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Therapeutic advances in alcohol-associated hepatitis

      Summary

      In recent years, there have been important advances in our understanding of alcohol-associated hepatitis (AH), which have occurred in parallel with a surge in clinical trial activity. Meanwhile, the broader medical field has seen a transformation in care paradigms based on emerging digital technologies. This review focuses on breakthroughs in our understanding of AH and how these breakthroughs are leading to new paradigms for biomarker discovery, clinical trial activity, and care models for patients. It portends a future in which multimodal data from genetic, radiomic, histologic, and environmental sources can be integrated and synthesised to generate personalised biomarkers and therapies for patients with AH.

      Keywords

      Introduction

      Alcohol-associated hepatitis (AH) is a syndrome characterised by jaundice and liver failure occurring in people who are actively drinking high levels of alcohol and who have been drinking excessively for a prolonged period.
      • Lucey M.M.P.
      • Morgan T.R.
      Alcoholic hepatitis.
      There is usually a sub-acute presentation with jaundice developing over 2 to 6 weeks and, at the time of admission to hospital, there is evidence of coagulopathy and, in many patients, evidence of decompensation manifest as ascites or encephalopathy. The severity of AH is conventionally determined by Maddrey’s discriminant function with a score greater than 31 being considered severe.
      EASL Clinical Practice Guidelines
      Management of alcohol-related liver disease.
      Expert consensus also equates a model for end-stage liver disease (MELD) score greater than 20 as severe AH.
      • Crabb D.W.
      • Im G.Y.
      • Szabo G.
      • Mellinger J.L.
      • Lucey M.R.
      Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases.
      Severe AH is associated with high short-term mortality despite cessation of alcohol use; 20% of patients will die within 28 days of admission and 30% within 90 days.
      • Mathurin P.
      • Thursz M.
      Endpoints and patient stratification in clinical trials for alcoholic hepatitis.
      In clinical trials conducted prior to 2000, the mortality associated with this condition was considerably higher, but the reason for improved survival is not yet clear.
      In recent years, there have been several breakthroughs in our understanding of the pathobiology of alcohol-associated liver disease (ALD). For decades, hypothesis-driven approaches were at the forefront of research. This has drastically changed so that our focus is now on unbiased approaches to discovery which have the potential to reveal new molecules, pathways, and genes. Genetic studies have identified new genes highly associated with alcohol use disorder (AUD), ALD and fibrosis.
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      Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits.
      ,
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      A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.
      Remote patient monitoring has also allowed for a new stream of digital data. Studies in transcriptomic and proteomic analysis have exploded, providing valuable large datasets. Multi-omics integration has been used to identify novel genes associated with alcohol dependence, which potentially overlap with neurodegenerative diseases.
      • Kapoor M.
      • Chao M.J.
      • Johnson E.C.
      • Novikova G.
      • Lai D.
      • Meyers J.L.
      • et al.
      Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases.
      Interestingly many of these genes regulate key inflammatory pathways that are dysregulated in ALD. Given substantial improvements in sequencing technology, computational bio- and clinical-informatics, these multimodal sources of data can eventually be integrated and individualised, and will hopefully lead to advances in personalised biomarkers and therapies. In this review, we have selected some of the key advances in trial design, immunology, genetics, microbiome, and digital technology that, in our opinion, will transform the management of AH in the next few years.

      Advances in trial design

      Whilst for many years there were few trials in the field of AH due to challenges in patient population, recruitment, and pharmacokinetics/drug safety in the setting of advanced liver disease, the number of both commercial- and investigator-led studies is currently increasing. However, one of the problems encountered in this field is the choice of trial endpoint. Traditionally, mortality at 28 days after enrolment in a trial has been used as a primary endpoint.
      • Mathurin P.
      • Thursz M.
      Endpoints and patient stratification in clinical trials for alcoholic hepatitis.
      The mortality rate at this time has steadily fallen, with approximately 20% of patients expected to die by this timepoint. Furthermore, side effects of treatment which may impact outcomes may continue to manifest after 28 days.
      • Vergis N.
      • Atkinson S.R.
      • Knapp S.
      • Maurice J.
      • Allison M.
      • Austin A.
      • et al.
      In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, and is associated with high circulating levels of bacterial DNA.
      Consensus is now forming around a 90-day timepoint when the expected mortality will be around 30%.
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      • Bataller R.
      • Chalasani N.P.
      • Kamath P.S.
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      • Mathurin P.
      • et al.
      Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA alcoholic hepatitis consortia.
      In patients who remain abstinent, the AH process normally resolves by 90 days but the drivers of mortality beyond this time are dominated by resumption of alcohol use.
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      • et al.
      Main drivers of outcome differ between short term and long term in severe alcoholic hepatitis: a prospective study.
      One further complication of using mortality as an endpoint is the increasing access to liver transplantation for this group of patients. Patients who have been transplanted are often classified the same as patients who have died on the basis that they would have died without a transplant and therefore represent a failure of therapy. However, there are no uniform criteria for transplantation selection and no biomarkers or scoring systems to accurately predict mortality risk, meaning that the outcome of a transplanted patient might not be inevitable mortality without the procedure.
      • Musto J.
      • Stanfield D.
      • Ley D.
      • Lucey M.R.
      • Eickhoff J.
      • Rice J.P.
      Recovery and outcomes of patients denied early liver transplantation for severe alcohol-associated hepatitis.
      Powering a trial sufficiently to see changes in mortality at 90 days is still likely to require over 300 patients, making this an unpopular choice of endpoint and forcing investigators to look for surrogate endpoints in phase II trials which are likely to predict mortality endpoints in phase III trials. The Lille score calculated after 7 days of treatment is gaining acceptance as an endpoint, as the proportion of patients who achieve a Lille score <0.45 appears to predict mortality at 90 days.
      • Mathurin P.
      • Thursz M.
      Endpoints and patient stratification in clinical trials for alcoholic hepatitis.
      However, the mechanisms of action of many putative treatments may take longer than 7 days to influence survival. An alternative endpoint is therefore the change in MELD score from baseline to 28 days.
      Advances in clinical trial methodology provide new opportunities to improve the management of AH.
      Recruitment to clinical trials in AH is often challenging. Whilst incidence rates are currently increasing, AH is less common than acute decompensation of alcohol-related cirrhosis and patients often present with comorbidities which make them unsuitable for clinical trials. It is important to avoid recruiting patients who rapidly improve immediately after admission to hospital as these patients are unlikely to benefit from any intervention and, if unbalanced allocation occurs, will create misleading results. Over the last 30 years, most studies have recruited patients with severe AH, defined as a Maddrey’s discriminant function score ≥32 with recent studies using MELD >20. Mortality amongst patients with ‘non-severe’ AH is around 10% at 90 days, indicating that this group of patients should also be considered for clinical trials.
      • Bennett K.
      • Enki D.G.
      • Thursz M.
      • Cramp M.E.
      • Dhanda A.D.
      Systematic review with meta-analysis: high mortality in patients with non-severe alcoholic hepatitis.
      However, as the risk of mortality varies substantially with severity of disease, it is critically important to stratify recruitment to treatment allocation in order to avoid biasing the outcomes. Similarly, inclusion of patients with MELD scores over 30, who often require renal replacement therapy and/or respiratory mechanical support, may adversely influence results due to a disease biology that is not amenable to therapeutic correction. Nevertheless, targeted therapies in these patients with the highest mortality are urgently needed.
      There are now numerous candidate therapies for AH which creates challenges for prioritisation and delivery of clinical trials. Clinical development of novel commercial products must follow a regulator prescribed pathway but many of the candidate drugs are already licensed for other indications and could be potentially repurposed for use in AH. Multi-arm, multistage and adaptive trial designs are efficient strategies for evaluating multiple interventions simultaneously.
      • Wason J.
      • Stallard N.
      • Bowden J.
      • Jennison C.
      A multi-stage drop-the-losers design for multi-arm clinical trials.
      These designs use pre-specified safety and therapeutic efficiency thresholds to eliminate underperforming treatment arms in the first stage so that recruitment is enhanced to better performing treatment arms in the second stage (Fig. 1). While this type of design has not been used to date in AH it has been well illustrated in the RECOVERY trial for COVID-19.

      Trial R. Protocol: Randomized Evaluation Of Covid-19 Therapy (RECOVERY) 2021 [cited 12-19-2021]; Available from: www.recoverytrial.net.

      Other innovations in trial designs include synthetic placebo arms, which are becoming a reality in non-alcoholic steatohepatitis (NASH) – given rich placebo and natural history datasets – but remain aspirational in AH. Pragmatic trials are also necessary given the unique nature of AH clinical trials which may not represent real-world experience and patients. Another recent trial trend relates to platform trials whereby the trial focus is on a disease rather than on a specific therapy. Many of these newer decentralised trial designs require significant historical data trends, skilled statistical support, and large numbers of target patients and therapies to become a reality.
      Figure thumbnail gr1
      Fig. 1Multi-arm, multistage trial designs may be used to evaluate the therapeutic efficacy of multiple interventions simulataneously and efficiently using robust criteria in the early stage to eliminate ineffective treatments.

      Therapeutic advances in target selection based on new pathobiology

      Controlling inflammation

      Transcriptomic characterisation of single cells using burgeoning advances in sequencing and bioinformatics technology has uncovered new paradigms in liver inflammation. For example, single-cell RNA sequencing of human liver cells revealed 20 distinct cell populations including hepatocytes, endothelial cells, cholangiocytes, hepatic stellate cells, B cells, conventional and non-conventional T cells, natural killer-like cells, and distinct hepatic monocyte/macrophage populations. Confirming previous findings, zonation of the hepatic tissue and zone-specific gene signatures were found.
      • MacParland S.A.
      • Liu J.C.
      • Ma X.Z.
      • Innes B.T.
      • Bartczak A.M.
      • Gage B.K.
      • et al.
      Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.
      Single-cell data revealed immune cell diversity of peripheral and liver monocytes in AH that highlighted cell-specific differences in monocyte responses.
      • Kim A.
      • Bellar A.
      • McMullen M.R.
      • Li X.
      • Nagy L.E.
      Functionally diverse inflammatory responses in peripheral and liver monocytes in alcohol-associated hepatitis.
      Heterogeneity of monocytes and macrophages is well established in ALD and these new studies provide further insights into the subtypes of pro- and anti-inflammatory monocytes and macrophages. These exciting new data raise questions about the dynamic role of the different immune cell populations in the liver and circulation during the disease process and progression of AH – these aspects of the inflammatory response and its relation to disease are yet to be defined.
      Some of the most important inflammatory mediators in AH are cytokines (Fig. 2, Fig. 3). Activation of the NLRP3 (NLR family pyrin domain containing 3) inflammasome following the combination of Toll-like receptor (TLR) engagement and endogenous damage-associated molecular patterns results in the cleavage and activation of caspase 1 and generation of interleukin (IL)-1β. IL-1β levels are increased in the serum of patients with AH and in animal models of the disease.
      • de Carvalho Ribeiro M.
      • Szabo G.
      Role of the inflammasome in liver disease.
      ,
      • Petrasek J.
      • Bala S.
      • Csak T.
      • Lippai D.
      • Kodys K.
      • Menashy V.
      • et al.
      IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice.
      Inhibition of IL-1β production by genetic targeting of the caspase 1 gene protects mice from steatosis, inflammation, and fibrosis in models of AH. In humans, IL-1β can be targeted in several ways. Anakinra blocks the IL-1 receptor thereby inhibiting downstream signalling from either IL-1β or IL-1α. Canakinumab is a monoclonal antibody targeting IL-1β directly and is licensed for use in autoinflammatory syndromes associated with IL-1β production, such as cryopyrin-associated periodic syndrome, familial Mediterranean fever and Stills disease.
      • Lachmann H.J.
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      • Leslie K.S.
      • Hachulla E.
      • Quartier P.
      • et al.
      Use of canakinumab in the cryopyrin-associated periodic syndrome.
      A recent trial in the US compared the use of anakinra in combination with zinc and pentoxifylline vs. corticosteroids in patients with severe AH, finding a numerical but non-significant survival advantage.
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      • Mitchell M.C.
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      • Szabo G.
      • Nagy L.E.
      • et al.
      Design and rationale of a multicenter defeat alcoholic steatohepatitis trial: (DASH) randomized clinical trial to treat alcohol-associated hepatitis.
      NIAAA
      Trial of anakinra (plus zinc) or prednisone in patients with severe alcoholic hepatitis (AlcHepNet).
      • Szabo G.
      • Mitchell M.C.
      • McClain C.J.
      • Dasarathy S.
      • McCullough A.J.
      • Nagy L.E.
      • et al.
      IL-1 receptor antagonist in combination with pentoxifylline and zinc for severe alcoholic hepatitis: a multicenter randomized double-bind placebo-controlled clinical trial.
      A new trial is currently underway to explore the efficacy of anakinra in a larger population. A small phase IIa trial of canakinumab has recently completed recruitment and is due to report in the near future.
      Multiomics is uncovering new molecular targets in AH.
      Figure thumbnail gr2
      Fig. 2Cellular interactions in AH in the liver.
      During metabolism of high doses of alcohol, hepatocytes are exposed to toxic alcohol metabolites, including acetaldehyde and reactive oxygen species that trigger hepatocyte damage. Damaged hepatocytes release chemokines to recruit inflammatory cells to the livers as well as DAMPs such as uric acid, ATP, HMGB1. Different macrophage populations including inflammatory and repair phenotypes are recruited from the bone marrow to the liver as well as neutrophil leukocytes. The liver milieu that is enriched in gut-derived pathogen-associated molecules and DAMPs activate these recruited innate immune cell as well as resident Kupffer cells to produce pro-inflammatory cytokines. Increased adhesion molecule expression on liver sinusoidal cells promotes recruitment of circulating inflammatory cells to the liver. Neutrophil activation is manifested in release of NETs in response to alcohol however these neutrophils are no longer capable to exert robust host defense mechanisms potentially contributing to decreased host defense in AH. In contrast to normal homeostasis where macrophages eliminate NETotic neutrophils, macrophages in AH have reduced phagocytic capacity. Hepatic Stellate cell activation can be triggered directly by the various PAMPs and DAMPs or via pro-inflammatory cytokines in AH. AH, alcohol-associated hepatitis; DAMPs, damage-associated molecular patterns; HMGB1, high mobility group box 1; HSC, hepatic stellate cell; IL-, interleukin-; LSEC, liver sinusoidal endothelial cell; MCP1, monocyte chemoattractant protein-1 (or CCL2); NETs, neutrophil extracellular traps; PAMPs, pathogen-associated molecular patterns; TNFα, tumour necrosis factor-α.
      Figure thumbnail gr3
      Fig. 3Molecular pathways involved in AH.
      Gut-derived PAMPs activate various TLRs. For example, LPS activates the TLR4/CD14 receptor complex and via the MyD88-dependent downstream pathway induces IRAK1/4 activation and downstream IKK and NF-κB activation. The NF-κB dimer of phosphorylated p65 and p50 translocates to the nucleus where through binding to the promoter regions of various chemokine and pro-inflammatory genes results in rapid activation of the pro-inflammatory cascade. Chemokines, TNFα, IL-6 and pro-IL-1β are produced. Processing of pro-IL-1β to bioactive IL-1β requires cleavage by caspase-1. Caspase-1 activation is triggered by activation of the intracellular sensor, NLRP3, leading to assembly of the inflammasome, a multiprotein complex, that activates caspase-1 from its proactive pro-caspase-1. The NLRP3 inflammasome is activated by a variety of DAMPs that include ATP, uric acid (both increased in AH). AH, alcohol-associated hepatitis; DAMPs, damage-associated molecular patterns; IL-, interleukin; LPS, lipopolysaccharide; NLRP3, NLR family pyrin domain containing 3; PAMPs, pathogen-associated molecular patterns; TLR, Toll-like receptor; TNFα, tumour necrosis factor-α.
      Cytokine activation that is pathognomonic in AH also leads to release of chemokines that recruit neutrophils to the liver. Recent studies have examined chemokine inhibitors such as cenicriviroc in preclinical models of AH.
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      • Lowe P.
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      • Catalano D.
      • Gyongyosi B.
      • Cho Y.
      • et al.
      Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis, and inflammation in mice.
      This is particularly relevant given ongoing trial activity with this compound in NASH.
      • Anstee Q.M.
      • Neuschwander-Tetri B.A.
      • Wong V.W.
      • Abdelmalek M.F.
      • Younossi Z.M.
      • Yuan J.
      • et al.
      Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design.
      ,
      • Ratziu V.
      • Sanyal A.
      • Harrison S.A.
      • Wong V.W.
      • Francque S.
      • Goodman Z.
      • et al.
      Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study.
      Recent studies have also linked cytokine activation to chemokine production through epigenetic mechanisms including superenhancers that can regulate groups of chemokines in tandem. This has led to investigation of therapies targeting transcription factors that regulate superenhancers such as bromodomain-containing protein 4.
      • Liu M.
      • Cao S.
      • He L.
      • Gao J.
      • Arab J.P.
      • Cui H.
      • et al.
      Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis.
      Epigenetic pathways focused on the transcription factor hepatocyte nuclear factor 4 (HNF4), which regulate hepatocyte reprogramming, have also been investigated recently and are discussed further below.

      Avoiding infection

      A paradox in AH is that even though the immune system is “activated”, infection and sepsis are common complications. This has led to a concept of “immune exhaustion” in AH which is under study and requires refinement. Clinical acumen and diligence are required to detect the early onset of infection in order to prevent progression to SIRS (systemic inflammatory syndrome) acute kidney injury and multi-organ failure.
      • Vergis N.
      • Atkinson S.R.
      • Thursz M.R.
      Assessment and management of infection in alcoholic hepatitis.
      Approximately 25% of patients with severe AH will develop incident (after admission to hospital) infection which has a significant impact on their chances of survival.
      • Vergis N.
      • Atkinson S.R.
      • Knapp S.
      • Maurice J.
      • Allison M.
      • Austin A.
      • et al.
      In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, and is associated with high circulating levels of bacterial DNA.
      ,
      • Louvet A.
      • Wartel F.
      • Castel H.
      • Dharancy S.
      • Hollebecque A.
      • Canva-Delcambre V.
      • et al.
      Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor.
      A number of immunological deficits have been described, which partially account for the observed immune paresis in liver failure and/or AH. A marked reduction in the oxidative burst function of neutrophils and monocytes – associated with reduced expression of components of the NADPH oxidase complex – has been observed.
      • Vergis N.
      • Khamri W.
      • Beale K.
      • Sadiq F.
      • Aletrari M.O.
      • Moore C.
      • et al.
      Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase.
      Ingestion of micro-organisms without killing them means that phagocytes may potentially behave as ‘Trojan horses’ disseminating bacteria systemically. In vitro, incubation of monocytes with N-acetyl cysteine restores their oxidative burst function. In vivo, a trial of prednisolone in combination with N-acetyl cysteine reported significantly lower rates of incident infection in patients with severe AH treated with the combination compared to prednisolone alone.
      • Nguyen-Khac E.T.T.
      • Piquet M.A.
      • Benferhat S.
      • Goria O.
      • Chatelain D.
      • Tramier B.
      • et al.
      Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis.
      In addition to defects in oxidative burst function, it has recently been shown in acute liver failure that failure to phagocytose micro-organisms in the portal circulation, due to exhausted sinusoidal macrophages and dysfunctional monocytes, leads to infection.
      • Triantafyllou E.
      • Gudd C.L.
      • Mawhin M.A.
      • Husbyn H.C.
      • Trovato F.M.
      • Siggins M.K.
      • et al.
      PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury.
      The monocyte and macrophage dysfunction may be corrected ex vivo with antibodies targeting the checkpoint inhibitor programmed cell death 1, creating novel possibilities for the restoration of immune function in patients with AH. Decreased phagocytic activity of macrophages in ALD has also been linked to reduced elimination of activated neutrophil leukocytes that form NETs (neutrophil extracellular traps).
      • Bukong T.N.
      • Cho Y.
      • Iracheta-Vellve A.
      • Saha B.
      • Lowe P.
      • Adejumo A.
      • et al.
      Abnormal neutrophil traps and impaired efferocytosis contribute to liver injury and sepsis severity after binge alcohol use.
      The role of neutrophils in AH remains to be fully elucidated.
      • Cho Y.
      • Szabo G.
      Two faces of neutrophils in liver disease development and progression.
      Using antibiotics prophylactically to prevent infection is an attractive option in this patient group. However, prophylactic treatment may give rise to antimicrobial resistance and also expose the patient to the risk of drug-induced liver injury. A trial of prednisolone plus augmentin (co-amoxyclav) vs. prednisolone alone has recently reported results indicating that the addition of antibiotics conferred no therapeutic benefit (In Press).

      Stimulating regeneration

      A characteristic feature of AH is the profound loss of liver function despite, in many cases, an adequate number of residual hepatocytes. There is clearly evidence of a regenerative response with bile ductular proliferation representing an expansion of progenitor cells, though this does not appear to be sufficient to restore normal liver function.
      • Dubuquoy L.
      • Louvet A.
      • Lassailly G.
      • Truant S.
      • Boleslawski E.
      • Artru F.
      • et al.
      Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis.
      A high proportion of hepatocytes express senescence makers, indicating that they are unable to proliferate in order to replace functional liver mass.
      • Sharma S.
      • Maras J.S.
      • Das S.
      • Hussain S.
      • Mishra A.K.
      • Shasthry S.M.
      • et al.
      Pre-therapy liver transcriptome landscape in Indian and French patients with severe alcoholic hepatitis and steroid responsiveness.
      Attempts to provide external liver support have not been successful in AH but novel approaches, including the inhibition of MKK4 (also known as MAPK24) to support regeneration, should be ready for clinical trials in the foreseeable future.
      • Wuestefeld T.
      • Pesic M.
      • Rudalska R.
      • Dauch D.
      • Longerich T.
      • Kang T.W.
      • et al.
      A Direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration.
      Furthermore, as our understanding of the epigenetic changes in AH improves, we may be able to target dysregulated genes which interfere with normal hepatocyte function.
      • Argemi J.
      • Latasa M.U.
      • Atkinson S.R.
      • Blokhin I.O.
      • Massey V.
      • Gue J.P.
      • et al.
      Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.
      IL-22 is a pleiotropic cytokine with potentially beneficial effects both in the gut and in the liver. IL-22 stimulates regeneration of epithelial cells, inhibits apoptosis and suppresses inflammation. F-652 is a recombinant fusion protein of IL-22 which was tested in a phase II trial in patients with moderate and severe AH. In this study, the efficacy of F-652 was compared to propensity matched patient cohorts for the rate of Lille response at day 7 and MELD response at day 28.
      • Arab J.P.
      • Sehrawat T.S.
      • Simonetto D.A.
      • Verma V.K.
      • Feng D.
      • Tang T.
      • 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.
      Strong safety data and encouraging efficacy results from this study have stimulated progression into a phase III trial.
      Granulocyte-colony stimulating factor (G-CSF) is another pleiotropic cytokine which has been evaluated in patients with AH. G-CSF mobilises CD-34+ haemopoietic stem cells which have been shown to migrate to the liver and stimulate hepatic progenitor cell proliferation.
      • Spahr L.
      • Lambert J.F.
      • Rubbia-Brandt L.
      • Chalandon Y.
      • Frossard J.L.
      • Giostra E.
      • et al.
      Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial.
      However, G-CSF has not conferred a consistent survival advantage in clinical trials, either in patients with AH or acute-on-chronic-liver failure.
      • Marot A.
      • Singal A.K.
      • Moreno C.
      • Deltenre P.
      Granulocyte colony-stimulating factor for alcoholic hepatitis: a systematic review and meta-analysis of randomised controlled trials.
      Further into the future, as regenerative technology advances, opportunities may develop in 3D printing, bioengineered scaffolding, and auxillary or cell-based xenotransplantation providing an armamentarium of regenerative hepatology solutions.

      Manipulation of the microbiome and gut epithelial integrity

      Ground-breaking discoveries from basic and preclinical research in recent years have provided new insights into ALD.
      • Fairfield B.
      • Schnabl B.
      Gut dysbiosis as a driver in alcohol-induced liver injury.
      Some of the most impactful findings are related to the gut-liver axis: specifically, the role of the fungal and viral gut biome, new insights into the complexity of innate immune cell populations and their activation, and a variety of potential non-invasive biomarkers of disease and disease outcomes. Advanced technologies from genomic, transcriptomic, and proteomic studies generated “big data” sets that provide novel information at molecular and cellular levels not seen before.
      Systemic and hepatic immune cell defects in AH warrant further investigations and may reveal new pathomechanisms.

      Gut-liver axis and complexity of dysbiosis

      While it has long been established that the gut-liver axis and alcohol-induced increases in gut permeability are important in the pathogenesis of ALD, recent studies have explored the wider effects of alcohol (beyond bacterial disbalance) on the gut microbiome(Fig. 4). The fungal mycobiome that contributes to both normal homeostasis and disease development is also disturbed by alcohol use.
      • Demir M.
      • Lang S.
      • Hartmann P.
      • Duan Y.
      • Martin A.
      • Miyamoto Y.
      • et al.
      The fecal mycobiome in non-alcoholic fatty liver disease.
      ,
      • Schnabl B.
      Update on the role of the gut microbiota on alcohol-associated liver disease.
      Candida is the most abundant genus in the faecal mycobiota in patients with AUD with or without liver disease, and serum anti-Saccharomyces cerevisiae is high in patients with AH, indicating a possible correlation between disease activity and the mycobiome in AH.
      • Lang S.
      • Duan Y.
      • Liu J.
      • Torralba M.G.
      • Kuelbs C.
      • Ventura-Cots M.
      • et al.
      Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis.
      Taking a step forward, the intestinal virome is also influenced by alcohol use and shows profound changes in AH. Unlike the microbiome that is characterised by decreased diversity in bacteria, increased viral diversity was reported in patients with ALD. The most significant changes in ALD samples were in Escherichia, Enterobacteriae, and Enterococcus phages that were over-represented in patients with AH. Interestingly, mammalian viruses including Parvoviridae and Herperviridae were also significantly increased in AH.
      • Jiang L.
      • Lang S.
      • Duan Y.
      • Zhang X.
      • Gao B.
      • Chopyk J.
      • et al.
      Intestinal virome in patients with alcoholic hepatitis.
      These new discoveries regarding components of the gut flora and their abnormalities in ALD and AH highlight the complexity of potential interactions between alcohol, gut microbiome, mycobiome, virome and the host in determining disease progression and outcomes.
      Figure thumbnail gr4
      Fig. 4Changes in the microbiome in patients with AH have been described by numerous groups and summarised by Fairfield.
      • Fairfield B.
      • Schnabl B.
      Gut dysbiosis as a driver in alcohol-induced liver injury.
      Reductions in Atopobium and multiple genera of short-chain fatty acid producers (from the families Lachnospiraceae and Ruminococcaceae) alongside enrichment of Streptococci, Bifidobacteria, Enterobacteria, Fusobacterium, Megasphaera, and Veillonella have been observed in patients with severe AH. AH, alcohol-associated hepatitis; LPS, lipopolysaccharide.
      In patients with ALD, and particularly AH, the abundance of E. faecalis increases substantially and in 30–40% of patients E. Faecalis expresses a cytolysin that is associated with high levels of mortality.
      • Duan Y.
      • Llorente C.
      • Lang S.
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      • Jiang L.
      • et al.
      Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.
      In animal models of AH, using highly selective phages to target cytolysin-positive E. Faecalis led to clearance of the species from the microbiome and improved the biochemistry, histology, and survival of mice. Alternative approaches for removing cytolysin-positive E. faecalis may include oral administration of targeted antibodies, encapsulated to avoid gastroduodenal degradation.
      It is challenging to change the microbiome using either pre- or pro-biotics, but faecal microbial transplantation (FMT), which potentially replaces all microbial communities in the small and large intestine, has been successfully tested in patients with AH.
      • Philips C.A.
      • Pande A.
      • Shasthry S.M.
      • Jamwal K.D.
      • Khillan V.
      • Chandel S.S.
      • et al.
      Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study.
      However, whilst further trials of FMT are conducted to evaluate efficacy, more research is required to understand the mechanisms through which FMT influences clinical outcomes. One further benefit of FMT is the intriguing finding of reduced alcohol craving after the procedure in patients with alcohol-related cirrhosis.
      • Bajaj J.S.
      • Gavis E.A.
      • Fagan A.
      • Wade J.B.
      • Thacker L.R.
      • Fuchs M.
      • et al.
      A randomized clinical trial of fecal microbiota transplant for alcohol use disorder.
      Replication and further understanding of this phenomenon is urgently required.

      Monitoring and treatment of epithelial integrity

      Breakdown of the intestinal epithelial barrier in AH leads to increased permeability and translocation of bacterial products into the portal circulation. Lipopolysaccharide and bacterial DNA in the portal circulation may engage with TLRs expressed on Kupffer cells in the hepatic sinusoids leading to the expression of pro-inflammatory cytokines and exacerbation of hepatitis.
      • Maccioni L.
      • Gao B.
      • Leclercq S.
      • Pirlot B.
      • Horsmans Y.
      • De Timary P.
      • et al.
      Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans.
      Damage to the epithelia may be caused directly by alcohol or by the accumulation of acetaldehyde due to the expression of alcohol dehydrogenase without expression of acetaldehyde dehydrogenase in epithelial cells. Furthermore, epithelial damage may be caused by changes in the intestinal microbiome.
      Measurement of gut permeability is challenging.
      • Skinner C.
      • Thompson A.J.
      • Thursz M.R.
      • Marchesi J.R.
      • Vergis N.
      Intestinal permeability and bacterial translocation in patients with liver disease, focusing on alcoholic aetiology: methods of assessment and therapeutic intervention.
      The absorption into blood and renal excretion of orally administered sugars has traditionally been used to measure paracellular leakage, but this is not feasible in patients with intravascular volume constraints or impaired renal function. Measurement of bacterial products in the systemic circulation is difficult to interpret. Normally these products would be rapidly removed by monocytes in the circulation or by Kupffer cells in the liver. The presence of bacterial 16S-ribosomal DNA (16S-rDNA) in the circulation may therefore reflect translocation, failure of phagocytic function or shunting across the liver or alternatively the products may arise through systemic infection. Work is currently ongoing to design fluorescent probes which can be administered orally and detected transdermally using point-of-care finger probes similar to pulse oximeters.
      • Maurice J.
      • Lett A.M.
      • Skinner C.
      • Lim A.
      • Richardson M.
      • Thomas A.P.
      • et al.
      Transcutaneous fluorescence spectroscopy as a tool for non-invasive monitoring of gut function: first clinical experiences.
      This technology should allow for both the detection and monitoring of increased gut permeability and therapeutic responses.
      FMT has been shown to improve outcomes in patients with severe AH but the mechanism underpinning this improvement is unknown. The proposed benefits include replacement of microbial colonies which induce epithelial damage and an increase of colonies which supply short-chain fatty acids to nourish the epithelial cells. The ability to monitor changes in gut permeability in real time would help us to understand this therapeutic intervention and hopefully to design specific drugs which avoid the problems of FMT.
      The poor level of mucosal integrity in patients with AH allows for translocation of microbial products into the portal venous system, leading to inflammation when these pathogen-associated molecular patterns encounter innate immune receptors such as TLRs expressed on Kupffer cells in the liver sinusoids. Alternative therapeutic strategies include removal of bacterial products (e.g. using antibodies to lipopolysaccharide)or suppressing TLR signalling to reduce inflammation.
      • Chen F.
      • Zou L.
      • Williams B.
      • Chao W.
      Targeting toll-like receptors in sepsis: from bench to clinical trials.
      Advances are occurring in our understanding of the gut-liver axis and liver regeneration as targets in AH.

      Genetic targets

      It has been known for some time that AUD and susceptibility to ALD is influenced by host genetic background.
      • Morgan M.Y.
      • Sharma M.
      • Atkinson S.R.
      Genetic and environmental susceptibility to alcoholic hepatitis.
      In twin studies the concordance for alcohol-related cirrhosis is 3-fold higher in monozygotic twins than in dizygotic twin pairs. Genetic association studies with candidate genes have identified patatin like phospholipase domain containing 3 (PNPLA3), hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) and SERPINA1 (serpin family A member 1) as susceptibility genes. Genome-wide association studies have identified a number of susceptible or protective loci for ALD. These include rs58542926 in TM6SF2 (transmembrane 6 superfamily member 2); rs641738 in MBOAT7 (membrane-bound O-acyltransferase domain containing 7), rs15052 in HNRNPUL1 (heterogeneous nuclear ribonucleoprotein U like 1), rs2642438 in MARC1 (mitochondrial amidoxime reducing component 1) and rs374702773 in FAF2 (fas associated factor family member 2). In studies specifically addressing AH, both PNPLA3 and HSD17B13 have been confirmed as susceptibility loci. The loss of function variant of HSD17B13, which confers protection against NASH, alcohol-related cirrhosis, and AH is a potential therapeutic target.
      • Stickel F.
      • Lutz P.
      • Buch S.
      • Nischalke H.D.
      • Silva I.
      • Rausch V.
      • et al.
      Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers.
      RNA interference (RNAi) technologies are now established in clinical medicine with the recent licensing of inclisiran, which targets PCSK9 (proprotein convertase subtilisin/kexin type 9).
      • Ray K.K.
      • Wright R.S.
      • Kallend D.
      • Koenig W.
      • Leiter L.A.
      • Raal F.J.
      • et al.
      Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.
      Both Arrowhead and Alnylam are currently testing RNAi directed at HSD17B13 as a treatment for non-ALD.
      Analysis of gene expression in liver tissue from patients with AH has the potential to reveal disease-associated pathways. Argemi and colleagues used analysis of gene expression to identify two common pathways which are dysregulated in AH.
      • Argemi J.
      • Latasa M.U.
      • Atkinson S.R.
      • Blokhin I.O.
      • Massey V.
      • Gue J.P.
      • et al.
      Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.
      Firstly, genes regulated by peroxisome proliferator activated receptor-γ were found to be upregulated in alcohol-related steatohepatitis but downregulated in AH. Secondly, genes regulated by HNF4a were downregulated in AH. HNF4a-regulated genes perform many of the crucial hepatocyte functions such as gluconeogenesis, albumin and coagulation factor synthesis, cytochrome P450 activity and bile transport. Dysregulation of these genes is associated with the expression of a foetal (P2) isoform of HNF4a which has opposing functions to the adult (P1) isoform. Suppression of the HNF4a-P2 isoform is theoretically feasible using RNAi techniques, while mRNA therapy has been used to overexpress HNF4a-P1 in rodent models.
      • Yang T.
      • Poenisch M.
      • Khanal R.
      • Hu Q.
      • Dai Z.
      • Li R.
      • et al.
      Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.
      Restoration of normal HNF4a signalling would be expected to re-establish liver synthetic functions.
      DUR-928 is an endogenous sulfated oxysterol which acts as an epigenetic regulator through inhibition of specific DNA methyltransferases, leading to upregulation of cell survival genes and downregulation of lipid biosynthesis genes.
      • Wang Y.
      • Lin W.
      • Brown J.E.
      • Chen L.
      • Pandak W.M.
      • Hylemon P.B.
      • et al.
      25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes.
      In a phase IIa trial in patients with moderate and severe AH, DUR-928 appeared to elicit favourable biochemical responses and Lille responses in comparison to matched historical controls. A phase IIb study is currently recruiting.

      Use of biomarkers to diagnose, monitor, and improve outcomes

      Molecular biomarkers

      Measurement of bacterial 16S-rDNA in whole blood samples using quantitative real-time PCR gives an indication of the risk of infection over the following 7 days.
      • Vergis N.
      • Atkinson S.R.
      • Knapp S.
      • Maurice J.
      • Allison M.
      • Austin A.
      • et al.
      In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, and is associated with high circulating levels of bacterial DNA.
      A point-of-care device for measuring 16S-rDNA is currently under evaluation and may find a role in clinical practice to predict or detect early infection. An alternative strategy is the use of prophylactic antibiotics to prevent infection in patients receiving corticosteroids. Unfortunately, the Antibiocor trial, which compared prednisolone against prednisolone plus co-amoxiclav, recently reported negative results.
      • Louvet A.
      • Labreuche J.
      • Dao T.
      • Thevenot T.
      • Oberti F.
      • Bureau C.
      • et al.
      Combination of amoxicillin/clavulanate and prednisolone in severe alcoholic hepatitis: results of the antibiocor randomized controlled trial.
      The reason for this disappointing outcome is not yet known, although the number of infections in the combination treatment arm was reduced.
      Cytokeratin-18 (CK18) is a structural cytoplasmic protein which is broken down and released into the blood as a result of apoptosis and cell death. High levels of the CK18-M30 fragment are found in patients with AH, making it a suitable biomarker to support the clinical diagnosis in the absence of a liver biopsy.
      • Bissonnette J.
      • Altamirano J.
      • Devue C.
      • Roux O.
      • Payancé A.
      • Lebrec D.
      • et al.
      A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis.
      However, very high levels (>5,000 IU/ml) of CK18-M30 also identify a subgroup of patients who, when treated with corticosteroids, achieve a 90-day survival advantage.
      • Atkinson S.R.
      • Grove J.I.
      • Liebig S.
      • Astbury S.
      • Vergis N.
      • Goldin R.
      • et al.
      In severe alcoholic hepatitis, serum keratin-18 fragments are diagnostic, prognostic, and theragnostic biomarkers.
      CK18 assay kits for in vitro diagnostic use are now available and licensed.
      An alternative biomarker which identifies patients who might benefit beyond 28 days from corticosteroid treatment is the neutrophil-to-lymphocyte ratio.
      • Forrest E.H.
      • Storey N.
      • Sinha R.
      • Atkinson S.R.
      • Vergis N.
      • Richardson P.
      • et al.
      Baseline neutrophil-to-lymphocyte ratio predicts response to corticosteroids and is associated with infection and renal dysfunction in alcoholic hepatitis.
      A neutrophil-to-lymphocyte ratio value can be derived from the routine blood count parameters and a value between 5 and 8 has been associated with improved 90-day survival.
      Biomarkers of macrophage activation, soluble CD163 and soluble CD206 as well as HMGB1 (high mobility group box 1) and osteopontin, a multifunctional protein involved in neutrophil activation, are increased in AH and correlate with increasing MELD scores. Furthermore, increased plasma levels of soluble CD14 predict 90-day mortality, soluble CD163 predicts infection and osteopontin predicts development of organ failure in AH.
      • Saha B.
      • Tornai D.
      • Kodys K.
      • Adejumo A.
      • Lowe P.
      • McClain C.
      • et al.
      Biomarkers of macrophage activation and immune danger signals predict clinical outcomes in alcoholic hepatitis.
      Other biomarkers under investigation include circulating microRNAs, microRNAs, and sphingolipid cargo associated with extracellular vesicles.
      • Sehrawat T.S.
      • Arab J.P.
      • Liu M.
      • Amrollahi P.
      • Wan M.
      • Fan J.
      • et al.
      Circulating extracellular vesicles carrying sphingolipid cargo for the diagnosis and dynamic risk profiling of alcoholic hepatitis.
      In patients with AH, miR-192 and miR-30a are increased
      • Momen-Heravi F.
      • Saha B.
      • Kodys K.
      • Catalano D.
      • Satishchandran A.
      • Szabo G.
      Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis.
      and, in one study, miR-201-5p, miR-146a-5p, and miR-26b-5p predicted mortality.
      • Yang Z.
      • Zhang T.
      • Kusumanchi P.
      • Tang Q.
      • Sun Z.
      • Radaeva S.
      • et al.
      Transcriptomic analysis reveals the MicroRNAs responsible for liver regeneration associated with mortality in alcohol-associated hepatitis.
      Profiling of AH-specific microRNA signatures is an active area of research.
      Genetic and digital biomarkers represent an opportunity for multimodal data streams that could one day enable the personalised care of patients with AH.

      Digital biomarkers

      Improvements in artificial intelligence, machine learning, and collection of much larger data streams from electronic medical records, remote patient monitoring, and sequencing data from biospecimens have allowed researchers to generate more powerful predictive analytic algorithms than was previously possible (Fig. 5).
      • Ahn J.C.
      • Connell A.
      • Simonetto D.A.
      • Hughes C.
      • Shah V.H.
      Application of artificial intelligence for the diagnosis and treatment of liver diseases.
      These types of approaches have allowed us to further refine traditional algorithms using more traditional techniques such as logistical regression. An example is the MELD score, which was generated by logistic regression – in recent studies, the predictive capabilities of the MELD score have been refined using additional non-biased variables.
      • Guo A.
      • Mazumder N.R.
      • Ladner D.P.
      • Foraker R.E.
      Predicting mortality among patients with liver cirrhosis in electronic health records with machine learning.
      • Kezer C.A.
      • Buryska S.
      • Ahn J.C.
      • Harmsen W.S.
      • Dunn W.
      • Singal A.K.
      • et al.
      The mortality index for alcohol-associated hepatitis: a novel prognostic score.
      • Ahn J.C.
      • Noh Y.K.
      • Rattan P.
      • Buryska S.
      • Wu T.
      • Kezer C.A.
      • et al.
      Machine learning techniques differentiate alcohol-associated hepatitis from acute cholangitis in patients with systemic inflammation and elevated liver enzymes Mayo.
      Similar predictive analytics have recently been used to help clinicians distinguish differential diagnoses such as cholangitis from AH.
      • Ahn J.C.
      • Noh Y.K.
      • Buryska S.
      • Rattan P.
      • Wu T.
      • Kezer C.A.
      • et al.
      Application of supervised machine learning techniques for classification of alcohol-associated hepatitis and acute cholangitis in patients with elevated liver enzymes and systemic inflammatory response.
      Figure thumbnail gr5
      Fig. 5Multimodal data integration for personalised therapy.
      Although these advances are exciting and will continue to improve over the coming years as we generate even larger data sets and better analytic capabilities, most of these have not been definitively able to improve upon traditional clinician diagnosis. The future will likely involve a combination of algorithm approaches that can refine differential diagnosis with ultimate clinician oversight of the process and final determination.
      • Ahn J.C.
      • Connell A.
      • Simonetto D.A.
      • Hughes C.
      • Shah V.H.
      Application of artificial intelligence for the diagnosis and treatment of liver diseases.
      This can be seen as akin to current clinical guidelines that provide suggestions for decision making with ultimate oversight by the clinician.

      Remote biomonitoring

      Remote biomonitoring encompasses the opportunities to measure biological and behavioural-related data from patients in real time. Biological data may include vital signs and physiologic data. This is exemplified most simply by Fitbit and other common commercial tools that enable easy collection of physiologic information.
      • Linton S.C.
      • De Boer C.
      • Tian Y.
      • Alayleh A.
      • Bouchard M.E.
      • Figueroa A.
      • et al.
      Effect of consumer-grade wearable device data on clinician decision making during post-discharge telephone calls after pediatric surgery.
      From a medical lens, many tools and vendors are available to collect more refined information relevant to patients with ALD, including weight, blood pressure, pulse, and even single-lead electrocardiograms, which can all provide early indications of liver decompensation and responses to various medications that may influence these parameters.
      • Ahn J.C.
      • Attia Z.I.
      • Rattan P.
      • Buryska S.
      • Allen A.M.
      • Kamath P.S.
      • et al.
      Development of the AI-Cirrhosis-ECG (ACE) Score: an electrocardiogram-based deep learning model in cirrhosis.
      The concept of physiologic remote patient monitoring has also expanded to digital technologies for behavioural monitoring. This is most relevant for AUD, where ecological momentary assessments can be ascertained from both active and passive cell phone data, including GPS tracking and behavioural assessments that may predict alcohol craving or relapse.
      • Wu T.
      • Simonetto D.A.
      • Halamka J.
      • Shah V.H.
      The digital transformation of hepatology: the patient is logged in.
      ,
      • McKay J.R.
      • Gustafson D.H.
      • Ivey M.
      • McTavish F.
      • Pe-Romashko K.
      • Curtis B.
      • et al.
      Effects of automated smartphone mobile recovery support and telephone continuing care in the treatment of alcohol use disorder: study protocol for a randomized controlled trial.
      Advances have also been made in monitoring of blood alcohol levels from a number of easily measurable body sources that can provide bloodless and remote blood alcohol estimations in patients.
      • Wozniak M.K.
      • Wiergowski M.
      • Namiesnik J.
      • Biziuk M.
      Biomarkers of alcohol consumption in body fluids - possibilities and limitations of application in toxicological analysis.

      New care models to monitor and treat AUD

      Patients with ALD have complex clinical and psychological profiles that are difficult for hepatologists alone to manage. ALD is a dual disease that requires focus on both the liver and the AUD. Many hepatologists at the current time do not have the capabilities to manage AUD.
      • Im G.Y.
      • Mellinger J.L.
      • Winters A.
      • Aby E.S.
      • Lominadze Z.
      • Rice J.
      • et al.
      Provider attitudes and practices for alcohol screening, treatment, and education in patients with liver disease: a survey from the American Association for the Study of Liver Diseases alcohol-associated liver disease special interest group.
      This includes the inability to recognise the benefits and deficiencies of tests that detect alcohol use, such as phosphatidylethanol and urinary ethyl glucuronide, lack of experience to prescribe FDA approved (acamprosate, naltrexone), and non-approved (baclofen) medications for AUD, and inability to provide behavioural interventions necessary to support the treatment of AUD. Many patients with ALD also have psychosocial challenges that complicate their management.
      • Winder G.S.
      • Fernandez A.C.
      • Klevering K.
      • Mellinger J.L.
      Confronting the crisis of comorbid alcohol use disorder and alcohol-related liver disease with a novel multidisciplinary clinic.
      This has led to the development of multidisciplinary management teams that include psychologists, social workers, and others. Models for integrated care include gastroenterologists or hepatologists, primary care physician, patient’s home and then a multidisciplinary clinic that may involve a social worker and a psychologist. There are algorithms that suggest which patients might benefit from this integrated care model.
      • Lucey M.R.
      • Singal A.K.
      Integrated treatment of alcohol use disorder in patients with alcohol-associated liver disease: an evolving story.
      These are based on the presence of AUD (assessed by the AUDIT score) and ALD (assessed by laboratory testing, history, and imaging).
      Initial descriptions of such models indicate improvements in quality of care in this patient population. An early description in 2013 by Addolorato et al.
      • Addolorato G.
      • Mirijello A.
      • Leggio L.
      • Ferrulli A.
      • D'Angelo C.
      • Vassallo G.
      • et al.
      Liver transplantation in alcoholic patients: impact of an alcohol addiction unit within a liver transplant center.
      reported that the presence of an alcohol addiction unit within a transplant centre reduced the risk of post-transplant relapse. Indeed, transplant centres are the most common setting for this type of multidisciplinary model. A more recent study by Mellinger et al.
      • Mellinger J.L.
      • Winder G.S.
      • Fernandez A.C.
      • Klevering K.
      • Johnson A.
      • Asefah H.
      • et al.
      Feasibility and early experience of a novel multidisciplinary alcohol-associated liver disease clinic.
      shows, even in the non-transplant setting, that rates of hospital admission and emergency room utilisation/person/month are reduced in a multidisciplinary model. Recommendations include colocation of the team, multidisciplinary approach, a focus on interpersonal team relations, novel approaches to patient encounters, and engagement with unaffiliated community and outreach locations. While there are a number of benefits to the multidisciplinary care model, barriers exist to their implementation outside of the transplant setting. Barriers include financial sustainability of the model, logistical complexity, inequities of the patient population, and the patient’s cognitive status.

      Conclusion

      Significant breakthroughs are occurring in the science of ALD that are now impacting patient care. Given the parallel transformative advances in biomedicine, there are tremendous opportunities for us to re-imagine how we care for patients with ALD using multimodal data and digital medicine to provide personalised and effective care for our patients.

      Abbreviations

      16S-rDNA, 16S-ribosomal DNA; AH, alcohol-associated hepatitis; ALD, alcohol-associated liver disease; AUD, alcohol use disorder; CK18, cytokeratin-18; FMT, faecal microbiota transplantation; G-CSF, granulocyte-colony stimulating factor; HNF4α, hepatocyte nuclear factor 4 α; HSD17B13, hydroxysteroid 17-beta dehydrogenase 13; MELD, model for end-stage liver disease; NASH, non-alcoholic steatohepatitis; PNPLA3, patatin like phospholipase domain containing 3; RNAi, RNA interference; TLR, Toll-like receptor.

      Financial support

      MT receives grant funding from the UK Medical Research Council and acknowledges support from NIHR Imperial Biomedical Research Centre .

      Authors’ contributions

      VS, GS and MT contributed equally to the writing, editing and proof reading of the paper.

      Conflict of interest

      GS receives funding from the National Institute on Alcoholism and Alcohol Abuse and National Institute on Aging.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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