SECTION 8
Hepatology 66.
NAFLD and Diabetes Lalit Kumar Meher, Sunil Kumar Kota
311
67.
Diabetic Hepatopathy Rajesh Upadhyay
314
68.
NAFLD – Where Do We Stand Today KK Lohani
319
69.
NASH: Do we Really have an Effective Treatment? Sandeep Satsangi, Ajay Duseja
322
70.
Alcoholic Hepatitis in India: Current Prospective and Management Suresh Kumar
326
71.
Ascites - From Basics to Bedside Harbir Kaur Rao, Rajinder Singh Gupta
329
72.
Approach to Hepatorenal Syndrome DN Amarapurkar
334
73.
Should we Treat Chronic Hepatitis B Carrier Mamun Al Mahtab, Sheikh Mohammad Fazle Akbar
336
74.
Hepatitis C: Paradigm Shift in the Management Samir R Shah, Vibhor Borkar
339
75.
Hepatocellular Cancer (HCC): Screening and Management Subrat Kumar Acharya, Sashi Bala Paul, Shalimar
342
NAFLD and Diabetes
C H A P T E R
66
Lalit Kumar Meher, Sunil Kumar Kota
INTRODUCTION
Non-alcoholic fatty liver disease includes a spectrum of condition ranging from simple steatosis to steatohepatitis (NASH-characterised by hepatocyte ballooning, lobular inflammation with or without fibrosis) to cirrhosis. NAFLD and diabetes share common risk factors like obesity and insulin resistance, but there exists a complex relationship between diabetes and NAFLD. One condition may accelerate the progression of other. Both the conditions have been found to increase the risk of macro-vascular and micro vascular complications.
EPIDEMIOLOGY AND NATURAL HISTORY
The overall prevalence of NAFLD in Asian countries varies from 9-40% and in western countries from 15-40%. In India, the prevalence of NAFLD is around 9-32% in the general population, but it is 12.5-87.5% in patients with type 2 diabetes mellitus as reported in various studies (Table 1). Data on NAFLD in type 1 diabetes mellitus are scanty. Taghar et al have reported prevalence of NAFLD of 44.4% in a series of 250 type 1 diabetes mellitus patients. Studies showing prevalence of NASH by liver biopsy in diabetes with NAFLD are scanty and it is estimated to be 63-87% which is much higher when compared to non-diabetics. Diabetes has also been associated with increased prevalence of substantial fibrosis in NASH. Diabetes has been demonstrated to be an independent risk factor for progression of advanced fibrosis in longitudinal studies. Patients with cirrhosis secondary to NASH are at increased risk of developing hepatocellular carcinoma (HCC). Moreover, HCC can occur in NASH with cirrhosis.
PATHOGENIC MECHANISMS OF DEVELOPMENT OF NAFLD IN DIABETES
Factors causing NAFLD and its progression in diabetes is not well understood, but are likely to be an interplay of genetic factor, disordered lipid metabolism, disturbance of glucose metabolism related to insulin resistance, increased oxidative stress, dysregulation of gut microbiota and inflammation. The “two hit ’’ hypothesis was proposed early, but the new proposed model for pathogenesis of NASH is “multiple parallel hits ’’ hypothesis. The main concept is that different events occur in parallel, not consecutively. A.
Genetic Factor
Polymorphism of adiponutrin/patanin like phospholipase domain 3(PNPLA3) has been be an important susceptible gene. Mutation of other genes like microsomal triglyceride transfer protein (MTP), apolipoprotin-c3 (Apo c3), genes encoding TNL-α, IL-6 and angiotensin-II receptor.
B.
Insulin Resistance
It leads to increased lipase activity leading increased release of free fatty acids (FFA) from adipose tissue to hepatic and systemic circulation. Insulin resistance also leads to up regulation of sterol regulatory element binding protein (SERB-1) which reduces the disposal of free fatty acid by inhibiting their uptake and oxidation by mitochondria.
C.
Lipid Toxicity
Toxic lipid metabolites play an important role in causing inflammation. The thought to contribute to NAFLD progression are cholesterol, diacylglycerol (DAG) and glycosphingolipid.
D.
Oxidative Stress and Hepatic Inflamation
The oxidative stress generated from reactive oxygen sepsis augments the inflammatory process by NFK-β, c-JunN terminal kinase activation and toll like receptor signalling.
E.
GUT Microbiota Dysbiosis and Endotoxemia
Modification of composition of gut microbiota (increased Firmicutes and decreased Bacteroides) could increase the permeability of gut and translocation of bacterial endotoxins such as lipopolysaccharides which can induce inflammation.
Table 1: Prevalence of NAFLD in diabetic patients in India Author Name Study Number Year of Subjects
Prevalance
Gupte et al
2004
100
34% (M: 38.6%, F: 29.5%)
Mohan V et al
2009
541
32% (M: 35.1%, F: 29.1%)
Uchil D et al
2009
1003
22.6% (M: 29%, F: 13.9%)
Prasant M et al
2009
204
35.7% (M: 38.1%, F: 26.4%)
SPRINT Study group(Sanjay Kalra et al)
2013
522
56.5% (M: 54.3%,F: 60%)
312
Hepatic steatosis increases liver insulin resistance in liver through accumulation of fatty acid metabolites like DAG. The effect of hepatic steatosis in rodent model seems to be linked to decrease signalling of IRS-1 and IRS-2 causing increase hepatic glucose production and impaired glycogen synthesis. There is also evidence that insulin secretion may be defective in people with NAFLD through sustained elevation of FFA leading to pancreatic β-cell lipotoxicity.
LINK OF DIABETIC COMPLICATIONS WITH NAFLD
HEPATOLOGY
significant difference in other histological pictures or improvement in ALT.
EFFECT OF NAFLD ON DEVELOPMENT OF DIABTES
NAFLD has been shown to be associated with increased prevalence of both micro-vascular and macro-vascular complications in diabetics. Cardiovascular disease is the leading cause of death in patients with advanced NAFLD. Presence of NASH appears to have greater risk than simple steatosis. NASH has also been shown to be associated with increased mortality from all causes and liver related causes. Few studies have shown increase presence of microalbuminuria and chronic kidney disease in patients with NAFLD, though it needs to be confirmed from larger prospective studies. There are studies showing higher prevalence of diabetic retinopathy in patients with diabetes and NAFLD. Presence of NAFLD has also been linked to increase risk left ventricular diastolic dysfunction in diabetes, but needs conformation by further studies.
TREATMENT
Main goal of treatment is to improve liver fibrosis. Unfortunately no treatment to date has been proven to prevent fibrosis in NASH in any large scale randomised controlled trial (RCT).
C.
Pioglitazone
Several studies including PIVENS have demonstrated significantly decrease in liver enzymes, hepatic steatosis, and inflammation, but no significant regression in fibrosis.
D.
Liraglutide
LEAN trial, the first RCT of liraglutide in NASH (both diabetics and non-diabetics) has demonstrated definite resolution of NASH, especially improvement in steatosis and ballooning but, there was no significant change in NAFLD activity score (NAS). So it can be a promising therapeutic option in type2 diabetes mellitus with NASH.
E.
DPP-4 Inhibitor
Only some short term clinical trials have been published and no study has demonstrated any improvement in histological picture of NASH.
F.
SGLT-2 Inhinitor
Though the administration of canaglifozin has been found to reduce liver aminotransferases and body weight its effect on NASH needs further study.
4.
Other Drugs
A.
STATIN- There is no convincing data on improvement in histological picture in NASH, but may reduce macro-vascular events in patients with dyslipidemia.
1.
Life Style Intervention
B.
Sustained weight loss has been associated with marked improvement in liver enzymes and hepatic steatosis, but not fibrosis.
Omega-3FATTY Acids- It has been demonstrated to reduce liver steatosis, liver inflammation and decrease in transaminases .
C.
Vitamin E - In PIVENS study higher rate of improvement in NAS score was demonstrated with vitamin E 800IU/day. There was also significant improvement in hepatic steatosis, inflammation and ballooning, but no improvement in fibrosis. But safety in long term use is a matter of concern.
D.
Pentoxifylline- In recent meta-analysis it has been demonstrated to improve transaminases, NAS and hepatic lobular inflammation, but no significant improvement in steatosis and ballooning. Few studies involving small number of patients have also reported improvement in fibrosis.
E.
Angiotensin Receptor Blockers- In a small study of 54 patients with NASH, Telmisartan group had greater improvement in hepatic steatosis, necroinflammation and fibrosis.
F.
Ursodeoxycholicacid - The clinical benefit has not been convincingly proved.
G.
Ezetimibe- In two small clinical trials it has been demonstrated to reduce transamineses and hs-CRP
2.
Bariatric Surgery
Though it is one of the definite modality of treatment for weight loss, there is no RCT as a treatment for NASH.
3.
Effect of Antidiabetic Medication
A.
Insulin
There is little direct evidence that insulin will improve histological picture of NASH. HbA1C reduction by insulin is more strongly associated with improvement in liver fibrosis .Large scale RCT is necessary to confirm any direct beneficial effect.
B.
Metformin
Several recent meta-analyses have concluded that metformin is not effective for treatment of NASH. TONIC trial has demonstrated improvement only in hepatocyte ballooning, but there is no
and improve NAS on liver biopsy, but needs RCT to prove efficacy. H.
Obeticholic Acid (Farsenoid X-Receptor Agonist) In FLINT trial higher rate of resolution of NASH, NAS and improvement in fibrosis score has been demonstrated and appears to be a promising agent.
J.P.Arab, R.Candia, R.Zapata et al. Management of nonalcoholic fatty liver disease:an evidence based clinical practice review. World J Gastroenterol 2014;14:12182-12201
4.
Juan Du, Yan-Yan Ma et al. Effect of pentoxyfylline on non-alcoholic fatty liver disease: A meta-analysis. World J Gastroenterol 2014;20:569-577
5.
D.G.Bouzianas, S.D.Bouzian, A.I.Hatzitolios. Potential treatment of non-alcoholic liver disease with long chain omega-3 polyunsaturated fatty acid. Nutr Reviews 2013;71:753-771
6.
S,Murlidhar, R.R.Henry, A.J.Sanyal et al. Efficacy and safty of Farsenoid X receptor agonist Obeticholic acid in patients with typr 2 diabetes and non-alcoholic fatty liver disease. Gastroentererology 2013;145:574-582
7.
S.Zelber Sags, A.Kesslor, E.Brazowsky et al. A double blind randomised placebo controlled trial of Orlistat for the treatment of non-alcoholic fatty liver disease. Clin Gastroenterol and Hepatol 2006;4:639-644
8.
G.Musso, R.Gambino, M.Cassader et al. A meta-analysis of randomised trials for the treatment of non-alcoholic fatty liver disease. Hepatology 2010;52:79-104
9.
N. Chalasani, Z.Younossi, J.E.Lavine et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the study of Liver Disease, American College of Gastroenterology Association. Hepatology 2012; 55:2005-2023
CONCLUSION
There are limited number of studies on epidemiology and natural history of NAFLD in diabetes. The relationship between diabetes and NAFLD is complex and is not clear. Lifestyle interventions aimed at weight loss remains the corner stone of management. Among the anti-diabetic drugs pioglitazone and liraglutide appears to be potentially useful. Other drug like obeticholic acid and pentoxifylline appears promising, but larger RCT is required to prove their efficacy before a firm recommendation.
REFERENCES
1.
2.
K.H Williams, N.A . Shackel, M.D Gorrel et al. Diabetes and Nonalcoholic fatty liver disease:A pathogenic Duo. Endocrine Reviews 2013; 34:84-129 E.Boettcher, G.Csako, F.Pucino et al. Metaanalysis:pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharm and thep 2012; 35:66-75
313
CHAPTER 66
3.
Diabetic Hepatopathy
C H A P T E R
67
Rajesh Upadhyay
INTRODUCTION
There is a high prevalence of diabetes in India estimated at 67 million. Asians have a high susceptibility for type II diabetes mellitus (DM), develop diabetes at younger age and have a higher risk of diabetes complications. Common complications reported are nephropathy, retinopathy, neuropathy, coronary artery disease, peripheral vascular disease and increased risk of infections. The prevalence, morbidity and mortality from liver disease has been largely overlooked. Liver disease is an important cause of death in type 2 diabetes. Diabetes, by most estimates, is now the most common cause of liver disease. Cryptogenic cirrhosis, of which diabetes is, by far, the most common cause, has become the third leading indication for liver transplantation. A large study of patients with & without Type II DM followed up for 10 years showed that the incidence of non-alcoholic CLD and HCC was 2 fold greater in diabetic patients compared when compared with non-diabetic patients. . In the population-based Verona study, cirrhosis was the fourth leading cause of death and accounted for 4.4% of diabetes-related deaths. The standardized mortality ratio (SMR), for cirrhosis was 2.52 compared with 1.34 for cardiovascular disease (CVD).1 Thus the importance of liver disease in diabetics has been grossly under estimated. Virtually the entire spectrum of liver disease is seen in patients with diabetes. Diabetes causes increased risk of acute liver failure, chronic non-alcoholic fatty liver disease (NAFLD), cirrhosis, hepatocellular carcinoma (HCC) and mortality due to liver diseases. Insulin resistance is the key pathogenic mechanism leading to fat deposition in liver. Multiple other factors such as oxidative stress, mitochondrial dysfunction and circulating cytokines in diabetics contribute to disease progression. Diabetes is an independent risk factor for fibrosis which is key determinant of progressive liver disease. 20-25% of diabetic patients with steatosis progress to steatohepatitis (NASH), out of which about 20% further progress to
Table 1: Diabetic Hepatopathy Liver diseases caused by diabetes
Liver diseases aggravated by diabetes
Glycogenic hepatopathy
NAFLD / NASH
Diabetic hepatosclerosis
NASH related Liver cirrhosis Hepto cellular carcinoma
cirrhosis over 10-15 years. Associated features of metabolic syndrome such as obesity, dyslipidaemia also add to risk and progression of early liver disease to liver fibrosis and cirrhosis. Liver diseases related to diabetes (either caused or aggravated by) may be called diabetic hepatopathy. It comprises of a number of conditions as shown in Table1.
NAFLD IN DIABETES- THE PROBLEM AND EPIDEMIOLOGY
Diabetes leads to a significantly increased prevalence and severity of NAFLD. NAFLD encompasses a broad spectrum of disease severity, ranging from isolated steatosis (NAFL) to a more severe form with variable degrees of inflammation, ballooning, liver cell necrosis and fibrosis defined as non-alcoholic steatohepatitis (NASH). Among the various histological features of NASH, fibrosis strongly correlates with end stage liver disease and higher mortality.2,3 Patients with diabetes have more fatty liver as compared to age, gender and BMI matched controls.4 Even in non-diabetic individuals it has been shown that increasing levels of HbA1c and insulin resistance is associated with increased risk of NAFLD.5 Impaired glucose tolerance and abnormal fasting glucose is present in 25% patients with simple steatosis versus 55% of those with NASH.6 In a large study of serial liver biopsies it was seen that patients with NASH, rather than NAFL, were more likely to be diabetic (56% vs 21%) and patients with advanced fibrosis or cirrhosis were more likely to be diabetic than those without advanced fibrosis (89% vs 47%).7 These evidences collectively show that diabetes confers the highest risk for NAFLD and specially NASH. The prevalence of NAFLD in Indian population ranges from 11-32% and about 4-5% have NASH. In comparison, the prevalence of NAFLD in diabetics is 60-65% and 2025% of these patients have NASH.8 When diabetes is associated with obesity the prevalence of NAFLD is >90% and that of NASH is 30-40%. In a recent study of obese Type II diabetic patients with normal liver enzymes who underwent liver biopsy, it was shown that more than 50% had NASH.9 In a large study the standardized mortality ratio of cirrhosis was higher in diabetics (2.52).10 The presence of diabetes is an independent risk factor for fibrosis in patient with NAFLD.11 There is also a higher risk and poorer prognosis of HCC in cirrhosis (esp. in association with hepatitis C).12 There is also evidence that diabetes impairs sustained viral response to antiviral therapy in chronic
315
Table 2: Non invasive scoring systems for severity of fibrosis Scoring System
Parameters / Calculation
Cut off for severe fibrosis / cirrhosis
APRI
1. AST Level
>1
2. Platelet count APRI=[{AST(IU/L) / AST _ULN (IU/L)} X100] / Platelet Count (109/L) FIB4
>3.25
1. Age 2. AST & ALT Levels
FIB4= age (year) x AST (IU/L) / Platelet Count < 1.45 has negative predictive value (109/L x [ALT (IU/L) ½] ELF (enhanced liver fibrosis) 1. Tissue inhibitor of metalloproteinases 1 (TIMP-1)
>10.51
2. Amino-terminal propeptide of type III procollagen (PIIINP) 3. Hyaluronic acid (HA) hepatitis C. Diabetes increases complications of cirrhosis such as rate of liver failure, higher mortality in refractory ascites & increased episodes of hepatic encephalopathy. Liver disease in diabetics is a major public health problem. It can be estimated that out of the 67 million diabetics in India, the prevalence would be NAFL in 40 million, NASH in >7 million and cirrhosis in >1.5 million. There is also an annual risk of about 2-3% of the cirrhotic patients developing hepatocellular carcinoma. NAFL is a relatively benign condition in general population with a risk of cirrhosis in <2% of population. On the other hand, NASH has a 10 fold higher risk of liver related death and doubling risk of cardio vascular disease. Identification and aggressive treatment of NASH in diabetics is important to prevent disease progression.
are higher only in the extremes of fibrosis, i.e., either no fibrosis or severe fibrosis. The Enhanced Liver Fibrosis (ELF) score is an ECM (Extra cellular matrix) marker set consisting of TIMP1, PIIINP & Hyaluronic acid. ELF score of 10.51 or above correlates with severe fibrosis. Newer techniques such as transient elestrography (Fibroscan) is more accurate and shows better correlation with Metavir scoring than APRI & FIB4 and is preferable where equipment and cost is not an issue. Liver biopsy followed by the use of Metavir scoring system remain the gold standard to assess degree of fibrosis. However, liver biopsies in our setting are infrequent due to high cost, invasiveness, associated morbidity and the need for expert interpretation.
TREATMENT OF NAFLD IN DIABETES
In a study, the prevalence of NAFLD in diabetics in India Diet and life style modification was 56.5% and the mean AST & ALT level was 54 U/L and 56 U/L respectively. It implies that patients with even a mild elevation of AST/ ALT are a risk factor for NAFLD/ NASH.
NASH DIAGNOSIS IN DIABETICS
The diagnosis of NASH in diabetics is no different than in general population and is based on non-invasive markers, liver fibroscan or liver biopsy. Some of the associated risk factors for NASH are: (1) Age > 45, (2) Obesity (BMI > 25 Kg/meter), (3) Low albumin, (4) Low platelet count & (5) High AST / ALT ratio. A number of non-invasive scoring systems have been devised for assessment of liver fibrosis. (Table 2). Simple blood tests such as AST, ALT and platelet counts are inexpensive and easily available. These levels can be used to calculate AST, platelet ratio index (APRI) and FIB4 scores which correlate with severity of fibrosis and can be used in resource limited settings such as our population. The sensitivity and specificity of these tests
Treatment of NAFLD / NASH is life style modification with diet and exercise, control of associated metabolic factors, optimization of diabetic control and use of specific drugs for NASH. Till date, however, there are no approved drugs for treatment of NASH. The most fundamental intervention is life style modification with diet and exercise which can lead to significant improvement in transaminases and histology. The recommended exercise is 40-45 minutes of brisk walking daily for at least 5 days of a week. A low caloric diet is advised in obese patients aiming for a gradual weight loss of 0.5-1kg/week. The goal should be for a 10% weight loss initially. Weight loss of >1.6kg/week can worsen histology. Weight reduction >7% sustained over 48wks is associated with histological improvement. Weight loss of 5-10% significantly reduces intrahepatic triglycerides by about 40%.13 However, less than 50% of Indian patients achieve the necessary weight loss due to poor compliance to diet and exercise.
CHAPTER 67
3. Platelet count
316
Table 3: Therapeutic agents for T2DM and their effect NAFLD/NASH in clinical trials Treatment
Mechanism of action
AST/ALT
Liver fat by imaging
Liver histology
HEPATOLOGY
Oral Metformin
Insulin-sensitizer
,
Unchanged
Pioglitazone
Insulin-sensitizer PPARγ agonist
Improved
Sitagliptin
DPP-4 inhibitor
n/a
n/a
Vildagliptin
DPP-4 inhibitor
n/a
Canagliflozin
Inhibits renal glucose reabsortion
n/a
n/a
Dapagliflozin
Inhibits renal glucose reabsortion
n/a
n/a
Exenatide
GLP-1 receptor agonist
n/a
Liraglutide
GLP-1 receptor agonist
Improved
n/a
n/a
Injectable
Insulin
Treatment of Associated Metabolic Factors
The association of obesity, dyslipidemia and hypertension is common in diabetes. Treatment of the associated metabolic factors is important to reduce the prevalence and severity of NAFLD. Obesity is treated with life style measures and orlistat has been effectively used for weight reduction. Bariatric surgery is an effective treatment for obesity and has been shown to markedly improve diabetes. It also improves histological features in NAFLD and smaller studies have shown regression in liver fibrosis, although there has been mild increase in fibrosis seen during long-term follow up. The drug of choice for dyslipidemia are statins which reduce lipid levels, cardiovascular risk and additionally improve AST / ALT levels, although its effect on liver histology remains controversial. The drug of choice for hypertension are angiotensin receptor blockers such as losartan & telmisartan which have also got liver protective effect and some small studies have shown a reduction in HCC risk.
Treatment of Diabetes in patients with liver disease
Optimizing control of blood sugar is important to prevent liver disease progression. While there are theoretical concerns about altered drug metabolism and hepatotoxicity, only patients with evidence of liver failure such as ascites, coagulopathy, or encephalopathy have altered drug metabolism Since most oral hypoglycaemic agents are metabolized in liver, there is a higher risk of hypoglycaemia and requires close blood sugar monitoring. The choice of oral hypoglycaemic drug should ideally be based on its ability to control blood sugar along with the ability to improve LFT, reduce hepatic fat and improve liver histology. Trials of OHA are scanty in patients with CLD. An overview of drugs and their ability to improve hepatic parameters is shown in Table 3. Insulin sensitizers such as biguanides and thiazolidinediones appear to be the most attractive option.
Metformin
This is the first line agent in management of Type II DM. In a large study despite improvement in HbA1c and weight there was no significance histological
improvement in liver.14 The use of metformin in diabetics with severe liver disease remains controversial. It also reduces the risk of HCC in patients with cirrhosis.15 In a recent retrospective analysis, patients with diabetes and cirrhosis using metformin had a longer median survival rates than those who discontinued metformin.1 It is now considered a useful drug in patients with compensated cirrhosis but is relatively contraindicated in patients with decompensated cirrhosis and individuals with ongoing alcohol abuse because of risk of lactic acidosis.
Thiazolidinediones (TZDS)
In the PIVENS study of non-diabetics with NASH, pioglitazone showed improvement in LFT and liver histology, although the effect on fibrosis was not significant.17 Pioglitazone showed a significant improvement in hepatic steatosis and necroinflammation in a 6 months study of diabetic patients (18). A recent study by Cusi et al19 showed a significant histological benefit in steatosis, NASH and fibrosis showing that pioglitazone may modify the natural history of liver disease in diabetes. Adverse effects of pioglitazone have always been a concern but congestive cardiac failure is rare and is related to diastolic dysfunction. Mild bone loss occurs mainly in females. An earlier concern about bladder cancer risk was recently dispelled by a prospective study showing lack of association between pioglitazone and bladder cancer.20
Sulphonylureas in Diabetic Patients with Liver Disease
Sulfonylureas are generally safe in patients with liver disease but may not overcome the insulin resistance and defects in insulin secretion seen in patients with coexistent alcoholic liver disease and pancreatic damage this group of drug is largely metabolized in liver. There has also been a concern about increased risk of HCC and overall mortality in diabetics.21 Sulfonylureas with a short half-life such as glipizide, glyburide or glimipride can be used in these patients. Gliclazide, is extensively metabolized in the liver and is relatively contraindicated in severe hepatic insufficiency.
α-Glucosidase inhibitors
The α-glucosidase inhibitors may be particularly useful in patients with liver disease because they act directly on the gastrointestinal tract to decrease carbohydrate digestion and glucose absorption thereby decreasing postprandial hyperglycemia
DPP – IV Inhibitors in NAFLD
These are widely prescribed as adjunctive oral therapy in Type II diabetic mellitus. They improve hepatic steatosis, liver inflammation in animal’s models of diet induced obesity.22 DPP-IV inhibition is associated with improved sugar control and reduced AST / ALT levels.23 Reduction of hepatic triglyceride has also been demonstrated. Overall DPP-IV inhibitors have modest effect in current studies and larger studies are required to establish their role in diabetes with NASH.
GLP-1 Agonists
A significant decrease in AST / ALT levels and hepatic steatosis was observed with liraglutide in a dose of 1.8mg in a meta-analysis of 6 RCTs.24 Another study showed a 42% relative reduction of intra hepatic triglyceride with the use of these agents. In the most comprehensive study to date, the LEAN trial showed benefit when 52 patients with biopsy-proven NASH were treated for 48 weeks with liraglutide at a dose of 1.8 mg per day.25 Only onethird of the population had T2DM, but overall patients were obese and had evidence of insulin resistance. After treatment, 39 % of liraglutide treated patients had resolution of NASH compared to only 9 % in the placebo arm. While fibrosis did not improve with liraglutide, more patients in the placebo arm experienced worsening of fibrosis (p = 0.04). Patients treated with liraglutide had a significant reduction of body weight, fasting plasma glucose and A1c levels. Overall treatment of NAFLD in diabetics with GLP-1 agonists appears attractive but larger long term studies are required.
SGLT2 Inhibitors
Studies have shown decrease in hepatic triglyceride and other inflammatory biomarkers when treated with these agents.26 The administration of canagliflozin (100 or 300 mg per day) for 52 weeks is associated with a reduction in plasma AST / ALT levels, especially at the higher dose, but their impact on liver histology is unknown.27
317
DIABETES & CIRRHOSIS
The drug treatment of diabetes in cirrhosis has already been discussed. Patients with compensated cirrhosis need special attention at nutrition and life style management. Optimal control of diabetes improves outcome. Patient with decompensated cirrhosis need management of complications. Outcome can be improved with nutrition, life style management, diabetes control, reduction of portal pressure in patients with large varices, and prevention of infection especially in those with ascites (A.F. protein < 1.5, S Creat > 1.2). Rational drug use and avoidance of hepatotoxic agents is important. Patients with cirrhosis should be vaccinated for hepatitis A & B.
GLYCOGENIC HEPATOPATHY
This is a relatively rare and under recognized entity. It occurs in poorly controlled type I diabetics usually in the age groups 8-25 years. Patients present with abdominal pain, hepatomegaly and significantly high transaminase levels (50-1600IU/L). Definitive diagnosis can be made on biopsy which shows markedly increased glycogen storage in hepatocyte cytoplasm and nuclei. There is usually no fat, inflammation or fibrosis in the liver. Treatment is to obtain strict blood sugar control which improves the condition within one month.
DIABETIC HEPATOSCLEROSIS
This is a micro vascular disease leading to deposition of collagen and basement membrane in peri-sinusoidal space and leads to high alkaline phosphatase level. The collagenisation correlates with diabetic macroangiopathy. The prevalence and clinical significance of this condition and treatment remains unclear. It is however, accepted that this condition represents a hepatic microvascular complication in diabetics.
CONCLUSION
Diabetic hepatopathy commonly leads to high prevalence of liver disease, high morbidity, and mortality. Specific liver diseases caused by diabetes are glycogenic hepatopathy and diabetic hepatosclerosis. Diabetes increases the prevalence of NAFLD and increases its severity with development of cirrhosis leading to high morbidity and mortality. It is also more commonly associated with hepatocellular carcinoma, especially in patients with Hepatitis C. Early diagnosis and aggressive management may prevent disease progression. Lifestyle modification with diet and exercise, treatment of associated metabolic factors, and optimal diabetes control, especially using oral hypoglycemic agents which also have beneficial effects on liver function and histology, is advantageous. Bariatric surgery may be considered in obese diabetics since it leads to weight loss and simultaneous improvement in
CHAPTER 67
A randomized double-blind trial evaluated the use of acarbose for the control of postprandial hyperglycemia in patients with compensated liver cirrhosis and type 2 diabetes. .Glycemic control improved significantly in both the fasting and postprandial state. In a recent placebocontrolled cross-over trial in patients with hepatic encephalopathy, acarbose significantly decreased fasting and postprandial glucose as well as A1C .There was also a reduction in blood ammonia levels, which paralleled an increase in bowel movement frequency. . While the labeling of acarbose has a warning for patients with liver disease, it appears to be safe and effective in patients with hepatic encephalopathy and type 2 diabetes.
Considering that these pharmacologic agents improve hyperglycemia, induce weight loss, and may improve insulin sensitivity, they are actively being explored for the treatment of NAFLD/NASH in patients with T2DM.
318
diabetes. Patients with end stage liver disease should be considered for liver transplantation. Screening for liver disease in diabetics is recommended in routine practice.
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9.
Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab 2015; 100:2231–8.
10. De Narci R, Loctelli F, Zoppini G et al. Cause – specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 1999; 22-756-61. 11. Hossain N, Afendy A, Stepanova M et al. independent predictors of fibrosis in patients with non-alcoholic fatty liver disease. Clin Gastroenteral Hepatol 2009; 7:1224-9. 12. Wang C, Wang X, Gong G et Al. increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer 2012; 130:1639-48. 13. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012; 142:711–25.
17. Sanyal, A.J., Chalasani, N., Kowdley, K.V., et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362:1675–1685DOI: 18. Belfort R, Harrison SA, Brown K, Darland C, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355:2297– 307. 19. Cusi K, Orsak B, Lomonaco R, Bril F, et al. Extended treatment with pioglitazone improves liver histology in patients with prediabetes or type 2 diabetes mellitus and NASH. Cusi et al, Ann Intern Med 2016. 20. Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 2015; 314:265–77. 21. Bowker, S.L., Majumdar, S.R., Veugelers, P., and Johnson, J.A. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006; 29:254–258. 22. Kern, M., Klöting, N., Niessen, H.G., Thomas, L., Stiller, D., Mark, M. et al. Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. PLoS One 2012; 7:e38744. 23. Iwasaki, T., Yoneda, M., Inamori, M., Shirakawa, J., et al. Sitagliptin as a novel treatment agent for non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology 2011; 58:2103–2105. 24. Armstrong MJ, Houlihan DD, Rowe IA, Clausen WH, et at. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther 2013; 37:234–42. 25. Armstrong MJ, Gaunt P, Aithal GP, Barton D, et al. Liraglutide safety and efficacy in patients with nonalcoholic steatohepatitis (LEAN): a multicentre, doubleblind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387:679–90. 26. Hayashizaki-Someya Y, Kurosaki E, Takasu T, et al. Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by cholinedeficient l-amino acid-defined diet in rats. Eur J Pharmacol 2015; 754:19–24. 27. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 2013; 56:2582–92.
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NAFLD – Where Do We Stand Today KK Lohani
INTRODUCTION
NAFLD is defined as the accumulation of fat in the liver (affecting more than 5% of hepatocytes) in the absence of significant intake of alcohol The spectrum of nonalcoholic fatty liver disese (NAFLD) ranges from simple steatosis (SS) that is relatively benign to NASH (nonalcoholic steatohepatitis) that has the potential to progress to cirrhosis with its subsequent complications including hepatocellular carcinoma. Ludwig in 1980 first time described “alcohol like liver disease that develops in people who are not heavy drinkers” and patients described in this study were females, obese and diabetic. In next two decades there was explosion of information on NAFLD in North America. In the first two decades importance of NAFLD in east was not so well recognized. In 2003 Prof FARRELL emphasized the importance of NAFLD in Asia – Pacific region in his Ocuda Lecture. In 2007 Asia–Pacific working party was formulated for guidelines on NAFLD and the working party estimated the prevalence of NAFLD in adult population from 5% to 30. For all practical purposes obesity, type 2 diabetes, dyslipidemia and metabolic syndrome are universal risk factors for NAFLD throughout the world. Risk factors in non-obese population in Asia are visceral fat deposition, recent increase in weight, high
cholesterol diet and genetic background. Central obesity poses a particular risk factor for NAFLD.
PATHOGENESIS (FIGURE 1)
The pathogenesis of NAFLD is closely linked to insulin resistance (IR) and to the development of metabolic syndrome. Insulin resistance contributes to increased delivery of fatty acids to liver because of increased lipolysis from expanded and inflamed adipose tissue. An excess of de novo fat synthesis in the liver, excess of dietary intake of fat, reduced –oxidation of fatty acids and decreased export of very low-density lipoprotein (VLDL) also contribute to the development of hepatic steatosis. Insulin resistance as studied by homeostasis model assessment for insulin resistance (HOMA-IR) has been shown in 83-98% of Indian patients with NAFLD . The development of NASH is believed to be due to a two-hit hypothesis of NAFLD, wherein hepatic steatosis is the “first hit”, followed by a second hit which could be oxidative stress and cytokines producing inflammation/ fibrosis and progression to NASH. Recent concept of “multiple hits” with lipotoxicity, inadequate hepatocyte regeneration, apoptosis and other multiple events acting in parallel is evolving.
CLINICAL FEATURES
NAFLD is usually asymptomatic, and is an incidental
Fig. 1: Pathogenesis of NAFLD
320
Lifestyle modification
SGPT>40 IU/mL History of DM, dyslipidemia, obesity
Treat metabolic syndrome components Exclude alcohol use, HBV, HCV
Insulin resistance
Dyslipidemia
HEPATOLOGY
statin (safe, CVD risk reduction)
Image liver with US (MRI or CT) Fatty liver
metformin pioglitazone
Hypertension
ARB (antifibrotic effects)
Liver-specific pharmacotherapy Pentoxifylline, vitamin E, UDCA (?)
Stiffness
Fibroscan
Fig. 3: Treatment of NAFLD Yes Liver biopsy
No Fat ++
NASH
Fatty liver
Fig. 2: Diagnosis of NAFLD diagnosis on ultrasonography or asymptomatic elevation of transaminases in the presence of metabolic features. Most patients being investigated for dyspepsia or abdominal discomfort find themselves getting diagnosed to have fatty liver on ultrasound. Ultrasound of abdomen performed for investigation of asymptomatic elevation of liver enzymes also may reveal fatty liver and point towards the existence of NASH. A palpable liver may be found on physical examination apart from overweight/obesity and elevated waist circumference (central obesity). Signs of hepatocellular failure may be discernible if cirrhosis ensues with its attendant complications. Extrahepatic associations of NAFLD are as follows:- CVD mortality, malignancies, PCOD, obstructive sleep apnea, metabolic syndrome, diabetes and hypothyroidism.
NATURAL HISTORY
NAFLD is histologically categorized into simple steatosis and steatohepatitis with dichotomous natural history. Relatively benign prognosis for steatosis while progressive liver disease leading to cirrhosis and HCC has been predicted for steatohepatitis. In patients with simple steatosis progression to cirrhosis may occur in 4-5% over a period of 8-15 years while NASH can progress to cirrhosis in over 25% patients over similar follow-up period; at initial biopsy 5-20% patients with NAFLD may have cirrhosis. Risk factors showing rapid progression in NAFLD are T2DM, obesity, older age and metabolic syndrome. NAFLD is important cause of cryptogenic cirrhosis and may not be appreciated in histology as with disease progression steatosis may disappear. NAFLD and cryptogenic cirrhosis have been shown to have increased risk of HCC. Recently, 2 studies have shown increased cv risk in patients with NAFLD.
DIAGNOSIS (FIGURE 2)
Elevated transaminases may or may not be seen in NAFLD. It has poor correlation with histological severity and, therefore, it is not appropriate to make the diagnosis of NASH. Ultrasound, CT scan, MRI have good sensitivity and specificity around 85% in detecting steatosis but can not detect inflammation and fibrosis which are characteristic of NASH. Fibroscan (transient elastography) has been evaluated for detecting liver fibrosis in NAFLD and has a good correlation with liver histology. It is therefore being increasingly used as a marker of fibrosis and NASH. NAFLD fibrosis score (a computer calculated score based on age, BMI, impaired fasting glucose or diabetes, AST-ALT ratio, albumin and platelets), is helpful in predicting NASH and fibrosis in patients with NAFLD. Other causes of hepatic steatosis such as use of certain drugs, chronic viral infection(HBV / HCV) surgical bypass procedures, total parenteral nutrition, coeliac disease, haemochromatosis or Wilson’s disease need to be excluded befere making diagnosis of NAFLD. As liver fat tends to diminish with increasing hepatic fibrosis, liver histology is not very helpful in making the diagnosis of NASH related cirrhosis or HCC. It is usually diagnosed on the presence of metabolic risk factors and exclusion of other causes of cirrhosis and HCC.
TREATMENT (FIGURE 3)
NAFLD patients who loose 10% of baseline body weight by a combination of diet and an intense exercise program achieved resolution of NASH and regression of fibrosis in 90% and 45% respectively.Adopting a Mediterranian diet has also been shown to reduce steatosis and insulin sensitivity. In addition to lifestyle interventions, there have been a number of drugs that have been tested in NAFLD patients with variable success. Please refer to the flow chart below. Emerging drug therapies include GLP 1 agonist and DPP 4 inhibitors, anti-fibrotic like simtuzumab and Nuclear Receptor Ligands like OCA. A small open label case series found that GLP 1 agonist and DPP 4 inhibitors improved grade of ballooning and fibrosis score in diabetic patients with NASH. A large phase IIb trial of
simtuzumab versus placebo in adults with compensated NASH related Cirrhosis is currently underway. Bariatric surgery in obese patients with BMI >30 is associated with significant improvement of NASH. But then, it should not be considered a primary treatment of NAFLD. Liver transplantation is an option for management of NASH related cirrhosis and HCC. Fatty liver is almost universal after 5 years of liver transplantation but recurrence of NASH, advanced fibrosis or cirrhosis is infrequent.
CONCLUSION
REFERENCES
1.
Farrell GC, et al. Guidelines for the assessment and management of NAFLD in the Asia- Pacific region: executive summary. J Gastroenterol Hepatolol 2007; 22:775-7.
Ratziu v et al. A position statement on NAFLD/NASH based on EASL 2009 special conference. J Hepatol 2010; 53:372-84
3.
Chalasani N et al. The diagnosis and management of NAFLD: practice guideline by American Ass for the study of liver disease, Hepatology 2012; 55:2005-23.
4.
Review Team, NAFLD/NASH, Global guidelines, World Gastroenterology organization, J Clin Gastroenterol 2014; 48:467-73
5.
Duseja A, Non Alcoholic Fatty Liver Disease, API Text book of Medicine, 10th edn. 2015, Editor YP Munjal, page 11901203.
6.
Taitani AA et al, Bariatric surgery improves histological features of NAFLD, j Gastrointest Surg. 2015, 19. 429-36, discussion 436-437.
7.
Khan FZ et al. Advances in NASH related hepatocellular carcinoma. World J Hepatology 2015; 7:2156-61.
8.
Singh T et al. NASH â&#x20AC;&#x201C; Newer Trends in Management: A US Perspective, Medicine Update vol 26, 2016, API, Chapter 236, 1205-1207.
9.
Upadhyay R et al, NASH â&#x20AC;&#x201C; Newer Trends in Management: An Indian Perspective, API Medicine Update 2016; 26:12081212.
10. Amarapurkar D., NASH for clinicians, API Medicine Update 2016; 26:1213-1219.
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CHAPTER 68
NAFLD is a major public health problem especially in patients of metabolic syndrome. Incidence is progressively rising and NAFLD/NASH will become leading cause of liver disease, cirrhosis and hepatocellular carcinoma in our country as well. The ideal management strategy has not yet been defined but lifestyle modification holds the key in combating the epidemic of this disease. Metformin, Statins, Vitamin-E and Pentoxyfyline are preferred pharmacotherapy in different guidelines for management of NAFLD. Bariatric surgery can be considered in refractory patients. Recently, global guidelines have been published by World Gastroenterology Association. And that is where we stand today.
2.
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69
NASH: Do we Really have an Effective Treatment?
INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) constitutes the spectrum of liver disease encompassing varying degrees of steatosis, inflammation, hepatocellular injury and fibrosis. NAFLD is considered to be the hepatic component of metabolic syndrome (MS) in view of the close association between these two conditions. The histological spectrum of NAFLD ranges from nonalcoholic fatty liver (NAFL) which is characterized by presence of steatosis accompanied by mild or no inflammation to non-alcoholic steatohepatitis (NASH) which is accompanied by inflammation and hepatocyte ballooning with or without associated fibrosis. NAFLD has been defined as the accumulation of fat in the liver in the absence of recent or ongoing intake of significant amount of alcohol. The significant amount of alcohol has been defined variably but a cut-off of intake up to 20 g/ day seems reasonable both for males and females. The natural history of NASH tends to parallel the more aggressive histological picture, with prospective cohort studies demonstrating a higher rate of morbidity and mortality compared to NAFL, particularly when fibrosis is present. Patients with NAFLD are not only at an increased risk for liver related mortality but are also predisposed to an increased incidence of diabetes mellitus (DM) and cardiovascular risk on follow-up. Insulin resistance (IR) is a key component involved in the pathogenesis of NAFLD and various studies have depicted a high prevalence of IR (7-55%) among Asian-Indians residing in India. It has also been demonstrated that Indians have a higher IR and hepatic triglyceride content when compared to other races suggesting that Indians are highly prone to develop NAFLD. Recent evidence indicates that hepatic fat content of Asian- Indians is almost twice in amount for similar body mass index (BMI) when compared to white Caucasians. In the general population of India, the prevalence of NAFLD is documented to be around 9-35% and this higher prevalence of NAFLD and the inter-ethnic difference noted is believed to be linked not only to factors relating to lifestyle but also to a strong underlying genetic predisposition. Among the various reasons postulated, polymorphisms of apolipoprotein C3 (APOC3) gene may be a phenomenon which is peculiar to Asian- Indians. It has been noted that Asian-Indians are less obese than their Western counterparts and this could be allowing a higher phenotypic expression of the APOC3 genetic polymorphism. Data has also suggested that iron overload and HFE gene mutations do not play a significant
Sandeep Satsangi, Ajay Duseja
role in the pathogenesis of NAFLD in patients in India which is in sharp contrast to the patients in the West. Even though NAFLD is growing to be an important cause of cryptogenic cirrhosis and hepatocellular carcinoma (HCC) in patients in India, it is noted that the histologic severity is often less at presentation when compared to data from the West. As mentioned earlier, NAFLD is a broad term encompassing simple steatosis (NAFL), NASH, NASH-related cirrhosis, and NASH-related HCC. The differentiation between NAFL and NASH is of utmost importance in determining the prognosis, risk of progression, need for pharmacological treatment and for assessing the liver-related and cardiovascular morbidity and mortality, which occurs more commonly in patients with NASH than in those with NAFL. NASH is usually a histologic diagnosis except in scenarios where hepatic fibrosis is diagnosed with the help of non-invasive modalities like Transient Elastography (Fibroscan). Suggested algorithm for the workup of patients with NAFLD has been depicted in Figure 1.
TREATMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE
Treatment of NAFLD/NASH is one of the most challenging fields in Hepatology today with lot of research going on in finding the new drugs in the treatment of such patients. The vital aspect underlying the therapeutic modalities in patients with NAFLD have centred around various risk factors associated with the disease. The various strategies involved in the management of patients with NAFLD include lifestyle modifications such as weight loss and exercise, treatment of risk factors such as control of DM, control of hyperlipidemia, hypertension and using various pharmacologic interventions to target the basic pathogenetic mechanisms involved with the progression of the disease. We describe below the available effective treatment modalities for patients with NAFLD/NASH and also the drugs which are in pipeline and would be available for clinical use in near future.
LIFESTYLE MODIFICATIONS & WEIGHT REDUCTION
Patients with NAFLD irrespective of their current body weight should be advised active lifestyle modifications in the form of regular exercise. Those patients who are overweight and obese should be encouraged to lose weight. Hepatic triglyceride content is shown to decrease with a 3%-5% weight loss; however randomized controlled studies have demonstrated that necroinflammation
Fig.1 - Diagnostic workup in patients with non-alcoholic fatty liver disease (NAFLD)
323
Patient with Fatty liver
Associated Metabolic syndrome
Rule out secondary causes of Fatty liver
Likely to be NAFLD
e.g.) Viral hepatitis, drugs etc.
CHAPTER 69
Aim to assess severity
-Age > 45 years -Female sex -Associated metabolic syndrome -High cytokeratin 18 Non-invasive modalities show evidence of high fibrosis
AST/ALT ratio >1 High AST/platelet ratio index (APRI) High NAFLD fibrosis score High liver stiffness measureemnt (LSM) by transient elastography
Consider Liver biopsy to rule out NASH
Fig.1: Diagnostic workup in patients with non-alcoholic fatty liver disease (NAFLD) decreases in the subgroup which achieved a weight loss of about 7%-9%. In a recent study enrolling 293 patients with NASH, it was shown that a weight reduction of >10% resulted in disappearance of steatosis in 90% and regression of fibrosis in 45% of patients. The exercise regimen should consist of brisk walking, jogging, or rhythmic aerobic exercises for a minimum of 45 min, 5 days per week, to achieve a target heart rate of 60–70% of the maximal heart rate. Considering the dietary aspects in patients with NAFLD, it is imperative to mention that isolated fat restriction in patients with NAFLD is a myth and energy restriction forms the major cornerstone in decreasing the hepatic steatosis. Recently in a randomized crossover trial, a Mediterranean diet based on olive oil, nuts, fruits, vegetables, fish, legumes, dairy products, and wine was compared with a low-fat/high-carbohydrate diet for 6 weeks and it was noted that a significant reduction in hepatic steatosis was observed in patients consuming a Mediterranean diet. There is paucity of data from India; however studies from the West have shown bariatric surgery to improve the histological components of NASH including fibrosis which improved in about 30% of patients. In severely obese patients (those with a BMI ≥ 40 or 35–40 with co-morbidities), bariatric surgery induces sustained
weight loss as well as result in remission of diabetes and reduce overall long-term mortality. After a bariatric procedure, the extent of weight loss achieved appears to be associated with the reduction in liver injury and in general the gastric bypass procedure seems more effective than gastric banding as this procedure achieves a greater loss of weight. Although bariatric surgery resolves NASH in patients in whom lifestyle therapy has failed, perioperative risks limit its application. More patients may be benefitted with this modality, if BMI cut-offs are reduced in Indian patients with NAFLD.
INSULIN SENSITIZATION
As mentioned earlier, IR plays an important role in the pathogenesis of NAFLD and development of NASH. By increasing the peripheral lipolysis, IR results in increased delivery of free fatty acids to the liver, leading to excess fat and increased beta-oxidation, which worsens the oxidative stress. Few studies had suggested the role of metformin in reducing the IR and improving the aminotransferases and histological features of NASH, however a recent meta-analysis concluded metformin to be not effective in patients with NASH. Thus, The 2012 American Association for the Study of Liver Disease (AASLD) guidelines do not recommend the use of metformin in adults with NASH.
HEPATOLOGY
324
Peroxisome proliferator-activated receptors (PPAR γ) are receptors present in the nucleus which play a vital role in glucose and lipid homeostasis. The landmark study, PIVENS trial enrolled nondiabetic patients with NASH and compared pioglitazone (PPAR γ agonist) to placebo, as well as vitamin E to placebo. It was demonstrated that patients who were given pioglitazone had significant reductions in steatosis, inflammation, hepatocyte ballooning, insulin resistance, and levels of liver enzymes. However, there exists a safety concern with the use of pioglitazone, as it has shown to cause weight gain and induce congestive cardiac failure. Because of the design of the clinical trials which evaluated use of pioglitazone in NASH, most of the guidelines suggest use of this drug in non-diabetic patients with histological NASH only. Elafibranor is the latest drug in this class and has an agonistic activity on both PPAR α and PPAR δ receptors. In the latest GOLDEN-505 trial, it was shown that elafibranor given at a dose of 120mg/day for 1 year resolved NASH without worsening fibrosis in a significantly higher number of patients when compared to those receiving placebo.
THE GLUCAGON LIKE PEPTIDE 1 (GLP1) PATHWAY
The GLP1 pathway decreases liver fatty acid accumulation through the activation of numerous genes such as PPAR α/γ which will enhance hepatic fatty oxidation, lipid export, and insulin sensitivity. In a recent randomized controlled study (LEAN study), Liraglutide (GLP1 receptor agonist) was assessed in 52 patients with NASH and DM. The investigators observed resolution of NASH in a significantly higher number of patients given liraglutide (39%) when compared to placebo (9%). This drug was also shown to have reduced the biomarkers of fibrosis, however larger studies need to be done to evaluate the ability of this drug to reduce fibrosis.
FARNESOID X RECEPTOR (FXR) PATHWAY
Obeticholic acid is an active ligand of the FXR receptor, which is a nuclear receptor actively involved in glucose, lipid and energy homeostasis. This receptor subfamily also plays a pivotal role in anti-inflammatory and antifibrosis pathways. In a recent landmark study, FLINT trial, it was shown that 25 mg obeticholic acid was more effective than placebo in improving liver histology in patients with NASH. In fact, fibrosis was also significantly reduced in patients who received obeticholic acid,
compared to patients given placebo. Pruritis was a major side effect of this drug, reported by 20% of patients, and a major safety concern which arose was the influence of this drug in altering the lipid profile by increasing the LDL– cholesterol and lowering the levels of HDL–cholesterol.
REDUCING OXIDATIVE STRESS
Oxidative stress is known to result in chronic tissue injury, leading to increased cell death and fibrogenesis. Vitamin E is considered to be the first line pharmacotherapy for non-diabetic patients with NASH. In the previously mentioned PIVENS trial, the authors demonstrated that a daily dose of 800 mg of vitamin E given for 96 weeks reduced steatosis, lobular inflammation and hepatocellular ballooning when compared to placebo. As for pioglitazone, most of the guidelines suggest use of vitamin E in non-diabetic patients with histological NASH only. However, important safety concerns were raised with the long term usage of vitamin E, as few studies reported increased incidence of hemorrhagic stroke and prostate cancer.
REDUCING FIBROSIS
Preventing the progression of fibrosis and achieving reversal of fibrosis has become a focus of intense research in the field of hepatology. Simtuzumab is an antibody against the enzyme lysyl oxidase-like-2 (LOXL2), which is overexpressed during development of liver fibrosis. This drug is currently being evaluated in a phase 2 study enrolling patients with NASH having stage 3 and 4 fibrosis.
NOVEL APPROACHES
Recent data is pointing an altered gut microbiome in patients with NAFLD and a study done from our institute has also demonstrated small intestinal bacterial overgrowth (SIBO) in patients with NAFLD. Altered gut microbiome and SIBO can contribute to significant endotoxemia and activation of inflammatory pathways in the liver. Several strategies are being evaluated to target this gut dysbiosis (using probiotics) and downstream inflammatory pathways (using caspase inhibitors) to prevent the progression of NASH. The novel drugs in the pipeline which are being evaluated for NASH are mentioned in Table no. 1.
CONCLUSIONS
The treatment of NASH has been a focus of intensive
Table 1: New drugs in pipeline in the management of NASH Drug
Trial
Mechanism of Action
Comments
Simtuzumab
NCT01672879
Anti-LOXL-2 antibodies
Inhibits formation and repair of extracellular matrix
Cenicriviroc
CENTAUR study
CCR2/CCR5 antagonist
Interferes with recruitment of monocytes, macrophages and HSCs upon liver injury
Emricasan
ENCORE-NF trial
Caspase inhibition
Prevents apoptosis
Sitagliptin
NCT01963845
DPP-IV inhibitors
Prevents degradation of GLP-1
GR-MD-02
NCT01899859
Galectin-3 inhibitor
Anti-fibrotic
JKB-121
NCT02442687
Toll-like receptor 4 inhibitor
Anti-inflmmatory
research in the field of hepatology with current treatment strategies aiming not only to decrease steatosis and inflammation, but also prevent the progression and promote resolution of hepatic fibrosis. However, an effective treatment would rely not only on pharmacologic interventions but also on intense lifestyle modifications in order to control the various risk factors (MS) involved in the pathogenesis and progression of this disease.
REFERENCES
1.
2.
Duseja A, Sharma B, Kumar A, Kapil S, Das A, Dhiman RK, et al. Nonalcoholic fatty liver in a developing country is responsible for significant liver disease. Hepatology. 2010; 52:2248â&#x20AC;&#x201C;9.
3.
Lassailly G, Caiazzo R, Pattou F, Mathurin P. Perspectives on Treatment for Nonalcoholic Steatohepatitis. Gastroenterology. 2016; 150:1835-48.
4.
Hardy T, Anstee QM, Day CP. Nonalcoholic fatty liver disease: new treatments. Curr Opin Gastroenterol. 2015; 31:175-83.
5.
Duseja A, Das A, Das R, Dhiman RK, Chawla Y, Bhansali A, et al. The clinicopathological profile of Indian patients with nonalcoholic fatty liver disease (NAFLD) is different from that in the West. Dig Dis Sci 2007; 52:2368-74.
6.
Than NN, Newsome PN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis. 2015; 239:192-202.
7.
Newsome PN. Entering the GOLDEN Age for Therapies in NASH. Gastroenterology. 2016; 150:1073-6.
Duseja A, Das R, Nanda M, Das A, Garewal G, Chawla Y. Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations. World J Gastroenterol 2005; 21:393â&#x20AC;&#x201C;5.
9.
Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2015; 21:3777-85.
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10. Duseja A. Nonalcoholic fatty liver disease in India - a lot done, yet more required! Indian J Gastroenterol. 2010; 29:217-25. 11. Ganesh S, Rustgi VK. Current Pharmacologic Therapy for Nonalcoholic Fatty Liver Disease. Clin Liver Dis.2016; 20:351-64. 12. Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, Bhadada S, Bhansali A. Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol. 2007; 6:222-6. 13. Hameed B, Terrault N. Emerging Therapies for Nonalcoholic Fatty Liver Disease. Clin Liver Dis. 2016; 20:365-85. 14. Kapil S, Duseja A, Sharma BK, Singla B, Chakraborti A, Das A, et al. Small intestinal bacterial overgrowth and toll-like receptor signaling in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2016; 31:213-21. 15. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142:1592-609.
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Duseja A, Singh SP, Saraswat VA, Acharya SK, Chawla YK, Chowdhury S, et al. Non-alcoholic Fatty Liver Disease and Metabolic Syndrome-Position Paper of the Indian National Association for the Study of the Liver, Endocrine Society of India, Indian College of Cardiology and Indian Society of Gastroenterology. J Clin Exp Hepatol. 2015; 5:51-68.
8.
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Alcoholic Hepatitis in India: Current Prospective and Management
INTRODUCTION
Alcohol is the world third largest risk factor for disease burden. Consumption of alcohol results in 2.5 million deaths each year.1 Alcoholic hepatitis is an acute inflammation of the liver, accompanied by the destruction of individual liver cells and scarring. Symptoms may include fever, jaundice, an increased white blood cell count, an enlarged, tender liver, and spider-like veins in the skin.2 It may develop due to large amount of alcohol for a long period and the outcome may range from abnormal liver functions with no symptoms to hepatic encephalopathy.3 The World Health Organization (WHO) estimates that 140 million people worldwide suffer from alcohol dependency, causing damage to lives and economies. In India, 15 people die every day – or one every 96 minutes – from the effects of drinking alcohol, reveals by an India Spend analysis of 2013 National Crime Records Bureau (NCRB) data. The per capita consumption of alcohol in India increased 38 percent. According to WHO data published in 2014 the total pure alcohol consumption among persons (age 15+) in liters per capita per year is 4.4 out of which 2.2 liters per capita per year is recorded consumptiion of alcohol where 2.2 liters per capita per year is unrecorded consumption. Mortality from alcoholic cirrhosis is declining in western nations but it is increasing in India.1
EPIDEMIOLOGY
Incidence is unknown in India but prevalence varies among different states.
Table 1: Laboratory diagnosis of alcoholic hepatitis Test
Comment
AST
Increased two to sevenfold, <400 IU/L, > ALT
ALT
Increased two to sevenfold, <400 IU/L
AST/ALT
Usually > 1
GGTP
Not specific to alcohol, easily inducible, elevated in all forms of fatty liver
Billirubin
May be markedly increased in alcoholic hepatitis despite modest elevation in alkaline phosphatase
ALP
Mildly elevated
ALT, Alanine aminotransferase, AST, Aspartate aminotransferase; GGTP, γ Glutamyl transpeptidase; ALP, Alkaline phosphatase
Suresh Kumar
Global status report on alcohol and health 2014 was released by WHO for India, Around 30% of total adult population consumes alcohol. 93% of alcohol consumes in the form of spirit. 7% in the form of beer and ≤1% in the form of wine. Highest alcohol consumption were found in Kerala (8 ltrs per annum) followed by Maharasthra and Punjab. 11% adult population in India indulged in heavy drinking or binge drinking.
ETIOLOGY AND PATHOPHYSIOLOGY
Quantity, gender, underlying viral hepatitis, genetics and obesity are the major etiological risk factors for the development of Alcoholic hepatitis. After alcohol consumption, it is mainly metabolised within hepatic parenchyma and also in GI tract. Alcohol is converted to acetaldehyde inside the liver cells by the enzyme alcohol dehydrogenase and cytochrome p450 (CYP2E1).
CLINICAL FEATURES
Presentation of Acute alcoholic hepatitis varies considerably. Some patients may presents with nonspecific symptoms like nausea, vomiting, diarrhoea, abdominal pain or discomfort. ALD may be found when the patient comes for alcohol related problems of other organs, i.e. pancreas, heart, brain and peripheral nerves, etc. Patients with Fatty liver (Steatosis) are usually well and asymptomatic or have nonspecific symptoms. Liver may be enlarged but non tender. Features of chronic liver disease are absent liver enzymes may be mildly raised.4 The patient may look quite well with nonspecific symptoms or very ill, malnourished with specific features of hepatic insufficiency or encephalopathy. Physical signs include enlarged tender liver, jaundice, ascitis pyrexia, spider angioma or signs of encephalopathy. Blood results may show anemia, leukocytosis, high bilirubin and enzymes, prolonged prothombin time and low albumin. They are prone to have infections.4
LABORATORY DIAGNOSIS (TABLE 1)
The diagnosis is based on a thorough history, physical examination, and investigation. History with for a reliable account of prolonged alcohol abuse, it is important to gain the trust of the patient. Often the collateral history from spouse, family members, and friends is useful. For
327
Alcoholic Hepatitis Alcohol abstinence Nutritional support Discrimination function >32 Or MELD 21 (with absence of co-morbidity)
CHAPTER 70
Treatment options
Preferred
Alternative
Prednisolone 32 mg p.o. daily for 4 weeks, Then taper for 4 weeks
Pentoxifyline 400 mg p.o. TID for 4 weeks
Fig. 1: Treatment Algorithm for alcoholic hepatitis assessment, various question formats, i.e. CAGE test, are helpful.
81%, when predicting 28-day outcome.7 In contrast, the modified DF had an overall accuracy of only 50%.7
PROGNOSTIC SCORES
Asymmetric Dimethylarginine (ADMA) Score
In clinical practice various scores are used to predict out come of alcoholic hepatitis. The single most reliable indicator of severity is the presence of hepatic encephalopathy.
Discriminant Function (DF) Score
The DF of Maddrey and coworkers is based on PT and billirubin levels and it is calculated as follows: DF= (4.6 × PT prolongation) + total serum billirubin in mg/dL.
MELD Score
Several retrospective studies have shown that the MELD score is useful in predicting 30- and 90-day mortality in patients with alcoholic hepatitis. Moreover, the MELD score seems to contain some practical and statistical advantages over Maddrey’s DF in predicting mortality among these patients. In a cohort of 73 patients with alcoholic hepatitis at the Mayo Clinic, the MELD score was the only independent predictor of mortality [5]. Likewise, in another much larger retrospective study of 202 patients with alcoholic hepatitis, the MELD score was found superior to not only Maddrey’s DF but also to the classical Child-Turcotte-Pugh (CTP) score.6
Glasgow Alcoholic Hepatitis score (GAHS)
The GAHS is one of the most recently described predictors of outcome in patients with alcoholic hepatitis. This scoring system uses 5 different variables, including age, bilirubin level, blood urea nitrogen (BUN) level, PT, and WBC count. The overall accuracy of GAHS, which was validated in 195 patients with alcoholic hepatitis, was
The ADMA score is the most recently proposed predictor of adverse clinical outcome in patients with severe alcoholic hepatitis. In a small prospective study of 27 patients with alcoholic hepatitis, the ADMA score was a better predictor of outcome than the CTP score, the DF, or the MELD scores.8 Other factors that correlate with poor prognosis include older age, impaired renal function, encephalopathy, and a rise in the WBC count in the first 2 weeks of hospitalization. Significantly raised serum γ-glutamyltransferase (γ - GT) and Mean Corpuscular Volume (MCV) are most important and valuable for detection of alcohol excess. However, moderate rise of γ -GT may be found in nonalcoholic fatty liver drugs like phenetoin causing enzyme induction. Liver function tests – Elevated Serum transaminase level ALT and AST are not specific. These are mildly raised in fatty liver. Characteristically, the AST: ALT ratio is about 2:1, and the absolute value of the ALT does not exceed 300 U/L unless a superimposed hepatic insult exists, such as paracetamol toxicity. If raised 5 times of normalreference range, other diagnoses such as viral or autoimmune hepatitis should be considered.10
HISTOLOGICAL FINDINGS
Liver biopsy is not routinely necessary to diagnose liver injury. For fatty liver, biopsy is rarely required and may be useful in excluding steatohepatitis or fibrosis. Inflammation and necrosis occurs, most prominently in the centrilobular area of hepatic acinus. Ballooning of
328
hepatocytes is classical. They compress sinusoids and lead to portal hypertension which is reversible.9
5.
Dunn W, Jamil LH, Brown LS, Wiesner RH, Kim WR, Menon KV, et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology 2005; 41:353-8. [Medline].
6.
Srikureja W, Kyulo NL, Runyon BA, Hu KQ. MELD score is a better prognostic model than Child- Turcotte-Pugh score or discriminant function score in patients with alcoholic hepatitis. J Hepatol 2005; 42:700-6. [Medline].
7.
Forrest EH, Evans CD, Stewart S, et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glascow alcoholic hepatitis score. Gut 2005; 54:14-5. Medline].
8.
Mookerjee RP, Malaki M, Davies NA, et al. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology 2007; 45:62-71.
9.
Sarin SK, Malhotra V, Nayyar A, Sundaram KR, Broor SL. Profile of alcoholic liver disease in an Indian hospital. A prospective analysis. Liver 1988; 8:132-7. PubMed PMID: 3393062.
CONCLUSION
Upto 40% patients with severe alcoholic hepatitis die within 6 months of onset of clinical syndromes. Alcoholic liver disease and alcoholic hepatitis is increasing in India. Early diagnosis and treatment can prevent development of cirrhosis and decompensation. Abstinence is the key factor in the mangement of alcoholic hepatitis.
HEPATOLOGY
ACKNOWLEDGEMENT
Author acknowledges Dr. Dipu Bharali for typing and ediiting the written part of the chapter.
REFERENCES
1.
WHO Global status report on alcohol and health 2014.
2.
Casanova J, Bataller R. Alcoholic hepatitis: Prognosis and treatment. Gastroenterol Hepatol 2014; 37:262-8.
3.
Potts JR, Goubet S, Heneghan MA, Verma S. Determinants of long-term outcome in severe alcoholic hepatitis. Aliment Pharmacol Ther 2013; 38:584-95.
4.
Mihas AA, Doos WG, Spenney JG. Alcoholic hepatitis--a clinical and pathological study of 142 cases. J Chronic Dis 1978; 31:461-72.
10. Nand N, Malhotra P, Dhoot DK. Clinical Profile of Alcoholic Liver Disease in a Tertiary Care Centre and its Correlation withType, Amount and Duration of Alcohol Consumption. J Assoc Physicians India 2015; 63:14-20.
Ascites - From Basics to Bedside
C H A P T E R
71
Harbir Kaur Rao, Rajinder Singh Gupta
INTRODUCTION
The term ascites denotes the pathological accumulation of fluid in the peritoneal cavity. Healthy men have
Table 1: Causes of Ascites Normal Peritoneum Portal hypertension (SAAG > 1.1g/ dL) 1. Hepatic congestion
Diseased peritoneum (SAAG < 1.1g/dL) Infections Bacterial peritonitis
Congestive heart failure Tuberculous peritonitis Constrictive pericarditis Fungal peritonitis
little or no fluid in the peritoneal cavity but women normally may have up to 20ml depending on the phase of menstrual cycle. Causes of ascites may be classified into two pathophysiologic categories: That associated with the normal peritoneum and that which occur due to a diseased peritoneum. Cirrhosis accounts for 84 percent of all cases of ascites, whereas Cardiac ascites, peritoneal carcinomatosis and mixed ascites resulting from cirrhosis and a second disease account for 10-15% of cases. Less common causes of ascites include massive hepatic metastasis, peritoneal tuberculosis, and pancreatitis and Nephrotic syndrome. Various causes of ascites are enumerated in Table 1.
Tricuspid insufficiency
HIV-associated peritonitis
Budd-Chiari syndrome
Malignant conditions
Veno-Occlusive disease
Peritoneal carcinomatosis
Pathogenesis of ascites is different in cases with cirrhosis and without the cirrhosis.
2. Liver Disease
Primary mesothelioma
Cirrhosis
Pseudomyxoma peritonei
Pathogenesis in Cirrhosis Cases
Alcoholic Hepatitis
Massive hepatic metastases
Fulminant hepatic failure Massive hepatic metastases Hepatic Fibrosis
Hepatocellular carcinoma Other Conditions Familial mediterranean fever
Acute Fatty liver of pregnancy
Vasculitis
3. Portal vein occlusion
Eosinophilic peritonitis
Hypoalbuminemia (SAAG < 1.1g/dL)
Granulomatous peritonitis
PATHOGENESIS
The presence of portal hypertension contributes to the development of ascites in patients who have cirrhosis. There is an increase in Intrahepatic resistance, causing increased portal pressure, but there is also vasodilatation of the splanchnic arterial system, which in turn results in an increase in portal venous inflow. Both of these abnormalities result in increased production of splanchnic lymph. Vasodilating factors such as vascular endothelial growth factor and nitric oxide are responsible for the vasodilatory effect. These hemodynamic changes cause activation of the RAAS with the development of hyperaldosteronism and hence sodium retention. These renal effects of increased aldosterone also contribute to the development of ascites. Sodium retention causes
Nephrotic syndrome
Cirrhosis
Protein- losing enteropathy
Portal Hypertension
Severe malnutrition with Anasarca Miscellaneous conditions (SAAG < 1.1g/dL) Chylous ascites Pancreatic ascites Bile ascites Nephrogenic ascites Myxedema (SAAG > 1.1g/ dL) Ovarian disease
Splanchnic vasodiltation
â&#x2020;&#x2018; Splanchnic pressure Lymph formation Formation of ascites
Plasma Volume Expansion
Arterial underfilling
Activation of vasoconstrictors and antinatriuretic factors
Sodium Retention
Fig. 1: Development of Ascites in Cirrhosis
HEPATOLOGY
330
fluid accumulation and expansion of extra cellular fluid volume which results in the formation of peripheral oedema and ascites. Sodium retention is the consequence of a homeostatic response caused by the under filling of arterial circulation secondary to arterial vasodilatation in the splanchnic vascular bed. Because the retained fluid is constantly leaking out of the intravascular compartment in to peritoneal cavity, the sensation of vascular filling is not achieved and the process continuous. Hypoalbuminemia and reduced oncotic pressure also contribute to the loss of fluid from the vascular compartment into the peritoneal cavity. Hypoalbuminemia is due to decreased synthetic function in the liver. Figure 1 is brief illustration of Pathogenesis of ascites in cirrhosis.
Pathogenesis in the Absence Of Cirrhosis
Ascites in the absence of cirrhosis generally results from peritoneal carcinomatosis, peritoneal infection or pancreatic disease. Peritoneal carcinomatosis can result from primary malignancies such as mesothelioma or sarcoma, secondary to abdominal malignancies such as gastric or colon adenocarcinoma, metastatic disease from breast or lung carcinoma or melanoma. Tumour cells lining the peritoneum produce a protein rich fluid that contributes to the development of ascites. Fluid from the extra cellular space is drawn into the peritoneum, further contributing to the development of ascites. Tuberculous peritonitis causes ascites via a similar mechanism; tubercles deposited on the peritoneum exude a proteinaceons fluid. Pancreatic ascites results from the leakage of pancreatic enzymes into the Peritoneum.
CLINICAL FEATURES
Symptoms and Signs
The history usually is one of increasing abdominal girth, with the presence of abdominal pain depending on the cause. Because most astices is secondary to chronic liver disease with portal hypertension, patients should be asked about risk factors for liver disease, especially alcohol consumption, transfusions, tattoos, injection drug use, a history of viral hepatitis or jaundice, and birth in an area endemic for hepatitis. A history of cancer or marked weight loss arouses suspicion of malignant ascites. Fever may suggest infected peritoneal fluid, including bacterial peritonitis (spontaneous or secondary). Patients with chronic liver disease and ascites are at greatest risk for developing spontaneous bacterial peritonitis. In immigrants, immunocompromised hosts, or severely malnourished alcoholics, tuberculous peritonitis should be considerd. Physical examination should emphasize signs of portal hypertension and chronic liver disease. Elevated jugular venous pressure may suggest right-sided congestive heart failure or constrictive pericarditis. A large tender liver is characteristic of acute alcoholic hepatitis or Budd-Chiari syndrome. The presence of large abdominal wall veins with cephalad flow also suggests portal hypertension; inferiorly directed flow implies hepatic vein obstruction. Signs of chronic liver disease include palmar erythema, cutaneous spider angiomas, gynecomastia, and muscle wasting. Asterixis secondary to hepatic encephalopathy
may be present. Anasarca results from cardiac failure or nephrotic syndrome with hypoalbuminemia. Finally, firm lymph nodes in the left superclavicular region or umbilicus may suggest intra-abdominal malignancy. The physical examination is relatively insensitive for detecting ascitic fluid. In general, patients must have at least 1500mL of fluid to be detected reliably by this method. Even the experienced clinician may find it difficult to distinguish between obesity and small-volume ascites. Abdominal ultrasound establishes the presence of fluid.
Physical Examination
Physical examination should include an assessment for signs of systemic disease. The presence of lymphadenopathy, especially supraclavicular lymphadenopathy (Vorchowâ&#x20AC;&#x2122;s node), suggests metastatic abdominal malignancy. Care should be taken during the cardiac examination to evaluate for elevation of jugular venous pressure (JVP); Kussmaulâ&#x20AC;&#x2122;s sign (elevation of the JVP during inspiration); a pericardial knock, which may be seen in heart failure of constrictive pericarditis; or a murmur of tricuspid regurgitation. Spider angiomas, palmar erythema, dilated superficial veins around the umbilicus (caput medusae), and gynecomastia suggest chronic liver disease. The abdominal examination should begin with inspection for the presence of uneven distention or an obvious mass. Auscultation should follow. The absence of bowel sounds or the presence of high-pitched localized bowel sounds points toward an ileus or intestinal obstruction. An umbilical venous hum may suggest the presence of portal hypertension, and a harsh bruit over the liver is heard rarely in patients with hepatocellular carcinoma. Abdominal swelling caused by intestinal gas can be differentiated from swelling caused by fluid or a solid mass by percussion; an abdomen filled with gas is tympanic, whereas an abdomen containing a mass or fluid is dull to percussion. The absence of abdominal dullness, however, does not exclude ascites, because a minimum of 1500 ml. of ascites fluid is required for detection on physical examination. Finally, the abdomen should be palpated to assess for tenderness, a mass, enlargement of the spleen or liver, or presence of a nodular liver suggesting cirrhoses or tumor. Light palpation of the liver may detect pulsations suggesting retrograde vascular flow from the heart in patients with right-sided heart failure, particularly tricuspid regurgitation.
EVALUATION
Once the presence of ascites has been confirmed, the etiology of the ascites is best determined by paracentesis. The left lower quadrant is preferred because of the greater depth of ascites and the thinner abdominal wall. Paracentesis is a safe procedure even in patients with coagulopathy; complications, including abdominal wall hematomas, hypotension, hepatorenal syndrome, and infection are infrequent. Once ascitic fluid has been extracted, its gross appearance should be examined. Turbid fluid can result from presence of infection or tumor cells. White, milky fluid
SAAG
>1.1 g/dL
Ascites protein <2.5g/dL
<1.1g/dL
Ascites protein >2.5g/dL Biliary leak
Cirrhosis Late Budd-Chiari syndrome Massive liver metastases
Heart failure/constrictive pericarditis Early Budd-Chiari syndrome IVC obstruction Sinusoidal obstruction syndrome
Nephrotic syndrome Pancreatitis Peritoneal carcinomatosis Tuberculosis
indicates a triglyceride level>200 mg/dL (and often >1000 mg/dL), which is hall mark of chylous ascites. Chylous ascites results from lymphatic disruption that may occur with trauma, cirrhosis, tumor, tuberculosis, or certain congenital abnormalities. Dark brown fluid can reflect a high bilirubin concentration and indicates biliary tract perforation. Black fluid may indicate the presence of pancreatic necrosis or metastatic melanoma. The ascitic fluid should be sent for measurement of albumin and total protein levels, cell and differential counts, and if infection is suspected, Gram’s stain and culture, with inoculation into blood culture bottles at the patient’s bed side to maximize the yield. A serum albumin level should be measured simultaneously to permit calculation of the serum ascites albumin gradient (SAAG). The SAAG is useful for distinguishing ascites caused by portal hypertension from non portal hypertensive ascites. (Figure 2). The SAAG reflects the pressure within the hepatic sinusoids and correlates with the hepatic venous pressure gradient. The SAAG is calculated by subtracting the ascitic albumin concentration from the serum albumin level and does not change with diuresis. A SAAG > 1.1g/ dL reflects the presence of portal hypertension and indicates the ascites is due to increased pressure in the hepatic sinusoids. According to Starling’s law, a high SAAG reflects the oncotic pressure that counterbalances the portal pressure. Possible causes include cirrhosis, cardiac ascites, hepatic vein thrombosis (Budd-Chirari Syndrome), sinusoidal obstruction syndrome (VenoOcclusive Disease), or massive liver metastases. A SAAG < 1.1g/dL indicates that the ascites is not related to portal hypertension, as in tuberculousis peritonitis, peritoneal carcinomatosis, or pancreatic ascites. For high-SAAG (> 1.1) ascites, the ascitic protein level can provide further clues to the etiology (Figure 2). An ascites protein level of >2.5 g/dL indicates that the hepatic sinusoids are normal and are allowing passage of protein into the ascites, as occurs in cardiac ascites, early BuddChiari syndrome, or sinusoidal obstruction syndrome. An ascitic protein level <2.5g/dL indicates that the hepatic sinusoids have been damaged and scarred and no longer allow passage of protein, as occurs with cirrhosis, late Budd-Chiari syndrome, or massive liver metastases. Pro-brain type natriuretic peptide (BNP) is a natriuretic hormone released by the heart as a result of increased
Further tests are indicated only in specific clinical circumstances. When secondary peritonitis resulting from a perforated hollow viscus is suspected, ascitic glucose dehydrogenase (LDH) levels can be measured. In contrast to “spontaneous” bacterial peritonitis, which may complicate cirrhotic ascites. Secondary peritonitis is suggested by an ascitic glucose level <50.0Mg/dL, an ascitic LDH level higher than the serum LDH level, and the detection of multiple pathogens on ascitic fluid culture. When pancreatic ascites is suspected, the ascitic amylase level should be measured and is typically >1000mg/dL. At least 50mL of fluid should be obtained and sent for immediate processing. Tuberculous peritonitis is typically associated with ascitic fluid lymphocytosis but can be difficult to diagnose by paracentesis. A smear for acid-fast bacilli has a diagnostic sensitivity of only 0 to 3%; a culture increases the sensitivity to 35-50%. In patients without cirrhosis, an elevated ascitic adenosine deaminase level has a sensitivity of>90%when a cut-off value of 30-45% U/L is used. When the cause of ascites remains uncertain, laparotomy or laparoscopy with peritoneal biopsies for histology and culture remains the gold standard.
Laboratory Evaluation
Laboratory evaluation should include liver biochemical testing, serum albumin level measurement, and prothrombin time determination (international normalized ratio) to assess hepatic function as well as a complete blood count to evaluate for the presence of cytopenias that may result from portal hypertension or of leukocytosis, anemia, and thrombocytosis that may result from systemic infection. Serum amylase and lipase levels should be checked to evaluate the patient for acute pancreatitis. Urinary protein quantitation is indicated when nephrotic syndrome, which may cause ascites, is suspected. In selected cases, the hepatic venous pressure gradient (pressure across the liver between the portal and hepatic veins) can be measured via cannulation of the hepatic vein to confirm that ascites is caused by cirrhosis. In some cases, a liver biopsy may be necessary to confirm cirrhosis.
Imaging
Abdominal ultrasound is useful in confirming the presence of ascites and in the guidance of paracentesis. Both ultrasound and CT imaging are useful in distinguishing between causes of portal and non-portal hypertensive ascites. Doppler ultrasound and CT can detect thrombosis of the hepatic veins (Budd-Chiari syndrome) or portal veins. In patients with non-portal hypertensive ascites, these studies are useful in detecting lymphadenopathy and masses of the mesentery and of solid organs such as the liver, ovaries, and pancreas. Furthermore, they permit directed percutaneous needle biopsies of these lesions. Ultrasound and CT are poor procedures for the detection of peritoneal carcinomatosis; the role of position emission tomography (PET) imaging is unclear.
331
CHAPTER 71
Fig. 2: Algorithm for the diagnosis of Ascites
volume and ventricular wall stretch. High levels of BNP in serum occur in heart failure and may be useful in identifying heart failure as the cause of high-SAAG ascites.
332
of fluid drained) accompanying LVP decrease the risk of post paracentesis circulatory dysfunction. TIPS is superior to LVP in reducing the reaccumulation of ascites but is associated with increased frequency of hepatic encephalopathy.
Refractory ascites
Large volume paracentesis (LVP) + albumin
Tuberculous Ascites
Dietary sodium restriction + diure�cs
Tuberculous involvement of the peritoneum is significant problem in the developing world including India. The incidence is higher in those with uncontrolled HIV disease, the urban poor, patients with cirrhosis and nursing home residents.
HEPATOLOGY
Ascites reaccumulation
Consider TIPS
Continue LVP with albumin as needed
Consider liver transplantation
Fig. 3: Treatment of Refractory Ascites Laparoscopy
Laparoscopy is an important test in the evaluation of some patients with non-portal hypertensive ascites (low SAAG) or mixed ascites. It permits direct visualization and biopsy of the peritoneum, liver, and some intraabdominal lymph nodes. Cases of suspected peritoneal tuberculosis or suspected malignancy with non-diagnostic CT imaging and ascitic fluid cytology are best evaluated by this method.
Treatment 1.
The initial treatment for cirrhotic ascites is restriction of sodium intake to 2 gl /day.
2.
When sodium restriction alone is inadequate oral diuretics typically the combination of spironolactone and furosemide are used. Spioronolactone is an aldosterone antagonist that inhabits sodium resorption in the distal convoluted tubule of kidney. Prolonged use of spironolactone may lead to hyponatremia, hyperkalemia and painful gynecomastia. In such cases amiloride 5-40mg/day may be substituted for speronolactone.
3.
Malignant acites does not respond to sodium restriction or diuretics. Patient may undergo large volume paracentesis (LVPâ&#x20AC;&#x2122;s), transcutaneous catheter placement or rarely creation of peritoneovenous shunt.
4.
Ascites caused by tuberculous peritonites is treated with standard antituberculous therapy.
Refractory Ascites
Refractory cirrhotic ascites is defined by the presence of ascites despite sodium restriction and maximal diuretic dose. Pharmacological therapy for these cases (Figure 3) include the addition of Midodrine and a adrenergic antagonist or clonidine an a2 adrenergic antagonist to diuretic therapy. These agents act as vasoconstrictors, counteracting splanchnic vasodilatalion. Beta blockers are often prescribed to prevent variceal hemorrhage in patient with cirrhosis.When medical tharpy alone is insufficient refractory ascites can be managed by repeated large volume paracentesis (LVP) or transjugular intrahepatic peritoneal shunt (TIPS) to decompress the hepatic sinusoids. I/V infusion of albumin (6-8 gm/l
The presenting symptoms include low grade fever, abdominal pain, anorexia and weight loss. Most patients have symptoms for months before the diagnosis is established. On physical examination patient may have generalized abdominal tenderness and distention. There may be clinically evident ascites. Ultrasonography or CT imaging of the abdomen reveals free or localated ascites in >80% of patients. Mantoux test is positive in 50% of cases. Ascitic fluid smear for AFB is usually negative and fluid cultures are positive in 35% cases. Ascitic fulid total protein is more than 3g/dL, LDH >90 units/ L or mononuclear cell predominant leucocytes >500/cc. Ascitic adenosine deaminase activity > 36-40 IU/L has a sensitivity of 100% and a specificity of 97% for diagnosis of tuberculous peritonitis. In doubtful cases laparoscopy confirms the diagnosis.
Malignant Ascites
Two-thirds of cases of malignant ascites are caused by peritoneal carcinomatosis. The most common tumors causing carcinomatosis are primary adenocarcinomas of the ovary, uterus, pancreas, stomach, colon, lung or breast. The remaining one-third is due to lymphatic obstruction or portal hypertension due to hapatocellular carcinoma or diffuses hepatic metastases. Patients present with non specific abdominal discomfort and weight loss associated with increased abdominal girth. Nausea or vomiting may be caused by partial or complete intestinal obstruction. Abdominal CT may be useful to demonstrate the primary malignancy or hepatic metastases but seldom confirms the diagnosis of peritoneal carcinomatosis. In patients with carcinomatosis, paracentesis demonstrates a low serum ascites-albumin gradient (<1.1 mg/dL), an increased total protein (> 2.5 g/dL), and an elevated white cell count (often both neutrophils and mononuclear cells) but with a lymphocyte predominance. Cytology is positive in over 95%, but laparoscopy may be required in patients with negative cytology to confirm the diagnosis and to exclude tuberculousis peritonitis, with which it may be confused. Malignant ascites attributable to portal hypertension usually is associated with an increased serum ascitesalbumin gradient (>1.1 g/dL), a variable total protein, and negative ascitic cytology. Ascites caused by peritoneal carcinomatosis does not respond to diuretics. Patient may be treated with periodic large-volume paracentesis for symptomatic relief. Intra peritoneal chemotherapy is some time used to shrink the tumor, but the overall prognosis is extremely poor, with only 10% survivor at 6 month. Ovarian cancers represent an
exception to this rule. With newer treatments consisting of surgical debulking and intraperitoneal chemotherapy, long term survival from ovarian cancer is possible.
Chylous Ascites
This is a accumulation of lipid rich lymph in the peritoneal cavity. Ascites fluid is milky in appearance with triglyceride level >1000 mg/dL. Usual causes in adults is lymphatic obstruction or leakage caused by malignancy especially lymphoma. Non malignant causes include postoperative trauma, cirrhosis, tuberculosis, pancreatitis and filariasis. It is intra peritoneal accumulations of massive amount of pancreatic secretion due either to disruption of pancreatic duct or to a pancreatic pseudocyst. Its most commonly seen in patients with chronic pancreatitis. Ascitic fluid is characterized by high protein level (>2.5 g/dL) but a low SAAG, Ascitic fluid amylase levels are in excess of 1000 units/L. Non surgical cases are treated by bowel rest, total parenteral nutrition and octreotide to decreased pancreatic secretion.
Spontaneous Bacterial Peritonitis
“Spontaneous” bacterial infection of ascitic fluid occurs in the absence of an apparent intraabdominal source of infection. It is seen with few exception in patients with ascites caused by chronic liver disease. Translocation of enteric bacteria across the gut wall or mesenteric lymphatic leads to seeding of the ascitic fluid, as may bactiremia from other sites. Approximately 20-30% of cirrhotic patients with ascites develop spontaneous peritonitis; however the incidence is >40% in patients with ascitic fluid total protein <1g/dL, probably due to decreased ascitic fluid osmotic activity. Virtually all cases of spontaneous bacterial peritonitis are caused by a monomicrobial infection. The most common pathogens are enteric gram-negative bacteria Ecoli, klebsiella Pneumonae or gram-positive bacteria. (Streptococcus pneumoniae, viridans streptococci, enterrococcus species). Anaerobic bacteria are not associated with spontaneous bacterial peritonitis.
Symptoms and Signs
Eighty to 90percent of patients with spontaneous bacterial peritonitis are symptomatic; in many cases the presentation is subtle. Spontaneous bacterial peritonites may be present in 10-20% of patients hospitalized with chronic liver disease, sometimes in the absence of any suggestive symptoms or signs. The most common symptoms are fever and abdominal pain, present in two-thirds of patients. Spontaneous bacterial peritonitis may also present with the change
333
Treatment
Empiric therapy for spontaneous bacterial peritonitis should be initiated with a third-generation cephalosporin (such as cefotaxime, 2 g intravenously every 8-12 hours, or ceftriaxon 1-2 gm I-V every 24 hours, or a combination of β-lactam/ β-lactamase agent (such as ampicillin/ sulbactam, 2g/1g intravenously every 6 hours). A course of 5-10 days is sufficient in most patients, or until the ascites fluid PMN count decreases to < 250 cells/cc. Kidney injury develops in up to 40% of patients and is a major cause of death. Intravenous albumin increases effective arterial circulating volume and renal perfusion, decreasing the incidence of kidney injury and mortality. Intravenous albumin, 1.5g/kg on day 1 and 1g/kg on day 3, should be administrated to patients at high risk for hepatorenal failure (ie, patients with baseline creatinine > 1mg/dl, blood urea nitrogen (BUN) > 30 mg/dL, or bilirubin > 4 mg/dL.
REFERENCES
1.
Hou W etal. Ascites: Diagnosis and Management, Medical Clinics of North America 2009; 9394:801-17 2. Zeller JL et al JAMA patient page. Abdominal paracentesis. JAMA 2008; 299:1216. 3. Jacob JT, et al. Acute forms of tuberculosis in adults Am J Med 2009; 122:12-7. 4. Tamsma J. The pathogenesis of malignant ascites, cancer treat Res 2007; 134:109-18. 5. Al. Ghamdi MY et al. Chylous ascites secondary to pancreatitis. Dig Dis Sci 2007; 52:2261-4. 6. Garcia. Tsao G et al. Management and treatment of patients with cirrhosis and portal hypertension. Am J Gastroenterology 2009; 104:1802-29. 7. Saab S etal. Oral antibiotic prophylaxis reduces spontaneous bacterial peritonitis occurrence and improves short terms survival in cirrhosis. A meta analysis. Am J Gastroenterology 2009; 104:993-1001. 8. Kathleen E, Corey and Lawrence S. Friedman; abdominal swelling and ascites; Harrison Principles of internal medicine 19th edition MC Graw Hill 2015;285-88 9. Brune R.Bacon; Cirrhosis and its complications; Harrison’s Principle of internal medicine 19th edition MC Graw Hill 2015;2058-2067 10. Burgess LJ, Swanepoel CG, Taljaard JJ. The use of adenosine deaminase as a diagnostic tool for peritoneal tuberculosis. Tuberculosis 2001; 81;243-248.
CHAPTER 71
Pancreatic Ascites
in mental status due to exacerbation or precipitation of hepatic encephalopathy, or sudden worsening of renal function. Physical examination typically demonstrates signs of chronic liver disease with ascites. Abdominal tenderness is present in <50% of patients and its presence suggests other causes.
Approach to Hepatorenal Syndrome
C H A P T E R
72
DN Amarapurkar
INTRODUCTION
Acute kidney injury (AKI) is common in cirrhosis but functional renal failure defined as Hepatorenal syndrome (HRS) accounts for 20% of AKI. HRS is reversible syndrome in patients with cirrhosis and ascites can appear spontaneously or follow precipitating event. HRS can be defined as presence of cirrhosis with ascites with serum creatinine more than 1.5 mg/dl, no improvement of serum creatinine (=/> 1.5mg/dl) after at least 48 hours of diuretic withdrawal and volume expansion with albumin 1gm/kg body weight per day for two days, absence of hypovolumic shock or severe infection requiring vasoactive drugs to maintain the arterial pressure, no current or recent treatment with nephrotoxic drugs, proteinuria less
Table 1: Diagnosis of AKI in Cirrhosis Parameter
Definition
Base line Serum Creatinine
Stable SCr ≤3 months If not available, a stable SCr closest to the current one If no previous SCr at all, use admission SCr
Definition of AKI
Increase in SCr > 26.5 umol/l (0.3mg/dL) > 48 hours, or Increase 50% from baseline
Staging
Stage 1 : Increase SCr > 26.4 umol/L (0.3mg/dL) or
Increase SCr > 1.5 – 2.0 x from baseline
Stage 2: Increase SCr > 2 – 3.0 x from baseline Stage 3: SCr > 3.0 x from baseline or
SCr > 352 umol/L (4,0mg/dL) with an acute increase of > 26.4 umol/L (0.3mg/dL) or Initiation of renal replacement therapy
than 500 gms/day and no micro hematuria. Evolving concepts of renal dysfunction in cirrhosis have been discussed by various international groups in the recent past. International ascites club defined HRS in 1996, 2007 and 2015 while kidney associations which defined renal failure in other instances also defined kidney failure in cirrhosis. KIDGO (kidney disease improving global outcome), RIFLE (risk, injury, failure, loss of function, end stage renal disease), AKIN (acute kidney injury network) and ADQI (acute dialysis quality initiative) are important amongst them.
DIAGNOSIS OF HRS (TABLE 1)
It is based on AKI stage 2 or 3 with already mentioned criteria remaining same. Diagnosis of chronic kidney disease in cirrhosis is based on criteria: GFR less than 60 ml/minute calculated using MDRD six formula. HRS type II is defined as a specific form of chronic kidney disease. As many of the cirrhotics have GFR less than 60 ml/minute with serum creatinine levels being normal. Acute on chronic kidney disease is defined as rise in serum creatinine 50% from the baseline or a rise of serum creatinine more than 0.3mg/dL in less than 48 hours in patients with cirrhosis with GFR less than 60 ml/minute for more than three months calculated by MDRD six formula. Cirrhosis Portal (sinusoidal) dysfunc�on
Increased cardiac output
Splenchnic/ systemic vasodilata�on
Decreased effec�ve arterial blood volume High output heart failure Ac�va�on of neurohormonal systems (RAAS, SNS, ADH)
Sodium and water reten�on
Renal vasoconstric�on
Ascites and hyponatremia
Decreased renal blood flow
HRS
Fig. 1: Pathophysiology of HRS
Structural renal disease e.g. ATN GN Post-renal obstruction
Pre-renal azotemia HRS-AKI Non-HRS AKI HRS CKD
Other CKD’s eg: Diabetic Nephropathy
PATHOPHYSIOLOGY OF HRS (FIGURE 1)
Renal vasoconstriction, oxidative stress and sluggish micro circulation are responsible for renal dysfunction. Portal hypertension leads to increase incidence of sheer stress on portal vessels. This leads to splanchnic vasodilation. Activation of various vasoconstrictor systems leads to renal vasoconstriction. Increased translocation of gut bacterial products from the bacterial infection can lead to increased vasodilators leading to splanchnic vasodilation which in turn leads to increased activation of various vasoconstrictor systems leading to renal vasoconstriction. Damage associated metabolic products (DAMS) and PAMS lead to increased oxidative stress and sluggish micro circulation leading to AKI. Infection is the most common precipitant of AKI in liver cirrhosis, while other precipitants are excessive diuretics, GI blood loss and large volume paracentesis. Inflammatory products cause changes in renal tubulus and micro vasculatures. Important amongst them are DAMS & PAMS and TNF alpha. AKI in cirrhosis have got a high mortality. 30 day mortality is around 40% while it is 5% in patients with cirrhosis who are hospitalized. 30 day mortality is increased even in patients who make complete recovery out of AKI. It holds true even in cirrhotic patients treated on outdoor basis.
MANAGEMENT OF HRS IN CIRRHOSIS
Management of AKI depends on diagnosis of AKI in cirrhotics (Figure 2). Withdrawal of diuretics and nephrotoxic drugs, treatment of infections when present, blood transfusion for GI blood loss, volume expansion with albumin should be given in AKI. With response to this treatment if AKI improves, you need to continue the treatment with close follow up. If there is no response or progression of AKI over 48 hours, it should be considered as HRS type I and should be treated with vasoconstrictors and albumin. The use of albumin in AKI has got multiple functions including oncotic pressure, capillary permeability, hemostatic effect, solubilization, transport, and metabolism, endothelial stabilization, antioxidants and immune modulators. Portal hypertension can also cause splanchnic vasodilatation which leads to endothelial dysfunction and also causes decrease extrahepatic blood volume leading to decrease capiallary permeability which in turn lead to the activation of vasoconstrictor causing renal hypo-perfusion. In recent studies Salerno demonstrated dose response curve of albumin infusion in
REFERENCES
1.
2. 3.
4. 5.
6. 7.
Pandey CK, Karna ST, Singh A, Pandey VK, Tandon M, Saluja V. Hepatorenal syndrome: A decade later. JAPI 2014; 62:36-42. Egerod Israelsen M, Gluud LL, Krag A. Acute kidney injury and hepatorenal syndrome in cirrhosis. J Gastroenterol Hepatol 2015; 30:236-43. Nassar Junior AP, Farias AQ, D’ Albuquerque LA, Carrilho FJ, Malbouisson LM. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PLoS One 2014:9;9:e107466. doi:10.1371/journal.pone.0107466. eCollection 2014 Wong F. The evolving concept of acute kidney injury in patients with cirrhosis. Nat Rev Gastroenterol Hepatol 2015; 12:711-9. Shah N, Kowalski A, Desai C, Lerma E. Hepatorenal syndrome. Dis Mon. 2016 Jun 29. pii: S0011-5029(16)300402. doi: 10.1016/j.disamonth.2016.05.009. [Epub ahead of print] Review. PubMed PMID: 27372112. Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, Moreau R, Jalan R, Sarin SK, Piano S, Moore K, Lee SS, Durand F, Salerno F, Caraceni P, Kim WR, Arroyo V, Garcia-Tsao G. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol 2015; 62:968-74.
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Fig. 2: Renal dysfunction in cirrhosis
improving survival of patients with cirrhosis. In addition to albumin, Terlipressin has shown to be effective in treatment of HRS. HRS reversal has been shown in as many as more than 30% patients. Bolus vs continuous infusion of Terlipressin has been shown to be more effective. Small dose of Terlipressin is required in these patients. Significantly less side effects are seen with 2mg Terlipressin over 24 hrs. The other option is Midodrine / Octreotide infusion has been shown to be effective, but its effectiveness is less than Terlipressin. The other option is norepinephrine which has been shown to be equally effective as Terlipressin. Meta-analysis shows equal efficacy of norepinephrine as compared to Terlipressin. Stage I AKI which reverses to normal has been shown to have 2% mortality while AKI if progresses to stage II has 29% mortality, Stage III has 50% mortality and with requirement to dialysis goes up to 55%. AKI stage II if non-progressive, has mortality of 7% while if it progress, mortality is 18% and with requirement of dialysis it goes beyond 50%. AKI stage III if does not progress, mortality is 21% while it progresses, mortality is more than 70%. Regression of stage of AKI is associated with improved survival. Continuous renal replacement therapy (CRRT) should be used with caution in patients with AKI. CRRT is preferred in the removal of inflammatory cytokines such as IL6 and TNF alpha. In type II HRS, TIPS (Transjugular intrahepatic portasystemic shunts) has been used anecdotally. Liver transplantation is definitive treatment for the AKI not responding to therapy. There is still a lot of debate as to when to perform simultaneous liver and kidney transplantation. The general consensus is to do simultaneous liver and kidney transplantation if AKI has been present for more than four weeks. For patients who receive a liver transplant alone, transient persistence of renal dysfunction post-transplant may require short term dialysis.
Should we Treat Chronic Hepatitis B Carrier
C H A P T E R
73
Mamun Al Mahtab, Sheikh Mohammad Fazle Akbar
ABSTRACT
Chronic hepatitis B virus (HBV) carrier state is not a single a disease entity, rather it covers a wide variety of pathological processes starting from minimal liver damage with variable levels of HBV replication as well as with potentials to develop life-threatening complications of HBV like liver cirrhosis, liver failure and hepatocellular carcinoma. These patients are not recommended for therapy because there are no effective therapeutic regimens for them, but they should be treated because they are living and permanent reservoirs of HBV and may also develop intractable liver damages. Thus, there is a need to develop alternative and new evidencebased therapy for these patients as well as other groups of patients. The authors of this manuscript have been working for more than a decade to develop immunetherapy for these patients. This submission will provide a comprehensive discussion about the reality of this problem and the therapeutic direction for them. After the discovery of hepatitis B virus (HBV) in 1970s, significant progresses has been made about virology, epidemiology, natural course, pathogenesis, prevention and therapy of HBV and its complications.1-3 Potent vaccines are now commercially available and several groups of drugs with antiviral and immune modulatory capabilities are available. These combined developments of basic and pharmacological aspects have contained further progress of HBV to some extent. However, effective and satisfactory regimens of management and therapy that would control further progression of HBV and manage HBV-related pathogenesis and complications are yet to be surfaced. One of the major obstacles to win over HBV is the existence of millions of so called â&#x20AC;&#x153;Chronic hepatitis B carriersâ&#x20AC;?, the entity and definition of which is difficult to ascertain and treatment and management of which remains in considerable gray zone. Prior to initiating a discussion about present status of therapy and management of chronic hepatitis B virus carriers, it is of utmost importance to have more insight about the definition and entity of these patients. In general term, patients expressing hepatitis B (HBV) DNA and hepatitis B surface antigen (HBsAg) without evidence of elevated alanine aminotransferase (ALT) are regarded as chronic hepatitis B virus carriers.4-7 There are several hundred million chronic HBV carriers in the global context. However, there are inherent limitations of these definitions and their clinical implications. A group of patients may be diagnosed as chronic HBV carriers
because the virological, biochemical and immunological markers of them may mimic inactive or healthy HBV carriers. They may appear to have sustained normalized of ALT with a natural seronegativity of hepatitis B e antigen (HBeAg) or seroconversion of HBeAg to antiHBe and/or serogenativity of hepatitis B surface antigen (HBsAg) and seroconversion of HBsAg to anti-HBs. On the other hand, there may be another group of patients, who will also be several hundred millions, who express ALT within normal limit at one point of assessment with HBV DNA and/or HBsAg and variable levels of HBeAg, anti-HBe, HBsAg, and anti-HBs would be regarded as chronic HBV carrier in clinical practice. The management strategy of patients with real inactive carrier state versus those with apparent inactive HBV carrier state assessed by measuring HBV-related markers at one point of clinical course should differ considerably.1-7 Almost all international and national liver organizations do not recommend any specific treatment measures for true inactive HBV carriers who have attained sustained control of HBV and liver damage for prolonged period of time (8-10). However, these patients are living and permanent reservoirs of HBV and in fact they are also responsible for transmission of HBV to healthy individuals. In spite of these facts, there is no recommendation for treatment of these patients, because there is no effective drug for them. These patients are in immune tolerance phase and harbor small amount of replicative HBV DNA and without any noticeable evidences of adequate host immunity to HBV and its products. The purpose of therapy would be to make them free of HBV. However, the available antiviral drugs are not effective to eradicate HBV in these patients. It should be clear that therapy is not recommended by AASLD, EASL, APASL, and other regional and national liver organizations because of the facts that there is no drug effective for these patients.8-10 And, it is not true that treatment is not needed for these patients. HBV is a very complex virus and once it enters into the human body, it remains in some form in those patients for decades and possibly for life even after negativity of all HBV-related markers including HBV DNA. Again, we must remember the limitations of assessing HBV DNA and HBV-related markers in real life situation. These are usually accomplished in sera in almost all patients and HBV status in the liver i.e. presence of HBV DNA and HBV-related antigens, remain unknown. Also, a matter of serious consideration is the fact that HBV DNA replicates in the liver. There may be cccDNA in the liver in absence of HBV DNA and HBsAg negativity in the sera, however,
these patients may still allow HBV replication due to alteration of life style, usage of immune suppressed drugs and other medications, and for several unknown factors those could not be elucidated properly till now. Of more importance is the reality of managing these patients in resource-constrained and developing countries of the world that harbor most chronic HBV-infected patients and the utility of recommendations by AASLD, EASL, and APASL cannot be fully applied in these countries.11,12
1.
A group of these patients represent inactive and healthy HBV carrier. They may allow active HBV replication, but do not exhibit evidences of liver damages.
2.
A second group may be negative for HBV-related markers and ALT at the helm of an assay of a single time. However, that may merely represent a state of natural course of HBV in remission phase and that may be succeeded by exacerbation phase in near future.
3.
In real life situation, a workable diagnosis of HBV carrier state is accomplished on the basis of retrieved data from sera, and the replicating site of HBV the liver remain mostly unattended by clinicians to assess chronic HBV carrier state.
4.
The expression that â&#x20AC;&#x153;treatment is not required for chronic HBV carrierâ&#x20AC;? represents grave flaws in Hepatology and related branches of medical science. Rather, it should be clearly mentioned that although treatment is required for these patients, that is not recommended because of lack of appropriate drug that would benefit these patients.
Next, it is of utmost importance to develop and design innovative and alternate therapy for these patients. And, that would provide insights regarding our role and those of others to develop alternate and evidence-based approach of drug development for containment of HBV and HBV-related diseases. As we mentioned, drugs are not recommended for these patients because there is no effective drug, but these patients may require therapy. It is natural query why antiviral drugs being so mighty are unable to control HBV and HBV-related complication in HBV-infected patients. There are several facts for these observations: 1.
2.
The immune modulation capacity of these drugs are neither appropriate in the context of quality or quantity. Some of these induce immune restoration in some patients as a secondary effect of HBV containment.
These facts indicate that some drug may be required to offer an effective therapy for chronic HBV carriers and immune-therapy became an area of development of innovative therapy for HBV-related pathologies.13,14 After the usage of antigen non-specific immune inducers in HBV-infected patients, HBV antigen-specific immune therapy has been initiated in these patients during the last two decades. HBsAg-based immune therapy was safe and effective initially but sustained control of HBV replication and containment of liver damages could not be accomplished with that approach and even various modifications of HBsAg-based immunity could not stand the test of time. With the understanding that HBcAgspecific immunity contain HBV replication and control liver damages and HBsAg-based immunity control HBV in the sera, a new therapeutic vaccine have been developed by our in-house studies and clinical trials15-18 and phase I/II/III clinical trials have been accomplished in patients with chronic hepatitis B (CHB) in Bangladesh. This HBsAg/HBcAg-based therapeutic vaccine is capable of inducing HBV-specific broad-based immunity and we are planning to use this therapeutic vaccine for treating chronic HBV carriers. The role of this therapeutic vaccine has been assessed in an animal model of HBV carrier state to see the feasibility of this therapeutic vaccine in asymptomatic, healthy and inactive HBV carriers. The data of trials in HBV transgenic mice, an animal model mimicking inactive and healthy HBV carrier is extremely exciting and it seems that this therapeutic vaccine may induce anti-HBs in HBV TM.19,20 In conclusion, all HBV-infected subjects should be treated, because patients with prolonged suppression of HBV replication and controlling liver damages may develop HBV-related complications and also may transmit HBV to heathy and HBV uninfected subjects. The challenge is how to treat? The available antiviral drugs would not be effective and a complete dependence on the future trials with innovative immune therapeutic agents represent hopes for the time being. However, irrespective of these developments, all chronic HBV carriers should be properly followed up and the avenue of drug development for these patients should be prioritized.
REFERENCES
All antiviral drugs for HBV have not been developed depending on the life cycle and pathogenesis of HBV. Rather, the most of these drugs were developed to control retroviral infection and just modified to conform in HBV situation.
1.
Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology 2015; 479-480, 672-686.
2.
Hadziyannis SJ, Vassilopoulos D, Hadziyannis E. The natural course of chronic hepatitis B virus infection and its management. Adv Pharmacol 2013; 67:247-291.
Accordingly, these drugs are capable of controlling or regulating replicative HBV satisfactorily and with vigor, but unable to control cccDNA and possibly extra-hepatic HBV DNA.
3.
Zeisel MB, Lucifora J, Mason WS, et al. Towards an HBV cure: state-of-the-art and unresolved questions--report of the ANRS workshop on HBV cure. Gut 2015; 64:1314-1326.
4.
Al-Mahtab, Akbar SM, Uddin H, Khan, SI, Rahman S. Early termination of immune tolerance state of hepatitis B virus
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On the basis of these facts, the following points may be considered as hotspots regarding management of chronic HBV carrier:
3.
338 5.
HEPATOLOGY
6.
7.
8.
9.
infection explains liver damage. World J Hepatol 2014; 6:621625
markers, innovative therapy, and global collaboration. J Gastroenterol 2011; 46:717-23
Jahan M, Islam MA, Akbar SM, Takahashi K, Tabassum S, Rahman A, Haque MA, Biswas J, Mishiro S, Al-Mahtab M. Anti-HBc Screening of Blood Donors in Bangladesh: Relevance to Containment of HBV Propagation. J Clin Exp Hepatol 2016; 6:115-8
13. Akbar SM, Al-Mahtab M, Jahan M, Yoshida O, Hiasa Y. Novel insights into immunotherapy for hepatitis B patients. Expert Rev Gastroenterol Hepatol 2016; 10:267-76.
Al-Mahtab M, Akbar SM, Rahman S, Kamal M, Khan MSI. Biochemical, virological, immunological and histopathological features of 702 incidentally detected chronic hepatitis B virus carriers in Bangladesh. Digestion 2012; 86:1-5 Al-Mahtab M, Rahman S, Akbar SM, Kamal M, Khan SI. Clinical use of liver biopsy for the diagnosis and management of inactive and asymptomatic hepatitis B virus carriers in Bangladesh. J Med Virol 2010; 82:1350-4. Koh C, Zhao X, Samala N, Sakiani S, Liang TJ, Talwalkar JA. AASLD clinical practice guidelines: a critical review of scientific evidence and evolving recommendations. Hepatology 2013; 58:2142-52. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012; 57: 167-85.
10. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016; 10:1-98 11. Akbar SM, Hiasa Y, Mishiro S, Onji M. Treatment of hepatitis B virus-infected patients: utility of therapeutic recommendations in developing countries. Expert Opin Pharmacother 2009; 10:1605-1614. 12. Akbar SM, Al-Mahtab M, Hiasa Y. Future aspects of therapy for hepatitis B virus infection: value of surrogate
14. Akbar SM, Al-Mahtab M, Hiasa Y. Designing Immune therapy for chronic hepatitis B. J Clin Exp Hepat 2014; 4:241246 15. Al-Mahtab M, Rahman S, Akbar SM, Khan SI, Uddin H, Karim F, Ahmed F. Combination therapy with antiviral drugs and hepatitis B vaccine in incidentally-detected and asymptomatic chronic hepatitis B virus carriers at Bangladesh. Viral Immunology 2010; 23:335-8. 16. Akbar SM, Al-Mahtab M, Uddin MH, Khan MSI. Scope and limitation of HBsAg-, HBcAg-, and HBsAg/HBcAg-based combined therapeutic vaccines in chronic HBV infection: Evidences from laboratory benches and patientâ&#x20AC;&#x2122;s bedsides. Hepatobiliary Pancreat Dis Int 2013; 12:363-9. 17. Akbar SM, Al-Mahtab M, Khan SI. Non-antigen-specific and antigen-specific immune therapies for chronic hepatitis B: Evidences from laboratory benches and patientâ&#x20AC;&#x2122;s bedsides. Expert Opion Biol Ther 2013; 13:1063-74. 18. Al-Mahtab M, Akbar SM, Aguilar JC, Uddin MH, Khan MS, Rahman S. Therapeutic potential of a combined hepatitis B virus surface and core antigen vaccine in patients with chronic hepatitis B. Hepatol Int 2013; 7:981-9. 19. Akbar SM, Chen S, Al-Mahtab M, Abe M, Hiasa Y, Onji M.. Strong and multi-antigen specific immunity by hepatitis B core antigen (HBcAg)-based vaccines in a murine model of chronic hepatitis B: HBcAg is a candidate for a therapeutic vaccine against hepatitis B virus. Antiviral Res. 2012; 96:5964. 20. Akbar SM, Yoshida O, Chen S, Aguilar AJ, Abe M, Matsuura B, Hiasa Y, Onji M. Immune modulator and antiviral potential of dendritic cells pulsed with both hepatitis B surface antigen and core antigen for treating chronic HBV infection. Antiviral Therapy 2010; 15:887-95.
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Hepatitis C: Paradigm Shift in the Management
INTRODUCTION
Hepatitis C virus (HCV) has affected over 150 million people around the world with global prevalence of 2-3%. Prevalence of HCV infection in India is 0.9 to 1.9%, which varies across the different regions of the country. Genotype 3 is the most common genotype in India, followed by genotype 1. Initially only interferon based treatments were available which were not well tolerated, especially in patients with cirrhosis. Since 2015, with the availability of generic directly acting antivirals (DAA), there has been a paradigm shift in the treatment of HCV in India.
EVALUATION OF THE PATIENT WITH HEPATITIS C
Most patients would be unaware of their infection. Screening if undertaken should be targeted to those at high risk of the infection. In India, common risk factors for transmission are unsafe injections and past history of blood transfusions prior to the year 2002, when testing for Hepatitis C became mandatory for all blood banks in India. Positive HCV antibody test needs to be followed by a HCV RNA test to confirm presence of the virus. HCV Antibody may be negative very early after the infection upto few weeks and in immune compromised states like patients on hemodialysis and those with HIV infection. HCV RNA test then is required for diagnosis of the infection. Genotyping and subtyping is done prior to treatment as certain treatment regimes are less effective in certain subtypes (e.g. Geno1a v/s. 1b) or ineffective in some (eg Sofosbuvir + Ledepasvir in Geno 3). With effective pan genotypic combinations like Sofosbuvir + Velpatsvir and Sofosbuvir + Daclatasvir this requirement should become irrelevant. Genotype (GT) 3 accounts for 54- 80% of cases in India. Initially Geno 3 was grouped with Geno 2 and considered it â&#x20AC;&#x153;easy to treatâ&#x20AC;?. With the advent of D.A.A.s it was realized that Geno 3 patients especially those with cirrhosis who have failed treatment in past are now a difficult to treat population with lower response rates in this genotype. Role of IL28B polymorphism has become less important in the era of new DAA as response rates are more than 90% in most situations. Assessment of clinical status and noninvasive assessment of fibrosis by imaging is important as presence of cirrhosis and decompensation and prior treatment failure may affect sustained virological response (SVR).
Samir R Shah, Vibhor Borkar
TREATMENT OF CHRONIC HEPATITIS C
Who should be treated?
In the ideal world all those having a hepatitis C virus infection needs treatment. Earlier when treatment was limited in safety and efficacy only patients with significant liver disease were identified for treatment. With safe and effective oral therapy now, only the cost of treatment remains the limiting factor. Treatment may be prioritized in certain patients who have high risk of progression like those with significant fibrosis or cirrhosis especially, ones with decompensated cirrhosis, HBV or HIV co-infection, HCV recurrence after liver transplantation, presence of clinically significant extra-hepatic manifestations and individuals who are at the risk of transmitting HCV. Counselling to stop alcohol consumption needs to be emphasized.
Goal of the treatment
The goal of therapy is to cure HCV infection in order to prevent the complications of HCV-related liver fibrosis and cirrhosis which can result in decompensation, HCC and death. The endpoint of therapy is a SVR, defined by undetectable HCV RNA 12-24 weeks after end of treatment. Once the virus is undetectable 12-24 weeks after end of treatment (SVR 12/24) the chances of recurrence are <1% and can be termed a cure in more than 99% of cases. In patients with advanced fibrosis and cirrhosis, HCV eradication reduces the rate of decompensation and may reduce however not abolish the risk of HCC surveillance for HCC by six monthly ultrasound will need to be continued even after viral clearance. Anti HCV tests remains positive in the majority despite successful viral clearance and should not raise concern of persistent or recurrent infection.
How to treat
Superior safety, efficacy and broader eligibility make oral DAA the preferred regime. No single DAA is known to be efficacious by itself. Combination of two or more DAAs for 12-24 weeks, with/without Ribavirin are currently recommended. Currently available combinations are tabulated in Table 1. Drug-Drug interactions need to be looked into before prescribing. All currently accepted combinations have response rates > 90%. The efficacy is lower in presence of decompensated cirrhosis especially in Genotype 3. Extending treatment duration to 24 weeks and addition of Ribavirin will then be needed to be considered to optimize response (Figure 1). Resistance is not known to Sofosbuvir but clinically relevant resistant
340
Table 1
Currently Available DAA Combinations
Table1: Currently available DAA combinations Combination
Protease Inhibitors
Polymerase Inhibitors
HEPATOLOGY
Nucleotide
NS5A Inhibitors
Geno
Availability In India
Nonnucleotide
1
Sofosbuvir
Ledipasvir
1,4,5,6
YES
2
Sofosbuvir
Velpatasvir
All
NO (likely in 2017)
3
Sofosbuvir
Daclatasvir
All
YES
Ombitasvir
1,4,5,6
NO
Elbasvir
1,4,5,6
NO
4
Paritaprevir/Ritonavir
5
Grazoprevir
1 Figure 1
Dasabuvir
Sof + Ledipasvir
2 Sof+ Velpatasvir
Choice of Regimes in Different Clinical Situations
4 Partiprevir/Ritonavir + Dasabuvir + Ombitasvir
NaĂŻve
Cirrhotic
Non Cirrhotic
8W
12 W
Treatment Experienced Decompensated
24 W *
24 W + Riba *
* Standard treatment duration of 12 Weeks need to be extended to 24 weeks and Riabvirin added in difficult to treat decompensated liver disease who have failed prior therapy
* Selected patients of Geno 1 who are naĂŻve, non cirrhotic with HCV viral load less than 200,000 IU/ml could be considered for shortened 8 weeks of duration of treatment
Fig. 1: Choice of Regimes in Different Clinical Situations variants are noted with other groups of DAAs. Pegylated Interferon based regime are not known to have any resistance. PegIFN and Ribavirin in combination with Sofosburvir for 12 weeks is recommended for difficult to treat patients who are prior non responders to current DAAs. Those not responding to currently available regimes will have the opportunity for treatment with the next generation of DAAs.
SPECIAL SUBGROUPS
HBV Coinfections
In patients with HBV- HCV co-infection, C virus is usually the predominant virus. HBVDNA may be low or undetectable. HCV should then be treated with
3
Sof + Daclatasvir
5 Grazoprevir + Elbasvir
same regimes as discussed previously. HBV replication should be monitored during and following the therapy as anti HBV treatment will need to be started to prevent reactivation of Hepatitis B after clearance of HCV.
HIV Coinfections
In HIV/HCV coinfection, there is higher rate of HCV persistence, faster progression to cirrhosis and end stage liver disease. Lower responses to Peginterferon and Ribavirin were noted but with DAA, the response in HCV mono infected and HIV/HCV coinfected patients are similar but drug to drug interactions will need to be kept in mind.
Pateints with Chronic Kidney Disease with/without hemodialysis
Standard Sofosbuvir based regimes are safe to be used in CKD with EGFR >30 ml/min and no dose adjustments are needed. Simeprevir, Daclatasvir, combination of Grazoprevir with Elbasvir and the triple combination of Ritonavir boosted Paritaprevir, Ombitasvir and Dasabuvir are all cleared by hepatic metabolism and can be used in patients with severe renal disease. Sofosbuvir is eliminated only by renal route and Sofosbuvir based regimes are not licensed for use in patients with end stage renal disease on dialysis and EGFR <30 ml/min. as concerns have been raised about higher concentrations of Sofosbuvir and its renally excreted metabolite. Although use of Sofosbuvir based regimes in advanced renal disease
have been reported in literature (despite it not being licensed for use) no dose adjustments are recommended for its use in this setting. Progressive deterioration of renal function has been noted in this setting. Non sofosbuvir based regime may be given in patients on dialysis but are effective only in Genotype 1 and as yet unavailable in India. Decision needs to be taken whether treatment for HCV can be postponed till after the renal transplant when it can be safe and efficacious.
REFERENCES
1.
European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C. Journal of Hepatology 2015; 63:199â&#x20AC;&#x201C;236.
2.
AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 2015; 62:932-54.
3.
Puri P, Saraswat VA, Dhiman RK, Anand AC, Acharya SK, Singh SP, Chawla YK, Amarapurkar DN, Kumar A, Arora A, Dixit VK, Koshy A, Sood A, Duseja A, Kapoor D, Madan K, Srivastava A, Kumar A, Wadhawan M, Goel A, Verma A, Shalimar, Pandey G, Malik R, Agrawal S. Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016. J Clin Exp Hepatol 2016; 6:119-45.
4.
Puri P, Anand AC, Saraswat VA, Acharya SK, Dhiman RK, Sarin SK, Singh SP,Chawla YK, Aggarwal R, Amarapurkar D, Arora A, Dixit VK, Sood A, Shah S, Duseja A, Kapoor D, Shalimar, Madan K, Pande G, Nagral A, Kar P, Koshy A, Puri AS, Eapen CE, Thareja S. Indian National Association for Study of the Liver (INASL)Guidance for Antiviral Therapy Against HCV Infection in 2015. J Clin Exp Hepatol 2015; 5:221-38.
5.
Puri P, Anand AC, Saraswat VA, Acharya SK, Dhiman RK, Aggarwal R, Singh SP, Amarapurkar D, Arora A, Chhabra M, Chetri K, Choudhuri G, Dixit VK, Duseja A,Jain AK, Kapoorz D, Kar P, Koshy A, Kumar A, Madan K, Misra SP, Prasad MV, Nagral A, Puri AS, Jeyamani R, Saigal S, Sarin SK, Shah S, Sharma PK, Sood A, Thareja S, Wadhawan M. Consensus Statement of HCV Task Force of the Indian National Association for Study of the Liver (INASL). Part I: Status Report of HCV Infection in India. J Clin Exp Hepatol 2014; 4:106-16.
Treatment of Acute HCV
Icteric illness following an acute HCV infection usually results in spontaneous clearance of the virus. However, acute HCV infections are usually asymptomatic, and may have high rate (50-90%) of chronicity. Hence, antiviral treatment should be considered in all acute HCV infections if HCV viremia persists beyond12 weeks. High SVR rates were reported with Peginterferon therapy in this situation which are being replicated in early studies with the oral DAAs. There is no indication of antiviral therapy as post exposure prophylaxis in the absence of documented HCV transmission.
Hemogloblinopathy and bleeding disorders
Interferon and Ribavirin free regimen with DAAs are now possible for HCV patients with hemogloblinopathy and bleeding disorders.
CONCLUSIONS
With the advent of DAAs, treatment of HCV now can result in a cure in more than 90% of patients. Strategies for
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Unless strict infection control practices are followed in the hemodialysis units reinfection of the HCV patient who is not a transplant candidate and continued non hemodialysis is always a possibility.
screening and early detection with access to care are now the challenges to be faced. Prevention of end stage liver disease and HCC with early recognition and treatment of HCV may still take decades to achieve but is a goal towards which we need to persevere.
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Hepatocellular Cancer (HCC): Screening and Management Subrat Kumar Acharya, Sashi Bala Paul, Shalimar
INTRODUCTION
The World Cancer report published in 2014 by the International Agency for Research on Cancer (IARC), WHO, documented that hepatocellular cancers (HCC) are the second most frequent cause of cancer related deaths in the world. As per this report, collated by 250 leading scientists from 40 countries, the most common causes of cancer death in 2012 were cancers of the lung (1.6 million, 19.4% of the total), liver (0.8 million, 9.1%), and stomach (0.7 million, 8.8%).1 During the last three decades, information on various aspects in HCC has exploded leading to improved prevention, diagnosis, staging and management. Liver transplant (LT) in HCC today is feasible and successful, with a 5 year survival reaching up to 70%. On the other hand, incidence of HCC globally has doubled and HCC related deaths have increased during the last two decades. Possible reasons for this rise include inadequate control strategies to ameliorate hepatitis B virus (HBV) and hepatitis C virus (HCV) infection which are the leading causes of HCC globally. Moreover, there is also a steady rise in the prevalence of lifestyle related diseases like non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease, which are also important causes of HCC. Between 1999 and 2009, at least 32 well evaluated guidelines on prevention, diagnosis, staging and management of HCC have been published. Most of these consensus recommendations have emanated from the developed world. Such recommendations, even though evidenced based, are often inadequate in resource constrained countries like India where the infrastructure for holistic approach to control and treat HCC is still inadequate and may be considered suboptimal.2 Moreover, due to substantial hepatic reserve, often liver diseases do not have specific phenotypic clinical manifestations. Usual clinical experience in India suggests that HCC most often presents clinically in very advanced stages when curative or even effective palliation cannot be offered to these sick patients. It is ironical to have such a dichotomy between rapid and substantial advancement in this area and transferring these benefits to those with HCC in India due to inadequate awareness and infrastructure. In this review, we provide a concise approach to HCC in relevance to our population.
EPIDEMIOLOGY RELEVANT TO INDIA
Globally, approximately 6 lakh new cases of HCC occur every year, which makes HCC the 5th most common cause of cancers affecting humans. The mortality is also very high; approximately 2.5 lakh deaths due to HCC occur
annually.3 In India, information on HCC is inadequate. From 1988 till December 2015, i.e over two and a half decades, only 74 publications have been listed in the PUBMED- all from tertiary care centers, on select areas and most studies include small samples. The cancer registries in India probably do not provide accurate estimates of HCC prevalence due to their predominant urban locations. The sources of information about cancers are from cytology, oncology sites, and municipal registers of death. HCC are diagnosed and treated by Gastroenterologists/ Hepatologists/ Transplant Surgeons as well as G.I. Surgeons. Most of the patients treated by these specialists are presumably are not listed in the registries. Furthermore, these days the diagnosis of HCC is made by non-invasive imaging techniques rather than by histology/ cytological techniques as used in almost all other cancers. Therefore, the collated information from oncology/cytology/pathology departments may not be having the records of considerable proportions of HCC cases. Lastly, cancers are not a reportable disease in India. National cancer registry program of the Indian Council of Medical Research (ICMR) has recently expanded to include 21 population based and 6 hospital based cancer registries. The last published registry data by ICMR available in the cancer registry website (www. ncrpindia.org) provides information on various cancers from 2012 to 2014. The other source of information is the report published by World Health Organization (WHO). According to the available data, the age adjusted incidence rate of HCC in India for men ranges from 0.7 to 7.5 per 100,000 population and, for women 0.2 to 2.2 per 100,000 population. The male: female ratio for HCC in India is 4:1.2 The age of presentation varies from 40 to 70 years. According to a recent study conducted by verbal autopsy in 1.1 million homes representing the whole country, the age standardized mortality rate for HCC in India for men is 6.8/100,000 and for women is 5.1/100,000.2 According to another study, the incidence of HCC in cirrhotics in India is 1.6% per year.4 The unpublished data from various tertiary care centers suggests that the incidence of HCC is increasing in India.2 Worldwide, the single largest risk factor in the development of HCC is cirrhosis of any etiology. Cirrhosis is present in about 70â&#x20AC;&#x201C;97% of those who have HCC.5,6 Among the etiologies, chronic HBV infection, chronic HCV infection, alcohol consumption, and aflatoxin exposure are important risk factors for HCC development.3 Less common causes include NAFLD, hereditary hemochromatosis, alpha-antitrypsin
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Why screening?
Fig. 1: The Barcelona Clinic Liver Cancer Staging System for HCC7 deficiency, autoimmune hepatitis, porphyrias, Wilsonâ&#x20AC;&#x2122;s disease, smoking and tobacco use. The distribution of these risk factors among patients with HCC is highly variable, depending on geographic region and race or ethnic group. Diabetes mellitus is also known to be associated with elevated risks of both HCC incidence and mortality. Indian studies have also corroborated these findings and cirrhosis of liver due to HBV, HCV, alcohol consumption, and aflatoxin exposure have been found to be the most important risk factors for HCC development. In addition to these, NAFLD is now increasingly being recognized in India as a cause of HCC. Diabetes, in addition to being a risk factor of HCC in India, has also been found to be associated with more advanced HCC and poor outcome.3
STAGING OF HCC AND ITS RELEVANCE
Five important factors influence the prognosis, type of therapy needed and the response to therapy, a) the underlying liver disease status, b) tumor burden at diagnosis, c) tumor infiltration into the vessels present in the liver, d) constitutional symptoms and e) spread of the tumor outside the confinements of the liver. In addition, the underlying etiology of the primary liver disease needs to be treated effectively to prevent subsequent recurrence of tumor and progress of the underlying liver disease. Any staging of HCC ideally should account for each of them. However, such an ideal staging system is yet to be devised. There is no worldwide consensus about the use of any HCC staging system, and the choice of system varies significantly by country. These staging systems include TNM, French staging, Okuda staging, Cancer of the Liver Italian Program (CLIP), Japan Integrated staging systems (JIS), Tokyo scores, Chinese University Prognostic Index (CUPI) and Barcelona Clinic Liver Cancer (BCLC) staging systems. The BCLC and CLIP staging systems are used most frequently in Europe, whereas the JIS system has been accepted as a standard in Japan. However, BCLC staging has been widely used as the standard means of assessing the prognosis as well as for allocation of treatment for patients with HCC.3 In this review, we will discuss only the BCLC staging system which is most commonly followed in India (Figure 1).
Whom To Screen
Throughout the globe, cirrhotic patients and those with advanced hepatic fibrosis irrespective of its etiology have been reported to have the highest incidence of HCC. If the annual risk of HCC development exceeds >1.5%, screening has been suggested by WHO as well as most of the guidelines due to its cost benefit aspect. In India, cohort follow up studies in cirrhotics have revealed an annual incidence of HCC of around 1.6%. Therefore, cirrhosis patients should be undergo regular surveillance for early HCC detection.5 High incidence rates of HCC are also observed in patients with chronic HBV infection, even without cirrhosis. Consequently, screening of this sub-group of patients depends on the regional incidence of HBV infection. INASL guidelines recommend screening for chronic HBV infected patients in males older than 40 years and in women older than 50 years.3 In addition, screening should be performed for all CHB patients with a family history of HCC. In India, fibroscan is now available in most tertiary care centers. There are now reports indicating identification of high risk candidates for HCC as per the liver stiffness value detected by fibroscan. However, more information is necessary to provide region specific guidelines to use fibroscan to identify high risk patients for HCC.
How to Screen
The effectiveness of HCC surveillance depends on adherence to screening and sensitivity of the surveillance method. Generally, surveillance utilization and sensitivity has been suggested to be at least 34% and 42%, respectively, for a meaning full screening strategy.8 Cost-effectiveness of screening by using abdominal USG has been reported in several studies and constitutes the backbone of all recommendations. In India, ultrasound is widely available, non-invasive and less inexpensive than any other imaging modalities. Itâ&#x20AC;&#x2122;s accuracy in detecting early HCC can be improved by an ultrasonologist experienced at HCC detection. It is preferable to conduct such screening of high risk population at tertiary care referral centers. The ideal screening interval for cirrhotic patients of six months has been suggested by most practice guidelines
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HCC usually clinically presents in advanced stages when therapeutic options are limited, treatment with a curative intent is not feasible and prognosis is dismal.2,3 Those patients who are diagnosed at an early stage can be offered curative options.2 The high risk conditions for development of HCC are well known. Surveillance of at-risk patients with simple, widely available and less expensive screening strategies- like ultrasonography at 6 monthly intervals- have been reported to detect small/ early HCCs. Such advancement in early cancer detection associated with cure is yet unusual in other solid cancers in human.
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Table 1: Survival of HCC with and without treatment as per BCLC staging7 BCLC Stage
Median survival without treatment
Survival with stage specific therapy
Type of therapy offered
Stage 0
>36 months
5 year survival in 80-90% patients
Resection, Ablation, LT
Stage A
36 months
5 year survival in 50-75% patients
Resection, Ablation, LT
Stage B
16 months
2 year median survival in 60% patients
TACE
Stage C
4- 6 months
8-12 months
TARE, Sorafenib
Stage D
< 4 months
Survival improvement is uncertain in patients with distant metastasis and poor liver function
Supportive
because it significantly improves sensitivity of early HCC detection compared to 12 months (70% vs 50%). A shorter screening interval of three months did not yield either earlier stage lesions or patients eligible for curative treatment and additionally increased cost. Additional biomarkers such as alfa-fetoprotein (AFP) and PIVKA II with abdominal ultrasonography have been reported to increase the sensitivity for early HCC detection, in patients at risk. However, elevated serum AFP has been documented in cirrhotic patients without HCC particularly in those with active ongoing inflammation and regeneration. A cut-off value of 20 ng/ml was shown to have a satisfactory level of specificity of AFP; however, sensitivity remained only 60%. Reducing the cut off level to below 20 ng/ml has been reported to cause high rate of false positivity. In an Indian study, estimation of AFP levels was not found to be sensitive enough and its addition did not enhance the detection frequency of HCC in cirrhotics.5 Therefore, INASL, AASLD and EASL do not recommend the inclusion of AFP levels in the screening tools in the surveillance programs for HCC detection.
Management
In the earlier section (staging of HCC), we briefly discussed about specific management of HCC depending upon the stage of HCC as per BCLC staging system. With treatment, irrespective of the stage of HCC, survival has been reported to improve substantially (Table 1).
Treatment of Very Early and Early HCC
In recent years, by surveillance of cirrhotic population, increased numbers of patients are detected with very early HCC. They can be subjected to curative options such as liver resection (LR), LT, and RFA. The early HCC which includes BCLC-A (Child A status, three tumors with largest â&#x2030;¤ 3cm, Okuda 1, PST 0, without vascular invasion or extrahepatic spread) for Indian context can also follow same strategies as in very early HCC, except for the fact that in such patients LT (if available) may be a better option than LR or RFA. However, studies comparing all the three
If small tumor and fulfills Milanâ&#x20AC;&#x2122;s criteria or UCSF transplant criteria without distant spread, despite poor liver function results are good with LT
forms of therapy in very early HCC in homogeneous population with similar liver reserve are unavailable. There are prospective as well retrospective studies comparing RFA and liver LR. LT is considered to be the best option for any HCC in a cirrhotic liver provided the patient satisfies the defined criteria for such therapy. LT removes the diseased cirrhotic liver as well as the tumor and corrects the sequelae of cirrhosis as well. However, at present, according to most expert opinions, LT in very early HCC is considered to be a second line therapy to RFA or LR because of its cost, accessibility, expertise, unavailability of organs, post transplant management strategies with follow-ups and regional prioritization as well as the type of LT (Diseased donor or Live-related LT). Moreover, LR or RFA provides almost similar overall and disease free survival. Table 2 summarizes the indications, long term results, recurrence rates and advantages of various therapies available for management of very early and early HCC.
Treatment of Intermediately advanced HCC
These patients can be subjected to liver transplant with good outcome, but the other curative options such as RFA and LR lacks adequate evidence as curative options in such patients. In absence of LT these patients are subjected to palliative therapy such as TACE or TARE.3
Transarterial chemoembolization (TACE)
TACE is a radiological interventional procedure in which sequential, intra-arterial injection of chemotherapeutic agents (usually doxorubicin, or epirubicin or a combination of mitomycin C, doxorubicin, and cisplatin) mixed with Lipiodol is injected through the artery feeding the tumor in the liver using image guided transarterial microcatheters followed by an embolising particles such as Gelfoam or preferably, calibrated particles to block the feeding artery after delivery of the chemotherapeutic agents to the tumor. These chemotherapeutic agents also cause damage to the surrounding hepatocytes and can leak into systemic circulation and therefore are associated
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Table 2: Summary of available therapies in Early and very early HCC in presence of Cirrhosis of liver
Tumor size, number and location Liver reserve and Portal hypertension (PHT)
Radio Frequency Ablation (RFA)
Liver Transplant (LT)
Usually small, â&#x2030;¤ 3 cm up to 3 tumors preferably located in one segment/ lobe. Single tumor up to 5 cm preferably in peripheral location and not in central locations.
Same as in LR but can be present in both lobes and can be offered even to those who do not satisfy criteria for surgery.
Liver reserve should be good (as assessed by Child status - preferably Child A/ MELD-10/ Indocyanine green clearance test may be used to assess hepatic reserve to prevent post hepatectomy liver failure.
To be avoided if tumor is on surface, near major vessels or gall bladder.
LT should be offered if with similar tumor characteristics as mentioned in LR and RFA, but the liver function is bad (Child B or C) and both RFA or LR are not possible
Preferable for centrally located tumors.
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Liver Resection (LR)
Good liver function is associated with better long term results.
Absence of PHT (HVPG < 10 mm Hg or absence of portosystemic collaterals in imaging and endoscopy) Availability of Skill & Expertise
LR should be done in preferably in high volume hepatobiliary surgical unit with expertise to recognize and treat the post operative liver failure as its complication
RFA should be preferably performed by a team of interventional trained Radiologist in combination with hepatologists
LT needs a team of well trained experts in transplant surgery, hepatology, radiology, pathology, transfusion services and infection control.
Over all 4 to 5 year survival
52-82%
30-81%
75-85%
Disease Free 3 to 5 year survival
50-76%
40-60%
70-80%
Recurrence rates in 1-2 years
30-50%
50-70%
5-10%
Complications
20-50%
4-10%
3-10%
Advantages
With good liver function and limited tumor burden it can have similar survival as LT.
Can be offered if surgery cannot be done due to lack of sufficient liver reserve, presence of PHT or hyperbilirubinemia. It can be used as a first line therapy due to its less invasive nature with much less complications than in surgery. It can be also used as a bridge to liver transplant
Removes diseased liver and the tumor and corrects the sequels of cirrhosis in long term. Can be used for salvage if LR and RFA fails or tumor recurs
In presence of organ shortage can be used as bridge to LT. Salvage transplant can be offered if liver function deteriorates or recurrence occurs. Also, resected specimen provides the tumor biology such as microvascular invasion, degree of differentiation and small satellite nodules all of which indicate high recurrence rate and therefore can be transplanted at a suitable time
346 1.00
Kaplan-Meier survival estimates, by size 1
Table 3: Absolute and relative contraindications to TACE and DEB-TACE
0.75
Absolute contraindications
0.50
Decompensated cirrhosis (jaundice, ascites, encephalopathy, recent variceal hemorrhage) Technical contraindications to intra-arterial treatment
0.25
Renal failure (serum creatinine> 2 mg/dl, glomerular filtration rate < 30 ml/min)
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0.00
Massive tumour involving both lobes 0
20
40
size 1 = < 5 size 1 = > 10
60
80
size 1 = 5-10
Fig. 1: Kaplan-Meier survival curve shows the survival of patients of TACE with different sizes of the mass at the time of treatment. Patients with a tumor size of less than 5 cm (blue curve) have a longer survival period than those with a mass size of 5-10 cm (red curve) or more than 10 cm (green curve) with hepatotoxicity as well as systemic side effects of the chemotherapeutic agents. To overcome these hepatic and systemic side effects, recently drug eluding beads (DEBs) have been developed. DEBs are produced from a biocompatible polyvinyl alcohol (PVA) hydrogel that has been modified with sulphonate groups for the controlled loading and delivery of chemotherapeutic drugs. DEBs occlude the blood flow to the target tissue and deliver a local and sustained dose of drug direct to the tumor and have been reported to cause less hepatic and systemic side effects with controlled delivery of the drug to the tumor over a longer period of time. Therefore, DEB based TACE is also known as DEB-TACE. Both TACE and DEB-TACE are used in repeated sessions with a follow up Triphasic CT or MR to evaluate the residual tumor tissue after 4 to 8 weeks of TACE or DEB-TACE. Usual recommendation is to do at best 4 sessions of such therapy over 6 month to 1 year in patients with HCC having BCLC-B status.3 Meta analysis and many randomized controlled trial have distinctly documented the survival benefit of the treatment in intermediately advanced unresectable HCC in whom RFA or LT is not possible. All these trials included patients with good liver function without distant spread and vascular invasion. Even these treatments have been used in early HCC in whom RFA or LR is not feasible with good results in terms of tumor control and survival. However, the survival rates subsequent to TACE as reported in various series have been variable. Reported 1, 2 and 5 year survival rates with TACE, as available in published literature, are 53-90%, 11-67%, and 8-26% respectively which seems to be better than untreated patients under similar conditions, as shown in Table 1. In one Indian study, patients with cirrhosis (Childs A and B) with HCC who were subjected to TACE- 1 to 4 sessions over 12 month of median follow up- had 1, 2 and, 3 year survival of 66 %, 47%, and 36.4% respectively.9 In this study the initial tumor size was main predictor of survival
Severely impaired portal vein blood flow (main or branch portal vein thrombosis, hepatofugal blood flow) Relative contraindications 1. Large tumour size (> 10 cms) 2. Bile duct occlusion or incompetent papilla due to stent or surgery 3. Untreated varices at high risk of bleeding 4. Segmental or branch portal vein thrombosis 5. Intense, non-correctable hepato-pulmonary shunt and the procedure (Figure 1) was well tolerated by most patients and mortality was less than 3 % during the study period. The above mentioned widely variable outcomes reported after TACE would indicate the importance of appropriate patient selection and expertise in the procedure. Liver function is the major determinant for selecting patients for TACE and survival benefits only have been documented in Child Pugh A or B7 patients in absence of ascites. Further, such patients should have clearly identified feeding vessels to the tumor which can be microcatheterised and can be isolated angiographically so that selective TACE can be performed for the segment in which the tumor is present. Such a strategy limits the hepatotoxicity and prevents embolization of the artery supplying the whole lobe of the liver, but needs expertise. An expert group recently recommended the absolute and relative contraindications for TACE treatment of HCC patients in the intermediate stage (Table 3).10 One of the absolute contraindication of TACE is main portal vein thrombosis (PVT), because arterial blockage in such patents may cause liver failure due to ischemic liver injury. However, many centers use TACE in selected patients with segmental portal vein branch invasion, though survival benefits in such patients is unclear. At our center and most other tertiary centres, if even after two sessions of TACE adequate tumor response (evidenced by absence of arterial enhancement of at least more than 50% of the viable tumor tissue as evaluated by Triple phase MR or CT) is not achieved, additional therapies are considered- including systemic agent sorafenib. With careful planning of technique, patient selection and strategy a median overall survival in excess of 20 months is usually achievable. The recent studies using DEB-TACE however have shown a marginal edge over TACE with reported median
Table 4: Milan’s Criteria for Liver Transplant in HCC (This does not include liver function status)11
Table 5: The UCSF criteria for liver transplantation in patients with HCC12
• One lesion smaller than 5 cm
• Single lesion ≤ 6.5 cm
• Up to 3 lesions smaller than 3 cm
• Multiple lesions ≤ 3 cm
• No extrahepatic manifestations
• Largest tumor diameter if multiple ≤ 4.5 cm
• No vascular invasion
• Total tumor diameter if multiple ≤ 8 cm
survival of about 48 to 52 months and distinctly lower side effects than the latter therapeutic procedure. HCC patients with PVT are not suitable for TACE, as mentioned earlier. Such patients have been found to have beneficial therapeutic outcomes in terms of survival and quality of life with internal radiotherapy. A radioisotope delivered to the tumor with a dose to cause tumor necrosis with minimal radiation injury to surrounding hepatic parenchyma is the aim of such therapies. A variety of radioisotopes, such as lodine-131, Yttrium-90, Rhenium-188, Holmium-166 etc have been shown to be effective in HCC. The TARE procedure is similar to TACE. Very small particles of glass or resin containing Yttrium-90 – a beta emitter with a tissue penetration of around 2.5 mm – are injected into the hepatic artery supplying the tumor and the isotope ultimately gets lodged in the tumor. Such treatment is safe and within first two weeks, maximum and optimal radiation is emitted from Yittrium-90 resulting in tumor necrosis. However, about 1 to 2 week prior to such therapy a thorough angiographic evaluation of coeliac, superior mesenteric, gastrodudenal, pancreaticoduodenal artery is done to assess the arterioportal shunt. Macro aggregated albumin (MAA) is used to evaluate the shunt fraction going to lungs. These precautions are undertaken to avoid isotope induced pneumonitis, gastric ulcers and pancreatitis etc. This may exclude a significant number of patients and also add to the cost. TARE has shown comparable efficacy in terms of local response, time to progression and superiority in terms of downstaging tumors when compared toTACE. In a multicenter trial from India, TARE using Rhenium-188 was found to be a safe, effective, and promising therapeutic option in patients with inoperable HCC with PVT. However, Rhenium is not available widely and Yittrium-90 microspheres have been commercialized and are used widely by now globally, including in India. Patients usually receive a single TARE treatment. The two main absolute contraindications to TARE are liver decompensation (serum total bilirubin > 2 mg/dL) and untreatable arteriovenous shunting. Based on current evidence, a recent expert consensus endorsed that TARE could be first-line therapy for the sub-group of intermediate stage patients who have well-preserved liver function (Child A) and high tumor burden (beyond the upto-7 rule) even with PVT. The reported results of TARE in the literature included patients with PVT, failure to TACE and patients with high tumor burden. These patients at best could have been treated by oral multikinase inhibitor sorafenib which has been reported to provide 3 month
survival benefit in about 40 to 44%. However, the median survival with TARE has been reported to be more than 12 months. Both TACE and TARE have been used to downstage the HCC to satisfy the criteria for LR and LT. The downstaging of HCC has gained immense attention even for those who have been listed for LT. While waiting for LT, about up to a quarter of patients can be delisted due to progression of the tumor, other tumor related complications and distant spread. Therefore, the present recommendations state that patients who are or are not being listed for LT should be tried for down staging, provided the liver function in them is good. Here, we will enumerate the two criteria for LT which are used worldwide. However in the present review, details of these criteria, their results and benefits are not being discussed. Some have argued that the Milan criteria (Table 4) are too restrictive for liver transplantation and that acceptable outcomes can still be achieved using more liberal tumor criteria. The liver transplant group at the University of California at San Francisco (UCSF) has championed the use of LT for larger tumor sizes and achieved outcomes similar to those achieved when the Milan criteria are used (Table 5). Over time with more expertise acquired in all the aspects of liver transplant and with above criteria to include patients with HCC for transplant has substantially improved recurrence free 5 survival rate up to 65-80 %. Such improved results have also resulted in bolder approach for Liver Transplant. One such example is “Rule of 7” in which tumor number is 7 and up to 7 cm in size who are transplanted with good results.13
Treatment of Advanced Hepatocellular Cancer
Before the promising results of TARE, patients with BCLC-C were only recommended to be treated with oral multikinase inhibitor Sorafenib. However, with increasing availability of TARE in India and as the cost is being gradually reduced with increasing expertise, it is being used more often. However, the results of such therapy in Indian patients are not yet available. None of the guidelines have recommended TARE in BCLC-C with good liver function, but such recommendations are likely to be included in future refreshed guidelines.
Sorafenib
Sorafenib is a multikinase inhibitor and down regulates various kinases responsible for hepatic cell proliferation. It acts against the serine–threonine kinases, Raf-1 and B-Raf downstream signals for Epidermal Growth Factor
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Transarterial radioembolisation (TARE)
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(EGF) receptors, vascular endothelial growth factor receptors (VEGFRs)- 1, 2, and 3 and platelet-derived growth factor receptor β (PDGFR-β). Each of these receptors and signals emanating there off are associated with limitless proliferative property of the HCC. All guidelines, including the INASL guidelines,2 recommend Sorafenib in BCLC-C HCC. These recommendations are based on two pivotal RCTs, (one conducted in west14) and the other one in Asia15 which documented an increase in median survival of between 2-3 months over placebo. The SHARP trial conducted in America and Europe included majority of patients with good liver functions (Child A in 95%) as well with good performance status (PS 0-1), and recruited 602 patients. The median survival in Sorafenib treated patients was 10.7 months in comparison to 7.9 months in those who received placebo {HR 0.69 (0.55– 0.87) P < 0.001}. The Asian trial included 216 patients (Sorafenib-150 and Placebo-76) but included also Child B patients and patients with distant metastasis. The median survival with Sorafenib and placebo was 6.5 and 4.2 months {HR 0.68 (95% CI 0.50−0.93); P = 0.014}.The most common side effects in both the studies were fatigue, diarrhoea and hand/foot skin reaction. Sorafenib has subsequently been evaluated as adjunctive therapy after RFA or LR in randomized studies but adjuvant treatment with Sorafenib was not found to improve the median recurrence free survival over RFA or LR. Additionally, sorafenib has been explored in combination with TACE and, while it appears safe, there is currently no data confirming that the combination confers an improvement over TACE alone.3 Presently there is no evidence that a combination of Sorafenib with other cytotoxic agents or targeted agents or hormonal therapy is superior to Sorafenib alone. The use of systemic chemotherapy (Dauxorubicin, Adriamycin, Oxaliplatin, Fluorouracil) has not been found to be reproducibly effective in management of HCC in randomized controlled trials.
Other Targeted therapies
Since the approval of sorafenib, a number of randomised first and second line trials have been reported using many molecular targeted therapy (brivanib, sunitinib, linifinib and the combination of sorafenib and erlotinib) in HCC, however with disappointing results.16
Immunotherapy for HCC
Cancer immunotherapy has been a subject of intense investigation for many decades. Recent understanding of tumor regulation by the immune microenvironment has advanced substantially which has led to identification of molecules that can block inhibitory signals and enable a cell-mediated anti-tumor response. So-called checkpoint inhibitors which block negative regulatory molecules such as the cytotoxic T-lymphocyte protein 4 (CTLA-4), the programmed cell death protein 1 (PD-1) and its ligand PD-L1, have revolutionized the treatment of melanoma and lung cancer. An initial report of 20 HCC patients treated with the CTLA-4 inhibitor tremelimumab,
reported a good safety profile and a radiological response rate of 18%17 The PD1 inhibitor nivolumab in HCC reported a response in around 20% in an initial report from an ongoing phase I study. Pivotal randomized trials comparing nivolumab with sorafenib are in progress and the combination of nivolumab with the CTLA-4 inhibitor ipilimumab are ongoing. Other immunotherapeutic approaches include vaccine strategies, adoptive cell therapy and gene therapy all of which are being explored.
External beam Radiotherapy
Better understanding of partial liver tolerance of radiation therapy and technological advances have improved the ability to deliver tumoricidal doses of radiation safely to HCCs, and have led to a resurgence of interest in curative-intent treatment of HCC using radiation therapy. Promising clinical data from multiple studies suggest that HCCs are indeed radiosensitive. Sustained local control rates ranging from 71% to 100% have been reported following 30–90 Gy delivered over 1–8 weeks. It is suggested that doses greater than 75 Gy result in more durable in-field local control than lower doses. Threedimensional conformal radiotherapy makes it possible to direct high-dose radiation to HCC with sparing of the surrounding non-tumoral liver parenchyma and represents a promising powerful technique which needs further validation. However, till more trials are available, radiation therapy cannot be recommended for management of HCC outside of clinical trials.
Supportive Care
In very advanced HCC such as in BCLC-D, the median survival is around 3 months and there is no therapy with evidence to treat these patients with an aim to improve their survival. However, all efforts should be made to improve the quality of life in such patients. These include management of pain using various narcotic and non narcotic agents. Radiotherapy can be used to alleviate pain in patients with bone metastasis and for relief of symptoms from pulmonary or lymph node metastases.3 Besides the pain, nutritional support and psychological support in such patients are important to improve quality of life. Further, the therapy in such patients should also include the treatment for underlying cause of the liver disease such as antivirals for HBV or HCV, which may improve the liver function status in general and thereby may improve the quality of life. However, evidence of such therapy in improving quality of life is needed in adequately designed trials. Similarly treatment of portal hypertension, ascites, infections and renal dysfunction may be needed in such patients depending upon individual patients’ need.
CONCLUSION
Advancements in knowledge about HCC biology, etiology, diagnosis, screening, staging and management have enhanced considerably during last 3 decades. Most important risk factor of HCC is cirrhosis of liver, irrespective of its etiology. Screening high risk patients to detect HCC in early stages when the tumor burden is small
with associated preserved liver function allows curative therapy in such patients, which includes liver resection, RFA and liver transplant. However, patients with HCC often present to tertiary care referral centers with onset of symptoms when the HCC is at an advanced stage. In such patients also, non-curative palliative care such as TACE, TARE and Sorafenib have been associated with improved survival benefit. Even palliative supportive care for very advanced HCC has improved. There are many efforts now to develop tumor biology specific therapy using targeted treatment at the molecular level, which in future is likely to provide further benefit to such patients.
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