Human serum albumin (HSA), used as an intravascular volume expander, was introduced during World War II as a substitute for blood or plasma. HSA is responsible for 80% of the colloid osmotic pressure of plasma; therefore, the intravenous administration of albumin is associated with a rapid increase in the circulating blood volume. However, albumin is more than a simple plasma volume expander. HSA has many other physiological functions, including the binding and transport of a wide variety of water-insoluble endogenous and exogenous substances, metals, and drugs.1, 2 HSA is also quantitatively the most important circulating antioxidant.3 Some of these properties are the basis for new potential therapeutic indications for HSA, such as in ischemic stroke and Alzheimer's disease.4, 5 It is well known that the oxidation or binding of HSA to endogenous ligands produced or accumulated under pathological conditions such as sepsis, diabetes, chronic renal failure, and cancer6–8 is associated with significant structural and functional modifications of the molecule of albumin that markedly affect its biological activity.9
The article by Jalan et al.10 in this issue of HEPATOLOGY adds liver cirrhosis to this list of diseases with profound structural and functional modifications of HSA. They investigated 80 healthy subjects, 12 patients with decompensated cirrhosis, and 22 patients with acute-on-chronic liver failure as defined by the development of acute deterioration of liver function with hepatic encephalopathy and/or hepatorenal syndrome in a close temporal relationship with a precipitating event. Albumin function was investigated with the spin-trapping technique combined with electron paramagnetic resonance spectroscopy using 16-doxyl stearic acid as the spin label and ethanol as the polar reagent. The electron paramagnetic resonance spectrum generated from the stearic acid spin label bound to albumin allowed the assessment of structural and functional characteristics of the protein. The binding constants and the ability of albumin to bind fatty acids were estimated by measurements of the concentration of the fatty spin label bound to albumin as well as the amount of unbound fatty acid spin label. From these parameters, the transport (substrate sorption, binding, and delivery to target organs) and detoxification (ability of albumin to bind toxic substances produced via metabolism) efficiency of albumin could be estimated. Additionally, certain parameters of the spectrum indicated the mobility of the fatty acid spin label at its binding site on albumin, which depends mainly on the protein conformation at the albumin binding site for fatty acids. The ischemia-modified albumin, measured as the capacity of albumin to chelate cobalt, was also assessed to determine if it could be used as a simple test of albumin function. During the exposure of albumin to ischemic conditions such as acute coronary syndrome, the N-terminal of the albumin molecule is modified by oxidative free radicals and reactive oxygen species, and this results in the generation of a molecule with a low binding affinity to heavy metals. Finally, the plasma malondialdehyde and 8-isoprotane F2α levels were determined as markers of oxidative stress.
The study revealed several important findings. First, all parameters estimating albumin function (functional capacity of the binding sites, transport efficiency, and detoxification efficiency) were severely compromised in patients with cirrhosis. Second, impairment in albumin function correlated closely with the degree of hepatic insufficiency; patients with acute-on-chronic liver failure were those with a more severe impairment of albumin function. Third, the plasma levels of ischemia-modified albumin with respect to the total serum albumin concentration were significantly increased in patients with cirrhosis, particularly in those with acute-on-chronic liver failure. Lastly, markers of oxidative stress were significantly increased in cirrhosis and also correlated with the degree of liver impairment. These findings are not surprising. Liver failure results in the accumulation of many water-insoluble endogenous substances that bind albumin sites and may alter albumin structure and function. On the other hand, acute-on-chronic liver failure is generally caused by bacterial infections or other conditions associated with an increased release of inflammatory mediators, which also cause the production of metabolic waste products that bind to albumin for transport and elimination. Finally, liver failure and sepsis are associated with increased oxidative stress.
The clinical consequences of the impairment of albumin function in cirrhosis are unknown, especially as they relate to the hyperdynamic circulation, but they could be important. The combination of hypoalbuminemia and impaired albumin function leads to a marked disturbance in the transport, metabolism, and excretion of many endogenous and exogenous substances that would exist as free compounds with the ability to react arbitrarily instead of being delivered to the appropriate sites. It also affects the pharmacokinetics and pharmacodynamics of many drugs and, therefore, the efficacy and side effects of treatments. Finally, although it has been traditionally thought that albumin damage has little effect on the antioxidant mechanism because of the rapid removal and degradation of the damaged molecules11 and rapid substitution with undamaged ones, this might not be the case in liver failure, in which the hepatic synthesis of albumin is seriously compromised. The increased oxidative stress, which is known to affect microcirculatory and cell functions in many organs, may play a contributory role in the multiorgan failure that characterizes acute-on-chronic liver failure.12
An infusion of HSA is now one of the most common treatments in hepatology. It reduces the prevalence of circulatory dysfunction after large-volume paracentesis from more than 75% when the procedure is performed without an albumin infusion to approximately 15% when it is used.13, 14 Impairment of circulatory function after paracentesis is not spontaneously reversible and is associated with a higher incidence of hospital readmission and shorter survival.14 HSA prevents type 1 hepatorenal syndrome and reduces mortality by more than 60% in patients with spontaneous bacterial peritonitis.15 Finally, HSA is an essential component in the treatment of type 1 hepatorenal syndrome with vasoconstrictors.16 Reversal of type 1 hepatorenal syndrome is significantly more frequent after the simultaneous administration of albumin and terlipressin than after the administration of terlipressin alone. Although these beneficial actions have been attributed to the plasma volume expansion effect of albumin, they may have a more complex mechanism. For example, the administration of albumin to patients with cirrhosis and spontaneous bacterial peritonitis leads to a prolonged improvement in circulatory function associated with an increase in peripheral vascular resistance.17, 18 This arterial vasoconstriction, which is not observed after the administration of synthetic plasma expanders, suggests a direct effect of albumin on microcirculation.
Albumin dialysis with the Molecular Absorbents Recirculating System (MARS) is a promising liver support system. It is safe and capable of eliminating water-soluble and protein-bound substances and improving hepatic encephalopathy, systemic circulatory dysfunction, and portal hypertension in patients with chronic liver failure. MARS therapy leads to long-term relief of intractable pruritus. Three large randomized controlled trials comparing MARS with standard medical therapy have recently been completed. The first demonstrated that in patients with cirrhosis, poor liver function, and grade III to IV hepatic encephalopathy, many of whom had hepatorenal syndrome, MARS was superior to standard medical therapy in the management of hepatic encephalopathy.19 The second trial has recently been reported in abstract form and suggests that MARS could be of value in the management of some subgroups of patients with fulminant hepatic failure.20 Finally, the third trial performed in patients with acute-on-chronic liver failure is still in the phase of result analysis. In the investigation by Jalan et al.,10 the effect of MARS on the functional capacity of the patient's circulating albumin was assessed. The study did not specify whether measurements were performed during or after the dialysis procedure. No significant changes in albumin function were observed. The authors' interpretation is that HSA in cirrhosis undergoes irreversible damage that cannot be reversed by MARS. An alternative explanation, however, is that the regeneration of albumin cannot be observed because the albumin-bound materials removed by MARS are rapidly replaced. Jalan et al.'s results raise two important points. The first is that the albumin concentrations in current MARS devices are probably insufficient to result in adequate removal of albumin-bound substances. The second is that estimation of the MARS effect requires the assessment of albumin-bound substances in the MARS circuit or in the charcoal and resin columns.
In summary, acute-on-chronic liver failure is a complex syndrome associated with a very high mortality rate. In addition to hepatic insufficiency, severe reduction of liver synthetic and excretory functions, and portal hypertension, there is an impairment in the function of many other organs and systems, including the cardiac and systemic circulation, kidneys, brain, adrenal glands, intestines, and defensive mechanisms against infection. This study by Jalan et al.10 opens an interesting area of research for exploring the role of albumin function in liver failure, understanding the mechanism of the therapeutic effect of albumin in cirrhosis, and improving the design of albumin dialysis in the management of acute-on-chronic liver failure.