Hepatology Highlights.

Abstract

Potential conflict of interest: Nothing to report. DR CELLS ROUND UP NEW TUBES Ryan Watkins1 and Sumera I. Ilyas2 Liver injury increases ductular reaction (DR) and contributes to the wound‐healing process, but how DR cells affect the local microenvironment is not fully understood. The slit guidance ligand 2 (SLIT2)/roundabout guidance receptor 1 (ROBO1) axis promotes angiogenesis in select solid tumors, but whether this signaling pathway induces intrahepatic angiogenesis in acute or chronic liver injury is unknown. Using murine liver injury models and human liver specimens, Coll et al. elucidate that SLIT2 secreted by DR cells binds ROBO1 on new endothelial cells and promotes neoangiogenesis in chronic liver injury. Administering mice a diet enriched in 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidin or a choline‐deficient, ethionine‐supplemented (CDE) diet results in DR expansion. This was paralleled by increased neoangiogenesis, which is diminished in mice heterozygous for ROBO1/2. Similar findings were demonstrated in a cohort of patients with alcohol‐associated liver disease (ARLD). Interestingly, SLIT2 serum levels correlated with disease severity in patients with alcohol‐associated hepatitis. In a separate cohort of patients with NAFLD or HBV infected and without cirrhosis, liver DR markers correlated with SLIT2‐ROBO1 signaling, indicating that this response is not specific to ARLD. Altogether, these findings suggest that intrahepatic angiogenesis mediated by DR cell SLIT2 expression in response to chronic liver injury is an important and clinically relevant process in liver repair. (Hepatology 2022;75:353‐69). THE CHOLESTATIC CONUNDRUM Daniel D. Penrice2 and Sumera I. Ilyas2 Patients with intestinal failure related to short bowel syndrome or other causes are often on prolonged parenteral nutrition (PN) and thus are at risk of developing PN‐associated cholestasis (PNAC). PNAC is characterized by persistent hyperbilirubinemia during PN administration. Although the development of PNAC is multifactorial, phytosterols present in the PN solution have been implicated in the process and shown to suppress hepatocyte farnesoid X receptor (FXR) signaling. FXR is activated by bile acids and plays a major regulatory role in the liver. El Kasmi et al. used a murine model of PNAC using the combination of dextran sodium sulfate–induced intestinal injury and PN infusion. In this model, the FXR agonist, GW4064, activated FXR signaling with restoration of bile acid transporter expression and normalization of the serum bile acid profile. Moreover, FXR agonism reduced hepatic macrophage infiltration with a consequent reduction in hepatic inflammation and cholestasis. These findings suggest that FXR agonists added to PN are a potential therapeutic strategy to decrease the incidence of PNAC. (Hepatology 2022;75:252‐66). CHECK THE TIME: IS CCA READY FOR IMMUNOTHERAPY? Caitlin B. Conboy3 and Sumera I. Ilyas2 Cancer initiation and progression are facilitated by an immunosuppressive tumor immune microenvironment (TIME), characterized by suppressive immune cells and immune checkpoint molecules. Immune checkpoint inhibitors (ICI) have transformed the treatment of many cancers, yet their efficacy in cholangiocarcinoma (CCA) is limited to date. Carapeto et al. sought to identify which immune checkpoints are salient in CCA and how their expression correlates with leukocyte infiltration, underlying genetic drivers, and patient survival. The investigators focused on a subset of patients with resected, fluke‐negative, and predominantly HBV/HCV‐negative intrahepatic CCA (N = 96). Using immunohistochemistry profiling, they identified that both immune cell (CD4+/CD8+ T cells, macrophages) and checkpoint molecule expression (lymphocyte activating 3 [LAG3], OX40, programmed cell death 1 [PD‐1], and T‐cell immunoglobulin and mucin‐domain containing 3) were decreased in the tumor center compared to the invasive margin. Only a small subset of patients had a “hot” TIME. In contrast, a signature of low T‐cell infiltration and high PD‐1 or LAG3 expression was associated with poor overall survival. Correlation of immune checkpoints and genetic mutations identified an association of BRCA1‐associated protein 1 loss‐of‐function mutation with increased expression of the immune checkpoint, B7H4. Tumors with a “cold” TIME have been inherently resistant to ICI therapy. However, broad profiling of the CCA TIME may facilitate development of, and predict response to, novel immunotherapy approaches. (Hepatology 2022;75:297‐308). ALCOHOL AND OBESITY ADDITIVELY INCREASE CIRRHOSIS RISK Gustavo Ayares4 and Juan Pablo Arab4 The relationship between alcohol and obesity on the risk of cirrhosis morbidity remains unclear given that some studies have demonstrated a reduction and others have demonstrated an additive or supra‐additive effect. To assess this interaction in a large population‐based study, Innes et al. used data from the UKB (United Kingdom Biobank) study and examined the relationship between body mass index (BMI) and alcohol intake on cirrhosis morbidity, which was defined by first‐time hospital admission for cirrhosis. Incidence of cirrhosis morbidity increased with alcohol intake and BMI independently. Excess cumulative incidence was highest for obese harmful drinkers (1.83%; 95% CI, 1.46–2.20), compared to harmful drinking alone (1.22%; 95% CI, 0.89–1.55), and obesity alone (0.4%; 95% CI, 0.34–0.46). These findings are consistent with previous studies that have demonstrated an additive effect of alcohol and BMI on the risk of liver disease. (Hepatology 2022;75:369‐78).