Arab, Juan Pablo

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 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.

The term, gut–liver axis, is used to highlight the close anatomical and functional relationship between the intestine and the liver. It has been increasingly recognized that the gut–liver axis plays an essential role in the development and progression of liver disease. In particular, in non‐alcoholic fatty liver disease and alcohol‐related liver disease, the two most common causes of chronic liver disease, a dysbiotic gut microbiota can influence intestinal permeability, allowing some pathogens or bacteria‐derived factors from the gut reaching the liver through the enterohepatic circulation contributing to liver injury, steatohepatitis, and fibrosis progression. Pathways involved are multiple, including changes in bile acid metabolism, intestinal ethanol production, generation of short‐chain fatty acids, and other by‐products. Bile acids act through dedicated bile acid receptors, farnesoid X receptor and TGR5, in both the ileum and the liver, influencing lipid metabolism, inflammation, and fibrogenesis. Currently, both non‐alcoholic fatty liver disease and alcohol‐related liver disease lack effective therapies, and therapeutic targeting of gut microbiota and bile acids enterohepatic circulation holds promise. In this review, we summarize current knowledge about the role of gut microbiota in the pathogenesis of non‐alcoholic fatty liver disease and alcohol‐related liver disease, as well as the relevance of microbiota or bile acid‐based approaches in the management of those liver diseases.

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.

The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.