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A 15 year old girl with fever, jaundice, haemolysis, and sudden clinical deterioration

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Q1: What does the liver biopsy show (see p 250)?

A portal triad with marked oedema and fibrosis extending towards other portal triads is shown in fig 1A. Focal mononuclear cell infiltrates, ductular proliferation, and interface hepatitis are also visible. In fig 1B, hepatocyte ballooning and lytic necrosis are associated with feathery degeneration.

These morphological findings are insufficient by themselves to establish a diagnosis since they are shared by a number of different liver diseases.

Q2: What is the most likely diagnosis?

The differential diagnosis in this case must include all the most important causes of fulminant hepatic failure (box 1). Nevertheless, fulminant Wilson's disease should be considered the leading diagnosis. The three most relevant clues pointing to Wilson's disease are the age of the patient, the presence of Coombs negative haemolytic anaemia, and the low serum alkaline phosphatase level. Liver biopsy findings are compatible with Wilson's disease, since the vast majority of Wilson's disease patients have evidence of fibrosis, despite widely varying levels and patterns of hepatic inflammation and injury.

Box 1: Main causes of fulminant hepatic failure

Drugs and toxins

  • Acetaminophen.

  • Halothane.

  • Isoniazid.

  • Valproate

  • Amanita phalloides.

Infections

  • Viral hepatitis (A to E).

  • Non-A to E hepatitis.

Vascular diseases

  • Budd-Chiari syndrome.

Metabolic diseases

  • Acute fatty liver of pregnancy.

  • HELLP syndrome.

  • Reye's syndrome.

  • Wilson's disease.

In other causes of fulminant hepatic failure, anaemia is not uncommon, and it is usually due to either bone marrow aplasia or coagulopathy and bleeding. Amanita phalloides releases a potent haemolysin, which, however, is not absorbed by the gastrointestinal tract and is not involved in the pathogenesis of signs and symptoms of the intoxication. An association between Budd-Chiari syndrome and haemolysis is reported only in patients where obstruction of the hepatic veins complicates paroxismal nocturnal haemoglobinuria (a chronic disease). Haemolysis is one of the cardinal manifestations of HELLP syndrome, which is a late complication of pregnancy: being due to red cell membrane injury, in patients with HELLP syndrome a peripheral blood smear must show red blood cell fragments and/or red blood cells with a thorny or spiculated surface.

A further possibility to be considered is leptospirosis, where haemolysis can contribute to anaemia, since exposure to environmental sources, in the present case, was possible or even likely. In Weil's syndrome, however, haemolytic anaemia is invariably of the microangiopathic type.

Course

The attending physicians considered fulminant Wilson's disease and leptospirosis, mainly in view of the history of exposure to rat excrement, the two most likely diagnoses. Direct and indirect methods of leptospira detection, including a search for leptospira DNA in the blood by the polymerase chain reaction, were negative. The hepatic copper content was 600 μg/g per dry weight (normal <50). The patient was listed for emergency liver transplantation, but she died of multiorgan failure 36 hours later before a suitable organ could be found. Permission to perform a postmortem examination was denied.

The results of genetic testing, performed on a blood sample sent to a reference laboratory, were obtained only several weeks later, and showed a compound heterozygote genotype (His1069Gln; Val1262Phe).

Discussion

Wilson's disease is a rare inborn error of metabolism (frequency between one in 30 000 and one in 100 000 live births), due to mutations in the recently discovered ATP7B gene. The Wilson's disease gene encodes for a P-type ATPase responsible for the transport of copper across cellular membranes, using ATP as an energy source.1 Dietary copper is absorbed in excess with respect to body requirements: since it is toxic, mainly through the generation of free radicals, in humans it is actively excreted via the hepatobiliary route. In the hepatocyte, the ATP7B protein has both a perinuclear location, where it is probably involved in delivering copper to apoceruloplasmin, and a plasma membrane location, where it may be responsible for the efflux of copper from the hepatocyte. Its function can be altered by a very large number of different disease specific mutations, including single base insertions and deletions, frame shifts and missense, non-sense, and splice site mutations (A continuously updated database can be freely downloaded at the web site of the University of Alberta.2) Most patients are compound heterozygotes. As a result of any of these mutations, progressive copper accumulation occurs. The excess copper is initially bound to metallothionein and distributed evenly throughout the cytoplasm. When the binding capacity of metallothionein is exceeded, copper is partly deposited in lysosomes, leading to hepatic dysfunction. It also leaks out into the blood and is deposited in the brain and other tissues.

The most common initial clinical manifestations of Wilson's disease are those of chronic liver disease, fulminant hepatic failure, neurological disease, and haemolysis; affected relatives of a proband can be identified in a presymptomatic stage by genetic screening.3 There appears to exist an association between age at the onset of symptoms and specific mutations: those predicted to destroy the function of the gene result in an age at presentation as young as 3 years (average 7.2 years),4 whereas the average age at presentation of homozygotes for the most commonly encountered His1069Gln mutation is 20 years. In compound His1069Gln heterozygotes, it is 15 years.5

The fulminant mode of presentation, which, for unknown reasons, is more common in females, is not exclusive of specific mutations6 and can represent a formidable challenge for the clinician.3 It occurs suddenly, without clear precipitating factors, and is almost invariably associated with haemolytic anaemia, as hepatocyte necrosis results in the massive release of copper ions into the circulation. Thus, signs include jaundice, haemoglobinuria, and renal failure; in this setting, diagnosis is a matter of extreme urgency, since, if the patient is not promptly considered for liver transplantation, prognosis is uniformly poor.

In patients with hepatic failure younger than 35 years, a high index of suspicion for fulminant Wilson's disease is needed. In addition, the presence of splenomegaly and of Coombs negative haemolysis favour Wilson's disease with respect to other causes of fulminant hepatic failure. By contrast, confirmatory tests for Wilson's disease (box 2) too often fail to add significant diagnostic information in this difficult setting. The value of biochemical tests, such as serum ceruloplasmin, serum copper concentration and urinary copper excretion, is limited by both false negative and false positive results. Kayser-Fleischer rings, golden brown deposits of copper encircling the iris and visible at slit lamp examination, are absent at the time of presentation in the majority of fulminant cases. Liver histology may show micronodular cirrhosis, without specific features; immunohistochemical techniques for copper staining are notoriously of little diagnostic value. Indeed, in fulminant forms, even measurement of the hepatic copper content, that many would consider the golden standard for diagnosis of Wilson's disease, may be below the diagnostic level, because of massive release of copper from necrotic hepatocytes. Due to the heterogeneity of the genetic defect, the time needed to perform genetic testing is usually too long to meet clinical needs, although it may be a feasible option in selected patients (for example, in subjects from Sardinia, where 85% of cases are due to only five mutations).7 For unclear reasons, serum alkaline phosphatase may be low (and sometimes unmeasurable) in fulminant Wilson's disease: a ratio of alkaline phosphatase to total serum bilirubin of less than 2, in association with an aspartate aminotransferase to alanine aminotransferase ratio of greater than 4 has been considered suggestive of wilsonian liver failure by some,8 but not by others.9

Box 2: Diagnostic tests for fulminant Wilson's disease

  • Serum ceruloplasmin concentration.

  • Serum copper concentration.

  • Urinary copper excretion.

  • Hepatic copper concentration.

  • Alkaline phosphatase to bilirubin ratio.

As soon as a diagnosis of fulminant Wilson's disease is contemplated, the patient should be promptly transferred to a hospital with an active liver transplantation programme. While awaiting for an organ, plasma exchange with fresh frozen plasma replacement should be instituted. This has been shown to be a more efficient method to remove copper from the circulation than haemodialysis, peritoneal dialysis, and haemofiltration, with net copper removal reaching up to 12 mg per session.10

Final diagnosis

Fulminant Wilson's disease.

References

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