Aprile Department of Internal Medicine, Nephrology and Health Sciences, University of Parma, Italy.

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1 Aprile 009 In questo numero di Emothal viene riportata la seconda parte dei posters presentati al V Congresso Nazionale SO. S. T. E. - S. I. T. E., che si è tenuto a Cagliari dal 6 al 8 Ottobre 008 Cardiac and liver involvement assessed by T* magnetic resonance (MRI T*) i n patients with thalassemia major Pattoneri P., Cassinerio E., Marcon A., Pedre t t i S., Zanaboni L., Dellegrottaglie S., Cappellini M. D., Roghi A. Department of Internal Medicine, Nephrology and Health Sciences, University of Parma, Italy. H e re d i t a ry Anemia Center, Department of Internal Medicine, Policlinico Foundation IRCCS, University of Milan, Italy; Department of Card i o l o g y, Niguarda Hospital, Milan, Italy I n t ro d u c t i o n. C a rdiac and hepatic dysfunctions derived from iron overload are common in patients with Thalassemia Major (TM), re p resenting the leading causes of mortality in adult patients. In TM patients cardiac and liver Magnetic Resonance Imaging (MRI) T*, a new, re p roducible and non invasive technique, has been recently used to evaluate iron content and to adapt an adequate iro n chelation therapy. More o v e r, the cardiac and liver depletion has been considered a major cause of i m p roved survival in TM patients. Aim of the study. To evaluate cardiac and liver involvement in TM patients assessed by MRI T*. Methods. 0 TM patients (54 males and 7 women, mean age ± 6 yrs) treated with various iron chelators underwent MRI T* to assess myocardial and liver iron overload. All patients underwent MRI T* at Cardiology and MRI Department A. De Gasperis at Niguarda Ca Granda Hospital in Milan. Patients were scanned with.5 T Magnetom Avanto Siemens; images were analyzed using a post-processing software (CMR Tools, Imperial College, London). Liver iron concentration (LIC) was calculated according the formula [(/(T*/000)] x We divided patients on the basis of normal cardiac and liver MRI T* (N group), cardiac or liver involvement (C or L group, respectively), and liver and cardiac involvement (LC). Normal cardiac T* was defined for value above 0 ms and normal LIC under 4. mg/g dry weight. R e s u l t s. Overall the median ferritin value was 0.5 ng/ml (range ng/ml) and pretransfusional mean hemoglobin (Hb) 9.4 ± 0. 7 g/dl. More o v e r, the mean iron intake was 0. 4 ± 0.08 mg/kg/day. Normal cardiac and liver MRI T* was found in 40 patients (%), patients (6%) had only cardiac iron overload (C g roup), 4 patients (%) only liver iron overload (L group) and 8 patients (%) had both card i a c and liver iron overload (LC group). At evaluation point, in N group the 50% of patients was in therapy with deferasirox, 7,5% with defero x a m i n e (DFO), 7,5% with DFO + deferiprone (DFP), 5% with DFP; in L group the 9% of patients was in therapy with deferasirox, 7% with DFO, 7% with DFO + DFP and 7% with DFP; in C gro u p Direttore Scientifico Vincenzo De Sanctis ( Fe r r a r a ) Comitato di Redazione Vincenzo Caruso ( C a t a n i a ), Paolo Cianciulli (Roma), Maria Concetta Galati ( C a t a n z a r o ), Maria Rita Gamberini ( Fe r r a r a ), Aurelio Maggio ( Pa l e r m o ) Comitato Editoriale Maria Domenica Cappellini ( M i l a n o ), Marcello Capra ( Pa l e r m o ), Gemino Fiorelli ( M i l a n o ), Eliana Lai ( C a g l i a r i ), Alfio La Ferla ( C a t a n i a ), Turi Lombardo ( C a t a n i a ), Carmelo Magnano ( C a t a n i a ), Roberto Malizia ( Pa l e r m o ), Giuseppe Masera ( M o n z a ), Lorella Pitrolo ( Pa l e r m o ), Luciano Prossomariti ( N a p o l i ), Michele Rizzo ( C a l t a n i s e t t a ), Calogero Vullo ( Fe r r a r a ) Segretaria di Redazione Gianna Vaccari ( Fe r r a r a ) International Editorial Board A. Aisopos (Athens, Greece), M. Angastiniotis (Nicosia, Cyprus), Y. Aydinok ( I z m i r, Tu r k e y ), D. Canatan (Antalya, Tu r k e y ), S. Fattoum ( Tunis, Tu n i s i a ), C. Kattamis (Athens, Greece), D. Malyali (Istanbul, Tu r k e y ), P. Sobti (Ludhiana, India), T. Spanos (Athens, Greece)

2 Rivista Italiana di Medicina dell Adolescenza - Volume 7, n., 009 the 4% of patients was in therapy with deferas i rox, 4% with DFO and 4% with DFO + D F P ; in LC group the 4% of patients was in therapy with deferasirox, 4% with DFO, % with D F O + DFP and % with DFP. Data are summarize in table below (Tabella ). P u r p o s e. O s t e o p e n i a / o s t e o- p o rosis is a significant cause of morbidity in beta-thalassemia M a j o r, producing re d u c e d bone strength and incre a s e d risk of fractures. As scanty data a re available for TI, we evaluated bone mineralization and related factors in a cohort of TI patients. Methods. 50 TI patients (9 M, F; mean age 9.6 ± 6.6 years) were scanned by dual energy X- ray absorptiometry at vertebral and femoral sites. The relationships between bone mineralization Tabella. PARAMETERS GROUP N GROUP C GROUP L GROUP CL N. of total pts (%) 40 (%) (6%) 4 (%) 8 (%) % of pts with DFO 5 (7.5 %) 9 (4%) (7%) (4%) % of pts with DFO + DFP (7.5%) (4%) 7 (7%) (%) % of pts with DFP (5%) 0 (0%) 7 (7%) (%) % of pts with deferasirox 0 (50%) 9 (4%) 6 (9%) (4%) Mean ferritin levels ± DS 87 ± ± 49 4 ± ± 78 (ng/ml) Significant diff e rences in ferritin levels were pre s e n t between groups (N vs LC p < 0.00, N vs L p < 0.00, L vs C and N vs C p = ns). C o n c l u s i o n s. The best iron chelation therapy in TM is still to be determined. Often the TM patients benefit by a combined therapy. In conclusion cardiac and liver MRI T can help for a better stratification of complications and might help to revise protocols for an adequate chelation therapy in!-thalassemia major. Bone mineralization in patients with beta-thalassemia intermedia (TI) Baldini I.M., Tampieri B., Forti S., Ulivieri F.M., Fasulo M.R. 4, Cesaretti C. 4, Marcon A. 4, Cassinerio E. 4, Zanaboni L. 4, Cappellini M.D. 4 UO of Internal Medicine A, Policlinico Foundation IRCCS, Milan, Italy; UO of Audiology, Policlinico Foundation IRCCS, University of Milan, Italy; Department of Nuclear Medicine, Policlinico Foundation IRCCS, University of Milan, Italy; 4 Hereditary Anemia Center, Department of Internal Medicine, Policlinico Foundation IRCCS, University of Milan, Italy Tabella. and demographic, haematological, endocrinometabolic parameters were evaluated with univariate and multivariate statistical analysis. R e s u l t s. A high prevalence of bone demineralization was found. The Table shows the re s u l t s as distributed on the basis of sex and site ( Tabella ). Mean vertebral T-score (-.58 ±.) was significantly lower than femoral (-.85 ±.6). Osteopenia/osteoporosis was found in 46 out of 50 patients (9%), with selective vertebral localization in 8 (6%) and femoral localization in (%); both sites were affected in 7 patients (74%). Univariate statistical analysis revealed significant correlations of BMI, extramedullary hematopoiesis masses, hypogonadism, serum ferritin and alkaline phosphatase with T-score in both sites. Age, haemoglobin and PTH serum Bone mineralization Vertebral Femoral Normal Total 5 (0%) (4%) T-score > - Males (4%) 6 (%) 4 Females (6%) 6 (%) Osteopenia Total 4 (48%) 4 (48%) - T-score -,5 Males 9 (8%) 0 (0%) Females 5 (0%) 4 (8%) Osteoporosis Total (4%) 4 (8%) T-score < -.5 Males 8 (6%) (6%) Females (6%) (%)

3 Atti Congresso So.STE concentrations were not correlated. Multivariate analysis confirmed the same correlations. C o n c l u s i o n s. Our study showed a high pre v a- lence of osteopenia/osteoporosis in TI patients, with prominent involvement of axial bone, and c o r relation between iron overload, gonadal dysfunction and excessive ineffective ery t h ro p o i e s i s and this complication. Close surveillance, preventive intervention and early management are m a n d a t o ry to secure normal bone health and i m p rove quality of life in this thalassemia synd ro m e. Valutazione non invasiva della fibrosi epatica in pazienti talasemici trasfusione dipendenti mediante transient elastography (TE) Borsellino Z., Di Marco V., Gagliardotto F., Cuccia L., Marocco M.R., Ruffo G.B., Saieva L., Cabibbi D., Alaimo G., Spataro F. 4 e Capra M. UOC Ematologia-Emoglobinopatie Osp. G. Di Cristina, ARNAS Civico, Palermo; UOC Gastroenterologia ed Epatologia, Dip. Biomedico di Medicina Interna e Specialistica. Università di Palermo; Servizio di Istologia Patologica Università di Palermo; 4 Servizio di Virologia, ARNAS Civico Palermo O b i e t t i v o. La Transient elastography (TE) è un metodo non invasivo per la valutazione della fibrosi epatica. L influenza del sovraccarico di ferro su questa metodica è ancora sconosciuta. Noi abbiamo valutato se tale metodica diagnostica può sostituire la biopsia epatica come strumento per la valutazione della fibro s i epatica in soggetti con accumulo di ferro posttrasfusionale e infezione da HCV post- trasfus i o n a l e. Pazienti. 56 pazienti con! talassemia omozigote, trasfusione dipendente, (età media 7.4), con HCV-RNA positivo, sottoposti anche a biopsia epatica. M e t o d i. La flogosi epatica è stata valutata utilizzando lo score METAVIR, la concentrazione del ferro nel fegato (LIC) è stata misurata mediante spettrometria ad assorbimento atomico e la misurazione della stiffness del fegato (LSM) è stata misurata in kpa mediante la TE con Fibro s c a n. Risultati. La stiffness del fegato aumenta proporzionalmente con lo stadio di fibrosi del fegato (r = 0.70; p > 0.00) indipendentemente dalla concentrazione di ferro nel fegato (r = 0.0; p = 0.9). La capacità di predizione della cirrosi dell AUROC era (95% CI: 0.95 to.000) con cut-off di 0 kpa con il 00% di sensibilità (95% CI: ) e il 95% di specificità (95% CI: ). La LSM era significativamente associata con i valori di transaminasi e lo stadio di fibrosi ma non con la ferritina, la LIC e la steatosi. Conclusioni. La LSM con la TE è uno strumento adeguato, attendibile e non-invasivo per la diagnosi di fibrosi epatica avanzata in pazienti con talassemia, indipendentemente dal grado di sovraccarico di ferro. Cardiac iron overload extimated by T* magnetic resonance (MRI T*) in a cohort of thalassemia major patients Cassinerio E., Roghi A.(), Zanaboni L., Pedrotti P., Dellegrottaglie S., Marcon A., Proto P., Cappellini MD. Hereditary Anemia Center, Department of Internal Medicine, Policlinico Foundation IRCCS, University of Milan, Italy; Department of Cardiology, Niguarda Hospital, Milan, Italy P o r p o u s e. C a rdiac iron overload can cause important morbidity and mortality in Thalassemia Major (TM) patients. Myocardial iron concentration can be assessed by MRI T*, a new, re p roducible and non invasive technique. Heart T* values under 0 ms are associated with a pro g ressive iron load and cardiac dysfunction; T* values under 0 ms a re predictive of increasing risk of heart failure. In this study we evaluate heart MRI T* values in a l a rge cohort of TM patients cared at Here d i t a ry Anemia Center in Milan (Italy). M e t h o d s. O n e - h u n d red twenty seven TM patients (54 males and 7 women, ± 6 yrs) u n d e rwent MRI T* to assess myocardial iro n overload from November 006 to October 007. MRI T* was performed at Cardiology and MRI Department A. De Gasperis at Niguarda Ca Granda Hospital in Milan. Patients were scanned with.5 T Magnetom Avanto Siemens; images w e re analysed using a post-processing software (CMR Tools, Imperial College, London). Card i a c function was also assessed by MRI. Normal values heart T* were defined above 0 ms. At time of evaluation 46 (6.%) patients were treated with d e f e roxamine (DFO), 9 (7.%) with deferipro n e (DFP), 6 (.6%) with combined therapy (DFO + DFP) and 56 (44%) with deferasirox for at least six months before MRI T*. R e s u l t s. Overall, the median ferritin value was 0 ng/ml (range ng/ml) and pretransfusional mean hemoglobin (Hb) 9.4 ±

4 Rivista Italiana di Medicina dell Adolescenza - Volume 7, n., 009 g/dl. More o v e r, the mean iron intake was 0. 4 ± 0.08 mg/kg/day. The mean cardiac T* value was 6. ±.4 (range ). Te n patients (7.9%) showed a T* < 0 ms, 5 patients (7.6%) had a T* between 0 and 0 ms and 8 patients (64.6%) had normal T* ( T * > 0 ms). Patients were divided accord i n g to cardiac T* values and chelation therapy at the time of evaluation (Tabella ). Le varianti emoglobiniche derivano da sostituzioni aminoacidiche a carico delle catene globiniche che costituiscono l emoglobina. Ad oggi sono state caratterizzate circa 000 varianti emoglobiniche che possono essere stabili e clinicamente asintomatiche, oppure determinare specifiche manifestazioni cliniche a seconda del difetto funzionale. Tra queste l emoglobina S (Hb S), C ed E rappresentano un importate problema sanitario e raggiungono frequenze elevate in Africa (Hb S e Hb C) e Sud Est Asiatico (Hb E). Tabella. MRI T* VALUES n. pt DFO n. pt DFP n. pt DFO+DFP n. pt EXJADE (%) (%) (%) (%) Under 0 ms 4 (40) 0 (0) (0) 4 (40) Between 0 and 0 ms 5 (4.8) (.9) (8.6) 6 (45.7) Above 0 ms 7 (.9) 8 (9.8) (.4) 6 (4.9) n. pt = number of patients No significant diff e rences of ferritin, Hb levels and iron intake were present between each gro u p. No significant correlation were found between heart T* and ferritin, Hb or iron intake. In patients with T* values under 0 ms, a re d u c- tion of LVEF were shown in the group with combined therapy or deferasirox (4 ± 9 and 5 0 ± %, respectively). All the other gro u p s showed a normal LV E F. Discussion and conclusions. Our data showed that there s no correlation between cardiac iro n overload measured by MRI T* and ferritin levels. We cannot demonstrate a diff e rent effect on cardiac T* by diff e rent iron chelators having a single MRI evaluation. Most of the patients tre a t e d with combined therapy or DFP started intensive chelation therapy because of reduction of LVEF or heart failure. Pro g ressive follow up and re p e a t e d MRI along time are warranted to design personalized chelation therapy. Caratterizzazione molecolare di varianti emoglobiniche in Lombarbia C e s a retti C., Refaldi C., Fasulo M.R., Cassinerio E., M a rcon A., Cappellini M.D. Centro Anemie Congenite, Dipartimento di Medicina Interna, Università degli Studi di Milano Fondazione IRCCS Policlinico, Mangiagalli e Regina Elena In questo studio riportiamo i dati molecolari re l a- tivi alle varianti emoglobiniche osservate nel nos t ro centro di riferimento per la Lombardia nel corso di consulenza genetica preconcezionale o per definizione del fenotipo ematologico. Tutti i campioni sono stati sottoposti ad analisi degli indici eritrocitari e delle frazioni emoglobiniche; l analisi dei difetti molecolari delle catene globiniche è stata effettuata mediante sequenziamento dire t t o del DNA e GAP-PCR. Dal 00 ad oggi sono stati individuati 6 soggetti affetti da varianti emoglobiniche di cui l 88% con anomalie sulla catena beta, il 7% sulla delta e il 5% sulle alfa; il 47% di tali soggetti è risultato avere un genotipo omozigote, o composto con un altra variante, o associato a un tratto alfa e/o beta talassemico. In tabella è riportato l elenco delle varianti emoglobiniche caratterizzate (Tabella 4). Sono state caratterizzate 6 diverse varianti beta con una prevalenza del 69% di Hb S, 0% di Hb C, 6% di Hb Lepore e % di Hb E. Sono state individuate 4 varianti con fenotipo talassemico (Hb Lepore, Hb E, Hb Monroe e Hb Knossos) e varianti con aumentata affinità per l ossigeno (Hb Andrew-Mineapolis, Hb San Diego e Hb Abruzzo). Le varianti coinvolgenti le catene alfa sono 6 di cui 4 sul gene alfa e due sul gene ibrido alfa-alfa derivante dalla delezione di.7kb. Tra le 4 varianti delta la Hb A Yialousa si conferma essere la più frequente (6%), mentre la Hb A Shepherds Bush è risultata una nuova variante mai descritta. 6

5 Atti Congresso So.STE Tabella 4. Varianti Beta n. origine Hb S beta 6(A) Glu>Val 99 Italia, Senegal, Nigeria, Ghana, Marocco Hb C beta 6(A) Glu>Lys 4 Burkina Faso, Costa d Avorio, Ghana, Italia Hb Lepore WB (delta fino a 87; beta da 6) 8 Italia Hb E beta 6(B8) Glu>Lys 5 Tailandia, Bangladesh, Filippine HbCamperdown beta 04(G6) Arg>Ser Italia Hb O-Arab beta (GH4) Glu>Lys Italia Hb Monroe beta 0(B) Arg>Thr Italia Hb Knossos beta 7(B9) Ala>Ser Egitto Hb Andrew-Minneapolis beta 44(HC) Ly s > A s n Italia Hb San Diego beta 09(G) Val>Met Italia Hb Abruzzo beta 4(H) His>Arg Italia Hb G-San José beta 7(A4) Glu->Gly Italia Hb Austin beta 40(C6) Arg>Ser Italia Hb City of Hope beta 69(E) Gly>Ser Italia Hb D-Ibadan beta 87(F) Thr>Lys Italia HbD-Los Angeles beta (GH4) Glu>Gln Italia Varianti Alfa n. origine Hb O-Padova alpha 0(B) Glu>Lys Italia Hb Rampa alpha 95(G) Pro>Ser Italia Hb Constant Spring alpha 4, Stop>Gln Asia Hb Icaria alpha 4, Stop>Lys Italia Hb G-Philadelphia alpha- 68(E7) Asn>Lys Nigeria Hb Hasharon alpha- 47(CE5) Asp>His Italia Varianie Delta n. origine Hb A-Yialousa delta 7(B9) Ala>Ser 7 Italia, Albania Hb A delta 6(A) Gly>Arg Ghana Hb A-Troodos delta 6(G8) Arg>Cys Italia Hb A Shepherds Bush delta 74(E8) Gly>Asp Italia 7