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Long-term albumin treatment in patients with cirrhosis and ascites

  • Author Footnotes
    † All authors contributed equally to the manuscript.
    Paolo Caraceni
    Correspondence
    Corresponding author. Address: U.O. Semeiotica Medica, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, IRCCS Azienda Ospedaliera-Universitaria di Bologna, Italy, Via Albertoni 15, 40138 Bologna, Italy.
    Footnotes
    † All authors contributed equally to the manuscript.
    Affiliations
    IRCCS Azienda Ospedaliera-Universitaria di Bologna, Italy

    Department of Medical and Surgical Sciences and Center for Biomedical Applied Research, Alma Mater Studiorum University of Bologna, Italy
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  • Author Footnotes
    † All authors contributed equally to the manuscript.
    Alastair O’Brien
    Footnotes
    † All authors contributed equally to the manuscript.
    Affiliations
    UCL Institute for Liver and Digestive Health, Upper 3rd Floor, Division of Medicine, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
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  • Author Footnotes
    † All authors contributed equally to the manuscript.
    Pere Gines
    Footnotes
    † All authors contributed equally to the manuscript.
    Affiliations
    Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBEReHD, Barcelona, Catalonia, Spain
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  • Author Footnotes
    † All authors contributed equally to the manuscript.

      Summary

      Although proposed for the first time several decades ago, the possibility that long-term human albumin could be effective for the treatment of patients with cirrhosis and ascites has become a topic of scientific and clinical discussion in the last decade. Long-term albumin administration represents a completely different treatment perspective compared to acute or short-term uses of albumin. Results from the ANSWER and the MACHT studies indicate that long-term albumin treatment can be effective, safe and able to modify the course of the disease provided that albumin is given at a sufficient dose and for a sufficient time to restore physiological levels and functions of the circulating molecule, which are compromised, at least partially, in patients with decompensated cirrhosis. Further clinical studies and randomised trials are warranted to confirm the clinical benefits of long-term albumin therapy. Important areas for further research include determining the precise target population, the biomarkers of response, the optimal dose and frequency of albumin infusions, the stopping rules, and the cost-effectiveness of treatment in different healthcare systems across the world, particularly in those where the logistical issues and costs related to the periodic intravenous infusions may represent an important limitation to the implementation of this innovative approach in clinical practice. In this review, we will critically analyse the available data on long-term albumin treatment, focusing on the differences that exist between studies, the controversial issues and the future perspectives.

      Keywords

      Introduction

      Human albumin (HA) administration is one of the most studied interventions in patients with decompensated cirrhosis.
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      Randomised-controlled trials (RCTs) have produced controversial data on the efficacy and safety of HA, likely because of the great variance in terms of indications, experimental design, type of patients enrolled, length of treatment, and dosage and frequency of infusions. Current HA indications include acute or short-term (maximum 2 weeks) administration. Although proposed for the first time several decades ago, the possibility that HA can be administered for much longer to treat patients with ascites has become a major topic of scientific and clinical discussion in the last few years.
      This review will critically analyse the available data, the controversial issues and the future perspectives related to long-term HA treatment, highlighting the differences that exist between studies and the other short-term uses of HA administration in patients with decompensated cirrhosis.

      The albumin molecule in patients with decompensated cirrhosis

      Albumin is synthesised by hepatocytes and continuously secreted into the circulation, without being stored in the liver.
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      Figure thumbnail gr1
      Fig. 1Properties of the albumin molecule and major changes occurring to the albumin molecule in patients with decompensated cirrhosis.
      Albumin image credit, molekuul.be - stock.adobe.com. LPS, lipopolysaccharide; PGE2, prostaglandin E2.
      In patients with decompensated cirrhosis, the albumin molecule undergoes both quantitative and qualitative changes. Hypoalbuminemia has been considered a marker of advanced liver disease for decades. It correlates with the severity of cirrhosis and independently predicts poor outcomes in these patients.
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      As a result of these changes, albumin becomes dysfunctional in decompensated cirrhosis, showing an impairment of binding, detoxification and antioxidant activities, which parallels the severity of the disease.
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      (Fig. 1).
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      As damage accumulates, the proportion of the albumin molecules maintaining a fully preserved structure declines according to the severity of the disease.
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      Interestingly, effective albumin concentration appears to discriminate the different stages of cirrhosis and predict outcomes significantly better than the total serum albumin concentration routinely measured by standard laboratory methods in daily clinical practice.
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      In patients with decompensated cirrhosis, circulating albumin is low; moreover, albumin is damaged and dysfunctional.
      In this perspective, exogenous HA infusions would aim at restoring the major physiological functions of the molecule by increasing the effective albumin concentration.

      Pathophysiological rationale for the use of albumin in patients with decompensated cirrhosis

      Studies on the use of HA infusions were first reported more than 70 years ago,
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      and all international guidelines currently recommend HA as the fluid of choice for volume expansion in patients with cirrhosis and ascites.
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      EASL clinical practice guidelines for the management of patients wit decompensated cirrhosis.
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      Both oncotic and non-oncotic properties of the albumin molecule are important to antagonise key events in the pathophysiology of decompensated cirrhosis, such as circulatory dysfunction and systemic inflammation.
      Clinical and experimental data have raised the possibility of HA infusions having other beneficial properties beyond volume expansion.
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      HA administration in patients with SBP improves systemic haemodynamics through mechanisms not directly related to volume expansion, but consistent with improved endothelial function.
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      HA also appeared to improve cardiac contractility in an experimental model of isolated perfused rat heart by reducing the activation of inflammatory mediators in the cardiac tissue.
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      Furthermore, cirrhosis associated prostaglandin E2-mediated immune dysfunction was improved following HA infusion
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      and analyses of samples from 2 trials in patients with cirrhosis demonstrated that HA can reduce systemic inflammation.
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      Finally, recent experimental evidence indicates that HA is internalised in immune cells and modulates their responses through interaction with endosomal toll-like receptor signalling.
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      Albumin internalizes and inhibits endosomal TLR signaling in leukocytes from patients with decompensated cirrhosis.
      Therefore, the potential benefits resulting from both the oncotic and non-oncotic properties of the molecule provide the rationale for exogeneous HA infusions aimed at counteracting the main pathogenic drivers of poor outcome in patients with decompensated cirrhosis, namely effective hypovolemia and systemic inflammation/immune dysfunction
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      Hemodynamic and systemic effects of albumin in patients with advanced liver disease.
      (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Potential pathophysiological events antagonised by the oncotic and non-oncotic properties of the albumin molecule in patients with cirrhosis and ascites.
      DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns.

      Long-term albumin treatment in patients with ascites

      Five to ten percent of patients with compensated cirrhosis develop ascites every year, which represents the most frequent decompensating event of cirrhosis.
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      Moderate and massive (grade 2 and 3) ascites usually requires long-term treatment, leads to recurrent hospitalisations, also caused by related complications (i.e., SBP, HRS, abdominal hernias, and restrictive ventilatory dysfunction), and impairs patient quality of life.
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      and a significantly lower recurrence of grade 2-3 ascites associated with higher transplant-free survival in the group receiving long-term HA for a median follow-up of 84 months.
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      More than 10 years after these pivotal studies, 3 clinical trials were published in 2018.
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      The ANSWER trial

      The ANSWER study,
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      • Foschi F.G.
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      a non-profit, Italian multicentre, open-label, pragmatic RCT, enrolled 431 patients with persisting non-complicated grade 2 and 3 ascites requiring the combination of an anti-mineralocorticoid drug (at least 200 mg/day) and furosemide (at least 25 mg/day) to receive either standard medical treatment (SMT) or SMT plus 40 g of HA twice a week for the initial 2 weeks and then 40 g once a week.
      HA administration improved the management of ascites, as the need for LVP and the incidence of refractory ascites decreased by about 50%. The incidence rate of other complications (i.e., SBP, non-SBP bacterial infections, hepatic encephalopathy [HE] grade III or IV, HRS type 1, renal dysfunction [serum creatinine >1.5 mg/dl], moderate hyponatremia or hyperkalemia) also decreased by 30-67%, leading to a 35% reduction in liver-related hospitalisations and a 45% reduction in days spent in hospital per year compared to the control group. A significantly better 18-month overall survival rate, which was the primary endpoint of the study, was observed in patients receiving albumin, with a 38% reduction in the hazard ratio for mortality. The multivariable risk analysis for 18-month all-cause mortality, considering transjugular intrahepatic portosystemic shunt (TIPS) placement or liver transplantation as competing events, showed that HA treatment was the sole variable associated with increased survival. Furthermore, patients receiving HA had a better quality of life and HA treatment was also cost-effective compared to standard therapy based on reimbursement rates from the Italian National Health Service. Finally, side effects were similar between the 2 groups and no episodes of volume overload related to HA occurred, and only very few mild allergic reactions to HA infusion were reported.
      A post hoc analysis has highlighted the importance of serum albumin concentration in the interpretation of the positive results of the study.
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      On-treatment serum albumin level can guide long-term treatment in patients with cirrhosis and uncomplicated ascites.
      With the schedule of HA administration followed in the ANSWER trial, serum albumin concentration increased from a median level of 3.1 g/dl to almost 4 g/dl after 1 month of treatment, and remained stable afterwards. In the control group, no increase above the baseline level was observed, so that the difference between the 2 groups (about 0.7–0.8 g/dl) was significant during the entire follow-up.
      Furthermore, in patients receiving long-term HA, serum albumin concentration at 1 month of treatment, but not baseline serum albumin, directly correlated with the probability of 18-month survival, with a serum concentration of 4 g/dl being the best discriminating cut-off to independently predict survival. The 2 baseline factors that independently predicted the achievement of this cut-off were serum albumin concentration and model for end-stage liver disease (MELD) score, so that the lower the baseline serum albumin or higher the MELD score, the lower the probability of reaching the threshold of serum albumin indicated above.
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      • et al.
      On-treatment serum albumin level can guide long-term treatment in patients with cirrhosis and uncomplicated ascites.
      The major limitation of the ANSWER study was of course related to its open-label design. However, although the absence of blinding reduces the internal validity of the study, the pragmatic design of the ANSWER trial could have produced an even higher external validity since other strengths, such as large sample-size, prolonged follow-up, and a hard primary endpoint, are satisfied. More important than blinding is the fact that weekly HA infusions led patients to be seen more frequently by healthcare professionals than those enrolled in the control group. Although patients in the ANSWER trial were usually not evaluated by physicians during the HA infusions and some of them received HA in residential services or even at home, it cannot be excluded a priori that the regular contacts with healthcare services and personnel may have produced a better general management, thus contributing to the improved outcomes. Again, the real-word assessment of the entire pathway of care related to the intervention under study is a core feature of pragmatic trials. It is also tempting to speculate that the need for regular intravenous infusions, if perceived by patients as beneficial to their health, could favour the adherence of such a challenging group of patients to their overall pathway of care and incentivise them to overcome logistical limitations when present.
      Finally, almost half of patients included in the ANSWER study had cirrhosis caused by hepatitis C, which remained untreated during the study, and patients with active alcoholism were not included. Thus, the effects of HA administration in those with alcohol-related cirrhosis and active drinking remain to be determined.

      The “refractory ascites trial”

      The core results of the ANSWER trial were confirmed by a prospective, non-randomised clinical trial performed in Padua, Italy, which enrolled 70 patients with cirrhosis and refractory ascites.
      • Di Pascoli M.
      • Fasolato S.
      • Piano S.
      • Bolognesi M.
      • Angeli P.
      Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites.
      Patients who received SMT + HA (20 g twice a week) had a significantly lower 24-month mortality than the 25 patients receiving the SMT. Treatment with HA was the sole independent protective factor against death and it was associated with a significantly lower cumulative incidence of re-hospitalisations due to HE, accumulation of ascites, and bacterial infections.

      The MACHT trial

      The midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation (MACHT) trial was a ground-breaking trial for 2 reasons.
      • Solà E.
      • Solé C.
      • Simón-Talero M.
      • Martín-Llahí M.
      • Castellote J.
      • Garcia-Martínez R.
      • et al.
      Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial.
      First, it is one of the first RCTs in patients with decompensated cirrhosis to evaluate the effect of combination therapy, midodrine (an alpha-adrenergic agonist) and HA, on clinical outcomes; and second, it used a primary endpoint that combines the most relevant complications of advanced cirrhosis (renal failure, hyponatremia, infections, HE and gastrointestinal bleeding). Previous RCTs in cirrhosis had evaluated a single therapy, usually a drug, to treat or prevent a single complication of the disease.
      • Solà E.
      • Pose E.
      • Campion D.
      • Piano S.
      • Roux O.
      • Simon-Talero M.
      • et al.
      Endpoints and design of clinical trials in patients with decompensated cirrhosis: position paper of the LiverHope Consortium.
      The rationale for combining a vasoconstrictor drug and HA was to normalise the impaired effective arterial blood volume thought to be responsible, at least in part, for some complications of cirrhosis.
      • Ginès P.
      • Solà E.
      • Angeli P.
      • Wong F.
      • Nadim M.K.
      • Kamath P.S.
      Hepatorenal syndrome.
      ,
      • Ginès P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      ,
      • Simonetto D.A.
      • Gines P.
      • Kamath P.S.
      Hepatorenal syndrome: pathophysiology, diagnosis, and management.
      This specific treatment combination was based on the positive results observed when using midodrine with HA for the treatment of HRS.
      • Angeli P.
      • Volpin R.
      • Gerunda G.
      • Craighero R.
      • Roner P.
      • Merenda R.
      • et al.
      Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.
      Unfortunately, the MACHT trial did not meet the primary endpoint and therapy with midodrine and HA was not associated with a reduction in the incidence of complications or mortality in patients with decompensated cirrhosis awaiting liver transplantation. The only positive effect found was a moderate suppression of activity of renin-angiotensin and sympathetic nervous systems, suggesting a beneficial effect on circulatory function.
      Speculation about possible causes of the lack of efficacy of combined therapy in the MACHT trial is challenging. One possibility is that midodrine, which has a relatively weak vasoconstrictor potency compared to that of terlipressin,
      • Ginès P.
      • Solà E.
      • Angeli P.
      • Wong F.
      • Nadim M.K.
      • Kamath P.S.
      Hepatorenal syndrome.
      ,
      • Cavallin M.
      • Kamath P.S.
      • Merli M.
      • Fasolato S.
      • Toniutto P.
      • Salerno F.
      • et al.
      Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
      did not produce sufficient vasoconstriction in the splanchnic arteries and therefore was not capable of improving effective arterial blood volume sufficiently. Alternatively, but not mutually exclusive, the dose of HA used in the study (40 g every 2 weeks) could have been insufficient to produce the expected haemodynamic and non-haemodynamic effects of HA.
      • Fernández J.
      • Clària J.
      • Amorós A.
      • Aguilar F.
      • Castro M.
      • Casulleras M.
      • et al.
      Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis.
      ,
      • Tufoni M.
      • Baldassarre M.
      • Zaccherini G.
      • Antognoli A.
      • Caraceni P.
      Hemodynamic and systemic effects of albumin in patients with advanced liver disease.
      In the treated group, serum albumin concentration increased from a mean of 30 g/L at baseline to a mean of 34 g/L at week 12. However, a similar increase was observed in patients from the placebo group, suggesting that the improvement was unrelated to therapy. Another possibility is that the duration of treatment was not long enough to cause a significant beneficial effect. In fact, because many patients were transplanted quite rapidly during the study, the mean duration of treatment in the midodrine and albumin group was less than 3 months. Finally, it is also theoretically possible that the hypothesis of the study was wrong. However, the hypothesis cannot be ruled out completely because the combined treatment fell short of achieving a normalisation of effective arterial blood volume.

      Acute and short-term treatment in patients with decompensated cirrhosis

      HA treatment given as a single administration or a short-term course (up to a maximum of 15 days), with the purpose of preventing or treating acute complications of decompensated cirrhosis, has been the main use of HA for the last 40 years.
      International guidelines consistently recommend HA infusion to prevent circulatory dysfunction after paracentesis and renal failure in patients with SBP or to diagnose and treat HRS.
      European Association for the Study of the Liver
      EASL clinical practice guidelines for the management of patients wit decompensated cirrhosis.
      ,
      • Biggins S.W.
      • Angeli P.
      • Garcia-Tsao G.
      • Ginès P.
      • Ling S.C.
      • Nadim M.K.
      • et al.
      Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases.
      HA is also recommended by international guidelines in algorithms of diagnosis and management of acute kidney injury and hypervolemic hyponatremia although solid evidence from clinical studies is still limited.
      European Association for the Study of the Liver
      EASL clinical practice guidelines for the management of patients wit decompensated cirrhosis.
      ,
      • Biggins S.W.
      • Angeli P.
      • Garcia-Tsao G.
      • Ginès P.
      • Ling S.C.
      • Nadim M.K.
      • et al.
      Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases.
      ,
      • Angeli P.
      • Ginès P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      ,
      • De Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII Faculty
      Baveno VII Renewing consensus in portal hypertension.
      In contrast, no benefits in survival were observed in RCTs assessing HA administration in patients with infections other than SBP.
      • Fernández J.
      • Angeli P.
      • Trebicka J.
      • Merli M.
      • Gustot T.
      • Alessandria C.
      • et al.
      Efficacy of albumin treatment for patients with cirrhosis and infections unrelated to spontaneous bacterial peritonitis.
      ,
      • Guevara M.
      • Terra C.
      • Nazar A.
      • Solà E.
      • Fernández J.
      • Pavesi M.
      • et al.
      Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study.
      ,
      • Thévenot T.
      • Bureau C.
      • Oberti F.
      • Anty R.
      • Louvet A.
      • Plessier A.
      • et al.
      Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial.
      Notably, HA infusion significantly increased the risk of pulmonary oedema in one of these studies.
      • Thévenot T.
      • Bureau C.
      • Oberti F.
      • Anty R.
      • Louvet A.
      • Plessier A.
      • et al.
      Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial.
      Negative results were also observed in patients presenting with an acute episode of HE.
      • Guevara M.
      • Terra C.
      • Nazar A.
      • Solà E.
      • Fernandez J.
      • Pavesi M.
      • et al.
      Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study.
      Finally, the results of a large, multicentre, open-label RCT assessing short-term HA administration to prevent complications in hospitalised patients have recently been published.
      • China L.
      • Freemantle N.
      • Forrest E.
      • Kallis Y.
      • Ryder S.D.
      • Wright G.
      • et al.
      A randomized trial of albumin infusions in hospitalized patients with cirrhosis.
      In the ATTIRE (Albumin to Prevent Infection in Chronic Liver Failure) study, 777 patients with cirrhosis hospitalised with a decompensating event were included in the analysis. The treatment arm received daily intravenous infusions of HA to increase and maintain a serum albumin level of at least 3.0 g/L throughout the trial treatment period of up to 14 days. The standard-care (control) group received HA only as recommended by guidelines,
      European Association for the Study of the Liver
      EASL clinical practice guidelines for the management of patients wit decompensated cirrhosis.
      ,
      • Biggins S.W.
      • Angeli P.
      • Garcia-Tsao G.
      • Ginès P.
      • Ling S.C.
      • Nadim M.K.
      • et al.
      Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases.
      after LVP, during SBP, or for HRS. There were no significant differences in the composite primary endpoint (infection, renal failure, or death) between treatment and control groups, despite the HA group receiving a significantly higher HA dose than the control group. The HA group also had more severe or life-threatening serious adverse events, especially pulmonary oedema or fluid overload.
      The trial’s greatest strength was the large number of patients recruited and multiple sites involved. Other strengths were that patients were recruited very soon after hospitalisation (on average 1 day) and time to event and threshold analyses were performed, the latter including missing data. Finally, and crucially for an open-label trial, ATTIRE achieved substantial differences in the amounts of 20% HA infused between the albumin-treated group and control patients, especially during the early part of the trial when an increased albumin level might have been expected to have benefit.
      ATTIRE had several limitations, most obviously it was not blinded. 90% of recruited patients had alcohol-induced cirrhosis and results may differ for other causes of liver disease. The components of the composite endpoint (infection, renal dysfunction, and mortality) were not equivalent in severity; however, these do represent a common disease trajectory and move in line with each other and the 3- and 6-month mortality outcomes were also null. Inevitably in a trial of this size, there was heterogeneity in patients recruited in terms of infection, antibiotic treatment and organ dysfunction and it is possible that a specific group of patients might have benefited who were not examined in the subgroup analyses. However, no biomarkers or clinical features that predict potential benefit from albumin infusions have been identified to enable stratification.
      Thus, the results of this study do not support the use of HA in patients admitted for worsening or onset of a complication of cirrhosis with the aim of preventing the development of further complications of the disease during hospitalisation.

      Long-term albumin treatment: what we have learnt so far?

      Areas for future research include defining the target population (stratified according to expected outcomes), and determining biomarkers of response, the optimal dose and frequency of albumin infusions, stopping rules, and the cost-effectiveness of treatment in different healthcare systems.
      It appears evident that the data on efficacy and safety of HA are quite heterogeneous, so that some clinicians and researchers emphasise the benefits of HA in many conditions of decompensated cirrhosis, whereas others are against any extension of its use beyond the few well-established indications.
      A strong scientific debate is currently ongoing regarding long-term HA administration in patients with ascites, which represents not only a novel indication, but also carries logistical and economic consequences inherent to the need for chronic periodic intravenous infusions that pose a challenge to its application in clinical practice.
      It would be unwise to propose long-term HA administration for all patients with ascites who can be quite different in terms of clinical phenotypes and prognosis. As for any other intervention, the objective should be to define the target subgroups for whom the benefits are significant, the modalities of administration in terms of dosage, frequency and length of treatment, the assessment of response, and the absolute and relative contraindications.
      Long-term albumin administration appears to be an effective and safe treatment able to modify the course of the disease. It could be speculated that treatment benefits occur when albumin is given at a sufficient dose and for a sufficient length of time to restore the physiological levels and presumably functions of the molecule.
      At present, the patients with cirrhosis who appear to be most likely to benefit from long-term HA treatment are those with relatively stable conditions and at least grade 2 non-complicated ascites despite a moderate dosage of diuretics. Patients who had recently resolved an acute complication of the disease yet still present with ascites are also amenable to treatment. For these types of patients, administration of long-term HA has recently been included among the medical treatment options for the management of ascites by the Italian Association for the Study of the Liver.
      Italian Association for the Study of the Liver (AISF)
      Portal hypertension and ascites: patient-and population-centered clinical practice guidelines by the Italian Association for the Study of the Liver (AISF).
      These recommendations also suggest the use of long-term HA in refractory ascites, because by adding HA some of the patients may become responsive to diuretics.
      • Di Pascoli M.
      • Fasolato S.
      • Piano S.
      • Bolognesi M.
      • Angeli P.
      Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites.
      It should be acknowledged, however, that Italy represents a sort of “unicum” with respect to other countries, since long-term HA treatment is reimbursed by the National Health System and is currently standard of care in many hepatology centres.
      A second important issue regards the modalities of treatment. At present, the available data indicate that a pair of conditions, strictly interrelated, need to be achieved in order to optimise long-term treatment: namely HA must be administered at a high enough dose to produce an impact on serum albumin concentration and for long enough to achieve the increase of serum albumin concentration needed for conferring beneficial clinical effects without the risk of volume overload.
      The first assumption is based on the comparison between the ANSWER and the MACHT trials
      • Caraceni P.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • Neri S.
      • Foschi F.G.
      • et al.
      Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.
      ,
      • Solà E.
      • Solé C.
      • Simón-Talero M.
      • Martín-Llahí M.
      • Castellote J.
      • Garcia-Martínez R.
      • et al.
      Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial.
      (Fig. 3). While HA administration did not significantly influence serum albumin concentration in the MACHT trial, it led to a significant increase in the ANSWER trial (up to a median of almost 4 g/dl after 1 month of treatment and significantly higher than controls throughout the 18-month follow-up) . These divergent findings were likely due to the lesser amount of HA infused in the MACHT trial, which was less than half the amount infused in the ANSWER trial.
      Figure thumbnail gr3
      Fig. 3Comparison between the ANSWER and the MACHT trials.
      Upper panel: main features related to albumin treatment. Medium panel: changes in the median serum albumin concentration in the ANSWER trial. Lower panel: changes in the median serum albumin concentration in the MACHT trial. HA, human albumin; M, midodrine; SMT, standard medical treatment.
      If increasing serum albumin concentration is a requirement for effective therapy, the question that arises is what target level should be aimed at during treatment. A post hoc analysis of the ANSWER database provides interesting information to clarify this issue.
      • Caraceni P.
      • Tufoni M.
      • Zaccherini G.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • et al.
      On-treatment serum albumin level can guide long-term treatment in patients with cirrhosis and uncomplicated ascites.
      First, the percentage of patients with normal serum albumin concentration (>3.5 g/dl) increased from 25% at baseline to almost 80% after 1 month of treatment. Second, the serum albumin concentration reached after 1 month of treatment independently and directly correlated with 18-month survival. Third, the best discriminating cut-off level of serum albumin concentration between patients receiving or not receiving HA was 4 g/dl.
      Thus, it appears that normalising serum albumin concentration should be the target to obtain good clinical outcomes, and a maximal benefit is reached with levels around 4 g/dl. Other observations support this assumption. In the pilot PRECIOSA trial, a pathophysiological study comparing the effects of high (1.5 g/kg every week) vs. low (1 g/kg every 2 weeks) doses of HA given for 12 weeks in patients with decompensated cirrhosis and severe circulatory dysfunction, the low dose protocol produced a significant increase in serum albumin concentrations without reaching the normal range, while the high dose protocol was able to normalise serum albumin in all patients with a median level close to 4 g/dl.
      • Fernández J.
      • Clària J.
      • Amorós A.
      • Aguilar F.
      • Castro M.
      • Casulleras M.
      • et al.
      Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis.
      Interestingly, only patients receiving high doses of HA presented a significant improvement of cardiocirculatory dysfunction and systemic inflammation.
      • Fernández J.
      • Clària J.
      • Amorós A.
      • Aguilar F.
      • Castro M.
      • Casulleras M.
      • et al.
      Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis.
      Furthermore, even though the normal lower limit of serum albumin concentration has been set at 3.5 g/dl, more than 90% of healthy individuals aged up to 80 years have a higher serum albumin concentration, which is often higher than 4 g/dl.
      • Campion E.W.
      • DeLabry L.O.
      • Glynn R.J.
      The effect of age on serum albumin leveld in healthy males: report from the normative aging study.
      Thus, the real physiological level of albumin in healthy individuals is at least around 4 g/dl.
      The second assumption is that the benefits of long-term HA become evident after weeks of treatment, usually 1-2 months. Interestingly, in the ANSWER trial, the Kaplan-Meier curves of survival and refractory ascites (and those of several other secondary endpoints [Caraceni, personal communication]) started to diverge after 1-2 months of treatment once the increase in the albumin concentration had occurred and stabilised. The negative results of the ATTIRE trials provide indirect support for this hypothesis. The median length of HA treatment in the ATTIRE study was only 8 days and, although the individualised protocol of administration significantly increased the very low baseline median serum albumin concentration (2.3 g/dl), it was not able to correct hypoalbuminemia, as the median serum albumin concentration reached a level little above 3 g/dl throughout the entire 14-day follow-up.
      • China L.
      • Freemantle N.
      • Forrest E.
      • Kallis Y.
      • Ryder S.D.
      • Wright G.
      • et al.
      A randomized trial of albumin infusions in hospitalized patients with cirrhosis.
      Thus, it could be that higher doses of HA are needed in these very sick patients, although such doses would likely lead to an unacceptable risk of pulmonary oedema if given over a short timeframe.
      It can be concluded that long-term HA represents a completely different treatment paradigm compared to all other acute or short-term uses (Table 1). Acute or short-term treatment can last one or more days, but no longer than 2 weeks. Such treatment is usually applied in hospitalised patients (except in some of the patients undergoing LVP or presenting with AKI) who are often very sick, with the goal of treating or preventing a specific acute complication. As treatment needs to become rapidly effective, high amounts of HA are often infused in a relatively short time raising safety issues related to volume overload, at least in some complications, such as non-SBP bacterial infections
      • Thévenot T.
      • Bureau C.
      • Oberti F.
      • Anty R.
      • Louvet A.
      • Plessier A.
      • et al.
      Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial.
      or HRS,
      • Wong F.
      • Pappas S.C.
      • Curry M.P.
      • Reddy K.R.
      • Rubin R.A.
      • Porayko M.K.
      • et al.
      Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome.
      and in patients admitted to hospital for an acute decompensation of the disease, as documented in the ATTIRE trial.
      • China L.
      • Freemantle N.
      • Forrest E.
      • Kallis Y.
      • Ryder S.D.
      • Wright G.
      • et al.
      A randomized trial of albumin infusions in hospitalized patients with cirrhosis.
      Table 1Differences between acute/short-term and long-term albumin administration.
      Acute/short-term albumin treatmentLong-term albumin treatment
      It can last one or more days up to 2 weeksIt lasts at least weeks, usually months or sometimes years
      Mostly hospitalised patients
      Patients undergoing large-volume paracentesis or presenting acute kidney injury can also receive albumin in outpatient settings.
      (regular wards/intensive care units)
      Outpatients (it can be started during hospitalisation)
      The goal is to treat or prevent acute complicationsThe goal is to treat ascites and influence the course of the disease by preventing complications
      Effects should occur in hours or daysThe effects become manifest usually after 1-2 months of treatment
      High daily doses of albumin are infused within a short timeframeLow doses of albumin are infused over a long timeframe
      Safety issues (pulmonary oedema) in some cirrhosis complications
      Infections unrelated to bacterial spontaneous peritonitis,56 hepatorenal syndrome type I,65 and worsening or onset of an acute cirrhosis complication requiring hospitalisation.62
      Logistic issues (periodic intravenous infusions)
      Patients undergoing large-volume paracentesis or presenting acute kidney injury can also receive albumin in outpatient settings.
      § Infections unrelated to bacterial spontaneous peritonitis,
      • China L.
      • Freemantle N.
      • Forrest E.
      • Kallis Y.
      • Ryder S.D.
      • Wright G.
      • et al.
      A randomized trial of albumin infusions in hospitalized patients with cirrhosis.
      hepatorenal syndrome type I,
      • Macdonald S.
      • Andreola F.
      • Bachtiger P.
      • Amoros A.
      • Pavesi M.
      • Mookerjee R.
      • et al.
      Cell death markers in patients with cirrhosis and acute decompensation.
      and worsening or onset of an acute cirrhosis complication requiring hospitalisation.
      • Starlinger P.
      • Ahn J.C.
      • Mullan A.
      • Gyoeri G.P.
      • Pereyra D.
      • Alva-Ruiz R.
      • et al.
      The addition of C-reactive protein and Von Willebrand factor to model for end-stage liver disease-sodium improves prediction of waitlist mortality.
      In contrast, long-term HA treatment lasts at least weeks, usually months or even years; it is usually initiated in relatively stable outpatients, but it can be started in hospitalised patients once complications are resolved, with the goal of controlling ascites and preventing other complications, thus modifying the course of the disease. Long-term HA doses are usually lower than those for acute indications and are distributed over a much longer timeframe, thus making treatment safe. In this regard, no cases of volume overload and pulmonary oedema have been described in the clinical trials assessing long-term administration,
      • Caraceni P.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • Neri S.
      • Foschi F.G.
      • et al.
      Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.
      • Di Pascoli M.
      • Fasolato S.
      • Piano S.
      • Bolognesi M.
      • Angeli P.
      Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites.
      • Solà E.
      • Solé C.
      • Simón-Talero M.
      • Martín-Llahí M.
      • Castellote J.
      • Garcia-Martínez R.
      • et al.
      Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial.
      in contrast to the significantly higher incidence reported in some of the studies evaluating short-term HA treatment.
      • Thévenot T.
      • Bureau C.
      • Oberti F.
      • Anty R.
      • Louvet A.
      • Plessier A.
      • et al.
      Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial.
      ,
      • China L.
      • Freemantle N.
      • Forrest E.
      • Kallis Y.
      • Ryder S.D.
      • Wright G.
      • et al.
      A randomized trial of albumin infusions in hospitalized patients with cirrhosis.
      ,
      • Wong F.
      • Pappas S.C.
      • Curry M.P.
      • Reddy K.R.
      • Rubin R.A.
      • Porayko M.K.
      • et al.
      Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome.
      The ATTIRE and ANSWER trials are examples of short- and long-term HA treatment, respectively (Table 2).
      Table 2Main features of the ANSWER and ATTIRE trial.
      ANSWER trialATTIRE trial
      Trial designMulticentre open-label RCTMulticentre open-label RCT
      Study populationPatients with stable cirrhosis and uncomplicated grade 2 and 3 ascitesPatients with cirrhosis hospitalised for worsening or onset of acute complications
      Intervention40 g of albumin twice a week for 2 weeks, then 40 g weekly up to a maximum of 18 monthsTargeted to achieve and maintain a serum albumin level >3.0 g/dl from day 3 up to a maximum of 14 days
      Primary endpoint18-month overall survivalComposite of incidence of all-cause infection, renal dysfunction and death between day 3 and 15
      ITT population (intervention/control)431 (218/213)777 (380/397)
      Baseline MELD score (intervention/control), median (IQR)12 (10–15) / 13 (10–16)19.5 (15.4–22.9) / 19.5 (15.4–23.4)
      Length of treatment in the intervention arm, median (IQR)14.5 (5.0–18.0) months8 (6–15) days
      Effect on serum albumin concentrationSignificant increase in the albumin arm (from 3.1 close to 4 g/dl)Significant increase in the albumin arm (from 2.3 to slightly above 3 g/dl)
      Impact on survivalSignificantly increased in the albumin armNo difference between the 2 arms
      Impact on cirrhosis complicationsSignificantly reduced incidence in the albumin armNo difference between the 2 arms
      Risk of pulmonary oedemaNoYes
      Based on all these considerations, it could be hypothesised that the goal of long-term HA administration should be to restore the physiological functions of albumin (both oncotic and non-oncotic properties), which are active against effective hypovolemia and systemic inflammation and are instead partially lost in patients with cirrhosis and ascites.
      • Bernardi M.
      • Angeli P.
      • Claria J.
      • Moreau R.
      • Gines P.
      • Jalan R.
      • et al.
      Albumin in decompensated cirrhosis: new concepts and perspectives.
      ,
      • Naldi M.
      • Baldassarre M.
      • Domenicali M.
      • Bartolini M.
      • Caraceni P.
      Structural and functional integrity of human serum albumin: analytical approaches and clinical relevance in patients with liver cirrhosis.
      ,
      • Tufoni M.
      • Baldassarre M.
      • Zaccherini G.
      • Antognoli A.
      • Caraceni P.
      Hemodynamic and systemic effects of albumin in patients with advanced liver disease.
      In practical terms, the goal of long-term treatment should be to fill the gap that exists between the baseline patient serum albumin concentration and the on-treatment target serum albumin concentration corresponding to the physiological levels observed in healthy individuals
      • Campion E.W.
      • DeLabry L.O.
      • Glynn R.J.
      The effect of age on serum albumin leveld in healthy males: report from the normative aging study.
      (Fig. 4). As the extent of this gap is variable depending mostly on the baseline level of serum albumin and on the severity of cirrhosis,
      • Caraceni P.
      • Tufoni M.
      • Zaccherini G.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • et al.
      On-treatment serum albumin level can guide long-term treatment in patients with cirrhosis and uncomplicated ascites.
      the need emerges to go beyond a fixed dosage and schedule of HA administration – as used in the ANSWER study – to a more individualised treatment approach. It also emerges that the target level should be reached in weeks and not days to avoid the risk of volume overload, particularly in patients who appear more prone to develop this complication due to predisposing conditions.
      Figure thumbnail gr4
      Fig. 4The “filling the gap” hypothesis.
      The goal of long-term albumin administration should be to fill the gap existing between the pre-treatment serum albumin concentration and the physiological serum albumin concentration observed in healthy individuals.
      • Starlinger P.
      • Ahn J.C.
      • Mullan A.
      • Gyoeri G.P.
      • Pereyra D.
      • Alva-Ruiz R.
      • et al.
      The addition of C-reactive protein and Von Willebrand factor to model for end-stage liver disease-sodium improves prediction of waitlist mortality.
      As the extent of the gap depends mostly on the pre-treatment serum albumin level and the severity of liver disease, the amount of HA needed to fill the gap (grey arrows) may vary at the individual patient level. The dotted black lines correspond to the lower (3.5 g/dl) and upper (5.0 g/dl) limits of the lab references for defining the normal range of serum albumin concentration measured with standard methods in daily clinical practice. The red line corresponds to the serum albumin concentration during treatment, which has been shown to be associated with optimal outcomes45. Modified from ref.
      • Caraceni P.
      • Tufoni M.
      • Zaccherini G.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • et al.
      On-treatment serum albumin level can guide long-term treatment in patients with cirrhosis and uncomplicated ascites.
      .
      From this perspective, the time-course changes of serum albumin concentration together with the clinical response in controlling ascites could be used as a guide to maximise the benefits of treatment, define stopping rules and optimise HA utilisation. Further investigations are warranted to support this hypothesis.

      Challenges and open issues related to long-term albumin treatment

      A number of important questions remain to be answered in clinical research on long-term HA administration in decompensated cirrhosis (Box 1).
      Areas for future research on long-term albumin treatment.
      Investigations on the efficacy of HA are hampered by the lack of an objective biomarker of treatment effect, which is at least partly responsible for the lack of dose-finding trials. In fact, all RCTs evaluating the efficacy of HA in different indications were performed using arbitrary doses, except for the ATTIRE trial,
      • China L.
      • Freemantle N.
      • Forrest E.
      • Kallis Y.
      • Ryder S.D.
      • Wright G.
      • et al.
      A randomized trial of albumin infusions in hospitalized patients with cirrhosis.
      in which a preliminary study was performed to assess the dose required to increase serum albumin levels above 3 g/dl.
      • China L.
      • Skene S.S.
      • Shabir Z.
      • Maini A.
      • Sylvestre Y.
      • Bennett K.
      • et al.
      Administration of albumin solution increases serum levels of albumin in patients with chronic liver failure in a single-arm feasibility trial.
      It remains unclear which candidate biomarker should be used to assess response to therapy. The post hoc analysis of the ANSWER trial showed that normalisation of serum albumin concentration at 1 month of therapy was associated with better outcomes and increasing serum albumin levels correlated with higher survival rates.
      • Caraceni P.
      • Tufoni M.
      • Zaccherini G.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • et al.
      On-treatment serum albumin level can guide long-term treatment in patients with cirrhosis and uncomplicated ascites.
      However, the possible usefulness of effective albumin concentration – a measure reflecting the portion of the albumin pool with normal structure and function – also merits investigation,
      • Baldassarre M.
      • Naldi M.
      • Zaccherini G.
      • Bartoletti M.
      • Antognoli A.
      • Laggetta M.
      • et al.
      Determination of effective albumin in patients with decompensated cirrhosis: clinical and prognostic implications.
      ,
      • Mehta G.
      • Jalan R.
      The "Alter Ego" of albumin in cirrhosis.
      as does the potential utility of biomarkers related to desirable effects on systemic inflammation, circulatory or liver function, such as C-reactive protein, fatty-acid binding proteins, copeptin or cell death markers.
      • Clària J.
      • Stauber R.E.
      • Coenraad M.J.
      • Moreau R.
      • Jalan R.
      • Pavesi M.
      • et al.
      Systemic inflammation in decompensated cirrhosis. Characterization and role in acute-on-chronic liver failure.
      ,
      • Starlinger P.
      • Ahn J.C.
      • Mullan A.
      • Gyoeri G.P.
      • Pereyra D.
      • Alva-Ruiz R.
      • et al.
      The addition of C-reactive protein and Von Willebrand factor to model for end-stage liver disease-sodium improves prediction of waitlist mortality.
      • Juanola A.
      • Graupera I.
      • Elia C.
      • Piano S.
      • Solé C.
      • Carol M.
      • et al.
      Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis.
      • Solà E.
      • Kerbert A.J.
      • Verspaget H.W.
      • Moreira R.
      • Pose E.
      • Ruiz P.
      • et al.
      Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis.
      • Macdonald S.
      • Andreola F.
      • Bachtiger P.
      • Amoros A.
      • Pavesi M.
      • Mookerjee R.
      • et al.
      Cell death markers in patients with cirrhosis and acute decompensation.
      The availability of biomarkers in clinical practice would also help physicians to answer some other open questions related to long-term treatment, such as the minimum effective dose and optimal intervals between infusions, stopping rules, and when HA is no longer needed owing to clinical improvement or futility.
      Another clinical issue requiring further investigation regards the more precise definition of the target population that can benefit from long-term HA therapy. Comparison of patients from ANSWER and MACHT trials indicate that patients from the former trial had less advanced cirrhosis, as indicated by lower median MELD scores (12-13 vs. 17-16, respectively). Therefore, the possibility exists that HA is less efficacious in patients with more severe liver insufficiency. This hypothesis is intriguing and warrants investigating; if proven, investigations should focus on the mechanism(s) underlying such an observation.
      It will also be important to perform studies comparing long-term HA treatment with TIPS, to assess whether one treatment is superior to the other for certain subgroups, and to determine whether they could be used sequentially for patients with ascites. Other aspects of albumin therapy also deserve attention. Given the high cost and low availability of albumin, particularly in developing countries, the issue of cost-effectiveness is very important. Results from the ANSWER trial show that therapy is cost-effective in Italy because the extra cost of HA administration is compensated for by the decrease in hospital readmissions related to prevention of cirrhosis complications.
      • Caraceni P.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • Neri S.
      • Foschi F.G.
      • et al.
      Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.
      Specific analyses performed in other areas of the world including direct and indirect costs are needed to get a full picture of the cost-effectiveness of long-term HA treatment worldwide. Finally, weekly HA infusions lasting about 30-60 minutes may also cause significant logistical problems related to availability of space, journey of patients from home to hospital, availability of nurses to perform intravenous infusions, and time required for treatment. All these issues have to be considered should long-term HA treatment be implemented for patients with decompensated cirrhosis.

      Conclusion

      Additional RCTs are needed to confirm the positive effects of long-term albumin administration on clinical outcomes.
      Results from the ANSWER trial represent an important step forward in the investigation of albumin as a therapeutic agent for patients with decompensated cirrhosis. Besides controlling ascites, long-term HA treatment appears to significantly prevent complications and hospitalisations and improve survival, thus representing one of the first potentially disease-modifying interventions for patients with cirrhosis and ascites. However, based on discordant findings and several open issues, further clinical studies and randomised trials are urgently warranted. In this regard, a large multicentre open-label RCT assessing the “effects of long-term administration of human albumin on subjects with decompensated cirrhosis and ascites” (PRECIOSA study; NCT03451292) is underway and the results are eagerly awaited, even if a double-blind design would have increased the strength of its findings.

      Abbreviations

      HA, human albumin; HE, hepatic encephalopathy; LVP, large-volume paracentesis; MELD, model for end-stage liver disease; RCT, randomised-controlled trial; SBP, spontaneous bacterial peritonitis; SMT, standard medical treatment; TIPS, transjugular intrahepatic portosystemic shunt.

      Financial support

      Paolo Caraceni: the authors’ research is funded and supported by the EU Horizon 2020 Programmes (Carbalive, Grant/Award Number: 634579; LiverHope, Grant/Award Number: 731875; Decision, Grant/Award Number: 847949). Alastair O’Brien: the author’s research is funded and supported by the National Institute for Health Research Health Technology Assessment grant awarded, ref No. 17/67/01. Pere Ginès: the authors’ research is funded and supported by the Instituto de Salud Carlos III through the Plan Estatal de Investigación Científica y Técnica y de Innovación ( PI 16/00043 and PI20/00579 ), cofunded by the European Regional Development Fund (FEDER), EU Horizon 20/20 Programme (LiverHope, Grant/Award Number: 731875) and from the Agència de Gestió d'Ajuts Universitaris i de Recerca ( AGAUR– 2017- SGR -01281 ).

      Authors’ contributions

      All authors contributed equally to the manuscript and approved the final draft for submission.

      Conflict of interest

      Dr. Caraceni reports research grants from Grifols SA and Octapharma SA and personal fees from Grifols SA, Kedrion Biopharma SpA, CSL Behring SA and Biotest SA. Dr. O’Brien reports no conflicts of interest. Dr. Ginès reports grants from Grifols and personal fees from CSL Behring.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      We thank Dr. Maurizio Baldassarre (University of Bologna, Italy) for the contribution given to Figures.

      Supplementary data

      The following are the supplementary data to this article:

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