5QuestionsWhat is the most likely cause of abnormal LFT in this patient ?Would you proceed to liver biopsy if viral, autoimmune, and metabolic markers are negative ?Should you stop statins ?How would manage this patient ?Would you recommend bariatric surgery ?
6Spectrum of Liver Disease in Diabetics Non Alcoholic Fatty live diseaseAlcoholic liver disease
7Spectrum of Liver Disease in Diabetics Chronic viral hepatitis especially HCV Autoimmune hepatitisWilson’s disease
8Spectrum of Liver Disease in Diabetics HemochromatosisSecondary iron overload
9Definition of Non-Alcoholic Fatty Liver Disease (NAFLD) Evidence of fatty accumulation in the liver by imaging or histologyAlcohol intake less than 21 and 14 drinks per week for men and women respectivelyNo causes for secondary fat accumulation eg drugs, TPN, starvation, etc
10Classification of NAFLD Non Alcoholic fatty liver NAFL (steatosis without inflammation)Non Alcoholic Steatohepatitis NASHLow Risk of progression to cirrhosisIncreased CDV mortalityIncreased risk of progression to cirrhosisIncreased risk of CDV mortality
16HSC: hepatic stellate cells Possible role of adipose tissue insulin resistance and lipotoxicity in the progression from NAFLD and NASH. (1) In the setting of obesity or T2DM, increased rates of lipolysis and plasma FFA, combined with hyperinsulinemia and hyperglycemia, stimulate excessive hepatic TG synthesis. (2) Steatosis in turn may (i) exacerbate hepatic insulin resistance, (ii) stimulate VLDL secretion, and (iii) increase mitochondrial beta-oxidation. If a new steadystate is achieved, only benign steatosis takes place. (3) If mitochondrial function cannot adapt to the increased FFA flux and respiratory oxidation collapses, lipid-derived toxic metabolites activate inflammatory pathways and hepatocyte lipotoxicity leading to.Endoplasmic reticulum stress and the unfolded protein response also participate in the pathogenesis of NASH. (4) The cross-talk between hepatocytes, macrophages, and hepatic stellate cells (HSC) determines the degree of the fibrogenic response and potential progression to cirrhosis. (From Cusi K. Non-alcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2009;16:141–9; with permission.Bacterial overgrowthHSC: hepatic stellate cells
30Summary of life style intervention studies: Diet and physical activity 123451.Lazo M et al. Diabetes Care Kantarzis K et al. Gut Promrat K et al. Hepatology St George A et al. J Gastro Hepatol Hallsworth K et al. Gut 2009
31Lifestyle Interventions Aim Hb A1c < 6.5Correct dyslipidemiaAlcohol consumption should be avoided or limited to one drink a day.10 % weight loss led to improvement in steatosis, necrosis, and inflammation; not fibrosis.Moderate exercise ( min/wk)alone can reduce steatosis but may not affect necroinflammation2-3 Cups of filtered coffee may prevent fibrosis ???Weight loss 1-2 pounds per week* Promrat, et al. Hepatology 2010** Dunn, et al. Hepatology 2008** Gunji. et al. Am J Gastro 2009** Moriya, et al. Alim Pharm Ther 2011***Ruhl , et al. Clin Gastro Hepatol 2005
33Summary of trials involving Pioglitazone therapy for NAFLD Abbreviations: RCT, randomized controlled trial; , improvement; , no effect.
34AASLD recommendations: Pioglitazone can be used to treat NASH in patients who have DM but long term safety and efficacy has not been establishedCaution in patient with impaired myocardial function
35Summary of trials involving Metformin therapy for NAFLD Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect.
36Summary of trials involving Vitamin E therapy for NAFLD Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect.effect
37Vitamin E: Safety Concerns Meta-analysis including 136,000 participants found taking Vitamin E supplements > 400 IU/day had a higher risk of all cause mortality*Vitamin E > 400 IU/day increases risk of prostate cancer in relatively healthy men***Miller et al . Annals of Internal Medicine 2005** Klein, et al. JAMA 2011
38AASLD Recommendations-Vit E “until further data supporting its effictiveness become available, vit E is not recommended to treat NASH in diabetics”
39Summary of trials involving UDCA therapy for NAFLD Abbreviations: n/a, not available;
40AASLD Recommendations Metformin and usrodeoxycholic acid do not induce histologic improvementNot recommended as specific therapies for NAFLD
41Summary of Bariatric surgery trials for NAFLD Abbreviations: n/a, not available; , improvement; , no effect
42AASLD Recommendation on Bariatric Surgery Premature to consider foregut surgery as an option to specifically treat NASHForegut surgery is not contra-indicated in otherwise eligible pts with NASH or NAFLD WITHOUT cirrhosisFor those with cirrhosis: type, safety and efficacy of foregut surgery is not established
43Statins CVD common cause of death for NAFLD and NASH Stratify risks and treat accordinglySeveral studies show NAFLD and NASH pts are not at increased risk of liver injury over general population*No RCTs with histological end points using statins to treat NASH*Chalasani, et al. Am J Gastro 2012
44GREACE Study: Safety of Statins in Patients with Abnormal LFT Cardiovascular outcomes studyAthyros et al Lancet 2010
45AASLD Recommendation on Statins “Given lack of evidence that patients with NAFLD and NASH are at increased risk for serious drug-induced liver injury from statins, they can be used to treat dyslipidemia in patients with NAFLD and NASH.”
46Take Home MessagesNAFLD is very common in diabetics who are at higher risk of cirrhosis and hepatocellular ca than the general populationViral, autoimmune and metabolic liver disease should be ruled out in diabetics with NAFLDLiver biopsy maybe considered in high risk patientsLifestyle modification is the cornerstone of treatmentNo drugs are currently recommendedStatins and fibrates are safe in NAFLD patients except in those with decompensated cirrhosis