Albumin Introduction Albumin is a much misunderstood protein, both physiologically and pharmacologically.

It is the most abundant extracellular protein in the body, and has a wide variety of roles. Until relatively recently, albumin containing solutions were popular as volume expanders (colloids). This situation has changed due to a raging controversy, which emerged in the late !!"s. The purpose of this tutorial is to instruct you on the physiologic role of albumin, to discuss its role in disease and nutrition and to loo# at is use pharmacologically. Learning Objectives To learn the physiologic role of albumin. To assess the role of albumin in nutrition and disease To discuss the pharmacologic role of albumin Albumin Physiology Albumin is the most abundant extracellular protein, its distribution is primarily intravascular. Albumin is the most abundant extracellular protein. It is a single polypeptide with $%$ amino acids and a molecular weight of &&,'""(. It is thus a medium si)ed compound (Ig* is $",""") which, in addition to being highly soluble, is small enough to pass through fenestrated endothelium, such as in the nephron. That proteinuria does not occur in normal people is conse+uent of a strong negative charge (,-. /), which rebuts the protein in the glomerulus. Albumin is manufactured in the liver at a rate !0 'g1day. The normal serum albumin is 2" to 3" grams per litre. There is no storage, no reserve. 4eing the ma5or source of oncotic pressure in health, it stands to reason that the rate of production of albumin is controlled by changes in colloid osmotic pressure and osmolality of extravascular liver space. The capacity for increased production is fairly low (can only increase by a factor of ' or 2). Increased synthesis is increased by the neuroendocrine system, chiefly by insulin, thyroid hormones and cortisol. Albumin is cataboli)ed at a rate of ! 0 ' g1day (the same rate as it was produced) by pinoctosis in cells ad5acent to the vascular endothelium. Albumin is not cataboli)ed in starvation6 under these circumstances, protein is derived from muscle, following exhaustion of fat stores. Although albumin is perceived as intravascular protein, the total extravascular albumin actually exceeds the total intravascular amount by 2"7. The ratio of albumin to water is, however higher in the intravascular space (the extracellular fluid is '12 interstitial and 12 intravascular), hence the colloidal effect. Albumin cyclically leaves the circulation, through the endothelial barrier at the level of the capillaries, passes into the interstitium and returns to the bloodstream through the lymph system via thoracic duct. The circulation half time for this process is & 0 % hours. 3 0 $7 of total intravascular albumin extravascates in this way per hour6 this rate of movement is #nown as the Transcapillary 8scape 9ate (T89), and this is determined by6 :apillary and interstitial free albumin concentration. :apillary permeability to albumin. ;ovements of solvent 1 solute. 8lectrical charges across the capillary wall.

The concentration of albumin in lymph protein content is approximately %"7 that of plasma. Albumin Physiological Role Albumin has a role in maintaining :<=, binding and transport, free radical scavenging, acid base balance, coagulation and vascular permeability. Physiologic Roles of albumin . ;aintenance of the colloid osmotic pressure (:<=). '. 4inding and transport, particularly of drugs. 2. >ree radical scavenging. 3. Acid base balance $. =ro and anti0coagulatory effects (inhibits platelet aggregation, enhances the inhibitioof factor ?a by antithrombin III). &. 8ffects on vascular permeability. inding and transport Albumin binds drn ugs and ligands, and therefore reduces the serum concentration of these compounds. An example is the serum calcium, the free (ioni)ed) concentration of which needs to be corrected for albuminThere are actually four binding sites on albumin and these have varying specificity for different substances. :ompetitive binding of drugs may occur at the same site or at different sites (conformational changes) @eg. warfarin and dia)epamA. The drugs that are important for albumin binding are6 warfarin (coumadin), digoxin, BCAI(C, mida)olam, thiopental. Although one would expect that low serum albumin is related to higher free drug levels, the relevence of a low albumin and drug binding is un#nown. Osmotic pressure Albumin is responsible for !" # $% & of osmotic pressure. According to Ctarling,-Ds e+uation, the flow of fluid out of capillaries is determined by a filtration constant multiplied by the net force driving fluid out of the capillary (hydrostatic pressure minus oncotic pressure) minus the osmotic gradient pulling the fluid out. CtarlingEs e+uation6 Transcapillary >low F # @(=cap G =i) 0 (=i G =cap )A 9emember that albumin is the main protein both in the plasma and in the interstitium and it is the :<= gradient rather than the absolute plasma value that is important6 this is what distinguishes hypoalbuminaemia derived from redistribution (capillary lea#) from that of pure full body deficiency. 'ree Radicals Albumin is a ma5or source of sulphydryl groups, these HthiolsH scavenge free radicals (nitrogen and oxygen species). Albumin may be an important free radical scavenger in sepsis. Acid ase alance Albumin is a negatively charged protein in high concentration in the plasma. It contributes heavily to what we call the ,-Ianion gap,-J6 the concentration of anions and cations in plasma should be e+ual, classically the anion gap is calculated as (Ba G K) 0 (:l) F A* (m8+1l). The remaining anions come predominantly from albumin, inorganic phosphate and hemoglobin. Thus, in hypoalbuminemic states, the anion gap should be narrowed.

Anticoagulant effects The anticoagulant and antithrombotic effects of albumin are poorly understood this may be due to binding nitric oxide radicals inhibiting inactivation and permitting a more prolonged anti0aggregatory effect. In diabetes, glycosylated albumin may increase the incidence of thrombotic events and atherosclerosis. (ascular Permeability It is possible that albumin has a role in limiting the lea#age from capillary beds during stress induced increases in capillary permeability. This is related to the ability of endothelial cells to control the permeability of their walls, and the spaces between them. Albumin may plug this gap or may have a deflecting effect, owing to its negative charge. This has led to the hypotheis that colloids are effective at maintaining vascular architecture. Albumin )ypoalbuminemia *erum albumin concentration falls due to decreased synthesis, increased catabolism, increased loss and redistribution. =lasma albumin concentration is calculated as6 intravascular albumin mass 1 plasma volume +auses of decreased plasma albumin6 . (ecreased synthesis. '. Increased catabolism @very slowA 2. Increased loss6 Bephrotic syndrome 8xudative loss in burns Laemorrhage *ut loss 3. 9edistribution6 Laemodilution Increased capillary permeability (lea#age into the interstitium) (ecreased lymph clearance. ,-I:apillary lea# syndrome,-J occurs in systemic inflammatory response syndrome. (ue to widespread damage to the capillary endothelium, there is increased loss of medium to high molecular weigh compounds, particularly albumin, into the extravascular space and therefore loss of the normal Ctarling relationship. ,hat diseases is hypoalbuminaemia associated -ith. Lypoalbuminemia is associated with liver and renal disease, =8T, CI9C 1 including burns, trauma. Mow preoperative albumin is an indicator of poor outcome from surgery. Liver /ysfunction Albumin is a poor mar#er of liver dysfunctionN prothrombin time is more reliable. Renal disease Albumin loss occurs in nephropathies (nephrotic syndrome). There is a small loss of albumin in dialysis circuits. Pre#0clampsia 1P023 In normal pregnancy there is an increase in plasma volume. In =8T there is a paradoxical decrease in plasma volume, widespread capillary lea# and albuminuria. *tress response Interleu#ins cause a mar#ed decease in synthesis of plasma proteins other than albumin.

In fact Albumin and Transferrins decrease in the stress response, a process often termed Hnegative acute phase proteinsH. IM& directly decreases the Oexpression of albumin messenger 9BA. <verall, the picture in the stress response is6 . Initial decrease in albumin associated with increase in acute phase proteins. '. Cubse+uent global increase in hepatic protein synthesisN including albumin. urns There is massive protein loss from the burn site P increased vascular permeability P decreased albumin synthesis P protein losing nephropathy. The use of albumin in patients with Q $7 burns after '3 hours has been recommended. 2rauma In trauma there is increased redistribution and transcapillary escape of albumin. *urgery (ecreased serum albumin preoperatively is an independent indicator of poor outcome. *epsis CI9C 0 associated with increased capillary permeability, due to the effects, amongst others, of bacterial endotoxin and cytotoxic T cells. In sepsis there is a profound reduction in plasma albumin associated with mar#ed fluid shifts. )ypoalbuminemia ,hat is the relationship bet-een serum albumin concentration and malnutrition. (ecreased albumin in adults is a mar#er of associated disease (a negative acute phase reactant) not a feature of isolated protein0energy malnutrition. Cerum albumin does not decrease significantly in starvation, although production is affected. The body maintains the serum albumin at the expense of muscular protein6 There is decreased synthesis, increased redistribution P decreased catabolism. ;oreover, albumin has a long half life, compared with pre0albumin. As a result, when the patientEs nutritional status is improving, the pre0albumin will tend to bounce bac# earlier. If critical illness persists, catabolism persists, and the levels of both of these mar#ers will remain low. In general it is unwise to rely on these as mar#ers of nutrition in critical care. Is there any relationship bet-een hypoalbuminemia and outcome. Mow serum albumin is an independent indicator of (poor) outcome in critical illness. There is a considerable body of evidence indicating that serum albumin is a prognostic indicator. *oldwasser ( !!/) suggests that albumin may well be an independent indicator of outcome in a variety of clinical settings. The lower the serum albumin plunges, the greater the mortality, morbidity, length of stay and complication rate. 4lunt ( !!%) and colleagues have shown that non0survivors in intensive care had lower mean albumin concentrations than survivors, and there was, significantly, no difference between the :<=s of the two groups. Albumin 2herapeutic 4ses 2here is no evidence that correcting hypoalbuminemia improves outcome, indeed therapeutic albumin administration may -orsen outcome. A number of strategies have utili)ed albumin as a therapeutic agent6 . :orrecting hypoalbuminemia to improve outcome ,-. no evidence of improvement. '. Using albumin as a hypertonic0hyperoncotic agent to reduce tissue prefusion, with or without diuretics ,-. no evidence of improvement.

2. >or volume replacement in cirrhosis (spontaneous bacterial peritonitis) ,-. some evidence. 3. As the colloid of choice in infants ,-. no evidence either way. $. In burns ,-. no evidence either way. &. >ollowing paracentesis for ascites ,-. no evidence. /. To treat nephrotic syndrome ,-. no evidence. %. As a colloid agent in critical illness6 little supportive evidence. A meta0analysis by the :ochrane :ollaboration (4;R Rune !!%), has suggested that the administration of albumin may, in fact, worsen outcome. Shilst this paper was heavily critici)ed in terms of methodology and outcome measures, it has had a significant impact on practice. A subse+uent widened meta0analysis (Sil#es ;; '"" ) found that albumin administration did not significantly alter outcome. The inclusion of albumin in ,-Icolloid versus crystalloid,-J debates has led to claims that the latter are safer than the former. Lowever these papers demonstrate the significant wea#nesses that exists in the performance of meta0analysis and the geographic bias in publication versus practice. ,hy -ould albumin be harmful. There are concerns about the manufacturing process of commercially available albumin6 :ommercially available albumin is fractionated in ethanol and purified and heat treated for " hours at &"o:. This process6 =robably alters the charge on albumin 0 ma#ing it more permeable. :ontains significant +uantities of residual ions 0 aluminum and vanadium. It appears that, without strong data supporting the use of this agent, and with alternatives available (hydroxyethyl starch), the continued prescription of albumin as a volume expander is neither clinically indicated nor cost effective. Bonetheless, there is little evidence to re5ect the use of this agent in itEs conventional setting 0 as a volume expander in babies and in burns. :urrently, albumin is the fluid of choice in preventing renal failure in patients with spontaneous bacterial peritonitis (Cort =, !!!). Albumin 5ey Points . Albumin is the most abundant extracellular protein, it,-Ds distribution is primarily intravascular. '. Albumin has a role in maintaining :<=, binding and transport, free radical scavenging, acid base balance, coagulation and vascular permeability. 2. Albumin is measured using 4:* or 4:=. This overestimates a low serum albumin. 3. Cerum albumin concentration falls due to decreased synthesis, increased catabolism, increased loss and redistribution. $. The serum albumin falls when patients become sic#, and comes bac# up when patients get better. The liver stops producing albumin in critical illness6 low albumin is a non specific mar#er of disease. &. 8dema formation is determined by the rate of fluid flux6 :<= is determined by total protein concentration, and the state of the lymphatic system. /. Lypoalbuminemia is associated with liver and renal disease, =8T, CI9C including burns, trauma and surgery. %. (ecreased albumin in adults is a mar#er of associated disease (a negative acute phase reactant) not a feature of isolated protein0energy malnutrition. It is a poor indicator of nutritional status (so too is prealbumin). !. Mow serum albumin is an independent indicator of (poor) outcome in critical illness.

". There is no evidence that correcting hypoalbuminemia improves outcome, indeed therapeutic albumin administration may worsen outcome.