J. S. Gavaler

Hypothalamic-Pituitary-Gonadal Dysfunction in Men Using Cimetidine

We studied the effect of cimetidine therapy (1200 mg per day by mouth for nine weeks) on the hypothalamic-pituitary-gonadal axis of seven men. There was a 43 per cent mean reduction in sperm count after therapy. The luteinizing hormone response to luteinizing hormone releasing factor was also reduced, and a statistically significnat rise in plasma testosterone occurred, although it was less than that before therapy. Gonadotropin responses to provocative clomiphene stimulation were inadequate when compared with those of controls. Cimetidine did not affect the responses of thyroid-stimulating hormone, prolactin, growth hormone and thyroxine to thyrotropin releasing factor. Caution is advisable in administration of cimetidine for prolonged periods to young men.

An evaluation of the respective roles of portosystemic shunting and portal hypertension in rats upon the production of gonadal dysfunction in cirrhosis.

To evaluate the differential effects of portal hypertension and portosystemic shunting upon the endocrine changes that occur in men with advanced chronic liver disease, male rats underwent either partial portal vein ligation or direct portocaval anastomosis. Testicular mass was found to be reduced in both models (p less than 0.05). Similarly, estradiol levels were found to be increased (p less than 0.05) in both models when compared with sham-operated controls. The increase in estradiol levels was greater in the animals with a complete shunt than in those animals with incomplete shunts developed as a consequence of portal hypertension (p less than 0.05). Luteinizing hormone levels were reduced (p less than 0.01) in the animals with the greater estradiol levels. As expected, testosterone levels were reduced (p less than 0.01) only in the animals with reduced luteinizing hormone levels. These data suggest that portosystemic shunting, and not portal hypertension per se, is responsible, at least in part, for the gonadal injury that occurs with advanced liver disease.

PANCREATITIS FOLLOWING LIVER TRANSPLANTATION

Since 1981, when the liver transplantation program was initiated at the University of Pittsburgh, we have been impressed with the prevalence of pancreatitis occurring following liver transplantation in patients transplanted for hepatitis B-related liver disease. To either confirm this clinical impression or refute it, the records of the 27 HbsAg+ patients and those of an additional 24 HbsAg- but HbcAb and/or HbsAb+ patients who underwent orthotopic liver transplantation were reviewed to determine the prevalence of clinical pancreatitis and hyperamylasemia (biochemical pancreatitis) following liver transplantation (OLTx). Post-OLTx hyperamylasemia occurred significantly more frequently in HbsAg+ patients (6/27) than it did in the HbsAg- patients (0/24) (P<0.05). More importantly, clinical pancreatitis occurred in 14% (4/27) of the HbsAg+ patients and 0% (0/24) of the HbsAg- patients. Interestingly, in each case, the pancreatitis was associated with the occurrence of acute hepatitis B infection of the allograft. Based upon these data, we conclude that pancreatitis occurring after liver transplantation is more common in patients transplanted for active viral liver disease caused by hepatitis B than in those with inactive viral liver disease. These observations suggest that pancreatitis occurring in, at least some cases following liver transplantation for viral liver disease, may result from hepatitis B virus infection of the pancreas.

THE PHYTOESTROGEN CONGENERS OF ALCOHOLIC BEVERAGES : CURRENT STATUS

Abstract The idea that alcoholic beverages might contain biologically active phytoestrogenic congeners stemmed from findings of overt feminization observed in alcoholic men with alcohol-induced cirrhosis. Specifically, in addition to being hypogonadal, these chronically alcohol-abusing men with cirrhosis frequently manifest gynecomastia, palmar erythema, spider angiomata, and a female escutcheon. These physical signs of exposure to active estrogen occur in the presence of normal or only minimally elevated levels of endogenous steroid estrogens. Because levels of circulating steroid hormones failed to provide a satisfactory explanation for the feminization observed, alternate explanations were considered. If the estrogenization observed was not entirely a function of tissue expose to steroid estrogens produced endogenously, then perhaps tissues were being exposed to exogenous estrogenic substances from dietary sources. Given the degree of alcohol abuse in the population in which hypotheses for feminization were being formed, alcoholic beverages became a prime candidate as a dietary source of exogenous estrogenic substances.

Cytomegalovirus infection and gastric emptying.

Gastrointestinal infection due to cytomegalovirus occurs frequently in liver transplant recipients. Upper gastrointestinal cytomegalovirus infection is associated with subjective complaints of nausea, a sense of abdominal fullness, and occasionally emesis and/or dysphagia. In order to determine whether these symptoms reflect a disruption of the normal motility of the stomach, the following study was performed. Eleven individuals who were evaluated for liver transplantation were prospectively recruited and studied as follows: (1) upper gastrointestinal endoscopy with biopsy of the gastric antral mucosa; (2) viral culture of the gastric mucosa; (3) a histologic examination of the gastric mucosa; and (4) a radionuclide gastric emptying study was obtained before and 4-8 weeks following successful liver transplantation. Prior to liver transplantation, none had symptoms of nausea, vomiting, or epigastric fullness. All were culture-negative for cytomegalovirus. All had endoscopic and histologic evidence of portal hypertensive gastropathy but none had antral erosions or ulcers. All demonstrated normal gastric emptying of a liquid meal. Following liver transplantation, 6 remained free of gastric cytomegalovirus while 5 developed a culture-confirmed gastric cytomegalovirus infection. Those that developed a gastric cytomegalovirus infection also had more gastric symptoms, and more gastric histologic abnormalities. Moreover, those with a gastric cytomegalovirus infection demonstrated enhanced gastric retention of a liquid meal (P less than 0.01).

Relationship between the diagnosis, preoperative evaluation, and prognosis after orthotopic liver transplantation

The purpose of this study was to identify which of the biochemical, immunological, or functional parameters derived before surgery as part of a systemic evaluation were helpful in predicting the frequency of rejection episodes, the chance of survival, and the cause risk of death (should death occur) of patients after orthotopic liver transplantation (OLTx). Ninety-eight adult patients who had an extensive preoperative protocol evaluation were studied before OLTx. The biochemical parameters assessed were albumin, prothrombin time, bilirubin, and ICG clearance. The immunologie parameters assessed included total lymphocytes, T3 cells, T4 cells, T8 cells, and the T4/T8 ratio. The degree of histocompatibility antigen (HLA) matching between the donor and- the recipient was also evaluated in 80 of the 98 patients studied.Most postoperative deaths occurred within 12 weeks of the procedure (24%; 24 of 98 patients); 13 patients (13%) died within the first 6 postoperative weeks, of either bacterial or fungal sepsis. An additional 14 patients (14%) died after the initial 6 postoperative weeks due, primarily of an acquired viral and/or protozoan infection (p < 0.01).During the first 6 weeks, survival was better for patients with cholestatic liver disease (ChLD, 93%, n = 45) and miscellaneous liver diseases (MISC, 100%, n = 10) than it was for those with parenchymal liver diseases (PLD, 77%, n = 43).Although albumin, prothrombin time, T4/T8 ratios, and per cent T8 cells were statistically different in patients with PLD as compared with those with ChLD, these parameters, as well as the per cent T4 cells, serum bilirubin level, per cent retention of ICG at 15 minutes, and the plasma ICG disappearance rate were not found to be of substantial help in predicting patient survival or nonsurvival.Moreover, neither the degree of HLA matching nor the number of rejection episodes differed between surviving and nonsurviving patients.The results of this study suggest that patients with PLD are at increased risk of early postoperative death after OLTx because of bacterial and/or fungal sepsis, as compared with patients operated upon for ChLD. Better pre-, intra-, and postoperative predictors of risk of death and complications are needed to reduce the early mortality observed after orthotopic liver transplantation.

Consequences of complete bile-duct ligation on the pubertal process in the male rat

Prepubertal male rats underwent bile-duct ligation or a sham operation. Sham-operated animals were divided into two groups: isocalorically-fed (matched to the bile-duct-ligated animals) and ad-libitum-fed animals. At 60 days of age (after puberty in a male rat) all animals were killed. Bile-duct-ligated animals had larger livers, greater bilirubin, greater bile acid, greater aspartate transaminase, and greater alkaline phosphatase levels and lower testosterone and luteinizing hormone levels in their serum than did the controls. Moreover, the testes and seminal vesicles were smaller in the bile-duct-ligated animals than in the controls. These data suggest that chronic cholestasis contributes, at least in part, to the pubertal and maturational failure that occurs with the chronic cholestatic diseases of childhood.

Hepatic regeneration: Effects of age, sex hormone status, prolactin, and cyclosporine

Clinical experience with orthotopic liver transplantation and the surgical approach to hepatic cancer have stimulated a renewed interest in the factors that initiate and regulate hepatocyte regeneration (1-6). In addition, this same experience has raised questions about the factors that determine the functional mass of the normal liver (1-6). Liver resertions and transplantation are both associated with a transient period of hepatic ischemia, injury, and reperfusion. In addition, allograft livers also are subjected to an immunological attack by the recipients immune system and potentially to cyclosporine-induced hepatotoxicity (3, 4). Each of these events must be followed by a hepatocellular regenerative response, if normal liver volume and function are to be maintained. It has been demonstrated rather well that the liver of humans increases in size progressively as the individual grows until approximately 31 years of age (7). Moreover, it can be concluded from these data that during an individuals mid-adult life that ones liver volume is rather stable and fixed at 25 -+ 1.2 ml/kg. As one matures into older adult life, however, the liver volume tends to decline with increasing age (8). Associated with these changes in liver volume with increasing age, it has been demonstrated that the rate of hepatocyte regeneration is