1. Ontario College of Family Physicians 51 st Annual Scientific Assembly Barry Lumb Fatty Liver Disease

2. Faculty/Presenter Disclosure Faculty: Dr. Barry Lumb Program: 51 st Annual Scientific Assembly Relationships with commercial interests: –NONE

3. Disclosure of Commercial Support This program has received NO financial support in any form This program has received NO in-kind support from any organization Potential for conflict(s) of interest: NONE

4. Mitigating Potential Bias NONE

5. NAFLD: Non-alcoholic fatty liver disease Definitions Definitions Epidemiology Epidemiology Pathogenesis Pathogenesis Diagnosis Diagnosis Interpretation of liver biochemistry Interpretation of liver biochemistry Prognosis Prognosis Management options Management options

6. NAFLD: Non-alcoholic liver disease NAFL: Simple fat accumulation, no inflammation or fibrosis NAFL: Simple fat accumulation, no inflammation or fibrosis NASH: Fat accumulation with varying degrees of inflammation and/or fibrosis NASH: Fat accumulation with varying degrees of inflammation and/or fibrosis NASH cirrhosis NASH cirrhosis

7. NAFLD Most common liver disorder Most common liver disorder Majority of previously diagnosed “ cryptogenic cirrhosis ” Majority of previously diagnosed “ cryptogenic cirrhosis ” Very high prevalence depending on modality used: Very high prevalence depending on modality used: Ultrasound – >15% Ultrasound – >15% MRI - >30% MRI - >30% Liver biopsy – 33% potential donors Liver biopsy – 33% potential donors Autopsy – 70% of obese, 35% of lean patients Autopsy – 70% of obese, 35% of lean patients NASH and cirrhosis in much smaller percent NASH and cirrhosis in much smaller percent

8. NASH “ Metabolic steatohepatitis ” “ Metabolic steatohepatitis ” Histologically indistinguishable from alcohol induced liver disease Histologically indistinguishable from alcohol induced liver disease Various grading systems Various grading systems Degree of inflammation Degree of inflammation Degree of fibrosis (ie. Risk of cirrhosis) Degree of fibrosis (ie. Risk of cirrhosis)

9. NAFLD: Non-alcoholic fatty liver disease NAFL: Non-alcoholic fatty liver NAFL: Non-alcoholic fatty liver NASH: Non-alcoholic steatohepatitis NASH: Non-alcoholic steatohepatitis NAFL NASH

10. “ Significant alcohol intake ” Amounts are unclear Amounts are unclear Balance between potential for liver disease versus probable protective effect of moderate alcohol Balance between potential for liver disease versus probable protective effect of moderate alcohol Probable higher risk in obesity, female, NAFLD Probable higher risk in obesity, female, NAFLD Male – 2 drinks per day Male – 2 drinks per day Female – maybe < 1 drink per day Female – maybe < 1 drink per day

11. NAFLD Predictors – Predictors – ? Female gender ? Female gender Obesity Obesity Diabetes Diabetes Age > 40 Age > 40 Metabolic syndrome Metabolic syndrome Obstructive sleep apnea Obstructive sleep apnea Hyperuricemia Hyperuricemia Polycystic ovary syndrome Polycystic ovary syndrome Hyperlipidemia (esp hypertriglyceridemia, low HDL Hyperlipidemia (esp hypertriglyceridemia, low HDL Ethnic variability (Hispanic origin) Ethnic variability (Hispanic origin)

12. Metabolic Syndrome Most predictive of NAFLD and NASH Most predictive of NAFLD and NASH Central obesity - BMI or W/H ratio Central obesity - BMI or W/H ratio Arterial hypertension Arterial hypertension Dyslipidemia ( ↑TG or ↓HDL) Dyslipidemia ( ↑TG or ↓HDL) Glucose intolerance/insulin resistance Glucose intolerance/insulin resistance

13. NAFLD Obesity and other risk factors are not universal Obesity and other risk factors are not universal Rule out other secondary causes of fatty liver Rule out other secondary causes of fatty liver Meds – amiodarone, methotrexate, tamoxifen, steroids Meds – amiodarone, methotrexate, tamoxifen, steroids Other rare conditions – Wilson’s, Starvation, Hepatitis C genotype 3, TPN Other rare conditions – Wilson’s, Starvation, Hepatitis C genotype 3, TPN

14. Pathogenesis: “ Two hit ” hypothesis First Hit First Hit Insulin resistance causes hyperinsulinemia Insulin resistance causes hyperinsulinemia Promotes FFA generation from adipose tissue Promotes FFA generation from adipose tissue Promotes de novo hepatic lipogenesis Promotes de novo hepatic lipogenesis May activate profibrotic cytokines May activate profibrotic cytokines Impaired balance between influx, synthesis of hepatic lipids versus export or oxidation Impaired balance between influx, synthesis of hepatic lipids versus export or oxidation Hepatic triglyceride accumulation in the liver (steatosis) Hepatic triglyceride accumulation in the liver (steatosis) Reduced hepatic export of VLDL Reduced hepatic export of VLDL

15. Pathogenesis: “ Two hit ” hypothesis Second hit Second hit Steatotic liver vulnerable to secondary injury Steatotic liver vulnerable to secondary injury Inflammation Inflammation Fibrosis Fibrosis Cirrhosis Cirrhosis

16. Pathogenesis: “ Two hit ” hypothesis Second Hit Second Hit Other mediators/factors cause oxidative injury Other mediators/factors cause oxidative injury Low anti-oxidant levels Low anti-oxidant levels Iron excess Iron excess Leptins – stimulate platelet derived growth factor Leptins – stimulate platelet derived growth factor Abnormal gut microbiome Abnormal gut microbiome Adiponectin – normally protective, reduced in NAFLD Adiponectin – normally protective, reduced in NAFLD

17. NAFLD - Diagnosis Usually asymptomatic – vague, non-specific symptoms Usually asymptomatic – vague, non-specific symptoms Incidental finding Incidental finding Hepatomegaly Hepatomegaly Liver chemistry testing Liver chemistry testing Ultrasound, CT, MRI Ultrasound, CT, MRI Screening in high risk individuals Screening in high risk individuals

18. NAFLD: Liver Biochemistry Mild to moderate ALT elevation Mild to moderate ALT elevation AST/ALT ratio <1 (unless cirrhotic) AST/ALT ratio <1 (unless cirrhotic) Versus alcohol >2 Versus alcohol >2 Very poor correlation between severity and ALT levels Very poor correlation between severity and ALT levels Possibly: Possibly: ↑ ferritin, IgA, GGT ↑ ferritin, IgA, GGT SMA, ANA positive SMA, ANA positive

19. Hepatocellular enzymes: AST, ALT Sensitive indicators of hepatocellular damage Sensitive indicators of hepatocellular damage AST many sources AST many sources ALT serum half life > AST ALT serum half life > AST Hepatocellular damage ALT elevation predominant Hepatocellular damage ALT elevation predominant AST:ALT ratio <1 AST:ALT ratio <1

20. Hepatocellular enzymes: AST, ALT ? Extent of investigation of ALT < 3 x normal ? Extent of investigation of ALT < 3 x normal < 6 months duration < 6 months duration Rule out Hepatitis B and C Rule out Hepatitis B and C Elevated Ferritin, Iron saturation >45 Elevated Ferritin, Iron saturation >45 Drugs Drugs Ultrasound Ultrasound NAFLD highly probable NAFLD highly probable

21. NAFLD: GGT Sensitive but non-specific indicator of biliary disease Sensitive but non-specific indicator of biliary disease Clarification of source of raised AP Clarification of source of raised AP Induced by ethanol, phenytoin and other drugs Induced by ethanol, phenytoin and other drugs Strong association with Strong association with BMI, NAFLD, alcohol, cholesterol, triglycerides, analgesic usage BMI, NAFLD, alcohol, cholesterol, triglycerides, analgesic usage

22. Alcohol and liver enzymes Prolonged intake Prolonged intake Depletion of hepatic AST and ALT but ALT predominant Depletion of hepatic AST and ALT but ALT predominant AST/ALT ratio > 2 AST/ALT ratio > 2 Total AST < 400 Total AST < 400 Frequently striking elevation of GGT Frequently striking elevation of GGT

23. NAFL or NASH? Significant red flags Significant red flags Clinical stigmata of chronic liver disease Clinical stigmata of chronic liver disease Spiders Spiders Splenomegaly Splenomegaly Elevated MCV Elevated MCV Elevated ferritin Elevated ferritin Low platlets (<140,000) Low platlets (<140,000) Imaging – “shrunken liver”, splenomegaly, ascites Imaging – “shrunken liver”, splenomegaly, ascites

24. NAFLD: ALT level Poor association between ALT level and degree of fatty infiltration, inflammation and fibrosis Poor association between ALT level and degree of fatty infiltration, inflammation and fibrosis Don’t let a low ALT talk you out of concern if other features present Don’t let a low ALT talk you out of concern if other features present

25. NAFLD: Imaging Ultrasound, CT, MRI Ultrasound, CT, MRI Reliable for moderate to severe fatty infiltration Reliable for moderate to severe fatty infiltration No association with NAFLD versus NASH, fibrosis No association with NAFLD versus NASH, fibrosis Associated features of cirrhosis Associated features of cirrhosis Fibroscan is promising for assessing degree of fibrosis Fibroscan is promising for assessing degree of fibrosis

26. NAFLD: Assessing severity Independent markers of progression to fibrosis Independent markers of progression to fibrosis Age > 50 (OR 14.1) Age > 50 (OR 14.1) DM (OR 12.5) – especially poorly controlled DM (OR 12.5) – especially poorly controlled BMI > 28 (OR 5.7) BMI > 28 (OR 5.7) Triglycerides >1.7 (OR 5) Triglycerides >1.7 (OR 5) Other markers of inflammation and fibrosis? Other markers of inflammation and fibrosis? IgA, hyaluronic acid levels IgA, hyaluronic acid levels Risk factors – DM, metabolic syndrome Risk factors – DM, metabolic syndrome

27. NAFLD: Liver Biopsy Only accurate confirmation of inflammation and/or fibrosis Only accurate confirmation of inflammation and/or fibrosis Exclusion of other causes of abnormal biochemistry Exclusion of other causes of abnormal biochemistry Value in absence of proven medical therapy controversial unless features of chronic liver disease Value in absence of proven medical therapy controversial unless features of chronic liver disease

28. NAFLD: Prognosis and progression Risk is unclear but: Risk is unclear but: Class 1 and 2 unlikely to progress Class 1 and 2 unlikely to progress Class 3 and 4 (NASH) Class 3 and 4 (NASH) Progressive fibrosis 25% at 5 years Progressive fibrosis 25% at 5 years Cirrhosis 15% at 5 years Cirrhosis 15% at 5 years Mortality related to underlying disease states Mortality related to underlying disease states Increased incidence of hepatocellular carcinoma if cirrhosis Increased incidence of hepatocellular carcinoma if cirrhosis

29. NAFLD: Management options Very few RCTs Very few RCTs Most studies are short duration Most studies are short duration AST and Ultrasound as surrogate markers are unreliable AST and Ultrasound as surrogate markers are unreliable Acceptable alcohol intake? Acceptable alcohol intake? Subsets of patients with different therapies? Subsets of patients with different therapies?

30. NAFLD: Management options Diet, exercise, weight loss!!?? Diet, exercise, weight loss!!?? Anti-oxidants - vitamin E 400 iU Anti-oxidants - vitamin E 400 iU Statins (no increased risk of hepatotoxicity) Statins (no increased risk of hepatotoxicity) Pioglitazone (Actos) Pioglitazone (Actos) Ursodeoxycholic acid (Urso) Ursodeoxycholic acid (Urso) Losartan Losartan Metformin Metformin