Nonalcoholic Fatty Liver Disease (NAFLD): Where are we today?

William M. Outlaw Internal Medicine Residency Wake Forest University

NAFLDPresentation 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

NAFLDBackground
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

NAFLDSpectrum of Disease
Steatosis

Steatohepatitis (NASH)

NAFLD
NASH with Fibrosis Cirrhosis

NAFLDWhy 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

NAFLDRisk Factors
*Obesity* Obesity Acquired Metabolic Disorders *DiabetesMellitus Diabetes Mellitus* *Hypertriglyceridemia* Hypertriglyceridemia Total Parenteral Nutrition Jejunoileal Bypass Surgery

Extensive Small Bowel Loss

Corticosteroids; Estrogens Amiodarone

Medications

Methotrexate; Tamoxifen
Diltiazem; Nifedipine

Occupational Exposures

Organic Solvents

NAFLDDemographics

Diabetes

High TG

Obesity
0 10 20 30 40 50 60 70

Prevalence (%)

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

NAFLDPathogenesis

Second Hit

First Hit
Insulin resistance Fatty acids

Steatosis
Lipid peroxidation

NASH

NAFLDNatural History
Steatosis generally follows a benign course NASH with fibrosis has increased liver-related morbidity and mortality Steatosis can progress to NASH fibrosis

NAFLDNatural History
Steatosis generally follows a benign course NASH with fibrosis has increased liver-related morbidity and mortality Steatosis can progress to NASH fibrosis
Worsened Improved/No Change
0 2 4 6 8 10 12 14

Inflammation/Fibrosis Steatosis

Patients
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

NAFLDSymptoms
Ascites GI bleeding Pruritus Edema RUQ pain Fatigue Asymptomatic
0 10 20 30 40 50 60 70

Prevalence (%)
Sanyal et al., 2003

NAFLDExam Findings
Ascites Splenomegaly Jaundice Edema Hepatomegaly Normal
0 5 10 15 20 25 30 35 40

Prevalence (%)
Sanyal et al., 2003

NAFLDLaboratory 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

NAFLDImaging
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

NAFLDHistological Spectrum
Cirrhosis

Time Progression

Fibrosis

Lobular Inflammation

Macrovesicular Steatosis

NAFLDSteatosis

Source: Ibdah 2003

NAFLDNASH (without fibrosis)

Source: Ibdah 2003

NAFLDNASH (with fibrosis)

Source: Ibdah 2003

NAFLDClinical 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. NAFLDPredictors 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.

NAFLDClinical 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.

NAFLDHow to Treat?
Insulin Sensitizers Antihyperlipidemics Antioxidants Cytoprotectants

First Hit
Insulin resistance Fatty acids

Second Hit
Steatosis
Lipid peroxidation

NASH

Weight Loss Diet/Exercise

NAFLDWeight 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

NAFLDInsulin Sensitizers
Metformin

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

NAFLDInsulin Sensitizers
Thiazolidinediones

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

NAFLDAntihyperlipidemics
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

NAFLDCytoprotectants
Ursodeoxycholic Acid 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

NAFLDAntioxidants
Vitamin E 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

NAFLDManagement 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

NAFLDLimitations of Studies

Few randomized trials Small study populations Short follow-up periods Minimal biopsy data

NAFLDConclusions
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