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Biomedical subjects

W Bernal

Publications and source records attributed to W Bernal.

9 recordsLinked to original sources
PubMed2000

The interleukin-1 and interleukin-10 gene polymorphisms in primary sclerosing cholangitis: no associations with disease susceptibility/resistance.

BACKGROUND/AIMS: Although primary sclerosing cholangitis is believed to be an autoimmune disorder, no tissue-specific auto-antibodies have yet been identified, and the strongest support for an autoimmune aetiology comes from HLA-association studies. Three different HLA haplotypes are associated with susceptibility to the disease and one with protection from it. These HLA haplotypes, however, do not account for all of the disease risk and genes outside the HLA region may also have a role in disease pathogenesis. The aim of this study was to investigate, for the first time, polymorphic genes/sites within the interleukin-1 and interleukin-10 genes in a large well-characterised group of patients. METHODS: Ninety-six patients and 96 control subjects were studied. A single base-exchange polymorphism at position +3953 in the first exon of the IL-1B gene, a penta-allelic repeat sequence in the IL-1 receptor antagonist gene (IL-1RN) and three single base-exchange polymorphisms at positions -592, -819 and -1082 in the IL-10 gene promoter were determined by standard PCR-based techniques. RESULTS: Overall, there was no significant difference in the distribution of any of the IL-1B, IL-1RN or IL-10 alleles or genes sequences comparing patients and controls. In addition, there was no difference when the patients were stratified for the presence and absence of the HLA DRB1*0301 (DR3) allele or concurrent inflammatory bowel disease. CONCLUSION: Neither the IL-1B +3953, IL-1RN microsatellites polymorphisms on chromosome 2q13 nor the IL-10 -592, -819, -1082 promoter gene polymorphisms on chromosome 1q31-32 are associated with susceptibility or resistance to primary sclerosing cholangitis.

Adult↗
PubMed2000

Acute liver failure.

Worldwide, viral infection is responsible for the majority of cases of acute liver failure, and the presence of co-existing chronic viral hepatitis may increase its severity. The newly described hepatotrophic viruses, hepatitis G virus and transfusion-transmitted virus, are unlikely to be major aetiological agents. In the USA and western Europe drug-induced hepatotoxicity is the most common cause, and most frequently results from acetaminophen. Hepatotoxicity caused by Ecstasy is increasingly important, particularly in young adults. Hepatic encephalopathy and cerebral oedema remain important and life-threatening complications, and their pathogenesis is not completely understood. The effects of the cerebral metabolism of the high levels of ammonia that circulate in hepatic failure appear to be important. Induced hypothermia is a promising modality of treatment for refractory cerebral oedema, but the only form of treatment known to improve survival is emergency liver transplantation. Living donor and auxiliary liver transplantation are likely to improve survival rates further and reduce the number of patients requiring long-term post-transplant immunosuppression.

Journal Article↗
PubMed1999

Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis.

Genetic involvement in type 1 autoimmune hepatitis (AIH) is indicated by a marked female preponderance and strong, well-established, human leukocyte antigen (HLA) associations. These associations, however, are not universal and a number of genes outside the major histocompatibility complex may also play a role in susceptibility to type 1 AIH. Prime candidates at present are those polymorphic genes encoding the proinflammatory and immunoregulatory cytokines. The aim of this study was to investigate, for the first time, 2 members of the interleukin-1 (IL-1) family (IL-1B and IL-1RN), 3 polymorphic sites in the interleukin-10 (IL-10) gene promoter (positions -1082, -819, and -592), and 2 polymorphisms in the tumor necrosis factor-alpha (TNF-alpha) promoter (positions -308 and -238) in type 1 AIH. The study was performed on 2 independently collected DNA banks, each with appropriate controls, and throughout the analysis associations described in the first set were confirmed in the second set. Standard polymerase chain reaction (PCR)-based genotyping techniques were used. Overall there were no significant differences in the distributions of the IL-1B and IL-10 alleles, genotypes, or haplotypes in either study set. In contrast we report a significant association between type 1 AIH and TNF*2 (first set: 34% of controls vs. 49% of patients, Pc =.014 and second set: 26% vs. 56%, P =.00008). However, TNF*2 is found in strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype and stratification analysis indicates that the association with TNF*2 is interdependent with HLA DRB1*0301. This is an indication that there is more than one susceptibility allele for type 1 AIH on chromosome 6p21.3.

Adolescent↗
PubMed1999

Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis.

BACKGROUND/AIMS: Primary sclerosing cholangitis is associated with the HLA haplotypes A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201 and DRB3*0101-DRB1*1301-DQA1*0103-DQB1* 0603. However, the interpretation of these genetic associations is controversial. One explanation may be that HLA-encoded susceptibility is due to other genes carried on these haplotypes such as the HLA class III tumor necrosis factor genes. The aim of the study was to investigate tumor necrosis factor genetics in a large series of well-defined patients. METHODS: One hundred and ten HLA genotyped patients and 126 control subjects were studied by polymerase chain reaction genotyping for 3 different tumor necrosis factor gene polymorphisms: -308, -238 and an Ncol restriction fragment length polymorphism in the lymphotoxin alpha gene. RESULTS: Overall, 58% of patients had the TNF2 allele, compared with 29% of controls, p(c) = 0.0001. No association was found with either of the other tumor necrosis factor polymorphisms examined. TNF2 was significantly increased in the presence of B8 and DRB3*0101 only, and was independent of DRB1*0301 (p(c)<0.04). The associations with B8 and TNF2 were stronger than the associations with any of the HLA class II alleles examined. CONCLUSION: HLA-encoded genetic susceptibility to primary sclerosing cholangitis may be determined by polymorphism within the HLA class III region, in particular with the TNF2 allele.

Adult↗
PubMed1999

Acute liver failure; clinical features and management.

Acute liver failure (ALF) is uncommon and may be associated with a high mortality rate. Its aetiology shows considerable geographical variation, with viral hepatitis the most common worldwide, whilst acetaminophen (paracetamol) induced hepatotoxicity forms the most common precipitant in many developed countries. Its management requires meticulous intensive care and the effective management of haemodynamic, septic and cerebral complications. The early identification of patients unlikely to survive without emergency liver transplantation is important to maximize the possibility of an available graft. Survival in those patients who undergo transplantation may be in excess of 75%.

Acetaminophen↗
PubMed1998

Use and outcome of liver transplantation in acetaminophen-induced acute liver failure.

Once defined clinical criteria are fulfilled in acetaminophen-induced hepatotoxicity, prognosis without orthotopic liver transplantation (OLT) may be very poor. In the present study, we examined the application and outcome of OLT in 548 patients admitted to a single center between 1990 and 1996. Four hundred twenty-four (77%) of the patients studied did not fulfill transplantation criteria, and 396 of these (93%) survived. The majority of the 28 nonsurvivors (7%) in this group fulfilled two of three combined criteria, and the finding of a high APACHE III score could be used as an indicator for the need for OLT. Of the 56 patients (45%) not listed, in only a small proportion was this caused by psychiatric reasons, and in the majority, it was a consequence of the rapid development of multiple organ failure and cerebral edema. This also applied to 24 (35%) of the 68 listed patients in whom the rapidity of clinical deterioration, reflected in increasing APACHE III scores, was such that even with the prompt availability of donor organs, OLT was not possible. In the final event, only 44 (35%) of those who fulfilled criteria underwent OLT, of whom 33 (75%) survived to leave the hospital. Survival was greatest in those receiving unreduced grafts, and markers of early graft function differed significantly between survivors and nonsurvivors. Liver transplantation is an effective treatment in a relatively small number of patients with acetaminophen-induced hepatotoxicity, and for a substantial proportion, transplantation was never an option because of the rapidity of clinical deterioration. APACHE III scoring may be of value in decision making and in better defining patients in clinical trials.

Acetaminophen↗
PubMed1998

Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure.

BACKGROUND/AIMS: High levels of tumor necrosis factor-alpha are associated with an increased risk of severe encephalopathy in acute liver failure, and experimental studies suggest that tumor necrosis factor-alpha plays a role in the development of acetaminophen (paracetamol)-induced liver injury and associated multiple organ failure. Inter-individual variations in the production of tumor necrosis factor-alpha have been linked to genomic polymorphisms within the tumor necrosis factor-alpha locus. This study examined whether specific tumor necrosis factor polymorphisms are associated with variations in the severity of clinical features in acetaminophen-induced acute liver failure. METHODS: Genotypes at the -308 tumor necrosis factor A and tumor necrosis factor B Nco1 polymorphic sites were determined in 97 patients with severe acetaminophen-induced hepatotoxicity and 109 controls, using polymerase chain reaction and restriction fragment length polymorphism. The relationship between liver injury, multiple organ failure and encephalopathy, determined retrospectively from clinical notes and genotype, was examined. RESULTS: No significant association was found between either tumor necrosis factor A or B genotype and parameters for multiple organ failure or liver injury. The tumor necrosis factor B1B1 genotype was significantly under-represented in those patients developing severe encephalopathy (p=0.03) and a multivariate logistic regression analysis confirmed the influence of tumor necrosis factor B genotype (p<0.01). The association was independent of the HLA class II allele DRB1*03, which is closely linked to the TNFB locus. CONCLUSIONS: The development of acute liver failure is unlikely to be primarily sepsis driven. However, the apparent protective effect of the tumor necrosis factor B1B1 genotype on the development of severe encephalopathy may be related to the effects of this genotype on tumor necrosis factor-alpha production in sepsis.

APACHE↗
PubMed1996

A community prevalence study of antibodies to hepatitis A and E in inner-city London.

The seroprevalence of antibodies to hepatitis E virus (HEV) and hepatitis A virus (HAV) was determined in a community-based sample in innercity London where socioeconomic conditions were expected to result in a high prevalence of antibodies to HAV, and in which the presence of immigrants from the developing world pose a risk of imported infection of both HAV and HEV. The seroprevalence of anti-HAV was 45.1% in UK born subjects and 69.7% in non-UK born subjects and each group showed differing patterns of age-specific seroprevalence. The seroprevalence rates of anti-HEV was 3.9% in UK born subjects and 8.8% in non-UK born subjects. The age-specific seroprevalence of the UK born group is suggestive of a cohort effect. The data suggest a low circulation of HEV in inner-city London, remaining uncommon relative to HAV.

Adolescent↗