What are the causes of hypoalbuminemia?

Causes of Hypoalbuminemia

Hypoalbuminemia is caused by multiple factors including inflammation, malnutrition, protein losses, and fluid overload, with inflammation often being the predominant factor in many clinical scenarios. 1

Major Causes of Hypoalbuminemia

Inflammation

• Inflammation is a primary driver of hypoalbuminemia through multiple mechanisms 1:
  • Inflammatory cytokines (TNF-α, IL-6) directly downregulate albumin synthesis in the liver 1
  • Inflammation increases the fractional catabolic rate of albumin 2
  • Acute phase response diverts hepatic protein synthesis away from albumin production 1
• C-reactive protein and other positive acute-phase proteins are inversely correlated with serum albumin levels 1

Nutritional Factors

• Protein-energy malnutrition reduces albumin synthesis due to inadequate protein substrate 1
• Reduced caloric intake contributes to decreased albumin production 2
• Chronic disease states often feature both inflammation and anorexia, creating a vicious cycle 2
• Inadequate dietary protein intake can independently lower serum albumin, though this effect is often overshadowed by inflammation 1

External Protein Losses

• Proteinuria/albuminuria in kidney disease 1
• Peritoneal dialysate losses in patients on peritoneal dialysis 1
• Protein-losing enteropathy in gastrointestinal disorders 1
• Extensive burns or wounds with protein-rich exudate 3
• Sequestration of protein-rich fluids in conditions like peritonitis, pancreatitis, mediastinitis, and cellulitis 3

Fluid Status Abnormalities

• Hemodilution from fluid overload can artificially lower measured albumin concentration 1
• Over-hydration, common in dialysis patients, contributes to hypoalbuminemia 1

Decreased Production

• Liver dysfunction or failure reduces albumin synthesis capacity 3
• End-stage renal disease affects protein metabolism and albumin synthesis 4
• Aging is associated with reduced albumin synthesis 1

Increased Vascular Permeability

• Sepsis and systemic inflammatory response syndrome increase transcapillary escape rate of albumin 5
• Critical illness can cause redistribution of albumin from intravascular to extravascular space 2

Clinical Context-Specific Causes

In Chronic Kidney Disease

• Combination of inflammation, malnutrition, and protein losses 1
• Dialysis-related protein losses and inflammation 4
• Metabolic acidosis affecting protein metabolism 1

In Heart Failure

• Hemodilution from fluid retention 5
• Cardiac cachexia and associated inflammation 5
• Reduced hepatic perfusion affecting albumin synthesis 5
• Increased intestinal wall edema potentially leading to protein-losing enteropathy 5

In Liver Disease

• Decreased synthetic function of the liver 3
• Portal hypertension leading to protein-losing enteropathy 6

In Critical Illness

• Capillary leak syndrome causing redistribution of albumin 2
• Hypermetabolic state with increased protein catabolism 2
• Inflammatory response to injury or infection 1

Clinical Implications

• Hypoalbuminemia is a powerful predictor of mortality in patients with chronic diseases 4, 2
• Low serum albumin at dialysis initiation or during maintenance dialysis indicates increased mortality risk 1
• Hypoalbuminemia predicts cardiovascular events in chronic kidney disease patients 1
• The presence of hypoalbuminemia should prompt evaluation for both inflammation and malnutrition 1

Diagnostic Approach

• Measure inflammatory markers (CRP, α1-acid glycoprotein) when hypoalbuminemia is detected 1
• Evaluate nutritional status including dietary protein and calorie intake 1
• Assess for potential sources of protein loss (urine, dialysate, GI tract) 1
• Consider fluid status and potential hemodilution effects 1