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With the introduction of interferon therapy for liver disease due to chronic viral hepatitis, it has become important to test individuals thought to have hepatitis C virus disease for the presence of the virus. Moreover, the current goal of therapy for hepatitis C virus-positive liver disease is to render the individual patient HCV-RNA negative. Recently, it has been reported that as many as one-third of the patients with hepatitis C virus liver disease test positive for the presence of mixed cryoglobulins. Few of these cryoglobulin-positive patients have overt disease manifestations of cryoglobulinemia, such as nephropathy, peripheral neuropathy and vasculitis. Because the cryoglobulins in patients with hepatitis C virus-positive disease are directed at hepatitis C virus epitopes, the precipitation of cryoglobulins from serum samples also effectively removes virus. When the viral carriage rate is low in terms of the number of genomes/unit serum, as occurs in cases that are partially treated, the serum can test negative for hepatitis C virus even by polymerase chain reaction, despite the presence of persistent viremia, if precautions preventing the precipitation of cryoglobulins prior to the removal of the sample for polymerase chain reaction testing are taken. From a group of 75 patients with hepatitis C virus-positive hepatitis seen at our institution in the last year (all HCV-RNA positive), 35% were found to test positive for the presence of cryoglobulins. Importantly, in all cases, the cryoglobulins collected tested strongly positive for HCV-RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper is an attempt to present some of the unusual indications for OLTx that are occasionally seen at transplant centers. It is not an all-encompassing treatise but rather an attempt to present the more usual of the unusual indications for OLTx. As such, it is a framework to which readers could add any we do not mention as and when they are encountered in their own practice.

Heatstroke is a potentially fatal disorder caused by an extreme elevation of body temperature. It is the most severe of the illnesses produced as a result of a high ambient temperature; however, it also may occur sporadically among individuals working or exercising in more favorable weather conditions, particularly early in their training before acclimatization occurs. The liver is a common site of tissue injury in cases of heatstroke and can be the site of fatal tissue injury in cases that survive the initial neurologic injury. Prompt early recognition of heatstroke as the entity responsible for a given patient's problems and effective early cooling with attention to expected complications can result in complete recovery in most cases. In a minority (< 10%) in whom neurologic injury has not resulted in an early death occurring within the first 2-3 days, the hepatic injury due to heatstroke can result in death that occurs a week or more after the onset of the heat stress, unless the liver is replaced. Recently, two such cases have been referred to the University of Pittsburgh for transplantation. On the basis of these two referrals and a review of the literature, we believe that this problem occurs more often than is currently appreciated, principally because of a lack of knowledge about the problem. In an attempt to correct this information deficit, this review was prepared.

HLA antigen profiles have been used to identify individuals who are likely not to respond to HBV vaccination. The majority of these reports have included either normal individuals or individuals with severe abnormalities of their immune system. The present investigation assessed the rate of HBV vaccination seroconversion in 132 individuals with chronic advanced liver disease who were referred for possible liver transplantation. Each was vaccinated using a serum-derived vaccine administered intramuscularly at three consecutive monthly clinic visits. As part of their transplant evaluation, each subject also underwent HLA typing for class I and class II antigens. Of the 132 subjects vaccinated, only 47% seroconverted and became HBsAb positive. There was no difference between types of liver disease. As expected, individuals older than 55 years of age responded less well than those younger than this cutoff age. No difference between seroconverters and nonresponders was evident for gender or any individual or combination of HLA antigens. In conclusion, individuals with advanced chronic liver disease seroconvert less often in response to HBV vaccination than do normal individuals. Moreover, unlike normals and the experience with other disease groups, no difference in conversion rates was evident for gender. Similarly, no difference in seroconversion rates was evident for the two major pathophysiologic types of chronic liver disease. Age greater than 55 years was associated with a reduced rate of seroconversion.

The effect of FK 506 on regeneration of the liver was studied in rats after a two-thirds partial hepatectomy after 60 min of ischemia of the unresected liver. The animals were divided into three distinct groups of 10 rats each. Group 1 (controls) received 0.5 ml saline solution intravenously 30 min after the induction of ischemia. Groups 2 and 3 were injected with FK 506 (0.3 mg/kg) intravenously 30 min after and 24 min before the induction of hepatic ischemia, respectively. The hepatic content of ATP and serum levels of ALT and lactate dehydrogenase were determined on each animal. In addition, the histological appearance and mitotic activity of the remnant liver was determined at regular 24-hr intervals after hepatic ischemia. All 10 control animals died within 72 hr. Treatment with FK 506 resulted in improved survival in groups 2 and 3 (30% and 80%, respectively). The improved survival seen in the FK 506-treated animals was reflected by a restoration of hepatic ATP content, a reduction in the serum levels of ALT and lactate dehydrogenase, an amelioration of hepatic necrosis and neutrophilic infiltration and an increase in the mitotic activity of the liver. These results suggest that FK 506 ameliorates the hepatic injury associated with ischemia/reperfusion and has a potent stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective agent when administered to organ donors before graft harvesting.

Establishing a diagnosis of fulminant Wilson's disease can be difficult because Kayser-Fleischer rings may not be present and parameters of copper metabolism, including serum and urinary copper, and serum ceruloplasmin levels are neither specific nor diagnostic. In this study, ratios of both the serum alkaline phosphatase to total bilirubin and aspartate transaminase to alanine transaminase were constructed to evaluate their usefulness in differentiating fulminant hepatic failure caused by Wilson's disease (n = 6) from other etiologies (n = 43). An analysis of the data showed that cutoff values of less than 2.0 for the alkaline phosphatase-total bilirubin ratio and greater than 4.0 for the aspartate transaminase ratio were associated with a diagnosis of fulminant hepatic failure caused by Wilson's disease only (P less than 0.001). The alkaline phosphatase-total bilirubin ratio of less than 2.0 provided 100% sensitivity and specificity in identifying fulminant hepatic failure caused by Wilson's disease from other types of fulminant hepatic failure.

The effect of the race of the donor on organ donation and on the outcome of clinical liver transplantation has not been addressed previously. The aims of this study were to determine: (1) the number of organs donated by each of the major racial groups of the United States, (2) the outcome of transplantation of these organs across racial groups, and (3) the pattern of liver disease that required transplantation in each of these racial groups. A significantly higher proportion of organs were donated by white non-Hispanic Americans than either black or Hispanic Americans. There was no significant difference in survival when an organ was transplanted between black and white Americans and vice versa. Postnecrotic cirrhosis from a variety of causes was the most common indicator affecting black and white recipients, while primary biliary cirrhosis and primary sclerosing cholangitis were uncommon in the black population. While the number of organs donated by blacks was low, it was, however, proportional to the number of black recipients in this study. Reasons for the low rate of donation by the black and white Hispanic population are discussed. It is concluded that race is not a criteria to be used in selection of donors for liver transplantation. Educational programs addressing issues of organ donation and transplantation directed towards the black and Hispanic populations are recommended.

The Veterans Administration entered the clinical liver transplant field in 1983 and continued its program through July 1988. During this time interval, from the 172 Veterans Administration Medical Centers in the United States, 146 contact calls were initiated to the single center authorized to do liver transplants for the Veterans Administration. One hundred one (69%) of these contact calls resulted in a patient evaluation. Of the 101 patients evaluated, 77 (76%) were accepted for liver transplantation (OLTx). Of these 77, 67 (87%) were transplanted. The reasons for denial of transplant evaluation were numerous and included metastatic cancer, active alcoholism, homosexuality, and a variety of concurrent medical problems. The reasons for denying liver transplantation after evaluation were similar and included concurrent medical problems that contraindicated transplantation (N = 14), metastatic cancer (N = 6), and liver disease of insufficient severity to justify transplantation (N = 3). The number of transplants performed annually by the Veterans Administration increased from one in 1983 to 21 in 1988. Seventeen second grafts and two third grafts were transplanted in 17 cases, resulting in a retransplant rate of 22%; 46% of the patients receiving a second graft survived. None of those receiving three grafts survived. The reasons for retransplantation included acute and/or chronic rejection (N = 6), hepatic artery thrombosis (N = 5), primary graft failure (N = 4), recurrent cancer (N = 2), fulminant hepatitis and portal venous emboli (one each). A total of 45 transplanted patients are still alive (67% of those transplanted).(ABSTRACT TRUNCATED AT 250 WORDS)

Several studies performed in alcoholics with advanced liver disease have demonstrated a positive correlation between the serum-ascites albumin gradient (SAAG) and measured portal venous pressure. A single study performed in 15 patients with exudative malignant ascites and 29 patients with alcoholic liver disease demonstrated that a SAAG of less than 1.1 was essentially diagnostic of a malignant origin of the ascites. In an effort to confirm and extend these observations to individuals with nonalcoholic liver disease, 24 patients with nonalcoholic liver disease and 11 with alcoholic liver disease undergoing orthotopic liver transplantation (OTLx) were studied. At the time of liver transplantation, each had their serum and ascitic fluid albumin levels determined, the gradient calculated, and their portal venous pressure (PVP) as well as the corrected portal venous pressure (PPc) measured directly. A significant correlation (r = 0.624) between the PPc and the SAAG was found in the 11 alcoholics (P less than 0.05). No such correlation existed for those with nonalcoholic liver disease (r = 0.398). Moreover, a SAAG less than 1.1 was found in three of nonalcoholics with cirrhosis in the absence of an abdominal malignancy. We conclude that (1) the SAAG and PPc are statistically related to each other in individuals with alcoholic liver disease but not in those with a nonalcoholic cause for cirrhosis, and (2) SAAG less than 1.1 is not diagnostic of abdominal malignancy but can occur in those with advanced nonmalignant hepatic disease.

The role of liver transplantation in 29 patients with fulminant and subacute hepatic failure due to a variety of different causes was examined by comparing the outcome and a variety of "hospitalization" variables. Transplanted patients (n = 13) were more likely to survive (p less than 0.05), were younger (p less than 0.05) and spent more time in the hospital (p less than 0.025) than did those who were not transplanted (n = 16). Despite spending a much longer time in the hospital, transplanted patients spent less time in the intensive care unit (p less than 0.05) in coma (p less than 0.01) and on a respirator (p less than 0.01) than did those not transplanted. Most importantly, the survival rate for transplanted patients was significantly improved (p less than 0.05) as compared to those not transplanted. We conclude that liver transplantation can be applied successfully to the difficult clinical problem of fulminant and subacute hepatic failure.

The branch chain to aromatic amino acid ratio is depressed in patients with advanced liver disease. Liver transplantation results in three different ratio response patterns: (1) no improvement, (2) transient improvement followed by decline, and (3) sustained improvement. In nine patients who underwent 12 transplantation procedures the ratio rose and remained above 2.5 during 70.0% +/- 14.8% of the postoperative period in survivors compared with 11.8% +/- 3.1% when transplantation was unsuccessful (p less than 0.001). At discharge survivors' ratios had risen from 1.5 +/- 0.1 to 3.2 +/- 0.2 (p less than 0.001). The ratio before death or retransplantation caused by graft failure was unchanged at 1.2 +/- 0.1. A persistently low branch chain to aromatic amino acid ratio after liver transplantation should prompt an aggressive search for reversible causes of liver dysfunction. If the ratio does not respond to appropriate therapy, efforts should be directed toward retransplantation.

The hypothalamic-pituitary-gonadal axis was evaluated in two groups of age-matched men with documented biochemical and histologic liver disease and compared to that of age-matched normal controls. Basal testosterone levels (p less than 0.05), spermatozoa concentrations (p less than 0.01), and seminal plasma volume (p less than 0.01) were reduced in the alcoholics studied with liver disease, but not the hemophiliacs with liver disease when compared to the normal controls. No difference in estradiol levels was noted between groups. Basal follicle-stimulating hormone and luteinizing hormone (LH) concentrations were increased (both p less than 0.01) in the alcoholics while only LH concentrations were increased (p less than 0.01) in the hemophiliacs compared to the normal controls. Gonadotropins (follicle-stimulating hormone and LH) and testosterone responses to clomiphene and to luteinizing hormone-releasing factor (LH only) in the alcoholic population studied, further distinguished the alcoholics from the hemophiliacs and the normal controls. The basal levels of the other anterior pituitary hormones (growth hormone and thyroid-stimulating hormone) as well as their provocative responses to thyrotropin-releasing hormone also distinguished the alcoholics from the hemophiliac population. Based upon these results, we propose that factors other than the liver disease per se are responsible for the disturbances of hypothalamic-pituitary-gonadal function observed in men with biochemically as well as histologically advanced stable liver disease.

Ultrasonography and computed tomography were used to determine hepatic volume in vivo. The data obtained were compared with the weight and volume of the same livers after surgical removal at the time of orthotopic hepatic transplantation. The relationship between hepatic weight and volume was found to be linear over a 16-fold range of weights and a 19-fold range of volumes. The sonographic results more closely paralleled the results obtained directly. These data demonstrate that both methods can determine, within acceptable limits, hepatic volume or weight. The sonographic technique, however, is more accurate than the computed tomography scan method as it allows the use of sagittal scanning of the liver, which is superior to the transverse scanning technique required by the computed tomography scanner. In addition, these results demonstrate that these methods might be applied in the future for better matching of donors and recipients of orthotopic liver transplants.

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 immunologic 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 less than 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 non-survival. 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.

The prevalence of impotence is increased in males who chronically abuse alcohol. Further, impotence may occur in the absence of liver disease in such men. In contrast, no data is available concerning the prevalence of impotence in nonalcoholic men with advanced liver disease. To investigate the relationship between alcohol and impotence in cirrhotic men, a self-administered questionnaire was completed by male alcoholic cirrhotics admitted to the medical service as well as by nonalcoholic cirrhotic liver transplant candidates admitted to the medical and surgical services of Presbyterian-University Hospital. Each participant was asked whether or not he had experienced impotence and if so, to report the frequency and duration of his impotence. The frequency of impotence was recorded on a weighted scale with four gradations: 4 = always; 3 = usually; 2 = sometimes; 1 = seldom. In addition, measures of hepatic injury and function as well as measures of the functional integrity of the hypothalamic-pituitary-gonadal axis for each subject evaluated were obtained. Fourteen of the 20 alcoholics with cirrhosis and 10 of the 40 nonalcoholic liver transplant candidates with cirrhosis reported a history of impotence. The association between impotence and alcohol abuse was significant. The impotence index developed by multiplying the frequency by the duration of impotency for each individual demonstrated a more severe degree of impotence in the alcoholics as compared to the nonalcoholics (p less than 0.01). The alcoholics also had lower plasma levels of testosterone and greater plasma levels of gonadotropins as compared to the nonalcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)

Basal T4, T3, TSH, prolactin and growth hormone levels were determined in several groups: patients with postnecrotic cirrhosis with hepatocellular carcinoma (n = 14); patients with postnecrotic cirrhosis but without hepatocellular carcinoma (n = 26); cholangiolar carcinoma (n = 9); and normal controls age-matched to within 5 yr of the liver disease subjects studied. In addition, TRH stimulation (400 micrograms TRH) was performed; TSH, prolactin and growth hormone responses over a 180-min time interval were evaluated for each subject. The responses observed varied between liver disease groups. The presence or absence of hepatocellular carcinoma was found to determine, at least in part, the type of response observed. Similarly, the presence or absence of hepatic encephalopathy determined, and/or reflected, at least in part, the type of response observed. Finally, for purposes of continuity, basal and TRH-stimulated levels of TSH, prolactin, growth hormone, T4 and T3 are compared in 3 settings of cirrhosis: alcoholic, nonalcoholic postnecrotic cirrhosis, and postnecrotic cirrhosis with hepatocellular carcinoma.

Basal and TRH-induced responses of T3, T4, TSH, GH, and PRL were determined before and 1 month after orthotopic hepatic transplantation in 41 patients (22 with primary biliary cirrhosis and 19 with primary sclerosing cholangitis). The responses of these patients before and after transplantation were compared to those of age-matched normal subjects. The results demonstrate that 1 month after successful hepatic transplantation, basal and TRH-induced TSH, GH, and PRL levels had decreased toward, but not completely to, normal levels.

Twenty-seven clinical and laboratory data and the subsequent clinical course of 93 consecutive adult patients who underwent orthotopic liver transplantation for various chronic advanced liver diseases were analyzed retrospectively to assess the risk factors of early major bacterial infection and death after the procedure. Forty-one patients (44%) had early major bacterial infection during hospitalization for orthotopic liver transplantation. The mortality rate was 70.7% in patients with early major bacterial infection and was 7.7% in patients without early major bacterial infection (p less than 0.001). Total serum bilirubin, total white blood cell count and polymorphonuclear cell count, IgG (all p less than 0.05) and plasma creatinine level (p less than 0.001) were higher in patients that developed early major bacterial infection than in those who did not. By step-wise discriminant analysis, the strongest risk factor for early major bacterial infection was the serum creatinine level, which achieved an accuracy of 69% for a creatinine level greater than 1.58 mg per dl. Seven variables (ascites, hepatic encephalopathy, elevated white blood and polymorphonuclear cell count, decreased helper to suppressor T cell ratio and elevated plasma creatinine and bilirubin levels) were associated with a significant increased risk for death. A step-wise discriminant analysis of these seven factors resulted in the demonstration of serum creatinine as the greatest risk factor for mortality. A preoperative serum creatinine either less than or greater than 1.72 mg per dl accurately predicts survival or death, respectively, in 79% of cases.(ABSTRACT TRUNCATED AT 250 WORDS)