Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements

Abstract

Serum albumin concentration (CP) is a remarkably strong prognostic indicator of morbidity and mortality in both sick and seemingly healthy subjects. Surprisingly, the specifics of the pathophysiology underlying the relationship between CP and ill-health are poorly understood. This review provides a summary that is not previously available in the literature, concerning how synthesis, catabolism, and renal and gastrointestinal clearance of albumin interact to bring about albumin homeostasis, with a focus on the clinical factors that influence this homeostasis. In normal humans, the albumin turnover time of about 25 days reflects a liver albumin synthesis rate of about 10.5 g/day balanced by renal (≈6%), gastrointestinal (≈10%), and catabolic (≈84%) clearances. The acute development of hypoalbuminemia with sepsis or trauma results from increased albumin capillary permeability leading to redistribution of albumin from the vascular to interstitial space. The best understood mechanism of chronic hypoalbuminemia is the decreased albumin synthesis observed in liver disease. Decreased albumin production also accounts for hypoalbuminemia observed with a low-protein and normal caloric diet. However, a calorie- and protein-deficient diet does not reduce albumin synthesis and is not associated with hypoalbuminemia, and CP is not a useful marker of malnutrition. In most disease states other than liver disease, albumin synthesis is normal or increased, and hypoalbuminemia reflects an enhanced rate of albumin turnover resulting either from an increased rate of catabolism (a poorly understood phenomenon) or enhanced loss of albumin into the urine (nephrosis) or intestine (protein-losing enteropathy). The latter may occur with subtle intestinal pathology and hence may be more prevalent than commonly appreciated. Clinically, reduced CP appears to be a result rather than a cause of ill-health, and therapy designed to increase CP has limited benefit. The ubiquitous occurrence of hypoalbuminemia in disease states limits the diagnostic utility of the CP measurement.

Keywords: albumin; cirrhosis; clearance; enteropathy; malnutrition; nephrosis; synthesis.

Figure 1

Relationship of serum albumin concentration to relative risk of mortality for 50- to 69-year-old male life insurance applicants. Notes: The dashed line indicates a relative risk of 1.0. The means and 95% confidence limits of relative mortality (medium follow-up of 12 years) are shown for groups of subjects with the mean serum albumin concentrations listed. Adapted from Fulks M, Stout RL, Dolan VF. Albumin and all-cause mortality risk in insurance applicants. J Insur Med. 2010;42(1):11–17. Copyright © 2010 Journal of Insurance Medicine.

Figure 2

Plot of albumin synthesis versus serum albumin (both normalized to the normal values) for subjects with acute and chronic liver disease.

Figure 3

Plot of the clearance of antipyrine (black), indocyanine green (red), or aminopyrine (blue) versus serum albumin (normalized to the normal value). Notes: The solid line is the expected relationship if clearance is proportional to serum albumin. Data from references 33–36.

Figure 4

Plot of either the total albumin synthesis rate relative to normal (red) or the urinary albumin excretion relative to total synthesis (black) versus the urinary albumin excretion in a series of nephrotic syndrome patients with varied diagnoses and no obvious liver disease. Note: Experimental data from references 56 and 57.

Figure 5

Plot of either the total albumin synthesis rate relative to normal (red) or the urinary albumin excretion relative to total synthesis (black) versus the serum albumin relative to normal. Note: Experimental data from references 56 and 57.

Figure 6

Plot of serum albumin versus the percent of an intravenous dose of ⁵¹Cr-labelled albumin collected over 4 days of stool sampling in 50 control subjects and 130 patients with hypoalbuminemia and no obvious liver or renal disease. Note: Experimental data from reference 63.

Figure 7

Plot of the percent of plasma albumin that is synthesized/day versus the percent of plasma albumin that is excreted into the GI tract/day in subjects with increased GI albumin clearance and hypoalbuminemia. Note: Experimental data from reference 63. Abbreviation: GI, gastrointestinal.

Figure 8

Distribution of all serum albumin concentrations measured in a single day at the Minneapolis Veterans Administration Hospital for outpatients and inpatients. Note: The heavy dashed line is the lower limit of normal (lowest 2.5% of values) and the short dashed line is the average value observed in a group of 50- to 69-year-old life insurance applicants.