Jessica Howell

The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma

BACKGROUND & AIMS Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patients mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous. METHODS We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n=1461) accrued from Europe, the United States and Asia. RESULTS Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p<0.001), transarterial chemoembolization (p<0.001) and sorafenib (p<0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study (p<0.001). CONCLUSIONS In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice. LAY SUMMARY Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC.

Hepatitis C recurrence: the Achilles heel of liver transplantation

Hepatitis C virus (HCV) infection is the most common indication for liver transplantation worldwide; however, recurrence post transplant is almost universal and follows an accelerated course. Around 30% of patients develop aggressive HCV recurrence, leading to rapid fibrosis progression (RFP) and culminating in liver failure and either death or retransplantation. Despite many advances in our knowledge of clinical risks for HCV RFP, we are still unable to accurately predict those most at risk of adverse outcomes, and no clear consensus exists on the best approach to management. This review presents a critical overview of clinical factors shown to influence the course of HCV recurrence post transplant, with particular focus on recent data identifying the important role of metabolic factors, such as insulin resistance, in HCV recurrence. Emerging data for genetic markers of HCV recurrence and their usefulness for predicting adverse outcomes will also be explored.

Prevention of materno-foetal transmission of hepatitis B in sub-Saharan Africa: the evidence, current practice and future challenges.

Hepatitis B (HBV) infection is highly endemic in sub‐Saharan Africa (SSA), where more than 8% of the population remain chronic HBV carriers. SSA has one of the highest HBV‐related liver cancer rates in the world (CA Cancer J Clin, 55, 2005, 74) and HBV‐related liver cancer is the most common cause of premature death in West Africa (Lancet Oncol, 9, 2008, 683; Hepatology, 39, 2004, 211). As such, HBV represents a significant global threat to health in the African continent. Most SSA countries have elected to vaccinate all children against HBV through the WHO‐sponsored Expanded Program of Immunization and the current recommendation from WHO‐AFRO is for birth‐dose HBV vaccination to prevent maternal/child transmission (MFT) and early horizontal transmission of HBV. However, in Africa, HBV vaccine coverage remains low and HBV birth‐dose vaccination has not been implemented. HBV transmission from mother to child in the early perinatal period therefore remains a significant contributor to the burden of HBV‐related disease in SSA. This review explores the evidence for materno‐foetal transmission of HBV in SSA, outlining current practice for HBV MFT prevention and identifying the significant challenges to implementation of HBV prevention in SSA.

Toll-like receptors in hepatitis C infection: implications for pathogenesis and treatment.

Hepatitis C virus (HCV) infection is a significant global health problem, affecting over 150 million people worldwide. While the critical role of the adaptive immune system in HCV infection is well‐established, the importance of the innate immune system in HCV infection has only been recognized in more recent years. Toll‐like receptors form the cornerstone of the innate immune response, and there is considerable evidence for their crucial role in hepatitis C infection. This review outlines recent advances made in our understanding of the role of Toll‐like receptor function in HCV infection, exploring how HCV manipulates host immunity to evade immune clearance and establish persistent infection despite leading to inflammatory hepatic damage.

Cyclosporine and tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation.

Toll‐like receptors (TLRs) play a key role in transplantation biology. The effect of immunosuppression on TLR function after liver transplantation is unknown. Peripheral blood mononuclear cells (PBMCs) from 113 post–liver transplant patients and 13 healthy controls were stimulated with TLR‐specific ligands [lipopolysaccharide (TLR4), pan‐3‐cys (P3C) (TLR2), Poly (I:C) (PIC) (TLR3), R848 (TLR7/8), and CpG (TLR9)] for 24 hours. PBMCs from 5 healthy controls were also cultured with therapeutic concentrations of cyclosporine A (CYA) and tacrolimus (TAC). Cytokine production was measured with enzyme‐linked immunosorbent assays and flow cytometry. PBMCs from patients on calcineurin inhibitors after liver transplantation produced less interleukin‐6 (IL‐6) and tumor necrosis factor α (TNFα) in response to TLR2 stimulation (IL‐6: P=0.02; TNFα: P=0.01), TLR4 stimulation (IL‐6: P=0.02; TNFα: P=0.01), and TLR7/8 stimulation (IL‐6: P=0.02; TNFα: P=0.02), compared with healthy controls. Both CD56bright and CD56dim natural killer (NK) cells from patients on calcineurin inhibitors also produced less interferon‐γ (IFNγ) with TLR7/8 stimulation compared with healthy controls (CD56bright: P=0.002; CD56dim: P=0.004). Similar findings were demonstrated in healthy PBMCs cultured with CYA (PBMCs: TLR2, IL‐6: P=0.005; TLR4, IL‐6: P=0.03, TNFα: P=0.03; TLR7/8, IL‐6: P=0.02, TNFα: P=0.01; CD56dim NK cells: TLR7/8, IFNγ: P=0.03). TAC impaired TLR4‐mediated IL‐6 and TNFα production by PBMCs (IL‐6; P = 0.02; TNFα P = 0.009). In conclusion, patients on calcineurin inhibitors had impaired inflammatory cytokine production in response to TLR2, TLR4, and TLR7/8 stimulation compared comparison with healthy controls. Importantly, TAC and CYA appear to have different effects on TLR signaling. Impaired TLR function has important repercussions for risk of infection, graft rejection, and disease recurrence after transplantation, and the different immunosuppressive profiles of CYA and TAC may guide the choice of therapy to improve disease outcomes. Liver Transpl 19:1099‐1107, 2013.

Early-onset versus late-onset nonanastomotic biliary strictures post liver transplantation: risk factors reflect different pathogenesis

Nonanastomotic biliary strictures (NAS) cause significant morbidity post liver transplantation. Timing of stricture development varies considerably, but the relationship between timing of stricture onset and aetiology has not been fully elucidated. Database analysis was performed on all adult patients undergoing liver transplantation between 1st January 1990 and 31st May 2008. Diagnosis of NAS required demonstration on at least two radiological studies. Early NAS were defined as developing <1 year post transplant (minimum 1‐year follow‐up) and late NAS developing >1 year post transplant (minimum 10‐year follow‐up). Ninety‐six of 397 patients developed NAS (24%); 54 were early‐onset NAS (56%) and 42 late‐onset NAS (44%). Primary sclerosing cholangitis (PSC) was the only risk factor for NAS overall (P = 0.001). However, when patients with PSC were excluded, older donor age was a significant risk for NAS (P = 0.003). Early‐onset NAS were associated with advanced donor age (P = 0.02), high MELD score (P = 0.001) and ABO‐identical grafts (P = 0.02), whereas late‐onset NAS were associated with PSC (P = 0.0008), bilio‐enteric anastomosis (P = 0.006) and tacrolimus (P = 0.0001). Advanced donor age is a significant risk for NAS in patients without PSC. Importantly, aetiology of NAS varies depending on time to stricture development, suggesting early‐onset and late‐onset NAS may have different pathogenesis.

On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable.

Toll-like receptor 3 and 7/8 function is impaired in hepatitis C rapid fibrosis progression post-liver transplantation.

Recurrence of hepatitis C (HCV) postliver transplant is universal, with a subgroup developing rapid hepatic fibrosis. Toll‐like receptors (TLRs) are critical to innate antiviral responses and HCV alters TLR function to evade immune clearance. Whether TLRs play a role in rapid HCV recurrence posttransplant is unknown. We stimulated peripheral blood mononuclear cells (PBMCs) from 70 patients with HCV postliver transplant with TLR subclass‐specific ligands and measured cytokine production, TLR expression and NK cell function. Rate of fibrosis progression was calculated using posttransplant liver biopsies graded by Metavir scoring (F0–4; R = fibrosis stage/year posttransplant; rapid fibrosis defined as >0.4 units/year). Thirty of 70 (43%) patients had rapid fibrosis progression. PBMCs from HCV rapid‐fibrosers produced less IFNα with TLR7/8 stimulation (p = 0.039), less IL‐6 at baseline (p = 0.027) and with TLR3 stimulation (p = 0.008) and had lower TLR3‐mediated monocyte IL‐6 production (p = 0.028) compared with HCV slow fibrosers. TLR7/8‐mediated NKCD56 dim cell secretion of IFNγ was impaired in HCV rapid fibrosis (p = 0.006) independently of IFNα secretion and TLR7/8 expression, while cytotoxicity remained preserved. Impaired TLR3 and TLR7/8‐mediated cytokine responses may contribute to aggressive HCV recurrence postliver transplantation through impaired immune control of HCV and subsequent activation of fibrogenesis.

Role of toll-like receptors in liver transplantation

Toll‐like receptors (TLRs) are pathogen recognition receptors that orchestrate the innate immune response and the subsequent adaptive immune response. TLRs can be triggered by exogenous ligands expressed by invading pathogens or by the release of endogenous ligands, such as that occurring through cellular injury during the transplantation process. They are now recognized to play an important role in many facets of transplantation biology, including rejection and tolerance, ischemia/reperfusion injury (IRI), and infections after transplantation. The role of TLRs in liver transplantation is unique with respect to other organ transplants because the portal circulation is a continuous source of TLR2 and TLR4 ligands, and this influences TLR signaling pathways, which have a central role in transplantation immunity. This review provides a critical update on recent data outlining the important role of TLRs in liver transplantation, and there is a particular focus on emerging advances in our understanding of rejection and tolerance, IRI, and infections after transplantation and on the ways in which these events may influence the recurrence of diseases such as hepatitis C infection after liver transplantation. Liver Transpl 20:270‐280, 2014.

The clinical role of circulating free tumor DNA in gastrointestinal malignancy

&NA; Circulating cell‐free DNA (cfDNA) is DNA released from necrotic or apoptotic cells into the bloodstream. While both healthy cells and cancer cells release cfDNA, tumors are associated with higher levels of tumor‐derived circulating cell‐free DNA (ctDNA) detectable in blood. Absolute levels of ctDNA and its genetic mutations and epigenetic changes show promise as potentially useful biomarkers of tumor biology, progression, and response to therapy. Moreover, studies have demonstrated the discriminative accuracy of ctDNA levels for diagnosis of gastrointestinal cancer compared with benign inflammatory diseases. Therefore, ctDNA detected in blood offers a minimally invasive and easily repeated “liquid biopsy” of cancer, facilitating real‐time dynamic analysis of tumor behavior that could revolutionize both clinical and research practices in oncology. In this review, we provide a critical summary of the evidence for the utility of ctDNA as a diagnostic and prognostic biomarker in gastrointestinal malignancies.