Review

Therapeutic advances in alcohol-associated hepatitis

Gyongyi Szabo3, Mark Thursz2,*, Vijay H. Shah1

Summary
In recent years, there have been important advances in our understanding of alcohol-associated hepatitis Keywords: Trial design;
Microbiome; Systemic
(AH), which have occurred in parallel with a surge in clinical trial activity. Meanwhile, the broader
inflammatory
medical field has seen a transformation in care paradigms based on emerging digital technologies. This response syndrome.
review focuses on breakthroughs in our understanding of AH and how these breakthroughs are leading
Received 18 January 2022;
to new paradigms for biomarker discovery, clinical trial activity, and care models for patients. It portends
received in revised form 3 March
a future in which multimodal data from genetic, radiomic, histologic, and environmental sources can be 2022; accepted 24 March 2022
integrated and synthesised to generate personalised biomarkers and therapies for patients with AH.
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
1
Introduction Carol M. Gatton Chairman of
7 Medicine, Mayo Clinic,
Alcohol-associated hepatitis (AH) is a syndrome diseases. Interestingly many of these genes regu- Rochester, MN, USA; 2Division
characterised by jaundice and liver failure occur- late key inflammatory pathways that are dysregu- of Digestive Diseases, Imperial
ring in people who are actively drinking high levels lated in ALD. Given substantial improvements in College, London, UK; 3Mitchell
T. Rabkin, M.D. Chair, Professor
of alcohol and who have been drinking excessively sequencing technology, computational bio- and
of Medicine, Harvard Medical
for a prolonged period.1 There is usually a sub- clinical-informatics, these multimodal sources of School, Chief Academic Officer,
acute presentation with jaundice developing over data can eventually be integrated and individu- Beth Israel Deaconess Medical
2 to 6 weeks and, at the time of admission to alised, and will hopefully lead to advances in per- Center and Beth Israel Lahey
Health, Boston, MA, USA
hospital, there is evidence of coagulopathy and, in sonalised biomarkers and therapies. In this review,
many patients, evidence of decompensation man- we have selected some of the key advances in trial * Corresponding author.
Address: Division of Digestive
ifest as ascites or encephalopathy. The severity of design, immunology, genetics, microbiome, and Diseases, Imperial College
AH is conventionally determined by Maddrey’s digital technology that, in our opinion, will trans- London, South Kensington
discriminant function with a score greater than 31 form the management of AH in the next few years. Campus, London, UK. SW7
2AZ; Tel.: +44 (0)20
being considered severe.2 Expert consensus also
7589 5111.
equates a model for end-stage liver disease (MELD) Advances in trial design
score greater than 20 as severe AH.3 Severe AH is Whilst for many years there were few trials in the E-mail address: m.thursz@
imperial.ac.uk (M. Thursz).
associated with high short-term mortality despite field of AH due to challenges in patient population,
cessation of alcohol use; 20% of patients will die recruitment, and pharmacokinetics/drug safety in https://doi.org/10.1016/j.jhep.
within 28 days of admission and 30% within 90 the setting of advanced liver disease, the number of 2022.03.025
days.4 In clinical trials conducted prior to 2000, the both commercial- and investigator-led studies is
mortality associated with this condition was currently increasing. However, one of the problems
considerably higher, but the reason for improved encountered in this field is the choice of trial
survival is not yet clear. endpoint. Traditionally, mortality at 28 days after
In recent years, there have been several break- enrolment in a trial has been used as a primary
throughs in our understanding of the pathobiology endpoint.4 The mortality rate at this time has
of alcohol-associated liver disease (ALD). For de- steadily fallen, with approximately 20% of patients
cades, hypothesis-driven approaches were at the expected to die by this timepoint. Furthermore,
forefront of research. This has drastically changed side effects of treatment which may impact out-
so that our focus is now on unbiased approaches to comes may continue to manifest after 28 days.8
discovery which have the potential to reveal new Consensus is now forming around a 90-day time-
molecules, pathways, and genes. Genetic studies point when the expected mortality will be around
have identified new genes highly associated with 30%.9 In patients who remain abstinent, the AH
alcohol use disorder (AUD), ALD and fibrosis.5,6 process normally resolves by 90 days but the
Remote patient monitoring has also allowed for a drivers of mortality beyond this time are domi-
new stream of digital data. Studies in tran- nated by resumption of alcohol use.10
scriptomic and proteomic analysis have exploded, One further complication of using mortality as
providing valuable large datasets. Multi-omics an endpoint is the increasing access to liver
integration has been used to identify novel genes transplantation for this group of patients. Patients
associated with alcohol dependence, which who have been transplanted are often classified the
potentially overlap with neurodegenerative same as patients who have died on the basis that

Journal of Hepatology 2022 vol. 76 j 1279–1290

Review
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.11
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 sur-
rogate 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 pro-
portion of patients who achieve a Lille score <0.45
appears to predict mortality at 90 days.4 However,
the mechanisms of action of many putative treat-
ments may take longer than 7 days to influence
survival. An alternative endpoint is therefore the
change in MELD score from baseline to 28 days.
Key point
Recruitment to clinical trials in AH is often
Advances in clinical trial challenging. Whilst incidence rates are currently
methodology provide new increasing, AH is less common than acute decom-
opportunities to improve
pensation of alcohol-related cirrhosis and patients
the management of AH.
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 inter-
vention 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.
Multi-arm, multi-stage trials (MAMS)
Standard Treatment Treatment
of care 1 2
Stage 1: N = 25 N = 25
Stage 2: N = 25 N = 25
Phase II
Stage 3: N = 25
Stage 4: N = 25
Lille response Lille response
< X% < X%
Phase III
Standard
of care
Fig. 1. Multi-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.
1280 Journal of Hepatology 2022 vol. 76 j 1279–1290
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 tri-
als.12 However, as the risk of mortality varies sub-
stantially 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 ur-
gently 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 regu-
lator prescribed pathway but many of the candi-
date 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 mul-
tiple interventions simultaneously.13 These designs
use pre-specified safety and therapeutic efficiency
thresholds to eliminate underperforming treat-
ment 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-19.14
Other innovations in trial designs include syn-
thetic placebo arms, which are becoming a reality
in non-alcoholic steatohepatitis (NASH) – given
Treatment Treatment
3 4
N = 25
N = 25
Lille response
< X%
Treatment
3
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 experi-
ence and patients. Another recent trial trend re-
lates 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.
Therapeutic advances in target selection
based on new pathobiology
Controlling inflammation
Transcriptomic characterisation of single cells us-
ing burgeoning advances in sequencing and bio-
informatics technology has uncovered new
paradigms in liver inflammation. For example,
single-cell RNA sequencing of human liver cells
revealed 20 distinct cell populations including he-
patocytes, endothelial cells, cholangiocytes, hepatic
stellate cells, B cells, conventional and non-
conventional T cells, natural killer-like cells, and
distinct hepatic monocyte/macrophage pop-
ulations. Confirming previous findings, zonation
of the hepatic tissue and zone-specific gene sig-
natures were found.15 Single-cell data revealed
immune cell diversity of peripheral and liver
monocytes in AH that highlighted cell-specific
differences in monocyte responses.16 Heterogene-
ity of monocytes and macrophages is well estab-
lished 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 dy-
namic role of the different immune cell pop-
ulations in the liver and circulation during the
disease process and progression of AH – these as-
pects 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 (Figs 2 and 3).
Activation of the NLRP3 (NLR family pyrin domain
containing 3) inflammasome following the combi-
nation 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)-1b. IL-1b levels
are increased in the serum of patients with AH and
in animal models of the disease.17,18 Inhibition of
IL-1b production by genetic targeting of the

Alcohol + metabolites

Hepatocyte damage ↑ MCP1

↑ CXCL and
other chemokines

↑ Pro-inflammatory
cytokines
DAMPs TNFα
IL-1α
IL-1β

↑ Neutrophil
Hepatic stellate cell activation
NET release
NETs Fibres
Neutrophil Kupffer cells
Macrophages ↓ Decreased
LSECs macrophage
phagocytosis
↑ Adhesion Stellate cell Diverse and efferocytosis
molecules activation macrophage Gut derived
↓ Fenestrae populations PAMPs

Fig. 2. Cellular 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 sinu-
soidal 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; TNFa, tumour necrosis
factor-a.

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Review

Stills disease.19 A recent trial in the US compared

PAMPs the use of anakinra in combination with zinc and
LPS
pentoxifylline vs. corticosteroids in patients with
severe AH, finding a numerical but non-significant
survival advantage.20–22 A new trial is currently
underway to explore the efficacy of anakinra in a
TLR CD14 TNFα, IL-1β, larger population. A small phase IIa trial of cana-
chemokines kinumab has recently completed recruitment and
release is due to report in the near future.
MyD88 Cytokine activation that is pathognomonic in
DAMPs
(ATP, uric acid) AH also leads to release of chemokines that recruit
neutrophils to the liver. Recent studies have
examined chemokine inhibitors such as cen-
IRAK1/4
icriviroc in preclinical models of AH.23 This is
particularly relevant given ongoing trial activity
NLRP3 with this compound in NASH.24,25 Recent studies
inflammasome
IKKα/β complex have also linked cytokine activation to chemokine
production through epigenetic mechanisms
including superenhancers that can regulate
pro-caspase-1 groups of chemokines in tandem. This has led to
p50 p65 investigation of therapies targeting transcription
NF-κB caspase-1 factors that regulate superenhancers such as
pro-IL-1β IL-1β bromodomain-containing protein 4.26 Epigenetic
pathways focused on the transcription factor he-
patocyte nuclear factor 4 (HNF4), which regulate
hepatocyte reprogramming, have also been
investigated recently and are discussed
TNFα, IL-1β, chemokines further below.
promoters

Avoiding infection
NF-κB
p50 p65 A paradox in AH is that even though the immune
system is “activated”, infection and sepsis are
Superenhancer Nucleus Cytoplasm common complications. This has led to a concept of
“immune exhaustion” in AH which is under study
Fig. 3. Molecular pathways involved in AH. Gut-derived PAMPs activate various TLRs. For and requires refinement. Clinical acumen and dili-
example, LPS activates the TLR4/CD14 receptor complex and via the MyD88-dependent down- gence are required to detect the early onset of
stream pathway induces IRAK1/4 activation and downstream IKK and NF-jB activation. The NF-
infection in order to prevent progression to SIRS
jB 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 acti- (systemic inflammatory syndrome) acute kidney
vation of the pro-inflammatory cascade. Chemokines, TNFa, IL-6 and pro-IL-1b are produced. injury and multi-organ failure.27 Approximately
Processing of pro-IL-1b to bioactive IL-1b requires cleavage by caspase-1. Caspase-1 activation is 25% of patients with severe AH will develop inci-
triggered by activation of the intracellular sensor, NLRP3, leading to assembly of the inflam- dent (after admission to hospital) infection which
masome, 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
has a significant impact on their chances of sur-
increased in AH). AH, alcohol-associated hepatitis; DAMPs, damage-associated molecular pat- vival.8,28 A number of immunological deficits have
terns; IL-, interleukin; LPS, lipopolysaccharide; NLRP3, NLR family pyrin domain containing 3; been described, which partially account for the
PAMPs, pathogen-associated molecular patterns; TLR, Toll-like receptor; TNFa, tumour necrosis observed immune paresis in liver failure and/or
factor-a.
AH. A marked reduction in the oxidative burst
function of neutrophils and monocytes – associ-
ated with reduced expression of components of the
caspase 1 gene protects mice from steatosis, NADPH oxidase complex – has been observed.29
Key point
inflammation, and fibrosis in models of AH. In Ingestion of micro-organisms without killing
Multiomics is uncovering humans, IL-1b can be targeted in several ways. them means that phagocytes may potentially
new molecular targets in Anakinra blocks the IL-1 receptor thereby inhibit- behave as ‘Trojan horses’ disseminating bacteria
AH. ing downstream signalling from either IL-1b or IL- systemically. In vitro, incubation of monocytes with
1a. Canakinumab is a monoclonal antibody tar- N-acetyl cysteine restores their oxidative burst
geting IL-1b directly and is licensed for use in function. In vivo, a trial of prednisolone in combi-
autoinflammatory syndromes associated with IL- nation with N-acetyl cysteine reported significantly
1b production, such as cryopyrin-associated peri- lower rates of incident infection in patients with
odic syndrome, familial Mediterranean fever and severe AH treated with the combination compared

1282 Journal of Hepatology 2022 vol. 76 j 1279–1290

to prednisolone alone.30 In addition to defects in data and encouraging efficacy results from this
oxidative burst function, it has recently been study have stimulated progression into a phase
shown in acute liver failure that failure to phago- III trial.
cytose micro-organisms in the portal circulation, Granulocyte-colony stimulating factor (G-CSF)
due to exhausted sinusoidal macrophages and is another pleiotropic cytokine which has been
dysfunctional monocytes, leads to infection.31 The evaluated in patients with AH. G-CSF mobilises CD-
monocyte and macrophage dysfunction may be 34+ haemopoietic stem cells which have been
corrected ex vivo with antibodies targeting the shown to migrate to the liver and stimulate hepatic
checkpoint inhibitor programmed cell death 1, progenitor cell proliferation.39 However, G-CSF has
creating novel possibilities for the restoration of not conferred a consistent survival advantage in
immune function in patients with AH. Decreased clinical trials, either in patients with AH or acute-
phagocytic activity of macrophages in ALD has also on-chronic-liver failure.40
been linked to reduced elimination of activated Further into the future, as regenerative tech-
neutrophil leukocytes that form NETs (neutrophil nology advances, opportunities may develop in 3D
extracellular traps).32 The role of neutrophils in AH printing, bioengineered scaffolding, and auxillary
remains to be fully elucidated.33 or cell-based xenotransplantation providing an
Using antibiotics prophylactically to prevent armamentarium of regenerative hepatol-
infection is an attractive option in this patient ogy solutions.
group. However, prophylactic treatment may give
rise to antimicrobial resistance and also expose the Manipulation of the microbiome and gut
patient to the risk of drug-induced liver injury. A epithelial integrity
trial of prednisolone plus augmentin (co-amox- Ground-breaking discoveries from basic and pre-
yclav) vs. prednisolone alone has recently reported clinical research in recent years have provided new
results indicating that the addition of antibiotics insights into ALD.41 Some of the most impactful
conferred no therapeutic benefit (In Press). findings are related to the gut-liver axis: specif-
ically, the role of the fungal and viral gut biome,
Stimulating regeneration new insights into the complexity of innate immune
A characteristic feature of AH is the profound loss cell populations and their activation, and a variety
of liver function despite, in many cases, an of potential non-invasive biomarkers of disease
adequate number of residual hepatocytes. There is and disease outcomes. Advanced technologies from
clearly evidence of a regenerative response with genomic, transcriptomic, and proteomic studies
bile ductular proliferation representing an expan- generated “big data” sets that provide novel infor-
sion of progenitor cells, though this does not mation at molecular and cellular levels not
Key point
appear to be sufficient to restore normal liver seen before.
function.34 A high proportion of hepatocytes ex- Systemic and hepatic im-
press senescence makers, indicating that they are Gut-liver axis and complexity of dysbiosis mune cell defects in AH
warrant further investiga-
unable to proliferate in order to replace functional While it has long been established that the gut- tions and may reveal new
liver mass.35 Attempts to provide external liver liver axis and alcohol-induced increases in gut pathomechanisms.
support have not been successful in AH but novel permeability are important in the pathogenesis of
approaches, including the inhibition of MKK4 (also ALD, recent studies have explored the wider effects
known as MAPK24) to support regeneration, of alcohol (beyond bacterial disbalance) on the gut
should be ready for clinical trials in the foreseeable microbiome(Fig. 4). The fungal mycobiome that
future.36 Furthermore, as our understanding of the contributes to both normal homeostasis and dis-
epigenetic changes in AH improves, we may be ease development is also disturbed by alcohol
42,43
able to target dysregulated genes which interfere use. Candida is the most abundant genus in the
37
with normal hepatocyte function. faecal mycobiota in patients with AUD with or
IL-22 is a pleiotropic cytokine with potentially without liver disease, and serum anti-Saccharo-
beneficial effects both in the gut and in the liver. IL- myces cerevisiae is high in patients with AH, indi-
22 stimulates regeneration of epithelial cells, in- cating a possible correlation between disease
44
hibits apoptosis and suppresses inflammation. F- activity and the mycobiome in AH. Taking a step
652 is a recombinant fusion protein of IL-22 which forward, the intestinal virome is also influenced by
was tested in a phase II trial in patients with alcohol use and shows profound changes in AH.
moderate and severe AH. In this study, the efficacy Unlike the microbiome that is characterised by
of F-652 was compared to propensity matched decreased diversity in bacteria, increased viral di-
patient cohorts for the rate of Lille response at day versity was reported in patients with ALD. The
7 and MELD response at day 28.38 Strong safety most significant changes in ALD samples were in

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Review
Escherichia, Enterobacteriae, and Enterococcus
phages that were over-represented in patients with
AH. Interestingly, mammalian viruses including
Parvoviridae and Herperviridae were also signifi-
cantly increased in AH.45 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.
In patients with ALD, and particularly AH, the
abundance of E. faecalis increases substantially and
in 30–40% of patients E. Faecalis expresses a cyto-
lysin that is associated with high levels of mortal-
ity.46 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, encapsu-
lated to avoid gastroduodenal degradation.
It is challenging to change the microbiome us-
ing 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.47 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
Alcohol
Alcohol
Intestinal lumen
LPS
Alcohol
Acetaldehyde
Gastrointestinal
epithelium LPS
Intact
bacteria
Portal venous system
Fig. 4. Changes in the microbiome in patients with AH have been described by numerous groups and summarised by Fairfield.41 Reductions in Atopobium
and multiple genera of short-chain fatty acid producers (from the families Lachnospiraceae and Ruminococcaceae) alongside enrichment of Streptococci, Bifi-
dobacteria, Enterobacteria, Fusobacterium, Megasphaera, and Veillonella have been observed in patients with severe AH. AH, alcohol-associated hepatitis;
LPS, lipopolysaccharide.
1284 Journal of Hepatology 2022 vol. 76 j 1279–1290
patients with alcohol-related cirrhosis.48 Replica-
tion and further understanding of this phenome-
non 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.49 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 intesti-
nal microbiome.
Measurement of gut permeability is chal-
lenging.50 The absorption into blood and renal
excretion of orally administered sugars has tradi-
tionally been used to measure paracellular leakage,
but this is not feasible in patients with intravas-
cular volume constraints or impaired renal func-
tion. Measurement of bacterial products in the
systemic circulation is difficult to interpret. Nor-
mally 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
Cytolysin
Monocytes
products may arise through systemic infection. recent licensing of inclisiran, which targets PCSK9
Work is currently ongoing to design fluorescent (proprotein convertase subtilisin/kexin type 9).55
probes which can be administered orally and Both Arrowhead and Alnylam are currently testing
detected transdermally using point-of-care finger RNAi directed at HSD17B13 as a treatment for
probes similar to pulse oximeters.51 This technol- non-ALD.
ogy should allow for both the detection and Analysis of gene expression in liver tissue from
monitoring of increased gut permeability and patients with AH has the potential to reveal
therapeutic responses. disease-associated pathways. Argemi and col-
FMT has been shown to improve outcomes in leagues used analysis of gene expression to identify
patients with severe AH but the mechanism un- two common pathways which are dysregulated in
derpinning this improvement is unknown. The AH.37 Firstly, genes regulated by peroxisome pro-
proposed benefits include replacement of micro- liferator activated receptor-c were found to be
bial colonies which induce epithelial damage and upregulated in alcohol-related steatohepatitis but
an increase of colonies which supply short-chain downregulated in AH. Secondly, genes regulated by
fatty acids to nourish the epithelial cells. The abil- HNF4a were downregulated in AH. HNF4a-
ity to monitor changes in gut permeability in real regulated genes perform many of the crucial he-
time would help us to understand this therapeutic patocyte functions such as gluconeogenesis, albu-
intervention and hopefully to design specific drugs min and coagulation factor synthesis, cytochrome
which avoid the problems of FMT. P450 activity and bile transport. Dysregulation of
The poor level of mucosal integrity in these genes is associated with the expression of a
patients with AH allows for translocation of mi- foetal (P2) isoform of HNF4a which has opposing
crobial products into the portal venous system, functions to the adult (P1) isoform. Suppression of
leading to inflammation when these pathogen- the HNF4a-P2 isoform is theoretically feasible us-
associated molecular patterns encounter innate ing RNAi techniques, while mRNA therapy has been
immune receptors such as TLRs expressed on used to overexpress HNF4a-P1 in rodent models.56
Kupffer cells in the liver sinusoids. Alternative Restoration of normal HNF4a signalling would be
therapeutic strategies include removal of bacterial expected to re-establish liver synthetic functions.
products (e.g. using antibodies to lipopolysa- DUR-928 is an endogenous sulfated oxysterol
ccharide)or suppressing TLR signalling to which acts as an epigenetic regulator through in-
Key point
reduce inflammation.52 hibition of specific DNA methyltransferases, lead-
ing to upregulation of cell survival genes and Advances are occurring in
Genetic targets downregulation of lipid biosynthesis genes.57 In a our understanding of the
gut-liver axis and liver
It has been known for some time that AUD and sus- phase IIa trial in patients with moderate and severe
regeneration as targets in
ceptibility to ALD is influenced by host genetic AH, DUR-928 appeared to elicit favourable AH.
background.53 In twin studies the concordance for biochemical responses and Lille responses in
alcohol-related cirrhosis is 3-fold higher in mono- comparison to matched historical controls. A phase
zygotic twins than in dizygotic twin pairs. Genetic IIb study is currently recruiting.
association studies with candidate genes have iden-
tified patatin like phospholipase domain containing Use of biomarkers to diagnose, monitor,
3 (PNPLA3), hydroxysteroid 17-beta dehydrogenase and improve outcomes
13 (HSD17B13) and SERPINA1 (serpin family A Molecular biomarkers
member 1) as susceptibility genes. Genome-wide Measurement of bacterial 16S-rDNA in whole blood
association studies have identified a number of sus- samples using quantitative real-time PCR gives an
ceptible or protective loci for ALD. These include indication of the risk of infection over the following
8
rs58542926 in TM6SF2 (transmembrane 6 super- 7 days. A point-of-care device for measuring 16S-
family member 2); rs641738 in MBOAT7 (membrane- rDNA is currently under evaluation and may find a
bound O-acyltransferase domain containing 7), role in clinical practice to predict or detect early
rs15052 in HNRNPUL1 (heterogeneous nuclear ribo- infection. An alternative strategy is the use of
nucleoprotein U like 1), rs2642438 in MARC1 (mito- prophylactic antibiotics to prevent infection in pa-
chondrial amidoxime reducing component 1) and tients receiving corticosteroids. Unfortunately, the
rs374702773 in FAF2 (fas associated factor family Antibiocor trial, which compared prednisolone
member 2). In studies specifically addressing AH, against prednisolone plus co-amoxiclav, recently
58
both PNPLA3 and HSD17B13 have been confirmed as reported negative results. The reason for this
susceptibility loci. The loss of function variant of disappointing outcome is not yet known, although
HSD17B13, which confers protection against NASH, the number of infections in the combination
alcohol-related cirrhosis, and AH is a potential ther- treatment arm was reduced.
apeutic target.54 RNA interference (RNAi) technolo- Cytokeratin-18 (CK18) is a structural cyto-
gies are now established in clinical medicine with the plasmic protein which is broken down and

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Review
Phone apps
Multi-omics
Demographics
Fig. 5. Multimodal data integration for personalised therapy.
Key point
Genetic and digital bio-
markers represent an op-
portunity for multimodal
data streams that could
one day enable the per-
sonalised care of patients
with AH.
1286
Remote
biomonitoring
Data
integration
Other
?
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.59 However, very high
levels (>5,000 IU/ml) of CK18-M30 also identify a
subgroup of patients who, when treated with cor-
ticosteroids, achieve a 90-day survival advantage.60
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.61 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 multi-
functional protein involved in neutrophil activa-
tion, 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.62 Other biomarkers under investigation
include circulating microRNAs, microRNAs, and
sphingolipid cargo associated with extracellular
Journal of Hepatology 2022 vol. 76 j 1279–1290
Algorithm
generation/ Personalized
Predictive therapy
analytics
vesicles.63 In patients with AH, miR-192 and miR-
30a are increased64 and, in one study, miR-201-
5p, miR-146a-5p, and miR-26b-5p predicted mor-
tality.65 Profiling of AH-specific microRNA signa-
tures is an active area of research.
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).66 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 pre-
dictive capabilities of the MELD score have been
refined using additional non-biased variables.67–69
Similar predictive analytics have recently been
used to help clinicians distinguish differential di-
agnoses such as cholangitis from AH.70
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 defini-
tively able to improve upon traditional clinician
diagnosis. The future will likely involve a
combination of algorithm approaches that can management teams that include psychologists,
refine differential diagnosis with ultimate cliniciansocial workers, and others. Models for integrated
oversight of the process and final determination.66 care include gastroenterologists or hepatologists,
This can be seen as akin to current clinical guide- primary care physician, patient’s home and then a
lines that provide suggestions for decision making multidisciplinary clinic that may involve a social
with ultimate oversight by the clinician. worker and a psychologist. There are algorithms
that suggest which patients might benefit from
Remote biomonitoring this integrated care model.78 These are based on
Remote biomonitoring encompasses the opportu- the presence of AUD (assessed by the AUDIT
nities to measure biological and behavioural- score) and ALD (assessed by laboratory testing,
related data from patients in real time. Biological history, and imaging).
data may include vital signs and physiologic data. Initial descriptions of such models indicate im-
This is exemplified most simply by Fitbit and other provements in quality of care in this patient pop-
common commercial tools that enable easy ulation. An early description in 2013 by Addolorato
collection of physiologic information.71 From a et al.79 reported that the presence of an alcohol
medical lens, many tools and vendors are available addiction unit within a transplant centre reduced
to collect more refined information relevant the risk of post-transplant relapse. Indeed, trans-
to patients with ALD, including weight, blood plant centres are the most common setting for this
pressure, pulse, and even single-lead electrocar- type of multidisciplinary model. A more recent
diograms, which can all provide early indications study by Mellinger et al.80 shows, even in the non-
of liver decompensation and responses to transplant setting, that rates of hospital admission
various medications that may influence and emergency room utilisation/person/month are
these parameters.72 reduced in a multidisciplinary model. Recommen-
The concept of physiologic remote patient dations include colocation of the team, multidis-
monitoring has also expanded to digital technolo- ciplinary approach, a focus on interpersonal team
gies for behavioural monitoring. This is most rele- relations, novel approaches to patient encounters,
vant for AUD, where ecological momentary and engagement with unaffiliated community and
assessments can be ascertained from both active outreach locations. While there are a number of
and passive cell phone data, including GPS tracking benefits to the multidisciplinary care model, bar-
and behavioural assessments that may predict riers exist to their implementation outside of the
alcohol craving or relapse.73,74 Advances have also transplant setting. Barriers include financial sus-
been made in monitoring of blood alcohol levels tainability of the model, logistical complexity, in-
from a number of easily measurable body sources equities of the patient population, and the patient’s
that can provide bloodless and remote blood cognitive status.
alcohol estimations in patients.75
Conclusion
New care models to monitor and Significant breakthroughs are occurring in the sci-
treat AUD ence of ALD that are now impacting patient care.
Patients with ALD have complex clinical and Given the parallel transformative advances in
psychological profiles that are difficult for hep- biomedicine, there are tremendous opportunities
atologists alone to manage. ALD is a dual disease for us to re-imagine how we care for patients with
that requires focus on both the liver and the AUD. ALD using multimodal data and digital medicine to
Many hepatologists at the current time do not provide personalised and effective care for
have the capabilities to manage AUD.76 This in- our patients.
cludes the inability to recognise the benefits and
deficiencies of tests that detect alcohol use, such Abbreviations
as phosphatidylethanol and urinary ethyl glucu- 16S-rDNA, 16S-ribosomal DNA; AH, alcohol-
ronide, lack of experience to prescribe FDA associated hepatitis; ALD, alcohol-associated liver
approved (acamprosate, naltrexone), and non- disease; AUD, alcohol use disorder; CK18,
approved (baclofen) medications for AUD, and cytokeratin-18; FMT, faecal microbiota trans-
inability to provide behavioural interventions plantation; G-CSF, granulocyte-colony stimulating
necessary to support the treatment of AUD. Many factor; HNF4a, hepatocyte nuclear factor 4 a;
patients with ALD also have psychosocial chal- HSD17B13, hydroxysteroid 17-beta dehydrogenase
lenges that complicate their management.77 This 13; MELD, model for end-stage liver disease; NASH,
has led to the development of multidisciplinary non-alcoholic steatohepatitis; PNPLA3, patatin like

Journal of Hepatology 2022 vol. 76 j 1279–1290 1287

Review
phospholipase domain containing 3; RNAi, RNA
interference; TLR, Toll-like receptor.
Financial support
MT receives grant funding from the UK Medical VS, GS and MT contributed equally to the writing,
Research Council and acknowledges support from editing and proof reading of the paper.
NIHR Imperial Biomedical Research Centre.
Conflict of interest
GS receives funding from the National Institute on
Alcoholism and Alcohol Abuse and National Insti-
tute on Aging.
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