The interactions between iron and copper in genetic iron overload syndromes and primary copper toxicoses in Japan

Abstract

Iron and copper are trace elements essential for health, and iron metabolism is tightly regulated by cuproproteins. Clarification of the interactions between iron and copper may provide a better understanding of the pathophysiology and treatment strategy for hemochromatosis, Wilson disease, and related disorders. The hepcidin/ferroportin system was used to classify genetic iron overload syndromes in Japan, and ceruloplasmin and ATP7B were introduced for subtyping Wilson disease into the severe hepatic and classical forms. Interactions between iron and copper were reviewed in these genetic diseases. Iron overload syndromes were classified into pre-hepatic iron loading anemia and aceruloplasminemia, hepatic hemochromatosis, and post-hepatic ferroportin disease. The ATP7B-classical form with hypoceruloplasminemia has primary hepatopathy and late extra-hepatic complications, while the severe hepatic form is free from ATP7B mutation and hypoceruloplasminemia, and silently progresses to liver failure. A large amount of iron and trace copper co-exist in hepatocellular dense bodies of all iron overload syndromes. Cuproprotein induction to stabilize excess iron should be differentiated from copper retention in Wilson disease. The classical form of Wilson disease associated with suppressed hepacidin25 secretion may be double-loaded with copper and iron, and transformed to an iron disease after long-term copper chelation. Iron disease may not be complicated with the severe hepatic form with normal ferroxidase activity. Hepatocellular dense bodies of iron overload syndromes may be loaded with a large amount of iron and trace copper, while the classical Wilson disease may be double-loaded with copper and iron.

Alanine Aminotransferase as the First Test Parameter for Wilson’s Disease

“…Based on ATP7B analysis and serum levels of CP, the primary copper toxicosis of WD in the studied patients was subtyped into two formsclassical and severe hepatic WD (Table 1). 1 Forty-five patients had typical features of the classical form, with two mutant alleles in ATP7B and low levels of serum CP (<20 mg/dL); two other patients had the severe hepatic form, with no mutation in ATP7B and normal levels of serum CP. Five patients had atypical classical forms, with one mutant allele of ATP7B.…”

“…The classical form is a primary copper-induced liver disease, which may be complicated by lenticular degeneration at a later stage, and which was initially described by SAK Wilson in 1912. [1][2][3] In addition to increased hepatic copper of 250 mg/g dry liver or more, two mutant alleles in the ATP7B gene and reduced serum levels of ceruloplasmin (CP) are found in typical cases. 1,3 Other subtype tests include detection of Kayser Fleischer rings, neuropsychiatric signs, and Coombsnegative hemolytic anemia.…”

“…[1][2][3] In addition to increased hepatic copper of 250 mg/g dry liver or more, two mutant alleles in the ATP7B gene and reduced serum levels of ceruloplasmin (CP) are found in typical cases. 1,3 Other subtype tests include detection of Kayser Fleischer rings, neuropsychiatric signs, and Coombsnegative hemolytic anemia. 1,3 The severe hepatic form is another copper-induced liver disease, the former name of which was idiopathic copper toxicosis, proposed by Scheinberg and Sternlieb in 1994.…”

“…1,3 Other subtype tests include detection of Kayser Fleischer rings, neuropsychiatric signs, and Coombsnegative hemolytic anemia. 1,3 The severe hepatic form is another copper-induced liver disease, the former name of which was idiopathic copper toxicosis, proposed by Scheinberg and Sternlieb in 1994. 1,[4][5][6] There are currently no tests for the severe hepatic form, other than detection of increased hepatic copper and urinary copper secretion, 1,6 and the new subtype tests proposed by Tatsumi et al 1 are combined results of normal CP levels and no mutations in ATP7B.…”

“…Another recommendation that Tatsumi et al 1 propose is a treatment for the copper toxicosis of WD. Every patient with WD should receive a short-term treatment trial involving anti-copper regimens, followed by life-long maintenance treatment.…”