NASH: It is not JUST a Fatty Liver. Karen F. Murray, M.D. Director of Hepatobiliary Program Children s Hospital and Regional Medical Center

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1 NASH: It is not JUST a Fatty Liver Karen F. Murray, M.D. Director of Hepatobiliary Program Children s Hospital and Regional Medical Center

2 Stages of Fatty Liver Disorders Fatty Liver 16-35% of Western Population 9.6% of Children 1/3 of Obese Children 16% 20% Steatohepatitis 25% Steatohepatitis with Fibrosis Steatohepatitis with Cirrhosis 30% 25% ESLD Liver Cancer

3 Risk Factors for NASH (Mortality ~ 3%) Central obesity Type 2 Diabetes Hypertriglyceridemia

4 (*BMI 30, or about 30 lbs overweight for 5 4 person) Obesity Trends* Among U.S. Adults BRFSS, 1991, 1996, No Data <10% 10% 14% 15% 19% 20% 24% 25% Source: Behavioral Risk Factor Surveillance System, CDC

5 NASH and Ethnicity Liver TG content by Mass. Spec. 2,287 subjects 32.1% Cauc., 48.3% AA, 17.5% Hispanic 33% had hepatic steatosis 45% Hispanic, 33% Cauc,, 24% AA 79% Normal ALT Risk in Hispanics: Insulin resistance, obesity Browning et al. Hepatology 2004; 40:

6 NASH - Pathogenesis Two Hits Steatosis Oxidative Stress

7 Pathophysiology of NAFLD Insulin resistance: Hyperinsulinemia Liver increased hepatic glucose production decreased hepatic glucose disposal Adipocytes: increased hormone-sensitive lipase activity elevated rates of triglyceride lipolysis enhanced FFA flux to the liver

8 Hepatic Steatosis in Insulin Resistance Browning and Horton, J Clin Invest. 2004;114:

9 Pathogenesis of Steatohepatitis TNF-α Kupffer cells Pro-inflammatory cytokines Fibrosis Additional cytokines Stellate cells adipocytes Free Fatty acids Hyperinsulinemia diet fat hepatocyte inflammation Proinflammatory products Slide care of Dr. Kris Kowdley

10 NASH Hepatic Mitochondrial Second Hit Abnormalities Second Hit Fatty Liver vs. NASH Both with Insulin Resistance NASH Outer membrane permeabilization Loss of Cristae Paracrystalline inclusions Sanyal, AJ; Gastroenterology 2001; 120:

11 NASH Hepatic Mitochondrial Abnormalities Sanyal AJ: Gastroenterology 2001;120:

12 NASH in Children Prevalence of fatty liver in Children 9.6% Obesity (90)%, acanthosis nigricans, hepatomegaly Boys 40% > girls 25-30% abdominal pain Typical age 12 years (2-17 years) Schwimmer JB et al. JPGN 2005: 41:513

13 NASH - Prognosis Adults 2-3% have NASH of which 20% will develop Cirrhosis / ESLD RR of Liver Cancer in men BMI>35 is 4.52 (Prostate = 1.34; All cancers = 1.52) Children 5-10% have advanced fibrosis / cirrhosis at diagnosis, 67% fibrosis Adolescent transplants for NASH Children with NASH have gotten HCC as adults

14 NASH Laboratory Features ALT, AST, GGT Dyslipidemia,, esp. TG Insulin (+/- Normal Glucose)

15 NASH Radiology US Echogenicity of liver > kidney CT Fatty Infiltration MRI- Allows for measurement of fat MRI Low Low sensitivity and specificity

16 How to decide when to do a liver Bx Ramesh and Sanyal, J Hepatol,, Feb 2005 ALT Rule out other causes of liver disease Causes found No causes found Metabolic syndrome present YES Will Bx change Rx NO BX Yes BX No Discuss risks/benefits Make patient aware of risks Of not doing Bx

17 Histology of NASH Ballooning degeneration Mallory s hyalin

18 Histology of Pediatric NAFLD / NASH

19 NASH - Treatment Weight loss Ursodiol Insulin sensitizing agents Antioxidants

20 Weight Loss Hickman et al., Gut. 2004;53:

21 Estimated fructose intake and weight trends in the U.S. % of population Intake (gm/person/day) overweight obese total fruc tose HFCS year Bray et al, Am J Clin Nutr, 2004, 79:537-43

22 All Children: Kcal Weight Management Recommendations and Physical Activity Stop high fructose soda

23 US Canadian UDCA Trial Lindor et al., Hepatology vol 39.

24 Insulin Sensitizing Agents Metformin Diabetic children insulin hepatic insulin resistance Non-Diabetic children NASH Pioglitazone in Non-diabetic NASH ALT

25 Vitamin E for NASH ALT, Alkaline Phosphatase No change in liver US Biopsies not done Lavine JE. J. Pediatr 2000; 136:

26 Pioglitazone & Vitamin E Pre treatment (10 X) Post treatment (10 X) Sanyal et al, Clin Gastroenterol and Hepatol, Dec 2004

27 The NASH CRN is born NIH sponsored consortium of 8 sites to study NASH Univ of Washington Cleveland Clinic / Mayo Johns Hopkins Indiana Univ UC San Diego UC San Francisco Virginia Commonwealth Univ St. Louis Univ

28 3 studies are underway Database all patients > 2 yrs +/- Diabetes Suspected NASH, bx not needed PIVENS: Placebo vs. Pioglitazone vs. Vit E TONIC: Placebo vs. Metformin vs. Vit E Non-DM, elevated ALT Biopsy proven

29 Summary The most common chronic liver disease in the USA and Europe Progression to advanced liver disease common Diagnosis suspected without bx Diagnosis and prognosis with biopsy only Treatments are available Studies underway