What are the causes of hypoalbuminemia?

Causes of Hypoalbuminemia

Hypoalbuminemia results from four primary pathophysiological mechanisms: decreased hepatic synthesis (most commonly from inflammation), increased protein loss, redistribution from intravascular to interstitial spaces, and hemodilution from fluid overload. 1, 2

Decreased Hepatic Synthesis

The most critical mechanism to understand is that inflammatory cytokines directly downregulate hepatic albumin synthesis, even when protein and caloric intake are adequate—this is the dominant cause in most hospitalized patients. 1, 2, 3

• Inflammation causes the same changes in serum protein levels as protein-energy malnutrition, making albumin primarily a marker of inflammation rather than nutritional status. 1
• C-reactive protein and other positive acute-phase proteins are inversely correlated with serum albumin levels, confirming inflammation as the driver. 1
• Critical illness and postoperative states result in reprioritization of hepatic protein synthesis away from albumin production, typically causing a 10-15 g/L decrease in albumin. 2

Liver dysfunction directly impairs synthetic capacity, particularly in cirrhosis and advanced liver disease. 2

Corticosteroid therapy increases net protein loss and drives catabolism, particularly in patients with Crohn's disease, while also causing anorexia and nausea that worsen nutritional status. 4, 2

Increased Protein Loss

Renal losses occur through:

• Nephrotic syndrome with severely increased albuminuria (≥300 mg/g uACR) presenting with hypoalbuminemia and edema. 1
• Peritoneal dialysis with albumin losses in dialysate, requiring higher protein intake (1.3 g/kg/day vs 1.2 g/kg/day for hemodialysis). 1, 2
• Hemodialysis through protein-leaking or medium cut-off membranes that increase albumin losses into dialysate. 5

Gastrointestinal losses include:

• Protein-losing enteropathy from gastrointestinal tract infiltration by neoplastic cells or inflammatory bowel disease. 2
• Advanced systemic mastocytosis with gastrointestinal infiltration causing worsening nutritional status. 2

Redistribution and Capillary Leak

Systemic inflammation increases capillary permeability, causing albumin transfer from vascular to interstitial compartments. 2

• Sepsis-induced capillary leak with increased fractional catabolic rate of albumin is a major contributor. 2, 3
• According to Starling's law, low plasma oncotic pressure related to hypoalbuminemia induces fluid shift from intravascular to interstitial space, facilitating cardiogenic pulmonary edema. 6

Hemodilution

Fluid overload decreases serum albumin concentration through dilutional effects. 1

• Over-hydration is a common feature in dialysis patients that contributes to hypoalbuminemia. 1
• Heart failure patients commonly develop hypoalbuminemia partly from hemodilution. 6, 7

Protein-Energy Malnutrition

While often overemphasized, true nutritional deficiency with sustained decrease in dietary protein and energy intake causes only modest falls in serum albumin. 1

• Protein-energy malnutrition is associated with higher rates of morbidity and mortality, but is rarely the sole cause of hypoalbuminemia. 1
• Malnutrition combined with inflammation creates a vicious cascade where inflammation induces anorexia and reduces effective use of dietary protein. 3

Disease-Specific Contexts

Chronic kidney disease and dialysis combine multiple mechanisms: inflammation, inadequate nutrition, dialysis-related losses, and metabolic acidosis. 1, 2

Heart failure causes hypoalbuminemia through malnutrition, inflammation, cachexia, hemodilution, liver dysfunction, protein-losing enteropathy, and increased transcapillary escape rate. 6, 7

Cirrhosis impairs hepatic synthetic capacity while causing portal hypertension and ascites. 8

Sepsis combines decreased synthesis from inflammatory cytokines with increased capillary leak and elevated fractional catabolic rate. 8, 3

Non-Nutritional Contributing Factors

Age: Older patients tend to have lower albumin levels and higher rates of comorbidities that compound hypoalbuminemia risk, including renal failure, malignancies, and frailty. 1

Comorbidities such as cardiovascular disease and diabetes mellitus contribute through multiple mechanisms. 1

Metabolic acidosis influences albumin metabolism, particularly in kidney disease. 1, 2

Longer hospital stays are independently associated with hypoalbuminemia development, reflecting disease severity and heightened inflammation. 1

Critical Pitfall to Avoid

The most common error is assuming hypoalbuminemia is solely due to malnutrition when inflammation is actually the primary driver. 1 Albumin is a negative acute-phase reactant that decreases during inflammation regardless of nutritional status, and failing to recognize this leads to inappropriate nutritional interventions when treating the underlying inflammatory process should be the priority. 9, 1, 3