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Biomedical subjects

Michael A Heneghan

Publications and source records attributed to Michael A Heneghan.

At least 19 recordsLinked to original sources
PubMed2006

Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.

BACKGROUND & AIMS: The natural history of chronic portomesenteric (PM) and portosplenomesenteric (PSM) venous thrombosis is defined poorly. Therapeutic options are limited, and are directed at the prevention of variceal bleeding and the control of abdominal pain related to gastrointestinal hyperemia. METHODS: Patients with extensive PM and PSM thrombosis were reviewed retrospectively to evaluate the efficacy of medical therapy and to determine which clinical variables had prognostic significance regarding long-term survival. RESULTS: Sixty patients, with a median age at diagnosis of 44 years (range, 18-68 y), were assessed. The median follow-up period was 3.5 years (range, 0.2-32.0 y). The overall survival rate was 73.3%, with 1- and 5-year survival rates of 81.6%, and 78.3%, respectively. One- and 5-year survival rates, excluding patients who died from malignancy-related causes, were 85.7% and 82.1%, respectively. Factors associated with improved survival included treatment with beta-blockers (P = .02; odds ratio [OR], .09; 95% confidence interval [CI], 0.01-0.70) and anticoagulation (P = .005; OR, 0.01; 95% CI, <0.01 to 0.26). Eighteen patients in total were anticoagulated, including 8 patients who had variceal bleeding, all of whom underwent endoscopic band ligation of esophageal varices before anticoagulation. By using Cox regression analysis, variables associated with reduced survival were the presence of ascites (P = .001; OR, 42.6; 95% CI, 5.03-360), and hyperbilirubinemia (P = .01; OR, 13.8; 95% CI, 1.9-100) at presentation. Six patients died of variceal hemorrhage. CONCLUSIONS: Patients with chronic PM and PSM venous thrombosis without underlying malignancy have an acceptable long-term survival. Treatment with beta-blockers and anticoagulation appears to improve outcome.

Adolescent↗
PubMed2006

Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis.

BACKGROUND/AIMS: Azathioprine is a key drug in the management of autoimmune hepatitis (AIH), with effects mediated via conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP), the latter controlled by thiopurine methyltransferase (TPMT). Our aims were to evaluate the role of TPMT genotyping and phenotyping and to examine 6-TG and 6-MMP metabolite levels in patients with AIH. METHODS: TPMT genotyping and phenotyping was performed on 86 patients with AIH, and metabolites evaluated in assessable patients. RESULTS: Eighty-six patients with AIH received azathioprine; 22 developed toxicity and 4/22 were heterozygous for TPMT alleles. Cirrhosis was more common amongst patients who developed toxicity (12/22 (54.5%) versus 19/64 (29.6%), P=0.043). Patients who required persistent prednisone at equivalent azathioprine doses had a higher mean fibrosis stage (P=0.044). TPMT activity, but not metabolites, was lower in patients with stage III/IV fibrosis versus stage I/II fibrosis (30+/-1.92 versus 35.2+/-1.93, P=0.044). Azathioprine dose significantly correlated with measured 6-TG levels (r=0.409, P<0.0001) and 6-MMP levels (r=0.387, P<0.001). CONCLUSIONS: Advanced fibrosis but not TPMT genotype or activity predicts azathioprine toxicity in AIH. Overlap in 6-TG and 6-MMP metabolite levels is noted whether or not steroid therapy is used to maintain remission.

Adolescent↗
PubMed2006

Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre.

BACKGROUND/AIMS: A few reports have suggested that AIH may be less severe in the elderly and may be underdiagnosed, but there is a paucity of data. METHODS: We have undertaken a systematic analysis of 164 consecutive patients (36 males, 128 females) with definite AIH (median score 23, range 18-28) attending our clinics, comparing those presenting at age >60 years (Group 1, n=43) with those presenting at <60 years (Group 2, n=121). RESULTS: Median (range) duration of follow-up was 9 years (1-28) in Group 1 and 14 years (1-33) in Group 2. Median ages (ranges) at presentation were: Group 1=65 (60-79) and Group 2=41 (6-59). Group 1 patients had a significantly increased incidence of ascites at presentation (p<0.001) and a lower incidence of relapse (42% vs. 70%, p=0.002), but there were no significant differences between the groups with respect to mode of onset (acute, insidious, asymptomatic), other clinical signs at presentation, biochemical parameters, types or titres of autoantibodies, incidence of histological cirrhosis, response to therapy or related side effects. There were also no significant differences in liver-related deaths or transplantation, or the frequencies of HLA DR3 or DR4 - although there was an increased frequency of the A1-B8-DR3/4 haplotype in Group 2 (40% vs. 22%, p=0.138). CONCLUSIONS: These findings suggest that AIH often presents in older patients, who frequently have severe disease. Active management in these patients can lead to a normal life expectancy.

Adult↗
PubMed2006

HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study.

Twin and family studies suggest there is a significant genetic component to primary biliary cirrhosis (PBC). However, the inability to replicate reported associations has been a recurring problem, with the only consistently reported genetic association that between PBC and HLA-DRB1*0801. However, recently even this has been questioned, and a number of novel associations have also been reported. We reinvestigated HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes in a total of 492 well-characterized PBC patients, 412 from the United Kingdom and an additional 80 patients from northern Italy. There was a clear and significant association with HLA-DRB1*0801 in both groups of patients compared to population-specific healthy controls (12% versus 4% in the UK patients, P=.00087, OR=3.05; and 18% versus 6% in the Italian patients, P=.021, OR=3.15). There were also significant protective associations with DRB1*11 in the Italian patients (28% versus 47%, P=.0071, OR=0.42), but not in the UK patients (8% versus 8%) and a protective association with DRB1*13 in both series (14% versus 20%, P=.042, OR=0.65 in the UK patients; and 10% versus 31%, P=.00092, OR=0.25 in the Italian patients). In conclusion, a complex relationship exists between HLA and PBC, and some genetic associations may be population specific.

Alleles↗
PubMed2006

Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipients.

Infertility is common in women with end-stage liver disease. Successful liver transplant (LT), however, can restore childbearing potential. Controversy exists regarding the most appropriate immunosuppressive regimen and timing of conception following LT. We report the outcomes of a review of all pregnancies occurring following LT at King's College Hospital, London, from 1988 to 2004. Seventy-one pregnancies were recorded in 45 women. Tacrolimus (60%) and cyclosporin A (38%) were the predominant primary immunosuppressive agents used. Median age at conception was 29 years (range, 19-42), with a median time from LT to conception of 40 months (range, 1-111). There were 50 live births, and no maternal or fetal deaths related to pregnancy. There were no graft losses. Median gestation was 37 weeks (range, 24-42) with a median birth weight of 2,690 g (range, 554-4,260). Caesarean section was performed in 40% of pregnancies. Complications included pregnancy-induced hypertension in 20%, preeclampsia in 13%, acute cellular rejection in 17%, and renal impairment in 11%. There was no statistically significant difference in complication rates observed between immunosuppressive groups. Pregnancies occurring within 1-year posttransplant had an increased incidence of prematurity, low birth weight, and acute cellular rejection compared to those occurring later than 1 year. In conclusion, this study confirms that favorable outcomes of pregnancy post-LT can be expected for the majority of patients. However, delaying pregnancy until after 1-year post-LT is advisable, since doing so maybe associated with a lower risk of prematurity.

Adult↗
PubMed2006

Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome.

BACKGROUND & AIMS: Budd-Chiari Syndrome (BCS) results from obstruction to hepatic venous outflow, with myeloproliferative disorder (MPD) accounting for up to 40% of cases. A number of BCS cases labelled as "idiopathic" do not fulfill the diagnostic criteria for MPD but have features suggestive of a latent form based on hyperplastic bone marrow and erythroid progenitor cell culture; these cases may subsequently develop overt MPD. A clonal mutation in JAK2 tyrosine kinase (JAK2V617F) occurs in a high proportion of patients with MPD and is of use in the characterization of latent MPD in BCS. METHODS: We performed allele-specific polymerase chain reaction to screen for JAK2V617F in subjects with BCS (n = 41) and polycythemia vera (PV) (n = 20) and in hematologically normal controls (n = 27). RESULTS: AK2V617F was detected in 24 of 41 (58.5%) subjects with BCS, 19 of 20 PV controls, and 0 of 27 hematologically normal controls. Mean hemoglobin concentration and hematocrit were significantly higher in patients with JAK2V617F. Bone marrow was hyperplastic in 16 of 41 subjects (12/16 JAK2V617F positive). Nine of 33 (27.3%) showed endogenous erythroid colony formation (7/9 JAK2V617F positive). Eleven of 41 subjects developed overt MPD (8/11 essential thrombocythemia, 3/11 PV) after the diagnosis of BCS (median, 49 months; range, 8-87 months), and in 90.9% of these JAK2V617F was detected. CONCLUSIONS: JAK2V617F occurs in a high proportion of patients with BCS. Latent MPD was missed in a substantial number of our subjects by using standard techniques. Such cases should be screened for JAK2V617F and carefully observed for the subsequent development of overt MPD.

Adolescent↗
PubMed2006

Change in model for end-stage liver disease score on the transplant waiting list predicts survival in patients undergoing liver transplantation.

Allocation of donor livers through the model for end-stage liver disease (MELD) score has resulted in a fall in waiting list deaths in the United States. Change in MELD score (DeltaMELD) whilst awaiting transplant has been suggested as a method of refining organ allocation. Our aims were to analyse the effect of DeltaMELD between listing and transplant, and examine its impact on patient survival, intensive care stay and hospital stay in 402 patients transplanted for chronic liver disease at a single centre. Patients who had a DeltaMELD score of >+1 point were more likely to die in hospital following transplant (P < 0.05) and had a significantly worse 12- and 36-month survival post transplant (P < 0.0001) when compared with patients with DeltaMELD <or=+1 (77.8% vs. 91.9% at 12 months; 72.1% vs. 83.6% at 36 months). This difference persisted even when in-hospital deaths were excluded (P = 0.0148). In a Cox-proportional hazards model, factors associated with reduced survival were DeltaMELD (P = 0.008), and transplant from intensive care (P < 0.001). In conclusion, change in MELD score whilst on the transplant waiting list has a significant effect on survival post-transplant although MELD score at the time of transplant appears to have the most significant effect on resource utilization.

Adult↗
PubMed2006

Cost-effectiveness of pharmacotherapy for autoimmune hepatitis.

In > 80% of patients with autoimmune hepatitis, steroid therapy alone or in combination with azathioprine results in disease remission. Treatment response results in reversal of fibrosis and excellent long-term survival in many patients, whereas untreated patients may expect a 10-year survival of < 30%. The use of azathioprine monotherapy (2 mg/kg/day) has gained widespread acceptance in maintaining remission in clinical practice. Although all patients with autoimmune hepatitis may not need treatment, particularly those with mild disease, alternative strategies are required in patients who have failed to achieve remission on standard therapy of steroids with or without azathioprine, or patients with azathioprine-induced drug toxicity. In such circumstances, the use of salvage therapy in the form of ciclosporin, tacrolimus or mycophenolate mofetil may be warranted. Liver transplantation is the treatment of choice for patients who present with subacute liver failure or decompensated cirrhosis. Salvage therapy results in an exponential rise in cost with each increment in therapeutic escalation. As an alternative to standard therapy, it has also been suggested that novel therapies such as ciclosporin, tacrolimus or mycophenolate mofetil be initiated to achieve remission. However, a > 10-fold cost differential exists between the charges associated with more potent immunosuppression and standard therapy. Therefore, in evaluating novel immunosuppression in autoimmune hepatitis, it behoves clinicians not only to consider end points pertaining to efficacy, but also end points pertaining to cost-effectiveness. Moreover, the exact role of pharmacogenomics and genotyping of thiopurine methyltransferase in patients with autoimmune hepatitis needs to be fully defined.

Adrenal Cortex Hormones↗
PubMed2005

Current management of the hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a serious complication of advanced liver disease. Historically, the development of HRS was considered a pre-terminal event due to a lack of efficacious therapy. Although liver transplantation remains the optimum therapy for HRS, many patients may be unsuitable for liver grafting. In addition, organ shortage may necessitate the institution of alternative pharmacological therapies to bridge patients to transplantation or to maintain renal function. This article reviews the definitions of Types-1 and -2 HRS, and addresses strategies for the prevention of the syndrome. It will also discuss management approaches to the cirrhotic patient with renal failure, specifically, assessment of novel vasoconstrictor therapies, such as vasopressin analogues, alpha-adrenoreceptor agonists, and the use of transjugular intra-hepatic shunts either alone or in combination with other therapeutic agents.

Journal Article↗
PubMed2005

Effect of donor age on survival of liver transplant recipients with hepatitis C virus infection.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation (OLT) in the United States. Recent studies from selected centers have suggested that older donor age is associated with worse outcomes after transplantation for HCV. METHODS: We analyzed the United Network for Organ Sharing Liver Transplant Registry database from April 1987 to March 2003 to examine predictors of death or retransplantation in patients with HCV. Univariate models for each predictor were evaluated. Factors significant in the univariate model were used to develop a multivariable model. RESULTS: Of 6,956 patients meeting the inclusion/exclusion criteria, 1,527 (22.0%) died or received retransplants during the first year after transplant. Recipients with graft failure were older, had greater serum creatinine levels, and were more likely to require mechanical ventilation and hemodialysis before transplant. Donors of patients with graft failure were older and more likely to have diabetes mellitus. In the multivariable regression model, predictors of graft failure at 1 year were donor age, recipient age, recipient creatinine greater than 2 mg/dL, and the requirement for mechanical ventilation for the recipient. CONCLUSIONS: Both older donor age and older recipient age plus markers of severity of disease, including requirement for mechanical ventilation and renal insufficiency, are negatively associated with survival after liver transplantation. These factors should be considered when assessing OLT recipient and donor candidacy in patients with HCV.

Age Factors↗
PubMed2005

The current status of living donor liver transplantation.

In response to the critical organ shortage, transplant professionals have utilized living donors in an attempt to decrease the mortality rate associated with waiting on the liver transplant list. Although the surgical techniques were first utilized clinically 15 years ago, application of LDLT has been somewhat limited by the steep learning curve associated with developing a program. Clinical success with LDLT in children was realized early in the experience and application of the techniques to the adult population has occurred more recently. Although transplant centers embark on LDLT with enthusiasm, the safety of the donor must always be at the forefront of the process. Potential donors must come to the decision to donate without pressure from members of the family or transplant team. He/she should also be assigned advocates who constantly promote the donor's best interest. Failure to adhere to strict donor evaluation protocols and standardized operative techniques could result in disastrous consequences.

Chronic Disease↗
PubMed2003

De-novo cholangiocarcinoma in the setting of recurrent primary sclerosing cholangitis following liver transplant.

Orthotopic liver transplantation is the only definitive therapeutic option in patients with primary sclerosing cholangitis (PSC) and end-stage liver disease. However, PSC recurs in up to 20% of patients transplanted for this indication. To date, no patient has been reported to develop cholangiocarcinoma (CCA) post-transplant, without biliary tract cancer having been present pretransplant. Here, we report recurrent PSC complicated by de-novo CCA in a 31-year-old man transplanted for PSC 8 years earlier. Cholangiocarcinoma was confirmed using a combination of computed tomography, cholangiography, positron emission tomography and histological examination of biliary cytology. He has since been successfully re-transplanted following preoperative chemo-radiotherapy. No viable tumor was identified in the explanted liver. This case establishes that long-term complications associated with PSC and biliary-enteric surgery such as CCA may become apparent in new grafts post-transplant.

Adult↗
PubMed2003

An evaluation of long-term outcomes after liver transplantation for cryptogenic cirrhosis.

Patients with cryptogenic cirrhosis (CC) comprise a significant proportion of liver transplant recipients. Poor outcome after transplantation has been reported by some centers, with fibrosis occurring in a significant proportion of patients. Outcome of 46 patients with CC who underwent transplantation between 1989 and 1999 at King's College Hospital London were compared with time-matched recipients who underwent transplantation for hepatitis C virus (HCV) cirrhosis (n = 58) and patients with alcohol-related cirrhosis (AC, n = 53) during the same time period. Mean follow-up was 46 +/- 37 months for CC patients, 41 +/- 31 months for AC patients, and 49 +/- 31 months for HCV patients. No protocol liver biopsy specimens were obtained, and biopsies were performed only for investigation of biochemical abnormalities. Acute cellular rejection occurred in 30% of CC, 26% of AC, and 37% of HCV patients (P = NS). Overall patient and graft survival at 1 year was 85% and 80% for CC patients, 87% and 81% for AC patients, and 91% and 82% for patients with HCV (P = NS). Five-year patient and graft survival was 81% and 77% for CC patients, 60% and 48% for AC patients, and 79% and 57% for HCV patients (Log rank; P =.369). Twenty-two percent of CC patients had inflammation on last evaluable liver biopsy, compared with 25% of patients who underwent transplantation for AC and 68% of patients who underwent transplantation for HCV. No patient who underwent transplantation for CC had histologic evidence of cirrhosis on last evaluable biopsy, compared with 2% of patients who underwent transplantation for AC and 16% of patients who underwent transplantation for HCV (Chi-squared = 13.053, P =.0015). These results suggest that CC is a favorable indication for OLT and that although a proportion of patients develop inflammation in the liver allograft, this does not result in significant graft dysfunction or loss.

Adolescent↗
PubMed2003

Frequency and nature of cytokine gene polymorphisms in hepatocellular carcinoma in Hong Kong Chinese.

BACKGROUND: The genetic basis of susceptibility to hepatocellular carcinoma (HCC) is poorly understood. Genomic DNA was available from 98 patients with HCC, 77 familial controls, 97 controls from Hong Kong and 96 Northern European controls (NECs). METHODS: Polymorphisms of interleukin (IL)-1beta; IL-1 receptor antagonist (IL-1RN); IL-10 promoter (positions -1082, -819, and -592); and tumor necrosis factor (TNF)-alpha promoter (TNF-a -238 and -308) were investigated. RESULTS: There was marked restriction in the distribution of the IL-1beta and IL-1RN genotypes among Chinese subjects with a predominance of the IL-1beta*1,1 and IL-1RN*1,1 (for unrelated controls compared with NECs only for IL-1beta: chi2 = 15.32, Pc = 0.000091 and for IL-1RN: chi2 = 16.08, Pc = 0.000061). For IL-10, the distribution of alleles was reversed in Chinese vs NECs. The TNFA*2 allele (TNFA -308 A), which is associated with high TNF-alpha production both in vivo and in vitro, was found in <10% of Chinese but was present in 33% of NECs (chi2 = 21.52, Pc <0.0000035). CONCLUSION: Though this study failed to highlight specific associations between any of the polymorphisms tested and the HCC in Hong Kong Chinese, the differences in the distribution of tested alleles may, in part, account for the increased susceptibility of the Chinese population to develop HCC.

Adolescent↗