B60 alcohol and drug induced liver disease

Question 1

What are the 3 forms of liver injury caused by chronic alcoholism

Answer 1

Fatty liver, alcoholic hepatic steatosis, preceeded by the acute version which occurs even after moderate drinking, fatty change.

Alcoholic hepatitis

Cirrhosis

Question 2

What are the molecular mechanisms driving fatty liver formation?

Answer 2

Excessive NADH formation by alcohol metabolism, to acetaldehyde then acetate, with NADH being generated each time.

as well as

Impaired assembly and secretion of lipoproteins by the liver.

Question 3

Describe alcohol metabolism in the liver

Answer 3

Most of the alcohol in the blood is metabolized to acetaldehyde
in the liver by three enzyme systems: alcohol
dehydrogenase, cytochrome P-450 isoenzymes, and catalase
(Fig. 7–10). Of these, the main enzyme involved in alcohol
metabolism is alcohol dehydrogenase, located in the cytosol of
hepatocytes. At high blood alcohol levels, however, the
microsomal ethanol-oxidizing system also has an important
role. This system involves cytochrome P-450 enzymes,
particularly the CYP2E1 isoform, located in the smooth ER.

Question 4

How is alcohol and its metabolites toxic to the liver?

Answer 4

1. Acetaldehyde - adduct formation with proteins, lipids, nucleic acid
2. ROS formation
3. Alcohol stimulating the release of endotoxins (LPS) by bacterial in the intestine, this LPS is absorbed into portal blood and reaches liver, causing inflammatory cytokine release, and infllammatory damage.

Question 5

What are the clinical features of hepatic steatosis?

Answer 5

Often totally asymptomatic.

Hepatomegaly, with mild elevation of ALP and bilirubin.

This stage is fully reversible with alcohol withdrawal.

Question 6

Clinical features of Alcoholic hepatitis

Answer 6

Can occur after a few weeks or months of consistent drinking.

Typically occurs after a bout of heavy drinking

Can be mild or very severe. Has a 10-20% risk of death. Repeated instances of acute alcoholic hepatitis is highly associated with cirrhosis development at an earlier stage than chronic alcoholism alone, in about 1/3 of people.

• tender hepatomegaly
• fever
• malaise
• weight loss
• hyperbilirubinemia
• elevated ALP
• ALAT and ASAT elevated
• Hepatic insufficiency

Question 7

What are the drugs that can cause liver damage/failure?

Answer 7

Predictable hepatotoxic agents: Cause liver damage at known concentrations in everyone at high/toxic doses.

• acetaminophen
• tetracycline
• antidepressants
• amanitin toxin
• alcohol

Unpredictable hepatotoxic agents: Cause liver damage sometimes in susceptible individuals at normal doses.

• Halothane
• Chlorpromazine
• Sulfonamides

Question 8

How do these drugs cause liver damage?

Answer 8

By direct toxicity to hepatocytes, followed by inflammatory damage.

Depending on the drug, various outcomes are possible such as: hepatocellular necrosis, cholestasis, steatosis, steatohepatits, fibrosis and vascular lesions.

Question 9

What abnormal hepatocyte feature is characteristic of alcoholic liver damage?

Answer 9

Mallory bodies. Inclusion bodies of eosinophilic keratin.