What is hemoglobinopathy H?

Hemoglobinopathy H (Hemoglobin H Disease)

Hemoglobin H disease is a form of alpha thalassemia characterized by the deletion or dysfunction of three out of four alpha-globin genes, resulting in the formation of unstable beta-globin tetramers (β₄) that precipitate within red blood cells, causing chronic hemolytic anemia with microcytosis. 1

Pathophysiology and Molecular Basis

HbH disease develops when severe alpha-chain deficiency leads to a relative excess of beta-globin chains, which then form unstable homotetramers (four beta chains bound together) instead of normal hemoglobin. 1 This occurs because:

• Normal hemoglobin requires balanced production of alpha and beta chains
• When three of the four alpha-globin genes are deleted or non-functional, alpha-chain production is severely reduced
• The excess beta chains spontaneously form β₄ tetramers (Hemoglobin H)
• These HbH tetramers are highly unstable and precipitate within red blood cells, forming inclusion bodies 1

Clinical Presentation

Patients with HbH disease typically maintain hemoglobin levels around 9-10 g/dL in steady state but may experience significant drops during hemolytic crises, potentially leading to shock or renal shutdown. 1 Key clinical features include:

• Chronic microcytic anemia with mean cell volume (MCV) consistently <80 fL 1
• Hemolytic anemia that is variably compensated and may worsen during physiologic stress (infection, pregnancy, surgery) 2
• Moderate symptoms ranging from mild fatigue to more significant anemia requiring occasional transfusions 1
• Splenomegaly may be present due to chronic hemolysis 2

The disease severity is intermediate between silent alpha thalassemia carriers and the lethal alpha thalassemia major (hydrops fetalis). 1

Diagnostic Approach

Initial Laboratory Findings

The diagnostic work-up begins with a complete blood count showing microcytic anemia (MCV <80 fL) with an elevated red blood cell count relative to the degree of anemia. 1, 3 Key laboratory features include:

• Low HbA2 levels (distinguishing it from beta thalassemia trait, which has elevated HbA2) 1
• Presence of HbH detected on hemoglobin electrophoresis or HPLC 1
• HbH inclusion bodies visible on peripheral blood smear with supravital staining (brilliant cresyl blue) 1
• Reticulocytosis reflecting ongoing hemolysis 3

Confirmatory Testing

High-performance liquid chromatography (HPLC) or capillary electrophoresis should be used as the primary diagnostic method to quantify HbH and other hemoglobin fractions. 3 The diagnostic algorithm includes:

1. Hemoglobin electrophoresis at alkaline pH (pH 8.6) as initial screening 3
2. HPLC quantification showing presence of HbH (typically 5-30% of total hemoglobin) 1, 3
3. Peripheral blood smear examination revealing HbH inclusion bodies (appearing as multiple small inclusions giving a "golf ball" appearance) 1
4. Targeted DNA sequencing of alpha-globin genes for definitive identification of the specific deletions or mutations 3

Parental Screening

Parents of affected individuals should be screened by evaluating the mean cell volume (MCV), which will be <80 fL in alpha thalassemia carriers. 1 This is critical for:

• Genetic counseling
• Identifying at-risk couples for future pregnancies
• Distinguishing from iron deficiency (though serum ferritin and transferrin saturation should also be measured) 3

Differential Diagnosis

HbH disease must be distinguished from beta-thalassemia trait, as both present with microcytic anemia, but HbH disease may require transfusions to prevent complications. 1 Key distinguishing features:

Feature	HbH Disease	Beta Thalassemia Trait
HbA2 level	Low or normal	Elevated (>3.5%)
HbH present	Yes	No
Hemolysis	Moderate to severe	Minimal
Clinical severity	Moderate anemia	Mild anemia

1

Management Principles

Monitoring and Supportive Care

Close monitoring of hemoglobin levels is essential, particularly during hemolytic crises when drops can be precipitous. 1 Management includes:

• Avoid oxidant drugs that can precipitate hemolysis (sulfonamides, antimalarials, dapsone) 4
• Folic acid supplementation (1 mg daily) to support increased red cell production 4
• Blood transfusions should be given only when strictly indicated (symptomatic anemia, hemolytic crisis) 4
• Iron chelation therapy may be required if repeated transfusions lead to iron overload 4

Critical Pitfalls to Avoid

Do not administer medicinal iron unless iron deficiency is biochemically proven (low serum ferritin and transferrin saturation), as patients with HbH disease are at risk for iron overload from chronic hemolysis and potential transfusions. 3 Additional cautions:

• Do not interpret HbA1c for diabetes monitoring in these patients without using assays validated for hemoglobinopathies 3
• Avoid aggressive phlebotomy as these patients are already anemic 1
• Monitor for complications during pregnancy, infection, or surgery when hemolysis may worsen 2

Prognosis

With optimal supportive treatment, patients with HbH disease have a projected life span of 50 to 60 years, with more than 90% surviving into adulthood. 4 The prognosis depends on:

• Severity of the specific genetic defect
• Frequency of hemolytic crises
• Development of iron overload from transfusions
• Access to comprehensive hematologic care 4

Genetic Counseling

Alpha thalassemia is a common cause of hydrops fetalis in Southeast Asian populations, accounting for 28-55% of non-immune hydrops fetalis cases. 1 Couples at risk (both carriers of alpha thalassemia trait) should receive:

• Prenatal genetic counseling
• DNA testing for alpha-thalassemia mutations
• Discussion of prenatal diagnosis options for future pregnancies 1