Proactive case finding of alcohol-related liver disease in high-risk populations: A systematic review.

BACKGROUND: Alcohol-related liver disease (ARLD) is often diagnosed at a late stage when mortality is unacceptably high. Earlier identification of ARLD may lead to reduced alcohol intake, participation in hepatocellular carcinoma surveillance and reduction in liver-related morbidity and mortality. People with alcohol use disorder (AUD) are at highest risk of ARLD. The aim of this systematic review was to understand the yield of proactive screening for ARLD amongst high-risk groups. METHODS: Embase, Medline, Scopus and grey literature were searched for studies describing proactive assessment for alcohol-related liver disease in people with a history of alcohol excess or diagnosed AUD. Outcomes of interest were fibrosis and cirrhosis detection rates, clinical outcomes, portal hypertension evaluation, attendance at follow-up and cost-effectiveness. RESULTS: Fifteen studies were identified for inclusion from 1115 returned by the search. Four key settings for patient engagement were identified as inpatient addiction services, outpatient addiction services, general acute hospital admissions and community outreach. Of these, acute hospital admissions were the highest yield for cirrhosis at 10.8%-29.6% and community outreach the lowest was 1.2%-2.3%. CONCLUSIONS: Targeted fibrosis assessment of high-risk populations for ARLD is feasible to conduct and identifies a proportion of patients at risk of advanced liver disease. The highest yield is amongst inpatients admitted with AUD. Prospective work is needed to establish which are the most effective and acceptable screening methods and the impact on long-term outcomes.

Mental Imagery to Reduce Alcohol-related harm in patients with alcohol use disorder and alcohol-related liver damaGE: the MIRAGE randomised pilot trial results.

OBJECTIVE: The healthcare burden of alcohol-related liver disease (ARLD) is increasing. ARLD and alcohol use disorder (AUD) is best managed by reduction or cessation of alcohol use, but effective treatments are lacking. We tested whether people with ARLD and AUD admitted to hospital could be recruited to and retained in a trial of Functional Imagery Training (FIT), a psychological therapy that uses mental imagery to reduce alcohol craving. We conducted a multicentre randomised pilot trial of treatment as usual (TAU) versus FIT+TAU in people admitted to hospital with ARLD and AUD. DESIGN: Participants were randomised to TAU (a single session of brief intervention) or FIT+TAU (TAU with one hospital-based FIT session then eight telephone sessions over 6 months). Pilot outcomes included recruitment rate and retention at day 180. Secondary outcomes included fidelity of FIT delivery, alcohol use, and severity of alcohol dependence. RESULTS: Fifty-four participants (mean age 49; 63% male) were recruited and randomised, 28 to TAU and 26 to FIT+TAU. The retention rate at day 180 was 43%. FIT was delivered adequately by most alcohol nurses. 50% of intervention participants completed FIT sessions 1 and 2. There were no differences in alcohol use or severity of alcohol dependence between treatment groups at day 180. CONCLUSION: Participants with ARLD and AUD could be recruited to a trial of FIT versus FIT+TAU. However, retention at day 180 was suboptimal. Before conducting a definitive trial of FIT in this patient group, modifications in the intervention and recruitment/retention strategy must be tested. TRIAL REGISTRATION NUMBER: ISRCTN41353774.

Quality standards for the management of alcohol-related liver disease: consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology ARLD special interest group.

OBJECTIVE: Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care. DESIGN: A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology ALD Special Interest Group developed the quality standards, with input from the British Liver Trust and patient representatives. RESULTS: The standards cover three broad themes: the recognition and diagnosis of people with ALD in primary care and the liver outpatient clinic; the management of acutely decompensated ALD including acute alcohol-related hepatitis and the posthospital care of people with advanced liver disease due to ALD. Draft quality standards were initially developed by smaller working groups and then an anonymous modified Delphi voting process was conducted by the entire group to assess the level of agreement with each statement. Statements were included when agreement was 85% or greater. Twenty-four quality standards were produced from this process which support best practice. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice and an audit tool provided. CONCLUSION: It is hoped that services will review their practice against these recommendations and key performance indicators and institute service development where needed to improve the care of patients with ALD.

Assessment of immune function and prediction of survival and infection in patients with severe alcoholic hepatitis: An exploratory study.

Background and Aim: Alcoholic hepatitis (AH), a severe complication of long-term alcohol misuse, has a 30% 90-day mortality. Infections are common and associated with higher mortality. There is currently no accurate method to predict infection in these patients. We aimed to test a measure of immune function, the QuantiFERON Monitor (QFM), in predicting clinical outcomes in patients with severe AH. Methods: Peripheral blood was taken at baseline, and QFM performed according to the manufacturer's instructions. In parallel, QFM samples were analyzed with a cytokine multiplex. Clinical outcomes of mortality at 28 and 90 days and development of infection were recorded prospectively. Results: Forty-nine patients were recruited (mean age 51, 59% male and mean discriminant function 57.8). Interferon (IFN)-γ release measured by standard QFM was significantly higher in survivors compared to non-survivors at 28 (102 vs 16 IU/mL, P = 0.02) and 90 days (115 vs 32 IU/mL; P = 0.046). The area under the receiver operating characteristic curve (AUROC) was 0.79 for 28-day mortality. IFN-γ, IL-10, and IL-23 release measured by multiplex were significantly lower in patients who developed a subsequent infection compared to those who did not (115 vs 27 IU/mL, P = 0.037; 457 vs 202 pg/mL, P = 0.008; and 1039 vs 663 pg/mL, p = 0.01, respectively). Conclusion: Immune dysfunction is associated with poorer outcomes in patients with severe AH. Measurement of IFN-γ release by standard QFM accurately predicts early mortality, which can be applied to clinical practice as a biomarker of survival. Adaptation of the test to measure IL-10 could be used as a biomarker of subsequent infection to guide clinical treatment decisions.

The Liverpool alcohol-related liver disease algorithm identifies twice as many emergency admissions compared to standard methods when applied to Hospital Episode Statistics for England.

BACKGROUND: Emergency admissions in England for alcohol-related liver disease (ArLD) have increased steadily for decades. Statistics based on administrative data typically focus on the ArLD-specific code as the primary diagnosis and are therefore at risk of excluding ArLD admissions defined by other coding combinations. AIM: To deploy the Liverpool ArLD Algorithm (LAA), which accounts for alternative coding patterns (e.g., ArLD secondary diagnosis with alcohol/liver-related primary diagnosis), to national and local datasets in the context of studying trends in ArLD admissions before and during the COVID-19 pandemic. METHODS: We applied the standard approach and LAA to Hospital Episode Statistics for England (2013-21). The algorithm was also deployed at 28 hospitals to discharge coding for emergency admissions during a common 7-day period in 2019 and 2020, in which eligible patient records were reviewed manually to verify the diagnosis and extract data. RESULTS: Nationally, LAA identified approximately 100% more monthly emergency admissions from 2013 to 2021 than the standard method. The annual number of ArLD-specific admissions increased by 30.4%. Of 39,667 admissions in 2020/21, only 19,949 were identified with standard approach, an estimated admission cost of £70 million in under-recorded cases. Within 28 local hospital datasets, 233 admissions were identified using the standard approach and a further 250 locally verified cases using the LAA (107% uplift). There was an 18% absolute increase in ArLD admissions in the seven-day evaluation period in 2020 versus 2019. There were no differences in disease severity or mortality, or in the proportion of admissions with decompensation of cirrhosis or alcoholic hepatitis. CONCLUSIONS: The LAA can be applied successfully to local and national datasets. It consistently identifies approximately 100% more cases than the standard coding approach. The algorithm has revealed the true extent of ArLD admissions. The pandemic has compounded a long-term rise in ArLD admissions and mortality.

Alcohol misuse in patients with alcohol-related liver disease: How can we do better? A narrative review of the literature.

BACKGROUND: Ongoing alcohol use is strongly associated with progressive liver damage and higher mortality in patients with alcohol-related liver disease (ArLD). Reduction in alcohol use is therefore the cornerstone of treatment to improve the long-term outcome of these patients. However, a large proportion of patients continue to use alcohol and do not access or engage with alcohol treatment services after a diagnosis of ArLD. We reviewed the literature on factors associated with ongoing alcohol consumption among patients with ArLD to identify barriers or facilitators to their accessing alcohol treatment. METHODS: A search of MEDLINE and EMBASE was conducted using search strategies relating to ArLD and the psychosocial factors hypothesized to influence alcohol reduction and/or abstinence. RESULTS: There were few relevant studies pertinent to this population group. Several studies reported a high prevalence of mental health diagnoses associated with the severity of alcohol dependence. Social and environmental factors were shown to be important determinants of alcohol use. Common themes perceived as barriers to treatment from qualitative interviews with ArLD patients across studies included poor communication between the clinical team and patient, lack of symptoms recognized by patients themselves, and perceived loss of control over their condition. CONCLUSIONS: We recommend that future clinical studies of patient cohorts with ArLD include detailed psychosocial assessments to capture information on mental health and social factors. Qualitative studies are required to explore the patient journey pre and post hospital admission, which should focus on identifying facilitators and barriers to accessing treatment. Well-designed, controlled studies are needed to identify patient, social, and environmental factors associated with relapse to alcohol use after a diagnosis of ArLD. These data will enable us to adapt our support for patients to enhance engagement with services and improve long-term outcomes.

The effect of increasing intestinal short-chain fatty acid concentration on gut permeability and liver injury in the context of liver disease: A systematic review.

BACKGROUND AND AIM: The gut barrier protects the liver through tight junctions, which are disrupted in liver disease either from dysbiosis, inflammation, or the effects of ingested compounds such as alcohol. Strengthening of the gut barrier may ameliorate liver injury of varying etiologies. Short chain fatty acids (SCFAs) have been shown to improve gut barrier function. This systematic review aims to synthesize all studies that have trialed SCFA supplementation as a therapy for liver disease. METHODS: A systematic review assessing the impact of SCFA supplementation on liver injury and intestinal permeability was conducted. All forms of intervention that specifically increased intestinal SCFA concentration and measured both liver injury and permeability were eligible. Two independent reviewers assessed each study for outcomes, risk of bias, and quality using checklists relevant to the study's methodology. RESULTS: Seventeen studies were identified; two utilized a human model (15 murine). Fifty-eight markers of liver injury were identified, with 26 different measures of permeability. Given the numerous designs, no meta-analysis was possible. SCFA supplements included oral and enteral butyrate, probiotics, and prebiotics. Fourteen studies demonstrated improved permeability. All studies showed a significant amelioration of liver injury. CONCLUSIONS: Short chain fatty acid supplementation to reduce intestinal permeability represents a potential therapy in a variety of liver disease models. A large number of outcome measures were reported however not all are practical in human studies. Future work should evaluate methods to increase luminal SCFA concentrations and the effect of this on gut permeability and liver inflammation in people with liver disease.

Mental Imagery to Reduce Alcohol-related harm in patients with alcohol dependence and alcohol-related liver damaGE: the MIRAGE pilot trial protocol.

INTRODUCTION: In the UK, alcohol use is the main driver of chronic liver disease and each year results in over 1 million unplanned hospital admissions and over 25 000 deaths from alcohol-related liver disease (ArLD). The only effective treatment to prevent progression of liver damage is reducing or ceasing alcohol consumption. Psychological and pharmacological therapies for alcohol misuse are ineffective in patients with ArLD. Functional imagery training (FIT) is a novel psychological therapy that builds on motivational interviewing techniques with multisensory imagery. This pilot trial aims to test the feasibility of training alcohol liaison nurses to deliver FIT therapy and of recruiting and retaining patients with ArLD and alcohol dependence to a randomised trial of FIT and treatment as usual (TAU) versus TAU alone. METHODS AND ANALYSIS: This is a randomised pilot trial of FIT and TAU versus TAU alone in 90 patients with ArLD and alcohol dependence admitted to one of four UK centres. The primary objectives are to estimate rates of screening, recruitment, randomisation, retention, adherence to FIT/TAU and a preliminary assessment of the FIT intervention in the ArLD population. Data from the pilot study will be used to finalise the design of a definitive randomised controlled trial to assess the effectiveness and cost-effectiveness of FIT. The proposed primary outcome measure for the definitive trial is self-reported alcohol use assessed using timeline follow-back. ETHICS AND DISSEMINATION: Research ethics approval was given by the Yorkshire and Humber-Bradford Leeds Research Ethics Committee (reference: 21/YH/0044). Eligible patients will be approached and written informed consent obtained prior to participation. Results will be disseminated through peer-reviewed open access journals, international conferences and a lay summary published on the Trials Unit website and made available to patient groups. TRIAL REGISTRATION NUMBER: ISRCTN41353774.

A UK survey on variation in the practice of management of choledocholithiasis and laparoscopic common bile duct exploration (ALiCE Survey).

BACKGROUND: The practice of managing suspected/confirmed common bile duct stones (CBDS) can vary significantly in the UK. We aimed to assess this variability in practice and challenges to form a basis for future consensus. METHODS: An electronic survey containing 40 questions on various aspects of management of CBDS was sent to surgeons who perform cholecystectomies via five surgical associations. RESULTS: A total of 132 surgeons responded to the survey. The speciality of surgeons includes upper gastro-intestinal (68%), general (18%), colorectal (12%), and others (2%). For patients with suspected CBD stones, 80% would choose magnetic resonance cholangio-pancreatography, and 14.4% would proceed to intra-operative imaging. Most surgeons preferred intra-operative cholangiogram over intra-operative ultrasound (83% vs 17%). For the treatment, 62.1% preferred a two-stage approach [endoscopic retrograde cholangio-pancreatography (ERCP) followed by laparoscopic cholecystectomy (LC)] and 33.4% chose a single-stage approach [LC + laparoscopic common bile duct exploration (LCBDE)]. Eighty (60.6%) responders performed LCBDE, and 19 (23.8%) of them performed > 10 LCBDEs in a year. Two third of surgeons (62.5%) preferred a trans-choledochal approach to CBDS. Half of the surgeons that perform LCBDE use a T-tube selectively and 1.6% routinely. The "availability of very good ERCP service" and "lack of formal training" were the two main reasons for surgeons not performing LCBDE. Both surgeons' speciality and whether they perform other complex laparoscopic surgery were significantly associated with choosing a two-stage approach over a one-stage approach (χ2 test, speciality p = 0.033, complex surgery p = 0.011). CONCLUSION: Our survey confirms the significant variability in the diagnosis and management of CBDS. The two-stage approach is still the most common way of managing CBDS in the UK. The main reasons for the low uptake of the single-stage approach are the availability of good ERCP service, lack of equipment and lack of formal training in the technique of LCBDE.

Trajectory of Serum Bilirubin Predicts Spontaneous Recovery in a Real-World Cohort of Patients With Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments. METHODS: We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment. RESULTS: data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin <0.8 x admission value at day 7), 'static' (bilirubin of >0.9 - <1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p < .001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores. CONCLUSIONS: We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy.

Alcohol's Impact on the Gut and Liver.

Alcohol is inextricably linked with the digestive system. It is absorbed through the gut and metabolised by hepatocytes within the liver. Excessive alcohol use results in alterations to the gut microbiome and gut epithelial integrity. It contributes to important micronutrient deficiencies including short-chain fatty acids and trace elements that can influence immune function and lead to liver damage. In some people, long-term alcohol misuse results in liver disease progressing from fatty liver to cirrhosis and hepatocellular carcinoma, and results in over half of all deaths from chronic liver disease, over half a million globally per year. In this review, we will describe the effect of alcohol on the gut, the gut microbiome and liver function and structure, with a specific focus on micronutrients and areas for future research.

Glucocorticoid treatment in patients with newly diagnosed immune thrombocytopenia switches CD14++ CD16+ intermediate monocytes from a pro-inflammatory to an anti-inflammatory phenotype.

Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4+ T-helper subset distribution and enhanced production of pro-inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4+ T-cell phenotypes. Glucocorticoids (GCs) are commonly used for first-line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14++ CD16+ ) in untreated patients with newly diagnosed ITP, with these cells displaying a pro-inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti-inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC-induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy.