Mark A. Aldersley

The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis

The biochemical response to ursodeoxycholic acid (UDCA)—so‐called “treatment response”—strongly predicts long‐term outcome in primary biliary cholangitis (PBC). Several long‐term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long‐term prognostic models of PBC using data from the UK‐PBC Research Cohort. We performed Coxs proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA‐treated participants. We used nonautomatic backward selection to derive the best‐fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver‐related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA‐treated participants. The best‐fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5‐, 10‐, and 15‐year risk scores were highly accurate (areas under the curve: >0.90). Conclusions: The prognosis of PBC patients can be accurately evaluated using the UK‐PBC risk scores. They may be used to identify high‐risk patients for closer monitoring and second‐line therapies, as well as low‐risk patients who could potentially be followed up in primary care. (Hepatology 2016;63:930–950)

Liver toxicity associated with sofosbuvir, an NS5A inhibitor and ribavirin use

Hepatitis C virus (HCV) infection is a major cause of end-stage liver disease and hepatocellular carcinoma. There have been rapid advances in HCV treatment with the development of oral direct-acting antivirals (DAAs). Studies have shown sustained virological response rates above 90% with combinations of DAAs, including patients with compensated cirrhosis. Thus far, significant drug toxicity has not been seen with these agents, but there is limited experience of using DAAs in decompensated HCV cirrhosis. This report describes the first experience of serious drug-induced hepatotoxicity with the new DAAs. The mechanism underlying these drug reactions is currently unknown. Few patients with decompensated cirrhosis have been treated with DAAs, so the exact pharmacokinetics in this population have not been characterised. In both cases presented here, patients were taking or had recently taken other drugs. It is possible that an unknown interaction or reaction to the drug combination caused the hepatotoxicity. Although the association with the DAAs is not proven these cases indicate that patients with advanced liver disease need close monitoring while on DAA therapy and if there is a significant unexplained deterioration in liver function the DAAs should be discontinued.

Intestinal permeability and liver disease

Increased intestinal permeability has for many years been implicated as a possible contributory factor in the development of encephalopathy and spontaneous bacterial peritonitis (SBP) seen in patients with cirrhosis. The majority of studies indicate that there is an increase in small intestinal permeability in cirrhotic patients and there is also evidence of an increase in patients with acute liver failure. The cause of these changes is unknown and whether they are related to the development of SBP and encephalopathy is unclear.

Assignment1 of GALGT encoding β-1,4N-acetylgalactosaminyl-transferase (GalNAc-T) and KIF5A encoding neuronal kinesin (D12S1889) to human chromosome band 12q13 by assignment to ICI YAC 26EG10 and in situ hybridization

A locus including the genes GLI, DDIT3, LRP1, SAS and CDK4 on 12q13 is frequently amplified in gliomas and sarcomas (Reifenberger et al., 1994; Forus et al., 1993). We have now mapped two further genes, ß-1,4 N-acetylgalactosaminyltransferase (GALGT) and human neuronal kinesin (KIF5A, D12S1889), to the same region. More specifically, GALGT and KIF5A map to the same 200-kb yeast artificial chromosome as GLI and DDIT3. ß-1,4N-acetylgalactosaminyltransferase (GM2/GD2 synthase) is an enzyme involved in the synthesis of complex gangliosides which have been suggested to have a role in neuronal functioning (Takamiya et al., 1996). Human neuronal kinesin is a member of the kinesin gene family. These proteins are involved in numerous cellular processes including organelle transport, maintenance of the endoplasmic reticulum, intermediate filament distribution, organisation of spindle microtubules, chromosome segregation, flagellar growth and positioning of developmental morphogens (Bloom and Endow, 1995). GLI is the human homologue of the Drosophila gene Cubitus interruptus (Ci), which is a transcription factor involved in the hedgehog signalling pathway, controlling cell fates and patterning in development (Altaba, 1997). It has recently been demonstrated in Drosophila that a cytoplasmic protein, Cos2 binds to microtubules and associates with Ci thereby directly controlling its activity (Sisson et al., 1997). It is of interest that the human homologue of Cos2 is actually human neuronal kinesin (or Kinesin HC) which we have now discovered maps to within, at most, 200 kb of GLI, its putative binding partner. ß-1,4N-Acetylgalactosaminyltransferase and neuronal kinesin are involved in neuronal cellular functioning and both map to a region known to be amplified in certain tumours. This data raises the possibility that these neuronally expressed genes are also amplified in malignancies, particularly gliomas.

Prostate-specific membrane antigen expression in the duodenum: implications in coeliac disease and immunotherapy for prostate cancer

THE LANCET • Vol 351 • May 23, 1998 1559 1 Bates ER, Topol EJ. Limitations of thrombolytic therapy for acute myocardial infarction complicated by congestive heart failure and cardiogenic shock. J Am Coll Cardiol 1991; 18: 1077–84. 2 Kroll MH, Hellums JD, McIntire LV, Schafer AI, Moake JL. Platelet and shear stress. Blood 1996; 88: 1525–40. 3 Ikeda Y, Murata M, Goto S. von Willebrand factor-dependent shearinduced platelet aggregation. Basic mechanism and clinical implications. Ann NY Acad Sci 1997; 811: 325–36. 4 Goto S, Salomon DR, Ikeda Y, Ruggeri ZM. Characterization of the unique mechanism mediating the shear-dependent binding of soluble von Willebrand factor to platelets. J Biol Chem 1995; 270: 23352–61. 5 Goto S, Sakai H, Ikeda Y, Handa S. Acute myocardial infarction plasma augments platelet thrombus growth in high shear rates. Lancet 1997; 349: 543–44.

Random Blood Alcohol Level Testing Detects Concealed Alcohol Ingestion in Patients With Alcoholic Liver Disease Awaiting Liver Transplantation

We read with great interest DiMartini and Dew’s discussion of the therapeutic and practical issues involved in the monitoring of alcohol use in patients listed for liver transplantation (LT). The liver unit at St. James’s University Hospital in Leeds is 1 of 7 LT units in the United Kingdom and performs adult LT 80 to 100 times each year. Patients with a diagnosis of alcohol-related liver disease (ALD) who are listed for LT in Leeds are required to sign a contract committing them to lifelong abstinence from alcohol. They also have to attend scheduled appointments for blood alcohol level (BAL) testing and consent to communitybased random BAL testing without prior notice. The timely identification of patients with ALD who are still drinking whilst they are on the transplant waiting list (WL) is crucial. We conducted a retrospective review of 206 patients with ALD who were abstinent from alcohol for at least 6 months and had been listed for transplantation between 2006 and 2011 inclusive (Fig. 1). Fifteen patients (7%) were removed from the WL because of ongoing alcohol ingestion, and the majority of these patients (9 or 60%) were identified through random BAL testing. Eight of these 9 patients previously had negative BAL results at scheduled appointments. Four patients had positive BAL results at planned appointments. The mean duration of abstinence at the time of listing was 18 months (range 5 6-60 months). Interestingly, the majority of relapses (73%) occurred within the first 6 months after listing, and these patients had a shorter average duration of abstinence of 13 months. Carbonneau et al. identified the duration of prelisting abstinence as an independent predictor of alcohol use on the WL, and our results support this; in addition, our observations favor the use of random BAL testing instead of scheduled testing to identify patients with ALD who return to drinking. The frequency of screening should perhaps be intensified in the first 6 months after listing because we have identified this period as the one in which most patients suffer a relapse into drinking. Only 2 patients who had previously claimed abstinence admitted to alcohol use on the WL at follow-up visits. We would exercise great caution in using patient disclosure as a means of identifying ongoing alcohol consumption because the rate of concealment of active drinking is likely to be significant, as noted by Hempel et al.

Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries

Please cite this article as: da Silva Filipe, A., Sreenu, V., Hughes, J., Aranday-Cortes, E., Irving, W.L., Foster, G.R., Agarwal, K., Rosenberg, W., Macdonald, D., Richardson, P., Aldersley, M.A., Wiselka, M., Ustianowski, A., McLauchlan, J., Thomson, E.C., Response to DAA Therapy in the NHS England Early Access Programme for Rare HCV Subtypes from Low and Middle Income Countries, Journal of Hepatology (2017), doi: http://dx.doi.org/ 10.1016/j.jhep.2017.06.035

Liver transplant listing for hepatitis C associated cirrhosis and hepatocellular carcinoma has fallen in the United Kingdom since the introduction of direct acting antiviral therapy

Following the introduction of direct‐acting antivirals (DAA), there have been reports of declining incidence of hepatitis C (HCV)‐related liver disease as a liver transplantation indication. In this study, we assessed the impact of DAA on liver transplant indications in the UK and waiting list outcomes for patients with HCV. We assessed UK adult elective liver transplant registrants between 2006 and 2017. The aetiology of liver disease at registration was reclassified using an accepted hierarchical system and changes were assessed over time and compared before and after the introduction of DAA. Registration UKELD scores and 1‐year waiting list outcomes were also compared. The proportion of waiting list patients registered with HCV‐related cirrhosis reduced after the introduction of DAA from 10.5% in 2013 to 4.7% in 2016 (P < 0.001). Alcohol‐related liver disease (ARLD) was the leading indication for liver transplantation followed by liver cancer (26.1% and 18.4% in 2016, respectively). The proportion of registrations with Hepatocellular carcinoma (HCC) associated with HCV reduced from 46.4% in 2013 to 33.7% in 2016 (P = 0.002). For patients with HCV‐related cirrhosis at one year the outcomes of death, transplantation, delisting due to improvement or deterioration and awaiting a graft at 1 year were similar. For patients with HCV‐related HCC, the proportion dying at 1 year reduced significantly from 2.9% to 0.0% (P = 0.04). These data demonstrate an association between DAA and reduced listing rates for HCV‐related cirrhosis and HCC, but no significant changes in waiting list outcomes other than reduced mortality in the HCC group.

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