dr. umesh khanna mumbai nash and nonalcoholic liver disease nash – nonalcoholic steatohepatitis

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  • DR. UMESH KHANNA MUMBAI NASH and nonalcoholic liver disease NASH NonAlcoholic SteatoHepatitis
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  • 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: S4126.
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  • NAFLD : Natural history over 813 years HCC, hepatocellular carcinoma; OLTx, liver transplantation. Journal of Hepatology 2008;48: S10412
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  • NonAlcoholic Fatty Liver Disease Histopathologic Spectrum Steatosis Steatohepatitis FibrosisCirrhosis Cancer 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.
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  • Introduction NAFLD 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: S4126.
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  • Non-Alcoholic Steatohepatitis [NASH] NASH Represents only a part of wide spectrum of non alcoholic fatty liver One of the leading causes of chronic liver disease [CLD] 3 rd most common cause of CLD in North America after alcoholic liver disease & Hepatitis C The most common cause of raised transaminases > 6 months
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  • 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
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  • 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
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  • 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: S4126.
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  • 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
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  • 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%
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  • Epidemiology: NALFD, NASH Name of the Percentage NAFLD in CountryAdults Japan9 30% China5 18% Korea18 % India5 28% Indonesia30% Malaysia17 % Singapore5% Prevalence of NAFLD In General Population In Asian Pacific Region
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  • Epidemiology: NALFD, NASH WesternEastern PopulationPopulation Age at Presentation4 th 8 th decade 4 th 8 th decade Prevalence20-30%-10% Obesity71% (30-100)44% (12-89) T2DM28% (2-55)34% (11-39) Hyperlipidemia38% (15-81)41% (28-81) Natural HistoryWorse with Limited data severe firbosis Chitturi Et al JGH 2004 NASH In Asia Pacific Future Shock!!
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  • NASH in India 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
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  • NAFLD: Risk factors Obesity Diabetes Hyperlipidemia Female sex
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  • 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: S4126.
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  • 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: S4126.
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  • NASH: Potential etiologies Hepat Mon. 2011;11(2):74-85
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  • NASH: Potential etiologies Hepat Mon. 2011;11(2):74-85
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  • NASH: Potential etiologies Hepat Mon. 2011;11(2):74-85
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  • 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
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  • NASH: Pathogenesis Impaired cholesterol esterification Choline deficiency Protein malnutrition Impaired export of VLDL from hepatocyte Insulin resistance increased lipolysis hyperinsulinemia
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  • NASH: Pathology Diagnosis of NASH depends on 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
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  • 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
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  • 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
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  • JAPI 2005;53: 195-99
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  • Histological Differential Diagnosis Hepatitis C Primary Biliary Cirrhosis Autoimmune hepatitis Alpha 1 anti trypsin deficiency Hemochromatosis
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  • 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: S10412
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  • 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: S10412
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  • NASH: Clinical features Most of the patients are asymptomatic 1/3 rd 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
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  • Laboratory findings Mild moderate elevations of S.Transaminases, typically AST in absence of cirrhosis Liver biopsy
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  • 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


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