CONCISE REVIEW IN MECHANISMS OF DISEASE
of approximately 0.6 mmol/L. HSA is a small (66 kd)
Albumin: Biochemical
Properties and Therapeutic
Potential
Gregory J. Quinlan,1 Greg S. Martin,2 and
Timothy W. Evans1
H
uman serum albumin (HSA) is an abundant mul-
tifunctional non-glycosylated, negatively charged
plasma protein, with ascribed ligand-binding and
transport properties, antioxidant functions, and enzymatic
activities.1 It is synthesized primarily in the liver and is
thought to be a negative acute-phase protein. Physiologi-
cally, albumin is responsible for maintaining colloid osmotic
pressure and may influence microvascular integrity and as-
pects of the inflammatory pathway, including neutrophil
adhesion and the activity of cell signaling moieties. Clini-
cally, albumin has been employed as a plasma expander in
many patient populations, although the evidence from meta
analyses2,3 and the recently published SAFE investigation4
suggests it does not afford a survival benefit over crystalloid
solutions when administered to the critically ill. However,
studies of albumin usage as a volume expander and albumin
dialysis therapy in patients with liver disease have led to some
encouraging results. This review aims to highlight current
thinking regarding albumin therapy in the critical care and
hepatological setting and also discusses other potential ther-
apeutic applications for its use based around the complex
biochemistry of this multifunctional plasma protein. Poten-
tial contraindications are also discussed.
Tertiary Structure and Biochemical
Characteristics of Albumin
Albumin normally accounts for over 50% of total
plasma protein content, being present at concentrations
Abbreviations: HSA, human serum albumin; NO, nitric oxide; ROS, reactive
oxygen species; RNS, reactive nitrogen species; COP, colloid oncotic pressure.
From the 1Department of Critical Care Medicine, Imperial College School of
Medicine, Royal Brompton Hospital, London, UK; and the 2Department of Pul-
monary and Critical Care Medicine, Emory University School of Medicine, At-
lanta, GA.
Received September 21, 2004; accepted March 21, 2005.
Address reprint requests to: Professor TW Evans, Royal Brompton Hospital,
Sydney Street, London SW3 6NP, United Kingdom. E-mail: t.evans@
rbh.nthames.nhs.uk; fax: (44) 207 351 8524.
Copyright © 2005 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.20720
Potential conflict of interest: G.J.Q., G.S.M., and T.W.E. have received non-
directed grants from agencies representing albumin manufacturers (Plasma Protein
Therapuetics Association).
globular protein composed of 585 amino acids, with few
tryptophan or methionine residues but an abundance of
charged residues such as lysine, and aspartic acids and no
prosthetic groups or carbohydrate. X-ray crystallography
has shown albumin to possess a heart-shaped tertiary
structure, but in solution HSA is ellipsoid. Some 67% of
the tertiary structure of HSA is composed of ␣-helices.
Indeed, the protein is composed of 3 homologous do-
mains (I-III), each containing two sub-domains (A and B)
composed of 4 and 6 ␣-helices respectively. The sub-
domains move relative to one another by means of flexible
loops provided by proline residues, which helps accom-
modate the binding of an array of substances, as does the
flexibility provided by domain-linking disulfide bridges.
Figure 1 depicts the tertiary structure with bound fatty
acids. HSA contains 35 cysteine residues, most of which
form disulfide bridges (17 in all), contributing to overall
tertiary structure. However, it also contains 1 free cys-
teine-derived, redox active, thiol (-SH) group (Cys-34),
which accounts for 80% (500 ␮mol/L) thiols in plasma .
The thiol moiety of Cys-34 is reactive and capable of
thiolation (HSA-S-R) and nitrosylation (HSA-S-NO),
processes that are thought to contribute to several in vivo
functions.
Physiologically, HSA exists predominantly in a re-
duced form (that is, with a free thiol, HSA-SH) and is
known as mercaptoalbumin. However, a small but signif-
icant proportion of the albumin pool exists as mixed dis-
ulfides (HSA-S-S-R); where (R) represents low-
molecular-weight, thiol-containing substances in plasma,
chiefly cysteine and glutathione. Mixed disulfide forma-
tion also increases as part of the aging process (reviewed by
Droge5) and during disease processes characterized by ox-
idative stress. Dimer formation is also theoretically possi-
ble (HSA-S-S-ASH), but in practice is unlikely to occur in
vivo because of stearic interference. However, this process
is known to occur ex vivo on purification and storage and
therefore may have implications related to certain aspects
of the therapeutic use of albumin.
Properties of Albumin
Ligand-Binding. HSA binds many endogenous and
exogenous compounds, including fatty acids, metal ions,
pharmaceuticals, and metabolites, with implications for
drug delivery and efficacy, detoxification, and antioxidant
protection. Several low- and high-affinity ligand-binding
sites have been identified on HSA, the first of which to be
identified (termed site I and II) are responsible for the
binding of most pharmaceuticals that interact with the
protein. Sites I and II are located in different domains and
1211
1212 QUINLAN, MARTIN, AND EVANS
Fig. 1. Tertiary structure of albumin showing the binding of seven
archidonic acid ligands is depicted. Illustration obtained from the RCSB
protein data bank PDB ID:1gnj by David S Goodsell Scripps Research
Institute. Primary reference source: Petitpas I, Gruene T, Bhattacharya AA,
Curry S. Crystal structures of human serum albumin complexed with
monounsaturated and polyunsaturated fatty acids. J Mol Biol
2001;314:955.
exhibit differential, but not always exclusive, ligand-bind-
ing affinities. Site I tends to bind relatively large hetero-
cyclic compounds or dicarboxylic acids. A diverse array of
unrelated compounds bind with high affinity to various
locations within this site, indicating adaptability. More-
over, this site is large and able to bind bulky endogenous
substances, including bilirubin and porphyrins. By con-
trast, site II (also known as the indole-benzodiazepine
site) is smaller and less flexible in nature, because binding
is more stereo-specific. Importantly, additional high-af-
finity binding areas are present within HSA for some
drugs and compounds that do not conform to either site I
or II. Furthermore, the binding domains of some sub-
stances such as digitoxin and the bile acids remains to be
elucidated; for a concise review on ligand-binding, see
Kragh-Hansen et al.6
Cysteine-34 binds drugs including cisplatin, D-peni-
cillamine, and N-acetyl-cysteine.6 Covalent interactions
(thiolations) also occur with endogenous, low-molecular-
weight, thiol-containing substances via disulphide bridge
formation. Higher oxidation states of cys-34 can also oc-
cur, resulting in the formation of sulfenic, sulfinic, or
sulfonic acid residues (Fig. 2), although levels seen in
normal plasma (bovine) are low.7 Both endogenous and
exogenous nitric oxide (NO) are known to interact with
cys-34 via electrophilic addition of the nitrosonium ion
HEPATOLOGY, June 2005
(NO⫹). Indeed, until recently NO was thought to circu-
late in plasma primarily as an S-nitroso HSA adduct and
to possess vasodilatory properties , augmented by NO
transfer to low-molecular-weight thiols.8 However, recent
in vitro and in vivo studies indicate that levels of s-nitroso-
albumin that form under biologically relevant conditions
in normal plasma are in the low nanomolar range (⬍10
nmol/L) and that several other reaction products of NO
contribute to the NO plasma sink.9 It is less clear to what
extent HSA contributes to NO binding in vivo under
pathological conditions, or to what extent the availability
of catalysts and or other NO-derived species impacts on
s-nitrosolation. Furthermore, recent studies using a tar-
geted s-nitrosoglutathione reductase murine model have
demonstrated the importance of nitroso-thiol turnover in
endotoxic shock.10 Further studies are required to deter-
mine HSA’s role under such circumstances. Key reactions
are summarized in Fig. 3.
Metal Cations. The N-terminal portion of HSA (N-
Asp-Ala-His-Lys-) binds Cu, Ni, and Co ions with high
affinity, whereas Au, Ag, and Hg ions bind to cysteine-34
(reviewed in Kragh-Hansen et al.6) HSA is also the major
Zn binding protein in plasma, although there is some
debate as to the nature of and location of its binding site.11
HSA has also been reported to possess a relatively weak,
nonspecific, latent iron-binding capacity.12 This is, how-
ever, unlikely to be of significance under normal circum-
stances in plasma, because the specific, high-affinity, iron-
binding protein transferrin binds all low-molecular-mass
ferric iron.
Antioxidant Functions. Aerobic metabolism is en-
ergy efficient. However, whereas oxygen-containing end
products of these processes are relatively innocuous, many
Fig. 2. Scheme gives an overview of the steps involved (highlighted in
blue) for the nitrosylation of Cys-34 of human serum albumin (HSA).
Nitric oxide (NO) requires an electron accepting catalyst (reactive tran-
sition metal ion, or metal-containing proteins) to favor such reactions.
Steps leading to Cys-34 oxidation and thiolation are highlighted in red.
Formation of higher oxidation states of HSA are also shown. RSH,
glutathione or free cysteine; Alb, albumin.
HEPATOLOGY, Vol. 41, No. 6, 2005
Fig. 3. Scheme depicts antioxidant (highlighted in blue) and the
pro-oxidant potential (highlighted in red) of human serum albumin (HSA).
The potential of iron and copper ions to catalyze the formation of the
extremely aggressive and damaging hydroxyl radical 䡠 OH (the Fenton
reaction) is shown. The potential ability of HSA to redox cycle these metal
catalysts exacerbates this pro-oxidant response when these metals have
access to Cys-34, in other words, when they are not bound at protected
sites on this protein or elsewhere. As shown, such metal salts also can
propagate membrane lipid peroxidation directly if stable lipid peroxides
are already present. Nitric oxide and bilirubin binding may provide an
indirect (supportive) antioxidant response attributable to albumin, as
both compounds have reported lipid-phase antioxidant function.
intermediates thereby formed are potentially, or directly,
extremely reactive in nature. Such reactive oxygen species
(ROS) can inflict damage on molecules, leading to the
accumulation of toxic end products and cellular dysfunc-
tion or damage. Normally, the body uses protective (i.e.,
antioxidant) and reparative systems that limit the effects
of oxidative stress. An antioxidant is any substance that
when present at low levels significantly diminishes or pre-
vents the oxidation of an oxidizable substrate, and may be
dietary, constitutive, or inducible in origin. Primary anti-
oxidants prevent ROS formation and include the iron-
binding antioxidant transferrin. Secondary antioxidants
scavenge pre-formed ROS. Examples include ascorbate
and superoxide dismutase. For the definitive text on ROS
in biology, see Gutteridge and Halliwell.13 Reactive nitro-
gen species (RNS) are nitrogen-centered species analo-
gous to ROS. Evidence indicates that such species are
formed in vivo; some, such as nitric oxide, contribute to
various biological signaling responses. Others, however,
are powerful oxidants and nitrating species capable of
damaging biomolecules; antioxidant protection also lim-
its the damage inflicted by RNS. Several such antioxidant
functions have been ascribed to HSA.
ROS/RNS Scavenging. HSA in plasma, or bovine se-
rum albumin in artificial systems, provides protection
from lipid peroxidation propagated by inorganic ROS
generated from xanthine oxidase/hypoxanthine.14 How-
ever, thiol oxidation occurs, indicating the cys-34 moiety
to be the source of the antioxidant protection afforded. In
QUINLAN, MARTIN, AND EVANS 1213
more recent studies, hydrogen peroxide (H2O2) and the
RNS peroxynitrite (ONOO⫺) have been shown to oxi-
dize cys-34 to a sulfenic acid derivative (HSA-SOH).15
This is subsequently converted to a disulfide with the
potential to be redox cycled to mercapto-albumin (HSA-
SH), thereby restoring antioxidant function (Fig. 2). In-
creased ROS and RNS formation have been implicated as
contributory factors in the onset and progression of crit-
ical illness.16 Albumin may provide effective extracellular
scavenging antioxidant protection under such circum-
stances. Thus, albumin supplementation has been shown
to replenish extracellular thiol status in patients with sep-
sis by means other than that which would be expected on
purely stoichiometric grounds.17 Moreover, such supple-
mentation was shown to improve thiol-dependent anti-
oxidant protection in plasma obtained from patients with
acute lung injury and to be associated with decreased lev-
els of oxidative markers (protein carbonyls),18 although
there was no difference in survival rates between groups.
Persistent hypoalbuminemia is also associated with per-
oxidation of erythrocyte membranes in patients undergo-
ing chronic hemodialysis, indicating that HSA protects
against lipid oxidation.19
In vitro studies have shown that bovine serum albumin
scavenges neutrophil-derived ROS, including hydrogen
peroxide, superoxide, and hypochlorous acid.20 Inflam-
matory cell-derived oxidants contribute to oxidative stress
during acute inflammation and the consequences thereof.
HSA could potentially reduce such effects through scav-
enging antioxidant actions in humans, which may, also
through modifying redox balance, regulate cell signaling
moieties active in mediating pro-inflammatory forces
(Fig. 3). In vitro, albumin has been shown to offer anti-
oxidant protection against the oxidative effects of carbon
tetrachloride and uremic toxins,21,22 findings with impli-
cations for both hepatic and renal failure. HSA may pro-
vide a supportive antioxidant role in vivo, through its
ability to bind and transport substances with known an-
tioxidant function, specifically, bilirubin and NO, which
are effective lipid phase antioxidants23,24 (Fig. 3). Biliru-
bin may also protect albumin from oxidant-mediated
damage.25
Metal-Binding. Heme is thought to possess pro-oxi-
dant properties through the redox properties of iron. HSA
is an effective heme-binding protein.26 Once bound to
albumin, such pro-oxidant properties are decreased, indi-
cating an antioxidant function,27 although under physio-
logical circumstances the heme-binding plasma protein
hemopexin provides most of this form of antioxidant pro-
tection.28 Free, or loosely bound, redox-active transition
metal ions (low molecular mass) are potentially extremely
pro-oxidant, having the ability to catalyze the formation
1214 QUINLAN, MARTIN, AND EVANS
of damaging and aggressive ROS from much more innoc-
uous organic and inorganic species (Fig. 3). In strictly
biological terms the 2 most important such metals are
iron and copper. In specific circumstances (certain disease
states and poisoning), these metal ions can become free of
constraints, which normally limit and control their reac-
tivity. By virtue of its high-affinity copper-binding site,
HSA limits copper-catalyzed oxidative damage to other
biomolecules by directing damage toward the albumin
molecule itself in a sacrificial fashion.29 In similar fashion,
HSA can limit damage caused by accidental biological
contamination by redox active metal ions such as vana-
dium, cobalt, and nickel. Although HSA iron-binding is
weak and nonspecific, it may offer antioxidant protection
when other specific protective stratagems become over-
whelmed, such as under conditions of iron overload or
pronounced hemolysis (Fig. 3).
Anti-Inflammatory Properties. Evidence indicates
that accessible thiol groups can signal inflammatory cell
regulatory changes dependent on their redox state.30
Thus, 25% albumin has been shown to modulate neutro-
phil/endothelial cell interactions after shock and resusci-
tation and to attenuate lung injury.31 Furthermore, HSA
augments intracellular glutathione levels and influences
activation of the ubiquitous transcription factor nuclear
factor-kappa B using both in vitro and in vivo protocols.32
Moreover, several recent studies using a rat model of
hemorrhagic shock have indicated that the type of resus-
citation fluid administered greatly influences proinflam-
matory responses, including lung apoptosis and rates of
neutrophil activation. Plasma albumin was found to be
the least proinflammatory of the fluids utilized.33 The
formation of sulfenic acid residues by cys-34 oxidation15
also may be a key factor determining signaling responses,
because recent evidence indicates that such groups impact
on cellular signaling functions, reviewed in Poole et al.34
Pro-oxidant Implications. Paradoxically, and in
common with other redox active antioxidant substances,
albumin can display pro-oxidant properties, through its
ability to redox cycle/recycle transition metal ions such as
iron and copper from the less reactive (ferric/cupric) to
more pro-oxidant (ferrous/cuprious) states (Fig. 3). Thus,
a recent study has shown that copper/HSA could become
pro-oxidant after fatty acid binding and subsequent
cys-34 oxidation.35 Iron has much less binding affinity for
HSA and is more likely to be recycled as a free agent able
to catalyze damaging ROS formation at sites distant from
HSA. Such an action is, therefore, potentially more dele-
terious. Indeed, HSA administration was reported re-
cently to be adversely associated with a decline in iron-
binding antioxidant protection in patients with acute
lung injury,18 an effect thought to be related to the redox
HEPATOLOGY, June 2005
cycling of iron. Intravenous albumin therefore may be
inadvisable in circumstances when pronounced extracel-
lular iron mobilization or overload are complicating fac-
tors.
Synthesis and Turnover. In healthy adults, albumin
synthesis occurs predominantly in polysomes of hepato-
cytes (10-15 g/day) and accounts for 10% of total liver
protein synthesis. Relatively small amounts of albumin
are hepatologically stored (⬍2 g), the majority being re-
leased into the vascular space. Approximately 30%-40%
of albumin synthesized is maintained within the plasma
compartment. The remaining pool is located within tis-
sues such as muscle and skin. Studies of radiolabeled al-
bumin catabolism in normal healthy young adult males
indicate a variation of half-life of between 12.7 and 18.2
days (mean, 14.8 days),36 although a dynamic exchange
between plasma and the interstitium occurs. Albumin
leaks from plasma at a rate of 5%/hour and is returned to
the vascular space at an equivalent rate through the lym-
phatic system. Synthesis is a constant process, regulated at
both transcriptional and posttranscriptional levels by spe-
cific stimuli, but change in interstitial colloid oncotic
pressure is thought to be the predominant regulatory in-
fluence.37 Albumin homeostasis is maintained by bal-
anced catabolism that is not well characterized, occurring
in all tissues. However, most albumin (40%-60%) is de-
graded in muscle, liver, and kidney. Plasma hyperalbu-
minemia is rare, whereas hypoalbuminemia is a feature of
a variety of pathological processes, including liver disor-
ders, cancer, and severe sepsis. Ascites formation is a com-
mon complication of cirrhosis and contributes to vascular
hypoalbuminemia. Perturbations in hepatic vascular con-
trol are thought to be responsible for ascites formation,
although the precise mechanisms remain a matter of de-
bate (reviewed in Arroyo38). However, cirrhosis in the
advanced stages is also characterized by protein wasting
and hence albumin depletion. The reasons for such dys-
function remain unresolved, but nutritional, metabolic,
and hormonal abnormalities and uncharacterized re-
sponses to the release of bioactive substances including
chemokines may contribute to hyopalbuminemia (re-
viewed in Tessari39).
The capillary bed is known to be hyperpermeable in
patients with sepsis, thereby leaking albumin. However,
the extent to which altered liver biosynthesis and rates of
catabolism contribute to the plasma albumin deficiency
seen in sepsis and critical illness remains uncertain. In-
deed, the half-life of HSA in patients with hypoalbumin-
emia supported with total parenteral nutrition is only 9
days, although rates of catabolism are normal.40 More-
over, catabolism actually may be decreased while the ex-
tracellular pool is increased, suggesting that HSA may be
HEPATOLOGY, Vol. 41, No. 6, 2005
spared or protected.41 Studies in healthy individuals given
endotoxin, as well as in the critically ill, indicate that
albumin synthesis increases under these circumstances,
even though hypoalbuminemia is common.42,43 By con-
trast, in animal models of sepsis and endotoxemia, de-
creased rates of liver albumin synthesis at the expense of
acute phase protein synthesis is detectable regardless of
nutritional support.44 Further studies in humans are re-
quired to resolve this controversy.
Colloid Oncotic Pressure. HSA is a relatively small
protein that accounts for some 75% of protein molecules
in plasma in healthy individuals. Because of its dispropor-
tionate contribution to the plasma protein pool, albumin
is also responsible for approximately 75% of plasma col-
loid oncotic pressure (COP). Oncotic pressure becomes
osmotic pressure as the negative charges surrounding the
protein molecules attract sodium, thus holding water. Its
remaining contribution to COP is due to the Donnan
effect attributable to its overall negative charge. More-
over, HSA may influence directly vascular integrity by
binding in the interstitial matrix and subendothelium and
reducing the permeability of these layers to large mole-
cules, and indirectly through its scavenging properties.
Albumin as Therapy in Critical Illness. HSA has
long been used to combat vascular collapse in severely ill
patients, customarily as an iso-oncotic (4%-5%) solution
for intravascular volume expansion; and as an hyperon-
cotic (20%-25%) solution for the maintenance of fluid
balance between compartments and the restoration of
COP. More recently, the benefits of HSA in supporting
the critically ill have been debated, not least because it is
expensive compared with synthetic colloid solutions.
Concerns have been raised regarding the distribution of
albumin in states of altered capillary permeability, such as
sepsis. However, clinical trials have confirmed that albu-
min remains a potent volume expander compared with
crystalloid solutions even under these circumstances.45
However, a recent study finding that bolus administra-
tion of 20% HSA to patients with sepsis led to a signifi-
cantly faster decline in plasma albumin compared with
healthy controls raises questions about longer-term effi-
cacy of albumin administration.46 Furthermore, in these
states of altered capillary permeability, the formation of
edema (such as pulmonary edema) is governed more by
hydrostatic pressure than COP.47 Colloid administration
to patients with acute lung injury does not worsen pul-
monary edema and may in fact reduce edema-producing
forces.48 A variety of meta-analyses have produced con-
flicting results regarding the risk and benefits of albumin
administration to critically ill patients. Specifically, the
1998 Cochrane Injuries Group concluded that albumin
administration may increase the risk of death,49 whereas a
QUINLAN, MARTIN, AND EVANS 1215
larger meta-analysis published subsequently found no dif-
ference in outcome.2 Systematic reviews have attempted
to elucidate potential reasons as to why albumin would
adversely affect outcome, but have failed to identify the
mechanism.50 However, in one of the largest clinical trials
ever conducted in critically ill patients, the SAFE study
randomized 7,000 critically ill patients needing fluid re-
suscitation to receive either 4% albumin or normal saline.
There were no differences between groups in survival,
measures of morbidity, and organ dysfunction, nor in
length of stay in the intensive care unit or hospital.4
Is albumin neither beneficial nor harmful in a thera-
peutic sense in the critically ill, despite its wide range of
potentially significant properties? We suggest that uncer-
tainty remains for a number of reasons. First, the wide
range of patients with critical illness that have been stud-
ied to date may conceal specific populations in which
HSA may be definitely beneficial or harmful. Indeed,
HSA is increasingly recognized as a “niche” drug, evi-
denced by its ability to significantly improve outcomes in
patients with cirrhosis complicated by spontaneous bac-
terial peritonitis.51 This is further supported by subgroup
analysis of the SAFE study,4 which has indicated that
albumin may have varying effects in different patient
groups. From these data, patients with traumatic brain
injuries may actually be harmed by albumin administra-
tion (relative risk for death ⫽ 1.62, P ⫽ .009), whereas
sepsis patients may derive benefit (relative risk ⫽ 0.87,
P ⫽ .06). Second, the use of albumin in all trials pub-
lished to date has concentrated on its volume-expanding
effects. The total dose administered may therefore be in-
appropriate if other, non-circulatory properties such as
those relating to antioxidant or anti-inflammatory capac-
ities are the desired end point. Such properties might
account for any disease-specific (i.e., niche) effects of HSA
therapy. Third, albumin may have valuable properties
when used as an adjunct with other therapies, as in hy-
poproteinemic patients with acute lung injury and acute
respiratory distress syndrome, where the combination of
HSA and furosemide therapy has been shown to improve
fluid balance, oxygenation, and hemodynamics.48 The
mechanisms responsible for the benefits observed in acute
lung injury and acute respiratory distress syndrome are
incompletely understood and may be specific to albumin
compared with synthetic colloids. There is no clear evi-
dence that pulmonary edema may be influenced by one
colloid more than another.47 The ability of HSA to bind
many drugs, sometimes irreversibly, is a complicated issue
that may impact on combinational therapies.52,53 Fur-
thermore, binding of biologically active moieties such as
NO (NO⫹), levels of which become elevated during crit-
1216 QUINLAN, MARTIN, AND EVANS HEPATOLOGY, June 2005

Table 1. Study Findings: Treatment of Cirrhosis by Albumin

Cirrhosis Treatment Albumin Comments

Ascites
Independent risk for renal
impairment
Hepatorenal syndrome
Common complication of
advanced cirrhosis
resulting in renal
failure
Spontaneous bacterial
peritonitis
Risk of renal impairment
potentiated
Paracentesis
Vasoconstrictor drugs
Renal replacement therapy
Non-nephrotoxic antibiotics
Plasma volume expansion
Plasma volume expansion
Combinational use
Paracentesis alone results in pronounced renal impairment
in a significant proportion of patients. In combination
with albumin volume expansion, this is almost
completely prevented
Albumin more effective than other volume expanders
Long-term albumin treatment together with the
administration of arterial vasoconstrictors reverses
hepatorenal syndrome in most patients, use of
vasoconstrictors alone is much less effective
Renal impairment develops in a third of patients treated
with antibiotics, but this was substantially decreased if
albumin is given in combination with antibiotics at time
of diagnosis, mortality was also lower

NOTE. Summarizes findings of studies into the use of intravenous albumin for the treatment of cirrhosis. It is not an exhaustive list. More detailed reviews of current
literature can be found in Arroyo38 and Grange and Amiot69 (used to compile this table).

ical illness, may influence the ability of HSA to bind other
ligands.54
Albumin as Therapy in Liver Disease
Historically albumin was used in patients with cirrho-
sis for vascular volume maintenance, because of its on-
cotic properties. As theories regarding the nature of
vascular control and ascites formation developed, and
with a better understanding of the use of diuretics and
other management strategies, the use of albumin for the
treatment of this condition declined. However, it is now
apparent that the volume-expanding properties of albu-
min, in combination with other therapeutic approaches,
is of clinical benefit to patients with cirrhosis, thereby
reducing the renal impairment that complicates liver dis-
ease38 (Table 1).
Recently albumin has been used not as a medium for
administration, but as a part of a hemodialysis regimen in
patients with hepatic failure, the so-called molecular ad-
sorbent recirculating system (MARS, for a review see Sen
et al.55). MARS uses an albumin-containing dialysate that
is regenerated by dialysis against buffered bicarbonate so-
lution subsequent to carbon and anion exchange column
treatment to combine the removal of toxins normally
cleared by the kidneys with those removed by the liver.
MARS has been used to treat liver dysfunction and failure
in more than 4,000 patients over the last 4 years56 and has
been shown to improve renal function and hemodynam-
ics, and to decrease brain edema and hepatic encephalop-
athy (reviewed in Mitzner et al.57). HSA avidly binds
toxins, including bilirubin, copper ions, and protein
breakdown products, substances that accumulate in pri-
mary liver diseases including cirrhosis,58 hepatitis C infec-
tion,59 and Wilson’s disease.60 There are also indications
for the treatment of secondary liver disease and during
posttransplantation complications. The ability of MARS
to remove other toxins and pro-inflammatory stimuli
such as lipopolysaccharides, chemokines, and lipid per-
oxidation end-products, xenobiotics and free heme/
hemoglobin, may have implications for limiting the
inflammatory response. Ample evidence exists of en-
hanced NO production during both chronic and acute
liver failure61 that may relate to adverse clinical events
such as renal impairment and circulatory dysfunction,
including hepatopulmonary syndrome. NO is specifi-
cally bound by HSA at position cys-34, MARS treat-
ment may therefore also help modulate circulatory NO
levels during liver failure, thereby protecting against
the cascade of other organ failures that accompany
acute liver disease. However, as previously stated, the
levels of s-nitroso-albumin found in healthy plasma
subjected to relevant physiological exposure with NO
are low. Caution should therefore be used when inter-
preting results of MARS trials in this context, with the
need for the true extent of s-nitrosylation to be deter-
mined under such pathological circumstances. There
may well be implications for hepatopulmonary syn-
drome, although studies in this area are somewhat lim-
ited. However, the MARS system has been used to treat
a small number of patients with ARDS.62
Contraindications. Recognized contraindications to
albumin therapy include a known allergy to albumin and
states in which fluid overload could be harmful (decom-
pensated congestive heart failure or hypertension, severe
anemia, etc.). Administration of certain colloids may be
contraindicated in specific patient populations, such as
dextrans or starches in patients with clinically significant
coagulopathies, or hetastarch to patients with severe sep-
sis.63 Whereas albumin has similar colligative properties
to these synthetic colloids, the adverse effect profile is less
HEPATOLOGY, Vol. 41, No. 6, 2005 QUINLAN, MARTIN, AND EVANS 1217

Table 2. Theoretical Pros and Cons Associated with Intravenous HSA Use
Theoretical Benefits Potential Adverse Effects Comments

Intravascular maintenance and volume
expansion
Drug interactions
Removal of endogenous toxins
Removal of exogenous toxins
Maintenance of extracellular redox status
Scavenging antioxidant protection
Heme-binding antioxidant protection
N-terminal metal-binding and antioxidant
protection
Nonspecific iron-binding and antioxidant
protection
Nitric oxide-binding
Fluid overload as plasma volume responds No enhanced outcome benefit compared with other
linearly to levels of HSA administered colloids, but less likely to see adverse drug reactions
Allergic reactions A rare occurrence may be associated with polymer
formation on storage of HSA
Manufacturer and batch variation in albumin Variable levels of reduced thiols present, higher oxidation
for clinical use. states seen. Bound reactive metal ions including
copper, iron, vanadium, and aluminum seen
Drug interactions The ability to bind an array of drugs may in some
instances aid drug transport and delivery but equally
some covalent interactions may be irreversible, thereby
compromising drug efficacy. Binding of other ligands
may also influence drug interactions with HSA
Increased interstitial clearance Enhanced albumin clearance when administered to
patients with sepsis
Liver dysfunction: HSA binds bilirubin, copper and nitric
oxide as well as other liver-derived toxins. May also
help remove pro-inflammatory substances such as
chemokines
Metal poisoning, and certain drugs
Plasma thiol repletion
Cys-34–mediated removal of hydrogen peroxide and other
ROS
High-affinity heme-binding may come into play when other
(hemopexin) antioxidant protection is overwhelmed or
deficient.
Brain trauma Adverse indications
High-affinity binding of reactive transition metal ions;
Copper, cobalt and nickel directs oxidative damage to
albumin rather than other biomolecules
Also pro-oxidant implications May offer antioxidant protection when other (transferrin)
iron-binding antioxidant protection is overwhelmed or
deficient. However, as HSA is redox active it can
potentially recycle iron to the more catalytically active
ferrous state
Nitric oxide-binding NO bound to HSA may represent a proportion of an in
vivo sink for this vasoactive gas, the actions of which
may be either beneficial or deleterious dependant on
circumstances and organ type.

NOTE. Treatment of the critically ill are described. This is not an exhaustive list, but it summarizes areas highlighted and cited in this review.

cumbersome, although it could be pro-oxidant under de-
fined circumstances with as yet unknown consequences.
Finally, HSA from different manufacturers may differ
markedly in terms of the types of metals bound to it and in
levels of oxidation.64 Albumin employed for clinical use
therefore may differ markedly from endogenous HSA.
Such batch differences may influence biochemical prop-
erties, and HSA can thereby vary in its ability to influence
adhesion molecule expression from endothelial cells in
culture.65 Furthermore, dimer and polymer formation on
storage may contribute to rare instances of allergic reac-
tions being seen,66 and vanadium contamination of com-
mercial batches of HSA has been shown to adversely
influence renal function in patients with coronary heart
disease.67 Table 2 describes theoretical/potential implica-
tions associated with intravenous albumin administra-
tion. A more complete description of possible adverse
effects from colloid administration can be found in a re-
cent review.68
Summary
Human serum albumin (HSA) has many physiological
and biochemical properties that render it relevant to many
aspects of the disordered vascular and cellular functions
that characterize the critically ill; particularly those af-
flicted by the systemic inflammatory response syn-
drome—sepsis, severe sepsis, and septic shock. The use of
albumin as a routine volume expanding agent in the in-
tensive care setting cannot be justified in terms of a mor-
tality or morbidity advantage over crystalloid solutions.
However, albumin may be beneficial in specific clinical
circumstances, such as in patients with cirrhosis compli-
cated by SBP, and its potential to modulate the inflam-
1218 QUINLAN, MARTIN, AND EVANS
matory response is, we suggest, worthy of further
exploration.
Acknowledgment: The authors thank the British
Heart Foundation, The Dunhill Medical Trust, The
Garfield Weston Trust and the David Boston Trust for
their support, and the U.S. National Institutes of Health
for support via grant HL-67739.
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