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Generalised oedema, lethargy, personality disturbance, and recurring nightmares in a young girl

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Q1: What is the likely diagnosis?

The low serum copper and caeruloplasmin concentrations, in the setting of abnormal liver function, hyponatraemia, and profound clotting disturbance point to a diagnosis of Wilson's disease with hepatic failure. In this case, hepatic involvement predominates despite background lethargy, personality change, and depression. The prominent abdominal veins, fluid retention, and ascites are the clinical manifestations of portal hypertension and decompensated liver disease, with poor synthetic function evidenced by a low serum albumin and greatly increased prothrombin time.

Her shortness of breath was secondary to abdominal distention and diaphragmatic splinting due to ascites. A polyclonal immunoglobulin rise is often seen in Wilson's disease and a raised serum B12, which is stored in the liver, is associated with hepatic necrosis.

Q2: What further investigations would confirm the diagnosis?

Classically, serum caeruloplasmin concentrations are very low in parallel with low serum copper levels. Though serum caeruloplasmin estimation alone is not specific enough to diagnose Wilson's disease, concentrations as low as in this case are unusual for any other diagnosis. Caeruloplasmin synthesis can be modestly reduced in decompensated liver disease of any aetiology or in acute liver failure. Protein losing enteropathy, nephrotic syndrome, and malnutrition will also reduce serum concentrations. Conversely, as its synthesis can be stimulated by oestrogens and it is an acute phase reactant, patients taking oral contraceptives or those with acute inflammatory change within the liver may have normal serum levels. In the series reported by Steindl and colleagues,1 12 out of 55 patients with Wilson's disease had a normal caeruloplasmin and no Kayser-Fleischer (KF) rings. Free copper concentrations can be calculated—though high values (>200 μg/l) suggest Wilson's disease, diagnosis based on such calculation lacks specificity and is dependent on the accuracy of copper and caeruloplasmin measurement.

A 24 hour copper estimation is a simple and useful confirmatory test with raised values (>100 μg/24 hours) invariably seen in symptomatic Wilson's disease. Concentrations in this case were greatly raised at 461 μg/24 hours (normal range 0–50). Care needs to be taken to ensure the collection is accurate and has not been contaminated (for example extraneous copper in tap water). Verification of the result by a repeat collection is advisable. Borderline values may be obtained in presymptomatic patients or heterozygotes, such results demand further investigation.

A liver biopsy, in itself, may not be diagnostic but is helpful in determining the extent of hepatic involvement and whether or not there is established cirrhosis. In this case, given the background coagulopathy, a transjugular liver biopsy was performed which confirmed established cirrhosis. Fibrosis and moderate inflammatory change was accompanied by extensive collapse of residual liver between regenerative nodules suggesting recent subacute necrosis. A mild increase in copper associated protein and copper accumulation in the hepatocellular nodules was felt to be consistent with Wilson's disease. Occasionally, despite gross hepatic copper excess, histochemical techniques may fail to demonstrate copper. Determination of hepatic tissue copper concentration by neutron activation analysis or atomic absorption spectrometry may clearly indicate hepatic copper overload. Concentrations greater than 250 μg/g dry weight are accepted as diagnostic of Wilson's disease.

Slit lamp examination to look for KF rings may also be helpful, although these are absent in 15%–50% of patients with an exclusively hepatic presentation.1 It should also be recognised that though KF rings are generally specific for Wilson's disease in children, this is not the case in older patients, where they may be associated with other types of chronic liver disease (usually with a cholestatic component) and non-hepatic diseases. In this case, because of the liver biopsy findings, copper result, and deteriorating clinical condition no slit lamp examination was performed.

Q3: What treatment options might you consider and how would you manage this young girl?

The two main treatment options are chelation treatment with penicillamine or referral to a liver unit for consideration for orthotopic liver transplant (OLT). Chelation therapy is the treatment of choice in patients with compensated liver disease. A satisfactory response, even in the setting of decompensated cirrhosis, ascites, and coagulopathy has been described, as long as encephalopathy has not developed,2 though early referral to a liver unit is preferable in the setting of deteriorating liver function as OLT is curative.

The usual starting dose is 250 mg daily increasing over a period of a few weeks to an eventual maintenance dose of 1.5 g daily. Approximately 20% of patients will experience side effects such as fever, rash, leucopenia, thrombocytopenia, and lymphadenopathy. An systemic lupus erythematosus-like syndrome and proteinuria may also occur. Trientine is an alternative chelating agent which may be used in those unable to take penicllamine. Elemental zinc inhibits gastrointestinal copper absorption but its long term effectiveness is unproven.

Success of therapy is judged by clinical improvement. This may be slow and 25% of patients with neurological presentations may initially deteriorate. The dose of penicillamine can be increased further if, despite adequate compliance, there has been no initial response. Liver function should improve and hepatic biopsy shows lessening of activity and reversion to inactive cirrhosis. KF rings fade and eventually disappear, mental performance improves, and neurological signs such as tremor and rigidity, lessen. Improvement in handwriting is a good test of progress. Given such improvement, the dose of penicillamine is reduced to a maintenance dose of 750–1000 mg daily. After two years, failure to respond implies the presence of irreparable tissue damage or poor compliance. A fulminant course may follow non-compliance in a previously well controlled patient.

In patients with decompensated liver disease unresponsive to medical therapy or presenting with fulminant hepatic failure, OLT is the treatment of choice.3 Given the extensive subacute necrosis on the liver biopsy, poor hepatic synthetic function and signs of liver decompensation our patient underwent urgent OLT, made an eventful recovery and was discharged home on standard immunosuppression. She has had three normal pregnancies and remains well six years after her transplant.

Discussion

Kinnear Wilson, in 1912, first used the term “progressive hepatolenticular degeneration” to describe a familial disorder with neurological disease, chronic liver disease, and KF rings. Wilson's disease is an autosomal recessive condition. TheWND gene, which encodes a membrane P-type ATPase transporter, is located on chromosome 13. Several specific mutations have been identified, the commonest in European populations being the H1069Q mutation with a frequency of between 26%–70%. The reported incidence is 1:30 000 giving a carrier frequency of approximately one in 90.

The functional disruption to the membrane transporter affects incorporation of copper into caeruloplasmin (a 132 Kda α-glycoprotein) and its excretion into bile. Positive copper balance results with accumulation of unbound copper in the liver. An array of extrahepatic disorders associated with Wilson's disease demonstrate the wider organ involvement. In addition to the well described KF ring (accumulation of copper in Descemet's membrane of the posterior cornea), renal tubular disease (leading to secondary renal stones, osteoporosis, or osteomalacia), arthritis, pancreatitis, cardiomyopathy, rhabdomyolysis, and a variety of endocrine disorders have been ascribed to end organ copper deposition.

Liver damage is evident early in the natural history. Hepatocytes are ballooned, show multiple nuclei, clumped glycogen, and glycogen vacuolation. Fatty change is usual. Kupffer cells are large, with stained copper tending to be within these, rather than hepatocytes. Mallory's bodies may be seen, simulating acute alcoholic hepatitis. All grades of change from periportal fibrosis, through submassive necrosis, to a coarse macronodular cirrhosis are seen. Cell injury is thought to result from oxidant damage. The wide variation in host response and clinical heterogeneity probably results from genetic and environmental influences on copper protective mechanisms. Knowledge of the specific genetic mutation does not allow precise prediction of subsequent clinical outcome.

Patients may be symptomatic or diagnosed after investigation of incidental liver function abnormality. Presenting features are either hepatic, neurological (movement disorders or rigid dystonia patterns), or psychiatric (depression, neuroses, personality changes). A degree of overlap is recognised, as illustrated by this case, where the predominant hepatic presentation was associated with personality change and depression. Such personality changes may be difficult to distinguish from the clinical syndrome of encephalopathy. In general, patients with the hepatic form are younger (less than 19 years), whereas patients presenting after the age of 20 frequently have neurological or psychiatric symptoms.

The pattern of hepatic presentation of Wilson's disease can be divided into fulminant hepatitis, chronic hepatitis, or cirrhosis. The fulminant type is characterised by progressive jaundice, hypoalbuminaemia, ascites, coagulopathy, encephalopathy, and renal failure. Virtually all patients are already cirrhotic. Hepatic necrosis may lead to a sudden flux of copper into the vascular compartment resulting in acute haemolysis, haemolytic anaemia, and raised serum bilirubin concentrations. The alkaline phosphatase/bilirubin ratio is usually low, unlike fulminant viral hepatitis. Chronic hepatitis usually presents between 10–30 years, with jaundice, high transaminases, and hypergammaglobulinaemia. Cirrhotic patients may present insidiously with signs of chronic liver disease and portal hypertension. Hepatocellular carcinoma complicating cirrhosis in Wilson's disease is rare.

Untreated Wilson's disease is progressive. Response to chelation therapy may be poor in patients with chronic hepatitis and the fulminant form is frequently fatal. Liver transplantation is potentially lifesaving and corrects the underlying metabolic abnormality. It is therefore vital to consider the diagnosis in a young person presenting with liver function abnormalities. Survival in patients transplanted for Wilson's disease was 79% at one year in one series.3 At Queen Elizabeth Hospital, Birmingham, between 1982 and 1995, 15 out of 1181 (1.3%) of transplants were for Wilson's disease, eight for fulminant presentations (mean age 15 years; range 7–24), and seven for chronic liver disease (mean age 20 years; range 11–48). Two patients in the fulminant group died in the immediate post-OLT period, however all patients with chronic presentations survived transplant and remain well.

Screening of siblings after appropriate genetic counselling is mandatory, each having a one in four chance of being affected. Figure 1shows the patient's family pedigree. Traditional screening involving physical examination, liver function tests, serum copper and caeruloplasmin measurement, basal 24 hour urinary copper estimation, and a careful slit lamp examination is now used alongside genetic testing. The typing of flanking microsatellite markers is now available routinely in most diagnostic laboratories. Where the index case has been identified this provides the most reliable method of determining the genetic status of the siblings or other relatives. However, such screening is not necessary for children of those affected, unless their partner is known to be a gene carrier, due to the autosomal recessive nature of the disease and sufficiently low gene carrrier rate. No known heterozygote has been reported to have developed disease symptoms. Therefore initiation of presymptomatic treatment should be reserved for those homozygous for the Wilson's gene.

Figure 1

Family pedigree showing affected homozygotes with Wilson's disease and heterozygous carriers.

Final diagnosis

Wilson's disease with hepatic failure.

References

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