FCPD by Dr Shahjada Seim

Fibrocalculous Pancreatic Diabetes (FCPD)
by Dr Shahjada Selim, BSMMU

1. Dr Shahjada Selim Assistant Professor Department of Endocrinology Bangabandhu Sheikh Mujib Medical University, Dhaka Email: [email protected] Fibrocalculous Pancreatic Diabetes (FCPD) 1

2. Et i o l og i c classi f ica t i on of d ia b e t e s melli tus ( AD A E x p er t Co mm ittee (1997) resistance w ith relative insulin deficiency  T y pe 1 d i abe t es ( β cell destruction, usually leading to absolute insulin deficienc y ) a. I mmune m ed i a t ed b. I d i opa t h i c  T y pe 2 d i abe t es ( m ay range from predo m inant l y insulin to a predo m inant l y secretory defect w ith insulin resistance) 2

3. Et i o l og i c classi f ica t i on of d ia b e t e s melli tus c on t d ….  Ot her spec ifi c t y pes Gene t i c de f ec t s of β ce l l f unc t i on Gene t i c de f ec t s i n i nsu li n ac t i on D i seases of t he exocr i ne pancreas e . g. F C P D E ndocr i nopa t h i es D rug - or che mi cal i nduced I n f ec t i ons U nco mm on f or m s of imm une - m ed i a t ed d i abe t es O t her gene t i c s y ndro m es so m e t im es assoc i a t ed w it h d i abe t es  G es t a ti onal d i abe t es me llit us (G D M ) 3

4. H I S T OR I CA L BACKGROUN D O F F C PD 1959 Zudei m a ’ s first description from Indonesia 1960 Shape r ’ s report from Uganda G eevarghese ’ s first study from Kerala, 1962 w orld ’ s largest series around 1700 patients cases - considered to be the Father of TCP 1962 Existence of FCPD confir m ed in Bra z il, Ken y a, - 1981 Nigeria and several countries in Asia eg. Thailand, Bangladesh, Sri Lanka 4

5. F C PD - I N TE RN A T I ONA L S T A T US Th i s en tit y w as not g i ven due recogn iti on 1985 T ill 1985 W H O s t udy group report i n t roduced t he t erm M a l nu t r iti on R e l a t ed D i abe t es M e llit us (M RD M) w here t he t erm F i broca l cu l ous P ancrea ti c D i abe t es ( F CPD ) w as i n t roduced 1997 AD A expe r t comm itt ee de l e t ed M RD M . F CP D now c l ass ifi ed as a sub t y pe under o t her spec ifi c t y pes as d i seases of t he E xocr i ne P ancreas 1998 P rov i s i onal report of W H O consu lti ng group ra tifi ed AD A recommenda ti on 5

6. F C PD D E FI N ITIO N (M oh a n et a l , 1985) D iabete s s e c onda ry t o non - al c oholi c c h r oni c pan c r eatiti s o f un c e r tai n etiolog y p r edominantl y s ee n i n t r opi c al de v elopin g c ount r ies 6

7. F C PD D EF I N I T I O N  S e v ere d i abe t es  A ssoc i a t ed w it h undernu t r i t i on  U sua ll y non ke t o t i c  P resence of pancrea t i c ca l cu l i on X - ray abdo m en or e v i dence of chron i c pancrea t i t i s on u l t rasound or C T  U sua ll y requ i res i nsu li n f or con t rol  U sua ll y seen i n poor peop l e 7

8. W O R L D W I DE D I S T R I BU T IO N O F M RDM ( F CPD) AND PDDM Re p r odu ce d f r o m W H O s t ud y G r ou p o n D i a b e t e s M e lli t u s ( 1985 ) w i th p erm i ss io n 8

9. D I AGNO ST I C CR I TE R I A F OR F C PD (MO HA N et a l , 1985) Mohan V . D i abe t o l og i a. 1985 ; 28 : 22 9 - 2 32. Occurrence i n t rop i cal coun t ry D i abe t es (WH O cr i t er i a) E v i dence of chron i c pancrea t i t i s P ancrea t i c ca l cu l i OR E RC P e v i dence of C P OR U l t rasound / C T f ea t ures Pl us h / o abd. P a i n / s t ea t orrhoea Pl us abnor m al pancrea t i c f unc t i on A bsence of o t her causes of C P ( eg. a l coho li s m ) 9

10. Classical t r iad o f pa i n F C P D A bdom i nal F CPD P ancrea ti c ca l cu l i D i abe t es 10

11. P L A I N ABDO M I NA L RAD I OGRAP H SHO W I NG M U L T I P L E P ANCRE A T I C CA L CU L I 11

12. U L T RAS O UN D IM A G E O F P ANCR E A S I N A F CP D PA T I ENT 12

13. END O SC O P I C RE T R OG RADE CH O L AN GIO P ANCRE A T OG RA M ( ERCP ) O F FCP D PA T I ENT 13

14. M acr o sc op i c a pp eara n c e o f p a n crea s i n FCP D 14

15. H is top a tho l o gy of p a n c r ea s i n F C PD D ense fi bros i s en ti re l y rep l ac i ng exocr i ne ti ssue 15

16. C L I N I CAL SPE C T RUM OF F C PD P R O NE • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • K E T O SI S R ESIS T ANC E K E T O SI S Mohan V et a l , Journal of A pp li ed Med i c i ne. 1996 ; 883-88 7 . 16

17. F CP D AN D KE T O S I S RES I S T ANCE P ancrea t i c a l pha ce l l be t a ce l l f unc t i on P ar t i al presen t a t i on of ( i nsu li n reser v e) ( g l ucagon) de f i c i ency L o w ad i pose m ass/ C arn i t i ne decreased supp l y of de f i c i ency non - es t er if e i d f a tt y ac i ds PR O T EC T IO N F R O M KE T O S I S 17

18. FCPD D O MI CRO V A S CU L AR CO M PL I C A T I ON S OCCU R ? MI CR O V ASCU L A R C OM P L I C A T IO N S DO N O T O CCUR I N SEC O NDA R Y F O R M S O F D I ABE T ES H arr i son ’ s T ex t book of D i abe t es ( 1981) 18

19. P reva l ences of Mi crovascu l ar and M acrovascu l ar d i abe ti c comp li ca ti ons i n sub j ec t s w it h F CP D compared w it h N I DD M pa ti en ts * p = . 4 c o m p are d to T y p e 2 di a b e t es M oh an V et al. J ou r n al o f Dia b e t es a n d i t s C omp lica t i on s. 2004 ; 18 : 264 - 270. P erce n t a g e o f s ubj ec ts w i th c o m pli ca t ion s T y p e 2 Dia b e t es ( n = 277) F C P D ( n = 277) R e t i nopa t hy N on - pro li f era t i v e P ro li f era t i v e N ephropa t hy P er i pheral neuropa t hy Macro v ascu l ar d i sease I n f arc t i on I schae mi a 37 . 2 31 . 4 5 . 8 15 . 25 . 3 5 . 4 6 . 5 36 . 1 32 . 9 3 . 6 10 . 1 20 . 9 2 . 2 2 . 5 * 19

20. F C P D W I T H O N A T URA L H I S T O R Y OF F C PD M ohan V et a l , I n t erna t i onal Journal of D i abe t es. 1995 ; 3 : 71 - 82. U T F C P D W I TH T C P (P R E- FC P D ) T C P - I GT C OM P L I C A T I O N S C OM P L I C A T I O N S N O R M A L GTT I GT C L I N I CA L D I AB E T ES 20

21. 21

22. F C PD - CAU SES O F D E A TH ( n = 29) ♦ D i abe t es R e l a t ed ( N eph r opa t hy e t c) - 10 ♦ P ancrea ti c cancer - - 8 4 ♦ I n f ec ti on / E mac i a ti on ♦ ♦ C hron i c P ancrea titi s R e l a t ed - 5 S urg i cal C omp li ca ti ons - 1 ♦ K e t o A c i dos i s - 1 M ohan V et a l , D i abe t es C are. 1996 ; 19 : 127 4 - 1278 22

23. J O P . Journal of P anc r eas. 2012 M ar 10 ; 13 ( 2 ): 205 - 209 23

24. P revale n ce AC P o f at FCP D a n d d ia b ete s sec ond a r y to ou r ce n tre fr o m 1991 - 2010 d i abe t es AC P ** . 155 *p f or t r end < . 001; **p f or t r end = . 155 P a pi ta R , Na z i r A , A nb a l a g a n V P , A nj a n a R M, P i t c hu m on i C , C h ar i S, M oh a n V . J ou r n a l o f P a n creas . 201 2 ; 13 : 20 5 - 9. P er i od of s t udy T o t al d i abe t es pa t i en t s reg i s t ered at t he cen t re N o. P re v a l ence of F C P D* N o . / P re v a l ence of secondary t o 1991 - 1995 23 , 788 371 ( 1 . 6 % ) 12 ( . 1 % ) 1996 - 2000 35 , 368 226 ( . 6 % ) 25 ( . 1 % ) 2001 - 2005 48 , 192 179 ( . 4 % ) 40 ( . 1 % ) 2006 - 2010 70 , 394 122 ( . 2 % ) 57 ( . 1 % ) T o t al cases P f or t rend* 177 , 742 898 ( . 5 % ) < . 001 134 ( . 1 % ) 24

25. C hange i n mean age at d i agnos i s of pa ti en t s w it h F CP D and d i abe t es secondary t o AC P dur i ng t he y ears 1991 t o 2010 P a pi ta R , Na z i r A , A nb a l a g a n V P , A nj a n a R M, P i t c hu m on i C , C h ar i S, J ou r n a l o f P a n creas . 201 2 ; 13 : 20 5 - 9. M oh a n V . 25

26. ET I O P A T HOG E N ES I S CASS AVA  L I M I T E D EXPE R I M E N T A L EVI D E NC E  N O D I R E C T P R OOF FOR CA SS A V A A S A P ANCR E A T I C T O XI N  MO S T OF T H E S T UD IE S AR E S H O R T - T E R M  M al nu triti o n - ? O vert - ? Mi cronu t r i ent  C assav a ( T a p i o ca) 26

27. G ene t i c st ud i es o n FC PD T YPE 2 DM F CPD T YPE 1 DM Ka mb o P K, Hi tm an G A, M oh an V . et al. Dia b e to l og ia . 1989;32:45 - 51 M oh an V a n d Hi tm an G A, Dia b e t es / M e t a bo lism Resea r ch a n d Revie w s. 2000 ; 16 : 454 - 457 T r y ps i nogen gene - N o assoc i a ti on RE G gene - N o assoc i a ti on INSULIN G ENE HLA-DQ β HLA-DQ α HLA-DR α 27

28. GEN E M U T A T I ON S ASSOC I A TE D W I T H FCP D G enetic alterations in the tr y psinog e n path w ay  Serum protease inhibitor Ka z al t y pe 1 (SPINK1)  Cationic tr y psin o gen (PRSS1)  Anionic tr y psin o gen (PRSS2)  Ch y m ot r y psi n o g en C (CTRC) 28

29. GEN E M U T A T I ON S ASSOC I A TE D W I T H FCP D Alteration in other genes  C y stic fibrosis trans m e m brane conductance regulator (CFTR)  Regenerating islet-derived genes 1α (RE G 1A & RE G 1B)  Cathepsin B (CTSB)  Angiotensin converting en z y m e (ACE)  Calciu m -sensing receptor (CASR) 29

30. ASSOC I A T I O N O F SP I N K GEN E W I T H FCP D P füt z er RH, Ba r m a d a MM , B r un skill A P , F i n ch R, Ha r t PS , Ne opto le mo s J, Fu r ey W F , W h i t c om b DC. SP INK1/ PS T I po l y mo r p h i s m s act as d isease mod i f ie r s in f a m ilial a n d i d i op a th ic c h r on ic p a n c r ea t i t is. G as t r o e nt e r o l o g y . 2000. W i t t H, Lu ck W , He nn ies HC et al. M ut a t i on s in th e g e n e e n c od i n g th e se r i n e p r ot ease i nh i b i to r , Ka z al t y p e 1 a r e ass o cia t ed w i t h c h r on ic p a n c r ea t i t is. Na tu r e G e n e t ics. 2000. Hassan Z , M oh an V , A li L et al, SP INK1 is a s u sce pt i b ili t y g e n e fo r f i b r o calc u l ou s p a n c r ea t ic d ia b e t es in s ub jec t s f r o m th e I nd ian s ub c ont i n e nt . A m e r ic a n J ou r n al of H um an G e n e t ics. 2002. 30

31. ASSOC I A T I O N O F SP I N K GEN E W I T H FCP D S c hn ei d er A , et al. SP INK1/ PS T I mut a t i on s a r e ass o cia t ed w i t h t r op ical p a n c r ea t i t is a n d t y p e II d ia b e t es m elli tu s in Ba ng la d esh G as t r o e nt e r o l og y . 2002. C h a nd ak G .R., I d r is M. M ., Re dd y D.N., B h askar S ., Sr i r am P . V . a n d S i ng h L . M ut a t i on s in th e p a n c r ea t ic sec r e to r y t r y p s in i nh i b i to r g e n e ( PS T I/ SP INK1) r a th er th an th e ca t i on ic t r y p s i nog en g e n e ( P R SS 1) a r e si gn i f ica n tl y ass o cia t ed w i t h t r op ical calci f ic p a n c r ea t i t is, J M ed G e n e t .,2002. N oon e P . G ., Zho u Z ., S il v e r m an L . M ., J o w ell P . S ., K no w les M .R., C oh n J. A ., C y s t ic f i b r o sis g e n e mut a t i on s a n d p a n c r ea t i t is r isk: r ela t i o n t o e p i th elial i o n t r a n s po r t a n d t r y p s i n i nh i b i to r g e n e mut a t i on s, G as t r o e nt e r o l o g y . 2001 31

32. C u rr e n t Th e o r i e s A bou t The Ae t iop a t hog e n e s i s o f F C PD fo r m a t i on F ac to r s F C P D S t ea to rr h ea I mp ai r ed G l u c o se T o le r a n ce P a n c r ea t ic ex o c r i n e d e f icie n cy E n v i r onm e n t al M al nut r i t i on E xcessi v e d ie t a r y o xi d a nt s a n d / or a nt i o xi d a nts Die t a r y to xi n s A ci n ar a n d B cell d a m a ge D u ct ob s t r u c t i on Calci t e s ton e De f ec t i v e B cell g r o w t h a n d r e p air G e n e t ic F ac to r s A ss o cia t i o n SP INK g e n e a n d oth er g e n es 32

33. MANA G E M E NT O F F C P D – P RINCI P L E S  T r ea t me nt of a bdo mi n a l p ai n  U s e of p a n c r ea t i c e n z ymes  Ma n a g eme nt of d ia b e t e s 33

34. M a n a g e m e nt of D i a b etes D i e t  P r i nc i p l es s i m il ar t o t hat of o t her t y pes of d i abe t es  M ore li beral ca l or i e I n t ake  H i gh p r o t e i n i n t ake 34

35. M a n a g e m e nt of D i a b etes Pharmacotherapy O r a l Antidiabetic D r ugs  S u l phon y ureas can be used i f β ce l l f unc ti on i s good  B i guan i des usua ll y not used as t he F CP D pa ti en t s are l ean I nsu li n  W ou l d be needed i n m a j or it y of t he cases t o ach i eve b l ood sugar con t rol i n F CP D pa ti en t s 35

36. He t e r ogene it y i n FCP D M oh a n V e t a l , D i a b e t ologi a . 1985 ; 28 : 229 - 232. 1. S y mpt o ms  A s y m p t o m a t ic  M a r ked s y mp t oms 2. Ca r boh y d r a t e i nto le r a n ce  N o r m al g l u c o se to le r a n ce  I G T  O v e r t d ia b e t es 3. B - cell r ese r v e  Good  P oor  Ne g li g i b le 4. Res pon se t o th e r a p y  Diet al on e  O r al a g e nt s  I n s u lin 5. Pr on e n ess t o ke to sis  Ke to sis - r esis t a n t  Ke to sis – p r one 6. E x o c r i n e d y s f un c t i o n  On l y a ft er p r o v o ca ti v e t es ts  Cli n ical s t ea to rr ho ea 7. E RCP  A b se n t t o m ild du c t al c h a ng es  M a r ked du c t al c h a ng es 8. His top a tho l o g y  M ild c h a ng es : calc u li  a b se n t o r s m all  M a r ked c h a ng es : ex t e n si v e  f i b r o sis, du c t al d ila t a t i on ,  mu l t i p le calc u li 36

37. 37 Thanks