John E. Hegarty

Bone density, vitamin D status, and disordered bone remodeling in end-stage chronic liver disease.

Abstract. Hepatic osteodystrophy occurs in up to 50% of patients with chronic liver disease (CLD). The aim of this study was to determine the relative contribution of increased resorption and decreased formation to hepatic osteodystrophy by measuring biochemical markers. Twenty-seven patients with advanced CLD (14 female, 13 male) were enrolled. Bone mineral density (BMD), measured at the lumbar spine, and femoral neck, were measured by dual energy X-ray absorptiometry (DXA); bone turnover was assessed using biochemical markers of bone formation and resorption. Based on WHO criteria, osteoporosis and osteopenia were present in 41% and 18% of patients, respectively. All three markers of bone resorption (free deoxypyridinoline, pyridinoline, and hydroxyproline) were increased significantly in patients with CLD. There was a less marked change in the markers of bone formation (osteocalcin, procollagen type 1 peptide, and bone alkaline phosphatase), resulting in a negative uncoupling index in 23/27 (85%) of the patients. Only two (7%) patients had biochemical changes consistent with osteomalacia. The results suggest that increased bone resorption is the predominant cause of hepatic osteodystrophy and therapeutic strategies should be designed to suppress bone resorption, especially in preparation for liver transplantation. Bone biomarkers may be useful alternatives to bone biopsy in evaluating hepatic osteodystrophy.

Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression

We report two cases of recurrence of primary biliary cirrhosis (PBC) in the transplanted liver whilst maintained on a FK506-based immunosuppressive regime, the first to be described. One patient experienced symptoms in association with the development of cholestasis. In both there was a persistence of serological markers of PBC and liver histology revealed florid bile duct destruction and a granulomatous reaction.

Chronic hepatitis C infection blocks the ability of dendritic cells to secrete IFN-α and stimulate T-cell proliferation

Summary.u2002 Dendritic cells (DCs) are likely to play a key role in the compromised T‐cell function associated with hepatitis C Virus (HCV) infection. However, studies of DC function in HCV‐infected patients to date have yielded conflicting findings possibly because of patient and virus heterogeneity. Here, we report the characterization of monocyte‐derived DCs obtained from a homogenous cohort of women who were infected with HCV genotype 1b following exposure to contaminated anti‐D immunoglobulin from a single donor source. Patients included in the study had not received anti‐viral therapy and all had mild liver disease. We show that phenotypically normal monocyte‐derived dendritic cells (MDDCs) (CD11c+HLA−DR+CD1a+CD14lo) can be obtained from these patients. These cells respond to both Poly(I:C) and LPS, by up‐regulating expression of CD86. They secrete high levels of IL‐8 and CCL5 in response to LPS, an indication that the MyD88‐dependent and MyD88‐independent signalling pathways downstream of TLR4 ligation are functioning normally. However, these cells are poor stimulators of T‐cell proliferation in allogeneic mixed lymphocyte reactions. Furthermore, patient MDDCs fail to secrete IFN‐α in response to poly(I:C) or IFN‐β stimulation. Altered DC function may contribute to impaired cellular immune responses and chronicity of disease following HCV infection in this cohort. An effective therapeutic vaccine for chronic HCV infection will most likely need to target DCs to elicit an appropriate cellular response; therefore, it is important to resolve how the DCs of different patient cohorts respond to stimulation via TLRs.

T Lymphocyte Subsets and Activation Status in Patients Following Liver Transplantation

Changes in T-lymphocyte subsets have previously been shown to relate to clinical events following liver transplantation and be of prognostic significance following renal transplantation. The aim of this study was to examine T lymphocyte subsets, their activation status and the mean fluorescence intensity of cell surface markers by flow cytometric analysis, in peripheral blood of patients following liver transplantation. Stable transplant patients (n=11) had a significantly higher level of activation (HLA-DR expression ) of all T cell subsets: CD3, CD4 and CD8 compared to healthy controls: 17.5% +/- 14.0 (mean +/- SD) vs 4.7 +/- 1.8 (p=0.04), 13.7% +/- 10.3 vs 4.3 +/- 1.7 (p=0.03) and 23.8% +/- 19.9 vs 3.6 +/- 2.4 (p=0.02) respectively. A further increase in activation status occurred in all T cell subsets in association with acute cellular rejection, reaching significance for the CD4+ population: 13.7% +/- 10.2 vs 23.3% +/- 20.6 (p=0.04). The mean fluorescence intensity of the CD3+DR- and CD3+ DR+ populations were increased to 1397 +/- 869 and 1282 +/- 810 following liver transplantation compared to values of 425 +/- 204 and 376 +/- 166 respectively for controls (p<0.05). T-lymphocytes maintain a high level of activation following liver transplantation and continue to express high levels of the surface marker CD3, which may account for the occurrence of acute cellular rejection despite immunosuppression in these patients.

Elevated circulating osteoprotegerin and reduced matrix-metalloprotease-9 in post-menopausal women with chronic Hepatitis C virus infection

The failure of the immune response to clear the Hepatitis C virus (HCV) results in chronic inflammation that leads to liver cirrhosis. In general, women have a better prognosis than men and this may be associated with increased levels of anti-inflammatory mediators that are positively regulated by female sex hormones. Our aim was to determine if a cohort of Irish women who acquired infection through administration of HCV genotype 1b-contaminated anti-D immunoglobulin from a single source, had altered levels of circulating cytokine levels compared to women who spontaneously resolved infection, men with HCV infection or age-matched healthy controls. Twenty post-menopausal women and 20 men with chronic HCV infection (genotype 1), 20 post-menopausal women who resolved infection and age and sex-matched controls were recruited for the study. Levels of circulating cytokines were assessed by ELISA. Circulating IL-6, Oncostatin-M, TNF-α, CXCL10, CCL18, VEGF and GM-CSF did not differ between groups. Both men and women with HCV had significantly elevated levels of circulating Osteoprotegerin (OPG). However, male but not female HCV patients had elevated levels of circulating Matrix Metalloprotease-9 (MMP-9). An increased OPG: MMP-9 ratio in the circulation of females compared to males with chronic HCV may help protect against HCV-associated liver disease and explain the slow progress of liver disease in this cohort.