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

1
Nonalcoholic Fatty Liver Disease (NAFLD)Where
are we today?

• William M. Outlaw
• Internal Medicine Residency
• Wake Forest University

2
NAFLDPresentation 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

4
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

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NAFLDSpectrum of Disease

• Steatosis
• Steatohepatitis (NASH)
• NASH with Fibrosis
• Cirrhosis

NAFLD
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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

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NAFLDRisk Factors
Obesity
Diabetes Mellitus
Hypertriglyceridemia
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NAFLDDemographics
Yu et al.. Nonalcoholic Fatty Liver Disease.
Reviews in Gastroenterological Disorders. 2002
2 (1)11-19
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NAFLDPathogenesis
Second Hit
First Hit
Steatosis
NASH
Lipid peroxidation
Insulin resistance ? Fatty acids
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NAFLDNatural 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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NAFLDNatural History

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

• Harrison et al. The Natural History of NAFLD A
  Clinical Histopathological Study. Am J Gastro
  2003 989 2042-7
• Matteoni et al. NAFLD A Spectrum of Clinical
  and Pathological Severity. Gastroenterology
  1999 116 1413-19

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NAFLDSymptoms
Sanyal et al., 2003
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NAFLDExam Findings
Sanyal et al., 2003
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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
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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
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NAFLDHistological Spectrum
Cirrhosis
Time Progression
Fibrosis
Lobular Inflammation
Macrovesicular Steatosis
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NAFLDSteatosis
Source Ibdah 2003
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NAFLDNASH (without fibrosis)
Source Ibdah 2003
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NAFLDNASH (with fibrosis)
Source Ibdah 2003
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NAFLDClinical Predictors

• Non-invasive predictors of NASH
• A. HAIR index (HTN ALT gt 40 Insulin
  Resistance)
• 2 are 80 Sensitive, 89 Specific of NASH
• B. BAAT index (BMIgt28 Age gt50 ALTgt2x nl
  incr. Triglycerides)
• 1 has 100 Negative Predictive Value for NASH

• Dixon et al. NAFLDPredictors of NASH and
  Fibrosis in the Severely Obese.
  Gastroenterology. 2001 121 91-100.
• Ratziu et al. Liver Fibrosis in Overweight
  Patients. Gastroenterology. 2000 118
  1117-1123.

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NAFLDClinical Predictors

• Patients at risk to develop NASH with fibrosis
• A. Age gt 45
• B. Obesity (BMI gt 31-32)
• C. Diabetes

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

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NAFLDHow to Treat?
Antioxidants
Insulin Sensitizers
Cytoprotectants
Antihyperlipidemics
Second Hit
First Hit
Steatosis
NASH
Insulin resistance ? Fatty acids
Lipid peroxidation
Weight Loss Diet/Exercise
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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 gt10 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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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

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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

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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

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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

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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

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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

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NAFLDLimitations of Studies

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

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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

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Acknowledgements
Dr. Jamal Ibdah Bill and Nedra Outlaw Elizabeth
Garwood Department of Internal Medicine Division
of Gastroenterology