Hemoglobin H Disease

Hemoglobin H (HbH) disease is a moderate to severe form of alpha-thalassemia (see this term) characterized by pronounced microcytic hypochromic hemolytic anemia.

Epidemiology

HbH disease is predominantly seen in Southeast Asia, the Middle East and the Mediterranean. Exact prevalence is not known but has been reported to be about 1/1,000,000 for severe forms of alpha-thalassemia in Northern Europe and North America.

Clinical description

Clinical features are highly variable and generally develop in the first years of life but may not develop until adulthood in some patients. Initial signs may be noticed only during routine hematologic analyses. Patients have variable microcytic hypochromic hemolytic anemia, splenomegaly (50 to 80%) and less commonly hepatomegaly (50%), mild jaundice (20-40%), and mild-to-moderate beta-thalassemia major (see this term)-like skeletal changes mainly affecting the face (30%). Hypersplenism and gallstones are also found, as well as acute episodes of hemolysis in response to oxidant drugs and infections. Hydrops fetalis (see this term) is present in very rare cases. Iron overload is common in older patients, even in the absence of transfusion, and is attributed to iron hyperabsorption. Growth retardation has been reported in children.

Etiology

HbH disease is usually caused by inactivation of three alpha-globin alleles leading to underproduction of alpha-globin chains of Hb, with the formation of beta-4 tetramers (HbH). HbH tetramers have a high affinity for oxygen, and are highly unstable, precipitating as toxic Heinz bodies. The formation of Heinz bodies predominates in mature red blood cells, leading to premature hemolysis rather than ineffective erythropoiesis. It is increased under oxidative stress, which explains the hyperhemolysis associated with infection or ingestion of oxidant drugs. The disease is caused by compound heterozygous or homozygous mutations in the HBA1 or HBA2 genes (16p13.3). The severity of the disease is related to its molecular basis: patients with non-deletional types of HbH disease, such as Constant Spring mutation, are more severely affected than those with the common deletional types.

Diagnostic methods

HbH disease should be considered in infants or children with mild-to-moderate microcytic hypochromic hemolytic anemia and hepatosplenomegaly. Heinz bodies can be detected on blood smears after cresyl blue staining. Hb biochemical analysis reveals the presence of HbH (5-30%). Diagnosis is confirmed by genetic testing.

Differential diagnosis

Differential diagnosis includes other hemolytic anemias and alpha-thalassemia X-linked intellectual deficit (ATRX, see this term).

Management and treatment

In the more common milder form, patients may require occasional blood transfusion therapy. In more severe cases, regular transfusions are needed. Splenectomy should be performed only in the presence of manifest hypersplenism, because it is associated with increased thromboembolic complications. Iron chelation can be needed, and iron overload should be monitored by serum ferritin levels and by liver magnetic resonance imaging (MRI).

Prognosis

Overall survival is variable but usually good. Many patients survive into adulthood but some have a more complicated course.