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Dr Shahjada Selim Assistant Professor

Department of EndocrinologyBangabandhu Sheikh Mujib Medical University, Dhaka

Email: selimshahjada@gmail.com

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