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The gene ATP7B responsible for Wilson's disease (WD) produces a protein which is predicted to be a copper-binding P-type ATPase, homologous to the Menkes disease gene (ATP7A). Various mutations of ATP7B have been identified. This study aimed to detect disease-causing mutations, to clarify their frequency and distribution, to determine whether genotype correlates with phenotype, and to determine the rate of abnormal findings in heterozygotes for the WD gene. We analyzed 41 unrelated Japanese WD families, including 47 patients. Twenty-one mutations, including nine novel ones, were identified. 2871delC (15.9%), 1708-5T-->G (11. 0%), and Arg778Leu (13.4%) were the most common mutations. 2871delC was detected mainly in eastern Japan and 1708-5T-->G in western Japan. The homozygotes for the 1708-5T-->G, 2871delC, or Arg778Leu mutations did not show a correlation with their phenotypes. Ceruloplasmin and copper levels were abnormally low in 28.6% and 35. 0% of heterozygotes, respectively. When patients and their families are screened for WD, a high rate of abnormal laboratory data in heterozygotes must be taken into account.

This short-term controlled trial demonstrated the biochemical efficacy and safety of iron reduction therapy for patients with CHC.

Background. Iron overload syndromes include a wide spectrum of genetic and acquired conditions. Recent studies suggest suppressed hepcidin synthesis in the liver to be the molecular basis of hemochromatosis. However, a liver with acquired iron overload synthesizes an adequate amount of hepcidin. Thus, hepcidin could function as a biochemical marker for differential diagnosis of iron overload syndromes.Methods. We measured serum iron parameters and hepcidin-25 levels followed by sequencing HFE, HJV, HAMP, TFR2, and SLC40A1 genes in 13 Japanese patients with iron overload syndromes. In addition, we performed direct measurement of serum hepcidin-25 levels using liquid chromatography-tandem mass spectrometry in 3 Japanese patients with aceruloplasminemia and 4 Italians with HFE-hemochromatosis. Results.One patient with HJV-hemochromatosis, 2 with TFR2-hemochromatosis, and 3 with ferroportin disease were found among the 13 Japanese patients. The remaining 7 Japanese patients showed no evidence for genetic basis of iron overload syndrome. As far as the serum hepcidin-25 was concerned, seven patients with hemochromatosis and 3 with aceruloplasminemia showed markedly decreased serum hepcidin-25 levels. In contrast, 3 patients with ferroportin disease and 7 with secondary iron overload syndromes showed serum hepcidin levels parallel to their hyperferritinemia. Patients with iron overload syndromes were divided into 2 phenotypes presenting as low and high hepcidinemia. These were then associated with their genotypes. Conclusion.Determining serum hepcidin-25 levels may aid differential diagnosis of iron overload syndromes prior to genetic analysis. (231 words)

This review of the copper-iron interaction in Wilson's disease was mainly based on ten patients (three females and seven males) studied in our institutes because the genetic tests of ATP7B for Wilson's disease of primary copper toxicosis and HFE for hemochromatosis, the biochemical parameters of copper and iron, and morphological studies on biopsied liver specimens were complete. All patients had hypoceruloplasminemia and hepatic lesions compatible with Wilson's disease. One patient was homozygous and nine patients were compound heterozygous for the mutations in ATP7B, and all patients were free from the major mutation, C282Y, of HFE. The biochemical parameters of iron metabolism were not specific, except for serum ferritin concentration. Judging from the traditional criteria, seven patients had hyperferritinemia. Histochemical iron was stained in the livers of seven patients and histochemical copper was found in nine patients. Microanalysis was more sensitive than histochemistry, detecting copper and iron accumulation in the hepatocellular lipofuscin particles of all patients. Using an improved fixative, intralipofuscin distribution was found to be different between cuprothionein and iron complexes. Iron overload in Wilson's disease might be worsened after treatment because of the close relation to hypoceruloplasminemia, in which the iron efflux from the liver to the circulation is disturbed.

In addition to hemochromatosis, aceruloplasminemia and ferroportin disease may be complicated by iron-induced multiple organ damage. Therefore, clinicopathological features should be evaluated in a wider range of genetic iron disorders. This study included 16 Japanese patients with genetic iron overload syndromes. The responsible genes were CP in four, HAMP in one, HJV in three, TFR2 in five, and SLC40A1 in three patients. No phenotype dissociation was observed in patients with the CP, TFR2, or HAMP genotypes. Two of the three patients with the HJV genotype displayed classic hemochromatosis instead of the juvenile type. Patients with the SLC40A1 genotype were affected by mild iron overload (ferroportin A) or severe iron overload (ferroportin B). Transferrin saturation was unusually low in aceruloplasminemia patients. All patients, except those with ferroportin disease, displayed low serum hepcidin-25 levels. Liver pathology showed phenotype-specific changes; isolated parenchymal iron loading in aceruloplasminemia, periportal fibrosis associated with heavy iron overload in both parenchymal and Kupffer cells of ferroportin B, and parenchyma-dominant iron-loading cirrhosis in hemochromatosis. In contrast, diabetes occurred in all phenotypes of aceruloplasminemia, hemochromatosis, and ferroportin disease B. In conclusion, clinicopathological features were partially characterized in Japanese patients with genetic iron overload syndromes.

Iron overload related to hypoceruloplasminemia may be clinically important, particularly in male patients with Wilson's disease.

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