Citations

AbstractBackground & AimsPhosphodiesterase‐5 inhibitors (PDE‐5‐I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side‐effects have been reported. Non‐selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE‐5‐I with NSBB and its impact on PH and ED in experimental cirrhosis.MethodsED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile‐duct‐ligation or carbon‐tetrachloride intoxication in rats. Corpus cavernosum pressure – a surrogate of ED ‐, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE‐5 signalling were analysed using PCR and western Blot.ResultsED in humans was related to severity of liver disease and to NSBB treatment. PDE‐5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side‐effects.ConclusionsED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE‐5‐I and NSBB improves ED and PH in experimental cirrhosis.

Background and Aims Reliance on exception points to prioritize children for liver transplantation (LT) stems from concerns that the Pediatric End‐Stage Liver Disease (PELD) score underestimates mortality. Renal dysfunction and serum sodium disturbances are negative prognosticators in adult LT candidates and various pediatric populations, but are not accounted for in PELD. We retrospectively evaluated the effect of these parameters in predicting 90‐day wait‐list death/deterioration among pediatric patients (<12 years) listed for isolated LT in the United States between February 2002 and June 2018. Approach and Results Among 4,765 patients, 2,303 (49.3%) were transplanted, and 231 (4.8%) died or deteriorated beyond transplantability within 90 days of listing. Estimated glomerular filtration rate (eGFR) (hazard ratio [HR] 1.09 per 5‐unit decrease, 95% confidence interval [CI] 1.06‐1.10) and dialysis (HR 7.24, 95% CI 3.57‐14.66) were univariate predictors of 90‐day death/deterioration (P < 0.001). The long‐term benefit of LT persisted in patients with renal dysfunction, with LT as a time‐dependent covariate conferring a 2.4‐fold and 17‐fold improvement in late survival among those with mild and moderate‐to‐severe dysfunction, respectively. Adjusting for PELD, sodium was a significant nonlinear predictor of outcome, with 90‐day death/deterioration risk increased at both extremes of sodium (HR 1.20 per 1‐unit decrease below 137 mmol/L, 95% CI 1.16‐1.23; HR per 1‐unit increase above 137 mmol/L 1.13, 95% CI 1.10‐1.17, P < 0.001). A multivariable model incorporating PELD, eGFR, dialysis, and sodium demonstrated improved performance and superior calibration in predicting wait‐list outcomes relative to the PELD score. Conclusions Listing eGFR, dialysis, and serum sodium are potent, independent predictors of 90‐day death/deterioration in pediatric LT candidates, capturing risk not accounted for by PELD. Incorporation of these variables into organ allocation systems may highlight patient subsets with previously underappreciated risk, augment ability of PELD to prioritize patients for transplantation, and ultimately mitigate reliance on nonstandard exceptions.

OBJECTIVES: Hepatic encephalopathy (HE) is common in advanced cirrhosis and is characterized by marked neuropsychiatric abnormalities. However, despite its severity and effects on brain function, the impact of HE on psychological status of patients has not been adequately assessed. The aim of this study was to evaluate the effect of HE on psychological status of patients and their informal caregivers. METHODS: Fifteen patients with cirrhosis and episodic or persistent HE and their corresponding informal caregivers were included. Semistructured interviews were performed in patients and caregivers. Quality of life (QoL) was assessed by the short-form 36 in both patients and caregivers, and the Zarit burden score was measured in caregivers. The analysis of interviews was performed using qualitative methodology. RESULTS: HE causes a major psychological impact on patients with HE. The first episode of HE caused a very significant impact that was reported with deep feelings, mainly of fear, anger, misery, anxiety, and sorrow, which persisted with time. Symptoms causing more psychological impact on patients were impaired ability to walk and speak. All effects were associated with a marked impairment in QoL. The psychological impact was also marked in caregivers who had a major burden, as assessed by the Zarit score. Moreover, QoL, particularly the mental component score, was markedly impaired in caregivers in intensity similar to that of patients. DISCUSSION: HE has a profound psychological impact on patients and their informal caregivers, associated with a marked negative influence on QoL. The psychological effects of HE on patients and caregivers should be evaluated and treated.

Background and Aims Alcoholic hepatitis (AH) is diagnosed by clinical criteria, although several objective scores facilitate risk stratification. Extracellular vesicles (EVs) have emerged as biomarkers for many diseases and are also implicated in the pathogenesis of AH. Therefore, we investigated whether plasma EV concentration and sphingolipid cargo could serve as diagnostic biomarkers for AH and inform prognosis to permit dynamic risk profiling of AH subjects. Approach and Results EVs were isolated and quantified from plasma samples from healthy controls, heavy drinkers, and subjects with end‐stage liver disease (ESLD) attributed to cholestatic liver diseases and nonalcoholic steatohepatitis, decompensated alcohol‐associated cirrhosis (AC), and AH. Sphingolipids were quantified by tandem mass spectroscopy. The median plasma EV concentration was significantly higher in AH subjects (5.38 × 1011/mL) compared to healthy controls (4.38 × 1010/mL; P < 0.0001), heavy drinkers (1.28 × 1011/mL; P < 0.0001), ESLD (5.35 × 1010/mL; P < 0.0001), and decompensated AC (9.2 × 1010/mL; P < 0.0001) disease controls. Among AH subjects, EV concentration correlated with Model for End‐Stage Liver Disease score. When EV counts were dichotomized at the median, survival probability for AH subjects at 90 days was 63.0% in the high‐EV group and 90.0% in the low‐EV group (log‐rank P value = 0.015). Interestingly, EV sphingolipid cargo was significantly enriched in AH when compared to healthy controls, heavy drinkers, ESLD, and decompensated AC (P = 0.0001). Multiple sphingolipids demonstrated good diagnostic and prognostic performance as biomarkers for AH. Conclusions Circulating EV concentration and sphingolipid cargo signature can be used in the diagnosis and differentiation of AH from heavy drinkers, decompensated AC, and other etiologies of ESLD and predict 90‐day survival permitting dynamic risk profiling.

Background and Aims Compared to other chronic diseases, patients with chronic liver disease (CLD) have significantly higher inpatient mortality; accurate models to predict inpatient mortality are lacking. Serum lactate (LA) may be elevated in patients with CLD due to both tissue hypoperfusion as well as decreased LA clearance. We hypothesized that a parsimonious model consisting of Model for End‐Stage Liver Disease (MELD) and LA at admission may predict inpatient mortality in patients with CLD. Approach and Results We examined all patients with CLD in two large and diverse health care systems in Texas (North Texas [NTX] and Central Texas [CTX]) between 2010 and 2015. We developed (n = 3,588) and validated (n = 1,804) a model containing MELD and LA measured at the time of hospitalization. We further validated the model in a second cohort of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 726). MELD‐LA was an excellent predictor of inpatient mortality in development (concordance statistic [C‐statistic] = 0.81, 95% confidence interval [CI] 0.79‐0.82) and both validation cohorts (CTX cohort, C‐statistic = 0.85, 95% CI 0.78‐0.87; multicenter cohort C‐statistic = 0.82, 95% CI 0.74‐0.88). MELD‐LA performed especially well in patients with specific cirrhosis diagnoses (C‐statistic = 0.84, 95% CI 0.81‐0.86) or sepsis (C‐statistic = 0.80, 95% CI 0.78‐0.82). For MELD score 25, inpatient mortality rates were 11.2% (LA = 1 mmol/L), 19.4% (LA = 3 mmol/L), 34.3% (LA = 5 mmol/L), and >50% (LA > 8 mmol/L). A linear increase (P < 0.01) was seen in MELD‐LA and increasing number of organ failures. Overall, use of MELD‐LA improved the risk prediction in 23.5% of patients compared to MELD alone. Conclusions MELD‐LA (bswh.md/meldla) is an early and objective predictor of inpatient mortality and may serve as a model for risk assessment and guide therapeutic options.

Background and Aims Hepatologists often determine whether transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) is preferred for patients with cirrhosis and severe aortic stenosis. The goal of this cohort study is to compare outcomes following TAVR and SAVR in patients with cirrhosis to inform the preferred intervention. Approach and Results Prospectively collected data on 105 consecutive patients with cirrhosis and aortic stenosis who underwent TAVR (n = 55) or SAVR (n = 50) between 2008 and 2016 were reviewed retrospectively. Two control groups were included: 2,680 patients without cirrhosis undergoing TAVR and SAVR and 17 patients with cirrhosis who received medical therapy alone. Among the 105 patients with cirrhosis, the median Society of Thoracic Surgeons score was 3.8% (1.5, 6.9), and the median Model for End‐Stage Liver Disease (MELD) score was 11.6 (9.4, 14.0). The TAVR group had similar in‐hospital (1.8% vs. 2.0%) and 30‐day mortality (3.6% vs. 4.2%) as the SAVR group. During the median follow‐up of 3.8 years (95% confidence interval, 3.0‐6.9), there were 63 (60%) deaths. MELD score (adjusted hazard ratio, 1.13; 95% confidence interval, 1.05‐1.21; P = 0.002) was an independent predictor of long‐term survival. In the subgroup of patients with MELD score <12, the TAVR group had reduced survival compared with the SAVR group (median survival of 2.8 vs. 4.4 years; P = 0.047). However, in those with MELD score ≥12, survival after TAVR, SAVR, and medical therapy was similar (1.3 vs. 2.1 vs. 1.6 years, respectively; P = 0.53). Conclusion In select patients with cirrhosis, both TAVR and SAVR have acceptable and comparable short‐term outcomes. MELD score, but not Society of Thoracic Surgeons score, independently predicts long‐term survival after TAVR and SAVR. For patients with MELD score <12, SAVR is a preferred procedure; however, neither procedure appears superior to medical therapy in patients with MELD score ≥12.