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: selimshahjada@gmail.com
Fibrocalculous Pancreatic
Diabetes (FCPD)
1

2. Etiologic classification of diabetes mellitus
(ADA Expert Committee (1997)
resistance with relative insulin deficiency
Type 1 diabetes (β cell destruction, usually leading
to absolute insulin deficiency)
a. Immune mediated
b. Idiopathic
Type 2 diabetes (may range from predominantly insulin
to a predominantly secretory defect with
insulin resistance)
2

3. Etiologic classification of diabetes mellitus
contd….
Other specific types
Genetic defects of β cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas e.g. FCPD
Endocrinopathies
Drug - or chemical induced
Infections
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with diabetes
Gestational diabetes mellitus (GDM)
3

4. HISTORICAL BACKGROUND OF FCPD
1959 Zudeima’s first description from Indonesia
1960 Shaper’s report from Uganda
Geevarghese’s first study from Kerala,
1962 world’s largest series around 1700 patients
cases - considered to be the Father of TCP
1962 Existence of FCPD confirmed in Brazil, Kenya,
- 1981 Nigeria and several countries in
Asia eg. Thailand, Bangladesh, Sri Lanka
4

5. FCPD - INTERNATIONAL STATUS
This entity was not given due recognition
1985
Till
1985 WHO study group report introduced the term
Malnutrition Related Diabetes Mellitus (MRDM)
where the term Fibrocalculous Pancreatic
Diabetes (FCPD) was introduced
1997 ADA expert committee deleted MRDM. FCPD now
classified as a subtype under other specific types
as diseases of the Exocrine Pancreas
1998 Provisional report of WHO consulting group
ratified ADA recommendation
5

6. FCPD DEFINITION (Mohan et al, 1985)
Diabetes secondary
to non- alcoholic chronic
pancreatitis of uncertain
etiology predominantly
seen in tropical
developing countries
6

7. FCPD DEFINITION
 Severe diabetes
 Associated with undernutrition
 Usually non ketotic
 Presence of pancreatic calculi on X-ray abdomen
or evidence of
chronic pancreatitis on ultrasound or CT
 Usually requires insulin for control
 Usually seen in poor people
7

8. WORLDWIDE DISTRIBUTION OF MRDM (FCPD) AND PDDM
Reproduced from WHO study Group on Diabetes Mellitus (1985) with permission
8

9. DIAGNOSTIC CRITERIA FOR FCPD
(MOHAN et al, 1985)
Mohan V. Diabetologia. 1985;28:229-232.
Occurrence in tropical country
Diabetes (WHO criteria)
Evidence of chronic pancreatitis
Pancreatic calculi
OR
ERCP evidence of CP
OR
Ultrasound/CT features
Plus h/o abd. Pain / steatorrhoea
Plus abnormal pancreatic function
Absence of other causes of CP (eg. alcoholism)
9

10. Classical triad of
pain
FCPD
Abdominal
FCPD
Pancreatic
calculi
Diabetes
10

11. PLAIN ABDOMINAL RADIOGRAPH SHOWING
MULTIPLE PANCREATIC CALCULI
11

12. ULTRASOUND IMAGE OF PANCREAS IN
A FCPD PATIENT 12

13. ENDOSCOPIC RETROGRADE
CHOLANGIOPANCREATOGRAM (ERCP) OF FCPD PATIENT
13

14. Macroscopic appearance of pancreas in FCPD
14

15. Histopathology of pancreas in FCPD
Dense fibrosis entirely replacing exocrine tissue
15

16. CLINICAL SPECTRUM OF FCPD
PRONE
• • • • • • • • •
• • • •
• • • • • • •
• • • • • • • •
• • • • • • • • •
• • • • • • • • •
• • • • • • • • •
• • • • • • • • •
KETOSIS RESISTANCE KETOSIS
Mohan V et al, Journal of Applied Medicine. 1996;883-887.
16

17. FCPD AND KETOSIS RESISTANCE
Pancreatic alpha cellbeta cell function
Partial presentation of
(insulin reserve) (glucagon) deficiency
Low adipose mass/ Carnitine
decreased supply of deficiency
non-esterifeid fatty
acids
PROTECTION FROM
KETOSIS
17

18. FCPD
DO MICROVASCULAR
COMPLICATIONS OCCUR?
MICROVASCULAR COMPLICATIONS DO NOT OCCUR
IN SECONDARY FORMS OF DIABETES
Harrison’s Textbook of Diabetes (1981)
18

19. Prevalences of Microvascular and Macrovascular diabetic
complications in subjects with FCPD compared with
NIDDM patients
* p = 0.04 compared to Type 2 diabetes
Mohan V et al. Journal of Diabetes and its Complications. 2004;18:264-270.
Percentage of subjects with complications
Type 2 Diabetes (n = 277) FCPD(n =277)
Retinopathy
Non-proliferative
Proliferative
Nephropathy
Peripheral neuropathy
Macrovascular disease
Infarction
Ischaemia
37.2
31.4
5.8
15.0
25.3
5.4
6.5
36.1
32.9
3.6
10.1
20.9
2.2
2.5*
19

20. FCPD WITHO
NATURAL HISTORY OF FCPD
Mohan V et al, International Journal of Diabetes. 1995;3:71-82.
UT FCPD WITH
TCP (PRE- FCPD) TCP- IGT COMPLICATIONS COMPLICATIONS
NORMAL GTT IGT CLINICAL DIABETES
20

21. 21

22. FCPD - CAUSES OF DEATH
(n = 29)
♦Diabetes Related (Nephropathy etc) - 10
♦ Pancreatic cancer -
-
8
4♦ Infection / Emaciation
♦
♦
Chronic Pancreatitis Related - 5
Surgical Complications - 1
♦Keto Acidosis - 1
Mohan V et al, Diabetes Care. 1996;19:1274-1278
22

23. JOP. Journal of Pancreas. 2012 Mar 10;13(2):205 - 20923

24. Prevalence
ACP
of
at
FCPD and diabetes secondary to
our centre from 1991-2010
diabetes
ACP**
0.155
*p for trend < 0.001; **p for trend =0.155
Papita R, Nazir A, Anbalagan VP, Anjana RM, Pitchumoni C, Chari S, Mohan V.
Journal of Pancreas. 2012 ;13:205-9.
Period of
study
Total diabetes
patients
registered at the
centre
No.
Prevalence of
FCPD*
No./ Prevalence of
secondary to
1991-1995 23,788 371 (1.6%) 12 (0.1%)
1996-2000 35,368 226 (0.6%) 25 (0.1%)
2001-2005 48,192 179 (0.4%) 40 (0.1%)
2006-2010 70,394 122 (0.2%) 57 (0.1%)
Total cases
P for trend* 177,742
898 (0.5%)
<0.001
134 (0.1%)
24

25. Change in mean age at diagnosis of patients with FCPD and
diabetes secondary to ACP during the years 1991 to 2010
Papita R, Nazir A, Anbalagan VP, Anjana RM, Pitchumoni C, Chari S,
Journal of Pancreas. 2012 ;13:205-9.
Mohan V.
25

26. ETIOPATHOGENESIS
CASSAVA
 LIMITED EXPERIMENTAL EVIDENCE
 NO DIRECT PROOF FOR CASSAVAAS A
PANCREATIC TOXIN
 MOST OF THE STUDIES ARE SHORT-TERM
 Malnutrition - ? Overt
- ? Micronutrient
 Cassava (Tapioca)
26

27. Genetic studies on FCPD
TYPE 2 DM FCPD TYPE 1 DM
Kambo PK, Hitman GA, Mohan V. et al. Diabetologia. 1989;32:45-51
Mohan V and Hitman GA, Diabetes / Metabolism Research and Reviews. 2000;16:454-457
Trypsinogen gene - No association
REG gene - No association
INSULIN GENE
HLA-DQβ
HLA-DQα
HLA-DRα
27

28. GENE MUTATIONS ASSOCIATED WITH FCPD
Genetic alterations in the trypsinogen pathway
 Serum protease inhibitor Kazal type 1 (SPINK1)
 Cationic trypsinogen (PRSS1)
 Anionic trypsinogen (PRSS2)
 Chymotrypsinogen C (CTRC)
28

29. GENE MUTATIONS ASSOCIATED WITH FCPD
Alteration in other genes
 Cystic fibrosis transmembrane conductance
regulator
(CFTR)
 Regenerating islet-derived genes 1α (REG1A &
REG1B)
 Cathepsin B (CTSB)
 Angiotensin converting enzyme (ACE)
 Calcium-sensing receptor (CASR)
29

30. ASSOCIATION OF SPINK GENE WITH FCPD
o Pfützer RH, Barmada MM, Brunskill AP, Finch R, Hart PS,
Neoptolemos J, Furey WF, Whitcomb DC. SPINK1/PSTI
polymorphisms act as disease modifiers in familial and idiopathic
chronic pancreatitis. Gastroenterology. 2000.
o Witt H, Luck W, Hennies HC et al. Mutations in the gene encoding
the serine protease inhibitor, Kazal type 1 are associated with
chronic pancreatitis. Nature Genetics. 2000.
o Hassan Z, Mohan V, Ali L et al, SPINK1 is a susceptibility gene for
fibrocalculous pancreatic diabetes in subjects from the Indian
subcontinent. American Journal of Human Genetics. 2002.
30

31. ASSOCIATION OF SPINK GENE WITH FCPD
o Schneider A, et al. SPINK1/PSTI mutations are associated with tropical
pancreatitis and type II diabetes mellitus in Bangladesh
Gastroenterology. 2002.
o Chandak G.R., Idris M.M., Reddy D.N., Bhaskar S., Sriram P.V. and Singh
L. Mutations in the pancreatic secretory trypsin inhibitor gene
(PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are
significantly associated with tropical calcific pancreatitis, J Med
Genet.,2002.
o Noone P.G., Zhou Z., Silverman L.M., Jowell P.S., Knowles M.R., Cohn
J.A., Cystic fibrosis gene mutations and pancreatitis risk: relation to
epithelial ion transport and trypsin inhibitor gene mutations,
Gastroenterology. 2001
31

32. Current Theories About The
Aetiopathogenesis of FCPD
formation
Factors
FCPDSteatorrhea
Impaired
Glucose
Tolerance
Pancreatic
exocrine
deficiency
Environmental
Malnutrition
Excessive dietary
oxidants and / or
antioxidants
Dietary toxins
Acinar and B cell
damage
Duct obstruction
Calcite stoneDefective B cell
growth and repair
Genetic Factors
Association SPINK
gene and other
genes
32

33. MANAGEMENT OF FCPD –
PRINCIPLES
 Treatment of abdominal pain
 Use of pancreatic enzymes
 Management of diabetes
33

34. Management of Diabetes
Diet
 Principles similar to that of other types of
diabetes
 More liberal calorie Intake
 High protein intake
34

35. Management of Diabetes
Pharmacotherapy
Oral Antidiabetic Drugs
 Sulphonyureas can be used if β cell function is good
 Biguanides usually not used as the FCPD
patients are lean
Insulin
 Would be needed in majority of the cases to
achieve
blood sugar control in FCPD patients
35

36. Heterogeneity in FCPD
Mohan V et al, Diabetologia. 1985;28:229-232.
1. Symptoms  Asymptomatic
 Marked symptoms
2. Carbohydrate intolerance  Normal glucose tolerance
 IGT
 Overt diabetes
3. B - cell reserve  Good
 Poor
 Negligible
4. Response to therapy  Diet alone
 Oral agents
 Insulin
5. Proneness to ketosis  Ketosis - resistant
 Ketosis – prone
6. Exocrine dysfunction  Only after provocative tests
 Clinical steatorrhoea
7. ERCP  Absent to mild ductal changes
 Marked ductal changes
8. Histopathology  Mild changes : calculi
 absent or small
 Marked changes : extensive
 fibrosis, ductal dilatation,
 multiple calculi
36

37. 37
Thanks