Recompensation in Cirrhosis: Biomarkers and Strategies

• Definition of Recompensated Cirrhosis
• Pathophysiology of Recompensated Cirrhosis According to the Etiologies
• Viral Hepatitis C
• Viral Hepatitis B
• Alcohol-Associated Cirrhosis
• Metabolic-Associated Steatotic Liver Disease
• Chronic Cholestatic Disease
• Biomarkers of Recompensation: Invasive and Noninvasive
• Invasive Biomarkers
• Noninvasive Biomarkers
• Current and Future Therapeutic Strategies in Decompensated Patients: Etiological, Portal Hypertension Treatments, Anti-Inflammatory Agents, Gut–Liver Axis, and Angiogenesis
• References

Abstract

The onset of decompensation in advanced chronic liver disease (ACLD) is a hallmark in natural history, with a poor prognosis and a significantly increased liver-related mortality. Etiological treatments for viral hepatitis or abstinence in cirrhosis due to alcohol abuse have demonstrated that some patients experience partial to complete clinical and analytical improvement, a stage termed “recompensation.” Although recompensation is primarily defined clinically based on treatable etiologies, it is still evolving for conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the need for specific biomarkers in hepatic recompensation, no biomarkers have been thoroughly studied in this context. Biomarkers identified in compensated ACLD (cACLD) following etiological treatment might be explored for recompensation. Although the pathophysiology mechanisms underlying the hepatic recompensation remain unclear, understanding the mechanism involved in cirrhosis decompensation could help identify potential targets for recompensation. This review provides an update on the hepatic recompensation concept, examines the existing data on invasive and non-invasive biomarkers, mainly in cACLD after cure, that could be raised in recompensation, and explores future therapeutic targets for the hepatic recompensation process.

The onset of decompensation in chronic advanced liver disease (ACLD) marks a pivotal moment in its natural history, leading to a significant reduction in survival over the subsequent 2 years. This strongly resembles the prognosis of aggressive oncological disease.[1] In the field of modern medicine, the treatment of decompensated ACLD (dACLD) has primarily focused on the management of complications associated with portal hypertension (PH) and hepatocellular dysfunction. Liver transplantation (LTx) has been regarded as the final therapeutic option for this patient population, given the long-standing perception that liver cirrhosis and its complications are irreversible.

Over the past two decades, literature derived mainly from studies on abstinence in alcohol-related liver disease (ALD)[2] [3] [4] [5] and chronic viral hepatitis B (HBV) and C (HCV) has begun to challenge this long-standing paradigm. The introduction of newer treatments, such as nucleoside(tide) analogs (NAs) for HBV[6] [7] [8] [9] and direct-acting antivirals (DAAs) for HCV, has played a significant role in this shift.[10] [11] [12] [13] These studies have demonstrated that some patients experience partial to complete clinical and analytical improvement, a phenomenon now termed “recompensation.” However, it was not until the Baveno VII consensus in 2022 that a formal definition was formulated. Although the initial definition was primarily clinical, it has provided a crucial framework for researchers to more precisely identify populations for recompensation-related studies. Nevertheless, further research is required to elucidate the molecular mechanisms underlying this phenomenon, as they remain unknown. A deeper understanding of these mechanisms will be essential for developing future therapeutic strategies, making the study of liver recompensation a compelling and critical area of investigation.

Definition of Recompensated Cirrhosis

As previously stated, complications of PH, such as ascites, portal hypertensive bleeding, or hepatic encephalopathy (HE), are the hallmarks of dACLD. Further decompensation is defined as the development of a second PH-driven decompensating event: recurrent variceal bleeding, recurrent ascites or EH, the development of hepatorenal syndrome, or spontaneous bacterial peritonitis. These mark a prognostic stage associated with even higher mortality than first decompensations and should be considered as a more advanced stage.[14] Consequently, many authors have referred to recompensation in their data as varying degrees of remission of these conditions.[2] [13]

However, the core themes remained consistent across the various studies, namely, the clinical manifestations of decompensation, the presence or absence of medical treatment, and the recovery of liver function.

As previously stated, the Baveno VII consensus conference established the first definition of recompensation, which included the following clinical criteria[14]:

1. Elimination/suppression/healing of the primary etiology of cirrhosis.

2. Resolution of ascites and HE, both without pharmacological treatment and absence of recurrent variceal bleeding for at least 12 months.

3. Stable improvement in liver function tests (LFTs) (e.g., albumin, international normalized ratio/INR, and total bilirubin [TBIL]).

Following the publication of these criteria, subsequent studies, mainly retrospective, have attempted to validate them across various populations and clinical scenarios (see [Table 1]). Although defining recompensation is crucial, these criteria primarily focus on ALD, and HBV- and HCV-related cirrhosis where the underlying cause can be potentially removed (see- [Fig. 1]). They also lack a clear threshold for “'improvement in LFT” and exclude certain patient groups, such as those with MASLD or transjugular intrahepatic portosystemic shunt (TIPS), highlighting the need for further refinement in the definition in future studies. Given the significant heterogeneity of the dACLD population regarding etiology, natural history, and treatment options, this review will offer different perspectives on the pathophysiology and evidence behind recompensated cirrhosis by etiology.

Pathophysiology of Recompensated Cirrhosis According to the Etiologies

Viral Hepatitis C

The epidemiology of chronic HCV has shifted significantly since the introduction of highly effective second-generation DAAs, which have led to a decline in complications associated with dACLD.[15] As a result, numerous questions have emerged concerning the natural history of patients who achieve sustained viral response (SVR). SVR leads to a significant reduction in hepatic venous pressure gradient (HVPG), thereby decreasing the risk of hepatic decompensation and promoting varices eradication.[16] [17] [18] [19]

Patients who achieve SVR also experience benefits such as regression of liver fibrosis,[20] patient-reported outcomes,[21] and even a reduction in the incidence of hepatocellular carcinoma (HCC), although not complete elimination,[22] as HCV has been shown to induce liver damage through direct cytopathic effects as well as immune-mediated mechanisms.[23]

Nevertheless, achieving SVR does not eliminate the risk of decompensation, particularly in patients with clinically significant portal hypertension (CSPH) before treatment.[17] Multiple studies have investigated the degree of clinical improvement in patients with decompensated cirrhosis following SVR. However, not all studies have demonstrated a significant impact on liver function improvement in these patients. This inconsistency may be due to the heterogeneity of the cohorts studied, the duration of follow-up, and the varying definitions used, as most studies were conducted before the Baveno criteria were established.[24] [25] [26] Notably, many studies have shown that the higher the degree of liver dysfunction, the lower the probability of liver function improvement.

In the context of very advanced liver disease, patients awaiting liver transplantation who achieve SVR can experience improved liver function and significant clinical improvement. Among patients listed for liver transplantation, 20 to 25% can be delisted after SVR due to the reversal of liver dysfunction, regardless of whether SVR was achieved with IFN-free regimens[27] or DAAs.[10] [28] Lower baseline model for end-stage liver disease (MELD) (<20) and the absence of ascites at the time of treatment initiation are the most significant parameters associated with the probability of being delisted. Moreover, long-term follow-up studies of delisted patients have demonstrated that only 10% of delisted patients may require re-listing, demonstrating the long-term beneficial impact post-SVR in decompensated patients.[10] [28]

Viral Hepatitis B

Continuous immune-mediated hepatitis caused by HBV infection leads to immune exhaustion, liver inflammation, and fibrosis, and the integration of its genome into the host DNA can strongly influence hepatocarcinogenesis even in the absence of ACLD.[29] Nevertheless, advances in vaccination and highly active NA therapy have changed the natural history of this disease, the former preventing infection and the latter preventing progression to cirrhosis and its complications,[29] promoting histological improvement and regression of fibrosis,[30] and even reducing the risk of HCC development.[31]

Given the above evidence of successful etiological control, many studies have been conducted to validate the Baveno VII criteria in this population. Studies in entecavir-treated patients have shown that higher viral DNA and AST/ALT levels, as well as improved LFTs (INR, albumin) and markers of PH severity (platelet count [PLT] and sodium) at baseline and follow-up (i.e., 48, 120, and 240 weeks) are predictors of recompensation, with rates of 56.2% at early follow-up and additional patients recompensating at a later time point. Interestingly, 86.8% of the patients who achieved recompensation in these studies maintained this status at 240 weeks of follow-up.[7] [9]

Furthermore, evidence derived from a multicentric Chinese cohort of decompensated patients treated with NAs[32] has indicated that there is a discrepancy in recompensation rates associated with the index decompensation (i.e., ascites, variceal bleeding, or ascites + variceal bleeding). Improved rates of recompensation and lower re-decompensating events were evident in patients with ascites compared with those with variceal bleeding. However, both the groups exhibited superior outcomes compared with their non-recompensated counterparts, with lower rates of death, liver transplantation, and HCC.

The presented findings highlight the crucial role of preserved baseline liver function, and in the context of HBV-related cirrhosis, it is evident that higher viral DNA, in conjunction with markers of liver inflammation (i.e., AST/ALT), indicate a more robust immune response, which is associated with factors conducive to recompensation. Nevertheless, the currently available data suggests that further elucidation is required about the concept of recompensation, not only about the etiology of cirrhosis but also in consideration of the index decompensation and the time necessary to achieve recompensation. This is because the natural history of recompensation may vary according to the specific decompensating event and the time elapsed since the initiation of etiological treatment.

Alcohol-Associated Cirrhosis

Alcohol consumption is associated with an increased burden of disease worldwide, with a particularly high impact in the European regions. Furthermore, ALD is one of the most important liver diseases in the Western world, complicating the course of other chronic liver diseases by adding morbidity and mortality. ALD-related ACLD has served as a benchmark pathology to understand the effects of etiology control on disease progression, as abstinence has long been shown to induce the reversal of histological, analytical, and clinical markers of disease, albeit dependent on disease stage and inter-individual variability, such as sexual or racial traits.[33] [34]

Prior to the introduction of the Baveno VII criteria, studies on liver transplantation waiting lists[2] [3] had already commenced investigating into the concept of delisting derived from enhanced liver function.[2] [3] This function was mainly defined through higher PLT, MELD <20, serum albumin >32 g/L, and the absence of ascites and/or HE. These studies concentrated on patients who were abstinent and had ALD-related cirrhosis. The findings not only reinforced the advantages of alcohol abstinence in this population but also revealed a delisting rate of approximately 8% due to improved liver function.

A recent observational and retrospective study aimed to validate the Baveno VII criteria in ALD patients with dACLD.[4] As with other chronic liver diseases, well-controlled etiology through abstinence, preserved liver function, and improved markers of PH (i.e., HVPG) and mean arterial pressure were identified as the most significant predictors of recompensation, with a concomitant reduction in liver- and all cause–related mortality. It is noteworthy that later events at follow-up (FU), such as re-decompensation (e.g., variceal bleeding) and development of HCC, were still present in 8.1% of the recompensated population.

In light of these observations, several relevant findings emerge regarding the establishment of ALD recompensation. These findings mainly concern favorable profiles in liver function, as with viral hepatitis, PH, and etiological control. Furthermore, abstinence adherence is a key factor in identifying which patients are likely to achieve this status. It is also important to note the benefits of recompensation while acknowledging the potential for re-decompensating events associated with known cirrhosis complications and alcohol consumption relapse, as the damage caused by the primary disease may create a “therapeutic window” effect. It is, therefore, imperative that this population is monitored with great care.

Metabolic-Associated Steatotic Liver Disease

MASLD is becoming one of the most important chronic liver diseases worldwide, with a gradual increase in its incidence and a prevalence reaching 30% globally.[35] The use of epidemiological modeling gives rise to further concerns, with the expectation that the complications of MASLD, such as dACLD or HCC, may increase 2- or even 3-fold by 2030.[36] The natural history of this condition has been extensively described, and there is evidence to suggest that the histological hallmarks of this disease (steatosis, inflammation, and fibrosis)[37] can be reversed through different types of interventions such as dietary,[38] [39] pharmacological,[40] [41] and bariatric.[42] [43]

However, the literature on recompensation in MASLD, as proposed by the Baveno VII consensus, remains limited. Additionally, this clinical setting differs significantly from other causes of ACLD in terms of its natural history. The HVPG thresholds for PH-related complications may vary considerably from those observed in other etiologies.[44] Furthermore, there is considerable interindividual susceptibility to the disease, which is attributable to the numerous factors involved (e.g., insulin resistance, endo- and paracrine signals, genetic interindividual susceptibility). Although a definition for histological regression exists, the clinical and laboratory parameters defining disease improvement and/or remission have yet to be clearly defined.[37] Also, Baveno VII does not include MASLD as a potentially curable or controllable etiology. This is due to the difficulty in defining an etiological treatment and its aforementioned overwhelming increase, which could influence the behavior of the liver transplant waiting list.[37]

Feng et al[37] have put forth several potential mechanisms of recompensation in MASLD that are analogous to those observed in other CLDs but with a particular focus on the amelioration of systemic inflammation caused by metabolic syndrome, which might be potential therapeutic targets. Examples of such therapies include peroxisome proliferator-activated receptor (PPAR) agonists, liver-targeted thyroid hormone receptor agonists, antifibrotics, vitamin E, statins, and even incretin mimetics.[35] [45] However, further research is needed to assess the safety and efficacy of these medications in decompensated MASLD patients for these to be accepted as an “etiological treatment” according to Baveno VII.

Nevertheless, some insight has been gained into potential avenues for further research, with the aim of more clearly defining the natural history of recompensation in patients with MASLD. These include the clinical trials with simtuzumab and selonsertib, which demonstrated that regression of cirrhosis was observed in 16% of patients with MASH-related cirrhosis,[46] the identification of disease-modifying factors, such as diabetes control, as conditions for achieving recompensation,[13] [37] as well as the active exploration of potential new treatments, such as resmetirom, whose phase 3 trial demonstrated a significant improvement in liver fibrosis,[41] or the ongoing TESLA-non-alcoholic-steatohepatitis trial, which is comparing the efficacy and safety of endoscopic gastric sleeve gastrectomy and laparoscopic sleeve gastrectomy.[47] This highlights that despite the complex and multifactorial nature of MASLD, a subgroup of patients may improve their liver function and maintain a compensated status with enhanced liver function, which may align with the current definition of recompensation; however, further research and follow-up data are still needed.

Chronic Cholestatic Disease

Primary biliary cholangitis (PBC) is perhaps the most studied chronic cholestatic disease, with an increasing prevalence but still considered a rare illness.[48] Although evidence supports the use of ursodeoxycholic acid (UDCA) to improve biochemistry, delay histological progression, and improve transplant-free survival,[48] almost 40% of patients do not respond to UDCA treatment. Therefore, several second-line treatments, such as obeticholic acid,[49] bezafibrate,[50] seladelpar, or elafibranor,[51] [52] have been proposed based on the different molecular targets in PBC.[53] Despite this intense research, remission in PBC remains elusive, and many scoring systems such as GLOBE, UK-PBC, or Paris-II have been proposed to further define an adequate response to treatment[48]; however, there is heterogeneity in the performance of these different validated models, and this could be one of the reasons for the exclusion of PBC as a “curable etiology” in the Baveno VII criteria.

Hofer et al, in an observational, retrospective, single-center study, evaluated the natural history of dACLD in patients with PBC, assessing the fulfillment of Baveno VII criteria for recompensation, adding Paris II criteria (alkaline phosphatase [ALP] decrease to ≤1.5× upper limit normal and bilirubin normalization) to better encompass PBC patients.[54] Despite the sample size (n = 42), this study illustrates the possibility of recompensation in this population, as 17% of patients achieved the established criteria, which was also associated with improved transplant-free survival compared with patients who remained decompensated (hazard ratio [HR]: 0.46 [95% CI: 0.10–2.21]; p = 0.035). As already mentioned in other studies, Hofer's findings emphasize the relevance of better pre-treatment liver function as a key factor in achieving recompensation, as well as the importance of etiological-specific analytical variables (i.e., ALP and TBIL) in refining the conceptualization of recompensation.[54]

Biomarkers of Recompensation: Invasive and Noninvasive

A biomarker is a measurable feature that indicates the response to an exposure or intervention and can be derived from molecular, histological, radiological, physical, or analytical sources.[55] Characterized effective biomarkers that are able to identify patients who are most likely to achieve the recompensation remains a challenging but compelling field of research.

To date, there are no biomarkers specifically studied in the context of hepatic recompensation. The available data are from studies that are mainly focused on the outcome of delisting for transplant waitlist, especially in HCV and alcohol-associated liver disease. Characterizing potential biomarkers could assist clinicians in developing treatment plans to promote recommendations in patients with decompensated cirrhosis, and in designing preventive interventions based on the risk of developing new decompensation in recompensated patients.

Potentially useful biomarkers can be broadly classified into invasive and noninvasive categories ([Fig. 2]).

Invasive Biomarkers

Among invasive biomarkers, the degree of hepatic fibrosis offers the greatest potential for diagnosing hepatic recompensation. It represents a histological finding, which is more likely to occur in compensated patients than in decompensated patients after the removal of the etiologic agent. However, it is not clear whether clinical recompensation is associated with the regression of fibrosis, although it seems reasonable to hypothesize that clinical recompensation could be accompanied by hepatic fibrosis regression. Biopsy studies have demonstrated that hepatic fibrosis can regress following etiological cure is possible, in patients with secondary biliary fibrosis,[56] HCV,[57] [58] HBV,[59] non-alcoholic steatohepatitis (NASH),[60] autoimmune hepatitis,[61] ALD,[34] and following bariatric surgery in patients with NASH.[62] Fibrosis regression is shaped by a multifaceted interplay of clinical–genetic–metabolic factors,[63] and is associated with an improvement in liver function and a reduction in liver-related complications.[46] [57] [58] [59] [60] [61] [64] For this reason, it is possible to suggest that regression of liver fibrosis may represent a very important step of the pathophysiologic structural substrate of hepatic recompensation. The changes of hepatic fibrosis will probably have to be considered an invasive diagnostic biomarker of hepatic recompensation, in the future re-definition. Nevertheless, more studies are needed to unify and describe the necessary change in liver fibrosis associated with the hepatic recompensation to refine its use as a diagnostic biomarker.

Another possible invasive diagnostic and prognostic biomarker for hepatic recompensation is the measurement of HVPG. The HVPG holds prognostic significance in liver disease progression, and its reduction through etiological treatment or non-selective β-blockers (NSBBs) therapy is associated with a decreased probability of decompensation, improved liver function, and prevention of both initial and further decompensation, which ultimately leads to better survival outcomes.[14] [65] [66] [67]

Elevated HVPG prior to etiological treatment,[16] [68] [69] along with persistent high HVPG during follow-up in patients with viral diseases,[70] or those adhering to alcohol abstinence,[71] [72] correlates with a low likelihood of hepatic recompensation and increased liver-related mortality.[4] [72]

Despite strong evidence regarding its role in disease progression, little is known about the value of HVPG after etiologic cure or the thresholds that predict recompensation. Preliminary data comparing HVPG with direct portal pressure suggest that HVPG closely mirrors direct portal pressure in the context of disease regression.[73] This implies that similar to its use in disease progression, HVPG may also serve as a reliable prognostic biomarker in recompensated patients, enabling better patient stratification and assessment of decompensation risk during follow-up.

Noninvasive Biomarkers

Noninvasive biomarkers could be based on different but complementary approaches: (a) a “biological” approach considering quantification of biomarkers in serum samples; and (b) a “physical” approach based on the spleen size, liver, and spleen stiffness using either ultrasound or elastography techniques.

The most commonly used biological biomarkers for monitoring liver disease progression are LFTs, which reflect the likelihood of decompensation.[65] After the etiological cure, the improvement in LFTs is correlated with a higher likelihood of recompensation.[4] [7] [9] [32] [74] [75] According to this, the Baveno VII definition[14] considers the stable improvement in LFTs (e.g., albumin, international normalized ratio/INR, and TBIL) as criteria of recompensation, whereby the improvement in LFTs and the liver function scores (Child-Pugh score and MELD score) could be considered as noninvasive biomarkers of recompensation; even so, a specific cut-off of these parameters and scores should be identified in the recompensated patients.

Low PLT, splenomegaly, and increased liver stiffness measurement (LSM) have been used to predict decompensation in patients with PH.[66] [76] Although it is reasonable to think these changes might play a role in compensation, this has not yet been demonstrated conclusively. Recent data from patients with compensated HCV who have been cured suggest that improvements in PLT count, associated with LSM values, can be useful for detecting CSPH and for risk stratification.[77] Therefore, PLT count and LSM may serve as noninvasive prognostic biomarkers in compensated patients.

Furthermore, a reduction in spleen size has been documented in patients who have achieved an HCV cure, and this reduction has been associated with decreased PH, increased PLT, and improved outcomes.[78] However, data on changes in spleen size in recompensated patients are lacking, and there is insufficient evidence to link spleen size reduction with a significant decrease in decompensation risk.

The development of portosystemic collaterals is a pathognomonic sign of PH, and their presence is indicative of PH. However, in the context of etiological cure, collaterals, including gastroesophageal varices, may disappear following treatment. Nonetheless, preclinical[79] and clinical studies show that, in some patients, collaterals can persist despite interventions such as liver transplantation,[80] [81] interferon treatment,[82] DAA therapy, and long-term alcohol abstinence.[68] [73] [83] [84] [85] Even in the absence of elevated pressure in the splanchnic territory (HVPG <10 mm Hg) after etiological treatment and recompensation, varices may persist, likely perfused at lower pressures. This persistence suggests that while collaterals are a specific sign of progression, their value in assessing regression and recompensation might be limited.

Alterations in liver and spleen biomechanical properties in cirrhosis can be measured using tissue elastography, notably transient elastography (TE), which assesses LSM and spleen stiffness measurement (SSM). TE is useful for diagnosing and monitoring compensated portal hypertension (CSPH). Both LSM and SSM strongly correlate with HVPG, particularly in (cACLD) due to viral hepatitis.[14] [86] [87] [88] Validated cut-off criteria based on LSM and platelet count are used for CSPH diagnosis and monitoring risk of decompensation in cACLD after HCV cure, even over long-term follow-up (>3 years).[14] [65] [70] [77] [86] [89] [90] SSM is now recommended as an additional tool for assessing PH. Given LSM's limitations, SSM may provide a more accurate assessment of CSPH and improve risk stratification.[88] However, these studies were limited to cACLD post-HCV cure, so further research is needed to validate LSM and SSM thresholds for patients with hepatic recompensation.

In the new era of biomarker development, high-throughput omics technologies, combined with advanced computational power and AI-driven methods, offer promising potential for discovering novel biomarkers for early diagnosis and long-term prognosis of hepatic recompensation, thus surpassing traditional approaches.[91] Notably, a set of lipid biomarkers linked to fibrosis regression has been proposed for noninvasive detection of fibrosis regression in cACLD, allowing differentiation between regressors and non-regressors after effective etiologic therapy.[63] However, significant advancements in the evidence base and maturity of multi-omics are needed for these biomarkers to transition into clinical practice as precision tools for personalized medicine.

In conclusion, while current data on invasive and noninvasive biomarkers primarily derive from studies on cACLD patients with HCV, further evidence is needed to validate their utility in hepatic recompensation. Prospective studies are required to identify biomarkers for prognosis, to pinpoint patients with a high likelihood of recompensation, and to assess long-term risk stratification for re-decompensation in recompensated patients.

Current and Future Therapeutic Strategies in Decompensated Patients: Etiological, Portal Hypertension Treatments, Anti-Inflammatory Agents, Gut–Liver Axis, and Angiogenesis

Although etiology-specific treatment is crucial for resolving liver-related events and improving liver regeneration,[2] [3] [4] [7] [8] [9] [10] [12] [27] success in achieving an etiologic cure is not sufficient in some group of patients.[11] In several patients, it can be challenging to accomplish liver regeneration, either because the liver disease is at a point of no return, beyond which recompensation is improbable, or because of the presence of some cofactors or comorbidities that may impact liver disease progression and increase the risk of decompensation. Such is the case in patients with SVR after DAA treatment in which the excess weight gain,[92] [93] [94] alcohol consumption, or the presence of steatosis or diabetes mellitus[95] all of which increase the risk of decompensation even if they had achieved a previous hepatic recompensation.

The presence of cofactors such as diabetes mellitus, insulin resistance, higher body mass index (BMI), and the components of the metabolic syndrome (i.e., dyslipidemia or abdominal obesity) have been associated with rapid progression and worsening disease prognosis, regardless of the etiology of cirrhosis, by interfering with the molecular pathways of fibrosis regression and liver regeneration.[3] [4] [24] [96] On the contrary, the control of these metabolic factors, like maintaining a lower BMI and the control of diabetes and insulin resistance, has been related to a higher probability of recompensation, in patients under sustained alcohol abstinence or antiviral treatment.[3] [4] [13] [24] [96] Accordingly, the control of these cofactors and components of metabolic syndrome could be an associated strategy in the maintenance of the compensated stage and help in the process of recompensation.

The specific treatment for metabolic syndrome, with metabolic bariatric surgery (MBS) (i.e., sleeve gastrectomy or Roux-en-Y anastomosis), is another valuable therapeutic strategy in those patients with MASLD/MASH, since some studies have shown that MBS allows the control-resolution of metabolic comorbidities, and offers several benefits (i.e., improvements in liver steatosis, decreasing low-grade inflammation and oxidative stress,[97] fibrosis, LFTs, and stimulating GLP-1 and peptide YY[98] secretion); therefore, it is likely these therapeutic strategies aimed at controlling metabolic comorbidities may help to keep the patient compensated regardless of the etiology.[37] [99] [100] Likewise, other specific pharmacological therapies for metabolic syndrome components, such as sodium-glucose cotransporter 2 inhibitors (SGLT2-i) and GLP-1 receptor agonists (GLP1-RA), are promising therapies in the future. However, the impact of weight loss and specific therapy of other components of the metabolic syndrome on the probability of improvement and recompensation needs to be clarified in future studies. Despite advances in the identification and control of the main cofactors and metabolic syndrome, it is not clear that patients with MASLD can achieve recompensation.[99] Therefore, actual data on recompensation in MASLD is almost inexistent.

In addition, several nonetiological treatments for hepatic decompensation are currently effective in controlling the decompensated events, by modulating the underlying pathophysiological mechanisms,[101] although these patients do not fulfill the definition of recompensation unless they can be withdrawn after the etiological cure without recurrence of the decompensated event. Among them, there are diuretics for ascites control, absorbable and nonabsorbable antibiotics (i.e., norfloxacin and rifaximin) that target bacterial translocation for primary and secondary prophylaxis of spontaneous bacterial peritonitis, and the hepatic encephalopathy treatment (i.e., lactulose and rifaximin).[14] [102]

However, achieving a compensated clinical state while using these treatments does not qualify as true recompensation, as a diagnosis of recompensation cannot be made if patients rely on them to remain compensated. This distinction highlights two separate clinical stages: recompensated patients (no ongoing treatment) and compensated patients (on treatment). Although clinically indistinguishable, it is essential to evaluate whether the risk of liver re-decompensation and long-term prognosis differ between these groups. Additionally, it is crucial to determine whether the prognostic cut-offs for noninvasive tests, such as LSM and platelet count, which are recommended for risk stratification in compensated patients with cACLD,[14] can also be applied to recompensated patients.

The use of NSBBs such as propranolol and carvedilol, as well as the placement of a TIPS, both of which can alter the natural history of cirrhosis by reducing PH[14] and improving survival, have been considered differently in the context of recompensation. While NSBBs are permitted as a concomitant treatment, TIPS, despite its ability to lower portal pressure and modify the disease course, is not currently regarded as an accepted treatment within the framework of the recompensation definition. Nonetheless, is important to recognize that recent data from retrospective and single-center studies have suggested TIPS is effective in controlling decompensation and improving liver function and survival,[103] to a similar extent as in patients with compensated cirrhosis.[104]

Although there has been interest in the potential use of TIPS as an adjunctive therapeutic strategy to promote hepatic recompensation in patients with continued CSPH despite etiological treatment, the evidence supporting TIPS in this role remains limited.

The use of statins represents another promising therapeutic strategy for portal PH that deserves consideration in the context of recompensation. Statins improve hepatic microvascular function, induce intrahepatic vasodilation, and alleviate endothelial dysfunction, primarily by enhancing intrahepatic nitric oxide production.[105] [106] [107] [108] [109] Additionally, they decrease hepatic stellate cell contractility through nitric oxide–independent mechanisms. This suggests their potential not only to further reduce portal pressure but also to serve as a useful adjunctive therapy in recompensated patients. However, further studies are necessary to clarify the role of statins in the recompensation of liver disease ([Fig. 2]).

Likewise, the use of drugs with anti-inflammatory and anti-fibrotic properties like PPAR agonists,[110] GLP-1 agonists liraglutide, semaglutide,[111] [112] sGC activators,[113] aspirin,[114] and dual or pan-FXR receptor agonists[115] [116] could be an associated strategy to the etiological treatments in the hepatic-recompensation process.

It is possible that the use of anticoagulant drugs, such as the direct-acting oral anticoagulant (DOAC) rivaroxaban[117] [118] or low-molecular-weight heparin,[119] could serve as a pharmacological strategy that promotes recompensation. These agents appear to delay the onset of hepatic decompensation, particularly the development of ascites. However, there is currently no clinical evidence specifically addressing their role within the context of recompensation.

Several drugs have been evaluated in preclinical models showing efficacy in the modulation of the inflammatory response, gut–liver axis, and hepatic-antifibrotic effect, and could be considered possible therapeutic strategies in the setting of hepatic recompensation. Some of them are: in the inhibition of CCR2-CCL2 chemokine pathway,[120] dual CCR2-CCR5 inhibitor (cenicriviroc),[121] [122] inhibition of TLR4 or inflammasome activation by TAK-242,[123] the apoptosis signal-regulating kinase 1 (ASK1) inhibitor selosertib,[124] pan-PPAR agonist lanifibranor (antifibrotic efficacy),[125] semaglutide (glucagon-like peptide-1 receptor agonist),[126] and the modulation of the inflammatory response by targeting the dysfunction of immune system cells (i.e., T cells functions in HBV) and targeting of recruitment or function of neutrophils in the ALD,[127] and in the modulation of angiogenesis (driver of liver fibrosis and PH),[128] [129] stimulation of vascular endothelial growth, mediated liver tissue repair, and fibrosis resolution.[130]

Further prospective clinical studies, in addition to research focused on uncovering the molecular mechanisms driving compensation, are required to refine the definition, guide the design of clinical trials, and identify potential therapeutic targets, to accelerate the hepatic recompensation process.

Conflict of Interest

The authors who have taken part in this study declare they have nothing to disclose regarding funding or conflict of interest concerning this manuscript.

^* Shared first author.

^# Shared corresponding author.

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Publication History

Article published online:
03 April 2025

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