A 15 –year-old girl presented with abdominal pain and diarrhoea for 3 days. She became jaundiced and a presumptive diagnosis of infective hepatitis was made, but serological tests were negative. She subsequently died of fulminant liver failure. At post-mortem her liver copper concentration was found to be grossly increased.
What is the probable diagnosis?
What kind of investigations should be carried out for her sister?
High liver copper concentration, indicates that the patient died of Wilson’ disease, which is an autosomal recessive disorder caused by mutations in the ATP7B gene, a membrane-bound copper transporting ATPase. Clinical manifestations are caused by copper toxicity and primarily involve the liver and the brain. Because effective treatment is available, it is important to make this diagnosis early. The patient’s sister should be screened for Wilson’s disease. Serum copper, Caeruloplasmin and urinary copper excretion may indicate if she also has the disease. A liver biopsy may be indicated. DNA analysis can assist in the confirmation of diagnosis.
Overview of copper metabolism
Copper is an essential trace element which is a component of many intracellular metalloenzymes, including Cytochrome oxidase, Tyrosinase, Superoxide dismutase, Lysyl oxidase and Dopamine β oxidase. Most of the copper in plasma is bound to Caeruloplasmin.
About 50% of the average daily dietary copper of around 25μmol (1.5 mg) is absorbed from the stomach and the small intestine. Absorbed copper is transported to the liver in portal blood bound to albumin and is exported to peripheral tissues mainly bound to caeruloplasmin and to a lesser extent to albumin.
Copper is present in all metabolically active tissues. The highest concentrations are found in liver and in kidney, with significant amount in cardiac and skeletal muscles and in bones. The liver contains 10% of the total body content of 1200 μmol(80mg). Excess copper is excreted in bile and then in to gut, and the fecal copper output(12.5 μmol/24 hours), is the sum of the unabsorbed dietary copper and that re-excreted in to the gut.
Both children and adults can develop symptomatic copper deficiency. Premature infants are the most susceptible since copper stores in liver are laid down in the third trimester of pregnancy. In adults copper deficiency is found in intestinal bypass surgeries or in patients who are on parenteral nutrition Symptoms range from bone disease to iron resistant microcytic hypochromic anemia.
Copper toxicity is uncommon and is mostly due to administration of copper Sulphate solutions. Oral copper Sulphate may lead to gastric perforation. Serum copper may be greatly elevated. Copper is toxic to many organs, but renal tubular damage is more common and is of major concern. Treatment is by chelation with Penicillamine.
The condition is characterized by excessive deposition of copper in the liver, brain, and other tissues. The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. Patients with Wilson disease usually present with liver disease during the first decade of life or with neuropsychiatric illness during the third decade. The diagnosis is confirmed by measurement of serum caeruloplasmin, urinary copper excretion, and hepatic copper content, as well as the detection of Kayser-Fleischer rings.
The genetic defect has been shown to affect the copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver. Many of the gene defects for ATP7B are small deletions, insertions, or missense mutations. Most patients carry different mutations on each of their 2 chromosomes. More than 200 different mutations have been identified, the most common of which is a change from a Histidine to a glutamine (H1069Q).
In Wilson disease, the processes of incorporation of copper into ceruloplasmin and excretion of excess copper into bile are impaired.The transport of copper by the copper-transporting P-type ATPase is defective secondary to one of several mutations in the ATP7B gene. The excess copper acts as a promoter of free radical formation and causes oxidation of lipids and proteins. Initially, the excess copper is stored in the liver and causes damage to the hepatocytes.
Defective copper incorporation into apo Ceruloplasmin leads to excess catabolism and low blood levels of Ceruloplasmin. Serum copper levels are usually lower than normal because of low blood Ceruloplasmin, which normally binds >90% of serum copper. As the disease progresses, non-Ceruloplasmin serum copper (“free” copper) levels increase, resulting in copper buildup in other parts of the body, such as the brain, leading to neurologic and psychiatric disease.
The frequency of Wilson disease in most populations is about 1 in 30,000–40,000.
Wilson disease may present as hepatitis, cirrhosis, or as hepatic decompensation. An episode of hepatitis may occur, with elevated blood transaminase enzymes, with or without jaundice, and then spontaneously regresses. Hepatitis often reoccurs, and most of these patients eventually develop cirrhosis.
Hepatic decompensation is associated with elevated serum bilirubin, reduced serum albumin and coagulation factors, ascites, peripheral edema, and hepatic encephalopathy. In severe hepatic failure, hemolytic anemia may occur because large amounts of copper derived from hepatocellular necrosis are released into the bloodstream. The association of hemolysis and liver disease makes Wilson disease a likely diagnosis.
The neurologic manifestations of Wilson disease typically occur in patients in their early twenties, although the age of onset extends into the sixth decade of life. The three main movement disorders include: dystonia, incoordination, and tremor. In some patients, the clinical picture closely resembles that of Parkinson disease. Sensory abnormalities and muscular weakness are not features of the disease.
A history of behavioral disturbances, with onset in the five years before diagnosis, is present in half of patients with neurologic disease. The features are diverse and may include loss of emotional control (temper tantrums, crying bouts), depression, hyperactivity, or loss of sexual inhibition.
Sunflower cataracts and Kayser-Fleischer rings (copper deposits in the outer rim of the cornea) may be seen. Electrocardiographic and other cardiac abnormalities have been reported but are not common.
- The presence of Kayser-Fleischer rings and caeruloplasmin levels of less than 20 mg/dL in a patient with neurologic signs or symptoms suggest the diagnosis of Wilson disease. If a patient is asymptomatic, exhibits isolated liver disease, and lacks corneal rings, the coexistence of a hepatic copper concentration of more than 250 mg/g of dry weight and a low serum ceruloplasmin level is sufficient to establish a diagnosis.
- Serum ceruloplasmin
- Serum Ceruloplasmin levels are low in newborns and gradually rise within the first 2 years of life. Approximately 90% of all patients with Wilson disease have ceruloplasmin levels of less than 20 mg/dL (reference range, 20-40 mg/dL).
- Ceruloplasmin is an acute phase reactant and may be increased in response to hepatic inflammation, pregnancy, estrogen use, or infection.
- Falsely low ceruloplasmin levels may be observed in any protein deficiency state, including nephrotic syndrome, malabsorption, protein-losing enteropathy, and malnutrition.
- Urinary copper excretion
The urinary copper excretion rate is greater than 100 mg/d
- Hepatic copper concentration
- This test is regarded as the criterion standard for diagnosis of Wilson disease.
- A liver biopsy with sufficient tissue reveals levels of more than 250 mcg/g of dry weight even in asymptomatic patients.
- Imaging Studies– CT and MRI of brain and abdomen can be carried out to confirm the diagnosis.
- Kayser-Fleischer rings– can only be diagnosed definitively by an ophthalmologist using a slit lamp. They are present in >99% of patients with neurologic/psychiatric forms of the disease and have been described very rarely in the absence of Wilson disease.
Figure- Showing Kayser –Fleischer ring in a patient suffering from Wilson’s disease
The mainstay of therapy for Wilson disease is pharmacologic treatment with chelating agents.
Chelating agents bind excess copper.
Ammonium tetrathiomolybdate is being used. This drug works as both a chelating agent and an inhibitor of copper absorption from the GI tract.
Penicillamine was previously the primary anticopper treatment but now plays a minor role because of its toxicity and because it often worsens existing neurologic disease if used as initial therapy.
Trientine is a less toxic chelator and is supplanting penicillamine when a chelator is indicated.
For patients with hepatitis or cirrhosis, but without evidence of hepatic decompensation or neurologic/psychiatric symptoms, zinc is the therapy of choice.
B6 and Dimercaprol can also be used as a part of the treatment.
Anticopper therapy must be given for life long. With treatment, liver function usually recovers after about a year, although residual liver damage is usually present. Neurologic and psychiatric symptoms usually improve between 6 and 24 months of treatment.
The major complications in patients with untreated Wilson disease are those associated with liver failure and a chronic, relentless course to cirrhosis.
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