Effectiveness of interferon-free therapy for the treatment of HCV-patients with compensated cirrhosis treated through the Irish early access program.

BACKGROUND: We investigated the real-world effectiveness of interferon-free regimens for the treatment of patients with compensated cirrhosis infected with hepatitis C virus (HCV). METHOD: Using the Irish national HCV treatment registry, the effectiveness and safety of interferon-free regimens for HCV-infected patients treated between April 2015 and August 2016, was determined. RESULTS: A SVR12 was achieved in 86% of subjects treated with sofosbuvir/ledipasvir ± ribavirin (SOF/LDV±RBV), 93% treated with paritaprevir, ombitasvir and ritonavir combined with dasabuvir ± ribavirin (3D±RBV) and 89% treated with sofosbuvir/daclatasvir ± ribavirin (SOF/DCV±RBV). The discontinuation rate was 5% and the on-treatment mortality rate was 1%. CONCLUSION: The availability of interferon-free regimens represents a significant breakthrough for the treatment of HCV infection. Treatments options, with high SVR12 rates, are now available for patients with compensated cirrhosis who were unsuitable for treatment with interferon-based regimens. Data obtained from studies conducted in real world practice provide robust information fundamental for input into future economic evaluations for agents used for the treatment of HCV infection.

Helicobacter pylori: prevalence of antimicrobial resistance in clinical isolates.

This study aims to determine the in vitro susceptibility of Helicobacter pylori to clarithromycin, metronidazole, amoxycillin and tetracycline, the four antibiotics commonly used in eradication therapies. These data are used to evaluate the efficacy of current empiric treatment of H. pylori infection in the Southern Region of Ireland. Culture is performed on gastric biopsy samples obtained from 147 consecutive patients undergoing gastroscopy for investigation of dyspepsia. Susceptibility testing to metronidazole, clarithromycin, amoxycillin and tetracycline is performed on the isolates by Etest. Isolates demonstrating clarithromycin resistance are subjected to polymerase chain reaction (PCR) amplification and nucleotide sequence analysis to identify the presence of point mutations in the peptidyltransferase region of the 23S rRNA gene previously associated with resistance to clarithromycin. Prevalence of H. pylori in the population studied was 31% (45 isolates). Antimicrobial resistance to metronidazole and clarithromycin was detected in nine (20%) and four (8.9%) of the isolates, respectively. A single isolate demonstrated co-resistance to metronidazole and clarithromycin (2.2%). No resistance was detected to either amoxycillin or tetracycline. The low level of resistance demonstrated among this group of isolates indicates that the empiric treatment currently in place in the Southern Region of Ireland is likely to be successful.

Liver transplantation for hepatitis C virus related cirrhosis.

Hepatitis C virus (HCV) related chronic liver disease is now the leading cause for liver transplantation in many centres. Virological recurrence is inevitable following liver transplantation. Excellent patient and graft survival are seen in the short-term, equivalent to that in patients transplanted for other causes of liver disease. However, histological evidence of disease recurrence or hepatitis is present in over half the patients within a year of transplantation, although a small percentage develop progressive cholestatic hepatitis with graft loss within a year. Cirrhosis can develop in the first year after transplantation and 28% of patients have evidence of cirrhosis by 5 years. There is little agreement over the factors that predict the recurrence of disease, development of cirrhosis within the graft and graft or patient survival. Graft loss due to HCV occurs in up to 9% at 5 years and the long-term prognosis may not be comparable to groups transplanted for other diseases. Patients with hepatocellular carcinoma may benefit from liver transplantation if the tumour is small and without vascular invasion. There are, as yet, no clear guidelines regarding the best combination of immunosuppressants in patients with HCV but viral clearance has been achieved with the use of interferon and ribavirin therapy post-operatively.

In vitro evidence for the presence of hematopoietic stem cells in the adult human liver.

Previous studies have identified novel lymphoid phenotypes in the adult human liver and provided evidence to suggest that lymphoid differentiation can occur locally in this organ. The aim of this study was to examine the adult human liver for the presence of hematopoietic stem cells that may provide the necessary precursor population for local hematopoietic and lymphoid differentiation. Hepatic mononuclear cells (HMNC) were extracted from normal adult liver biopsy specimens using a combination of mechanical disruption and enzymatic digestion. The stem cell marker CD34 was found on 0.81% to 2.35% of isolated HMNCs by flow cytometry. CD34(+) HMNCs were positively selected using magnetically labeled beads, and the enriched population was further examined for surface markers characteristically expressed by immature hematopoietic cells and early progenitors. CD45 was expressed by 49% (+/-23%) of CD34(+) HMNCs, indicating their hematopoietic origin. CD38, one of the first markers to be expressed by developing progenitor cells was found on 50% (+/-22%) of CD34(+) HMNCs indicating the presence of both pluripotent stem cells and committed precursors. The majority (90%) of CD34(+) HMNCs coexpressed the activation marker human leukocyte antigen DR, consistent with actively cycling cells. Functional maturation of these hepatic progenitors was shown by the detection of multilineage hematopoietic colony formation after tissue culture. Erythroid (BFU-E), granulocyte-monocyte (CFU-GM), and mixed colonies (CFU-GEMM) were detected after culture of unseparated HMNCs and the enriched CD34(+) HMNC population; 14.3 +/- 13.2 (mean +/- SD) BFU-E, 3.1 +/- 3.1 CFU-GM, and 0.4 +/- 0.9 CFU-GEMM per 1 x 10(5) unseparated HMNCs and 16.0 +/- 9.5 BFU-E and 1.7 +/- 0.9 CFU-GM were identified per 2.4 x 10(3) CD34(+) HMNCs plated. The detection of surface markers characteristic of immature hematopoietic cells and colony formation in tissue culture provides evidence for the presence of hematopoietic stem cells and early progenitor cells in the adult human liver. This would suggest that the adult human liver continues to contribute to hematopoiesis and may be an important site for the differentiation of lymphohematopoietic cells involved in disease states, such as autoimmune hepatitis and graft rejection after liver transplantation.

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

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.

Predicting bone loss following orthotopic liver transplantation.

BACKGROUND: Hepatic osteodystrophy occurs in the majority of patients with advanced chronic liver disease with the abnormalities in bone metabolism accelerating following orthotopic liver transplantation (OLT). AIMS: To examine changes in bone mineral density (BMD) following OLT and to investigate factors that lead to bone loss. METHODS: Twelve patients had BMD (at both the lumbar spine (LS) and femoral neck (FN)) and biochemical markers measured preoperatively and for 24 months following OLT. RESULTS: BMD was low in 75% of patients prior to OLT and decreased significantly from baseline at the LS at three months and the FN at six months. BMD began to increase thereafter at both sites, approaching baseline values at the LS by 12 months. Bone formation markers, osteocalcin and procollagen type I carboxy propeptide, decreased immediately post-OLT, with a concomitant increase seen in the resorption markers pyridinoline and deoxypyridinoline. This resulted in a negative uncoupling index early post-OLT, that rebounded to positive values after six months. There was a significant correlation between the change in the uncoupling index between six and three months which preceded the increase in BMD at 12 months. The decrease in BMD recorded early post-OLT correlated with vitamin D levels at three months. CONCLUSIONS: Results suggest that increased resorption and inadequate formation are the major contributors to additional bone loss following OLT. Non-invasive biochemical markers precede later changes in BMD in this patient group following OLT and may have a role in investigating and planning intervention strategies to prevent bone loss in future studies.

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.

Tranexamic acid for severe bleeding gastric antral vascular ectasia in cirrhosis.

BACKGROUND: It is believed that severe portal hypertensive gastropathy probably accounts for most non-variceal bleeding episodes in patients with cirrhosis. Gastric antral vascular ectasia (GAVE) also occurs in these patients. It is not clear whether it is a variant of portal hypertensive gastropathy or a distinct condition. PATIENT: A patient, a 66 year od woman, with cirrhosis initially diagnosed as having portal hypertensive gastropathy and subsequently classified as GAVE is described. She required transfusion with a total of 130 units of packed red cells for gastrointestinal blood loss. RESULTS: The bleeding did not respond to portal decompression with TIPS or beta blockers. Following treatment with oral tranexamic acid she has not required further blood transfusion over a period of 30 months. CONCLUSION: Tranexamic acid may be a useful treatment for refractory bleeding due to gastric antral vascular ectasia in patients with cirrhosis.

Changes in peripheral blood double-negative T-lymphocyte (CD3+ CD4- CD8-) populations associated with acute cellular rejection after liver transplantation.

Circulating CD3+ T lymphocytes that express neither the CD4 nor CD8 surface molecules (double-negative T lymphocytes) are phenotypically and functionally distinct from single-positive CD3+CD4+ and CD3+CD8+ lymphocytes and are thought to represent a distinct T-cell lineage. The presence of low numbers of double-negative T cells in healthy individuals and the increase observed in association with lymphoproliferative disorders, graft-versus-host disease, and autoimmune diseases suggest a pathogenic or immunoregulatory role for this population of T lymphocytes. In this study, peripheral blood double-negative T cells were assessed quantitatively using three-color flow cytometry in 10 patients after liver transplantation during a 6-week period. During this time, 12 episodes of histologically proven acute cellular rejection occurred in 8 patients. The median postoperative baseline double-negative T-cell count expressed as a proportion of the CD3+ T cells was 2.4 +/- 1.2 (median +/- SD; n = 10), which was identical to a control group of healthy adults (2.5 +/- 2.4; n = 9). Circulating numbers of double-negative T cells were increased significantly during acute cellular rejection (6.8 +/- 6.7; P < .001; n = 12). After pulse corticosteroid therapy for rejection, there was a significant decrease in the double-negative T-cell population (3.5 +/- 5.0 v 6.8 +/- 6.7; P = .01). No significant changes occurred in the double-negative T-cell count in the absence of clinical events (2.4 +/- 3.5; n = 73). These findings are consistent with a role for double-negative T cells in the initiation of acute cellular rejection or a possible regulatory role in the immunologic changes associated with rejection.

Resolution of paraneoplastic bile duct paucity following successful treatment of Hodgkin's disease.

We report the case of a 21-year-old woman who developed severe adult onset ductopenia in association with Hodgkin's lymphoma. Chemotherapy resulted in a remission of her Hodgkin's disease (HD) and significant improvement in liver function with resolution of the hepatic and biliary duct histological abnormalities, a therapeutic success not previously described in the literature.

Orthotopic liver transplantation for veno-occlusive disease complicating autologous bone marrow transplantation.

BACKGROUND: Veno-occlusive disease of the liver is a serious and often life-threatening complication after bone marrow transplantation. Although risk factors for the development of veno-occlusive disease have been postulated, there is no precise method for accurately identifying those patients who are at risk and for whom early intervention and treatment would have maximum potential benefit. Liver transplantation has been advocated as a treatment for veno-occlusive disease in selected patients. METHODS: In this report, we describe a patient who underwent liver transplantation for life-threatening veno-occlusive disease after autologous bone marrow transplantation for acute lymphoblastic leukemia. RESULTS: Liver engraftment was achieved, but the patient developed Pneumocystis pneumonia, which failed to respond to pentamidine. The patient died 6 months after liver transplantation. CONCLUSIONS: While acknowledging the limited experience of orthotropic liver transplantation in this patient population, we suggest its consideration as a feasible, potentially beneficial treatment option in patients with severe veno-occlusive disease after bone marrow transplantation.