LAUSR

Alcoholic hepatitis (AH) is a severe form of alcohol-associated liver disease (ALD) with high short-term mortality attributed to hepatic decompensation, renal failure, bacterial infection, or portal hypertension [1, 2]. Although mechanisms of pathogenesis require further refinement, excessive alcohol consumption is believed to increase intestinal permeability, disrupt gut flora, and enable translocation of bacteria that induce liver injury and inflammation [3]. Yet, even in the absence of cirrhosis, individuals with AH may develop sequelae of advanced liver disease including portal hypertension. Endothelial dysfunction plays a predominant role in pathogenesis, with damaged endothelium expressing a provasoconstrictive, prothrombotic, proinflammatory, and proangiogenic phenotype that leads to downstream pathophysiology of portal hypertension. Given multiple mechanisms contributing to disease progression, pathogenic molecules of endothelial cell disruption and dysregulation have potential to serve as non-invasive biomarkers of disease severity and prognostication in AH. Various mechanisms have been identified in the multifactorial phenotypic alterations of endothelial cells. Specifically, endothelial cell dysfunction has been associated with increased intrahepatic vascular resistance due to altered nitric oxide synthase function resulting in reduced nitric oxide production by sinusoidal endothelial cells [4, 5]. In addition to this provasoconstrictive effect, sinusoidal thrombosis has been implicated through the formation of neutrophil extracellular traps (NETs) that may initiate or propagate coagulation [6]. Hilscher et al. further clarified this association by identifying the role of volume and pressure impact within sinusoids modulating NET-induced fibrin thrombi, thereby linking this prothrombotic effect to the pathogenesis of portal hypertension [7]. Certainly, sinusoidal endothelial cells mediate proinflammatory signaling in hepatic immune response [8] and participate in crosstalk with contractile hepatic stellate cells in the early steps of liver fibrogenesis [9, 10]. Concurrent to fibrosis, endothelial cells also participate in angiogenesis through multiple postulated mechanisms, including autocrine signaling stimulated by structural changes in sinusoids that further promote fibrogenesis and contribute to portal hypertension [10]. Much of the modeling for endothelial damage and consequent changes leading to portal hypertension have been established in the setting of chronic liver disease. However, we are increasingly recognizing similar pathogenesis in severe alcoholic hepatitis. In this issue of Hepatology International, Blaya et al. [11] take the necessary step to unify the pathogenic mechanisms of AH and development of portal hypertension by demonstrating correlation between increased markers of endothelial dysfunction and outcomes of AH. They also propose the use of pathogenic markers of endothelial cell function as promising biomarkers of disease. The authors first presented an analysis of multiple markers of endothelial dysfunction, including vascular cell adhesion protein (VCAM)-1, intercellular adhesion molecule (ICAM)-1, E-selectin, P-selectin, von Willebrand factor (vWF), von Willebrand factor domain A2 (vWF-A2), and ADAMST13. They profiled plasma levels of these biomarkers from a test and validation cohort of patients with histologically proven alcoholic hepatitis compared to patients with compensated alcoholic cirrhosis, heavy drinking but no liver disease, and healthy controls, and then evaluated biomarker association with disease severity and clinical outcomes. Notably, they identified that patients with severe AH and evidence of elevated portal pressures (mean HPVG 18.24 mmHg and 19.18 mmHg in the test and validation cohorts, respectively) demonstrated higher levels of endothelial cell markers compared to controls. Among the various biomarkers, VCAM-1 emerged as the marker with significant increase in AH patients with greater severity of disease (MELD ≥ 21). The authors also found significant correlation between increased plasma levels of VCAM-1 and overall clinical disease severity and outcomes. Plasma levels of VCAM-1 positively * Vijay Shah [email protected]