Management of liver disease

Several studies have clearly established that albumin is effective in preventing or treating specific complications of cirrhosis. Recent studies suggest that long-term albumin administration to patients with decompensated cirrhosis may act as a disease-modifying agent, easing the control of ascites, preventing the development of major complications and improving patient survival

Hypoalbuminaemia is a typical feature of cirrhosis and represents an important and adverse prognostic factor. It results from both a decreased synthesis by liver cells and, to a lesser extent, to other factors such as plasma volume expansion diluting the extracellular fluid protein content, due to the renal retention of sodium and water, and an increased trans-capillary escape rate of albumin, which leads to the protein being lost in the extravascular space.

Several studies have clearly established that albumin is effective in counteracting the haemodynamic dysfunction of advanced cirrhosis, which results from an arterial vasodilation located mainly in the splanchnic area and represents a common background for the development of several complications. These favourable effects are likely due not only to volume expansion but also to the non-oncotic properties of albumin, such as its anti-oxidant and scavenger activities, and its ability to modulate immune responses and preserve capillary integrity and permeability.¹ These non-oncotic properties assume further relevance in the light of several investigations which show that patients with advanced cirrhosis serum albumin undergo several molecular alterations that endanger these functions.^2-5 Moreover, the pathophysiological background of decompensated cirrhosis is characterised by a sustained pro-inflammatory and pro-oxidant state responsible for cardiovascular and multiorgan dysfunction.⁶

Indications for albumin administration in cirrhosis

Prevention of renal failure in spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) is a frequent and life-threatening infection of ascitic fluid. The diagnosis is based on the presence of >250 polymorphonuclear cells/mm3 in ascites, in the absence of an intra-abdominal source of infection or malignancy.⁷ Even without the occurrence of septic shock, SBP leads to a pro-inflammatory cytokine storm that further impairs cardiovascular dysfunction. The ensuing worsening in effective volaemia can lead to acute kidney injury (AKI), with the phenotype of hepatorenal syndrome (HRS) or acute tubular necrosis (ATN), which occurs in about 30% of cases and is a main cause of death.⁸ Indeed, SBP-related in-hospital mortality rates can be as high as 20%, despite the resolution of infection.⁷ A prospective randomised study has shown the administration of a high dose of albumin (1.5g/kg at diagnosis and 1g/kg on day 3) in addition to antibiotic treatment decreases the incidence of renal failure (from 30% to 10%) and improves in-hospital and three-month survival.⁹ The capacity of albumin to improve the outcome of patients with SBP has been confirmed in a meta-analysis of randomised trials.¹⁰

The amount of albumin to be administered in this setting and whether all patients have to be treated has not been fully defined. In fact, it would appear that patients at high risk of developing renal failure (baseline bilirubin >4mg/dl and/or creatinine >1.0mg/dl) benefit most from albumin administration, suggesting that it could be restricted to high-risk patients. However, two large subsequent retrospective studies showed that the incidence of poor outcome in low-risk patients not treated with albumin is not negligible. It has also been reported that a reduced-dose regimen of albumin (1.0g/kg on day 1 and 0.5g/kg on day 3) is as effective as the standard regimen in preventing renal failure and reducing mortality. However, these results still need to be confirmed by further prospective studies in larger patient populations. Thus, to date, the European Association for the Study of the Liver recommends that all patients with SBP should receive intravenous albumin at the higher dosage in addition to antibiotics.¹¹

Diagnosis and treatment of hepatorenal syndrome

HRS is a potentially reversible AKI that occurs in patients with advanced cirrhosis, ascites and liver failure, associated with marked circulatory dysfunction.⁸ HRS is the clinical manifestation of a severe intra-renal vasoconstriction. This results from impaired effective volaemia secondary to both arterial vasodilation and cardiac dysfunction (cirrhotic cardiomyopathy), which lead to a striking compensatory activation of vasoconstrictor systems such as the renin–angiotensin system, sympathetic nervous system, and arginine vasopressin.¹² Moreover, inflammation-induced kidney damage likely plays a relevant concomitant role.⁶

The diagnosis of HRS requires the exclusion of other forms of AKI.^8,11 Ongoing diuretic treatment should be withdrawn. The differential diagnosis between HRS and pre-renal AKI is based on the failure to improve serum creatinine after two days of plasma volume expansion, which is preferentially performed with albumin administration (recommended dose: 1g/kg of body weight per day, up to a maximum of 100g/day). The presence of renal structural damage or urinary tract obstruction should be excluded by ultrasonography. Urinalysis abnormalities such as elevated urine sodium concentration, haematuria, proteinuria or presence of casts would suggest ATN. However, the differential diagnosis between HRS and ATN is not always easy, even with the assessment of urinary biomarkers of renal tubular damage.^13,14

Once diagnosis is established, the most effective treatment of HRS includes the administration of vasoconstrictors (mostly terlipressin) in association with intravenous albumin (20-40g/day up to two weeks).¹¹ This treatment improves renal function in about 40% of cases and leads to the resolution of HRS in about one-third of cases. Survival is only improved in the short term, but this is unsurprising, as patients with HRS usually have a very advanced cirrhosis. Interestingly, the association of terlipressin plus albumin is more effective than terlipressin alone.¹⁵

These favourable effects are amenable to an improvement of effective volaemia, which not only results from plasma volume expansion, but is also due to improvements in stroke work and peripheral vascular resistance, as shown by comparing the effect of albumin and hydroxyethyl starch.¹⁶ These results suggest an effect of albumin on endothelial function, as plasma Von Willebrand-related antigen only decreased in patients treated with albumin and serum nitrates and nitrites only increased in patients treated with hydroxyethyl starch. Furthermore, albumin infusion was also able to restore an impaired cardiac contractility in an experimental model of cirrhosis.¹⁷

Prevention of paracentesis-induced circulatory dysfunction

Large volume paracentesis (LVP) is the current treatment of choice for patients with tense and refractory ascites.¹¹ The removal of large volumes of ascitic fluid can be followed by paracentesis-induced circulatory dysfunction (PICD), defined as a significant increase (>50%) in plasma renin activity six days after LVP. PICD is a circulatory dysfunction characterised by an exacerbation of arteriolar vasodilation, reduction of effective blood volume, rapid re-accumulation of ascites, increased risk of HRS, water retention with dilution hyponatraemia and shortened survival. In several randomised trials, albumin was able to lower the incidence of PICD and showed its superiority when compared with other plasma expanders. On the basis of such evidence, both American and European guidelines recommend the administration of 8g albumin/l of tapped ascites, when more than 5l of ascites are removed.^11,18 Due to high cost and potential low availability of albumin, many alternatives have been tested, also including vasoconstrictors. However, in support of current recommendations, a meta-analysis of randomised trials has confirmed that albumin not only reduces the occurrence of PICD more efficiently than any other plasma expander or vasoconstrictor but is also able to lower the incidence of hyponatraemia and improve survival.¹⁹

Controversial indications for albumin in cirrhosis

Bacterial infections other than SBP

Bacterial infections are very common complications of liver cirrhosis and represent a major cause of hospitalisation and death in patients with advanced disease. As reported above, it has long been recognised that renal failure develops in about one-third of patients with SBP. It has become clear that even non SBP-related infections can be followed by renal failure (about 25% of cases), which is also a major predictor of mortality in this setting.⁷

Data on the effect of albumin administration to patients with non SBP-related infections are few.

A randomised study showed that the administration of albumin (1.5g/kg at diagnosis and 1g/kg at day 3) in association with antibiotics was able to improve circulatory and renal functions with respect to the administration of antibiotics alone. However, no significant effects on the incidence of renal failure were seen and the cumulative three-month survival did not differ between the two groups, even though an advantage in the albumin group was found after adjusting according to variables with independent predictive value.²⁰ Similar results were reported by a subsequent large randomised trial, as albumin infusion delayed the onset of renal failure but did not improve renal function or survival at three months.²¹ Moreover, pulmonary oedema developed in 8/96 (8.3%) patients in the albumin group. Thus, further studies are needed to clarify the role of albumin administration in this setting, mainly aimed at identifying those patients who are most at risk of developing infection-induced complications and mortality.

Hypervolaemic hyponatraemia

Hypervolaemic hyponatraemia (serum sodium <135mmol/l) is frequently seen in patients with cirrhosis and ascites and is associated with a poor outcome.²² Although hyponatraemia can occur spontaneously, it is often induced by diuretic administration, LVP without albumin infusion, bacterial infections and renal failure. Such a complication results from effective hypovolaemia secondary to splanchnic arterial vasodilatation, which, in turn, impairs renal free water generation and evokes the non-osmotic secretion of vasopressin. Thus, beside diuretic withdrawal and water restriction, volume expansion with albumin has been proposed and many physicians commonly prescribe albumin in cirrhotic patients with hyponatraemia.²² Nevertheless, because of the lack of controlled clinical trials, albumin administration in this setting is not recommended by current guidelines.¹¹

Hepatic encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome complicating acute and chronic liver failure. HE is classically attributed to the accumulation of several substances (mostly ammonia) produced in the gut and normally metabolised by the liver. However, in recent years, an important pathophysiological role of other factors, such as inflammation, bacterial translocation and oxidative stress, has been demonstrated.²³ Thanks to its anti-oxidant and anti-inflammatory properties, albumin might be useful to counteract these mechanisms. A clinical study compared the effect of volume expansion with 4.5% albumin or colloid in patients with diuretic-induced HE, showing a reduction in plasma ammonia levels in both groups, possibly due to an increase in urinary excretion. However, an improvement in mental state was only observed in those patients treated with albumin, in whom there was a concomitant reduction in oxidative stress.²⁴ A subsequent randomised clinical showed that the combination of lactulose plus albumin was more effective than lactulose alone in the treatment of overt HE.²⁵ Interestingly, a greater reduction in plasma levels of arterial ammonia, pro-inflammatory cytokines and endotoxins occurred in patients who received albumin. Even though HE remains an unclear indication to albumin administration, these data suggest that the detoxification properties of albumin may have a role in the treatment of this condition.

New perspective: long-term albumin administration in decompensated cirrhosis

The efficacy of long-term albumin administration to patients with cirrhosis and ascites has long be debated. However, the investigations devoted to this matter are relatively few. In 1999, a prospective clinical trial randomised 126 hospitalised patients with ascites to receive diuretics associated or not with low doses of albumin (12.5g/day). Then, they were followed as outpatients receiving 25g/week of albumin, for a median follow-up of 20 months.²⁶ Albumin improved the response rate to diuretics and reduced the recurrence rate of ascites but had no effect on survival. Further data analysis showed that the beneficial effects of albumin were only seen in patients receiving an intermediate dose of diuretics (K-canrenoate 200mg/day plus furosemide 25mg/day), and the cost/benefit ratio was only favourable to albumin in the first in-hospital part of the study. A subsequent trial performed by the same research group in 100 consecutive cirrhotic patients admitted for first-onset ascites and followed for a median time of 84 months, reported that long-term albumin administration (25g/week for the first year, then 25g every two weeks) was able to reduce ascites recurrence and increase patient survival with respect to standard medical treatment.²⁷ Unfortunately, the relatively low number of patients in this study prevented to reach firm conclusions and, at present, long-term albumin treatment in this patient setting is not recommended by current guidelines.¹¹

Over the last year, three studies assessing the effect of long-term albumin administration to patients with decompensated cirrhosis were published. The ANSWER study, a non-profit, multicentre, randomised, open-label, pragmatic clinical trial enrolled patients with cirrhosis and persisting non-complicated ascites.²⁸ Patients were randomised to either standard medical treatment (SMT; 213 patients), which included albumin administration for well-established indications, or SMT plus 40g albumin (HA) twice a week for the initial two weeks and then 40g/week (218 patients). The primary endpoint, 18-month overall mortality, was reached, as a significantly lower mortality was seen in the albumin arm. As far as the secondary endpoints were concerned, the cumulative incidence rate of paracentesis was reduced by 54% and the incidence of refractory ascites by 46% in the SMT+HA arm.

The cumulative incidence of complications of cirrhosis, including SBP, non-SBP bacterial infections, episodes of renal dysfunction, hyponatremia, hyperkalaemia, HRS and severe HE, was also significantly lowered by albumin administration. The ANSWER study also assessed quality of life, which ameliorated in the SMT+HA arm, and the number and duration of hospitalisations, which were significantly reduced. Therefore, long-term albumin administration resulted to be cost-effective.

The main results of the ANSWER trial have been confirmed by a prospective, non-randomised clinical trial, which enrolled patients with cirrhosis and refractory ascites.²⁹ The 45 patients who received albumin (20g twice a week) up to 24 months had a significantly lower mortality than the 25 patients receiving the standard of care. Moreover, the cumulative incidence of re-hospitalizations due to complications of cirrhosis, such as hepatic encephalopathy, accumulation of ascites and bacterial infections, was significantly lower in patients treated with albumin. However, the midodrine albumin in cirrhotic patients awaiting liver transplantation (MACHT) study, challenged these results.³⁰ This placebo controlled clinical trial randomised 87 patients to receive either 40g albumin every 15 days plus the α1-receptor agonist midodrine (from 15 to 30mg/day according to their pressor response) and 86 to receive SMT and placebos for a planned follow up of 12 months. Despite a mild improvement in effective volaemia, no differences were seen in either the probability of developing complications, which was the primary end-point of the study or survival.

The discrepancies between these studies can be explained by differences in protocol, patient characteristics, sample size, and, mainly, albumin dose and duration of its administration. In fact, treatment largely exceeded one year in the ANSWER study, while was about two months in the MACHT trial due to high rate of liver transplantation. Furthermore, the amount of albumin administered in the MACHT trial was about half with respect to the ANSWER study. This accounts for the lack of effect on serum albumin concentration in the former, while a significant and sustained increase by 0.6–0.8g/l occurred in the latter.

Although several issues pertaining to patient features and dose and schedule of albumin administration require further investigation, long-term albumin treatment appears a most promising treatment for patients with decompensated cirrhosis, able to not only ease the control of ascites, but also to influence the course of the disease.

References

1. Garcia-Martinez R et al. Albumin: Pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology 2013;58:1836–46.
2. Jalan R et al. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Hepatology 2009;50:555–64.
3. Oettl K et al. Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival. J Hepatol 2013;59:978–83.
4. Domenicali M et al. Posttranscriptional changes of serum albumin: clinical and prognostic significance in hospitalized patients with cirrhosis. Hepatology 2014;60:1851–60.
5. O’Brien AJ et al. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med 2014;20:518–23.
6. Bernardi M et al. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015;63:1272–84.
7. Wong F et al. International Ascites Club. Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club. Gut 2005;54:718–25.
8. Angeli P et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol 2015;62:968–74.
9. Sort P et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403–9.
10. Salerno F, Navickis RJ, Wilkes MM. Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials. Clin Gastroenterol Hepatol 2013;11:123–30.
11. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69:406–60.
12. Arroyo V, Terra C, Ginès P. Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol 2007;46:935–46.
13. Belcher JM et al. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 2014;60:622–32.
14. Ariza X et al. Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis. PLoS One 2015;10:e0128145.
15. Ortega R et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 2002;36:941–8.
16. Fernández J et al. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 2005;42:627–34.
17. Bortoluzzi A et al. Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms. Hepatology 2013;57:266–76.
18. Runyon BA. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009;49:2087–107.
19. Bernardi M et al. Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials. Hepatology 2012;55:1172–81.
20. Guevara M et al. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. J Hepatol 2012;57:759–65.
21. Thevenot T et al. Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. J Hepatol 2015;62:822–30.
22. Bernardi M, Zaccherini G. Approach and management of dysnatremias in cirrhosis. Hepatol Int 2018;12:487–99.
23. Azhari H, Swain MG. Role of peripheral inflammation in hepatic encephalopathy. J Clin Exp Hepatol 2018;8:281–5.
24. Jalan R, Kapoor D. Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid. Clin Sci (Lond) 2004;106:467–74.
25. Sharma BC et al. Randomized controlled trial comparing lactulose plus albumin versus lactulose alone for treatment of hepatic encephalopathy. J Gastroenterol Hepatol 2017;32:1234–9.
26. Gentilini P et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial. J Hepatol 1999;30:639–45.
27. Romanelli RG et al. Long-term albumin infusion improves survival in patients with cirrhosis and ascites: an unblinded randomized trial. World J Gastroenterol 2006;12:1403–7.
28. Caraceni P et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018;391:2417–29.
29. Di Pascoli M et al. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int 2019;39:98–105.
30. Solà E et al. Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial. J Hepatol 2018;69:1250–9.