THALASSEMIA SYNDROMES

THALASSEMIA SYNDROMES

•The thalassemia syndromes are inherited disorders of α- or ß-globin biosynthesis.

• The reduced supply of globin diminishes production of hemoglobin tetramers

•synthesis of the unaffected globins proceeds at a normal rate. Unbalanced accumulation of α and ß subunits causing hypochromia and microcytosis.

CLINICAL MANIFESTATlONS OF  THALASSEMIA SYNDROMES

•Mutations causing thalassemia can affect any step in the pathway of globin gene expression:–Transcription–processing of the mRNA precursor translation–Post-translational metabolism of the ß-globin

• The most common forms arise from mutations that derange splicing of the mRNA precursor or prematurely terminate translation of the mRNA.

•Hypochromia and microcytosis reduced amounts of hemoglobin tetramers

•in heterozygotes (-thalassemia trait), this is the only abnormality seen. Anemia is minimal.

• In more severe homozygous states, unbalanced globin accumulation

• causes accumulation of highly insoluble unpaired chains.

•They form toxic inclusion bodies that kill developing erythroblasts in the marrow. 

•The surviving RBCs bear a burden of inclusion bodies that are detected in the spleen

• shortening the RBC life span and producing severe hemolytic anemia.

•The resulting profound anemia stimulates erythropoietin release and compensatory erythroid hyperplasia

•Erythroid hyperplasia can become exuberant and produce masses of extramedullary erythropoietic tissue in the liver and spleen.

•Massive bone marrow expansion deranges growth and development.

•Children develop characteristic "chipmunk" facies due to maxillary marrow hyperplasia and frontal bossing.

Thinning and pathologic fracture of long bones and vertebrae may occur due to cortical invasion by erythroid elements and profound growth retardation.

•Hemolytic anemia causes hepatosplenomegaly, leg ulcers, gallstones, and high-output congestive heart failure.

•Chronic transfusions with RBCs improve oxygen delivery, suppress the excessive ineffective erythropoiesis, and prolong life

•iron overload, usually prove fatal by age 30 years.

•When both  alleles on one chromosome are deleted, the locus is called -thal-1; when only a single  allele on one chromosome is deleted, the locus is called -thal-2.

•90–95% of the hemoglobin is hemoglobin Barts (tetramers of chains).•-Thalassemia-2 trait is an asymptomatic, silent carrier state.•-Thalassemia-1 trait resembles -thalassemia minor. 

HbH disease

•HbA production is only 25–30% normal.

•Fetuses accumulate some unpaired chains (Hb Barts; -chain tetramers).

• In adults, unpaired chains accumulate and are soluble enough to form 4 tetramers called HbH.

• HbH forms few inclusions in erythroblasts and precipitates in circulating RBC.

• Patients with HbH disease have thalassemia intermedia characterized by moderately severe hemolytic anemia but milder ineffective erythropoiesis.

• Survival into midadult life without transfusions is common.

HYDROPS FETALIS

•The homozygous state for the -thalassemia-1 cis deletion (hydrops fetalis) causes total absence of -globin synthesis.

•No physiologically useful hemoglobin is produced beyond the embryonic stage.

• Excess globin forms tetramers called Hb Barts (4), which has a very high oxygen affinity.

• It delivers almost no O2 to fetal tissues, causing tissue asphyxia, edema (hydrops fetalis), congestive heart failure, and death in utero.

Diagnosis and Management of Thalassemias

•The diagnosis of -thalassemia major is readily made during childhood on the basis of severe anemia accompanied by the characteristic signs of massive ineffective erythropoiesis:

•Hepatosplenomegaly

•profound microcytosis

• a characteristic blood smear 

• and elevated levels of HbF, HbA2, or both.

Many patients require chronic hypertransfusion therapy designed to

maintain a hematocrit of at least 27–30% so that erythropoiesis is suppressed

•Splenectomy is required if the annual transfusion requirement (volume of RBCs per kilogram of body weight per year) increases by >50%.

• Folic acid supplements may be useful.

• Vaccination with Pneumovax in anticipation of eventual splenectomy is advised

• close monitoring for infection, leg ulcers, and biliary tract disease.

• Many patients develop endocrine deficiencies as a result of iron overload

• Early endocrine evaluation is required for glucose intolerance, thyroid dysfunction, and delayed onset of puberty or secondary sexual characteristics.

thalassemia intermedia

•Have similar stigmata but can survive without chronic hypertransfusion.

•A number of factors can aggravate the anemia, including infection, onset of puberty, and development of splenomegaly and hypersplenism.

• Some patients may eventually benefit from splenectomy.

Thalassemia minor (i.e., thalassemia trait)

•usually presents as profound microcytosis and hypochromia with target cells

•only minimal or mild anemia.

•The mean corpuscular volume is rarely >75 fL

•hematocrit is rarely <30–33%.

• Hemoglobin analysis classically reveals an elevated HbA2 (3.5–7.5%), but some forms are associated with normal HbA2 and/or elevated HbF.

• Genetic counseling and patient education are essential.

•Patients with -thalassemia trait should be warned that their blood picture resembles iron deficiency and can be misdiagnosed.

• They should eschew empirical use of iron, yet iron deficiency can develop during pregnancy or from chronic bleeding .

•Persons with -thalassemia trait may exhibit mild hypochromia and microcytosis usually without anemia. HbA2 and HbF levels are normal.

• Affected individuals usually require only genetic counseling.

• HbH disease resembles -thalassemia intermedia, with the added complication that the HbH molecule behaves like moderately unstable hemoglobin.

• Patients with HbH disease should undergo splenectomy if excessive anemia or a transfusion requirement develops.

• Oxidative drugs should be avoided.

• Iron overload leading to death can occur in more severely affected patients.

Transfusional Hemosiderosis

•Chronic blood transfusion can lead to bloodborne infection, alloimmunization, febrile reactions, and lethal iron overload .

• A unit of packed RBCs contains 250–300 mg iron (1 mg/mL).

•The iron assimilated by a single transfusion of two units of packed RBCs is thus equal to a 1- to 2-year intake of iron.

• Iron accumulates in chronically transfused patients because no mechanisms exist for increasing iron excretion

• Vitamin C should not be supplemented because it generates free radicals in iron excess states.

•Patients who receive >100 units of packed RBCs usually develop hemosiderosis.

•The ferritin level rises, followed by early endocrine dysfunction (glucose intolerance and delayed puberty), cirrhosis, and cardiomyopathy.

•Liver biopsy shows both parenchymal and reticuloendothelial iron.

• The superconducting quantum-interference device (SQUID) is accurate at measuring hepatic iron but not widely available. Cardiac toxicity is often insidious.

•Early development of pericarditis is followed by dysrhythmia and pump failure.

• The onset of heart failure is ominous

CHELATING AGENTS

• long-term transfusion support prompts one to institute therapy with iron-chelating agents.

•Desferoxamine (Desferal) is for parenteral use.

•Its iron-binding kinetics require chronic slow infusion via a metering pump.

• The constant presence of the drug improves the efficiency of chelation and protects tissues from occasional releases of the most toxic fraction of iron—low-molecular-weight iron.

•Desferoxamine is relatively nontoxic.

•Occasional cataracts, deafness, and local skin reactions, including urticaria, occur. Skin reactions can usually be managed with antihistamines.

•Negative iron balance can be achieved, even in the face of a high transfusion requirement.

•To enjoy a significant survival advantage, chelation must begin before 5–8 years of age in -thalassemia major.

•Deferasirox is an oral iron-chelating agent.

•Single daily doses of 20 to 30 mg/kg deferasirox produced reductions in liver iron concentration comparable to desferoxamine in long-term transfused adult and pediatric patients.

•Deferasirox produces some elevations in liver enzymes and slight but persistent increases in serum creatinine, without apparent clinical consequence.

• Other toxicities are similar to those of desferoxamine.

• Its toxicity profile is acceptable, although long-term effects are still being evaluated

Experimental Therapies

•Bone Marrow Transplantation, Gene Therapy, and Manipulation of HBF

•Bone marrow transplantation provides stem cells able to express normal hemoglobin; it has been used in a large number of patients with  thalassemia and a smaller number of patients with sickle cell anemia.
• Early in the course of disease, before end-organ damage occurs, transplantation is curative in 80–90% of patients.
• In highly experienced centers, the treatment-related mortality is <10%.
•Gene therapy of thalassemia and sickle cell disease has proved to be an elusive goal.