What conditions are associated with decreased haptoglobin levels?

Conditions Associated with Decreased Haptoglobin

Decreased haptoglobin is primarily a marker of hemolysis (both intravascular and extravascular) and liver cirrhosis, with all types of hemolytic disease causing marked depletion regardless of the site of red cell destruction. 1

Primary Causes

Hemolytic Conditions

• All types of hemolytic disease cause markedly decreased plasma haptoglobin levels, without significant differences between intravascular versus predominantly extravascular hemolysis 1
• Haptoglobin depletion occurs because it binds free hemoglobin from lysed red cells, and becomes depleted in the presence of large amounts of free hemoglobin 2
• The complex of haptoglobin with hemoglobin is metabolized in the hepatic reticuloendothelial system 3

Liver Disease

• Liver cirrhosis is associated with diminished haptoglobin values due to decreased hepatic synthesis 1
• Haptoglobin levels normalize after liver transplantation, confirming the hepatic production defect 1
• In chronic viral hepatitis C, haptoglobin serum levels are significantly lower than controls (0.56 ± 0.36 versus 0.90 ± 0.35 g/L, P < 0.001), even in patients without cirrhosis 4
• Haptoglobin levels correlate negatively with fibrosis scores and periportal necrosis in hepatitis C patients 4

Myeloproliferative Disorders

• Myelofibrosis shows low haptoglobin (<32 mg/dL) in approximately 33% of patients 5
• Factors strongly correlating with decreased haptoglobin in myelofibrosis include high JAK2 allele burden and ongoing treatment with JAK inhibitors 5
• This decrease does not associate with low hemoglobin levels, positive Coombs test, or abnormal liver function tests 5

Important Clinical Distinctions

Conditions NOT Associated with Decreased Haptoglobin

• Anemia from bone marrow failure shows normal haptoglobin levels 1
• Acute gastrointestinal or chronic diffuse blood loss maintains normal haptoglobin 1
• End-stage kidney disease does not decrease haptoglobin 1
• Patients with strongly positive direct antiglobulin test or high cold agglutinin titer but no evidence of active hemolysis have normal haptoglobin values 1

Effect of Inflammation

• Inflammation and acute phase responses markedly increase haptoglobin levels as it is an acute-phase protein 1, 3
• However, in patients with both hemolysis and concomitant acute-phase response, hemolysis-dependent haptoglobin depletion is not attenuated—the hemolysis effect predominates 1
• This makes haptoglobin a reliable marker for hemolysis even in the presence of inflammation 1

Clinical Pitfalls and Interpretation

False Positives (Inappropriately Low Values)

• Improper specimen preparation 2
• Cirrhosis (decreased production rather than hemolysis) 1, 2
• Elevated estrogen states 2
• Hemodilution 2

False Negatives (Inappropriately Normal/High Values)

• Hypersplenism 2
• Medications such as androgens and corticosteroids 2
• Concomitant inflammation may mask mild hemolysis, though significant hemolysis still depletes haptoglobin 1

Diagnostic Reliability

Plasma haptoglobin depletion is a reliable marker for the instant diagnosis of accelerated red cell destruction irrespective of the site of hemolysis or the presence of inflammation. 1 The capacity to predict hemolysis is limited only in patients with liver cirrhosis where decreased haptoglobin production is the primary mechanism 1.