Diagnosis of thalassemia (adults and children)

INTRODUCTION — The thalassemias are a group of hemoglobinopathies in which the normal ratio of alpha globin to beta globin production is disrupted due to a genetic variant in one or more alpha or beta globin genes. This abnormal alpha chain to beta chain ratio causes the unpaired chains to precipitate, leading to destruction of red blood cell (RBC) precursors in the bone marrow (ineffective erythropoiesis) and in the circulation (hemolysis). Individuals with thalassemia have variable degrees of anemia and extramedullary hematopoiesis, which in turn can cause bone changes, impaired growth, and iron overload.

This topic review discusses the clinical manifestations and diagnosis of alpha and beta thalassemia, the two most common forms. Thalassemias involving delta, gamma, epsilon, and zeta chains are rare and are usually not associated with significant disease outside of the neonatal period.

The pathogenesis and treatment of thalassemia, including the role of hematopoietic stem cell transplantation, monitoring of iron stores, and iron chelation, are discussed in detail separately.

●Genetics – (See "Molecular genetics of the thalassemia syndromes".)

●Pathogenesis – (See "Pathophysiology of thalassemia".)

●Treatment – (See "Management of thalassemia" and "Alpha thalassemia major: Prenatal and postnatal management".)

●Chelation therapy – (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

●Transplant – (See "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia" and "Thalassemia: Management after hematopoietic cell transplantation".)

EPIDEMIOLOGY — Thalassemia (from the Greek word thalassa [sea]) refers to a group of inherited hemoglobinopathies that arose in certain regions of the world (sub-Saharan Africa, the Asian-Indian subcontinent, Southeast Asia, Mediterranean region) in which malaria is (or was) endemic.

Thalassemias are one of the most common of the hemoglobinopathies, second only to sickle cell disease [1,2]. It has been estimated that 5 percent of the world's population has at least one thalassemia variant allele, with as many as 900,000 individuals with clinically significant disease expected during the early 21^st century, the majority in Southern China, India, and Southeast Asia [3,4].

●Alpha thalassemia – Alpha thalassemia is highly prevalent in Southern China, Malaysia, and Thailand [5]. Mild forms are also commonly encountered in individuals with African ancestry. Individuals with Asian ancestry may carry the alpha thalassemia-1 trait (two alpha gene deletions in cis; aa/--); these individuals are at greater risk of hydrops fetalis. Individuals of African ancestry typically carry the alpha thalassemia-2 trait (two alpha gene deletions in trans; a-/a-) and are unlikely to develop hydrops fetalis.

●Beta thalassemia – Beta thalassemia is present in Africa with an estimated heterozygote frequency of approximately 3 to 4 percent (varies by geography) [6].

International migration has contributed to greater genetic diversity and increased prevalence of thalassemia in other countries and around the world.

OVERVIEW OF SUBTYPES AND DISEASE SEVERITY — Thalassemias are characterized by reduced production of the alpha or beta chains that form the hemoglobin molecule. The decrease in one type of globin chain (alpha or beta) causes an imbalance in the normal alpha to beta chain ratio. (See "Pathophysiology of thalassemia", section on 'Globin chain imbalance'.)

The degree of alpha-beta imbalance and the properties of the excess chains that accumulate drive the clinical phenotype, as summarized in the table (table 1). The magnitude of ineffective erythropoiesis is the proximate driver of the severity of anemia and iron overload (even in the absence of transfusions). This is why coinheritance of alpha and beta thalassemia can ameliorate symptoms. (See "Pathophysiology of thalassemia", section on 'Combinations of hemoglobin variants'.)

The types of thalassemia are summarized briefly here and discussed in more detail separately. (See "Pathophysiology of thalassemia" and "Molecular genetics of the thalassemia syndromes".)

Alpha thalassemias — There are four alpha globin genes (two genes at the alpha globin locus inherited from each parent). Alpha thalassemia is caused by reduced production of alpha chains and accumulation of excess beta-like chains. The severity of phenotype increases with loss of one, two, three, or four functioning alpha globin alleles. Nondeletional variant alleles such as hemoglobin Constant Spring (Hb CS) tend to cause more severe phenotypes than the deletional alleles (--/aa^CS tends to be more severe than aa/a-) [7]. The reason for this is not well understood, but it is speculated that it might have to do with the biochemical instability of the alpha chain arising in reduced amounts from the abnormal allele, producing oxidative damage in early erythropoiesis.

●Hemoglobin Barts – Hemoglobin Barts (Hb Barts) is a complete lack of alpha chains (--/--). Alpha chains are used to make fetal hemoglobin (Hb F, alpha2 gamma2), and severe anemia occurs during fetal development, with hydrops fetalis. When there are no alpha chains to pair with gamma chains, the only hemoglobin produced is Hb Barts (tetramers of gamma globin). Hb Barts is often fatal before birth unless in utero transfusions are administered. (See "Alpha thalassemia major: Prenatal and postnatal management".)

●Hemoglobin H disease – Hemoglobin H (Hb H) disease is loss of three alpha chain genes (--/a-). When alpha chains are reduced, beta chains pair together to form Hb H (tetramers of beta globin). Some Hb F is also produced in the fetus and infant, and some Hb A is produced after the fetal to adult hemoglobin switch. The genotype can be "deletional" (--/a-) or nondeletional (--/aa^t, in which the "t" stands for a mutant alpha chain such as Hb CS). Deletional forms are more common in individuals with ancestry from Africa and Asia; nondeletional forms, especially Hb CS, are more common in those with Mediterranean ancestry. (See "Molecular genetics of the thalassemia syndromes", section on 'Failed translation termination: Hb constant spring'.)

The clinical severity in Hb H disease is variable. Most individuals are symptomatic at birth but typically do not require regular transfusions. Anemia is generally mild (typical hemoglobin, 9 to 11 g/dL; typical mean corpuscular volume [MCV], 62 to 77 fL) and neonatal jaundice may be present [8-10]. Some individuals are asymptomatic; some have more severe anemia and require episodic transfusions during periods of increased hemolysis (from infection), with pregnancy (dilutional anemia), or if they develop an aplastic crisis (from parvovirus) [11]. In some, disease can deteriorate into transfusion dependence. Hb H is readily oxidized, and the red blood cells (RBCs) are susceptible to oxidant stress such as from infection or oxidizing drugs. (See 'Anemia' below.)

Approximately 70 percent of individuals with Hb H disease develop complications associated with ineffective erythropoiesis and extramedullary hematopoiesis, including some degree of iron overload by adulthood (even with minimal or no transfusion history), and hepatosplenomegaly [11-13]. A smaller proportion (10 to 20 percent) have other symptoms related to chronic hemolysis, extramedullary hematopoiesis, or iron overload, such as gallstones, bone deformities, or growth impairment, respectively. Leg ulcers are also common. (See 'Clinical manifestations' below.)

A condition known as acquired Hb H disease can occur with clonal evolution of a hematopoietic stem cell with an alpha globin variant (such as in a myelodysplastic syndrome). (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Acquired hemoglobin H disease'.)

●Alpha thalassemia minor – Alpha thalassemia minor is a loss of two alpha chain genes (--/aa or -a/-a). Heterozygosity for the alpha thalassemia-1 trait (--/aa) is more common in individuals with Asian ancestry; homozygosity for alpha thalassemia-2 trait (-a/-a) is more common in individuals of African ancestry. This is a clinically mild condition characterized by mild anemia, hypochromia, and microcytosis without other clinically obvious manifestations.

●Alpha thalassemia minima – Alpha thalassemia minima (also called silent carrier) is a loss of a single alpha-chain gene (aa/-a). This is an asymptomatic carrier state. Anemia is absent, RBCs are not microcytic (although mild hypochromia may be noted on the blood smear), and hemoglobin analysis is normal (there is no Hb H).

Alpha thalassemia minor or minima may remain undiagnosed, or they may be detected incidentally on a routine complete blood count (CBC) during evaluation of an unrelated condition or with reproductive testing and counseling.

Beta thalassemias — There are two beta globin genes (one inherited from each parent). Beta thalassemia is caused by reduced production of beta chains and accumulation of excess alpha chains. This may be due to variants that reduce the expression of beta globin (beta⁺) or completely eliminate beta globin expression (beta⁰). The severity of disease correlates with the amount of normal beta globin production. Terminology has shifted from using the "major, intermedia, minor" designation to referring to the disorder as transfusion-dependent or non-transfusion-dependent.

●Transfusion-dependent – Individuals with beta thalassemia who require regular transfusions due to severe anemia and/or significant complications of extramedullary hematopoiesis are referred to as having transfusion-dependent beta thalassemia (TDT). Previously this was designated as beta thalassemia major, Cooley's anemia, or Mediterranean anemia; it also included some cases of beta thalassemia intermedia. The genotype may be beta⁰/beta⁰, beta⁺/beta⁰, or beta⁺/beta⁺ with severely reduced beta globin production. Another possible genotype is compound heterozygosity for hemoglobin E (Hb E/beta thalassemia); Hb E is a beta⁺ type of mutation. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb E'.)

These individuals have minimal to no beta globin chain production and consequently little to no Hb A. Since the Hb F to Hb A transition occurs after birth, symptoms typically manifest during late infancy (approximately 6 to 12 months) [14-18]. Presentations of TDT can be remarkably heterogeneous depending on the aggressiveness of therapy and other mitigating factors. Without treatment, the disorder is characterized by severe anemia, manifestations of extramedullary hematopoiesis, and complications of iron overload. (See 'Clinical manifestations' below.)

●Non-transfusion-dependent – Individuals with a less-severe phenotype (typically, anemia that does do not require regular transfusions) are referred to as having non-transfusion-dependent beta thalassemia (NTDT). Previously this was mostly designated as beta thalassemia intermedia. These individuals are often homozygous or compound heterozygous for a beta⁺ thalassemia variant or heterozygous for a beta⁰ thalassemia variant. The typical age of presentation is two to four years [19]. Genotypes are listed in the table (table 2).

Clinical presentations are heterogeneous [9]. Some individuals never require transfusions; others develop transfusion dependence in the third to fourth decade or during periods of erythropoietic stress (infections, pregnancy). Some develop findings associated with extramedullary hematopoiesis and some do not. Most develop iron overload, although the age at which this occurs is highly variable [9,20]. (See 'Complications of extramedullary hematopoiesis' below and 'Complications of iron overload' below.)

●Beta thalassemia minor – Beta thalassemia minor (also called beta thalassemia trait) is a carrier condition in which an individual is heterozygous for a beta⁺ or beta⁰ thalassemia mutation. Beta thalassemia minor is often an asymptomatic carrier state. Individuals with beta thalassemia minor may have mild anemia; most are asymptomatic but exhibit marked microcytosis that can be mistaken for iron deficiency. (See 'Differential diagnosis' below.)

CLINICAL MANIFESTATIONS

Severity and age of onset — Clinical manifestations of the thalassemias range from asymptomatic carrier status to profound abnormalities including severe anemia, extramedullary hematopoiesis, skeletal and growth deficits, and iron overload, with a dramatically shortened life expectancy in the absence of aggressive treatment [1,9,14,15,19].

The severity of clinical features correlates with the number of functioning globin chains that are lost and the ratio of alpha to beta chains. In some individuals with beta thalassemia, higher levels of fetal hemoglobin (Hb F) such as in hereditary persistence of fetal hemoglobin (HPFH) may ameliorate severity [21,22]. Coinheritance of alpha and beta thalassemia can occur and can modify the phenotype as well. (See 'Overview of subtypes and disease severity' above and "Pathophysiology of thalassemia", section on 'Combinations of hemoglobin variants'.)

An example of the frequency of different clinical findings was illustrated in a retrospective review of 584 individuals with beta thalassemia (classified as beta thalassemia intermedia, which is now termed non-transfusion-dependent thalassemia [NTDT]) [23]. Most were adults, approximately half were receiving regular transfusions, and approximately half had undergone splenectomy:

●Osteoporosis – 23 percent

●Extramedullary hematopoiesis (radiologic evidence) – 21 percent

●Hypogonadism – 17 percent

●Cholelithiasis (by ultrasound) – 17 percent

●Thrombosis – 14 percent

●Pulmonary hypertension – 11 percent

●Abnormal liver function – 10 percent

●Leg ulcers – 8 percent

●Hypothyroidism – 6 percent

●Heart failure – 4 percent

●Diabetes mellitus – 2 percent

The age of onset differs for alpha and beta thalassemia:

●Alpha thalassemia – Anemia can develop in utero in individuals with Hb Barts and hemoglobin H (Hb H) disease.

●Beta thalassemia – Because hemoglobin switching happens after birth (from Hb F, containing gamma globin, to Hb A, containing beta globin), the thalassemia phenotype generally begins to manifest during the first year of life (typically, around the age of 6 months); newborns are asymptomatic [19].

Anemia — The presence and severity of anemia correlates with the number of functioning globin chains and the amounts of chains produced. Other factors include the specific genotype, patient age and comorbidities, genetic variation, and environmental factors such as oxidant exposure. (See "Pathophysiology of thalassemia", section on 'Mechanisms of anemia'.)

●Severe anemia (thalassemia major; transfusion-dependent thalassemia [TDT]) – A markedly reduced hemoglobin level is consistent with hydrops fetalis/Hb Barts, which presents in utero and typically is not compatible with live birth, or beta thalassemia major, which presents at 6 to 12 months of age. In Hb Barts, fetal death usually occurs during the late-second through mid-third trimester or within a few hours of birth. Occasional live births have been reported, some following use of intrauterine transfusion [24-27]. (See "Nonimmune hydrops fetalis", section on 'Anemia' and "Intrauterine fetal transfusion of red blood cells" and "Alpha thalassemia major: Prenatal and postnatal management".)

•Untreated infants with severe anemia have pallor, jaundice, dark urine from hemolysis, irritability, and abdominal swelling from hepatosplenomegaly, which may be followed by high-output heart failure, failure to thrive, and infection [28-30]. (See 'Complications of hemolysis' below.)

•The hemoglobin may be as low as 3 to 4 g/dL. There is typically marked hypochromia and microcytosis, bizarre red blood cell (RBC) morphology (picture 1), and an increased RBC count. Laboratory evidence of non-immune hemolysis is present (table 3). (See 'CBC and hemolysis testing' below.)

•Sites of extramedullary hematopoiesis expand, causing skeletal abnormalities of the face and long bones, hepatosplenomegaly, and kidney enlargement. Splenomegaly due to hemolysis may be exacerbated by extramedullary hematopoiesis and liver disease from iron overload. Late symptoms of iron overload can affect the heart, liver, endocrine organs, and others. (See 'Complications of extramedullary hematopoiesis' below.)

•These individuals require chronic transfusions. (See "Management of thalassemia", section on 'Regular transfusions'.)

Some individuals with Hb H disease may also have severe anemia and become transfusion-dependent. Profound anemia is more characteristic of beta thalassemia than Hb H disease, but the hemoglobin level does not distinguish between alpha and beta thalassemia.

●Moderate anemia – Moderate anemia is generally seen in non-transfusion-dependent thalassemia; this was previously called thalassemia intermedia. Moderately severe Hb H disease was often also included in the term thalassemia intermedia. These individuals can develop severe anemia requiring episodic transfusions during periods of erythropoietic stress (infection, pregnancy), and their disease can deteriorate into transfusion dependence, especially later in adulthood. In a retrospective series of 584 individuals with beta thalassemia intermedia, mean hemoglobin was 7.5 to 10.5 g/dL [23]. In a retrospective series of 131 individuals with Hb H disease, most had hemoglobin levels of 8 to 11 g/dL [8]. Approximately 30 to 50 percent of individuals with Hb H disease have received at least one transfusion.

●Mild anemia and/or microcytosis – Mild anemia with microcytosis, or microcytosis alone, is consistent with thalassemia minor. The hemoglobin is usually >10 g/dL, and there is not a large component of ongoing hemolysis or ineffective erythropoiesis. A 2008 retrospective review involving 217 individuals with beta thalassemia trait described other subtle symptoms [31]. Approximately two-thirds were aware of their diagnosis. Compared with controls, the individuals with beta thalassemia minor/trait were more likely to have lethargy and fatigue and to seek medical attention for fever.

Because individuals with TDT are under constant erythropoietic stress (if not optimally transfused), they are more susceptible to infections, drugs, or nutritional deficiencies that interfere with RBC production. Common examples include aplastic crisis due to parvovirus B19 infection and hypoplastic crises due to infection, oxidant drug exposure (especially in alpha thalassemia/Hb H disease), or folate deficiency.

Complications of hemolysis

Jaundice and pigment gallstones — Bilirubin (pigment) gallstones and biliary tract inflammation may be a prominent feature of chronic hemolytic anemia, especially in children and adults with TDT. (See "Overview of gallstone disease in adults", section on 'Clinical manifestations'.)

Cholecystitis or cholangitis are rare, and cholecystectomy is rarely indicated in the absence of clinically obvious symptoms.

Hepatosplenomegaly — Hepatosplenomegaly may be due to chronic hemolysis, extramedullary hematopoiesis in the liver and spleen, and hepatic iron deposition; in the past, viral hepatitis acquired from transfusions also contributed. In TDT without iron chelation, hepatomegaly typically develops within the first few years of life. The risk of hepatocellular cancer may be increased, and screening is typically warranted if cirrhosis or bridging fibrosis is present [32]. (See "Management of thalassemia", section on 'Monitoring and management of disease complications'.)

Splenomegaly is common in TDT and can occur in non-transfusion-dependent disease. In thalassemia minor, the spleen is not usually palpable, but spleen size is often abnormally large on ultrasound imaging [31,33,34]. Findings can include early satiety, shortened survival of transfused RBCs, or progressive worsening of anemia. Unlike sickle cell disease, individuals with thalassemia are not functionally asplenic (unless they undergo splenectomy). Indications for splenectomy and pre- and post-splenectomy care are reviewed separately. (See "Management of thalassemia", section on 'Role of splenectomy'.)

Complications of extramedullary hematopoiesis — Ineffective RBC production in the bone marrow due to death of developing RBC precursors is referred to as ineffective erythropoiesis. When this happens in thalassemia, sites of erythropoiesis develop outside the bone marrow (extramedullary). (See "Pathophysiology of thalassemia", section on 'Ineffective erythropoiesis'.)

Skeletal changes — Skeletal changes are common in TDT and can cause:

●Facial deformities – Marked changes can occur in facial structure (picture 2), with frontal bossing, delayed pneumatization of the sinuses, marked overgrowth of the maxillae, "jumbling" of the upper incisors, and increased prominence of the malar eminences, producing the characteristic "chipmunk facies" and dental malocclusion [35].

●Changes in body habitus – The ribs and bones of the extremities can become box-like and eventually convex, and premature fusion of the epiphyses resulting in characteristic shortening of the limbs, particularly the arms. Changes in the hands and feet become somewhat less prominent in the second decade of life (if the child survives) because the hematopoietically active "red" bone marrow is replaced by inactive "yellow" marrow near the end of the first decade. Changes in the shape of the skull, pelvis, and spine may become more pronounced as hematopoiesis continues in these sites. (See "Overview of hematopoietic stem cells", section on 'Sites of hematopoiesis'.)

●Osteopenia/osteoporosis – Osteopenia and osteoporosis occur due to widening of the bone marrow spaces [36]. Widening of the diploic spaces in the skull can produce characteristic "hair-on-end" radiographic appearance [37].

Osteopenia affects up to 45 percent of individuals with TDT (beta thalassemia), and osteoporosis occurs in 15 to 50 percent [38]. Untreated, osteoporosis can lead to vertebral fractures, with spinal deformities, back pain, and impaired growth [39-41]. Predictors of fracture include male sex, older age, hypothyroidism, delayed puberty, diabetes, heart disease, and hepatitis [38,41]. Other contributing factors may include genetic variation, vitamin deficiencies, excess iron stores, and toxicities of iron chelators [39,42-55].

●Bony masses – In the most severely symptomatic children, erythroid bone marrow may invade the bony cortex and break through bone, setting up masses of ectopic erythroid cell colonies in the thoracic or pelvic cavities or sinuses (image 1). These expanding masses can behave clinically like tumors, causing spinal cord compression and other abnormalities [56].

●Pain – Bone pain may be caused by osteoporosis, expansion of the bone marrow space, and other bone changes [36]. In a prospective series of 252 individuals 12 years or older with TDT (alpha or beta), 64 percent reported pain in the previous four weeks; approximately half had pain daily or weekly, and in most, it was moderate to very severe [57]. As with other chronic pain syndromes, depression, anxiety, and reduced quality of life can occur [58].

These changes may be partially prevented or partially reversed by chronic transfusions, especially if initiated early in childhood, although most individuals will retain some sequelae.

Iron overload — Iron overload is common in TDT and some cases of NTDT. Causes include ineffective erythropoiesis, which promotes increased intestinal iron uptake, and transfusional iron overload. Iron overload is not seen in individuals with thalassemia minor/trait/minima. (See "Pathophysiology of thalassemia", section on 'Iron overload'.)

Excess iron stores can cause toxicity in the liver, heart, endocrine organs, and others [59,60]. (See 'Growth impairment' below and 'Hepatosplenomegaly' above and 'Endocrine and metabolic abnormalities' below and 'Heart failure and arrhythmias' below.)

The prevalence and severity of iron overload are changing as more individuals are managed with iron chelation from an early age. As an example, an individual with TDT (beta thalassemia major) who receives chronic transfusions without chelation therapy may develop severe iron overload in childhood, whereas some children who receive adequate iron chelation starting in childhood may remain free of excess iron stores. Individuals with NTDT (beta thalassemia) may develop iron overload in adulthood. In a series of 168 adults with NTDT (beta thalassemia; mean age 35 years), the mean liver iron concentration estimated by magnetic resonance imaging (MRI) was 8.4 mg/g dry liver weight (normal, <2 mg/g dry weight) [59].

These observations provide the rationale for early screening for iron overload and the use of chelation therapy when instituting a chronic transfusion program or when the individual develops evidence of excess iron stores. (See 'Rule out iron deficiency' below and "Management of thalassemia", section on 'Assessment of iron stores and initiation of chelation therapy'.)

Growth impairment — Growth impairment in thalassemia is multifactorial. It may be exacerbated by chronic anemia, effects of extramedullary hematopoiesis on bones, and endocrine dysfunction from excessive iron stores affecting growth and puberty. The likelihood is proportional to disease severity. Contributing factors include [1]:

●Chronic anemia (see 'Anemia' above)

●Ineffective erythropoiesis, leading to a hypermetabolic state as well as impaired bone development (see 'Skeletal changes' above)

●Nutrient deficiencies (folate, zinc, vitamin E) related to hypermetabolic state and chelation therapy (see 'Endocrine and metabolic abnormalities' below)

●Excess iron stores, causing endocrinopathies such as hypogonadism with delayed puberty (see 'Endocrine and metabolic abnormalities' below)

●Toxicities of iron chelation therapy (see "Iron chelators: Choice of agent, dosing, and adverse effects")

The adolescent growth spurt is often delayed. In a study involving 361 children and adults from the Thalassemia Clinical Research Network, approximately one-fourth had short stature independent of age and type of thalassemia, and the median age of menarche in those with hypogonadism was 17 years [61].

A comprehensive approach that proactively addresses all of these factors is most likely to be effective. (See "Management of thalassemia", section on 'Routine evaluations and monitoring'.)

Complications of iron overload

Endocrine and metabolic abnormalities — Endocrine and metabolic abnormalities are common in TDT; these are attributable, at least in part, to chronic iron overload [62-68].

●Hypogonadism – Hypogonadism results from pituitary iron deposition. Primary and secondary characteristics of sexual development are usually delayed for females and males [47]. Common findings in females include delayed menarche, impaired breast development, and oligomenorrhea or amenorrhea. Males often have sparse facial and body hair. Decreased libido may occur in both sexes, possibly related to iron overload.

●Hypothyroidism – Hypothyroidism may be caused by iron deposition in the thyroid gland and occasionally in the pituitary gland.

●Insulin resistance and diabetes – Insulin resistance from iron deposition in pancreatic islet cells can affect carbohydrate metabolism and cause glucose intolerance (often in the teenage years) or diabetes [69]. Iron chelation appears to improve glucose intolerance [70]. Diabetes increases the risk of cardiac complications [71]. (See 'Heart failure and arrhythmias' below.)

●Growth impairment – (See 'Growth impairment' above.)

Most individuals with increased iron stores have at least one endocrinopathy; hypogonadism is consistently the most common abnormality reported [61,64,65]. Accumulating evidence suggests iron chelation can arrest the progression of the endocrine abnormalities and in some cases reverse them, although data for the latter are limited [72]. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

Increased hematopoiesis with high cellular turnover can cause metabolic abnormalities including hyperuricemia and gouty nephropathy. Gouty arthritis is rare before the second or third decade. (See "Asymptomatic hyperuricemia".)

The hypermetabolic state may also cause deficiencies of folate, zinc, and vitamin E. Zinc deficiency may be exacerbated by iron chelation therapy [73-75]. Vitamin D deficiency is common, especially in adolescents, although it is not clear how this compares with the general population [61]. Vitamin B12 and B6 (pyridoxine) are usually normal.

Heart failure and arrhythmias — Cardiac complications are a common feature of transfusion-dependent beta thalassemia and may occur less commonly in mid-adulthood in any form of NTDT, especially if there is iron overload. Heart failure and arrhythmias can be fatal [76].

The causes are multifactorial and include anemia, cardiac iron deposition, diabetes, vascular dysfunction due to oxidative stress, pulmonary arterial hypertension (PH), high cardiac output related to chronic tissue hypoxia and increased pulmonary vascular resistance, vitamin D deficiency, and others [77-84]. The general consensus is that iron accumulation plays the most significant role and can cause myocardial fibrosis and necrosis [85]. However, the interpretation of iron-related heart damage is evolving; cardiotoxicity from oxygen radicals or free iron may also play an important role.

●Anemia-related cardiac dilatation is nearly universal in severe disease until transfusions are instituted. There can be resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and increased cardiac output [84]. (See 'Anemia' above.)

●Later in the disease course, cardiac iron deposition can cause sterile pericarditis, arrhythmias (supraventricular and ventricular), restrictive cardiomyopathy, and heart failure. In a study that compared electrocardiogram (ECG) findings with the degree of iron overload in the heart (based on MRI) in 78 individuals with thalassemia, repolarization abnormalities (QT interval prolongation, left shift of the T-wave axis) and bradycardia were the strongest indicators of excess cardiac iron deposition [86]. Echocardiography or radionuclide ventriculography may demonstrate reduced left ventricular ejection fraction (LVEF), decreased atrial function, and/or an abnormal right ventricle relaxation pattern [76,87-89]. (See 'Iron overload' above.)

The diagnosis of cardiac dysfunction in thalassemia must take into account the altered hemodynamics due to chronic anemia as well as the extent of iron overload. Cardiac consultation is appropriate to obtain a baseline assessment of cardiac status based on findings on the ECG and echocardiogram (or other cardiac function assessment). MRI to assess cardiac iron overload is appropriate in many cases, including as a baseline prior to starting chronic transfusion therapy. The timing of MRI depends on expected degree of iron overload, which in turn depends on severity of thalassemia, number of transfusions, and adherence to chelation therapy.

A 2013 consensus statement from the American Heart Association emphasized the importance of assessing cardiac iron overload using MRI and of initiating intensive chelation therapy for those with increased cardiac iron [84]. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

Pulmonary abnormalities and PH — Most individuals with transfusion-dependent beta thalassemia have mild abnormalities of pulmonary function, including restrictive and small airway obstructive defects, hyperinflation, decreased maximal oxygen uptake, and abnormal anaerobic thresholds. Although abnormal findings are common on pulmonary function testing, symptoms are relatively infrequent. The mechanism of these pulmonary function abnormalities is not well understood; they do not appear to correlate with iron burden, severity of anemia, or degree of hemolysis, and they are not corrected by transfusions [90]. After splenectomy, profound thrombocytosis increases the risk for pulmonary vascular obstruction.

Adults may develop pulmonary hypertension (PH), the cause of which is not entirely clear and may include prior splenectomy, older age, chronic hemolysis with decreased nitric oxide (NO) availability, cardiac iron overload, platelet activation, and smoking [91-96].

In a 2014 retrospective study that included 1309 patients with beta thalassemia (approximately three-fourths TDT and one-fourth NTDT), 47 (3.6 percent) were considered to have a high likelihood of PH based on a tricuspid regurgitant jet velocity of ≥3.2 m/second on transthoracic echocardiography [95]. Of 33 who underwent right heart catheterization, 31 were found to have PH with a mean pulmonary artery pressure ≥25 mm Hg. Risk factors for developing PH were age (odds ratio [OR] 1.1 per one-year increase) and splenectomy (OR 9.3; 95% CI 2.6-33.7). Similar rates of PH (approximately 4 percent) have been reported in alpha thalassemia (Hb H disease) [96].

Thrombosis — TDT is considered a hypercoagulable state, although the magnitude of thrombosis risk is challenging to determine [97]. Most studies find the risk of thromboembolic events to be greater in what was previously called thalassemia intermedia than in thalassemia major syndromes. Venous events are more frequently seen than arterial, but both occur, and arterial events may be more common in thalassemia major [98,99]. A variety of sites of thromboembolism have been reported, including central nervous system, lungs, abdominal vasculature, and deep veins of the arms and legs [100,101].

The overall incidence of thromboembolism appears to be decreasing [64,100]. In a 2006 study involving over 8000 patients (median age, 30 years), thromboembolism was seen in 1.65 percent [99]. Venous events were seen in 57 percent (mostly in individuals who had undergone splenectomy), arterial events occurred in 40 percent (more common with more severe thalassemia), and combined arterial and venous events were seen in 3 percent. In the subgroup with thalassemia major, arterial events were more common. Splenectomy may carry an increased risk for portal vein thrombosis related to effects on the abdominal vascular beds [102,103].

Risk factors for thrombosis include older age, female sex, prior splenectomy, cardiomyopathy, and diabetes; these conditions are likely to contribute to thromboembolism risk independently of the thalassemia diagnosis [99,104]. A number of mechanisms have been proposed related to thrombocytosis, platelet activation, RBC aggregation, endothelial hyperactivity, and impaired function of the heart, liver, and endocrine organs [105-107]. Laboratory markers that correlate with thromboembolic risk are under investigation [108]. Regular transfusions appear to decrease the risk of thromboembolic disease, although thromboembolism alone is rarely the sole indication for initiating regular transfusions. Luspatercept has also been demonstrated to increase thrombosis risk in individuals with TDT who have undergone splenectomy. (See "Management of thalassemia", section on 'Decision to initiate regular transfusions' and "Management of thalassemia", section on 'Luspatercept for transfusion-dependent beta thalassemia'.)

Leg ulcers — Leg ulcers are common in individuals with thalassemia, regardless of whether the disease is transfusion-dependent. Possible risk factors and mechanisms include age, iron overload, and reduced tissue oxygenation [109-111].

Cancer — Scattered reports have emerged raising the question of whether patients surviving into adulthood with thalassemia have an increased risk of cancer.

As an example, a report from 2015 that examined over 2500 individuals with thalassemia enrolled over a 14-year period and followed for an additional five years found a 50 percent increase in cancer incidence compared with a population cohort of 10,000 individuals without thalassemia [112]. Hematologic malignancies, and "abdominal cancers" accounted for almost all of the increase. The former was attributed to the high rates of cell turnover, bone marrow injury, and immunologic effects of chronic transfusion. The abdominal cancer risk might be due to hepatocellular carcinomas arising in chronically damaged and cirrhotic livers due to iron overload, hepatitis from transfusion-transmitted viral infections, and other comorbidities. In support of this hypothesis was the >9-fold elevation of abdominal cancers in heavily transfused iron overloaded patients.

DIAGNOSTIC EVALUATION — The diagnostic evaluation depends on the personal and family history and available laboratory results.

History and physical examination — The history focuses on the following:

●Family history (FH)

•FH of thalassemia can help determine type and severity of thalassemia.

•FH of sickle cell disease or trait or other hemoglobinopathies can suggest compound syndromes.

•The FH may include anemia without a specific diagnosis.

•A negative FH does not eliminate the possibility of thalassemia since both parents may be asymptomatic carriers.

●Age of onset – Onset at or before birth suggests alpha thalassemia major; onset in infancy (6 to 12 months) suggests transfusion-dependent beta thalassemia. Diagnosis later in life suggests a milder form. (See 'Overview of subtypes and disease severity' above and 'Severity and age of onset' above.)

●Severity of symptoms

•History of gallstones suggests possible chronic hemolysis.

•History of jaundice or dark urine suggests significant hemolysis.

•Impaired growth or skeletal changes suggest significant extramedullary hematopoiesis.

●Examination – Those with severe disease may also have evidence of hemolysis and extramedullary hematopoiesis such as jaundice, skeletal abnormalities, or splenomegaly.

The family or clinician may be contacted with positive results from prenatal testing or from a newborn screening test. The evaluation of these individuals is the same as for those suspected to have thalassemia based on other information. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Population screening (eg, routine newborn screen)'.)

Laboratory testing — Initial testing includes a complete blood count (CBC), review of the blood smear, and iron studies. Iron studies are required to evaluate for iron deficiency and iron overload. In appropriate patients, hemoglobin analysis and/or genetic testing is appropriate to confirm the diagnosis.

Bone marrow evaluation is not required, but, if performed, it will reveal hyperplasia that is unusual in the degree to which there is a preponderance of immature erythroblasts. There may be bizarre morphology of erythroid progenitors, with poorly hemoglobinized erythroblasts that have inclusion bodies similar to Heinz bodies. There may be megaloblastic changes, especially if folate is deficient (due to increased requirements with hemolysis).

CBC and hemolysis testing — The following findings are consistent with thalassemia:

●Microcytic anemia – Microcytic, hypochromic anemia is typical in all thalassemia syndromes except asymptomatic carriers (algorithm 1). In transfusion-dependent beta thalassemia and hemoglobin H (Hb H) disease there is profound hypochromic, microcytic anemia accompanied by bizarre red blood cell (RBC) morphology (picture 1 and picture 3) [14,15]. Mild microcytosis or anemia may be seen in thalassemia minor (picture 4). The CBC may be normal in thalassemia minima/trait. Specific values for the hemoglobin concentration in different thalassemia syndromes are listed above (see 'Anemia' above). Other RBC abnormalities may also be present in more severe disease, including extreme hypochromia, poikilocytosis, target cells, teardrop cells, and cell fragments.

RBC inclusions representing precipitated globin chains may be seen on routine Wright-Giemsa staining and are more easily appreciated using supravital stains such as methyl violet or brilliant cresyl blue (picture 5), although special stains are not part of routine laboratory testing for thalassemia [113].

●High RBC count; mildly increased reticulocyte count – The RBC count is increased in thalassemias. This is especially true in more severe disease but may also occur in thalassemia minor. The reticulocyte count may be slightly increased, but not to the extent that would be expected for the severity of anemia, especially in beta thalassemia. An increased RBC count is often helpful in distinguishing thalassemia from iron deficiency anemia, although other testing is required. (See 'Differential diagnosis' below.)

●Hemolysis – Testing for hemolysis includes lactate dehydrogenase (LDH), indirect (unconjugated) bilirubin, haptoglobin, and Coombs testing (table 3). Thalassemia causes non-immune hemolysis, with high LDH, high indirect bilirubin, low haptoglobin, and negative Coombs testing. If the diagnosis of thalassemia is very likely, the Coombs testing may be omitted. The other testing for hemolysis (LDH, bilirubin, haptoglobin) is useful as a baseline for monitoring the course of the disease and the response to therapy. In thalassemia minor, evidence of hemolysis is typically absent (overt or on laboratory testing). (See "Overview of hemolytic anemias in children", section on 'Serum LDH, haptoglobin, and plasma free hemoglobin' and "Diagnosis of hemolytic anemia in adults", section on 'High LDH and bilirubin; low haptoglobin'.)

●Normal WBC and platelet count – Thalassemia does not directly affect white blood cells (WBCs) and platelets. Leukocytosis may signify an infection. However, many individuals with thalassemia have chronically elevated neutrophil counts for reasons that are not always clear. Some laboratory cell counters will misclassify nucleated red blood cells (NRBCs) as WBCs. Mild cytopenias due to hypersplenism may develop later in the disease course. WBCs, platelets, and NRBCs may increase dramatically after splenectomy.

Other testing related to the need for blood transfusions includes a detailed blood type (and crossmatching for those with severe anemia). For those with very severe disease, human leukocyte antigen (HLA) typing may be appropriate for possible hematopoietic stem cell transplantation. (See "Pretransfusion testing for red blood cell transfusion" and "Management of thalassemia", section on 'Decision to pursue allogeneic HSCT'.)

Rule out iron deficiency — Iron deficiency must be ruled out when evaluating for thalassemia (algorithm 1). Laboratory findings that distinguish iron deficiency from thalassemia are summarized in the table (table 4):

●Iron deficiency is the most common cause of microcytic anemia. Even if thalassemia is diagnosed, iron deficiency may be present. Treatment of iron deficiency (and determination of the cause) is essential to avoid preventable complications. (See "Treatment of iron deficiency anemia in adults".)

●Concomitant iron deficiency can interfere with protein-based testing for thalassemia by altering the ratio of normal hemoglobins (lowering Hb A2). (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Patient with suspected thalassemia'.)

●A third benefit for individuals ultimately diagnosed with thalassemia is that the iron studies will help determine if iron overload is present. (See 'Iron overload' above.)

Iron stores should be tested even when the diagnosis of thalassemia is likely, such as in an individual with a known family history of thalassemia and no evidence for dietary deficiency. Most laboratories will not perform hemoglobin analysis in an individual with suspected thalassemia until iron studies have been performed, to avoid unnecessary hemoglobinopathy testing in an individual with iron deficiency, as well as to ensure optimal interpretation of the results of the hemoglobin analysis. Population screening is an exception.

In straightforward cases, serum ferritin and transferrin saturation may be sufficient to rule out iron deficiency; in more complex cases, a full iron studies panel may be more useful. The sequence of testing (iron studies obtained before hemoglobin analysis or concurrently) can be individualized based on the urgency of evaluations and the burdens and costs of returning for a separate blood draw.

Distinguishing features between thalassemia and iron deficiency are summarized in the table (table 4). Because of the high rate of erythroid cell turnover, the serum iron level (and in turn, the transferrin saturation [TSAT]) are usually elevated in thalassemia, with the exception of thalassemia minor/minima [14]. Serum ferritin levels may be quite elevated if iron overload is present. Low serum ferritin is not seen in thalassemia unless there is concomitant iron deficiency.

Hemoglobin analysis and genetic testing — Hemoglobin analysis and/or genetic testing is required to confirm the diagnosis of thalassemia. (See 'Diagnostic confirmation' below.)

What test to order — Two decisions that need to be made are whether to use genetic testing or protein-based testing (or both), and, if genetic testing is done, whether to evaluate alpha globin genes or beta globin genes (or both).

●Genetic versus protein testing

•Genetic testing is required for precise diagnosis and is especially important in carrier detection, prenatal testing, and genetic counseling. Selected United States testing laboratories are listed in the table (table 5).

With the exception of the neonatal period, the diagnosis of alpha thalassemia minor or minima can only be made by DNA testing, and DNA testing is usually required to confirm the diagnoses of Hb H disease and less common forms of beta thalassemia such as delta-beta or gamma-delta-beta thalassemia. Electrophoresis or high performance liquid chromatography (HPLC) can show Hb Barts and/or Hb H in a neonate with alpha thalassemia. Genetic testing can be done by gene sequencing or a number of other methods. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis" and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Molecular genetic (DNA-based) methods'.)

•If genetic testing is not available, hemoglobin can be analyzed using a number of protein chemistry methods. The most commonly used are HPLC and various hemoglobin electrophoresis techniques. HPLC is becoming routine in many resource-rich settings and can be performed on a blood spot such as that used for newborn screening. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Protein chemistry methods' and 'Rule out iron deficiency' above.)

•If an individual has been heavily transfused, genetic testing may be preferable, since protein-based methods will be affected by proteins from transfused RBCs, whereas transfused RBCs will not alter the results of genetic testing.

•The need to repeat testing depends on the quality and experience of the testing laboratory and the extent to which appropriate genes or proteins are analyzed.

●Alpha versus beta thalassemia testing

•For neonates or infants <6 months of age with suspected thalassemia (based on a finding of microcytosis and/or anemia), alpha thalassemia is the more likely diagnosis since beta globin is not produced in this age group and beta thalassemias are unlikely to be clinically apparent.

•For older individuals, the likely thalassemia (alpha or beta) may be predicted from family history and/or clinical or laboratory features described above. However, clinical findings alone cannot be used to distinguish between alpha and beta thalassemia. (See 'Clinical manifestations' above.)

●Caveats

•Transfusions – If a transfusion was administered in the preceding three to four months, some of the transfused blood will be included in the sample used for a protein-based analysis, leading to increased Hb A and relative decreases in the other hemoglobins. Transfusion does not affect the results of genetic testing.

•Iron deficiency – Iron deficiency can skew the hemoglobin pattern and should be evaluated (and corrected, if present) in virtually all patients. (See 'Rule out iron deficiency' above.)

Interpretation — Typical findings of the different thalassemia syndromes are summarized in the table (table 1).

Examples include:

●Hb Barts and/or Hb H – Hb Barts (gamma chain tetramers) or Hb H (beta chain tetramers) is consistent with alpha thalassemia. Greater percentage of tetramers suggests more severe syndrome. Absence of fetal hemoglobin (Hb F), adult hemoglobin (Hb A), and Hb A2 suggests alpha thalassemia major. Hb Barts of 20 to 40 percent within one to two days after birth is the hallmark of Hb H disease in the newborn [8]. In older children or adults with Hb H disease, there may be a higher than average percentage of Hb F and Hb H (approximately 5 to 30 percent). Lower levels of Hb Barts (3 to 8 percent) or no Hb Barts is characteristic of alpha thalassemia minor (algorithm 1).

If a protein-based method has demonstrated findings consistent with an alpha thalassemia syndrome (or if testing for the alpha thalassemia minor or minima carrier states is indicated), DNA-based analysis is used. This may involve sequencing to detect point mutations such as Hb Constant Spring (Hb CS) or other methods to look for gene deletions. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Patient with suspected thalassemia' and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Molecular genetic (DNA-based) methods'.)

●Increased Hb F and/or increased Hb A2 – Increases in Hb F or Hb A2 are consistent with a beta thalassemia syndrome but not specific. Hb A2 is a minor adult hemoglobin that uses delta globin chains instead of beta globin chains (see "Structure and function of normal hemoglobins", section on 'Hb A2'). Concomitant iron deficiency may suppress the Hb A2 level into or even below the normal range [114]. An Hb A2 of approximately 5 percent (with a small percentage of Hb F and >90 percent Hb A) is consistent with beta thalassemia trait. [115]. However, the Hb A2 level may be normal in some individuals with delta-beta or gamma-delta-beta thalassemia trait or when beta thalassemia trait is coinherited with a delta globin gene variant [115-117]. Thus, a normal Hb A2 level does not eliminate the possibility of beta thalassemia trait. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Patient with suspected thalassemia' and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Protein chemistry methods'.)

More complex patterns may be associated with coinheritance of the sickle cell variant or other abnormal hemoglobins. (See "Overview of compound sickle cell syndromes" and "Pathophysiology of thalassemia", section on 'Combinations of hemoglobin variants'.)

Diagnostic confirmation — The diagnosis of a thalassemia is best confirmed by globin gene testing. If DNA testing is not available, the diagnosis of the more severe forms can be inferred based on the results from hemoglobin analysis as described above. (See 'Hemoglobin analysis and genetic testing' above.)

Differential diagnosis — The major condition in the differential diagnosis of thalassemias is iron deficiency. Other causes of microcytic anemia and other causes of target cells may also require consideration (table 6). (See "Microcytosis/Microcytic anemia".)

●Iron deficiency – Like thalassemia, iron deficiency anemia is a microcytic anemia that can cause markedly abnormal RBC morphologies including hypochromic/microcytic cells, target cells, and other abnormal morphologies (picture 6). The RBC count, reticulocyte count, and iron studies are the most useful distinguishing laboratory tests (table 4). All individuals being evaluated for thalassemia should have iron studies performed. (See 'Rule out iron deficiency' above and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

●ACD/AI – Like in thalassemia, in anemia of chronic disease/anemia of inflammation (ACD/AI) the ferritin can be normal to increased. An inflammatory or infectious disorder or malignancy is usually the underlying cause. Unlike thalassemia, most individuals with ACD/AI have normocytic anemia with no abnormalities on hemoglobin analysis. Unlike thalassemia, the conditions that cause ACD/AI are acquired, typically in adulthood.

●Other inherited anemias – Pyruvate kinase (PK) deficiency, unstable hemoglobin disorders, and glucose-6 phosphate dehydrogenase (G6PD) deficiency can cause anemia with abnormal RBC morphologies. Like thalassemia, there may be a positive family history of anemia. Unlike thalassemia, in most other inherited anemias, the RBC count is not increased, microcytosis is absent or mild, skeletal changes are absent, and hemoglobin analysis does not show the typical findings for alpha thalassemia (Hb Barts, Hb H) or beta thalassemia (increased Hb F or Hb A2).

●Liver disease and other causes of target cells – Target cells can be caused by liver disease, splenectomy, or any disorder that increases the lipid content of the RBC membrane. Like thalassemia, these conditions may be associated with anemia, and some cases of liver disease may be accompanied by iron overload. Unlike thalassemia, these conditions are acquired and typically present in adulthood. Unlike thalassemia, these conditions will not show manifestations of extramedullary hematopoiesis and will have normal findings on hemoglobin analysis. (See "Burr cells, acanthocytes, and target cells: Disorders of red blood cell membrane", section on 'Target cells'.)

Reproductive testing and counseling — Preconception or prenatal testing for thalassemia is appropriate in individuals with thalassemia and their first-degree relatives if previous testing has been incomplete or has not been done. Testing is also appropriate for those with a reasonable likelihood of thalassemia based on ethnicity, country of origin, or any other patient concerns. These individuals require genetic counseling and partner testing to assess their risk of conceiving a child with severe thalassemia. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis" and "Management of thalassemia", section on 'Reproductive testing and genetic counseling'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Beta thalassemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Disease overview – Alpha and beta thalassemia are hemoglobinopathies in which reduced production of alpha globin chains (alpha thalassemia) or beta globin chains (beta thalassemia) cause an imbalance in the alpha to beta ratio. Excess unpaired chains precipitate, causing ineffective erythropoiesis and hemolysis. The table summarizes common syndromes and genotypes (table 1). Terminology has shifted from thalassemia major, intermedia, and minor to focus on whether the disease is transfusion-dependent (TDT) or non-transfusion-dependent (NTDT). (See 'Overview of subtypes and disease severity' above.)

●Clinical findings – Manifestations range from asymptomatic carrier to profound anemia and associated abnormalities. Untreated iron overload can cause endocrine dysfunction, liver disease, and heart failure. Alpha thalassemia findings are present at birth; beta thalassemia findings develop at 6 to 12 months. (See 'Clinical manifestations' above.)

•Alpha thalassemia major is usually fatal in utero with hydrops fetalis. (See "Alpha thalassemia major: Prenatal and postnatal management".)

•TDT (beta thalassemia) presents with severe anemia. Untreated, disease progresses to complications of hemolysis (jaundice, gallstones, hepatosplenomegaly), extramedullary hematopoiesis (skeletal deformities (picture 2), iron overload, impaired growth), pulmonary abnormalities, thrombosis, and leg ulcers. (See 'Anemia' above and 'Complications of hemolysis' above and 'Complications of extramedullary hematopoiesis' above and 'Complications of iron overload' above.)

•Hemoglobin H (Hb H) disease (alpha thalassemia) and NTDT (beta thalassemia) have variable anemia, hemolysis, extramedullary hematopoiesis, and iron overload.

•Beta thalassemia minor and alpha thalassemia minor and minima are generally asymptomatic; thalassemia minor may cause mild anemia and/or microcytosis.

●Evaluation – Thalassemia may be suspected at any age with symptomatic or unexplained microcytic anemia, classical examination findings, positive family history, or positive newborn screen. A negative family history does not eliminate the diagnosis. (See 'History and physical examination' above.)

●Laboratory – Initial testing includes complete blood count (CBC), blood smear review, hemolysis testing, and iron studies (at minimum, ferritin) (algorithm 1).

•Thalassemia causes microcytic anemia, increased red blood cell (RBC) count, and nonimmune hemolysis. These findings are nonspecific and may be absent in mild forms. The blood smear may show target and teardrop cells (picture 1). In thalassemia minor (or alpha thalassemia minima), the CBC may be normal or show mild anemia and/or microcytosis. (See 'CBC and hemolysis testing' above.)

•Iron studies are required to evaluate iron deficiency and overload and to ensure accuracy of hemoglobin analysis (table 4). (See 'Rule out iron deficiency' above.)

•Hemoglobin analysis or genetic testing determines the type of thalassemia. Hb Barts (gamma chain tetramers) or Hb H (beta chain tetramers) are consistent with alpha thalassemia. Increased fetal hemoglobin (Hb F) or Hb A2 are consistent with beta thalassemia but not specific. DNA-based testing is required for alpha thalassemia minor or minima; testing laboratories are listed in the table (table 5). (See 'Hemoglobin analysis and genetic testing' above.)

•The differential diagnosis includes iron deficiency, anemia of chronic disease/anemia of inflammation, inherited microcytic anemias, and liver disease. (See 'Differential diagnosis' above.)

●Diagnosis – Diagnosis is best confirmed by genetic testing. If genetic testing is unavailable, severe forms can be diagnosed by hemoglobin analysis. (See 'Diagnostic confirmation' above.)

●Reproductive – Reproductive counseling and testing are appropriate in individuals with thalassemia, first-degree relatives, reproductive testing, and certain ancestries, countries of origin, or other concerns. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis" and "Management of thalassemia", section on 'Reproductive testing and genetic counseling'.)

●Management – (See "Management of thalassemia" and "Iron chelators: Choice of agent, dosing, and adverse effects" and "Alpha thalassemia major: Prenatal and postnatal management" and "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia".)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.