Alan J. Wigg

Outcomes following liver transplantation for seronegative acute liver failure: experience during a 12-year period with more than 100 patients.

Seronegative hepatitis is a common cause of acute liver failure (ALF) requiring liver transplantation. The primary aim of this study was to examine outcomes following transplantation in this group and to identify factors associated with early (<2 months) mortality. Patients studied were 110 consecutive cases of seronegative ALF transplanted at the Queen Elizabeth Hospital, Birmingham, between January 1992 and January 2004. Univariate analysis of 44 pretransplantation recipient, donor, and operative variables was performed initially to identify factors associated with early posttransplantation mortality. Variables identified as significant or approaching significance were analyzed using stepwise multiple logistic regression analysis. Survival following transplantation for seronegative hepatitis was 83%, 81%, and 73% at 2, 12, and 60 months, respectively. The majority (71%) of deaths occurred within the 1st 2 months and sepsis / multiorgan dysfunction was the most common cause of early death. Univariate analysis revealed 9 variables predicting early death. Subsequent multivariate analysis identified high donor body mass index (BMI; a possible surrogate marker for hepatic steatosis) as the most important predictor of early death (P = .009; odds ratio, 1.2; 95% confidence interval, 1.0‐1.3). Recipient age >50 (P = .015; odds ratio, 4.2; 95% confidence interval, 1.3‐14.1) and non‐Caucasian recipient ethnicity (P = .015; odds ratio, 4.9; 95% confidence interval, 1.2‐19.2) were other variables associated with early death on multivariate analysis. This study specifically examined factors that determine the early outcome of transplanted seronegative ALF patients. In conclusion, we found that donor and recipient factors identify patients who have a high chance of early death after transplantation. (Liver Transpl 2005;11:27–34.)

Efficacy of a Chronic Disease Management Model for Patients With Chronic Liver Failure

BACKGROUND & AIMS Despite the economic impacts of chronic liver failure (CLF) and the success of chronic disease management (CDM) programs in routine clinical practice, there have been no randomized controlled trials of CDM for CLF. We investigated the efficacy of CDM programs for CLF patients in a prospective, controlled trial. METHODS Sixty consecutive patients with cirrhosis and complications from CLF were assigned randomly to groups given intervention (n = 40) or usual care (n = 20), from 2009 to 2010. The 12-month intervention comprised 4 CDM components: delivery system redesign, self-management support, decision support, and clinical information systems. The primary outcome was the number of days spent in a hospital bed for liver-related reasons. Secondary outcomes were rates of other hospital use measures, rate of attendance at planned outpatient care, disease severity, quality of life, and quality of care. RESULTS The intervention did not reduce the number of days patients spent in hospital beds for liver-related reasons, compared with usual care (17.8 vs 11.0 bed days/person/y, respectively; incidence rate ratio, 1.6; 95% confidence interval, 0.5-4.8; P = .39), or affect other measures of hospitalization. Patients given the intervention had a 30% higher rate of attendance at outpatient care (incidence rate ratio, 1.3; 95% confidence interval, 1.1-1.5; P = .004) and significant increases in quality of care, based on adherence to hepatoma screening, osteoporosis and vaccination guidelines, and referral to transplant centers (P < .05 for all). CONCLUSIONS In a pilot study to determine the efficacy of CDM for patients with CLF, patients receiving CDM had significant increases in attendance at outpatient centers and quality of care, compared with patients who did not receive CDM. However, CDM did not appear to reduce hospital admission rates or disease severity or improve patient quality of life. Larger trials with longer follow-up periods are required to confirm these findings and assess cost effectiveness.

Radiotherapy for hepatocellular carcinoma: Systematic review of radiobiology and modeling projections indicate reconsideration of its use

Background and Aims:  External beam radiotherapy currently has a limited role in the treatment of hepatocellular carcinoma (HCC). The purpose of this article was to review available radiobiological data on HCC and normal liver and incorporate these data into radiobiological models that may be used to explain and improve treatment.

Heterozygous recipient and donor HFE mutations associated with a hereditary haemochromatosis phenotype after liver transplantation

We observed the development of phenotypic hereditary haemochromatosis in a non-hereditary haemochromatosis liver transplant recipient, following transplantation with a liver from a C282Y heterozygous donor. No cause for secondary iron overload was identified. Subsequent sequencing of the HFE gene of both donor and recipient revealed a strong candidate for a novel pathogenic HFE mutation. In the recipient, heterozygosity for a single base substitution in exon 1, g.18 G>C, resulting in the substitution of arginine by serine at codon 6 (R6S), was detected. This R6S variation is likely to represent a novel pathogenic missense mutation of the HFE gene. An interaction between R6S heterozygosity in the recipient and C282Y heterozygosity in the donor liver is the most likely explanation for the development of iron overload in this patient. The report suggests that an hepatic defect is required for expression of hereditary haemochromatosis and that the intestinal HFE genotype is not the exclusive determinant of iron status. It also raises the possibility that a hereditary haemochromatosis phenotype may result from transplantation of C282Y heterozygous donor livers into recipients with heterozygous pathogenic HFE mutations. This possibility may have significant implications for the common practice of transplanting C282Y heterozygous livers.

Percutaneous thermal ablation for primary hepatocellular carcinoma: A systematic review and meta‐analysis

Percutaneous thermal ablation using radiofrequency ablation (RFA) and microwave ablation (MWA) are both widely available curative treatments for hepatocellular carcinoma. Despite significant advances, it remains unclear which modality results in better outcomes. This meta‐analysis of randomized controlled trials (RCT) and observational studies was undertaken to compare the techniques in terms of effectiveness and safety.

Liver resection and transplantation offer similar 5-year survival for Child-Pugh-Turcotte A HCC-patients with a single nodule up to 5 cm: A multicenter, exploratory analysis

BACKGROUND AND AIM The current guideline of the American Association for the Study of Liver Diseases recommends liver resection for Child-Pugh-Turcotte A patients with a single hepatocellular carcinoma, total serum bilirubin ≤ 1 mg/dL and absence of significant portal hypertension. This subset of patients would have a long-term survival comparable to transplantation. The main aim of this study is to evaluate the survival rates in patients with a single nodule ≤ 5 cm following resection. METHODS Medical records of 105 Child-Pugh-Turcotte A patients who underwent liver resection between 1997 and 2009 were analyzed in 3 countries. RESULTS One, 3-, and 5-year survival rate was 97%, 83%, and 66%, respectively, and no variable that can be assessed prior to liver resection predicted survival probabilities. CONCLUSIONS Liver resection offers 5-year survival similar to transplantation for Child-Pugh-Turcotte A patients with hepatocellular carcinoma and a single nodule up to 5 cm, independently of any patient baseline characteristics.

Current controversies surrounding liver transplantation for hepatocellular carcinoma.

Liver transplantation (LT) for hepatocellular carcinoma (HCC) has progressed rapidly over the last decade from a futile therapy to the first choice therapy for suitable patients. Excellent outcomes of LT for HCC can be largely attributed to the use of the Milan Criteria, which have restricted LT to patients with early stage tumors. These criteria may be conservative, and it is likely that a subset of patients with tumors beyond these criteria can have acceptable outcomes. However, there is currently insufficient data to accept more liberal criteria as a standard of care, and a higher quality evidence base must be achieved to prevent poor utilization of valuable donor liver resources. In the future, it is probable that more sophisticated selection criteria will emerge incorporating aspects of tumor biology beyond tumor size and number. Dropout from the waiting list due to tumor progression remains a clinical challenge particularly in regions with prolonged waiting times. Priority allocation using HCC MELD points is a practical and transparent solution that has successfully reduced waitlist dropout for HCC patients. Further refinements of the HCC MELD point system are required to ensure equity of access to LT for non‐HCC patients and prioritization of HCC patients with the highest risk of dropout. Improving the evidence base for pre‐LT locoregional therapy to prevent waitlist dropout is an urgent and difficult challenge for the LT community. In the interim transplant clinicians must restrict the use of these therapies to those patients who are most likely to benefit from them.

Liver support systems: promise and reality.

Effective liver support is needed for a variety of indications. A large number of both biological (containing hepatocytes) and non‐biological extracorporeal liver support systems have been described in the literature over the last 50 years. Despite this, there is a paucity of good quality randomized control data examining the effectiveness of these therapies in human liver failure. In this review article, we examine the available data, with particular emphasis on the current front runners, the MARS® and HepatAssist® systems. Other problems associated with the development of these liver support systems are also discussed. Although promising in animal studies, we conclude that the use of these technologies is not supported currently by a sufficient evidence base to recommend them for routine clinical use and that a lack of understanding about the critical functions required of a liver support system is retarding a more rational approach to the design of these systems.

High local recurrence of early-stage hepatocellular carcinoma after percutaneous thermal ablation in routine clinical practice.

Background and aim The risk of local tumour progression (LTP) and factors predicting LTP following percutaneous thermal ablation (PTA) of early-stage hepatocellular carcinoma (HCC) have not been well studied in non-trial settings and may be underestimated. We aimed to assess these outcomes in a multicentre study. Patients and methods This was a retrospective review of consecutive patients with early-stage HCC treated with a curative intent across three tertiary Australian centres between 2006 and 2012 with either radiofrequency ablation or microwave ablation. The primary endpoint was LTP and multivariate analysis was carried out to identify the independent predictors of LTP. Results In total 145 HCC nodules were treated in 126 patients (78% men, mean±SD age 62±10 years) with a mean±SD follow-up of 13.5±13 months. Local recurrence was observed in 23.4% (34/145). Mean±SD LTP-free survival was 46.9±3.6 months. For HCC nodules 2 cm or less, local recurrence rates were lower (15.9%), with a mean±SD LTP-free survival of 48.8±4.2 months. Poorly differentiated HCC [hazard ratio (95% confidence interval)=4.8 (1.1–20.4), P=0.032] and pretreatment &agr;-fetoprotein more than 50 kIU/l [8.2 (1.7–39.0), P=0.008] were independent predictors of LTP. LTP rates were not significantly different between the radiofrequency ablation and the microwave ablation groups (22.8 vs. 25.8%, P=0.7). There were six (4.8%) procedure-related adverse events, but no deaths. Conclusion Local recurrence after PTA for early-stage HCC is high in routine clinical practice. Poorly differentiated HCC and pretreatment &agr;-fetoprotein are important, independent predictors of LTP. Further well-designed randomized controlled trials with larger sample sizes using adjuvant therapies in combination with PTA to decrease LTP rates are warranted.

Maintenance of integrity and function of isolated hepatocytes during extended suspension culture at 25°C

Abstract: Isolated hepatocytes in suspension provide a number of advantages for use in bioartificial liver device, however, poor stability of this cell preparation at physiological temperatures is an apparent barrier preventing their use. We therefore investigated the integrity and differentiated function of isolated rat hepatocytes under conditions of mild hypothermia. Isolated hepatocytes were suspended in a bicarbonate buffered saline medium, supplemented with glucose and bovine serum albumin (BSA), and maintained for 48 h at 25 °C on a rotary shaker under an atmosphere of 95% O2 and 5% CO2. Under these conditions there was no significant decline in cell viability and good preservation of cellular morphology on transmission electron microscopy for at least 24 h. Isolated hepatocytes in suspension at 25 °C were also able to maintain normal Na +  and K +  ion gradients. The cellular energy status ([ATP], ATP/ADP ratio, cytoplasmic and mitochondrial redox potentials), metabolic function (urea synthesis and ammonia removal), albumin synthesis and phase I and phase II drug detoxification activity of these cells were also maintained for at least 24 h post isolation. These observations demonstrate the robust nature of mildly hypothermic isolated hepatocytes in suspension and encourage further studies re‐examining the feasibility of using this cell preparation in bioartificial livers.