Table 1.

Gaps in Knowledge and Research Priorities for AH

Area of study	What we know and do not know	Potential approaches to filling gaps
Histology	AH histology is very similar to NASH histology; some unique features of AH histology are reported. It is not known if specific histologic subsets are linked to specific molecular pathways and distinct clinical outcomes	Studies to determine if there are distinct histologic subsets of AH, eg, classic steatohepatitis versus steatohepatitis with cholestasis with or without fibrosis.
Clinical AH definition	AH is diagnosed based on clinical syndrome. The natural history of these clinical variants is not well- characterized.	Longitudinal cohort studies are needed to classify the clinical variants of AH and relate them to outcomes and specific molecular targets for therapy.
Grading AH severity	Many score systems have been generated to assess the severity of AH. Their ability to comprehensively model disease severity and outcomes in a validated manner is modest.	Prospective studies with adjudicated outcomes to develop models that will provide more accurate short-term, intermediate-term, and long-term risk stratification.
Biomarker	There are no biomarkers for diagnosis of early stages of ALD or AH.	There is an urgent need for biomarker development in the context of longitudinal studies and clinical trials to identify the risk, diagnosis, and therapeutic response for AH.
Genetics	Female gender and PNPLA3 mutations are genetic risk factors for AH. The role of other gene variants and combinations of SNPS remains unknown.	GWAS and deep sequencing in well-defined clinical cohorts where genetic variants and combinations of variants can be linked to the risk of AH, severity of AH, and response to treatments.
Intestinal factors	Gut bacterial overgrowth, dysbiosis, and increased gut permeability contribute to the pathogenesis of ALD/AH. The mechanisms by which this occurs is not fully understood.	Studies of the sterol and bile acid biome, both unbiased and hypothesis-driven mechanistic studies to define the role of the microbiome and the intestinal barrier in AH.
Innate immunity	Activation of LPS–TLR-4–TNF-α, activation of Kupffer cells and neutrophils contribute to the pathogenesis of ALD/AH. The role of specific macrophage phenotypes and modulation of injury versus repair by the innate immune system are not fully understood.	Hypothesis-driven mechanistic studies to define the role of individual cell types and the potential roles of neutrophils in causing injury and also promoting repair.
Adaptive immunity	Evidence suggests adaptive immunity is activated in AH. Its role in AH is incompletely understood.	Specific hypothesis-driven mechanistic studies to clarify the role of adaptive immunity in AH.
Impairment of liver regeneration	Hepatocyte proliferation is suppressed while ductular reaction/liver progenitor cell proliferation is markedly increased in AH. The metabolic, cellular, and molecular basis for this is partly understood.	Factors driving the repair response and potential impairment of the repair response such as stem cell activation, proliferation, differentiation factors, and bone marrow need clarification in focused mechanistic studies.
Therapeutic targets	Many potential therapeutic targets against inflammation have been identified. Some of hepatoprotective targets are also discovered. It is not known if “one size fits all” in terms of therapeutic targets.	Pathophysiologic studies are needed to clarify the molecular homogeneity versus heterogeneity of AH and to determine if there are common targets or variable activation of injury pathways.
Clinical trials	Several trials are now in early phases. However, beyond steroids the evidence base to support other drugs for AH is scant.	Multitude of proof-of-concept studies to validate various therapeutic targets followed by larger efficacy and safety trials, validation of endpoints in prospective cohort studies, and identification of more homogeneous patient populations. Studies are particularly required in those with a Maddrey index of 20–31 who are currently not considered for drug treatment but still have an unacceptably high mortality.
Long-term outcomes	Continued alcohol consumption has been linked to recurrent hospitalization and mortality. However, the social behavioral economic factors driving this have not been clarified and leveraged to improve long-term outcomes.	Development of comprehensive models of care that include behavioral approaches, social and financial support have to be combined with pharmacologic therapies to improve outcomes of AH.

AH, alcoholic hepatitis; ALD, alcoholic liver disease; GWAS, genome-wide association studies; LPS, lipopolysaccharide; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain-containing protein 3; SNPS, single nucleotide polymorphisms; TLR, Toll-like receptor; TNF, tumor necrosis factor.