nonalcoholic fatty liver disease (nafld): where are we today?
TRANSCRIPT
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Nonalcoholic Fatty Liver Disease (NAFLD):
Where are we today?
William M. Outlaw
Internal Medicine Residency
Wake Forest University
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NAFLD—Presentation Outline
• Background • Disease Continuum • Relevance• Risk Factors• Pathogenesis• Natural History • Clinical Features• Treatment• Conclusions
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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
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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
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NAFLD—Spectrum of Disease
Steatosis
Steatohepatitis (NASH)
NASH with Fibrosis
Cirrhosis
NAFLD
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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
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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
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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
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Insulin resistance
Fatty acids
SteatosisLipid peroxidation
NASH
NAFLD—Pathogenesis
First Hit
Second Hit
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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
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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
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NAFLD—Symptoms
0 10 20 30 40 50 60 70
Prevalence (%)
Asymptomatic
Fatigue
RUQ pain
Edema
Pruritus
GI bleeding
Ascites
Sanyal et al., 2003
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NAFLD—Exam Findings
0 5 10 15 20 25 30 35 40
Prevalence (%)
Normal
Hepatomegaly
Edema
Jaundice
Splenomegaly
Ascites
Sanyal et al., 2003
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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
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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
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NAFLD—Histological Spectrum
Macrovesicular Steatosis
Lobular Inflammation
Fibrosis
Cirrhosis
Tim
e P
rogr
essi
on
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NAFLD—Steatosis
Source: Ibdah 2003
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NAFLD—NASH (without fibrosis)
Source: Ibdah 2003
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NAFLD—NASH (with fibrosis)
Source: Ibdah 2003
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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.
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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.
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Insulin resistance
Fatty acids
Steatosis
Lipid peroxidation
NASH
CytoprotectantsInsulin SensitizersAntihyperlipidemics
First HitSecond Hit
Weight Loss
Diet/Exercise
Antioxidants
NAFLD—How to Treat?
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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
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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
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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
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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
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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
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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
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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
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NAFLD—Limitations of Studies
Few randomized trials
Small study populations
Short follow-up periods
Minimal biopsy data
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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
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Acknowledgements
Dr. Jamal Ibdah
Bill and Nedra Outlaw
Elizabeth Garwood
Department of Internal Medicine
Division of Gastroenterology