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Role of cell adhesion molecules in leukocyte recruitment in the liver and gut.

This article reviews the evidence that adhesion molecules are critical in leukocyte recirculation and pathogenesis of diseases affecting the closely related tissues of the liver and gut, which offer novel opportunities for treatment.

Benign recurrent intrahepatic cholestasis with secondary renal impairment treated with extracorporeal albumin dialysis

Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive condition characterized by intermittent episodes of pruritis and jaundice that may last days to months. Treatment is often ineffective and symptoms, particularly pruritis, can be severe. Extracorporeal albumin dialysis (molecular adsorbent recycling system, MARS) is a novel treatment which removes albumin bound toxins including bilirubin and bile salts. We describe a case of a 34-year-old man with BRIC and secondary renal impairment who, having failed standard medical therapy, was treated with MARS. The treatment immediately improved his symptoms, renal and liver function tests and appeared to terminate the episode of cholestasis. We conclude that MARS is a safe and effective treatment for BRIC with associated renal impairment.

Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study

BACKGROUND Wilsons disease is a genetic disorder in which copper accumulates in the liver, brain, and other tissues. Therapies are limited by efficacy, safety concerns, and multiple daily dosing. Bis-choline tetrathiomolybdate (WTX101) is an oral first-in-class copper-protein-binding molecule that targets hepatic intracellular copper and reduces plasma non-ceruloplasmin-bound copper (NCC) by forming tripartite complexes with albumin and increasing biliary copper excretion. We aimed to assess the efficacy and safety of WTX101 in the initial or early treatment of patients with Wilsons disease. METHODS We did this open-label, phase 2 study at 11 hospitals in the USA and Europe. We enrolled patients (≥18 years) with Wilsons disease who were untreated or had received no more than 24 months of treatment with chelators or zinc, had a Leipzig score of 4 or more, and had NCC concentrations above the lower limit of the normal reference range (≥0·8 μmol/L). Eligible patients received WTX101 monotherapy at a starting dose of 15-60 mg/day on the basis of baseline NCC concentrations for the first 4-8 weeks, with response-guided individualised dosing for the remaining weeks up to week 24. Investigators, other hospital personnel, and patients were aware of the identity of the treatment. The primary endpoint was change in baseline NCC concentrations corrected for copper in tetrathiomolybdate-copper-albumin complexes (NCCcorrected) at 24 weeks, with treatment success defined as achievement or maintenance of normalised NCCcorrected (≤2·3 μmol/L [upper limit of normal]) or achievement of at least a 25% reduction in NCCcorrected from baseline at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT02273596. FINDINGS Between Nov 24, 2014, and April 27, 2016, 28 patients were enrolled and received WTX101; 22 (79%) patients completed the study up to week 24. At 24 weeks, 20 (71%, 95% CI 51·3-86·8; p<0·0001) of 28 patients met the criteria for treatment success: 16 (57%) treated with WTX101 either achieved or maintained normalised NCCcorrected concentrations and 4 (14%) had at least a 25% reduction from baseline NCCcorrected. Mean NCCcorrected was reduced by 72% from baseline to week 24 (least squares mean difference -2·4 μmol/L [SE 0·4], 95% CI -3·2 to -1·6; p<0·0001). No cases of paradoxical drug-related neurological worsening were recorded. Liver function was stable in all patients, although reversible increased concentrations of asymptomatic alanine or aspartate aminotransferase, or γ-glutamyltransferase, without increased bilirubin, occurred in 11 (39%) of 28 patients who received at least 30 mg/day. 11 serious adverse events were reported in seven (25%) patients and included psychiatric disorders (six events in four patients), gait disturbance (one event), elevated liver aminotransferases (two events in two patients, one with agranulocytosis), and decline in neurological functioning (one event, likely due to natural disease progression although causality could not be ruled out). The seven serious adverse events categorised as psychiatric disorders and as gait disturbance were assessed as unlikely to be related to the study drug, whereas the remaining four events were possibly or probably related. INTERPRETATION Our findings indicate that WTX101 might be a promising new therapeutic approach for Wilsons disease, with a unique mode of action. In view of its once-daily dose and favourable safety profile, WTX101 could improve the treatment of patients with this debilitating condition. FUNDING Wilson Therapeutics AB.

Metallic cough and pyogenic liver abscess.

The curious symptom of a metallic cough in association with a pyogenic hepatic abscess should heighten awareness of a fistula. We describe a 78-year-old female with severe diverticular disease, on long-term steroid treatment for polymyalgia rheumatica. She developed a pyogenic liver abscess, treated initially by antimicrobial therapy, and subsequently drained by ultrasound and computed tomography-guided percutaneous transhepatic pigtail catheterization. This was complicated by a fistulous communication between the abscess cavity and the bronchus, confirmed by radiology. After repeated attempts at drainage and antimicrobial therapy the abscess cavity, including the hepatobronchial fistula, resolved.

Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency

Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme. The severity of the resulting disease depends on the nature of the underlying mutation and magnitude of its effect on enzymatic function. Wolmans disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months. Cholesteryl ester storage disorder arises later in life and is less severe, although the two diseases share many common features, including dyslipidaemia and transaminitis. The prevalence of these diseases has been estimated at one in 40 000 to 300 000, but many cases are undiagnosed and unreported, and awareness among clinicians is low. Lysosomal acid lipase deficiency-which can be diagnosed using dry blood spot testing-is often misdiagnosed as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hereditary dyslipidaemia, or cryptogenic cirrhosis. There are no formal guidelines for treatment of these patients, and treatment options are limited. In this Review we appraise the existing literature on Wolmans disease and cholesteryl ester storage disease, and discuss available treatments, including enzyme replacement therapy, oral lipid-lowering therapy, stem-cell transplantation, and liver transplantation.

Hepatic features of Wilson disease

In Wilson disease (WD) defective AT7B function leads to biliary copper excretion and pathologic copper accumulation, particularly in liver and brain, where it induces cellular damage. Liver disease most often precedes neurologic or psychiatric manifestations. In most patients with neurologic or psychiatric symptoms there is some degree of liver disease at the time of disease presentation. Hepatic manifestations of WD can be extremely variable. Patients with clinically asymptomatic WD are often found by family screening or identified on routine laboratory testing. Others may have a clinical picture of chronic active hepatitis or of end-stage liver disease with cirrhosis. A minority present with acute liver failure, often on the background of advanced fibrosis. Complications from liver disease may be related to portal hypertension and concomitant liver disease may accelerate the course of liver disease. Liver cancer may occur in patients with WD, most commonly when cirrhosis and inflammation are present. The prognosis of patients with WD is excellent, especially for those without cirrhosis at the time of diagnosis, but requires timely initiation of appropriate therapy specific for WD and for the patients liver disease independent of WD.

Interventions to improve the uptake of screening across a range of conditions in ethnic minority groups : a systematic review

Screening programmes are well established in cancer, and are now being implemented in other conditions. An effective screening programme leads to early disease detection and improved outcomes but its impact is dependent on the quality of the test and the proportion of the target population participating. A further consideration is that uptake of screening by minority groups is low.

The role of the chronic care model in promoting the management of the patient with rare liver disease

ABSTRACT Introduction: The chronic care model (CCM) provides a holistic approach for managing chronic illnesses. Patients with rare liver diseases (RLD) have complex needs, impaired quality of life and often life-threatening complications. Most RLD meet the criteria for a long-term chronic condition and should be viewed through the prism of CCM. We aimed to ascertain whether the CCM has been considered for the frequently-encountered RLD. Methods: MEDLINE®/PubMed®/Cochrane/EMBASE were searched to identify publications relating to the use of the CCM for the management of six RLD. We identified 33 articles eligible for inclusion. Results: Six, eleven, one, thirteen, two and zero studies, discussed individual components of the CCM for autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cirrhosis (PSC), Wilsons disease (WD), alpha-1 antitrypsin deficiency (A1AD) and lysosomal acid lipase deficiency (LALd) respectively. We have not identified studies using the full CCM for any of the aforementioned RLD. Discussion: Unlike in common chronic conditions e.g. diabetes, there has been limited consideration of the use of CCM (or its components) for the management of RLD. This may reflect a reluctance of the clinical community to view these diseases as chronic or lack of healthcare policy investment in rare diseases in general.

PWE-076 What is the meaning of low lysosomal acid lipase (lal) levels in the hepatology and metabolic clinic?

Introduction LAL deficiency (LALd) is a rare autosomal recessive condition of deficiency or underexpression of the enzyme LAL which leads to the excessive accumulation of cholesteryl esters and triglycerides in various organs especially the liver. Patients often present with hepatosplenomegaly, deranged liver function tests (LFTs), hyperlipidaemia, gastrointestinal symptoms, and hepatic failure. LALd is often misdiagnosed as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cryptogenic cirrhosis or type IIa or b hyperlipoproteinaemia. Aim To develop a model for LALd testing in the hepatology and metabolic clinics using dried blood spotting (DBS). Method We carried out a systematic literature review and worked closely with paediatricians, hepatologists, metabolic consultants and endocrinologists to develop a screening algorithm for LALd. With the support of industry partners, we obtained DBS test kits and started testing suitable patients. The DBS tests were sent for processing to an external laboratory in Glasgow. Results To date we have tested 122 adult patients (M:F 2.4:1). The mean LAL levels were 0.56 nmol/punch/hour (range 0.08–1.26 nmol/punch/hour) (Figure 1). We identified 27 (22.5%) patients with LAL levels below the reference range (0.37–2.30 nmol/punch/hr). Almost half of these patients were eventually diagnosed with NAFLD/NASH (48.15%) (Figure 2). The control enzyme, beta galactosidase, was used on two occasions to test sample quality and one sample was regarded as of poor quality. Abstract PWE076 Figure 1 LAL levels of patients tested in the hepatology and metabolic clinics Abstract PWE076 Figure 2 Final diagnoses of patients with LAL activity below the normal range Conclusion The genotype to phenotype presentation has not been clearly elucidated for LALd. More than 40 mutations have been identified each leading to variable enzymatic expression. Traditionally, if the LAL levels are less than 0.15, control enzymes are used to test sample quality. In good quality samples, levels of <0.03 are considered diagnostic. Yet, there is no consensus on interpreting levels between 0.03–0.37. These could be carriers or LALd or patients with mutations allowing expression of adequate levels of LAL. The significance of this observation merits further investigation especially in associating LAL levels with full mutation analysis. Furthermore, the large proportion of low levels of LAL in NASH/NALD patients may suggest an alternative mechanism of fat accumulation in hepatocytes through impaired degradation of cholesteryl esters and triglycerides. Disclosure of Interest None Declared

PTU-087 Developing Models of Engagement in a New Migrant Population: Results from a Large Scale Hepatitis B & C Testing Study in the UK Nepali Community

Introduction The UK Nepali community has grown by over 900% since 2004, when settlement rights were introduced for ex-Gurkha servicemen and their dependants. Nepal sits between India and China; two countries with higher rates of hepatitis B & C, but rates in the UK Nepali population is unknown Methods The Nepali community has multiple castes and religious beliefs. Little is known about disease and healthcare perception, and focus group sessions were held before testing. National ethics approval was obtained, and testing sessions were held in community venues centrally located to known population clusters in Surrey, UK. Study advertising was limited to existing Nepali language media and word of mouth, following concerns raised by the activity of far right groups. Fingerprick testing was used, with community leaders helping to facilitate testing. Questionnaires were used for possible risk associations including: blood transfusions, surgery, and place of origin. Results 1005 Nepali individuals (age > 18 yrs, Male = 45%) were tested over 17 sessions from Mar 2013 - Jan 2015. A total of 973 individuals were included in final analysis (mean age 63 yrs, range 19–86). Median length of stay in the UK was 36 months, with 18 individuals (1.8%) present in the UK for more than 10 years HBsAg was detected in 3 (0.31%) and HCVAb in 4 (0.41%) separate individuals; showing low rates of infection. HBsAg patients had absent or low level HBV DNA (<300iu/ml), and all HCV patients were RNA negative, with no evidence of cirrhosis in attending patients on follow-up (5/7). Hepatitis B core Ab (HBcAb) was detected in 93 individuals (9.6%), mean age 67 yrs (22–84 yrs) Regression analysis showed no statistical associations with HBsAg / HCVAb presence; but HBcAb was significantly associated with male gender and fewer years spent at school (p = 0.002 and p = 0.02 respectively) Conclusion Rates of active CVH were very low in the Nepali community, but with higher rates of previous HBV exposure, which may have implications for ongoing testing programmes. Given the absence of a common religious or cultural forum to target this new community, we used detailed focus group sessions and developed strong community links to produce a successful community-based approach to engagement, which we hope will act as a model of testing in other communities. Disclosure of Interest None Declared