Non-alcoholic steatohepatitis (NASH) is a disease where fat accumulates in the liver in people who drink little or no alcohol. It is increasingly common in Western countries, especially in obese and diabetic patients. Insulin resistance and the accumulation of fat in the liver are thought to cause liver inflammation and damage. While many patients are asymptomatic, NASH can progress to cirrhosis in some cases over many years. Weight loss through diet and exercise is the best treatment option to reduce fat in the liver.

1. Non Alcoholic Steatohepatitis

2. What is it? Epidemiology Pathogenesis Clinical Features and Diagnosis Clinical Course Treatment

3. Non alcoholic fatty liver disease Clinico-histopathological entity Histological features resemble alcohol induced liver disease Associated with negligible or no alcohol intake Spectrum of disease Steatosis Steatohepatitis cirrhosis Leading cause of cryptogenic cirrhosis Increasingly recognised

4. Epidemiology Occurs worldwide Greater in western populations USA 3% of lean individuals 19% of obese 50% of morbidly obese/diabetics ♀ > ♂ Associated with type 2 diabetes, obesity, hypertension and hyperlipidaemia

5. Pathogenesis Not fully known Insulin resistance Additional oxidative injury

6. Excessive Triglyceride accumulation Excessive import of free fatty acids Increased delivery (obesity, rapid weight loss) Excess conversion of carbohydrates and proteins to triglycerides (overfeeding, TPN) Reduced export of FFA Impaired VLDL synthesis or secretion Impaired beta-oxidation of FFA to ATP

7. Fatty Acids in the Hepatocyte

8. Insulin Resistance Key role Insulin resistance leads to changes in lipid metabolism Increased peripheral lipolysis, triglyceride synthesis and hepatic uptake of FFA Shift from carbohydrate to FFA beta oxidation Free fatty acids Inducers of cytochrome p-450 Leads to hepatotoxic free oxygen radical species

9. Insulin Resistance

12. Additional defects Antioxidants Free radicals deplete antioxidants Glutathione, vit E, beta-carotene, vit C Iron Insulin resistance associated with increased hepatic iron levels Heterozygous for the haemochromatosis gene mutation Leptin Deficiency leads to massive obesity Leptin may contribute to development of fibrosis Intestinal Microbes Endogenous ethanol and acetaldehyde production which leads to hepatic injury Endotoxin production

13. Clinical Features and Diagnosis Usually asymptomatic Fatigue, malaise, abdominal pain Often incidental diagnosis AST and ALT elevated in 90% AST/ALT < 1 Liver biopsy

14. Clinical Course NAFLD have only slightly lower overall survival than the general population Better prognosis than alcoholic hepatitis Alcoholic hepatitis 38 to 50% progress to cirrhosis NASH 8 to 26 % progress to cirrhosis Little change in LFTs throughout course of disease Can recur following transplant

15. Treatment No proven effective treatment Gradual weight loss 10% over 6-12 months Associated diabetes, hypertension and hyperlipidaemia should be treated Vitamin E Metformin Pioglitazone

16. Summary asymptomatic in most cases obesity, diabetes mellitus, hypertension and hyperlipidaemia are frequent associated features increase plasma ALT the commonest liver function test abnormality NASH accounts for most cases of isolated increased plasma transaminase activity of otherwise unknown cause liver biopsy rarely needed long-term prognosis is favourable graduated weight loss is the best available treatment