Hospital Medicine

Beta thalassemia

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I. What every physician needs to know.

Thalassemias are disorders of hemoglobin synthesis. Beta (β-) thalassemia results from an abnormality of one or both β-globin genes.

Several hundred mutations of the β-globin gene are known that result in either diminished (β+ thalassemia) or absent β globin (βo thalassemia).

These mutations result in a wide spectrum of phenotypes. Patients are categorized according to their severity of anemia and symptoms are grouped into thalassemia major (a severe homozygous or compound heterozygous condition, also called Cooley's anemia), intermedia and minor (a mild heterozygous condition also known as trait or minima).

II. Diagnostic Confirmation: Are you sure your patient has beta thalassemia?

Thalassemia is diagnosed with hemoglobin electrophoresis. In βo thalassemia, no hemoglobin A1 is produced and both hemoglobin F and A2 are markedly elevated. In β+ thalassemia, some hemoglobin A1 is produced, the amount varying with the severity of the mutation, hemoglobin F is usually elevated and A2 is usually elevated above 3.4%.

A. History Part I: Pattern Recognition:

In cases of thalassemia major, infants are usually normal at birth but then become increasingly anemic over the next few months. If not treated, they will show signs of failure to thrive within the first year of life. Children maintain normal growth pattern if regular transfusions are received but can develop signs of iron overload by age 10 years if iron chelation are not used prophylactically. The first indication of iron overload is the absence of pubertal growth spurt and failure of menarche. Later onset anemia suggests intermedia subtype of β thalassemia. Beta Thalassemia Intermedia encompasses disorders with wide spectrum of clinical presentation. Spectrum of severity can range from those with haemoglobin level of 6 grams/deciliter (g/dL) with severe disability to asymptomatic cases with haemoglobin of 10-12 g/dL in mild phenotype of beta thalassemia intermedia. Iron overload in this category typically presents in the fourth decade of life. There is high incidence of pigmented gall stones, skeletal deformities, arthritis, chronic leg ulcers and thrombotic events, especially post splenectomy. Beta Thalassemia minor or beta thalassemia trait carries no symptoms except for mild fatigue reported in studies. Diagnosis is made by chance during routine blood work or identified when family members of severe thalassemics are screened. Normal hemoglobin with low mean corpuscular volume (MCV) is noted. It is commonly misdiagnosed and treated for iron deficiency. If unusually high plasma iron or serum ferritin is encountered in beta thalassemia trait one should rule out coexisting hemochromatosis or iron supplementation. Women carriers can develop moderately severe anemia during pregnancy.

B. History Part 2: Prevalence:

Thalassemia is a genetic disorder. It is most prevalent in the Mediterranean regions, the Middle East, Pakistan, India, Southeast Asia, and is also found in West and Central Africa. Though rare, it can also be found in people with any other racial/ethnic background.

C. History Part 3: Competing diagnoses that can mimic beta thalassemia.

Diagnosis of Homozygous beta thalassemia is not difficult. Congenital sideroblastic anemias and juvenile chronic myelogenous leukemia should be distinguished from beta thalassemia in early childhood. Congenital sideroblastic anemia also presents with microcytic anemia, however, marrow findings are characteristic and should assist in diagnosis. Juvenile chronic myelogenous leukemia has high haemoglobin F like beta thalassemia but several laboratory findings like absence of elevated haemoglobin A 2 level, decrease in carbonic anhydrase, primitive cells in the marrow favors the diagnosis of juvenile chronic myelogenous leukemia.

Thalassemias are hemolytic anemias and can be confused with other hemolytic anemia. They are different in that thalassemias tend to have a low MCV. Because of that they are often confused with iron deficiency anemias, a diagnosis that is important to exclude. Most thalassemia patients are at risk for iron overload and iron supplementation could be harmful.

D. Physical Examination Findings.

Beta thalassemia major

Usually no signs at birth, but infants then develop progressive anemia and failure to thrive in the first months of life. Inadequate transfusions lead to bony deformities from marrow hyperplasia. Bony deformities in severe beta thalassemia typical present in childhood with bossing of the skull, oversized maxillary region leading to dental problems from malocclusion, and mongoloid facial appearance. Hepatosplenomegaly is characteristically seen from extramedullary erythropoiesis or hemolysis. Wasting with fevers and hyperuricemia can be seen as a result of hypermetabolic state.

Iron overload can present with endocrinal dysfunction that manifests physical findings such as growth retardation, delayed puberty and secondary sexual characteristics, and hypogonadism. Skin pigmentation as part of bronze diabetes and signs of heart failure and arrhythmias can develop by third decade of life if iron chelator therapy not initiated.

Beta thalassemia intermedia

This type covers a wide variety of disabilities and can be very mild or severe. As noted above beta thalassemia intermedia patients with severe disease can develop growth and developmental retardation, arthritis, bone pain, splenomegaly, and chronic ulcerations above the ankles.

Beta thalassemia minor

This is usually asymptomatic and not associated with any disabilities or the need for blood transfusions. Minor fatigue reported in some studies. Severe anemia in pregnant carries reported as well.

E. What diagnostic tests should be performed?

Medical history: chronicity of anemia, ethnic/racial background, family history

Physical findings: signs of anemia (pallor, shortness of breath), jaundice, splenomegaly

Laboratory: complete blood count (CBC), peripheral blood smear, hemoglobin electrophoresis

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Complete blood count

Depending on the subtype of thalassemia, in severe cases hemoglobin levels at diagnosis can be very low (2-3g/dl), MCV is low and white cells and platelets may be elevated as a sign of a very active bone marrow. Question an elevated lymphocyte count (see peripheral smear below).

Hemolytic laboratory tests

Reticulocyte count, lactate dehydrogenase (LDH) and total bilirubin are usually elevated.

Peripheral blood smear

Red blood cells (RBCs) can be hypochromic and there can be marked microcytosis and anisopoikilocytosis, target cell formation and basophilic stippling. Nucleated red cells are common (do not mistake these for lymphocytes: question an elevated lymphocyte count and verify they are not nucleated red cells).

Ferritin

This is often elevated as a sign of iron overload and is anticipated to be elevated by the end of first decade of life in children with beta-thalasemmia major receiving regular transfusions and no chelation therapy. Iron overload can also develop in beta-thalassemia intermedia who do not receive frequent transfusions. Mechanism of iron load in this scenario is secondary to increased iron absorption. Iron overload presents in the fourth decade of life in this setting. Iron overload state does not occur in the natural course of beta-thalassemia trait unless patient has been receiving iron supplements after being misdiagnosed as iron deficient or has concomitant hemosiderosis.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Echocardiogram is useful to diagnose cardiomyopathy from cardiac siderosis or chronic anemia.

Evidence suggested that liver iron concentration is a good surrogate marker of body iron burden. Accurate measurement and mapping of liver iron with magnetic resonance imaging (MRI) of the liver is an extremely efficient approach to monitor effectiveness of chelation therapy. T2 MRI has also been used to assess myocardial iron load.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

X-rays can show “Sun-ray” appearance of long bones and pharynges. This, however, is not necessary in establishing the diagnosis.

III. Default Management.

Blood transfusion.

A. Immediate management.

For hemoglobin significantly below the patient's baseline, especially in symptomatic patients, immediate blood transfusion should be considered.

Maintaining hemoglobin between 9.5 to 14 g/dL will allow normal growth and development devoid of permanent skeletal complications in a child.

However, maintaining a pretransfusion hemoglobin around 9.5 g/dL seems to avoid frequent transfusions and iron overload state while maintaining normal childhood physical development.

B. Physical Examination Tips to Guide Management.

Thalassemia patients should be monitored for symptoms of anemia (shortness of breath, hypoxia, tachycardia). These symptoms should improve with blood transfusion.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Hemoglobin levels should be monitored to make sure they appropriately rise with transfusion (around 1g/dl per unit of blood for adult patients). An inappropriate rise or drop in hemoglobin may be a sign of hemolytic transfusion reaction due to antibody formation. This can happen several days after the transfusion (delayed hemolytic transfusion reaction) and would result in an acute drop in hemoglobin at that time.

D. Long-term management.

Most patients with more severe forms of thalassemia are maintained on regular RBC transfusions (usually every 4 weeks) to maintain stable and sufficient hemoglobin levels for normal growth. RBCs should be washed and filtered to remove white blood cells and plasma proteins there by reducing the risk of immune responses.

Care has to be taken to identify and treat related iron overload.

Hydroxyurea may be effective in patients with thalassemia intermedia but is usually not beneficial in transfusion dependent thalassemia major.

Bone marrow transplantation can be curative and is considered for severe cases.

Folic acid supplementation is recommended for everyone.

Various approaches to augment fetal haemoglobin with butyrate analogues, erythropoietin, and other cytotoxic drugs have shown promise in certain mutant variants of beta-thalassemia like homozygotic haemoglobin Lepore.

Somatic gene therapies are being explored and are currently in experimental phase.

E. Common Pitfalls and Side-Effects of Management

Iron deficiency anemia has to be ruled out and iron supplementation is inappropriate in most patients.

IV. Management with Co-Morbidities

The most frequent and concerning side effect of transfusion for thalassemia is iron overload. This can occur after a total of 10 to 20 units of blood and can result in liver toxicity, cardiotoxicity and dysfunction of endocrine organs. Iron chelation is essential.

Prophylactic iron chelators should be started within the first 2-3 years of life in transfusion dependent severe beta thalassemia cases.

Deferoxamine is the first line choice for iron chelation; however, it is available in parenteral form only. Can be given subcutaneous via abdominal pump started when ferritin level reaches 1000 micorgrams/deciliter (mcg/dL).

Intravenous infusion of deferoxamine should be considered in heavy iron overload cases with cardiac and endocrinal manifestations.

Goal is to keep ferritin level less than 1500 mcg/dL.

Oral iron chelators that are currently available include deferiprone and deferasirox.

Avoid vitamin C supplementation because it generates free radicals in iron excess states.

Severe but rare allergic reaction to deferoxamine infusion can develop and can be controlled in part with addition of 5-10 milligrams of hydrocortisone in the infusion.

A. Renal Insufficiency.

Deferasirox causes persistent increase in serum creatinine, without apparent consequence.

B. Liver Insufficiency.

Hemolytic anemia can cause hepatosplenomegaly, along with high output heart failure, chronic leg ulcers, and pigmented gall stones.

Extramedullary hemopoiesis can also lead to hepatosplenomegaly.

Iron overload can lead to liver toxicity and fibrosis. Liver biopsy is the gold standard to diagnose iron overload and the extent of liver damage. Ferritin is cheap and readily available, but not a very reliable surrogate marker for overload. MRI liver also can assist in estimating hepatic iron load.

SQUID (superconducting quantum interference device) is accurate at measuring hepatic iron but not widely available.

Deferasirox produces some elevation in liver enzymes.

C. Systolic and Diastolic Heart Failure

Iron overload can result in early pericarditis, followed by arrhythmias and then cardiac failure. Iron chelation and monitoring for these conditions is essential.

Prolonged severe anemia can also lead to heart failure.

Deferasirox may be effective for removing excess cardiac iron.

D. Coronary artery disease or peripheral vascular disease

There are conflicting studies on the risk of coronary artery disease and peripheral vascular disease in thalassemia. Severe anemia should probably be avoided and the effect of iron overload on cardiac function has to be taken into account.

E. Diabetes or other Endocrine issues

Iron absorption is increased in people with thalassemias and even in infrequently transfused individuals iron overload can result in endocrine dysfunction including diabetes, hypothyroidism, hypoparathyroidism, hypogonadism, and delayed growth. Vitamin D deficiency is common and people with thalassemia tend to have lower bone density. Besides strict iron chelation, it is important to monitor for these endocrine insufficiencies and to initiate treatment as needed.

F. Malignancy

Patients with malignancies are often anemic which could compound the anemia from the thalassemia.

G. Immunosuppression (HIV, chronic steroids, etc).

Patients receiving blood transfusions should routinely be monitored for human immunodeficiency virus (HIV), hepatitis C virus and other blood borne pathogens.

H. Primary Lung Disease (COPD, Asthma, ILD)

Patients with primary lung disease may be more symptomatic from the thalassemia related anemia. Transfusion reactions such as transfusion related acute lung injury (TRALI) should not be overlooked in these patients.

I. Gastrointestinal or Nutrition Issues

Vitamin D deficiency is more pronounced in patients with thalassemia and should be screened for. Several reports suggest deficiency of other key vitamins and minerals despite proper nutritional intake, which may be due to altered metabolism related to an increased bone marrow turnover.

J. Hematologic or Coagulation Issues

Patients with thalassemia, especially after splenectomy and with high platelet counts might be hypercoagulable.

Chronic small pulmonary emboli can lead to pulmonary hypertension over time.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

L. Skin issues

Skin pigmentation can be noted in iron overload.

Painful subcutaneous skin nodules at the site of deferoxamine injection can develop.

M. Nervous system issues

Neurosensory toxicity is noted in 30% of patients receiving deferoxamine treatment.

Hearing loss, and ocular toxicity in the form of night and color blindness and visual field loss is reported.

Massive deposition of extramedullary hematopoietic tissue can cause neurological complications.

A. Sign-out considerations While Hospitalized.

Hospitalized patients should be observed for worsening anemia as well as acute or delayed transfusion reactions.

B. Anticipated Length of Stay.

If the admission is for symptomatic anemia, the patient may be discharged after blood transfusion. If admitted for other reasons, the secondary reason will determine the length of stay.

C. When is the Patient Ready for Discharge.

The patient is ready for discharge, when he/she has symptomatically recovered and is stable.

D. Arranging for Clinic Follow-up

Patients with severe thalassemia should be followed by a hematologist. If the patient already has a hematologist, he/she should be informed about the patient's admission and follow-up arranged.

1. When should clinic follow up be arranged and with whom?

Usually, the patient can resume his/her routine follow-up with hematology as already scheduled.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

A CBC on the day of discharge can be helpful during follow-up.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

CBC should be done prior to transfusion. In patients on iron chelation, a ferritin and comprehensive metabolic profile should be monitored once a month. Endocrine functions should be checked in patients with iron overload.

E. Placement Considerations.

Most patients can be managed in the outpatient setting. Transfusion therapy can be set up through infusion centers. Central venous access (usually a port-a-cath) may be necessary in patients with difficult access.

F. Prognosis and Patient Counseling.

The prognosis for thalassemia depends on the severity of the phenotype. Mild cases have a normal life expectancy. The survival of more severe cases depends on how well symptoms and complications are prevented with blood transfusions and how effective iron chelation is in preventing complications from associated iron overload.

Every patient with severe beta thalassemia should receive genetic counselling. Screening should be offered to the family members.

Spouses or partners of carriers should be screened. If positive, they should be offered prenatal diagnosis of the fetus if pregnancy occurs.

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

People with thalassemia should be taking folic acid. They should receive their regular vaccinations on time and should be vaccinated against pneumococcus and meningococcus, in case of splenectomy. Infections should be treated early. Prophylactic transfusions can prevent complications and readmissions. Iron chelation is essential to prevent complications associated with iron overload.

Due to bony deformities of the skull and maxilla beta thalassemia major patients are prone to dental issues, ear-nose-throat problems. Routine otolaryngology and dental surveillance is recommended.

Physical growth should be monitored. If stunted or puberty is delayed, patient should be evaluated and monitored for endocrinal insufficiencies and started on hormone therapies.

Patients on iron chelators should be monitored for side effects. If on oral deferiprone, weekly white cell count should be obtained to monitor for neutropenia and agranulocytosis.

Routine physical examination should include evaluation for signs and symptoms of iron overload (cirrhosis, heart failure), signs of infection, signs of drug toxicity from iron chelation, signs and symptoms of severe anemia either from aplastic crisis, or hemolysis from stressors like infection or beta thalassemia itself.

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