Research methodologies to address clinical unmet needs and challenges in alcohol-associated liver disease

Abstract

Alcohol-associated liver disease (ALD) is emerging worldwide as the leading cause of liver-related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital American Association for the Study of Liver Diseases meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused on (a) studying disease burden of ALD using large administrative databases, (b) developing biomarkers for noninvasive diagnosis of alcohol-associated hepatitis (AH) and estimation of disease prognosis, (c) identifying therapeutic targets for ALD and AH, (d) deriving accurate models to predict prognosis or posttransplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient-selection criteria for liver transplantation, and (e) examining qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long-term outcomes in patients with ALD.

FIGURE 1

Keratin 18 (K18 or M65) was measured in healthy controls (HC) and in patients with liver disease. Patients with NASH all had liver biopsies with a NAFLD Activity Score ≥ 4; patients with alcohol use disorder (AUD) were in alcohol treatment programs (all had normal serum bilirubin); patients with moderate alcohol-associated hepatitis (AH) were hospitalized with MELD ≤ 20; patients with severe AH were hospitalized with MELD > 20. Solid line (> 2000) represents lower limit for diagnosis of AH, and dotted line (500) represents the upper limit of normal value

FIGURE 2

Pathophysiology of alcohol-associated liver disease and AH. (A) Alcohol-mediated increased gut permeability with leaky gut results in translocation of pathogen-associated molecular patterns and bacterial lipopolysaccharides (LPS) through the portal vein. (B) Schematic representation of the hepatic lobule with hepatocytes and sinusoids lined with liver sinusoid endothelial cells (LSECs) containing macrophages and neutrophils, and space of Disse containing HSCs. (C) LPS binds to membrane and cytosolic receptors of hepatocyte immune cells, macrophages, HSCs, and sinusoidal endothelial cells. LPS and its binding protein complex activates toll-like receptor-4 on the surface of hepatic macrophages, leading to an inflammatory cascade and signaling of chemokines and cytokines. The inflammasome complex (pro-IL-1β and caspase-1) activates pro-caspase-1 to generate IL-1β. (D) The metabolism of alcohol to acetaldehyde causes direct hepatocyte injury with generation of reactive oxygen species, leading to mitochondrial dysfunction, oxidative stress, and hepatocyte apoptosis. Damage associated molecular patterns released from the injured hepatocytes, especially HMGB-1 (high mobility group box protein 1) and microRNA-122, perpetuate ongoing hepatocyte injury. (E) Extracellular vesicles released from injured hepatocytes along with chemokines and cytokines recruit neutrophils from the bone marrow to the hepatic circulation and sinusoids. The inflammatory cascade cross talks with sinusoidal cells, resulting in activation of LSECs and HSCs, leading to portal hypertension and laying down of collagen with development of fibrosis

FIGURE 3

Research strategies to address clinical unmet needs in the background of the current algorithm in the management of ALD. Boxes highlighted in gray-yellow depict the clinical unmet needs and research methodologies to address the corresponding unmet need. LT, liver transplantation