Biomedical subjects
G P Aithal
Publications and source records attributed to G P Aithal.
Immunosuppression, IBD, and risk of lymphoma.
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High serum IgG4 concentrations in patients with sclerosing pancreatitis.
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Role of polymorphisms in the interleukin-10 gene in determining disease susceptibility and phenotype in inflamatory bowel disease.
Interleukin-10 (IL-10) has a key role in regulating mucosal inflammation. The role of functional polymorphisms at positions -627 and -1117 in the IL-10 gene as candidate susceptibility loci in inflammatory bowel disease and their importance in determining disease extent were evaluated in 159 patients with ulcerative colitis (83 left-sided; 76 extensive), 90 patients with Crohn's disease (22 small bowel; 29 large bowel; 39 both), and 227 controls. Genotyping was performed either by PCR-RFLP assays (-627 site) or SSCP analysis (-1117 site). An excess of -627A allele was observed in patients with left-sided colitis (52%) compared with controls (33%; P = 0.004) suggesting that IL-10 may influence the extent of the disease. These results were not replicated in a newly recruited group (N = 100) of patients with UC. We conclude that polymorphisms at -627 and -1117 sites in the IL-10 gene do not contribute to the susceptibility to IBD or determining the extent of the disease in our population.
Association of single nucleotide polymorphisms in the interleukin-4 gene and interleukin-4 receptor gene with Crohn's disease in a British population.
Interleukin-4 (IL-4) is an important cytokine in mucosal immunity and plays a critical role in the development of colitis in T-alpha cell receptor mutant mice. Functionally significant polymorphisms have been described in the genes encoding IL-4 and IL-4 receptor. To examine the role of these polymorphisms in disease susceptibility 98 patients with ulcerative colitis, 86 patients with Crohn's disease and 321 healthy controls were genotyped for polymorphisms at position -34 in the IL-4 gene and codon 576 in the IL-4 receptor gene. Thirty-two percent of patients with Crohn's disease carried one or two copies of the variant allele for IL-4 compared with 16% of the controls (P = 0.002). Forty-one percent of patients with Crohn's disease carried one or two copies of the variant IL-4 receptor allele compared with 31% of the controls (P = 0.09). Fifteen percent of patients with Crohn's disease carried combination of both (IL-4 and IL-4 receptor) variant alleles compared with 4% of the controls (P = 0.005). Association with alleles resulting in high IL-4 transcription and enhanced signalling activity suggests that IL-4 may have a role in the pathogenesis of Crohn's disease.
Review article: the risk of lymphoma associated with inflammatory bowel disease and immunosuppressive treatment.
Lymphoma complicating inflammatory bowel disease is well described. Whether the risk of lymphoma is increased by immunosuppressive treatment with azathioprine, 6-mercaptopurine or infliximab is a common concern among patients and physicians considering using these agents. This review aims to quantify the lymphoma risk in inflammatory bowel disease and the added risk attributable to these treatments. The evidence from published cases is that lymphomas occur at sites of active inflammatory bowel disease more often than expected for this to be a chance association. Studies on inflammatory bowel disease populations are conflicting, with some follow-up studies from large inflammatory bowel disease clinics showing an increase in lymphoma incidence, while other population-based studies show little or no increase in risk of lymphoma. A small increase in lymphoma risk in inflammatory bowel disease, perhaps 2-3-fold, may be compatible with both sets of data. Studies of the risks associated with immuno- suppression are less satisfactory, with smaller numbers of patients and relatively short follow-up. The available evidence would support a further increase in lymphoma risk associated with immunosuppressive treatment in inflammatory bowel disease of around fivefold compared to no immunosuppressive use, and tenfold compared to the general population. The risks appear to be less than that associated with renal and hepatic transplant-related immunosuppression. Infliximab treatment is still too new to make a full assessment of its long-term safety, but post-marketing surveillance currently suggests that lymphoma risk may not be any greater than that associated with azathioprine and 6-mercaptopurine. Population-wide surveillance for lymphoma in inflammatory bowel disease would be required to narrow the confidence intervals on these estimates of lymphoma risk in inflammatory bowel disease and immunosuppressive treatment.
Steering azathioprine safely: lessons from pharmacogenetics.
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Is clinical examination an art?
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Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions.
BACKGROUND/AIM: Due to an absence of specific markers, the diagnosis of drug-induced hepatotoxicity is necessarily based on circumstantial evidence and is often inaccurate. We have evaluated the use of the clinical diagnostic scale (CDS) in the causality assessment of hepatotoxic adverse drug reaction (ADR) reports. METHODS: 135 hepatic adverse ADRs reported to the Committee on Safety of Medicines in North East England 1992-6 were evaluated. Initially, "International Consensus Criteria" were used to classify reactions as "drug-related", "drug-unrelated" and "indeterminate". Using the CDS, each ADR was then categorised as either definite drug hepatotoxicity (score >17), probable (14-17), possible (10-13), unlikely (6-9), or drug hepatotoxicity excluded (<6). RESULTS: 49 ADRs were considered drug-related, 65 unrelated and 21 indeterminate. Reports classified as drug-related by consensus criteria scored higher on the CDS, with a median score of 12, range: 8-15, than either the indeterminate (8; [3-12]) or drug-unrelated reports (5; [2-11]) (p<0.0001). A CDS score of >9, identified 88% of the cases classified as drug-related hepatotoxicity by consensus criteria and excluded 98% of those unrelated to the drugs. CONCLUSIONS: CDS scoring correlates well with the international consensus classification and may be a useful tool in the routine evaluation of suspected hepatotoxic drug reactions.
Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis.
The mechanism by which diclofenac-induced hepatotoxicity occurs is unclear, even though covalent modification of proteins by diclofenac metabolites appears to be important in pathogenesis, either by altering protein function or by eliciting an immune response. Adduct formation may be due to metabolism of diclofenac via an alternative pathway rather than via its major 4'-hydroxylation pathway mediated by the cytochrome P450 CYP2C9. We hypothesized that possession of variant CYP2C9 alleles might be a risk factor for diclofenac-induced hepatotoxicity, since the allelic variants CYP2C9*2 and CYP2C9*3 may be associated with impaired metabolism compared to the wild-type (CYP2C9*1). To investigate in more detail the effects of the polymorphisms on diclofenac metabolism in human liver, the kinetics of diclofenac 4-hydroxylation by human liver microsomes of known CYP2C9 >genotype were examined. An overall difference in Vmax and Vmax/Km between samples homozygous for CYP2C9*1 and heterozygous for CYP2C9*2 or CYP2C9*3 was detected (P = 0.044). However, on subgroup analysis, there was no significant difference between samples homozygous for CYP2C9*1 and heterozygous for CYP2C9*2, although there was a borderline difference between the samples homozygous for CYP2C9*1 and those heterozygous for CYP2C9*3 (P = 0.057). The relationship between CYP2C9 genotype and susceptibility to diclofenac-induced hepatotoxicity was further examined by genotyping 24 patients with diclofenac-induced hepatotoxicity together with 100 healthy controls for the CYP2C9*2 and CYP2C9*3 alleles. CYP2C9 genotype frequencies for CYP2C9*2 and CYP2C9*3 were similar in patients and controls. To assess whether diclofenac-induced hepatotoxicity was due to rare CYP2C9 mutations, the upstream sequence (-1 to -1000) and all exons and exon-intron boundaries of CYP2C9 from four subjects who had suffered severe hepatotoxicity was determined. However, no new polymorphisms were detected. We therefore found no evidence that polymorphism in CYP2C9 is a determinant of diclofenac-induced hepatotoxicity.
Accuracy of hepatic adverse drug reaction reporting in one English health region.
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Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.
BACKGROUND: The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C9*2 and CYP2C9*3 differ from the wild type CYP2C9*1 by a single aminoacid substitution in each case. The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement. METHODS: Patients with a daily warfarin dose requirement of 1.5 mg or less (low-dose group, n=36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic control group, n=52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C9*2 and CYP2C9*3 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties encountered during the induction of warfarin therapy and bleeding complications in the low-dose and clinic control groups. FINDINGS: The odds ratio for individuals with a low warfarin dose requirement having one or more CYP2C9 variant alleles compared with the normal population was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5.97 [2.26-15.82]) and have increased risk of major bleeding complications (rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic controls. INTERPRETATION: We have shown that there is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.
Chest pain in achalasia is an age-dependent phenomenon.
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Subclinical esophageal peristaltic dysfunction during the early phase following a stroke.
Evaluation of swallowing following stroke has previously concentrated on the oropharyngeal phase. We have studied whether there is esophageal dysmotility during the early phase following stroke in patients with no clinical evidence of oropharyngeal dysfunction. Twenty-five patients with a clinical diagnosis of stroke, and CT scan confirmation, without swallowing abnormalities at bedside evaluation were studied. Each subject had two esophageal manometric studies, one between days 3-5 after the stroke and the second during the third week after the stroke. Mean percentage (+/-SE) of completed peristaltic events increased from 57.8 +/- 5.9 (days 3-5) to 77.3 +/- 3.9 (week 3) (P = 0.005). Mean propagation of peristalsis (+/-SE) between 10 and 5 cm above the lower esophageal sphincter increased from 2.9 +/- 0.2 cm/sec (days 3-5) to 3.7 +/- 0.3 cm/sec (week 3) (P = 0.003). We have demonstrated subclinical peristaltic dysfunction in the smooth muscle segment of the esophagus in stroke patients with relatively preserved oropharyngeal function.
Portal hypertension secondary to arterio-portal fistulae: two unusual cases.
A 62-year-old male presented with variceal haemorrhage. Investigation demonstrated a fistula between the left gastric artery and portal vein with a porto-systemic gradient of 35 mm Hg. Variceal bleeding was controlled by a transcatheter embolisation of the fistula, but the patient died of septicaemia three weeks later. The second patient, a 42-year-old male who presented with variceal bleeding was shown to have diffuse arterio-venous fistulae involving the right lobe of the liver with a portosystemic gradient of 25 mm Hg. In this case the variceal bleeding was successfully controlled by insertion of a transjugular intrahepatic portosystemic shunt (TIPS). The pathogenesis of portal hypertension in arterioportal fistulae and the role of interventional radiological techniques in the management of variceal bleeding in these patients is discussed.
Measurement of carbohydrate-deficient transferrin (CDT) in a general medical clinic: is this test useful in assessing alcohol consumption.
The aim of this study was to measure serum carbohydrate-deficient transferrin (CDT) in consecutive patients attending a general medical clinic with a range of alcohol intakes to determine its value in assessing such intake. Eighty-one consecutive patients (42 male, 39 female) aged 20-85 years (median = 49.5 years) attending an out-patient clinic were selected for the study. Each patient completed an alcohol diary detailing the units of alcohol consumed in the previous week, a CAGE questionnaire and an alcohol history, and underwent conventional blood tests including mean corpuscular volume (MCV), liver function tests, and gamma-glutamyl transferase (GGT). CDT was estimated using an enzyme immunoassay (CDTect, Pharmacia). The group comprised of 17 teetotallers, 28 light (<100 g/week), 23 moderate (100-400 g/week), and 13 heavy (>400 g/week) drinkers. Median serum CDT for heavy drinkers (25.5 U/l) was significantly higher than for the rest (median = 17 U/l, Kruskal-Wallis test, P = 0.01). Serum CDT correlated significantly with the CAGE score (Mann-Whitney test, P = 0.01), but poorly with alcohol diary records (r = 0.1, P = 0.4). However the correlations between GGT and diary records (r = 0.43, P = 0.001) and MCV with diary records (r = 0.5, P < 0.001) were significant. Sensitivity, specificity, and positive predictive value for elevated serum CDT were 69, 81 and 41% respectively in detecting heavy drinking. The positive predictive values for the various parameters were 43% for elevated serum GGT, 41% for raised erythrocyte MCV, and 75% for a positive score on the CAGE questionnaire. When a combination of the markers CDT, GGT, and MCV was used, elevation in two of the three markers detected heavy drinking with sensitivity of 85%, specificity of 88%, and positive predictive value of 61%. We conclude that, in out-patients with a wide range of alcohol intakes conventional markers such as serum GGT and erythrocyte MCV were more suitable than serum CDT for assessing alcohol intake. Serum CDT when used in combination with serum GGT and erythrocyte MCV was useful in detecting heavy drinking. The importance of careful history-taking including a standardized questionnaire is emphasized.