Hypoalbuminemia: Pathogenesis and Clinical Significance

Abstract

Hypoalbuminemia is associated with inflammation. Despite being addressed repeatedly in the literature, there is still confusion regarding its pathogenesis and clinical significance. Inflammation increases capillary permeability and escape of serum albumin, leading to expansion of interstitial space and increasing the distribution volume of albumin. The half-life of albumin has been shown to shorten, decreasing total albumin mass. These 2 factors lead to hypoalbuminemia despite increased fractional synthesis rates in plasma. Hypoalbuminemia, therefore, results from and reflects the inflammatory state, which interferes with adequate responses to events like surgery or chemotherapy, and is associated with poor quality of life and reduced longevity. Increasing or decreasing serum albumin levels are adequate indicators, respectively, of improvement or deterioration of the clinical state. In the interstitium, albumin acts as the main extracellular scavenger, antioxidative agent, and as supplier of amino acids for cell and matrix synthesis. Albumin infusion has not been shown to diminish fluid requirements, infection rates, and mortality in the intensive care unit, which may imply that there is no body deficit or that the quality of albumin "from the shelf" is unsuitable to play scavenging and antioxidative roles. Management of hypoalbuminaemia should be based on correcting the causes of ongoing inflammation rather than infusion of albumin. After the age of 30 years, muscle mass and function slowly decrease, but this loss is accelerated by comorbidity and associated with decreasing serum albumin levels. Nutrition support cannot fully prevent, but slows down, this chain of events, especially when combined with physical exercise.

Keywords: albumin infusion; albumin mass; albumin scavenger; capillary permeability; fractional synthesis rate albumin; growth; hypoalbuminemia; immune response; inflammation; interstitial space; pregnancy; puberty; serum albumin binding protein; serum albumin indicator of inflammatory activity; serum albumin risk factor; vascular endothelial growth factor.

Figure 1

Schematic representation of albumin flux, synthesis, and degradation. Solid arrows: transmembrane transport. Dashed arrows: Synthesis in liver; Degradation: intracellular proteolysis. Gain: Increase in total body albumin. Loss: decrease in total body albumin. Reduction: reducing oxidized total boyd albumin. The length of the black oval represents albumin mass, which is diminished due to more rapid intracellular breakdown in liver and proliferating cells. It is uncertain, whether cell volume is stable, while it is certain that cell solids are decreased in inflammatory conditions. Fluxes are represented by the size of arrows crossing the cell walls between liver, plasma, interstitium, and cell. They are larger (higher transmembrane flux) in inflammation than in health. It is possible that only a part of the flux entering the interstitium enters the cell, but rather (especially in inflammation after oxidation or scavenging) turns back to the plasma and is then reduced or degraded in the liver. The size of the quadrangles represents the volume of the different compartments and their grey intensity, the concentration of serum albumin. The size of cell mass in health and inflammatory states have been depicted to be identical although this is uncertain; cell mass may be increased, while cell solids are decreased. In health, net hepatic albumin output enters the plasma, and from there, it gets limited access to the interstitium at a low rate and, subsequently, to the cells. In these compartments, albumin serves as antioxidant and scavenger and to a very limited degree as supplier of amino acids for cell proliferation. Oxidized and otherwise damaged albumin is broken down in the liver or reduced for renewed antioxidation or scavenging. In inflammatory states, these functions are upregulated depending on the severity of the inflammatory insult, increasing fluxes from plasma to interstitium by increased capillary permeability. Albumin synthesis may increase, but oxidation of and scavenging by albumin will be upregulated. Similarly, albumin serves as intracellular amino acid donor for cell proliferation at a much higher rate than in health. Consequently, breakdown of albumin is higher in inflammatory states than in health, leading to decreased albumin mass despite potentially increased synthesis. These processes have been described in the literature, but have not been quantified. Transport into the cell as depicted in Figure 1 may be exaggerated and reentry of serum albumin from the interstitium into the plasma underestimated.