Arab, Juan P

SummaryBackgroundAlcohol use and alcohol‐associated liver disease (ALD) burden are increasing in young individuals.AimTo assess host factors associated with this burden.MethodsNational Health and Nutrition Examination Survey (NHANES), National Inpatient Sample (NIS), and United Network for Organ Sharing (UNOS) databases (2006‐2016) were used to identify individuals with harmful alcohol use, ALD‐related admissions, and ALD‐related LT listings respectively.ResultsOf 15 981 subjects in NHANES database, weighted prevalence of harmful alcohol use was 17.7%, 29.3% in <35 years (G1) versus 16.9% in 35‐64 years (G2) versus 5.1% in ≥65 years (G3). Alcohol use was about 11 and 4.7 folds higher in G1 and G2 versus G3, respectively. Male gender and Hispanic race associated with harmful alcohol use. Of 593 600 ALD admissions (5%, 77%, and 18% in G1‐G3 respectively), acute on chronic liver failure (ACLF) occurred in 7.2%, (7.2 in G2 vs 6.7% in G1 and G3, P < 0.001). After controlling for other variables, ACLF development among ALD hospitalizations was higher by 14% and 10% in G1 and G2 versus G3, respectively. Female gender and Hispanic race were associated with increased ACLF risk by 8% and 17% respectively. Of 20,245 ALD LT listings (3.4%, 84.4%, and 12.2% in G1‐G3 respectively), ACLF occurred in 28% candidates. Risk of severe (grade 2 or 3) ACLF was higher by about 1.7 fold in G1, 1.5 fold in females and 20% in Hispanics.ConclusionYoung age, female gender, and Hispanic race are independently associated with ALD‐related burden and ACLF in the United States. If these findings are validated in prospective studies, strategies will be needed to reduce alcohol use in high risk individuals to reduce burden from ALD.

Assessment of bone density is an important part of liver transplantation (LT) evaluation for early identification and treatment of osteoporosis. Dual‐energy X‐ray absorptiometry (DXA) is currently the standard clinical test for osteoporosis; however, it may contribute to the appointment burden on LT candidates during the cumbersome evaluation process, and there are limitations affecting its accuracy. In this study, we evaluate the utility of biomechanical analysis of vertebral images obtained during dual‐energy abdominal triple‐phase computed tomography (TPCT) in diagnosing osteoporosis among LT candidates. We retrospectively reviewed cases evaluated for LT between January 2017 and March 2018. All patients who underwent TPCT within 3 months of DXA were included. The biomechanical computed tomography (BCT) analysis was performed at a centralized laboratory (O.N. Diagnostics, Berkeley, CA) by 2 trained analysts blinded to the DXA data. DXA‐based osteoporosis was defined as a T score ≤−2.5 at the hip or spine. BCT‐based osteoporosis was defined as vertebral strength ≤4500 N for women or ≤6500 N for men or trabecular volumetric bone mineral density ≤80 mg/cm3. Comparative data were available for 91 patients who had complete data for both DXA and BCT: 31 women and 60 men, age 54 ± 11 years (mean ± standard deviation), mean body mass index 28 ± 6 kg/m2. Using DXA as the clinical reference, sensitivity of BCT to detect DXA‐defined osteoporosis was 83.3% (20/24 patients) and negative predictive value was 91.7%; specificity and positive predictive value were 65.7% and 46.5%, respectively. BCT analysis of vertebral images on triple‐phase computed tomography, routinely obtained during transplant evaluation, can reliably rule out osteoporosis in LT candidates. Patients with suspicion of osteoporosis on TPCT may need further evaluation by DXA.

AbstractVasoactive drugs form the mainstay of therapy for two of the most important complications of liver disease: hepatorenal syndrome (HRS) and acute variceal bleed (AVB). With cumulative evidence supporting the use in cirrhosis, terlipressin has been recommended for the management of HRS and AVB. However, owing to the safety concerns, terlipressin was not approved by food and drug administration (FDA) until now. In this review, we discuss the pharmacology and the major practice‐changing studies on the safety and efficacy of terlipressin in patients with cirrhosis particularly focusing on existing indications like AVB and HRS and reviewing new data on the expanding indications in liver disease. The references for this review were identified from PUBMED with MeSH terms such as “terlipressin,” “hepatorenal syndrome,” “varices, esophagal and gastric,” “ascites” and “cirrhosis.” Terlipressin, a synthetic analogue of vasopressin, was introduced in 1975 to overcome the adverse effects of vasopressin. Terlipressin is an effective drug for HRS reversal in patients with liver cirrhosis and acute‐on‐chronic liver failure. There is documented mortality benefit with terlipressin therapy in HRS and AVB. Adverse effects are common with terlipressin and need to be monitored strictly. There is some evidence to support the use of this drug in refractory ascites, hepatic hydrothorax, paracentesis‐induced circulatory dysfunction and perioperatively during liver transplantation. However, terlipressin is not yet recommended for such indications. In conclusion, terlipressin has stood the test of time with expanding indications and clear prerequisites for clinical use. Our review warrants a fresh perspective on the efficacy and safety of terlipressin.

Alcohol‐associated liver disease (ALD) is a major driver of global liver related morbidity and mortality. There are 2.4 billion drinkers (950 million heavy drinkers) and the lifetime prevalence of any alcohol use disorder (AUD) is 5.1%‐8.6%. In 2017, global prevalence of alcohol‐associated compensated and decompensated cirrhosis was 23.6 million and 2.5 million, respectively. Combined, alcohol‐associated cirrhosis and liver cancer account for 1% of all deaths worldwide with this burden expected to increase. Solutions for this growing epidemic must be multi‐faceted and focused on both population and patient‐level interventions. Reductions in ALD‐related morbidity and mortality require solutions that focus on early identification and intervention, reducing alcohol consumption at the population level (taxation, reduced availability and restricted promotion), and solutions tailored to local socioeconomic realities (unrecorded alcohol consumption, focused youth education). Simple screening tools and algorithms can be applied at the population level to identify alcohol misuse, diagnose ALD using non‐invasive serum and imaging markers, and risk‐stratify higher‐risk ALD/AUD patients. Novel methods of healthcare delivery and platforms are needed (telehealth, outreach, use of non‐healthcare providers, partnerships between primary and specialty care/tertiary hospitals) to proactively mitigate the global burden of ALD. An integrated approach that combines medical and AUD treatment is needed at the individual level to have the highest impact. Future needs include (1) improving quality of ALD data and standardizing care, (2) supporting innovative healthcare delivery platforms that can treat both ALD and AUD, (3) stronger and concerted advocacy by professional hepatology organizations, and (4) advancing implementation of digital interventions.

Background and Aims Interleukin‐22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol‐associated hepatitis (AH). F‐652 is a recombinant fusion protein of human interleukin‐22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F‐652 in patients with moderate and severe AH. Approach and Results A phase‐2 dose‐escalating study was carried out. F‐652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End‐Stage Liver Disease [MELD] scores: 11‐20) and severe AH (MELD scores: 21‐28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity‐matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half‐life of F‐652 following the first dose was 61‐85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day‐7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down‐regulated, and regeneration markers were up‐regulated at days 28 and 42. Conclusions F‐652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo‐controlled trials to test the efficacy of F‐652 in AH.

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches based on a profound understanding of its pathogenesis to halt disease progression to advanced fibrosis or cirrhosis and cancer. The pathogenesis of NAFLD involves a complex interaction among environmental factors (i.e., Western diet), obesity, changes in microbiota, and predisposing genetic variants resulting in a disturbed lipid homeostasis and an excessive accumulation of triglycerides and other lipid species in hepatocytes. Insulin resistance is a central mechanism that leads to lipotoxicity, endoplasmic reticulum stress, disturbed autophagy, and, ultimately, hepatocyte injury and death that triggers hepatic inflammation, hepatic stellate cell activation, and progressive fibrogenesis, thus driving disease progression. In the present review, we summarize the currently available data on the pathogenesis of NAFLD, emphasizing the most recent advances. A better understanding of NAFLD/NASH pathogenesis is crucial for the design of new and efficient therapeutic interventions.