Journal of Parenteral and Enteral

Nutrition
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Reviews: Role of Albumin in Human Physiology and Pathophysiology

John P. Doweiko and Dominic J. Nompleggi
JPEN J Parenter Enteral Nutr 1991 15: 207
DOI: 10.1177/0148607191015002207
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Reviews
Role of Albumin in Human Physiology and
JOHN P. DOWEIKO, M.D.

AND

Pathophysiology

DOMINIC J. NOMPLEGGI, M.D., PH.D.

From the Department of Medicine and Nutritional Support Services, New England Deaconess Hospital, and the Hematology and
Gastroenterology Divisions, Brigham and Womens Hospital, Boston Massachusetts

ABSTRACT. Albumin is one of the major products of hepatic

protein synthesis. Although it is a small molecule, it is an
important diagnostic and prognostic determinant, as well as a
useful therapeutic agent. A review of the evolution and structure of albumin as well as a description of its colloidal and
buffering properties is presented. Synthesis, distribution, and

catabolism, the major determinants of serum albumin level, are

discussed. Emphasis is given to those mechanisms responsible
for the regulation of these processes, including the importance
of nutritional status on substrate availability, energy supply,
and hormonal modulation. (Journal of Parenteral and Enteral
Nutrition 15
:207-211, 1991)

Albumin, the predominant product of hepatic protein

synthesis, has assumed dual importance both as a diagnostic and prognostic determinant in various disease
states and as a useful therapeutic agent. It is one of the
most ubiquitous constituents of the human body and has
multiple roles in its physiology. Despite its relative abundance, albumin has been among the more engimatic

antiparallel fashion to form a domain. Thus, each domain

is a cylindrical structure composed of six parallel polypeptide chains. The outside of the cylinder is mainly
polar and the central channel of the domain is lined
by hydrophobic residues producing a sanctuary and potential binding site for other hydrophobic species.
Three domains together compose the albumin molecule
(Fig. 1).
A large number of proline molecules in the segments

proteins. The importance of this protein was first recognized by Ancell in 1837.~ Since then, its complexities
have

only begun

to unfold.

EVOLUTION AND STRUCTURE OF ALBUMIN

a-Fetoprotein is the fetal counterpart of adult albumin;

the two share similar properties. The genes for the two
are on the same chromosome in mice; in humans it is
known that the albumin gene is on chromosome number
four. Albumin, a-fetoprotein, and myoglobin probably
evolved from the same ancestral gene about 300-500
million years ago.34 Over millennia, this primordium was
via a process of tandem amplification, a random process occurring during mitosis, which after generating two adjacent sequences, enhances probability of
a similar replication process.3 The multiple disulfide
bridges which help to stabilize the albumin molecule
developed at a later time, and myoglobin, its descendant
hemoglobin, and a-fetoprotein all diverged later from
this ancestral gene.
Albumin, compared to other plasma proteins, is a
relatively small molecule, consisting of a single polypeptide chain of 584 amino acids.5 It has a total molecular
weight of 69,000 Dalton, arranged predominantly into a
helices held together by 17 disulfide bridgeS.3 The architectural unit of the molecule is the subdomain.5 Each
subdomain corresponds to the product of the primordial
gene and consists of three contiguous a helices arranged
in parallel.5 A pair of subdomains face each other in an

between subdomains allows one to move in relation to

another. So binding of molecules by albumin may
change the spatial orientation of subdomains to promote
or inhibit other potential binding sites on albumin for
other molecules. Thus, the molecule has a highly organized, mainly hydrophobic internal structure stabilized
by disulfide bonds between half cystine residues and a
more flexible surface that is mainly hydrophilic. The
ellipsoidal shape of the molecule gives a solution of
albumin the property of very low viscosity.&dquo;

triplicated

Reprint requests: John

P.

Doweiko, MD, Division of Hematology,

75 Francis Street, Boston, MA 02215.

Brigham and Womens Hospital,

COLLOIDAL AND BUFFERING PROPERTIES

OF ALBUMIN

During health, the human body contains a total of

about 200 g of albumin. The normal serum albumin level
is 3.5 to 5.0 g/dL accounting for about 50% of the serum
proteins. An important function of albumin in normal
physiology is its role in fluid distribution throughout the
body because of its colloidal properties. Colloid oncotic
pressure is a function of the number of particles within
a compartment and is independent of their composition.
Within the intravascular space, albumin provides up to
75% of the normal oncotic pressure, 4,6,9,10,12 especially
below 3 g/dL, with little relative increase in this function
above this level.&dquo; Albumin provides a greater oncotic
effect than anticipated because of Gibbs-Donnan equilibrium : A difference in the concentration of large, charged
molecules such as albumin on either side of a semipermeable membrane prevents migration of small diffusable
ions. Tissue oncotic pressure varies among organs and is
a proportion of that of plasma. 11 Because of its charge,
207

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208

antigenically identical to the prevalent molecule but

differ in electrophoretic pattern.1,4,18 The genotype contains two autosomal codominant alleles for albumin, the
expression of which determines the albumin phenotype.

6-

FIG. 1. A conceptual model of the albumin molecule. Each subdomain

consists of three contiguous polypeptide chains arranged in parallel, as
indicated by the arrows. Two subdomains face each other in an antiparallel fashion to form a domain. Three domains together form the
complete molecule.

large extravascular pool, albumin

has a major role in the regulation of the fluid concentration of different tissues.11,12 Although some tissues such
as skin contain relatively large amounts of albumin,
much of this is bound to the tissue and is unavailable to
exert its full oncotic effect. 13
Because of its unique composition and abundance,
albumin plays an important role in acid-base physiology.
The molecule contains a number of histidine residues,
each with a pKa close to 7.4, making the protein able to
function as a blood buffer.&dquo; However, it is relatively less
important in this capacity than hemoglobin.14 Approximately two thirds of the normal anion gap originates
from plasma proteins,15 and albumin with its net charge
of negative 19 at normal serum pH is responsible for
almost half of the normal anion gap. Therefore, changes
in the level of serum albumin may contribute to changes
in serum acid-base status. Any increase in serum albumin
level increases the anion gap.15 Related to this, alkalemia
may cause release of hydrogen ions from albumin and
other plasma proteins, thus increasing their net ionic
charge and therefore the anion gap: A chloride-responsive metabolic alkalosis results.15 A decrease in serum
albumin may reduce the anion gap, contributing toward
a metabolic alkalosis: &dquo;primary hypoproteinemic alkalosis.&dquo;16 One study has shown that a decrease of albumin
of 1 g/dL decreases the normal anion gap by 3 mEq/liter
and causes an increase in serum bicarbonate by 3.5 mM/
dL.16 Another study has shown that although hypoalbuminemia tends to cause a low anion gap, there is no way
of predicting the individual anion gap from albumin
levels alone.17
water solubility and the

PHENOTYPIC VARIANTS OF ALBUMIN

Albumin may exist in man as genetic or less frequently

posttranscriptional variants, which for the most part are

Over 80 albumin variants have been identified.2 Most of

these variants exist in the heterozygous state; homozygous allotypes are very rare.19 Although some variant
albumins may be harmful, most heterozygotes are
healthy. However, the variants may have subtle alterations in properties.
Pedigree analysis of genetic variants has confirmed
that the genes for albumin are inherited by Mendelian
codominant autosomal alleles.4,7 Different albumin types
are found to reflect population differences, with the
highest frequency occurring in American Indians and the
lowest within Eurasian peoples.2o
There is a condition of analbuminemia: Essentially
total absence of serum albumin. This is common in pigs,
but rare in humans. So far, 18 families with the syndrome
have been identified. There is an unexpected paucity of
sequellae from this condition beyond mild edema.2 This
is perhaps because the small amount of albumin that is
available has a half-life nearly 10 times the normal and
also because increases in other plasma substances such
as globulins and lipids counter the lack of albumin.
The most common exogenously induced albumin variant is bisalbuminemia.7,21 This is transient, nonhereditary albumin variant which is present in serum in concentrations much less than normal albumin. Its production has been associated with aging, drugs, especially the
penicillins, and pancreatitis.2o
SYNTHESIS OF ALBUMIN AND ITS REGULATION

The serum albumin concentration is the outcome of a

number of processes occurring simultaneously. These
include synthesis and catabolism, which are somewhat
independent. The state of hydration22 and the intravascular and extravascular distribution are also important
variables.
Albumin synthesis is unique to the adult liver23 which
normally contains about 750 mg of the newly synthesized
molecule. The average daily synthesis of 12 to 25 g can
account for up to 50% of hepatic productive efforts at
any one time,24 but less than 10% of the total hepatic
anabolic function per day.22 Albumin synthesis consumes
about 6% of daily nitrogen intake.44

Only one half to one third of all hepatocytes produce

albumin at any one time.6 Polysomes which are bound
to the endoplasmic reticulum produce albumin which is
exported from the hepatocyte. These are very sensitive
to the concentration of tryptophan.~ Polysomes which
are free within the cytosol of the hepatocyte produce
albumin which is needed for intracellular use by the
hepatocyte and which is not exported.
In culture, hepatocytes synthesize blood proteins except albumin at a basal rate. This indicates that regulation of albumin production is unlike that of the majority
of other plasma proteins.25 With normal nutrition and
hormonal environment, the principal regulator of synthesis seems to be the oncotic pressure near the synthetic
site. Albumin synthesis is not sensitive to serum levels

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209
per se, but to the colloidal oncotic pressure near the
synthetic site. This seems to be a property of osmoreceptors sensitive to the interstitial environment of the
hepatocytes. Because of this, albumin synthesis tends to
be reciprocal with that of globulins in serum.4,25,26

The

hepatic synthetic capacity for albumin depends

complex interaction between the quantity and
quality of nutrients, route of intake and the ratio of total
protein and caloric fuel substances. 17 Caloric deprivation
causes a decrease in the hepatic synthesis of albumin of
as much as 50% within 24 hour1,4,28 and this persists as
long as the deficiency continues. The deficiency state
decreases albumin synthesis out of proportion to total
hepatic protein production, and repletion has a greater
upon

effect on albumin than on other proteins.429 The direction of reduction is along the same vector as that of
glycogen removal during fasting: from the portal canals
toward the hepatic venules. 31
The mechanism of attenuation of albumin synthesis
depends upon the duration of deprivation. Early during
the deficiency state, there is disaggregation of free and
endoplasmic-bound polysomes. 31,32 This results in a
decrease in the rate of initiation of albumin mRNA
translation.33 However, there is no major alteration
in the hepatocyte content of polysomes or albumin
mRNA.32,34,35 Thus, the albumin synthetic system is sustained and poised for a rapid recovery. 4,32,35 This is unlike
the situation with other hepatically synthesized proteins
during states of deprivation.25 This mechanism may be
common to the pathophysiology of decreased albumin
synthesis associated with conditions other than nutritional deficiencies.36
During the early period of nutritional deficiency, 50 to
90% of the amino acids that go into albumin production
4
are derived from breakdown of intrahepatic proteins.4
This is in contrast to other hepatically synthesized proteins which are produced from amino acids obtained from
the catabolism of muscle proteins. During more prolonged periods of starvation there occurs a reduction in
the number of mRNAs for albumin.44 This mechanism
is a slower response to the deprivation and is not rapidly

reversible.33
The disaggregation of polysomes and the resulting
decrease in albumin synthesis can be reversed within
minutes by a single feeding of amino acids.31,32 However,
not all amino acids have the same capacity to promote
this change. The albumin synthesizing system is very
sensitive to tryptophanl and this amino acid seems to
play a special role in enhancing rRNA and mRNA polymerases for albumin,31 and thereby albumin mRNA

synthesis.
Amino acids other than tryptophan also stimulate
albumin synthesis and these same amino acids also stimulate urea production.6,31,3, The urea cycle may have a
more important role in normal physiology than only
nitrogen disposal. 32,38 Conversely, the urea cycle may play
a role in protein synthesis.1,31,32,38 If albumin synthesis is
increased, urea production is also, and albumin synthesis
is reduced when urea synthesis is attenuated. 32.39
Although the supply of amino acids to the albumin

synthetic

site is

important , 40

the energy

supply

is also

important.-5 Energy supply

may take

precedence

in the

physiology of albumin production. Because of

compensatory mechanisms noted above, there is little or
no change in the amino acid concentration in the interstitium or cytosol of the hepatocyte in the fasted or fed
state. So the decrease in albumin synthesis with fasting
is not primarily due to decreased availability of amino
acids.35 The refeeding of glucose alone leads to restoration of polysome aggregation and albumin synthesis.
Therefore, energy rather than amino acid supply more
directly determines polysome aggregation and consequent albumin synthesis under normal circumstances. 15
normal

In addition to nutritional parameters, the hormonal

milieu of the hepatocyte is also important to albumin

synthesis. Cortisone, thyroid hormone, growth hormone,

sex hormones, and insulin alter albumin production and
are additive.1,40 In media devoid of hormones,
hepatic synthesis of albumin is decreased remarkably

their effects

This is associated with a decrease in albumin mRNA

indicating decreased transcription of the albumin gene.25
Particular hormones may act in other ways. Albumin
synthesis and degradation correlate with thyroid hormone levels and plasma T3 is inversely related to plasma
albumin concentration.2 Control of RNA and ribosomal
production appears to be an important aspect of thyroidal regulation of albumin synthesis.1,4 Cortisol may
promote binding of ribosomes to endoplasmic reticulum,
thus increasing the albumin synthetic rate. Insulin deficiency has been associated with decreased albumin
production,43 but insulin is necessary only for maximal
and not basal albumin production,l,4O probably acting by

increasing gene transcription. 18,42,44

RELEASE OF ALBUMIN FROM THE HEPATOCYTE AND
DISTRIBUTION IN THE BODY FLUIDS

The original product of albumin synthesis contains a

six amino acid terminus not found on albumin which
circulates in the blood. This sequence directs albumin
from ribosomes into secretory pathways and then is
cleaved off as one of the last events in albumin production. The parent albumin molecule with the extra amino
acid sequence is found in small amounts in serum especially with rapid albumin production. The newly formed
albumin is not stored in the hepatocyte45 but is released
directly into the hepatic interstitium via an energydependent process.46 From the interstitium, the albumin
molecules then move into the sinusoid and hepatic venous drainage.47.48 The concentration of potassium in the
hepatocyte is important in facilitating release of albumin
from the hepatocyte into extracellular fluid4: As the
intracellular potassium concentration declines, so does
release of albumin from the hepatocyte.~ Hepatic lymph
drainage is not important in the normal flow of newly
synthesized albumin from hepatocyte to circulating

plasma.6,40

The newly synthesized albumin becomes part of the

hepatic venous drainage and rapidly distributes throughout the plasma pool, with equilibrium of 90% throughout
the plasma within 2 minutes or two to three circulations.1,4,40 The intravascular space comprises 30 to 40%
of the total exchangeable albumin pool,1.1.40.49..)(I while the

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210
extravascular pool makes up the remaining 60 to 70%.
The extravascular compartment is composed of two
units, each with its own rate of distribution of intravascular albumin into the compartment. 51 One compartment
is made of tissues with discontinuous capillaries such as
liver, spleen, and gut and has the more rapid rate of
distribution with a half-time of 6 hour, and the second
compartment is composed of tissues with continuous
capillaries such as skeletal muscle and skin and has a
slower rate of distribution with a half-time of 28 hour.52
Therefore, there are three pharmacokinetic compartments of albumin distribution: The intravascular compartment and a two-part extravascular compartment.52
Because of these dynamics, after the plasma equilibrium phase, intravascular albumin equilibrates within
the extravascular space at a rate of almost 6% per
hour.l4,953 Therefore, during health, the plasma half-life
of infused albumin is about 24 hour.855 However, infusions of concentrated albumin solutions in normal subjects may increase the transcapillary flux of albumin by
as much as 3-fold.56 The extravascular distribution of
albumin varies among different organs.4 Skin, which
composes only 6% of total body weight, contains 11 to
18% of the total body albumin 20 and 30 to 40% of the
total extravascular p001.40,52 In the normal state, skeletal
muscle contains about 15% of the total albumin pool.4>52
Most viscera contain insignificant amounts of exchangeable albumin .40 The liver, the site of albumin production,
contains less than 1% of the albumin pool. Because of
this distribution, skin contains 64% of extravascular
water, and skeletal muscle 17%.6 Over one-third of a

of life span.4 Unlike the situation in which

nutritional intake is normal, during states of caloric and
protein deprivation, exogenously administered albumin
may increase its own catabolism and slow the normal
rate of synthesis of albumin by the liver. 4,28,58
Albumin synthesis and catabolism are not interdependent4: One can change without change in the
other. Before reaching the catabolic site(s), albumin has
to egress from plasma, and then traverse and equilibrate
with an extravascular compartment. Although the exact
location and nature of the catabolic site(s) are obscure, 41
catabolism is receptor independent and not a localized
entity. 40 Probably all organs participate to some extent
in total daily catabolism with the normal liver degrading
about 10% of the total catabolic pool.51

regardless

CONCLUSIONS

its relatively small size, albumin is one of the

abundant of the plasma proteins. The molecule has
major importance in human physiology because of its
colloidal properties, and it plays a less important role in
the acid-base physiology of the human organism. Each
molecule is composed of three units, or domains, which

Despite

most

together to give the molecule its unique binding

properties.
Albumin is synthesized exclusively by the liver. Its
synthesis depends upon a complex interaction of the
nutritional state, the hormonal milieu, and the interstitial environment of the hepatocyte. During health,
plasma albumin, which composes 30 to 40% of the total
fluid overload can accumulate within these two organs albumin pool, is maintained at a steady level. The comwith a paucity of clinical signs.~ The complex distribution plex interactions between the synthesis, distribution, and
dynamics of albumin makes the serum level a poor indi- catabolism of the molecule have recently begun to unfold.
Of these processes, the latter remains the most enigcator of total albumin stores in the body.52
Complete equilibration between the intra- and extra- matic.
vascular albumin pools takes 7 to 10 days.52 Entry of
albumin into the interstitium is via intracellular vesicles
of the capillary endothelium and this is independent of
water and ion flow which occurs via interendothelial
junctions .50 The independence of albumin and ion/water
flow allows for a large, stable extravascular mass of
albumin which can be mobilized into plasma when
needed there .41,5 This also makes albumin the major
protein of edema fluid, composing 1 g/dL of edema of
cardiac, renal, and liver disease, and 2 g/dL in lymphedema. In many disease states, the normal ratio between
body compartments is disrupted, and this alone will
change the serum albumin concentration.22 As an example, prolonged immobilization increases extravascular
albumin at the expense of intravascular albumin .12 Normally, 80% of the albumin which moves into the interstitium returns to the intravascular space via the thoracic
duct within 48. 40,57
CATABOLISM OF ALBUMIN

The half-life of albumin is 17 to 19 days,49 and about

4% of the exchangeable pool is degraded per day.4 Albumin has a high total catabolic rate in comparison with
other plasma proteins, but because of its abundance it
has a low fractional catabolic rate. Albumin is degraded

function

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