Download etoh hepatitis - UCSF | Department of Medicine

JVD 11/02
UPDATE ON ETOH HEPATITIS
CURRENT EPIDEMIOLOGY
• ETOH liver disease affects about 2 million people in the US, 50% of heavy drinkers who are
hospitalized display some evidence of ETOH hepatitis, 25,000 deaths/year.
• ETOH liver disease develops after “threshold” dose of ethanol has been consumed: 600 kg per
men, 150-300 kg per women. This is equivalent to 8 12-oz beers, 1L wine, or 0.5 pint of distilled
spirit daily for 20 years.
• Mortality from ETOH hepatitis is determined by severity of disease: mild disease (bili <5.0 mg/dl)
carries a 100% disease survival at one month, 78% survival in 3 years; while severe disease ( DF
>32 using formula 4.6 (PT-control) + Tbili) carries a 50 % one month mortality. Hepatic
encephalopathy can also be used as a marker for severity, and carries a poor prognosis.
• Cofactors associated with the development of alcoholic liver disease: not all alcoholics get liver
disease.
o Hereditary variations: under investigation of HLA subtypes, ADH polymorphisms.
o Gender: females are not only more susceptible to liver disease at lower doses, but also
tend to progress even during abstinence, likely due to decreased levels of gastric ADH
and impaired upregulation of fatty acid metabolism.
o Etoh liver injury correlates strongly and inversely with nutritional status, likely due to
inadequate intake of antioxidant vitamins and excess intake of polyunsaturated fats.
o Viral liver disease: additive risk for developing liver disease.
FASCINATING PATHOPHYSIOLOGY AND PATHOLOGY
• Ethanol is oxidized by ADH to acetaldehyde which is then oxidized by ALDH to acetate, these are
cytoplasmic enzymes. When overwhelmed, the MEOS (microsomal ethanol oxidizing system)
and catalase (perixomes and mitochondrial enzyme) are responsible for oxidation. While ADH
uses reduces NAD+ to NADH, MEOS enzymes oxidizes NADPH to NADP+, thus producing
oxygen radicals. Gastric ADH plays a role in first pass metabolism.
•
Redox alteration: NADH excess provoke steotosis by stimulating fatty acid synthesis and
inhibiting fatty acid oxidation resulting in accumulation in hepatocytes where they become
esterfied and form triglycerides. NADH also interferes with gluconeogenesis, and ultimately
prevents reoxidation of NADH.
• Oxidant stress: free radical formation from MEOS oxidation, excess NADH mobilizing iron from
ferritin, which when reduced, form hydroxyl radicals and from inflammatory cell superoxide
formation. This results in lipid peroxidation (enhanced with polyunsaturated fats),
mitochondrial DNA damage and dysfunction. This is enhanced by depletion of natural antioxidants such as vitamin A, E and glutathione.
• Acetaldehyde accumulates as its metabolism is slowed down, thus becoming a substrate for
aldehyde oxidase and xanthine oxidase, which also produces free radicals. Acetaldehyde can also
react with specific amino acids on the cellular proteins, impairing cellular activities resulting in
hepatocellular swelling.
• Inflammatory haven: presence of cytokines (IL-1, IL-6, IL-8, and TNF-alpha), mostly released
form “primed” kupffer cells in presence of low grade endotoxemia. Autoimmunity may play a
role as the altered hepatocellular proteins can act as neoantigens and activate cellular immunity.
• Stellate cells are activated to proliferate and synthesize collagen, forming perisinusoidal fibrosis.
• Hypermetabolism increase liver cell oxygen consumption and thus causing pericentral tissue
hypoxia.
WHAT IS THE TYPICAL AND NOT SO TYPICAL PRESENTATIONS
• Clinical symptoms: anorexia, nausea, vomiting, mild abdominal pain.
• Physical exam reveals: hepatomegaly (75%), jaundice (60%), ascites (30%), hepatic
encephalopaty (44%), fever (25%).
•
!
Laboratory patterns:
o AST/ALT ratio usually >2, rarely exceed more that 300 (very important in distinguishing
ETOH from other viral or toxin injuries, if more >300 suspect other non-alcoholic acute
injury, ratio> 3 strongly suggestive)
o Tbili and alk phos: usually elevated and this elevation persist even after transaminases
normalize. Tbili in combination with PT, are the main predictors of liver disease
severity, so always calculate the DF for prognosis. DF has been criticized because of its
lack of specificity, and some experts propose that the addition of a classic liver biopsy
(classic steatosis, neutrophil inflammation and Mallory bodies) increases its specificity.
This is impractical in many cases, and others have proposed using circulating neutrophil
count (>5500/mm) as a surrogate for biopsy because it correlates with neutrophil
inflammation.
o Macrocytic anemia, leukocytosis
Liver biopsy is the gold standard: reveals macrovesicular steatosis (60-95%), ballooning
degeneration (60-90%), Mallory bodies 70%), neutrophillic inflammation (50-85%), and
pericellular fibrosis (50%).
UPDATE ON TREATMENT OPTIONS—WHAT’S COMING
! Abstinence: will improve survival, but may not when acutely ill.
! Nutrition: malnutrition is associated with poor prognosis. Many small studies have looked at
nutritional supplementation in hospitalized patients showing no benefit in survival. Most recently,
enteral feeding with medium chain triglycerides has been studied against steroid use and had
comparable results, in both short term and long term survival.
! Corticosteroids: Most recently, Raymond et al. reported in the NEJM, 1992, a DBRCT of 64
patients with severe ETOH hepatitis (DF>32 or HE) and biopsy proven; excluding patients with
GI bleed, presence of bacterial infection, HIV, anticoagulation therapy, or co-hepB infection.
They received methylprednisolone for 28 days, then a 4-week taper and reported improved
survival, both short term (2-month) 88% vs. 45% and long term (6 month) 84% vs. 45%. NO
serious side effects reported. The American College of Gastroenterology presently recommends
steroids in severe ETOH hepatitis and NOT to be given if diagnosis is uncertain or in presence of
GI bleed, renal failure or infection.
! Pentoxifylline: inhibits synthesis and activity of TNF, one DBRCT of 100 patients with DF >32 ,
treated with pentoxifylline 400 mg TID for 4 weeks reported a decreased mortality 25% vs. 46 %
(placebo) and 4 weeks and reduced incidence of hepatorenal syndrome, 8.2% vs. 35% (placebo).
Not compared to steroids.
! Propylthiouracil: theoretically may help with the hypermetabolic state in liver disease, but two
small studies have had negative results.
! Calcium channel blockers: may inhibit kupffer cell activation that is dependent on calcium
transport, small trial of amlodipine had negative results.
! Antioxidants: S-adenosyl-methionine (glutathione precursor), silymarin, vitamins A and E are
being tested in patients with chronic ETOH liver disease, thus far unsatisfactory results.
! Colchicines: both anti-inflammatory and anti-fibrotic effects, one study with positive results in
chronic liver disease, however this has not been confirmed.
References:
Maher, J. Advances in Liver Disease: Treatment of Alcoholic Hepatitis. J of Gastro and Hepatology.
Vol. 17., 2002.
Raymond et al. A randomized trial of prednisolone in patients with severe etoh hepatitis. NEJM. Vol.
326, 1992.
Imperiale et al. Do corticosteroids reduce mortality form alcoholic hepatitis? Annal of Int Med. Vol. 113.,
1990.