Causes and mechanisms of hypoalbuminaemia

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)

Capillary leak: an important cause of hypoalbuminaemia

Introduction

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 conditions TER may increase several fold (2, 3). Thus, Fleck et al. (3) have demonstrated that TER increased significantly after cardiopulmonary bypass surgery, and suggested 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 mediators 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.

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 intravascular 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 extravascular space and protein intake (Fig. 1; Table 2). In Figure 2 some well known and some hypothetical factors influencing albumin metabolism are summarized. 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.

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

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CAUSES AND MECHANISMS OF HYPOALBUMINAEMIA

Table 1 The distribution of albumin in normal human body (modified 1) Extravascular albumin Amount per organ g/70 kg BW Skin Muscle Liver Gut Subcutis etc.

100 96 6 18 22

Plasma

118

1

Fraction of total EV1 %

Concentration in fluid g/l

41 10–15 40 10–15 3 — 7 25–30 9 16 Intravascular albumin 49 42

Ev, extravascular volume.

Fig. 2 Some known and hypothetical clinically important factors influencing albumin metabolism. Protein intake stimulates albumin synthesis under normal conditions. Various cytokines such as interleukin-1 and interleukin-6 exert 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 liver. From the intravascular space albumin extravasates to the interstitial compartment. Breakdown of albumin occurs in different organs (see text). N, nutrition; S, synthesis; SA, serum albumin; TER, transcapillary escape rate; D, degradation.

Table 4 Transcapillary escape rate (TER) and serum concentration of albumin before and after subcutaneous interleukin-2 (4) Serum albumin(g/l)

mean+sd

Albumin degradation: Albumin leak:1 1

After

Before

46+1

43+3*

9.4+2.7

After 14.9+3.3**

*P50.01. **P50.001.

Table 2 Causes of hypoalbuminaemia Increased loss

TER(%/h)

Before

Decreased production Protein intake; Albumin synthesis;

Increase in transcapillary escape of albumin.

concentration. However, any rapid changes in serum albumin concentration, i.e. changes within a few hours, are unlikely to be induced by changes in albumin synthesis alone. Down-regulation of albumin synthesis may take many hours up to a few days. I shall not discuss in extenso the reaction of albumin synthesis to the different stimuli listed in Table 5, but concentrate on our own recent work investigating albumin synthesis under special conditions, i.e. at high altitude and in metabilic acidosis. For general review of regulation of albumin synthesis, I refer to the excellent text book by Peters Th jr. (1).

Albumin metabolism at high altitude We hypothesised that exposure to high altitude would down-regulate albumin synthesis by the diminished oxygen supply under those conditions. Therefore, we exposed healthy volunteers to high altitude in the Swiss mountains. The subjects were investigated at 500 m (metabolic ward at the University of Berne, Switzerland) and some 2 weeks later on Capanna Margherita, an alpine resort at 4559 m. The subjects either walked (active ascent) or were flown by helicopter (passive ascent) from 3500 m to the peak altitude of 4559 m because we wanted to differentiate between effects by high altitude and by physical exercise (5). On day 2 after ascent serum albumin was significantly higher in both groups, an effect which was related to

CLINICAL NUTRITION

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.

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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)

Albumin synthesis (FSR, %/d) Serum albumin (g/l)

Base line

Acidosis

8.3+1.3

6.3+1.1**

44.8+2.6

43.8+2.1*

*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 Albumin synthesis in metabolic acidosis Many catabolic conditions are associated with metabolic acidosis. In intensive care patients with severe muscle wasting despite adequate nutrient supply, metabolic 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 metabolic 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.

1. Peters Th jr. (ed.). All about albumin. Academic press San Diego, London. 1996, pp 1–432 2. Ballmer P E, Ochsenbein A F, Schu¨tz-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, Ku¨ng 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 5. Imoberdorf R, Garlick P J, McNurlan M A, Casella G A, Peheim E, Turgay M, Ba¨rtsch P, Ballmer P E. Enhanced synthesis of albumin and fibrinogen at high altitude. J Appl Physiol 2001; 90: 528–537 6. McNurlan M A, Esse´n P, Thorell A, Calder A G, Anderson S E, Ljungqvist O, Sandgren A, Grant I, Tja¨der I, Ballmer P E, Wernerman J, Garlick P J. Response of protein synthesis in human skeletal muscle to insulin: an investigation with L[2H5]phenylalanine. Am J Physiol 1994; 267: E102–E108 7. Ballmer P E, McNurlan M A, Hulter H N, Anderson S E, Garlick P J, Krapf R. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest 1995; 95: 39–45 8. Kleger G-R, Turgay M, Imoberdorf R, McNurlan M A, Garlick P J, Ballmer P E. Acute metabolic acidosis decreases muscle protein synthesis but not albumin synthesis in humans. Submitted