NON-ALCOHOLIC FATTY LIVER DISEASE IN TYPE 2

DIABETES

Mark TutschkaPGY3 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 4th 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

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

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

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