Wilson’s Disease: Gastrointestinal Features

Abstract

Wilson’s disease is an autosomal recessive disorder that causes copper to accumulate in various tissues throughout the body. Carriers occur at a rate of approximately one in 100, but the disease occurs in 1–4 per 100,000. Disease found early can be treated, but advanced disease may require a liver transplant.

Gastrointestinal symptoms associated with the disease are:

Combination of liver disease with neuropsychiatric disturbances

Symptoms related to end-stage liver disease or acute liver failure

Clinical signs and findings include:

Elevated aminotransferases

Acute or chronic hepatitis

Fulminant hepatic failure

Cirrhosis/end-stage liver disease with portal hypertension

Ascites/fluid retention

Esophageal/rectal varices

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Wilson’s disease is an autosomal recessive disorder that causes copper to accumulate in various tissues throughout the body. Carriers occur at a rate of approximately one in 100, but the disease occurs in 1–4 per 100,000. Disease found early can be treated, but advanced disease may require a liver transplant [1].

Gastrointestinal symptoms associated with the disease are [1, 2]:

• Combination of liver disease with neuropsychiatric disturbances

• Symptoms related to end-stage liver disease or acute liver failure

Clinical signs and findings include [1, 2]:

• Elevated aminotransferases

• Acute or chronic hepatitis

• Fulminant hepatic failure

• Cirrhosis/end-stage liver disease with portal hypertension

  • Ascites/fluid retention

  • Esophageal/rectal varices

  • Portal hypertensive gastropathy

  • Hemorrhagic diathesis

  • Hepatic encephalopathy

• Kayser–Fleischer rings

• Sunflower cataracts

• Skin manifestations of chronic liver disease

  • Spider telangiectasias

  • Gynecomastia

  • Jaundice/icterus

  • Muehrcke’s lines, Terry’s nails

  • Palmar erythema

• Osteoarthritis

• Cardiac findings

• Nephrocalcinosis

• Chondrocalcinosis

• Hypercalciuria

• Depression

• Mood lability

• Psychosis

• Cognitive decline

• Tremor

• Dysarthria/aphasia

• Ataxia/bradykinesia

• Infertility/increased risk of miscarriage

• Hypoparathyroidism

The pathogenesis is based on a genetic defect in the excretion of copper [3]:

• Autosomal recessive

• Mutations in the ATP7B gene on chromosome 13

  • Reduction in the ATP7B function results in decreased biliary copper excretion

  • Increased copper accumulation in hepatic and extrahepatic tissues

  • Excess copper released into circulation and taken up by central nervous system

Typical liver pathology shows [3]:

• Liver biopsy dry weight 75 μg/g copper

• Liver biopsy histology varies with stage (see Fig. 69.1)

  • Early: hepatic steatosis, mitochondria with crystalline deposits and dilated cristae with advancing fibrosis

  • Later: lysosomal deposits of copper and copper metallothionein

  • Late stage: hepatocellular disruption with advanced cirrhosis and fibrosis

  • Acute liver failure: apoptosis and necrosis on the background of advanced fibrosis

• Copper staining of liver biopsy

  • Copper staining positive nodules with nearby areas absent for copper staining (regenerative areas)(see Fig. 69.2)

  Fig. 69.1

  

  Photomicrograph of liver biopsy specimen from a patient with Wilson’s disease showing periportal region with spotty necrosis (focal inflammatory cell infiltration and hepatocellular pleomorphism indicating focal hepatocellular necrosis). There is also fatty change and a large Mallory body in the center. Hematoxylin and eosin, ×400

  Fig. 69.2

  

  Photomicrograph of liver biopsy specimen a periportal region showing copper deposition (black granules) in the hepatocytes. Copper stain ×400

The diagnosis is made by considering [3]:

• Family history

• Genetic testing with two mutations of ATP7B

• Physical examination

  • Kayser–Fleischer rings

  • Neuropsychiatric disturbances

• Imaging

  • MRI/CT brain detects changes in the basal ganglia or pons or thalamus

• Laboratory testing

  • Depressed levels of serum alkaline phosphatase for the degree of jaundice

  • Alkaline phosphatase:bilirubin level ratio <4

  • Aspartate aminotransferase/alanine aminotransferase (AST:ALT) >2.2

  • Serum copper >200 μg/dL

  • Serum free copper >20 μg/dL

  • Low ceruloplasmin <20 mg/dL

  • 24 h urinary copper

    • One hundred micro grams per 24 h (in the presence of Kayser–Fleischer rings)

    • Forty micro grams per 24 h (in the presence of liver biopsy consistent with Wilson’s disease)

• Liver biopsy with hepatic copper >75 μg/g dry weight

The differential diagnosis of Wilson’s disease should include [2, 3]:

• Nonalcoholic fatty liver disease

• Acute or chronic hepatitis

  • Viral hepatitis

  • Autoimmune hepatitis/overlap syndromes

• Fatty acid oxidation metabolism disorder

• Mitochondrial disorder

The treatment involves [2, 3]:

• Penicillamine 20 mg/kg/day by mouth to a maximum of 2 g/day

• Trientine 750–1,500 mg by mouth three to four times a day (adults)

• Zinc salts 150 mg by mouth three times a day (adults)

• Liver transplant