Abnormal hemoglobinopathies refer to a group of hereditary disorders caused by structural abnormalities in globin chains. Over 90% of cases involve single amino acid substitutions, while rarer abnormalities include double amino acid substitutions, deletions, insertions, chain elongations, and chain fusions. Structural abnormalities can occur in any of the globin chains, with the β-globin chain being the most commonly affected. Alterations in globin chain structure may lead to changes or abnormalities in hemoglobin function and physiochemical properties. These include reduced solubility leading to aggregates (such as hemoglobin S), alterations in oxygen affinity, formation of unstable hemoglobins, or methemoglobins, with primary clinical manifestations being hemolysis, cyanosis, and vascular obstruction. The vast majority of these conditions are autosomal dominant.
Sickle Cell Anemia
Also known as hemoglobin S (HbS) disease, this condition is primarily observed in individuals of African descent. It is caused by the substitution of glutamic acid with valine at the sixth position of the β-globin chain. Under hypoxic conditions, HbS forms spiral polymers with very low solubility, causing red blood cells to distort into sickle shapes. These changes result in the following pathological manifestations:
- Hemolysis: The mechanical fragility and reduced deformability of these cells make them prone to both extravascular and intravascular hemolysis.
- Vascular obstruction: The rigidity of red blood cells contributes to blockages in microcirculation; this is also associated with inflammatory activation of endothelial cells.
Heterozygous individuals generally do not experience anemia or sickling, while homozygous individuals develop clinical symptoms starting around six months of age. The main clinical features include:
- Hemolysis: Manifestations involve jaundice, anemia, and hepatosplenomegaly.
- Acute Events: Acute exacerbations or crises often occur, with vaso-occlusive crises being the most common. These can cause pain or dysfunction in limbs or organs and may even lead to necrosis. Other acute events include aplastic crises, megaloblastic anemia crises, and splenic sequestration crises, all of which can escalate rapidly and become life-threatening.
Sickling can be observed during red blood cell deformation tests, and hemoglobin electrophoresis can confirm the presence of HbS, aiding diagnosis. The treatment involves symptomatic management, including the prevention and treatment of acute events and crises. Management strategies include infection control, fluid resuscitation, and blood transfusions. Hydroxyurea can induce the synthesis of HbF, which has anti-sickling properties and can moderate symptoms and reduce pain to some extent. Allogeneic hematopoietic stem cell transplantation provides a curative option for this condition. Monitoring and management of iron overload are necessary for patients undergoing repeated blood transfusions.
Unstable Hemoglobinopathies
Unstable hemoglobinopathies arise from amino acid substitutions or deletions in the globin chain, leading to changes in the spatial structure of hemoglobin and the formation of unstable hemoglobins. Over 120 types of unstable hemoglobins have been identified. Unstable globin chains can precipitate inside cells, forming Heinz bodies, which reduce the deformability of red blood cells and increase membrane permeability, making them more prone to destruction in the spleen. These conditions follow an autosomal dominant inheritance pattern, with heterozygous individuals being affected. Mild cases may not exhibit anemia, but fever or exposure to oxidative drugs can trigger hemolysis. Heinz body formation tests, as well as the isopropanol and heat denaturation tests, often yield positive results. Special treatment is generally unnecessary, but infection control and avoidance of sulfonamides and other oxidative drugs are recommended.
Hemoglobin M (HbM) Disease
HbM disease results from amino acid substitutions in globin chains that make heme iron susceptible to oxidation to the ferric (Fe3+) state. To date, seven variants of this disease have been identified. HbM disease is rare, follows an autosomal dominant inheritance pattern, and occurs in heterozygous individuals. Symptoms may include cyanosis, although hemolysis is generally not prominent. Laboratory findings typically reveal elevated methemoglobin levels, usually not exceeding 30%, as well as abnormal hemoglobin absorption spectra. Treatment is not required for this condition.
Hemoglobinopathies with Abnormal Oxygen Affinity
These disorders arise from amino acid substitutions in globin chains that alter the three-dimensional structure of hemoglobin, resulting in abnormal oxygen affinity (either increased or decreased) and shifts in the oxygen dissociation curve (leftward or rightward). These changes affect the capacity of hemoglobin to release oxygen to tissues.
Decreased oxygen affinity hemoglobinopathies do not impair the oxygen delivery function of hemoglobin, and arterial oxygen partial pressure and tissue oxygenation remain normal. However, elevated methemoglobin levels may cause cyanosis.
Increased oxygen affinity hemoglobinopathies are associated with impaired oxygen dissociation, reducing arterial oxygen saturation and resulting in tissue hypoxia. Compensatory erythrocytosis may develop as a consequence. Increased oxygen affinity conditions are more clinically and pathologically significant. Measuring the oxygen dissociation curve can aid in differentiating this condition from polycythemia vera. Symptomatic treatment may be required if significant blood hyperviscosity syndrome develops.
Other Hemoglobinopathies
HbE disease results from the substitution of glutamic acid with lysine at the 26th position of the β-globin chain. Due to the similar physicochemical properties of glutamic acid and lysine, the substitution has limited impact on hemoglobin stability and function. This condition follows an autosomal incomplete dominant inheritance pattern. Heterozygous individuals are asymptomatic, while homozygous individuals experience mild hemolysis and microcytic hypochromic anemia, with increased target cell percentages (25%–75%). HbE disease is the most common abnormal hemoglobinopathy. Hemoglobin electrophoresis can detect HbE levels as high as 90%. HbE is unstable in the presence of oxidizing agents, often yielding a positive isopropanol test result.