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- Gatta, A., Verardo, A. & Bolognesi, M. Intern Emerg Med (2012) 7: 193. doi:10.1007/s11739-012-0802-0
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Hypoalbuminemia is frequently observed in hospitalized patients and it can be associated with several different diseases, including cirrhosis, malnutrition, nephrotic syndrome and sepsis. Regardless of its cause, hypoalbuminemia has a strong predictive value on mortality and morbidity. Over the years, the rationale for the use of albumin has been extensively debated and the indications for human serum albumin supplementation have changed. As the knowledge of the pathophysiological mechanisms of the pertinent diseases has increased, the indications for intravenous albumin supplementation have progressively decreased. The purpose of this brief article is to review the causes of hypoalbuminemia and the current indications for intravenous administration of albumin. Based on the available data and considering the costs, albumin supplementation should be limited to well-defined clinical scenarios and to include patients with cirrhosis and spontaneous bacterial peritonitis, patients with cirrhosis undergoing large volume paracentesis, the treatment of type 1 hepatorenal syndrome, fluid resuscitation of patients with sepsis, and therapeutic plasmapheresis with exchange of large volumes of plasma. While albumin supplementation is accepted also in other clinical situations such as burns, nephrotic syndrome, hemorrhagic shock and prevention of hepatorenal syndrome, within these contexts it does not represent a first-choice treatment nor is its use supported by widely accepted guidelines.
KeywordsHuman serum albuminHypoalbuminemiaAlbumin infusionLiver cirrhosisParacentesis
Hypoalbuminemia is associated with several pathological conditions. It can often be observed in elderly and/or malnourished patients, but also in severe medical conditions, such as septic shock or decompensated liver cirrhosis. In some instances, hypoalbuminemia is part of the pathophysiology of the disease, while in others it should be considered an epiphenomenon. The indications for human serum albumin supplementation have changed over time. In general, as the knowledge of the pathophysiological mechanisms of the relevant diseases has increased, the indications for intravenous albumin supplementation have progressively decreased.
The purpose of this brief article is to review the causes of hypoalbuminemia and the current indications for intravenous administration of albumin.
Synthesis and metabolism of human serum albumin
In mammals, albumin is the most represented plasma protein . Human serum albumin is a single peptide chain protein of 585 aminoacids with a molecular weight of 66,438 Da; it is structured in three homologous domains with 17 disulfide bonds, the configuration of which is 68 % alpha helix [2–5]. Human albumin is encoded by the ALB gene, which provides for the synthesis of pre-proalbumin in the liver. This is then converted into proalbumin, the main intracellular form of albumin. Once synthesized, the Golgi apparatus of the human hepatocytes removes a 6-aminoacid sequence of the proalbumin peptide chain, to complete the synthesis of albumin, which is then secreted . There are genetic variants of albumin (bisalbumins or alloalbumins), which may have altered binding properties .
A healthy human being of about 70 kg produces up to 14 g of albumin a day. This means that the hepatic synthesis of albumin consists of about 200 mg/kg body weight/day, to allow for a serum range of 35–45 g/L and a total body content of about 300 g of albumin [6, 7]. Albumin has a half-life of approximately 21 days, considering a 4 % daily degradation rate . After being synthesized in the liver from aminoacids deriving from protein muscle catabolism or intestinal absorption , albumin is secreted into the blood stream (it is not stored by the liver) and it distributes to all body tissues. As albumin distributes into the hepatic interstitial space, it is important to consider that the concentration of colloids into this space is probably an osmotic regulator for hepatic albumin synthesis, possibly the main one in the absence of stressful conditions [7, 9]. Albumin synthesis is decreased by cytokines such as interleukin-1 (IL-1)  and 6 (IL-6) and tumor necrosis factor α (TNFα) . Insulin is required for an adequate synthesis , while corticosteroids have a double effect: they increase albumin synthesis combined with insulin or aminoacids, but they also increase albumin catabolism . Several studies have shown that serum albumin (albumin in the intravascular system) normally crosses vessel walls and distributes into the extravascular space of the whole body, but especially the skin . The exchange rate between intra- and extravascular volume (transcapillary escape rate) is about 5 % per hour of the intravascular albumin content . As far as the distribution of secreted albumin is concerned, after 2 h most of it (about 90 %) is still within the intravascular space, where its half-life is 15–16 h. Almost 10 % of albumin is lost every day from this compartment . The distribution of albumin is well defined by a two-compartment model: 40 % (120 g) is situated in the vascular system and 60 % (180 g) in the extravascular space . Albumin enters the intravascular space in two ways: (1) from the extravascular space, by lymphatic drainage; (2) from the hepatocytes, through the space of Disse to the sinusoids [7, 13, 14]. The mechanism of albumin degradation has not yet been completely defined. Apparently it is a random process equally affecting neo-synthesized and ‘old’ albumin molecules. It has been suggested that albumin breakdown can occur in most organs of the body: skin and muscle (40–60 %), liver (<15 %), bone marrow and endothelium [1, 6, 7]. It has been reported that kidney degrades about 10 % of albumin, while up to 10 % leaks into the gastrointestinal tract . The urinary loss is minimal in healthy subjects (usually <20 mg/day) .
Functions of human serum albumin
Due to its distribution, human albumin plays a pivotal role in the maintenance of homeostasis. Serum albumin is the main regulator of colloid osmotic pressure: it represents about 80 % of normal plasma colloid-oncotic pressure and 50 % of protein content . Normal levels of plasma proteins, especially albumin, prevent the development of edema, providing a balance between hydrostatic and colloid-osmotic pressure within vessels.
Serum albumin can bind several different substances and transports several different hormones, such as thyroid and fat-soluble hormones. Moreover, it transports long-chain fatty acids to the liver, unconjugated bilirubin, metals and ions (i.e., calcium ions) . Drug binding of serum albumin plays a pivotal role in the pharmacokinetics and distribution of several drugs, affecting their half-life, their blood levels as free molecules and thus their metabolism . Albumin also serves as a plasma buffer, maintaining physiological pH levels, and it prevents photo-degradation of folic acid [15, 16]. Albumin also has antioxidant properties and is involved in the scavenging of oxygen free radicals implicated in the pathogenesis of inflammatory diseases [5, 7]; it is crucial for heme-Fe scavenging, providing protection against free heme-Fe oxidative damage . Albumin serves as a significant reservoir for signaling molecules and nitric oxide (NO) . Indeed, serum albumin may represent a circulating endogenous reservoir of NO and may act as an NO donor . Albumin also has effects on blood coagulation: it exerts a heparin-like action and inhibits platelet aggregation [7, 12]. Therefore, albumin is not just a regulator of plasma oncotic pressure, but it can be considered, for all intents and purposes, an actual drug, with complex pharmacological activity. Taking into account albumin vital role in transporting drugs and endogenous compounds, its involvement in the metabolism of several endogenous substances , and its possible action as a detoxifying agent , the use of albumin dialysis (molecular adsorbent recirculating system, MARS) was proposed in artificial liver support devices as a treatment option for liver failure [19, 20]. Pharmacological functions of albumin have not yet been fully recognized, and, apart from albumin dialysis, they have not yet found widely accepted clinical applications.
Hypoalbuminemia, clinical significance and causes
Hypoalbuminemia is defined by a serum albumin <35 g/L, although clinically significant hypoalbuminemia is probably identified by levels <25 g/L. Hypoalbuminemia is commonly observed in elderly patients, especially those who are institutionalized and/or hospitalized, and in patients with malnutrition or advanced-stage chronic diseases . Low serum albumin levels are risk factors and a predictor of morbidity/mortality regardless of the implicated disease . Indeed, patients who have low albumin on hospital admission have higher mortality, longer hospital stays and are more likely to be re-admitted after discharge . In addition, Gibbs et al.  found that preoperative serum albumin was the strongest predictor of mortality and morbidity after surgery. However, it is not clear whether this is due to the fact that hypoalbuminemia merely identifies malnourished patients . In these subjects, hypoalbuminemia may be simply a marker of severe protein malnutrition, which is the cause of increased morbidity/mortality, or it may be a negative risk factor per se .
A decreased serum concentration of albumin can be caused by a decrease in energy or amino acids supply, impaired liver synthesis, increased loss, increased tissue catabolism or distributional issues . Hypoalbuminemia is frequently observed during acute disease states as albumin is a negative acute-phase protein. In pathological conditions such as sepsis, infection or trauma, or after major surgery, the level of serum albumin is reduced by about 10–15 g/L within 1 week of the event . The reasons for this reduction are to be found in the combination of reduced hepatic synthesis, increased leakage into the interstitial space, and accelerated catabolism. The decrease in albumin synthesis during inflammation can probably be partially ascribed to the effect of monocytic products such as IL-1 , and to IL-6 and TNFα . The normal displacement of albumin from the vascular to the interstitial compartment (transcapillary escape rate) accounts for ten times the amount of synthesized albumin [6, 24]; it is 5 % of the intravascular volume per hour [25, 26]. Therefore, the transcapillary escape rate plays a major role in acute changes of serum albumin concentration. As a matter of fact, in several diseases, and particularly in patients with sepsis and other inflammatory conditions, the increased vascular permeability increases the transcapillary loss of albumin, participating into the development of hypoalbuminemia . In a condition of sepsis, this process becomes much faster: the impairment in endothelium integrity causes an increased capillary loss, even 13 times higher compared to normal values, and a huge reduction in serum albumin [1, 26]. An increased shift of water and albumin into the interstitium causes the “relative” dilution of protein in the capillary space, a reduction in colloid oncotic pressure, with subsequent decreased shift of water from the tissue .
Causes of hypoalbuminemia, classified according to the main pathogenetic mechanism
Genetic abnormalities (synthesis of defective albumin, mutations causing analbuminemia)
Acute liver failure
Acute and chronic hepatitis
Nutritional deficiencies (low-protein diets)
Chronic metabolic acidosis
Alteration in distribution
Hemodilution (e.g., pregnancy)
Decreased lymphatic clearance (e.g., during major surgery)
Increase in transcapillary escape rate (e.g., major surgery and trauma, heart failure, fluid loss, vasculitis, diabetes, cardiopulmonary bypass surgery, infections, sepsis, shock, ischemia/reperfusion, hypothyroidism, burns, extensive skin diseases)
Increased loss through kidney, skin, bowel
Extensive burns, extensive skin diseases
Therapeutic use of albumin
Intravenous administration of human albumin to treat hypoalbuminemia is a controversial issue; this is consistent with the principle that hypoalbuminemia is often a “symptom” rather than a primary process . In addition, patients with congenital analbuminemia may be symptom-free and perfectly healthy , even though it has been hypothesized that most cases of analbuminemia do not survive gestation . Thus, in patients with hypoalbuminemia, the priority should be the treatment of the underlying condition which causes/is associated with hypoalbuminemia . For instance, in elderly patients, conditions contributing to malnutrition should be handled: these include medications causing a decrease in appetite, thyroid dysfunction, diabetes, malabsorption, depressive syndromes, and cognitive impairment. Overall, the purpose of albumin administration is not the correction of the oncotic pressure per se, but the correction of hypovolemia and fluid depletion. Indeed, human albumin is used mainly in acute conditions, for the correction of fluid loss and restoration of blood volume, and in few, selected chronic situations with low levels of serum albumin [30, 31]. Albumin is also used when the administration of non-protein colloids is contraindicated .
Human albumin solution is usually available at concentrations of 4–5 % and 20–25 %. After infusion of human albumin, the distribution into the extravascular space is complete in 7–10 days. About 10 % of infused albumin is removed from the vessels in <2 h. Another 75 % distributes into the extravascular space within the next 2 days .
The main obstacle to the use of albumin is its cost. To date, human serum albumin has been produced by fractionation of human plasma, which is generally available in limited supplies . The development of industrial methods to produce recombinant human albumin through recombinant DNA technology is under way . While reviewing the usefulness of albumin supplementation, we have analyzed cirrhotic and non-cirrhotic patients separately.
Therapeutic use of albumin in non-cirrhotic patients
Intravenous supplementation of albumin has been proposed for resuscitation from shock in the acute stage of most illnesses. The Cochrane Collaborative Group, having analyzed published studies involving critically ill patients with hypovolemia, burns or hypoproteinemia, concluded that there is no evidence that albumin reduces mortality when compared with cheaper alternatives such as saline . In non-cirrhotic patients with severe sepsis or septic shock, current guidelines recommend fluid resuscitation with either albumin or artificial colloids or cristalloids [33, 34]. Indeed, in patients in intensive care units with trauma, severe sepsis or acute respiratory distress syndrome, the use of either 4 % albumin or normal saline for purposes of fluid resuscitation resulted in similar outcomes at 28 days . In addition, the outcome of resuscitation with albumin and saline were similar irrespective of the patients’ baseline serum albumin concentration . On the other hand, subsequent subgroup analyses of the SAFE study showed that albumin may decrease the risk of death in patients with sepsis compared to saline , but it may increase mortality rate in critically ill patients with traumatic brain injury . The beneficial effect of albumin-containing solutions for the resuscitation of patients with sepsis was confirmed in a recent meta-analysis, which demonstrated that in these patients albumin administration is associated with lower mortality compared with other fluid resuscitation regimens .
During therapeutic plasmapheresis, the use of albumin can only be considered if volume plasma exchanges are extensive, >20 mL/kg in one session or >20 mL/kg/week in more than one session . Otherwise, for reasons of cost-effectiveness, it is reasonable to use crystalloids [40–42]. In hemorrhagic shock, the administration of albumin is a second-choice measure, which should be considered only when there is no response to high dose crystalloids and when non-protein colloids are ineffective or contraindicated . The use of albumin may be occasionally appropriate when the use of non-protein colloids is contraindicated, such as in pregnancy and breast-feeding, acute liver failure, oligoanuric renal failure, dialysis with severe hemostasis impairment and very low serum albumin levels (under 20 g/L), hypersensitivity reactions [12, 31, 43, 44]. Albumin administration may be indicated for major surgery such as hepatic resection >40 % or large bowel resections, if serum albumin levels remain under 20 g/L, even with normal volemia [30, 31, 45]. In nephrotic syndrome, albumin supplementation, in association with diuretics and corticosteroids, has been proposed in patients with severe hypoalbuminemia, severe hypovolemia, acute pulmonary edema and/or acute renal failure . Albumin is more effective than diuretics alone in enhancing diuresis and natriuresis , but it is commonly accepted that albumin infusion should be limited to patients with severe hypoalbuminemia and those who are unresponsive to treatment with diuretics at maximal doses . Human albumin has usually no indication in the treatment of malnourished patients. In this context, the correct treatment is the optimization of protein and energy intake [7, 31]. There is no indication for the administration of human albumin for burns during the first 24 h, when capillary permeability is still high [31, 48]. Subsequently, albumin 5 % has been proposed using different doses according to the amount of body surface area involved .
Therapeutic use of albumin in cirrhotic patients
In cirrhosis, concentrated solutions of albumin are used mostly as plasma-expander when there is severe impairment of effective plasma volume, such as after large volume paracentesis, in spontaneous bacterial peritonitis and in type 1 hepatorenal syndrome [49, 50]. The infusion of albumin results in a significant improvement of effective plasma volume in patients with cirrhosis .
Large volume paracentesis is the first-line treatment in patients with large ascites and for refractory ascites . The procedure should be accompanied by the administration of albumin, at a dose of 8 g/L of ascitic fluid removed, to prevent circulatory dysfunction. In patients undergoing large volume paracentesis of more than 5 L, the use of plasma expanders other than albumin is not recommended because they are less effective in the prevention of post-paracentesis circulatory dysfunction . Five litres is the customary cutoff below which albumin infusion is not recommended . As demonstrated by several studies and randomized trials, albumin infusion reduces the incidence of circulatory dysfunction, morbidity and mortality in cirrhotic patients with tense ascites undergoing large-volume paracentesis, compared with artificial colloids, vasoconstrictors and no treatment [18, 50–53]. A recent meta-analysis has confirmed that albumin infusion reduces the risk of post-paracentesis circulatory dysfunction in patients with cirrhosis and tense ascites, compared with no treatment or with alternative treatments, it decreases the occurrence of hyponatremia and it reduces mortality .
Spontaneous bacterial peritonitis should be treated with the association of antibiotics and infusion of albumin at a concentration of 20–25 %. In patients with ascites and spontaneous bacterial peritonitis, the administration of albumin (plus antibiotic therapy) reduces the incidence of renal impairment and improves in-patient survival [50, 54–58]. Patients who clearly benefit from albumin expansion are those at risk of renal failure (serum creatinine >1 mg/dL and/or bilirubin >4 mg/dL). Albumin is given at an arbitrary dose of 1.5 g/kg of body weight on diagnosis and 1 g/kg on day 3 [50, 59]. Albumin acts as a plasma expander but also attenuates endothelial dysfunction increasing peripheral vascular resistance . Moreover, in patients with spontaneous bacterial peritonitis, it may improve cardiac contractility, probably by linking/scavenging negative inotropic substances such as cytokines, nitric oxide and bile salts .
The vasopressin analog terlipressin, together with albumin administration, is the first-line treatment for type 1 hepatorenal syndrome (syndrome with rapid and progressive impairment in renal function) . In this setting, albumin is usually given at 1 g/kg body weight on day 1, followed by 20–40 g/day . In patients with hepatorenal syndrome, albumin, in association with the infusion of vasoconstrictors, contributes to maintaining adequate renal perfusion and to restoring renal function [60, 61]. There are no indications for the use of albumin as a stand-alone treatment. Terlipressin plus albumin is also effective in 60–70 % of patients with type 2 hepatorenal syndrome (syndrome with stable or slow progressive impairment in renal function), but there are insufficient data on the impact of this treatment on clinical outcomes .
There is no clear indication for the use of albumin in cirrhosis in clinical conditions other than those discussed above. Albumin administration has been proposed to treat hyponatremia in patients with decompensated cirrhosis, because it seems to improve serum sodium concentration; however, data are limited . Albumin was shown to be effective in improving the rate of response and preventing recurrence of ascites in patients receiving diuretics [46, 62], but these results also need to be confirmed in large randomized trials. In refractory ascites, possibly the most controversial indication, albumin infusion has been proposed for patients in particularly unstable conditions, severe hypovolemia and hypoalbuminemia [51, 61–64]. In contrast, the current recommendations for first-line treatment of refractory ascites are discontinuation of diuretics and repeated large-volume paracentesis (plus albumin administration) [50, 65].
In conclusion, the indication for intravenous albumin administration has progressively decreased over the last decade. In patients with hypoalbuminemia, the priority remains diagnosing and treating the underlying condition. Albumin is a high-priced drug and its use should be limited to clinical conditions in which its efficacy has been clearly proven.
Conflict of interest