Medical Disclaimer
  • For Educational Purposes Only: This content is intended for educational reference and should not be used for clinical decision-making.
  • Not a Substitute for Professional Judgment: Always consult your local protocols, institutional guidelines, and supervising physicians.
  • Accuracy Not Guaranteed: While all content has been prepared to the best of my knowledge and ability, errors or omissions may exist.
  • Verify Before Acting: Users are responsible for verifying information through authoritative sources before any clinical application.
AI Assistance Notice
The clinical content and references are curated and reviewed by myself; however, AI was used to assist in organizing, paraphrasing, and formatting the information presented.
Quick Reference
  • Normal Range: 6.0-8.3 g/dL
  • SI Units: 60-83 g/L
  • Normal A/G Ratio: 1.2-2.2
  • Protein Gap (Normal): 2.5-3.5 g/dL
  • Sample Type: Serum
  • Key Point: Total of albumin + globulins; interpret with albumin for meaningful assessment

Test Description

What is Total Protein?

Total protein measures the combined concentration of all proteins in the blood serum, primarily consisting of albumin and globulins.

What Information Does It Provide?

  • Liver synthetic function
  • Nutritional status
  • Immune system activity

The Two Major Fractions

Total protein is composed of:

  • Albumin (60%):
    • Normal range: 3.5-5.5 g/dL
    • Synthesized exclusively by the liver
    • Maintains oncotic pressure and transports substances
    • Marker of liver synthetic function and nutritional status
  • Globulins (40%):
    • Normal range: 2.0-3.5 g/dL
    • Includes alpha-1, alpha-2, beta, and gamma globulins (immunoglobulins)
    • Produced by the liver and immune system
Total Protein Relationship
Total Protein = Albumin + Globulins

The globulin concentration is calculated by subtracting albumin from total protein. This calculated value is used to determine the albumin/globulin (A/G) ratio.

Globulin Fractions

Serum protein electrophoresis (SPEP) can separate globulins into specific fractions:

  • Alpha-1 globulins: Include alpha-1 antitrypsin, alpha-1 acid glycoprotein (acute phase reactants)
  • Alpha-2 globulins: Include haptoglobin, ceruloplasmin, alpha-2 macroglobulin
  • Beta globulins: Include transferrin, complement components, beta-lipoproteins
  • Gamma globulins: Immunoglobulins (IgG, IgA, IgM, IgD, IgE) produced by plasma cells

Sample Collection

Total protein is typically measured from a serum sample obtained by standard venipuncture. The test is performed using automated chemistry analyzers with biuret or dye-binding methods. Patient position and prolonged tourniquet application can affect results.

Normal Ranges

Total protein levels are relatively consistent across adult populations, with minor variations based on age and hydration status. Reference ranges may vary slightly between laboratories depending on the assay method used.

Swipe to see more
Population Normal Range (g/dL) SI Units (g/L)
Adults (general) 6.0-8.3 60-83
Albumin Component 3.5-5.5 35-55
Globulin Component 2.0-3.5 20-35
A/G Ratio 1.2-2.2 1.2-2.2
Protein Gap (TP - Albumin) 2.5-3.5 25-35

Important Considerations

  • Position effects: Total protein increases by approximately 0.3-0.5 g/dL when standing versus lying down due to fluid shifts
  • Tourniquet time: Prolonged tourniquet application (>1 minute) can increase protein concentration by 5-10% due to hemoconcentration
  • Hydration status: Dehydration increases total protein, while overhydration (IV fluids) decreases it
  • Pregnancy: Total protein decreases in pregnancy due to hemodilution and increased blood volume
  • Age variations: Elderly patients may have slightly lower total protein due to decreased albumin synthesis
Clinical Significance

Elevated Total Protein (Hyperproteinemia)

Elevated total protein is less common than low protein and is typically due to increased globulin production, dehydration, or monoclonal gammopathies. True elevations usually require further investigation with serum protein electrophoresis.

Dehydration and Hemoconcentration

  • Volume depletion: Decreased plasma volume concentrates all proteins proportionally
  • Severe vomiting or diarrhea: Leads to fluid loss and hemoconcentration
  • Inadequate fluid intake: Particularly in elderly or critically ill patients
  • Diabetic ketoacidosis: Osmotic diuresis causes fluid loss and relative hyperproteinemia

Chronic Inflammatory States

  • Chronic infections: Tuberculosis, osteomyelitis, endocarditis cause increased immunoglobulin production
  • Autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis
  • Chronic liver disease: Cirrhosis with portal hypertension leads to polyclonal gammopathy
  • Inflammatory bowel disease: Crohn's disease and ulcerative colitis increase acute phase proteins

Monoclonal Gammopathies (Most Critical)

  • Multiple myeloma: Malignant proliferation of plasma cells producing monoclonal immunoglobulin (M-protein spike on SPEP)
  • Waldenström macroglobulinemia: Lymphoplasmacytic lymphoma producing IgM monoclonal protein
  • MGUS: Monoclonal gammopathy of undetermined significance - premalignant condition requiring monitoring
  • Light chain disorders: May not elevate total protein if kidney dysfunction causes protein loss

Decreased Total Protein (Hypoproteinemia)

Low total protein is more common clinically and can result from decreased synthesis (liver disease, malnutrition), increased loss (renal, gastrointestinal), or dilution (fluid overload). The pattern of albumin and globulin changes helps identify the underlying cause.

Decreased Synthesis - Liver Disease

  • Chronic liver disease/cirrhosis: Impaired hepatic synthesis of albumin; albumin falls first and most dramatically
  • Acute hepatic failure: Severe hepatocellular injury reduces protein synthesis capacity
  • Hepatocellular carcinoma: Advanced disease impairs synthetic function
  • Alcoholic liver disease: Chronic alcohol consumption damages hepatocytes and reduces albumin production

Decreased Synthesis - Malnutrition

  • Protein-calorie malnutrition: Kwashiorkor (protein deficiency) and marasmus (calorie deficiency)
  • Malabsorption syndromes: Celiac disease, Crohn's disease, short bowel syndrome
  • Chronic illness: Cancer cachexia, COPD, heart failure reduce protein intake and increase catabolism
  • Eating disorders: Anorexia nervosa, severe dietary restriction

Protein Loss - Renal

  • Nephrotic syndrome: Glomerular damage allows massive proteinuria (>3.5 g/day), primarily albumin loss
  • Diabetic nephropathy: Progressive glomerular damage leads to increasing proteinuria
  • Glomerulonephritis: Inflammatory damage to glomeruli increases permeability
  • Amyloidosis: Protein deposition in kidneys causes nephrotic-range proteinuria

Protein Loss - Gastrointestinal

  • Protein-losing enteropathy: Inflammatory bowel disease, intestinal lymphangiectasia
  • Severe burns: Extensive protein loss through damaged skin and increased catabolism
  • Chronic diarrhea: Protein lost in stool from mucosal inflammation or infection
  • Exudative ascites: Protein-rich fluid accumulation in peritoneal cavity

Dilutional Hypoproteinemia

  • Intravenous fluid administration: Large volume crystalloid resuscitation dilutes serum proteins
  • SIADH: Syndrome of inappropriate antidiuretic hormone causes water retention and dilution
  • Congestive heart failure: Fluid retention dilutes protein concentration
  • Pregnancy: Physiologic increase in plasma volume causes relative hypoproteinemia
Interpretation Guidelines

Albumin/Globulin (A/G) Ratio

The A/G ratio provides valuable diagnostic information by comparing the two major protein fractions. The ratio is calculated by dividing albumin by globulins (total protein minus albumin).

A/G Ratio Calculation
A/G Ratio = Albumin ÷ (Total Protein - Albumin)

Normal range: 1.2-2.2. Values outside this range suggest disproportionate changes in albumin or globulin fractions.

Swipe to see more
A/G Ratio Interpretation Common Causes
Low (<1.2) Decreased albumin or increased globulins Chronic liver disease, nephrotic syndrome, myeloma, chronic inflammation
Normal (1.2-2.2) Proportional protein fractions Normal state or proportional changes (dehydration, dilution)
High (>2.2) Increased albumin or decreased globulins Immunodeficiency, leukemia, genetic agammaglobulinemia (rare)

Protein Gap Analysis

The protein gap (calculated globulin level) is obtained by subtracting albumin from total protein. An elevated protein gap (>3.5 g/dL) suggests increased globulin production and warrants further investigation with serum protein electrophoresis (SPEP).

When Protein Gap is Elevated (>3.5 g/dL)

  • Order SPEP: To identify monoclonal vs polyclonal gammopathy
  • Monoclonal pattern (M-spike): Suggests myeloma, MGUS, Waldenström's - requires hematology referral
  • Polyclonal pattern: Diffuse elevation of gamma globulins suggests chronic inflammation, infection, or autoimmune disease
  • Consider UPEP: Urine protein electrophoresis to detect light chains (Bence Jones protein)

Pattern Recognition

Swipe to see more
Pattern Total Protein Albumin A/G Ratio Typical Cause
Liver Disease Low-Normal Low Low Decreased synthesis of albumin > globulins
Nephrotic Syndrome Low Very Low Low Selective loss of albumin in urine
Multiple Myeloma High-Normal Low-Normal Low Monoclonal protein production (check SPEP)
Chronic Inflammation Normal-High Normal-Low Low Polyclonal globulin increase (check SPEP)
Dehydration High High Normal Hemoconcentration (proportional increase)
IV Fluid Overload Low Low Normal Dilution (proportional decrease)

When to Order Additional Testing

Consider serum protein electrophoresis (SPEP) when:

  • Protein gap >3.5 g/dL (calculated globulins elevated)
  • Unexplained elevation in total protein without dehydration
  • Low A/G ratio (<1.0) without obvious cause
  • Clinical suspicion of multiple myeloma (anemia, bone pain, renal insufficiency, hypercalcemia - CRAB criteria)
  • Recurrent infections suggesting immunodeficiency or immunoglobulin disorder

Consider urine protein electrophoresis (UPEP) when:

  • SPEP shows monoclonal protein (to detect Bence Jones protein/light chains)
  • Clinical suspicion of light chain disease despite normal SPEP
  • Nephrotic-range proteinuria to characterize protein type
Interfering Factors

Factors That Increase Total Protein

  • Patient position: Standing or sitting increases total protein by 0.3-0.5 g/dL compared to lying down due to fluid shift from intravascular to interstitial space
  • Prolonged tourniquet application: Venous stasis for >1 minute causes hemoconcentration and can increase protein by 5-10%
  • Dehydration: Any cause of volume depletion concentrates serum proteins proportionally
  • Exercise: Strenuous exercise before blood draw can transiently increase protein levels
  • Medications: Anabolic steroids, growth hormone, insulin (increase protein synthesis)

Factors That Decrease Total Protein

  • IV fluid administration: Crystalloid resuscitation dilutes serum proteins; can be significant in critically ill patients
  • Recumbent position: Lying flat for extended periods (hospitalized patients) causes fluid shift and dilution
  • Pregnancy: Hemodilution from increased blood volume physiologically decreases total protein
  • Medications: Drugs causing protein loss or decreased synthesis
    • Estrogens (decrease albumin synthesis)
    • Oral contraceptives (similar to estrogen effect)
    • Nephrotoxic drugs (NSAIDs, aminoglycosides causing proteinuria)
    • Chemotherapy agents (may suppress hepatic protein synthesis)
  • Hemolysis: Can interfere with some assay methods, causing falsely low results

Preanalytical Variables

  • Sample handling: Delayed processing or improper storage can affect results
  • Lipemia: Severe hypertriglyceridemia can interfere with biuret method, causing falsely elevated results
  • Icterus: Severe hyperbilirubinemia may interfere with certain assays
  • Paraproteins: Very high monoclonal proteins can cause assay interference

Assay Method Differences

Total protein can be measured by different methods:

  • Biuret method: Most common, measures peptide bonds - considered reference method
  • Dye-binding methods: Coomassie blue or other dyes - may give slightly different results than biuret
  • Refractometry: Less commonly used, can be affected by other dissolved substances

Reference ranges should be method-specific. Results from different methods may not be directly comparable.

Clinical Pearls
  • "Always interpret total protein WITH albumin": Total protein in isolation has limited value. The relationship between total protein, albumin, and calculated globulins (protein gap and A/G ratio) provides the diagnostic information. A normal total protein can hide significant abnormalities in individual fractions.
  • The "60/40 rule": Albumin normally comprises ~60% of total protein, globulins ~40%. This creates the normal A/G ratio of 1.2-2.2. When this ratio is disrupted, investigate why one fraction is disproportionately affected.
  • Protein gap >4 g/dL = SPEP: When calculated globulins (total protein minus albumin) exceed 4.0 g/dL, there's likely a significant increase in immunoglobulins. Order SPEP to distinguish between monoclonal (M-spike suggesting myeloma/MGUS) and polyclonal (broad-based elevation suggesting inflammation) patterns.
  • Don't miss dilutional hypoproteinemia: In hospitalized patients receiving IV fluids or those with heart failure/SIADH, low total protein may simply reflect dilution. Check trends before and after fluid administration, and correlate with hematocrit to identify hemodilution.
  • Nephrotic syndrome triad: Look for the pattern of very low albumin + low total protein + normal-to-low A/G ratio. This selective loss of albumin (smaller protein preferentially filtered) is the hallmark of glomerular disease. Check urine protein, lipid panel (hyperlipidemia), and look for edema.
  • Cirrhosis creates a paradox: Advanced liver disease shows low albumin (decreased synthesis) but may have normal or even elevated globulins (polyclonal increase from gut antigen exposure and immune dysregulation). Result: low-normal total protein with low A/G ratio. SPEP shows diffuse polyclonal pattern.
  • "CRAB" criteria for myeloma screening: When elevated protein gap or M-spike is found, evaluate for myeloma complications: Calcium (hypercalcemia), Renal dysfunction, Anemia, Bone lesions. Add quantitative immunoglobulins, free light chains, and skeletal survey.
  • Position matters more than you think: Blood drawn with patient sitting versus lying can differ by 0.5 g/dL for total protein. For trending values in hospitalized patients, note whether labs were drawn from bedridden patient versus patient sitting in chair or standing.
  • Tourniquet time = hemoconcentration: If tourniquet is left on for several minutes during difficult venipuncture, protein can be falsely elevated by 5-10%. If total protein seems unexpectedly high, consider repeating with optimal technique.
  • High total protein + normal albumin = hyperglobulinemia: When total protein is elevated but albumin is normal, globulins must be increased. This narrows the differential to dehydration (both up proportionally - check albumin), chronic inflammation (polyclonal), or monoclonal gammopathy (order SPEP immediately).
  • MGUS is common in elderly: Monoclonal gammopathy of undetermined significance (MGUS) affects ~3% of people over 50 and ~5% over 70. Small M-spike on SPEP with protein gap 3.5-4.5 g/dL may represent MGUS. Requires monitoring as ~1% per year progress to myeloma.
  • Albumin falls before total protein in malnutrition: In protein-calorie malnutrition, albumin (shorter half-life marker of visceral protein stores) decreases before total protein becomes obviously low. Low-normal total protein with disproportionately low albumin suggests early nutritional deficiency.
  • Burns cause dramatic protein loss: Extensive burns (>20% BSA) lose significant protein through exudative wounds and have increased catabolism. Total protein and albumin fall rapidly. Aggressive nutritional support is critical, but expect persistently low values during acute phase.
  • Pregnancy reference ranges differ: Normal pregnancy causes physiologic decrease in total protein and albumin due to expanded blood volume (hemodilution). Don't overcall hypoproteinemia in pregnant patients - use pregnancy-specific reference ranges (total protein may be 5.5-7.5 g/dL in third trimester).
  • Isolated low globulins are rare: If total protein is low but albumin is normal, calculated globulins must be low. This is uncommon and suggests immunodeficiency (primary or secondary), protein-losing enteropathy affecting globulins, or assay error. Verify with repeat testing and immunoglobulin quantification.
References
  1. Kratz, A., Ferraro, M., Sluss, P. M., & Lewandrowski, K. B. (2004). Laboratory reference values. New England Journal of Medicine, 351, 1548-1564.
  2. Lee, M. (Ed.). (2009). Basic skills in interpreting laboratory data. Ashp.
  3. Farinde, A. (2021). Lab values, normal adult: Laboratory reference ranges in healthy adults. Medscape. https://emedicine.medscape.com/article/2172316-overview?form=fpf
  4. Nickson, C. (n.d.). Critical Care Compendium. Life in the Fast Lane • LITFL. https://litfl.com/ccc-critical-care-compendium/
  5. Farkas, Josh MD. (2015). Table of Contents - EMCrit Project. EMCrit Project. https://emcrit.org/ibcc/toc/
Back to Liver Panel All Lab Values