Glenn K. Bonney

Circulating markers of biliary malignancy: opportunities in proteomics?

Cholangiocarcinoma, a primary liver tumour that arises from biliary epithelial cells, is increasing in incidence and has poor prognosis. Diagnosis is difficult, particularly in patients with primary sclerosing cholangitis, who are at risk of developing the disease. Timely diagnosis is essential because surgical resection in early disease remains the only cure. The lack of a sensitive and specific early diagnostic marker and of alternative treatments are the main reasons why patients have limited survival. The use of proteomic-based approaches, which analyse the physiological or pathological complement of proteins (ie, the proteome) in cells, tissues, or biological fluids, has received substantial interest in biomarker discovery. Proteomics complements genomic studies and examines functional end-units quantitatively and qualitatively, including post-translational modifications which might vary with disease and might have key roles in protein function or localisation. Major advances in technology and bioinformatics have enhanced proteomic studies, resulting in increased understanding of the pathogenesis of many diseases and in biomarker discovery with effective use of tissues, cell lines, and biological fluids. We review the current status and promise of proteomic-based approaches in biomarker discovery for cholangiocarcinoma.

Donor risk index and MELD interactions in predicting long-term graft survival: a single-centre experience.

Introduction. Feng et al. described the donor risk index (DRI) in North American liver transplant recipients. We evaluated the effect of the DRI and model for end-stage liver disease (MELD) score on liver transplant recipients from a single center in the United Kingdom. Method. Prospectively, collected data of all patients transplanted at our center between January 1995 and December 2005 were included in the analysis (n=1090). Outcomes evaluated included patient-censored and death-censored graft survival. Outcomes of liver transplantation from “high” and “low” DRI groups (≥1.8 and <1.8, respectively) on patients categorized into low (<15), intermediate (15-30), and high (>30) MELD categories were analyzed. Results. MELD at transplant was the only significant predictor of patient survival. MELD at transplant and DRI more than 1.7 were associated with a poorer graft survival (P=0.03). There was a trend toward poorer graft survival in high DRI grafts transplanted in low and “intermediate” MELD categories (P=0.47 and 0.006, respectively). However, in the high MELD category, there was a similar graft survival for both high and low DRI grafts. Conclusion. Patients with low and intermediate MELDs at transplantation may be better served by a low DRI graft, whereas patients with high MELD may not be compromised by receiving a high DRI graft.

Indication for treatment and long-term outcome of focal nodular hyperplasia

INTRODUCTIONnUnlike malignant liver tumours, the indications for hepatic resection for benign disease are not well defined. This is particularly true for focal nodular hyperplasia (FNH). Here we summarize a single-centre experience of the diagnosis and management of FNH.nnnMATERIALS AND METHODSnUsing a prospectively collected database, a retrospective analysis of consecutive patients who were managed at our centre for FNH between January 1997 and December 2006 was performed.nnnRESULTSnThe cohort was divided into two groups of patients: those who were managed surgically (n=15) and those managed conservatively (n=37). There was no correlation between tumour size and number of lesions with oral contraceptive use (p=0.07 and 0.90, respectively) and pregnancy (p=0.45 and 0.60, respectively). However, tumour size (p=0.006) and number of lesions (p=0.02) were associated with the occurrence of pain in these patients. Pain was the commonest symptom of patients (13/15) who were managed surgically. All patients underwent radiological imaging before diagnosis. The sensitivities of ultrasound, CT scanning and MRI scanning in characterizing these lesions were 30%, 70% and 87%, respectively. There were no postoperative deaths and three postoperative complications that were successfully managed non-operatively. With a median follow-up of 24 months in the surgically treated group, one patient has developed recurrent symptoms of pain. CONCLUSION. In this series, there was no mortality directly due to the surgical procedure and a modest morbidity, justifying surgical resections in selected patients.

Shotgun proteomics of human bile in hilar cholangiocarcinoma

The need to find biomarkers for hepatobiliary diseases including cholangiocarcinoma (CCA) has led to an interest in using bile as a proximal fluid in biomarker discovery experiments, although there are inherent challenges both in its acquisition and analysis. The study described here greatly extends previous studies that have started to characterise the bile proteome. Bile from four patients with hilar CCA was depleted of albumin and immunoglobulin G and analysed by GeLC‐MS/MS. The number of proteins identified per bile sample was between 378 and 741. Overall, the products of 813 unique genes were identified, considerably extending current knowledge of the malignant bile proteome. Of these, 268 were present in at least 3 out of 4 patients. This data set represents the largest catalogue of bile proteins to date and together with other studies in the literature constitutes an important prelude to the potential promise of expression proteomics and subsequent validation studies in CCA biomarker discovery.

Outcomes in right liver lobe transplantation: a matched pair analysis.

Split liver transplantation (SLT) has proven to be an effective technique of increasing the donor pool and thereby reducing adult and paediatric waiting list mortality. There remains concern regarding complications in adult recipients. Here, we compare SLT with matched whole liver grafts. Adult recipients of primary extended right lobe grafts (ERL) were matched to recipients of whole liver transplantations (WLTs) according to the following criteria: model of end‐stage liver disease (MELD) score, recipient age, indication for liver transplantation and year of transplantation. Twenty‐seven pairs of recipients were transplanted for chronic liver disease. The overall 30‐day patient survival rates after ERL and WLT were 88.9% and 92.5% and 3‐year survival rates after SLT and WLT were 77.8% and 85.2% respectively (log‐ranku2003=u20030.38). Two patients with SLTs had hepatic artery thromboses and were retransplanted with none from the WLT group. The prevalence of a biliary leak was higher among the SLT group (nu2003=u20034) compared with none in the WLT group (Pu2003=u20030.05). Patients with preoperative hyponatraemia showed a trend towards poorer survival after SLT compared with WLT. Our data suggest that SLT with extended right liver lobes, although not significantly different, shows a trend towards a poorer outcome.

Role of neoadjuvant chemotherapy in resectable synchronous colorectal liver metastasis; An international multi-center data analysis using LiverMetSurvey.

The use of neo‐adjuvant chemotherapy in resectable synchronous liver metastasis is ill defined. The aim of this study was to evaluate neo‐adjuvant chemotherapy on outcomes following liver resection for synchronous CLM.

Increasing the Donor Pool: Consideration of Prehospital Cardiac Arrest in Controlled Donation After Circulatory Death for Liver Transplantation

Donor warm ischemia has implications for outcomes after liver transplantation (LT) using organs from donation after circulatory death (DCD) donors. Prehospital cardiac arrest (PHCA) before donation may generate a further ischemic insult. The aim of this single‐center study of 108 consecutive DCD LT procedures was to compare the outcomes of PHCA and non‐PHCA cohorts. A review of a prospectively collected database of all DCD grafts transplanted between January 2007 and October 2011 was undertaken to identify donors who had sustained PHCA. The unit policy was to consider such donors when transaminase levels were ≤4 times the normal range and had an improving trend. Twenty‐six of the 108 DCD transplants were from DCD donors with PHCA, and 82 were in the non‐PHCA cohort. A comparative analysis of the PHCA and non‐PHCA cohorts showed better short‐term results (a low incidence of acute kidney injury) for the PHCA group but satisfactory long‐term results for both groups with no significant differences in graft or patient survival between them. In conclusion, a careful donor selection policy for including PHCA DCD donors with normalized liver function tests or transaminase levelsu2009≤u20094 times the norm resulted in successful transplantation and could boost the donor pool with no adverse outcomes. Liver Transpl 20:63‐71, 2014.

Successful treatment of cerebral tuberculosis in a liver transplant recipient

A 62-year-old male of Pakistani origin, who had undergone orthotopic liver transplantation (OLT) for hepatitis C cirrhosis 4 years previously, presented with increasing confusion, lethargy, and vomiting of 4 days’ duration. There were no specific localizing neurological signs. There was no history of fever, weight loss, or respiratory problems. He did not give any history of having contracted tuberculosis (TB), although his sister had been treated for pulmonary TB 5 years previously. The patient had been resident in the United Kingdom for more than 30 years and traveled to Pakistan every 2 to 3 years but had not made any trips after his transplant. A pretransplant chest X-ray had not revealed any evidence of TB, and a Mantoux test had been negative. He had received 300 mg of isoniazid (INH) daily for 6 months post-OLT for latent TB infection according to the unit protocol for high-risk patients. His posttransplant course had been largely uneventful with no episodes of acute rejection, and cyclosporine and azathioprine immunosuppression was maintained. A contrast-enhanced computed tomography (CT) scan of the brain showed discrete ring-enhancing lesions in the right occipital lobe and the cerebellum with surrounding vasogenic edema and a mass effect (Fig. 1). There were additional pulmonary lesions on a chest CT scan. A stereotactic brain biopsy revealed a liquefied purulent material, from which Mycobacterium tuberculosis grew in a culture. The patient was started on triple-drug antitubercular therapy with INH, rifampicin, and pyrazinamide with pyridoxine for 9 months, following which his neurological status improved. His graft function remained stable throughout his treatment course, but he required multiple readmissions for social reasons. A repeat CT scan 3 years after his craniotomy showed complete resolution of the lesion (Fig. 2). He made a complete recovery and remains well 40 months after the completion of treatment.

Outcomes after liver transplantation of patients with Indo-Asian ethnicity.

Background The impact of ethnicity on outcomes after orthotopic liver transplantation (OLT) is unclear. The British Indo-Asian population has a high incidence of liver disease but its contribution to the national deceased donor pool is small. We evaluated access to and outcomes of OLT in Indo-Asians. Methods We compared 182 Indo-Asians with white patients undergoing OLT. Matching criteria were transplantation year, liver disease, age, sex. Donor and recipient characteristics, postoperative outcomes, including patient and graft survival, OLT era (early, 1987–2001; late, 2002–2011) were compared. Survival was also analyzed by underlying disease—acute liver failure (ALF) and chronic liver failure. Results Indo-Asians had higher diabetes incidence. There were no differences in waiting time for transplantation, despite smaller body size and more uncommon blood groups (B, AB) among Indo-Asians. In the early era, patient survival for Indo-Asians with ALF was worse when compared to whites. In the late era, graft and patient survival at 1, 2, and 5 years were similar between groups. Conclusion This study demonstrates that Indo-Asian patients have equal access to OLT and comparable outcomes to whites in the United Kingdom. Survival has improved among Indo-Asian patients; this may be attributable to careful patient selection in case of ALF, though improvement of patient management may have contributed.

Benign Biliary Strictures

The aetiology of benign biliary strictures is diverse [1]. In the recent past, the most common cause of benign biliary strictures in Western countries appears to be postoperative causes, while in Asia it is due to infection such as Clonorchis sinensis in parts of Southern China [1]. This may no longer hold with the growing affluence in Asia and the influx of Asian immigrants into the West. The aetiology of benign biliary strictures can be broadly classified into postoperative, inflammatory, and others.