1
Dr Shahjada Selim Assistant Professor
Department of EndocrinologyBangabandhu Sheikh Mujib Medical University, Dhaka
Email: [email protected]
Fibrocalculous Pancreatic Diabetes (FCPD)
2Etiologic 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)
3Etiologic 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)
4HISTORICAL BACKGROUND OF FCPD1959 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
5FCPD - INTERNATIONAL STATUS
This entity was not given due recognition1985Till
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 Pancreas1998 Provisional report of WHO consulting group ratified ADA recommendation
6FCPD DEFINITION (Mohan et al, 1985)
Diabetes secondary
to non- alcoholic chronic pancreatitis of
uncertain etiology predominantly seen in
tropical developing countries
7FCPD 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
8WORLDWIDE DISTRIBUTION OF MRDM (FCPD) AND PDDM
Reproduced from WHO study Group on Diabetes Mellitus (1985) with permission
9DIAGNOSTIC CRITERIA FOR FCPD
(MOHAN et al, 1985)
Mohan V. Diabetologia. 1985;28:229-232.
Occurrence in tropical countryDiabetes (WHO criteria)
Evidence of chronic pancreatitis
Pancreatic calculiOR
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)
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Classical triad ofpain
FCPDAbdominal
FCPD
Pancreatic calculi
Diabetes
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PLAIN ABDOMINAL RADIOGRAPH SHOWINGMULTIPLE PANCREATIC CALCULI
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ULTRASOUND IMAGE OF PANCREAS INA FCPD PATIENT
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ENDOSCOPIC RETROGRADECHOLANGIOPANCREATOGRAM (ERCP) OF
FCPD PATIENT
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Macroscopic appearance of pancreas in FCPD
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Histopathology of pancreas in FCPD
Dense fibrosis entirely replacing exocrine tissue
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CLINICAL SPECTRUM OF FCPD
PRONE
• • • • • • • • •
• • • •• • • • • • •• • • • • • • •• • • • • • • • •• • • • • • • • •• • • • • • • • •
• • • • • • • • •
KETOSIS RESISTANCE KETOSIS
Mohan V et al, Journal of Applied Medicine. 1996;883-887.
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FCPD AND KETOSIS RESISTANCE
Pancreatic alpha cellbeta cell functionPartial presentation of
(insulin reserve) (glucagon) deficiency
Low adipose mass/ Carnitine decreased supply of deficiency non-esterifeid fatty
acids
PROTECTION FROM KETOSIS
18FCPD
DO MICROVASCULARCOMPLICATIONS
OCCUR?
MICROVASCULAR COMPLICATIONS DO NOT OCCUR IN SECONDARY FORMS OF DIABETES
Harrison’s Textbook of Diabetes (1981)
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Prevalences of Microvascular and Macrovascular diabeticcomplications in subjects with FCPD compared with
NIDDM patients
* p = 0.04 compared to Type 2 diabetesMohan 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*
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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
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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
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JOP. Journal of Pancreas. 2012 Mar 10;13(2):205 - 209
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PrevalenceACP
ofat
FCPD and diabetes secondary toour centre from 1991-2010
diabetes
ACP**
0.155*p for trend < 0.001; **p for trend =0.155Papita 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 casesP for trend* 177,742
898 (0.5%)<0.001
134 (0.1%)
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Change in mean age at diagnosis of patients with FCPD anddiabetes 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.
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ETIOPATHOGENESIS
CASSAVA
LIMITED EXPERIMENTAL EVIDENCE
NO DIRECT PROOF FOR CASSAVA AS A PANCREATIC TOXIN
MOST OF THE STUDIES ARE SHORT-TERM
Malnutrition - ? Overt
- ? Micronutrient
Cassava (Tapioca)
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Genetic studies on FCPD
TYPE 2 DM FCPD TYPE 1 DM
Kambo PK, Hitman GA, Mohan V. et al. Diabetologia. 1989;32:45-51Mohan V and Hitman GA, Diabetes / Metabolism Research and Reviews. 2000;16:454-457
Trypsinogen gene - No associationREG gene - No association
INSULIN GENEHLA-DQβ
HLA-DQα
HLA-DRα
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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)
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GENE MUTATIONS ASSOCIATED WITH FCPDAlteration 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)
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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.
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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
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Current Theories About TheAetiopathogenesis of FCPD
formation
Factors
FCPDSteatorrhea
Impaired Glucose Tolerance
Pancreatic exocrine deficiency
Environmental
Malnutrition
Excessive dietary oxidants and / or antioxidantsDietary toxins
Acinar and B cell damage
Duct obstruction
Calcite stoneDefective B cell growth and repair
Genetic Factors
Association SPINK gene and other genes
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MANAGEMENT OF FCPD –PRINCIPLES
Treatment of abdominal pain
Use of pancreatic enzymes
Management of diabetes
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Management of Diabetes
Diet Principles similar to that of other types of diabetes More liberal calorie Intake High protein intake
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Management of Diabetes
PharmacotherapyOral Antidiabetic Drugs
Sulphonyureas can be used if β cell function is good Biguanides usually not used as the FCPD patients
are leanInsulin
Would be needed in majority of the cases to achieve blood sugar control in FCPD patients
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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
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Thanks