The ontogeny of liver copper metabolism in the guinea pig: Clues to the etiology of Wilson's disease

Abstract

The normal human neonate has a copper profile indistinguishable from Wilson's disease, and we have previously postulated that this disease is caused by genetic failure to switch from the fetal to adult mode of copper metabolism. This study validates the developing guinea pig as a suitable animal in which to study copper ontogeny. At birth, liver copper concentrations are 7 times higher than in adults and serum copper and ceruloplasmin are 27 and 21% of adult values, respectively. A 53% fall in liver copper occurs in the 4 days after birth. This is associated with a marked increase in bile copper output, which does not parallel increasing bile flow. Liver copper falls, and serum copper and ceruloplasmin increase to near adult levels in the 30 days after birth. Until the sixtieth day of gestation, liver copper was significantly increased in copper-stressed littermates, although paradoxically at birth, concentrations were significantly lower. In copper-stressed fetal animals, bile copper output increased markedly before birth. Metallothionein was the dominant copper-binding protein in the fetal liver but a minor component in the adult. Superoxide dismutase activity only developed after birth. We conclude that the postnatal switch from the fetal to adult mode of copper metabolism involves activation of biliary excretion and ceruloplasmin export as well as changes in the association of copper with hepatic copper proteins. Similarities between the fetus and Wilson's disease suggest that this disease is caused by failure of this postnatal adaptation process.

Heavy metal content in liver and kidneys of grey seals (Halichoerus grypus) in various life stages correlated with metallothionein levels: Some metal—binding characteristics of this protein

“…Our finding (Fig. 2) that MT levels are significantly higher in fetuses than in adults and particularly higher than in juveniles corresponds to data for terrestrial species [15,16]. In sheep, MT declines significantly during the last trimester [17], with an increase in metal excretion [18] as a consequence.…”

Specific Oxidase Activity of Cord Serum Ceruloplasmin in the Newborn

“…This biochemical profile is comparable to that of patients with Wilson's disease, whose pathogenesis may be due to a perpetuation of fetal copper metabolism (1)(2)(3). This biochemical profile is comparable to that of patients with Wilson's disease, whose pathogenesis may be due to a perpetuation of fetal copper metabolism (1)(2)(3).…”

Heavy Metal Content in Liver and Kidneys of Grey Seals (Halichoerus Grypus) in Various Life Stages Correlated With Metallothionein Levels: Some Metal-Binding Characteristics of This Protein

“…Our finding (Fig. 2) that MT levels are significantly higher in fetuses than in adults and particularly higher than in juveniles corresponds to data for terrestrial species [15,16]. In sheep, MT declines significantly during the last trimester [17], with an increase in metal excretion [18] as a consequence.…”