Hemoglobin H disease (HbH) is a form of alpha thalassemia in which moderately severe
anemia develops due to reduced formation of alpha globin chains. In this condition, as in the other
forms of thalassemia, there is an imbalance of globin chains needed to form hemoglobin. Normally,
there are four genes to produce alpha globin chains. When three out of four of these genes become
inactive, there are too few alpha globin chains to combine with beta chains and give rise to normal
hemoglobin (hemoglobin A). The excess beta globin chains then combine with each other to form
hemoglobin H, which is the origin of the name "hemoglobin H disease."

While most individuals with HbH do not require transfusions, there is heterogeneity in the clinical
course. This is an important component of the counseling for the family at the first clinic visit. HbH
caused by deletion of three genes (deletional HbH) is less severe than cases in which two genes are
deleted and the third gene has a point mutation (non-deletional HbH). HbH Constant Spring (HCS) is the
most common form of non-deletional HbH in the United States.

In California, all newborns with HbH are identified through newborn screening, followed by
identification of the alpha globin gene deletions or mutations by the Hemoglobin Reference Laboratory
located at Children’s Hospital & Research Center Oakland. Older patients who are seen for the first time
should have DNA testing to identify alpha globin gene deletions and the presence of the Constant Spring
(CS) mutation. If only two alpha genes are deleted and the CS mutation is absent, further testing for
uncommon mutations should be done. These patients should not be categorized as deletional HbH.
Patients with HbH should also be screened for beta globin gene mutations with multiplex PCR. The
complete genotype is used as the basis for discussion of a future clinical course and genetic counseling.

Routine care

Patients should be seen frequently in the first year after diagnosis to establish hemoglobin level and
monitor growth. Communication with the primary care provider is also important so that care can be
coordinated. Later visits to a thalassemia center should occur once or twice a year, and routine health
maintenance should be provided by the primary care provider. Patients with HCS should be followed
closely by the thalassemia center because of the potential for severe anemia, growth delay, iron
overload, and the need for splenectomy. All routine childhood vaccines should be completed and
seasonal influenza vaccine given every year. All patients should receive folic acid, 0.5 to 1.0 mg per day.

Management of fever

Owing to the risk of severe anemia during infections in HCS, such patients should be seen on the same
day in the clinic or emergency room. Patients with deletional HbH can usually be seen in the clinic on the
next day, unless an ER visit is warranted by the symptoms. A blood count with reticulocyte count and
bilirubin level should be obtained. An admission for observation or transfusion may be needed if the
hemoglobin has fallen below baseline. Antibiotic treatment is determined by assessing the source of
infection. All splenectomized patients with fever should be seen on the same day and started on
antibiotics (ceftriaxone is preferred). An admission is recommended until sepsis can be excluded.
Oxidant drugs, which cause hemolysis in G6PD deficiency, should be avoided.

Splenectomy

Splenectomy is not required for deletional HbH disease. It may be required for patients with HCS when
there are multiple episodes of sudden fall in hemoglobin level requiring transfusion, or if anemia is
severe and affecting growth.

Transfusion therapy

Common infectious diseases, such as common cold or viral fever, can lead to a rapid fall in hemoglobin
level in HCS patients. The fall in hemoglobin level in HbH patients is much smaller, and the development
of severe anemia needing transfusion is unlikely. Transfusions are given when hemoglobin falls below 6
g/ dL. As mentioned above, splenectomy is recommended if there is a need for frequent transfusions.
There is little role for chronic transfusion therapy such as that given to individuals with beta thalassemia
major.

Iron overload

Iron overload occurs in adults with HbH. In HCS, there is early iron overload that may need treatment.
Patients’ ferritin and liver iron concentration should be monitored and measured via MRI or
ferritometer.

Outreach

Patients should be provided with a card that shows the diagnosis and emergency contact number for
their hematology service. Clinical summaries should be sent to the primary care provider with treatment
recommendations. Families should be given a letter for school to explain the need for clinic visits.
Children are allowed to determine their own limits of activity during physical education with no routine
restrictions.

Adults with HbH

Genetic counseling is extremely important for adults. Ideally, a full testing of an adult patient’s partner
for alpha and beta thalassemia mutations should be performed. At a minimum, testing for alpha
thalassemia trait should be done to determine any risk for alpha thalassemia major which can be fatal to
a fetus.

Patients with HbH who become pregnant should be monitored for further drop in hemoglobin level.
Most of these patients will not need transfusions. Pregnant patients with HCS need close observation
and should start regular transfusions if hemoglobin drops below 7 g/ dL. Transfusions are performed
every three to four weeks with the aim of maintaining pre- and post-transfusion hemoglobin levels at 9
and 12 g/dL, respectively.

All adults should have echocardiograms to screen for pulmonary hypertension, more frequently in those
who are splenectomized. Older patients, particularly with HCS, should be evaluated for fatigue, difficulty
in coping at work, and family stress.

Conclusions

Deletional HbH is asymptomatic during infancy and childhood, although deficits in growth may appear
among older children. These individuals should receive all routine care through a primary care physician,
with periodic evaluation by a hematology center. The key points are counseling the family and adopting
strategies to avoid blood transfusion. In contrast, HCS is a potentially serious disease that needs close
follow-up by a thalassemia specialty center to plan for emergency and elective transfusions, measure
iron overload, monitor growth failure, and evaluate the need for splenectomy.

Treating Hemoglobin H disease

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.