Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes.

BACKGROUND & AIMS: The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. METHODS: We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010-2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. RESULTS: The median API in the 169 countries was 54 [IQR 34.9-76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03-0.60; p = 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03-0.79; p = 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02-0.40; p = 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02-0.65; p = 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02-0.41; p = 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). CONCLUSIONS: The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. IMPACT AND IMPLICATIONS: We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.

Active alcohol consumption is associated with acute-on-chronic liver failure in Hispanic patients.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe clinical entity associated with elevated short-term mortality. We aimed to characterize patients with decompensated cirrhosis according to presence of ACLF, their association with active alcohol intake, and long-term survival in Latin America. METHODS: Retrospective cohort study of decompensated cirrhotic in three Chilean university centers (2017-2019). ACLF was diagnosed according EASL-CLIF criteria. We assessed survival using competing-risk and time-to-event analyses. We evaluated the time to death using accelerated failure time (AFT) models. RESULTS: We included 320 patients, median age of 65.3±11.7 years old, and 48.4% were women. 92 (28.7%) patients met ACLF criteria (ACLF-1: 29.3%, ACLF-2: 27.1%, and ACLF-3: 43.4%). The most common precipitants were infections (39.1%), and the leading organ failure was kidney (59.8%). Active alcohol consumption was frequent (27.7%), even in patients with a prior diagnosis of non-alcoholic fatty liver disease (NAFLD) (16.2%). Ninety-two (28.7%) patients had ACLF (ACLF-1: 8.4%, ACLF-2: 7.8%, and ACLF-3: 12.5%). ACLF patients had a higher MELD-Na score at admission (27 [22-31] versus 16 [12-21], p<0.0001), a higher frequency of alcohol-associated liver disease (36.7% versus 24.9%, p=0.039), and a more frequent active alcohol intake (37.2% versus 23.8%, p=0.019). In a multivariate model, ACLF was associated with higher mortality (subdistribution hazard ratio 1.735, 95%CI: 1.153-2.609; p<0.008). In the AFT models, the presence of ACLF during hospitalization correlated with a shorter time to death: ACLF-1 shortens the time to death by 4.7 times (time ratio [TR] 0.214, 95%CI: 0.075-0.615; p<0.004), ACLF-2 by 4.4 times (TR 0.224, 95%CI: 0.070-0.713; p<0.011), and ACLF-3 by 37 times (TR 0.027, 95%CI: 0.006-0.129; p<0.001). CONCLUSIONS: Patients with decompensated cirrhosis and ACLF exhibited a high frequency ofactive alcohol consumption. Patients with ACLF showed higher mortality and shorter time todeath than those without ACLF.

Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure.

BACKGROUND & AIMS: Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated with increased circulating levels of small-molecule metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphology and central metabolic pathways with emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients with acutely decompensated (AD) cirrhosis, with and without ACLF. METHODS: The study included samples from patients with AD cirrhosis (108 without and 128 with ACLF) and 41 healthy individuals. Leukocyte mitochondrial ultrastructure was visualized by transmission electron microscopy and cytosolic and mitochondrial metabolic fluxes were determined by assessing NADH/FADH2 production from various substrates. Plasma GDF15 and FGF21 were determined by Luminex and acylcarnitines by LC-MS/MS. Gene expression was analyzed by RNA-sequencing and PCR-based glucose metabolism profiler array. RESULTS: Mitochondrial ultrastructure in patients with advanced cirrhosis was distinguished by cristae rarefication and swelling. The number of mitochondria per leukocyte was higher in patients, accompanied by a reduction in their size. Increased FGF21 and C6:0- and C8:0-carnitine predicted mortality whereas GDF15 strongly correlated with a gene set signature related to leukocyte activation. Metabolic flux analyses revealed increased energy production in mononuclear leukocytes from patients with preferential involvement of extra-mitochondrial pathways, supported by upregulated expression of genes encoding enzymes of the glycolytic and pentose phosphate pathways. In patients with ACLF, mitochondrial function analysis uncovered break-points in the TCA cycle at the isocitrate dehydrogenase and succinate dehydrogenase level, which were bridged by anaplerotic reactions involving glutaminolysis and nucleoside metabolism. CONCLUSIONS: Our findings provide evidence at the cellular, organelle and biochemical levels that severe mitochondrial dysfunction governs immunometabolism in leukocytes from patients with AD cirrhosis and ACLF. LAY SUMMARY: Patients at advanced stages of liver disease have dismal prognosis due to vital organ failures and the lack of treatment options. In this study, we report that the functioning of mitochondria, which are known as the cell powerhouse, is severely impaired in leukocytes of these patients, probably as a consequence of intense inflammation. Mitochondrial dysfunction is therefore a hallmark of advanced liver disease.

Rectal colonization by resistant bacteria increases the risk of infection by the colonizing strain in critically ill patients with cirrhosis.

BACKGROUND & AIMS: It remains unclear whether rectal colonization with multidrug-resistant organisms (MDROs) is prevalent and predisposes to infections by the same pathogens in patients with cirrhosis. METHODS: Two series of critically ill patients were evaluated. In the Barcelona cohort, 486 consecutive patients were prospectively evaluated, 129 with and 357 without cirrhosis (2015-2016). Rectal swabs were performed at admission and weekly thereafter (until intensive care unit [ICU] discharge) to detect MDRO colonization. Risk factors for colonization and infection by MDROs were evaluated. A retrospective cohort from Frankfurt (421 patients with cirrhosis; 2010-2018) was investigated to evaluate MDRO rectal colonization in another epidemiological scenario. RESULTS: In the Barcelona cohort, 159 patients were colonized by MDROs (32.7%), 102 (64.2%) at admission and 57 (35.8%) during follow-up. Patients with cirrhosis showed higher rates of rectal colonization at admission than those without cirrhosis (28.7% vs. 18.2%, p = 0.01) but similar colonization rates during ICU stay. Extended-spectrum beta-lactamase-Enterobacterales were the most frequent MDROs isolated in both groups. Colonization by MDROs independently increased the risk of infection by MDROs at admission and during follow-up. Risk of new infection by the colonizing strain was also significantly increased in patients with (hazard ratio [HR] 7.41) and without (HR 5.65) cirrhosis. Rectal colonization by MDROs was also highly prevalent in Frankfurt (n = 198; 47%; 131 at admission [66.2%] and 67 [33.8%] during follow-up), with vancomycin-resistant enterococci being the most frequent colonizing organism. Rectal colonization by MDROs was also associated with an increased risk of infection by MDROs in this cohort. Infections occurring in MDR carriers were mainly caused by the colonizing strain. CONCLUSION: Rectal colonization by MDROs is extremely frequent in critically ill patients with cirrhosis. Colonization increases the risk of infection by the colonizing resistant strain. LAY SUMMARY: Rectal colonization by multidrug-resistant organisms (MDROs) is a prevalent problem in patients with cirrhosis requiring critical care. The pattern of colonizing bacteria is heterogeneous with relevant differences between centers. Colonization by MDROs is associated with increased risk of infection by the colonizing bacteria in the short term. This finding suggests that colonization data could be used to guide empirical antibiotic therapy and de-escalation policies in patients with cirrhosis.

Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. RESULTS: Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. CONCLUSIONS: Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.

Management and Outcomes of Bleeding Within 30 Days of Colonic Polypectomy in a Large, Real-Life, Multicenter Cohort Study.

BACKGROUND & AIMS: Management of delayed (within 30 days) postpolypectomy bleeding (DPPB) has not been standardized. Patients often undergo colonoscopies that do not provide any benefit. We aimed to identify factors associated with therapeutic intervention and active bleeding after DPPB. METHODS: We performed a retrospective study of 548 patients with bleeding within 30 days after an index polypectomy (DPPB; 71.9% underwent colonoscopy, 2.6% underwent primary angiographic embolization, and 25.5% were managed without intervention) at 6 tertiary centers in Spain, from January 2010 through September 2018. We collected demographic and medical data from patients. The primary outcomes were the need for therapeutic intervention and the presence of active bleeding during colonoscopy. RESULTS: A need for therapeutic intervention was associated independently with the use of antithrombotic agents, hemoglobin decrease greater than 2 g/dL, hemodynamic instability, and comorbidities (P < .05). The bleeding point during colonoscopy was identified in 344 patients; 74 of these patients (21.5%) had active bleeding. Active use of anticoagulants (odds ratio [OR], 2.6; 95% CI, 1.5-4.5), left-sided polyps (OR, 1.95; 95% CI, 1-3.8), prior use of electrocautery (OR, 2.6; 95% CI, 1.1-6.1), and pedunculated polyp morphology (OR, 1.8, 95% CI, 1-3.2) significantly increased the risk of encountering active bleeding. We developed a visual nomogram to estimate the risk of active bleeding. Overall, 43% of the cohort did not require any hemostatic therapy. Rebleeding (<6%) and transfusion requirements were low in those managed without intervention. CONCLUSIONS: In a study of patients with DPPB, we found that almost half do not warrant any therapeutic intervention. Colonoscopy often is overused for patients with DPPB. We identified independent risk factors for active bleeding that might be used to identify patients most likely to benefit from colonoscopy.

Mixed Fibrinolytic Phenotypes in Decompensated Cirrhosis and Acute-on-Chronic Liver Failure with Hypofibrinolysis in Those With Complications and Poor Survival.

BACKGROUND AND AIMS: Patients with liver disease acquire complex changes in their hemostatic system, which results in a fragile rebalanced status. The status of the fibrinolytic system is controversial, as is the role of fibrinolytic dysfunction in bleeding and thrombosis in patients with cirrhosis. Here, we aimed to determine fibrinolytic status and its relationship with outcome in acutely ill patients with cirrhosis. APPROACH AND RESULTS: We assessed plasma fibrinolytic potential in a large cohort of patients with acutely decompensated cirrhosis (AD, n = 52) or acute-on-chronic liver failure (ACLF, n = 57). Compared with 40 healthy volunteers, median clot lysis times (CLTs) were shorter in patients with AD but comparable to controls in patients with ACLF. However, the variability in CLTs in patients was much larger than in healthy controls, and in both patient groups, a proportion of patients had clearly prolonged or shortened CLTs. The variability in CLTs in patients was not readily explained by variations in plasma levels of key fibrinolytic proteins. However, CLTs were clearly related to clinical characteristics, with longer CLTs in patients with sepsis and patients with any organ failure (as defined by the European Foundation for the Study of Chronic Liver Disease organ failure scores). CLTs were not different between patients that did or did not experience bleeding or a thrombotic event during follow-up. Baseline CLTs were substantially longer in patients that died within 30 days of admission. CONCLUSIONS: Our study demonstrates a mixed fibrinolytic phenotype in acutely ill patients with cirrhosis with baseline hypofibrinolysis associated with sepsis, organ failure, and short-term mortality. These associations may be explained by defective clearance of intraorgan microthrombi that have been proposed to drive organ failure.

Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). METHODS: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. RESULTS: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). CONCLUSIONS: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.

Plasma Exchange: An Effective Rescue Therapy in Critically Ill Patients With Coronavirus Disease 2019 Infection.

OBJECTIVES: Infection by severe acute respiratory syndrome coronavirus-2 can induce uncontrolled systemic inflammation and multiple organ failure. The aim of this study was to evaluate if plasma exchange, through the removal of circulating mediators, can be used as rescue therapy in these patients. DESIGN: Single center case series. SETTING: Local study. SUBJECTS: Four critically ill adults with coronavirus disease 19 pneumonia that failed conventional interventions. INTERVENTIONS: Plasma exchange. Two to six sessions (1.2 plasma volumes). Human albumin (5%) was used as the main replacement fluid. Fresh frozen plasma and immunoglobulins were administered after each session to avoid coagulopathy and hypogammaglobulinemia. MEASUREMENTS AND MAIN RESULTS: Serum markers of inflammation and macrophage activation. All patients showed a dramatic reduction in inflammatory markers, including the main cytokines, and improved severity scores after plasma exchange. All survived to ICU admission. CONCLUSIONS: Plasma exchange mitigates cytokine storm, reverses organ failure, and could improve survival in critically ill patients with coronavirus disease 2019 infection.

Meropenem population pharmacokinetics in patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Meropenem pharmacokinetics (PK) may be altered in patients with cirrhosis, hampering target attainment. We aimed to describe meropenem PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under meropenem treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate meropenem exposure to assess the PTA. RESULTS: Fifty-four patients were enrolled in the study. Data were best described by a one-compartment linear model. The estimated typical mean value for clearance (CL) was 8.35 L/h and the estimated volume of distribution (V) was 28.2 L. Creatinine clearance (CLCR) and MELD score significantly influenced meropenem CL, and acute-on-chronic liver failure (ACLF) significantly affected V. Monte Carlo simulations showed that a lower meropenem dose would be needed as CLCR decreases and as the MELD score increases. Patients with ACLF would have lower peak meropenem concentrations but similar steady-state concentrations compared with patients with no ACLF. CONCLUSIONS: Our study identified two new covariates that influence meropenem PK in patients with decompensated cirrhosis in addition to CLCR: MELD score and ACLF. Dosing regimens are recommended to reach several PK/PD targets considering these clinical variables and any MIC within the susceptibility range.

Coagulation Failure in Patients With Acute-on-Chronic Liver Failure and Decompensated Cirrhosis: Beyond the International Normalized Ratio.

Balanced hemostasis with hypocoagulable and hypercoagulable features may occur in acute-on-chronic liver failure (ACLF). The characteristics and prognostic impact of the coagulation profile in ACLF are unknown. Consecutive patients with ACLF (n = 36) and acute decompensation (AD; n = 24) were included. Blood samples for thromboelastometry (TE) were obtained at admission and 72 hours thereafter. The coagulation profile was evaluated in patients with and without ACLF and in those with and without systemic inflammatory response syndrome. The impact of the coagulation profile on transfusion requirements, bleeding events, and short-term survival was assessed. At admission, patients with ACLF showed more hypocoagulable characteristics compared to AD subjects, with prolonged time to initial fibrin formation and clot formation time and decreased maximum clot firmness and alpha-angle values. TE parameters worsened at 72 hours in ACLF but improved in patients with AD. Prevalence of a hypocoagulable profile (three or more TE parameters outside range) was significantly higher in patients with ACLF either at admission (61% versus 29% in AD; P = 0.03) or during follow-up. Hypocoagulability correlated with systemic inflammation and was associated with higher 28-day (45% versus 16%; P = 0.02) and 90-day (52% versus 19%; P = 0.01) mortality rates but not with transfusion requirements or bleeding. Prolonged time to initial fibrin formation (extrinsic TE assay >80 seconds) and Model for End-Stage Liver Disease score at baseline were independent predictors of 28-day mortality. Conclusion: Patients with ACLF frequently show hypocoagulable features with prolonged time to initial fibrin formation and clot formation time and reduced clot firmness; these alterations worsen after admission, correlate with systemic inflammation, and translate into higher short-term mortality; hypofibrinolysis could contribute to organ failure in ACLF.

Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival. PATIENTS: 407 patients with ACLF and 235 patients with acute decompensation (AD). RESULTS: 152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%). CONCLUSION: Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.

Prevalence, risk factors and response to treatment of extra-intestinal manifestations in patients with inflammatory bowel disease.

INTRODUCTION: Patients with inflammatory bowel disease can experience extra-intestinal manifestations that may cause significant morbidity. AIMS: To describe the prevalence, characteristics, treatment and evolution of extra-intestinal manifestations in inflammatory bowel disease patients treated in our hospital and to identify associated risk factors. METHODS: This was a retrospective, observational, case-control study. All inflammatory bowel disease patients with extra-intestinal manifestations were considered as cases and inflammatory bowel disease patients without extra-intestinal manifestations were considered as controls. RESULTS: Six hundred and nineteen patients with inflammatory bowel disease (327 Crohn's disease, 265 ulcerative colitis, 27 indeterminate colitis) were included in the study; 16.5% experienced at least one extra-intestinal manifestation (CI 95% 13.5-19.5; n = 102). The most frequent extra-intestinal manifestations observed were musculoskeletal (n = 50; 40%) and cutaneous manifestations (n = 50; 40%). With regard to treatment, arthropathies were treated with non-steroidal anti-inflammatory drugs (31%) and corticosteroids (19%, oral or intra-articular), and the majority of the cutaneous manifestations were managed with corticosteroids. Overall, the efficacy of extra-intestinal manifestation treatment was 90% and only 13% of patients had a recurrence of extra-intestinal manifestations. The multivariate analysis showed that female gender (p = 0.012; OR = 1.61; 95% CI 1.11-2.34) and the severity of inflammatory bowel disease (p = 0.009; OR = 1.65; 95% CI 1.13-2.4 if immunosuppressant therapy alone, or p = 0.029; OR = 2.28; 95% CI 1.09-4.78 if in combination with adalimumab) were associated with an increased risk of developing extra-intestinal manifestations. CONCLUSIONS: The most frequent extra-intestinal manifestations in our environment were musculoskeletal and cutaneous manifestations. Female gender and a more severe disease were associated with a higher risk of developing extra-intestinal manifestations. Individualized treatment of extra-intestinal manifestations is effective and the risk is low in our series.

Mercaptopurine and inflammatory bowel disease: the other thiopurine.

BACKGROUND: Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited. AIMS: To assess the possible therapeutic indications, efficacy and safety of mercaptopurine as an alternative to azathioprine in inflammatory bowel disease. METHODS: Retrospective observational study in patients treated with mercaptopurine in a total cohort of 1,574 patients with inflammatory bowel disease. RESULTS: One hundred and fifty-two patients received mercaptopurine, 15.7% of these patients as an initial thiopurine, 5.3% after azathioprine failure, and 79% after azathioprine intolerance. In 52.6% of patients (n = 80), adverse effects of mercaptopurine occurred, resulting in withdrawal in 49 of them. Mercaptopurine was effective in 39% of cases (95% CI 31-48%). In the remaining patients, failure was due mainly to withdrawal due to side effects (55.1%) and therapeutic step-up (33.7%). The average total time of mercaptopurine exposure was 36 months (IQR: 2-60). Myelotoxicity with mercaptopurine was more common in patients with intermediate TPMT activity than in those with normal activity (p = 0.046). CONCLUSIONS: In our setting, mercaptopurine is primarily used as a rescue therapy in patients with azathioprine adverse effects. This could explain its modest efficacy and the high rate of adverse effects. However, this drug is still an alternative in this group of patients, before a therapeutic step-up to biologics is considered.

What is the real-life maintenance mesalazine dose in ulcerative colitis?

OBJECTIVE: To describe how mesalazine (MSZ) is used in our practice in ulcerative colitis (UC), at what dose, and the success rate (regarding adherence to therapy). METHODS: Observational, transversal study, including all patients with UC and with MSZ maintenance therapy seen from September 2014 to February 2015 at two IBD units in Spain. Treatment adherence was measured by the Morisky-Green scale. RESULTS: We included 203 patients (mean MSZ dose: 2.6 ± 1.0 g/d; median of treatment: 19.5 months [IQR: 8-48]). Doses < 2 g/d were used in 15.3% of cases, 2-2.9 g/d doses in 35.0%, 3-3.9 doses in 29.5%, and ≥ 4 g/d doses in the remaining 20.2%. A single daily dose was preferred in 51.2% of cases, two doses in 33.0% and three doses in 15.8%. A different MSZ brand had been previously used in 36.6% of patients. In 134 cases (66%), the maintenance dose had been increased during a flare-up, and in 49 (36.6% of cases) this higher dose had been kept for maintenance (dose ≥ 4 g/d in 36 patients). During the MSZ therapy, 14 patients (6.9%) suffered mild side effects (21.4% altered liver function tests). Therapy adherence was good in 81.8% of cases. CONCLUSIONS: Half of our UC patients take high MSZ doses (≥ 3 g/d) as maintenance therapy, with acceptable safety and good adherence. Half of all patients take a single daily dose, and one third needed a different commercial brand during therapy. Opting for a higher MSZ maintenance dose is a possible strategy for a satisfactory maintenance therapy.

Implementation and evaluation of early gastroscopy for patients with dyspepsia and warning signs in Primary Care. / Implantación y evaluación de una prestación de gastroscopia precoz para pacientes con dispepsia y datos de alarma en Atención Primaria.

INTRODUCTION: Dyspepsia is a common disorder in both Primary (PC) and Specialised Care (SC). Gastroscopy is recommended at the start of the study if there are warning signs, although it is not always available in PC. OBJECTIVES AND METHODS: We developed a pilot project establishing an early gastroscopy programme for patients with dyspepsia and warning signs in PC, subsequently extending it to the entire healthcare area. The aim was to evaluate the requirements, impact and opinion of this service at the PC level. Demographic, symptomatic and endoscopic variables on the patients referred to SC from the pilot centre were recorded. A satisfaction survey was conducted among the PC physicians. RESULTS: The one-year pilot study and the first year of implementation of the programme were evaluated. A total of 355 patients were included (median age 56.4 years; IQR 45.5-64.3); 61.2% (56.1-66.3%) were women. The waiting time for examination was 1.5 weeks (IQR 1.5-2.5). Gastroscopy was correctly indicated in 82.7% (78.4-86.3%) of patients. The median number of requests per month was 1.1 per 10,000 adults (range 0.8-1.6). Monthly referrals to SC clinics from the pilot centre fell by 11 subjects (95% CI 5.9-16) with respect to the previous median of 58 (IQR 48-64.5). Almost all those polled (98.4%) considered the programme useful in routine practice. CONCLUSIONS: The availability of an early gastroscopy programme in PC for patients with dyspepsia and warning signs reduced the number of referrals to SC.

Terlipressin therapy is associated with increased risk of colonisation with multidrug-resistant bacteria in patients with decompensated cirrhosis.

BACKGROUND: Patients with cirrhosis are susceptible to develop bacterial infections that trigger acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Infections with multidrug-resistant organisms (MDRO) are associated with deleterious outcome. MDRO colonisation frequently proceeds MDRO infections and antibiotic therapy has been associated with MDRO colonisation. AIM: The aim of the study was to assess the influence of non-antibiotic medication contributing to MDRO colonisation. METHODS: Three hundred twenty-four patients with AD and ACLF admitted to the ICU of Frankfurt University Hospital with MDRO screening were included. Regression models were performed to identify drugs associated with MDRO colonisation. Another cohort (n = 129) from Barcelona was included to validate. A third multi-centre cohort (n = 203) with metagenomic sequencing data of stool was included to detect antibiotic resistance genes. RESULTS: A total of 97 patients (30%) were identified to have MDRO colonisation and 35 of them (11%) developed MDRO infection. Patients with MDRO colonisation had significantly higher risk of MDRO infection than those without (p = 0.0098). Apart from antibiotic therapy (odds ratio (OR) 2.91, 95%-confidence interval (CI) 1.82-4.93, p < 0.0001), terlipressin therapy in the previous 14 days was the only independent covariate associated with MDRO colonisation in both cohorts, the overall (OR 9.47, 95%-CI 2.96-30.23, p < 0.0001) and after propensity score matching (OR 5.30, 95%-CI 1.22-23.03, p = 0.011). In the second cohort, prior terlipressin therapy was a risk factor for MDRO colonisation (OR 2.49, 95% CI 0.911-6.823, p = 0.075) and associated with risk of MDRO infection during follow-up (p = 0.017). The validation cohort demonstrated that antibiotic inactivation genes were significantly associated with terlipressin administration (p = 0.001). CONCLUSIONS: Our study reports an increased risk of MDRO colonisation in patients with AD or ACLF, who recently received terlipressin therapy, while other commonly prescribed non-antibiotic co-medications had negligible influence. Future prospective trials are needed to confirm these results.

Spectrum, Screening, and Diagnosis of Alcohol-related Liver Disease.

Alcohol-related liver disease (ALD) represents one of the leading causes of chronic liver disease and is a major cause of liver-related deaths worldwide. ALD encompasses a range of disorders including simple steatosis, alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Patients with underlying ALD and continued heavy alcohol consumption can also develop an episode of acute-on-chronic liver injury called alcohol-associated hepatitis, the most severe form of the disease, which portends a poor prognosis. The most important risk factor for the development of ALD is the amount of alcohol consumed. Individual susceptibility to progression to advanced fibrosis among heavy drinkers is likely determined by a combination of behavioral, environmental, genetic, and epigenetic factors, but the mechanisms are largely unknown. The only effective therapy for ALD is prolonged alcohol abstinence. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. In clinical practice, the histological assessment for ALD diagnosis is uncommon, and it is usually based on the medical history, clinical manifestations, and laboratory and imaging tests. Several promising biomarkers that can have both diagnostic and prognostic value in patients with ALD have been identified in recent years. This review provides an overview of the clinical spectrum of ALD, the diagnostic approach of the disease from different perspectives as well as current diagnostic and prognostic biomarkers.