Fatty liver disease: What do we know?

Transcription

1 Fatty liver disease: What do we know? Prof. Dr. Claus Niederau Katholische Kliniken Oberhausen ggmbh St. Josef-Hospital Academic Teaching Hospital University of Duisburg-Essen

2 NAFLD Non-Alcoholic Fatty Liver Disease NASH Non-Alcoholic Steato-Hepatitis

3 Differentiation between ASH and NASH by daily alcohol consumption > 20 g < 20 g Alcoholic Steato-Hepatitis (ASH) Non-Alcoholic Steato-Hepatitis (NASH)

4 Ludwig J et al. Mayo Clin Proc 1980; 55: Non-Alcoholic Steato-Hepatitis = NASH 20 Mayo Clinic patients with an hithero unnamed disease hepatomegaly abnormal ALT histology: fatty changes, lobular hepatitis, fibrosis mimicks alcohol hepatitis in absence of alcohol intake findings associated with obesity and diabetes mellitus

5 Epidemiology of NAFLD % of subjects in general populations have NAFDL % of subjects with BMI > 30 have NAFLD % of subjects with diabetes type 2 have NAFLD 5 % of subjects with NAFLD have a normal BMI

6 BMI 30 in the USA BRFSS, 1985 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

7 BMI 30 in the USA BRFSS, 1986 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

8 BMI 30 in the USA BRFSS, 1987 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

9 BMI 30 in the USA BRFSS, 1988 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

10 BMI 30 in the USA BRFSS, 1989 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

11 BMI 30 in the USA BRFSS, 1990 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

12 BMI 30 in the USA BRFSS, 1991 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

13 BMI 30 in the USA BRFSS, 1992 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

14 BMI 30 in the USA BRFSS, 1993 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

15 BMI 30 in the USA BRFSS, 1994 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

16 BMI 30 in the USA BRFSS, 1995 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

17 BMI 30 in the USA BRFSS, 1996 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

18 BMI 30 in the USA BRFSS, 1997 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

19 BMI 30 in the USA BRFSS, 1998 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

20 BMI 30 in the USA BRFSS, 1999 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

21 BMI 30 in the USA BRFSS, 2000 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

22 BMI 30 in the USA BRFSS, 2001 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

23 BMI 30 in the USA BRFSS, 2002 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

24 BMI 30 in the USA BRFSS, 2003 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

25 BMI 30 in the USA BRFSS, 2004 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

26 BMI 30 in the USA BRFSS, 2005 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

27 BMI 30 in the USA BRFSS, 2006 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

28 BMI 30 in the USA BRFSS, 2007 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

29 BMI 30 in the USA BRFSS, 2008 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

30 BMI 30 in the USA BRFSS, 2009 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

31 BMI 30 in the USA BRFSS, 2010 no data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

32 Causes of NAFLD and NASH nutritional Obesity Alcohol Mal-nutrition (fasting, Kwashiorkor) Jejunoileal bypass Parenteral feeding metabolic Type 2 diabetes mellitus Hyperlipidemia, Reye s syndroms chronic disease CED Wilson disease Right ventricular failure Cystic fibrosis infectious chronische Hepatitis B/C Fulminant acute viral hepatitis HIV infection tuberculosis endocrine Cushing disease Hypothreosis Acromegaly drugs and toxins Amiodarone Glucocorticoids Methotrexate Tetracyclines pregnancy hyperemesis gravidarum acute fatty liver

33 NASH: Natural history NAFLD NASH Cirrhosis HCC 10 % / 10 years 10 % / 10 years 10 % / 10 years

34 NASH - pathogenesis Iron, leptin, adiponectin, decrease in antioxidants, intestinal bacteria Second Hit First Hit Insulin resistance NAFLD Lipid peroxidation NASH Fatty acids

35 Risk of progression in NASH risk for progression associated with initial degree of inflammation and fibrosis histology is the gold standard to estimate this risk fibroscan is the best non-invasive test for advanced fibrosis also in NASH however it is more difficult to do when compared to hepatitis C Chalasani N et al. Hepatology 2012:55:

36 Increased GT/ALT, bright liver on ultrasound, and obesity: What to do next? loose weight be abstinent from alcohol (good control of diabetes) liver biopsy to estimate risk for fibrosis if there is NASH

37 Angulo P. N Engl J Med 2002;346:

38 ALT and total mortality adults followed in Mayo outpatient clinics from Relative Mortality Risk 2.5 UNL 40 U/l men women ALT (U/L) Lee TH, et al. Hepatology 2008;47:880-7

39 and diabetes mellitus in NAFLD/NASH Carotid-Artery Intimal Thickness in Patients with NASH Look for cardiovascular disease Targher G et al. N Engl J Med 2010;363:

40 NASH: Therapeutic options Weight reduction (diet, sports) Anti-oxidants (e.g. vitamin E) Insulin sensitizers (metformin, glitazones) Ursodeoxycholic acid Others (betaine, anti-tnf, pentoxyfillin) Bariatric surgery

41 RCT testing the effects of weight loss in 30 NASH patients ALT BMI Pomrat et al. Hepatology 2010; 51:121-9.

42 Fasting in obesity: another cause of liver injury? Capron JP et al. Dig Dis Sci 1982; 27:

43 Rapid weight reduction and NAFLD 41 obese patients with median weight loss of 34 kg: reduction of fat in the liver, but new inflammation and fibrosis in 24 % of patients in particular in those with the most dramatic weight reduction Andersen et al. J Hepatol 1991;12: obese patients with median weight loss of 32 kg: reduction of fat in the liver but new inflammation in 26 % of patients Luycx et al. Int J Obes Metabol Disord 1998;22:222-6

44 Insulin sensitizers in NAFLD/NASH Angelico F et al. Cochrane Database Syst Rev 2007; 24: CD Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Chinese Biomedical Database 3 RCTs: - 2 with major methodology problems - none with blinded outcome assessment - 2 with some benefit for metformin (improvement of GPT and liver echography) - 1 pioglitazone trial (histology improved) insufficient data to support or refute the drugs improving insulin resistance Limited information suggests a favourable role of such drugs. Larger and better trials are needed.

45 Anti-oxidants in NAFLD and NASH Lirussi F et al. Cochrane Database Syst Rev 2007; 24: CD Cochrane Central Register of Controlled Trials (2006), MEDLINE, EMBASE, Chinese Biomedical Database 6 trials identified: 2 of high quality and 4 of low quality antioxidants with significant, though not clinically relevant amelioration of GOT, but not of GPT as compared to control histological data too limited to draw conclusions insufficient data to support or refute the use of antioxidants for NASH

46 PIVENS RCT in 247 NASH adults without diabetes Primary outcome: Histological improvement in NASH p=0,001 for vitamin E n.s. for pioglitazone Sanyal et al. N Engl J Med 2010;362:

47 TONIC RCT of metformin and vitamin E vs. placebo in 173 NAFLD and NASH patients aged 8-17 years Primary goal of TONIC: differences in ALT No difference betweeen the groups at 90 or 120 months Lavine et al. JAMA. 2011;305:

48 Randomized UDC studies in NASH: no effects on inflammation and fibrosis Leuschner UF et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial (n=48) Hepatology 2010;52: Lindor KD et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial (n=107) Hepatology 2004;39:770-8.

49 Other drugs for treatment of NASH Clofibrat lipid reduction, in particular of triglyceride rich VLDL Little/ no effect Gemfibrozil reduction of FFA release into peripheral tissue Little/ no effect Betaine activates phospholipid synthesis Little data N-acetylcysteine glutathione prodrug free radical scavanger Little/ no effect Pentoxyfillin phosphodiesterase inhibitor raises camp and PKA inhibits TNF, leukotriens inflammation and innate immunity Little data in NASH better data in ASH

50 Bariatric surgery for NASH in obese patients Cochrane Database 2010;11 (ISSN X). 21 prospective or retrospective cohort studies show improvement on steatosis or inflammation no randomised clinical trials fulfilling Cochrane criteria benefits of bariatric surgery for patients with NASH unclear

51 890 patients with massive obesity (BMI > 35-40) and bariatric surgery (University of Lilles, ) baseline 1 year 5 years BMI GT (U/l) HBa1c (%) 7,0 5,9 6, Fibrosis (Metavir) 0,91 0,75 0,6 Steatosis (%) Lassailly et al. AASLD 2011, A215

52 Therapeutic recommendations in NASH Obese patients should loose weight by hypocaloric diet alone or in conjunction with increased physical activity Vitamin E (800 IU/d) first choice in patients without diabetes - consider that vitamin E may increase cancer risks Pioglitazone may be used - consider that its long-term risk and benefit are unknown Metformin, statins, and UDC should not be used Inhalt Bariatric surgery is not contraindicated in NASH - it is premature to recommend it for treatment of NASH AASLD and AGA practice guidlines on NASH. Hepatology 2012:55: