Liver in Wilson Disease - Clinical Tree

Abbreviations

ALT

alanine aminotransferase

AMA

antimitochondrial antibody

ANA

antinuclear antibody

AST

aspartase aminotransferase

FDA

Federal Drug Administration

HAV

hepatitis A virus

HBV

hepatitis B virus

HCV

hepatitis C virus

ICC

Indian childhood cirrhosis

PCR

polymerase chain reaction

SMA

smooth muscle antibody

Wilson disease is an autosomal recessive inherited disorder of copper transport that leads to toxic accumulation of copper in the liver, with subsequent release of hepatic copper and deposition in other sites such as the brain. Phenotypically, Wilson disease is highly variable but is clinically characterized primarily by hepatic disease and neurologic symptoms. Although recognized as a distinct entity as early as 1912 because of the association of cirrhosis and degeneration of the basal ganglia, Wilson disease was diagnosed solely on clinical grounds until 1952 when the distinctive combination of low serum ceruloplasmin and increased urinary copper was noted. The underlying defect is the absence or dysfunction of a copper-transporting ATPase, ATP7B, localized primarily in vesicles of the trans-Golgi network in the canalicular area of the hepatocyte. The ATP7B protein is primarily expressed in liver, kidney, and placenta, and is related to a similar protein, ATP7A, that is more widely expressed and is mutated in Menkes disease, an X-linked disorder manifested by copper deficiency.

Copper is a cofactor in a number of critical enzymatic pathways necessary for cellular respiration, iron homeostasis, pigment formation, antioxidant defense, and connective tissue biosynthesis. Specific metabolic pathways have evolved to handle copper in biologic systems because of its extreme reactivity, and homeostasis is highly regulated by gastrointestinal absorption and excretion. The healthy adult human maintains total body copper stores of approximately 100 mg. An average daily diet contains 5 mg copper; a large percentage is absorbed in stomach and duodenum; newly absorbed copper is rapidly cleared by the liver, the main organ regulating copper homeostasis, which regulates storage and excretion into bile. There is no enterohepatic circulation, and copper excreted into bile is not reabsorbed.

ATP7B transfers copper from the cytosol of the hepatocyte into the lumen of the trans-Golgi network, where it is incorporated into copper-dependent enzymes. As the copper concentration within the hepatocyte increases, ATP7B moves from the trans-Golgi network to the canalicular pole of the cell, where it sequesters copper into cytoplasmic vesicles. Copper is discharged at the cell membrane into the bile canaliculus and subsequent drop in cytosolic copper concentration triggers movement of the ATP7B protein moves back to the trans-Golgi network. The liver also synthesizes and secretes ceruloplasmin, a ferroxidase that plays an essential role in iron homeostasis and also serves as the principal protein involved in copper transport in blood. Approximately 95% of circulating plasma copper is bound to ceruloplasmin, which, however, plays no role in copper excretion into bile.

Incidence and Demographics

Wilson disease has a worldwide distribution and occurs in all ethnic groups. The carrier rate is roughly 1 in 90. The calculated frequency of two mutant alleles is 1 in 7026, much higher than the disease frequency in most populations of around 1 in 30,000. In a few areas such as Sardinia where the incidence of clinical disease is as high as 1 in 10,000, a founder effect may be detected by the presence of mutation unique to the population.

Clinical Manifestations

Presentation in Wilson disease is classified as hepatic or neurologic ( Table 8.1 ). Wilson disease usually presents in children with liver involvement manifested by asymptomatic elevation of serum transaminases, chronic hepatitis and cirrhosis, or acute liver failure. The average age in patients with hepatic presentation is 10 to 13 years, although individuals have presented with liver disease in the sixth decade or later; the neurologic presentation is later by about 10 years. The oldest described patients to date were in their seventies at presentation. Neuropsychiatric problems are common in adults and include dystonia, tremor, personality changes, and cognitive impairment; the underlying changes in the basal ganglia due to copper deposition include cavitary degeneration, gliosis, and neuronal loss. The reason for preferential deposition of copper in the basal ganglia with relative sparing of the motor and sensory cortex is unknown. Although the disease has been considered to be fatal by age 30 if untreated, the identification of older patients with Wilson disease indicates that the disease spectrum may be wider than previously appreciated.

Table 8.1

Clinical and Genetic Features of Wilson Disease

Finding
Liver abnormalities	Increased AST or ALT levels, especially in those younger than 40 yr, with chronic hepatitis pattern of injury progressing to cirrhosis Fulminant hepatic failure with hemolytic anemia
Neurologic abnormalities	Neurologic abnormalities, behavioral, or psychiatric problems, with or without associated liver disease Kayser-Fleisher rings are present in almost all patients with neurologic disease
Demographics	Diagnosed in all age groups, but most commonly presents in first through fourth decade of life All ethnic groups
Genetics	Autosomal recessive 1:30,000 disease prevalence Mutation in ATP7B copper transport gene Over 600 mutations have been described Most patients are compound heterozygotes
Treatment	d -Penicillamine and other copper chelation therapies Avoidance of foods with high copper content Zinc maintenance therapy interferes with copper absorption

ALT , Alanine aminotransferase; AST , aspartase aminotransferase.

Wilson disease may also present as fulminant hepatic failure accompanied by antibody-negative hemolytic anemia because of sudden release of excess copper from necrotic hepatocytes. This fulminant presentation is more common in women by a ratio of 4 to 1. Ceruloplasmin levels are unreliable in the setting of acute liver failure, but if the alkaline phosphatase/total bilirubin ratio is greater than 4 along with AST:ALT ratio less than 2.2, then Wilson disease is considered highly likely. ATP7B genotypes resulting in truncated protein may be more likely to produce fulminant hepatic failure.

Kayser-Fleisher rings due to deposition of copper in Descemet’s membrane are found in 50% to 60% of patients with clinically apparent liver disease in most populations; however, they may be absent in young patients. Virtually all patients with neurologic manifestations will have Kayser-Fleisher rings, which are an indication that hepatic necrosis has released free copper into the circulation. Endocrine, renal, cardiac, and skeletal abnormalities may be found in up to 10% of patients with Wilson disease, and are manifested by findings such as hypoparathyroidism, infertility, nephrolithiasis, cardiomyopathy, and arthritis.

The diagnosis of Wilson disease depends on multiple factors and no single test is diagnostic. In patients with unexplained liver disease, the combination of Kayser-Fleischer rings, serum ceruloplasmin less than 20 mg/dL, and 24-hour urine copper greater than 100 μg is considered diagnostic of Wilson disease ( Table 8.2 ). However, urinary copper excretion may be less than 100 μg over 24 hours in 16% to 23% of patients with Wilson disease, and greater than 40 μg over 24 hours may be a better threshold for diagnosis. If one of these criteria is not met, liver biopsy is indicated for histology and copper quantification. If the liver contains 250 or less μg copper per gram of dry weight, molecular testing may be needed for establishment of diagnosis. Ceruloplasmin is low because the copper-free form released from hepatocytes in Wilson disease is rapidly degraded. However, the protein is an acute phase reactant and may be normal in 5% of affected patients; the positive predictive value of a low ceruloplasmin is only 6%. Notably, ceruloplasmin is normally low in newborns, making it an unreliable test for newborn screening of Wilson disease. Serum copper in Wilson disease is usually low because of low ceruloplasmin levels, but is unreliable as a diagnostic test.

Table 8.2

Key Laboratory and Clinical Findings in Wilson Disease

Test	Value	Reference Values	Comments
24-hour urinary copper level	>100 µg/day (symptomatic patients)	3–50 µg/day	May be increased with penicillamine challenge test; latter not reliable in young children
Hepatic copper content	>250 µg/g dry weight	<50 µg/g dry weight	Analysis of severely cirrhotic biopsies may yield false negative because of irregular distribution of copper; not reliable in (sub)massive necrosis of fulminant hepatitis cases
Ceruloplasmin level, serum	<200 mg/L	250–630 mg/L	Acute phase reactant; may be normal in up to 20% of Wilson disease patients
Kayser-Fleisher rings	Present	Absent	Best visualized on slit lamp examination; present in ∼50%–60% of patients

Urinary copper is elevated, often greater than 100 μg over 24 hours, and is very helpful in the diagnosis of Wilson disease. However, high levels can be seen in biliary disease or in autoimmune hepatitis, and clinical correlation is required. Testing urinary copper excretion after penicillamine challenge may be informative in adults but may not be useful in young children with mild liver disease.

Radiologic Features

Radiographic findings in Wilson disease are related to disease stage; irregular contours on computed tomography and parenchymal heterogeneity on ultrasound are common findings. Small, hypointense nodules on T2-weighted magnetic resonance imaging have also been described.

Pathology

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