NASH and nonalcoholic liver disease Dr. Umesh Khanna Mumbai NASH – NonAlcoholic SteatoHepatitis

Introduction Non-alcoholic fatty liver diseases [NAFLD] represents a spectrum of diseases ranging from “simple steatosis,” which is considered relatively benign, to Non alcoholic steatohepatitis (NASH) and NAFLD-associated cirrhosis and end-stage liver disease Has become a common cause of liver transplant Also been identified as an important risk factor for development of primary liver cancer , mostly due to NAFLD-associated cirrhosis J Lipid Res. 2009 April; 50: S412–6.

NAFLD : Natural history over 8–13 years HCC, hepatocellular carcinoma; OLTx, liver transplantation. Journal of Hepatology 2008;48: S104–12

NonAlcoholic Fatty Liver Disease Histopathologic Spectrum Steatosis Steatohepatitis Cancer Fibrosis Cirrhosis Progression to cirrhosis and cancer have been documented from few studies in the Asian Pacific Region but still exact magnitude of the problem is not known.

Introduction NAFLD However, Health dilemma for the recent 3 decades provoking quite less concerns in the past However, Nowadays, its prevalence has grew to 30% in the United States general population and like other gastrointestinal disorders it also grew in developing countries NAFLD is rapidly becoming a worldwide public health problem* It is the most common liver disease in the United States and, indeed, worldwide Hepat Mon. 2011;11(2):74-85 ;* J Lipid Res. 2009 April; 50: S412–6.

Non-Alcoholic Steatohepatitis [NASH] Represents only a part of wide spectrum of non alcoholic fatty liver One of the leading causes of chronic liver disease [CLD] 3rd most common cause of CLD in North America after alcoholic liver disease & Hepatitis C The most common cause of raised transaminases > 6 months

Introduction NASH was coined by Ludwig et al in 1980 while describing a Series of patients of non-alcoholic, diabetic patients, mostly females, in whom Liver histology was consistent with alcoholic liver disease but did not have a history of alcohol consumption

Epidemiology: NALFD, NASH Problems In Studying Epidemiology Of NAFLD And NASH Lack of definitive laboratory test Studies dependence on different definitions Published series with biopsy confirmation are selected cases that have presented to medical attention Values of alcohol consumption in published series ranged from < 20 gm/week to <140 gm/week

Epidemiology: NALFD, NASH Prevalence of NAFLD Appears to be increasing, in part due to the increasing numbers of adult and pediatric individuals who are obese or overweight or have metabolic syndrome or type 2 diabetes, all major risk factors for development of NAFLD J Lipid Res. 2009 April; 50: S412–6.

Epidemiology: NALFD, NASH Problems in Assessing NAFLD In Asian Pacific Region Inaccurate evaluation of alcohol abuse Infrequent use of liver test in general practice Lack of presentation of asymptomatic individual Burden of viral hepatitis Reluctance to do liver biopsy Lack of awareness of the severity Pursued slowly progressive nature Considered as a disease of affluence Chitturi S, Farrell G, George J JGH 2004

Epidemiology: NALFD, NASH Steatosis Most common cause of raised transaminases & affects 10-24 % of gen.population while only 2-3 % of gen.population have steatohepatitis In pts undergoing liver biopsy, the prevalence ranges NAFLD [NonAlcoholic Fatty Liver Disease] - 15-39% Steatohepatitis - 1.2-4.8%

Epidemiology: NALFD, NASH Prevalence of NAFLD In General Population In Asian Pacific Region Name of the Percentage NAFLD in Country Adults Japan 9 – 30% China 5 – 18% Korea 18 % India 5 – 28% Indonesia 30% Malaysia 17 % Singapore 5%

Epidemiology: NALFD, NASH NASH In Asia Pacific – Future Shock!! Western Eastern Population Population Age at Presentation 4th – 8th decade 4th – 8th decade Prevalence 20-30% -10% Obesity 71% (30-100) 44% (12-89) T2DM 28% (2-55) 34% (11-39) Hyperlipidemia 38% (15-81) 41% (28-81) Natural History Worse with Limited data severe firbosis Chitturi Et al JGH 2004

NASH in India India Among pts from India, Many diabetics but very few studies on NASH Among pts from India, 50 – 70% had one of the 3 risk factors – diabetes, obesity, hyperlipidemia Mean age of pts is 35 – 55 yrs Predominant in men NASH constitute 6% of all chr.hepatitis cases

NAFLD: Risk factors Obesity Diabetes Hyperlipidemia Female sex

NALFD: Etiology To date, major gaps remain in our understanding of the etiology of NAFLD and why it progresses Generally agreed that dysregulation of lipid metabolism is involved Furthermore, it seems likely that dysregulation of the immune response plays an important role, particularly in progression J Lipid Res. 2009 April; 50: S412–6.

NAFLD: Factors that may impact Any or all metabolic pathways may play a role in NAFLD and its progression dependent on an individual's cohort of genes and genetic and epigenetic interactions. The question mark indicates that little evidence is available supporting an influence, but that, hypothetically, one may exist J Lipid Res. 2009 April; 50: S412–6.

NASH: Potential etiologies Hepat Mon. 2011;11(2):74-85

NASH: Potential etiologies Hepat Mon. 2011;11(2):74-85

NASH: Potential etiologies Hepat Mon. 2011;11(2):74-85

NASH: Pathogenesis Increased delivery of fatty acids to liver Obesity Starvation Increased synthesis of fatty acids in liver excess carbohydrate ( TPN ) Decreased mitochondrial beta oxidation of fatty acids Carnitine deficiency Mitochondrial dysfunction Decreased incorporation of triglycerides into functional VLDL Impaired apolipoprotein synthesis

NASH: Pathogenesis Impaired cholesterol esterification Choline deficiency Protein malnutrition Impaired export of VLDL from hepatocyte Insulin resistance increased lipolysis hyperinsulinemia

NASH: Pathology Diagnosis of NASH depends on Liver biopsy features : Histopathological features & Exclusion of alcohol as the cause of disease Liver biopsy features : Steatosis polymorphonuclear and / mononuclear hepatocyte ballooning and necrosi, mallory hyaline,glycogenated nuclei,metamitochondria and fibrosis indistinguishable from alcoholic liver disease

NASH: Pathology Steatosis in NASH – macrovesicular Inflammation of steatohepatitis is predominantly lobular, [whereas intense portal inflammation with interface activity is seen in chronic viral, autoimmune & drug indued hepatitis] But in children , NASH may have portal infiltrate Neutrophilic cells in lobular inflammatory infiltrate Balloon degeneration – recognized form & characteristic finding in NASH Mallory hyaline may be +/- Characteristic of alcoholic hepatitis

NASH: Pathology Pattern of fibrosis Initial collagen deposition in perivenular & peri sinusoidal spaces of Zone 3 . Chicken wire fibrosis Fibrosis – in 66% pts While 25% have severe fibrosis And 14% have well established cirrhosis

JAPI 2005;53: 195-99

JAPI 2005;53: 195-99

Histological Differential Diagnosis Hepatitis C Primary Biliary Cirrhosis Autoimmune hepatitis Alpha 1 anti trypsin deficiency Hemochromatosis

NALFD: Clinical features NAFLD Largely asymptomatic condition that may reach an advanced stage before it is suspected or diagnosed Symptoms such as right upper quadrant discomfort, fatigue and lethargy have been reported in up to 50% of patients but are uncommon modes of presentation Most patients with NAFLD are diagnosed after they are found to have hepatomegaly, or more commonly, unexplained abnormalities of liver blood tests performed as part of routine health checks or during drug monitoring (e.g., statin therapy) Journal of Hepatology 2008;48: S104–12

NALFD: Clinical features On examination Most patients are centrally obese and dorsocervical lipohypertrophy (a ‘‘buffalo hump”) appears to be a particular feature of the fat distribution in patients with advanced NAFLD Features of PCOS (hyperandrogenism) should be sought in young women with suspected NAFLD Journal of Hepatology 2008;48: S104–12

NASH: Clinical features Most of the patients are asymptomatic 1/3rd present with Nonspecific constitutional symptoms like weakness, fatigue & malaise Rapid onset of Fulminant hepatic failure NASH d//t drugs like nucleoside analogues, tetracyclines Hepatomegaly , splenomegaly Presence of ascites, spider angiomata – indicate development of cirrhosis Alcoholic hepatitis - symptomatic

Laboratory findings Mild – moderate elevations of S.Transaminases, typically <4 times the upper normal limit ALT level > AST in absence of cirrhosis Liver biopsy

Diagnosis Clinical history Exclusion of significant alcohol intake Pursue dietary history, medication, occupational exposure to organic solvents Family history of liver disease Other causes of CLD – infections, metabolic heriditary & autoimmune causes to be ruled out Liver biopsy – confirm diagnosis & for prognostic information

Difference between NASH and alcoholic hepatitis JAPI 2005;53: 195-99

Natural course Steatosis Steatohepatitis Cirrhosis Steatosis – good prognosis Steatohepatitis , cirrhosis – bad prognosis

NALFD: Treatment Currently, the only accepted treatment for NAFLD regardless of stage is lifestyle modifications These include weight loss by a combination of decreased caloric intake and increased physical activity Of potential importance is choice of diet, for example, low fat/high carbohydrate versus high fat/low carbohydrate Another option, generally available only for the morbidly obese, is bariatric surgery An important caveat for both treatment approaches Rapid weight loss by any means is to be avoided because it can cause NAFLD progression J Lipid Res. 2009 April; 50: S412–6.

NASH: Treatment Treatment options are limited Weight Reduction: wt loss – normalization of s.aminotransferases. Means of wt loss is important not the amount of wt loss Recommended wt loss – 230 g/day or 1.6 kg/week Diet : 45 -100 g high quality animal protein <100g carbohydrates <10 g fat per day providing 600 -800 kcal

NASH: Treatment Ursodeoxycholic acid : Has membrane stabilizing / cytoprotective / immunological effect 10-15 mg/kg/day for 6-12 months Significant improvement in transaminases levels and degree of steatohepatitis

NASH: Treatment Liver Transplantation : NASH – A relative contraindication Many of pts with NASH with CLD who underwent Liver Transplant – redeveloped NASH in the new donor liver ( 2/3 cases ) & 1/3rd cases – liver transplantation is unsuccessful

Newer treatment modalities Inhibition of macrophage activation: Anti oxidant ( Vit E ) glutathione prodrugs Antibiotics, preprobiotics Anti cytokines ( anti TNF alpha antibodies, pentoxiphylline )

Newer treatment modalities Protect hepatocyte ATP stores PARP inhibitors Minimize CYP2F activity Dietary modification ( avoid fats ) Insulin sensitizers : pioglitazone Antiobesity drugs : sibutramine, orlistat Antilipid drugs : Simvastatin, Procusol

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