Late onset of Wilson's disease in a family with genetic haemochromatosis

We report the coexistence of Wilson's disease and genetic haemochromatosis in one family. The diagnosis of genetic haemochromatosis was established in a 52-year-old man. Among his siblings, one 57-year-old sister and one 55-year-old brother had decreased copper and ceruloplasmin levels in serum and increased urinary copper excretion. The sister shared the same human leucocyte antigen haplotypes and was homozygous for the HFE mutation C282Y, like the propositus. However, she had normal liver iron content and increased liver copper content. Her dietary copper intake was probably excessive. The association of Wilson's disease and genetic haemochromatosis is rare and has only been described twice. The onset of Wilson's disease after 50 years of age is rare; Wilson's disease should be considered in any patient with unexplained chronic liver disease; an excess in liver copper content might be induced by excessive dietary input in a susceptible individual.     

Fulminant hepatic failure resulting from coexistent Wilson's disease and hepatitis E.

Fulminant hepatic failure resulting from hepatitis E and coexistent Wilson's disease was diagnosed in a six year old girl six weeks after returning from a holiday in India. Wilson's disease was diagnosed on the basis of histological evidence of hepatocellular copper deposition, confirmed by biochemical estimation of liver copper concentration. Although severely damaged, the liver was non-cirrhotic. Hepatitis E virus (HEV) was diagnosed by nested polymerase chain reaction, the specificity of which was confirmed by direct sequencing of amplified DNA. Replication of HEV within the liver at the time of diagnosis was confirmed by selective amplification of the antigenomic strand of the virus obtained from total liver RNA. The patient had an orthotopic liver transplantation without recurrence of hepatitis and remains well at 19 months. Viral excretion, recorded by serial amplification of HEV RNA extracted from stool samples, persisted for 30 days after liver grafting. Severe vitiligo, present preoperatively, dramatically improved after liver grafting and institution of immunosuppressive treatment. This case suggests that viral infection may play a part in the acute decompensation seen in some cases of Wilson's disease.     

Long-term results of liver transplantation for Wilson's disease

Wilson's disease is a hereditary defect in hepatic copper metabolism, causing hepatic, neurological and/or psychiatric manifestations. For patients with severe disease, liver transplantation is the treatment of choice. The aim of this study was to report the long-term outcome of patients who underwent liver transplantation for Wilson's disease. PATIENTS AND METHODS: Thirteen patients with Wilson's disease, transplanted in Lyon France between January 1987 and May 2006, were including in this study: eight women and five men, aged eight to 53 years (median 20 years, seven children and six adults). The diagnosis of Wilson's disease was established before liver transplantation. RESULTS: The indication for liver transplantation was chronic (69%) or fulminant liver failure (31%). The median follow-up after liver transplantation was 10 years with 100% patient survival. Copper metabolism returned to normal in all patients. None of the patients with exclusive liver disease required chelation treatment after liver transplantation and none developed neurological symptoms of Wilson's disease. CONCLUSION: Liver transplantation totally reverses the abnormalities of copper metabolism and subsequent hepatic failure, but the course of neurological symptoms remains unpredictable. Long-term patient survival can be excellent without occurrence of neurological complications.     

44-jährige Patientin mit fulminantem Leberversagen

The 44-year old female patient was admitted with acute hepatic failure and extensive haemolysis under the preliminary diagnosis of Wilson's disease. General characteristic criteria of Wilson's disease as Kayser-Fleischer ring, low serum copper and low ceruloplasmin levels were not observed. The preliminary diagnosis of acute Wilson's disease was established on the basis of the characteristic laboratory values with an AP/bilirubin ratio <2, an AST/ALT ratio >4, accompanying hemolysis and a highly elevated cupruresis. The definitive diagnosis of Wilson's disease was verified after orthotopic liver transplantation by quantitative copper evaluation in the explanted liver. The case represents the yet oldest patient reported with an acute manifestation of Wilson's disease.     

Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson's disease.

To investigate the diagnostic value of 24-hr urinary copper excretion testing after penicillamine challenge in the diagnosis of Wilson's disease, 75 consecutive children referred for a variety of liver problems and in whom parameters of copper metabolism had been investigated were analyzed retrospectively. Seventeen had Wilson's disease, 22 had autoimmune chronic active hepatitis, 6 had primary sclerosing cholangitis, 12 had chronic liver disease of various etiologies, 4 had cryptogenic acute liver failure, 6 had acute hepatitic illnesses and 8 had a variety of disorders featuring normal liver histological appearance. Serum ceruloplasmin and total copper levels were significantly lower in Wilson's disease patients compared with all other groups, but three children with Wilson's disease had normal ceruloplasmin levels and seven had normal total copper levels. No significant difference was found for free serum copper levels and liver copper content between Wilson's disease patients and the other groups. Baseline 24-hr urinary copper excretion was significantly higher in Wilson's disease patients compared with that of the other patients, but six children with Wilson's disease had levels just above the upper limit of normal, overlapping with values obtained in three children with liver failure, two with acute hepatitis, two with autoimmune chronic active hepatitis and three with primary sclerosing cholangitis. The 24-hr urinary copper excretion after penicillamine challenge proved the most accurate single diagnostic test; levels more than 25 mumol/24 hr were present in 15 of 17 patients with Wilson's disease, but in only 1 child with liver failure of the 58 with other disorders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Wilson's disease

Wilson's disease is an autosomal, recessive-inherited disorder of impaired biliary copper excretion that results in the accumulation of copper in various organs including the liver, the cornea and the brain. The Wilson's disease gene on chromosome 13 codes for a copper transporting P-type ATPase-ATP7B. More than 60 mutations of this gene have been described. The diagnosis of Wilson's disease is based on clinical findings and laboratory abnormalities and can be made if two of the following symptoms are present: Kayser-Fleischer rings; topical neurologic symptoms; and low serum ceruloplasmin levels. In less typical cases diagnosis requires various other tests of copper metabolism. Effective medical treatment with copper chelators (D-penicillamine, trientine) or zinc results in symptomatic improvement and normal life expectancy. Orthotopic liver transplantation is indicated in advanced cases with hepatic decompensation or in patients with fulminant Wilson's disease.     

Value of molecular analysis of Wilson's disease in the absence of tissue copper deposits: a novel ATP7B mutation in an adult patient

Wilson's disease (WD) is a disorder of copper metabolism leading to copper accumulation in the liver and in extrahepatic organs, such as brain and cornea. We present a patient with liver disease who did not fulfil the biochemical criteria for WD. Mutational analysis was necessary to make the diagnosis and show a new mutation. Our case supports the use of mutation analysis in cases with unclear liver disease and suggests that the spectrum of WD is broader than currently assumed.     

Striking variability of hepatic copper levels in fulminant hepatic failure

Two cases of acute hepatic failure are reported in which the diagnosis of Wilson's disease was considered because of low serum ceruloplasmin, low serum copper levels and high 24 h urinary copper. Case 1 had Kayser-Fleischer rings, haemolysis and a high 24 h urinary copper, and so Wilson's disease was confidently diagnosed. Case 2 had high urinary copper excretion, but [64Cu] study indicated a 24:2 h ratio of 0.7 and made the diagnosis of Wilson's disease uncertain. Both patients underwent orthotopic hepatic transplantation, and multiple biopsies were taken from the resected specimen in order to estimate hepatic copper levels. In both cases, hepatic copper levels revealed considerable variation: 0.8-5.2 mumol/g dry wt (case 1) vs 0.02-12.65 mumol/g dry wt (case 2). In case 1, only two of 14 levels were within the diagnostic range for Wilson's disease (greater than 4 mumol/g dry wt), whereas hepatic copper levels in case 2 were in the Wilsonian disease range in three of 16 specimens. These results were in contrast to uniformly high hepatic copper levels in one patient with established cirrhosis secondary to Wilson's disease and two cases of primary biliary cirrhosis. This report indicates that hepatic copper levels vary greatly in acute liver failure, and that estimates from a single biopsy specimen may be misleading as to the cause of the underlying liver disease.     

Diagnosis of Wilson's disease: an experience over three decades

BACKGROUND: Wilson's disease is a rare but treatable condition that often presents diagnostic dilemmas. These dilemmas have for the most part not been resolved by the identification and cloning of the Wilson's disease gene. AIMS: To report our experience over three decades with patients with Wilson's disease in order to illustrate the diverse patterns of presentation and thereby broaden the approach to diagnosis. METHODS: Clinical and laboratory findings of 30 patients with Wilson's disease were reviewed. RESULTS: Twenty two patients presented with liver manifestations (eight with fulminant hepatic failure and 14 with chronic liver disease), three with neurological disease, and one with haemolysis; four were asymptomatic siblings of patients with Wilson's disease. Seventy per cent were diagnosed within six months of the onset of symptoms, but diagnosis was delayed for up to nine years. Age range at diagnosis was wide (7-58 years) and five patients were over 40. In patients presenting with non-fulminant disease, 18% had neither Kayser-Fleischer rings nor low caeruloplasmin concentrations. Increased liver copper concentrations were found in all but one patient who had undergone six years of penicillamine treatment. In fulminant hepatic failure (n=8) additional features helpful in the diagnosis included evidence of haemolysis, increased urinary copper (range 844-9375 microg/24 h), and a high non-caeruloplasmin copper (range 325-1743 microg/l). CONCLUSIONS: The diagnosis of Wilson's disease still depends primarily on the evaluation of clinical and laboratory evidence of abnormal copper metabolism. No one feature is reliable, but the diagnosis can usually be made provided that it is suspected. Wilson's disease should be considered in patients of any age with obscure hepatic or neurological abnormalities.     

Fulminant Wilson's disease treated with postdilution hemofiltration and orthotopic liver transplantation

A 22-yr-old woman presented with fulminant Wilson's disease. The diagnosis was suspected clinically and was later confirmed with chemical and pathologic studies. She presented with acute hepatic failure, hemolysis, and acute anuric renal failure. Postdilution hemofiltration and continuous arteriovenous hemofiltration with oral D-penicillamine allowed removal of a total of 95,700 micrograms of copper; 78,665 micrograms of the total were removed via postdilution hemofiltration alone. On the 57th day, the patient received successful liver and renal transplants. We found that the determination of serum copper was instrumental in the diagnosis of fulminant Wilson's disease, that postdilution hemofiltration allowed a rapid removal of copper in the presence of renal failure, and that, finally, orthotopic liver transplantation should be performed early in the clinical course of these patients. This patient is the longest survivor of this serious condition.     

Observations on copper associated protein in childhood liver disease.

Hepatic copper concentrations were compared with staining grades of copper associated protein (CAP) and histochemical copper in liver sections from 44 patients (one fetus, one pre-term infant, four term infants, eight normal children, 16 children with various liver diseases, and 14 patients with intrahepatic cholestasis of childhood (IHCC)). A similar comparative study of hepatic copper concentration with CAP and histochemical copper was performed in 21 patients with Wilson's disease. CAP occurred in the fetus, pre-term infant, and term infants without liver disease. This suggests that CAP is a normal constituent of the hepatocyte and is not a consequence of liver disease or biliary obstruction. CAP was not seen when hepatic copper concentration was normal; it was absent in eight children with no evidence of liver disease, eight children with non-cirrhotic liver disease, and seven of eight children with cirrhosis. When hepatic copper concentration exceeded 4.0 mumol/g dry liver weight grade 2 or grade 3 staining for CAP and histochemical copper was found in the fetus, pre-term infant, infants, and IHCC. CAP was found in IHCC only in the presence of raised hepatic copper levels, supporting evidence of a relationship between copper and CAP. In 17 of 21 patients with Wilson's disease hepatic copper concentrations exceeded 4 mumol/g. Positive staining for CAP was seen in seven of these patients being usually grade 1. CAP is a normal associated protein, present when hepatic copper concentrations are increased in normal liver cells. It is usually absent in hepatocytes from Wilson's disease despite similar hepatic copper levels. CAP may represent material which protects the hepatocyte from the toxic effects of copper.     

Oral zinc in Wilson disease--an alternative to D-penicillamine

Recently Brewer et al. reported the possibility of an oral zinc therapy in Wilson's Disease. We treated a 19 years old patient with decompensated liver cirrhosis due to Wilson's disease with zinc-sulphate. D-Penicillamine had to be withdrawn since proteinuria occurred under treatment. After the discontinuation of D-Penicillamine an increase of serum copper almost up to normal range was observed; concomitantly urinary copper elimination decreased. Under oral zinc sulphate therapy (145 mg/day) a drop of serum copper level was achieved and liver function improved: serum albumin, gamma globulins and prothrombin time reached normal values. The patient did not complain any side effects during oral zinc sulphate therapy. Oral zinc therapy in Wilson's Disease may be regarded as an alternative to D-Penicillamine treatment when this drug has to be discontinued because of side effects.     

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) leading to the diagnosis of Wilson's disease

Authors describe the case of a patient suffering from Thrombotic Thrombocytopenic Purpura--Hemolytic-Uremic syndromee. Any cause of the disease was not found, except signs of liver injury. The etiology of indefinite liver disease that had been diagnosed several years before was examined. Wilson's disease was considered as a final eventuality. The finding of 488 micrograms of copper in the dry liver tissue confirmed the diagnosis of Wilson's disease in the end.     

Copper metabolism in hypercupremic human livers. Studies of its subcellular distribution, association with binding proteins and expression of mRNAs.

In the present study we have used differential centrifugation, size exclusion chromatography, Western and Northern blotting to investigate the subcellular distribution of hepatic copper, the association of the metal with hepatic copper binding proteins and the expression of specific mRNAs for copper binding proteins in liver tissue from two patients with Wilson's disease, two patients with chronic liver disease and two patients with normal hepatic copper levels. Unlike previous studies the present results fail to show any gross differences in subcellular distribution of copper between the livers, with most of the copper being found in the soluble supernatant where it is associated with metallothionein. Caeruloplasmin mRNA levels were reduced in the two patients with Wilson's disease and also in a patient with fulminant hepatic failure. It remains to be confirmed if the reduction of caeruloplasmin mRNA is specific for Wilson's disease. Levels of mRNAs for copper zinc superoxide dismutase and metallothionein were variable and not related to liver copper.     

Copper kinetics in liver disease

The plasma clearance and the liver uptake of intravenously administered (64)Cu were significantly impaired in four patients with Wilson's disease. These defects were unlikely to be simply expressions of the high liver copper concentration as the plasma clearance and hepatic uptake of (64)Cu were normal in four patients with primary biliary cirrhosis, in whom the liver copper concentration was raised to a degree comparable to that in Wilson's disease. The normal liver uptake and plasma clearance of (64)Cu in three patients with other forms of hepatocellular disease suggest that impaired liver cell function does not have a significant effect. The precise nature of the defect in copper transport in Wilson's disease remains to be elucidated; it is possible that delayed uptake of copper by the hepatic lysosomes may account for the toxic effects of the metal.     

Failure of simple biochemical indexes to reliably differentiate fulminant Wilson's disease from other causes of fulminant liver failure.

Serum, urine and tissue biochemical findings were studied in 21 cases of fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in fulminant Wilson's disease were significantly different from those found in other cases of fulminant liver failure, but differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in fulminant Wilson's disease than in other categories of fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non-Wilsonian fulminant liver failure would erroneously be assigned a diagnosis of fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase-to-bilirubin ratio (< 0.57) in any category of fulminant liver failure suggested a significantly worse prognosis than in cases with higher ratios (chi 2, Yates' corrected = 5.37, p = 0.02). In the Wilson's disease group, serum and hepatic copper and ceruloplasmin concentrations were normal in 4/21, 2/15 and 2/19, respectively, whereas urinary copper level was elevated in 18/18 and was the most valuable test in diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of the iron and copper content of the liver for the differential diagnosis of chronic liver diseases

Liver iron and copper concentrations were estimated in 395 patients undergoing hepatological examination. Relations to clinical, morphological and laboratory data were evaluated. Liver iron concentrations were not significantly different in chronic hepatitis of viral, toxic or immunological origin. Liver iron levels exceeding 100 mg/100 g dry liver tissue (normal range up to 300 mg/100 g) were only found in idiopathic hemochromatosis (n = 8), in a patient with prophyria cutanea tarda and in a multiple transfused patient who suffered from aplastic anemia. Liver copper content was significantly increased in primary biliary cirrhosis compared to chronic hepatitis of other origin. Apart from untreated Wilson's disease (n = 3) copper levels higher than 25 mg/100 g dry liver tissue (normal range up to 6 mg/100 g) were measured in chronic active hepatitis B (n = 2), primary biliary cirrhosis (n = 9) and in chronic hepatitis of uncertain origin (n = 3). Therefore excess accumulation of copper in the liver was typical of Wilson's disease but less diagnostic than severely elevated liver iron stores of idiopathic hemochromatosis.     

Diagnosis of Wilson's disease presenting as fulminant hepatic failure

The clinical course, results of standard laboratory tests, parameters of copper metabolism, and hepatic morphology in 9 cases (3 of our own and 6 from the literature) of Wilson's disease presenting as fulminant hepatic failure were compared with the findings in 5 cases of idiopathic fulminant hepatic failure. Patients with Wilson's disease were usually younger, and 7 of the 9 patients had Kayser-Fleischer rings. Patients with idiopathic fulminant hepatic failure had elevated 24-h urinary copper, decreased ceruloplasmin, and low or normal serum copper. Fulminant hepatic failure with Wilson's disease differed from idiopathic fulminant hepatic failure by the following biochemical findings: (a) higher copper levels in serum, urine and liver; (b) less pronounced elevations of transaminase levels; (c) higher concentrations of total bilirubin; and (d) lower hemoglobin values. Serum copper was the most useful biochemical test in diagnosing Wilson's disease before death. At autopsy, only hepatic copper concentrations clearly separated the two groups. Serial serum copper levels (antemortem) and quantitative analysis of hepatic copper (after recovery or postmortem) in patients with fulminant hepatic failure should help to exclude Wilson's disease.     

Poor cognitive development and abdominal pain: Wilson's disease

An 8-year-old boy was referred to our hospital because of learning disabilities. His general cognitive functions were below the level for age, and he was diagnosed with dysphasia. The boy was transferred to a special class for children with learning problems. Three months later he was again referred to us because of acute epigastric pain. The only abnormal laboratory finding was a slightly elevated level of alanine aminotransferase. Although the symptoms disappeared in a few days, the transaminase levels remained above normal for the next 6 months. Further diagnostic work-up revealed low serum ceruloplasmin concentration and high 24-h urinary copper excretion. The hepatic copper concentration in liver biopsy was high (2900 microg/g dry weight), confirming the diagnosis of Wilson's disease. Brain MRI showed slight changes in white matter. The patient's asymptomatic sister was also diagnosed with Wilson's disease. Both siblings started penicillamine therapy and a copper-restricted diet. The copper content of the household water was found to be above average and a new plumbing system was installed. After 1 year from the initiation of the therapy, the transaminase concentrations normalized and both siblings were free of symptoms. After 2 years of therapy the patient was able to return to normal school. Wilson's disease must be borne in mind, when children are evaluated because of poor school performance, especially if they complain of abdominal symptoms.     

Liver copper concentration in Wilson''s disease: Effect of treatment with ''anti-copper'' agents

Serial copper determinations have been made on the livers of 10 patients with Wilson's disease. Two were studied before and eight after the start of treatment in order to assess the effect, if any, on the concentration of the metal. In two patients who were receiving no therapy and in one in whom it had been discontinued, the level of copper rose. In the latter patient, resumption of treatment then resulted in a fall in the level of copper in the liver. A similar fall was seen in seven patients on continuous therapy. In one patient, a very poor complier, there was a tendency for the liver copper concentration to rise over a 5-year period. All three therapies investigated--penicillamine, trientine and tetrathiomolybdate--when taken regularly, appear to be effective in reducing liver copper levels. Sixty-nine single determinations of liver copper have been plotted against time on treatment. This shows that the copper concentration falls rapidly in the first year. Thereafter, there is no linear relationship between the duration of treatment and liver copper. Poor compliers have a higher liver copper concentration than do good compliers. Determinations made from different portions of the liver showed that in only one of 19 examples was there an overlap between the near normal and the abnormal range. The principal mechanism of action of 'anti-copper' agents in Wilson's disease appears to be the mobilization of copper from the tissues, but a secondary detoxifying action may come into play later.