia, bloating, constipation and amenorrhea are some of the symptoms of bulimia nervosa. Physical examination may reveal bilateral

APPROACH TO THE PATIENT (FIGURE 1)

The first step is to access the duration of anorexia from the history, whether it is of acute onset or chronic. Acute onset anorexia is mainly associated with infections, oral disorders, major surgery, etc. Chronic underlying medical disorders, medications, psychiatric disorders are associated with prolonged anorexia.7 Proper examination of the individual to access signs of wasting, fever, features of bulimia (e.g. loss of teeth, enamel, knuckle ulcerations and calluses). Abdominal examination to access tenderness, distension, free fluid and abdominal lump should be performed. Proper psychiatric and behavioural status should be looked for, and the social and economic status of the patient must be considered. One should look for enlarged lymphnodes, as tuberculosis is a major cause of anorexia in our country and also enlarged neck nodes sometime indicates GI malignancy.7 The review of system should focus on signs and symptoms that are associated with disorders that commonly cause anorexia.8 These include fever, cough, pain, shortness of breath, palpitations and evidence of neurological diseases. Gastrointestinal disturbances, including dysphagia, nausea and vomiting, change in bowel habits should be sought for. Travel history, use of alcohol and cigarettes and all the medications should be reviewed and the patient should be questioned about the previous illness and surgery as well as diseases in the family. Risks for HIV infection should be sought for.9 As part of the history it is important to determine the duration and pattern of anorexia, including past fluctuations in weight and whether weight loss is progressive or stabilized.8 Anorexia in a person whose weight has been stable for many years andwho has presented with history of weight loss that is progressive, are more worrisome and require more immediate followup. Other factors to consider, include intention to lose weight, decreased caloric intake, physical activity and age of the patient. New onset anorexia or dyspepsia in elderly may be a warning feature of underlying malignant diseases. Following questions should be answered in a case of anorexia: 1.

Is a disease process causing the symptoms?

Is it secondary to other symptoms (e.g., nausea)?

Is the patient troubled by the symptoms?

Is the family worried about the eating habits?

How much weight has been lost?

Is the decreased appetite a new symptom?

If so, did it start after an upsetting event, such as the death of a family member or friend?

Physical examination

Diagnostic testing

In patients with positive findings on history or physical examination, further testing should be focused on confirming the suspected diagnosis. When the history and physical examination do not indicate a likely diagnosis, a basic diagnostic evaluation should include: 1.

Laboratory testing: Complete blood count with differential, chemistries (electrolytes, glucose, calcium, renal and hepatic function, thyroid stimulating hormone), hemoglobinA1c, urinalysis, stool hemoccult, and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).9

Diagnostic imaging: Chest radiograph.

If a GI cause is suspected, endoscopy and colonoscopy with biopsies may be helpful.

We do not recommend CT scanning in the initial workup, although CT scan may be indicated based on history or physical examination. Further studies should be based on results of these initial tests. Despite an appropriate initial evaluation, a clear cause for anorexia is often not found. Watchful waiting for one to six months is preferable to a battery of testing with low diagnostic yield.10 As organic disease is rarely found in patients with a normal physical examination and initial diagnostic testing, a waiting period of one to six months is unlikely to result in an adverse outcome.11 On follow-up, careful attention should be paid to dietary history, possibility of psychosocial causes, surreptitious drug intake, and new manifestations of occult illness.

TREATMENT

Home remedies for loss of appetite12 1.

Indian Gooseberry (amla)

Ginger

Black Pepper

Cardamom (elaichi)

Carom Seeds (ajwain)

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Worrying about not eating can further affect the appetite. It is better to include variety in food served and food according to choice of the patient.12 Try not to skip meals. Make an effort to eat regularly even if it is only a few bites. Small frequent meals and snacks throughout the day are advised. Some people may have a better appetite in the morning, better to advice a large breakfast in them.11,13 Try eating a bedtime snack. If care has been taken for someone with cancer, try not to blame them for not eating. Do not bribe or threaten them to get them to eat.

Make meals appealing and fun12

Appetite is very much affected by how food looks and by the eating environment. An appealing food in an atmosphere of fun may do the trick. Recognize that what is appealing one day may not be the same the next day.

Make every calorie count

We should advice to prevent weight loss by increasing the nutritional value of the food served, especially with calories and protein. Allow to eat whatever and whenever the person wants. Small snacks and meals every 1–2 hours throughout the day is a preferred option. Eat well during times when the appetite returns.12 Keep healthy, high-protein, high-calorie snacks available so they are ready to eat when patient’s appetite returns. Eat food high in calories and protein when the appetite is poor. These foods include fish, chicken, turkey, eggs, cheese, milk, ice cream, yogurt, beans and lentils. Add butter to vegetables, cooked cereal and rice to add fat and calories.12 Between meals, sips of drinks with high calories and protein are advisable. Add sugar syrup, honey or jelly to vegetables, meats, cereals, waffles and rolls to add calories.13 Increase the protein and calorie content of milk products. Double the protein and calorie content of whole milk by adding powdered dry milk. Try doing light exercise or walking before meals, in fresh air if possible. Increased activity just before eating and fresh air both stimulate the appetite. Eating atmosphere should be pleasant and relaxed, preferably with friends and family members whenever possible. Eating with someone else distracts attention from food and can increase the amount consumed.12 Physicians may prescribe drugs to stimulate appetite in some cases. These drugs may include megestrol (Megace) or corticosteroids (steroids).13 Some people claim that marijuana helps increase their appetite. To date, studies haven’t shown for certain, that marijuana can effectively improve appetite.11 The management of anorexia depends on the specific underlying cause. Treatment strategies include, but are not limited to, pharmacologic therapy (eg, infections,

CHAPTER 34

Several prospective studies have verified the importance of a complete physical examination in evaluating anorexia and the unexplained weight loss.10 It should start with weight determination and documentation of vital signs. The clinician should assess the overall appearance, skin changes (eg. turgors, scar from prior surgery, melanoma or spider angiomata and stigmata of other disorders),oral thrush or dental diseases, thyroid gland enlargement, presence of lymphadenopathy, pallor, icterus, cardiopulmonary status, hepatosplenomegaly, abdominal mass, breast/prostate abnormalities, rectal examination with stool hemoccult, and any neurologic deficit.9,10 In observational studies, abnormal physical findings were common among those with malignancy.10

Keep mealtimes and snacks flexible

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endocrinopathies), surgery/radiation (eg, malignancy), behavioral therapy (eg, depression, anorexia nervosa) and/or nutritional support (eg, dementia, dysphagia). The medications most often used in the early 2000s include mirtazapine (Remeron), a tetracyclic antidepressant; cyproheptadine (Periactin), an antihistamine; dronabinol (marinol, THC), an antiemetic; nandrolone, oxymetholone, and oxandrolone, which are anabolic steroids related to the male sex hormone testosterone; and megestrolacetate (Megace), a synthetic derivative of the female sex hormone progesterone. In addition to these prescription drugs, fish oil (eicosapentaenoic acid or EPA) has been recommended as an alternative or complementary treatment forundesired weight loss.

REFERENCES

1. Bales CW, Ritchie CS. Sarcopenia, weight loss, and nutritional frailty in the elderly. Annu Rev Nutr 2002; 22:309. 2.

Bistrian BR. Nutritional assessment. In: Goldman L, Schafer AI, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011: chap 221.

Flacker JM, Kiely DK. Mortality-related factors and 1-year survival in nursing home residents. J Am Geriatr Soc 2003; 51:213.

6. Arnold R. Care of dying patients and their families. Goldman-Cecil Medicine; 25th edition; New York, Elsevier Saunders, 2015, Chap 3; p9-14. 7.

Mcquaid K. Approach to the patient with Gastrointestinal disease; Goldman-Cecil Medicine; 25th edition; New York, Elsevier Saunders, 2015, Chap 132; 850-866.

Marton KI, Sox HC JR, Krupp JR. Involuntary weight loss: diagnostic and prognostic significance. Ann Intern Med 1981; 95:568.

Sudenski S, Ferruci L. Clinical problems of aging; Harrison’s Principles of Internal Medicine; 18th edition; Mc Graw-Hill, 2012, Chap 72; 571-580.

10. Metalidis C, Knockaert DC, Bobbaers H, Vanderschueren S. Involuntary weight loss. Does a negative baseline evaluation provide adequate reassurance? Eur J Intern Med 2008; 19:345. 11. Robbins LJ. Evaluation of weight loss in the elderly. Geriatrics 1989; 44:31.

3. Ganong William F. Central regulation of visceral function. In: Review of medical physiology; 23rd edition, USA, Mc Graw-Hill, 2010; 235-240.

12. http://www.cancer.ca/en/cancer-information/diagnosisand-treatment/managing-side-effects/loss-of-appetite/?regi on=on#ixzz4EokLIlgq.

13. McMinn J, Steel C, Bowman A. Investigation and management of unintentional weight loss in older adults. BMJ 2011; 342:d1732.

Refie Carol M. Weight loss. Harrison’s Principles of Internal Medicine; 17th edition; Chap 41; 255-256.

C H A P T E R

Practical Approach to Blood Vomiting

INTRODUCTION

Hematemesis is defined as vomiting of blood, which is indicative of bleeding from the esophagus, stomach, or duodenum.1 Hematemesis includes vomiting of bright red blood, suggestive of recent or ongoing bleeding, and dark material (coffee-ground emesis), which suggests bleeding that had stopped some time ago. Hemetemesis is often accompanied by melena which is black tarry stool that results from degradation of blood to hematin or other hemochromes by intestinal bacteria. Gastrointestinal bleeding can be classified as overt, occult or obscure. Overt Gastro-Intestinal (GI) bleeding is visible and can present in the form of hematemesis, “coffee-ground” emesis, melena, or hematochezia. Occult bleeding refers to bleeding which is not clinically visible as it is microscopic bleeding. Obscure GI bleeding refers to recurrent bleeding in which a source is not identified after upper endoscopy and colonoscopy. It may be either overt or occult. Depending upon the site, gastrointestinal bleeding can be classified as either upper or lower GI beed. Upper GI bleeding is hemorrhage originating from the esophagus to the ligament of Treitz, at the duodenojejunal flexure and lower GI bleeding originates from a site distal to the ligament of Treitz. Hemetemesis is a manifestation of acute severe upper Gastro-Intestinal bleed. Acute GI bleeding is a major cause of hospital admissions in the United States, which is estimated at 300000 patients annually. Upper GI tract bleed is approximately four times more common than that of lower GI tract and is a major cause of morbidity and mortality. Acute GI bleeding is more common in men than women and its prevalence increases with age. The most common causes of acute upper GI bleeding are peptic ulcer disease including from the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), variceal hemorrhage, Mallory-Weiss tear and neoplasms including gastric cancers. Other relatively common causes include esophagitis, erosive gastritis/duodenitis, vascular ectasias and Dieulafoy’s lesions.1 Esophageal varices and peptic ulcer disease are major causes of upper GI bleeding in both Eastern and Western societies. Severe GI bleed is defined as documented gastrointestinal bleeding accompanied by shock or orthostatic hypotension, and a decrease in the hematocrit value by at least 6% or a decrease in the hemoglobin level of at least 2 g/dL, or requires transfusion of at least two units of packed red blood cells.1 Patients with severe GI bleeding

Jatinder K Mokta

require admission for resuscitation and treatment.

INITIAL EVALUATION (FIGURE 1)

The initial evaluation of the patient with bloody vomiting involves an assessment of the hemodynamic stability and resuscitation, and if necessary diagnostic studies (usually endoscopy) with the goal of both diagnoses and when possible, treatment of the specific disorder. Evaluation of the patient includes a history, physical examination, laboratory tests, and in some cases, nasogastric lavage. The information gathered as a part of initial evaluation is used to guide decisions regarding triage, resuscitation, empiric medical therapy and diagnostic testing. Past Medical History - Patients should be asked about prior episodes of upper GI bleeding, since up to 60 percent of patients bleed from the same lesion.2 In addition, the patient’s past medical history should be reviewed to identify important co-morbid conditions. Potential bleeding sources suggested by a patient’s past medical history include: •

Varices or portal hypertensive gastropathy in a patient with a history of liver disease or alcohol abuse.

•

Peptic ulcer disease in a patient with a history of Helicobacter pylori, nonsteroidal antiinflammatory drug (NSAIDs) use, or smoking and epigastric discomfort.

•

Cameron’s erosions in patient with history of large hiatal hernia.

•

Aorto-enteric fistula in a patient with a history of an abdominal aortic aneurysm or an aortic graft.

•

Angiodysplasia in a patient with renal disease, aortic stenosis, or hereditary hemorrhagic telangiectasia.

•

Malignancy in a patient with a history of smoking, alcohol abuse, or H. pylori infection.

•

Marginal ulcers (ulcers at an anastomotic site) in a patient with a gastroenteric anastomosis.

Comorbid illnesses may influence patient management in the setting of an acute upper GI bleed. Comorbid illnesses may: •

Make patients more susceptible to hypoxemia (eg, coronary artery disease, pulmonary disease). Such patients may need to be maintained at higher hemoglobin levels than patients without these

disorders.

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•

Predispose patients to volume overload in the setting of fluid resuscitation or blood transfusions (eg, renal disease, heart failure). Such patients may need more invasive monitoring during resuscitation.

•

Result in bleeding that is more difficult to control (eg, coagulopathies, thrombocytopenia, significant hepatic dysfunction). Such patients may need transfusions of fresh frozen plasma or platelets.

•

Predispose to aspiration (eg, dementia, hepatic encephalopathy). Endotracheal intubation should be considered in such patients.

Symptom assessment — Patients should be asked about symptoms as part of the assessment of the severity of the bleed and as a part of the evaluation for potential bleeding sources. Symptoms that suggest the bleeding is severe include orthostatic dizziness, confusion, angina, severe palpitations, and cold/clammy extremities. Specific causes of upper GI bleeding may be suggested by the patient’s symptoms:3 •

Peptic ulcer: Epigastric or right upper quadrant pain

•

Esophageal ulcer: Odynophagia, gastroesophageal reflux, dysphagia.

•

Mallory-Weiss tear: Emesis, retching, or coughing prior to hematemesis.

•

Variceal hemorrhage or portal hypertensive gastropathy: Jaundice, weakness, fatigue, anorexia, abdominal distention.

•

Malignancy: Dysphagia, early satiety, involuntary weight loss, cachexia.

Physical examination — The physical examination is a key component of the assessment of hemodynamic stability. Signs of hypovolemia include:3 •

Mild to moderate tachycardia.

•

Blood volume loss of at least 15 percent: Orthostatic hypotension (a decrease in the systolic blood pressure of more than 20 mmHg and/or an increase in heart rate of 20 beats per minute when moving from recumbency to standing).

•

hypovolemia:

Resting

Blood volume loss of at least 40 percent: Supine hypotension.

The presence of abdominal pain, especially if severe and associated with rebound tenderness or involuntary guarding, raises concern for perforation. If any signs of an acute abdomen are present, further evaluation to exclude a perforation is required prior to endoscopy. Finally, as with the past medical history, the physical examination should include a search for evidence of significant comorbid illnesses. Laboratory data — Laboratory tests that should be obtained in patients with acute upper gastrointestinal bleeding include a complete blood count, serum

chemistries, liver tests, and coagulation studies. In addition, serial electrocardiograms and cardiac enzymes may be indicated in patients who are at risk for a myocardial infarction, such as older adults, patients with a history of coronary artery disease, or patients with symptoms such as chest pain or dyspnea. The initial hemoglobin in patients with acute upper GI bleeding will often be at the patient’s baseline because the patient is losing whole blood. With time (typically after 24 hours or more) the hemoglobin will decline as the blood is diluted by the influx of extravascular fluid into the vascular space and by fluid administered during resuscitation. It should be kept in mind that overhydration can lead to a falsely low hemoglobin value. The initial hemoglobin level is monitored every two to eight hours, depending upon the severity of the bleed. Patients with acute bleeding should have normocytic red blood cells. Microcytic red blood cells or iron deficiency anemia suggest chronic bleeding. Because blood is absorbed as it passes through the small bowel and patients may have decreased renal perfusion, patients with acute upper GI bleeding typically have an elevated blood urea nitrogen (BUN)-to-creatinine or urea-to-creatinine ratio (>20:1 or >100:1, respectively).4,5 The higher the ratio, the more likely the bleeding is from an upper GI source.4

GENERAL MANAGEMENT (FIGURE 2)

Triage — Resuscitation of a hemodynamically unstable patient begins with assessing and addressing the ABCs (ie, airway, breathing, circulation) of initial management. All patients with hemodynamic instability (shock, orthostatic hypotension) or active bleeding (manifested by hematemesis, bright red blood per nasogastric tube, or hematochezia) should be admitted to an intensive care unit for resuscitation and close observation with automated blood pressure monitoring, electrocardiogram monitoring, and pulse oximetry. Foley catheter placement is mandatory to allow a continuous evaluation of the urinary output as a guide to renal perfusion. Other patients can be admitted to a regular medical ward, all admitted patients with the exception of lowrisk patients receive electrocardiogram monitoring. Outpatient management may be appropriate for some low-risk patients. General support — Patients should receive supplemental oxygen by nasal cannula and should receive nothing per mouth. Two large caliber (16 gauge or larger) peripheral intravenous catheters or a central venous line should be inserted who need close monitoring during resuscitation. Elective endotracheal intubation in patients with ongoing hematemesis or altered respiratory or mental status may facilitate endoscopy and decrease the risk of aspiration. Fluid resuscitation — Adequate resuscitation and stabilization is essential prior to endoscopy to minimize treatment-associated complications.6 According to the 2008 SIGN guideline, either colloid or crystalloid solutions may be used to attain volume restoration prior to administering blood products7 A rough guideline for the total amount of crystalloid fluid volume needed to correct

the hypovolemia is the 3-for-1 rule. Replace each milliliter of blood loss with 3 mL of crystalloid fluid. This restores the lost plasma volume. Patients with severe coexisting medical illnesses, such as cardiovascular and pulmonary diseases, may require pulmonary artery catheter insertion to closely monitor hemodynamic cardiac performance profiles during the early resuscitative phase. If the blood pressure fails to respond to initial resuscitation efforts, the rate of fluid administration should be increased.

It is particularly important to avoid overtransfusion in patients with suspected variceal bleeding, as it can precipitate worsening of the bleeding [9]. Transfusing patients with suspected variceal bleeding to a hemoglobin >10 g/dL (100 g/L) should be avoided. Patients with active bleeding and a low platelet count (< 50,000/microL) should be transfused with platelets. Patients with a coagulopathy that is not due to cirrhosis (prolonged prothrombin time with INR >1.5) should be transfused with fresh frozen plasma (FFP). The management of coagulopathies in patients with cirrhosis is more complicated because the INR is not an accurate measure of hemostasis in patients with cirrhosis because it only reflects changes in procoagulant factors. Provided the patient is hemodynamically stable, urgent endoscopy can usually proceed simultaneously with transfusion and should not be postponed until the coagulopathy is corrected. However, in patients with an INR ≥3, attempt to correct the INR to <3 prior to starting an endoscopy, with additional FFP being given after the endoscopy if high-risk stigmata for recurrent bleeding were found or if endoscopic therapy was performed and the INR is still >1.5. This approach is based on data that suggest endoscopy is safe in patients who are mildly to moderately anticoagulated.11 In addition, because packed red blood cells do not contain coagulation factors, transfusion of a unit of FFP should be considered after every four units of packed red blood cells.12 Platelet transfusions should also be considered in patients with life-threatening bleeding who have received antiplatelet agents such as aspirin or clopidogrel.13 If the patient is taking the medications because of a recent (less than one year) vascular stent placement or acute coronary syndrome, when possible, a cardiologist should be consulted prior to stopping the agent or giving a platelet transfusion.

189

Acid suppression

Patients admitted to the hospital with acute upper GI bleeding are typically treated with a proton pump inhibitor (PPI). Patients with acute upper GI bleeding can be started empirically on an intravenous (IV) PPI. It can be started at presentation and continued until confirmation of the cause of bleeding. Once the source of the bleeding has been identified and treated (if possible), the need for ongoing acid suppression can be determined. Several studies have examined the role of acid suppression given before or after endoscopy (with or without therapeutic intervention).14 In the setting of active upper GI bleeding from an ulcer, acid suppressive therapy with H2 receptor antagonists has not been shown to significantly lower the rate of ulcer rebleeding.15-17 By contrast, high dose antisecretory therapy with an intravenous infusion of a PPI significantly reduces the rate of rebleeding compared with standard treatment in patients with bleeding ulcers.18 Lao et al have demonstrated that highdose intravenous omeprazole can accelerate the resolution of stigmata of recent hemorrhage and reduce the need for endoscopic therapy.19 The suggested dosing of intravenous pantoprazole and esomeprazole is 80-mg bolus followed by 8-mg/h infusion. The infusion is continued for 48-72 hours. Oral and intravenous PPI therapy also decrease the length of hospital stay, rebleeding rate, and need for blood transfusion in patients with high-risk ulcers treated with endoscopic therapy. PPIs may also promote hemostasis in patients with lesions other than ulcers. This likely occurs because neutralization of gastric acid leads to the stabilization of blood clots.20

Prokinetics

Both erythromycin and metoclopramide have been studied in patients with acute upper GI bleeding. The goal of using a prokinetic agent is to improve gastric visualization at the time of endoscopy by clearing the stomach of blood, clots, and food residue. Erythromycin should be considered in patients who are likely to have a large amount of blood in their stomach, such as those with severe bleeding. A reasonable dose is 3 mg/kg intravenously over 20 to 30 minutes, 30 to 90 minutes prior to endoscopy.

Erythromycin

Erythromycin has also been compared with nasogastric lavage. A randomized trial with 253 patients that compared erythromycin alone with nasogastric lavage alone and nasogastric lavage plus erythromycin found that the quality of visualization did not differ significantly among the three groups.21 In addition, there were no differences among the groups with regard to procedure duration, rebleeding rates, need for second endoscopy, number of transfused units of blood, and mortality.

Somatostatin and its analogs

Somatostatin, or its analog octreotide, is used in the treatment of variceal bleeding and may also reduce the risk of bleeding due to nonvariceal causes.22 In patients

CHAPTER 35

Blood transfusions — The decision to initiate blood transfusions must be individualized. Initiate blood transfusions if the hemoglobin is < 7 g/dL (70 g/L) for most patients (including those with stable coronary artery disease), with a goal of maintaining the hemoglobin at a level ≥ 7 g/dL (70g/L).8-10 Try to maintain the hemoglobin at a level of ≥ 9 g/dL (90 g/L) for patients at increased risk of suffering adverse events in the setting of significant anemia, such as those with unstable coronary artery disease. However, patients with active bleeding and hypovolemia may require blood transfusion despite an apparently normal hemoglobin

MEDICATIONS

190

SEVERE GI BLEED OR HEMATEMSIS

HISTORY, PHYSICAL EXAMINATION, RESUSCITATION, ADMISSION TO ICU

GASTROENTEROLOGY

BLOOD GROUPING AND CROSS MATCH,CBC,LFT,RFT, COAGULATION TEST, ECG, CXR, NASOGASTRIC TUBE, GASTRIC LAVAGE, GE-CONSULTATION

PPI may be started before endoscopy if pep�c ulcer is suspected. If the pa�ent is known or suspected to have chronic liver disease, consider beginning octreo�de Upper endoscopy ( generally within 6-12 hr of arrival ) and speciﬁc endoscopic treatment for ulcer, varices etc.

Fig. 1: Algorithm for the initial management of severe upper gastrointestinal (UGI) bleeding. CBC-Complete blood count, LFT – liver function test, RFT – renal function test, ECGelectrocardiogram, CXR – Chest X-Ray, GE- Gastroenterologist. with suspected variceal bleeding, octreotide is given as an intravenous bolus of 50 mcg, followed by a continuous infusion at a rate of 50 mcg per hour. Octreotide is not recommended for routine use in patients with acute nonvariceal upper GI bleeding, but it can be used as adjunctive therapy in some cases. A meta-analysis has shown that vasoactive drugs (e.g., octreotide, somatostatin, terlipressin [a long-acting vasopressin analog]) are as effective as sclerotherapy for controlling variceal bleeding and cause fewer adverse events.23

Antibiotics for patients with cirrhosis

Bacterial infections are present in up to 20 percent of patients with cirrhosis who are hospitalized with gastrointestinal bleeding; up to an additional 50 percent develop an infection while hospitalized. Such patients have increased mortality. Meta-analyses have suggested that administration of an antibiotic to cirrhotic patients with variceal bleeding is associated with a decrease in the rates of mortality and bacterial infections.24-25 The optimal type and duration of antibiotic is unknown. The most commonly prescribed antibiotics are fluoroquinolones, including oral norfloxacin, 400 mg twice daily, intravenous ciprofloxacin, 400 mg every 12 hours, intravenous levofloxacin, 500 mg every 24 hours, and intravenous ceftriaxone, 1 g every 24 hours, administered for seven days.

Anticoagulants and antiplatelet agents

When possible, anticoagulants and antiplatelet agents should be held in patients with upper GI bleeding. However, the thrombotic risk of reversing anticoagulation should be weighed against the risk of continued bleeding without reversal, and thus the decision to discontinue medications or administer reversal agents needs to be individualized.

SPECIFIC DIAGNOSTIC STUDY AND MANAGEMENT

Upper endoscopy

In patients with acute upper GI bleeding, upper endoscopy is considered the investigation of choice.26 Early upper endoscopy within 24 h of presentation is recommended in most patients with acute upper GI bleeding to confirm diagnosis and has the benefit of targeted endoscopic treatment, resulting in reduced morbidity, hospital length of stay, risk of recurrent bleeding and the need for surgery.27 Patients with major bleeding and highrisk endoscopic findings (e.g., varices, ulcers with active bleeding or a visible vessel) benefit from endoscopic hemostatic therapy, while patients with low-risk lesions (e.g., clean-based ulcers, nonbleeding Mallory-Weiss tears, erosive or hemorrhagic gastropathy) who have stable vital signs and hemoglobin, and no other medical problems, can be discharged home. The Forrest classification (Fig. 3) is used to categorize findings during endoscopic evaluation of bleeding peptic ulcers, as follows: active spurting bleeding (Forrest IA); oozing bleeding (Forrest IB); pigmented protuberance or nonbleeding visible vessel (NBVV; Forrest IIA); adherent clot (Forrest IIB); flat pigmented spot (Forrest IIC); and clean-based ulcer (Forrest III).1 Patients with major stigmata of ulcer hemorrhage (spurting, NBVV, or adherent clot) benefit most from endoscopic hemostasis, whereas those with a flat spot or clean based ulcer do not. Endoscopic grading of esophageal varices is subjective. Small varices that is, those occupying less than one third of the lumen, are less than 5 mm in diameter, whereas large varices are greater than 5 mm in diameter. Patients with large esophageal varices, Child (or Child-Pugh) class C cirrhosis, and red color signs on varices have the highest risk of variceal bleeding within 1 year.1 Endoscopic variceal ligation combined with Pharmacological therapy (somatostatin or its analogues octreotide and vapreotide; terlipressin) is the preferred therapy for control of acute esophageal variceal bleeding. Endoscopic variceal ligation is preffered therapy for initial control of bleeding and prevention of rebleeding, and is associated with fewer complications than endoscopic sclerotherapy and requires fewer sessions to achieve variceal obliteration.1 Most commonly used endoscopic classification of Gastric varices, described by Sarin et al. divides gastric varices into four groups: •

GOV1 (74%) – when esophageal varices extend into the lesser curvature

•

GOV2 (16%) – when esophageal varices extend into the fundus

•

IGV1 (8%) – isolated fundic varices without esophageal varices

•

IGV2 (2%) – isolated antral varices

In patients who bleed from gastric fundal varices, endoscopic variceal obturation using tissue adhesives such as cyanoacrylate is preferred, where available. Otherwise, EVL is an option. A TIPS (transjugular intrahepatic portosystemic shunt) should be considered in patients in whom hemorrhage from fundal varices

191

Acute Upper GI-Bleed or Hemetemesis

Ulcer

(active bleeding, NBVV, or Clot )

Combination endoscopic hemostasis ( eg epinephrine inection and multipolar electro-

Flat pigmented spot or clean base

Oral PPI and early discharge

EVL + IV vasoactive drug (eg, octreotide or Terlipresine )

Mallory-weiss tear

Active Bleeding

No active Bleeding

Endoscopic therapy

No endoscopic therapy

ICU for 1-2 day Ward for 2-3 day

Ward for 1-2 days

Discharge

High dose PPI (IV Bolus+Infusion for 72 hrs) followed by oral PPI

Fig. 2: Algorithm for the endoscopic and medical management of severe GI â&#x20AC;&#x201C; hemorrhage, following hemodynamic stabilization. IV, intravenous; NBVV, nonbleeding visible vessel; PPI, proton pump inhibitor; EVL, Endoscopic Variceal Ligation

Fig. 3: Endoscopic stigmata of recent peptic ulcer bleeding. A, Active bleeding with spurting. B, Visible vessel (arrow) with an adjacent clot. C, An adherent clot. D, Slight oozing of blood after washing in the center of an ulcer without a clot or visible vessel. cannot be controlled or in whom bleeding recurs despite combined pharmacological and endoscopic therapy.

upper gastroduodenal bleeding are 92%-98% and 30%100%, respectively.26

The reported sensitivity and specificity of endoscopy for

Risks of upper endoscopy include aspiration, side-effects

CHAPTER 35

Major stigmata

Esophageal Varices

192

from sedation, perforation, and increased bleeding while attempting therapeutic intervention. The airway should be secured by endotracheal intubation in the case of massive upper GI bleeding.

GASTROENTEROLOGY

The practice of routine second look endoscopy after hemostasis is achieved on first endoscopy remains controversial. The 2010 International Consensus Recommendations did not recommend routine use of second look endoscopy but stated it may be useful in selected patients with high risk of re-bleeding27 Other diagnostic tests - In cases of acute upper GI bleeding where upper endoscopy is non-diagnostic in which a bleeding site cannot be identified or treated, the next investigation depends on the patient’s hemodynamic stability. If the patient is unstable with large volume upper GI blood loss, patient should proceed to urgent surgery, such as an exploration and partial gastrectomy for uncontrolled bleeding gastric ulcer.28 Intraoperative endoscopy may be a useful adjunct during surgery to help localize the source of bleeding. If the patient is hemodynamically stable with low volume bleeding, repeat endoscopy may be considered. Other diagnostic tests for acute upper GI bleeding include CT angiography, catheter angiography and nuclear scintigraphy, which can detect active bleeding, deep small bowel enteroscopy, and rarely, intraoperative enteroscopy.29 Upper GI barium studies are contraindicated in the setting of acute upper GI bleeding because they may interfere with subsequent investigations or surgery,30 and due to the risk of barium peritonitis if there is a pre-existing perforation of the bowel wall.

RISK STRATIFICATION

Endoscopic, clinical, and laboratory features may be useful for risk stratification of patients who present with acute upper GI bleeding, and the use of risk stratification tools is recommended by the International Consensus Upper Gastrointestinal Bleeding Conference Group.27 Factors associated with rebleeding identified in a metaanalysis included:31 •

Hemodynamic instability (systolic blood pressure less than 100 mmHg, heart rate greater than 100 beats per minute)

•

Hemoglobin less than 10 g/L

•

Active bleeding at the time of endoscopy

•

Large ulcer size (greater than 1 to 3 cm in various studies)

•

Ulcer location (posterior duodenal bulb or high lesser gastric curvature)

Risk scores — For acute upper GI bleeding, risk scores such as the Rockall Score and Glasgow Blatchford Score (GBS) have been developed and validated.32 While the Rockall score uses endoscopic findings, the GBS is based upon the patient’ s clinical presentation such as systolic blood pressure, pulse, presence of melena, syncope, hepatic disease, cardiac failure and laboratory parameters such as blood urea nitrogen and hemoglobin. Therefore,

the GBS may be best suited for initial risk evaluation of suspected acute upper GI bleeding, such as in the emergency department setting A simpler version of the score, known as the modified Glasgow Blatchford score, is calculated using only the blood urea nitrogen, hemoglobin, systolic blood pressure, and pulse. The score ranges from 0 to 16. A prospective study of the modified score found that it performed as well as the full Blatchford score and that it outperformed the Rockall score with regard to predicting the need for clinical intervention, rebleeding, and mortality.33 However, for these systems to be successful, the risk stratification system must be tied directly to decisions regarding patient discharge. None of the published risk scores has yet been adopted widely. As a general rule, patients who meet the following criteria can be discharged home: •

Have stable vital signs

•

Have a normal hemoglobin

•

Have a likely bleeding source identified on upper endoscopy

•

Have a source of bleeding that is not associated with a high risk of rebleeding (eg, variceal bleeding, active bleeding, bleeding from a Dieulafoy’s lesion, or ulcer bleeding with high-risk stigmata)

•

Have no comorbidities

However, the decision to discharge a patient also depends upon individual-patient factors, such as reliability for follow-up and confidence in the diagnosis. If patients do not meet these criteria, patient should be admitted in a monitored setting or intensive care unit (depending upon the severity of bleeding, comorbidities, and stability of vital signs). Most patients who have received endoscopic treatment for high-risk stigmata should be hospitalized for 72 hours to monitor for rebleeding, since most rebleeding occurs during this time.

CONCLUSION

Hemetemesis is a manifestation of acute severe GI bleeding can be caused by a wide range of pathologies. Esophageal varices and peptic ulcer disease are major causes of upper GI bleeding in both Eastern and Western societies. In patients with active GI bleeding who are unstable, acute resuscitation should precede any investigations. Upper endoscopy is the mainstay of initial investigations and deciding the specific therapy.

REFERENCES

2. 3.

Savides TJ, Jensen DM. Gastrointestinal Bleeding. In: Feldman M, Frience S, Brandt LJ, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9th Edition. Elsevier Medicine 2010 Palmer ED. The vigorous diagnostic approach to uppergastrointestinal tract hemorrhage. A 23-year prospective study of 1,4000 patients. JAMA 1969; 207:1477. Cappell MS, Friedel D. Initial management of acute upper gastrointestinal bleeding: from initial evaluation up to gastrointestinal endoscopy. Med Clin North Am 2008; 92:491.

21. Pateron D, Vicaut E, Debuc E, et al. Erythromycin infusion or gastric lavage for upper gastrointestinal bleeding: a multicenter randomized controlled trial. Ann Emerg Med 2011; 57:582. 22. Imperiale TF, Birgisson S. Somatostatin or octreotide compared with H2 antagonists and placebo in the management of acute nonvariceal upper gastrointestinal hemorrhage: a meta-analysis. Ann Intern Med 1997; 127:1062. 23. D’Amico G, Pietrosi G, Tarantino I, Pagliaro L: Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: A Cochrane meta-analysis. Gastroenterology 2003; 124:1277-91. 24. Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L. Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding. Cochrane Database Syst Rev 2002; (2):CD002907. 25. Soares-Weiser K, Brezis M, Tur-Kaspa R, et al: Antibiotic prophylaxis of bacterial infections in cirrhotic inpatients: A meta-analysis of randomized controlled trials. Scand J Gastroenterol 2003; 38:193-200. 26. Lhewa DY, Strate LL. Pros and cons of colonoscopy in management of acute lower gastrointestinal bleeding. World J Gastroenterol 2012; 18:1185-1190 [PMID: 22468081 DOI: 10.3748/wjg.v18.i11.1185] 27. Barkun AN, Bardou M, Kuipers EJ, Sung J, Hunt RH, Martel M, Sinclair P. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010; 152:101-113 [PMID: 20083829 DOI: 10.7326/0003-4819-152-2-20100119000009] 28. British Society of Gastroenterology Endoscopy Committee. Non-variceal upper gastrointestinal haemorrhage: guidelines. Gut 2002; 51:iv1-iv6 [PMID: 12208839] 29. Jaskolka JD, Binkhamis S, Prabhudesai V, Chawla TP. Acute gastrointestinal hemorrhage: radiologic diagnosis and management. Can Assoc Radiol J 2013; 64:90-100 [PMID: 23245297 DOI: 10.1016/j.carj.2012.08.001] 30. Jutabha R, Jensen DM. Management of upper gastrointestinal bleeding in the patient with chronic liver disease. Med Clin North Am 1996; 80: 1035-1068 [PMID: 8804374] 31. García-Iglesias P, Villoria A, Suarez D, et al. Meta-analysis: predictors of rebleeding after endoscopic treatment for bleeding peptic ulcer. Aliment Pharmacol Ther 2011; 34:888. 32. Rockall TA, Logan RF, Devlin HB, Northfield TC. Selection of patients for early discharge or outpatient care after acute upper gastrointestinal haemorrhage. National Audit of Acute Upper Gastrointestinal Haemorrhage. Lancet 1996; 347:1138-1140 [PMID: 8609747] 33. Cheng DW, Lu YW, Teller T, et al. A modified Glasgow Blatchford Score improves risk stratification in upper gastrointestinal bleed: a prospective comparison of scoring systems. Aliment Pharmacol Ther 2012; 36:782. 34. Saltzman JR, Tabak YP, Hyett BH, et al. A simple risk score accurately predicts in-hospital mortality, length of stay, and cost in acute upper GI bleeding. Gastrointest Endosc 2011; 74:1215. 35. Hyett BH, Abougergi MS, Charpentier JP, et al. The AIMS65 score compared with the Glasgow-Blatchford score in predicting outcomes in upper GI bleeding. Gastrointest Endosc 2013; 77:551.

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Richards RJ, Donica MB, Grayer D. Can the blood urea nitrogen/creatinine ratio distinguish upper from lower gastrointestinal bleeding? J Clin Gastroenterol 1990; 12:500. 5. Mortensen PB, Nøhr M, Møller-Petersen JF, Balslev I. The diagnostic value of serum urea/creatinine ratio in distinguishing between upper and lower gastrointestinal bleeding. A prospective study. Dan Med Bull 1994; 41:237. 6. Baradarian R, Ramdhaney S, Chapalamadugu R, et al. Early intensive resuscitation of patients with upper gastrointestinal bleeding decreases mortality. Am J Gastroenterol 2004; 99:619. 7. [Guideline] Scottish Intercollegiate Guidelines Network (SIGN). Management of acute upper and lower gastrointestinal bleeding. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2008 Sep. (SIGN publication; no. 105): 8. Duggan JM. Gastrointestinal hemorrhage: should we transfuse less? Dig Dis Sci 2009; 54:1662. 9. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368:11. 10. Qaseem A, Humphrey LL, Fitterman N, et al. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2013; 159:770. 11. Wolf AT, Wasan SK, Saltzman JR. Impact of anticoagulation on rebleeding following endoscopic therapy for nonvariceal upper gastrointestinal hemorrhage. Am J Gastroenterol 2007; 102:290. 12. Maltz GS, Siegel JE, Carson JL. Hematologic management of gastrointestinal bleeding. Gastroenterol Clin North Am 2000; 29:169. 13. ASGE Standards of Practice Committee, Anderson MA, Ben-Menachem T, et al. Management of antithrombotic agents for endoscopic procedures. Gastrointest Endosc 2009; 70:1060. 14. Dorward S, Sreedharan A, Leontiadis GI, et al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst Rev 2006; CD005415. 15. Gisbert JP, González L, Calvet X, et al. Proton pump inhibitors versus H2-antagonists: a meta-analysis of their efficacy in treating bleeding peptic ulcer. Aliment Pharmacol Ther 2001; 15:917. 16. Kaviani MJ, Hashemi MR, Kazemifar AR, et al. Effect of oral omeprazole in reducing re-bleeding in bleeding peptic ulcers: a prospective, double-blind, randomized, clinical trial. Aliment Pharmacol Ther 2003; 17:211. 17. Lau JY, Sung JJ, Lee KK, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000; 343:310. 18. Chan WH, Khin LW, Chung YF, et al. Randomized controlled trial of standard versus high-dose intravenous omeprazole after endoscopic therapy in high-risk patients with acute peptic ulcer bleeding. Br J Surg 2011; 98:640. 19. Lau JY, Leung WK, Wu JC, et al. Omeprazole before endoscopy in patients with gastrointestinal bleeding. N Engl J Med 2007; 356:1631-40. 20. Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978; 74:38.

C H A P T E R

Indications, Contraindications & Long Term Care in Liver Transplantation

“Good surgeons know how to operate, better ones when to operate, and the best when not to operate”

INTRODUCTION

Liver transplantation (LT) is a widely accepted & standard lifesaving therapy foradvanced chronic liver disease and acute liver failure. Although, medical management provides a temporizing measure, unlike LT, it is not a definitive cure for the complications of end-stage liver disease (ESLD). Advances in surgical technique, anesthesiology, intensive care unit management and immunosuppression combined with the increased awareness of transplantation have allowed for excellent long-term success. This has in turn led to an exponential increase in the transplant candidates and recipients. Unfortunately, livers remain a scarce resource, and the growth in the transplant waiting list far exceeds the supply of organs. Available organs must be distributed by a regulated and organized system in a fair and equitable manner, with the allocation system being based on the tenets of justice, utility, autonomy, benevolence and nonmalfeasance. It is hence vital to have a clear understanding of the indications and contraindications for LT to maximize appropriate use of this limited resource. It is also prudent to always remind oneself that these indications are dynamic and may keep changing with emerging data.

PRINCIPLES OF DEFINING INDICATIONS

Before listing the disease specific indications for LT, it is necessary to define the principles on which these indications need to be formulated. Selection is based primarily on risk of death without a transplant. Patients are considered for elective transplantation if they have an anticipated length of life or survival in theabsence of transplantation that is less than that obtained with a liver transplant; with no effective medical or surgical alternatives to transplantation. All patients selected for the elective adult liver transplant list must have a projected 5-yearsurvival after transplantation of >70%. Indications for LT are also based on the ability of transplantation to improve quality of life. An integral part of defining principles is that all patients need to be regularly reviewed to ensure that they continue to meet criteria andhave not improved or become too sick to benefit from transplantation. In addition to lowered life expectancy, (anticipated length of life <18 months), and unacceptable quality of life, indications for elective paediatric transplantation

Mohamed Rela

includegrowth failure or impairment, reversible neurodevelopmental impairment due to liver disease, and the likelihood of irreversible end organ damage in the absence of LT.

BROAD INDICATIONS FOR LT (TABLE 1)

These can be classified into those diseases which lead to chronic liver disease and those which result in acute liver failure. Other indications include early or late graft failure resulting from a myriad of causes including primary non function, hepatic artery thrombosis, chronic rejection or disease recurrence. In Countries where objective scoring systems like MELD are used for allocation, the sickest get transplanted first. There are certain conditions where higher MELD points are awarded to those who would otherwise have a low calculated MELD. This is done by giving weightage to their pathology, which would have a high mortality rate without LT. These are classified as “MELD exceptions” and are awarded points, and reevaluated every 3 months. Conditions included in the MELD exceptions are hepatocellular carcinoma-within Milan Criteria (single tumour less than 5cm or 3 tumours each no more than 3 cm in size with an absence of macrovascular invasion and distant metastases), Hilar cholangiocarcinomapostneoadjuvant therapy, cystic fibrosis, portopulmonary hypertension, familial amyloid polyneuropathy, hepatopulmonary syndrome and primary hyperoxaluria. Indications for LT are mainly based on the DDLTpredominant healthcare system prevalent in the west. These data have justifiably been extrapolated to the LDLT setting. Due to the inherent difference in the donation, LDLT may have certain ethical barriers to overcome and the question of “double equipoise” (balance of risk-benefit between the donor and recipient) should always be kept in mind before recklessly expanding the indications for LT beyond the realm of DDLT. Irrespective of etiology, many patients with cirrhosis in the absence of an index complication such as ascites or variceal hemorrhage will not develop hepatic decompensation; although patients with cirrhosis have diminished survival compared to the populationas a whole. It is vital to appreciate that the mererecognition of cirrhosis per se does not automatically indicate the need for LT. It is the occurrence of major complications which predict drastically decreased survival which shouldprompt discussion about a possible role for LT. Complications of ESLD include hepatic encephalopathy,

195

Table 1: Indications for Liver Transplantation Acute Liver Failure Chronic Liver Disease

Early Graft Failure

Child pugh c

Variceal bleed

Meld >15

Hepatopulmonary syndrome

Portopulmonary hypertension

Hepatic encephalopathy

Hepatorenal syndrome

Diuretic resistant ascites

Spontaneous bacterial peritonitis

Hepatocellular carcinoma

Primary nonfunction Hepatic artery thrombosis Chronic rejection

CHAPTER 36

Late Graft Failure

Biliary cirrhosis Recurrent disease renal dysfunction, fluid overload, variceal bleed, refractory ascites, spontaneous bacterial peritonitis and hepatopulmonary syndrome (HPS) amongst others. LT offers a survival benefit in HPS, with 76% of LT recipients surviving 5 years compared to 26% of matched patients with equivalent severity of hypoxemia and liver disease who are not transplanted. The recognition of renal dysfunction in a patient with cirrhosis has a dramatic effect on prognosis, with a substantial increase in the risk of mortality. The risk of death increases 7-fold in patients with renal dysfunction, with 50% of patients with cirrhosis dying within a month of the onset of renal dysfunction. Patients with cirrhosis who develop SBP have a one year mortality of 60%, thus making even the index episode of SBP an indication for LT. Certain cholestatic pathologies like primary biliary cirrhosis, have specific validated objective scoring systems which help guide the clinician. Apart from these, subjective symptoms like intractable pruritus are also an indication for LT in these diseases. Indications and listing of patients with acute liver failure follow well defined criteria, which include the validated King’s college criteria, Clichy criteria and the ALFED criteria. There are country specific criteria for supra-urgent listing of patients, like the UNOS-status 1(USA), UKallocation policy etc. All these criteria follow a common theme which include fulminant hepatic failure fulfilling the King’s college hospital criteria, acute Wilson’s disease or Budd-Chiari syndrome, post liver transplantation hepatic artery thrombosis within 3 weeks (UNOS-7 days), presence of primary nonfunction of the liver graft-defined by objective parameters within 7 days of LT, a live liver donor with who develops severe liver failure within 4 weeks of the donor operation. Supraurgent listing in children follows a slightly different schema with LT being offered to children under two years of age with INR >4 or grade 3-4 encephalopathy.

CONTRAINDICATIONS (TABLE 2)

Due to the ever increasing gap between supply and demand with regards to the liver graft, it is imperative that patients who are unlikely to benefit from LT not be offered a liver; this should be done in an objective and impartial manner. The decision not to transplant affect

the patient, their family in an irreversibly emotional and life changing manner; a hard decision which the treating physician must take. Hence, contraindications for liver transplantation and the delisting criteria are as important as the indications for LT itself. They tend to be dynamic and different between centers, depending on local expertise and level of comfort. There are both absolute and relative contraindications. There are general principles based on which LT may be contraindicated for a particular patient; exceptions to the rule always exist. If the prospective candidate wereto be found physiologically unfit or unlikely to survive the stress of the surgery (advanced cardiac or pulmonary disease), or if there was active sepsis; it would be imprudent to offer the patient LT. In patients with metastatic disease, where the survival after transplantation may be too short to justify the risks of transplantation, LT should not be offered. Other contraindications include states where the postoperative quality of life may be unacceptable to the patient, those with severe intractable depression. A more relative contraindication is when the surgical team deems the surgery technically impossible (extensive venous thromboses); this depends on the expertise of the team and can vary between centres. Another absolute contraindication is when the patient wishes to exercise his autonomy and does not want an operation or is likely to be noncompliant. Absolute contraindications have certain objective criteria; exponential advances in healthcare have moved the goalpost, whichis likely to be pushed further. Contraindications include severe PH (MPAP> 50mmHg) where the post transplant mortality is close to 100%, recent myocardial infarction, FiO2 ≥50% indicating ventilator dependence, PEEP > 10mmHg suggestive of ARDS, amongst others. Relative contraindications reflect the changing trends due to emerging data in this nascent medical field, a few of which include treated extrahepatic malignancy (> 2 year period from treatment), HIV, Age (> 75 years) and moderate Pulmonary hypertension (MPAP 35-50mmHg).

196

Table 2: Contraindications for Liver Transplantation Absolute

Compensated cirrhosis, CTP < 7 Severe PH (MPAP> 50mmHg) Recent myocardial infarction FiO2 ≥50%- ventilator dependence PEEP > 10mmHg- ARDS Angiosarcoma

GASTROENTEROLOGY

Active substance abuse Uncontrolled extrahepatic infection Brain death Relative

Treated Extrahepatic malignancy (>2 year period from treatment) Cholangiocarcinoma Technical /operative challenge Age > 75 years Mod Pulm-HT (MPAP 35-50mmHg) No psychosocial support Psychiatric illness

LONG TERM CARE

With continued surgical experience and advances in organ preservation, intraoperative and perioperative care, immunosuppression, graft monitoring, and transplant care protocols, the majority of adult and pediatric recipients now live 10 to 20 years following the transplant operation. Following LT, recipients have gone on to win Olympic medals, play professional soccer, and become ambassadors for organ donation and transplantation. However, as recipients return to their daily lives, they encounter significant challenges, including medical treatments and follow-up, immunosuppression medications and their side effects, difficulties with employment, and stressors in their interpersonal relationships. As survival continues to improve, more attention is being paid to the patient’s quality of life. Long-term survivors represent a novel patient population who require a multidisciplinary approach to opti mize medical/ surgical treatments, psychosocial issues, achievement of milestones (graduation, marriage, employment, family establishment), health-related quality of life (HRQOL), and further survival. Transition to successful employment requires recovery of functional status and strength, maintenance of attention and concentration, development of personal confidence in the recipient, and overcoming fears of infection or job discrimination related to the posttransplant status. In a 20-year followup study, 50% of pediatric LT survivors were working or were homemakers. An“ideal LT survivor” is one with a stable first allograft function on monotherapy, normal growth, and absence of the most common complications of immunosuppression, a goal which every clinician works towards. Malignancy screening, optimal treatment of recurrent disease and adequate management of metabolic disease are the crucial

strategies upon which a successful& robust post-LT care system is based on. Recommendations include strict adherence to cancer screening regimens to compensate for the increased risk of certain malignancies. Improved risk factor management to reduce and prevent long term cardiovascular, metabolic and renal disease. Treatment of recurrent viral hepatitis to improve long-term graft and patient survival. Transplant recipients are at a higher risk of acquiring infections than healthy individuals; vaccination is therefore highly recommended, ideally before immunosuppression is started. Despite the excellent outcomes of pregnancies after LT, these gestations are considered high risk and should be monitored and managed by an experienced team of maternal-fetal medicine specialists in concert with the patient’s transplant physicians. Unusual transplant-related complications have been reported, including intestinal volvulus secondary to internal hernia and thrombosis of infrarenalaortohepatic graft due to compression from the gravid uterus. Therapeutic adjustments may also be necessary to accommodate pregnancy-related issues in transplant recipients. The use of oral contraceptives in LT recipients depends on allograft function and certain drugs may be contraindicated. Paediatric LT recipients who transition to adult care share many similarities in care needs with adult populations, but important differences exist. Paediatric patients have a longer lifetime exposure to immunosuppressive treatments and resulting adverse effects than many adult recipients. As immunosuppression contributes to increased risks of malignancy, infection, renal disease and cardiovascular disease, an emphasis on the minimization of immunosuppression will have far-reaching beneficial consequences on the patient. Children experience a significant improvement in social competence after LT; body weight, head circumference, and anthropometrics improve as well. Some children may experience academic and psychosocial disabilities. As children grow, they become more concerned about their own health and body image, and may experience less pleasure than ordinary teenagers, which may result in a poor relationship with peers. The support of the family and the transplant team play an important role in the patient’s quality of life.In a particular study only one third of the 10-year survivors met the criteria for the ideal survivor and 23% of the children had repeated a grade or been held back. Overall, compared to healthy peers, long-term survivors of pediatric LT have lower physical HRQOL, some physical disability, and less health care utilization. Some of these results stem from the ever-difficult transi tion from pediatric to adult transplant patient. This adolescent transition remains a critical period in the paediatric LT recipient’s course and is associated with non compliance(upto 45%), poor follow-up, and even graft dysfunction and loss. Although survival outcomes

for paediatric LT have remained consistently excellent, much progress can be made through further refinements and protocols optiÂmizing posttransplant care, development and social support framework. Once they have transitioned into adulthood, similar issues of weight gain, hypertension and renal dysfunction can occur and will be treated as they would be in adults.

CONCLUSION

Long-term survival following LT continue to improve. Tosustain this encouraging trend and maximize longevity, the effects of comorbidities and recurrent disease will need to be minimized. Dose-reductions of immunosuppressive agents, weight reduction and screening programmes for malignancies help prevent comorbidities. Continued studies on immune tolerance and immunosuppressionminimizing tactics may have great potential in reducing their adverse effects. In addition, further studies to define and fine tune exiting protocols are needed to ensure ongoing progress in extending the longevity and quality of liver of a LT recipient.

197

CHAPTER 36

The ultimate goal of LT is to provide a survival benefit to those who need it most and to be able to provide this benefit to the most individuals possible. Identifying appropriate candidates for LT is a complex process that requires a multidisciplinary approach. Survival after liver transplantation has progressively improved, which has led to an expansion in the indications and contraindications for transplant. The methods and scoring systems for

liver allocation have also evolved over time, reflecting advances in the understanding and ability to treat various disease proÂcesses.

C H A P T E R

A Practical Approach to a Person with Positive HBsAg

ABSTRACT

Chronic hepatitis B (CHB) is one of the important public health problems worldwide. Two billion people worldwide have been infected with HBV and ~ 350 million chronic carriers. Chronic HBV infection confers a significant risk of developing life-threatening complications such as cirrhosis of liver and hepatocellular carcinoma (HCC). A positive HBsAg in the blood indicates the presence of an acute or chronic HBV infection. HBsAg becomes detectable in serum usually within 4 to 10 weeks of exposure to HBV and is generally present in serum before there is significant elevation in serum aminotransferases. If the acute infection is cleared, HBsAg will disappear within 4 to 6 months and anti-HBs is detectable in serum few weeks later. Chronic HBV infection is defined as the persistence of HBsAg beyond 6 months. During this period when HBsAg has been cleared but anti-HBs has not yet become detectable (often referred to as the “window period”), the only detectable marker of infection is the hepatitis B core IgM antibody (anti-HBc IgM). Presence of anti-HBs, with absence of HBsAg, indicates immunity to HBV infection resulting from either vaccination or resolution of a prior infection. Occasionally, both anti-HBs and HBsAg are positive in the setting of chronic infection. In this case, although the HBs antibody is present, it is unable to neutralize the HBsAg, and the host remains chronically infected. Patients who are found to be HBsAg positive should undergo serologic and virologic work-up to fully characterize the status of the hepatitis B infection, specifically HBeAg, anti-HBe, and HBV DNA viral load. The results of these tests provide prognostic information and will guide us regarding antiviral treatment. The clinical utility of hepatitis B genotype is not yet well defined. A liver biopsy provides useful information regarding HBV disease activity and is an important factor to decide whether to initiate antiviral therapy. Serum ALT and HBV DNA levels are, in general, good markers of disease activity; In some cases marked inflammation may be present on liver biopsy in the setting of a normal ALT and minimally elevated HBV DNA. Similarly, the liver may appear histologically normal despite a markedly elevated HBV DNA level. Highly sensitive PCR-based quantization of HBV DNA makes it possible to precisely determine pre-treatment HBV load and monitor HBV DNA response during

Salimur Rahman

treatment. HBV DNA level, HBeAg status, degree of hepatic histological activity and fibrosis, and serum transaminases are the most important parameters in determining indication, regimen, and duration of HBV treatment. Pegylated interferon (alfa-2a,2b), lamivudine, adefovir, telbivudine, entecavir and tenofovir are all approved HBV treatment and advantages and disadvantages of each agent is important in choosing the best option for each individual patient with CHB. HBV infection confers a greatly elevated risk of developing HCC, even in the absence of cirrhosis. Screening for HCC with liver ultrasound exam every 6 months in HBVinfected populations is recommended.

KEYWORDS

HBsAg,Chronic hepatitis,HCC.

1. INTRODUCTION

associated with active HBV replication, infectivity, and hepatic inflammation. Depending on the mode of HBV transmission, spontaneous seroconversion from HBeAg to anti-HBe is variable. Most patients underwent seroconversion remain sustained remission of HBV infection that is associated with normal transaminases and a low or undetectable level of serum HBV DNA although serum HBsAg may remain positive.

been shown to stop the progression of liver disease and decrease the risk of HCC.

2. CLINICAL PRESENTATION OF CHRONIC HBV INFECTION

According to EASL, the natural history of hepatitis B acquired early in life can be describe in 5 phases: immune tolerant phase, immune reactive HBeAg-positive phase, inactive HBV carrier state, HBeAg-negative CHB and HBsAg-negative phase.

The next phase is the immune reactive HBeAg-positive phase which is characterized by positive HBeAg , relatively lower level of replication compared to the immune tolerant phase reflected by low serum HBV DNA levels, increased or fluctuating levels of aminotransferases, moderate or severe liver necroinflammation. During inactive HBV carrier state phase, there is seroconversion from HBeAg to anti-HBe, very low HBV-DNA level < 2,000 IU/ml,or undetectable serum HBV DNA and normal serum aminotransferases. Approximately 70-80% remain in inactive HBV carriers indefinitely. HBeAg-positive CHB (10-20%) may present with a high level of HBV DNA, elevated transaminases and hepatic inflammation. Inactive HBV carriers spontaneously lose HBsAg 0.5% annually. HBeAg-negative CHB seroconversion from HBeAg to anti-HBe antibodies during the immune reactive phase or may develop after years or decades of the inactive carrier state. This phase is associated with low rates of prolonged spontaneous disease remission. HBsAg-negative phase is characterized by HBsAg loss, negative HBV- DNA in serum, positive anti-HBc with or without anti-HBs in serum.3 Documentation of repeatedly normal ALT based on serial ALT measurements 3-4 months apart for at least a year is needed to determine whether a patient truly has normalization of ALT commonly referred as persistently normal ALT 4. Spontaneous HBsAg seroclearance has been reported to occur at a rate of 0.5–1 % per year in patients with chronic HBV infection.5 HBsAg seroclearance is generally accompanied by undetectable serum HBV DNA, normalization of liver biochemistries, and improved liver histology.6 However, HCC has also been reported in a small percent of these patients, the risk being higher in those with cirrhosis, HCV coinfection, or older age at the time of HBsAg seroclearance.7

Chronic Hepatitis B (CHB)

Chronic hepatitis B is defined as chronic necroinflammatory disease of the liver caused by persistent infection with HBV. It can be subdivided into HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) 1.

HBeAg-positive CHB

Patients with HBeAg-positive CHB present with positive HBsAg and HBeAg in serum that is

HBeAg-negative CHB

Patients with HBeAg-negative CHB present with positive HBsAg, but negative HBeAg in serum that is associated with active HBV replication, elevated transaminases, and hepatic inflammation. Pathologically, it is secondary to mutant viral infection in HBV pre-core or pre-core promoter region. Currently, HBeAg-negative CHB represents the most common type of CHB, particularly in European, African and Middle East countries of the Mediterranean Basin.

Chronic HBV infection and HBV cirrhosis

The annual incidence of cirrhosis has been estimated to be 2–6 % for HBeAg-positive and 8–10 % for HBeAgnegative patients. The higher rate of cirrhosis among HBeAg-negative patients is related to older age and more advanced liver disease at presentation. Among HBeAgpositive patients, the rate of cirrhosis development is higher in those who remained HBeAg positive during follow-up. Additional factors have been identified to be associated with progression to cirrhosis: habitual alcohol intake, concurrent infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV), high levels of HBV replication, and patients who had HBeAg reversion, HBV genotype (C> B).8,9 Coarse liver , splenomegaly, and hypoalubuminemia are indicative of cirrhosis and liver biopsy provides histological diagnosis. Patients with HBV-cirrhosis can be compensated or decompensated. The later presents with esophageal bleeding, ascites, hepatic encephalopathy, hyperbilirulinemia, and/or coagulopathy. Those with decompensated HBV cirrhosis should be referred for liver transplant evaluation.

Chronic HBV infection and HCC

The annual incidence of HCC has been estimated to be <1 % for non cirrhotic. 2-3% for chronic HBV infected patients patients with or without cirrhosis. Additional risk factors for HCC include coinfection with HCV, a family history of HCC 10, habitual alcohol intake, high levels of HBV replication, HBV genotype C>B 11, and core promoter mutations 12, as well as obesity, diabetes, and smoking 13.

3. INDICATIONS OF TREATMENT IN CHRONIC HBV INFECTION (FIGURES 1, 2 AND 3)

The indications for treatment are based mainly on the combination of three criteria: serum HBV DNA levels, serum ALT levels and severity of liver disease assessed by clinical evaluation, liver biopsy or noninvasive methods (fibroscan) and also taking into account age, health status,

CHAPTER 37

In immune tolerant phase, patients are positive for HBeAg with high HBV DNA levels but a normal serum ALT. Liver biopsy usually shows no or minimal histological changes2.

199

200

Chronic HBV Infected Patient

Decompensated Cirrhosis

Severe reactivation of Chronic HBV

Compensated Cirrhosis*

● HBV DNA > 2000 IU/ml if normal ALT,

GASTROENTEROLOGY

HBV DNA Detectable

● HBV DNA detectable if elevated ALT

● Treat

● Histology not needed

● Histology should be

● Consider LT of no stabilization

Treat immediately

obtained or assess ﬁbrosis noninvasively.*

*Cirrhosis by non-invasive markers means Liver stiffness ≥11 kPa (by Fibroscan) or APRI ≥2.0

Fig. 1: Treatment indications for chronic HBV-infected patients with cirrhosis or reactivation of chronic HBV infection Non-cirrhotic HBeAg positive Chronic HBV infected patient

VIRAL LOAD

HBV DNA

<2000IU/mL

2000-20,000IU/mL

>20,000 IU/mL

ALT

Any

Fibrosis

@ $ • • •

• If elevated ALT, exclude other causes • Assess fibrosis noninvasively • Monitor 3 monthly • Individualize liver biopsy@ • Treat if moderate to severe inflammation or significant fibrosis.$

ALT1-2x ULN or N

ALT>2x ULN

• Assess fibrosis noninvasively • Monitor 3 monthly • Individualize liver biopsy@ • Treat if moderate to severe inflammation or significant fibrosis.$

• Observe for 3 months, if no concerns of hepatic decompensation • Treat if no seroconversion • Obtain histology or assess ﬁbrosis noninvasively.$

Biopsy if non-invasive tests suggest evidence of significant fibrosis, ALT persistently elevated, Age >35 yr. or family h/o HCC or cirrhosis. Moderate to severe inflammation on liver biopsy means either Hepatic activity index by ishak activity score >3/18 or METAVIR activity score A2 or A3 Significant fibrosis on liver biopsy means F≥2 by METAVIR fibrosis score or ishak fibrosis stage ≥ 3 Liver stiffness ≥ 8 kPa (by Fibroscan) or APRI ≥1.5 indicates significant fibrosis; Liver stiffness ≥ 11 kPa (by Fibroscan) or AIR1 ≥2.0 indicates cirrhosis

Fig. 2: Treatment indications for noncirrhotic HBeAg-positive chronic HBV-infected patients family history of HCC or cirrhosis and extrahepatic manifestations. •

Decompensated cirrhosis and detectable HBV DNA, treatment with NA(s).14,15 and they should be considered for liver transplantation at the same time.

•

Compensated cirrhosis and HBV DNA level 2000 IU/ml even with normal ALT. Liver biopsy is recommended, but noninvasive assessment of fibrosis is another option.

•

Severe reactivation of chronic HBV infection.

•

Treatment may be started in pre-cirrhotic chronic

201

Non-cirrhotic HBeAg negative Chronic HBV infected patient VIRAL LOAD

ALT

Fibrosis

ALT > ULN

Persistently normal • Assess fibrosis noninvasively • Monitor ALT 3-6 monthly and DNA 6-12 monthly • Individualize liver biopsy@ • Treat if moderate to severe inflammation or significant fibrosis.$

ALT1-2x ULN or N

• Assess fibrosis noninvasively • Individualize liver biopsy@ • Treat if moderate to severe inflammation or significant fibrosis.*

ALT1-2x ULN

• Observe for 3 months, if no concerns of hepatic decompensation • Treat if no seroconversion • Obtain histology or assess ﬁbrosis noninvasively.$

Fig. 3: Treatment indications for noncirrhotic HBeAg-negative chronic HBV-infected patients HBV infected patients with persistently elevated ALT levels 2 times the upper limit of normal (ULN) (at least 1 month between observations) and HBV DNA level 20,000 IU/ml if HBeAg positive and 2000 IU/ml if HBeAg negative. In such patients, liver biopsy or noninvasive method may be used for the estimation of the extent of fibrosis is useful in patients who start treatment.

4. CURRENT AVAILABLE THERAPY

Anti-HBV treatments are either immuno- modulators or oral nucleos(t)ide analogs (NA). Immuno-modulators available in most countries are the conventional IFN, PEG-IFN-α2a and PEG-IFN-α2b. Oral NA consist of the first generation drugs lamivudine and adefovir, and the newer generations entecavir, telbivudine and tenofovir. IFN based therapy is given for a finite duration. Although IFN-based therapy is associated with more side effects compared to NA, it has a higher likelihood of sustained off-treatment response. In HBeAg-negative patients, young age, female, high serum ALT levels, low serum HBV DNA were associated with a higher chance of achieving sustained response with PEG-IFN therapy15. As a potent immune modulator, IFN has both direct and indirect anti-HBV effect although its precise mechanisms remain to be defined. IFN is the first FDA approved agent for HBV infection. The course of IFN treatment is 48 weeks that offers a small, but certain opportunity of HBsAg clearance. Reactivation of HBV infection occurs in approximately 10-15% of patients who responded to treatment, most commonly

within a year after discontinuing IFN treatment. IFN is administrated by subcutaneous injection, associated with side effects and represents an expensive treatment regimen.

Lamivudine (LAM)

As a nucleoside analogue, LAM inhibits HBV DNA replication by suppressing HBV DNA . LAM represents a safe, cost-effective, and convenient HBV treatment regimen, but it does not result in HBsAg clearance and treatment duration is not for definite period. Risk of resistance is very high. Dose is 100mg daily.

Adefovir (ADV) Dipivoxil

Adefovir dipivoxil is a prodrug of ADV and a nucleotide analogue of adenosine monophosphate that inhibits HBV DNA replication by suppressing HBV DNA polymerase. Dose is 10mg daily.

Entecavir

Entecavir, a carbocyclic analogue of 2-deoxyguanosine, inhibits HBV replication at three different steps: the priming of HBV DNA polymerase, the reverse transcription of the negative strand HBVDNA from the pregenomic RNA, and the synthesis of the positive strand HBVDNA. The approved dose of entecavir for nucleosidenaive patients is 0.5 mg daily orally and for lamivudinerefractory/resistant patients is 1.0 mg daily orally. Doses should be adjusted for patients with estimated creatinine clearance ≤ 50 mL/min.

Telbivudine/LdT

Telbivudine is an L-nucleoside analogue with potent

CHAPTER 37

@ $ • • •

HBV DNA >2000IU/mL

HBV DNA <2000IU/mL

202

Tenofovir

GASTROENTEROLOGY

2 years with undetectable HBV DNA documented on three separate occasions, 6 months apart 23 .

antiviral activity against HBV. Recommended dose is 600 mg daily in empty stomach.

REFERENCES

Tenofovir disoproxil fumarate is a nucleotide analogue that was first approved for the treatment of HIV infection as Viread (tenofovir only) or Truvada (tenofovir plus emtricitabine as a single pill) and was approved for the treatment of chronic hepatitis B in 2008. Daily dose is 300 mg in empty stomach.

5. GOALS OF HBV TREATMENT

EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. Journal of Hepatology 2012; 57:167–185.

Papatheodoridis GV, Manolakopoulos S, Liaw YF, Lok A. Follow-up and indications for liver biopsy in HBeAgnegative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol 2012; 57: 196-202 [PMID: 22450396 DOI: 10.1016/j. jhep.2011.11.030]

Manno M, Camma C, Schepis F, Bassi F, Gelmini R, Giannini F, et al. Natural history of chronic HBV carriers in northern Italy: morbidity and mortality after 30 years. Gastroenterology 2004; 127:756–763.

Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002; 123:1084-1089.

Chen YC, Jeng WJ, Chu CM, Liaw YF. Decreasing levels of HBsAg predict HBsAg seroclearance in patients with inactive chronic hepatitis B virus infection. Clin Gastroenterol Hepatol 2012; 10:297–302.

Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000; 118:554–559.

Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 2003; 37:19–26.

The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC and death. This goal can be achieved if HBV replication can be suppressed in a sustained manner. Then, the accompanying reduction in histological activity of CHB decrease the risk of cirrhosis and the risk of HCC, 16. However, chronic HBV infection can not be completely eradicated due to the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes, which may explain HBV reactivation 17,18,19 . Moreover, the HBV genome integrates into the host genome and might favour oncogenesis and the development of HCC.20-22

6. PREDICTORS OF HBV TREATMENT RESPONSE

Clinical, biochemical, and virological predictive factors to HBV treatment response is important for planning and monitoring HBV treatment. A low level of pre-treatment serum HBV DNA, high levels of ALT and histological activity, a history of adulthood HBV infection, and nonAsian ethnic origin have been associated with higher sustained response rates to IFN treatment15.

7. ON-TREATMENT MONITORING AND DURATION OF THERAPY •

During NA therapy, HBeAg, anti-HBe (in patients with HBeAg-positive) and ALT should be monitored every 3 months.

•

The HBV DNA level should be measured at month 3 and 6 of therapy and then every 3–6 months if agents with a low genetic barrier.

•

Renal function and bone profile should be monitored at least every 3 months if TDF or ADV is used and muscle symptoms and muscle weakness should be monitored during telbivudine therapy.

•

Duration of therapy with IFN is 48 weeks and unknown for NAs. But treatment with NAs can be stopped in HBeAg positive CHB after at least 1 year, preferably after 3 years of additional therapy after HBeAg seroconversion with undetectable HBV DNA by PCR and persistently normal ALT levels and HBeAg negative CHB and after HBsAg loss following either anti-HBs seroconversion or at least 12 months of a post-HBsAg clearance consolidation period or after treatment for at least

WHO. Department of Communicable Diseases Surveillance and Response. Hepatitis B. Available from: URL: http://

www.who.int/csr/disease/hepatitis/HepatitisB_ whocdscsrlyo2002_2.pdf 2. Tram TT, Martin P. Hepatitis B: epidemiology and natural history. Clin Liver Dis 2004; 8:255-266.

10. Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 2000; 92:1159–1164. 11. Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005; 97:265–272. 12. Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology 2003; 124:327–334. 13. Yuan JM, Govindarajan S, Arakawa K, Yu MC. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the US. Cancer 2004; 101:1009–1017. 14. Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, et al. Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol 2010; 52:176–182. 15. Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing WF, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with

decompensated chronic hepatitis B liver disease. Hepatology 2011; 53:62–72.

-negative liver diseases. Proc Natl Acad Sci USA 1981; 78:3906–3910.

15. Bonino F, Marcellin P, Lau GK, Hadziyannis S, Jin R, Piratvisuth T, Germanidis G, Yurdaydin C, Diago M, Gurel S, Lai MY, Brunetto MR, Farci P, Popescu M, McCloud P. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 2007; 56:699-705 [PMID: 17127704 DOI: 10.1136/ gut.2005.089722].

19. Brechot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, PaterliniBrechot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely ‘‘occult’’? Hepatology 2001; 34:194–203.

16. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351:1521–1531.

18. Brechot C, Hadchouel M, Scotto J, Fonck M, Potet F, Vyas GN, et al. State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and

20. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology 2004; 127:S56–S61. 21. Bonilla GR, Roberts LR. The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma. J Hepatol 2005; 42: 760–777. 22. Pollicino T, Saitta C, Raimondo G. Hepatocellular carcinoma: the point of view of the hepatitis B virus. Carcinogenesis 2011; 32:1122–1132. 23. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update, Hepatol Int 2016; 10:1–98.

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17. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008; 49:652–657.

203

C H A P T E R

Practical approach to Chronic Diarrhoea

INTRODUCTION

Originated from the Greek word “diárrhoia”, which correctly means : “to flow through”, Diarrhoea (both acute & chronic) is one of the major ailments of the modern society. According to American Gastroenterologists Association, chronic diarrhoea should be defined as “a decrease in fecal consistency lasting for four or more weeks”.1 Chronic diarrhoea is present at a rate of 3-5% in the general population, has a major bearing on the life quality and increases the financial burden on the

Table 1: Causes of Diarrhoea Inflammatory:

Secretory:

Dysmotility:

• Inflammatory Bowel Disease (Crohn’s Disease, Ulcerative colitis) • Immune-mediated mechanism for inflammation (Graft vs Host Reaction, Allergy due to food,etc) • Bacterial, Viral & Fungal Infections • Injury due to Radiation exposure • Neoplasias of the gut • Exogenous, osmotic & endogenous laxatives • Chronic ingestion of ethanol • Tumors which cause the production of hormones (Gastrinomas, Mastocytosis, Carcinoid,etc.) • Deficiencies of disaccharides • Intolerance to gluten, saccharides, polyols • Decreased absorption from the bowel due to resection, disease or fistula • Addison’s disease • Prokinetic Drugs • Irritable bowel syndrome • Thyroid disorders • Vagotomy operations

Steatorrhoea:

• Digestion problems in the lumen • Malabsorption from the mucosa • Lymphatic obstruction

Self-induced:

• Disorders of diet and eating • Munchausen syndrome

Iatrogenic:

• Vagotomy • Cholecystectomy • Ileal resection

Sanjay Tandon

patients. The uniqueness in its diagnosis is that it can be differentiated from acute diarrhoea in not being selflimited and persists until treated.2 The causes are givenin Table 1. Approach History Taking

Examination

Lab. Diagnosis & Evaluation

Treatment

HISTORY TAKING

The following questions should be specifically asked when one is taking the history of a suspected case of chronic diarrhoea: •

Duration of illness ( >4 weeks pointing towards presence of chronic diarrhoea)

•

Constant/Episodic Diarrhoea

•

Age of the patient (as old age patients can be suffering from chronic diarrhoea due to some malignancy)

•

Whether the patient gets up from his sleep in the night to defecate (secretary/inflammatory diarrhoea)

•

Is diarrhoea affected by fasting? (pointing towards food intolerance, etc)

•

Source of water consumption (eg. well water can cause giardiasis)

•

History of travel (eg. camping in endemic parasitic areas)

•

History of hospitalization (iatrogenic)

•

History of supplementary medications (sorbitol, used as a base in certain supplements, can cause diarrhoea as it is an osmotically active sugar)

•

Is the patient an alcoholic? (alcoholic patients can have insufficiency of the pancreas)

•

Is the patient diabetic? (motility of the gut is affected)

EXAMINATION

General Examination

Examination for lymphadenopathy, can help significantly as it is a major sign pointing towards neoplasias and chronic infections. Significant weight loss can be a feature of malignancies or chronic infections.

towards the presence of small bowel disease, celiac diseases.10

Eye examination

If there are signs of episcleritis, the diarrhoea can be linked to inflammatory bowel disease. Signs of exopthalmos can be attributed to hyperthyroidism as a cause for the diarrhoea.

Skin examination

Blistering rashes of itchy nature (dermatitis herpetiformis), are present in one-fourth patients who suffer from celiac disease.5 Particular skin changes can also be seen in patients suffering from Carcinoid syndrome, Addison’s disease and glucagonoma.6 Look for scars (Post-surgical causes of diarrhoea)

•

Bowel sounds (Hypermotile causes of diarrhoea)

• Presence of tenderness inflammatory causes) •

(Infectious

causes,

Presence of mass (Malignant causes)

RECTAL EXAMINATION

For presence of blood •

Anoscopy: Presence of ulcers & impacted stools can be detected by anoscopy.

OTHER SIGNS6

Serological testing can be done to detect the presence of celiac disease.

•

If diarrhoea is more than a liter per day, estimation of vasoactive intestinal polypeptide, histamine, calcitonin & substance P should be done.7

STOOL TESTS

Based on clinical diagnosis, stool tests should be conducted specifically, but in complicated cases, a “broad nest” method of testing the stool should be applied. Categorization of the diarrhoea on the basis of its cause is an important pre-requisite in the management of a patient with chronic diarrhoea. Although a planned collection is preferable but random stool collection is more practical and possible. The stool sample should be checked for the following: A.

Presence of occult blood

Presence of white blood cells

pH level of the sample

Sudan stain for detection of fat in the sample

Culture of the stool sample

•

Patients suffering from amyloidosis show signs of orthostatic hypotension and peripheral neuropathy.

Laxative Abuse

•

Patients of Inflammatory Bowel disease and Whipple’s disease show signs of arthritis.

Electrolyte levels and osmolality of the sample

Occult Blood & White Blood Cells:

•

Presence of tremors indicate hyperthyroidism.

•

A patient of colitis can present with signs of chronic liver disease.

Basically show the possibility of inflammatory type of diarrhoea

•

Wright stain: Sensitivity 70%, specificity 50% for leucocytes

•

White Blood cells in the stool also point towards the probability of ulcerative colitis

•

Blood in the stool may be caused by bleeding in the digestive tract

LABORATORY DIAGNOSIS & EVALUATION

Blood Tests

Complete Blood Count Erythrocyte Sedimentation Rate Fasting, post-prandial sugar with HbA1c

B. pH:

HIV I & II (ELISA)

•

A low pH of less than 6 is suggestive of a malabsorption of carbohydrates

Electrolytes

Detection of fats :

Liver Function Tests

•

Sudan stain is the gold standard test for the quantitative evaluation of fat in stool of the sample collected

•

A three day collection of the stools for evaluation of the fat unabsorbed by the gut has been a practiced test for malabsoption for a long time and is still used by gastroenterologists. 11

•

The faecal fat concentration which is gram faecal fat/100 grams of wet stool weight, usually corresponds well with the total fat excretion. 12-16 Breath Test for fat malabsorption7 :

Kidney Function Tests

Thyroid Function Tests Vitamin B12 and Folic acid Ferritin C-Reactive Protein •

Presence of organic diseases can be detected by an increase in the ESR, decrease in albumin levels and hemoglobin.8 9

•

A decrease in the iron levels in the blood points

CHAPTER 38

ABDOMINAL EXAMINATION

•

205

206

GASTROENTEROLOGY

Breath tests for fat malabsoption offer an inviting substitute to stool tests.

•

Bacterial infection is an unusual cause of chronic diarrhoea in hosts which are immunocompetent.

Absorption of 14 C-triolein is used as a substitute to fecal fat. The test evaluates absorption as well as lipolysis. Fat absorption tests established on isotopes without radioactivity have been produced employing a variety of 13C substrates. A triglyceride with a long chain collected from algae 13C Hiolein is being employed for these tests involving its administration orally in the quantity of 2mg/kg with a rice prepration, and consequently the breath having 13CO2 is evaluated using mass spectrometry. This test is equally sensitive and specific as compared with that of 14C-triolein.

•

Plesiomonas and Aeromonas require special techniques.

•

Stool ELISA can be done to detect GIARDIA.

•

Ova and parasites can be detected

Stool electrolyte level

Stool osmotic gap: 290 – 2([Na+] + [K+]) •

Gap < 50 mOsm/Kg: Pure secretory diarrhoea

•

Gap > 125 mOsm/Kg: Pure osmotic diarrhoea

•

Gap 50-125 mOsm/kg: Mixed or mild carbohydrate malabsorption

Evaluation of laxative abuse4:

•

Barium enema to test for cathartic colon (ahaustral right colon)

Osmolality of the sample •

Not used to calculate gap

•

Sigmoidoscopy for gross presence of melanosis coli (microscopic form is often a normal variant)

•

Useful in cases of unexplained diarrhoea

•

Alkalinization assay of stool: phenolphthalein, some anthraquinones, and rhubarb turn red; bisacodyl turns purple-blue

•

Low measured stool osmolality (< 290 mOsm/Kg) suggestive of contamination with water or dilute urine

•

Spectrophotometry* or thin-layer chromatography of urine or stool water: detects anthraquinones, bisacodyl, phenolphthalein; can detect anthraquinones 32 hr after one dose

Endoscopic & Histological evaluation:

•

Measurement of stool osmolality: only useful if <250 mOsm per kilogram (implying dilution of stool with water or urine)

In a patient of chronic diarrhoea , where there is a probability of malabsorption, diagnostic checkups should be in the direction of pancreatic or small bowel malabsorption.

•

In an outpatient department, to evaluate rectum , unprepared rigid sigmoidoscopy was employed for a long time, but in chronic diarrhoea patients, the preferred choice is flexible endoscopy.

•

If the symptoms point towards colorectal malignancies, screening colonoscopy can be employed.17-20

•

If the patient is below the age of 45 years, a positive diagnosis can be made with the help of characteristic symptoms of functional bowel disease, normal screening blood tests and normal examination.

•

However, patients below the age of 45 years with abnormal symptoms and chronic diarrhoea should resort to flexible sigmoidoscopy as the diagnostic results are different from the use of colonoscopy in this age segment.

•

If the patient is above this age-group, suffering from chronic diarrhoea, colonoscopy is the choice of evaluation. It is more sensitive than the use of barium enema.

•

For celiac disease, Antiedomysium antibody testing is the choice of investigation. To examine for the presence of small bowel enteropathies, upper gastrointestinal endoscopy with distal duodenal biopsies should be employed.

•

Enteroclysis or barium follow through should be reserved for suspected patients of small bowel

*These tests are usually done in a commercial or referral laboratory. The stool specimen should be liquid and frozen. A “laxative survey” request will usually result in chromatographic, spectrophotometric, and other methods of detecting anthraquinones, bisacodyl, phenolphthalein, castor oil, mineral oil, magnesium, and phosphate. Docusate sodium, the active ingredient in Colace, can be detected by thin-layer chromatography but is not measured in the currently available laxative screens. E.

Evaluation of the loss of protein7: Proteins are broken down into amino acids in the lumen of the gut with the help of enzymes released by pancreas before absorption starts actively. A problem in digestion of these products is a rare phenomenon and hence, evaluation of protein malabsorption is a rarity in clinical settings. Even then, few methods which have been explained are:

•

Faecal clearance of α1-antitrypsin107

•

Faecal clearance of radiolabelled albumin,108

Stool Culture:

•

Infections usually point towards inflammatory diarrhoea

TREATMENT OF CHRONIC DIARRHEA

207

If there is chronic diarrhea, adopt the following approach:

Initial management algorithm based on features accompanying diarrhea. (Taken from M Camilleri: Clin Gastroenterol Hepatol. 2:198,2004) TREATMENT Can be of the following types: Suppressive

Empirical

Curative

malabsorption having a normal distal duodenal histology. SUPPRESSIVE

irritable bowel syndrome. b.m. bowel movement. (Reprinted from M Camilleri: Clin Gastroenterol Hepatol. 2:198,2004). ● For many chronic conditions, suppressing the underlying cause can help control chronic diarrhea. RADIOLOGICAL EXAMINATION Examples: Algorithm for management when abnormal findings • X-Ray Chest (To rule out primary tuberculosis) -withdrawal of lactose from the diet of patients for lactase deficiency. on limited screen for organic disease. Hb, are identified • Ultrasound of the abdomen hemoglobin; Alb, albumin; MCV, meanagents corpuscular -In patients suffering from Idiopathic Inflammatory Bowel Disease, employing anti-inflammatory and volume; MCH, mean corpuscular hemoglobin; OSM, osmolality. glucocorticoids is useful • C.E.C.T. (Reprinted from M Camilleri: Clin Gastroenterol Hepatol. -In patients with pancreatic insufficiency, pancreatic enzyme replacement is beneficial STEPWISE EVALUATION OF HOSPITALIZED PATIENTS WITH 2:198,2004) -In medullary carcinoma of thyroid, prostaglandin inhibitors like indomethacin are useful 4 DIARRHOEA-InOFcases UNDETERMINED with bile acid ORIGIN. malabsorption,

bile acid sequestrants are beneficial SUPPRESSIVE -In patients suffering from malignant carcinoid syndrome, analogues suchconditions, as octreotides can is • somatostatin For many chronic suppressing the Confirmation and review of results of outpatient useful underlying cause can help control chronic diarrhoea. evaluation.-PPIs are beneficial for the gastric hypersecretion of gastrinomas. Examples:

Day 1

Measurement of stool weight or volume on normal diet. Urine laxative screening by thin-layer chromatography. EMPIRICAL

Withdrawal of lactose from the diet of patients for lactase deficiency.

- In patients suffering from idiopathic inflammatory Stool alkalinization assays.cause of chronic diarrhea cannot be found, ● If the specific empirical therapy may be employed. bowel disease, employing anti-inflammatory ●Loperamide, diphenoxylate and other mild opiates are beneficial in watery diarrheas of mild to moderate Measurement of stool sodium, potassium, sulfate, agents and glucocorticoids is useful phosphate,nature. stool osmolality; calculation of stool osmotic ●Tincture of opium or codeine can be employed for treatment watery with diarrheas of severe nature. - In of patients pancreatic insufficiency, pancreatic gap. ●To avoid toxic megacolon, in patients with severe Inflammatory bowel disease, application of antimotility enzyme replacement is beneficial.

Days 2–4

drugs should be avoided.

In medullary carcinoma of thyroid, prostaglandin Imposition●ofIn 72-hr fast with suffering intravenous (If - diabetic patients from hydration chronic diarrhea, α2-adrenergic agonists like Clonidine should be used. inhibitors like indomethacin are useful. diarrhoea stops completely in 24 hr, there is no need to Its adverse effect includes postural hypotension. continue fast. Secretory diarrhoea often decreases greatly - In cases with diarrhea bile acid ● In patients of Inflammatory bowel disease, suffering from chronic diarrhea, andmalabsorption, urgency can be bile acid with fasting, but continues with 200 g of stool per 24 hr.). sequestrants are beneficial. alleviated with the help of drugs like Alosetron and other 5-HT3 receptor antagonists.

Monitoring of daily stool weights.

In patients suffering from malignant carcinoid such as

PPIs are beneficial for the gastric hypersecretion of gastrinomas.

syndrome, somatostatin analogues Days 5–8 CURATIVE ● If the etiology is assessed correctly, treatment is curative like resection can of a iscolorectal octreotides useful. cancer, Imposition of diet containing 75–100 g of fat per 24 hr. Monitoring of 24-hr mean stool weight and fat content on days 6, 7, and 8.

TREATMENT OF CHRONIC DIARRHOEA

Initial management algorithm based on features accompanying diarrhoea. p.r., per rectum; IBS,

EMPIRICAL

•

If the specific cause of chronic diarrhoea cannot be found, empirical therapy may be employed.

CHAPTER 38

1. Exclude hospital based problems (drugs, operative procedures) 2. Look for blood per rectum (Biopsy, colonoscopy) 3. If the features suggest malabsorption, do biopsy, aspiration and imaging (small bowel) 4. If the pain increases or subsides after movement of bowel, suspect incomplete evacuation, test for IBS 5. If there are no features of malabsorption, consider functional diarrhea, exclude lactose, sorbitol

GASTROENTEROLOGY

208

•

Loperamide, diphenoxylate and other mild opiates are beneficial in watery diarrhoeas of mild to moderate nature.

•

Tincture of opium or codeine can be employed for treatment of watery diarrhoeas of severe nature.

•

To avoid toxic megacolon, in patients with severe Inflammatory bowel disease, application of antimotility drugs should be avoided.

•

In diabetic patients suffering from chronic diarrhoea, α2-adrenergic agonists like clonidine should be used. Its adverse effect includes postural hypotension.

•

In patients of Inflammatory bowel disease, suffering from chronic diarrhoea, diarrhoea and urgency can be alleviated with the help of drugs like Alosetron and other 5-HT3 receptor antagonists.

CURATIVE

•

If the etiology is assessed correctly, treatment is curative like resection of a colorectal cancer, discontinuation of a specific drug, antibiotic administration for Whipple’s disease or tropical sprue.

NOTE

•

For all chronic diarrhoea patients, an important part of the management is the repletion of fluid and electrolytes.

•

In patients suffering from chronic steatorrhea, replacement of fat-soluble vitamins is also beneficial.

REFERENCES

Approach to the adult with chronic diarrhoea in resourcerich settings [Internet]. Uptodate.com. 2016 [cited 6 September 2016]. Available from: http://www.uptodate. com/contents/approach-to-the-adult-with-chronicdiarrhoea-in-resource-rich-settings

2. An Approach to Chronic Diarrhoea Shobna J Bhatia, Praveen Mathew. 3.

Practical Tips for the Diagnosis and Management of Chronic Diarrhoea David A. Johnson, MD.

Evaluation of Chronic Diarrhoea [Internet]. 1st ed. 2016 [cited 2 September 2016]. Available from: http://www.aafp. org/afp/2011/1115/p1119.pdf

5. Rodrigo L. Celiac disease. World J Gastroenterol. 2006; 12:6585-6593.

[Internet]. 1st ed. 2016 [cited 2 September 2016]. Available from: http://smh.mans.edu.eg/files/pdf/gastro/chronic_ diarrhoea.pdf

Donowitz M, Kokke FT, Saidi R. Evaluation of patients with chronic diarrhoea. New England Journal of Medicine 1995; 332:725-9.

Bertomeu A, Ros E, Barragán V, et al. Chronic diarrhoea with normal stool and colonic examinations: organic or functional? J Clin Gastroenterol 1991;13:531–6.

Read NW, Krejs GJ, Read MG, et al. Chronic diarrhoea of unknown origin. Gastroenterology 1980; 78:264–71.

10. Ackerman Z, Eliakim R, Stalnikowicz R, et al. Role of small bowel biopsy in the endoscopic evaluation of adults with iron deficiency anemia. Am J Gastroenterol 1996; 91:2099– 102. 11. Duncan A, Hill PG. A UK survey of laboratory-based gastrointestinal investigations. Ann Clin Biochem 1998; 35:492–503. 12. Bo-Linn GW, Fordtran JS. Fecal fat concentration in patients with steatorrhea. Gastroenterology 1984;87:319–22. 13. Roberts IM, Poturich C, Wald A. Utility of fecal fat concentrations as screening test in pancreatic insufficiency. Dig Dis Sci 1986; 31:1021–4. 14. Lembcke B, Grimm K, Lankisch PG. Raised fecal fat concentration is not a valid indicator of pancreatic steatorrhea. Am J Gastroenterol 1987; 82:526–31. 15. Bai JC, Andrush A, Matelo G, et al. Fecal fat concentration in the differential diagnosis of steatorrhea. Am J Gastroenterol 1989; 84:27–30. 16. Benini L, Caliari S, Bonfante F, et al. Fecal fat concentration in the screening of steatorrhea. Digestion 1992; 53:94–100. 17. Guillem JG, Forde KA, Treat MR, et al. Colonoscopic screening for neoplasms in asymptomatic first-degree relatives of colon cancer patients. A controlled, prospective study. Dis Colon Rectum 1992; 35:523–9. 18. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med 2000; 343:162–8. 19. Bazzoli F, Fossi S, Sottili S, et al. The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer. Gastroenterology 1995; 109:783–8. 20. Hunt LM, Rooney PS, Hardcastle JD, et al. Endoscopic screening of relatives of patients with colorectal cancer. Gut 1998; 42:71–5. 21. [Internet]. Dx.doi.org. 2016 [cited 2 September 2016]. Available from: http://dx.doi.org/10.1016/S15423565(04)00003-5.