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Thalassemia
Overview
Normal adult hemoglobin (HbA) consists of a tetramer made up of two alpha-globin and two beta-globin subunits. T he alpha globin gene is f ound on chromosome 16 and is duplicated, which means that each somatic cell with its pair of homologous chromosomes contains 4 copies of the alpha chain gene. T he gene encoding beta globin only has two copies, one present on each of the pair of chromosome 11. T halassemia results when mutations af f ecting the genes involved in Hb biosynthesis lead to decreased Hb production. T he clinical phenotype results f rom both the diminished amount of the particular globin chain as well as f rom the resultant chain imbalance that occurs because of normal production of the other globin chain. It might be important to note that the clinical phenotype becomes most apparent at 6-9 months of age; due to the f etal to adult hemoglobin switch that occurs at that age (see f igure below). T he common f orms include alpha and beta thalassemias depending on the gene af f ected.

Beta thalassemia
Genet ics/et iology
Upwards of 100 mutations have been described that decrease beta chain synthesis. Most of these are point mutations, and interf ere with processes such as splicing, chain termination, and promoter sites resulting in def ective gene transcription or translation.

Mutations f all into two classes: B0 ref ers to mutations that cause no beta globulin to be produced B+ describes mutations that result in a diminished but not absent quantity of beta globulin. T he severity of these mutations can vary depending on the amount of normal beta globulin that is produced Depending the class of mutation present and the gene dosage (i.e. heterozygous or homozygous) patients can present with dif f ering severity of disease Beta thalassemia major: ref ers to a severe clinical phenotype that occurs when patients are homozygous or compound heterozygous f or more severe beta chain mutations (e.g. severe B+/B+ mutations, B+/B0, B0/B0) Beta thalassemia intermedia: An in between clinical phenotype with heterogenous genetic mutations that still allow f or some Beta chain production (e.g. B+/B0, B+/B+). Some rare cases also exist in which both beta and alpha mutations coexist Beta thalassemia minor/ thalassemia trait: a mild clinical phenotype when one normal copy of the beta globulin gene is present (e.g. B+/B, B0/B)

Alpha thalassemia
Genet ics/et iology
Many mutations can af f ect the alpha globin gene, but the most common are gene deletions

As mentioned previously, there are 4 copies of the alpha gene in each somatic cell. T hus, phenotypes increase in severity as the number of f unctional alpha genes decreases Silent carrier : ref ers to patients with one alpha gene deletion, they are clinically asymptomatic. (e.g. a-/aa) Alpha thalassemia trait : these patients have two alpha gene deletions, and very mild phenotypes. Gene deletions can both be present on the same chromosome, or divided between the two chromosomes which has relevance f or the patients of f spring. (e.g. aa/ or a/a-) Hemoglobin H disease : named ref lecting the presence of the beta tetramer HbH (B4) f ound in red cells. Causes moderately severe anemia. Occurs with three alpha chain deletions (e.g. a/) Hydrops fetalis: the most severe f orm, caused by 4 alpha gene deletions (e.g. /). Becomes manif est later in f etal development, when the f etus transitions f rom using early embryonic globin alleles (gamma2/zappa2) to later f etal alleles (gamma2/alpha2). Red cells contain gamma-globin tetramers (Hb Bart) which are inef f ective at delivering oxygen to tissues, causing anoxia, edema, hepatosplenomegaly. Historically was not compatible with lif e, but aggressive in-utero and lif elong transf usions may save individuals with this condition

Presentation
Signs and symptoms Shortness of breath, fatigue, and weakness (anemia) Mechanism(s) Secondary to anemia Def icient synthesis of the beta chain of hemoglobin causes red cells have low HbA levels, thus explaining their phenotype and impaired ability to transport oxygen Imbalance between alpha and beta globin production leads to a precipitation of the relatively overabundant alpha globin chain within the RBCs their precursors Hepatomegaly Inef f ective erythropoiesis leads to activation of extramedullary erythropoiesis in areas such as the spleen, liver, lymph nodes, and the thorax. Hepatomegaly can result f rom a number of mechanisms; extramedullary erthyropoiesis, hepatitis due to chronic transf usion associated inf ections, and iron overload. Bone pain and fragility fractures Caused by two major mechanisms: Destruction of the cortex leading to weakening of the bone Secondary to Osteopenia/osteoporosis (mechanism above) Cardiac failure and arrhythmias Splenomegaly Secondary to anemia and iron overload Secondary to extramedullary hemotopoiesis Can also be due to extravascular hemolysis causing a hypertropic response in the spleen. Gallstones Bilirubin stones Lif elong hemolytic state causes increased bilirubin deposition in the gallbladder

Malnutrition Bronze skin

Rapidly growing erythrocyte precursors compete f or nutrients and can cause malnutrition Cutaneous iron deposition damages the skin and enhances melanin production by the melanocytes.

Complications
N Engl J Med. 2005 Sep 15;353(11):1135-46 Complication Iron overload (see iron metabolism section) Mechanism A combination of f actors, including inef f ective erythropoiesis and tissue hypoxia, lead to increased iron absorption via the GI tract; via hepcidin inhibition. T his Iron is usually transf errin bound, however, when the total amount of iron exceeds the transf errin binding limits, reactive oxygen species are produced through the f enton reaction Compounded by lif e long transf usions Iron deposition occurs in visceral organs (mainly in the endocrine glands, the heart, and the liver) causing f ailure. Endocrinopathies Due to iron deposition in multiple endocrine glands inducing damage to those glands. Hypogonadism, hypothyroidism, hypoparathyroidism, hypopituitarism, testicular/ovarian f ailure, diabetes are among the complications

Hemolysis

Alpha globin precipitation leads to cell membrane damage Mature red cells with alpha precipitate inclusions and membrane damage are more prone to sequestration and extravascular hemolysis within the spleen

Cortical destruction and impaired bone growth

Uncompensated anemia creates a strong stimulus through erythropoietin (EPO) signalling to ramp up erythropoiesis. T his causes erythroid hyperplasia within the bone marrow, which expands and destroys adjacent areas of bone such as the cortex, impairing bone growth and creating malf ormations

Arterial and RBC membrane dysf unction increases the expression of negatively charged venous phosphatidylserines, which have been shown to induce platelet activation. thromboembolism Def ormed RBCs may directly induce vascular damage RBCs and platelets carry higher levels of ROS (f enton reaction, described above) Further hypothesis include a chronic hypercoaguable state, due to abnormal levels of coagulation f actors in thalassemia patients.

Treatment
Curr Gastroenterol Rep. 2007 Mar;9(1):74-82. Ann N Y Acad Sci. 2010 Aug;1202:237-43. Transfusions: Regular blood transf usions to ensure non-anemic states and prevent some of the disease complications (Target Hb 90-100 g/L) Leukodepletion techniques are used to ensure less alloimmunization and non-hemolytic transf usion reactions. Testing f or viruses is done to reduce transf usion transmitted inf ections Iron chelation: Deferoxamine/deferiprone work by binding serum iron and clearing it via the urine. Def eriprone has been shown to improve cardiac f unctioning (lef t ventricular ejection f raction; LVEF) in patients with thalassemia major. Endocrine therapy: Administration of the def icient hormones (sex hormones and thyroid hormones) Use of f ertility agents to induce spermatogenesis and achievement of pregnancy osteoclast inhibitors (bisphosphonates) to prevent osteopenia and osteoporosis. Splenectomy and cholecystectomy: Splenectomies of ten assist with reducing transf usion requirements Cholecystectomies are of ten required to the presence of bilirubin stones in the gallbladder.