International E-publication: Publish Projects, Dissertation, Theses, Books, Souvenir, Conference Proceeding with ISBN.  International E-Bulletin: Information/News regarding: Academics and Research

An Insight into the Aetiology of Tropical Chronic Pancreatitis and Fibrocalculous Pancreatic Diabetes

Author Affiliations

  • 1 St. Xavier’s College (Autonomous) Kolkata, INDIA

Int. Res. J. Medical Sci., Volume 1, Issue (2), Pages 5-14, March,28 (2013)

Abstract

Pancreatitis is a heterogeneous diseases with hereditary and non-hereditary transmission, manifesting itself in acute and chronic forms. Tropical chronic Pancreatitis prevalent in the peri-equitorial tropical regions is a juvenile form of non-alcoholic, idiopathic, calcific pancreatitis with progressive deterioration of the endocrine function leading to diabetes, termed as Fibrocalculous Pancreatic Diabetes (FCPD). This review aims to delineate the genetic insight that traces the relationship of TCP and FCPD as well as causal or modifier role of metabolic stress factors and environmental toxins. The review intends to show a three- hit model as the causal strategy for FCPD. Different studies have thrown light on familial aggregation as the probable basis to consider the genetic predisposition of the disease. Majority of studies done on this aspect favour calling FCPD as the later stage of TCP , although some reports from Bangladesh consider TCP and FCPD as two separate entities. If we go by the view of majority, then FCPD is the logical end-point of TCP. Hence, the suspected genes whose malfunctioning leads to TCP and FCPD are SPINK1 N34S mutation, causing inappropriate activation of trypsinogen to trypsin within pancreatic parenchymal cells and prevents maintenance of integrity of pancreatic acinar cells. CTSB (Cathepsin B) polymorphism (Leu26Val, C595T, T663C, and Ser53Gly) is recorded in good number of TCP patients but its involvement in progression to FCPD is still not clear. CASR (calcium sensing receptor) gene mutation increases risk of TCP and its progress to FCPD.CTRC (Chymotrypsin C) gene mutation is recorded both in TCP and FCPD patients preventing protease and anti-protease balance thereby enhancing supertrypsin activity and auto-digestion of pancreatic parenchymal cells. Some epistatic gene interaction is also predicted between SPINK1 and CTSB genes. Hence, defects in the above mentioned genes are considered to be the first hit for initiating TCP and FCPD. Metabolic stress factors like high carbohydrate and low protein diet along with lifestyles such as excessive smoking, drinking dealing with occupational chemicals causes oxidative stress and decrease in total anti-oxidant capacity considered as the second hit for FCPD. Increased amount of free radical due to oxidative stress has a direct bearing on the immunological functioning of the body. Cell-mediated immunity and auto-immunity due to release of sequestered pancreatic antigen was found in FCPD patients. Hence, immunological malfunction acts as the third hit to enhance progress of TCP (clinically symptomised by severe pain, fibrosis, calcification and progressive endocrine malfunction) to FCPD.

References

  1. Mahurkar S., Reddy D.N., Rao G.V., Chandak G.R., Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis World, J Gastroenterol, 15(3), 264-9 (2009)
  2. Sarner M. and Cotton P.B., Definitions of acute and chronic pancreatitis, Clinical gastroenterology, 984 13:865
  3. Steer M.L., Waxman I. and Freedman S., Chronic pancreatitis, N Engl J Med., 332, 1482–1490 (1995)
  4. 4.Barman K.K., Premalatha G. and Mohan V., Tropical chronic pancreatitis, Postgrad Med J., 79, 606–615 (2003)
  5. 5.Mohan V., Premalatha G. and Pitchumoni C.S., Tropical chronic pancreatitis: an update, J Clin Gastroenterol, 36, 337-46 (2003)
  6. Sandhyamani S., Mucoid vasculopathy and the nutritional imbalance metabolic syndrome In: Silverlines, ed, K. Radhakrishnan, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, 141-154 (2004)
  7. Sandhyamani S., Valiathan M.S. and Saxena H.M.K., Cardiovascular changes in induced malnutrition, In: SERC Research Highlights, New Delhi: Department of Science and Technology, 29-36 (1995)
  8. Geevarghese P.J., Calcific Pancreatitis, Vargheese Publishing House: Bombay, 79, (1985)
  9. Mohan V., Barman K.K., Rajan V.S., Chari S.T. and Deepa R., Natural history of endocrine failure in tropical chronic pancreatitis: a longitudinal follow-up study, J Gastroenterol Hepatol, 20, 1927-34 (2005)
  10. Khan A.A. and Ali L., Tropical calcific pancreatitis and FCPD in Bangladesh, J Gastroenterol Hepatol, 48-52 (1997)
  11. Rossi L., Pfutzer R.H., Parvin S., Ali L., Sattar S, Kahn A.K., SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh, Pancreatology, 242–245 (2001)
  12. Afsana F., Ahmad S., Hossain F.M., Latif Z.A., Pancreatic Calculi among Young Diabetics – An Observational StudyJournal of Diabetology, 1 (2010)
  13. Consensus statement, International workshop on types of diabetes peculiar to the tropics, 17–19, October 1995, Cuttack, India, Acta Diabetologica Latina, 33, 62-4 (1996)
  14. National Diabetes Data Group, Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance, Diabetes,28, 1039-57 (1979)
  15. WHO Expert Committee on Diabetes Mellitus, Second Report. Geneva: WHO, Technical Report Series 646, (1980)
  16. WHO Study Group,Report on diabetes mellitus WHO technical report series, No 727, Geneva: WHO, (1985)
  17. Hoet J.J., Tripathy B.B., Rao R.H. and Yajnik C.S., Malnutrition and diabetes in the tropics, Diabetes Care,19, 1014-17 (1996)
  18. Tripathy B.B. and Samal K.C., Overview and consensus statement on diabetes in tropical areas, Diabetes Metab Rev,13, 63-76 (1997)
  19. Zuidema P.J., Cirrhosis and disseminated calcification of the pancreas in patients with malnutrition, Trop Geogr Med,11, 70-74 (1959)
  20. Shaper A.G., Aetiology of chronic pancreatic fibrosis with calcification seen in Uganda, Br Med J, 1607-1609 (1964)
  21. Sonnet J., Brisbois P. and Bastin J.P., Chronic pancreatitis with calcifications in Congolese Bantus, Trop Geogr Med, 18, 97-113 (1966)
  22. Davies J.N.P., Endomyocardial fibrosis in Uganda, East Afr Med J, 25, 10 (1948)
  23. Steiner I.O., Hutt M.S.R., Vascular changes in the idiopathic peripheral gangrene of the tropics, Trop Geogr Med,24, 219-225 (1972)
  24. Decker G.A.G., Samson I.D., and Schmaman A., Abdominal aneurysm in South African Negroes due to intimomedial mucoid degeneration, Br J Surg, 64, 513-516 (1977)
  25. Delange F., Endemic goitre and thyroid function in Central Africa. In: Falkner S, Kretchmer N, eds. Monographs in paediatrics, Basel: Karger, 2, 1-171 (1974)
  26. Abu-Bakare A., Taylor R., Gill G.V. and Alberti K.G.M.M., Tropical or malnutrition-related diabetes: a real syndrome? The Lancet, 17, 1135-1138 (1986)
  27. Geevarghese P.J., Pillai V.K., Joseph M.P. and Pitchumoni C.S., The diagnosis of pancreatogenous diabetes mellitus, J Assoc Physicians, India 10, 173-180 (1962)
  28. Balakrishnan V., Tropical pancreatitis In: V. Balakrishnan ed. Epidemiology, pathogenesis and etiology in chronic pancreatitis in India, Trivandrum: Indian Society of Pancreatology, St. Joseph’s Press, 81-85 (1987)
  29. Chandraprasert S., Samranvej P., Arthachinta S. and Isarasena S., Diabetes mellitus and tropical form of chronic calcific pancreatitis in Thailand, Australian and New Zealand, Journal of Medicine, 316-20 (1976)
  30. Mohan V., Ahmed M.R., Ramachandran A., et al., Clinical profile of tropical pancreatic diabetes at Madras, In: Balakrishnan V., ed. Chronic pancreatitis in India Trivandrum: Indian Society of Pancreatology, 97-104 (1987)
  31. Zuidema P.J., Calcification and cirrhosis of the pancreas in patients with deficient nutrition, Doc. Med. Geograph. Trop. Amsterdam, 229 (1955)
  32. Zuidema P.J., Cirrhosis and disseminated calcification of the pancreas in patients with malnutrition: Trop Geog Med, 11, 70-74 (1959)
  33. Shaper A.G., Chronic pancreatic disease and protein malnutrition: Lancet; ii: 1223-1224 (1960)
  34. Geevarghese P.J., Calcific Pancreatitis, Varghese Publishing House, (1986)
  35. Pitchumoni C.S., Familial Pancreatitis. In: Pancreatic Diabetes. K.N. Pai, C.R. Soman and R. Varghese, Eds.; Geo Printers, Trivandrun, 46-8 (1970)
  36. Balakrishnan V., Tropical Pancreatitis. In: Maladies dupancreas exocrine, B. Bernades and M. Bugier, Eds.; Doin, Paris, (In Press) 37.Mohan V., Chari S., Hitman G.A., et al., Familial aggregation in Tropical Fibrocalculous Pancreatic Diabetes, Pancreas 4, 690-93 (1989)
  37. Gaboriaud C., Serre L., Guy-Crotte O., Forest E., Fontecilla-Camps J.C., Crystal structure of human trypsin 1: unexpected phosphorylation of Tyr151, J Mol Biol., 259, 995–1010 (1996)
  38. Ohmuraya M., Hirota M., Araki M., Mizushima N., Matsui M., Mizumoto T., Haruna K., Kume S., Takeya M., Ogawa M., et al., Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice, Gastroenterology, 129, 696–705 (2005)
  39. 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., 39, 347–351 (2002)
  40. Hassan Z., Mohan V., Ali L., Allotey R., Barakat K., Faruque M.O., Deepa R., McDermott M.F., Jackson A.E., Cassell P., et al., SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Indian subcontinent, Am J Hum Genet., 71, 964–968 (2002)
  41. Bhatia E., Choudhuri G., Sikora S.S., Landt O., Kage A., Becker M. and Witt H., Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations, Gastroenterology, 123, 1020–1025 (2002)
  42. Witt H., Luck W., Hennies H.C., Classen M., Kage A., Lass U., Landt O. and Becker M., Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis, Nat Genet., 25, 213–216 (2000)
  43. Rakesh Kr. Mishra, Chromosome to genome
  44. Bhatia E., Durie P., Zielenski J., Lam D., Sikora S.S., Choudhuri G., Tsui L.C., Mutations in the cystic fibrosis transmembrane regulator gene in patients with tropical calcific pancreatitis, Am J Gastroenterol. 95, 3658–3659 (2000)
  45. 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, 121, 1310–1319 (2001)
  46. Szilágyi L., Kénesi E., Katona G., Kaslik G., Juhász G. and Gráf L., Comparative in vitro studies on native and recombinant human cationic trypsins, Cathepsin B is a possible pathological activator of trypsinogen in pancreatitis, J Biol Chem., 276, 24574–24580 (2001)
  47. Mahurkar S., Idris M.M., Reddy D.N., Bhaskar S., Rao G.V., Thomas V., Singh L., Chandak G.R., Association of cathepsin B gene polymorphisms with tropical calcific pancreatitis, Gut., 55(9), 1270-5 (2006)
  48. Boonyasrisawat W., Pulsawat P., Yenchitsomanus P.T., Vannasaeng S., Pramukkul P., Deerochanawong C., Sriussadaporn S., Ploybutr S., Pasurakul T., Banchuin N., Analysis of the reg1alpha and reg1beta gene transcripts in patients with fibrocalculous pancreatopathy, Southeast Asian J Trop Med Public Health, 33, 365–372 (2002)
  49. Mahurkar S., Bhaskar S., Reddy D.N., Rao G.V., Chandak G.R., Comprehensive screening for reg1alpha gene rules out association with tropical calcific pancreatitis, World J Gastroenterol.13, 5938–5943 (2007)
  50. Hawrami K., Mohan V., Bone A., Hitman G.A., Analysis of islet regenerating (reg) gene polymorphisms in fibrocalculous pancreatic diabetes, Pancreas, 14, 122–125 (1997)
  51. Mahurkar S., Bhaskar S., Reddy D.N., Prakash S., Rao G.V., Singh S.P., Thomas V., Chandak G.R., TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes, BMC Med Genet., 80 (2008)
  52. Bhaskar S., Reddy D.N., Mahurkar S., Rao G.V., Singh L., Chandak G.R., Lack of significant association of an insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene with tropical calcific pancreatitis, BMC Gastroenterol., 6, 42 (2006)
  53. Rosendahl J., Witt H., Szmola R., Bhatia E., Ozsvári B., Landt O., Schulz H.U., Gress T.M., Pfützer R., Löhr M., et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis, Nat Genet.40, 78–82 (2008)
  54. Felderbauer P., Klein W., Bulut K., Ansorge N., Dekomien G., Werner I., Epplen J.T., Schmitz F. and Schmidt W.E., Mutations in the calcium-sensing receptor: a new genetic risk factor for chronic pancreatitis? Scand J Gastroenterol, 41, 343–348 (2006)
  55. Murugaian E.E., Premkumar R.M., Radhakrishnan L. and Vallath B., Novel mutations in the calcium sensing receptor gene in tropical chronic pancreatitis in India, Scand J Gastroenterol., 43, 117–121 (2008)
  56. Kambo P.K., Hitman G.A., Mohan V., Ramachandran A., Snehalatha C., Suresh S., Metcalfe K., Ryait B.K. and Viswanathan M., The genetic predisposition to fibrocalculous pancreatic diabetes, Diabetologia, 32(1), 45-51 (1989)
  57. Balakrishnan V., Sauniere J.F., Hariharan M., Sarles H., Diet, pancreatic function, and chronic pancreatitis in south India and France, Pancreas, 30-5 (1988)
  58. Esther Sathiaraj, Shilpa Gupta, Madhulika Chutke, Swapna Mahurkar, Magnus Jeyraj Mansard G. Venkat Rao D. Nageshwar Reddy, Malnutrition is not an etiological factor in the development of tropical pancreatitis – A case-control study of Southern Indian patients, Tropical gastroenterology,
  59. Barbezat G.O. and Hansen J.D.L., The exocrine pancreas and protein calorie malnutrition, Pediatrics, 42, 77 (1968)
  60. Narendranathan M., Cheriyan A., Lack of association between cassava consumption and tropical pancreatitis syndrome, J Gastroenterol Hepatol.,9(3), 282-5 (1994)
  61. Mathangi D.C., Deepa R., Mohan V., et al., Long term ingestion of cassava (tapioca) does not produce diabetes or pancreatitis in the rat model, Int J Pancreatol, 27, 203-8 (2000)
  62. Verlaan M., Roelofs H.M., van-Schaik A. et al., Assessment of oxidative stress in chronic pancreatitis patients, World J Gastroenterol., 12, 5705-10 (2006)
  63. Braganza J.M., Schofield D., Snehalatha C. and Mohan V., Micronutrient antioxidant status in tropical compared with temperate-zone chronic pancreatitis, Scand J Gastroenterol., 28, 1098-104 (1993)
  64. Bhardwaj P., Garg P.K., Maulik S.K. et al., A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis, Gastroenterology, 136, 149-159 (2009)
  65. Chouduary A., Garg P.K. and Tandon R.K., The role of oxidative stress in tropical pancreatitis and effect of antioxidants supplementation on pain in patients with tropicalpancreatitis, J Gastroenterol. Hepatol., 16 (2001)
  66. Balakrishnan V., Sauniere J.H. and Hariharan M, et al. Diet, pancreatic function and chronic pancreatitis in South India and France, Pancreas, 3, 30-5 (1988)
  67. Whitcomb D.C., Gorry M.C. and Preston R.A., et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene, Nat Genet, 14, 141-5 (1996)
  68. Mohan V. and Premalatha G., Fibrocalculous pancreatic diabetes, International Journal of diabetes, 71-82 (1995)
  69. Bhatia E., Choudhuri G. and Sikora S.S., et al., Tropical calcific pancreatitis: strong association with SPINK 1 trypsin inhibitor mutation, Gastroenterology, 123, 1020-5 (2002)
  70. Mohan V., Ramachandran A. and Viswanathan M., Two case reports of macrovascular complications in fibrocalculous pancreatic diabetes, Acta Diabetol, 26, 345-9 (1989)