Click here to load reader
Upload
aabbccddeeee
View
8.519
Download
10
Tags:
Embed Size (px)
DESCRIPTION
Citation preview
MOLECULAR BASIS OF THALASSEMIAChris Chan ([email protected])
Louis Chiu ([email protected])
Lok Tin Liu ([email protected])
Janet Lui ([email protected])
Signed Up Presentation Date: January 13th, 2010
PHM 226, 2010Instructor: Dr. Jeffrey Henderson
THALASSEMIA:THALASSA (SEA) HAIMA (BLOOD)
‘Mediterranean Anemia’- 1st published in 1925
Genetic autosomal recessive blood disease Reduced rate of synthesis of globin chains in
hemoglobin Decreased oxygen carrying capacity of
hemoglobin: Anemia
HEMOGLOBIN A
Fetal Hemoglobin (2 alpha, 2 gamma)
Hemoglobin A2 (2 alpha, 2 delta) Small amounts in body
α
αβ
β
ALPHA THALASSEMIA
Alpha Thalassemia: deficient/absent alpha subunits Excess beta subunits Excess gamma subunits newborns
Tetramers formed: Hemoglobin H adults Hemoglobin Bart’s newborns
Five types: Silent Carrier Trait (Minor) Hemoglobin H Disease Major (Hemoglobin Bart’s) Hemoglobin Constant Spring
β/γ
β/γ
β/γ β/
γ
GENETIC BASIS OF ALPHA THALASSEMIA
Encoding genes on chromosome 16 (short arm) Each cell has 4 copies of the alpha globin gene
Each gene responsible for ¼ production of alpha globin
4 possible mutation states: Loss of ONE gene silent carrier Loss of TWO genes thalassemia minor (trait) Loss of THREE genes Hemoglobin H
Accumulation of beta chains Association of beta chains in groups of 4 Hemoglobin H
Loss of FOUR genes Hemoglobin Barts NO alpha chains produced ∴ only gamma chains present Association of 4 gamma chains Hemoglobin Barts
CLINICAL OUTCOMES OF ALPHA THALASSEMIA
Silent carriers • asymptomatic • “normal”
Alpha Thalassemia minor (trait)• no anemia• microcytosis
-unusually small red blood cells due to fewer Hb in RBC• “normal”
Alpha Thalassemia intermedia (“Hemoglobin H”)• microcytosis & hemolysis (breakdown of RBC)
- results in severe anemia• bone deformities• splenomegaly (enlargement of spleen)• “severe and life threatening”
CLINICAL OUTCOMES OF ALPHA THALASSEMIA
Alpha Thalassemia major• Hb Bart’s • fatal hydrops fetalis
- fluid build-up in fetal compartments, leads to death
• occurs in utero Hemoglobin Constant Spring
• most common form of alpha thalassemic defects in Southeast Asia
• similar to HbH but no microcytosis• anemia is more severe than other alpha thalassemic
variants• greater growth delay than HbH patients
TREATMENTS FOR ALPHA THALASSEMIA
Silent Carrier – no treatment req’d Hemoglobin Constant Spring – form of Silent Carrier – no
treatment req’d Trait (Minor) – no treatment req’d Hemoglobin H Disease – Folate
avoid iron supplements avoid sulfa drugs (already prone to hemolytic crises), and
other drugs/combinations that may increase risk of hemolytic anemia
Major (Hemoglobin Bart’s) –RBC transfusion while still in womb, else fetus is stillborn or dies shortly
BETA THALASSEMIA
Beta Thalassemia: deficient/absent beta subunits 200 point mutations possible, deletions less likely In any region with high levels of thalassemia, one
or two mutations predominate, but DIFFERENT mutations were found in different populations
Commonly found in Mediterranean, Middle East, Asia, and Africa
Three types: Trait Intermedia Major (Cooley anemia)
May be asymptomatic at birth as HbF functions
GENETIC BASIS OF BETA THALASSEMIA Encoding genes on chromosome 11 (short arm) Each cell contains 2 copies of beta globin gene
beta globin protein level = alpha globin protein level Suppression of gene more likely than deletion
2 mutations: beta-+-thal / beta-0-thal “Loss” of ONE gene thalassemia minor (trait) “Loss” of BOTH gene complex picture
2 beta-+-thal thalassemia intermedia / thalassemia major
2 beta-0-thal thalassemia major beta-+-thal / beta-0-thal thalassemia major
Excess of alpha globin chains
CLINICAL OUTCOMES OF BETA THALASSEMIA
Beta Thalassemia minor (trait)• asymptomatic • microcytosis• minor anemia
Beta Thalassemia intermedia• symptoms similar to Cooley Anemia but less severe
Beta Thalassemia major (Cooley Anemia)• most severe form • moderate to severe anemia• intramedullary hemolysis (RBC die before full development)• peripheral hemolysis & splenomegaly• skeletal abnormalities (overcompensation by bone marrow)• increased risk of thromboses • pulmonary hypertension & congestive heart failure
TREATMENT FOR BETA THALASSEMIA
Trait – no treatment req’d Intermedia Major (Cooley anemia)
Regular folate supplementation RBC transfusion (Splenectomy may decrease need for
transfusions) to maintain [Hgb] ~9-10g/dL Increased GI iron absorption due to low levels of
hepcidin Normally inhibits ferroportin (transmembrane
transporter for iron-storing/-transporting cells) Increased ferroportin activity increases iron uptake from
GI by duodenal enterocytes Blood transfusions iron accumulation iron
overload
IRON OVERLOAD & TREATMENT
Iron overload - the liver becomes fully loaded with iron, and subsequent accumulation in and damage to other organs and tissues occurs
Iron chelating agents – bind to free iron, increasing solubility and facilitating excretion Deferoxamine (Desferal) – IV or subcutaneous Deferasirox (Exjade) – oral suspension tablet Deferiprone (Ferriprox) oral
no longer licensed for use in Canada ?
DEFEROXAMINE MESYLATE
Desferal – by Novartis IV or subcutaneous (IM is ok), poor oral absorption First line, complexes with iron ferrioxamine
(water soluble) excreted through kidney
Image from: http://en.wikipedia.org/wiki/Deferoxamine
DEFERASIROX Exjade – Novartis
Oral suspension tablet High iron affinity Biliary excretion via glucoronidation
Image from: http://en.wikipedia.org/wiki/Deferasirox
DEFERIPRONE
Ferriprox – by Apotex Indicated for treating iron overload in patients
with thalassemia major when desferoxamine is contraindicated/inadequate Combination therapy of desferoxamine + deferiprone
is more effective than monotherapy
BUT, it is no longer licensed for use in Canada Interesting read:
Controversy between Apotex & Sick Kid’s Hospital physician-researcher Nancy Olivieri Reported to lead to progressive hepatic fibrosis
(disputed) http://firstclinical.com/journal/2009/0902_Olivieri.pdf Google: apotex, olivieri, ferriprox
Image from: http://en.wikipedia.org/wiki/Deferiprone
REFERENCESButler, C. (2009). About Thalassemia. Cooley’s Anemia Foundation. Retrieved from:
http://www.thalassemia.org/index.php?option=com_content&view=article&id=19&Itemid=27
Conran, N., & Costa, F. (2009) Hemoglobin disorders and endothelial cell interactions. Clinical Biochemistry, 42, 1824-1838
e-Therapeutics (2009). Exjade. Retrieved from e-CPS Online Product Monograph
e-Therapeutics (2010). Desferal. Retrieved from e-CPS Online Product Monograph
Hemoglobin Synthesis. (2002). Retrieved Jan. 9, 2010, from http://sickle.bwh.harvard.edu/hbsynthesis.html
Ho, P. J., & Thein, S. L. (2000). Gene regulation and deregulation: a globin perpsective. Blood Reviews, 17, 78-93
Lexi-Comp (2010). Deferasirox. Retrieved from Lexi-Drugs Online database
Lexi-Comp (2010). Deferoxamine. Retrieved from Lexi-Drugs Online database
Thalassemia Overview. (1999). Retreived Jan. 9, 2010 from http://sickle.bwh.harvard.edu/thalover.html
Rassi, F.E, Cappellini, M.D., Inati, A., Taher, A. (2008) Beta-thalassemia intermedia: An overview. Pediatric Annals, 37 (5), 322-329
Singer, S.T. et al (2009) Hemoglobin H-constant spring in North America: An alpha thalassemia with frequent complications. American Journal of Hematology, 84(11), 759-761
Weatherall, D.J. (2004). Thalassemia: the long road from bedside to genome. Nature, 5, 1-7
Muncie, HL Jr, Campbell, J. (2009). Alpha and beta thalassemia. Am Fam Physician, 80 (4), 339-44. Schrier, SL. (1994). Thalassemia: pathophysiology of red cell changes. Annu Rev Med , 45, 211-8.
Ceci, A., Felisi, M., De Sanctis, V., & De Mattia, D. Pharmacotherapy of iron overload in thalassaemic patients [Abstract]. Expert Opinion on Pharmacotherapy, 4(10), 1763-1774.
Roberts D, Brunskill S, Doree C, Williams S, Howard J, Hyde C. Oral deferiprone for iron chelation in people with thalassaemia. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004839. DOI: 10.1002/14651858.CD004839.pub2.
Thompson Reuters. (2009). Thalassemia – Chronic. Retrieved from http://www.thomsonhc.com.myaccess.library.utoronto.ca/hcs/librarian/PFActionId/hcs.external.RetrieveDocument/eid/112153002/DocId/CR2016C/ContentSetCode/DISEASEDEX-GMCR#drugTreatmentSection
SUMMARY Alpha Thalassemia
Lack of alpha globins & excess beta globins; mostly result of deletions
Loss of 1 gene Silent Carrier “Normal” Loss of 2 genes Alpha Thalassemia minor “Normal” Loss of 3 genes Hemoglobin H “severe & life threatening”
Folate Loss of 4 genes Hemoglobin Barts mostly fatal RBC
transfusions Beta Thalassemia
Lack of beta globins & excess alpha globins; mostly result of point mutations
1 gene mutated Beta Thalassemia minor “Normal” 2 genes mutated clinical outcomes determine diagnosis
(Thalassemia Intermedia or Cooley Anemia) regular Folate Supplementation & RBC transfusions
Side Effect of Chronic RBC Transfusions Iron Overload Treat with iron chelating agents (Deferoxamine, Deferasirox, Deferiprone)
ALSO INFORMATION ON SLIDES 2, 6, 7 AND 13