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Hepatic Glutamine Synthetase Deficiency in Fatal Hyperammonemia after Lung Transplantation

Mendel Tuchman, MD; Gary R. Lichtenstein, MD; B.S. Rajagopal, PhD; Mark T. McCann, BA; Emma E. Furth, MD; Joseph Bavaria, MD; Paige B. Kaplan, MD; James B. Gibson, MD, PhD; and Gerard T. Berry, MD
[+] Article, Author, and Disclosure Information

From the University of Minnesota, Minneapolis, Minnesota; and the Hospital of the University of Pennsylvania, The Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Grant Support: In part by public health service grants 1PO1HD32652 from the National Institute of Child Health and Human Development and R01-DK47870 from the National Institute of Diabetes and Digestive and Kidney Diseases. Requests for Reprints: Mendel Tuchman, MD, Box 400, Mayo Building, University of Minnesota Hospitals, Minneapolis, MN 55455. Current Author Addresses: Drs. Tuchman and Rajagopal and Mr. McCann: Department of Pediatrics, University of Minnesota Hospitals, 516 Delaware Street South East, Minneapolis, MN 55455.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;127(6):446-449. doi:10.7326/0003-4819-127-6-199709150-00005
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Background: The cause of severe acquired hyperammonemia, an uncommon but often fatal complication of organ transplantation and chemotherapy for cancer, is obscure.

Objective: To test the hypothesis that liver glutamine synthetase deficiency may explain hyperammonemia in patients who have had organ transplantation or are receiving chemotherapy.

Design: Case report.

Patients: Two patients who had fatal hyperammonemia after orthotopic lung transplantation.

Measurements: Liver tissue was analyzed to determine the activities of two urea cycle enzymes and glutamine synthetase. Western blot assays for hepatic glutamine synthetase were performed to determine whether glutamine synthetase deficiency resulted from reduced enzyme levels.

Results: Activities of carbamoyl phosphate synthetase I and ornithine carbamoyltransferase in the liver were normal. The activity of hepatic glutamine synthetase was markedly reduced (in patient 1, 12% of the mean value in controls; in patient 2, 28% of the mean value in controls), and a concomitant reduction in the amount of glutamine synthetase protein was observed.

Conclusion: Hyperammonemia after transplantation was associated with hepatic glutamine synthetase deficiency in two patients, but the causal relation between these two conditions must be further studied.


Grahic Jump Location
Figure 1.
Nonhomogeneous distribution of enzymes in the hepatocytes of an acinar sinusoid as they are linearly distributed from the protal triad to the region of the central vein or terminal hepatic venule.231

The specific enzymatic reactions shown are for an individual periportal and perivenous hepatocyte. The glutamine synthetase (GS) and ornithine aminotransferase (OAT) enzyme activities are expressed exclusively in the first three cell layers that surround the central vein (that is, the region of zone 3 of the liver lobule), whereas the urea cycle enzymes are concentrated within the periportal hepatocytes. However, the urea cycle enzyme activities are higher in zone 1 (immediately surrounding the portal triad) than in zone 2. Squares represent hepatocytes, circles represent hepatic mitochondria, and the interrupted line on either side of the linear array of hepatocytes represents the lining of the space of Disse. α-KG = α-ketoglutarate; Arg = arginine; ASA = argininosuccinate; Asp = aspartate; ATP = adenosine triphosphate; Cit = citrulline; CO = carbon dioxide or bicarbonate; CP = carbamoyl phosphate; CPS I = carbamoyl phosphate synthetase I; Gln = glutamine; Glu = glutamate; NH = ammonia; Orn = ornithine; P5C = delta -pyrroline 5-carboxylate; P5CDH = 1-pyrroline-5-carboxylate dehydrogenase.

Grahic Jump Location




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