Pathophysiology
Summary
Fatty liver disease (FLD) is common hepatobiliary pathology and often occurs in the context of alcohol use and metabolic dysfunction. FLD initially manifests as steatosis, and can progress to steatohepatitis and eventually cirrhosis.
Alcoholic fatty liver disease (AFLD) occurs in the setting of chronic alcohol use. Ethanol is metabolized to acetaldehyde in the liver by the enzyme acetaldehyde dehydrogenase, which catalyzes the conversion of acetaldehyde & NAD+ to acetate & NADH. Excessive alcohol intake depletes NAD+, resulting in insufficient NAD+ for fatty acid beta oxidation, leading to fatty acid accumulation in the liver.
Acute symptoms (hangover) develop due to the accumulation of acetaldehyde. Repeated ingestion of ethanol exacerbates the chronic shortage of NAD+, eventually leading to the buildup of fat in the liver known as steatosis. Histologically, steatosis appears as hepatocytes filled with vesicles of fat, described as microvesicular steatosis or macrovesicular steatosis depending on the size of the fat globules.
In AFLD, zone 3 (centrilobular) initially exhibits fatty changes (steatosis), which can progress to alcoholic steatohepatitis if left untreated. Alcoholic hepatitis is marked by hepatocyte damage, which results in the release of pro-inflammatory cytokines and neutrophilic infiltrate and signs of inflammation on histopathology. These damaged hepatocytes exhibit ballooning and may progress to necrosis. Fibrosis also initially begins in zone 3, and may progress to cirrhosis, which increases the risk of hepatocellular carcinoma (HCC). Alcoholic hepatitis leads to increased AST & ALT, typically with an AST to ALT > 2:1, as well as elevated gamma glutamyl transpeptidase (GGT).
Non-alcoholic fatty liver disease (NAFLD) presents similarly to AFLD, but is typically associated with metabolic syndrome, a constellation of symptoms associated with obesity, insulin resistance, dyslipidemia, and hypertension.
Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD that likely results from excessive visceral adipose tissue, which secretes pro-inflammatory cytokines and contributes to insulin resistance—in turn, disrupting fatty acid metabolism. NASH features inflammatory conditions similar to alcoholic steatohepatitis, including hepatocyte ballooning and neutrophil infiltration. In NASH, both ALT & AST are increased, although ALT is usually higher than AST. NASH may progress to cirrhosis if left untreated.
Reye syndrome is characterized by a triad of encephalopathy, liver microvesicular fatty change, and elevated serum transaminases. It is associated with aspirin administration to children with viral infections likely developing from from mitochondrial injury and the subsequent inhibition of fatty acid metabolism, though the exact pathophysiology is unknown.
Lesson Outline
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FAQs
Ethanol is converted to acetaldehyde in the liver by the enzyme alcohol dehydrogenase. This conversion requires NAD+ for oxidation, which is reduced to NADH. Excessive alcohol consumption depletes NAD+, resulting in insufficient amounts for fatty acid beta oxidation. This impairment leads to a buildup of fatty acids in the liver, resulting in steatosis, which is the earliest stage of alcoholic liver disease.
h3>What are the histological findings in alcoholic hepatitis?Alcoholic hepatitis is a progression from steatosis and is marked by hepatocyte damage and inflammatory infiltration. Damaged hepatocytes may balloon and can progress to necrosis. These hepatocytes often contain pink densities called "Mallory bodies. Fibrosis typically begins near the liver's central vein, which is also the initial site of fatty changes.
NAFLD and alcoholic fatty liver disease both involve fat accumulation in liver cells, known as steatosis. Both conditions can advance to steatohepatitis, leading to fibrosis and potentially cirrhosis. However, NAFLD is usually found in individuals who consume little or no alcohol and is often linked to metabolic syndrome, whereas alcoholic fatty liver disease is associated with chronic alcohol use.
Reye's syndrome is a rare condition that predominantly affects children who have recently had a viral infection and have taken aspirin. The syndrome impacts both the liver and brain, causing severe neurological symptoms. In the liver, Reye's syndrome leads to mitochondrial damage, impairing β-oxidation of fatty acids. This results in the accumulation of small fat globules in liver cells, known as microvesicular fatty change, along with inflammation.
Metabolic syndrome is a significant risk factor for the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH), and potentially to fibrosis and cirrhosis. Metabolic syndrome is characterized by the presence of at least two of the following conditions: obesity, insulin resistance, dyslipidemia, or hypertension. These conditions disrupt normal fatty acid metabolism, leading to increased fatty acid retention in the liver and accelerating the progression of liver disease.
