Thalassemia natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]


The natural history of thalassemia depends on the severity of the globin chain defect. Mild thalassemias have an indolent clinical course, and patients can be asymptomatic for years. The prognosis is favorable for mild thalassemias. Major thalassemia usually result in significant symptoms. The prognosis of major thalassemias is worse, and patients typically die from complications of iron overload in various organs due to excess red blood cell transfusions. Complications of iron deposition in various organs must be managed accordingly.

Natural History

The natural history of thalassemia depends on the subtype of thalassemia.

  • Mild thalassemias: For patients with mild thalassemias, such as alpha-thalassemia silent carrier, alpha-thalassemia trait, or beta-thalassemia minor, the disease course does not result in significant symptoms or complications. These patients sometimes require transfusions throughout their lives. In most cases, these patients can lead normal lives. The natural history of mild thalassemias does not alter life expectancy in most cases.
  • Severe thalassemias: For patients with severe thalassemias, such as HbH disease, Hb Barts, or beta-thalassemia major, the disease course begins with severe symptoms including shortness of breath and fatigue. Children born with beta-thalassemia major (Cooley's anemia) can be normal at birth but develop severe anemia during the first two years of life. This is followed by the need for transfusions, initially at a low frequency. The frequency of transfusions increases as the disease course progresses. After many transfusions, iron deposition begins to occur in various organs, including the heart, thyroid, and liver. This process, known as hemosiderosis, cause result in organ failure. Death is an unfortunate and inevitable part of the natural history of major thalassemias. The most severe form of alpha-thalassemia major (Hb Barts or hydrops fetalis) causes stillbirth (death of the unborn baby during birth or the late stages of pregnancy).[1] In some cases, a live baby can be delivered, but death occurs soon after birth. Mothers who deliver a baby with hydrops fetalis from alpha-thalassemia major have a 75% risk for toxemia of pregnancy.[1]
  • Natural history in the setting of pregnancy: In some cases, persons with thalassemia major can have normal pregnancies.[2] Greater than 400 successful pregnancies have been documents in women with thalassemia. Ovarian hyperstimulation syndrome has been described in patients with thalassemia. Other clinical findings that have been noted in pregnant patients with thalassemia include hypersplenic crises and worsening cardiac function. Twin and triplet pregnancies are more common in patients with thalassemia. Importantly, there is no increased risk of miscarriage in pregnant patients with thalassemia compared to the general population.[2]


Iron overload

The complications of thalassemia are largely related to iron overload from repeated transfusions. Each unit of packed red blood cells contains 200mg of iron. Iron overload is further exacerbated by the costs of iron chelation therapy to treat iron overload and the nonadherence with chelation therapy. The mortality rate is nearly 50% from iron overload complications.[3] Iron deposition can occur in various organs.

  • Cardiac failure: Thalassemia can cause increased cardiac workload, since the heart must pump more forcefully and/or more quickly in order to compensate for the relative oxygen deficit from abnormal red blood cells.[4] Infiltrative cardiomyopathy can occur with iron overload from repeated transfusions from thalassemia. This usually manifests as diastolic dysfunction. There are two phenotypes for cardiac failure: the dilated phenotype which consists of left ventricular dilatation and impaired contractility, and the restrictive phenotype which consists of restrictive left ventricular filling along with pulmonary hypertension and right heart failure. Signs and symptoms of iron overload in the heart include shortness of breath, chest pain, decreased exercise tolerate, edema, elevated jugular venous pressure, crackles, and occasionally abdominal distension. The diagnosis of cardiac iron overload typically involves obtaining an echocardiogram (to assess for diastolic and systolic dysfunction). Echocardiogram can show a sparkled appearance of the involved chambers (from iron deposits) and sometimes a decreased ejection fraction). EKG typically shows low-voltage QRS complexes, due to the impaired electrical conduction through a disease heart containing significant iron. MRI with T2 star sequences can be of great benefit, as this particularly assess for iron deposition in the heart.[5] Laboratory workup that can assist with diagnosis includes measurement of troponin and nt-proBNP.[5] Treatment of iron deposition in the heart involves use of beta-blockers, ACE inhibitors, inotropes (which improve systolic dysfunction), and lusitropes (which improve diastolic dysfunction).
  • Thyroiditis: Infiltrative thyroiditis can occur with iron overload from repeated transfusions from thalassemia. Signs and symptoms of iron overload in the thyroid gland include fatigue, cold intolerance, coarse hair, constipation, weight gain, palpable thyroid (goiter), decreased deep-tendon reflexes. Iron deposition in the thyroid can be assessed via thyroid ultrasound and measurement of thyroid-stimulating hormone (TSH) and free thyroxine (t4) levels. Treatment of iron deposition in the thyroid involves thyroid hormone replacement, typically with levothyroxine 1.7 mcg/kg/day.[5]
  • Hepatic failure: Infiltrative hepatitis can occur with iron overload from repeated transfusions from thalassemia. Signs and symptoms include right upper quadrant pain, jaundice, dark urine, clay-colored stools, nausea, and tender hepatomegaly. Diagnostic considerations include liver ultrasound, CT of the abdomen, MRI of the abdomen, assessment of liver function tests (total bilirubin, AST, ALT, albumin, alkaline phosphatase. Treatment of iron overload in the liver involves consideration of liver transplant and diuretics.[5]
  • Pancreatic insufficiency: Infiltrative pancreatitis can occur with iron overload from repeated transfusions from thalassemia. Iron deposition in the pancreas causes both exocrine and endocrine dysfunction. Exocrine dysfunction involves inability of the pancreas to release digestive enzymes, and endocrine dysfunction involves the inability of the pancreas to release insulin and glucagon. Signs and symptoms include hyperglycemia (which can lead to diabetes), diarrhea, steatorrhea, weight loss. Diagnostic workup involves CT or ultrasound of the pancreas, measurement of lipase, measurement of amylase, and measurement of insulin and glucagon levels. Therapy involves replacement of pancreatic enzymes and hormones. The treatment regimen can consist of a complex combination of enzymes and hormones which sometimes requires close monitoring by an endocrinologist.
  • Hyperpigmentation: Infiltrative dermatitis can occur with iron overload from repeated transfusions from thalassemia. Signs and symptoms include bronze discoloration of the skin, or hyperpigmentation. A skin biopsy can be done to confirm iron deposition in the skin, but this is not typically needed. There is no particular treatment for this, aside from iron chelation.
  • Hypogonotropic hypogonadism: Gonadal dysfunction can occur with iron overload from repeated transfusions from thalassemia. Signs and symptoms include decreased sexual desire, decreased fertility, and loss of secondary sexual characteristics associated with decline in sex hormones.[2] Treatment sometimes involves testosterone supplementation.

Psychiatric effects

Thalassemias can adversely effect a person's psychologic well-being.[6] It has been shown that thalassemia is associated with a higher rate of various psychiatric conditions, including:

  • Depression
  • Anxiety
  • Stress

For these reasons, it is highly important to assess for these conditions proactively in patients with thalassemia.[6]


Infections are also a complication of frequent transfusions. Certain infections were found to be present in high prevalence in patients undergoing transfusions in the 1980s. The infections that have been associated with repeated transfusions for thalassemia include:

  • Hepatitis B: This has been found at a seroprevalance of 3% in patients who were transfused for thalassemia.[7]
  • Hepatitis C: This has been found at a seroprevalance of 18.2% in patients who were transfused for thalassemia.[7]
  • HIV: This has been found at a seroprevalance of 1.5% in patients who were transfused for thalassemia.[7]
  • Syphilis: This has been found at a seroprevalance of 0% in patients who were transfused for thalassemia. Although it was not found to be present in this study, there still exists a theoretical risk for acquiring syphilis from blood transfusion.[7]
  • Cytomegalovirus: This virus can exacerbate the low hemoglobin found in patients with thalassemia since the virus causes bone marrow suppression and further blood count suppression.
  • Parvovirus B19: This virus can exacerbate the low hemoglobin found in patients with thalassemia since the virus causes pure red cell aplasia (PRCA).
  • Malaria: This parasite can exacerbate the low hemoglobin found in patients with thalassemia since the parasite causes hemolysis and further decreases in hemoglobin. However, patients with thalassemia can have heterozygote advantage, in which patients who are heterogyzyte for thalassemia are protected against infection with malaria.


Over the past 20 years, the prognosis for thalassemia has improved significant, as supportive measures like transfusions are now more readily available and safer.[8] Advanced in iron chelation therapy have also contributed to the improved outcomes for patients with thalassemia. In general, the prognosis of thalassemias depends on the subtype: severe defects in globin chain production are more likely to result in worse prognosis.

  • Alpha-thalassemias
    • Alpha-thalassemia silent carrier: The prognosis for silent carriers of alpha-thalassemia (loss of 1 alpha-globin chain) is excellent. These patient lives normal lives with no significant transfusion requirements. Life expectancy is similar as persons with no thalassemia.
    • Alpha-thalassemia trait: Patients with alpha-thalassemia trait (loss of 2 alpha-globin chains) have an excellent prognosis. In rare cases, patients with alpha-thalassemia trait require transfusions, but their life expectancy is similar as persons without thalassemia.
    • HbH disease: Patients with HbH disease (loss of 3 alpha-globin chains) have a somewhat poor prognosis, as these patients can have significant transfusion requirements. One major causes of death includes iron overload leading to cardiac failure.
    • Hb Barts: Patients with Hb Barts (loss of 4 alpha-globin chains) have the worst prognosis amongst all thalassemias. These patients typically die in utero from hydrops fetalis.
  • Beta-thalassemias
    • Beta-thalassemia minor: These patients are usually asymptomatic. Prognosis is favorable and is excellent compared to all other forms of beta-thalassemia.
    • Beta-thalassemia intermedia: The prognosis for beta-thalassemia intermedia is fairly good. Iron accumulation in organs is less common since they do not receive many blood transfusions. These patients generally do not develop hypothyroidism or hypogonadism. Women with beta-thalassemia intermedia can have normal pregnancies. Given that cardiac systolic function is usually preserved, cardiac disease does not usually contribute towards a poor prognosis for patients with beta-thalassemia intermedia.
    • Beta-thalassemia major (Cooley's anemia): The prognosis for beta-thalassemia major is generally poor, as patients have severe defects in beta-globin production and thus are susceptible to treatment-related complications. These patients typically die from iron deposition in the heart (infiltrative cardiomyopathy) due to repeated blood transfusions. In 71% of patients with beta-thalassemia major, cardiovascular etiology will be the cause of death.[8] Other common complications that contribute to a poor prognosis are development of hepatitis B, hepatitis C, and HIV from blood transfusions. Venous thrombosis contributes to morbidity and sometimes mortality.


  1. 1.0 1.1 Munkongdee T, Vattanaviboon P, Thummarati P, Sewamart P, Winichagoon P, Fucharoen S; et al. (2010). "Rapid diagnosis of alpha-thalassemia by melting curve analysis.". J Mol Diagn. 12 (3): 354–8. PMC 2860472Freely accessible. PMID 20190015. doi:10.2353/jmoldx.2010.090136. 
  2. 2.0 2.1 2.2 Origa R, Piga A, Quarta G, Forni GL, Longo F, Melpignano A; et al. (2010). "Pregnancy and beta-thalassemia: an Italian multicenter experience.". Haematologica. 95 (3): 376–81. PMC 2833066Freely accessible. PMID 19903676. doi:10.3324/haematol.2009.012393. 
  3. Srivastava A, Shaji RV (2017). "Cure for thalassemia major - from allogeneic hematopoietic stem cell transplantation to gene therapy.". Haematologica. 102 (2): 214–223. PMC 5286930Freely accessible. PMID 27909215. doi:10.3324/haematol.2015.141200. 
  4. Traisrisilp K, Jatavan P, Tongsong T (2017). "A retrospective comparison of pregnancy outcomes between women with alpha-thalassaemia 1 trait and normal controls.". J Obstet Gynaecol. 37 (8): 1000–1003. PMID 28599577. doi:10.1080/01443615.2017.1313822. 
  5. 5.0 5.1 5.2 5.3 Taher AT, Viprakasit V, Musallam KM, Cappellini MD (2013). "Treating iron overload in patients with non-transfusion-dependent thalassemia.". Am J Hematol. 88 (5): 409–15. PMC 3652024Freely accessible. PMID 23475638. doi:10.1002/ajh.23405. 
  6. 6.0 6.1 Adib-Hajbaghery M, Ahmadi M, S P (2015). "Health Related Quality of Life, Depression, Anxiety and Stress in Patients with Beta-Thalassemia Major.". Iran J Ped Hematol Oncol. 5 (4): 193–205. PMC 4779154Freely accessible. PMID 26985352. 
  7. 7.0 7.1 7.2 7.3 Manisha S, Sanjeev K, Seema N, Dilip C, Rashmi D (2015). "A Cross-Sectional Study on Burden of Hepatitis C, Hepatitis B, HIV and Syphilis in Multi-Transfused Thalassemia Major Patients Reporting to a Government Hospital of Central India.". Indian J Hematol Blood Transfus. 31 (3): 367–73. PMC 4465515Freely accessible. PMID 26085723. doi:10.1007/s12288-014-0462-5. 
  8. 8.0 8.1 Galanello R, Origa R (2010). "Beta-thalassemia.". Orphanet J Rare Dis. 5: 11. PMC 2893117Freely accessible. PMID 20492708. doi:10.1186/1750-1172-5-11.