Ethanol and Liver Disease

Introduction

Alcoholic cirrhosis has a far graver prognosis than other etiologies of cirrhosis.

Only 1/3^rd of patients with fatty liver progress to cirrhosis.

Alcohol toxicity is dose dependent (men 3-4 drinks/day, women 2 drinks/day)

Alcoholism is characterized by Tolerance, Physical Impairment, Craving, and a genetic component.

Cravings are worse for cirrhotics because of a poorly characterized phenomena related to portal shunting

Transplant and subsequent treatments are covered by Medicaid; no one is rejected because of ability to pay.

Alcoholic Hepatitis

RISK FACTORS include:

GENDER – women are much more susceptible to EtOH and its consequences than men. Sex sensitivity related to biochemical processes (e.g. enzyme activity, lipid peroxidation, cytokines) as well as to body fat.

HEPATITIS C – having Hepatitis C while an alcoholic is correlated to a worse prognosis. Earlier onset of symptoms, 8 x’s increased risk of developing cirrhosis, and an 81% chance of developing liver cancer.

OBESITY – if a person is obese (BMI greater than 30) then they are more prone to developing cirrhosis for the same amount of EtOH. Obesity µ fat in liver µ stellate cell activation Þ cirrhosis.

HIGH FAT DIET -Rats fed EtOH and high fat diet developed cirrhosis, rats given the same amount of EtOH but on a low fat diet did not develop cirrhosis. Unsaturated fats (the ones good for the heart) are actually worse for the alcoholic liver compared to saturated fats. Saturated fats may actually prevent some of the damage due to EtOH.

Mechanisms of Injury

Acetaldehyde – will form adducts with proteins. These adducts are immunogenic and may give rise to auto-antibodies. Both processes (ADH and MEOS) used to metabolize EtOH in the body produce acetaldehyde as an intermediate.

Hypoxia – zone III uses MEOS (Microsomal Ethanol Oxidation System.) ADH (Alcohol Dehydrogenase) uses a ½ O₂ whereas MEOS uses a whole O₂ per cycle, therefore zone III uses more oxygen) This is why the damage from EtOH starts near the central vein.

Cytokines – EtOH changes the intestinal epithelium so that more LPS (endotoxin) gets into the body.

ethanol causes endotoxin release which activates NF-kB signalling pathways that produces TNF

TNF then causes oxidative tissue injury and produces oxidized intermediates that cause more endotoxin release

Endotoxin activates Küpffer cells, which then produce TGFb and TNFa . TGFb and TNFa are elevated in EtOH liver disease; the higher the level the more severe the disease is.

NF-k b , a transcription factor that is activated by LPS and cytokines. It activates additional cytokines and adhesion molecules.

TNF Þ inflammation; levels are elevated in EtOH liver disease. The higher the level the worse the disease

TGF-b Þ fibrosis

Ito cells get a double hit; TNF from hepatocyte lipid peroxidation, TGF-b from Küpffer cell with endotoxin

Neutrophils – IL-8 and Adhesion molecules bring PMN’s to the liver. IL-8 is produced by Küpffer cells activated by endotoxin and TNF. IL-8 stimulates endothelial cells to generate ICAM-1. (ICAM-1 makes PMN’s stick to the sinusoid)

Acetaldehyde

Forms adducts

Auto-antibodies

Hypoxia

Causes damage in areas with normally low O₂ tension

Injury around the central veins

Cytokines

NF-k b

TNF Þ inflammation

TGF-b Þ Ito cell activation (fibrosis)

IL-8 Þ PMN’s brought to the liver

Treatment

Long term management – get the patient to stop drinking

Steroids – work by suppressing the immune system and cytokine production

Liver transplantation – an effective form of treatment. Survival rates for transplants due to EtOH liver disease are not much better or worse than the rates for other commonly transplanted conditions. 6 months of sobriety are required to be considered.