20.0 - HEMOGLOBIN H DISEASE AND ITS VARIANTS
The gene frequencies of alpha-thalassemia exceed those of beta-thalassemia. The loss of alpha-gene function may be secondary to a deletional or nondeletional mutation. Nondeletional mutations are more severe. The inactivation of one alpha-globin gene is insignificant. The inactivation of two alpha-globin genes causes a very mild microcytic, hypochromic anemia. The loss of function of three alpha-globin genes is called hemoglobin H disease. People with hemoglobin H disease have a variable phenotype that can range from mild symptoms to those similar to thalassemia major. Due to phenotypic variability or in utero intervention, more patients with this disorder are being reported.
Hemoglobin H disease is a serious health problem in Southeast Asia and southern China. Thousands of affected patients live in the Middle East, the Mediterranean region, and North America. Many patients require intermittent transfusions. The clinical severity is strongly influenced by the type of mutation. Deletions on chromosome 16 are responsible for 75 percent of hemoglobin H mutations, and these deletions cause a milder form of the disorder. The remaining 25 percent of patients with hemoglobin H disease have two deletions plus a point mutation or insertion in the alpha-globin gene. Nondeletional hemoglobin H is often severe and likely to require transfusions. In both groups, however, there is marked phenotypic variability.
The diagnosis of hemoglobin H may be difficult. Hemoglobin H and hemoglobin Barts are fast-moving hemoglobins that may appear on electrophoresis. However, they are unstable and often go undetected. Patients with hemoglobin H disease have greater than 20 percent hemoglobin Barts at birth. Hemoglobin Barts rapidly disappears on electrophoresis after birth. Since hemoglobin H and hemoglobin Barts are unstable, electrophoresis may fail to detect these abnormalities.
The state of California screens newborns for hemoglobin H disease utilizing high performance liquid chromatography to measure hemoglobin Barts. Newborns with greater than 20 percent hemoglobin Barts undergo DNA testing to distinguish more severe, nondeletional hemoglobin H, such as hemoglobin H–Constant Spring from deletional hemoglobin H disease. High performance liquid chromatography or hemoglobin electrophoresis cannot reliably detect nondeletional mutations.
20.2 Hemoglobin H deletion
After the newborn period, the diagnosis of deletional hemoglobin H disease is often made only after the detection of complications such as cholelithiasis, exacerbation of the anemia induced by infection, or the findings of splenomegaly and growth failure. The mean hemoglobin in deletional hemoglobin H is quite variable but averages 9.5 g/dL. Twenty-nine to 50 percent of patients with deletional hemoglobin H require intermittent transfusion therapy, but the need for chronic transfusion therapy is uncommon. Pregnancy is often associated with an increased severity of anemia, as well as pre-eclampsia, and may necessitate transfusion.
Iron overload and iron-induced heart failure are increasingly being noted in adult patients not receiving intermittent transfusions. Serum ferritin levels usually underestimate the magnitude of iron overload. Iron deposits in nontransfused patients are in the ferrihydride form, which causes more damage than the goethite iron that results from transfusion. Earlier therapeutic intervention for iron overload in nontransfused hemoglobin H disease is indicated.
Hemoglobin H–Constant Spring is the most common nondeletional alpha-thalassemia mutation associated with hemoglobin H disease. Hemoglobin H–Constant Spring disease has significantly more ineffective erythropoiesis. The laboratory and clinical course of hemoglobin H–Constant Spring disease is more severe than hemoglobin H disease. The average hemoglobin is 2 g/dL less than in deletional hemoglobin H disease. The mean corpuscular volume is a near-normal 72 fL, compared to 59 fL for deletional hemoglobin H disease. Most patients have moderately severe splenomegaly, and over 50 percent require splenectomy. Splenectomy often results in improved hemoglobin levels but is associated with a high rate of portal vein thrombosis. Ninety percent of patients with hemoglobin H–Constant Spring disease have been intermittently transfused, and up to 40 percent have required repeated transfusions, particularly in early infancy and in later adulthood. Iron overload occurs in 75 percent of patients by adulthood. Rarely, hemoglobin H–Constant Spring disease and other nondeletional hemoglobin H disorders have caused fatal hydrops fetalis syndrome.
Homozygous alpha-thalassemia, caused by a deletion of all four alpha-globin genes, leads to the formation of high levels of hemoglobin Barts in utero. Hemoglobin Barts has an extremely high oxygen affinity, and therefore delivers little oxygen to fetal tissues. The severe hypoxia results in cardiac failure, massive ascites, and intrauterine death. Congenital malformations associated with homozygous alpha-thalassemia include hypospadias, other genitourinary defects, and limb malformations. Infants surviving to delivery without prenatal intervention are usually hydropic and commonly have neurological impairment. Intrauterine transfusions following early detection of homozygous alpha-thalassemia have resulted in the birth of several nonhydropic infants, some but not all of whom have no significant neurological abnormalities or congenital anomalies. Affected infants who survive gestation and the neonatal period subsequently require chronic transfusion therapy or may be appropriate candidates for hematopoietic stem cell transplantation.
Occasionally, infants with homozygous alpha-thalassemia are born without hydrops, even in the absence of intrauterine transfusions. Nondeletional, highly unstable alpha-globin gene mutations may result in a hemoglobin H genotype, causing hydrops fetalis. In pregnancies known to be at risk, chorionic villous sampling with molecular analysis identifies homozygous alpha-thalassemia within the first months.
The ethical issues of managing a fetus known to have homozygous alpha-thalassemia are complex. Obstetric complications and the necessity for long-term transfusion therapy are serious considerations. Increased risk of both maternal and fetal morbidity should be included in counseling families at risk for an affected fetus. Education, screening, and counseling of the family are essential.
20.3 Recommendations for care
Often the patient with hemoglobin H is asymptomatic and is unprepared for the acute complications that occur during infection, pregnancy, and drug exposure. In particular, these include hemolytic and aplastic anemic episodes. Folic acid supplements and avoidance of oxidative compounds and medications are recommended. In mild cases, biannual visits are adequate. In more severe cases, more frequent visits are indicated. At routine visits, growth, development, facial bone deformity, dental status, and hepatosplenomegaly should be monitored. Routine monitoring of hemoglobin levels is required.
Patients with hemoglobin H disorders develop neonatal anemia. Splenomegaly and hypersplenism are relatively common. Splenectomy usually ameliorates the severe anemia noted in nondeletional hemoglobin H cases. Splenectomy may be required at a very young age in transfusion-dependent cases. Prophylactic antibiotics and infection precautions are similar to other splenectomy patients. Thrombosis prevention is indicated in cases requiring splenectomy. Low-dose aspirin or other anticoagulants may be used.
Ongoing monitoring of iron stores with quantitative imaging of the liver is indicated because of the unreliability of serum ferritin tests. In nontransfused patients, imaging should be initiated in early adolescence. Cardiac function monitoring is indicated. The frequency is determined by the anemia and the iron-overload status. Gallstones frequently occur in hemoglobin H disease, and cholecystectomy is indicated in symptomatic patients. Bone-density measurement should be initiated in early adolescence. Pregnancy requires more frequent monitoring because of the risk of severe anemia and pre-eclampsia.