Am Fam Physician. 2022;105(3):272-280
Author disclosure: No relevant financial relationships.
Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective production of alpha- or beta-globin chains may result in ineffective erythropoiesis, premature red blood cell destruction, and anemia. Chronic, severe anemia in patients with thalassemia may result in bone marrow expansion and extramedullary hematopoiesis. Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels. Hemoglobin electrophoresis may reveal common characteristics of different thalassemia subtypes, but genetic testing is required to confirm the diagnosis. Thalassemia is generally asymptomatic in trait and carrier states. Alpha-thalassemia major results in hydrops fetalis and is often fatal at birth. Beta-thalassemia major requires lifelong transfusions starting in early childhood (often before two years of age). Alpha- and beta-thalassemia inter-media have variable presentations based on gene mutation or deletion, with mild forms requiring only monitoring but more severe forms leading to symptomatic anemia and requiring transfusion. Treatment of thalassemia includes transfusions, iron chelation therapy to correct iron overload (from hemolytic anemia, intestinal iron absorption, and repeated transfusions), hydroxyurea, hematopoietic stem cell transplantation, and luspatercept. Thalassemia complications arise from bone marrow expansion, extramedullary hematopoiesis, and iron deposition in peripheral tissues. These complications include morbidities affecting the skeletal system, endocrine organs, heart, and liver. Life expectancy of those with thalassemia has improved dramatically over the past 50 years with increased availability of blood transfusions and iron chelation therapy, and improved iron overload monitoring. Genetic counseling and screening in high-risk populations can assist in reducing the prevalence of thalassemia.
Thalassemia is a group of autosomal recessive hemoglobinopathies involving ineffective production of normal alpha- or beta-globin chains, which can lead to ineffective erythropoiesis, premature red blood cell destruction, and anemia. Other common hemoglobinopathies (e.g., sickle cell disease) arise from production of abnormal globin chains. This article summarizes key evidence regarding the diagnosis and treatment of thalassemia for primary care physicians.
| Recommendation | Sponsoring organization |
|---|---|
| Avoid using hemoglobin to evaluate patients for iron deficiency in susceptible populations. Instead, use ferritin. | American Society for Clinical Laboratory Science |
| Do not repeat hemoglobin electrophoresis (or equivalent) in patients who have a prior result and who do not require therapeutic intervention or monitoring of hemoglobin variant levels. | American Society for Clinical Pathology |
Epidemiology
Thalassemia prevalence is highest in Africa, India, the Mediterranean, the Middle East, and Southeast Asia. Incidence in these regions may be decreasing because of prevention programs involving premarital and preconception counseling and testing.1–4
Approximately 5% and 1.5% of the world population are carriers of alpha- and beta-thalassemia, respectively.1,4
Thalassemia affects 6 per 100,000 conceptions in the Americas.5 Data specific to the United States are lacking, but California has an estimated incidence of 1 in 10,000 and 1 in 55,000 for alpha- and beta-thalassemia, respectively.4,6
Pathophysiology
Hemoglobin (Hb) comprises an iron-containing heme ring and four globin chains: two alpha and two nonalpha (beta, delta, gamma).7–9 See diagram at https://www.aafp.org/afp/2009/0815/p339.html#afp20090815p339-f1. HbF is the most common type in newborns. By six months of age, HbA is predominant. Clinically significant thalassemia presents with reduced HbA production.7,8
Table 11,10,11 and Table 210–12 detail alpha- and beta-thalassemia subtypes.
| Subtype | Chromosome 16 mutation* | Signs and symptoms | Hb and MCV |
|---|---|---|---|
| Silent carrier (alpha-thalassemia minima) | One of four gene deletions | Normal Hb and hematocrit, asymptomatic | Normal |
| Trait (alpha-thalassemia minor) | Two of four gene deletions† | Microcytosis, possibly mild anemia, asymptomatic | Hb slightly subnormal; MCV < 80 μm3 (80 fL) |
| Deletional HbH disease (alpha-thalassemia intermedia) | Three of four gene deletions | Mild to moderate anemia, ineffective erythropoiesis, skeletal abnormalities‡ | Hb = 6.9 to 10.7 g per dL (69 to 107 g per L); MCV = 46 to 76 μm3 (46 to 76 fL) |
| Nondeletional HbH disease (Hb Constant Spring) | Mutant allele causing reduced alpha-globin activity | More severe phenotype than deletional HbH disease; moderate to severe anemia, splenomegaly, gallstones, decreased bone density, growth retardation; often requires transfusion | Hb = 3.8 to 8.7 g per dL (38 to 87 g per L); MCV = 48.7 to 80 μm3 (48.7 to 80 fL) |
| Alpha-thalassemia major with Hb Bart’s disease | Four of four gene deletions | Nonimmune hydrops fetalis, usually fatal without treatment | Transfusion dependence if surviving |
| Subtype | Chromosome 11 mutation* | Signs and symptoms |
|---|---|---|
| Beta-thalassemia trait | Single gene defect | Asymptomatic |
| Beta-thalassemia intermedia | Two genes defective (mild to moderate impairment in beta-globin production) | Symptoms similar to beta-thalassemia major but with variable severity; may have mild to moderate anemia, and may require intermittent or regular transfusions |
| Beta-thalassemia major | Two genes defective (severe impairment in beta-globin production) | Ineffective erythropoiesis, resulting in severe anemia, gallstones, skeletal abnormalities† (due to bone marrow expansion), hepatosplenomegaly (causing abdominal distension), jaundice, and pallor; requires lifelong blood transfusions starting by six to 24 months of age |
Screening and Prevention
A complete blood count should be performed in all pregnant patients to screen for thalassemia. A low mean corpuscular volume warrants Hb electrophoresis. It is also reasonable to obtain Hb electrophoresis for those in high-risk ethnic groups (African, West Indian, Mediterranean, Middle Eastern, and Southeast Asian).13
Preconception genetic counseling and testing should be discussed with patients who have risk factors (first-degree relative with thalassemia, history of stillbirth, high-risk ethnicity, and low mean corpuscular volume).13
Prenatal diagnosis is performed via chorionic villus sampling at 10 to 12 weeks’ gestation or amniocentesis after 15 weeks’ gestation.13
Newborn screening for thalassemia varies by state. HbSS, beta-thalassemia/HbS, and HbS/C are the only hemoglobinopathies considered to be core conditions on the U.S. Recommended Uniform Screening Panel. Other hemoglobinopathies are listed as secondary conditions, but neither alpha- nor beta-thalassemia is included on this list.14
Diagnosis
SIGNS AND SYMPTOMS
Thalassemia is generally asymptomatic in trait and carrier states.10,11
Moderate to severe microcytic anemia can occur in intermediate and major types of thalassemia, presenting as fatigue, lightheadedness, and syncope, as well as poor growth in children. Active hemolysis may cause hyperbilirubinemia, jaundice, and gallstones.10
Erythropoietin stimulation from chronic anemia may induce signs of bone marrow expansion (pseudotumors, frontal bossing, maxillary hypertrophy, malar prominence, depressed nasal bridge) and extramedullary hematopoiesis (hepatosplenomegaly).10,11
Nonimmune hydrops fetalis occurs in alpha-thalassemia major/Hb Bart’s disease.11
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