alpha thalassemia

**Genetics / pathophysiology** - Four α-globin genes (two on each chromosome 16: αα/αα). Alpha thalassemia is mostly due to gene DELETIONS (contrast with β-thalassemia, which is mostly point mutations in the splice site/promoter of the single β gene on chromosome 11). - Decreased α-chains lead to excess β-chains (in adults) or γ-chains (in fetuses/neonates). Free β4 tetramers (HbH) and γ4 tetramers (Hb Bart's) form. These are soluble and less toxic than the free α-chains in β-thalassemia, so there is less ineffective erythropoiesis. Hemolysis (extravascular, in the spleen) predominates. - HbH (β4) and Hb Bart's (γ4) have very high oxygen affinity and do not release O2 to tissues, so they are functionally useless for oxygen delivery.

**Genotype-phenotype (number of genes deleted)** - 1 gene (-α/αα): silent carrier. Asymptomatic with normal CBC. - 2 genes: alpha thalassemia trait (minor), mild microcytic anemia. - Cis deletion (--/αα): more common in Asians (Southeast Asia, China), with higher risk of severe disease in offspring. - Trans deletion (-α/-α): more common in African populations, with lower risk of severe offspring because neither chromosome has both genes deleted. - 3 genes (--/-α): HbH disease. Moderate to severe microcytic hemolytic anemia, splenomegaly, jaundice, and HbH inclusions (Heinz body-like, "golf ball" RBCs with brilliant cresyl blue or supravital stain). HbH appears on electrophoresis. - 4 genes (--/--): Hb Bart's hydrops fetalis. This is incompatible with life, with in utero or early neonatal death due to severe anemia, high-output heart failure, and edema. There is no HbF (which needs α-chains), so there is no functional hemoglobin. It is seen with maternal complications (preeclampsia, polyhydramnios, postpartum hemorrhage). Intrauterine transfusion or transplant is rarely possible.

**Diagnosis** - CBC: low MCV (often <70), low MCH, normal or high RBC count, normal or mildly elevated RDW. - Peripheral smear: microcytic, hypochromic cells, target cells, and basophilic stippling. - Iron studies: normal or high ferritin and iron (rules out iron deficiency). - Hemoglobin electrophoresis: usually NORMAL in silent carriers and trait in adults, so it is a diagnosis of exclusion. It shows HbH in HbH disease and Hb Bart's in neonates (newborn screen). Definitive diagnosis is by DNA/gene deletion analysis. - Mentzer index (MCV/RBC count) <13 favors thalassemia, and >13 favors iron deficiency.

**Contrast with beta thalassemia** - Beta: chromosome 11, point mutations, HbA2 and HbF elevated on electrophoresis, presents after about 6 months once HbF falls, and has "crew-cut" skull X-ray, frontal bossing, and extramedullary hematopoiesis in major disease. - Alpha: chromosome 16, deletions, electrophoresis normal in trait, presents in utero or at birth if severe.

**Management** - Silent carrier or trait: no treatment, and genetic counseling. Avoid unnecessary iron therapy. - HbH disease: folic acid supplementation, transfusions as needed, avoid oxidant drugs (sulfonamides) and iron overload, splenectomy for hypersplenism, and chelation if iron overload is present. - Hydrops fetalis: prenatal diagnosis (chorionic villus sampling or amniocentesis) and counseling. Intrauterine transfusion is occasionally attempted. - Curative option: hematopoietic stem cell transplantation.

**High-yield pearls** - Microcytic anemia with a normal ferritin and a normal electrophoresis in an Asian or African patient points to alpha thalassemia trait. - Heinz-like inclusions of HbH are seen with brilliant cresyl blue. - Hb Bart's (γ4) is seen in neonates, and HbH (β4) in older children and adults. - Thalassemia carriers have some protection against Plasmodium falciparum malaria, which explains the geographic distribution of the disease. - Complications of chronic disease include iron overload (from transfusions and increased GI absorption), gallstones (pigmented), splenomegaly, and hemochromatosis-like organ damage.