Intern Emerg Med (2012) 7 (Suppl 3):S193–S199
DOI 10.1007/s11739-012-0802-0
WARD MEDICINE
Hypoalbuminemia
Angelo Gatta • Alberto Verardo • Massimo Bolognesi
Ó SIMI 2012
Abstract 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 mor-
tality 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 supplementa-
tion is accepted also in other clinical situations such as
burns, nephrotic syndrome, hemorrhagic shock and pre-
vention of hepatorenal syndrome, within these contexts it
does not represent a first-choice treatment nor is its use
supported by widely accepted guidelines.
A. Gatta
A. Verardo
M. Bolognesi
Department of Medicine, University of Padova, Padua, Italy
A. Gatta (&)
Department of Medicine, Azienda Ospedaliera Università di
Padova, Clinica Medica 5, Via Giustiniani 2, 35128 Padua, Italy
e-mail: angelo.gatta@unipd.it
Keywords Human serum albumin
Hypoalbuminemia

Albumin infusion
Liver cirrhosis
Paracentesis
Introduction
Hypoalbuminemia is associated with several pathological
conditions. It can often be observed in elderly and/or
malnourished patients, but also in severe medical condi-
tions, such as septic shock or decompensated liver cirrho-
sis. 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 intra-
venous administration of albumin.
Synthesis and metabolism of human serum albumin
In mammals, albumin is the most represented plasma
protein [1]. 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 syn-
thesis of pre-proalbumin in the liver. This is then con-
verted into proalbumin, the main intracellular form of
albumin. Once synthesized, the Golgi apparatus of the
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human hepatocytes removes a 6-aminoacid sequence of
the proalbumin peptide chain, to complete the synthesis of
albumin, which is then secreted [4]. There are genetic
variants of albumin (bisalbumins or alloalbumins), which
may have altered binding properties [5].
A healthy human being of about 70 kg produces up to
14 g of albumin a day. This means that the hepatic syn-
thesis 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, con-
sidering a 4 % daily degradation rate [8]. After being
synthesized in the liver from aminoacids deriving from
protein muscle catabolism or intestinal absorption [6],
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 syn-
thesis, possibly the main one in the absence of stressful
conditions [7, 9]. Albumin synthesis is decreased by
cytokines such as interleukin-1 (IL-1) [10] and 6 (IL-6) and
tumor necrosis factor a (TNFa) [7]. Insulin is required for
an adequate synthesis [7], while corticosteroids have a
double effect: they increase albumin synthesis combined
with insulin or aminoacids, but they also increase albumin
catabolism [7]. 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 [11]. The
exchange rate between intra- and extravascular volume
(transcapillary escape rate) is about 5 % per hour of the
intravascular albumin content [12]. As far as the distribu-
tion 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 [12]. 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 [6]. 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 mol-
ecules. 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 gastro-
intestinal tract [1]. The urinary loss is minimal in healthy
subjects (usually \20 mg/day) [7].
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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 [7]. Normal levels of plasma
proteins, especially albumin, prevent the development of
edema, providing a balance between hydrostatic and col-
loid-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) [5]. 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
[7]. 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 prop-
erties 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, pro-
viding protection against free heme-Fe oxidative damage
[5]. Albumin serves as a significant reservoir for signaling
molecules and nitric oxide (NO) [17]. Indeed, serum
albumin may represent a circulating endogenous reservoir
of NO and may act as an NO donor [5]. Albumin also has
effects on blood coagulation: it exerts a heparin-like action
and inhibits platelet aggregation [7, 12]. Therefore, albu-
min 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 [7], and its possible
action as a detoxifying agent [18], the use of albumin
dialysis (molecular adsorbent recirculating system, MARS)
was proposed in artificial liver support devices as a treat-
ment 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 prob-
ably identified by levels \25 g/L. Hypoalbuminemia is
commonly observed in elderly patients, especially those
who are institutionalized and/or hospitalized, and in
Intern Emerg Med (2012) 7 (Suppl 3):S193–S199
patients with malnutrition or advanced-stage chronic dis-
eases [21]. Low serum albumin levels are risk factors and
a predictor of morbidity/mortality regardless of the
implicated disease [6]. 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 [10]. In addition, Gibbs et al. [22] found
that preoperative serum albumin was the strongest pre-
dictor of mortality and morbidity after surgery. However,
it is not clear whether this is due to the fact that hypo-
albuminemia merely identifies malnourished patients [6].
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 [6].
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 [6]. Hypoalbuminemia
is frequently observed during acute disease states as albu-
min 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 [23]. The
reasons for this reduction are to be found in the combina-
tion 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 [23], and to IL-6 and TNFa [7]. 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 concentra-
tion. As a matter of fact, in several diseases, and particu-
larly in patients with sepsis and other inflammatory
conditions, the increased vascular permeability increases
the transcapillary loss of albumin, participating into the
development of hypoalbuminemia [7]. 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 [27].
In several clinical conditions, hypoalbuminemia is
caused by more than one mechanism. For instance, in
cirrhosis there is an impaired hepatocyte synthesis, and also
increased transcapillary escape rate [28]. Subjects with
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diabetes have a decreased synthetic rate (which improves
with insulin infusion) [7], and also increased transcapillary
escape rate [12]. During major surgery, there is an
increased albumin transcapillary escape rate [12] and a
reduction in the flow rate of lymph [7], while in myxedema
an increased extravascular pool of albumin is associated
with a decreased catabolic rate [7]. Thus, it is not easy to
classify the causes of hypoalbuminemia; a tentative scheme
is reported in Table 1.
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 [29]. In addition,
patients with congenital analbuminemia may be symptom-
free and perfectly healthy [24], even though it has been
hypothesized that most cases of analbuminemia do not
survive gestation [5]. Thus, in patients with hypoalbumi-
nemia, the priority should be the treatment of the under-
lying condition which causes/is associated with
hypoalbuminemia [24]. For instance, in elderly patients,
Table 1 Causes of hypoalbuminemia, classified according to the
main pathogenetic mechanism
Reduced synthesis
Genetic abnormalities (synthesis of defective albumin, mutations
causing analbuminemia)
Cirrhosis
Acute liver failure
Acute and chronic hepatitis
Malabsorption syndromes
Nutritional deficiencies (low-protein diets)
Critical illnesses
Diabetes
Chronic metabolic acidosis
Increased catabolism
Infections, Sepsis
Cancer
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
Nephrotic syndrome
Extensive burns, extensive skin diseases
Protein-losing entheropathy
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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 [31].
Human albumin solution is usually available at con-
centrations 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 [12].
The main obstacle to the use of albumin is its cost. To
date, human serum albumin has been produced by frac-
tionation of human plasma, which is generally available in
limited supplies [5]. The development of industrial meth-
ods to produce recombinant human albumin through
recombinant DNA technology is under way [5]. 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 ana-
lyzed 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 [32]. 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
[35]. In addition, the outcome of resuscitation with albumin
and saline were similar irrespective of the patients’ base-
line serum albumin concentration [36]. 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 [37], but it may increase mor-
tality rate in critically ill patients with traumatic brain
injury [38]. The beneficial effect of albumin-containing
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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 resuscita-
tion regimens [39].
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 [31]. 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 [31].
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 vol-
emia [30, 31, 45]. In nephrotic syndrome, albumin supple-
mentation, in association with diuretics and corticosteroids,
has been proposed in patients with severe hypoalbuminemia,
severe hypovolemia, acute pulmonary edema and/or acute
renal failure [31]. Albumin is more effective than diuretics
alone in enhancing diuresis and natriuresis [46], 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
[47]. Human albumin has usually no indication in the treat-
ment 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 per-
meability is still high [31, 48]. Subsequently, albumin 5 %
has been proposed using different doses according to the
amount of body surface area involved [31].
Therapeutic use of albumin in cirrhotic patients
In cirrhosis, concentrated solutions of albumin are used
mostly as plasma-expander when there is severe impair-
ment of effective plasma volume, such as after large vol-
ume 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 [49].
Large volume paracentesis is the first-line treatment in
patients with large ascites and for refractory ascites [50].
The procedure should be accompanied by the
Intern Emerg Med (2012) 7 (Suppl 3):S193–S199
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 pre-
vention of post-paracentesis circulatory dysfunction [50].
Five litres is the customary cutoff below which albumin
infusion is not recommended [18]. 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 cir-
culatory 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 [18].
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 [59]. Moreover, in
patients with spontaneous bacterial peritonitis, it may
improve cardiac contractility, probably by linking/scav-
enging negative inotropic substances such as cytokines,
nitric oxide and bile salts [49].
The vasopressin analog terlipressin, together with
albumin administration, is the first-line treatment for type 1
hepatorenal syndrome (syndrome with rapid and progres-
sive impairment in renal function) [34]. In this setting,
albumin is usually given at 1 g/kg body weight on day 1,
followed by 20–40 g/day [50]. 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 [50].
There is no clear indication for the use of albumin in
cirrhosis in clinical conditions other than those discussed
S197
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 [50]. 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 pro-
posed for patients in particularly unstable conditions,
severe hypovolemia and hypoalbuminemia [51, 61–64]. In
contrast, the current recommendations for first-line treat-
ment 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 None.
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