Sage Journals: Discover world-class research

Abstract

Alcohol-associated liver disease (ALD) is a complex disease with rapidly increasing prevalence. Although there are promising therapeutic targets on the horizon, none of the newer targets is currently close to an Food and Drug Administration approval. Strategies are needed to overcome challenges in study designs and conducting clinical trials and provide impetus to the field of drug development in the landscape of ALD and alcoholic hepatitis. Management of ALD is complex and should include therapies to achieve and maintain alcohol abstinence, preferably delivered by a multidisciplinary team. Although associated with clear mortality benefit in select patients, the use of early liver transplantation still requires refinement to create uniformity in selection protocols across transplant centers. There is also a need for reliable noninvasive biomarkers for prognostication. Last but not the least, strategies are urgently needed to implement integrated multidisciplinary care models for treating the dual pathology of alcohol use disorder and of liver disease for improving the long-term outcomes of patients with ALD.

Keywords

AH ALD cirrhosis transplantation

The burden of alcohol-related liver disease (ALD) has been increasing in recent years.^1–5 The coronavirus pandemic has further exacerbated the problem by creating an upsurge in excessive alcohol consumption and consequently, morbidity and mortality attributable to ALD.⁶ For example, during the pandemic, there was over twofold increase in ALD-related hospitalizations and alcoholic hepatitis (AH)-related liver transplant (LT) waitlist additions.^1,2 At present, ALD is the most common indication for LT in the United States.^2,5

The current management strategies include treatment of alcohol use disorder (AUD), the use of corticosteroids for severe AH, management of cirrhosis and its complications, and LT in severe ALD.^7,8 Corticosteroid, currently the only and a first-line pharmacological therapy for severe AH remains a suboptimal treatment. Response rates as determined by a Day 7-Lille score of ⩽0.45 (Figure 1) are 50–60%. In non-responders, early LT (eLT) is a viable alternative. However, it can be applied in only about 3–4% of all the severe AH patients.⁸

Figure 1.

Algorithm in the management of AH.

Despite the proven benefit of treatment of AUD in ALD patients, it is rarely used in clinical practice.^9,10 Multidisciplinary integrated care models have been shown to be effective; yet, implementation in clinical practice remains challenging.^10–12 Furthermore, ineligibility for corticosteroids in 40–50% of severe AH patients, response rate of 50–60% among those who are eligible, and survival benefit lasting only for a short-term period of 1 month limit their widespread and homogeneous use.^13–22 Moreover, LT although beneficial in ALD can only be applied to 3–4% of highly select severe AH patients with an excellent psychosocial support.^23,24 As criteria for patient selection for LT in AH remain subjective, there remains significant heterogeneity in the use of this modality of treatment across providers and centers.²⁵ In the light of these limitations, the quest for novel, diverse therapeutic agents remain a worthy and much needed endeavor. In this review, we will discuss the emerging therapeutic targets in ALD, current challenges, and future directions. Since experimental targets are guided by current understanding of pathophysiologic mechanisms, we will begin with a review of pertinent pathophysiology to create a framework for understanding the therapeutic targets.

Pathophysiology of ALD

The spectrum of liver injury in ALD from ranges from steatosis, steatohepatitis (inflammation and hepatocyte death), fibrosis, and ultimately cirrhosis and its complications.^26–28 The pathogenesis includes direct ethanol induced liver injury via its metabolism, and indirect injury via changes in gut permeability leading to endotoxemia, immune-mediated inflammation, and impaired liver regeneration.^27,29,30 Ethanol is metabolized by alcohol dehydrogenase into acetaldehyde, which is further metabolized by acetaldehyde dehydrogenase into acetate. Once acetaldehyde dehydrogenase is saturated, ethanol is channeled to other metabolic pathways including the cytochrome P450 2E1 (CYP 2E1) system.³¹ The metabolism of ethanol via this system results in production of reactive oxygen species with many downstream effects such as activation of lipid peroxidase reactions, inhibition of membrane antioxidant enzyme activity, bio-membrane dysfunction, mitochondrial damage, and cell death.^27,32 The ensuing inflammation and cell damage causes release of damage-associated molecular patterns that attract inflammatory cells and induce sterile inflammation.²⁷ The process involves the formation of inflammasomes and the release of proinflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin 1 (IL1).^33,34

Alcohol also exerts a direct effect on the gastrointestinal tract. It disrupts the tight junctions of the intestinal epithelial barrier, inducing an increase in gut permeability.^35,36 This increased permeability increases bacterial translocation and delivery of pathogen-associated molecular patterns including endotoxin into the portal circulation.^30,35,37 These gut-derived endotoxins act through toll-like receptor 4 (TLR-4) to activate innate immune cells, release chemokines and cytokines such as IL-1, IL-6, and monocyte chemoattractant protein MCP1, and upregulate proinflammatory and profibrotic pathways.^33,34,36,38

Alcohol also induces changes in the gut microbial flora in both small and large intestines.^39,40 One study found reduced numbers of bifidobacteria, lactobacillus, and enterococcus species in the stool cultures of individuals who habitually consumed alcohol.³⁹ In addition, jejunal aspirates of individuals who consume alcohol excessively have been shown to have more abundant coliforms compared to controls.⁴⁰ Reduced fungal biodiversity has also been described in severe AH.⁴¹

Alcohol induces metabolic and cellular changes which contribute to liver inflammation.^42,43 It upregulates several proteins including carbohydrate-responsive element binding protein, steroid response binding protein-1c, and glucose-responsive transcription factor, that mediate hepatic steatosis.^44–47 It is also thought to induce insulin resistance in adipose tissues, resulting in an increase in circulating non-esterified fatty acids.^48,49 Alcohol also affects other regulators of steatosis including the liver X receptor (LXR), farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) α.⁴⁹ The resultant accumulation of free fatty acids in the liver induces hepatic inflammation by activating TLR-4-mediated inflammatory pathways, activating inflammasome and stimulating chemokine production.^43,50–52

Alcohol-induced changes in iron metabolism have also been implicated in ALD. Alcohol is believed to upregulate iron absorption by downregulating expression of hepcidin^53,54 The resultant iron overload contributes to ethanol induced oxidative stress by activating Kupffer and hepatic stellate cells, and triggering ferroptosis, a programmed iron-dependent cell death.⁵³

AH is characterized by hepatocyte injury, inflammation, ballooning degeneration, disruption of the cytoskeleton, and formation of Mallory–Denk bodies.⁵⁵ In addition to hepatocyte damage, there is direct impairment of liver regeneration, especially in patients with severe refractory AH. A study of explanted livers from patients undergoing salvage transplants for AH revealed a lack of proliferative hepatocytes and a diminished expression of cytokines involved in liver regeneration.²⁹ The same study also demonstrated an accumulation in the livers of affected patients, of a substantial amount of hepatic progenitor cells which are inefficient at yielding mature hepatocytes.²⁹

Emerging therapeutic targets

The above pathophysiologic mechanisms have been the targets of investigational therapies for the treatment of ALD in recent years. While some have yielded no benefit, others have shown varying degrees of promise and are currently the subject of further investigation.⁵⁶ Experimental agents have aimed at inhibiting inflammatory pathways including blockade of gut liver axis activation, reducing oxidative stress, inhibiting apoptosis, and promoting liver regeneration. More recently, interest has arisen in targeting metabolic pathways with the aim of inhibiting steatosis – an important shared underlying mechanism of injury in alcohol and non-alcohol-mediated liver disease. Published clinical trials of agents targeting the aforementioned pathophysiologic mechanisms and ongoing clinical trials for ALD treatment are summarized in Table 1.

Table 1.

Currently ongoing clinical trials in ALD.

Trial title (brief)	Trial design	Intervention	Study population	Primary outcome (s) of interest	Target pathway	NCT number
Phase 1
Safety evaluation of FMT in severe AH	Double-blinded randomized placebo-controlled trial	FMT	Patients with SAH	-Survival in treatment group	Gut–liver axis modification	NCT05006430
Safety evaluation of FMT in severe AH	Double-blinded randomized placebo-controlled trial	FMT	MELD score > 15 and/or MDF ⩾ 32	-Change in gut microbiome population associated with severe AH patients at 4, 6, 9, and 12 weeks	Gut–liver axis modification	NCT05006430
Safety and efficacy of IMM 124-E for patients with severe AH	Multicenter randomized placebo-controlled	IMM 124-E (Hyperimmune Bovine Colostrum)	MELD ⩾ 20 but ⩽28 with <7 days of steroid treatment, or treatment naive	Safety	Gut–liver axis modification	NCT01968382
Phase 2
DUR-928 in patients with AH	Open-label dose-escalation trial	DUR-298	Part A: patients with MELD 11–20	-Safety and tolerability	Liver regeneration boosting	NCT03917407
			Part B: patients with a MELD score of 21–30	-Pharmacodynamic of DUR-298: liver biochemistry
				Quality of life
				Biomarkers of inflammation (IL-6, IL-8 and CRP)
				Biomarkers of liver cell death (cytokeratin 18), measured at baseline, Day 7, and Day 28
A phase IIb study in subjects with AH to evaluate safety and efficacy of DUR-928 treatment	Randomized, double-blind, placebo-controlled	DUR-298	Patients with MELD 21–30 and MDF ⩾ 32	90-day mortality or LT comparing 30 mg or 90 mg of DUR-928, and placebo	L\Boosting liver regeneration	NCT03917407
TAK-242 in patients with acute AH	Randomized, double-blind, placebo-controlled, multicenter	TAK-242	Acute decompensating event with a clinical and/or liver biopsy diagnosis of AH	Change in CLIF-C	Inflammatory pathway inhibition (TLR 4 signaling inhibitor)	NCT04620148
TAK-242 in patients with acute AH	Randomized, double-blind, placebo-controlled, multicenter	TAK-242		ACLF score (chronic liver failure consortium organ failure acute on chronic liver failure score) from baseline to Day 8	Inflammatory pathway inhibition (TLR 4 signaling inhibitor)	NCT04620148
Phase III
Fecal microbial transplantation in severe AH	Open-label, single-arm trial	FMT	Severe AH	Mortality at 28 days, 90 days, and 1 year	Gut–liver axis modification	NCT04758806
Comparison of bovine colostrum versus placebo in treatment of severe AH: A randomized double-blind controlled trial	Randomized controlled, parallel, double-blind trial	Bovine colostrum	Severe AH MDF > 32	Survival at 3 months	Gut–liver axis modification	NCT02473341
	Randomized controlled, parallel, double-blind trial	Bovine colostrum	MELD ⩾ 21	Survival at 3 months	Gut–liver axis modification	NCT02473341
NAC to reduce infection and mortality for AH	Randomized controlled, open-label trial	NAC	Severe AH	Improvement in monocyte oxidative burst at 24 h and at 5 days	Oxidative stress inhibition	NCT03069300
NAC to reduce infection and mortality for AH	Randomized controlled, open-label trial	NAC	MDF > 32		Oxidative stress inhibition	NCT03069300
Phase IV
Efficacy and safety of S-adenosyl-l-methionine in treatment of AH with cholestasis	Randomized, parallel, open-label trial	Ademethionine	AH	Response rate of serum total bilirubin at 6 weeks	Oxidative stress inhibition	NCT02024295
			Serum total bilirubin from 2 to 10× ULN
			ALP > 1.5× ULN or GGT > 3× ULN
G-CSF in AH	Randomized control parallel, open-label trial	G-CSF	Severe AH DF of ⩾ 32	Survival at 3 months	Boosting liver regeneration	NCT03703674
Unspecified phase
Utility of the use of NAC associated with conventional treatment in patients with severe AH (Maddrey > 32)	Randomized controlled, multicenter parallel and open trial	NAC	Severe AH	All-cause mortality at 6 months	Oxidative stress inhibition	NCT05294744
Efficacy of monotherapy versus combination therapy of corticosteroids with G-CSF in severe AH patients	Randomized controlled open-label trial	G-CSF	Severe AH, DF of ⩾32	Improvement in CTP (Child-Pugh Score) and MELD in at 28 days and 180 days	Boosting liver regeneration	NCT04066179
Fecal microbiota therapy in steroid ineligible AH	Randomized controlled, parallel open-label trial	Fecal microbiota therapy	Steroid ineligible severe AH (MELD) ⩾ 20 and MDF ⩾ 32)	Mortality at 3 months	Gut–liver axis modification	NCT05285592
Fecal microbiota therapy in steroid ineligible AH	Randomized controlled, parallel open-label trial	Fecal microbiota therapy	Steroid ineligible severe AH (MELD) ⩾ 20 and MDF ⩾ 32)	LT-free survival	Gut–liver axis modification	NCT05285592
Integrating care for patients with alcohol liver disease and AUDs	Single-arm, open-label trial	ICP	Patients with clinical or biopsy-proven alcohol-associated cirrhosis or acute AH	Acceptability of and retention to the ICP	Integrated AUD treatment	NCT05375682
Alcohol treatment outcomes following early versus standard LT for SAH	Randomized controlled single-blinded trial	Integrated AUD treatment	Patients who have undergone LT for AH	Treatment engagement	Integrated AUD treatment	NCT03845205
				Alcohol relapse
				Post-LT survival
Corticosteroids in AH	Randomized controlled double-blinded trial	Corticosteroids	Biopsy proven Severe AH (MDF ⩾ 32) with spontaneous liver function improvement within day admission and days 5–10 of admission	Mortality at 90 days	Inflammatory pathway inhibition	NCT03160651
ALD and gut microbiome	Randomized controlled double-blinded trial	VSL #3 112.5 Capsule (probiotic)	Adults with diagnosis of AUD and ALD	Sex differences within ALD (from baseline to 6 months)	Gut–liver axis modification	NCT05007470
ALD and gut microbiome	Randomized controlled double-blinded trial	VSL #3 112.5 Capsule (probiotic)	Adults with diagnosis of AUD and ALD	Sex differences in the rate abstinence and the proportion of resolution of ALD as measured by the MDF, MELD-Na score, GAHS, and transaminases	Gut–liver axis modification	NCT05007470
CytoSorb® in patients with acute on chronic liver failure	Prospective case–control	Device: CytoSorb® treatment	Patients with ACLF due to severe AH in combination with systemic inflammation and ACLF grade ⩾2	-Safety and tolerability	Inflammatory pathway inhibition	NCT05131230
CytoSorb® in patients with acute on chronic liver failure	Prospective case–control	Device: CytoSorb® treatment		-Effectiveness by comparing the proportion of patients in each group with ACLF grade < 2 at the end of Day 7	Inflammatory pathway inhibition	NCT05131230
Effect of omega 5 fatty acid as an adjuvant treatment to prednisone in patients with severe AH	Randomized controlled double blinded trial	Dietary supplement: omega 5 fatty acid supplement	Patients with severe AH treated with prednisone	30-day survival	Influencing metabolic pathways – PPAR γ agonist	NCT03732586

ACLF, acute on chronic liver failure; AH, alcoholic hepatitis; ALD, alcohol-associated liver disease; ALP, alkaline phosphatase; AUD, alcohol use disorder; G-CSF, granulocyte colony-stimulating factor; GGT, gamma-glutamyl transferase; FMT, fecal microbiota transplant; ICP, Integrated care program; LT, liver transplant; MDF, Maddrey discriminant function; MELD, model for end-stage liver disease; NAC, N-acetylcysteine; PPAR, peroxisome proliferator-activated receptor; SAH, severe acute alcoholic hepatitis; ULN, upper limit of normal.

Inhibition of inflammatory pathways

IL1 inhibition

Canakinumab

Canakinumab is a fully human monoclonal antibody which blocks inflammation by targeting IL-1β and subsequently, the IL-6 signaling pathway.^57,58 The anti-inflammatory effect of canakinumab has been employed in the treatment of rheumatologic conditions.⁵⁸ It has also been explored in diabetes and atherosclerotic cardiovascular disease^57,59 The IL-1 signal inhibition in alcoholic hepatitis trial, a multicenter randomized controlled trial (RCT) investigated the effect of canakinumab in 48 patients with biopsy confirmed AH who had discriminant function ⩾ 32 and model for end-stage liver disease (MELD) ⩽ 27 at baseline visit (Table 1).⁶⁰ Compared to the placebo group, the canakinumab-treated group demonstrated a higher rate of histological improvement (58.3 versus 41.7%). In an adjusted exploratory analysis, the canakinumab-treated group demonstrated improvement in alanine aminotransferase (p = 0.02), mononuclear cell infiltration (p = 0.06), and histology (p = 0.04). However, there was no significant improvement noted in MELD and Lille scores.⁶¹

Anakinra

Anakinra, an IL-1 receptor antagonist blocks IL-1α and IL-1β biologic activity. Findings from a multicenter trial, defeat alcoholic steatohepatitis trial comparing the efficacy of Anakinra in combination with zinc and pentoxifylline to that of prednisolone in the treatment of severe AH, suggested lower mortality at 180 days.⁶² Results are awaited from a recently completed multicenter, randomized, double-blinded, placebo-controlled trial investigated the effect of Anakinra combined with zinc versus prednisone in patients with severe AH (MELD 20–35).⁶³

Initial studies suggested that pentoxifylline might be beneficial in reducing acute kidney injury and hepatorenal syndrome (HRS) in severe AH.⁶⁴ A subsequent network meta-analyses of 22 RCTs concluded that pentoxifylline has no benefit in severe AH patients.⁶⁴ Although anti-TNFα agents (infliximab and etanercept) initially showed promise in smaller studies, successive studies revealed unacceptable infection and mortality rates.^65–68 Caspase inhibitors, selonsertib and emricasan, have also not shown any survival benefit. The study investigating emricasan in patients with severe AH and contraindications to steroid therapy was terminated due to concerns about toxicity and bioavailability of the drug.^69,70

Modulating gut–liver axis and inflammation

Fecal microbiota transplant

Fecal microbiota transplant (FMT) has been explored as a potential way to ameliorate gut dysbiosis in AH.⁷¹ FMT has previously been tremendously successful in the treatment of recurrent Clostridioides difficile infection but is now being explored in other gastrointestinal diseases.^72,73 An open-label trial comparing 90-day survival in corticosteroids, pentoxifylline, nutritional therapy, or FMT in male patients with AH revealed an improved mortality at 1 month and 3 months in the group treated with FMT compared to all the other groups. Improvement in infections, inflammation, and oxidative stress were also noted.⁷⁴ More recently, in a retrospective study comparing FMT to standard of care among patients with AH, the incidence of ascites, hepatic encephalopathy, critical infection, and need for hospitalization were found to be lower in the FMT group compared to the SOC group. There was also a trend toward improvement in mortality at 3 years.⁷⁵ Findings from further ongoing trials investigating this are awaited (Table 1). FMT can also be a double-edged sword, with its additional benefit on reducing alcohol use relapse. In a pilot randomized trial on 20 patients with alcohol-associated cirrhosis, FMT-treated patients compared to those receiving placebo showed a significant reduction in craving (90 versus 30%), lower urinary ethylglucoronide levels, (p = 0.03), and an improvement in psychosocial quality of life and cognition.⁷⁶

Probiotics

Studies exploring the role of various combinations of probiotics including Bacillus subtilis and Enterococcus faecium, Lactobacillus casei as well as Bifidobacterium and Lactobacillus have shown varying degrees of benefit. The areas of improvement have included reduction in endotoxemia, improvement in liver function,⁷⁷ improvement in neutrophilic phagocytic function, and a decrease in TLR expression.^39,78 One US-based trial that had been investigating the safety and efficacy of Lactobacillus rhamnosus GG compared to placebo on MELD score after 30 days was terminated due to lack of funding.⁷⁹ Another trial investigating the therapeutic effect of Lactobacillus rhamnosus R0011/acidophilus R0052 on primary outcome of liver enzymes at 7 days has been completed but results are yet to be published.⁸⁰

Bovine colostrum

Bovine colostrum, the first milk produced from cows after parturition is immunoglobulin rich and has been shown to decrease bacterial translocation and endotoxemia in rats.^81,82 The rationale for its use is that IgG and lactoferrin, both present in bovine colostrum can neutralize endotoxemia within the lumen and portal system. The IgG can also bind to the lymphoid tissue of leaky gut and reduce permeability.^83,84 A randomized double-blinded placebo-controlled trial aiming to compare bovine colostrum versus placebo in treatment of severe AH (BASH) is currently recruiting participants in India (Table 1). A second trial investigating the safety and efficacy of hyperimmune bovine colostrum enriched with IgG anti-LPS, IMM I24-E in patients with severe AH (MELD 20–28) on steroids is ongoing (Table 1).

Antimicrobial agents

Rifaximin, a minimally absorbed broad spectrum antibiotic agent, has been shown to decrease endotoxemia.⁸⁵ However, clinical trials with this agent did not yield any significant benefit in patients with AH.^86,87 Other microbial agents including amoxicillin plus clavulanic acid as well as a combination of meropenem, vancomycin, and gentamycin also failed to demonstrate any survival benefit in severe AH patients.^88,89

Phage therapy

Patients with AH have been shown to have higher fecal counts of cytolysin producing E. faecalis species, which have been correlated with increased severity and mortality in AH. In a recent study, targeting this cytolysin using a bacteriophage abolished ethanol-induced liver disease in humanized mice. These interesting findings are yet to be translated in humans.^90,91

Inhibition of oxidative stress

Antioxidants

N-acetylcysteine

N-acetylcysteine (NAC), an antioxidant, has shown some benefit in AH in combination with corticosteroids.⁹² An RCT involving 174 participants randomized to NAC plus prednisolone versus prednisolone alone showed improved mortality at 1 month with decreased rates on infection and HRS. However, there was no survival benefit at 3 months or 6 months.⁹² A subsequent systematic review and network meta-analysis of 22 RCTS found an improvement in survival with NAC combined with corticosteroids.⁶⁴ An RCT investigating the impact of prednisolone plus NAC versus prednisolone alone on several AH outcomes is currently recruiting participants (Table 1).

S-adenosyl methionine

S-adenosyl methionine (SAMe), a methyl donor, facilitates generation of glutathione from homocysteine. Abnormal methionine metabolism has been implicated in the pathophysiology of liver disease.^93,94 Findings on the benefit of SAMe in alcohol-associated cirrhosis have been conflicting.^95,96 Other RCTs are currently ongoing to investigate the role of SAMe in ALD patients (Table 1).

Metadoxine

Metadoxine, a combination of pyridoxine and pyrrolidone carboxylate, has been shown to protect against ethanol-induced glutathione depletion in animal models.⁹⁷ An open-label RCT including 70 patients randomized to treatment with metadoxine plus glucocorticoids versus glucocorticoids alone showed an improvement in mortality at 30 and 90 days, and a reduction in encephalopathy in the metadoxine-treated group compared with the glucocorticoid only group.⁹⁸ Another open-label RCT of 135 patients showed improved survival at 3 months and 6 months in patients treated with metadoxine plus prednisone compared with those treated with prednisone alone as well as among those treated with metadoxine plus pentoxifylline compared to pentoxifylline alone.⁹⁹ While these studies suggest a potential role for metadoxine in treatment of AH, double-blinded placebo-controlled trials are needed.

A placebo-controlled RCT testing the efficacy of Vitamin E in mild to moderate AH did not find any benefit on liver function.¹⁰⁰ Similarly, studies of antioxidant cocktails including various combinations of β-Carotene, Vitamin C (ascorbic acid), desferrioxamine, selenium, zinc, manganese, copper, magnesium, folic acid, and Coenzyme Q did not prove beneficial.^101–103

Boosting liver regeneration

Hepatic regenerating agents

Granulocyte colony stimulating factor

Granulocyte colony stimulating factor (G-CSF), a glycoprotein, that has shown effectiveness in mobilizing bone marrow stem cells and neutrophils with hepatoprotective effects of regeneration and repair has been associated with accelerated recovery and improved survival after liver injury.^104,105 Consequently, it has been tested as a potential treatment agent for AH based on its potential to stimulate liver regeneration.¹⁰⁶ An earlier pilot RCT evaluating the efficacy of G-CSF plus standard of care compared to standard of care alone found an improvement in survival with G-CSF at 3 months.¹⁰⁷ Subsequent studies have also demonstrated benefit, including among steroid non-responsive patients.^108,109 A meta-analysis of 7 RCTs including 336 patients with AH evaluating the effect of GCSF on risk of infection and risk of death after 90 days found a reduced risk of death in the Asian studies mainly due to reduced risk of infection, but not in two studies reported from Europe.¹¹⁰ Clearly, larger studies are needed in the West to substantiate the status of G-CSF in the management algorithm of AH patients.

Interleukin-22

IL-22 is a member of the IL-10 family that has pro-proliferative, antioxidant, antisteatotic, and antimicrobial properties.^111–113 Treatment with IL-22 has previously been shown in murine models to ameliorate alcohol-induced liver injury.¹¹⁴ An open-label phase II dose-escalating trial of F652, a recombinant fusion protein consisting of human IL-22 and human IgG2 fragment crystallizable with similar mechanism of action to native IL-22 found significant improvements in MELD score and serum aminotransferases at Days 28 and 42 from baseline. The drug was also associated with a decrease in levels of cytokines and extracellular vesicles.¹¹⁵ Findings from another study which sought to further shed light on the role of IL-22 using hepatic biopsies from patients with AH are yet to be published.^116,117

Sulfated oxysterol

Sulfated oxysterol (DUR-298) is an endogenous regulatory molecule that has been shown in murine models to exhibit anti-inflammatory and antifibrotic effects.¹¹⁸ Findings from a phase II open-label, dose-escalation study were promising. There were significant improvements in bilirubin, MELD, and Lille scores.¹¹⁹ Another open-label, dose-escalation study to assess the safety and pharmacodynamics signals of DUR-928 in patients with AH is currently recruiting participants (Table 1). Results will shed light on potential benefit or lack thereof of DUR-298 in treatment of AH.

Several other agents including insulin and glucagon, propylthiouracil, and anabolic steroids have shown no benefit while others are promising.^120–122

Potential future targets

Metabolic-associated fatty liver disease (MAFLD) and ALD, although distinct entities, share certain underlying mechanisms of hepatic steatosis and resultant hepatic injury.¹²³ As described in the pathophysiology section, alcohol induces metabolic and cellular changes. It upregulates proteins that mediate hepatic steatosis, increase de novo lipogenesis, and induces insulin resistance in adipose tissue.^48,49 Regulators of de novo lipogenesis including LXR, FXR, and PPAR have been considered potentially viable targets in the treatment of MAFLD and could prove to be beneficial targets in ALD as well.¹²⁴

FXR receptor agonists

FXR activation has beneficial effects in decreasing de novo lipogenesis. Obeticholic acid, a semisynthetic FXR agonist, regulates homeostasis and reduces accumulation of toxic bile acids and has shown promise in the treatment of MAFLD.^125,126 However, a phase II RCT evaluating its role in ALD was terminated due to hepatotoxicity concerns. Several other FXR ligands are in multiple stages of development and may prove beneficial but this remains to be seen.^126–129

LXR inverse agonists

LXR promotes hepatic steatosis by increasing de novo lipid synthesis, hepatic fatty acid uptake, and impairing lipid droplet triglyceride hydrolysis.^130–132 LXR inverse agonists may be useful in inhibiting alcohol-associated steatosis and are currently under investigation as potential targets in MAFLD.¹³³ It is yet unclear, if this agent will prove useful in managing ALD.

PPAR agonists

PPARs-α, -δ, and -γ play major roles in the liver, muscle, and adipose tissues, respectively. Targeting these receptors results in oxidative fatty acid metabolism and energy disposal.^134,135 PPAR-α and PPAR-δ agonists including bezafibrate and pioglitazone have shown varying degrees of promise in MAFLD trials.^136–138 More recently, Lanofibranor, a pan-PPAR receptor agonist, showed benefit in producing resolution of non-alcoholic steatohepatitis in a recently published phase IIb trial.¹³⁹ Although the benefit or lack thereof of these agents in ALD is yet to be demonstrated, the findings from MAFLD trials are promising.

Non-pharmacological treatment modalities

Nutritional support

Malnutrition is a common among patients with ALD, particularly those with acute severe AH, and has been associated with worse outcomes.¹⁴⁰ Although intensive enteral nutrition has no proven survival benefit, inadequate calorific intake <21.5 kcal/kg per day has been associated with a higher frequency of complications including infections.¹⁴¹ Therefore, adequate nutrition that includes adequate protein intake and correction of specific nutrient deficits should be provided.¹⁴²

Treatment of AUD

Current AH treatment targets, although useful in the short term, do not provide any long-term mortality benefit. Continued alcohol consumption remains a major determinant of long-term prognosis.^143,144 In one French multicenter study, severe relapse occurred in 20% of post-LT patients and of these, 35% developed recurrent alcohol-related cirrhosis.¹⁴⁵ Accordingly, patients with ALD should undergo screening for possible AUD using tools such as the AUDIT questionnaire.¹⁴⁶ Those with comorbid AUD should receive appropriate treatment with the goal of achieving long-term abstinence and preventing relapse.⁸ Both psychosocial and pharmacological interventions are beneficial.²¹ In a recently published retrospective cohort of 9635 patients with AUD who were followed for a mean period of 9.2 years, patients who received medical therapy for AUD were found to have 63% lower odds of being diagnosed with ALD and those with preexisting comorbid ALD were found to have a 65% lower odds of developing hepatic decompensation.¹⁴⁷

Pharmacological agents approved by the Food and Drug Administration (FDA) in the United States include acamprosate, disulfiram, and naltrexone. Non-FDA-approved agents including baclofen, gabapentin, topiramate, and varenicline have shown varying degrees of benefit (Table 2).^148–152 Newer targets are also being explored. A recently published double-blinded RCT including 93 patients evaluated the effectiveness of psilocybin-assisted psychotherapy versus psychotherapy with placebo (diphenhydramine) in the treatment of AUD. The authors found a 13.9% reduced heavy drinking days in the psilocybin-treated group. No serious adverse events were reported.¹⁵³

Table 2.

Pharmacotherapies for management of AUD.

Medication	Mechanism of action/efficacy	Dose	Contraindications
Naltrexone^151,154,155	Mu-opioid receptor antagonist which has shown benefit in reducing alcohol consumption and risk of relapse to heavy drinking	Initial: 25–50 mg daily orally Maintenance: titrate to 50–100 mg daily IM: 380 mg monthly	Avoid in patients on opioids for pain management And in patients with acute hepatitis, hepatic failure or Child-Pugh class C
Acamprosate^151,156,157	Glutamate neurotransmission modulator which has shown efficacy in reducing risk of any drinking and maintaining abstinence from alcohol	666 mg three times daily orally	Avoid in patients with CrCL ⩽30 ml/min
Acamprosate^151,156,157		Dose adjustment required in patients with CrCl of 30–50 ml/min	Avoid in patients with CrCL ⩽30 ml/min
Disulfiram^155,158,159	Aldehyde dehydrogenase inhibitor which has shown efficacy in maintaining abstinence from alcohol when taken under supervised conditions	Loading dose: 250–500 mg/day orally Maintenance dose: 250 mg daily (range: 125–500 mg/day) orally	Avoid use within 12 h of alcohol consumption. Not recommended for the purpose of reducing drinking
Nalmefene^155,160,161	Mu and deLTa opioid receptor antagonist and partial kappa opioid receptor agonist which has shown benefit in reducing total alcohol consumption in patients with AUD	18 mg orally daily as needed	Hypersensitivity to nalmefene or any of its components
Topiramate^162–164	Inhibitor of mesocorticolimbic dopamine release that has shown benefit in reducing cravings and alcohol drinking, increasing duration of abstinence and decreasing heavy drinking days	Loading dose: 25 mg once daily orally Maintenance: titrate dose by 25 mg per week for 4 weeks then by 50 mg per week to maximum of 300 mg per day in divided doses	Serious hypersensitivity to topiramate or any of its components
Baclofen^162,165,166	γ-amino butyric acid GABA_B agonist that has shown benefit in increasing length of time to relapse and achieving higher abstinence rates than placebo	Initial dose: 5 mg three times daily Maintenance dose: up-titrate dose every 3–5 days to a maximum of 15 mg three times daily	Serious hypersensitivity to Baclofen or any of its components
Gabapentin^162,167,168	GABA receptor modulator that has been shown benefit in increasing abstinent days and prolonging time to return to heavy drinking	Initial dose: 300 mg daily Maintenance dose: up-titrate by 300 mg every 2 days to a maximum dose of 600 g three times daily	Serious hypersensitivity to gabapentin or any of its components
Varenicline^162,169,170	Partial α4β2 nicotinic acetylcholine agonist which has shown limited benefit in AUD patients, particularly those who smoke	Initial: 0.5 mg once daily orally Maintenance: titrate by 0.5 mg every four days to a maintenance dose of 1 mg twice daily Dose adjustment required in severe renal disease	Serious hypersensitivity to varenicline or any of its components

AUD, alcohol use disorder.

Psychosocial interventions are also beneficial in the treatment of AUD. A meta-analysis of 13 studies comprising 1945 patients with chronic liver disease revealed significantly lower rates of abstinence and relapse among patients who received an integrated therapy that combined cognitive behavioral therapy and motivational enhancement therapy with comprehensive medical care.¹⁷¹ An integrated multidisciplinary care approach which involves collaboration between a variety of clinicians including hepatologists, addiction specialists, psychiatrist, psychologists, nurses, and social workers is optimal and should be the aim when feasible.^10,172 In a recent study of 89 patients with ALD who were not in the transplant evaluation process, had had less than 6 months of sobriety and who were willing to engage in AUD treatment, a multidisciplinary ALD clinic was found to be attainable. In addition, among the 38 patients followed through the study period, the intervention was associated with decreases in average MELD scores and hospital utilization.¹⁷³ While findings from this study suggest feasibility, more work is needed to evaluate barriers, feasibility, and implementation models in diverse practice settings.

Liver transplantation

LT is beneficial in the treatment of severe liver disease from various etiologies including alcohol. Traditionally, many centers maintained 6-month abstinence requirements in attempts to select patients with low risk of relapse.^174,175 Evidence supporting this duration of abstinence is however conflicting.^176–178 Several studies have shown excellent outcomes among select patients receiving eLT with abstinence duration of <6 months, with relapse of alcohol use similar to those receiving traditional LT after minimum 6 months of abstinence.^179–182 However, a recent prospective RCT comparing early with traditional LT failed to demonstrate non-inferior alcohol relapse rates among recipients of eLT.¹⁸³

Among patients with severe AH, the short-term mortality risk is such that they may not survive long enough to qualify for LT using prolonged abstinence requirements.²⁴ eLT might represent the only option for meaningful survival, especially among subsets who do not respond to medical therapy.^8,25,184 A fast-growing body of evidence supports the use of eLT among eligible patients.^24,180 Professional societies recommend eLT in carefully selected patients who are experiencing their first episode of severe AH, have good social support, and who have minimal psychiatric comorbidities.^21,185 Lack of social support, comorbid psychiatric conditions, polysubstance use, and a history of non-compliance with medical treatment have been associated with increased risk of relapse.¹⁸⁶ However, it should be acknowledged that significant barriers exist to eLT including insurance approval, sociocultural issues, organ shortage as well as concerns about lack of insight and an inability to maintain a therapeutic relationship on the patients’ part.^187,188 In addition, concerns have also been raised about disparities in organ distribution with studies showing a disproportionate representation of white, privately insured males among transplant recipients.^180,189

Challenges and future directions

Despite the progress in the understanding the pathophysiology and potential therapeutic targets in recent years, little progress has been made in the realm of pharmacologic management. There have been several challenges in the drug development for ALD and AH since the funding of four consortia by the National Institute on Alcohol Abuse and Alcoholism over a decade ago.

Liver disease-related challenges

Lack of universally effective treatments

Presently, corticosteroids remain the only treatment with a robust supporting body of evidence. Their benefit is however observed in only about 60% of patients with severe AH and their use is not recommended patients with moderate AH.^14,21 The population with moderate AH, although considered to have a more favorable prognosis, still experience significant mortality rates of as high as 10% in the short-term period.¹⁹⁰ Nonetheless, there are currently no specific treatments other than nutrition and hydration support for them.²¹ Effort is needed to address this gap and develop safer and effective therapies for this population.

Lack of predictive biomarkers for treatment response

In patients with severe AH, there is a need for predictive biomarkers to optimize and personalize corticosteroid use to likely responders. The neutrophil to lymphocyte ratio (NLR) has recently shown promise in this regard. A retrospective analysis of 789 patients from the Steroids or Pentoxifylline for Alcoholic Hepatitis trial revealed that among the 393 patients who received steroids, NLR was useful in predicting corticosteroid-related mortality benefit. In addition, they found that substituting NLR for white cell count in the Glasgow Alcoholic Hepatitis Score was a strong predictor of 28 and 90-day survival.¹⁹¹ A recent retrospective multicenter study identified a therapeutic window with MELD score of 25–39, with best possible response to corticosteroids.¹⁹² Although Keratin 18 (K18) has been shown to be associated with severity and with corticosteroid response in severe AH, most non-invasive biomarkers including K-18 are not yet available for routine use in clinical practice.^193,194 Other biomarkers that have been studied for predicting mortality include procalcitonin, SIRs, and neutrophils and have shown varying degrees of utility.^195,196 Further research into potential biomarkers for diagnosis and risk stratification of ALD are needed.

Heterogeneity of ALD

ALD is a complex heterogenous disease with multiple pathways in its pathophysiology. Furthermore, none of the animal models so far can mimic the human phenotype of AH with organ failure and potential for high short-term mortality. For instance, while neutrophilic infiltration has been shown to be prominent in human phenotypes of alcohol-associated steatohepatitis, animal models demonstrate little to no neutrophilic infiltration

LT-related challenges

Heterogeneity of the selection process

Among ALD patients who qualify for LT, significant barriers exist to access. In addition, there is significant heterogeneity in the selection process. A study of LT centers in the United States found that about half of centers were not adhering to criteria used in the seminal Franco-Belgian study.¹⁸⁷ In addition, a recently published study of LT protocols in 100 LT centers revealed that 70% reported no minimum sobriety requirements, while 21% centers still require minimum 6 months of sobriety. Other themes in many transplant protocols include insight into AUD, social support, and ability to maintain a therapeutic relationship with the transplant team.

In addition, there were significant differences in practices surrounding pre- and post-transplant monitoring of alcohol use.¹⁹⁷

Lack of accurate predictors of relapse

Most LT programs seek to allocate organs to patients with minimal risk of relapse. However, there is currently no recognized consensus definition of relapse.¹⁶² As harmful alcohol use after LT impacts long-term survival, the clear definition of clinically relevant relapse to alcohol use needs to be homogenized.^162,144 Furthermore, there is a need for more accurate tools and models to predict clinically relevant alcohol relapse after LT.^198,199 Given lack of resources currently, there is a need for dedicated efforts to support patients in the post-transplant setting and reduce risk of relapse to harmful alcohol use.

Ethical challenges in LT

The allocation of organs from a scarce deceased donor pool to patients with ALD who are still drinking raises questions about fairness and equity of organ allocation. Given the perpetual gap between demand and supply, the allocation of organs to patients with ALD could potentially mean the withholding of those organs from patients with liver disease due to causes other than alcohol. As a growing number of organs are being allocated to patients with ALD, effort must be made to ensure that organ distribution is equitable.²⁰⁰

AUD-related challenges

Despite benefits of treating AUD, it continues to be undertreated in patients with ALD with high rates of relapse to alcohol use.^148,198 For example, in a retrospective study of 35,682 veterans with cirrhosis and AUD, only 14% received AUD treatment including 12% who received behavioral therapy alone and 1% who received both behavioral and pharmacotherapy.⁹

Patient-level challenges

At the patient level, denial of extent of alcohol use could prevent adequate assessment of AUD severity. Furthermore, psychological barriers such as the perception of stigma, feelings of guilt, and shame may impede treatment uptake.²⁰¹ Patients may also have competing demands on their time that preclude meaningful participation in treatment programs.^202,203 In addition, in severely ill patients, the extent of debilitation may be such that patients feel too sick to focus on seeking treatment for their AUD. Emphasis should be placed on de-stigmatizing AUD treatment and creating less cumbersome treatment processes.

Systemic- and provider-level challenges

Systemic barriers to AUD treatment include insurance coverage levels, limited resources, and lack of integrated multidisciplinary structures.¹⁰ Provider-level barriers include knowledge constraints and low comfort level due to lack of adequate training to address AUD in ALD patients.²⁰⁴ An approach integrating pharmacological and behavioral therapy is optimal, but not consistently utilized.²¹ In the light of the recent proliferation of telehealth usage during the COVID pandemic, studies investigating the role of telemedicine in promoting multidisciplinary care are needed.²⁰⁵

Clinical trial-related challenges

Challenges with study design

There is a paucity of studies that incorporate standard of care, that is, corticosteroids, management of organ failures, AUD treatment, and LT. Stratified randomization allows the grouping of trial participants into strata first based on factors that could affect prognosis and then randomizing within those strata. This kind of design could help improve the power and reduce the chances of a type 1 error in small AH trials that incorporate standard of care.²⁰⁶ Adaptive trial designs which utilize accumulating data to decide how to modify aspects of an ongoing study, without undermining the validity and integrity of the trial can also be used. They are of advantage because they are flexible, can allow for smaller trial size, and increase the chances of success.²⁰⁷ The use of these designs in AH trials can allow for early termination of trials with no benefit and facilitate the finding of significant effects when they do exist.²⁰⁷

Challenges with recruitment and retention

Another issue with AH trials is suboptimal recruitment and retention.²⁰⁸ There are several reasons for this including but not limited to lack of interest in research, desire to concentrate on abstinence, lack of transportation for follow-up visits, and feeling too sick to participate. Structural, system-level barriers especially coordinator time in prescreening and recruitment of patients are important limiting adequate number of participants.²⁰⁹ Study design to ease the burden on participants as well as research personnel, establishment of protocols for real-time tracking of and response to lack of follow-up; provision of adequate educational materials and improved communication between study teams and potential participants, and financial support for participation in trials.²⁰⁹

Conclusion

In conclusion, ALD is a complex disease with rapidly increasing prevalence. Although there are promising therapeutic targets on the horizon, currently none of the newer targets is close to an FDA approval. Strategies are needed to overcome challenges in study designs and conducting clinical trials and provide impetus to the field of drug development in the landscape of ALD and AH. Management of ALD is complex and should include therapies to achieve and maintain alcohol abstinence, preferably delivered by a multidisciplinary team. Although associated with clear mortality benefit in select patients, the use of eLT still requires refinement to create uniformity in selection protocols across transplant centers. There is also a need for reliable noninvasive biomarkers for prognostication. Last but not the least, strategies are urgently needed to implement integrated multidisciplinary care models for treating the dual pathology of AUD and of liver disease for improving the long-term outcomes of patients with ALD.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Ashwani K. Singal

References

Bittermann

Mahmud

Abt

. Trends in liver transplantation for acute alcohol-associated hepatitis during the COVID-19 pandemic in the US. JAMA Netw Open 2021; 4: e2118713.

Cholankeril

Goli

Rana

, et al. Impact of COVID-19 pandemic on liver transplantation and alcohol-associated liver disease in the USA. Hepatology 2021; 74: 3316–3329.

Moon

Curtis

Mandrekar

, et al. Alcohol-associated liver disease before and after COVID-19-an overview and call for ongoing investigation. Hepatol Commun 2021; 5: 1616–1621.

Jinjuvadia

Liangpunsakul

, and Translational Research and Evolving Alcoholic Hepatitis Treatment Consortium. Trends in alcoholic hepatitis-related hospitalizations, financial burden, and mortality in the United States. J Clin Gastroenterol 2015; 49: 506–511.

Lee

Vittinghoff

Dodge

, et al. National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States. JAMA Intern Med 2019; 179: 340–348.

Barbosa

Cowell

Dowd

. Alcohol consumption in response to the COVID-19 pandemic in the United States. J Addict Med 2021; 15: 341–344.

Avila

Dufour

Gerbes

, et al. Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting. Gut 2020; 69: 764–780.

Singal

Mathurin

. Diagnosis and treatment of alcohol-associated liver disease: a review. JAMA 2021; 326: 165–176.

Rogal

Youk

Zhang

, et al. Impact of alcohol use disorder treatment on clinical outcomes among patients with cirrhosis. Hepatology 2020; 71: 2080–2092.

10.

DiMartini

Leggio

Singal

. Barriers to the management of alcohol use disorder and alcohol-associated liver disease: strategies to implement integrated care models. Lancet Gastroenterol Hepatol 2022; 7: 186–195.

11.

Leggio

Lee

. Treatment of alcohol use disorder in patients with alcoholic liver disease. Am J Med 2017; 130: 124–134.

12.

Lucey

Singal

. Integrated treatment of alcohol use disorder in patients with alcohol-associated liver disease: an evolving story. Hepatology 2020; 71: 1891–1893.

13.

Thursz

Richardson

Allison

, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015; 372: 1619–1628.

14.

Imperiale

McCullough

. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Ann Intern Med 1990; 113: 299–307.

15.

Maddrey

Boitnott

Bedine

, et al. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978; 75: 193–199.

16.

Ramond

Poynard

Rueff

, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992; 326: 507–512.

17.

Szabo

Kamath

Shah

, et al. Alcohol-related liver disease: areas of consensus, unmet needs and opportunities for further study. Hepatology 2019; 69: 2271–2283.

18.

Mathurin

O’Grady

Carithers

, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 2011; 60: 255–260.

19.

Liangpunsakul

Puri

Shah

, et al. Effects of age, sex, body weight, and quantity of alcohol consumption on occurrence and severity of alcoholic hepatitis. Clin Gastroenterol Hepatol 2016; 14: 1831.e1833–1838.e1833.

20.

Louvet

Thursz

Kim

, et al. Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo-a meta-analysis of individual data from controlled trials. Gastroenterology 2018; 155: 458.e458–468.e458.

21.

Singal

Bataller

Ahn

, et al. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol 2018; 113: 175–194.

22.

Crabb

Szabo

, et al. Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American association for the study of liver diseases. Hepatology 2020; 71: 306–333.

23.

Kim-Schluger

Shenoy

, et al. Early liver transplantation for severe alcoholic hepatitis in the United States–a single-center experience. Am J Transplant 2016; 16: 841–849.

24.

Mathurin

Moreno

Samuel

, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011; 365: 1790–1800.

25.

Mathurin

. Early liver transplantation for acute alcoholic hepatitis: We can’t say no. J Hepatol 2021; 75: 718–722.

26.

Lefkowitch

. Morphology of alcoholic liver disease. Clin Liver Dis 2005; 9: 37–53.

27.

Dunn

Shah

. Pathogenesis of alcoholic liver disease. Clin Liver Dis 2016; 20: 445–456.

28.

Levene

Goldin

. The epidemiology, pathogenesis and histopathology of fatty liver disease. Histopathology 2012; 61: 141–152.

29.

Dubuquoy

Louvet

Lassailly

, et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut 2015; 64: 1949–1960.

30.

Mathurin

Deng

Keshavarzian

, et al. Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology 2000; 32: 1008–1017.

31.

Gao

Bataller

. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011; 141: 1572–1585.

32.

Bailey

Cunningham

. Contribution of mitochondria to oxidative stress associated with alcoholic liver disease1 1This article is part of a series of reviews on “Alcohol, Oxidative Stress and Cell Injury”. The full list of papers may be found on the homepage of the journal. Free Radic Biol Med 2002; 32: 11–16.

33.

Szabo

Petrasek

Bala

. Innate immunity and alcoholic liver disease. Dig Dis 2012; 30: 55–60.

34.

McClain

Hill

Schmidt

, et al. Cytokines and alcoholic liver disease. Semin Liver Dis 1993; 13: 170–182.

35.

Bjarnason

Peters

Wise

. The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet 1984; 1: 179–182.

36.

Rao

. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 2009; 50: 638–644.

37.

Szabo

Bala

. Alcoholic liver disease and the gut-liver axis. World J Gastroenterol 2010; 16: 1321–1329.

38.

Petrasek

Mandrekar

Szabo

. Toll-like receptors in the pathogenesis of alcoholic liver disease. Gastroenterol Res Pract 2010; 2010: 710381.

39.

Kirpich

Solovieva

Leikhter

, et al. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol 2008; 42: 675–682.

40.

Hartmann

Seebauer

Schnabl

. Alcoholic liver disease: the gut microbiome and liver cross talk. Alcohol Clin Exp Res 2015; 39: 763–775.

41.

Lang

Duan

Liu

, et al. Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis. Hepatology 2020; 71: 522–538.

42.

Wang

Gao

Zakhari

, et al. Inflammation in alcoholic liver disease. Annu Rev Nutr 2012; 32: 343–368.

43.

Mavrelis

Ammon

Gleysteen

, et al. Hepatic free fatty acids in alcoholic liver disease and morbid obesity. Hepatology 1983; 3: 226–231.

44.

Liangpunsakul

Ross

Crabb

. Activation of carbohydrate response element-binding protein by ethanol. J Investig Med 2013; 61: 270–277.

45.

Chan

Kaplowitz

. Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model. J Hepatol 2006; 45: 717–724.

46.

You

Fischer

Deeg

, et al. Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP). J Biol Chem 2002; 277: 29342–29347.

47.

Marmier

Dentin

Daujat-Chavanieu

, et al. Novel role for carbohydrate responsive element binding protein in the control of ethanol metabolism and susceptibility to binge drinking. Hepatology 2015; 62: 1086–1100.

48.

Carr

Correnti

. Insulin resistance in clinical and experimental alcoholic liver disease. Ann N Y Acad Sci 2015; 1353: 1–20.

49.

Jeon

Carr

. Alcohol effects on hepatic lipid metabolism. J Lipid Res 2020; 61: 470–479.

50.

Csak

Ganz

Pespisa

, et al. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 2011; 54: 133–144.

51.

Joshi-Barve

Barve

Amancherla

, et al. Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes. Hepatology 2007; 46: 823–830.

52.

Petrasek

Iracheta-Vellve

Csak

, et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc Natl Acad Sci U S A 2013; 110: 16544–16549.

53.

Guo

Liu

, et al. Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets. Cell Mol Life Sci 2022; 79: 201.

54.

Xiong

Lin

, et al. Advances in the therapeutic application and pharmacological properties of kinsenoside against inflammation and oxidative stress-induced disorders. Front Pharmacol 2022; 13: 1009550.

55.

Theise

. Histopathology of alcoholic liver disease. Clin Liver Dis 2013; 2: 64–67.

56.

Tornai

Szabo

. Emerging medical therapies for severe alcoholic hepatitis. Clin Mol Hepatol 2020; 26: 686–696.

57.

Ridker

Howard

Walter

, et al. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 2012; 126: 2739–2748.

58.

Ruperto

Brunner

Quartier

, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367: 2396–2406.

59.

Ridker

Everett

Thuren

, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377: 1119–1131.

60.

Vergis

Patel

Bogdanowicz

, et al. IL-1 signal inhibition in alcoholic hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo-controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis. Trials 2021; 22: 792.

61.

Vergis

Patel

Bogdanowicz

, et al. OS034 - Il-1beta signal inhibition in acute alcoholic hepatitis: a multicentre, randomised, double-blind, placebo-controlled phase 2 trial of canakinumab therapy (ISAIAH). J Hepatol 2022; 77: S34–S35.

62.

Nct. Efficacy Study of Anakinra, Pentoxifylline, and Zinc Compared to Methylprednisolone in Severe Acute Alcoholic Hepatitis. https://clinicaltrials.gov/show/NCT01809132 (2013, accessed 2022).

63.

Nct. Trial of Anakinra (Plus Zinc), G-CSF, or Prednisone in Patients With Severe Alcoholic Hepatitis. https://clinicaltrials.gov/show/NCT04072822 (2019).

64.

Singh

Murad

Chandar

, et al. Comparative effectiveness of pharmacological interventions for severe alcoholic hepatitis: a systematic review and network meta-analysis. Gastroenterology 2015; 149: 958.e912–970.e912.

65.

Naveau

Chollet-Martin

Dharancy

, et al. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004; 39: 1390–1397.

66.

Spahr

Rubbia-Brandt

Frossard

, et al. Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized controlled pilot study. J Hepatol 2002; 37: 448–455.

67.

Menon

Stadheim

Kamath

, et al. A pilot study of the safety and tolerability of etanercept in patients with alcoholic hepatitis. Am J Gastroenterol 2004; 99: 255–260.

68.

Boetticher

Peine

Kwo

, et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology 2008; 135: 1953–1960.

69.

Nct. Selonsertib in combination with prednisolone versus prednisolone alone in participants with severe alcoholic hepatitis (AH). https://clinicaltrials.gov/show/NCT02854631 (2016, accessed December 2022).

70.

Nct. Study of IDN-6556 in patients with severe alcoholic hepatitis and contraindications to steroid therapy. https://clinicaltrials.gov/show/NCT01912404 (2013, accessed December 2022).

71.

Philips

Pande

Shasthry

, et al. Healthy Donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study. Clin Gastroenterol Hepatol 2017; 15: 600–602.

72.

Rohlke

Stollman

. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap Adv Gastroenterol 2012; 5: 403–420.

73.

Benech

Sokol

. Fecal microbiota transplantation in gastrointestinal disorders: time for precision medicine. Genome Med 2020; 12: 58.

74.

Philips

Phadke

Ganesan

, et al. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis. Indian J Gastroenterol 2018; 37: 215–225.

75.

Philips

Ahamed

Rajesh

, et al. Long-term outcomes of stool transplant in alcohol-associated hepatitis-analysis of clinical outcomes, relapse, gut microbiota and comparisons with standard care. J Clin Exp Hepatol 2022; 12: 1124–1132.

76.

Bajaj

Gavis

Fagan

, et al. A randomized clinical trial of fecal microbiota transplant for alcohol use disorder. Hepatology 2021; 73: 1688–1700.

77.

Han

Suk

Kim

, et al. Effects of probiotics (cultured Lactobacillus subtilis/Streptococcus faecium) in the treatment of alcoholic hepatitis: randomized-controlled multicenter study. Eur J Gastroenterol Hepatol 2015; 27: 1300–1306.

78.

Stadlbauer

Mookerjee

Hodges

, et al. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J Hepatol 2008; 48: 945–951.

79.

Nct. Novel therapies in moderately severe acute alcoholic hepatitis. https://clinicaltrials.gov/show/NCT01922895 (2013, accessed December 2022).

80.

Nct. Effect of probiotics on gut-liver axis of alcoholic hepatitis. https://clinicaltrials.gov/show/NCT02335632 (2015, accessed December 2022).

81.

Dohler

Nebermann

. Bovine colostrum in oral treatment of enterogenic endotoxaemia in rats. Crit Care 2002; 6: 536–539.

82.

Sangild

Vonderohe

Melendez Hebib

, et al. Potential benefits of bovine colostrum in pediatric nutrition and health. Nutrients 2021;13: 2551.

83.

Struff

Sprotte

. Bovine colostrum as a biologic in clinical medicine: a review–Part II: clinical studies. Int J Clin Pharmacol Ther 2008; 46: 211–225.

84.

Kelly

. Bovine colostrums: a review of clinical uses. Altern Med Rev 2003; 8: 378–394.

85.

Bass

Mullen

Sanyal

, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362: 1071–1081.

86.

Kimer

Meldgaard

Hamberg

, et al. The impact of rifaximin on inflammation and metabolism in alcoholic hepatitis: a randomized clinical trial. PloS One 2022; 17: e0264278.

87.

Jiménez

Ventura-Cots

Sala

, et al. Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis: a pilot study (RIFA-AH). Liver Int 2022; 42: 1109–1120.

88.

Nct. Efficacy of antibiotic therapy in severe alcoholic hepatitis treated with prednisolone. https://clinicaltrials.gov/show/NCT02281929 (2014, accessed December 2022).

89.

Nct. The Effect of gut sterilisation on macrophage activation in patients with alcoholic hepatitis. https://clinicaltrials.gov/ct2/show/record/NCT03157388 (2017, accessed December 2022).

90.

Duan

Llorente

Lang

, et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019; 575: 505–511.

91.

Tang

van der Donk

. The sequence of the enterococcal cytolysin imparts unusual lanthionine stereochemistry. Nat Chem Biol 2013; 9: 157–159.

92.

Nguyen-Khac

Thevenot

Piquet

, et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 2011; 365: 1781–1789.

93.

Lee

Sadda

Mendler

, et al. Abnormal hepatic methionine and glutathione metabolism in patients with alcoholic hepatitis. Alcohol Clin Exp Res 2004; 28: 173–181.

94.

Avila

Berasain

Torres

, et al. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 2000; 33: 907–914.

95.

Medici

Virata

Peerson

, et al. S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial. Alcohol, Clin Exp Res 2011; 35: 1960–1965.

96.

Mato

Camara

Fernandez

Paz

, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol 1999; 30: 1081–1089.

97.

Calabrese

Calderone

Ragusa

, et al. Effects of Metadoxine on cellular status of glutathione and of enzymatic defence system following acute ethanol intoxication in rats. Drugs Exp Clin Res 1996; 22: 17–24.

98.

Higuera-de

Tijera

Servín-Caamaño

Cruz-Herrera

, et al. Treatment with metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis. Ann Hepatol 2014; 13: 343–352.

99.

Higuera-de

Tijera

Servín-Caamaño

Serralde-Zúñiga

, et al. Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis. World J Gastroenterol 2015; 21: 4975–4985.

100.

Mezey

Potter

Rennie-Tankersley

, et al. A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. J Hepatol 2004; 40: 40–46.

101.

Pares

Planas

Torres

, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 1998; 28: 615–621.

102.

Phillips

Curtis

Portmann

, et al. Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis–a randomised clinical trial. J Hepatol 2006; 44: 784–790.

103.

Stewart

Prince

Bassendine

, et al. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J Hepatol 2007; 47: 277–283.

104.

Yannaki

Athanasiou

Xagorari

, et al. G-CSF–primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol 2005; 33: 108–119.

105.

Di Campli

Zocco

Saulnier

, et al. Safety and efficacy profile of G-CSF therapy in patients with acute on chronic liver failure. Dig Liver Dis 2007; 39: 1071–1076.

106.

Spahr

Lambert

Rubbia-Brandt

, et al. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatol 2008; 48: 221–229.

107.

Singh

Sharma

Narasimhan

, et al. Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study. Am J Gastroenterol 2014; 109: 1417–1423.

108.

Singh

Keisham

Bhalla

, et al. Efficacy of granulocyte colony-stimulating factor and N-Acetylcysteine therapies in patients with severe alcoholic hepatitis. Clin Gastroenterol Hepatol 2018; 16: 1650.e1652–1656.e1652.

109.

Shasthry

Sharma

Shasthry

, et al. Efficacy of granulocyte colony-stimulating factor in the management of steroid-nonresponsive severe alcoholic hepatitis: a double-blind randomized controlled trial. Hepatology 2019; 70: 802–811.

110.

Marot

Singal

Moreno

, et al. Granulocyte colony-stimulating factor for alcoholic hepatitis: a systematic review and meta-analysis of randomised controlled trials. JHEP Rep 2020; 2: 100139.

111.

Wolk

Witte

, et al. Biology of interleukin-22. Semin Immunopathol 2010; 32: 17–31.

112.

Kong

Feng

Mathews

, et al. Hepatoprotective and anti-fibrotic functions of interleukin-22: therapeutic potential for the treatment of alcoholic liver disease. J Gastroenterol Hepatol 2013; 28: 56–60.

113.

Gao

Xiang

. Interleukin-22 from bench to bedside: a promising drug for epithelial repair. Cell Mol Immunol 2019; 16: 666–667.

114.

Park

Zheng

, et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 2010; 52: 1291–1300.

115.

Arab

Sehrawat

Simonetto

, et al. An open-label, dose-escalation study to assess the safety and efficacy of IL-22 agonist F-652 in patients with alcohol-associated hepatitis. Hepatology 2020; 72: 441–453.

116.

Nct. Protective Immune Mechanisms in Alcoholic Hepatitis. https://clinicaltrials.gov/ct2/show/record/NCT01918462. (2013, December 2022).

117.

McCallum

Masterton

. Liver transplantation for alcoholic liver disease: a systematic review of psychosocial selection criteria. Alcohol Alcohol 2006; 41: 358–363.

118.

Kim

Lin

. DUR-928, an endogenous regulatory molecule, exhibits anti-inflammatory and antifibrotic activity in a mouse model of NASH. In: Emerging Trends Conference: Emerging Trends in Non alcoholic Fatty Liver Disease, Washington, DC, March 17–18, 2017.

119.

Hassanein

Stein

Flamm

, et al. Safety and efficacy of DUR-928: a potential new therapy for acute alcoholic hepatitis. Hepatology 2019; 70: 1483A–1484A.

120.

Trinchet

Balkau

Poupon

, et al. Treatment of severe alcoholic hepatitis by infusion of insulin and glucagon: a multicenter sequential trial. Hepatology 1992; 15: 76–81.

121.

Halle

Pare

Kaptein

, et al. Double-blind, controlled trial of propylthiouracil in patients with severe acute alcoholic hepatitis. Gastroenterology 1982; 82: 925–931.

122.

Rambaldi

Iaquinto

Gluud

. Anabolic-androgenic steroids for alcoholic liver disease: a cochrane review. Am J Gastroenterol 2002; 97: 1674–1681.

123.

Ikejima

Kon

Yamashina

. Nonalcoholic fatty liver disease and alcohol-related liver disease: from clinical aspects to pathophysiological insights. Clin Mol Hepatol 2020; 26: 728–735.

124.

Neuschwander-Tetri

. Therapeutic landscape for NAFLD in 2020. Gastroenterology 2020; 158: 1984.e1983–1998.e1983.

125.

Zhang

, et al. Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20: 13493–13500.

126.

Modica

Gadaleta

Moschetta

. Deciphering the nuclear bile acid receptor FXR paradigm. Nucl Recept Signal 2010; 8: e005.

127.

Mudaliar

Henry

Sanyal

, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 574.e571–582 e571.

128.

Schonewille

de Boer

Groen

. Bile salts in control of lipid metabolism. Curr Opin Lipidol 2016; 27: 295–301.

129.

Nct. Trial of obeticholic acid in patients with moderately severe alcoholic hepatitis (AH). https://clinicaltrials.gov/show/NCT02039219 (2014, accessed December 2022).

130.

Wang

Kory

BasuRay

, et al. PNPLA3, CGI-58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice. Hepatology 2019; 69: 2427–2441.

131.

Zhou

Febbraio

Wada

, et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARγ in promoting steatosis. Gastroenterology 2008; 134: 556.e551–567.e551.

132.

Chen

Liang

, et al. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci 2004; 101: 11245–11250.

133.

Griffett

Welch

Flaveny

, et al. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis. Mol Metab 2015; 4: 353–357.

134.

Bojic

Huff

. Peroxisome proliferator-activated receptor δ: a multifaceted metabolic player. Curr Opin Lipidol 2013; 24: 171–177.

135.

Risérus

Sprecher

Johnson

, et al. Activation of peroxisome proliferator–activated receptor (PPAR) δ promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 2008; 57: 332–339.

136.

Sanyal

Chalasani

Kowdley

, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675–1685.

137.

Bril

Kalavalapalli

Clark

, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol 2018; 16: 558.e552–566.e552.

138.

Nemoto

Saibara

Ogawa

, et al. Tamoxifen-induced nonalcoholic steatohepatitis in breast cancer patients treated with adjuvant tamoxifen. Intern Med 2002; 41: 345–350.

139.

Francque

Bedossa

Ratziu

, et al. A Randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med 2021; 385: 1547–1558.

140.

Mendenhall

Moritz

Roselle

, et al. Protein energy malnutrition in severe alcoholic hepatitis: diagnosis and response to treatment. The VA Cooperative Study Group #275. JPEN J Parenter Enteral Nutr 1995; 19: 258–265.

141.

Moreno

Deltenre

Senterre

, et al. Intensive enteral nutrition is ineffective for patients with severe alcoholic hepatitis treated with corticosteroids. Gastroenterology 2016; 150: 903.e908–910.e908.

142.

Cordoba

Lopez-Hellin

Planas

, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol 2004; 41: 38–43.

143.

Potts

Goubet

Heneghan

, et al. Determinants of long-term outcome in severe alcoholic hepatitis. Aliment Pharmacol Ther 2013; 38: 584–595.

144.

Altamirano

López-Pelayo

Michelena

, et al. Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: prediction and impact on long-term survival. Hepatology 2017; 66: 1842–1853.

145.

Erard-Poinsot

Dharancy

Hilleret

M-N

, et al. Natural history of recurrent alcohol-related cirrhosis after liver transplantation: fast and furious. Liver Transpl 2020; 26: 25–33.

146.

Johnson

Lee

Vinson

, et al. Use of AUDIT-based measures to identify unhealthy alcohol use and alcohol dependence in primary care: a validation study. Alcohol Clin Exp Res 2013; 37: E253–E259.

147.

Vannier

AGL

Shay

JES

Fomin

, et al. Incidence and progression of alcohol-associated liver disease after medical therapy for alcohol use disorder. JAMA Netw Open 2022; 5: e2213014.

148.

Burnette

Nieto

Grodin

, et al. Novel agents for the pharmacological treatment of alcohol use disorder. Drugs 2022; 82: 251–274.

149.

Kranzler

Soyka

. Diagnosis and pharmacotherapy of alcohol use disorder: a review. JAMA 2018; 320: 815–824.

150.

Addolorato

Leggio

Ferrulli

, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 2007; 370: 1915–1922.

151.

Jonas

Amick

Feltner

, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 2014; 311: 1889–1900.

152.

Mason

Quello

Goodell

, et al. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med 2014; 174: 70–77.

153.

Bogenschutz

Ross

Bhatt

, et al. Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry 2022; 79: 953–962.

154.

Rosner

Hackl-Herrwerth

Leucht

, et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 2010; 12: CD001867.

155.

Yoo

Cholankeril

Ahmed

. Treating alcohol use disorder in chronic liver disease. Clin Liver Dis 2020; 15: 77–80.

156.

Chick

Howlett

Morgan

, et al. United Kingdom multicentre acamprosate study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol 2000; 35: 176–187.

157.

Rosner

Hackl-Herrwerth

Leucht

, et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev 2010; 9: CD004332.

158.

Skinner

Lahmek

Pham

, et al. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One 2014; 9: e87366.

159.

Fuller

Gordis

. Does disulfiram have a role in alcoholism treatment today? Addiction 2004; 99: 21–24.

160.

Palpacuer

Duprez

Huneau

, et al. Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders: a systematic review with direct and network meta-analyses on nalmefene, naltrexone, acamprosate, baclofen and topiramate. Addiction 2018; 113: 220–237.

161.

Palpacuer

Laviolle

Boussageon

, et al. Risks and benefits of nalmefene in the treatment of adult alcohol dependence: a systematic literature review and meta-analysis of published and unpublished double-blind randomized controlled trials. PLoS Med 2015; 12: e1001924.

162.

Arab

Izzy

Leggio

, et al. Management of alcohol use disorder in patients with cirrhosis in the setting of liver transplantation. Nat Rev Gastroenterol Hepatol 2022; 19: 45–59.

163.

Blodgett

Del Re

Maisel

, et al. A meta-analysis of topiramate’s effects for individuals with alcohol use disorders. Alcohol Clin Exp Res 2014; 38: 1481–1488.

164.

Johnson

Ait-Daoud

Bowden

, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 2003; 361: 1677–1685.

165.

Pierce

Sutterland

Beraha

, et al. Efficacy, tolerability, and safety of low-dose and high-dose baclofen in the treatment of alcohol dependence: a systematic review and meta-analysis. Eur Neuropsychopharmacol 2018; 28: 795–806.

166.

Addolorato

Caputo

Capristo

, et al. Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol 2002; 37: 504–508.

167.

Brower

Myra Kim

Strobbe

, et al. A randomized double-blind pilot trial of gabapentin versus placebo to treat alcohol dependence and comorbid insomnia. Alcohol Clin Exp Res 2008; 32: 1429–1438.

168.

Pani

Trogu

Pacini

, et al. Anticonvulsants for alcohol dependence. Cochrane Database Syst Rev 2014; 2: CD008544.

169.

Litten

Ryan

Fertig

, et al. A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med 2013; 7: 277–286.

170.

McKee

Harrison

O’Malley

, et al. Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 2009; 66: 185–190.

171.

Khan

Tansel

White

, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review. Clin Gastroenterol Hepatol 2016; 14: 191–202.

172.

Winder

Fernandez

Mellinger

. Integrated care of alcohol-related liver disease. J Clin Exp Hepatol 2022; 12: 1069–1082.

173.

Mellinger

Winder

Fernandez

, et al. Feasibility and early experience of a novel multidisciplinary alcohol-associated liver disease clinic. J Subst Abuse Treat 2021; 130: 108396.

174.

Lucey

Brown

Everson

, et al. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg 1997; 3: 628–637.

175.

Everhart

Beresford

. Liver transplantation for alcoholic liver disease: a survey of transplantation programs in the United States. Liver Transpl Surg 1997; 3: 220–226.

176.

De Gottardi

Spahr

Gelez

, et al. A simple score for predicting alcohol relapse after liver transplantation: results from 387 patients over 15 years. Arch Intern Med 2007; 167: 1183–1188.

177.

Jauhar

Talwalkar

Schneekloth

, et al. Analysis of factors that predict alcohol relapse following liver transplantation. Liver Transpl 2004; 10: 408–411.

178.

Perney

Bismuth

Sigaud

, et al. Are preoperative patterns of alcohol consumption predictive of relapse after liver transplantation for alcoholic liver disease? Transpl Int 2005; 18: 1292–1297.

179.

Weeks

Sun

McCaul

, et al. Liver transplantation for severe alcoholic hepatitis, updated lessons from the world’s largest series. J Am Coll Surg 2018; 226: 549–557.

180.

Herrick-Reynolds

Punchhi

Greenberg

, et al. Evaluation of early vs standard liver transplant for alcohol-associated liver disease. JAMA Surg 2021; 156: 1026–1034.

181.

Lee

Chen

Haugen

, et al. Three-year results of a pilot program in early liver transplantation for severe alcoholic hepatitis. Ann Surg 2017; 265: 20–29.

182.

Carrique

Quance

Tan

, et al. Results of early transplantation for alcohol-related cirrhosis: integrated addiction treatment with low rate of relapse. Gastroenterology 2021; 161: 1896.e1892–1906.e1892.

183.

Louvet

Labreuche

Moreno

, et al. Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study. Lancet Gastroenterol Hepatol 2022; 7: 416–425.

184.

Louvet

Naveau

Abdelnour

, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 2007; 45: 1348–1354.

185.

Lucey

Mellinger

, et al. Introducing the 2019 American association for the study of liver diseases guidance on alcohol-associated liver disease. Liver Transpl 2020; 26: 14–16.

186.

Lim

Curry

Sundaram

. Risk factors and outcomes associated with alcohol relapse after liver transplantation. World J Hepatol 2017; 9: 771–780.

187.

Hasanin

Dubay

McGuire

, et al. Liver transplantation for alcoholic hepatitis: a survey of liver transplant centers. Liver Transpl 2015; 21: 1449–1452.

188.

Choi

Benhammou

Yum

, et al. Barriers for liver transplant in patients with alcohol-related hepatitis. J Clin Exp Hepatol 2022; 12: 13–19.

189.

Lee

Mehta

Platt

, et al. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis. Gastroenterology 2018; 155: 422.e421–430.e421.

190.

Samala

Gawrieh

Tang

, et al. Clinical characteristics and outcomes of mild to moderate alcoholic hepatitis. GastroHep 2019; 1: 161–165.

191.

Forrest

Storey

Sinha

, et al. Baseline neutrophil-to-lymphocyte ratio predicts response to corticosteroids and is associated with infection and renal dysfunction in alcoholic hepatitis. Aliment Pharmacol Ther 2019; 50: 442–453.

192.

Arab

Díaz

Baeza

, et al. Identification of optimal therapeutic window for steroid use in severe alcohol-associated hepatitis: a worldwide study. J Hepatol 2021; 75: 1026–1033.

193.

Bissonnette

Altamirano

Devue

, et al. A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis. Hepatology 2017; 66: 555–563.

194.

Atkinson

Grove

Liebig

, et al. In severe alcoholic hepatitis, serum keratin-18 fragments are diagnostic, prognostic, and theragnostic biomarkers. Am J Gastroenterol 2020; 115: 1857–1868.

195.

Altamirano

Miquel

Katoonizadeh

, et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014; 146: 1231–1239.

196.

Michelena

Altamirano

Abraldes

, et al. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology 2015; 62: 762–772.

197.

Lim

Kwong

Jafri

, et al. Heterogeneity in center practices in liver transplantation for alcohol-associated liver disease in the United States. Am J Gastroenterol 2022; 117: 1530–1535.

198.

Pfitzmann

Schwenzer

Rayes

, et al. Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl 2007; 13: 197–205.

199.

Chuncharunee

Yamashiki

Thakkinstian

, et al. Alcohol relapse and its predictors after liver transplantation for alcoholic liver disease: a systematic review and meta-analysis. BMC Gastroenterol 2019; 19: 150.

200.

Andreoni

Zarrinpar

. The sobering complexities of alcoholic liver disease and decisions for transplant. JAMA Surgery 2021; 156: 1034–1035.

201.

Dimartini

Dew

. Monitoring alcohol use on the liver transplant wait list: therapeutic and practical issues. Liver Transpl 2012; 18: 1267–1269.

202.

Verissimo

Grella

. Influence of gender and race/ethnicity on perceived barriers to help-seeking for alcohol or drug problems. J Subst Abuse Treat 2017; 75: 54–61.

203.

Weinrieb

Van Horn

DHA

Lynch

, et al. A randomized, controlled study of treatment for alcohol dependence in patients awaiting liver transplantation. Liver Transpl 2011; 17: 539–547.

204.

Johnson

Ghosh

Daniels

, et al. Clinicians’ perspectives and perceived barriers to caring for patients with alcohol use disorder and cirrhosis. Addict Sci Clin Pract 2022; 17: 9.

205.

Weiner

Bandeian

Hatef

, et al. In-person and telehealth ambulatory contacts and costs in a large US insured cohort before and during the COVID-19 pandemic. JAMA Netw Open 2021; 4: e212618.

206.

Kernan

Viscoli

Makuch

, et al. Stratified randomization for clinical trials. J Clin Epidemiol 1999; 52: 19–26.

207.

Kairalla

Coffey

Thomann

, et al. Adaptive trial designs: a review of barriers and opportunities. Trials 2012; 13: 145.

208.

Zweben

Barrett

Berger

, et al. Recruiting and retaining participants in a combined behavioral and pharmacological clinical trial. J Stud Alcohol Suppl 2005; 15: 72–81; discussion 65.

209.

Comerford

Lourens

Liangpunsakul

, et al. Challenges in patient enrollment and retention in clinical studies for alcoholic hepatitis: experience of the TREAT consortium. Alcohol Clin Exp Res 2017; 41: 2000–2006.

Therapeutic targets in alcohol-associated liver disease: progress and challenges

Abstract

Keywords

Pathophysiology of ALD

Emerging therapeutic targets

Inhibition of inflammatory pathways

IL1 inhibition

Canakinumab

Anakinra

Modulating gut–liver axis and inflammation

Fecal microbiota transplant

Probiotics

Bovine colostrum

Antimicrobial agents

Phage therapy

Inhibition of oxidative stress

Antioxidants

N-acetylcysteine

S-adenosyl methionine

Metadoxine

Boosting liver regeneration

Hepatic regenerating agents

Granulocyte colony stimulating factor

Interleukin-22

Sulfated oxysterol

Potential future targets

FXR receptor agonists

LXR inverse agonists

PPAR agonists

Non-pharmacological treatment modalities

Nutritional support

Treatment of AUD

Liver transplantation

Challenges and future directions

Liver disease-related challenges

Lack of universally effective treatments

Lack of predictive biomarkers for treatment response

Heterogeneity of ALD

LT-related challenges

Heterogeneity of the selection process

Lack of accurate predictors of relapse

Ethical challenges in LT

AUD-related challenges

Patient-level challenges

Systemic- and provider-level challenges

Clinical trial-related challenges

Challenges with study design

Challenges with recruitment and retention

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References