Nonalcoholic Fatty Liver Disease (NAFLD):

Where are we today?

William M. Outlaw

Internal Medicine Residency

Wake Forest University

NAFLD—Presentation Outline

• Background • Disease Continuum • Relevance• Risk Factors• Pathogenesis• Natural History • Clinical Features• Treatment• Conclusions

Defining NAFLD…

Clinico-pathologic syndrome encompassing a wide range of fatty liver disease in the absence of significant alcohol intake

(2 drinks or fewer daily) and other common causes of steatosis

NAFLD—Background

• Zelman et al. reported association of obesity with fatty liver in 1958

• A number of investigators noted liver failure in obese patients undergoing intestinal bypass surgery

• Ludwig et al. coined “non-alcoholic steatohepatitis” in 1980

NAFLD—Spectrum of Disease

Steatosis

Steatohepatitis (NASH)

NASH with Fibrosis

Cirrhosis

NAFLD

NAFLD—Why Study it?

• Prevalence of NAFLD 13-18% and that of NASH specifically 2-3%

• NAFLD is a disease of all sexes, ethnicities, and age groups (peak 40-49)

• NAFLD is the leading cause of cryptogenic cirrhosis

NAFLD—Risk Factors

Acquired Metabolic Disorders

*Obesity*

*Diabetes Mellitus*

*Hypertriglyceridemia*

Total Parenteral Nutrition

SurgeryJejunoileal Bypass

Extensive Small Bowel Loss

Medications

Corticosteroids; Estrogens

Amiodarone

Methotrexate; Tamoxifen

Diltiazem; Nifedipine

Occupational Exposures Organic Solvents

Obesity

Diabetes Mellitus

Hypertriglyceridemia

NAFLD—Demographics

0 10 20 30 40 50 60 70

Prevalence (%)

Obesity

High TG

Diabetes

Yu et al.. Nonalcoholic Fatty Liver Disease. Reviews in Gastroenterological Disorders. 2002; 2 (1):11-19

Insulin resistance

Fatty acids

SteatosisLipid peroxidation

NASH

NAFLD—Pathogenesis

First Hit

Second Hit

NAFLD—Natural History• Steatosis generally follows a benign course• NASH with fibrosis has increased liver-related

morbidity and mortality• Steatosis can progress to NASH ± fibrosis

NAFLD—Natural History

1. Harrison et al. The Natural History of NAFLD: A Clinical Histopathological Study. Am J Gastro 2003; 98:9; 2042-7

2. Matteoni et al. NAFLD: A Spectrum of Clinical and Pathological Severity. Gastroenterology 1999; 116; 1413-19

0 2 4 6 8 10 12 14

Patients

Improved/No Change

Worsened

Inflammation/FibrosisSteatosis

•Steatosis generally follows a benign course

•NASH with fibrosis has increased liver-related morbidity and mortality

•Steatosis can progress to NASH ± fibrosis

NAFLD—Symptoms

0 10 20 30 40 50 60 70

Prevalence (%)

Asymptomatic

Fatigue

RUQ pain

Edema

Pruritus

GI bleeding

Ascites

Sanyal et al., 2003

NAFLD—Exam Findings

0 5 10 15 20 25 30 35 40

Prevalence (%)

Normal

Hepatomegaly

Edema

Jaundice

Splenomegaly

Ascites

Sanyal et al., 2003

NAFLD—Laboratory Findings

• Mild elevation of ALT most common

• Elevated fasting glucose, triglycerides and depressed HDL with insulin resistance

• Elevated PT and low albumin with cirrhosis

Normal labs do not rule out NAFLD

NAFLD—Imaging

• Ultrasound

• Computed Tomography

• Magnetic Resonance Imaging

Current non-invasive modalities are unable to detect NASH with or without fibrosis

Saadeh et al. The Utility of Radiological Imaging in NAFLD. Gastroenterology 2002; 123: 745-750

NAFLD—Histological Spectrum

Macrovesicular Steatosis

Lobular Inflammation

Fibrosis

Cirrhosis

Tim

e P

rogr

essi

on

NAFLD—Steatosis

Source: Ibdah 2003

NAFLD—NASH (without fibrosis)

Source: Ibdah 2003

NAFLD—NASH (with fibrosis)

Source: Ibdah 2003

NAFLD—Clinical Predictors

Non-invasive predictors of NASH:

A. HAIR index (HTN; ALT > 40; Insulin Resistance)≥ 2 are 80% Sensitive, 89% Specific of NASH

B. BAAT index (BMI>28; Age >50; ALT>2x nl; incr. Triglycerides)

≤ 1 has 100% Negative Predictive Value for NASH

1. Dixon et al. NAFLD—Predictors of NASH and Fibrosis in the Severely Obese. Gastroenterology. 2001; 121: 91-100.

2. Ratziu et al. Liver Fibrosis in Overweight Patients. Gastroenterology. 2000; 118: 1117-1123.

NAFLD—Clinical Predictors

Patients at risk to develop NASH with fibrosis:

A. Age > 45

B. Obesity (BMI > 31-32)

C. Diabetes

1. Angulo et al. Independent predictors of liver fibrosis in patients with NASH. Hepatology. 2000; 30: 1356-1362.

Insulin resistance

Fatty acids

Steatosis

Lipid peroxidation

NASH

CytoprotectantsInsulin SensitizersAntihyperlipidemics

First HitSecond Hit

Weight Loss

Diet/Exercise

Antioxidants

NAFLD—How to Treat?

NAFLD—Weight Loss/Exercise

Palmer et al. Gastroenterology 1990--39 obese patients, no primary liver disease--Retrospective analysis after weight loss--Lower ALT seen in patients with >10% weight loss

Anderson et al. Journal Hepatology 1991--41 obese patients with biopsy-proven NAFLD--Low calorie diet (~400 kcal/d) x 8 months then re-biopsied--Most improved, but 24% with worse fibrosis/inflammation--Histological worsening associated with rapid weight loss

NAFLD—Insulin Sensitizers

Marchesini et al. Lancet 2001--20 patients, biopsy-proven NASH

--14 metformin (500 tid) x 4 months; 6 controls

--ALT & OGTT improved in metformin

Nair et al. Gastroenterology (in press)--22 patients, biopsy-proven NASH

--Received metformin 20 mg/kg/d x 12 months

--Improvement in ALT & insulin sensitivity

--No improvement in liver histology

Metformin

NAFLD—Insulin Sensitizers

Neuschwander et al. Journal of Hepatology 2003--30 patients biopsy-proven NASH and elevated ALT

--Received rosiglitazone 4 mg bid x 6 months

--Significant improvement of ALT and insulin sensitivity

Azuma et al. Hepatology (in press)--12 patients biopsy-proven NASH

--Received 15 mg qd pioglitazone x 3 months

--Significant improvement in ALT

Thiazolidinediones

NAFLD—Antihyperlipidemics

Laurin et al. Hepatology 1996--16 patients biopsy-proven NASH

--Received clofibrate 2 g/d x 12 months

--No significant improvement in ALT or histology

Basaranoglu et al. Journal Hepatology 1999--46 patients biopsy-proven NASH followed 4

months

--23 received gemfibrozil, 23 no treatment

--74% patients in gemfibrozil group had lower ALT

--30% patients no treatment group had lower ALT

NAFLD—Cytoprotectants

Laurin et al. Hepatology 1996

--24 patients with biopsy-proven NASH

--Treated with UDCA 13-15 mg/kg/d x 12 months

--63% had improved ALT and steatosis

--No significant improvement in inflammation/fibrosis

Lindor et al. Gastroenterology (in press)

--Randomized controlled double-blind study

--168 patients with biopsy-proven NASH

--82 received UDCA and 86 no treatment x 12 months

--No significant improvement in ALT or histology

Ursodeoxycholic Acid

NAFLD—Antioxidants

Hasegawa et al. Aliment Pharmacol Ther 2001--22 patients, 10 steatosis and 12 biopsy-proven NASH--6 months standard diet followed by Vitamin E 100 IU tid x 12 mo--Steatosis group showed improvement in ALT after diet--NASH group showed improvement in ALT after Vitamin E--40% NASH patients had histological improvement after Vitamin E

Kugelmas et al. Hepatology 2003--16 patients with biopsy-proven NASH followed for 3 mo--9 received diet/exercise and Vitamin E 800 IU qd--7 diet/exercise only--Vitamin E conferred no significant improvement in ALT

Vitamin E

NAFLD—Management Summary

• Gradual, sustained weight loss hallmark therapy

• Rapid weight loss potentially detrimental

• Gemfibrozil, Vitamin E and insulin sensitizers require further study

• Clofibrate and UDCA do not appear useful in NASH patients

NAFLD—Limitations of Studies

Few randomized trials

Small study populations

Short follow-up periods

Minimal biopsy data

NAFLD—Conclusions• NAFLD affects up to 15% of the US population

• Steatosis is relatively benign, but NASH has significant morbidity/mortality risk

• Insulin resistance and cellular damage are the key pathogenetic mechanisms

• Sustained gradual weight loss and exercise are hallmark therapies

• Insulin sensitizers, cytoprotectants, antioxidants may play role in future for those who fail conservative therapy

Acknowledgements

Dr. Jamal Ibdah

Bill and Nedra Outlaw

Elizabeth Garwood

Department of Internal Medicine

Division of Gastroenterology