Mervyn H. Davies

Selection of patients for liver transplantation and allocation of donated livers in the UK

Background: The increasing shortfall between the number of patients who would benefit from liver transplantation and the availability of donor livers means that rationing has to occur. The processes of selection of patients for transplantation and for allocation of donor livers should be done according to ethical and, where possible, evidence-based criteria so that there is clarity and that the competing requirements of equity, justice, utility and benefit can be balanced. Methods: To achieve these goals for patients in the United Kingdom in need of transplantation, we have developed guidelines for the selection of patients to the national waiting list based on the risk of death without a transplant and the ability of the procedure to improve the recipient’s quality of life. Guidelines have been developed for both those with acute liver failure and chronic liver disease. Allocation will depend on matching of the donor liver to the recipient. Results: The proposed system, to be introduced into the UK compares with some other systems, where different models for selection and allocation have been introduced.

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10−8), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2 > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non–human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2 > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Liver transplantation following donation after cardiac death: An analysis using matched pairs

Grafts from donation after cardiac death (DCD) donors are used to increase the number of organs available for liver transplantation. There is concern that warm ischemia may impair graft function. We compared our DCD recipients with a case‐matched group of donation after brain death (DBD) recipients. Between January 2002 and April 2008, 39 DCD grafts were transplanted. These were matched with 39 DBD recipients on the basis of identified variables that had a significant impact on mortality. These were used to individually match DCD and DBD patients with similar predictive mortality. We compared patient/graft survival, primary non‐function (PNF), and rates of complications. Of all liver transplants, 6.1% were DCD grafts. PNF occurred twice in the DCD group. The incidence of nonanastomotic biliary strictures (NABS; 20.5% versus 0%, P = 0.005) and hepatic artery stenosis (HAS; 12.8% versus 0%, P = 0.027) in the DCD group was higher. One‐year (79.5% versus 97.4%, P = 0.029) and 3‐year (63.6% versus 97.4%, P = 0.001) graft survival was lower in the DCD group. Three‐year patient survival was also lower (68.2% versus 100%, P < 0.0001). Our study is the first to use case‐matched patients and compare groups with similar predictive mortality. There was a higher incidence of NABS and HAS in the DCD group. NABS were likely a result of warm ischemia. HAS may have been due to ischemia or arterial injury during retrieval. The DCD group had significantly poorer outcomes, but DCD grafts remain a valuable resource. With careful donor/recipient selection, minimization of ischemia, and good postoperative care, acceptable results can be achieved. Liver Transpl 15:1072–1082, 2009.

Emergency Subtotal Hepatectomy: A New Concept for Acetaminophen-Induced Acute Liver Failure : Temporary Hepatic Support by Auxiliary Orthotopic Liver Transplantation Enables Long-term Success

Introduction:Acetaminophen (paracetamol) overdose (AOD) has recently emerged as the leading cause of acute liver failure (ALF) in the United States, with an incidence approaching that seen in the United Kingdom. We describe a new way to treat AOD ALF patients fulfilling Kings College criteria for “super-urgent” liver transplantation. Methods:Beginning in June 1998, we have been piloting a clinical program of subtotal hepatectomy and auxiliary orthotopic liver transplantation (ALT) for AOD ALF. Our technique is based on the following principles: (1) subtotal hepatectomy; (2) auxiliary transplantation of a whole liver graft; (3) gradual withdrawal of immunosuppression after recovery. Results were compared with patients who had undergone an orthotopic liver transplantation (OLT) for AOD ALF in the same period. Quality of life comparisons were made using the SF36 questionnaire. Results:Thirteen patients underwent this procedure between June 1998 and March 2005. Median survival is 68 months (range, 0–102 m). Actual survival data show that 9 of 13 patients are alive (69%) compared with 7 of 13 OLT patients (54%). One ALT patient required a retransplantation with an OLT due to hepatic vein thrombosis, and immunosuppression is therefore maintained. The other 8 surviving ALT patients are off immunosuppression. These 8 ALT patients have normal liver function and have a better quality of life compared with the 7 surviving OLT patients. Conclusion:Our results with this new technique are encouraging: 69% actual survival, no long-term immunosuppression requirement, and improved quality of life in the 62% successful cases.

A combined liver-pancreas en-bloc transplant in a patient with cystic fibrosis.

We report a case of combined liver-pancreas en-bloc transplant for a patient with cystic fibrosis (CF) and insulin dependent diabetes mellitus (IDDM). A combined liver-pancreas transplant for a patient with CF has been described only once before in the literature with orthotopic liver and heterotopic pancreas and kidney transplant (1). Here we present a new and more efficient en-bloc technique for combined liver-pancreas transplant.

Tacrolimus in liver transplantation.

Tacrolimus has been in clinical use for ten years. It was launched in a hail of publicity following the successful treatment of cases with apparently irreversible rejection using conventional immunosuppressive therapies. Since that time, the overall experience with the drug has increased considerably. The purpose of this article is to review tacrolimus comprehensively, including evidence derived from major clinical trials, to enable the reader to become familiar with its clinical role, including a comparison with its main competitor, cyclosporin. Tacrolimus was discovered in 1984, it predominantly acts via inhibition of T-cell mediated immunity, and to a lesser extent B-cell humoral immunity. The agent was introduced into clinical medicine in 1989 and was soon shown to be a highly effective immunosuppressive agent, receiving approval in 1994 by the Food and Drug Administration (FDA) for primary immunosuppression in adult and paediatric liver transplantation. Tacrolimus has proved to be a major development in transplantation. Whilst the available data have been hindered to some extent by deficiencies of trial design in the major studies, there is still more comparative clinical data available for tacrolimus than for any of its predecessors. The overall balance of risk benefit is considered by many to be tipped in favour of tacrolimus; it is likely that with more long-term follow-up results becoming available in liver and other solid organ transplants, the benefits will appear clearer.

The value of MELD and sodium in assessing potential liver transplant recipients in the United Kingdom

As the result of the widening gap between supply and demand of organs for liver transplantation, efforts to improve allocation have become an increasingly important yet controversial subject. The MELD score has been adopted in the USA but its usefulness has rarely been examined in Europe. We carried out an intention to treat analysis of 422 patients placed on our transplant waiting list over a 5‐year period. We examined multiple variables to investigate the value of MELD, sodium and other factors in predicting post‐transplant outcomes. MELD at transplant was the most important indicator of post‐transplant outcomes. In addition, delta‐MELD and hyponatreamia were significant at predicting, which patients placed on the waiting list would not proceed to transplant. While a move to allocating solely by MELD is not justified in the UK allocation system, there is value in using MELD, delta‐MELD and hyponatreamia in making decisions regarding the allocation of organs. This may subsequently help to improve overall outcomes.

Subtotal hepatectomy and whole graft auxiliary transplantation for acetaminophen-associated acute liver failure.

BACKGROUND An acetominophen overdose (AOD) is the leading cause of acute liver failure (ALF) in the UK and USA. For patients who meet the Kings College Hospital criteria, (mortality risk > 85%), an emergency orthotopic liver transplantation (OLT) is conventionally performed with subsequent life-long immunosuppression. A new technique was developed in 1998 for AOD-induced ALF where a subtotal hepatectomy (right hepatic trisectionectomy) and whole graft auxiliary liver transplant (WGALT) was performed with complete withdrawal of immunosupression during the first year post-operatively. RESULTS During 1998-2010, 68 patients were listed for an emergency transplantation for AOD ALF at our institution: 28 died waiting, 16 underwent OLT and 24 a subtotal hepatectomy with WGALT. Eight OLT (50%) and 16 WGALT remain alive (67%); actuarial survival at 5 years OLT 50%, WGALT 63%, P = 0.37. All patients who had successful WGALT are off immunosuppression. Poor prognostic factors in the WGALT group included higher donor age (40.4 versus 53.9, P = 0.043), requirements for a blood transfusion (4.3 versus 7.6, P = 0.0043) and recipient weight (63.1 versus 54 kg, P = 0.036). CONCLUSION Although OLT remains standard practice for AOD-induced ALF, life-long immunosuppression is required. A favourable survival rate using a subtotal hepatectomy and WGALT has been demonstrated, and importantly, all successful patients have undergone complete immunosuppression withdrawal. This technique is advocated for patients who have acetominophen hepatotoxicity requiring liver transplantation.

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.

The use of clonidine with diuretic therapy in the treatment of refractory ascites in patients with cirrhosis awaiting liver transplantation

We have read the comprehensive review article by Cardenas and Gines that details the management of ascites, hyponatraemia, hepatorenal syndrome, bacterial infections, hepatic encephalopathy and variceal bleeding in patients with decompensated chronic liver disease.1 It is well recognised that such conditions alter pre-, peri- and post-orthotopic liver transplant (OLT) outcomes. However, there is one important issue around …