Thalassemia

Introduction

Definition: Inherited defects in globin chain synthesis, named according to globin chain whose synthesis is affected. Most common forms result from reduced synthesis of structurally normal hemoglobins.

Epidemiology: Most pathogenic alleles of the globin genes located on chromosomes 11 and 16. Most ethnic groups have been affected, but the most common are in the Mediterranean area and near equatorial regions of Asia and Africa. Malaria seems to exert heterozygote selection upon genes for hemogloinopathies.

General Pathophysiology–reduced or absent globin chainsÞ ß Hb tetramersÞ hypochromia and microcytosis.

Unbalanced synthesis of individual subunits Þ Ý free or unpaired gamma-globulin chains which are either highly insoluble or incapable of releasing O₂ normallyÞ Accumulation of unpaired globulin subunits (a and n)Þ symptoms.

Reduced hemoglobin results in hyperplasia of the erythroid compartment in the bone marrow Þ

Expansion of the physical bone marrow cavity, with thinning of the bony cortex

Ineffective erythropoiesis, with intramedullary destruction of red cell precursors and wasted metabolic energy

Increased erythropoietin stimulates enhanced absorption of iron from the diet.

Clinical Classifications

Thalassemia major (Cooley’s anemia, homozygous thalassemia) – inheritance of two severe (b -zero) genes. Results in life-long transfusion dependence Þ early death from CHF, infection without transfusion, and early clinical iron overload. b chain synthesis is absent or <5% of normal.

Thalassemia intermedia – inheritance of two mild (b -plus), one severe (b -zero), or two b -zero genes with heterozygous a thalassemia (reduces the excess of a chains). Chronic transfusion is not required. Patients develop iron overload in their 20-30’s without transfusion. b -chain synthesis is reduced to 5-30% of normal.

Thalassemia minor – due to a single mutation present with a normal b globin gene. Patients have microcytosis, hypochromia, basophilic stippling, and mild or minimal anemia. There is usually an increase in HbA2 (a 2d 2) and/ or HbF (a 2n 2). This disease is often confused with iron deficiency. b /a ratio is 0.5-0.7.

(1) b-Thalassemia major – Primary defect: Reduced or absent production of b chains Þ excess a and n subunits.

Presentation: severe anemia, hepatosplenomegaly, growth retardation; marrow hyperplasia, osteoporosis, frontal bossing, maxillary prominence, pathologic Fx, extramed.hematopoiesis, Fe deposition(all organs),early death(heart failure/infection)

Pathophysiology: Excess of a chains Þ spleen is overwhelmed, tetramers accumulate and precipitate to inclusion bodies. These are oxidized and covalently cross-link to spectrin and damage RBC membrane. Immature developing erythroblasts are destroyed in bone marrow (ineffective erythropoiesis), or are released with inclusion bodies which shortens the life span due to removal by the spleen, liver, or bone marrow (hemolysis).

Deficient O₂ capacityÞ Ý erythropoietinÞ erythroid bone marrow hyperplasia. Diverted metabolic energy goes to make RBC’sÞ growth failure, susceptibility to infection, and overabs. of iron with storage in liver, spleen, other organs

Specific organ systems affected:

Skeleton: hypertrophy/expansion of marrow, osteoporosis, persistent hematopoiesis in distal bones, pathological Fx

Liver and gall bladder: hepatomegaly due to Ý erythropoiesis and CHF. Cirrhosis can occur. Viral hepatitis is common. Excess production of bilirubin and cholesterol (due to hemolysis) Þ pigmented gall stones.

Heart: dilation and hyperplasia due to anemia. Hemosiderosis later in life. Inadequate chelation Þ heart failure.

Growth/endocrine: growth retardation, delayed puberty, hypogonadism. Zinc deficiency is common.

GI: overabsorption leads to iron overload with deposition in liver, spleen, heart, skin, endocrine organs. Iron has an oxidative effect. Stored in macrophages and hepatocytes.

Impact of iron overload: hypogonadism, diabetes mellitus, impaired growth hormone secretion, hyperpigmentation due to melatonin, hypoparathyroidism, hypothyroidism and deficiency of vitamin C and E.

Spleen: Splenomegaly can be reversed by transfusion. Hypersplenism usually develops as indicated by Ý transfusion requirement, neutropenia, and thrombocytopenia. Splenectomy is usually needed by end of second decade. Thalassemics, after splenectomy, have Ý risk of sepsis due to iron overload and impairment of macrophages.

Diagnosis: appears 6-24 months after birth (Hgb F turns off); gradual anemia (pallor, poor growth); hepatosplenomegaly, mostly fetal Hb; low retic

Smear: hypochromia, hemoglobin piled in center (target cell), spherocytes, Howell-Jolly bodies.

Treatments: Transfusion: goal is to Ý Hgb levels and suppress erythropoiesis. Intermittent transfusion can prevent CHF and permit growth. To keep erythropoiesis turned off, nadir Hb should be > 10 gm/dL (hypertransfusion) or > 12 gm/dL (supertransfusion). All the risks of transfusion (alloimmunization, infection, iron, allergic reaction) apply.

Splenectomy: when transfusion requirement increases. Use of antibiotic prophylaxis is imperative.

Iron Chelation: Currently, desferrioxamine B given SQ or IV by a pump over 8-24 hours/day. Iron is an oxidant, therefore supplemental antioxidants (vitamins C and E) are necessary. Oral chelators are being developed.

Bone Marrow Transplantation: mostly done in Italy. Results are excellent as long as no significant alloimmunization or liver disease. Early transplant is cost-effective and improves quality of life. Risks are same as other BMT.

Prenatal Diagnosis: has drastically reduced the number of deaths in Italy and Greece.

(2) a-Thalassemia – Chromosome 16 has four copies of the a -gene. Most are gene deletions; severity is determined by number of genes deleted. 3 copies present = a thal 2 trait (silent carrier); 2 copies = a thal 1 trait; 1 copy = HbH disease; 0 copies = HbBarts (n 4), hydrops fetalis. n 4 (Hb Barts) and b 4 (HbH) tetramers are not as damaging as a 4 tetramers (since they do not oxidize spectrin). a -chains are needed to make HbF; total deletion causes hydrops fetalis.

Epidemiology: deletions in SE Asians tend be cis; in Africans they are trans so a thalassemia major is the most common cause of non-immune hydrops in San Francisco and SE Asia, but has never been described in persons of African ancestry.