IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab.

BACKGROUND AND AIMS: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH. METHODS: Participants with biopsy-confirmed AH and discriminant function ≥32 but Model for End-Stage Liver Disease ≤27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle. RESULTS: Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04). CONCLUSIONS: CAN therapy in severe AH participants with Model for End-Stage Liver Disease ≤27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79; ClinicalTrials.gov, Number: NCT03775109.

Diet modifies the association between alcohol consumption and severe alcohol-related liver disease incidence.

It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. This study aimed to investigate if the association between alcohol consumption and severe ALD is modified by diet. This prospective study included 303,269 UK Biobank participants. Alcohol consumption and diet were self-reported. The diet score was created from 4 items selected using LASSO. Cox proportional hazard model showed that the diet score was monotonically associated with severe ALD risk, adjusted for sociodemographics, lifestyle factors, and alcohol consumption. Relative excess risk due to interaction analysis indicated that having a higher ALD diet score and a higher alcohol consumption simultaneously confers to 2.44 times (95% CI: 1.06-3.83) higher risk than the sum of excess risk of each factor. In this work, we show that people who have a poor diet might be more susceptible to severe ALD due to alcohol consumption.

Association of five diet scores with severe NAFLD incidence: A prospective study from UK Biobank.

AIM: This study aimed to contrast the associations of five common diet scores with severe non-alcoholic fatty liver disease (NAFLD) incidence. MATERIALS AND METHODS: In total, 162 999 UK Biobank participants were included in this prospective population-based study. Five international diet scores were included: the 14-Item Mediterranean Diet Adherence Screener (MEDAS-14), the Recommended Food Score (RFS), the Healthy Diet Indicator (HDI), the Mediterranean Diet Score and the Mediterranean-DASH Intervention for Neurodegenerative Delay score. As each score has different measurements and scales, all scores were standardized and categorized into quartiles. Cox proportional hazard models adjusted for confounder factors investigated associations between the standardized quartiles and severe NAFLD incidence. RESULTS: Over a median follow-up of 10.2 years, 1370 participants were diagnosed with severe NAFLD. When the analyses were fully adjusted, participants in quartile 4 using the MEDAS-14 and RFS scores, as well as those in quartiles 2 and 3 using the HDI score, had a significantly lower risk of severe incident NAFLD compared with those in quartile 1. The lowest risk was observed in quartile 4 for the MEDAS-14 score [hazard ratio (HR): 0.76 (95% confidence interval (CI): 0.62-0.94)] and the RFS score [HR: 0.82 (95% CI: 0.69-0.96)] and as well as in quartile 2 in the HDI score [HR: 0.80 (95% CI: 0.70-0.91)]. CONCLUSION: MEDAS-14, RFS and HDI scores were the strongest diet score predictors of severe NAFLD. A healthy diet might protect against NAFLD development irrespective of the specific approach used to assess diet. However, following these score recommendations could represent optimal dietary approaches to mitigate NAFLD risk.

In severe alcohol-related hepatitis, acute kidney injury is prevalent, associated with mortality independent of liver disease severity, and can be predicted using IL-8 and micro-RNAs.

BACKGROUND: The prevalence, prediction and impact of acute kidney injury (AKI) in alcohol-related hepatitis (AH) is uncertain. AIMS: We aimed to determine AKI incidence; association with mortality; evaluate serum biomarkers and the modifying effects of prednisolone and pentoxifylline in the largest AH cohort to date. METHODS: Participants in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial with day zero (D0) creatinine available were included. AKI was defined by modified International Club of Ascites criteria; incident AKI as day 7 (D7) AKI without D0-AKI. Survival was compared by Kaplan-Meier; mortality associations by Cox regression; associations with AKI by binary logistic regression; biomarkers by AUROC analyses. RESULTS: D0-AKI was present in 198/1051 (19%) participants; incident AKI developed in a further 119/571 (21%) with available data. Participants with D0-AKI had higher 90-day mortality than those without (32% vs. 25%, p = 0.008), as did participants with incident AKI compared to those without D0-AKI or incident AKI (47% vs. 25%, p < 0.001). Incident AKI was associated with D90 mortality adjusted for age and discriminant function (AHR 2.15, 1.56-2.97, p < 0.001); D0-AKI was not. Prednisolone therapy reduced incident AKI (AOR 0.55, 0.36-0.85, p = 0.007) but not mortality. D0 bilirubin and IL-8 combined, miR-6826-5p, and miR-6811-3p predicted incident AKI (AUROCs 0.726, 0.821, 0.770, p < 0.01). CONCLUSIONS: Incident AKI is associated with 90-day mortality independent of liver function. Prednisolone therapy was associated with reduced incident AKI. IL-8 and several miRNAs are potential biomarkers to predict AKI. Novel therapies to prevent incident AKI should be evaluated in AH to reduce mortality.

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.

Parenclitic Network Mapping Identifies Response to Targeted Albumin Therapy in Patients Hospitalized With Decompensated Cirrhosis.

INTRODUCTION: The efficacy of targeted albumin therapy in the management of decompensatory events in cirrhosis is unclear, with different reports showing conflicting results. It is possible that only certain subgroups of patients may benefit from targeted albumin administration. However, extensive conventional subgroup analyses have not yet identified these subgroups. Albumin is an important regulator of physiological networks and may interact with homeostatic mechanism differently in patients according to the integrity of their physiological network. In this study, we aimed to assess the value of network mapping in predicting response to targeted albumin therapy in patients with cirrhosis. METHODS: This is a substudy of the ATTIRE trial, a multicenter randomized trial conducted to assess the effect of targeted albumin therapy in cirrhosis. Baseline serum bilirubin, albumin, sodium, creatinine, CRP, white cell count (WCC), international normalized ratio, heart rate, and blood pressure of 777 patients followed up for 6 months were used for network mapping using parenclitic analysis. Parenclitic network analysis involves measuring the deviation of each patient from the existing network of physiological interactions in a reference population. RESULTS: Overall network connectivity and deviations along the WCC-CRP axis predicted 6-month survival independent of age and model for end-stage liver disease in the standard care arm. Patients with lower deviation along the WCC-CRP axis showed lower survival in response to targeted albumin administration over a 6-month follow-up period. Likewise, patients with higher overall physiological connectivity survived significantly less than the standard care group after targeted albumin infusion. DISCUSSION: The parenclitic network mapping can predict the survival of patients with cirrhosis and identify patient subgroups that do not benefit from targeted albumin therapy.

Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial.

Background: Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. Methods: In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. Findings: Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. Interpretations: Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. Funding: Wellcome Trust and Department of Health and Social Care.

Associations between an inflammatory diet index and severe non-alcoholic fatty liver disease: a prospective study of 171,544 UK Biobank participants.

BACKGROUND: Although non-alcoholic fatty liver disease (NAFLD) is linked to inflammation, whether an inflammatory diet increases the risk of NAFLD is unclear. This study aimed to examine the association between the Energy-adjusted Diet Inflammatory Index (E-DII) score and severe NAFLD using UK Biobank. METHODS: This prospective cohort study included 171,544 UK Biobank participants. The E-DII score was computed using 18 food parameters. Associations between the E-DII and incident severe NAFLD (defined as hospital admission or death) were first investigated by E-DII categories (very/moderately anti-inflammatory [E-DII < - 1], neutral [E-DII - 1 to 1] and very/moderately pro-inflammatory [E-DII > 1]) using Cox proportional hazard models. Nonlinear associations were investigated using penalised cubic splines fitted into the Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors. RESULTS: Over a median follow-up of 10.2 years, 1489 participants developed severe NAFLD. After adjusting for confounders, individuals in the very/moderately pro-inflammatory category had a higher risk (HR: 1.19 [95% CI: 1.03 to 1.38]) of incident severe NAFLD compared with those in the very/moderately anti-inflammatory category. There was some evidence of nonlinearity between the E-DII score and severe NAFLD. CONCLUSIONS: Pro-inflammatory diets were associated with a higher risk of severe NAFLD independent of confounders such as the components of the metabolic syndrome. Considering there is no recommended treatment for the disease, our findings suggest a potential means to lower the risk of NAFLD.

Extra-hepatic morbidity and mortality in alcohol-related liver disease: Systematic review and meta-analysis.

BACKGROUND: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol-related liver disease (ALD) are therefore at risk from both extra-hepatic and hepatic disease. AIMS: This review synthesises information about non-liver-related mortality in persons with ALD. METHODS: A systematic literature review was performed to identify studies describing non-liver outcomes in ALD. Information about overall non-liver mortality was extracted from included studies and sub-categorised into major causes: cardiovascular disease (CVD), non-liver cancer and infection. Single-proportion meta-analysis was done to calculate incidence rates (events/1000 patient-years) and relative risks (RR) compared with control populations. RESULTS: Thirty-seven studies describing 50 302 individuals with 155 820 patient-years of follow-up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol-related fatty liver the rate of non-liver mortality was 43.4/1000 patient-years, whereas in alcoholic hepatitis the rate of non-liver mortality was 22.5/1000 patient-years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6-3.8), from non-hepatic cancer 2.2 (1.6-2.9) and from infection 8.2 (4.7-14.3). CONCLUSION: Persons with ALD are at high risk of death from non-liver causes such as cardiovascular disease and non-hepatic cancer.

Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: Data from the ATTIRE trial.

Background: Nonselective B-blockers (NSBBs) are believed to have pleiotropic effects beyond reducing portal pressure. However, studies also report potential harm in patients hospitalized with cirrhosis and ascites. We therefore investigated whether NSBB use at ATTIRE trial entry (Albumin to prevent infection in chronic liver failure, 2016-19) was associated with increased renal or cardiovascular dysfunction, compared the incidence of infection and plasma markers of systemic inflammation, and examined mortality at 28-days, 3 and 6-months. Methods: In ATTIRE patients grouped by NSBB use at trial entry, we studied infection at baseline, hospital acquired infection and organ dysfunction during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. Findings: There were no differences in renal or cardiovascular dysfunction between patients treated with NSBBs or not, during days 3-15 of hospitalization, despite elevated serum creatinine in NSBB patients at hospitalisation. Use of NSBBs was associated with a significant reduction in infection at hospitalization (p = 0.006), lower white cell counts throughout hospital stay (p < 0.001) and reduced plasma procalcitonin (p = 0.009) and interlukin-8 levels (p = 0.04) at baseline, but markers of bacterial translocation and systemic inflammation were the same in treatment groups. There was no reduction in hospital acquired infections in patients taking NSBBs and no beneficial impact on mortality at 28-days, 3 and 6-months. Interpretations: Our real-world data from a completed randomised trial show that use of NSBBs in decompensated cirrhosis patients is safe during hospitalisation. We also show a potential anti-inflammatory role for NSBBs which may be mediated by a downregulation of IL-8 induced leucocytosis, that was associated with reduced infection at baseline but not a survival benefit. Funding: Wellcome Trust and Department of Health and Social Care.

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.

Hepatocellular Carcinoma Risk Scores Predict Patients Under Surveillance at Low Risk of Benefit and High Risk of Harm.

AIMS: Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with cirrhosis. Multiple risk scores aim to stratify HCC risk, potentially allowing individualized surveillance strategies. We sought to validate four risk scores and quantify the consequences of surveillance via the calculation of numbers needed to benefit (NNB) and harm (NNH) according to classification by risk score strata. METHODS: Data were collected on 482 patients with cirrhosis during 2013-2014, with follow-up until 31/12/2019. Risk scores (aMAP, Toronto risk index, ADRESS HCC, HCC risk score) were derived from index clinic results. The area under the receiving operating characteristic curve (AUC) was calculated for each. Additionally, per-risk strata, NNB was calculated as total surveillance ultrasounds per surveillance diagnosed early HCC (stage 0/A) and NNH as total ultrasounds performed per false positive (abnormal surveillance with normal follow-up imaging). RESULTS: 22 (4.6%) patients developed HCC. 77% (17/22) were diagnosed through surveillance, of which 13/17 (76%) were early stage. There were 88 false positives and no false negatives (normal surveillance result however subsequent HCC detection). Overall NNB and NNH were 241 and 36, respectively. No score was significantly superior using AUC. Patients classified as low risk demonstrated no surveillance benefit (AMAP, THRI) or had a high NNB of > 300/900 (ADRESS HCC, HCC risk score), with low NNH (24-38). CONCLUSION: Given the lack of benefit and increased harm through false positives in low-risk groups, a risk-based surveillance strategy may have the potential to reduce patient harm and increase benefit from HCC surveillance. CLINICAL TRIALS REGISTRATION: This was not a clinical trial and the study was not pre-registered.

Evaluating the Role of Antibiotics in Patients Admitted to Hospital With Decompensated Cirrhosis: Lessons From the ATTIRE Trial.

INTRODUCTION: Hospital-acquired infections (HAI) are common in cirrhosis with antibiotics frequently used to prevent infections, but their efficacy for this role is unknown. To investigate this, we used Albumin to Prevent Infection in Chronic Liver Failure (ATTIRE) data to evaluate whether antibiotic use in patients without infection prevented HAI. METHODS: In ATTIRE patients without infection at baseline grouped by antibiotic prescription or not, we studied HAI during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. RESULTS: Two hundred three of 408 patients prescribed antibiotics at enrollment did not have infection and they were more unwell than noninfected patients not given antibiotics. There were no differences in subsequent HAI comparing antibiotic treated (39/203, 19.2%) to nonantibiotic treated (73/360, 20.3%; P = 0.83). Twenty-eight-day mortality was higher in antibiotic-treated patients ( P = 0.004) likely reflecting increased disease severity. Matching groups using propensity scoring revealed no differences in HAI or mortality. In noninfected patients at enrollment treated with/without rifaximin, there were no differences in HAI ( P = 0.16) or mortality, confirmed with propensity matching. Patients given long-term antibiotic prophylaxis at discharge had no differences in 6-month mortality compared with nonantibiotic patients, although antibiotic-treated patients had more infections at trial entry, with numbers too small for matching. DISCUSSION: Half of antibiotics at study entry were given to patients without an infection diagnosis which did not reduce the overall risk of HAI or improve mortality. This supports prompt de-escalation or discontinuation of antibiotics guided by culture sensitivities at 24-48 hours after commencement if no infection and the patient is improving.

ASEPTIC: primary antibiotic prophylaxis using co-trimoxazole to prevent SpontanEous bacterial PeritoniTIs in Cirrhosis-study protocol for an interventional randomised controlled trial.

BACKGROUND: Bacterial infection is a major cause of mortality in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is a serious and common infection in patients with cirrhosis and ascites. Secondary prophylactic antibiotic therapy has been shown to improve outcomes after an episode of SBP but primary prophylaxis to prevent the first episode of SBP remains contentious. The aim of this trial is to assess whether primary antibiotic prophylaxis with co-trimoxazole improves overall survival compared to placebo in adults with cirrhosis and ascites. METHODS: The ASEPTIC trial is a multicentre, placebo-controlled, double-blinded, randomised controlled trial (RCT) in England, Scotland, and Wales. Patients aged 18 years and older with cirrhosis and ascites requiring diuretic treatment or paracentesis, and no current or previous episodes of SBP, are eligible, subject to exclusion criteria. The trial aims to recruit 432 patients from at least 30 sites. Patients will be randomised in a 1:1 ratio to receive either oral co-trimoxazole 960 mg or an identical placebo once daily for 18 months, with 6 monthly follow-up visits thereafter (with a maximum possible follow-up period of 48 months, and a minimum of 18 months). The primary outcome is overall survival. Secondary outcomes include the time to the first incidence of SBP, hospital admission rates, incidence of other infections (including Clostridium difficile) and antimicrobial resistance, patients' health-related quality of life, health and social care resource use, incidence of cirrhosis-related decompensation events, liver transplantation, and treatment-related serious adverse events. DISCUSSION: This trial will investigate the efficacy, safety, and cost-effectiveness of co-trimoxazole for patients with liver cirrhosis and ascites to determine whether this strategy improves clinical outcomes. Given there are no treatments that improve survival in decompensated cirrhosis outside of liver transplant, if the trial has a positive outcome, we anticipate widespread adoption of primary antibiotic prophylaxis. TRIAL REGISTRATION: ClinicalTrials.gov NCT043955365 . Registered on 18 April 2020. Research ethical approval was granted by the Research Ethics Committee (South Central - Oxford B; REC 19/SC/0311) and the Medicines and Healthcare products Regulatory Agency (MHRA).

Association of gamma-glutamyltransferase levels with total mortality, liver-related and cardiovascular outcomes: A prospective cohort study in the UK Biobank.

Background: Gamma-glutamyltransferase (GGT) levels in the blood can be a sensitive marker of liver injury but the extent to which they give insight into risk across multiple outcomes in a clinically useful way remains uncertain. Methods: Using data from 293,667 UK Biobank participants, the relationship of GGT concentrations to self-reported alcohol intake and adiposity markers were investigated. We next investigated whether GGT predicted liver-related, cardiovascular (CV) or all-cause mortality, and potentially improved CV risk prediction. Findings: Higher alcohol intake and greater waist circumference (WC) were associated with higher GGT; the association was stronger for alcohol with evidence of a synergistic effect of WC. Higher GGT concentrations were associated with multiple outcomes. Compared to a GGT of 14.5 U/L (lowest decile), values of 48 U/L for women and 60 U/L for men (common upper limits of 'normal') had hazard ratios (HRs) for liver-related mortality of 1.83 (95% CI 1.60-2.11) and 3.25 (95% CI 2.38-4.42) respectively, for CV mortality of 1.21 (95% CI 1.14-1.28) and 1.43 (95% CI 1.27-1.60) and for all-cause mortality of 1.15 (95% CI 1.12-1.18) and 1.31 (95% CI 1.24-1.38). Adding GGT to a risk algorithm for CV mortality reclassified an additional 1.24% (95% CI 0.14-2.34) of participants across a binary 5% 10-year risk threshold. Interpretation: Our study suggests that a modest elevation in GGT levels should trigger a discussion with the individual to review diet and lifestyle including alcohol intake and consideration of formal liver disease and CV risk assessment if not previously done. Funding: British Heart Foundation Centre of Research Excellence Grant (grant number RE/18/6/34217), NHS Research Scotland (grant number SCAF/15/02), the Medical Research Council (grant number MC_UU_00022/2); and the Scottish Government Chief Scientist Office (grant number SPHSU17).

Randomised trial of intravenous thiamine and/or magnesium sulphate administration on erythrocyte transketolase activity, lactate concentrations and alcohol withdrawal scores.

Alcohol withdrawal syndrome (AWS) occurs in 2% of patients admitted to U.K. hospitals. Routine treatment includes thiamine and benzodiazepines. Laboratory studies indicate that thiamine requires magnesium for optimal activity, however this has not translated into clinical practice. Patients experiencing AWS were randomized to three groups: (group 1) thiamine, (group 2) thiamine plus MgSO4 or (group 3) MgSO4. Pre- and 2-h post-treatment blood samples were taken. AWS severity was recorded using the Glasgow Modified Alcohol Withdrawal Score (GMAWS). The primary outcome measure was 15% change in erythrocyte transketolase activity (ETKA) in group 3. Secondary outcome measures were change in plasma lactate concentrations and time to GMAWS = 0. 127 patients were recruited, 115 patients were included in the intention-to-treat analysis. Pre-treatment, the majority of patients had normal or high erythrocyte thiamine diphosphate (TDP) concentrations (≥ 275-675/> 675 ng/gHb respectively) (99%), low serum magnesium concentrations (< 0.75 mmol/L) (59%), and high plasma lactate concentrations (> 2 mmol/L) (67%). Basal ETKA did not change significantly in groups 1, 2 or 3. Magnesium deficient patients (< 0.75 mmol/L) demonstrated less correlation between pre-treatment basal ETKA and TDP concentrations than normomagnesemic patients (R2 = 0.053 and R2 = 0.236). Median plasma lactate concentrations normalized (≤ 2.0 mmol/L) across all three groups (p < 0.001 for all groups), but not among magnesium deficient patients in group 1 (n = 22). The median time to achieve GMAWS = 0 for groups 1, 2 and 3 was 10, 5.5 and 6 h respectively (p < 0.001). No significant difference was found between groups for the primary endpoint of change in ETKA. Co-administration of thiamine and magnesium resulted in more consistent normalization of plasma lactate concentrations and reduced duration to achieve initial resolution of AWS symptoms.ClinicalTrials.gov: NCT03466528.