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Biomedical subjects

T L Wright

Publications and source records attributed to T L Wright.

At least 55 records · Page 3Linked to original sources
PubMed1999

Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease.

PURPOSE: The pharmacokinetic behavior of fosphenytoin (FOS), the water-soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT. METHODS: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated. RESULTS: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects. CONCLUSIONS: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly.

Adult↗
PubMed1999

GB virus C (GBV-C/HGV) and E2 antibodies in children preliver and postliver transplant.

The association of GB virus type C (GBV-C) virus and clinical disease is uncertain. The role of GBV-C and (Envelope) E2 antibody in children with liver transplants has not been determined. This study's aim is to examine the prevalence of GBV-C in children with liver transplants, to assess the relationship of GBV-C to posttransplant hepatitis, and to determine the role of E2 antibodies. Sera from 34 children, preliver and postliver transplant, between 1989-1996 were tested for GBV-C (Ribonucleic acid) RNA by the automated Abbott LCx PCR assay. Anti-E2 antibodies were detected by an Abbott immunoassay. Recent posttransplant liver biopsies were examined for hepatitis. The results of the study determined that pretransplant, four children (12%) were GBV-C RNA positive. Posttransplant, 14 (42%) children were GBV-C RNA positive. The GBV-C RNA positive conversion rate was 33% (CI 17.2-55.7%). Patients received blood products from a mean of 68 +/- 34 donors, which correlated with GBV-C acquisition. There was no difference in the incidence (32%versus 36%; p = 0.726) or severity (grade 2.00 versus 0.68; p = 0.126) of posttransplant hepatitis in the liver biopsies of GBV-C RNA negative and/or positive children, respectively. Pretransplant, nine of 32 children were anti-E2 positive. Posttransplant, eight of 32 children were anti-E2 positive, including five children who were anti-E2 positive pretransplant. Of nine children who were anti-E2 positive and GBV-C RNA negative pretransplant, three became GBV-C RNA positive posttransplant. The results of this study conclude that the prevalence of GBV-C infection in children postliver transplantation is high and that blood product transfusions correlate with GBV-C acquisition. Also, no correlation was found between GBV-C RNA and the incidence or severity of posttransplant hepatitis. Finally, E2 antibody presence before transplantation failed to provide complete protection from GBV-C acquisition.

Adolescent↗
PubMed1998

Quantitation of hepatitis G and C viruses in the liver: evidence that hepatitis G virus is not hepatotropic.

Hepatitis G virus (HGV) is prevalent in patients with chronic liver disease and has been previously detected in liver specimens. However, it is unknown whether the virus is replicating in the liver or is simply a contaminant from serum. We sought to determine whether HGV was hepatotropic and to determine whether coinfection with HGV and hepatitis C virus (HCV) influenced the level of either virus. Virus was quantitated using branched DNA (bDNA) assay for both HGV and HCV in the liver explants and pretransplant serum samples from 30 transplant recipients: Group I, HGV/HCV coinfection (n = 10); group II, HCV infection alone, (n = 8); group III, HGV alone (n = 12). In patients with coinfection HCV (RNA) titers in liver were consistently higher than those for HGV RNA (median 1.13 x 10(8) and 360,000 Eq/g respectively, P < .01). The ratio of liver/serum viral RNA was significantly higher for HCV than for HGV (median 129 and 0.3 respectively, P < .01). Levels of HCV RNA were similar in patients with HCV infection alone versus those with HGV/HCV coinfection (median; liver = 1.15 x 10(7) vs. 1.13 x 10(8) Eq/g, serum = 500,000 vs. 200,000 Eq/mL) and levels of HGV RNA in liver and serum were similar in patients with HGV infection alone compared to those with HGV/HCV coinfection (median; liver = 1.2 x 10(6) vs. 4.0 x 10(5) Eq/g, serum = 4.5 x 106 vs. 2.6 x 10(6) Eq/mL). Levels of either virus appeared unaffected by the presence of an additional virus. The high ratio of HCV RNA levels in liver compared to serum is consistent with its known hepatotropism, but this pattern was not observed for HGV. The median liver/serum ratio of HGV RNA was less than unity, a finding consistent with serum contamination of liver tissue. Thus we conclude that the liver is not the main site of HGV replication.

Flaviviridae↗
PubMed1998

Incidence and clinical consequences of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin.

Mutations in the "a" determinant of the surface gene have been associated with failure of hepatitis B immunoglobulin (HBIg) prophylaxis. We compared sequences from the surface and polymerase regions of hepatitis B virus (HBV) from 4 patients who failed high-dose HBIg therapy with two control groups: HBIg-treated patients who remained hepatitis B surface antigen (HBsAg)-negative (n = 4) and HBV-infected transplant recipients who never received HBIg (n = 4). Mutations within the surface and overlapping polymerase region were more common in patients failing HBIg than controls (P = .03), and mutations in the region of the "a" determinant were present only in patients failing HBIg. To examine the relationship between HBIg failure and duration of therapy, five additional treatment failures from a second transplantation center were sequenced (total with HBIg failure = 9). Mutations in the "a" determinant developed in 1 of 3 patients receiving HBIg for less than 6 months compared with 5 of 6 patients failing HBIg after 6 months of therapy (P = .23). The most frequently identified amino acid substitution was glycine to arginine at position 145 (present in 4 of 6 patients who failed HBIg after at least 6 months of treatment). A unique mutation within the YMDD motif (methionine to leucine) was present in 1 patient who failed HBIg treatment and who received a short course of ganciclovir. We conclude that the emergence of mutations in the "a" determinant accounts for some, but not all, treatment failures in patients receiving HBIg prophylaxis. Mutations in other regions of the S gene were more common in patients failing HBIg than controls, suggesting that domains other than the "a" determinant may be important.

Adult↗
PubMed1998

Cholestatic hepatitis C in liver allografts.

Some liver allograft recipients with hepatitis C virus (HCV) infection develop hyperbilirubinemia, which might be the result of a cholestatic variant of hepatitis C. We evaluated all liver biopsy samples from 6 liver transplant recipients who had polymerase chain reaction-positive HCV infection and histologic evidence of hepatitis and jaundice and compared them with liver biopsy samples from a control group of transplant recipients with HCV hepatitis without jaundice. Patients with known ductopenic rejection, biliary obstruction, or co-infection with hepatitis A or B were excluded from the study. Measurement of viral titers and genomic typing were performed when possible. Six patients developed hepatitis and jaundice, with maximum bilirubin levels ranging from 5.8 to 47.6 mg/dL. In this group, 5 (83%) had moderate interface hepatitis (control group, 15%), 6 (100%) had confluent necrosis (control group, 12%), 5 (83%) had bridging fibrosis (control group, 18%), 4 (67%) had significant hepatocyte swelling (control group, 9%), 4 (67%) had prominent ductular proliferation (control group, 3%), and 6 (100%) had mild duct damage and inflammation (control group, 53%). All 6 of the patients with cholestasis had allograft failure. Of these, three allografts were available for review, which did not reveal occult obstruction, rejection, or duct loss. All patients in the control group have retained their allografts. In 4 patients with cholestasis, the median HCV RNA titer was 93.97 mEq/mL, with a mean of 54.19 mEq/mL (control mean = 5.2 mEq/mL). Five patients also underwent viral genomic typing: 2 with type 1a, 2 with type 1b, and 1 with mixed type 1a and 1b. Cholestasis in patients with posttransplantation hepatitis C may be caused by an aggressive HCV infection that exhibits histologic features of confluent necrosis, hepatocyte swelling, and/or ductular proliferation. Viral titers are often increased in such patients.

Bilirubin↗
PubMed1998

Hepatitis after liver transplantation: the role of the known and unknown viruses.

This study was designed to determine the cause of posttransplantation hepatitis in patients undergoing transplantation for liver disease of nonviral cause; the role of acquired hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis G virus (HGV) in posttransplantation hepatitis; and the course of posttransplantation hepatitis of unknown cause. Two hundred forty-three patients underwent transplantation for nonviral liver diseases (mean age, 48 years; 103 men, 140 women). Serological and virological assays for HBV and HCV were performed pretransplantation to exclude preexisting infection and posttransplantation to investigate the cause of posttransplantation hepatitis. Histology was graded on all available biopsy specimens; posttransplantation hepatitis was assessable in 150 patients. Posttransplantation hepatitis was present in 29% (44 of 150) of the patients after a median follow-up of 47 months (range, 1 to 101 months). Actuarial survival was significantly lower in patients with posttransplantation hepatitis compared with patients without (71% v 89% at 5-year follow-up; P = .03). HCV and HBV were identified posttransplantation in 14% and 9% of patients with hepatitis, respectively. After the exclusion of HCV and HBV infection, 22% (33 of 150) of the patients had posttransplantation hepatitis of unknown cause. HGV was present in 58% of these patients, but HGV was equally prevalent in patients without posttransplantation hepatitis. When patients with HBV and HCV were excluded, there was no difference in survival between patients with posttransplantation hepatitis compared with patients without (P = .08, log-rank test). Posttransplantation hepatitis was present in approximately 30% of the patients undergoing transplantation for nonviral diseases, with a median follow-up of 47 months. Known hepatitis viruses (HBV, HCV) were present in one fourth of the patients with posttransplantation hepatitis; 22% (33 of 150) of the patients had hepatitis of unknown cause, suggesting that other, as yet undiscovered, hepatitis viruses may exist.

Adult↗
PubMed1998

Hepatitis C virus in the transplant setting.

Hepatitis C virus (HCV)-associated end-stage liver disease is a leading diagnosis in patients undergoing liver transplantation, accounting for approximately 20-25% of transplantations in many centres. In spite of universal viral recurrence, early post-transplantation infection generally results in indolent disease with good graft and patient survival, at least for the first 5-7 years, comparable to those observed in other patients undergoing transplantation for non-viral end-stage liver disease. The full consequences of HCV recurrence are however beginning to be delineated with development of progressive liver failure observed with longer follow-up in a still unknown proportion of patients. Factors which may influence the outcome include viral load at transplantation and the type/amount of immunosuppression. Currently, the only available drugs are interferon and ribavirin, alone and in combination, used either therapeutically when the disease has fully developed, or prophylactically early after transplantation. Unfortunately, interferon has been used with limited success and with concerns about toxicity. Ribavirin monotherapy has been ineffective in producing meaningful results. Preliminary results on combination therapy are promising, both when administered before hepatitis develops or when histologic disease is present. Current antiviral therapy is however unable to eliminate HCV in the liver transplant setting, suggesting that indefinite treatment designed to suppress the effects of virus may be necessary. Major therapeutic advances for HCV infection are awaited.

Antiviral Agents↗
PubMed1998

Antienvelope antibodies are protective against GBV-C reinfection: evidence from the liver transplant model.

An assay for the detection of antibody against the second envelope (E2) protein of GB virus type C (GBV-C) has been developed. Early reports suggested that this antibody was a marker of viral clearance, yet it is unknown whether anti-E2 is protective against further GBV-C infection. The primary aims were to determine (1) if posttransplantation immunosuppression alters the prevalence of anti-E2; and (2) if anti-E2 positivity pretransplantation protects against acquisition of GBV-C infection posttransplantation. Fifty-four recipients who underwent orthotopic liver transplantation for end-stage liver disease of nonviral etiologies were tested for GBV-C RNA using a PCR-based assay and anti-E2 antibodies by an enzyme-linked immunoassay. Anti-E2 was present in 35% and in 46% of patients pre- and posttransplantation, respectively. Anti-E2 positivity pretransplantation was strongly associated with anti-E2 positivity after transplantation (P < 0.001); 83% of patients with anti-E2 prior to transplantation remained anti-E2-positive after transplantation. A negative association between presence of GBV-C viremia and presence of anti-E2 was found in all patients tested either prior to or following transplantation (P=0.03). Acquisition of GBV-C infection was significantly lower in patients who were anti-E2-positive prior to transplantation (2/13) compared to those who were anti-E2-negative (12/26) (P=0.05). It is concluded that immunosuppression does not reduce the prevalence of anti-E2 after transplantation in those who are seroreactive prior to transplantation. Anti-E2 appears to be a neutralizing antibody whose presence at the time of liver transplantation protects against acquisition of GBV-C infection in the peritransplantation period.

Adult↗
PubMed1997

Antibody to the host cellular gene-derived epitope GOR-1 in liver transplant recipients with hepatitis C virus infection.

The presence of anti-GOR was determined in paired pre-orthotopic liver transplantation (pre-OLT) and post-OLT sera from 87 OLT patients with hepatitis C virus infection. Before OLT, 48/87 patients were seropositive for anti-GOR, but this marker had no relationship with the clinical and biochemical parameters, or viremia level. Anti-GOR was less commonly detected in patients infected with genotype 3a, compared with genotypes 1 and 2, which might be related to the less conserved nature of the proposed shared epitope (amino acid sequence 9-18) in genotype 3a isolates. After OLT (median follow-up 16 months), anti-GOR was detected in 31/87 patients and it had no correlation with the clinical and biochemical parameters, viremia level, histologic disease activity, and clinical outcome. Changes in anti-GOR status (before OLT versus after OLT) were also not related to any of the clinical parameters. Although anti-GOR is commonly detected in OLT patients infected with hepatitis C virus genotypes 1 and 2, it has no clinical or prognostic significance.

Adult↗
PubMed1997

Mutation of human keratin 18 in association with cryptogenic cirrhosis.

Mutations in 11 of the more than 20 keratin intermediate filaments cause several epidermal and oral associated diseases. No disease-associated mutations have been described in keratin 8 or 18 (K8/18) which are the major keratin pair in simple-type epithelia, as found in the liver, pancreas, and intestine. However, transgenic mice that express mutant keratin 18 develop chronic hepatitis, and have an increased susceptibility to drug-induced hepatotoxicity. Also, ectopic expression of epidermal K14 in mouse liver results in chronic hepatitis, and disruption of mouse K8 leads to embryo lethality with extensive liver hemorrhage. We tested if patients with liver disease of unknown cause may harbor mutations in K18. We describe a his127-->leu (H127L) K18 mutation in a patient with cryptogenic cirrhosis that is germline transmitted. The K18 H127L isolated from the liver explant, or after expression in bacteria, showed an altered migration on two-dimensional gel analysis as compared with normal human liver or bacterially expressed K18. Electron microscopy of in vitro assembled K18 H127L and wild type K8 showed an assembly defect as compared with normal K8/18 assembly. Our results suggest that mutations in K18 may be predispose to, or result in cryptogenic cirrhosis in humans.

Chromosome Mapping↗
PubMed1997

Hepatitis G virus in patients with cryptogenic liver disease undergoing liver transplantation.

To examine the prevalence of hepatitis G virus (HGV) in end-stage liver disease of unknown cause and the role of HGV infection in posttransplantation hepatitis, we studied 46 patients undergoing liver transplantation (mean age, 50 years; M:F, 18:28) with cryptogenic cirrhosis. HGV RNA was detected by polymerase chain reaction (PCR) and was quantified by a branched DNA (bDNA) assay. The prevalence of HGV RNA was determined in samples collected before and after liver transplantation and was found to be 22% and 67%, respectively. We evaluated the prevalence of posttransplantation hepatitis in 25 patients, 16 of whom were HGV-positive and 9 were HGV-negative. The proportion of patients with hepatitis was not significantly different in the two groups (38% in HGV-positive and 22% in HGV-negative patients). The median histological scores were significantly higher in liver biopsies from patients with HGV infection than in those without HGV infection (2 [range, 0-14] and 1 [range, 0-3]; P = .01), but the histological scores were low overall. The duration of follow-up was similar in the two groups. HGV RNA levels were not correlated with the severity of liver disease based on histological score (r = -.08). Graft survival and patient survival were not significantly different. We concluded that liver disease was frequent (32%) after transplantation in patients with a pretransplantation diagnosis of cryptogenic cirrhosis, although the disease was generally mild. Although HGV RNA was demonstrable in the majority (67%) of patients after transplantation, there was no relationship between the presence of HGV RNA and the presence of posttransplantation liver disease. The finding of posttransplantation hepatitis in the absence of known viruses (A-G), suggests that other, as-yet-unidentified viruses may be important.

Adult↗
PubMed1997

The clinical course of transplantation-associated de novo hepatitis B infection in the liver transplant recipient.

Transmission of hepatitis B infection from hepatitis B surface antigen (HBsAg)-negative antibody to hepatitis B core (anti-HBc)-positive liver donors has been previously described. The long-term outcome of these transplant-associated de novo hepatitis B patients has not been well described and may affect future use of donor organs that are anti-HBc-positive. We describe the experience in our first 332 transplants, performed before exclusion of anti-HBc-positive liver donors. Nine of these 332 (3%) donors were anti-HBc positive. Three of these 9 (33%) recipients developed transplant-associated de novo hepatitis B infections compared with only 2 of 323 (0.5%) recipients who received anti-HBc-negative donor livers (P = .00014). Of our 9 recipients of anti-HBc-positive livers, 6 (67%) are alive, and no deaths or allograft failures have been related to complications of hepatitis B. Only 1 of 5 patients (20%) with de novo hepatitis B has developed significant graft dysfunction with an average follow-up of more than 7 years (range 63-124 months). The 1 recipient with allograft dysfunction related to de novo hepatitis B has significantly elevated viremia levels (average HBV DNA 460 pg/mL) compared with the other de novo hepatitis B recipients (average HBV DNA 23-58 pg/mL). In summary, anti-HBc-positive donors are more likely to transmit hepatitis B infections to recipients, but these de novo infections usually have a mild clinical course and do not seem to adversely affect long-term patient survival. Hepatitis B-related allograft dysfunction, when it occurs, is associated with higher levels of viral replication. With our current donor shortage, perhaps anti-HBc-positive donors could be used in very selected recipient populations.

Biopsy↗