William Gelson

The pattern of late mortality in liver transplant recipients in the United Kingdom.

Background. Late survival is not improving after liver transplantation. In this study, possible reasons for this were investigated. Methods. Mortality rates and causes of death were ascertained in 4483 adult primary liver allograft recipients surviving 1 year or more from engraftment, identified through the UK Transplant Database and transplanted between 1994 and 2007. Associations with death, cause of death, and retransplantation were assessed. Results. Mortality in those surviving beyond 1 year in UK liver transplant recipients was more than twice that expected in the general population and had not improved during the study period, independent of cause of liver disease, recipient age, recipient gender, and donor age. The major causes of death were malignancy (30.6%), multisystem failure (10.0%), infection (9.8%), cardiac disease (8.7%), and graft failure (9.8%). Associations with death after 1 year were pretransplant etiologies alcohol-related liver disease (hazard ratio [HR]=2.10), autoimmune hepatitis or cryptogenic (HR=1.68), hepatitis C virus (HR=2.51), and hepatocellular carcinoma (HR=4.19). Associations with retransplantation were recipient age (HR=0.95 per year), donor age (HR=1.02 per year), and hepatitis C virus (HR=2.04). Hepatocellular carcinoma and recipient age were associated with cancer-related death (odds ratio=1.87 and 1.02 per year). Recipient age was associated with cardiac death (odds ratio=1.06 per year). Conclusions. Strategies to reduce late mortality after liver transplantation are required. These may include prevention of disease recurrence, improved recipient selection, and addressing risk factors for death in late survivors of liver transplantation.

Histological changes in HCV antibody–positive, HCV RNA–negative subjects suggest persistent virus infection

It is unclear whether hepatitis C virus (HCV) has been eradicated or persists at a low level in HCV antibody–positive HCV RNA–negative individuals. The natural history and liver histology are not well characterized. One hundred seventy‐two HCV antibody–positive, serum HCV RNA–negative patients underwent diagnostic liver biopsy between 1992 and 2000 and were followed a median 7 years (range, 5–12). Patients with any possible cause of liver injury other than HCV were excluded. A single histopathologist scored sections using Ishak criteria. Characterization of the inflammatory infiltrate in selected cases used a novel semiquantitative technique and compared with HCV RNA–positive patients and healthy controls. One hundred two patients were excluded because of a risk factor for liver injury other than HCV. Seventy patients met the study criteria; four (5.7%) became HCV RNA–positive during follow‐up. Sixty‐six cases remained HCV RNA–negative; five (7.5%) had a normal liver biopsy; 54 (82%) had fibrosis (stage 2 or 3 in 16 (24%)). Nonviremic cases revealed expanded portal tracts (P < 0.05), with fewer CD4+ (P < 0.05) and more CD8+ cells (P < 0.05) than healthy controls, but were indistinguishable from HCV RNA–positive cases for these parameters. Lobular CD4 staining, absent in healthy controls, was noted in both HCV RNA–negative and –positive cases and was more marked in the latter (P < 0.05) with a sinusoidal lining cell distribution. Conclusion: Nonviremic HCV antibody–positive patients have a liver biopsy that is usually abnormal. Fibrosis was present in most with similar inflammatory infiltrate to viremic cases. The presence of a CD8+ rich inflammatory infiltrate suggests an ongoing immune response in the liver, supporting the view that HCV may persist in the liver in the majority of HCV RNA–negative cases. (HEPATOLOGY 2008;48;1737‐1745.)

Switching to Sirolimus-Based Immune Suppression After Liver Transplantation Is Safe and Effective: A Single-Center Experience

Background. Sirolimus is unlicensed for use in liver transplantation because of concerns over safety, particularly in regard to hepatic artery thrombosis and excess mortality. However, sirolimus offers potential advantages over calcineurin inhibitor-based immunosuppression, relating to its renal sparing and antiproliferative properties. Methods. A review was undertaken of 148 liver transplant patients converted to sirolimus over 10 years at a single center. Results. The main indications for sirolimus were renal impairment and hepatitis C virus fibrosis. One hundred eleven (75%) patients remained on sirolimus after median follow-up of 1006 days. Mean (±standard deviation) glomerular filtration rate improved significantly from 59±29 mL/min preconversion to 72±39 mL/min at censor point (P<0.05). Improvement in glomerular filtration rate was most marked in patients converted for renal impairment. Liver function tests remained stable or improved, particularly in patients transplanted for hepatitis C virus. Side effects attributed to sirolimus occurred in 101 (68%) patients requiring withdrawal in 20 patients (14%). Moderate increases in serum lipids were observed and controlled effectively with statins. The incidence of proteinuria increased postconversion but had no deleterious impact on renal function. No episodes of hepatic artery thrombosis were observed. Conclusions. Sirolimus was safe and may improve outcome in selected patients after liver transplantation.

CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection

Background & Aims Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection. Methods Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls in relation to clinical outcome. Results Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p = 0.003), independent of male sex (p = 0.04), CMV positivity (p = 0.003), previous HBV infection (p = 0.007), and age (p = ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p <0.001), portal tract inflammatory grade (p = 0.035), prothrombin time (p <0.001) and bilirubin (p = 0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p = 0.009) with an age-adjusted hazard ratio of 0.93 (0.90–0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p = 0.001) independent of other factors. Conclusions CD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection.

Hepatic and intestinal schistosomiasis after orthotopic liver transplant

Schistosomiasis affects 200 to 250 million people worldwide. Hepatic schistosomiasis is a well‐recognized cause of chronic liver disease and portal hypertension. There are no previous reports of schistosomiasis post liver transplantation. We report on 2 cases of schistosomiasis in liver transplant recipients— a case of gastric schistosomiasis and a case of hepatic schistosomiasis. A discussion of the pathology of schistosomal infection and a rationale for screening potential liver transplant recipients from endemic areas follows. (Liver Transpl 2005;11:1603–1607.)

Beta-blockers in cirrhosis patients with refractory ascites

could not represent cirrhosis severity in this study. The study endpoint was HCC incidence over 1 year after the start of observation. Patients who developed HCC within 1 year were included in those with a follow-up duration <1 year. Therefore, patients with HCC or suspicion of HCC on enrollment were excluded from this study. It is impossible to avoid any bias because this study is a retrospective cohort study. We think that the method of this study is the next best method of ensuring that the experimental and control groups are similar in the absence of randomization, as Prof. Sherman described. Our findings are consistent with those recently published from Hong Kong. A recent meta-analysis, which included our results, demonstrated a reduction in HCC incidence with oral antiviral agents. The risk reduction of HCC by nucleos(t)ide analogs needs to be confirmed in other long-term studies of ETV or tenofovir with high antiviral potency.

Albumin Reduces Paracentesis-Induced Circulatory Dysfunction and Reduces Death and Renal Impairment among Patients with Cirrhosis and Infection: A Systematic Review and Meta-Analysis

Background. Studies have suggested that albumin has a value in cirrhotic patients undergoing paracentesis but its value in infection and sepsis is less clear. We planned to perform a meta-analysis of the risk of adverse outcomes in cirrhotic patients with and without albumin use. Methods. We searched MEDLINE and EMBASE in January 2013 for randomized studies of cirrhotic patients that reported the risk of adverse events and mortality with albumin and no albumin exposure. We performed random effects meta-analysis and assessed heterogeneity using the I2 statistic. Results. Our review included 16 studies covering 1,518 patients. The use of albumin in paracentesis was associated with significantly reduced risk of paracentesis-induced circulatory dysfunction (OR 0.26 95%, CI 0.08–0.93) and there was a nonsignificant difference in death, encephalopathy, hyponatraemia, readmission, and renal impairment. Compared to the other volume expanders, albumin use showed no difference in clinical outcomes. In cirrhotic patients with any infection, there was a significant reduction in mortality (OR 0.46 95%, CI 0.25–0.86) and renal impairment (OR 0.34 95%, CI 0.15–0.75) when albumin was used. Conclusion. The use of albumin in cirrhotic patients is valuable in patients with any infection and it reduces the risk of circulatory dysfunction among patients undergoing paracentesis.

Early recurrence of neurocysticercosis after orthotopic liver transplant

A 38-year-old Caucasian male underwent orthotopicliver transplantation for alcohol-related cirrhosis. Hehad been abstinent for 2 years but decompensated withvariceal bleeding, hepatic encephalopathy, and hepato-renal syndrome. He had resided in Southeast Asia formany years and denied previous neurological prob-lems. Pretransplant gastrointestinal work-up includedfecal examination, which was normal, and upper gas-trointestinal endoscopy, which demonstrated featuresof portal hypertension only.Transplantation was uncomplicated, and the patientinitially received tacrolimus, azathioprine, and pred-nisolone immune suppression. Histological examina-tion of the explanted liver demonstrated alcohol-relatedcirrhosis but no other features. The allograft donor hadno history of or risk factors for neurocysticercosis, andrecipients of renal allografts from the same donor haveremained well.The patient was readmitted 1 month postoperativelywith 2 grand mal seizures. Neurological examinationwas unremarkable. Electrolytes, C-reactive protein,and eosinophils were normal; serum tacrolimus levelswere subtherapeutic at 4.5 g/L.Gadolinium-enhanced magnetic resonance imagingof the brain demonstrated multiple small, ring-enhanc-ing lesions on T1WI with extensive surrounding edemaon T2WI, localized mostly in the subcortical white mat-ter (Fig. 1A; arrows). Cerebrospinal fluid analysis dem-onstrated protein 0.56 g/L, neutrophils 6/ L, andlymphocytes 35/ L. Cerebrospinal fluid electroimmu-notransfer blot, against cysticercosis antigens, wasstrongly positive, confirming the diagnosis of neurocys-ticercosis. The patient commenced carbamazepine, anincreased dose of prednisolone and praziquantel 75mg/kg in 3 divided doses.Following a loss of consciousness, the patient wasreadmitted 4 months later. Magnetic resonance imag-ing demonstrated regression of the previous lesions butalso new lesions (Fig.1B; arrows demonstrate new le-sions), confirming active disease. Treatment with al-bendazole 15mg/kg/day for 3 months was instituted.He has remained well through 3 years’ follow-up, withmagnetic resonance imaging demonstrating inactivedisease (Fig. 1C).Neurocysticercosis is the commonest helminthic in-fection of the brain and is due to the ingestion of foodcontaminated with Taenia Solium eggs.

Features of immune senescence in liver transplant recipients with established grafts

Immune senescence is the normal process whereby the human immune system ages, but becomes less effective. We investigated whether liver transplant recipients have features of immune senescence. Lymphocytes from 97 liver transplant recipients with established grafts and 41 age‐matched and sex‐matched controls were subjected to an 8‐color flow cytometry assay that measured expression of killer cell lectin‐like receptor subfamily G member 1, cluster of differentiation 127 (CD127), CD45RO, CD27, CD28, CD4, CD8, and CD57. Lymphocyte telomere length was assessed by flow‐fluorescence in situ hybridization. Cases were compared with controls for each marker of immune senescence using a Mann‐Whitney U test. For liver transplant recipients, linear regression analyses identified associations between markers of immune senescence and clinical or demographic characteristics. Lymphocytes from liver transplant recipients expressed more phenotypic markers of maturity than did lymphocytes from controls. Lymphocyte telomeres were shorter in liver transplant recipients than in controls. Age, hepatocellular carcinoma at transplantation, and skin malignancy developing after transplantation were associated independently with shortened lymphocyte telomeres. Increasing age and previous cytomegalovirus infection were associated independently with phenotypic markers of lymphocyte maturity. Thus, lymphocytes from liver transplant recipients are older “biologically” than lymphocytes from age‐matched and sex‐matched controls. Hepatocellular carcinoma at transplantation, subsequent skin malignancy, and previous cytomegalovirus infection are associated with lymphocyte senescence in liver transplant recipients. Liver Transpl 16:577‐587, 2010.

Minichromosome maintenance protein‐2–positive portal tract lymphocytes distinguish acute cellular rejection from hepatitis C virus recurrence after liver transplantation

Hepatitis C virus (HCV) is a leading indication for liver transplantation worldwide, but graft infection with HCV frequently leads to hepatic fibrosis. Acute cellular rejection (ACR) can be difficult to distinguish confidently from HCV, even with histology, but accurate diagnosis is critical because treatment of ACR may accelerate HCV‐related graft injury. Immunohistochemistry was undertaken on 99 liver biopsies from 31 patients with HCV graft infection, 22 patients with ACR, and 11 patients with HCV infection and unexplained graft dysfunction to investigate whether lymphocyte expression of minichromosome maintenance protein‐2 (Mcm‐2), a marker of licensed cell cycle entry, assessed in a novel semiautomated system could distinguish between ACR and graft infection with HCV. The portal tract area was greater in ACR than in HCV graft infection (P = 0.027), but there was considerable overlap. However, both the number of Mcm‐2–positive lymphocytes per portal tract and the number of Mcm‐2–positive lymphocytes per millimeter squared of portal tract distinguished between ACR and HCV graft infection (P < 0.0001). A cutoff value of 107 positive cells per portal tract had a sensitivity of 81.8% and a specificity of 91.9% (positive predictive value of 66.67% and negative predictive value of 95.75%). Of 11 HCV‐infected patients with an uncertain diagnosis, 7 were deemed ultimately to have HCV graft infection, and 4 had superimposed corticosteroid‐responsive ACR. The number of Mcm‐2–positive cells per portal tract and per millimeter squared of portal tract again distinguished clearly between the groups (P = 0.012). In conclusion, lymphocyte Mcm‐2 expression is a useful adjunct to histology in differentiating between HCV graft infection and ACR. Patients with a low number of Mcm‐2–positive portal tract lymphocytes are less likely to have ACR. Liver Transpl 15:306–312, 2009.