What is the pathogenesis of alcoholic liver disease?

Ethanol metabolism raises the NADH/NAD ratio, promoting fat accumulation; acetaldehyde damages hepatocyte proteins; and Kupffer cell TNF-alpha release generates reactive oxygen species, causing centrilobular (zone 3) necrosis and stellate-cell-driven fibrosis.

Clinical relevance. Understanding the redox, acetaldehyde, and TNF-alpha mechanisms explains the fat, inflammation, and fibrosis of ALD.

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Pathogenesis of alcoholic liver disease

Multiple mechanisms link alcohol metabolism to fat accumulation, inflammation, and fibrosis.

Altered redox state

• Ethanol is oxidised in the liver, raising the NADH/NAD ratio.
• This increases fatty acid synthesis and reduces oxidation, causing hepatic fat accumulation (steatosis), mainly in zone 3.

Acetaldehyde toxicity

• Acetaldehyde (from ethanol oxidation) binds hepatic proteins and contributes to cell damage.

Inflammation and fibrosis

• TNF-alpha released from Kupffer cells generates reactive oxygen species, causing centrilobular (zone 3) necrosis and tissue injury.
• Stellate cells transform into collagen-producing myofibroblasts, driving fibrosis (perivenular fibrosis can progress to cirrhosis).

Drug interaction

• Alcohol induces the microsomal ethanol oxidising system (MEOS), enhancing the toxicity of drugs such as paracetamol.