Falla Hepática Aguda Sobre Crónica 2024

Recent advances in clinical practice
Recent advances in the prevention and treatment of

decompensated cirrhosis and acute-on-chronic liver
Gut: first published as 10.1136/gutjnl-2023-330584 on 25 March 2024. Downloaded from http://gut.bmj.com/ on April 12, 2024 by guest. Protected by copyright.
failure (ACLF) and the role of biomarkers
Jonel Trebicka ‍ ‍,1,2 Ruben Hernaez ‍ ‍,3,4,5 Debbie Lindsay Shawcross ‍ ‍,6
Alexander L Gerbes7
► Additional supplemental ABSTRACT

material is published online The progression of cirrhosis with clinically significant WHAT IS ALREADY KNOWN ON THIS TOPIC
only. To view, please visit the ⇒ Decompensated cirhosis empases and spectrum
journal online (https://doi.org/ portal hypertension towards decompensated cirrhosis
10.1136/gutjnl-2023-330584). remains clinically challenging and the evolution towards of disorders, from stable decompensated
1 acute-on-chronic liver failure (ACLF), with one or more cirrhosis to unstable decompensated cirrhosis,
Department of Internal pre-acute-on-l iver-failure (ACLF) to ACLF
Medicine B, University of extrahepatic organ failures, is associated with very high
Münster, Munster, Germany mortality. In the last decade, significant progress has ⇒ Several key pathogenic mechanism has been
2
European Foundation for the been made in the understanding of the mechanisms implicated in the diagnosis, progression
Study of Chronic Liver Failure, leading to decompensation and ACLF. As portal and treatment of such disease including
Barcelona, Spain inflammatory biomarkers and microbiome
3 hypertension advances, bacterial translocation across
Gastroenterology and
Hepatology, Michael E. DeBakey an impaired gut barrier culminates in endotoxaemia, phenotypes.
Veterans Affairs Medical Center, systemic inflammation and cirrhosis-associated immune
WHAT THIS STUDY ADDS
Houston, Texas, USA dysfunction (CAID). Gut-derived systemic inflammation
4
VA HSR&D Center for and CAID have become the logical targets for innovative ⇒ There are established guidances by the
Innovations in Quality, regulatory agencies that can support
Effectiveness and Safety, therapies that prevent hepatic decompensation episodes
and the progression to ACLF. the development of newer diagnostic/
Michael E. DeBakey VA Medical
Center, Houston, Texas, USA Furthermore, classification of disease and biomarker prognostic tools and therapies in the field of
5
Gastroenterology, Baylor discovery to personalise care have advanced in the field. decompensated cirrhosis/ACLF
College of Medicine, Houston,
This review discusses progress in biomarker discovery ⇒ We provide several concepts for therapeutic
Texas, USA research development that can help in the
6
Institute of Liver Studies, Kings and personalisation of treatment in decompensated
College London, London, UK cirrhosis and ACLF. regulatory process.
7
Department of Medicine
II, University Hospital LMU,
HOW THIS STUDY MIGHT AFFECT RESEARCH,
Munich, Germany PRACTICE OR POLICY
INTRODUCTION ⇒ Understanding the scope of each specific
Correspondence to Cirrhosis is a common chronic condition asso- biomarker will tailor trials in ACLF to improve
Professor Jonel Trebicka, ciated with high morbidity and mortality. The clincial care in these patients.
Department of Internal Medicine
B, University of Münster,
development of decompensation, that is, ascites,
Munster, Germany; hepatic encephalopathy (HE) and variceal bleeding,
jonel.trebicka@e fclif.com increases the healthcare burden due to frequent form of AD and is determined by the development
hospital admissions and the yearly mortality rate of hepatic and/or non-hepatic organ failures associ-
Received 4 February 2024 from less than 1% to 10%–50%.1 The prognosis of ated with a very high short-term mortality, as high
Accepted 12 March 2024
decompensated patients also depends on the time of as 20%–80%, within 28 days.4
development of the decompensation. While a slow The pathogenetic mechanisms underpinning
development of ascites or jaundice represents a the development of complications in cirrhosis
non-acute decompensation (NAD), the rapid devel- are mainly related to the presence of clinically
opment of those defines an acute decompensation significant portal hypertension (CSPH) defined as
(AD).2 These clinical pathways are distinctly charac- hepatic-venous pressure gradient (HVPG) equal
terised by the velocity, severity and clinical urgency to or greater than 10 mm Hg.5 Subsequently, the
of the occurring event(s). Non-elective/emergency circulatory shifts related to portal hypertension
hospitalisation due to existing decompensation may may generate either underperfusion or conges-
© Author(s) (or their represent a viable stratum to distinguish AD from tion, resulting in shear stress-induced endothelial
employer(s)) 2024. Re-use NAD since it implies clinical relevance and urgency dysfunction of sensitive organs and impairing their
permitted under CC BY-NC. No for medical intervention. While NAD features a regular function.1 Further, systemic inflammation
commercial re-use. See rights
and permissions. Published slow and progressive development of complica- caused by the progression of hepatic inflammation,
by BMJ. tions, AD is characterised by a more severe and organ dysfunction or individual precipitating events
accelerated clinical course, leading to the develop- constitutes a primary driver of disease progression
To cite: Trebicka J,
ment of its distinct subphenotypes and, frequently, in NAD and AD.2 Systemic inflammation is mainly
Hernaez R, Shawcross DL,
et al. Gut Epub ahead of progression towards acute-on-chronic liver failure related to the development of AD and ACLF, with
print: [please include Day (ACLF). The NAD pathway may also constitute a continuous increase of systemic inflammation
Month Year]. doi:10.1136/ a transitioning hub to a state of recompensated surrogates across AD and ACLF grades (number
gutjnl-2023-330584 cirrhosis.3 ACLF characterises the most aggressive of organ failures).4 However, it must be mentioned
Trebicka J, et al. Gut 2024;0:1–10. doi:10.1136/gutjnl-2023-330584 1
that treatment of portal hypertension using transjugular intra- biomarkers must be measured in individual patients to guide
hepatic portosystemic shunt (TIPS) may prevent further decom- initiation of the most appropriate therapy.
pensation6 and thereby NAD/AD and organ failures.
While the mechanisms driving the development of NAD/AD
are shared, the stage of decompensation guides the standard of BIOMARKER-GUIDED TREATMENTS
care, in particular due to the level and number of organ dysfunc- In 2015, the Food and Drug Administration (FDA)—National
tion (online supplemental table 1). This review aims to dissect Institutes of Health Joint Leadership Council harmonised the
the evidence on biomarker guidance of therapies and recent terms used in translational science and medical product devel-
advances in the prevention and treatment of AD and ACLF but opment with a focus on study endpoints and biomarkers. As
avoids overlap with recent reviews addressing definitions of aeti- a result, the BEST (Biomarkers, EndpointS and other Tools)
ology, ACLF and post-transplant outcomes. resource was published, which clarifies biomarker definitions,
describes their hierarchical relationships, connections and
dependencies among the terms it contains.11 BEST recommends
CURRENT RECOMMENDED THERAPIES a comprehensive description of the biomarker and proposed to
The PREDICT study included patients with AD at hospital specify the biomarker according to its biological plausibility (ie,
admission. At the baseline visit, the medical history was recorded, relevance to the ACLF condition) and its measurement method
in terms of previous decompensations, in order to map the and units for consistency when reporting such biomarker evalua-
trajectory of disease before admission.7 Using data from more tion. Using neutrophil gelatinase-associated lipocalin (NGAL) as
than 1200 patients, PREDICT showed that patients transiting an example, Ariza et al studied urine and plasma NGAL concen-
from NAD to AD had a more benign prognosis than patients trations in 148 patients with ACLF and 716 without ACLF. The
developing ACLF, who recorded a relatively short history of authors found that urine NGAL was an independent predictor
cirrhosis. PREDICT further identified three clusters of patients of the development of ACLF and of 28- day transplant-free
with different clinical trajectories.7 However, the treatments mortality and that hepatic LCN2 gene expression was markedly
of different complications should be adopted and stratified upregulated in patients with ACLF.12 In addition, urinary NGAL
according to the course of decompensation. Although the treat- may differentiate between the aetiologies of acute kidney injury
ments are shared, the situation and mode of application may (AKI) in cirrhosis, as shown recently by Gambino et al,13 thereby
differ between NAD and AD. For example, in AD presenting determining the utility of terlipressin in AKI.
with overt HE, acute rifaximin administration would be of no The BEST framework can guide novel therapies in ACLF and
help. Nevertheless, this is a standard secondary prophylaxis in understanding the taxonomy of each category can guide the
NAD. Similarly, one aims to differentiate between the different design of future studies in the field (figure 1).
types of ascites and their differential treatment.Online supple- A diagnostic biomarker is used to detect or confirm the pres-
mental table 1 illustrates how the clinical situation and the ence of a disease or condition of interest or to identify a subtype
course of disease may influence treatment regimens, as already of disease. The utility of a diagnostic biomarker is determined by
currently recommended.5 8–10 its ability to accurately diagnose the condition of interest against
While stratification according to the stage and the course of the reference standard as shown by sensitivity, specificity or area
disease leads to personalisation of care, individualisation of care under the receiver operating characteristics curve (AUROC).11
requires more than that. In order to predict and guide treatment, Phase angle (PhA) is a low-cost nutritional marker obtained from
Figure 1 Biomarkers, endpoints and other tools biomarker classification proposed by the Food and Drug Administration.11 We included some
examples adapted to ACLF to demonstrate how each biomarker clarifies and describes their hierarchical relationships, connections and dependencies.
ACLF, acute-on-chronic liver failure; AD, acute decompensation; AKI, acute kidney injury; CLIF, chronic liver failure; HRS, hepatorenal syndrome; NGAL,
neutrophil gelatinase-associated lipocalin; PREDICT, predicting acute-on-chronic liver failure in cirrhosis.
2 Trebicka J, et al. Gut 2024;0:1–10. doi:10.1136/gutjnl-2023-330584
point-of-care bioelectrical impedance analysis avoiding radiation In ACLF, we usually encounter predictive and prognostic
exposure and validated against CT. In 163 patients spanning biomarkers and while they seem synonymous, they are not. A
the spectrum of cirrhosis, Ruiz-Margáin et al showed that PhA predictive biomarker in ACLF would identify patients who are
had an AUROC of 0.70 (95% CI 0.61 to 0.79), and 5.6 was more likely to have a favourable (or unfavourable response) to
identified as the best cut-off value, yielding a sensitivity of 94% a particular treatment. For example, Jachs et al found in 159
and a specificity of 63%.14 More specifically, in ACLF, Pose et patients with clinically stable decompensated cirrhosis that those
al, using untargeted metabolomics in 42 patients with decom- with a decrease in von Willebrand factor ≥5% were deemed to
pensated cirrhosis and 25 participants from the LIVERHOPE- be ‘responders’ to application of non-selective beta-blockers as
SAFETY trial (simvastatin+rifaximin vs placebo) identified determined by HVPG response.21 As a result, when designing
functional pathways associated with ACLF and generated a trials in ACLF, predictive biomarkers not only help to personalise
metabolomicbased signature characteristic of ACLF.15 The meta- therapies in the field but can also enrich sample size calculation
bolic signature can change in response to treatment and serve as when designing clinical trials. Du et al developed a predictive
a diagnostic biomarker to distinguish ACLF from AD. Another score so clinicians can identify the subgroups who may benefit
example of a diagnostic biomarker was provided by Fernández from plasma exchange- centred artificial liver support system
et al, who used plasma renin concentration as a biomarker of (ALSS) therapy in patients with hepatitis B-ACLF. In a cohort
circulatory dysfunction to assess the effect of antibiotics plus of 601 patients, they found that patients with a PALS score 6–9
albumin vs antibiotics alone in a randomised clinical trial of 118 could still benefit from ≥6 sessions of ALSS therapy compared
patients with cirrhosis.16 The authors concluded that treatment with ≤2 sessions (63.6% vs 97.0%, p<0.05). The score is a
with antibiotics plus albumin decreased circulatory dysfunction. composite of the presence of cirrhosis, total bilirubin, presence
We use monitoring biomarkers to repeatedly assess disease of infection, HE and INR.22
progression or response to treatment. This type of biomarker In contrast, a prognostic biomarker in ACLF would be used to
is particularly important in the development and trials of identify the likelihood of a clinical event or progression in patients
new drugs or devices. A classic example is the monitoring who already have ACLF. Weiss et al showed in two prospective
of cholesterol levels in response to statins. In ACLF, such multicentre large cohorts from (CANONIC (discovery, n=831)
an example is the composite CLIF- C-ACLF score (CLIF- C- and PREDICT (validation, n=851)) that models including
ACLF=10×(0.33×CLIF COFs+0.04×age+0.63×ln (white metabolites (CLIF- C MET)—here the prognostic composite
blood cell (WBC) count)–2)).17 The score ranges from 0 to biomarker—reflecting SI, mitochondrial dysfunction and sympa-
100 and is used to monitor ACLF progression or response to thetic system activation were superior to prognostic short-term
treatment.18 Ripoll et al designed a prospective, multicentre, mortality using established clinical scores (eg, MELDNa).23 Such
open, 1:1-randomised, controlled parallel-group trial (LIVER- prognostic biomarkers are also used in clinical trials as a method
HERO) to compare the 12-month liver transplant-free survival to identify patients who might have a higher risk of developing
in patients assigned to TIPS compared with the standard of care the event of interest, and, as such, enable enrichment of trials
(terlipressin and albumin). While transplant-free survival is the and reduce sample size (figure 1).
primary endpoint, creatinine serves as a monitoring biomarker When developing new drugs or treatments, ACLF research
and the authors will assess reversal of hepatorenal syndreom may be interested in biomarkers that are measured before or
(HRS)- AKI at 3–12 months or the response to the assigned after the patients are exposed to the treatment of interest: this is
treatment.19 what the FDA calls a safety biomarker. Bilirubin and aminotrans-
When it is the purpose of the biomarker to show the biolog- ferases are the most common safety biomarkers used in drugs
ical response, either beneficial or harmful, after a particular with potential hepatotoxicity. Agarwal et al recently reported
treatment, we apply a response biomarker with two subtypes: on a randomised clinical trial in 32 patients undergoing a novel
the pharmacodynamic biomarker and the surrogate biomarker. liver dialysis device (DIALIVE), and the primary outcome
The term ‘surrogate’ endpoint in ACLF requires further clarifi- was at least one serious adverse event between days 1 and 10.
cation. The FDA defines a ‘surrogate endpoint biomarker’ as a Several biomarkers were used to monitor serious adverse events,
response biomarker that serves as an endpoint used in clinical including platelet count drops and severe hypotension, which
trials as a substitute for a direct measure of how a patient feels, can be applied as safety biomarkers.24
functions or survives. A surrogate endpoint does not measure Finally, susceptibility/risk biomarkers indicate the potential
clinical benefit per se but rather is expected to predict clinical of developing a disease (eg, ACLF) in an individual who does
benefit or harm based on epidemiological, therapeutic, patho- not currently have a clinically apparent disease. Trebicka et al
physiological or other scientific evidence. There are variations identified a particular phenotype in the PREDICT study, namely
of such surrogate endpoints (Table of Surrogate Endpoints That pre-ACLF, in patients who later developed ACLF, in a cohort
Were the Basis of Drug Approval or Licensure | FDA): validated of 1071 patients without ACLF. The formula provided by this
surrogate endpoint, reasonably likely surrogate endpoint and study shows how a composite biomarker can determine the
candidate surrogate endpoint, depending on the degree of scien- susceptibility risk for the development of ACLF.7
tific evidence supporting such association between the surrogate In summary, these FDA biomarker classifications applied to
endpoint and the desired outcome. ACLF can assist researchers in novel trial designs in the field
Another very commonly used surrogate endpoint is HVPG, of ACLF, facilitating and expediting future regulatory approval.
which has been shown to predict major liver outcomes (eg, vari-
ceal bleeding). A randomised placebo-controlled trial to assess
whether nitric oxide (NO)-independent soluble guanylyl cyclase ONGOING STUDIES, NOVEL DRUGS AND OTHER
(sGC) activator BI 685509 has an effect on HVPG in patients APPLICATIONS
with CSPH is currently running.20 In the aforementioned study Over the last decade, we have largely focused on the treatment
by Pose et al, the authors also identified plasma metabolites that of two major mechanisms, portal hypertension and systemic
were modified following treatment with simvastatin plus rifax- inflammation, as well as the main precipitants of decompensa-
imin in patients with decompensated cirrhosis.15 tion, such as infection, bacterial translocation and organ failure.
Figure 2 An overview of the main therapeutic approaches in patients with cirrhosis to prevent decompensation and progression to acute-on-
chronic liver failure. Created with BioRender.com with publication licence. TLR-4, toll-like receptor 4.
Therapies in patients with cirrhosis and CSPH to prevent 1000 patients showed that use of NSBBs reduced the rate of
hepatic decompensation and progression to ACLF patients developing sepsis within 1 year to approximately
The pathophysiology of CSPH in patients with cirrhosis is half, while the dose did not play a major role. 32 The BOPPP
underpinned by profound peripheral arterial vasodilatation and trial (NCT05872698), which will complete recruitment in
circulatory dysfunction. Activation of neurohormonal systems 2024, is a prospective multicentre randomised-controlled
drives renal sodium and water retention.25 This fragile balance trial comparing carvedilol with placebo in 764 patients
maintains organ function in a stable state, but as portal hyper- with cirrhosis and grade 1 oesophageal varices to determine
tension advances, bacterial translocation across an impaired gut
whether carvedilol does indeed improve decompensation-
barrier culminates in endotoxaemia, systemic inflammation and
free survival (figure 3A).
cirrhosis-associated immune dysfunction (CAID).1 26 Gut barrier
Anticoagulation has been studied as a tool to prevent not
damage arises from endothelial damage, which is exacerbated
by reduced gut microbial diversity with an increase in patho- only portal vein thrombosis but also decompensation. 33 The
biont species. These pathobionts, which frequently translocate IMPORTAL study, a meta-a nalysis using individual data of
from the mouth, drive gut inflammation, mucosal degradation patients with cirrhosis and PVT showed that anticoagulation
and enhanced ammonia production.27 28 Gut-derived systemic (independent of the drug) had a significant effect on survival
inflammation and CAID, therefore, become the logical targets of patients with recanalisation of portal vein thrombosis. 34
for therapies that prevent hepatic decompensation episodes and Moreover, rivaroxaban improved survival and decompensa-
the progression to ACLF, which is often precipitated by infection tion in patients with cirrhosis with moderate liver dysfunc-
and sterile inflammation (figure 2).29 tion in a double-b lind, placebo-c ontrolled trial, particularly
Therapeutic targets for patients with cirrhosis and CSPH in patients with a maximal Child-P ugh-Turcotte score of 7. 35
have historically focused on counteracting peripheral arte- Finally, aetiological cure prevents further decompensation
rial vasodilatation, that is, non- s elective beta blockers and mortality in cirrhotic patients with ascites as the single
(NSBB), which was shown to be a mainstay therapy that may
first decompensating event. 36
have benefits beyond the prevention of variceal bleeding.
The most effective therapy to reduce portal pres-
Indeed, the PREDESCI study showed that in addition to
reducing ascites, long- t erm administration of NSBB may sure is TIPS. Early or pre-e mptive TIPS is recommended
decrease the occurrence of ascites. 30 In a meta- a nalysis in patients at high risk of rebleeding after haemostasis,
with 352 patients with compensated cirrhosis, the risk of despite the presence of HE at admission. A study enrolling
decompensation was lower with carvedilol than in controls, more than 2000 patients clearly showed that the presence
mainly due to a reduced risk of ascites; the risk of death was of HE has no influence on the development of post-T IPS
also lower with carvedilol. 31 A recent study analysing over encephalopathy. 37
Figure 3 Key landmark clinical trials in cirrhosis in patients with compensated cirrhosis and clinically significant portal hypertension (A) and in
patients with decompensated cirrhosis (B). (A) Illustrates recently published phase 2a/b and 3 clinical trials in patients with compensated cirrhosis
and clinically significant portal hypertension with the outcome of improved decompensation-free survival. These include trials of non-specific beta
blockers, rifaximin-α, statins, testosterone, granulocyte colony-stimulating factor (GCSF)/autologous CD133 stem cell therapy and faecal microbiota
transplantation (FMT). The trials highlighted in green bars are positive, light red bars negative and in grey bars are still recruiting or await reporting.
(B) Illustrates recently published phase 2a/b and 3 clinical trials in patients with decompensated cirrhosis with the main outcome of survival. These
include trials of human albumin solution, midodrine, simvastatin, cotrimoxazole, GCSF and GCSF in combination with growth hormone/erythropoietin.
HVPG, hepatic venous pressure gradient; SAEs, serious adverse events; SBP, spontaneous bacterial peritonitis; SMT, standard medical therapy. Created
with BioRender.com with publication licence.
Gut-derived systemic inflammation and CAID as a target of outcomes in cirrhotic patients, ranging from the development
therapy of encephalopathy and infection to reducing AMR rates. More-
As the gut drives endotoxaemia and low-grade systemic inflam- over, in the recent PROFIT trial, FMT decreased microbial-
mation, manipulating the gut microbiome towards health will associated ammonia production and augmented ammonia
reduce bacterial translocation, the predisposition to spontaneous excretion via anaerobic metabolism of L-aspartate to hippurate,
bacterial peritonitis (SBP) and also lower blood ammonia, which providing proof of concept that FMT enhances ammonia metab-
has recently been shown to predict hospitalisation, liver-related olism, central in the pathogenesis of HE in cirrhosis.42 Finally,
complications and mortality.27 Therefore, dietary interven- testosterone therapy in men with low serum testosterone safely
tions with increased consumption of fruit, vegetables, fibre and increases muscle mass, bone mass and haemoglobin.43 Increased
fermented food substances, prebiotics (lactulose), probiotics and muscle mass may indirectly lower blood ammonia and improve
synbiotics should be evaluated.38 There is robust data now to outcomes. Therefore, testosterone treatment could merit a larger
suggest that rifaximin-α not only reduces the recurrence of overt scale investigation.
HE39 but may also favourably manipulate the gut microbiome. The role of toll-like receptor 4 (TLR-4) as a mediator of gut-
A recent mechanistic randomised-controlled trial showed that derived systemic inflammation has been highlighted (figure 2).
rifaximin-α suppressed oralisation of the gut, reducing levels It is upregulated in patients with cirrhosis and attenuated by
of mucin- degrading sialidase-rich species, Streptococcus spp, rifaximin-α.28 TAK-242 is a small molecule that selectively binds
Veillonella atypica and parvula, Akkermansia and Hungatella. and inhibits TLR-4 and will be examined in a multicentre Euro-
Rifaximin-α also promoted a TNF-α-enriched and interleukin- pean phase 2 study (A-TANGO) (NCT04620148) in combina-
25-enriched intestinal microenvironment, augmenting antibacte- tion with granulocyte colony-stimulating factor (G-CSF) (which
rial responses to invading pathobionts and promoting gut barrier promotes hepatic regeneration) which commenced in 2023.
repair. Interestingly, patients on rifaximin-α were less likely to Statins are anti-inflammatory agents, blocking the action of
develop infection.28 Faecal microbiota transplant (FMT) is eNOS downregulators, such as oxidised low- density lipopro-
a well- established treatment, acting as a ‘whole ecosystem’ tein, TNF-α and caveolin-1, with antifibrotic effects which may
approach to restore the homeostatic balance of gut microbiota. not only reduce portal hypertension but also have a favourable
An open-label phase I pilot study of 10 patients with cirrhosis impact on decompensation-free survival. Inhibition of HMG-
treated with rectally instilled FMT restored gut- microbiota CoA reductase can result in increased nitric oxide bioavailability
diversity and improved HE. However, there were limitations in through inhibition of the Rho-ROCK pathway with the poten-
attributing results to FMT alone as patients were treated concur- tial to treat endothelial dysfunction.44 In a study of simvastatin
rently with broad-spectrum antibiotics, whereas those allocated versus placebo for prevention of variceal rebleeding, there was
to standard care were not.40 A further 10-patient phase I trial no impact on bleeding but, remarkably, a survival benefit in those
using FMT capsules was associated with improved duodenal with Child-Pugh-Turcotte A/B cirrhosis but not C.45 However, in
mucosal microbial diversity, gut microbial diversity, antimicro- a small, recently published randomised-controlled trial in patients
bial peptide expression and reduced lipopolysaccharide-binding with cirrhosis and CSPH, atorvastatin, while safe, did not reduce
protein.41 FMT, therefore, could represent a promising non- HVPG, liver-related complications or mortality.45 In the LIVER-
antimicrobial therapeutic strategy to improve an array of clinical HOPE study, simvastatin was examined at high (40 mg) and low
doses (20 mg) with rifaximin-α 1200 mg daily versus placebo. CAID. G-CSF stimulates the bone marrow to release ‘immature’
The higher dose of simvastatin led to more serious adverse events neutrophils which are programmed to secrete pro-inflammatory
with no favourable impact on clinical outcomes.46 Over 84 000 cytokines on stimulation and do not exhibit effector functions
patients were analysed from the VOCAL database.47 Of these, (ie, antimicrobial functions, such as ROS production, degranu-
over 46 000 received no statin therapy, 22 000 received statins lation, NET formation) that characterise mature neutrophils.58
at initial presentation and a further 15 000 received statins only However, while mobilisation of stem cells might be beneficial,
during the observation period. Statin exposure was correlated the effect on monocytes and macrophages might be proinflam-
with the prevention of ACLF, and all patients had an indica- matory and could worsen CAID and predispose it to infection.
tion for statin treatment outside of prevention of decompensa- Several studies (figure 3B) suggested that G-CSF daily for 5 days
tion. In the efficacy study of LIVERHOPE, the combination of vs standard medical therapy offered a survival benefit,59–62 but
simvastatin with rifaximin did not prevent ACLF development, two recent large multicentre European studies in both compen-
nor did it have a survival benefit in decompensated patients.48 sated (REALISTIC)63 (figure 3A) and decompensated cirrhosis
Therefore, statins in cirrhosis seem beneficial for the traditional (GRAFT)64 have contradicted these findings. Therefore, caution
indications, but not specifically in the prevention of complica- is required and a recommendation on G-CSF is not possible at
tions of cirrhosis.5 this point in time.
Human albumin as a drug Novel targets and therapies in development of ACLF

Albumin, synthesised exclusively by the liver, is the most abun- Figure 4 summarises the novel targets and therapies in preclin-
dant plasma protein, and is a major contributor to plasma ical or early phase development of ACLF. Overall, therapies of
oncotic pressure. It also serves as a pleiotropic scavenger, revers- interest largely target the downstream sequelae of toxic metab-
ibly binding to many toxic metabolites, inflammatory mediators olites and systemic inflammation, including inflammasome
and reactive oxygen species accompanying endotoxaemia and pathways and serve as immune modulators or promote hepatic
systemic inflammation.49 It is well established and used in the regeneration.27
prevention and treatment of circulatory dysfunction and renal The innate immune system detects pathogen- associated
failure associated with large-volume paracentesis and SBP and molecular patterns (PAMPs) via specific pattern recognition
it has been incorporated in international guidelines. However, receptors (PRRs). An example is the binding of lipopolysac-
its benefit in the treatment of decompensated cirrhosis remains charide and other gut microbial-derived metabolites to TLR-4,
a matter of intense debate. In the ANSWER study performed present on the surface of hepatic macrophages and Kupffer cells
on 442 patients with persistent ascites, 40 g of human albumin, following bacterial translocation across the gut barrier into the
given weekly for up to 18 months, led to a 38% reduction in portal vein.26 65 This leads to the activation of nuclear factor-κB
the HR for mortality.50 This was accompanied by a 50% reduc- and interferon regulatory factor, inducing the release of proin-
tion in the incidence of refractory ascites, a reduction in renal flammatory cytokines.66 This culminates in chronic low-grade
dysfunction and HE and a reduction in SBP and non-SBP infec- systemic inflammation, which over time leads to loss of toler-
tions. Real-world evidence on long-term albumin treatment in ance to antigen exposure and an augmented proinflammatory
patients with decompensated cirrhosis in Italy51 demonstrated response.26 Targeting gut-derived PAMPs, therefore, has poten-
that administration of albumin led to a considerable reduction tial in treating and preventing the development of ACLF and
in ascites complications and hospitalisation. Moreover, a recent can be achieved by manipulation of the gut microbiome with
double-blind, placebo- controlled trial in cognitively impaired rifaximin-α28 and FMT41 as discussed previously or via a non-
outpatients showed that albumin significantly improved psycho- antibiotic gut decontaminating product such as CARBALIVE.
metric tests over 5 weeks.52 Conversely, the MACHT trial in CARBALIVE, a novel engineered orally ingested macroporus
patients with decompensated cirrhosis awaiting liver trans- carbon bead, binds toxins and cytokines with a molecular weight
plantation did not show any benefit.53 The ATTIRE trial with up to 70 kDa.67 This has the potential to ameliorate systemic
777 patients with decompensated cirrhosis and serum albumin and gut inflammation. Also, large- volume plasma exchange
<30 g/L also showed no benefit, with a higher number of patients may be beneficial in removing toxins in ACLF. The APACHE
in the albumin arm suffering severe adverse and life-threatening trial (NCT037002920) is a phase 3 multicentre, randomised-
events.54 This could be attributed to rapid albumin infusion and/ controlled, parallel-group, open-label study evaluating plasma
or targeting rather high plasma levels of albumin leading to fluid exchange using 5% human serum albumin in 380 patients with
overload-derived complications and thus should be avoided.55
ACLF.
The PRECIOSA study (NCT03451292) is currently exploring
Similarly, a phase 2 multicentre, randomised- controlled,
in patients with decompensated cirrhosis, with or without ACLF,
open- label study evaluates the effects of the intraperitoneal,
whether albumin at a dose of 1.5 g/kg (maximum 100 g/session)
liposomal formulation VS-01 in patients with ACLF and ascites
every 8–12 days over 1 year will offer a survival benefit. The
(NCT05900050). The intraperitoneally administered liposomes
MICROB- PREDICT albumin trial (NCT05056220) will vali-
adsorb ammonia and other toxic metabolites. This is achieved
date predictive biomarkers of response to treatment with long-
using transmembrane pH-gradient liposomes containing citric
term albumin.56
acid. Once inside the peritoneum, uncharged ammonia diffuses
out of the bloodstream into the peritoneal cavity and across the
Targeting hepatic regeneration as a therapy liposomal bilayer membrane, where it becomes trapped due to
The discovery of bone marrow participation in hepatic regen- its positive charge. Other toxins, including urea, can be removed
eration led to the use of G-CSF as an experimental therapy in by the same mechanism.68
patients with decompensated cirrhosis.57 G-CSF induces haema- The products of necrotic cells are known as damage-associated
topoietic stem cell mobilisation into the peripheral blood with molecular patterns. These also generate an inflammatory
neutrophil activation. This has been postulated to overcome the response mediated via PRRs, which physiologically stimulate
functional immunoparesis in patients with advanced cirrhosis and tissue repair.69 In the context of a patient with cirrhosis, it may
Figure 4 Novel targets and therapies for acute-on-chronic liver failure. The Figure illustrates novel targets and therapies that are in early
development and/or phases 1 and 2 trials for acute-on-chronic liver failure. G-CSF, granulocyte colony-stimulating factor; RIPK, receptor interacting
protein kinase; TLR, toll-like receptor. Created with BioRender.com with publication licence.
drive ACLF. Non-apoptotic cell death results in necroptosis and synthesis of glutamine via the enzyme glutamine synthetase.
pyroptosis and is the predominant form of cell death in ACLF.70 L-o rnithine phenylacetate lowers ammonia in patients with
Necroptosis mediated by activation of the receptor-interacting decompensated cirrhosis and has been shown to be safe. 82 A
protein kinases 1 and 3 forming necrosomes drives inflamma- phase 2 study of L-o rnithine phenylacetate in patients with
tion and organ dysfunction and may be associated with progres- cirrhosis and HE showed a shorter time to clinical improve-
sion and severity of ACLF, especially in alcohol-related liver ment when compared with standard medical therapy (lactu-
disease and infection.71 Pyroptosis results from non-canonical lose and rifaximin) with reduced intensive care stay. 83
inflammasome activation, which in turn is associated with ACLF Cell therapy is an alternative approach for the treat-
development.72 Currently, disulfiram is an effective inhibitor ment of regenerative failure in ACLF. Mesenchymal cells
of non- canonical inflammasome and, thereby, pyroptosis.73 can be isolated from bone marrow, other adult tissues, for
Currently, a phase 2a trial of disulfiram in high-risk AD and example, adipose or embryonic sources, for example, umbil-
ACLF is in progress. ical cord. As the availability of donor tissues often limits this
Ammonia is also a key driver of the production of reac- approach, interest has moved towards using induced plurip-
tive oxygen species and systemic inflammation. Ammonia otent stem cells with or without G-C SF. Human allogenic
impairs neutrophil function by reducing chemotaxis and liver-d erived progenitor cells are currently under investiga-
phagocytosis and increasing spontaneous oxidative burst 74; tion in ACLF in a phase 2b randomised placebo-c ontrolled,
this has been associated with 3-m onth and 1-y ear mortality double-b lind multicentre study (NCT04229901). In patients
in patients with cirrhosis. 75 In patients with ACLF, myostatin with alcohol-r elated hepatitis, a phase 2 study showed that
and hyperammonaemia are associated with higher mortality human allogenic liver-d erived progenitor cells were safe and
and prolonged ICU stays. 76 77 Ammonia also upregulates improved markers of systemic inflammation and liver injury
myostatin expression, 78 which contributes to sarcopenia and over a 3-m onth period without a survival benefit. 84
frailty by reducing muscle mass. 79 Ammonia-lowering strat-
egies are thus key in ameliorating CAID and the increased
risk of infection as a driver of hepatic decompensation and CHALLENGES AND OPPORTUNITIES
ACLF. 80 L-o rnithine aspartate (LOLA), when added to lact- Clinical stratification as an example of prognostication
ulose and rifaximin in an RCT in patients with cirrhosis and Patient heterogeneity poses significant challenges for
severe HE, resulted in a lower 28-d ay mortality than with managing individuals and designing clinical trials, espe-
lactulose and rifaximin alone. 81 LOLA removes ammonia via cially in complex diseases. Existing classifications rely on
two distinct mechanisms: by the synthesis of urea and by the outcome- p redicting scores, potentially missing crucial
elements contributing to heterogeneity and impacting prog- for example, what is the added value to drug development
nostic insights. To address patient heterogeneity at hospital or what are the anticipated consequences if the biomarker is
admission, the Decision project developed a tool called unsuitable for its proposed use.
ClustALL, a computational pipeline addressing diverse clin- Finally, to determine the evidence to support the use of
ical data challenges, such as mixed types, missing values and biomarkers in novel therapy development in ACLF, inves-
collinearity. ClustALL enables unsupervised identification tigators need to provide not only the biological rationale
of robust patient stratifications, 85 which was applied to the for the use of the biomarker but also evidence supporting
PREDICT study. 86 ClustALL revealed several distinct stratifi- the relationship between the biomarker and the condition
cations at hospital admission, including markers of impaired or clinical outcome of interest and the analytical perfor-
liver function, organ dysfunction count and precipitating mance (online supplemental figure 3). The latter is particu-
events, of which one stratification determined three patient larly important because a novel biomarker needs to provide
clusters characterised by typical clinical features, but also enough data on reliability/agreement 89 before providing
exposing prognostic value. These findings were validated biomarker measurement cut- o ffs. Additionally, it will be
in the independent ACLARA-study. 87 Therefore, ClustALL important to provide performance characteristics of the
may guide future clinical trial design by stratification of existing measurement methods, the biological variability
patient populations for a specific treatment. 85 of the biomarker in different settings (eg, compensated
cirrhosis vs unstable decompensated cirrhosis, pre- ACLF
and ACLF), and the minimum magnitude of the biomarker
Practical aspects and applicability of biomarkers change expected to affect clinical decisions. Altogether, we
The use of novel biomarkers for drug and trial development suppose the study is designed to study the diagnostic accu-
in ACLF implies a long road ahead (online supplemental racy of a particular biomarker. We recommend considering
figure 1). The applicability depends on regulations set by the sample size to ensure adequate power to detect the clin-
regulatory agencies, for example, FDA, shaping the research ically important difference, control for multiple compar-
towards future therapy and/or biomarker regulatory isons, ensure that investigators collect and address key
approval (see https://www.fda.gov/drugs/biomarker-qual- threats in the internal (biases/confounding) as well external
ification-program/list-qualified-biomarkers) To date, only validity and minimise missing data. 90 91
one biomarker has been approved by the Center for Drug
Evaluation and Research, and the Center for Biologics Eval-
uation and Research Biomarker Qualification Programme CONCLUSIONS
database. Using ACLF, cirrhosis and end-s tage liver disease Novel concepts dealing with different courses of cirrhosis as
as keywords, the magnitude of the complex shear modulus well as pathogenetic mechanisms have enhanced our under-
|G*|, a parameter corresponding to tissue ‘stiffness’ as standing and given rise to many approaches for diagnosis
measured by magnetic resonance elastography, is the single and personalised approaches to treatment. Yet, prevention
biomarker that met the FDA regulations (https://force-dsc. and treatment of ACLF remains a huge challenge for several
my.site.com/ddt/s/). The FDA approved the context of its reasons. Timing of prevention of ACLF may be different
use as ‘a diagnostic biomarker to prescreen patients with with different approaches. The dynamics of systemic inflam-
clinical risk factors for chronic liver disease for enrolment mation and the influence of portal pressure may deter-
in clinical trials to identify those at high risk of having histo- mine the choice of rationale and the specific treatment or
pathologic findings of significant fibrosis (≥F2), advanced treatment combination. Biomarker development to guide
fibrosis (≥F3) or cirrhosis (F4) on liver biopsy’. There is decisions is underway and needs to be robustly tested and
clearly an unmet need in biomarker development in ACLF. prospectively validated in the clinic. Repurposed drugs
In addition, one may be probably more familiar with drug- and other approaches from critical care medicine may be
induced liver injury (DILI) as a stopping rule and from the appropriate at different stages of the disease, as highlighted
2009 report where a combination of AST/ALT and bilirubin above. Despite controversial and sometimes disappointing
set forth the standard of DILI. Nonetheless, we think this will results, significant research has influenced the field. Many
likely change in the future following the use of proteomic novel studies are underway and will change the future land-
profiling to identify such candidates as recently shown for scape. Personalised care and certification of biomarkers are
DILI. 88 We propose using the evidentiary framework and crucial in this complex disease.
guidance drafted by the FDA (online supplemental figure Twitter Ruben Hernaez @ruben_hernaez and Debbie Lindsay Shawcross @
2). The needs assessment for a novel biomarker in ACLF DebbieShawcros1
includes the limitations of the current biomarkers and how
Contributors Study concept and design: JT, RH, DLS and ALG; drafting the
this proposed biomarker will promote drug/therapy devel- manuscript: JT, RH, DLS and ALG; critical revision of the manuscript: JT, RH, DLS
opment in areas of ACLF where there is an unmet medical and ALG; submission of the manuscript: JT. JT, RH, DLS and ALG authors share,
need or how such novel biomarker can address a partic- respectively, first and last authorship.
ular aspect of ACLF pathophysiology more efficiently or Funding JT was supported by the German Research Foundation (DFG) project ID
effectively. The context of use (online supplemental figure 403224013–SFB 1382 (A09), by the German Federal Ministry of Education and
2) includes two components: (a) the biomarker category— Research (BMBF) for the DEEP-HCC project and by the Hessian Ministry of Higher
Education, Research and the Arts (HMWK) for the ENABLE and ACLF-I cluster
previously described, either ACLF- r elated or treatment- projects. The MICROB-PREDICT (project ID 825694), DECISION (project ID 847949),
related and (b) the biomarker’s proposed use in drug GALAXY (project ID 668031), LIVERHOPE (project ID 731875) and IHMCSA (project
development (purpose of use in drug development, the stage ID 964590) projects have received funding from the European Union’s Horizon
of drug development, patient population or model system 2020 research and innovation programme. Dr. Hernaez is a core investigator at the
Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413), Michael
and/or the therapeutic mechanism of action for which the
E. DeBakey VA Medical Center. The manuscript reflects only the authors’ views, and
biomarker is intended to have value). Third, benefits and the European Commission is not responsible for any use that may be made of the
risks assessment are important in biomarker development, information it contains. In addition, the views expressed in this article are those of

the authors and do not necessarily reflect the position or policy of the Department of 17 Jalan R, Saliba F, Pavesi M, et al. Development and validation of a prognostic
Veterans Affairs or the US government score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol
2014;61:1038–47.
Competing interests RH and ALG as an editor of the journal or an Editorial
18 Gustot T, Fernandez J, Garcia E, et al. Clinical course of acute-on-chronic liver failure
Board Member. JT has received speaking and/or consulting fees from Versantis, Gore,
syndrome and effects on prognosis. Hepatology 2015;62:243–52.
Boehringer-Ingelheim, Falk, Grifols, Genfit and CSL Behring.
19 Ripoll C, Platzer S, Franken P, et al. Liver-HERO: hepatorenal syndrome-acute kidney
Patient consent for publication Not applicable. injury (hrs-aki) treatment with transjugular intrahepatic portosystemic shunt in
Provenance and peer review Commissioned; externally peer reviewed. patients with cirrhosis-a randomized controlled trial. Trials 2023;24:258.
20 Reiberger T, Berzigotti A, Trebicka J, et al. The rationale and study design of two phase
Supplemental material This content has been supplied by the author(s). II trials examining the effects of BI 685,509, a soluble Guanylyl cyclase activator, on
It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not clinically significant portal hypertension in patients with compensated cirrhosis. Trials
have been peer-reviewed. Any opinions or recommendations discussed are 2023;24:293.
solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all 21 Jachs M, Hartl L, Simbrunner B, et al. Decreasing von Willebrand factor levels
liability and responsibility arising from any reliance placed on the content. upon nonselective beta blocker therapy indicate a decreased risk of further
Where the content includes any translated material, BMJ does not warrant the Decompensation, acute-on-chronic liver failure, and death. Clin Gastroenterol Hepatol
accuracy and reliability of the translations (including but not limited to local 2022;20:1362–73.
regulations, clinical guidelines, terminology, drug names and drug dosages), and 22 Du L, Ma Y, Zhou S, et al. A Prognostic score for patients with acute-on-chronic liver
is not responsible for any error and/or omissions arising from translation and failure treated with plasma exchange-centered artificial liver support system. Sci Rep
adaptation or otherwise. 2021;11:1469.
Open access This is an open access article distributed in accordance with the 23 Weiss E, de la Peña-Ramirez C, Aguilar F, et al. Sympathetic nervous activation,
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the
permits others to distribute, remix, adapt, build upon this work non-commercially, metabolomic prognostic models (CLIF-C MET). Gut 2023;72:1581–91.
and license their derivative works on different terms, provided the original work is 24 Agarwal B, Cañizares RB, Saliba F, et al. Randomized, controlled clinical trial of the
properly cited, appropriate credit is given, any changes made indicated, and the use DIALIVE liver dialysis device versus standard of care in patients with acute-On-
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Falla Hepática Aguda Sobre Crónica 2024

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Recent advances in clinical practice

Recent advances in the prevention and treatment of

► Additional supplemental ABSTRACT

Human albumin as a drug Novel targets and therapies in development of ACLF

8 Trebicka J, et al. Gut 2024;0:1–10. doi:10.1136/gutjnl-2023-330584

Trebicka J, et al. Gut 2024;0:1–10. doi:10.1136/gutjnl-2023-330584 9

10 Trebicka J, et al. Gut 2024;0:1–10. doi:10.1136/gutjnl-2023-330584

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