β地中海贫血的影像学表现

Radiological Manifestations of Radiological Manifestations of ββ--ThalassemiaThalassemia Vijay G. Sankaran, HMS III Gillian Lieberman, MD Our PatientOur Patient „„ A 7 year old boy presenting in 1980 to the King Faisal A 7 year old boy presenting in 1980 to the King Faisal Specialist Hospital in Riyadh, Saudi Arabia.Specialist Hospital in Riyadh, Saudi Arabia. „„ The child presented to the hospital with severe anemia, The child presented to the hospital with severe anemia, hepatosplenomegaly, and alterations in facial hepatosplenomegaly, and alterations in facial morphology.morphology. „„ This patient was found to have This patient was found to have ββ--thalassemia major.thalassemia major. „„ The child was initially seen in April of 1980 and a The child was initially seen in April of 1980 and a splenectomy was performed in June of 1980.splenectomy was performed in June of 1980. Our Patient: Chest XOur Patient: Chest X--Ray Taken on Ray Taken on Presentation Before SplenectomyPresentation Before Splenectomy Courtesy of Dr. F.M. Hall Findings: - Initial trabecular and cortical thinning - Later trabecular coarsening - Osteopenia Our Patient: Chest and Abdominal Plain Our Patient: Chest and Abdominal Plain Films Following Films Following SplenectomySplenectomy Courtesy of Dr. F.M. Hall Absence of the SpleenVertebrae Show Bone-in-Bone AppearanceImpaired Ossification at the Ilium-Ischium-Pubic Interface Our Patient: Plain Films of the HandsOur Patient: Plain Films of the Hands Courtesy of Dr. F.M. Hall Normally the red marrow is restricted to central flat bones Our Patient: Plain Film of the SkullOur Patient: Plain Film of the Skull Courtesy of Dr. F.M. Hall Diploic Space WideningHair on End Appearance of SkullParanasal Sinuses (Except Ethmoid) Filled with Marrow Radiological Findings in Untreated Radiological Findings in Untreated ββ-- ThalassemiaThalassemia „„ The first published description of The first published description of ββ--thalassemiathalassemia in 1927 by Cooley and in 1927 by Cooley and colleagues, noted the bone changes as characteristic of the disecolleagues, noted the bone changes as characteristic of the disease.ase. „„ Many of these findings can occur in other marrow infiltrative/ eMany of these findings can occur in other marrow infiltrative/ expansive xpansive diseases (i.e. SCD, diseases (i.e. SCD, GaucherGaucher, , leukemiasleukemias, , metsmets, etc.), but they generally , etc.), but they generally occur to a greater extent in untreated occur to a greater extent in untreated ββ--thalassemiathalassemia due to the due to the extensive degree of marrow expansion (can often be up to 15extensive degree of marrow expansion (can often be up to 15--30 fold 30 fold increased).increased). „„ The marrow expansion destroys The marrow expansion destroys medullarymedullary trabeculaetrabeculae with initial with initial cortical and cortical and trabeculartrabecular thinning and subsequent thinning and subsequent trabeculartrabecular coarsening. coarsening. As a result, the bones become weak and can easily fracture.As a result, the bones become weak and can easily fracture. Hemoglobin is Only Stable as a Tetramer of Hemoglobin is Only Stable as a Tetramer of Two Two αα-- and Two and Two ββ--GlobinGlobin PolypeptidesPolypeptides Adapted from: http://en.wikipedia.org/wiki/Hemoglobin A Review of the A Review of the PathophysiologyPathophysiology of of ββ-- ThalassemiaThalassemia Adapted from: Rund & Rachmilewitz, N Engl J Med, 2005 Sep 15;353(11):1135-46. Toxicity Due to Precipitates of Toxicity Due to Precipitates of αα--GlobinGlobin Lead to Ineffective Lead to Ineffective ErythropoiesisErythropoiesis BFU-E CFU-E Proerythroblast Erythroblast Reticulocyte Erythrocyte Ineffective Erythropoiesis Ineffective Ineffective ErythropoiesisErythropoiesis and Expansion of and Expansion of ErythroidErythroid ProgenitorsProgenitors Normal Erythropoiesis: Ineffective Erythropoiesis: The Resulting The Resulting ErythroidErythroid Hyperplasia Leads Hyperplasia Leads to Marrow Expansion & to Marrow Expansion & ExtramedullaryExtramedullary HematopoiesisHematopoiesis Adapted from: O’Malley, Mod Pathol. 2007 Apr;20(4):405-15. Companion Patient #1: Companion Patient #1: ErythroidErythroid Hyperplasia Leads to Hyperplasia Leads to ““CobwebbingCobwebbing”” and a Course and a Course TrabecularTrabecular PatternPattern Adapted from: Tyler et al., Clin Radiol. 2006 Jan;61(1):40-52 Also Notice Gallstones, Which Occur Due to Elevated Unconjugated Bilirubin Our Patient: Skull FindingsOur Patient: Skull Findings Courtesy of Dr. F.M. Hall Diploic Space Widening CompanianCompanian Patient #2: Skull Vault Marrow Patient #2: Skull Vault Marrow Expansion of Expansion of DiploicDiploic SpaceSpace Adapted from: Tyler et al., Clin Radiol. 2006 Jan;61(1):40-52 T1-weighted MRI (Saggital Section) Companion Patient #3: Companion Patient #3: ExtramedullaryExtramedullary HematopoiesisHematopoiesis in Untreated in Untreated ββ--ThalassemiaThalassemia Adapted from: Tyler et al., Clin Radiol. 2006 Jan;61(1):40-52 Can see expansion into spleen, liver, and potentially paraspinal masses as in this patient. Chest Plain Film Chest T1-Weighted MRI (Coronal Section) Treatment of Treatment of ββ--ThalassemiaThalassemia While 95% of patients with While 95% of patients with ββ--thalassemiathalassemia live in the live in the developing world and dondeveloping world and don’’t receive adequate t receive adequate treatment, we can currently treat this disease by treatment, we can currently treat this disease by regular transfusions and ironregular transfusions and iron--chelationchelation in patients with in patients with access to care.access to care. The major The major chelatorchelator for iron has been for iron has been desferrioxaminedesferrioxamine (DFX). Currently newer iron (DFX). Currently newer iron chelatorschelators (including orally (including orally bioavailablebioavailable ones like ones like deferasiroxdeferasirox) are available, ) are available, though there is limited experience with their use.though there is limited experience with their use. Companion Patient #4: Skeletal Dysplasia Companion Patient #4: Skeletal Dysplasia Due to DFX TreatmentDue to DFX Treatment Adapted from: Tyler et al., Clin Radiol. 2006 Jan;61(1):40-52 Metaphyseal Bands & Growth Arrest Lines In Addition to RicketsIn Addition to Rickets--Like Bone Changes, There is Like Bone Changes, There is a Reduced Growth Velocity With DFX Therapya Reduced Growth Velocity With DFX Therapy Adapted from: De Sanctis et al., Eur J Pediatr. 1996 May;155(5):368-72. Companion Patient #5: Even with Iron Companion Patient #5: Even with Iron ChelationChelation, Iron Deposition Becomes a Major , Iron Deposition Becomes a Major ProblemProblem Adapted from: http://emedicine.medscape.com/article/369012-imaging Abdominal Section Through Liver with T2* MRI (Iron is Low Signal Here) Excellent Quantitative Assessment of Iron Excellent Quantitative Assessment of Iron Burden by T2* MRI MethodsBurden by T2* MRI Methods Adapted from: Cohen et al., Hematology Am Soc Hematol Educ Program. 2004:14-34. Could better and more effective Could better and more effective treatments for treatments for ββ--thalassemiathalassemia be be developed?developed? Reversing the FetalReversing the Fetal--toto--Adult Hemoglobin Switch to Adult Hemoglobin Switch to Develop Better Therapies for Develop Better Therapies for ββ--ThalassemiaThalassemia Adapted from: Weatherall, Nat Rev Genet. 2001 Apr;2(4):245-55. Potential to Develop Better Potential to Develop Better HbFHbF--Inducing Inducing Therapies by Targeting the Major Regulator of the Therapies by Targeting the Major Regulator of the Hemoglobin Switch, BCL11AHemoglobin Switch, BCL11A Adapted from: Michelson, Science. 2008 Dec 19;322(5909):1803-4. Sankaran et al., Science. 2008 Dec 19;322(5909):1839-42. Sankaran et al., Nature. 2009 Aug 27;460(7259):1093-7. SummarySummary „„ We illustrated the skeletal alterations that can be seen on plaiWe illustrated the skeletal alterations that can be seen on plain films n films in in ββ--thalassemiathalassemia.. „„ We explored the We explored the pathophysiologypathophysiology of this phenomenon and touched of this phenomenon and touched on other pertinent radiological findings (i.e. on other pertinent radiological findings (i.e. extramedullaryextramedullary hematopoiesishematopoiesis).). „„ TThe radiologic changes seen with chronic iron he radiologic changes seen with chronic iron chelationchelation were were discussed.discussed. „„ We mentioned the use of modern MRI methods (T2*) to We mentioned the use of modern MRI methods (T2*) to quantitatequantitate iron burden.iron burden. „„ Finally, we touched on potential new therapeutic avenues that cFinally, we touched on potential new therapeutic avenues that could ould ameliorate ameliorate ββ--thalassemiathalassemia.. 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Developmental and species--divergent divergent globinglobin switching are driven by BCL11A, switching are driven by BCL11A, NatureNature 2009, 460, 10932009, 460, 1093--1097.1097. AcknowledgmentsAcknowledgments Thanks for your attention!Thanks for your attention! Dr. Ferris M. HallDr. Ferris M. Hall Dr. Gillian LiebermanDr. Gillian Lieberman Dr. David LiDr. David Li Dr. Wei LinDr. Wei Lin Maria Maria LevantakisLevantakis Michael LarsonMichael Larson Slide Number 1 Our Patient Our Patient: Chest X-Ray Taken on Presentation Before Splenectomy Our Patient: Chest and Abdominal Plain Films Following Splenectomy Our Patient: Plain Films of the Hands Our Patient: Plain Film of the Skull Radiological Findings in Untreated β-Thalassemia Hemoglobin is Only Stable as a Tetramer of Two α- and Two β-Globin Polypeptides A Review of the Pathophysiology of β-Thalassemia Toxicity Due to Precipitates of α-Globin Lead to Ineffective Erythropoiesis Ineffective Erythropoiesis and Expansion of Erythroid Progenitors The Resulting Erythroid Hyperplasia Leads to Marrow Expansion & Extramedullary Hematopoiesis Companion Patient #1: Erythroid Hyperplasia Leads to “Cobwebbing” and a Course Trabecular Pattern Our Patient: Skull Findings Companian Patient #2: Skull Vault Marrow Expansion of Diploic Space Companion Patient #3: Extramedullary Hematopoiesis in Untreated β-Thalassemia Treatment of β-Thalassemia Companion Patient #4: Skeletal Dysplasia Due to DFX Treatment In Addition to Rickets-Like Bone Changes, There is a Reduced Growth Velocity With DFX Therapy Companion Patient #5: Even with Iron Chelation, Iron Deposition Becomes a Major Problem Excellent Quantitative Assessment of Iron Burden by T2* MRI Methods Could better and more effective treatments for β-thalassemia be developed? Reversing the Fetal-to-Adult Hemoglobin Switch to Develop Better Therapies for β-Thalassemia Potential to Develop Better HbF-Inducing Therapies by Targeting the Major Regulator of the Hemoglobin Switch, BCL11A Summary References Acknowledgments