Prevalence and clinical impact of alcohol withdrawal syndrome in alcohol-associated hepatitis and the potential role of prophylaxis: a multinational, retrospective cohort study

Alcohol withdrawal syndrome; Alcohol-associated hepatitis; BenzodiazepinesSíndrome de abstinencia alcohólica; Hepatitis asociada al alcohol; BenzodiazepinasSíndrome d'abstinència d'alcohol; Hepatitis associada a l'alcohol; BenzodiazepinesBackground The prevalence and impact of alcohol withdrawal syndrome (AWS) in patients with alcohol-associated hepatitis (AH) are unknown. In this study, we aimed to investigate the prevalence, predictors, management, and clinical impact of AWS in patients hospitalized with AH. Methods A multinational, retrospective cohort study enrolling patients hospitalized with AH at 5 medical centres in Spain and in the USA was performed between January 1st, 2016 to January 31st, 2021. Data were retrospectively retrieved from electronic health records. Diagnosis of AWS was based on clinical criteria and use of sedatives to control AWS symptoms. The primary outcome was mortality. Multivariable models controlling for demographic variables and disease severity were performed to determine predictors of AWS (adjusted odds ratio [OR]) and the impact of AWS condition and management on clinical outcomes (adjusted hazard ratio [HR]). Findings In total, 432 patients were included. The median MELD score at admission was 21.9 (18.3–27.3). The overall prevalence of AWS was 32%. Lower platelet levels (OR = 1.61, 95% CI 1.05–2.48) and previous history of AWS (OR = 2.09, 95% CI 1.31–3.33) were associated with a higher rate of incident AWS, whereas the use of prophylaxis decreased the risk (OR = 0.58, 95% CI 0.36–0.93). The use of intravenous benzodiazepines (HR = 2.18, 95% CI 1.02–4.64) and phenobarbital (HR = 2.99, 95% CI 1.07–8.37) for AWS treatment were independently associated with a higher mortality. The development of AWS increased the rate of infections (OR = 2.24, 95% CI 1.44–3.49), the need for mechanical ventilation (OR = 2.49, 95% CI 1.38–4.49), and ICU admission (OR = 1.96, 95% CI 1.19–3.23). Finally, AWS was associated with higher 28-day (HR = 2.31, 95% CI 1.40–3.82), 90-day (HR = 1.78, 95% CI 1.18–2.69), and 180-day mortality (HR = 1.54, 95% CI 1.06–2.24). Interpretation AWS commonly occurs in patients hospitalized with AH and complicates the hospitalization course. Routine prophylaxis is associated with a lower prevalence of AWS. Prospective studies should determine diagnostic criteria and prophylaxis regimens for AWS management in patients with AH

Bariatric Surgery Is Associated with Alcohol-Related Liver Disease and Psychiatric Disorders Associated with AUD

Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated. A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching. The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85-1.95], ALD [OR: 1.29; 95% CI: 1.22-1.37], cirrhosis [OR, 1.39; 95% CI: 1.37-1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37-3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD. Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency. The online version contains supplementary material available at 10.1007/s11695-023-06490-w

Pancreatic steatosis and iron overload increases cardiovascular risk in non-alcoholic fatty liver disease

ObjectiveTo assess the prevalence of pancreatic steatosis and iron overload in non-alcoholic fatty liver disease (NAFLD) and their correlation with liver histology severity and the risk of cardiometabolic diseases.MethodA prospective, multicenter study including NAFLD patients with biopsy and paired Magnetic Resonance Imaging (MRI) was performed. Liver biopsies were evaluated according to NASH Clinical Research Network, hepatic iron storages were scored, and digital pathology quantified the tissue proportionate areas of fat and iron. MRI-biomarkers of fat fraction (PDFF) and iron accumulation (R2*) were obtained from the liver and pancreas. Different metabolic traits were evaluated, cardiovascular disease (CVD) risk was estimated with the atherosclerotic CVD score, and the severity of iron metabolism alteration was determined by grading metabolic hiperferritinemia (MHF). Associations between CVD, histology and MRI were investigated.ResultsIn total, 324 patients were included. MRI-determined pancreatic iron overload and moderate-to severe steatosis were present in 45% and 25%, respectively. Liver and pancreatic MRI-biomarkers showed a weak correlation (r=0.32 for PDFF, r=0.17 for R2*). Pancreatic PDFF increased with hepatic histologic steatosis grades and NASH diagnosis (p<0.001). Prevalence of pancreatic steatosis and iron overload increased with the number of metabolic traits (p<0.001). Liver R2* significantly correlated with MHF (AUC=0.77 [0.72-0.82]). MRI-determined pancreatic steatosis (OR=3.15 [1.63-6.09]), and iron overload (OR=2.39 [1.32-4.37]) were independently associated with high-risk CVD. Histologic diagnosis of NASH and advanced fibrosis were also associated with high-risk CVD.ConclusionPancreatic steatosis and iron overload could be of utility in clinical decision-making and prognostication of NAFLD

Osimertinib in advanced EGFR-T790M mutation-positive non-small cell lung cancer patients treated within the Special Use Medication Program in Spain : OSIREX-Spanish Lung Cancer Group

AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain. Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016-December 2018) from 30 sites. Primary objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources. 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted. This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Clinical trial registration number : NCT03790397

Development and validation of an image biomarker to identify metabolic dysfunction associated steatohepatitis: MR-MASH score

[Background and Aims] Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) requires histology. In this study, a magnetic resonance imaging (MRI) score was developed and validated to identify MASH in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Secondarily, a screening strategy for MASH diagnosis was investigated.[Methods] This prospective multicentre study included 317 patients with biopsy-proven MASLD and contemporaneous MRI. The discovery cohort (Spain, Portugal) included 194 patients. NAFLD activity score (NAS) and fibrosis were assessed with the NASH-CRN histologic system. MASH was defined by the presence of steatosis, lobular inflammation, and ballooning, with NAS ≥4 with or without fibrosis. An MRI-based composite biomarker of Proton Density Fat Fraction and waist circumference (MR–MASH score) was developed. Findings were afterwards validated in an independent cohort (United States, Spain) with different MRI protocols.[Results] In the derivation cohort, 51% (n = 99) had MASH. The MR–MASH score identified MASH with an AUC = .88 (95% CI .83–.93) and strongly correlated with NAS (r = .69). The MRI score lower cut-off corresponded to 88% sensitivity with 86% NPV, while the upper cut-off corresponded to 92% specificity with 87% PPV. MR–MASH was validated with an AUC = .86 (95% CI .77–.92), 91% sensitivity (lower cut-off) and 87% specificity (upper cut-off). A two-step screening strategy with sequential MR–MASH examination performed in patients with indeterminate-high FIB-4 or transient elastography showed an 83–84% PPV to identify MASH. The AUC of MR–MASH was significantly higher than that of the FAST score (p < .001).[Conclusions] The MR–MASH score has clinical utility in the identification and management of patients with MASH at risk of progression.David Marti-Aguado (DMA) is the recipient of a Joan Rodés (JR22/00002) and Río Hortega award (CM19/00212), Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation). He also received an award from the University of Valencia (UV-RI_MID-1528578) to carry out a Doctorate in International Mobility Stay at the University of Pittsburgh Medical Center (Pittsburgh, PA, USA), and a grant Grupo de Investigación Emergente (CIGE/2022/37) from Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana, Spain.Peer reviewe

Binge drinking at time of bariatric surgery is associated with liver disease, suicides, and increases long-term mortality

Binge drinking; Bariatric surgery; Liver diseaseConsum excessiu d'alcohol; Cirurgia bariàtrica; Malalties hepàtiquesConsumo excesivo de alcohol; Cirugía bariátrica; Enfermedades hepáticasBackground and Aims: Alcohol use disorder has been reported in patients undergoing bariatric procedures, but the pattern of alcohol consumption has not been evaluated. We investigated the prevalence, risk factors, and impact of binge drinking (BD) at the time of surgery and during follow-up. Methods: A prospective, longitudinal study of subjects undergoing bariatric surgery was included in the LABS-2 registry between 2006 and 2009. Participants with AUDIT questionnaire at the time of surgery and a minimum of 12 months follow-up were included. BD was defined as consuming ≥5 drinks on at least 1 occasion in the previous month. Liver biopsies were obtained during bariatric procedures in not all cases. Survival analysis was performed with the adjusted Cox regression model and competing risk. Results: A total of 2257 subjects were included, with a median follow-up of 79 months. The prevalence of BD at time of surgery was 12%, and it raised up to 23% during follow-up. Patients with BD predominantly had a binge eating disorder (OR=1.35 [95% CI: 1.04–1.76]), regularly consumed fast food [OR=1.4 (95% CI: 1.07–1.85)] and used other drugs (OR=2.65 [95% CI: 1.74–4.04]). Within liver biopsies evaluation, BD showed higher hepatic iron deposits (OR=3.00 [95% CI: 1.25–7.21]). BD at the time of surgery was associated with a higher risk of BD during follow-up (OR=10.49 [95% CI: 7.86–14.00]) and long-term mortality (HR: 3.21 [95% CI: 1.67–6.18]). Specific causes of death in these patients with BD were liver disease (p=0.020), suicide (p=0.015), neoplasms (p=0.034), and respiratory (p=0.025). Conclusions: The prevalence of BD in patients undergoing bariatric surgery is high and increases the risk of postoperative liver disease, suicides, and long-term mortality.LABS-2 was funded by a cooperative agreement by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Grant numbers: Data Coordinating Center -U01 DK066557; Columbia-Presbyterian—U01-DK66667 (in collaboration with Cornell University Medical Center CTSC, Grant UL1-RR024996); University of Washington—U01-DK66568 (in collaboration with CTRC, Grant M01RR-00037); Neuropsychiatric Research Institute—U01-DK66471; East Carolina University—U01-DK66526; University of Pittsburgh Medical Center—U01 DK66585 (in collaboration with CTRC, Grant UL1-RR024153); Oregon Health & Science University—U01-DK66555. Ramon Bataller received lectures fee from Abbvie and Gilead. Hugo López-Pelayo received funds for training from Lundbeck and for elaborating training materials from Advanz Pharma. Joaquin Cabezas consults, advises, is on the speakers’ bureau, and received grants from Gilead. He is on the speakers’ bureau and received grants from Abbvie. Ramon Bataller is a recipient of NIAAA grants U01AA021908, U01AA020, and NIDDK P30DK120531821. Meritxell Ventura-Cots, Carlos Fernández-Carrillo, Edilmar Alvarado-Tapias, and Ana Clemente are recipients of a scholarship grant for study extension abroad, sponsored by the Spanish Association for the Study of the Liver (AEEH). Meritxell Ventura-Cots is recipient of a Joan Rodes award from the ISCII (JR19/00015) and the PI22/01770 grant from the ISCIII—Fondos Feder. Edilmar Alvarado-Tapias is a recipient of a Joan Rodes award from the ISCII (JR20/00047) and the PI21/01995 grant from the ISCIII- Fondos Feder. David Martí-Aguado is a recipient of the Joan Rodes award ISCIII (JR22/00002) and a scholarship grant for study extension abroad, sponsored by the University of Valencia (UV-RI_MID-1528578). Elisa Pose is a recipient of the PI22/00910 grant from the ISCIII—Fondos Feder. Josepmaria Argemi is a recipient of the PI20/01663 grant from the ISCIII- Fondos Feder and an award from the “Fundación Echebano” (Pamplona, Spain). Hugo López-Pelayo is a recipient of the PI20/00760 grant from the ISCIII—Fondos Feder, 2020I004 grant from Plan Nacional sobre Drogas, and 101045870 from DG Justice-European Commission. The remaining authors have no conflicts to report

Digital Pathology Enables Automated and Quantitative Assessment of Inflammatory Activity in Patients with Chronic Liver Disease

Traditional histological evaluation for grading liver disease severity is based on subjective and semi-quantitative scores. We examined the relationship between digital pathology analysis and corresponding scoring systems for the assessment of hepatic necroinflammatory activity. A prospective, multicenter study including 156 patients with chronic liver disease (74% nonalcoholic fatty liver disease-NAFLD, 26% chronic hepatitis-CH etiologies) was performed. Inflammation was graded according to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network system and METAVIR score. Whole-slide digital image analysis based on quantitative (I-score: inflammation ratio) and morphometric (C-score: proportionate area of staining intensities clusters) measurements were independently performed. Our data show that I-scores and C-scores increase with inflammation grades (p ρ = 0.85–0.88), but only moderate for NAFLD (ρ = 0.5–0.53). I-score (p = 0.008) and C-score (p = 0.002) were higher for CH than NAFLD. Our MATLAB algorithm performed better than QuPath software for the diagnosis of low-moderate inflammation (p p < 0.001). In conclusion, quantitative and morphometric metrics of inflammatory burden obtained by digital pathology correlate well with pathologists’ scores, showing a higher accuracy for the evaluation of CH than NAFLD

Automated Whole-Liver MRI Segmentation to Assess Steatosis and Iron Quantification in Chronic Liver Disease

[EN] Background: Standardized manual region of interest (ROI) sampling strategies for hepatic MRI steatosis and iron quantification are time consuming, with variable results. Purpose: To evaluate the performance of automatic MRI whole-liver segmentation (WLS) for proton density fat fraction (PDFF) and iron estimation (transverse relaxometry [R2*]) versus manual ROI, with liver biopsy as the reference standard. Materials and Methods: This prospective, cross-sectional, multicenter study recruited participants with chronic liver disease who underwent liver biopsy and chemical shift-encoded 3.0-T MRI between January 2017 and January 2021. Biopsy evaluation included histologic grading and digital pathology. MRI liver sampling strategies included manual ROI (two observers) and automatic wholeliver (deep learning algorithm) segmentation for PDFF- and R2*-derived measurements. Agreements between segmentation methods were measured using intraclass correlation coefficients (ICCs), and biases were evaluated using Bland-Altman analyses. Linear regression analyses were performed to determine the correlation between measurements and digital pathology. Results: A total of 165 participants were included (mean age 6 standard deviation, 55 years +/- 12; 96 women; 101 of 165 participants [61%] with nonalcoholic fatty liver disease). Agreements between mean measurements were excellent, with ICCs of 0.98 for both PDFF and R2*. The median bias was 0.5% (interquartile range, 20.4% to 1.2%) for PDFF and 2.7 sec(-1) (interquartile range, 0.2-5.3 sec(-1)) for R2* (P,.001 for both). Margins of error were lower for WLS than ROI-derived parameters (-0.03% for PDFF and 20.3 sec(-1) for R2*). ROI and WLS showed similar performance for steatosis (ROI AUC, 0.96; WLS AUC, 0.97; P = .53) and iron overload (ROI AUC, 0.85; WLS AUC, 0.83; P = .09). Correlations with digital pathology were high (P < .001) between the fat ratio and PDFF (ROI r = 0.89; WLS r = 0.90) and moderate (P < .001) between the iron ratio and R2* (ROI r = 0.65; WLS r = 0.64). Conclusion: Proton density fat fraction and transverse relaxometry measurements derived from MRI automatic whole-liver segmentation (WLS) were accurate for steatosis and iron grading in chronic liver disease and correlated with digital pathology. Automated WLS estimations were higher, with a lower margin of error than manual region of interest estimations.Supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (grant PI19/0380), and Gilead Sciences (grant GLD19/00050).Marti-Aguado, D.; Jimenez-Pastor, AM.; Alberich-Bayarri, Á.; Rodríguez-Ortega, A.; Alfaro-Cervello, C.; Mestre-Alagarda, C.; Bauza, M.... (2022). Automated Whole-Liver MRI Segmentation to Assess Steatosis and Iron Quantification in Chronic Liver Disease. Radiology. 302(2):345-354. https://doi.org/10.1148/radiol.2021211027345354302