Fiona Gordon

In Vitro Steroid Resistance Correlates with Outcome in Severe Alcoholic Hepatitis

Steroids improve the outcome in alcoholic hepatitis (AH), but up to 40% of patients fail to respond adequately. Interleukin‐2 (IL‐2) exacerbates steroid resistance in vitro. We performed a prospective study to determine if intrinsic steroid sensitivity correlates with response to steroids in individuals with severe AH and if IL‐2 receptor blockade can reverse this. Peripheral blood mononuclear cells (PBMCs) were isolated from 20 patients with AH and a Maddreys score >32. Patients were treated with oral prednisolone plus full supportive measures. Clinical resistance to oral steroid treatment was defined as a drop in serum bilirubin of <25% within 7 days or death within 6 months. In vitro steroid resistance was measured in PBMC using the dexamethasone suppression of lymphocyte proliferation assay and repeated after the addition of the anti‐IL‐2 receptor (anti‐CD25) monoclonal antibody, basiliximab. Suppression of lymphocyte proliferation <60% was considered to indicate steroid resistance. In all, 82% (9/11) of in vitro steroid‐resistant patients were dead at 6 months as compared to 21% (2/9) of steroid‐sensitive patients (P = 0.03). Similarly, 91% (10/11) of in vitro steroid‐resistant patients failed to show a significant fall in bilirubin at day 7 as compared to 44% (4/9) of steroid‐sensitive patients (P < 0.05). Basiliximab improved the maximal proliferation count in 91% (10/11) of in vitro steroid‐resistant patients (P = 0.003). Conclusion: Clinical outcome of steroid therapy in this patient cohort correlated with in vitro steroid resistance. IL‐2 blockade improved in vitro steroid sensitivity. This suggests that intrinsic lack of steroid sensitivity may contribute to poor clinical response to steroids in severe AH. IL‐2 receptor blockade represents a possible mechanism to overcome this. (HEPATOLOGY 2011;)

Liver disease and cirrhosis because of Khat chewing in UK Somali men: a case series.

admission, the patient died of hepatic failure complicated with sepsis. An autopsy revealed severe atrophy of the liver, which weighed only 360 g, and diffuse hepatocyte necrosis. Several studies indicate that TNF-a has a pivotal role in suppressing HBV replication by its synergistic effects with interferons (8); thus, inactivation of TNF-a could theoretically lead to HBV reactivation. Indeed, this case report demonstrates that adalimumab could precipitate hepatitis B reactivation, even in a patient with resolved HBV infection, and lead to lethal hepatic failure. Thus, careful monitoring for hepatitis B reactivation should be performed even in HBsAg-negative individuals with positive anti-HBV serology during treatment with antiTNF-a agents such as adalimumab.

Of pigs and pregnancy

In March, 2007, a 31-year-old woman was advised by her midwife to attend the antenatal department at St Michael’s Hospital, because she had been itching all over her body for a week. She was 24 weeks pregnant. She had been pregnant twice before. Her fi rst pregnancy had ended in miscarriage, at 11 weeks, and her second in intrauterine death, at 30 weeks. The cause of intrauterine death had not been identifi ed; a thrombophilia screen and liver function tests had given normal results. The medical history was otherwise unremarkable. The patient had no rash. Blood pressure, and fi ndings on basic neurological examination, were normal. Although she was not jaundiced, and had no signs of chronic liver disease, liver function was very abnormal (fi gure); blood test results were otherwise normal. Ultrasonography of the fetus, and doppler ultrasonography of the umbilical artery (UA), showed nothing abnormal. An autoantibody screen was negative; tests showed no evidence of recent or active infection with hepatitis A, B, or C viruses, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, adenovirus, parvovirus B19, toxoplasma, chlamydia, Mycoplasma pneumoniae, or Q fever. HIV-antibody testing gave a negative result. Histopathology of a liver biopsy sample showed no fi brosis or cirrhosis; however, we saw a patchy lymphocytic infi ltrate, and interface hepatitis (ie, piecemeal necrosis). These fi ndings were consistent with autoimmune active chronic hepatitis. We therefore gave the patient a steriod. The patient had no apparent risk factors for hepatitis E: she had not recently been abroad, had not eaten any unusual foods, and did not live in an area of increased risk. Nonetheless, as part of our routine screen, we sent a blood sample to a reference laboratory, to test for hepatitis E. During the remainder of the pregnancy, we assessed the patient weekly, estimating fetal weight, measuring the amniotic fl uid volume index (AFI), and doing doppler ultrasonography of the UA. Results were normal, except for a transiently reduced AFI, and increased pulsatility of the UA, at 27 weeks. We gradually reduced the dose of the steriod, so it was discontinued at just over 27 weeks. Just before discontinuation, liver function test results started to improve; at around the same time, we received the hepatitis E test results. Hepatitis E IgM and genotype 3 RNA were detected, indicating recent, autochthonous infection. We subsequently documented the presence of IgG, indicating seroconversion. At 34 weeks, the patient’s membranes ruptured, so labour was induced by administration of prostaglandin. A healthy baby, weighing 1∙85 kg, was delivered. Hepatitis E is caused by a small, non-enveloped virus with an RNA genome. Transmission is faecal-oral; waterborne epidemics have been described in some resource-poor countries, such as Sudan (Darfur) and India. The virus is found in pigs. Contact with pigs, or with certain foods (shellfi sh, pig liver, venison, boar), seems to be linked to sporadic infections in developed countries. Since 2004, the number of reported cases of hepatitis E in the UK has substantially increased. White men more than 55 years of age, living in coastal or estuarine areas, have been especially vulnerable. People whose infection seems unrelated to travel have a virus with genotype 3, closely related to that found in British pigs. Hepatitis E virus can cause no symptoms, selflimiting hepatitis, or acute liver failure; immunocompromised patients are at risk of chronic infection. In late pregnancy, infection can be especially severe, and cause fetal infection; infection causing jaundice is associated with intrauterine death, stillbirth, and premature delivery. We do not think that infection with hepatitis E caused our patient’s previous stillbirth, since, at the time of assessment, her infection was acute. However, hepatitis infection may have caused the transient probable fetal distress at 27 weeks; we were unable to measure fetal antibodies, to test this hypothesis. In common with others, we believe that testing for hepatitis E should be routine in the UK, in cases of suspected viral hepatitis.

The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α.

Rifaximin‐α reduces the risk of recurrence of overt hepatic encephalopathy. However, there remain concerns regarding the financial cost of the drug. We aimed to study the impact of treatment with rifaximin‐α on healthcare resource utilisation using data from seven UK liver treatment centres.

Hepatitis C – Assessment to Treatment Trial (HepCATT) in primary care: study protocol for a cluster randomised controlled trial

BackgroundPublic Health England (PHE) estimates that there are upwards of 160,000 individuals in England and Wales with chronic hepatitis C virus (HCV) infection, but until now only around 100,000 laboratory diagnoses have been reported to PHE and of these 28,000 have been treated. Targeted case-finding in primary care is estimated to be cost-effective; however, there has been no robust randomised controlled trial evidence available of specific interventions. Therefore, this study aims to develop and conduct a complex intervention within primary care and to evaluate this approach using a cluster randomised controlled trial.Methods/designA total of 46 general practices in South West England will be randomised in a 1:1 ratio to receive either a complex intervention comprising: educational training on HCV for the practice; poster and leaflet display in the practice waiting rooms to raise awareness and encourage opportunistic testing; a HCV risk prediction algorithm based on information on possible risk markers in the electronic patient record run using Audit + software (BMJ Informatica). The audit will then be used to recall and offer patients a HCV test. Control practices will follow usual care. The effectiveness of the intervention will be measured by comparing number and rates of HCV testing, the number and proportion of patients testing positive, onward referral, rates of specialist assessment and treatment in control and intervention practices. Intervention costs and health service utilisation will be recorded to estimate the NHS cost per new HCV diagnosis and new HCV patient initiating treatment. Longer-term cost-effectiveness of the intervention in improving quality-adjusted life years (QALYs) will be extrapolated using a pre-existing dynamic health economic model. Patients’ and health care workers’ experiences and acceptability of the intervention will be explored through semi-structured qualitative interviews.DiscussionThis trial has the potential to make an important impact on patient care and will provide high-quality evidence to help general practitioners make important decisions on HCV testing and onward referral. If found to be effective and cost-effective the intervention is readily scalable and can be used to support the implementation of NICE recommendations on HCV case-finding.Trial registrationISRCTN61788850. Registered on 24 April 2015; Protocol Version: 2.0, 22 May 2015.

PWE-287 Breath volatile analysis for the recognition of harmful drinking, cirrhosis and hepatic encephalopathy

Introduction Hepatic encephalopathy (HE) is a neuropsychiatric state which may complicate cirrhosis following the accumulation of toxic substances that cross the blood-brain barrier and affect brain function. Cirrhosis or portal-systemic shunting results in the accumulation of substances in the blood that may undergo alveolar gas exchange to be excreted in the breath. The aim of this work was to investigate the use of breath analysis as a non-invasive and simpler means of diagnosing HE, cirrhosis and harmful drinking. Methods A bespoke breath-sampling device was used to sample one litre of breath through adsorbent tubes from patients with alcohol-related cirrhosis with (n=11) and without HE (n=23), non-alcoholic cirrhosis without HE (n=19), harmful drinkers without cirrhosis (n=7), inflammatory respiratory disease (n=18), and healthy controls (n=15). Compounds trapped on these tubes were released via thermal desorption and analysed by gas chromatography mass spectrometry for separation and detection. Multivariate discriminant analysis was used to identify volatile organic compounds to differentiate patients according to disease status and build models for disease classification. Results Models based on the presence or absence of volatiles were tested in the patient groups. HE was correctly classified in 91.0% of patients with alcoholic cirrhosis. Patients with cirrhosis could be discriminated from those without cirrhosis with 100% accuracy in drinkers. In patients without clinical signs of HE, alcohol was correctly predicted as the underlying cause of cirrhosis in 82.6% of patients and non-alcoholic causes of cirrhosis were correctly determined in 84.2% of patients. Non-alcoholic cirrhosis, alcoholic cirrhosis, and harmful drinking could also be discriminated from healthy controls with a sensitivity of 89.5%, 97.1% and 100%, respectively. Conclusion Breath volatiles can be used to aid the diagnosis of HE, cirrhosis, and harmful levels of drinking, therefore breath testing may offer a means to detect liver conditions non-invasively at earlier and more treatable stages. Competing interests None declared.

Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial

Many direct‐acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C‐ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open‐label study. Treatment‐naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment‐experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment‐naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment‐experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12‐week arm, with and without RBV, respectively, and 94% (17/18) in the 16‐week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8‐week arm), 1 discontinued due to vomiting/cellulitis (16‐week arm), and 2 discontinued (consent withdrawn/lost to follow‐up). SVR12 was not affected by the presence of resistance‐associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. Conclusion: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment‐naive and peginterferon/RBV–experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113‐2126)

PWE-091 Can screening for poor prognosis improve care for patients with end stage liver disease?

Introduction Liver disease is the 3rdcommonest cause of premature death in the UK. The end of life care strategy (Department of Health, 2008) noted many patients do not die in a place of their choosing, and that difficulties exist amongst physicians in identifying the dying process. Data from the Royal Free demonstrated that only 19% of patients assessed unsuitable for liver transplantation were referred to palliative care services, a median of 4 days before death. Across the United Kingdom between 2007–2011 81% of patients with alcoholic liver disease died in hospital, compared to 48% with cancer (Office of National Statistics). Opportunities for advanced care planning in this population are missed. We aimed to design and validate a tool to identify inpatients with liver disease who stand to benefit from palliative care assessment and advanced care planning, and to create a model of care for such patients. Method The department of health document ‘Getting it Right: improving end of life care for people living with liver disease’ and the NHS North East document ‘Framework for supportive care in advanced liver disease’ identify evidence based factors which are predictive of death in liver disease. Five of these factors (Childs Pugh C, >2 admissions within last 6 months, continued use of alcohol, unsuitable for liver transplantation, pre-admission WHO performance status >2) were assimilated into a screening tool. Results The tool was retrospectively applied to all patients admitted to the Bristol Royal Infirmary with a diagnosis of cirrhosis over 90 consecutive days from 1stJuly 2013 (n = 47). Based on the ‘Gold Standard Care’ framework question (“would you be surprised if your patient was not alive in one year”) mortality one year post admission was calculated. Sensitivity and specificity for predicting one year mortality when 2, 3 or 4 poor prognostic criteria were positive were analysed (see Table 1). On this basis, an admission score of 3 or more criteria was considered a “positive” poor prognosis screen.Abstract PWE-091 Table 1 Number of criteria positive Number(n = 47) Sensitivity (1 year mortality) Specificity (1 year mortality) ≥2 37 100 62 ≥3 21 81 81 ≥4 3 10 96 Conclusion The tool has been successfully trialled and audited locally over the past year. Patients who screen positive are highlighted for discussion at a weekly hepatology MDT. Assuming MDT agreement this triggers a consultant led poor prognosis discussion with the patient, a poor prognosis letter to the GP, and involvement of the palliative medicine team to assist with symptom control and advance care planning. Communication skills training has been delivered to consultants and junior staff by the palliative medicine team. Disclosure of interest None Declared.