Charalambos Gustav Antoniades

The importance of immune dysfunction in determining outcome in acute liver failure.

Acute liver failure (ALF) shares striking similarities with septic shock with regard to the features of systemic inflammation, progression to multiple organ dysfunction and functional immunoparesis. While the existence of opposing systemic pro- and anti-inflammatory profiles resulting in organ failure and immune dysfunction are well recognised in septic shock, characterization of these processes in ALF has only recently been described. This review explores the evolution of the systemic inflammation in acute liver failure, its relation to disease progression, exacerbation of liver injury and development of innate immune dysfunction and extra-hepatic organ failure as sequelae. Defects in innate immunity are described in hepatic and extra-hepatic compartments. Clinical studies measuring levels of pro- and anti-inflammatory cytokines and expression of the antigen presentation molecule HLA-DR on monocytes, in combination with ex-vivo experiments, demonstrate that the persistence of a compensatory anti-inflammatory response syndrome, leading to functional monocyte deactivation, is a central event in the evolution of systemic immune dysfunction. Accurate immune profiling in ALF may permit the development of immunomodulatory strategies in order to improve outcome in this condition.

Reduced monocyte HLA‐DR expression: A novel biomarker of disease severity and outcome in acetaminophen‐induced acute liver failure

Acute liver failure (ALF) shares striking similarities with septic shock where a decrease in HLA‐DR expression on monocytes is associated with disease severity and predicts outcome. We investigated monocyte HLA‐DR expression in ALF in relation to inflammatory mediator levels and clinical outcome. Monocyte HLA‐DR expression was determined in 50 patients with acetaminophen‐induced ALF (AALF) and 20 non–acetaminophen‐induced ALF (NAALF). AALF patients were divided into dead/transplanted (AALF‐NS, n = 26) and spontaneous survivors (AALF‐S, n = 24). Fifty patients with chronic liver disease (CLD) and 50 healthy volunteers served as controls. Monocyte HLA‐DR expression was determined by double‐color flow‐cytometry with monoclonal antibodies detecting HLA‐DR and monocyte specific CD14. Serum levels of interleukin (IL) ‐4, ‐6, ‐10, tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ were concomitantly measured by ELISA. Compared to healthy volunteers (75%) and CLD (67%) monocyte HLA‐DR percentage expression was lower in AALF (15%, P < .001) and NAALF (22 %, P < .001). Compared to AALF‐S, AALF‐NS had lower monocyte HLA‐DR % (11% vs. 36%, P < .001) and higher levels of IL‐4, IL‐6, IL‐10 and TNF‐α (P < .001). HLA‐DR percentage negatively correlated with INR, blood lactate, pH and levels of encephalopathy (r = −0.8 to −0.5, P < .01), IL‐10 (r = −0.8, P < .0001), TNF‐α (r = −0.4, P = .02). HLA‐DR percentage level ≤15% has a 96% sensitivity and 100% specificity and 98% accuracy in predicting poor prognosis. In conclusion, the strong relationship of monocyte HLA‐DR expression with indices of disease severity, mediators of inflammation and outcome indicates a key role for this molecule as a biomarker of disease severity and prognosis. (HEPATOLOGY 2006;44:34–43.)

High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.

BACKGROUND & AIMS Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters. METHODS In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken. RESULTS For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (p<0.001). CONCLUSIONS Treatment with HVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction.

Liver transplantation in patients over 60 and 65 years: An evaluation of long‐term outcomes and survival

With increased demand for liver transplantation (LT), outcomes of older recipients have been subjected to greater scrutiny, as previous studies have demonstrated poorer survival outcomes. Outcomes of 77 patients aged > 65 yr (group 1) who underwent transplantation between 1988 and 2003 at Kings College Hospital, London, were compared with all recipients aged between 60 and 64 yr (group 2, n = 137) and 202 time‐matched control patients with chronic liver disease aged between 18‐59 yr (group 3). Patient survival at 30‐days for groups 1, 2, and 3 were 99%, 94%, and 94%, respectively (P = not significant [NS]). At 1‐yr, survival in the 3 groups was 82%, 86%, and 83%, respectively (P = NS), and at 5‐yr patient survival was comparable (73%, 80%, and 78%, respectively) (P = NS). Episodes of acute cellular rejection (ACR) were fewer in the older cohorts (43% vs. 45% vs. 61%, P = 0.0016), although there was no significant difference identified in the numbers of patients in each group who experienced ACR (P = 0.16). A similar but nonsignificant trend was identified for rates of chronic rejection among the groups. In conclusion, these data suggest that survival of patients over 60 and 65 yr undergoing LT is satisfactory, at least in the first 5‐yr posttransplantation. In addition, patients over 65 yr experience less rejection, with good graft survival. Thus, LT should not be denied to patients >65 yr on the basis of age alone, once a comprehensive screen for comorbidity has been undertaken. Liver Transpl 13:1382–1388. 2007.

Secretory leukocyte protease inhibitor: a pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure.

Acetaminophen‐induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF‐κB) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen‐DR (HLA‐DR), and lipopolysaccharide (LPS)‐stimulated levels of NF‐κBp65, tumor necrosis factor alpha (TNF‐α) and interleukin (IL)‐6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)‐SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (α)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h‐mψ) in areas of necrosis. H‐mψ and circulating monocytes in AALF exhibited an anti‐inflammatory phenotype and functional characteristics; typified by reductions in NF‐κBp65, TNF‐α, and IL‐6 and preserved IL‐10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti‐inflammatory characteristics which were reversed by inhibiting the activity of SLPI. Conclusion: SLPI is a pivotal mediator of anti‐inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF. (Hepatology 2014;59:1564‐1576)

Admission levels and early changes in serum interleukin‐10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis

Backround & Aim: Immunoparesis contributes to prognosis in acute liver failure (ALF) and decompensated cirrhosis, a phenomenon thought to be mediated by the anti‐inflammatory cytokine interleukin (IL)‐10. We investigated the prognostic value of admission IL‐10 levels and their evolution during the early phase of treatment in intensive care, in comparison to the pro‐inflammatory cytokines IL‐6 and tumour necrosis factor (TNF)‐α.

Current and future management of chronic hepatitis C infection

Current treatment for patients with chronic hepatitis C virus (HCV) infection consists of the combination of pegylated interferon and ribavirin. This treatment regimen achieves a sustained virological response, defined as undetectable HCV RNA 6 months after treatment cessation, in 50% of patients overall. There is therefore a need for new treatments to improve the sustained virological response rate and reduce the number of adverse effects associated with pegylated interferon and ribavirin. This review examines the current management of chronic HCV infection, including who is eligible for treatment, the optimum duration of treatment, and management of side effects. New drugs in development, such as HCV-specific protease inhibitors, polymerase inhibitors, immune modulators and ribavirin analogues, are outlined, and their role in the treatment armamentarium is discussed, whether used alone or in combination with existing treatments.

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.

Mitochondrial toxicity associated with HAART following liver transplantation in an HIV‐infected recipient

Antiretroviral therapy is not uncommonly associated with drug toxicities, and hepatotoxicity occurs in approximately 20% of individuals prescribed antiretroviral therapy. Mitochondrial toxicity causing lactic acidosis is a rare but fatal complication that has been described in some HIV‐infected patients treated with nucleoside analogue reverse transcriptase inhibitors. In this report, we describe the course of an HIV‐infected patient receiving antiretroviral therapy who developed lactic acidosis after liver transplantation for HCV‐induced liver disease. (Liver Transpl 2004;10:699–702.)

Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis.

Graphical abstract