What is haptoglobin?

Haptoglobin: Function and Clinical Significance

Haptoglobin is a plasma glycoprotein primarily produced in the liver that binds free hemoglobin released during hemolysis, preventing oxidative damage to tissues and facilitating hemoglobin clearance from circulation. 1

Structure and Genetics

• Haptoglobin is a tetrameric protein composed of two α/β dimers connected by disulfide bridges 2
• In humans, the haptoglobin gene is polymorphic with three major phenotypes:
  • Hp 1-1 (homozygous): Most effective at binding free hemoglobin and suppressing inflammation
  • Hp 2-2 (homozygous): Least biologically active
  • Hp 2-1 (heterozygous): Moderately active 3

Primary Functions

1. Hemoglobin binding: Captures free hemoglobin released during hemolysis, preventing:

   • Kidney injury
   • Iron loss
   • Oxidative damage to tissues 1, 3

2. Immune modulation:

   • Acts as an immunosuppressor of lymphocyte function
   • Modulates helper T-cell type 1 and type 2 (Th1/Th2) balance 3

3. Acute phase reactant:

   • Increases during inflammation, infection, and malignancy
   • Part of the body's response to tissue injury 4, 2

Clinical Significance

Diagnostic Value

• Hemolysis detection: Low haptoglobin is a sensitive marker for hemolytic processes 1

  • When free hemoglobin is released during hemolysis, haptoglobin binds to it and the complex is rapidly cleared by the liver, depleting haptoglobin levels
  • Decreased haptoglobin with elevated lactate dehydrogenase (LDH) and bilirubin confirms hemolysis 1

• Inflammatory marker: Elevated haptoglobin indicates acute phase response in various inflammatory conditions 1

Interpretation of Haptoglobin Levels

• Decreased levels indicate:

  • Hemolytic conditions (intravascular or extravascular hemolysis)
  • Liver disease (decreased production)
  • Malnutrition 1, 2

• Elevated levels indicate:

  • Inflammatory conditions
  • Infections
  • Malignancies
  • Tissue damage 1, 2

• Normal or high haptoglobin effectively rules out active hemolysis 1

Clinical Applications

Hemolytic Conditions Assessment

• In suspected hemolysis, haptoglobin should be measured alongside LDH and bilirubin 1
• In paravalvular leaks after valve surgery, haptoglobin measurement is part of routine follow-up to detect hemolysis 5
• Very low haptoglobin with hemoglobinuria and hemosiderinuria suggests intravascular hemolysis 1

Disease Associations

• Haptoglobin phenotypes may be associated with susceptibility to various conditions:
  • Cardiovascular diseases
  • Diabetes
  • Infectious diseases (tuberculosis, HIV, malaria)
  • Cancer 3, 2

Pitfalls in Interpretation

• False negatives (normal haptoglobin despite hemolysis):

  • Concurrent inflammatory conditions (may mask hemolysis by elevating baseline haptoglobin)
  • Medications like androgens and corticosteroids 6

• False positives (low haptoglobin without hemolysis):

  • Liver disease (decreased production)
  • Improper specimen preparation
  • Hemodilution 6

Clinical Approach

When evaluating haptoglobin levels:

1. Interpret in conjunction with other laboratory findings (LDH, bilirubin, reticulocyte count)
2. Consider the patient's clinical context and inflammatory status
3. Follow up with appropriate additional testing based on suspected diagnosis 1