Wilson's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Wilson's Disease, including details on treatment, causes, symptoms, medication.

A brand new mechanism for copper toxicity.

Brewer GJ

Department of Human Genetics, University of Michigan Medical School, 5024 Kresge Building II, Ann Arbor, MI 48109-0534, USA; Department of Internal Medicine, University of Michigan Medical School, 5024 Kresge Building II, Ann Arbor, MI 48109-0534, USA.

Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Lang PA, Schenck M, Nicolay JP, Becker JU, Kempe DS, Lupescu A, Koka S, Eisele K, Klarl BA, Rübben H, Schmid KW, Mann K, Hildenbrand S, Hefter H, Huber SM, Wieder T, Erhardt A, Häussinger D, Gulbins E, Lang F. Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease. [Abstract reproduced by permission of Nat Med 2007;13:164-170].

Published 3 September 2007 in J Hepatol, 47(4): 621-2.
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