Case Report

A young male of Indian and African descent with known thalassemia intermedia presented to his hematologist’s office with acute mid back pain after lifting boxes overhead.  His past medical history is significant for mixed a and b  thalassemia intermedia complicated by iron overload, endocrinopathy, osteoporosis and a right ulna and radius fracture in 2008.  The patient requires at least three blood transfusions per year for severe anemia. 

            Lumbar radiographs demonstrate severe osteopenia, hepatomegaly, splenomegaly and a wedge compression fracture of the T12 vertebral body (Figure 1).  The MRI demonstrates diffusely hypointense bone marrow on the T1 and T2-weighted images, most consistent with a marrow infiltrative process, likely secondary to patient’s anemia and an enlarged, diffusely hypointense liver on the T1-weighted images, consistent with iron infiltration in this clinical setting (Figure 2, Figure 3).  A DEXA scan from January 2010 reports lumbar Z score of -4.9, consistent with severe osteoporosis. 

Discussion

            Thalassemia is a hemoglobinopathy characterized by abnormal globin production of the a globin chain, b globin chain or both (3).  Approximately five percent of the global population has a globin variant, however, only 1.7% of people are heterozygous for a and b thalassemia (1).  Thalassemias can occur in any populations; a thalassemia is more common in Mediterranean countries, Africa, Middle East, and Southeast Asia . Similarly, b Thalassemia is commonly seen in Mediterranean, Middle Eastern, India, Pakistan and Southeast Asian countries (3). 

            Reduced rate of synthesis and imbalance subsequent of the alpha and beta chains results in defective hemoglobin production, damage to the red cell precursors and red cells from accumulation of globin subunits (3,6).  b thalassemia leads to reduced or absent production of the b globin chain and accumulation of a chains.  Two genes, one on each chromosome 11, control b globin synthesis (6).  Hundreds of known point mutations affect b globin synthesis to a variable degree (3).  Heterozygotes have a mild microcytic anemia and homozygotes have thalassemia intermedia or major depending on the clinical severity.  Beta thalassemia major requires blood transfusions from an early age, leads to growth failure, bony deformities, pathologic fractures, hepatosplenomeagaly and jaundice.  Clinical manifestations of b thalassemia intermedia range from chronic hemolytic anemia with mild symptoms to transfusion dependent disease with a severity similar to thalassemia major (2, 3).

            Two genes on each chromosome 16 control a globin chain production (2,5).  In forms of a thalassemia, three functioning genes result in a silent carrier state.  Two functioning genes cause minor disease or trait state.   Alpha thalassemia intermedia, or Hemoglobin H (HbH) disease is characterized by b chain tetramers and results when there is one functioning gene.  Clinically HbH causes microcytic anemia, hemolysis and splenomegaly.  Four gene deletion or Hemoglobin Bart’s leads to gamma chain tetramers and is usually incompatible with life resulting in fatal hydrops fetalis (2,3,5)

            Because of the variable genetics and complex physiologic responses to the disease and therapy, thalassemias have clinical variability.  The severity of the disease is directly related to the amount of globin chain imbalance.  In b thalassemia, a chains accumulate in the marrow and in red blood cells leading to ineffective marrow erythropoiesis, hemolysis and a hypochromic microcytic anemia.  Alpha thalassemia will have hemolysis, however, less deficiency in erythropoiesis as the b chains are soluble in the marrow.  To compensate for the anemia, those affected by b thalassemia will increase hemoglobin A2 (a2d2) and hemoglobin F (d2g2).  Alpha thalassemia will not exhibit increased hemoglobins as the a chain is limiting.  Progressive splenomegaly occurs as the spleen is repetitively exposed to red cells with inclusions (3).

            The abnormal hemoglobin in thalassemia has increased affinity for oxygen leading to tissue hypoxia, which is a strong stimulus for erythropoietin.  High levels of erythropoietin result in dyserythropoietic marrow and contribute to facial and skull deformities as well as porous long bones.  This can lead to sinus and ear infections as well as pathologic fractures (3).

            Osteoporosis has a multifactorial pathogenesis in thalassemias from bone marrow expansion, endocrine dysfunction and iron overload.  Marrow expansion mechanically interrupts bone formation and leads to cortical thinning and increased fragility.  Hemosiderosis of the pituitary gonadotrophic cells and gonads causes hypogonadotrophic state in which there is high bone turnover with an enhanced resorptive phase.  Furthermore, iron in bone impairs osteoid maturation (4). 

            Iron deposition is the most important cause of morbidity and mortality in thalassemia.  In b  thalassemia intermedia and major, intestinal absorption of iron is increased and deposited into the kupffer cells of the liver and macrophages as well as in the spleen.  Over time iron will deposit in the liver parenchyma leading to cirrhosis.  Similarly iron accumulates in the parathyroid glands, pituitary gland, pancreas and myocardium.  Complications are diabetes, hypoparathyroidism, hypothalamic-pituitary dysfunction with hypothyroidism and hypogonadism, and most lethal being heart failure (2,3).  Liver deposition and ferritin levels may not reflect severity of cardiac involvement. T2 echo sequenced MRI may be useful to evaluate the myocardium as it is more sensitive to hemosiderin deposition (1).  Ferritin levels are commonly used to monitor iron overload.  Improved outcome has been shown when ferritin levels are less than 2500mg/ml, however this value is unreliable when liver disease is present (1).

            Our patient has mixed a and b thalassemia which has shown to have better prognosis and milder clinical course because less a chain imbalance (3,6). 

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References

1. Rund, D & Rachmilewitz, E . (2005).  B-Thalassemia.  New England Journal of Medicine 353 (11), 1135-1146.

2. Herbert LM & Campbell JS. (2009) Alpha and Beta Thalassemia.  American Family Physician 80 (4), 339-344

3. Weatherall David J, "Chapter 47. The Thalassemias: Disorders of Globin Synthesis" (Chapter 47). Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal, JT: Williams Hematology, 8e: http://www.accessmedicine.com/content.aspx?aID=6123722.

4. Voskaridou, E & Terpos E. (2004).  New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia.  British Journal of Haematology. 127 (127-139)

5. Bleibel SA et al. (2009, August)  Alpha Thalassemia. eMedicine WebMD. Retrieved March 5, 2011, from http://emedicine.medscape.com/article/206397-overview

6. Takeshita K. (2010, September) Beta Thalassemia.  eMedicine WebMD.  Retrieved March 5, 2011 from http://emedicine.medscape.com/article/206490-overview