De novo cryptogenic hepatitis after sustained eradication of hepatitis C following liver transplantation.

Patients with recurrent hepatitis C (HCV) after liver transplantation (OLT) are often treated with interferon and ribavirin in an attempt to eradicate HCV and prevent cirrhosis. We report four patients who developed de novo cryptogenic hepatitis following sustained eradication of recurrent HCV, which led to decompensated liver disease in two patients, both of whom required listing for retransplantation. Between September 2000 and October 2001, 38 consecutive patients with recurrent HCV were treated with interferon alpha 2b and ribavirin, of whom eight patients (21%) developed a sustained response to HCV eradication. Four of these patients developed cryptogenic hepatitis, which led to decompensated cirrhosis in two patients. Both patients were listed for retransplantation but died on the waiting list. No etiology for liver disease was identified despite extensive investigations in all four patients including postmortem analysis in the two patients. We hypothesize that these individuals developed an aberrant immune response leading to allograft injury whose severity may be determined by underlying haplotype, degree of immunosuppression, presence/absence of HCV, and duration of treatment. We have not found any similar reports in the literature but anticipate more cases to be reported given the universal use of antiviral therapy for recurrent HCV.

Pilot study of pegylated interferon alfa-2b and ribavirin for recurrent hepatitis C after liver transplantation.

UNLABELLED: Recurrent hepatitis C is often treated with an interferon and ribavirin combination therapy, but the results have been disappointing. Given the promising results reported with pegylated interferon and ribavirin for hepatitis C, we were interested in evaluating the effectiveness of this treatment in liver transplant recipients with recurrent hepatitis C (HCV). METHODS: Between November 2001 and September 2002, patients with recurrent HCV were screened to determine if they were eligible for treatment. Liver function tests, HCV-RNA, and liver biopsies were performed on all patients prior to treatment. HCV-RNA was repeated at 3 months, the end of treatment (EOT), and 6 months after EOT for patients who were HCV-RNA negative at EOT. Patients were prospectively followed after starting weekly pegylated interferon alfa-2b 1.5 mcg/kg per week and ribavirin 800 mg per day (Schering-Plough, Kenilworth, NJ, USA) with folic acid 1 mg per day. RESULTS: Thirty-nine patients eligible for treatment displayed a median age of 50.4 years. Eighteen patients completed treatment, 4 remain on treatment, and 17 were intolerant. Sustained HCV-RNA eradication occurred in 66.7% of patients who completed treatment. Side effects led to treatment withdrawal in 17 patients (43.6%) In an intention-to treat analysis, sustained HCV-RNA eradication occurred in 30.8% of patients. CONCLUSION: Side effects are an important limiting factor in the treatment of recurrent HCV with pegylated interferon and ribavirin. However, these results are encouraging as sustained HCV eradication occurred in at least 66.7% of patients who completed treatment. Prospective randomized trials are required to assess the effectiveness of this treatment and its impact on quality of life and histology.

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.

Synthesis of ((t)Bu3SiNH)2ClW triple bond WCl(NHSi(t)Bu3)2 and its degradation via NH bond activation.

Treatment of NaW2Cl7(THF)5 with 4 equiv of (t)Bu3SiNHLi afforded the C2 W(III) dimer [((t)Bu3SiNH)2WCl]2 (1, d(W triple bond W) = 2.337(2) A), which is a rare, primary amide M2X4Y2 species. Its degradation provided evidence of NH bond activation by the ditungsten bond. Addition of 2 equiv of (t)Bu3SiNHLi or TlOSi(t)Bu3 to 1 yielded H2 and hydride ((t)Bu3SiN)2((t)Bu3SiNH)WH (2, d(WH) = 1.67(3) A) or ((t)Bu3SiN)2((t)Bu3SiO)WH (3). Thermolysis (60 degrees C, 16 h) of 1 in py gave ((t)Bu3SiN)2WHCl(py) (4-py, 40-50%), ((t)Bu3SiN)2WCl2(py) (6-py, 10%), and ((t)Bu3SiN)2HW(mu-Cl)(mu-H)2W(NSi(t)Bu3)py2 (5-py2, 5%), whereas thermolysis in DME produced ((t)Bu3SiN)2WCl(OMe) (7, 30%), ((t)Bu3SiN)2WCl2 (6, 20%), and ((t)Bu3SiN)2HW(mu-Cl)(mu-H)2W(NSi(t)Bu3)DME (5-DME, 3%). Compound 7 was independently produced via thermolysis of 4-py and DME (-MeOEt, -py), and THF and ethylene oxide addition to hydride 2 gave ((t)Bu3SiN)2((t)Bu3SiNH)WO(n)Bu (8) and ((t)Bu3SiN)2((t)Bu3SiNH)WOEt (9), respectively. Dichloride 6 was isolated from SnCl4 treatment of 1 with the loss of H2. Sequential NH bond activations by the W2 core lead to "((t)Bu3SiN)2WHCl" (4) and subsequent thermal degradation products. Thermolysis of 1 in the presence of H2C=CH(t)Bu and PhC triple bond CPh trapped 4 and generated ((t)Bu3SiN)2W((neo)Hex)Cl (10) and a approximately 6:1 mixture of ((t)Bu3SiN)2WCl(cis-CPh=CPhH) (11-cis) and ((t)Bu(3)SiN)2WCl(trans-CPh=CPhH) (11-trans), respectively. Thermolysis of the latter mixture afforded ((t)Bu3SiNH)((t)Bu3SiN)WCl(eta2-PhCCPh) (12) as the major constituent. Alkylation of 1 with MeMgBr produced ((t)Bu3SiN)2W(CH3)2 (13), as did addition of 2 equiv of MeMgBr to 6. X-ray crystal structure determinations of 1, 2, 5-py2, 6-py, 11-trans, and 12 confirmed spectroscopic identifications. A general mechanism that features a sequence of NH activations to generate 4, followed by chloride metathesis, olefin insertion, etc., explains the formation of all products.

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.

Cerebral oedema and increased intracranial pressure in chronic liver disease.

BACKGROUND: Cerebral oedema is a cause of morbidity and mortality in fulminant hepatic failure but has not been well documented as a complication of chronic liver diseases. We report here the development of cerebral oedema and increased intracranial pressure in 12 patients with chronic liver disease. METHODS: Between July 1, 1987, and Dec 31, 1993, we studied 12 patients aged 29-67 years with end-stage chronic liver disease. All the patients had cirrhosis, portal hypertension, hypoprothrombinaemia, hepatic encephalopathy, and decreased serum concentrations of albumin (<25 g/L). During the study, the patients developed signs of increased intracranial pressure and had documented intracranial hypertension, cerebral oedema, or both. Intracranial hypertension was suspected on physical examination and confirmed by epidural catheters. We detected cerebral oedema by computed axial tomography of the head and necropsy of the brain when possible. FINDINGS: All the patients had intracranial hypertension and cerebral oedema. Two patients had successful treatment of cerebral hypertension with improvement of intracranial pressure such that orthotopic liver transplantation was undertaken. Both patients became neurologically normal after transplantation. Eight patients had only a transient response to treatment and died of cerebral oedema before a transplant could be done. INTERPRETATION: Cerebral oedema and increased intracranial pressure can occur in chronic liver disease and presents as neurological deterioration. Treatment guided by monitoring of intracranial pressure can lead to the reversal of intracranial hypertension, but in most patients cerebral oedema contributes to death or places them at too high a risk for liver transplantation.

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.

Brainstem auditory evoked potentials in liver transplant candidates.

BAEPs were recorded on 18 patients before, and/or after liver transplantation. Clinical assessment included 5 standardized scales. Data were divided by stringent criteria into 2 groups: clinical hepatic encephalopathy present (HE) or absent (nonHE). Dependent variables were BAEP configuration and I-V, I-III and III-V IPLs. The following comparisons were made: all patients vs. controls; HE vs. controls; nonHE vs. controls; HE vs. nonHE. BAEP configuration changes were not significantly associated with HE. I-V and III-V IPLs were prolonged for all patients, nonHE patients, and HE patients vs. controls; I-III IPL differences were not significant. There were no correlations between BAEP variables and EEG grade or grades on any single clinical scale. The results suggest that BAEP IPLs (especially the I-V IPL) are a sensitive, although not specific, measure of HE and may be sensitive enough to detect incipient HE.

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.

Desperate appliances: a short review of therapies for fulminant hepatic failure.

In this work, we review the current status of accepted and experimental therapies for fulminant hepatic failure, we attempt to estimate chances of success and outline a protocol by which such therapies tested.

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.