Mark E. Mailliard

Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantation

Background. Lipoatrophic diabetes is an insulin resistance syndrome characterized by the complete or partial lack of adipose tissue and disturbances in lipid and glucose metabolism. Nonalcoholic steatohepatitis (NASH) is a well-described change in liver pathology consisting of steatosis, hepatitis, and fibrosis that can be associated with lipoatrophic diabetes. Results. This article describes the first reported case of lipoatrophic diabetes with NASH leading to liver failure and liver transplantation. Before transplantation, the patient required 600–700 U of insulin/day. After transplantation, a dramatic decline in her insulin requirements was observed, despite corticosteroids. Eighteen months after transplantation, her glycemic control worsened, and she developed recurrent NASH on serial liver biopsies. Conclusions. NASH associated with lipoatrophic diabetes can recur after liver transplantation, and in this case, was accompanied by increased insulin requirements. These results suggest that the development of NASH itself may contribute to the insulin resistance observed in lipoatrophic diabetes.

Characteristics and Regulation of Hepatic Glutamine Transport

Glutamine is an important amino acid because of its key role in the transfer of both carbon and nitrogen between tissues in the body. Specific tissues are usually associated with either net synthesis or net utilization of glutamine, but the liver plays a central role in glutamine homeostasis, in that it can shift to function in either capacity. This capability, along with the localization of urea biosynthesis in the periportal hepatocytes, focuses attention on the transport mechanisms in hepatocytes for uptake and release of glutamine. Active transport of glutamine by hepatocytes is mediated by a Na(+)-dependent activity termed system N, which exhibits a rather narrow substrate specificity mediating uptake of histidine and asparagine as well as of glutamine. This secondary active transport system allows for the net accumulation of glutamine against a concentration gradient and maintenance of intracellular concentrations of glutamine between 4 and 8 mM in the face of a plasma concentration of 0.6 mM. Utilization of the Na+ electrochemical gradient as a driving force ensures that the system N carrier catalyzes a unidirectional transport event favoring the cytoplasm. It is obvious from the glutamine gradient across the plasma membrane that efflux of this amino acid is typically slower than accumulation; measurement of saturable, Na(+)-independent glutamine transport by system L substantiates this proposal. However, it is clear that under certain metabolic conditions the liver represents a source of glutamine for other tissues in the body and net efflux must occur. The system N transport activity in hepatocytes is regulated by hormones such as insulin, glucagon, and glucocorticoids, as demonstrated both in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of the polymerase chain reaction for cytomegalovirus to the development of hepatitis in liver transplant recipients

In a pilot study, the polymerase chain reaction was found to be more sensitive than standard viral culture methods for the detection of cytomegalovirus, particularly from blood and tissues. We therefore applied this technique to 71 serially collected liver biopsies from 16 orthotopic liver transplant patients. All patients were CMV-seropositive (n=15) or seroconverted (n=1). Seven patients (9 biopsies) had histologically proved CMV hepatitis, and all these biopsies were CMV PCR—positive. Six of these 7 patients had a prior liver biopsy that was CMV PCR-positive, but culture and histology-negative, an average of 13.2±6.9 days before the histologically positive biopsy. The 7th patient was not biopsied prior to the diagnostic biopsy. Three patients had 7 liver biopsies that were CMV PCR-positive, but histologically negative for CMV hepatitis. Two of these three had CMV infection confirmed by viral culture of blood or liver biopsy. The remaining 6 patients had a total of 26 liver biopsies that were negative for CMV by PCR, culture, and histology. Among liver transplant patients, CMV PCR performed on liver biopsy specimens correctly identified all histologically proven cases of CMV hepatitis. CMV PCR positivity in liver tissue did not correlate with latent infection and preceded the development of CMV hepatitis or other meaningful CMV infection in 8 of 10 patients.

Impairment of glucagon-induced hepatic system a activity by short-term ethanol administration in the rat

BACKGROUND/AIMS System A is a membrane-bound, hormonally regulated carrier of amino acids that is induced by liver regeneration and impaired by ethanol. The mechanism of ethanol inhibition of system A is unknown; this study examines the effects of ethanol on the subcellular expression of system A activity following hormonal induction. METHODS Following hormonal treatment and short-term ethanol administration to rats, isolated liver Golgi and plasma membrane vesicles were examined for system A transport, and the kinetic parameters were determined. RESULTS Four hours after ethanol administration, the initial rate of system A activity was depressed 30% +/- 9% and 19% +/- 7% into Golgi and plasma membrane vesicles, respectively. The affinity constant of 2-(methylamino)-isobutyric acid uptake was unchanged between control and ethanol-treated vesicles, regardless of their subcellular origin. However, the maximal velocity of system A transport decreased from 1030 to 850 pmol.mg-1 protein.10 s-1 in Golgi vesicles and from 740 to 355 pmol.mg-1 protein.10 s-1 in plasma membrane vesicles. CONCLUSIONS Ethanol impairs hormonally induced system A activity in Golgi as well as in the plasma membrane vesicles. Ethanol potentially reduces glucagon induction of system A activity through an impairment of carrier biosynthesis or expression.

The effects of peptide histidine isoleucine on antral gastrin and somatostatin

The present studies were directed to determine whether peptide histidine isoleucine (PHI) affects expression of the gastrin and somatostatin genes and whether such effects may be functionally linked. In separate experiments, the effects of PHI on medium gastrin and somatostatin concentrations, the incorporation of 35S-labelled amino acids into newly synthesized gastrin and somatostatin, and steady state gastrin and somatostatin mRNA were determined. PHI inhibited basal expression of the gastrin gene at all levels examined, while no significant effect on basal somatostatin gene expression could be detected. PHI also decreased carbachol-stimulated antral gastrin release and simultaneously increased somatostatin release. However, in contrast to its structural analogues, secretin and gastric inhibitory peptide, the immunoneutralization of endogenous somatostatin by the administration of specific antibodies did not affect significantly the capacity of PHI to inhibit gastrin release into the culture medium stimulated by carbachol. The results of these studies indicate that PHI exerts a physiological inhibitory effect on antral gastrin cells and that this inhibition may occur at several steps along the biosynthetic pathway. In addition, unlike its structural analogues, PHI inhibition of carbachol-stimulated gastrin release is not functionally linked to its stimulatory effects on somatostatin release.