Hepatic copper stores

Anke et al. 1975). Due to the antagonistic effect of sulfur, the lambs developed a secondary copper deficiency that in turn led to an induced encephalomalacia folloiving depletion of hepatic copper stores. 

Several recent reports document a symptomatic copper deficiency in premature infants and have included one subject receiving total parenteral alimentation. Premature infants have relatively small hepatic copper stores and probably require more than the term infant (Cordano aJ., 1964). Copper deficiency is generally seen in association with iron deficiency, but the anemia and weakness do not respond to iron therapy alone. 

Which agent b most effective for longterm oral therapy to reduce hepatic copper stores in... 

Reports of human copper deficiency are limited and suggest that severe nutrient deficiency coupled with malabsorption is required for this disease state to occur. Infants fed an exclusive cows milk diet are at risk for copper deficiency. Cows milk not only has substantially less copper than human milk but the bioavailability is also reduced. High oral intake of iron or zinc decrease copper absorption and may predispose an individual to copper deficiency. Other infants at risk include those with (1) prematurity secondary to a lack of hepatic copper stores (2) prolonged diarrhea and (3) intestinal malabsorption syndromes. Even the premature liver is capable of impressive copper storage. By 26 weeks gestational age the liver already has 3 mg of copper stored. By 40 weeks gestational age, the hepatic liver has 10-12 mg copper stored with the majority being deposited in the third trimester. Iron and zinc... 

The hepatic uptake of diet-derived copper occurs via the copper transporter 1 (Ctrl), which transports copper with high affinity in a metal-specific, saturable fashion at the hepatocyte plasma membrane (Lee et al., 2001 Klomp et al., 2002). After uptake copper is bound to metallothionein (MT), a cytosolic, low molecular weight, cystein-rich, metal binding protein. MT I and MT II are ubiquitously expressed in all cell types including hepatocytes, and have a critical role to protect intracellular proteins from copper toxicity (Palmiter, 1998 Kelley and Palmiter, 1996). The copper stored in metallothionein can be donated to other proteins. Specific pathways allow the intracellular trafficking and compartmentaUzation of copper, ensuring adequate cuproprotein synthesis while avoiding cellular toxicity (Fig.21.1). 

High levels of zinc stimulate the synthesis of metallothionein in the small intestines. The elevated levels of metallothionein then serve as a depot for the binding of high levels of zinc consumed in subsequent meals. The induced protein has been shown to limit the amount of zinc entering the bloodstream with consumption of a high-zinc diet (Menard ef o/., 1981). High doses of copper can induce metallothionein synthesis to the same extent as can zinc. At levels near those found in the diet, zinc is a potent inducer while copper is only a weak inducer. Normally, hepatic metaiiothionein contains mainly zinc, whereas kidney metallothionein contains copper and, when present in the diet, cadmium. The copper entering the liver may be stored in hepatic metallothionein and released into the plasma in ceruloplasmin or secreted in the bile later. 

We now turn to the question of how copper may be directly involved in iron metabolism, relying on the comprehensive paper of Lee et al, 40) which reports an in vivo study on iron metabolism in copper-deficient swine. They found evidence for abnormalities of iron metabolism at four major sites the duodenal mucosa, the reticuloendothelial system (R-E), the hepatic parenchymal cells, and the normoblasts. For the first three tissues, each of which can concentrate, store, and release iron, copper deficiency leads to an impairment in the release of iron. 

On the other hand, the disease may rapidly deteriorate and resanble fulminant hepatic failure with massive jaundice, hypoalbuminemia, ascites, severe coagulation defects, hyperammonania and hepatic encephalopathy. Hepatocellular neCTOsis results in the release of large amounts of stored copper. Hypercupriania results in hemolysis and severe hemolytic anemia compUcates acute hver disease. Although Wilson disease is a rare disease, in patients presenting with fiilminant hepatic failure it is not uncommon and accounts for 6-12% of patients with fulminant hepatic failure referred for anergency hver transplantation. 

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