From prognostication to therapeutics: Four key questions to accelerate the development of therapeutics for patients with acute-on-chronic liver failure

Abstract

Acute-on-chronic liver failure (ACLF) has come a long way as a clinical concept within the hepatology and liver transplant communities. Though the term was proposed in 1995, the first recognition of the entity along with a consensus definition emerged in 2009. Subsequently, the entity has sparked great interest, inspired several consensus conferences, and inspired national societies to form professional ACLF affinity groups (eg, special interest group). Multicenter consortia have been established all over the world to study this condition, including the North American Consortium for the Study of End-Stage Liver Disease, Chronic Liver Failure consortium, Asian Pacific Association for the Study of Liver Diseases ACLF Research Consortium, Chronic Liver disease Evolution And Registry for Events and Decompensation, and the LiverHope Consortium. Collectively, these consortia have enrolled tens of thousands of patients with or at risk for ACLF across dozens of countries and characterized in detail the predictors, pathogenesis, and progression of patients with ACLF. Perhaps most importantly, they have produced essential data characterizing the excess morbidity and mortality that patients with ACLF face, making a compelling case for the urgent need for therapeutic strategies for this condition.

Acute-on-chronic liver failure (ACLF) has evolved enormously as a clinical concept within the hepatology and liver transplant communities. Though the term was proposed in 1995, the first recognition of the entity along with a consensus definition emerged in 2009. Subsequently, the entity has inspired several consensus conferences and inspired national societies to form professional ACLF affinity groups (eg, special interest groups). Multicenter consortia have been established all over the world to study this condition, including the North American Consortium for the Study of End-Stage Liver Disease (NACSELD),¹ European Association for the Study of the Liver-Chronic Liver Failure consortium,² Asian Pacific Association for the Study of Liver Diseases ACLF Research Consortium (AARC),³ Chronic Liver disease Evolution And Registry for Events and Decompensation,⁴ and the LiverHope Consortium.⁵ Collectively, these consortia have enrolled tens of thousands of patients with or at risk for ACLF across dozens of countries and characterized in detail the predictors, pathogenesis, and progression of patients with ACLF. Perhaps most importantly, they have produced essential data characterizing the excess morbidity and mortality that patients with ACLF face, making a compelling case for the urgent need for therapeutic strategies for this condition.

Despite this foundational work, there are currently no approved therapeutics specifically for ACLF. Instead, management consists of mitigating portal hypertensive complications (eg, rifaximin for hepatic encephalopathy, carvedilol for preventing variceal bleeding, terlipressin for acute kidney injury hepatorenal syndrome) and applying generic strategies for managing the critically ill (eg, volume resuscitation, empirical antimicrobial administration). Several bridge therapies such as plasma exchange have been shown to provide short-term, non-transplant advantage, yet an effect on long-term survival has not been demonstrated.⁶ However, these trials are based on small sample sizes and with limited wide-spread applicability. Moreover, there is a need to understand and intervene at different disease stages and pathophysiologic factors that underlie the development and progression of ACLF. These include severe inflammation and increased cytokine levels, aggravated portal hypertension and hemodynamic changes, increased vulnerability to infections due to immune paresis, and coagulation derangement. We have known about these factors and triggers for many years. What is preventing us from moving forward with developing targeted therapeutics for ACLF? Although there are many unanswered questions, we highlight several key questions that the ACLF community should address urgently to advance therapeutic development.

1. Key questions

1.1. What are the pathophysiological mechanisms that distinguish ACLF from acute decompensated cirrhosis?

Key pathophysiological features that have been identified in patients with ACLF have included systemic inflammation (as evidenced by high levels of proinflammatory cytokines), immune dysregulation (characterized by immune paralysis), oxidative stress (eg, excess production of reactive oxygen species), mitochondrial dysfunction, and metabolic perturbances (eg, altered glucose metabolism, lipid profiles, and amino acid turnover).⁷ Yet, the extent to which these factors actually trigger ACLF, perpetuate ACLF, or are simply biomarkers of the underlying process remains to be fully characterized. Large longitudinal cohorts with detailed characterization of these factors before, during, and after the development of ACLF are necessary to definitively identify pathophysiologic mechanisms, especially those that could be targeted for the development of therapeutics.

1.2. Which indices should we use to risk stratify patients for therapeutic development in ACLF?

A number of indices that predict mortality in patients with ACLF have been studied—some that are specific to ACLF (eg, CLIF-C-ACLF, NACSELD, AARC) and others that are not (eg, MELD score, SOFA score).^8–13 More recently, artificial intelligence has been applied to improve ACLF mortality prediction, but with trade-offs such as increased model complexity and poor transparency of the models.^14–17 Not surprisingly, indices that have been developed in patients with ACLF and that assess organ function have been shown to be superior in mortality prediction than general prognostic models (eg, MELD score, SOFA score). Of note, the ACLF-specific risk scores have been shown to be useful to identify subgroups of patients who are unlikely to recover from their ACLF, and would either benefit from early liver transplantation or in whom additional intervention would be futile.^18–20

At the current time, 4 major societies (AASLD, American College of Gastroenterology, European Association for the Study of the Liver, APASL) have developed consensus statements that address the management of patients with ACLF, but none of the statements have converged on a single index to use for either clinical care or research.^20–23 In clinical practice, this is not an issue, as each of the ACLF-specific indices (CLIF-C-ACLF, NACSELD, and AARC) has advantages in certain clinical scenarios and for specific etiologies. For example, the AARC model may have greater clinical relevance for a patient presenting with jaundice and ascites from alcohol-associated hepatitis, acute reactivation of hepatitis B, or drug-induced liver injury, whereas the NACSELD model may offer advantages in the setting of communicating futility to the patient’s loved ones given its simplicity. The CLIF-C-ACLF score has the advantage of identifying high-risk patients with the inclusion of organ failure in the definition. The 3 indices are well-suited for clinical practice, as they consist of variables that are readily clinically available; they are reliable, reproducible, and allow for risk stratification of patients into various ACLF grades that predict mortality. For therapeutic development, however, the optimal index must possess additional characteristics, including a high level of granularity (for strong discriminatory power between the natural history of decompensated cirrhosis and ACLF), sensitivity to change (to determine the effect of interventions), and high floor and low ceiling effects (to capture the entire spectrum of disease, especially at the early stage). There is a need for convergence of the various consortia and filter out patients of different stages of liver disease, from the clinic to the ward to the intensive care unit. Challenges of some of the prognostic scores remain that organ failure or use of SOFA score form the basis of defining the entry criteria. This might be too late for new treatments to show efficacy.

1.3. What biomarkers should be used to predict the development of ACLF?

In terms of drug discovery, biomarkers that identify patients with cirrhosis who are at increased risk of developing ACLF are of critical importance to define the target population for randomized clinical trials investigating preventive drugs for ACLF. Although ACLF more frequently develops in patients with advanced liver and kidney dysfunction, standard laboratory parameters used in the assessment of patients with cirrhosis are not accurate enough to be used for early detection of ACLF. To date, there are no established biomarkers for this purpose, but recent approaches have revealed promising candidates. A recent meta-analysis investigating biomarkers associated with the development of different outcomes in patients with cirrhosis reported 4 biomarkers that are related to ACLF development: plasma interleukin-6, cystatin-C, NGAL, and TNF-α.²⁴ A separate multicenter study involving metabolomic analyses of serum samples from over 600 patients with cirrhosis identified clusters of microbially-produced metabolites that yielded a strong prediction of ACLF development as well as short-term mortality.²⁵ Further studies are needed to validate these findings and explore other potential biomarker candidates.

1.4. What are the relevant endpoints for ACLF clinical trials?

ACLF patients have high short-term (28-day) and mid-term (90-day) mortality, ranging from 30% to 50%, respectively. The first 1 week is generally considered the “golden window,” the period where SIRS and sepsis develop.²⁶ It is during this period when decisions for transplant are generally required to be made.^27,28 There is a need to have therapies to improve the outcome and reduce the severity of illness in this time frame. But, a large proportion of patients do survive with current medical therapies. Although transplant-free survival is a well-accepted primary endpoint for studies enrolling patients with compensated and decompensated cirrhosis,²⁹ this is not the most clinically relevant outcome. Given the high-risk of recurrent clinical decompensation after recovery from ACLF in addition to progressive frailty/sarcopenia related to both acute and chronic illnesses, early liver transplantation may offer the patient greater benefits in terms of overall survival and quality of life.^30,31 Notable exceptions are patients with specific conditions, such as alcohol-associated hepatitis and acute reactivation of chronic hepatitis B, in whom removal of the precipitant may be swift and allow for the return of relatively normal liver function. Some examples of more targeted endpoints could be as follows: (1) reversal of organ failure to organ dysfunction or normal status using the CLIF-C-ACLF score, or (2) reduction of liver failure, from AARC grade III to grade II or I, (3) reduction in MELD score by >5. In fact, just avoidance of liver transplant, as is implied by the outcome of transplant-free survival, may leave the patient in a state of clinical “purgatory,” in which they are neither sick enough to obtain a donor liver offer nor well enough to function normally. Quality of life and reversal of ACLF at 1 year should be more useful, much in consonance with the concept of recompensation. Etiology-driven approaches to prevent “ACLF again” should be developed and RCTs should aim at investigating the prevention of ACLF development.²¹ This issue underscores the importance of recognizing ACLF as a distinct clinical entity that warrants targeted therapeutics. Steps to harmonization of definition and clarity on endpoints for different cohorts of patients would help the field to move forward.

2. Concluding remarks

ACLF is a high-mortality condition that we will increasingly encounter in clinical practice due to the rising prevalence of individuals with advanced liver diseases worldwide. In the relatively short-term, direct bedside management strategies—such as optimizing fluid resuscitation, initiation of appropriate antimicrobial regimens, and proactive treatment of acute kidney injury—need ongoing refinement and standardization across all ACLF patients.²⁰ However, targeted therapeutics are urgently needed. We have identified 4 key questions that we believe represent barriers to the development of therapeutics that could be addressed by the ACLF physician community. These 4 questions underscore the need for a global conference of key ACLF stakeholders, including clinicians, patients, national funding institutes, and regulatory agencies, with the single goal of putting forth a consensus statement to: (1) establish ACLF as a clinical entity consisting of a homogenous cohort of patients distinct from decompensated cirrhosis, (2) agree upon a single prognostic index to risk stratify ACLF patients for clinical trials, and (3) identify acceptable clinical endpoints for ACLF clinical trials. These goals are achievable and robust evidence-based data would help development of therapeutic strategies for ACLF.

Abbreviations:

AARC

Asian Pacific Association for the Study of Liver Diseases ACLF Research Consortium

ACLF

acute-on-chronic liver failure

CLIF

Chronic Liver Failure

NACSELD

North American Study for End-Stage Liver Diseases