NON-ALCOHOLIC FATTY LIVER DISEASE IN TYPE 2 DIABETES

Mark Tutschka PGY3 Internal Medicine

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

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?

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 5% of mortality leading cause of death among diabetics, accounting for ~4 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

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

NAFLD / NASH

NAFLD NASH

Effects of Insulin Resistance

www.cwu.edu/~geed/543/fatty%20acid%20metabolism.ppt

Tolman K G et al. Ann Intern Med 2004;141:946-956

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

NAFLD – Inflammation & Steatohepatitis

Dowman J K et al. QJM 2010;103:71-83

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

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

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, a ratio >1 suggests advanced disease  AlkP and Bilirubin are less frequently elevated  Liver enzyme elevation does not correlate with liver histology

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

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

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

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 <2 has NPV >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

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)

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

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

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

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

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”

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

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; 1200-1500 for >200lbs  Unsupervised, moderate exercise focusing on walking (goal of 200min/week)

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

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

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