Metal-induced hepatotoxicity

RS Britton - Seminars in liver disease, 1996 - thieme-connect.com
RS Britton
Seminars in liver disease, 1996thieme-connect.com
The liver is an important site of iron and copper deposition in overload conditions, and
elevated hepatic concentrations of these metals can result in hepatocellular injury. 14 The
two main causes of iron overload in humans are increased iron absorption (as occurs in
hereditary hemochromatosis) and parenteral administration (eg, transfusions as a source of
iron in patients with refractory anemias). The liver is a major recipient of excess iron, and
massive deposition of iron within hepatocytes can lead to the development of fibrosis and …
The liver is an important site of iron and copper deposition in overload conditions, and elevated hepatic concentrations of these metals can result in hepatocellular injury. 14 The two main causes of iron overload in humans are increased iron absorption (as occurs in hereditary hemochromatosis) and parenteral administration (eg, transfusions as a source of iron in patients with refractory anemias). The liver is a major recipient of excess iron, and massive deposition of iron within hepatocytes can lead to the development of fibrosis and cirrho~ is.'.~ Excess iron can be stored as ferritin in the cytoplasm and in lysosomes, or as lysosomal hemosiderin. The hepatic concentration of iron is an important factor in determining toxicity, since removal of excess iron by phlebotomy or chelation results in clinical improvement.
Hepatic copper overload leads to progressive liver injury and eventual cirrhosis in Wilson disease and Indian childhood cirrho~ is.~,~ Copper is absorbed in the intestine and transported by albumin to the liver. After hepatic uptake, copper can be incorporated into coppercontaining enzymes or into ceruloplasmin, which is then exported into the blood. Copper in the cytoplasm is predominantly bound to metallothionein, and any excess copper is excreted into the bile mainly through a lysosome-to-bile pathway. Hepatic copper accumulation results from a reduction in the biliary excretion of copper, as occurs in patients with Wilson disease, biliary obstruction, or chole~ tasis.~.~ This review will describe the mechanisms of hepatotoxicity induced by iron or copper overload, focusing on two major hypotheses: the oxidative injury hypothesis and the lysosomal injury hypothesis. These hypotheses concerning metal-induced hepatic damage are not mutually exclusive, since there is evidence of oxidative damage to lysosomal lipids that may contribute to lysosoma1 injury in both iron and copper overload. Evidence of damage to other hepatic organelles and to DNA after
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