This position paper from the Italian Association for the Study of the Liver (AISF) and the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) reviews the evidence for the use of albumin in several settings related to liver cirrhosis. They outline recommendations based on evidence, highlight areas where there is a suggestion of benefit and outline where the evidence is insufficient to make clear clinical decisions.
Albumin was first used as an agent for fluid resuscitation, and since that initial indication has been trialled in other areas. Many widely-used indications do not have a clear basis in clinical evidence. Albumin administration has been demonstrated to prevent post-paracentesis circulatory dysfunction (PPCD) after large volume paracentesis. It has also demonstrated efficacy at preventing renal failure in spontaneous bacterial peritonitis (SBP), and benefit when used with vasoconstrictors in treating hepatorenal syndrome (HRS). There is a high cost associated with the use of albumin, and particularly in Italy, it is prescribed in cirrhosis for conditions without a solid indication. On that basis, the AISF and SIMTI have produced this position paper to explore circumstances where albumin is of proven benefit and where it may play a role despite unclear evidence.
Albumin accounts for the majority of circulating plasma protein in healthy individuals; synthesised by hepatocytes at a rate of 10–15 g per day, around 5% leaves the circulation every hour and is returned by the lymphatic system. The circulatory half-life of endogenous albumin is 16–18 hours, while the total half-life is 12–19 days. It is a key modulator of fluid distribution, accounting for 70–80% of the oncotic effect of plasma, although it has a wider biological role – scavenging and neutralising reactive oxygen and nitrogen species, transporting molecules and modulating immune and inflammatory responses.
Hypoalbuminaemia is a feature of cirrhosis, resulting from decreased hepatocyte synthesis, dilution of extracellular fluid and increased catabolism and is an independent prognostic factor. Advanced cirrhosis can result in circulatory dysfunction and chronic inflammation – meaning that patients become functionally hypovolaemic, predominantly because of splanchnic visceral vasodilation. Activation of the renin-angiotensin-aldosterone system (RAAS) and other compensatory mechanisms occurs, and as disease becomes more advanced, a drop in cardiac output can occur. Another feature of cirrhosis is a constant state of moderate systemic inflammation, typically a result of increased intestinal permeability resulting in the transposition of bacterial proteins, and also resulting in splanchnic vasodilation.
One of the predominant therapeutic aims of albumin therapy in cirrhosis is to maintain an effective circulating volume. Albumin is a potent plasma expander, exerting positive effects on circulatory function, and its other properties can have a positive effect on cardiac contractility. International guidelines recommend that albumin solution can be used to manage some of the complications of cirrhosis, particularly the prevention of PPCD and SBP-induced renal failure and the management of HRS. In Italy, a recognised indication is the long-term treatment of ascites refractory to diuretic therapy. The AISF and SIMTI recommend that serum albumin levels should not be used as a guide to whether or not it is appropriate to prescribe albumin.
Paracentesis is the first-line treatment for diuretic refractory ascites. By decreasing intra-abdominal pressure, venous return is boosted. However, an excessive drop in peripheral resistance can lead to a decrease in effective circulating volume – this can lead to a marked activation of the RAAS which has been noted to persist for months. Albumin infusion counteracts this effect in its role as a plasma expander. Studies have demonstrated that when more than 5 litres of ascites are removed, albumin solution is effective at preventing PPCD; when less than 5 litres are removed, the incidence of PPCD is low, and alternative fluids have been shown to be as effective at preventing PPCD – although large volumes of saline should be avoided. Vasoconstrictors have been explored in this setting but with limited sample sizes and variable results to date. Meta-analysis has shown that albumin is significantly better at preventing PPCD and hyponatraemia, and also demonstrated a previously unidentified mortality benefit. One randomised controlled trial to date has explored a standard dose of albumin versus a reduced dose, with similar findings – although the small sample size precludes a clear recommendation.
Recommendations from the ASIF-SIMTI are that albumin solution should be given at 6–8 grams per litre of ascites drained, when >5 litres are drained alternative plasma expanders should not be used. Vasoconstrictor use should be limited to trials at present. It is advisable to infuse albumin slowly – although there are no studies examining infusion rates.
Spontaneous bacterial peritonitis is a life-threatening infection of ascites, and around a third of those who contract it develop renal impairment – which is itself a negative prognostic factor. The renal function deterioration is caused by abrupt deterioration of circulatory function, and is mediated by pro-inflammatory and vasoactive processes, resulting in effective hypovolaemia and impaired end-organ perfusion. Albumin solution improves circulatory dysfunction, countering this process; other properties of albumin may also account for a rise in systemic vascular resistance. The initial randomised controlled trial showed a drop in the rate of renal failure from 33 to 10%, alongside significant drops in both the in-hospital mortality (29% control versus 10% with albumin) and the 3-month mortality (41% versus 22%). Recent studies have suggested the benefit to lower-risk patients may be uncertain, while there is no clear evidence on whether reduced doses of albumin could show the same effect. A meta-analysis has backed up the initial finding of reduced renal disease and mortality with albumin therapy.
Hepatorenal syndrome is renal failure occurring in a patient with advanced liver disease without another clear cause. It has a poor prognosis, with a median survival of less than 2 weeks. The main pathophysiological process in the more acute type-1 disease is marked renal artery vasoconstriction, usually as a result of severely reduced effective circulating volume due to splanchnic vasodilation and inadequate cardiac output. It is largely a diagnosis of exclusion. Most data on treatment relates to type 1 disease, with findings that treatment should be initiated as soon as possible, the most effective treatment demonstrated is a vasoconstrictor plus albumin solution. Terlipressin has been the most studied vasopressor and combination treatment has shown to produce full reversal in 40–50% of cases, other vasoconstrictors have not demonstrated the same level of efficacy. Meta-analysis has shown that combined treatment is able to improve short-term survival.
The following are recommendations from the ASIF and SIMTI which are not based on direct evidence, and are thus subject to considerably less certainty:
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