1. NON-ALCOHOLIC FATTY LIVER DISEASE IN TYPE 2 DIABETES Mark Tutschka PGY3 Internal Medicine

2. Objectives  Understand the epidemiologic significance of NAFLD in T2DM  Appreciate the basic pathophysiology of NAFLD and it’s relationship to T2DM  Appreciate the clinical features and diagnostic approach to fatty liver disease in diabetic patients  Review the treatment implications of concomitant T2DM and NAFLD

3. Diabetes – A Growing Problem  285MM individuals WW; ~3MM Canadians and >20MM U.S.  Among Americans, T2DM accounts for ~17% of all deaths in persons >25 y.o.  The direct healthcare cost of diabetes consumes 2.5-15% of healthcare budgets  WHO predicts WW prevalence of 6.4% by 2030, a 60% increase since 1995 and a 39% rise from 2000  In 2004-5, 9MM Ontarians were diagnosed with diabetes, a 113% rise over the previous decade ICES Report: The Growing Prevalence of Diabetes in Ontario: Are We Prepared?

4. Diabetes and NAFLD - Epidemiology  Liver disease is a major contributor to diabetes-related morbidity and mortality  DM is the leading cause of liver disease in Western Countries  Standardized mortality ratio for cirrhosis vs. CVD is 2.57 vs. 1.34  Cirrhosis is the 4 th leading cause of death among diabetics, accounting for ~4- 5% of mortality  NAFLD is common  20-30% of adults in the Western World are estimated to have NAFLD  NAFLD is present in 34-74% of all diabetic patients and in nearly 100% of obese diabetics  Among patients with NAFLD, 50% have NASH and 19% have cirrhosis at the time of diagnosis

5. NAFLD – What is it?  Defined as fatty liver disease in the absence of EtOH consumption greater than 20g/day  Histologically indistinguishable from alcoholic hepatitis  Encompasses a spectrum or liver pathology  Steatosis - simple fatty infiltration of the liver  NASH / steatohepatitis – steatosis plus inflammation, necrosis and fibrosis Progresses to cirrhosis in up to 20% of patients

6. NAFLD / NASH NAFLD NASH

7. Effects of Insulin Resistance Tolman K G et al. Ann Intern Med 2004;141:946-956 www.cwu.edu/~geed/543/fatty%20acid%20metabolism.ppt

8. NAFLD – Pathophysiology  insulin mediated suppression of lipolysis impaired  increased FFA supply to liver  Hyperinsulinemia up-regulates lipogenic transcription factors  increased de novo hepatic FFA synthesis   hepatic fat content overwhelms liver’s ability to oxidize excess fatty acid  NAFLD patients increase VLDL- TG secretion, but impaired secretion of apoB100, limiting TG export Adams L A et al. CMAJ 2005;172:899-905 Lipogenic transcription factors

9. NAFLD – Inflammation & Steatohepatitis Dowman J K et al. QJM 2010;103:71-83

10. NAFLD / NASH – Natural History  Limited prospective follow-up of patients with NAFLD  Patients with NAFLD in the absence of NASH generally follow a benign course  SMR of 1.34 (1.00-1.76) compared to the general population  NAFLD progression to NASH is infrequent relative to progression of alcoholic fatty liver  3-26% versus 38-50%  NASH progresses slowly, typically over years / decades  5 and 10 year survival rates of 67% and 59% respectively  15-20% of NASH patients develop cirrhosis, of these 30-40% incur liver-related mortality

11. NAFLD – Clinical Features  NAFLD is seen in patients with features of the metabolic syndrome  Obesity: 70-100% have NAFLD  T2DM: 34-75%  Hyperlipidemia: 20-80%  Metabolic syndrome: one-third  Most patients are asymptomatic; signs of chronic liver disease are rare  Liver enzymes fluctuate in NAFLD  Within normal limits at any given time in ~80% of patients  Mild elevations are typical  Ferritin and transferin saturation levels are elevated in >50% of patients  Significance of elevated Fe studies is unclear

12. NASH – Clinical Features  Patients who progress to NASH typically remain asymptomatic  Serum AST and ALT are increased in ~90% of patients  AST/ALT ratio is usually 1 suggests advanced disease  AlkP and Bilirubin are less frequently elevated  Liver enzyme elevation does not correlate with liver histology

13. NAFLD / NASH - Diagnosis  Suspect NAFLD in any diabetic  Present in >50% of patients  Check liver enzymes in all diabetics  Consider co-existing liver pathology: alcoholic, viral & autoimmune hepatitis, hemachromatosis, Wilson’s disease and α -antitrypsin deficiency  Consider contributing factors, particularly drugs  Glucocorticoids, estrogens, tamoxifen, methotrexate, zidovudine, amiodarone, ASA  Other: TPA, intestinal bypass surgery, rapid weight loss, HIV infection, IBD, bacterial overgrowth, HCV (genotype 3), PCOS, hypothyroidism

14. NAFLD / NASH - Diagnosis  U/S is useful but has limitations  Sensitivity/specificity – 64%/97% overall, 91%/93% in patients with >30% steatosis  PPV 62-89%  NPV 94%  No utility for NAFLD vs. NASH or for staging  Operator dependent - significant intra- and inter- observer variability  CT has similar diagnostic utility

15. NAFLD / NASH – Diagnosis, cont’d  A positive U/S in the absence of concomitant liver disease is typically sufficient to diagnose NAFLD  Liver biopsy can distinguish NAFLD from NASH  Severity can also be determined  Liver biopsy is not routinely suggested, consider if:  Uncertainty regarding diagnosis  Manifestations of chronic liver disease  Splenomegaly  Cytopenias  Abnormal iron studies

16. NAFLD / NASH – Diagnosis, cont’d  Scoring systems have been proposed to determine if fibrosis is present in the setting of NAFLD  BARD  BMI ≥28 – 1 point; AST/ALT ratio ≥0.8 – 2 points; diabetes present – 1point  Score 90% for advanced fibrosis  AST/ALT ratio (cut-off 0.8)  Sensitivity 74%, specificity 78% NPV 93% for advanced fibrosis  NAFLD Fibrosis Score  Six variables: age, hyperglycaemia, BMI, PLT count, albumin, AST/ALT ratio  NPV 92%, PPV 72%  Online calculator available

17. Liver Disease & Diabetes – Management Principles  Liver disease does not significantly change the general approach to management of the diabetic patient  Diet and exercise remain a foundation for management  The approach to pharmacologic therapy is essentially unchanged  Hepatic drug metabolism is relatively preserved until patients have evidence of liver failure (ascites, coagulopathy, encephalopathy)

18. Liver Disease & Diabetes – Management Principles, cont’d  Metformin  Effective first-line therapy in all but the most advanced liver disease patients  At high levels of hepatic impairment ? Increased risk of lactic acidosis  Modest aminotransferase benefits reported in trials of metformin in NASH  TZDs (pioglitazone)  Pioglitazone safe in liver disease despite safety concerns raised by troglitazone  As an insulin sensitizer, a mechanistically rational choice in patients with NASH  Trials in patients with NASH have shown benefit ranging from improved aminotransferases to improved histology Evidence insufficient to recommend TZDs first-line for NASH, however this is an active research area Prompt histological recurrence with discontinuation, lack of proven long-term benefit and persistent safety concerns (CHF, liver disease) are barrier to wider use  Not currently recommended in patients with baseline LFTs >2.5x ULN

19. Liver Disease & Diabetes – Management Principles, cont’d  Sulfonylureas  Generally safe; patients w/significant hepatic impairment may be more prone to lows  Mechanistically not “rational” since they fail to target insulin resistance  Agents with a shorter half-life (glyburide) generally preferred  Meglitinides (repaglinide)  Limited data regarding safety in liver patients  Not associated with hepatic toxicity  Hepatic clearance – titrate up from a low dose  α- glucosidase inhibitors  Mechanistically rationale – “gut specific”, therefore no insulin stimulation and less chance of lows in patients with hepatic dysfunction  RCT of 100 patients demonstrated improved glycemic parameters and decreased ammonia formation  Generally safe in liver patients, however label cautions against use in liver disease because of known mild transaminitis and rarely severe liver disease

20. Liver Disease & Diabetes – Management Principles, cont’d  Insulin  Reasonable to use in patients with significant hepatic impairment  Factors affecting insulin requirements are significant – monitor patients and adjust doses carefully Decreased requirement 2 o to impaired hepatic gluconeogenesis and decreased hepatic insulin clearance Increased requirement 2 o to insulin resistance

21. NAFLD/ NASH Principles of Management  Patients with NAFLD generally do not require “treatment”  Biopsy-proven NASH and patients where NASH is suspected (for example by scoring systems) should be considered for more aggressive follow-up  Lifestyle modification (weight loss and exercise) are the main “treatment”  There are no approved pharmacologic treatments for NASH  Guidelines / expert opinion generally do not recommend routine use of any pharmacologic agent

22. NAFLD/ NASH Management – Lifestyle Modification  A recent systematic review commented on studies evaluating diet, exercise and weight loss for management of NAFLD  Limited data and “considerable heterogeneity” was noted among the various studies identified in the systematic review  Diagnostic criteria /quantitative assessment of NAFLD/NASH  Inclusion and exclusion criteria  Objective monitoring of exercise and use of validated dietary assessment methods  Lack of long-term data  Despite limitations, the authors concluded that lifestyle interventions “producing weight loss significantly improve liver lipid”

23. NAFLD / NASH Managment – Lifestyle Modification, cont’d  Diet restriction combined with physical activity lowers hepatic enzymes and decreases steatosis when BMI / weight decreases of 7-10% are achieved  Weight loss should be gradual (i.e. 1.5kg/week) - rapid weight loss may accelerate NAFLD  NASH  Optimal dietary composition is not well studied  High intake of simple carbohydrates and low intake of polyunsaturated fat is thought to be harmful  Long-term, prospective studies with hard endpoints are lacking

24. Lifestyle Modification, cont’d  A recent (2010) RCT demonstrated significant improvement by way of lifestyle modification among patients with NASH  28 patients, randomized 2:1 to intervention vs. placebo (65 patients screened)  Inclusion criteria: elevated AST or ALT, BMI 25-40, no other liver disease  Liver biopsy after 2 week run-in of self monitored diet/exercise  Enrolled based on biopsy proven steatohepatitis  Q12 week fasting blood glucose, liver enzymes. Biopsy after 48weeks  Placebo group attended group session providing basic education regarding NASH, physical activity, diet and weight control  Intervention group: “intensive, state-of-the-art weight loss intervention” based on the Diabetes Prevention Program, LOOK AHEAD”  Target 7-10% weight loss over 6 months and then maintain  Diet: 25% fat; 1000-1200kcal for 200lbs  Unsupervised, moderate exercise focusing on walking (goal of 200min/week)

25. Lifestyle Modification, cont’d  Results  Groups were similar for age, sex, BMI, waist circ., LFTs, lipid profile, HbA1C, metabolic syndrome, anti-glycemic meds  All but one patient completed the study (intervention group)  Weight: -8.7kg vs. -0.5kg (p=.005) Greater weight loss was achieved by non-diabetics  Liver enzymes: ALT improved significantly (p=.01) in the intervention group; there was no significant difference in AST  On biopsy, overall hepatic steatosis and NASH disease activity decreased significantly in the intervention group (p=.05)  Percent weight loss from baseline correlated significantly with  ALT, decreased steatosis and decreased NASH disease activity

26. Pharmacotherapy  Metformin:  Cochrane Review concluded “improvement in liver enzymes and steatosis without effect on liver histology”  TZDs (pioglitazone):  Improve liver enzymes / steatosis  Conflicting histological results: favourable to no benefit  Discontinuation reverses benefit  Long-term treatment – concern regarding CHF, ? hepatotoxcity  Vitamin E:  Conflicting results ranging from no benefit to improved enzymes and steatosis  Debate continues

27. Pharmacotherapy  Ursodeoxycholic Acid (UDCA):  Cochrane Review – no significant improvement in LFTs or mortality  Statins:  Generally safe to use in NASH, but no proven hepatic benefit. Recommended only for lipid-related risk factor modification