Pegylated interferon for recurrent hepatitis C in liver transplant recipients with renal failure: a prospective cohort study.

BACKGROUND: Hepatitis C (HCV) universally recurs following orthotopic liver transplantation (OLT), representing an important cause for retransplantation. Although it is often treated with interferon and ribavirin, ribavirin is contraindicated in the presence of renal failure. In this setting of renal failure, pegylated-interferon monotherapy may be useful for recurrent HCV in liver transplant patients. METHODS: Between June 2001 and November 2002, patients with recurrent HCV were screened to determine if they were eligible for treatment. Renal failure was defined as serum creatinine greater than 1.8 mg/dL. HCVRNA and liver biopsies were performed prior to treatment, end of treatment (EOT) and 6 months after EOT for those who were HCV-RNA negative at EOT. Patients were followed prospectively after starting weekly pegylated-interferon alpha 2b 1.0 microg/kg (Schering-Plough, Kenilworth, NJ, USA). RESULTS: Among the 45 patients with recurrent HCV screened, 9 were eligible, including 8 men and 1 woman of average age 55 years. Eight patients were intolerant to the treatment requiring discontinuation within the first 3 months. Two patients developed a sustained response to HCV eradication. One patient who completed treatment has normal liver tests but is still viremic. CONCLUSIONS: Pegylated-interferon alpha 2b is poorly tolerated in liver transplant recipients with recurrent HCV and chronic renal failure. Larger, prospective studies are required to determine the optimum duration of treatment and the impact of treatment on histology and quality of life.

Isolated intestinal transplantation for intestinal failure.

OBJECTIVE: Parenteral nutrition sustains life in patients with intestinal failure. However, some experience life-threatening complications from parenteral nutrition, and in these individuals intestinal transplantation may be lifesaving. METHODS: This is a retrospective review of 28 consecutive isolated small bowel transplants performed in eight adults and 20 children between December 1993 and June 1998 at the University of Nebraska Medical Center. RESULTS: The 1-yr patient and graft survivals were 93% and 71%, respectively. The causes of graft loss were hyperacute rejection (n = 1), acute rejection (n = 5), vascular thrombosis (n = 1), and patient death (n = 1). The median length of time required until full enteral nutrition was 27 days. All 28 patients have experienced acute rejection of their small bowel grafts and rejection led to graft failure in five. Jaundice and/or hepatic fibrosis was present preoperatively in 17 of the 28 recipients and hyperbilirubinemia was completely reversed in all patients with functional grafts within 4 months of transplantation. Three patients developed post-transplant lymphoproliferative disease (11%). Three recipients developed cytomegalovirus enteritis and all were successfully treated. CONCLUSIONS: Patient survival after intestinal transplantation is comparable to parenteral nutrition for patients with intestinal failure. Better immunosuppressive regimens are needed to decrease the risk of graft loss from acute rejection. The incidence of posttransplant lymphoproliferative disorder is higher after intestinal transplantation than after other solid organ transplants and the risk of cytomegalovirus enteritis is low with the use of cytomegalovirus seronegative donors. Liver dysfunction in the absence of established cirrhosis can be reversed.

Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) for most patients is a terminal complication of chronic inflammatory and fibrotic liver disease. With regrettably few exceptions, treatment is largely palliative, and long-term survival is rare. However, the major causes of HCC worldwide are known and preventable. Hepatitis B and C exist only in man; the viruses have no known non-human reservoirs. Transmission of the viruses can be interrupted by vaccination against hepatitis B virus infection and improvements in medical techniques for hepatitis C, for which no vaccine has yet been developed.

Low incidence of intraspousal transmission of hepatitis C virus after liver transplantation.

Although the incidence of spousal transmission of hepatitis C virus (HCV) in chronic carriers is extremely low (1.4% to 8%), hepatitis C recurrence after liver transplantation is common with markedly increased serum HCV RNA levels. Thus, partners of these patients may be at higher risk of acquiring infection. This study evaluates the prevalence of spousal transmission of hepatitis C after liver transplantation. Twenty-two of 25 couples who were eligible agreed to the retrospective study. Twenty-two patients (17 males, 5 females) and spouses (5 males, 17 females) were studied with respective mean ages of 50.2 years (35 to 65 years) and 46.9 years (33 to 66 years). Liver enzymes, second-generation enzyme-linked immunosorbent assay (ELISA) for antibody to HCV (anti-HCV) and HCV RNA by polymerase chain reaction (PCR), and branched DNA assay were performed. HCV-associated antibodies were detected in 1 of 22 (5%) spouses and 21 of 22 (95%) patients (P < .0001). Nineteen of 22 (86%) patients tested positive by PCR with a mean value of 16,218,100 Eq/mL (464,700 to 51,980,000). All spouses including the only ELISA anti-HCV positive spouse tested negative by PCR (P < .0001). Eight of 21 spouses tested negative for anti-HCV pretransplantation, (13 of 21 pretransplantation were not tested). Estimated mean duration of hepatitis C infection in patients was 14 years (3 to 40 years). Mean patient follow-up posttransplantation was 654.5 days (141 to 1,959 days). Mean duration of marriage was 22.6 years (2.5 to 46 years). No risk factors other than exposure to index patients were observed in spouses. The incidence of spousal transmission of HCV in liver transplantation remains low (5%) and similar to chronic carriers of HCV.

The nature of complications following liver biopsy in transplant patients with Roux-en-Y choledochojejunostomy.

Liver biopsy is an important diagnostic tool in the management of patients following orthotopic liver transplant. We evaluated complications following percutaneous liver biopsy in a group of liver transplant patients who had Roux-en-Y choledochojejunostomies fashioned as part of their biliary reconstruction during liver transplantation. Complications were divided into two major groups: septic complications (including fever, symptomatic bacteremia, cholangitis, infected hematoma and hypotension related to sepsis) and bleeding (defined as hypotension requiring volume expansion greater than 500 cm3 or blood transfusion, hemothorax, intrahepatic or peritoneal hemorrhage and hemobilia occurring within 1 wk of liver biopsy). One hundred ninety-two biopsies were performed in 46 patients with choledochojejunostomies, and 118 biopsies were carried out in an age- and sex-matched control group of patients with choledochocholedochostomy biliary anastomosis. There were no septic complications in the choledochojejunostomy patients and one (0.32%) septic complication in the choledochocholedochostomy patients (NS). Eight bleeding complications occurred (2.6%) in eight patients (8.3%). Five (2.6%) occurred in five (10.8%) of the choledochojejunostomy patients, vs. three (2.5%) in three (6.5%) choledochocholedochostomy patients (NS). None of the bleeding complications required surgical intervention or was fatal. We conclude that liver biopsy in posttransplant patients with Roux-en-Y choledochojejunostomies is a safe procedure and that the incidences of complications were similar in our two groups. The negligible incidence of septic complications in the choledochojejunostomy patients does not appear to warrant the administration of prophylactic antibiotics, as has been previously suggested.

gamma-Aminobutyric acid localization and function as modulator of cholinergic neurotransmission in rat antral mucosal/submucosal fragments.

gamma-Aminobutyric acid, a neurotransmitter in the central nervous system, has been shown to be present in and synthesized and secreted by rodent and feline myenteric plexus neurons. The aims of the present studies were to measure gamma-aminobutyric acid concentrations and synthesis and to establish cellular localization and uptake of gamma-aminobutyric acid by immunocytochemistry and autoradiography, respectively, within mucosal and submucosal tissues of the rat antrum. Direct demonstration of [3H]gamma-aminobutyric acid release and the effects of exogenous gamma-aminobutyric acid and muscimol, a GABA alpha agonist, on [3H]acetylcholine release from antral mucosal/submucosal fragments were examined in perifusion experiments. gamma-Aminobutyric acid content and synthesis, as reflected by glutamic acid decarboxylase activity, were present within antral mucosa at levels two to three times that of the body and muscular layers of both the gastric body and antrum. gamma-Aminobutyric acid was identified immunocytochemically, principally in mucosal epithelial cells of the antrum. Exogenous gamma-aminobutyric acid and muscimol were capable of stimulating acetylcholine release through a GABA alpha receptor-mediated mechanism that was abolished by tetrodotoxin. These results indicate that gamma-aminobutyric acid is present in and taken up by epithelial cells of the gastric antrum and that gamma-aminobutyric acid is capable of being synthesized by antral mucosal/submucosal tissues. Furthermore, these studies suggest that a peripheral gamma-aminobutyric acid mechanism that may modulate cholinergic neurotransmission and endocrine cell function exists within the antrum.

Sjögren's syndrome in patients with primary biliary cirrhosis.

Symptomatology and objective findings of Sjögren's syndrome were evaluated in 38 consecutive patients with primary biliary cirrhosis. Symptoms of Sjögren's syndrome were present in 18 (47.4%) patients, but were severe enough to warrant therapy in only four (10.5%). Nineteen patients consented to evaluation for Sjögren's syndrome, which included Schirmer's I test, measurement of parotid flow rate and serum autoantibodies, labial minor salivary gland biopsy and human leukocyte antigen typing. Histological changes diagnostic of Sjögren's syndrome were present in five patients (26.3%). All five patients had symptoms of Sjögren's syndrome and three had abnormal Schirmer's I tests, but none had corneal ulcerations or decreased parotid flow rates. Results of serological tests and human leukocyte antigen typing were not similar to those described in patients with primary Sjögren's syndrome but were similar to those described in patients with rheumatoid arthritis and Sjögren's syndrome. These findings indicate that Sjögren's syndrome associated with primary biliary cirrhosis is a form of secondary Sjögren's syndrome resembling that associated with rheumatoid arthritis.

In-hospital mortality as a function of body mass index: an age-dependent variable.

In a retrospective review of 8428 hospital admissions, the relationship between age, sex, disease category, body mass index, and mortality during hospitalization was examined. Records were analyzed for adult admissions whose principal diagnosis fell into one of three categories: malignant disease, heart and cerebrovascular disease, and other diseases. In this study, age, disease category, and body mass index were predictors of survival; sex and race were not. Predicted mortality calculated by logistic regression was greatest at the extremes of body weight in all age groups and in each disease category describing a U-shaped relationship. Obesity was associated with higher mortality only when subjects were 100% or more overweight, whereas being at or below ideal weight was usually associated with increased mortality. Lowest mortality occurred at moderate overweight. The deleterious effects of extremes of body weight take on increasing importance the older the age of the patient. Underweight seems to be a more important predictor of mortality than overweight in older hospitalized subjects. The higher mortality in thin patients could not be explained by weight loss between hospitalizations.

Randomized trial of chlorambucil for primary biliary cirrhosis.

Twenty-four patients with primary biliary cirrhosis were entered into a prospective, randomized trial of chlorambucil therapy. Thirteen patients received chlorambucil (0.5-4 mg/day) and 11 patients received no therapy; all have been followed for 2-6 yr (mean, 4.1 yr). Two control but no treated patients died. Average serum bilirubin, serum aspartate aminotransferase activities, and albumin levels improved or remained unchanged in treated patients but worsened in controls. Serum alkaline phosphatase levels did not change in either group. Immunoglobulin M levels decreased and became normal in all treated patients but in only 3 control patients. Liver biopsy histology revealed an improvement in inflammatory cell infiltrate in treated patients in comparison with controls, but no significant change in degree of fibrosis or the histologic stage of disease. Side effects of therapy included bone marrow suppression necessitating discontinuation of the drug in 4 patients. These findings indicate that chlorambucil therapy may retard the progression of primary biliary cirrhosis. Whether such therapy will ultimately decrease morbidity and improve survival in this disease can only be demonstrated by large-scale, placebo-controlled trials.

Adequate diet prevents hepatic coma in dogs with Eck fistulas.

The conventional animal model of human portal systemic encephalopathy is the dog with Eck fistula. Dogs fed standard dog chow after Eck fistula manifest anorexia, weight loss, hepatic atrophy and encephalopathy. This study was done to determine the natural history of dogs undergoing Eck fistulas when adequate nutrition is maintained with a palatable diet. Twenty-four mongrel dogs were divided into four groups--Eck fistula fed standard dry dog chow (EF-SC) (n equals nine); sham operated fed standard chow (SO-SC) (n equals five); Eck fistula fed a liquid (Isocal) diet (EF-LD), LD), and sham operated fed a liquid diet (SO-LD) (n equals five). Dogs were sacrificed when they had clinical signs of encephalopathy or up to 120 days after operation. EF-SC dogs had a daily caloric intake approximately 40 per cent of that of the other groups. Two EF-SC dogs died of sepsis within two weeks of the operation, the other seven became encephalopathic between 46 and 91 days (a mean of 63.6 +/- 15.6). No other dogs had signs of neurologic deterioration. EF-SC dogs lost 19 +/- 9 per cent body weight and the serum albumin level decreased 14.5 per cent while the other groups maintained body weight and serum albumin levels. Both EF-SC and EF-LD groups had decreased liver weight to body weight ratios (LW X 100/BW) compared with sham operated upon dogs reflecting hepatic atrophy (1.97 +/- 0.7 and 2.2 +/- 0.23 versus 3.04 +/- 0.85 and 3.48 +/- 0.44). Results of histologic examination of the liver revealed hepatocyte atrophy, deglycogenation and lipid accumulation in EF dogs. We conclude from these data that providing dogs with Eck fistula a palatable diet prevents weight loss and malnutrition, but not hepatic atrophy. The lack of neurologic signs in well nourished dogs suggests to us that data concerning hepatic coma from the standard Eck fistula model should be interpreted with extreme caution.

Reactivation of chronic hepatitis B virus infection by cancer chemotherapy.

Two patients referred for cancer chemotherapy were found to be chronic, asymptomatic hepatitis B surface antigen (HBsAg) carriers. They had normal serum aminotransferase levels, but their sera were positive for HGsAg and antibody to hepatitis B e antigen. Both patients developed acute, icteric hepatitis within 3 months of starting cycled chemotherapy. In both cases, the disease seemed to be caused by a recurrence of type B hepatitis; it was accompanied by a marked increase in HBsAg titer and the appearance of hepatitis B virus DNA and DNA polymerase in the serum. One patient had a second episode of acute hepatitis after a second course of chemotherapy, but both patients ultimately recovered and became seronegative for HBsAg. Thus, it seems that cancer chemotherapeutic agents can reactivate type B hepatitis in asymptomatic HBsAg carriers. This reactivation is most likely due to an increase in hepatitis B virus synthesis followed by a rebound in host immune responses to hepatitis B virus infection when therapy is stopped. Such a phenomenon could have important implications for the therapy of chronic hepatitis B virus infection.

False aneurysm formation following arteriographic intimal dissection: serial studies in 2 patients.

Two patients with metastatic islet-cell carcinoma underwent multiple hepatic artery catheterizations for streptozotocin infusion. An intimal flap was raised during one of the initial arteriographic procedures and a false aneurysm developed. The progression of the aneurysm was documented on sequential studies. False aneurysm formation appears to be a relatively unappreciated complication of intimal dissection, and these 2 cases permitted observation of their natural history.