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Biomedical subjects

M A Heneghan

Publications and source records attributed to M A Heneghan.

At least 19 recordsLinked to original sources
PubMed2006

The impact of diabetes mellitus on fibrosis progression in patients transplanted for hepatitis C.

Despite the recognition of numerous factors for aggressive hepatitis C virus (HCV) recurrence after liver transplantation (LT) our understanding of this phenomenon is incomplete. We tested the hypothesis that diabetes mellitus (DM) was implicated. One hundred sixty-three patients undergoing primary LT for HCV from 1990 to 2004 were evaluated and biopsies were scored according to the modified Ishak score. Severe recurrence of HCV was defined as a fibrosis score > or = 4 within 6 years of LT. Risk factors assessed included recipient, donor and transplant variables. Fifty-four patients (33.1%) had a fibrosis score > or = 4 at the end of the study period. Factors associated with progression to severe fibrosis was donor age (p = 0.008) especially donor age >55 (p = 0.038, HR 2.43), pre-LT DM (p = 0.039, HR 2.68) and DM post-LT (p = 0.004, HR 3.28). The combination of receiving a liver from a donor older than 55 years and having DM post-LT was associated with an 8.38-fold risk of progression to severe fibrosis (p = 0.000124) when compared to patients not diabetic post-LT who received livers from donors aged <55 years. These data indicate that diabetic status is one of the more important variables determining the severity of HCV recurrence and is synergistic with donor age. This observation may provide an additional management opportunity to modify the impact of HCV recurrence.

Adult↗
PubMed2006

Myeloma associated amyloidosis presenting as subacute liver failure.

Multiple myeloma related amyloidosis is rare and its presentation with subacute liver failure (SALF) has not been reported. A case is described of a 46 year old woman presenting with a six week history of nausea, abdominal pain, and jaundice. Routine tests failed to establish a cause. Computed tomography showed a small volume liver consistent with SALF. Emergency liver transplantation was not undertaken because of the suspicion of underlying malignancy. At necropsy, liver biopsy showed amyloid deposition and bone marrow biopsy showed multiple myeloma. Thus, amyloidosis should be added to the list of potential causes of SALF.

Amyloidosis↗
PubMed2005

Anti-interleukin 2 receptor antibodies and mycophenolate mofetil for treatment of steroid-resistant rejection in adult liver transplantation.

BACKGROUND: Steroid-resistant rejection (SRR) results in significant morbidity and mortality from the adverse effects of rescue therapy and in graft loss from chronic rejection. In our knowledge, the efficacy and safety of anti-interleukin (IL) 2r antibodies (daclizumab and basiliximab) for the treatment of SRR in adult liver transplantation has not previously been evaluated. METHODS: Twenty-five patients received either daclizumab or basiliximab as rescue therapy for SRR. Outcome and biochemical parameters were recorded before and after treatment with an anti-IL-2r antibody. RESULTS: The median time from transplantation to SRR was 25 days. Secondary immunosuppression included mycophenolate mofetil in 18 patients. Twelve patients (48%) had complete resolution of SRR. Aspartate transaminase levels normalized at a median of 37 days (range, 1-168 days). In 13 patients (52%) progressive hepatic dysfunction developed. Four of these patients received another transplant, and 6 patients had chronic rejection. Three patients died with graft failure. Of 16 patients with acute cellular rejection, 12 (75%) had resolution, 2 had chronic rejection, 1 required a repeat transplantation, and 1 died with graft failure. In contrast, all 9 patients with established chronic rejection in their pretreatment biopsy continued to have significant graft dysfunction, with 4 having persistent chronic graft dysfunction, 3 requiring repeat transplantation, and 2 dying with graft failure. CONCLUSION: Twelve (48%) of 25 patients who received an anti-IL-2r antibody because of SRR were successfully treated. All successfully treated patients had ongoing acute cellular rejection at liver biopsy (75%), whereas patients with histologic evidence of chronic rejection responded poorly.

Adolescent↗
PubMed2002

Characteristics of autoimmune hepatitis in patients who are not of European Caucasoid ethnic origin.

BACKGROUND: Significant diversity in disease severity has been identified for autoimmune disorders among different ethnic groups but there is a lack of data on autoimmune hepatitis (AIH) in populations other than those of European Caucasoid (EC) or Japanese extraction. AIMS: To assess the clinical features, response to therapy, and eventual outcome in AIH patients of non-EC ethnicity. METHODS: A retrospective review of a regularly updated database of patients with AIH referred to liver outpatient clinics at King's College Hospital, London, since 1983. RESULTS: Twelve patients were identified (10 female; six African, five Asian, one Arabic; median age at presentation 30 years (range 12-58)) who satisfied international criteria for type 1 (11 cases) or type 2 (one case) AIH. Nine (75%) had cholestatic serum biochemistry and three (25%) had mild biliary changes on liver biopsy without definitive features of primary biliary cirrhosis or cholangiographic evidence of primary sclerosing cholangitis. Four showed a complete biochemical response to standard prednisolone with or without azathioprine therapy, three partial, and five no response. Four have required liver transplantation for intractable disease. By comparison with 180 EC patients with definite AIH attending during the same period, the non-EC patients were younger (p<0.05), presented with cholestatic biochemistry (p=0.014), and morphological biliary features more frequently (p<0.0005) and showed a poorer initial response to standard therapy (p<0.0005). CONCLUSIONS: Clinical expression of AIH in non-EC patients seems to differ in important respects from that in EC or Japanese patients. Management of such patients is challenging and may require alternative or more aggressive treatment strategies.

Adolescent↗
PubMed2001

Expression of Fas antigen (CD95) in peripheral blood lymphocytes and in liver-infiltrating, cytotoxic lymphocytes in patients with hepatocellular carcinoma.

BACKGROUND: Fas-expressing cytotoxic T lymphocytes (CTLs) are important antitumor immune effector cells in patients with hepatocellular carcinoma (HCC). The role of transforming growth factor beta 1 (TGF-beta1) in modulating the expression of Fas by CTLs is not known in HCC. The objectives of this study were to characterize the expression of Fas by CTLs and natural killer (NK) cells among peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) in patients with HCC and to correlate the association, if any, with serum TGF-beta1 levels. METHODS: PBLs from 18 patients with HCC and TILs from 5 HCC liver specimens were isolated, and Fas expression was analyzed by three-color flow cytometry. The results were compared with results from normal control volunteers (n = 19 individuals). Serum TGF-beta1 levels in patients with HCC were measured by enzyme-linked immunosorbent assay. RESULTS: The median percentage of Fas expression by CD3 positive T cells was significantly higher in patients with HCC compared with normal controls (54.37% vs. 32.03%, respectively; P = 0.0036), and this was attributable solely to Fas expression by CD4 positive PBLs (54.46% vs. 34.90%, respectively; P = 0.0234). In contrast, Fas expression was significantly higher in all the subtypes of TILs (CD3 positive, CD4 positive, CD8 positive, NK cells, and natural T cells) compared with controls (all P values were < 0.001). Tumor size was inversely proportional to the TGF-beta1 levels (correlation coefficient [r] = -0.725; P < 0.0001), which were correlated inversely with Fas expression by CD4 positive PBLs (r = -0.516; P = 0.01). CONCLUSIONS: In patients with HCC, TILs exhibit significantly increased expression of Fas compared with PBLs that may enhance their susceptibility to apoptotic mechanisms. Larger tumors were associated with lower serum TGFbeta1 levels, and this was correlated with greater Fas expression by CD4 positive PBLs.

Adult↗
PubMed2001

Conversion from cyclosporine to FK506 in adult liver transplant recipients: a combined North American and European experience.

BACKGROUND: Although cyclosporine (CsA) made clinical liver transplantation possible, side effects and development of rejection have limited its use. In some patients, conversion to tacrolimus has been necessary to abrogate side effects and to preserve allograft function. METHODS: The results of conversion from CsA to tacrolimus were studied retrospectively in 94 liver allograft recipients from a North American and a European transplant center (Duke University Medical Center, Durham, NC, and Hopital Beaujon, Clichy, France). RESULTS: Forty-seven of 94 patients (50%) were converted for steroid-resistant acute rejection. Conversion was successful in 91% of these patients, whereas 9% of patients developed chronic rejection. A further nine patients were converted for chronic allograft rejection with positive results in eight of nine grafts. Mean serum bilirubin in these nine patients was 8.7 mg/dl before conversion and 2.1 mg/dl 6 months after conversion (P=0.02). Nine patients were converted due to inability to wean steroid. Of these, six patients remains steroid free 1 year after conversion. Twenty-three patients (24%) were converted for nephrotoxicity with a reduction in serum creatinine from 167+/-36 mmol/L to 119+/-28 mmol/L 1 year after conversion (P=0.006). Eight of 11 patients converted for neurotoxicity improved after conversion. Conversion to tacrolimus had no effect on seizure frequency or memory loss. CONCLUSIONS: These results suggest that conversion to tacrolimus from CsA is an appropriate paradigm for graft rescue and treatment of a variety of side effects after liver transplant. However, some situations such as memory loss and hypertension may require other strategies.

Adult↗
PubMed2001

Graft dysfunction mimicking autoimmune hepatitis following liver transplantation in adults.

In children, a type of graft dysfunction associated with autoimmune features has been described. We have identified 7 adult liver-transplant (LT) recipients from a series of over 1,000 consecutive transplant recipients who presented between 0.3 years and 7.2 years following transplantation with characteristic symptoms, autoantibody profiles, and histologic findings of autoimmune disease. The indications for transplantation were Ecstasy overdose, alcohol-related cirrhosis, primary sclerosing cholangitis (PSC) (2), primary biliary cirrhosis (PBC), hepatitis C cirrhosis, and cryptogenic cirrhosis. Two patterns of de novo autoantibody development were noted; anti-liver-kidney-microsome (LKM) antibody development at high titer in association with an aspartate transaminase (AST) > 500 and antinuclear (ANA) and antismooth muscle (AMA) antibody development at titers >1/80 with lower AST levels. All cases had elevated IgG. Liver biopsies showed changes of an autoimmune-type hepatitis with portal and periportal hepatitis in association with a marked infiltrate of plasma cells, lymphocytes, and bridging collapse. Two patients lost their grafts because of the disease. Patients were treated with reintroduction of steroids and azathioprine in cases in which it had been withdrawn. Major histocompatibility class I and II mismatching did not incur risk. Eight of 12 liver allografts were acquired from either DRB*0301- or DRB*0401-positive donors, and 4 recipients were DRB*0301-positive. This series illustrates that both symptoms and histologic findings of graft dysfunction compatible with autoimmune hepatitis (AIH) exist in adult LT recipients. Graft loss may be a consequence. This entity may represent a specific type of rejection that should currently be classified as "graft dysfunction mimicking autoimmune hepatitis."

Adult↗
PubMed2001

Biliary stricture secondary to donor B-cell lymphoma after orthotopic liver transplantation.

Biliary complications after orthotopic liver transplantation (OLT) lead to considerable morbidity and occasional mortality after surgery. Bile duct strictures secondary to localized lymphoproliferative disorder of the porta hepatis is rare, with only 12 cases reported in the English literature. Posttransplant lymphoproliferative disorder develops in up to 9% of liver allograft recipients. We describe 2 adult patients who developed Epstein-Barr virus-associated localized B-cell lymphoma of donor-tissue origin confined to the porta hepatis 3 and 5 months after OLT. Both patients were administered cyclosporine (CyA) and prednisone as primary immunosuppression. One patient was administered basiliximab as induction therapy. Neither patient had CyA trough levels greater than 250 ng/mL. Both patients were treated with a hepatojejunostomy, 75% reduction in immunosuppression therapy, and acyclovir. One patient had complete involution of the tumor, and the second patient had an 80% reduction of the tumor at the 2-year follow-up visit. This report illustrates the need to consider localized lymphoma post-OLT as a cause of obstructive jaundice even within the first 6 months after surgery. Aggressive reduction of immunosuppression in conjunction with acyclovir remains a highly effective therapy.

Acyclovir↗
PubMed2001

Relationship of anti-Lewis x and anti-Lewis y antibodies in serum samples from gastric cancer and chronic gastritis patients to Helicobacter pylori-mediated autoimmunity.

Lewis (Le) antigens have been implicated in the pathogenesis of atrophic gastritis and gastric cancer in the setting of Helicobacter pylori infection, and H. pylori-induced anti-Le antibodies have been described that cross-react with the gastric mucosa of both mice and humans. The aim of this study was to examine the presence of anti-Le antibodies in patients with H. pylori infection and gastric cancer and to examine the relationships between anti-Le antibody production, bacterial Le expression, gastric histopathology, and host Le erythrocyte phenotype. Anti-Le antibody production and H. pylori Le expression were determined by enzyme-linked immunosorbent assay, erythrocyte Le phenotype was examined by agglutination assays, and histology was scored blindly. Significant levels of anti-Le(x) antibody (P < 0.0001, T = 76.4, DF = 5) and anti-Le(y) antibody (P < 0.0001, T = 73.05, DF = 5) were found in the sera of patients with gastric cancer and other H. pylori-associated pathology compared with H. pylori-negative controls. Following incubation of patient sera with synthetic Le glycoconjugates, anti-Le(x) and -Le(y) autoantibody binding was abolished. The degree of the anti-Le(x) and -Le(y) antibody response was unrelated to the host Le phenotype but was significantly associated with the bacterial expression of Le(x) (r = 0.863, r(2) = 0.745, P < 0.0001) and Le(y) (r = 0.796, r(2) = 0.634, P < 0.0001), respectively. Collectively, these data suggest that anti-Le antibodies are present in most patients with H. pylori infection, including those with gastric cancer, that variability exists in the strength of the anti-Le response, and that this response is independent of the host Le phenotype but related to the bacterial Le phenotype.

Adolescent↗
PubMed2001

Management and outcome of pregnancy in autoimmune hepatitis.

BACKGROUND: There is a paucity of data in the literature on the risks associated with, and optimal management of, pregnancy in patients with autoimmune hepatitis (AIH). AIMS: To assess maternal and fetal outcomes in relation to clinical management of pregnancy in a large cohort of patients with well defined AIH. METHODS: A review of all known pregnancies in 162 females with definite AIH attending our clinics between 1983 and 1998, with respect to treatment, natural history, and outcome. RESULTS: Thirty one live births (one twin) resulted from 35 pregnancies in 18 women (seven with cirrhosis). Median age at conception was 28 years (range 18-36). Two patients presented with AIH de novo during pregnancy. At conception, in 15 pregnancies patients had been receiving azathioprine alone or (in nine) with prednisolone, in seven prednisolone alone, and in one cyclosporin. Fetal loss at > or =20 weeks' gestation occurred in two instances. Flares in disease activity occurred during four pregnancies and within three months of delivery in a further four. Among the 31 children born (median follow up 10 years) only two abnormalities have been identified: Perthes' disease in one and severe mental and physical handicap in a second who was born prematurely following decompensation of the mother's liver disease. Neither mother was receiving azathioprine. CONCLUSIONS: Successful completion of pregnancy is a realistic expectation for patients with well controlled AIH. Treatment options vary, but azathioprine appears to be generally safe and without adverse outcomes for mother or baby. Vigilance is required, however, and patients need to be monitored carefully during pregnancy and for several months post partum.

Adolescent↗
PubMed2001

Cholestatic diseases of liver transplantation.

Cholestasis is a common finding after liver transplantation and usually signifies graft dysfunction. The most important factor in the evaluation of patients with cholestasis is an awareness of the disorders that commonly arise along a time continuum post-transplant. Therefore, the approach to cholestasis requires a systematic review of biochemical, histological, and radiographic data. This article considers the causes of cholestasis in liver transplant recipients, excluding those associated with biliary anastomotic stricturing. These causes include conditions as diverse as ischemia reperfusion injury, ABO blood group incompatibility, hepatic arterial thrombosis, cytomegalovirus infection, fibrosing cholestatic hepatitis secondary to hepatitis B and C viruses, recurrent primary sclerosing cholangitis, recurrent primary biliary cirrhosis, and chronic rejection. Also examined are management issues pertinent to these conditions and strategies used in preventing or diminishing the effects of cholestasis once established.

Adult↗
PubMed2001

Digestive disease week 2001. American association for the study of liver diseases. 19-23 May 2001, Atlanta, GA, USA.

All aspects of hepatology were represented at this year's meeting of the American Association for the Study of Liver Diseases (AASLD), although the meeting was dominated by a proliferation of information in the arena of viral hepatitis. In an international multicenter study of over 1000 treatment-naive patients with hepatitis C virus (HCV) infection, sustained virological response was found in 56% of patients who received PEGylated interferon (IFN) alpha-2a (Pegasys; F Hoffmann-La Roche) in combination with ribavirin (Virazole; ICN Pharmaceuticals), versus 45% in patients who received IFN alpha-2b and ribavirin therapy, and 30% of patients who received PEG. This is a significant improvement on currently licensed therapy and will define practice patterns for the next decade. In other areas, novel therapies such as silymarin for cholestatic liver disease, L-dT (Novirio Pharmaceuticals Inc), herbal therapy, combination therapies including amantadine and mycophenolate mofetil (Roche Holding) for viral hepatitis, and long-acting octreotide (Sandostatin LAR Depot; Novartis) for portal hypertension, were presented. This review represents the best of AASLD at DDW 2001.

Journal Article↗
PubMed2000

Relationship of blood group determinants on Helicobacter pylori lipopolysaccharide with host lewis phenotype and inflammatory response.

As Lewis a (Le(a)) and Lewis b (Le(b)) blood group antigens are isoforms of Lewis x (Le(x)) and Lewis y (Le(y)) and are expressed in the gastric mucosa, we evaluated whether the patterns of expression of Le(x) and Le(y) on Helicobacter pylori lipopolysaccharides reflected those of host expression of Le(a) and Le(b). When 79 patients (secretors and nonsecretors) were examined for concordance between bacterial and host Le expression, no association was found (chi(2) = 5.734, 3 df, P = 0.125), nor was there a significant difference between the amount of Le(x) or Le(y) expressed on isolates from ulcer and chronic gastritis patients (P > 0.05). Also, the effect of host and bacterial expression of Le antigens on bacterial colonization and the observed inflammatory response was assessed. In ulcer patients, Le(x) expression was significantly related to neutrophil infiltration (r(s) = 0.481, P = 0.024), whereas in chronic gastritis patients significant relationships were found between Le(x) expression and H. pylori colonization density (r(s) = 0.296, P = 0.03), neutrophil infiltrate (r(s) = 0.409, P = 0. 001), and lymphocyte infiltrate (r(s) = 0.389, P = 0.002). Furthermore, bacterial Le(y) expression was related to neutrophil (r(s) = 0.271, P = 0.033) and lymphocyte (r(s) = 0.277, P = 0.029) infiltrates. Thus, although no evidence of concordance was found between bacterial and host expression of Le determinants, these antigens may be crucial for bacterial colonization, and the ensuing inflammatory response appears, at least in part, to be influenced by Le antigens.

Adolescent↗
PubMed1999

Microsatellite instability in sporadic colorectal carcinoma is not an indicator of prognosis.

Fifty sporadic colorectal carcinomas diagnosed in 1991 were analysed for microsatellite instability at four loci. Five of 50 (10 per cent) tumours showed replication errors (RERs) at two or more loci and were classed as RER-positive (RER+). A further five showed RERs at one locus only. A significant association (Fisher exact test) was found between RER+ tumours and location in the proximal colon, exophytic shape, size >5 cm, histological margin, lymphoid reaction, and near-diploid DNA content. There was no significant difference for age, sex, grade, mucin production, p53 protein overexpression or Duke's stage. There was no significant difference in survival as measured over a 60-month follow-up period. The findings, though limited by the small case numbers involved, show an association between RER positivity in sporadic colorectal tumours and certain clinico-pathological features. They do not suggest a better clinical outcome for sporadic RER+ tumours.

Adenocarcinoma↗
PubMed1999

Liver transplantation for malignant disease.

For many patients with malignant disease of the liver, liver transplantation offers the only opportunity for clinical cure or prolonged palliation. As a result of organ scarcity, patients are increasingly selected on the basis of tumour stage and with the predictable likelihood of prolonged survival in mind. Consequently, 3- and 5-year survival rates of 72% and 68% respectively have been described for patients transplanted with hepatocellular carcinoma for tumours measuring less than 5 cm in diameter or up to three in number. Moreover, many centres are developing adjuvant and neo-adjuvant therapeutic protocols to minimize the risks of disease recurrence following transplantation for malignancy. In this chapter, we review the current knowledge in relation to transplantation for hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cholangiocarcinoma, metastatic neuroendocrine tumours, secondary solid tumours and other rarer malignancies.

Carcinoma, Hepatocellular↗