Antiretroviral hepatotoxicity in human immunodeficiency virus-infected patients.

BACKGROUND: Drug hepatotoxicity is a potentially serious adverse reaction of antiretroviral therapy in human immunodeficiency virus-infected patients. The impact of this problem in the routine treatment of patients with human immunodeficiency virus infection is poorly defined. OBJECTIVES: Our aim was to determine what clinical features are associated with hepatotoxicity in human immunodeficiency virus-infected patients receiving antiretroviral therapy. METHODS: Consecutive patients in a primary care-based human immunodeficiency virus clinic were evaluated for hepatotoxicity. Clinic records were used to obtain patient characteristics, as well as independent variables including CD4+ count, coexisting hepatitis C and current alcohol use. RESULTS: Sixty-five patients taking antiretroviral therapy were evaluated. Twenty-four were identified to have antiretroviral hepatotoxicity. An age over 40 years (P=0.019), an absolute CD4+ count of less than 310 cells/mL (P=0.002) and coexisting hepatitis C infection (P=0.035) were significantly associated with hepatotoxicity. Patients older than 40 years had a sevenfold increased risk (risk ratio, 6.9; 95% confidence interval, 1.7-27.3) and those with an absolute CD4+ count of less than 310 cells/mL had a tenfold increased risk (risk ratio, 10.2; 95% confidence interval, 2.5-41.9) for antiretroviral hepatotoxicity, in comparison with those who were younger or who had a greater absolute CD4+ count. Of the eight patients documented to have coexisting hepatitis C infection, six (75%) were in the antiretroviral hepatotoxicity group. CONCLUSIONS: An age older than 40 years and an absolute CD4+ count of less than 310 cells/mL were significantly associated with antiretroviral-induced hepatotoxicity. The majority of our patients with chronic hepatitis C had hepatotoxicity from antiretroviral therapy.

Prevalence of hepatitis B markers and measles, mumps, and rubella antibodies among Jewish refugees from the former Soviet Union.

OBJECTIVE: To assess the prevalence of hepatitis B virus (HBV) infection and immunity to measles, mumps, and rubella among refugees from the former Soviet Union (FSU). DESIGN: Descriptive study. SETTING: Soviet Immigrant Health Care Program, Sinai Samaritan Hospital, Milwaukee, Wis. PATIENTS: Consecutive sample of 496 Jewish refugees from the FSU presenting for new arrival screening from December 1, 1990, through January 11, 1993. OUTCOME MEASURES: Hepatitis B surface antigen (HBsAg), hepatitis B core antibody, hepatitis B surface antibody, and measles, mumps, and rubella antibodies. RESULTS: At least one hepatitis B marker was detected in 22% of the refugees, and HBsAg was detected in 0.4%. The rate of HBV infection (any marker present) increased with increasing age, ranging from 4% among those aged 0 through 19 years to 31% among those aged 50 through 59 years (chi 2 test for trend, 13.5; P < .001). Among those aged 0 through 19 years, 19% lacked antibody to measles, 8% lacked antibody to mumps, and 13% lacked antibody to rubella. Refugees who were less than 30 years of age were more than twice as likely to lack antibodies to measles, mumps, or rubella compared with those who were 30 years of age or older (relative risk, 2.8; 95% confidence interval, 1.8 to 4.2; P < .001). CONCLUSIONS: In our sample of Jewish refugees from the FSU (primarily Ukraine, Russia, and Belorussia), the rate of HBsAg positivity was low, suggesting that routine screening for HBV infection is not needed. Seronegativity to measles, mumps, and rubella was relatively common among those less than 30 years old. Those refugees who were born after 1957 should be given combined measles, mumps, and rubella vaccine unless their written documentation indicates previous receipt of these antigens according to the immunization schedule recommended in the United States.

Liver transplantation following preoperative closure of intrapulmonary shunts.

Intrapulmonary shunts producing basal resting hypoxemia and necessitating the continual use of supplemental oxygen by two cirrhotic men were closed prior to liver transplantation with octreotide acetate, a somatostatin analogue. The closure of these shunts was monitored by serial blood gas determinations and shunt estimations using two different techniques. Partial closure of the shunts with preoperative octreotide acetate administration allowed liver transplantation to proceed with successful engraftment and eventual permanent closure of the shunts. Currently, both patients are alive and well with normal liver function and blood gases and, most important, have no requirement for supplemental oxygen.

Effect of isolated portal hypertension on Kupffer cell function.

The increased incidence of infection in cirrhotics may in part be attributable to dysfunction of the reticuloendothelial system (RES) in removing pathogens from the circulation. The portosystemic shunting (PSS) that results from portal hypertension in cirrhotics may compromise RES function by allowing enteric pathogens to be shunted away from the Kupffer cells. A well-characterized model of portal hypertension induced by partial portal vein ligation (PVL), in which there is no hepatic parenchymal cell damage, was used. Kupffer cell function is unaltered and the effect of PSS alone on overall RES function can be evaluated. In addition to the usual immunologically inert [99mTc]sulfur colloid, an actual pathogen was also evaluated. PVL and sham-ligated rats were given either [99mTc]sulfur colloid or E. coli via the ileocolic vein. The right femurs, lungs, livers and spleens of the animals receiving 99mTc were excised and the radioactivity counted. The lungs, livers, and spleens of the animals receiving E. coli were liquefied and the bacteria were quantified. For both groups the ratios of 99mTc or E. coli in the lung, spleen, and femur to liver were calculated. PVL rats had significantly more 99mTc in the lung, spleen, and femur than the sham rats. There were also significantly more E. coli in the lungs for PVL rats but no significant difference in the spleen counts. These results imply that even in the absence of Kupffer cell dysfunction, PSS alters reticuloendothelial system function by causing a greater distribution of pathogens to the periphery. This altered distribution may contribute to an increased susceptibility to infection in cirrhotics.

Prophylactic versus emergency sclerotherapy of large esophageal varices prior to liver transplantation.

From January 1985 through July 1987, adult patients accepted for liver transplantation with large esophageal varices were enrolled in a study evaluating the use of prophylactic vs emergency sclerotherapy. Six hundred forty-eight subjects received prophylactic sclerotherapy, and 172 received emergent sclerotherapy. Esophageal stricture formation was increased 12.9-fold (P < 0.001), esophageal perforation 6.4-fold (P < 0.005), and postsclerotherapy bleeding esophageal ulcers 3.7-fold (P < 0.001) in those receiving emergency sclerotherapy as opposed to prophylactic sclerotherapy. These differences were even greater if the number of sclerotherapy sessions rather than the number of patients was used as the denominator for the comparisons. In total, 19.6% of emergency sclerotherapy cases were associated with an untoward outcome of sclerotherapy; only 1.9% of cases receiving prophylactic sclerotherapy experienced an untoward outcome (P < 0.001). These data demonstrate that emergency sclerotherapy is associated with a greater prevalence of complications and support earlier studies that show that sclerotherapy prevents variceal bleeding over the short term. The data also suggest that when applied to patients with large varices awaiting orthotopic liver transplantation, it enhances the chance of a patient surviving to be transplanted by preventing a variceal bleed and the spiral of liver failure and death that frequently follows an episode of acute variceal bleeding.

Effect of ethanol on Kupffer cell function.

Kupffer cells are resident macrophages in the liver and are important in both local and systemic immune responses. We evaluated the ability of Kupffer cells in vitro to respond to immune stimulation after both acute exposure to ethanol and after long-term ethanol consumption of ethanol. Triplets of female Wistar rats were fed a liquid diet containing 0, 12, or 36% ethanol isocalorically for 112 days. When killed, the Kupffer cells were isolated by collagenase perfusion and adhered to plastic 24-well plates. They were then stimulated with 10 micrograms/ml lipopolysaccharide for 4.5 hr. Synthesis of procoagulant activity (PCA) and tumor necrosis factor (TNF), expressions of macrophage response to immune stimuli, were measured by a one-step clotting assay and L929 cytotoxicity assay, respectively. Within each of the 10 triplets, PCA and TNF levels were normalized and expressed as a percentage of the zero ethanol isocaloric control rat. The high ethanol group had significantly lower baseline and stimulated PCA and TNF levels than the low ethanol group. For evaluation of the effect of acute exposure to ethanol, Kupffer cells were stimulated with lipopolysaccharide and varying concentrations (0-400 mg/dl) of ethanol. Cells were incubated for 4.5 hr and assayed for PCA and TNF activity. There was dose-dependent inhibition of PCA and TNF, with increasing concentrations of ethanol. These results indicate that whereas exposure to high levels of ethanol depresses Kupffer cell function, lower levels may be immunostimulatory.

Viral hepatitis. Preexposure and postexposure prophylaxis.

Rational strategies for preventing viral hepatitis are being developed as the epidemiology of the disease is becoming better defined. A vaccine is available only for hepatitis B. Other prophylactic strategies are based on avoidance of high-risk behavior and use of immune globulin. Universal vaccination for hepatitis B is now recommended.

Procoagulant activity and tumor necrosis factor in rat hepatic allograft rejection.

We used a model of rat hepatic allograft rejection to evaluate levels of procoagulant activity and tumor necrosis factor during acute cellular rejection. ACI livers were transplanted into Lewis rats, and Lewis-to-Lewis isografts and unoperated animals served as controls. Animals were killed on days 1, 2, 3, 4, 5, 6, 7 and 9. Splenic mononuclear cells were obtained by Ficoll-Hypaque gradients. Collagenase perfusion, metrizamide gradients and centrifugal elutriation were used to isolate Kupffer cells. Procoagulant activity assay of the splenic and Kupffer cells was done using a one-step clotting assay. Tumor necrosis factor was assayed using an L929 cytotoxicity assay. Histological evidence of acute rejection began on the 4th postoperative day, and rats died by the 9th or 10th postoperative day. Splenic procoagulant activity was significantly elevated in rejecting rats on day 4 and remained elevated until death. In contrast, Kupffer-cell procoagulant activity was elevated over controls by day 3 and remained significantly elevated until death. The tumor necrosis factor levels were elevated from day 1 and remained so until death. The data indicate that procoagulant activity is synthesized both by peripheral monocytes and locally by Kupffer cells and that procoagulant activity and tumor necrosis factor levels rise during hepatic allograft rejection. Because procoagulant activity and tumor necrosis factor mediate immune functions that are postulated to be important in acute rejection (immune cell adherence, vascular thrombosis and delayed-type hypersensitivity), these elevations may contribute to the pathogenesis of acute rejection.

Colonic disease in cirrhosis. An endoscopic evaluation in 412 patients.

Colonic disease is relatively uncommon in cirrhosis. To determine the prevalence of colonic lesions in cirrhosis of all types, cirrhotics evaluated for possible liver transplantation underwent combined pan upper endoscopy and colonoscopy. The patients were divided into two main groups, 248 with parenchymal liver disease (nonviral and viral) and 164 with cholestatic liver disease. The prevalence of the various colonic lesions identified was: polyps, 8.4%; nonspecific edema, 19.9%; inflammatory changes, 11.6%; hemorrhoids, 25.2%; and rectal varices, 3.6%. Normal findings were present in 42.4%. Except for an increased prevalence (P less than 0.05) of edema and a reduced prevalence (P less than 0.001) of inflammatory changes in the parenchymal liver disease group, the prevalence for all other lesions was similar in the two groups. Esophageal varices were present in most patients with hemorrhoids and in all with rectal varices. The degree of portal hypertension and/or disease severity was associated with hemorrhoids but not with rectal varices. The higher prevalence of inflammatory changes in the cholestatic group was because one fourth of this group had an inflammatory bowel disease.

Prevalence of endoscopic findings in 510 consecutive individuals with cirrhosis evaluated prospectively.

Upper gastrointestinal hemorrhage is one of the more important complications of cirrhosis and a major cause of death in such patients. The main sites of bleeding are esophageal varices, gastritis, and peptic ulcers. In order to determine the prevalence of either potential bleeding lesions or of other endoscopic findings in hemodynamically stable individuals with various etiologies of cirrhosis, 510 consecutive cirrhotic patients, evaluated for possible orthotopic liver transplantation (OLTx) underwent an upper gastrointestinal endoscopy for combined diagnostic and therapeutic purposes. The patients were divided into two main groups: 319 patients with parenchymal liver disease and 191 patients with cholestatic liver disease. Gastritis was found significantly more often in patients with parenchymal liver disease than in those with cholestatic liver disease (49.8% vs 30.9%; P less than 0.001). In contrast, the prevalence of esophagitis, esophageal and gastric varices, gastric ulcer, duodenal ulcer, and duodenitis was similar in both groups. Normal endoscopic findings were present in 5.0% of the parenchymal group and 11.5% of the cholestatic group (P less than 0.02). Ascites and encephalopathy were found significantly more often in subjects with parenchymal liver disease as compared to those with cholestatic liver disease. Portal hypertension and its degree, as assessed by the presence and size of esophageal varices, was similar in both groups, and in both groups there was a statistically significant qualitative trend of increasing prevalence of esophageal varices with increasing severity of disease as estimated using Pugh-Child's criteria.

Orthotopic liver transplantation for alcoholic liver disease.

Alcohol abuse is the most common cause of end-stage liver disease in the United States, but many transplant centers are unwilling to accept alcoholic patients because of their supposed potential for recidivism, poor compliance with the required immunosuppression regimen and resulting failure of the allograft. There is also concern that alcohol-induced injury in other organs will preclude a good result. From July 1, 1982, to April 30, 1988, 73 patients received orthotopic liver transplants at the University of Pittsburgh for end-stage alcoholic liver disease. Fifty-two (71%) of these were alive at 25 +/- 9 mo (mean +/- S.D.) after transplantation, when a phone survey of these patients, their wives/husbands, and their physicians was performed to evaluate their subsequent use of alcohol, current medical condition and employment. Data obtained were compared with those for nonalcoholic patients selected as transplant controls. The recidivism rate has been 11.5%, with most patients drinking only socially. Fifty-four percent of the survivors are employed, 21% classify themselves as homemakers and only 11 (21%) are unable to work. Twenty-one patients died after transplantation; the most frequent cause of death was sepsis (43%), and intraoperative death was the next most common cause (28.6%). These data demonstrate that alcoholic patients can be transplanted successfully and achieve good health not significantly different from that of individuals transplanted for other causes. Thus orthotopic liver transplantation is a therapeutic option that should be considered for individuals with end-stage alcoholic liver disease who desire such therapy.

Serum-ascites albumin gradients in nonalcoholic liver disease.

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.

Does primary sclerosing cholangitis occurring in association with inflammatory bowel disease differ from that occurring in the absence of inflammatory bowel disease? A study of sixty-six subjects.

Primary sclerosing cholangitis often occurs in association with inflammatory bowel disease, particularly ulcerative colitis but also Crohn's disease of the colon either with or without terminal ileal disease. Little data exist as to the effect of inflammatory bowel disease on the presenting symptoms, radiological features, response to liver transplantation, and potential risk of bile duct carcinoma in individuals with primary sclerosing cholangitis. In an effort to answer these questions, 66 patients with primary sclerosing cholangitis were studied. The definitive diagnosis of primary sclerosing cholangitis in each was accomplished using cholangiography, which in each case demonstrated characteristic beading, ectasia and stricturing of the intrahepatic and extrahepatic bile ducts. Inflammatory bowel disease was present in 47 (71.2%) patients. Thirty nine (59.1%) had ulcerative colitis; their mean age was 42.5 +/- 11.6 yr (mean +/- SD), and the male/female ratio was 2.9:1. In addition, eight patients (12.1%) had Crohn's colitis; their mean age was 40.5 +/- 6.5 yr, and the male/female ratio of this group was 1:1. Nineteen patients (28.8%) had primary sclerosing cholangitis without any inflammatory bowel disease; their mean age was 42.0 +/- 12.1 yr, and the male/female ratio in this group was 0.72:1. Seventy-two percent of the patients without inflammatory bowel disease had either jaundice, pruritus or fatigue at presentation compared with 41% of the patients with inflammatory bowel disease (p less than 0.05). In contrast, abnormal liver function tests were more common as the first manifestation of liver disease in the latter group (38% vs. 11%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

T-lymphocyte subsets in gut and blood of liver transplant recipients with and without cytomegalovirus gastroenteritis.

The effects of orthotopic liver transplantation (OLTx) and cytomegalovirus (CMV) gastroenteritis on the type of mononuclear cells within the upper gastrointestinal tract were determined. Nineteen liver transplant recipients were studied both before and after transplantation. Each underwent a pan-upper gastrointestinal endoscopy with biopsy of the antrum and duodenum before and four weeks following liver transplantation. A panel of monoclonal antibodies prepared against HLA-DR, NK, IL-2R, T11, T4, T8, and B1 cell surface antigens was used to examine the tissues. Before OLTx, none of the 19 subjects studied had clinical or histologic evidence for CMV gastroenteritis. Following OLTx, five of the 19 subjects had CMV gastroenteritis. The number of HLA-DR positive staining lymphocytes present in biopsies obtained post-OLTx was significantly greater (P less than 0.005) than those present in biopsies obtained pre-OLTx regardless of the presence or absence of CMV gastroenteritis. No difference in the intensity of HLA-DR antigen expression between pre- and post-OLTx biopsies and those with and without CMV gastroenteritis was evident. No difference in the number of natural killer (NK) cells and the number of cells expressing the interleukin-2 receptor (IL-2R) was evident between biopsies obtained pre- and post-OLTx. In contrast, the number of T lymphocytes bearing the T11, T4, and T8 markers and the calculated T4/T8 ratio differed between biopsies obtained pre- and post-OLTx and between those positive for CMV gastroenteritis post-OLTx and those without evidence for CMV gastroenteritis either before or after OLTx, although these changes were not consistent throughout the gastrointestinal tract.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver transplantation for alcoholic liver disease: a consideration of reasons for and against.

Orthotopic liver transplantation is a clinical procedure that has been accepted widely as the treatment of choice for individuals with advanced chronic liver disease. As such, its application to the important clinical problem of alcoholic liver disease is inevitable. The arguments for and against liver transplantation for individuals with advanced alcoholic liver disease are presented.