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NASH and nonalcoholic liver disease

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

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NASH and nonalcoholic liver disease

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  1. NASH and nonalcoholic liver disease Dr. UmeshKhanna Mumbai NASH – NonAlcoholicSteatoHepatitis

  2. 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.

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

  4. NonAlcoholicFatty Liver Disease Histopathologic Spectrum SteatosisSteatohepatitis 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.

  5. 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: S412–6.

  6. 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] • 3rdmost common cause of CLD in North America after alcoholic liver disease & Hepatitis C • The most common cause of raised transaminases> 6 months

  7. Introduction • NASH • was coined by Ludwig et alin 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

  8. 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

  9. 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.

  10. 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

  11. 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%

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

  13. Epidemiology: NALFD, NASH 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 NASH In Asia Pacific – Future Shock!! Chitturi Et al JGH 2004

  14. 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

  15. NAFLD: Risk factors Obesity Diabetes Hyperlipidemia Female sex

  16. 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.

  17. 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.

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

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

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

  21. 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

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

  23. NASH: Pathology • Diagnosis of NASH depends on • Histopathologicalfeatures & • Exclusion of alcohol as the cause of disease • Liver biopsy features : • Steatosispolymorphonuclear and / mononuclear hepatocyte ballooning and necrosi, malloryhyaline,glycogenatednuclei,metamitochondria and fibrosis indistinguishable from alcoholic liver disease

  24. 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 induedhepatitis] • 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

  25. 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

  26. JAPI 2005;53: 195-99

  27. JAPI 2005;53: 195-99

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

  29. 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

  30. NALFD: Clinical features • On examination • Most patients are centrally obese and dorsocervicallipohypertrophy (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

  31. 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

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

  33. 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

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

  35. Natural course • Steatosis • Steatohepatitis • Cirrhosis • Steatosis – good prognosis • Steatohepatitis , cirrhosis – bad prognosis

  36. 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.

  37. 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

  38. 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

  39. 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

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

  41. 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

  42. Thank You!

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