Thalassemia natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

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.
• 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 causes stillbirth (death of the unborn baby during birth or the late stages of pregnancy).

Complications

Iron overload

The complications of thalassemia are largely related to iron overload from repeated transfusions. 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. 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. Laboratory workup that can assist with diagnosis includes measurement of troponin and nt-proBNP. 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.

• 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.

• 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.

Infections

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.PMC4465515
• Hepatitis C: This has been found at a seroprevalance of 18.2% in patients who were transfused for thalassemia.PMC4465515
• HIV: This has been found at a seroprevalance of 1.5% in patients who were transfused for thalassemia.PMC4465515
• 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.PMC4465515
• Cytomegalovirus
• Parvovirus B19
• Malaria:

Prognosis

Over the past 20 years, the prognosis for thalassemia has improved significant, as supportive measures like transfusions are now more readily available and safer. 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 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.
  • Beta-thalassemia intermedia: The prognosis for beta-thalassemia intermedia is fairly good. Iron accumulation in organs is less common. 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. 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.