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Causes and mechanisms of hypoalbuminemia

Article in Clinical Nutrition · July 2001

DOI: 10.1054/clnu.2001.0439 · Source: PubMed

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Clinical Nutrition (2001) 20(3): 271–273
& 2001 Harcourt Publishers Ltd
doi:10.1054/clnu.2001.0439, available online at http://www.idealibrary.com on

Causes and mechanisms of hypoalbuminaemia

P. E. BALLMER
Department of Internal Medicine, Kantonsspital Winterthur, Switzerland (Correspondence to: PEB, Department of Internal Medicine,
KantonsspitalWinterthur, CH-8400 Winterthur, Switzerland)

Introduction Capillary leak: an important cause of hypoalbuminaemia

Albumin is the single most abundant plasma protein
with a molecular weight of about 66 kDa. Albumin is
exclusively synthesised in the liver. Once synthesised
albumin molecules are secreted into the blood stream and
extravasate from the intravascular space to the interstitial
space. The fate of albumin molecules leaving the
intravascular compartment is less clear. It appears that
albumin breakdown occurs directly from the intravas-
cular compartment, possibly by the endothelial cells. The
kidney degrades about 10% of albumin and up to 10%
seems to be leaking into the gastrointestinal tract. Most
of albumin is disappearing through muscle and skin (1).
However, albumin occurring in the interstitial space
returns by the lymphatic flow back to the intravascular
compartment. Thus, in inflammatory disease the return
of albumin by the lymph increases several-fold and
balances the substantial loss of albumin by the leaky
capillary membrane. In Table 1 the distribution of
albumin in the normal human body is summarised.
Mechanisms of hypoalbuminaemia
In general, hypoalbuminaemia is not the result of a
decrease in albumin synthesis alone as widely believed,
but a multifactorial process involving several processes
such as synthesis, breakdown, leakage to the extra-
vascular space and protein intake (Fig. 1; Table 2). In
Figure 2 some well known and some hypothetical
factors influencing albumin metabolism are summar-
ized. I do not intend to discuss the mechanisms of
hypoalbuminaemia in a broad sense, but some crucially
important factors from a clinical point of view.
Clinical conditions causing hypoalbuminaemia
Hypoalbuminaemia can be divided into three categories
according to the extent of low serum albumin (Table 3).
The division into categories is of limited help because
overlap in disease does not allow strong conclusions to
be drawn from the severity of hypoalbuminaemia to a
specific disease. However, in general the more severe the
disease, the lower is the serum albumin concentration.
After synthesis of albumin in the liver, the molecules are
secreted to the intravascular compartment and from there
albumin leaves the blood, a process called transcapillary
escape of albumin. The transcapillary escape rate of
albumin (TER) occurs at about 5% per hour under
physiologic conditions, i.e. 5% of the intravascular
albumin escapes per hour. Under inflammatory condi-
tions TER may increase several fold (2, 3). Thus, Fleck et
al. (3) have demonstrated that TER increased signifi-
cantly after cardiopulmonary bypass surgery, and sug-
gested that the inflammatory response to surgery would
be an important factor causing albumin leakage.
In our own study, we were looking at the potential
mechanisms for the increase in TER (4). We hypothesised
that interleukin-2 would be an important pathogenic
factor causing increased capillary leakage of albumin.
We investigated patients with advanced melanoma
undergoing immunotherapy with both interferon-a and
interleukin-2. TER was measured by injecting 5 mCi
radioiodinated albumin 6 h after the last subcutaneous
interleukin-2 injection (1.56106 Cetus units). Indeed,
TER increased in every subject after interleukin-2
injection and serum albumin also decreased significantly
(4). The major results of that study are summarized in
Table 4. We concluded from the study that, in line with
the literature, immediate effects on serum albumin
occurred by increases in TER, and that any typical
acute-phase reaction may increase TER. The specific
mediator causing the changes in TER could not be
defined with certainty. Possible direct or indirect media-
tors affecting TER of albumin were identified as
interleukin-2, interferon-a and interleukin-6. However,
the acute-phase reaction is always caused by different
cytokines, hormones and nervous stimuli. I believe that it
will remain difficult to exactly identify which will be the
single most likely factor causing increases in capillary
membrane escape of albumin in an acute-phase reaction.
Hypoalbuminaemia by decreases in albumin synthesis
In Table 5, major factors decreasing albumin synthesis
are given. Reduced albumin synthesis may be an
important additional reason of low serum albumin

271
272 CAUSES AND MECHANISMS OF HYPOALBUMINAEMIA

Table 1 The distribution of albumin in normal human body

(modified 1)

Extravascular albumin
Amount Fraction of Concentration in
per organ total EV1 fluid
g/70 kg BW % g/l
Skin 100 41 10–15
Muscle 96 40 10–15
Liver 6 3 —
Gut 18 7 25–30
Subcutis etc. 22 9 16 Fig. 2 Some known and hypothetical clinically important factors
Intravascular albumin influencing albumin metabolism.
Plasma 118 49 42 Protein intake stimulates albumin synthesis under normal conditions.
1 Various cytokines such as interleukin-1 and interleukin-6 exert
Ev, extravascular volume.
inhibitory action on albumin synthesis, may increase breakdown and
capillary escape of albumin. Hormones, e.g. thyroid hormones and
glucocorticoids, have stimulatory effects on albumin synthesis.
Acidosis was shown to inhibit albumin synthesis and contribute to
hypoalbuminaemia (7). Whether hypoxia and physical exercise may
have an effect on albumin metabolism is not well understood.

Table 3 Categories of hypoalbuminaemia according to the severity of

the decrease in serum albumin

Serum albumin 520 g/l

Nephrotic syndrome
Protein loosing gastroenteropathy
Sepsis
Serum albumin 20–23 g/l
Liver cirrhosis
Glomerulonephritis
Serum albumin 23–30 g/l
Acute-phase reactions, e.g. carcinoma, viral infection etc.
Protein-energy malnutrition
Fig. 1 Causes of hypoalbuminaemia.
Albumin production is dependent on nutrient intake in particular on
protein ingestion. The liver is the exclusive site of albumin synthesis.
After synthesis, albumin is secreted to the blood without storage in the Table 4 Transcapillary escape rate (TER) and serum concentration of
liver. From the intravascular space albumin extravasates to the albumin before and after subcutaneous interleukin-2 (4)
interstitial compartment. Breakdown of albumin occurs in different
Serum albumin(g/l) TER(%/h)
organs (see text). N, nutrition; S, synthesis; SA, serum albumin; TER,
transcapillary escape rate; D, degradation. Before After Before After
mean+sd 46+1 43+3* 9.4+2.7 14.9+3.3**
Table 2 Causes of hypoalbuminaemia *P50.01.
**P50.001.
Increased loss Decreased production
Albumin degradation: Protein intake;
Albumin leak:1 Albumin synthesis;
1
Albumin metabolism at high altitude
Increase in transcapillary escape of albumin.
We hypothesised that exposure to high altitude would
down-regulate albumin synthesis by the diminished
concentration. However, any rapid changes in serum oxygen supply under those conditions. Therefore, we
albumin concentration, i.e. changes within a few hours, exposed healthy volunteers to high altitude in the Swiss
are unlikely to be induced by changes in albumin mountains. The subjects were investigated at 500 m
synthesis alone. Down-regulation of albumin synthesis (metabolic ward at the University of Berne, Switzerland)
may take many hours up to a few days. and some 2 weeks later on Capanna Margherita, an
I shall not discuss in extenso the reaction of albumin alpine resort at 4559 m. The subjects either walked
synthesis to the different stimuli listed in Table 5, but (active ascent) or were flown by helicopter (passive
concentrate on our own recent work investigating ascent) from 3500 m to the peak altitude of 4559 m
albumin synthesis under special conditions, i.e. at high because we wanted to differentiate between effects by
altitude and in metabilic acidosis. For general review of high altitude and by physical exercise (5).
regulation of albumin synthesis, I refer to the excellent On day 2 after ascent serum albumin was significantly
text book by Peters Th jr. (1). higher in both groups, an effect which was related to

Table 5 Different factors influencing albumin synthesis
Nutrition (protein)
Acute-phase reaction
Cytokines
Liver function impairment
Acidosis
Other factors, e.g. hormones
some dehydration at high altitude. On day 3 albumin
synthesis was measured by a flooding dose of [2H5ring]-
phenylalanine (6). Whereas high altitude exposure alone
showed no significant increase in the rate of albumin
synthesis, combined physical exercise and high altitude
exposure significantly raised albumin synthesis (5). We
concluded from these studies that physical exercise
would be an important, although not yet further
characterized, signal for stimulating synthesis rate of
albumin.
Albumin synthesis in metabolic acidosis
Many catabolic conditions are associated with meta-
bolic acidosis. In intensive care patients with severe
muscle wasting despite adequate nutrient supply, meta-
bolic acidosis might be an important factor effecting
protein catabolism. As a first step, therefore, we
investigated whether chronic metabolic acidosis would
down-regulate albumin synthesis in healthy subjects.
Albumin synthesis was measured at baseline by a
flooding dose of [2H5ring]phenylalanine and after
7 days in acidosis induced by ingestion of ammonium
chloride (7). The volunteers were on a constant meta-
bolic diet and were treated with either 2.1 or 4.2 mmol/
kg body weight NH4Cl. The high dose of NH4Cl induced
a significant down-regulation in albumin synthesis (see
Table 6). In a second study, acute acidosis induced by
4.2 mmol NH4Cl/kg body weight, showed no effect on
albumin synthesis rate. In this study, muscle protein
synthesis was also measured and dropped significantly
(8). Our investigations opened a new spectrum in the
study of albumin metabolism. We believe that acidosis
might be a, so far, underestimated pathogenic factor in
regulating protein metabolism.
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CLINICAL NUTRITION 273
Table 6 Albumin synthesis (fractional synthesis rate, FSR) and serum
concentration in healthy volunteers under chronic metabolic acidosis
induced by ingestion of 4.2 mmol NH4Cl/kg body weight (modified 7)
Base line Acidosis
Albumin synthesis 8.3+1.3 6.3+1.1**
(FSR, %/d)
Serum albumin 44.8+2.6 43.8+2.1*
(g/l)
*P50.05.
**P50.01.
In summary, I have focussed on some particular
aspects of albumin metabolism. I have not intended to
review the subject in a general and wide sense but in my
very personal view. I hope that this will stimulate further
discussion and help to understand in a more profound
sense the metabolism of this exciting protein.
References
1. Peters Th jr. (ed.). All about albumin. Academic press San Diego,
London. 1996, pp 1–432
2. Ballmer P E, Ochsenbein A F, Schütz-Hofmann S. Transcapillary
escape rate of albumin positively correlates with plasma albumin
concentration in acute but not in chronic inflammatory disease.
Metabolism 1994; 43: 697–705
3. Fleck A, Raines G, Hawker F, Trotter J, Wallace P I, Ledingham
I M, Calman K C. Increased vascular permeability: a major
cause of hypoalbuminaemia in disease and injury. Lancet 1985; i:
781–784
4. Ballmer-Weber B K, Küng E, Dummer R, Burg G, Ballmer P E.
Interleukin-2 induced increase of vascular permeability without
decrease of the intravascular albumin pool. Br J Cancer; 1995; 71:
78–82
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