alcoholic liver diseases Flashcards
metabolism of alcohol
may be by the stomach (minor) or liver (major). in the liver, alcohol is broken down by alcohol dehydrgenase, cytochrome P4502E1, and catalase (very minor.
At low quantities of alcohol, alcohol dehydrogenase does all the metabolism; at higher quantities CYP2E1 must help. CYP2E1 is upregulated in alcoholics and generates more free radicals than alcohol dehydrogenase.
both enzymes make acetaldehyde, which is converted to acetate by aldehyde dehydrogenase.
What are some of the liver pathologies that may be associated with alcohol?
fat accumulation
alcoholic hepatitis
cirrhosis
What is fat accumulation of alcohol?
earliest response to fat ingestion and present in mor than 90% of heavy drinkers. Appears within a few hours of a binge but resolves with abstinence.
What is alcoholic hepatitis?
necroinflammation +/- fat infiltration, and fibrosis.
Why is alcoholic hepatitis important?
severe form of the disease is associated with high short-term mortality.
Pts with alcoholic hepatitis are 9X more likely to develop cirrhosis than pts with fatty liver alone.
How does acetaldehyde contribute to alcoholic hepatitis?
reactive and toxic intermediate: induces headache, nausea, and flushing.
EtOH and acetaldehyde metab make more NADH:NAD. Apparently, increased NADH:NAD ratios cause impaired gluconeogenesis and impaired lipid metabolism. This decreases the cell’s ATP supply and induces hepatic steatosis
How does reactive oxygen species play into alcoholic hepatitis?
they are produced by EtOH metabolism, esp. by the CYP2E1 system. oxidative stress promotes hepatocyte necrosis and apoptosis. Alcoholics become deficient in antioxidants like glutathione and vitamin E. Free radicals also initiate lipid peroxidation (damage to lipid membranes), which can cause inflammation and fibrosis.
How does LPS contribute to alcoholic hepatitis?
found on the outer wall of gram neg bacteria. Alcoholism alters gut permeability such that there are incr. LPS levels in pts with alcoholism. LPS in the liver binds and activates Kupffer cells, which stumulate TNF-a and other cytokines. TNF-a stimulates mitochondria to make ROSes and cause cell death.
How is hypoxia connected with alcoholic liver disease?
chronic alcohol use increases oxygen use by hepatocytes near the blood supply in the portal vein ,decreasing the supply of oxycen in places further away from the blood supply (centrilobar area, zone 3).
Alcoholic hepatitis: dx
clinical and pathological dx
history of heavy alcohol use.
fever under 101, hepatomegaly, jaundice, ascites, and anorexia. May also present with encephalopathy or bleeding. Don’t need all symptoms to make this diagnosis.
Dx of alcoholic hepatitis
rule out other causes of fever. look for liver tenderness, ascites, and jaundice. Also look for other signs of chronic liver disease (spider telenictasias, palmar erythema, gynecomastia, etc). 90% have steatosis. AST/ALT elevated but usually under 400. AST:ALT ration OVER 2
liver histology suggestive of alcoholic hepatitis
liver necrosis, Mallory bodies, infiltration by neutophils, perivenular distribution of inflammation.
Prognosis of acute hepatitis
22% develop cirrhosis within 13 yrs: bad news for cirrhosis.
If they also have HCV infection, they stay in hosiptal longer and are 2X more likely to die. Maddrey discriminant function of 32 or above, kidney involvement, and high fibroses are all poor prognostic indicators.
Management of alcoholic hepatitis
- Attend to associated problems in addition to liver tx: dementia, kidneys, pancreas, etc
- Coricosteroids if DF>32 or if encephalopathic. EXCLUDE INFECTION first. (methyl-prednisone for 28 days, then taper).
- Nutritional support. helps reduce the risk of infection. difficult, however: pts are anotexic from cytokines, malapsorption from altered intestinal wall, catabolic state in muscles and visceral proteins.
- Pentoxifyline: TNF-a inhibitor.
- liver transplant?
What factors increase the risk of cirrhosis in an alcoholic pt?
HCV, obesity, smoking.
