Hemoglobin H Inclusions: Associated Conditions
Hemoglobin H (HbH) inclusions are primarily associated with alpha-thalassemia, specifically HbH disease, which results from severe reduction in alpha-globin chain production affecting three of the four alpha-globin genes. 1, 2
Primary Association: Alpha-Thalassemia and HbH Disease
HbH disease is the most common form of thalassemia intermedia and represents the condition most strongly associated with HbH inclusions. 2 The disease occurs when alpha-globin chain production is reduced to approximately the output of a single alpha-globin gene, leading to formation of HbH (β₄ tetramers) due to the relative excess of beta chains. 1
Genetic Mechanisms
Deletional forms: Most commonly result from double heterozygosity for alpha⁰-thalassemia (deletion of both linked alpha-globin genes) combined with alpha⁺-thalassemia (single alpha-globin gene deletion), producing the --/-α genotype. 2
Non-deletional forms: Occur from interactions between alpha⁰-thalassemia with non-deletional mutations (α^T^α or α^T^) or with abnormal hemoglobins such as Hb Constant Spring, Hb Paksé, Hb Quong Sze, and Hb Pak Num Po. 2 These non-deletional mutations typically cause more severe clinical expression with greater anemia, significant splenomegaly, and higher transfusion requirements. 2, 3
Detection in Alpha-Thalassemia Carriers
HbH inclusions can be detected in heterozygous alpha-thalassemia carriers (alpha-thalassemia trait), though they are rare. 4 The majority of carriers investigated—including those with deletion of a single or two alpha-globin genes and those with non-deletion lesions—have rare red blood cells with HbH inclusions, with no significant difference in frequency related to the specific alpha-globin genotype. 4
Diagnostic Utility
Diagnosis of HbH disease involves hemoglobin electrophoresis showing the presence of HbH and peripheral blood smear examination revealing HbH inclusion bodies. 1
Parents of affected individuals can be screened by evaluating mean cell volume (MCV), which will be <80 fL in thalassemia carriers. 1
Rare Association: Alpha-Thalassemic Hemoglobinopathies
HbH inclusions may rarely appear in specific alpha-globin chain variants, such as homozygosity for Hb Agrinio [α29(B10)Leu→Pro]. 5 In one reported case, a patient homozygous for this highly unstable variant initially presented with very rare Hb H inclusions at 12 months of age, though these were not detected at 13 years despite persistent mild thalassemia intermedia phenotype. 5
Clinical Context and Severity
In steady state, patients with HbH disease typically maintain hemoglobin levels around 9-10 g/dL. 2
During hemolytic crises—frequently triggered by acute infections with high fever—hemoglobin levels may drop significantly, potentially leading to shock or renal shutdown. 2
Non-deletional HbH disease demonstrates greater ineffective erythropoiesis, hemolysis, higher transfusion burden, and increased complication risks compared to deletional mutations. 3
High HbH levels exacerbate anemia by negatively influencing tissue oxygenation, and both HbH and alpha-thalassemic hemoglobin variants reduce red cell survival within bone marrow and circulation. 6
Key Diagnostic Pitfall
Do not confuse HbH disease with beta-thalassemia trait—both present with microcytic anemia (MCV <80 fL), but HbH disease is part of the non-transfusion-dependent thalassemia spectrum and may require transfusions to prevent cardiovascular and other complications as patients age. 7