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Previous Volume 344:1580-1587 May 24, 2001 Number 21 Next

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ABSTRACT

Background About 10 percent of patients who undergo liver transplantation have cryptogenic liver disease. In animal models, the absence of heteropolymeric keratins 8 and 18 or the presence of mutant keratins in hepatocytes causes or promotes liver disease. We have previously described a mutation in the keratin 18 gene in a patient with cryptogenic cirrhosis, but the importance of mutations in the keratin 8 and keratin 18 genes in such patients is unclear.

Methods We tested for mutations in the keratin 8 and keratin 18 genes in purified genomic DNA isolated from 150 explanted livers and 89 peripheral-blood specimens from three groups of patients: 55 patients with cryptogenic liver disease; 98 patients with noncryptogenic liver disease, with causes that included alcohol use, autoimmunity, drug use, and viral infections; and 86 randomly selected inpatients and outpatients who provided blood to the hematology laboratory.

Results Of the 55 patients with cryptogenic liver disease, 3 had glycine-to-cysteine mutations at position 61 (a highly conserved glycine) of keratin 8, and 2 had tyrosine-to-histidine mutations at position 53 of keratin 8. These mutations were not detected in the patients with other liver diseases or in the randomly selected patients. In transfected cells, the glycine-to-cysteine mutation limited keratin-filament reorganization when the cells were exposed to oxidative stress. In contrast, the tyrosine-to-histidine mutation destabilized keratin filaments when transfected cells were exposed to heat or okadaic acid stress.

Conclusions Mutations in the keratin 8 gene may predispose people to liver disease and may account for cryptogenic liver disease in some patients.

Source Information

From the Gastroenterology Section, Palo Alto Veterans Affairs Medical Center and Stanford University School of Medicine, Palo Alto, Calif. (N.-O.K., M.B.O.); the Department of Transplantation, California Pacific Medical Center, San Francisco (R.G.); and the Gastroenterology Section, San Francisco Veterans Affairs Medical Center, San Francisco (T.L.W.).

Address reprint requests to Dr. Ku at the Palo Alto Veterans Affairs Medical Center, Mail Code 154J, 3801 Miranda Ave., Palo Alto, CA 94304.

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