PIERO LUIGI ALMASIO CATTEDRA DI GASTROENTEROLOGIA UNIVERSITA OF PALERMO

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1 Steatosi e Steatoepatite PIERO LUIGI ALMASIO CATTEDRA DI GASTROENTEROLOGIA UNIVERSITA OF PALERMO

2 Alcoholic liver disease Liver damage resulting from long-term alcohol consumption Histological features: - Mallory bodies - inflammatory neutrophils infiltrate - macrovesicular and/or microvesicular steatosis - fibrosis (ranging from perivascular foci to fibrous septa and cirrhosis) Non-alcoholic Steatohepatitis (NASH) Named by Ludwig in 1980 to identify a disease of liver associated with the pathological features most commonly seen in alcoholic liver disease in patients who had negligible alcohol consumption.

3 Metabolic Pathway to Liver Disease NAFLD & NASH NASH No fat HCC Cirrhosis Fibrosis + Necroinflammation N A F Time Pure Fatty Liver L D

4 Factors Associated with NAFLD PRIMARY NAFLD Metabolic factors Obesity, Diabetes, Hyperglycemia, Hyperlipidemia Rapid weight loss, Acute starvation, i.v. Glucose, TPN SECONDARY NAFLD Surgical procedures Drugs Jejunal by-pass, Gastroplasty, Bilio-pancreatic diversion Extensive small bowel resection Amiodarone, Perhexiline maleate, Glucocorticoids Synthetic estrogens, Tamoxifen Miscellaneous factors Jejunal diverticolosis with bacterial overgrowth Partial lipodystrophy Abetalipoproteinemia

5 Problems in the Diagnosis of Metabolic Liver Disease 1. Diagnosis by exclusion (liver biopsy) 2. High prevalence of associated conditions 3. Frequent association with well-known etiologic agents 4. Slow course 5. Lack of therapeutic options

6 Worldwide Prevalence of Viral Hepatitis & Metabolic Diseases HBV 360 HCV Diabetes Obesity 500 HIV Millions

7 Prevalence of Elevated ALT Levels in US 15,676 adult US citizens (NHANES III) Total prevalence: 7.9% High alcohol consumption, hepatitis B and C infection, and high transferrin saturation were found in 31% The large majority was unexplained Unexplained ALT elevation was associated with high BMI, enlarged waist, increased triglycerides and insulin, low HDL-cholesterol (+ type 2 DM and hypertension in females) Alcohol HCV HFE HBV 2+ Clark et al, Am J Gastroenterol 2003

8 Risk Factors for Steatosis in Italy The prevalence of steatosis increases in heavy drinkers (46%) and obesity (76%), compared with controls (16%) All cases vs. Heavy Drinkers vs. Obesity 16% Controls Heavy Drinkers Obesity Obesity + Alcohol Steatosis was exceedingly common in heavy drinkers with obesity (94%) Obesity increased the risk compared with heavy drinkers, whereas alcohol further increased the risk when added to obesity Elevated ALT and triglycerides are marker of steatosis Bellentani et al, Ann Intern Med 2000

9 NAFLD in Obesity and Diabetes Steatosis NASH Lean Obese Diabetes Reviewed by Neuschwander & Caldwell, Hepatology 2003

10 HOMA-Insulin Resistance and BMI 7.0 Insulin Resistance (%) (Nonalcoholic fatty liver; r = 0.08) (Controls; r = 0.38) Body Mass Index (kg/m 2 ) Marchesini et al, Am J Med 1999

11 Non-alcoholic Steatohepatitis Criteria for diagnosis Rigorous exclusion of alcohol consumption - detailed personal history - interrogation of family members - biochemical markers (?) - GGT values, MCV, AST/ALT ratio - desialylated transferrin, mitochondrial isoenzyme of AST Absence of: - serologic evidence of HBV and/or HCV infection - clinical and/or laboratory features of autoimmune hepatitis and metabolic liver diseases.

12 Laboratory Mild elevation of AST and ALT (>1.5x) ALT > AST (if AST>ALT, then fibrosis or cirrhosis) Hyperglycemia (caused by DM present in 1/3 of cases) Hyperlipidemia (mainly raised triglycerides) in 20-25% 25% Abnormal iron indices (common, but do not indicate genetic Hemochromatosis) Neuschwander and Caldwell, Hepatology 2003

13 Criteria for diagnosis: histology Liver biopsy that shows - macrovesicular fatty degeneration (steatosis) - portal and/or lobular inflammation with or without - Mallory (hyaline) bodies - ballooning degeneration - fibrosis (grade 1-3) or cirrhosis

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22 Non-alcoholic Steatohepatitis Therapeutic Options Weight loss Adequate diet for hyperlipidemia Drug treatment of hyperlipidemia Correct therapy of diabetes? Ursodeoxycholic acid? Anti-oxidants drugs Vitamin E Glutathione? Insulin-sensitizing sensitizing agents Metformin? Phlebothomy (iron overload)