Ian A. Rowe

The impact of disease recurrence on graft survival following liver transplantation: a single centre experience

Many diseases that cause liver failure may recur after transplantation. A retrospective analysis of the rate and cause of graft loss of 1840 consecutive adults receiving a primary liver transplant between 1982 and 2004 was performed to evaluate the rate of graft loss from disease recurrence. The risk of graft loss from recurrent disease was greatest, when compared to primary biliary cirrhosis (PBC), in those transplanted for hepatitis C virus (HCV) [hazard ratio (HR) 11.6; 95% confidence interval (CI) 5.1–26.6], primary sclerosing cholangitis (PSC) (HR 6.0; 95% CI 2.5–14.2) and autoimmune hepatitis (AIH) (HR 4.1; 95% CI 1.3–12.6). The overall risk of graft loss was also significantly greater in HCV (HR 2.1 vs. PBC; 95% CI 1.5–3.0), PSC (HR 1.6 vs. PBC; 95% CI 1.2–2.3) and AIH (HR 1.6; 95% CI 1.0–2.4) than in PBC. There was no statistically significant difference in the risk of graft loss because of recurrent disease, when compared with PBC, for patients transplanted for alcohol related liver disease, nonalcoholic steatohepatitis and fulminant hepatic failure. Disease recurrence is a significant cause of graft loss particularly in HCV, PSC and AIH. Recurrent disease, in part, explains the increased overall risk of graft loss in these groups.

Hepatitis C Virus Infects the Endothelial Cells of the Blood-Brain Barrier

BACKGROUND & AIMS Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS. METHODS We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culture-derived HCV were used to study the ability of endothelial cells to support viral entry and replication. RESULTS Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis. CONCLUSIONS Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.

Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: Individual patient data meta-analysis of the LEAD program

Non‐alcoholic fatty liver disease has reached epidemic proportions in type 2 diabetes (T2D). Glucagon‐like peptide‐1 analogues are licensed in T2D, yet little data exist on efficacy and safety in liver injury.

Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis.

Acute alcoholic hepatitis (AH) is a severe manifestation of alcoholic liver disease with a grave prognosis. Pentoxifylline, an oral antitumour necrosis factor agent, has been reported to reduce mortality and incidence of hepatorenal syndrome (HRS) in severe alcoholic hepatitis (SAH).

A dual role for hypoxia inducible factor-1α in the hepatitis C virus lifecycle and hepatoma migration

Background & Aims Hepatitis C virus (HCV) causes progressive liver disease and is a major risk factor for the development of hepatocellular carcinoma (HCC). However, the role of infection in HCC pathogenesis is poorly understood. We investigated the effect(s) of HCV infection and viral glycoprotein expression on hepatoma biology to gain insights into the development of HCV associated HCC. Methods We assessed the effect(s) of HCV and viral glycoprotein expression on hepatoma polarity, migration and invasion. Results HCV glycoproteins perturb tight and adherens junction protein expression, and increase hepatoma migration and expression of epithelial to mesenchymal transition markers Snail and Twist via stabilizing hypoxia inducible factor-1α (HIF-1α). HIF-1α regulates many genes involved in tumor growth and metastasis, including vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β). Neutralization of both growth factors shows different roles for VEGF and TGFβ in regulating hepatoma polarity and migration, respectively. Importantly, we confirmed these observations in virus infected hepatoma and primary human hepatocytes. Inhibition of HIF-1α reversed the effect(s) of infection and glycoprotein expression on hepatoma permeability and migration and significantly reduced HCV replication, demonstrating a dual role for HIF-1α in the cellular processes that are deregulated in many human cancers and in the viral life cycle. Conclusions These data provide new insights into the cancer-promoting effects of HCV infection on HCC migration and offer new approaches for treatment.

Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: Time to reconsider immunosuppression regimens?

Nonalcoholic fatty liver disease is an independent risk factor for chronic kidney injury (CKI), yet the impact of liver transplantation (LT) on renal function in this at‐risk group is not known. We compared the post‐LT renal function of patients with nonalcoholic steatohepatitis (NASH) and a matched comparison group. Forty‐eight consecutive patients who underwent transplantation for NASH between 2000 and 2008 in a single UK center were compared to non‐NASH patients who were matched by age, sex, Model for End‐Stage Liver Disease score, and estimated glomerular filtration rate (eGFR; calculated with the Modification of Diet in Renal Disease formula). In comparison with non‐NASH patients, NASH patients had a significantly lower eGFR 3 months after LT (eGFR difference = 8.85 mL/minute/1.73 m2, 95% confidence interval = 2.93‐14.77). After adjustments for the effects of the body mass index, tacrolimus levels, diabetes mellitus, hypertension, and hepatocellular carcinoma, the difference between the groups remained significant 3 months after LT (P = 0.001). These data were then analyzed at numerous time points after LT (6, 12, and 24 months), and the time did not significantly affect the difference between the groups (P = 0.17). Within 2 years, 31.2% of the NASH patients (15/48) had developed stage IIIb CKI, whereas only 8.3% of the non‐NASH patients (4/48) did (P = 0.009). In conclusion, this study has identified NASH as an independent risk factor for renal dysfunction after LT. Renal‐sparing immunosuppression regimens should be considered at the time of LT to reduce the development of kidney injury in NASH patients. The optimization of such regimens requires a prospective study. Liver Transpl 17:1292–1298, 2011.

HTLV-1 in solid-organ transplantation: current challenges and future management strategies.

Human T-cell lymphotrophic virus (HTLV)-1 has been reported after solid-organ transplantation, with a related fatal outcome in less than five cases. The natural history of HTLV-1 transmission from donor to recipient is unknown in this setting, because available screening platforms are suboptimal in low-prevalence areas and there is a lack of long-term follow-up. Minimizing organ wastage due to false-positive screening and avoiding donor-derived HTLV-associated diseases remain the goal. To date, only six HTLV-naive organ recipients from four donors (only one had confirmed HTLV) have developed HTLV-associated disease after transplantation. All of these cases were described in countries or from donors from HTLV-endemic regions. To the best of our knowledge, there have been no reported cases of donor-derived HTLV-1–associated death after organ transplantation in the world. Based on data from low-prevalence countries (Europe and the United States) and the current shortage of donor organs, it appears plausible to authorize the decision to transplant an organ without the prior knowledge of the donor’s HTLV-1 status. Currently, it is not possible to exclude such transmission and recipients should be informed of the possible inadvertent transmission of this (and other) infections at the time of consent. In those cases where HTLV-1 transmission does occur, there may be a therapeutic window in which use of antiviral agents (i.e., zidovudine and raltegravir) may be of benefit. The development of national/international registries should allow a greater understanding of the extent and consequences of transmission risk and so allow a more evidence-based approach to management.

A comparative quality assessment of evidence-based clinical guidelines in endocrinology.

Evidence‐based clinical guidelines in endocrinology attempt to improve and standardize patient care. There has been an expansion in guideline production although some of the heterogeneous methods used to assess the quality of the underlying evidence base might limit interpretation and implementation.

Paracrine signals from liver sinusoidal endothelium regulate hepatitis C virus replication

Hepatitis C virus (HCV) is a major cause of global morbidity, causing chronic liver injury that can progress to cirrhosis and hepatocellular carcinoma. The liver is a large and complex organ containing multiple cell types, including hepatocytes, sinusoidal endothelial cells (LSEC), Kupffer cells, and biliary epithelial cells. Hepatocytes are the major reservoir supporting HCV replication; however, the role of nonparenchymal cells in the viral lifecycle remains largely unexplored. LSEC secrete factors that promote HCV infection and transcript analysis identified bone morphogenetic protein 4 (BMP4) as a candidate endothelial‐expressed proviral molecule. Recombinant BMP4 increased HCV replication and neutralization of BMP4 abrogated the proviral activity of LSEC‐conditioned media. Importantly, BMP4 expression was negatively regulated by vascular endothelial growth factor A (VEGF‐A) by way of a VEGF receptor‐2 (VEGFR‐2) primed activation of p38 MAPK. Consistent with our in vitro observations, we demonstrate that in normal liver VEGFR‐2 is activated and BMP4 expression is suppressed. In contrast, in chronic liver disease including HCV infection where there is marked endothelial cell proliferation, we observed reduced endothelial cell VEGFR‐2 activation and a concomitant increase in BMP4 expression. Conclusion: These studies identify a role for LSEC and BMP4 in HCV infection and highlight BMP4 as a new therapeutic target for treating individuals with liver disease. (Hepatology 2014;59:375–384)

Operator training requirements and diagnostic accuracy of Fibroscan in routine clinical practice

Background Fibroscan is a quick, non-invasive technique used to measure liver stiffness (kPa), which correlates with fibrosis. To achieve a valid liver stiffness evaluation (LSE) the operator must obtain all the following three criteria: (1) ≥10 successful liver stiffness measurements; (2) IQR/median ratio <0.30 and (3) ≥60% measurement success rate. Objectives To assess the operator training requirements and the importance of adhering to the LSE validity criteria in routine clinical practice. Methods We retrospectively analysed the LSE validity rates of 2311 Fibroscans performed (1 August 2008 to 31 July 2011) in our tertiary liver outpatients department at the University Hospital Birmingham, UK. The diagnostic accuracy of Fibroscan was assessed in 153 patients, by comparing LSE (valid and invalid) with the modified Ishak fibrosis stage on liver biopsy. Results Learning curve analysis highlighted that the greatest improvement in validity of LSE rates occurs in the operator’s first 10 Fibroscans, reaching 64.7% validity by the 50th Fibroscan. The correlation between LSE and the fibrosis stage on liver biopsy was superior in patients with a valid LSE (n=97) compared with those with an invalid LSE (n=56) (rs 0.577 vs 0.259; p=0.022). Area under receiving operating characteristics for significant fibrosis was greater when LSE was valid (0.83 vs 0.66; p=0.048). Using an LSE cut-off of 8 kPa, the negative predictive value of valid LSE was superior to invalid LSE for the detection of significant (84% vs 71%) and advanced fibrosis (100% vs 93%). Conclusions Fibroscan requires minimal operator training (≥10 observed on patients), and when a valid LSE is obtained, it is an accurate tool for excluding advanced liver fibrosis. To ensure the diagnostic accuracy of Fibroscan it is essential that the recommended LSE validity criteria are adhered to in routine clinical practice.