What are the causes of hypoalbuminemia?

What Causes Hypoalbuminemia?

Hypoalbuminemia results from four primary mechanisms: inflammation-driven suppression of hepatic synthesis (the most common cause in hospitalized patients), external protein losses (renal, gastrointestinal, or dialysate), decreased hepatic synthetic capacity (liver disease), and hemodilution from fluid overload. 1, 2, 3

Primary Mechanisms of Hypoalbuminemia

1. Inflammation and Acute Phase Response (Most Common in Hospitalized Patients)

• Inflammatory cytokines directly downregulate hepatic albumin synthesis even when protein and caloric intake are adequate, making inflammation the predominant cause of hypoalbuminemia in acute illness. 1, 2
• Albumin functions as a negative acute-phase reactant, meaning its levels decrease during any inflammatory response regardless of nutritional status. 4, 1
• In hospitalized patients, hypoalbuminemia typically reflects systemic inflammation and disease severity rather than malnutrition. 1
• The presence of acute or chronic inflammation limits the specificity of serum albumin as a nutritional marker. 4

2. External Protein Losses

Renal Losses:

• Nephrotic syndrome causes severely increased albuminuria (≥300 mg/g or ≥30 mg/mmol on urine albumin-to-creatinine ratio) with associated edema and hyperlipidemia. 4, 2
• Peritoneal dialysis leads to ongoing protein losses into the dialysate, contributing to hypoalbuminemia in this population. 2
• Hemodialysis can cause albumin loss through the dialyzer membrane, particularly with newer medium cut-off membranes, with approximately 60% of HD patients having albumin concentrations <4.0 g/dL. 5

Gastrointestinal Losses:

• Protein-losing enteropathy from inflammatory bowel disease, intestinal lymphangiectasia, or GI malignancy causes significant albumin loss. 2
• Inflammatory bowel disease contributes through both direct protein loss and inflammatory cytokine effects. 2

3. Decreased Hepatic Synthesis

• Chronic liver disease or cirrhosis impairs synthetic capacity even in early stages, leading to progressive hypoalbuminemia. 2, 6
• Liver dysfunction represents a primary cause of reduced albumin production independent of other factors. 7, 3

4. Hemodilution and Volume Overload

• Hemodilution from excess crystalloid administration or volume overload commonly contributes to hypoalbuminemia by diluting the existing albumin pool. 2, 3
• This mechanism is frequently overlooked but represents a significant contributor in hospitalized patients receiving intravenous fluids. 2

5. Malnutrition (Less Common Than Previously Thought)

• Sustained decrease in dietary protein and energy intake causes only modest albumin decline over time. 4, 2
• In the absence of inflammation and/or dilution with crystalloid, development of hypoalbuminemia in response to malnutrition alone is slow compared with the rapid change caused by inflammatory redistribution or dilution. 3
• Malnutrition alone rarely causes significant hypoalbuminemia without concurrent inflammation or other factors. 1

Disease-Specific Contexts

Chronic Kidney Disease and Dialysis

• Multifactorial causes include inflammation, inadequate nutrition, dialysis losses, and metabolic alterations resulting in protein-energy wasting. 4, 2, 5
• Approximately 60% of maintenance hemodialysis patients have albumin <4.0 g/dL. 5

Heart Failure

• Hypoalbuminemia results mainly from the malnutrition-inflammation complex syndrome, hemodilution, liver dysfunction, protein-losing enteropathy, increased transcapillary escape rate, and nephrotic syndrome. 7, 8
• Low plasma oncotic pressure from hypoalbuminemia facilitates cardiogenic pulmonary edema according to Starling's law. 7

Sepsis and Critical Illness

• Inflammatory cytokine release causes rapid suppression of hepatic albumin synthesis. 1
• Increased capillary permeability leads to transcapillary albumin leak into the interstitial space. 3

Critical Pitfalls to Avoid

• Do not assume hypoalbuminemia equals malnutrition—inflammation is often the primary driver even with adequate nutrition, particularly in hospitalized patients. 1, 2
• Missing occult inflammation leads to misdiagnosis, as albumin decreases during any inflammatory response. 2
• Overlooking fluid status causes misinterpretation, as hemodilution from volume overload commonly contributes. 2
• Ignoring medication effects such as corticosteroids, which increase protein catabolism and worsen hypoalbuminemia. 2
• Not checking for proteinuria can lead to missed diagnosis of nephrotic syndrome. 2

Diagnostic Approach to Identify the Cause

• Measure C-reactive protein (CRP) first to determine if hypoalbuminemia is inflammation-driven rather than from protein loss or malnutrition. 1, 2
• Obtain urine albumin-to-creatinine ratio (uACR) to detect renal protein loss and identify nephrotic syndrome. 1, 2
• Check comprehensive metabolic panel to assess liver function (PT/INR, bilirubin) and kidney function (creatinine, BUN). 1, 2
• Perform stool studies if diarrhea is present to evaluate for protein-losing enteropathy or infectious causes. 2
• Assess fluid status and recent crystalloid administration to identify hemodilution. 2