METABOLIC LIVER DISEASE
Wilson disease (hepatolenticular
degeneration) is a genetic disorder of copper metabolism resulting in the
accumulation of toxic levels of copper in various organs. It affects the liver
(fatty change, chronic hepatitis, and micronodular cirrho-sis), cornea
(Kayser-Fleischer rings [copper deposition in Descemet’s membrane]), and brain
(neurological and psychiatric manifestations, movement disorder).
Diagnosis is established by
demonstrating decreased serum ceruloplasmin levels, increased tissue copper
levels (liver biopsy), and increased urinary copper excre-tion. Treatment
includes copper chelators (D-penicillamine); liver transplantation is curative.
The disease is autosomal
recessive, and the WD gene (ATP7B on
chromosome 13) codes for a hepatocyte canalicular copper-transporting ATPase.
Damage to the gene leads to a decreased biliary excretion of copper. Wilson
disease presents in children or adolescents with liver disease.
Hemochromatosis is a disease of increased
levels of iron, leading to tissue injury.
Hereditary (primary) hemochromatosis is a recessive disorder of the HFE gene on chromosome 6p. The most
common mutation of the HFE gene is
the C282Y muta-tion, which increases small intestine absorption of iron. Secondary hemochromato-sis can follow transfusions for
chronic anemias. Hemochromatosis affects 5 times as many males as females, and
the disease is common in people of Northern European descent.
Hemochromatosis can cause
micronodular cirrhosis and hepatocellular carcinoma (200 times the normal risk
ratio); secondary diabetes mellitus; hyperpigmented skin (“bronzing”);
congestive heart failure and cardiac arrhythmias; and hypogonadism. Diagnosis
is established by demonstrating markedly elevated serum iron and fer-ritin or
increased tissue iron levels (Prussian blue stain) on liver biopsy. Treatment
deficiency is an autosomal recessive
disorder characterized by pro-duction of defective α-1-antitrypsin (α1-AT), which accumulates in hepatocytes and
causes liver damage and low serum levels of α1-AT.
α1-AT is produced by the SERPINA1 gene (chromosome 14); >75 gene variants are described. Normal individuals are homozygous PiMM. Heterozygotes have inter-mediate
levels of the enzyme. Homozygous PiZZ
have severe reductions (10% of normal) in enzyme levels.
α-1-antitrypsin deficiency affects the liver
(micronodular cirrhosis and an increased risk of hepatocellular carcinoma) and lungs
(panacinar emphysema). Microscopi-cally, PAS positive, eosinophilic cytoplasmic
globules are found in hepatocytes. Treatment includes smoking
abstinence/cessation to prevent emphysema; liver transplantation is curative.
Reye syndrome is a rare,
potentially fatal disease that occurs in young children with viral illness
(varicella or influenza) treated with aspirin. The disease mechanism is
unknown; mitochondrial injury and dysfunction play an important role. Reye
causes hepatic fatty change (microvesicular steatosis) and cerebral
edema/encephalopathy. There is complete recovery in 75% of patients, but those
that do not recover may experience permanent neurologic deficits. Coma and
death may result. Treatment is supportive.
Nonalcoholic fatty liver
disease is a disease of lipids accumulating in hepatocytes that is not
associated with heavy alcohol use. It occurs equally in men and women, and is
strongly associated with obesity, hyperinsulinemia, insulin resistance, and
type 2 diabetes mellitus.
The pathogenesis involves
lipid accumulation in hepatocytes that can progress to steatohepatitis
(NASH—nonalcoholic steatohepatitis) and finally cirrhosis. Nonal-coholic fatty liver
disease is a diagnosis of exclusion.