Radiological Manifestations of -...

Radiological Manifestations of Radiological Manifestations of ββ--ThalassemiaThalassemia

Vijay G. Sankaran, HMS IIIGillian 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. HallAbsence 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


Normally the red marrow is restricted to central flat bones

Our Patient: Plain Film of the SkullOur Patient: Plain Film of the Skull


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


Diploic

Space Widening

CompanianCompanian

Patient #2: Skull Vault Marrow Patient #2: Skull Vault Marrow Expansion of Expansion of DiploicDiploic

SpaceSpace


T1-weighted MRI(Saggital

Section)

Companion Patient #3: Companion Patient #3: ExtramedullaryExtramedullary HematopoiesisHematopoiesis

in Untreated in Untreated ββ--ThalassemiaThalassemia


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


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. extramedullaryextramedullaryhematopoiesishematopoiesis).).

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 quantitatequantitateiron 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..

ReferencesReferencesCunningham, M.J., Cunningham, M.J., SankaranSankaran, V.G., Nathan, D.G., and , V.G., Nathan, D.G., and OrkinOrkin S.H. S.H. ““The The ThalassemiaThalassemia Syndromes.Syndromes.”” Nathan and Nathan and OskiOski’’ss Hematology of Hematology of Infancy and ChildhoodInfancy and Childhood, , 77thth editionedition, S.H. , S.H. OrkinOrkin, D.G. Nathan, D. Ginsburg, D.E. Fisher, A.T. Look, S.E. , D.G. Nathan, D. Ginsburg, D.E. Fisher, A.T. Look, S.E. LuxLux, eds. (Philadelphia, PA: W.B. , eds. (Philadelphia, PA: W.B. Saunders Company), 2009,Saunders Company), 2009, pp. 1015pp. 1015--1106.1106.

RundRund, D. and , D. and RachmilewitzRachmilewitz, E. Beta, E. Beta--thalassemiathalassemia, , The New England Journal of MedicineThe New England Journal of Medicine 2005, 353, 11352005, 353, 1135--1146.1146.

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AcknowledgmentsAcknowledgments

Thanks for your attention!Thanks for your attention!

Dr. Ferris M. HallDr. Ferris M. HallDr. Gillian LiebermanDr. Gillian Lieberman

Dr. David LiDr. David LiDr. Wei LinDr. Wei Lin

Maria Maria LevantakisLevantakisMichael LarsonMichael Larson

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