Efectes de l'administració de l'ornitina fenilacetat (OCR-002) en pacients amb cirrosi hepàtica i hemorràgia digestiva alta

Hepatic encephalopathy (HE) is a major complication of cirrhosis associated with high mortality and poor quality of life. Multiple risk factors have been classically associated with the development of HE, including upper gastrointestinal bleeding (UGIB). UGIB induces a status of hyperammonemia through the intraluminal digestion of blood nitrogenous compounds by colonic bacteria. In addition, the catabolic status caused by gastrointestinal bleeding provokes an increase in ammoniagenesis in different tissues. Ammonia and its transformation to glutamine in the astrocyte appear to be a key factor in HE development and pathogenesis. Current strategies for the treatment of HE have been focused on lowering ammonia production. Ornithine phenylacetate (OP) is a new drug proposed as an ammonia scavenger, our first trial proved that OP is a safe and well tolerated drug in decompensated cirrhotics, and confirmed the mechanism of action: decrease plasma ammonia by inducing its appearance as phenylacetylglutamine in urine. In the second trial we assess OP efficacy in lowering plasma ammonia levels vs. placebo in cirrhotic patients after UGIB. The primary outcome was a decrease in venous plasma ammonia during the first 24h of 25 µmol/L, this outcome was not archived, but dose of 10g/day proved to decreases plasma ammonia in cirrhotic patients, especially in Child-Pugh C patients, the data suggest that higher doses of OP might be required in Child-Pugh A and B patients to maximize ammonia elimination, and proved once again the proposed mechanism of action as well as the safety of the drug. L'encefalopatia hepàtica (EH) és una complicació de la cirrosis hepática associada a un augment de la mortalitat i a una disminució en la qualitat de vida. El desenvolupament de l'EH s'ha associat amb múltiples factors de risc, entre ells destaca l'hemorràgia digestiva alta (HDA). L'HDA indueix un estat d'hiperamonièmia secundari a la digestió dels components nitrogenats de la sang arribada a nivell intestinal per part de la flora colònica. A més a més l'HDA provoca un estat catabòlic que causa un augment de l'amoniagènesi en diferents teixits. L'amoni a través de la seva transformació en glutamina a nivell astrocitari sembla el factor clau en el desenvolupament de l'EH. Fins ara els tractament per a l'EH s'han centrat en la disminució de la producció d'amoni. L'ornitina fenilacetat (OP) és un nou fàrmac que s'ha postulat com a eliminador d'amoni. El nostre primer assaig clínic demostra que l'OP és un fàrmac segur i ben tolerat en pacients amb cirrosis hepàtica descompensats per una HDA, a més amés en confirma el mecanisme d'acció: la disminució d'amoni plasmàtic a través de la formació de fenilacetilglutamina i posterior eliminació en orina. El segon assaig clínic compara l'eficàcia de l'OP contra placebo en disminuir l'amoni plasmàtic en pacients cirròtics descompensats per una HDA. L'objectiu principal era assolir una disminució de l'amoni plasmàtic, per part del grup que va rebre OP, durant les primeres 24h de 25 µmol/L. Aquest objectiu no va ser assolit, però la dosis administrada de 10g/24h va demostrar que disminuir l'amoni plasmàtic durant tot l'estudi, especialment en els pacients amb Child-Pugh C. Les dades obtingudes suggereixen que els pacient amb Child-Pugh A i B podrien necessitar dosis majors de fàrmac. L'estudi confirma un cop més el mecanisme d'acció del fàrmac, així com la seva seguretat i tolerabilitat

Estudi descriptiu de factors associats a l'encefalopatia hepàtica en pacients en llista de transplantament hepàtic

L' encefalopatia hepàtica és un complicació greu de la cirrosis. S'ha observat que pot aparèixer en presència o absència de factors precipitants i amb diferents graus de disfunció hepàtica; fet que fa pensar en la participació de factors predisposants genètics en els desenvolupament de la mateixa, sent la diana d'aquest estudi analitzar les característiques epidemiològiques, complicacions, tractament i dades analítiques que presenten els pacients en llista de transplantament hepàtic tot i estratificant-los entre aquells que han presentat encefalopatia hepàtica i aquells que no; per en un segon temps analitzar les variacions en la regió promotora del gen de la glutaminass

Deaths of Despair: A Scoping Review on the Social Determinants of Drug Overdose, Alcohol-Related Liver Disease and Suicide

Death of despair; Health inequalities; Public healthMuerte de desesperación; Desigualdades en salud; Salud públicaMort de desesperació; Desigualtats en salut; Salut públicaBackground: There is a lack of consensus on the social determinants of Deaths of Despair (DoD), i.e., an increase in mortality attributed to drug overdose, alcohol-related liver disease, and suicide in the United States (USA) during recent years. The objective of this study was to review the scientific literature on DoD with the purpose of identifying relevant social determinants and inequalities related to these mortality trends. Methods: Scoping review focusing on the period 2015–2022 based on PubMed search. Articles were selected according to the following inclusion criteria: published between 1 January 2000 and 31 October 2021; including empirical data; analyzed DoD including the three causes defined by Case and Deaton; analyzed at least one social determinant; written in English; and studied DoD in the USA context only. Studies were excluded if they only analyzed adolescent populations. We synthesized our findings in a narrative report specifically addressing DoD by economic conditions, occupational hazards, educational level, geographical setting, and race/ethnicity. Results: Seventeen studies were included. Overall, findings identify a progressive increase in deaths attributable to suicide, drug overdose, and alcohol-related liver disease in the USA in the last two decades. The literature concerning DoD and social determinants is relatively scarce and some determinants have been barely studied. However different, however, large inequalities have been identified in the manner in which the causes of death embedded in the concept of DoD affect different subpopulations, particularly African American, and Hispanic populations, but blue collar-whites are also significantly impacted. Low socioeconomic position and education levels and working in jobs with high insecurity, unemployment, and living in rural areas were identified as the most relevant social determinants of DoD. Conclusions: There is a need for further research on the structural and intermediate social determinants of DoD and social mechanisms. Intersectional and systemic approaches are needed to better understand and tackle DoD and related inequalities

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

Effects of Albumin on Survival after a Hepatic Encephalopathy Episode: Randomized Double-Blind Trial and Meta-Analysis

Albúmina; Assaig clínic; MetanàlisiAlbumin; Clinical trial; Meta-analysisAlbúmina; Ensayo clínico; MetaanálisisNo therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode. Methods: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient’s data for survival including two clinical trials (BETA and ALFAE) was performed. Results: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo (p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44; 95% CI, 0.21–0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02). Conclusions: Repeated doses of albumin might be beneficial for patient’s survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.This work was supported by grants ICI14/00352 and PI/18/00947 from Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (ERDF/ESF, “Investing in your future”—Una manera de hacer Europa). MVC and MST are both recipients of Juan Rodes grants from ISCIII. JG is a recipient of a research intensification grant from the ISCIII. CIBERehd is supported by ISCIII. ACS is a recipient of the Rio Hortega grant from ISCIII. The work was independent of all funding

Duration of the acute hepatic encephalopathy episode determines survival in cirrhotic patients

Altres ajuts: MST is a recipient of a Río Hortega grant from Instituto de Salud Carlos III, Spain. JG is a recipient of a Research Intensification grant from Instituto de Salud Carlos III, Spain. MVC is a recipient of a scholarship grant for study extension abroad, sponsored by the Spanish Association for the Study of the Liver. CIBERehd is supported by Instituto de Salud Carlos III, Spain.Episodes of hepatic encephalopathy (HE) have been related to low survival rate. However, the relation between its clinical evolution and mortality has not been assessed. A retrospective analysis of 245 cirrhotic patients admitted for an acute episode of HE (⩾grade 2) or who developed an HE episode after an upper gastrointestinal bleeding (UGIB) event was performed to assess the relation between time in HE and transplant-free survival. Median (IQR) time in HE was 48 h (24-96 h) in the whole cohort. Patients who presented a longer time in HE (>48 h; n = 89) exhibited a lower transplant-free survival at 28 days (67.2% versus 88.9%, p 48 h, when comparing patients according to baseline HE grade (2 versus ⩾3) or model for end-stage liver disease (MELD) function (⩽15 versus >15). Time in HE was also an independent risk factor for mortality at each time point, hazard ratio (HR) (95 CI%) 28 days 2.59 (1.39-4.84); 90 days 1.98 (1.28-3.1) and 365 days 1.5 (1.08-2.19). The duration of the acute HE episode determines survival in cirrhotic patients independently of liver function and baseline HE grade

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

Impact of ornithine phenylacetate (OCR-002) in lowering plasma ammonia after upper gastrointestinal bleeding in cirrhotic patients

Ornithine phenylacetate (OP) has been proven effective in lowering ammonia plasma levels in animals, and to be well tolerated in cirrhotic patients. A trial to assess OP efficacy in lowering plasma ammonia levels versus placebo in cirrhotic patients after an upper gastrointestinal bleeding was performed. The primary outcome was a decrease in venous plasma ammonia at 24 hours. A total of 38 consecutive cirrhotic patients were enrolled within 24 hours of an upper gastrointestinal bleed. Patients were randomized (1:1) to receive OP (10 g/day) or glucosaline for 5 days. The primary outcome was not achieved. A progressive decrease in ammonia was observed in both groups, being slightly greater in the OP group, with significant differences only at 120 hours. The subanalysis according to Child-Pugh score showed a statistically significant ammonia decrease in Child-Pugh C-treated patients at 36 hours, as well as in the time-normalized area under the curve (TN-AUC) 0-120 hours in the OP group [40.16 μmol/l (37.7-42.6); median (interquartile range) (IQR)] versus placebo group [65.5 μmol/l (54-126); p = 0.036]. A decrease in plasma glutamine levels was observed in the treated group compared with the placebo group, and was associated with the appearance of phenylacetylglutamine in urine. Adverse-event frequency was similar in both groups. No differences in hepatic encephalopathy incidence were observed. OP failed to significantly decrease plasma ammonia at the given doses (10 g/day). Higher doses of OP might be required in Child-Pugh A and B patients. OP appeared well tolerated

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH