M. Bruce

Source and characterization of hepatic macrophages in acetaminophen‐induced acute liver failure in humans

Acetaminophen‐induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h‐mϕ) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h‐mϕ in both aggravation and resolution of liver injury. The role of h‐mϕ in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C‐C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h‐mϕ infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C‐C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation‐derived (MAC387+) or resident proliferating (CD68/Ki67+) h‐mϕ in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2‐dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h‐mϕ were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)‐6, IL‐10, and transforming growth factor‐β1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls. Conclusion: In AALF, the h‐mϕ population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2‐dependent recruitment of circulating monocytes. The presence of h‐mϕ within an anti‐inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF. (HEPATOLOGY 2012)

Neutrophil gelatinase—Associated lipocalin predicts acute kidney injury in patients undergoing liver transplantation

Postoperative acute kidney injury (AKI) increases morbidity and mortality after liver transplantation (LT). Novel methods of assessing AKI including cystatin C (CyC) and neutrophil gelatinase–associated lipocalin (NGAL) have been identified as potential markers of AKI. We compare the ability of standard renal markers (serum creatinine [sCr], estimated glomerular filtration rate [eGFR] and intensive therapy unit organ failure scores with CyC and NGAL to predict AKI within the first 48 hours after LT. 95 patients (median age 50 [interquartile range = 41‐59], 60% male) underwent LT (25% with acute liver failure). AKI was defined according to the Acute Kidney Injury Network criteria. Severe AKI was classified as ≥stage 2. NGAL (urine [u] and plasma [p]) and CyC concentrations taken immediately after transplantation on admission to the Liver Intensive Care Unit were compared with standard markers of renal function. Predictive ability was assessed using the area under the curve generated by receiver operator characteristic analysis (AUROC) and logistic regression. Day 0 sCr, uNGAL, pNGAL, CyC, and eGFR predicted AKI as did SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. APACHE II and pNGAL were the most powerful predictors of severe AKI (APACHE II AUROC = 0.87 [0.77‐0.97], P < 0.001; pNGAL AUROC = 0.87 [0.77‐0.92], P < 0.001). Using multivariate logistic regression, APACHE II (odds ratio 1.64/point [95% confidence interval = 1.22‐2.21, P = 0.001] and pNGAL [odds ratio = 1.01/ng/mL [95% confidence interval = 1.00‐1.02], P = 0.002) retained independent significance. A “renal risk score” using APACHE II > 13 and pNGAL > 258 ng/mL was calculated with a score of ≥1 having a 100% sensitivity and 76% specificity for severe AKI. In conclusion, a combination of NGAL and APACHE II predicts AKI with high sensitivity and specificity after LT. Liver Transpl 16:1257‐1266, 2010.

King's Score: an accurate marker of cirrhosis in chronic hepatitis C

Objectives Histological assessment of patients with chronic hepatitis C infection is no longer performed routinely; consequently, a simple test is needed to identify patients with significant hepatic fibrosis. Methods Data were collected, retrospectively, on 923 consecutive patients undergoing percutaneous liver biopsy for chronic hepatitis C at Kings College Hospital between 1 January 2000 and 30 June 2006; 602 patients were accepted to form the training set and a further 105 patients to form the validation set. Results On liver biopsy, 132 (22%) had cirrhosis (Ishak F5–6) in the training set and 19 (18%) in the validation set. Factors found by multivariate analysis to be associated with fibrosis in the training set were used to construct the Kings Score: age×aspartate aminotransferase×international normalized ratio ÷ platelets. Area under receiver operating characteristic curves for predicting cirrhosis and significant fibrosis (F3–6) were 0.91 and 0.79, respectively. A Kings Score of greater than or equal to 16.7 predicted cirrhosis in 34% of patients (odds ratio 36.2, 95% confidence interval, 22.0–59.6; P<0.0001) with sensitivity 86%, specificity 80% and a high negative predictive value of 96%; a score greater than or equal to 12.3 predicted F3–6 (odds ratio 33.9, 95% confidence interval, 15.2–34.4; P<0.001). The validation set confirmed the utility of this index, area under receiver operating characteristic curves 0.94 and 0.89 for cirrhosis and F3–6, respectively. Conclusion The Kings Score is a simple and accurate index for predicting cirrhosis in chronic hepatitis C. Patients with a score of less than 16.7 have a low risk of cirrhosis.

Actin‐free Gc globulin: A rapidly assessed biomarker of organ dysfunction in acute liver failure and cirrhosis

Reductions in serum levels of Gc globulin, a hepatically synthesized component of the extracellular actin scavenger system responsible for complexing circulating actin and attenuating intravascular microthrombus formation, are associated with poor outcome in acute liver failure. Clinically applicable assays of the important actin‐free fraction (Af‐Gc) have not been available until now. We measured actin‐free Gc globulin levels with a novel, rapid assay in 61 cases of acute liver failure (ALF) and in 91 patients with cirrhosis (40 of whom were clinically unstable with extrahepatic organ dysfunction), and studied associations with liver dysfunction, extrahepatic organ dysfunction, indices of disseminated coagulation, and outcome. Reductions in Af‐Gc levels mirrored hepatic dysfunction and organ dysfunction in both groups, and discriminated patients with poor prognosis from those with good prognosis in the ALF cohort. Levels were lowest in patients with ALF (10% of control values), but levels were also markedly reduced in both unstable (28%) and stable (44%) patients with cirrhosis. Associations with markers of disseminated intravascular coagulation were seen in both groups, most notably in the cirrhosis cohort, supporting a pathophysiological role for reduced Af‐Gc in the evolution of organ dysfunction. In acetaminophen‐induced ALF, Af‐Gc identified patients with poor prognosis as well as did the Acute Physiology and Chronic Health Evaluation (APACHE II) score (area under the receiver operating characteristic curve, 0.7), and in cirrhosis, Af‐Gc was an independent predictor of mortality by multifactorial analysis. In conclusion, the importance of Af‐Gc reductions in the development of multiple organ dysfunction in ALF and cirrhosis is highlighted, probably resulting from reduced hepatic production and peripheral exhaustion of this arm of the extracellular actin scavenger system. Liver Transpl 13:1254–1261, 2007.

Predicting the development of acute kidney injury in liver cirrhosis--an analysis of glomerular filtration rate, proteinuria and kidney injury biomarkers.

The timely diagnosis of acute kidney injury (AKI) in liver cirrhosis is challenging.

Tenofovir-based combination therapy for HIV/HBV co-infection: factors associated with a partial HBV virological response in patients with undetectable HIV viraemia.

Objective:The aim of this study was to identify and describe patients with detectable hepatitis B virus (HBV) DNA in the presence of undetectable HIV RNA after 48 weeks of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or lamivudine (3TC) treatment. Design:Case–control study. Cases or delayed responders were defined as detectable HBV DNA (>20 IU/ml) with undetectable HIV RNA (<40 c/ml) after 48 weeks TDF/3(F)TC combination therapy. Controls or virological responders were defined as both undetectable HIV and HBV after 48 weeks TDF/3(F)TC therapy. Results:Twenty-three cases were identified and matched to 24 controls. 87% cases and 46% controls were eAg-positive (P = 0.005). Nine of 23 (39%) cases and seven of 24 (29%) controls had 3TC monotherapy prior to TDF. Similar proportions had 3TC/FTC resistance pre-TDF (30% cases, 24% controls). The cases had significantly higher baseline HBV DNA pre-3TC (median 1.2 × 108 vs. 3.1 × 106IU/ml; P = 0.009) and pre-TDF (1.1 × 108 vs. 2.6 × 104 IU/ml; P = 0.012). Sixteen of 23 cases eventually achieved undetectable HBV DNA after 42.2 (27.2, 54.9) months. Six of 23 still have detectable HBV DNA after 46.2 (28.2, 65.6) months. Only one delayed responder patient developed a new 3(F)TC mutation and they received intensification with entecavir and achieved undetectable HBV DNA. No patient developed TDF resistance. Conclusion:We report the largest series of HIV/HBV co-infected patients failing to achieve undetectable HBV after 48 weeks TDF/3(F)TC despite undetectable HIV viraemia. This outcome was associated with positive eAg and higher baseline HBV DNA. Our data suggest that clinicians should not intensify therapy with entecavir unless there is evidence of new 3TC/FTC mutations as the majority of patients go on to suppress HBV. TDF resistance was not seen.

Development and validation of an efficient in-house real-time reverse transcription polymerase chain reaction assay for the quantitative detection of serum hepatitis delta virus RNA in a diverse South London population.

Hepatitis delta virus (HDV) causes both acute and chronic hepatitis, always in the presence of hepatitis B. Analysis of global HDV isolates has shown that at least eight genotypes exist. HDV RNA quantitation and genotyping are important tools in the diagnosis and management of infected individuals. There is, as yet, no commercially available quantitative HDV RNA assay. Several laboratories have developed in-house assays, but equivalent detection and quantitation across all HDV genotypes has not been demonstrated. In this study, the development of an in-house real-time reverse transcription polymerase chain reaction (RT PCR) assay is described to quantify HDV RNA in serum or plasma. Its efficiency was validated by testing 99 samples from patients with known chronic HDV infection, along with 22 samples from individuals without HDV. The assay has a dynamic range of 6.4×10(2) to 6.4×10(8)copies/mL. Amplicons of the quantitative PCR can be directly used for sequence analysis and genotyping. HDV-1, HDV-5 and HDV-6 were identified, reflecting the areas of origin of our cohort of patients. The ability to genotype and to accurately quantify HDV RNA levels in the more recently discovered African genotypes will be important for investigating the natural history of HDV in this group, compared to those with genotype 1 disease.

Violence and crime among male inpatients with severe mental illness: attempting to explain ethnic differences

BackgroundStudies report that in the UK, among men with severe mental illness (SMI), those of black Caribbean ethnicity display increased risk of aggressive behaviour, criminal convictions, and schizophrenia. The study aimed to compare aggressive behaviour and criminal convictions among men with SMI of white British, black Caribbean and black African ethnicity, and to explore factors associated with differences across ethnicities.MethodSample 1 included 1,104 male inpatients with SMI. Sample 2 included a representative sub-sample of 165 who completed interviews, and authorized access to medical and criminal files. Ethnicity was self-ascribed.ResultsStaff-rated violence prior to admission, self-reported aggressive behaviour, and convictions for non-violent and violent crimes differed among men with SMI of different ethnicities. Relative to men with SMI of white British ethnicity, those of black African ethnicity showed decreased risk of aggressive behaviour, and those of black Caribbean ethnicity showed elevated risk of convictions for non-violent, and marginally, for violent crimes. Relative to men with SMI of black African ethnicity, those of black Caribbean ethnicity showed elevated risk of aggressive behaviour and criminal convictions. Proportionately more of the men of both black African and black Caribbean ethnicity, than those of white British ethnicity, presented schizophrenia spectrum disorders. Multivariate analyses failed to identify factors that would explain differences in aggressive behaviour, and criminal convictions across ethnic groups.ConclusionsDifferences in four different measures of aggressive and antisocial behaviour among men with SMI of different ethnicities were observed but factors associated with these differences were not found.

Unmet needs and antisocial personality disorder among Black African and Caribbean service users with severe mental illness

Purpose – The main objective of the study is to investigate unmet needs of Black African and Caribbean Heritage (BAH) patients with and without a concurrent diagnosis of antisocial personality disorder (ASPD).Design/methodology/approach – A total of 79 participants were recruited from ten psychiatric inpatient wards across two hospital sites in South London. Personality disorder was assessed using the SCID‐II for DSM‐IV, the prevalence of unmet needs was assessed by The Camberwell Assessment of Need Short Assessment Schedule and substance misuse problems measured using well validated drug and alcohol use disorder identification tools.Findings – The presence of a concurrent ASPD was independently associated with a greater number of unmet needs. ASPD was associated with lower qualifications and a greater risk of homelessness and substance misuse. Unmet need was associated with lower qualifications and substance misuse. In a stepwise linear regression model alcohol dependence and drug misuse were the most si...

CXCL10 levels identify individuals with rapid fibrosis at 12 months post-transplant for hepatitis C virus and predict treatment response

Recurrent hepatitis C virus (HCV) infection is universal post‐transplantation. Fibrosis (F) stage ≥2 at 12 months identifies patients with rapid fibrosis progression. Antiviral therapy (AVT) remains the only option to attenuate fibrosis progression. We hypothesized that CXCL10 levels can distinguish between slow and fast fibrosis progression at 12 months, development of F ≥ 4 post‐transplantation, and help predict treatment response in patients undergoing AVT.