Haptoglobin: Function and Clinical Significance
Haptoglobin is a blood plasma glycoprotein that binds free hemoglobin to prevent oxidative damage and kidney injury following hemolysis, while also functioning as an acute phase protein that increases during inflammation. 1
Biochemical Properties and Function
Haptoglobin is primarily synthesized in the liver and has several critical biological functions:
Primary function: Binds free hemoglobin released during hemolysis, preventing its toxic effects 2
- Forms stable Hb-Hp complexes that are rapidly cleared by CD163 receptors on monocytes/macrophages 3
- Prevents renal damage and iron loss that would otherwise occur from free hemoglobin filtration
- Acts as an antioxidant by preventing hemoglobin-mediated oxidative reactions
Acute phase protein: Levels increase during inflammation, infection, tissue damage, or malignancy 1
Immunomodulatory effects: Functions as an immunosuppressor of lymphocyte function and modulates helper T-cell balance 4
Genetic Polymorphism
In humans, haptoglobin exists in three major phenotypes with different biological activities 4:
- Hp 1-1: Most effective at binding free hemoglobin and suppressing inflammatory responses
- Hp 2-2: Least biologically active
- Hp 2-1: Intermediate activity
These phenotypes are determined by inherited allelic variants and may influence individual predisposition to various diseases.
Clinical Applications
Diagnostic Value
Hemolysis detection: Decreased haptoglobin is a sensitive marker of hemolysis as it becomes depleted when binding free hemoglobin 2
- Normal or elevated levels effectively rule out active hemolysis 1
Component of liver fibrosis panels: Used in combination with other biomarkers in non-invasive assessment of liver fibrosis 5
- Included in FibroTest algorithm along with α2-macroglobulin, apolipoprotein A1, total bilirubin, GGT, age and sex 5
Inflammatory marker: Elevated levels indicate acute phase response in various inflammatory conditions 1
Interpretation Challenges
False negatives for hemolysis can occur with:
- Inflammation (as haptoglobin increases as an acute phase reactant)
- Medications such as androgens and corticosteroids
- Hypersplenism 2
False positives (artificially low levels) can occur with:
- Improper specimen preparation
- Cirrhosis
- Elevated estrogen states
- Hemodilution 2
Clinical Pearls
When interpreting haptoglobin levels, always consider the patient's inflammatory status, as inflammation can mask hemolysis by elevating baseline haptoglobin levels 1
In hemolytic conditions, haptoglobin is typically the first marker to become abnormal and the last to normalize 2
For comprehensive hemolysis evaluation, haptoglobin should be measured alongside other markers like LDH, bilirubin, and reticulocyte count 5
Post-translational modifications of haptoglobin, particularly glycosylation patterns, are being studied as potential biomarkers for various pathological conditions including malignancies 6, 7