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  • Review Article
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The role of alcohol and smoking in pancreatitis

Abstract

Chronic alcohol use has been linked to chronic pancreatitis for over a century, but it has not been until the last decade that the role of alcohol in chronic pancreatitis has been elucidated in animals and, only in recent years, in human populations. Although a dose-dependent association between alcohol consumption and chronic pancreatitis may exist, a staistical association has been shown only with the consumption of ≥5 alcoholic drinks per day. Smoking also confers a strong, independent and dose-dependent risk of pancreatitis that may be additive or multiplicative when combined with alcohol. Alcohol increases the risk of acute pancreatitis in several ways and, most importantly, changes the immune response to injury. Genetic factors are also important and further studies are needed to clarify the role of gene–environment interactions in pancreatitis. In humans, aggressive interventional counseling against alcohol use may reduce the frequency of recurrent attacks of disease and smoking cessation may help to slow the progression of acute to chronic pancreatitis.

Key Points

  • Studies suggest that a threshold of approximately 5 alcoholic drinks per day must be exceeded before the risk of chronic pancreatitis in individuals who drink alcohol exceeds that of the nondrinking population

  • Only a minority of patients with pancreatitis have a significant history of alcohol consumption, suggesting that most patients have a complex genetic disorder that is similar to other chronic inflammatory diseases

  • Smoking is a dose-dependent risk factor for pancreatitis, and its effects are additive or multiplicative when combined with alcohol

  • Chronic alcohol use at high daily doses (that is, ≥5 drinks daily) increases susceptibility to, and severity of, acute pancreatitis and accelerates the progression of chronic pancreatitis

  • Aggressive counseling leading to reduced alcohol consumption may reduce the likelihood of recurrent acute pancreatitis

  • Smoking cessation may slow the progression of chronic pancreatitis

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Figure 1: Progression from pre-acute pancreatitis to chronic pancreatitis.
Figure 2: Distribution of self-reported alcohol consumption and smoking among patients with chronic pancreatitis in the North American Pancreatitis Study 2 (NAPS2).
Figure 3: Alcohol consumption and risk of pancreatitis in participants of the Copenhagen City Heart Study.60
Figure 4: Absolute risk of pancreatitis, and hazard ratios, according to smoking status in participants of a Danish study.128
Figure 5: Working model of the sites and systems in which alcohol and smoking modify pancreatitis risk and progression.

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References

  1. Whitcomb, D. C. Acute pancreatitis. N. Engl. J. Med. 354, 2142–2150 (2006).

    PubMed  Google Scholar 

  2. Katz, M., Carangelo, R., Miller, L. J. & Gorelick, F. Effect of ethanol on cholecystokinin-stimulated zymogen conversion in pancreatic acinar cells. Am. J. Physiol. 270, G171–G175 (1996).

    CAS  PubMed  Google Scholar 

  3. Lu, Z., Karne, S., Kolodecik, T. & Gorelick, F. S. Alcohols enhance caerulein-induced zymogen activation in pancreatic acinar cells. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G501–G507 (2002).

    CAS  PubMed  Google Scholar 

  4. Pandol, S. J. et al. Ethanol diet increases the sensitivity of rats to pancreatitis induced by cholecystokinin octapeptide. Gastroenterology 117, 706–716 (1999).

    CAS  PubMed  Google Scholar 

  5. Papachristou, G. I., Papachristou, D. J., Morinville, V. D., Slivka, A. & Whitcomb, D. C. Chronic alcohol consumption is a major risk factor for pancreatic necrosis in acute pancreatitis. Am. J. Gastroenterol. 101, 2605–2610 (2006).

    PubMed  Google Scholar 

  6. Etemad, B. & Whitcomb, D. C. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 120, 682–707 (2001).

    CAS  PubMed  Google Scholar 

  7. Friedreich, N. in Cyclopedia of the Practice of Medicine (William Wood, New York, 1878).

    Google Scholar 

  8. Whitcomb, D. C. et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat. Genet. 14, 141–145 (1996).

    CAS  PubMed  Google Scholar 

  9. Whitcomb, D. C. Mechanisms of disease: Advances in understanding the mechanisms leading to chronic pancreatitis. Nat. Clin. Pract. Gastroenterol. Hepatol. 1, 46–52 (2004).

    PubMed  Google Scholar 

  10. Whitcomb, D. C. Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 45, 317–322 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kloppel, G. & Maillet, B. Pseudocysts in chronic pancreatitis: a morphological analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas 6, 266–274 (1991).

    CAS  PubMed  Google Scholar 

  12. Kloppel, G. & Maillet, B. The morphological basis for the evolution of acute pancreatitis into chronic pancreatitis. Virchows Arch. A Pathol. Anat. Histopathol. 420, 1–4 (1992).

    CAS  PubMed  Google Scholar 

  13. Bordalo, O. et al. Newer concept for the pathogenesis of chronic alcoholic pancreatitis. Am. J. Gastroenterol. 68, 278–285 (1977).

    CAS  PubMed  Google Scholar 

  14. Braganza, J. M. Pancreatic disease: a casualty of hepatic “detoxification”? Lancet 2, 1000–1003 (1983).

    CAS  PubMed  Google Scholar 

  15. McKim, S. E., Uesugi, T., Raleigh, J. A., McClain, C. J. & Arteel, G. E. Chronic intragastric alcohol exposure causes hypoxia and oxidative stress in the rat pancreas. Arch. Biochem. Biophys. 417, 34–43 (2003).

    CAS  PubMed  Google Scholar 

  16. Schneider, A. & Whitcomb, D. C. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract. Res. Clin. Gastroenterol. 16, 347–363 (2002).

    PubMed  Google Scholar 

  17. Deng, X. et al. Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats. Am. J. Pathol. 166, 93–106 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lankisch, P. G. et al. Natural history of acute pancreatitis: a long-term population-based study. Am. J. Gastroenterol. 104, 2797–2806 (2009).

    PubMed  Google Scholar 

  19. Gukovsky, I. et al. A rat model reproducing key pathological responses of alcoholic chronic pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G68–G79 (2008).

    CAS  PubMed  Google Scholar 

  20. Whitcomb, D. C. & Barmada, M. M. A systems biology approach to genetic studies of pancreatitis and other complex diseases. Cell. Mol. Life Sci. 64, 1763–1777 (2007).

    CAS  PubMed  Google Scholar 

  21. Friedman, S. L. Mechanisms of hepatic fibrogenesis. Gastroenterology 134, 1655–1669 (2008).

    CAS  PubMed  Google Scholar 

  22. Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    CAS  PubMed  Google Scholar 

  23. Sarles, H. et al. The pancreatitis classification of Marseilles, Rome 1988. Scand. J. Gastroenterol. 24, 641 (1989).

    CAS  PubMed  Google Scholar 

  24. Sarles, H. Proposal adopted unanimously by the participants of the Symposium, Marseilles 1963. Bibliotheca Gastroenterologica 7, 7–8 (1965).

    Google Scholar 

  25. Shrikhande, S. V. et al. Comparison of histological features and inflammatory cell reaction in alcoholic, idiopathic and tropical chronic pancreatitis. Br. J. Surg. 90, 1565–1572 (2003).

    CAS  PubMed  Google Scholar 

  26. Stevens, T., Conwell, D. L. & Zuccaro, G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am. J. Gastroenterol. 99, 2256–2270 (2004).

    CAS  PubMed  Google Scholar 

  27. Ammann, R. W., Heitz, P. U. & Kloppel, G. Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long-term study. Gastroenterology 111, 224–231 (1996).

    CAS  PubMed  Google Scholar 

  28. Takeyama, Y. Long-term prognosis of acute pancreatitis in Japan. Clin. Gastroenterol. Hepatol. 7, S15–S17 (2009).

    PubMed  Google Scholar 

  29. Birgisson, H. et al. Acute pancreatitis: a prospective study of its incidence, aetiology, severity, and mortality in Iceland. Eur. J. Surg. 168, 278–282 (2002).

    CAS  PubMed  Google Scholar 

  30. Eland, I. A., Sturkenboom, M. J., Wilson, J. H. & Stricker, B. H. Incidence and mortality of acute pancreatitis between 1985 and 1995. Scand. J. Gastroenterol. 35, 1110–1116 (2000).

    CAS  PubMed  Google Scholar 

  31. Frey, C. F., Zhou, H., Harvey, D. J. & White, R. H. The incidence and case-fatality rates of acute biliary, alcoholic, and idiopathic pancreatitis in California, 1994–2001. Pancreas 33, 336–344 (2006).

    PubMed  Google Scholar 

  32. Gislason, H. et al. Acute pancreatitis in Bergen, Norway. A study on incidence, etiology and severity. Scand. J. Surg. 93, 29–33 (2004).

    CAS  PubMed  Google Scholar 

  33. Lindkvist, B., Appelros, S., Manjer, J. & Borgstrom, A. Trends in incidence of acute pancreatitis in a Swedish population: is there really an increase? Clin. Gastroenterol. Hepatol. 2, 831–837 (2004).

    PubMed  Google Scholar 

  34. O'Farrell, A., Allwright, S., Toomey, D., Bedford, D. & Conlon, K. Hospital admission for acute pancreatitis in the Irish population, 1997–2004: could the increase be due to an increase in alcohol-related pancreatitis? J. Public Health (Oxf.) 29, 398–404 (2007).

    CAS  Google Scholar 

  35. Roberts, S. E., Williams, J. G., Meddings, D. & Goldacre, M. J. Incidence and case fatality for acute pancreatitis in England: geographical variation, social deprivation, alcohol consumption and aetiology—a record linkage study. Aliment. Pharmacol. Ther. 28, 931–941 (2008).

    CAS  PubMed  Google Scholar 

  36. Tinto, A. et al. Acute and chronic pancreatitis—diseases on the rise: a study of hospital admissions in England 1989/1990–1999/2000. Aliment. Pharmacol. Ther. 16, 2097–2105 (2002).

    CAS  PubMed  Google Scholar 

  37. Lankisch, P. G., Karimi, M., Bruns, A., Maisonneuve, P. & Lowenfels, A. B. Temporal trends in incidence and severity of acute pancreatitis in Luneburg County, Germany: a population-based study. Pancreatology 9, 420–426 (2009).

    PubMed  Google Scholar 

  38. Yadav, D. & Lowenfels, A. B. Trends in the epidemiology of the first attack of acute pancreatitis: a systematic review. Pancreas 33, 323–330 (2006).

    PubMed  Google Scholar 

  39. Sand, J., Valikoski, A. & Nordback, I. Alcohol consumption in the country and hospitalizations for acute alcohol pancreatitis and liver cirrhosis during a 20-year period. Alcohol Alcohol. 44, 321–325 (2009).

    PubMed  Google Scholar 

  40. Dite, P. et al. Incidence of chronic pancreatitis in the Czech Republic. Eur. J. Gastroenterol. Hepatol. 13, 749–750 (2001).

    CAS  PubMed  Google Scholar 

  41. Lankisch, P. G., Assmus, C., Maisonneuve, P. & Lowenfels, A. B. Epidemiology of pancreatic diseases in Luneburg County. A study in a defined german population. Pancreatology 2, 469–477 (2002).

    CAS  PubMed  Google Scholar 

  42. Lin, Y. et al. Nationwide epidemiological survey of chronic pancreatitis in Japan. J. Gastroenterol. 35, 136–141 (2000).

    CAS  PubMed  Google Scholar 

  43. Spanier, B. W., Dijkgraaf, M. G. & Bruno, M. J. Trends and forecasts of hospital admissions for acute and chronic pancreatitis in the Netherlands. Eur. J. Gastroenterol. Hepatol. 20, 653–658 (2008).

    PubMed  Google Scholar 

  44. Yang, A. L., Vadhavkar, S., Singh, G. & Omary, M. B. Epidemiology of alcohol-related liver and pancreatic disease in the United States. Arch. Intern. Med. 168, 649–656 (2008).

    PubMed  Google Scholar 

  45. Yadav, D. et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch. Intern. Med. 169, 1035–1045 (2009).

    PubMed  PubMed Central  Google Scholar 

  46. Layer, P. et al. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 107, 1481–1487 (1994).

    CAS  PubMed  Google Scholar 

  47. Lowenfels, A. B. et al. Racial factors and the risk of chronic pancreatitis. Am. J. Gastroenterol. 94, 790–794 (1999).

    CAS  PubMed  Google Scholar 

  48. Morton, C., Klastsky, A. L. & Udaltsova, N. Smoking, coffee and pancreatitis. Am. J. Gastroenterol. 99, 731–738 (2004).

    PubMed  Google Scholar 

  49. Frulloni, L. et al. Chronic pancreatitis: report from a multicenter Italian survey (PanCroInfAISP) on 893 patients. Dig. Liver Dis. 41, 311–317 (2009).

    CAS  PubMed  Google Scholar 

  50. Ammann, R. W., Akovbiantz, A., Largiader, F. & Schueler, G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 86, 820–828 (1984).

    CAS  PubMed  Google Scholar 

  51. Andersen, B. N., Pedersen, N. T., Scheel, J. & Worning, H. Incidence of alcoholic chronic pancreatitis in Copenhagen. Scand. J. Gastroenterol. 17, 247–252 (1982).

    CAS  PubMed  Google Scholar 

  52. Marks, I. N., Bank, S. & Louw, J. H. Chronic pancreatitis in the Western Cape. Digestion 9, 447–453 (1973).

    CAS  PubMed  Google Scholar 

  53. Robles-Diaz, G., Vargas, F., Uscanga, L. & Fernandez-del Castillo, C. Chronic pancreatitis in Mexico City. Pancreas 5, 479–483 (1990).

    CAS  PubMed  Google Scholar 

  54. Talamini, G. et al. Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer. Dig. Dis. Sci. 44, 1301–1311 (1999).

    Google Scholar 

  55. Whitcomb, D. C. et al. Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology 8, 520–531 (2008).

    PubMed  PubMed Central  Google Scholar 

  56. Witt, H., Apte, M. V., Keim, V. & Wilson, J. S. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 132, 1557–1573 (2007).

    CAS  PubMed  Google Scholar 

  57. Chari, S. T. et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin. Gastroenterol. Hepatol. 4, 1010–1016 (2006).

    PubMed  Google Scholar 

  58. Raina, A. et al. Evaluation and management of autoimmune pancreatitis: experience at a large US center. Am. J. Gastroenterol. 104, 2295–2306 (2009).

    PubMed  PubMed Central  Google Scholar 

  59. Corrao, G., Bagnardi, V., Zambon, A. & Arico, S. Exploring the dose-response relationship between alcohol consumption and the risk of several alcohol-related conditions: a meta-analysis. Addiction 94, 1551–1573 (1999).

    CAS  PubMed  Google Scholar 

  60. Kristiansen, L., Gronbaek, M., Becker, U. & Tolstrup, J. S. Risk of pancreatitis according to alcohol drinking habits: a population-based cohort study. Am. J. Epidemiol. 168, 932–937 (2008).

    PubMed  Google Scholar 

  61. Irving, H. M., Samokhvalov, A. V. & Rehm, J. Alcohol as a risk factor for pancreatitis. A systematic review and meta-analysis. JOP 10, 387–392 (2009).

    PubMed  Google Scholar 

  62. Lankisch, P. G., Lowenfels, A. B. & Maisonneuve, P. What is the risk of alcoholic pancreatitis in heavy drinkers? Pancreas 25, 411–412 (2002).

    PubMed  Google Scholar 

  63. Yadav, D., Eigenbrodt, M. L., Briggs, M. J., Williams, D. K. & Wiseman, E. J. Pancreatitis: prevalence and risk factors among male veterans in a detoxification program. Pancreas 34, 390–398 (2007).

    PubMed  Google Scholar 

  64. Szabo, G., Mandrekar, P., Oak, S. & Mayerle, J. Effect of ethanol on inflammatory responses. Implications for pancreatitis. Pancreatology 7, 115–123 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Bell, R. L., Rodd, Z. A., Lumeng, L., Murphy, J. M. & McBride, W. J. The alcohol-preferring P rat and animal models of excessive alcohol drinking. Addict. Biol. 11, 270–288 (2006).

    PubMed  Google Scholar 

  66. Lieber, C. S. & DeCarli, L. M. The feeding of ethanol in liquid diets. Alcohol Clin. Exp. Res. 10, 550–553 (1986).

    CAS  PubMed  Google Scholar 

  67. Lieber, C. S. & DeCarli, L. M. Liquid diet technique of ethanol administration: 1989 update. Alcohol Alcohol. 24, 197–211 (1989).

    CAS  PubMed  Google Scholar 

  68. Tsukamoto, H. et al. Severe and progressive steatosis and focal necrosis in rat liver induced by continuous intragastric infusion of ethanol and low fat diet. Hepatology 5, 224–232 (1985).

    CAS  PubMed  Google Scholar 

  69. Tsukamoto, H., Towner, S. J., Yu, G. S. & French, S. W. Potentiation of ethanol-induced pancreatic injury by dietary fat. Induction of chronic pancreatitis by alcohol in rats. Am. J. Pathol. 131, 246–257 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Deng, X., Wood, P. G., Eagon, P. K. & Whitcomb, D. C. Rapid adaptation of pancreatic exocrine function to short term alcohol feeding in rats. Pancreatology 5, 183–195 (2005).

    CAS  PubMed  Google Scholar 

  71. Deng, X., Wood, P. G., Eagon, P. K. & Whitcomb, D. C. Chronic alcohol-induced alterations in the pancreatic secretory control mechanisms. Dig. Dis. Sci. 49, 805–819 (2004).

    CAS  PubMed  Google Scholar 

  72. Deng, X. & Whitcomb, D. C. Neurohormonal control of the exocrine pancreas. Curr. Opin. Gastroenterol. 14, 362–368 (1998).

    CAS  Google Scholar 

  73. Deng, X. et al. PYY inhibits CCK stimulated pancreatic secretion through the area postrema in unanesthetized rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R645–R653 (2001).

    CAS  PubMed  Google Scholar 

  74. Nordback, I., Pelli, H., Lappalainen-Lehto, R. & Sand, J. Is it long-term continuous drinking or the post-drinking withdrawal period that triggers the first acute alcoholic pancreatitis? Scand. J. Gastroenterol. 40, 1235–1239 (2005).

    CAS  PubMed  Google Scholar 

  75. Wilson, J. S. & Apte, M. V. Role of alcohol metabolism in alcoholic pancreatitis. Pancreas 27, 311–315 (2003).

    CAS  PubMed  Google Scholar 

  76. Criddle, D. N. et al. Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites. Proc. Natl Acad. Sci. USA 101, 10738–10743 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lieber, C. S. ALCOHOL: its metabolism and interaction with nutrients. Annu. Rev. Nutr. 20, 395–430 (2000).

    CAS  PubMed  Google Scholar 

  78. Apte, M. V. & Wilson, J. S. Stellate cell activation in alcoholic pancreatitis. Pancreas 27, 316–320 (2003).

    CAS  PubMed  Google Scholar 

  79. Nordback, I. H., Olson, J. L., Chacko, V. P. & Cameron, J. L. Detailed characterization of experimental acute alcoholic pancreatitis. Surgery 117, 41–49 (1995).

    CAS  PubMed  Google Scholar 

  80. Laposata, E. A. & Lange, L. G. Presence of nonoxidative ethanol metabolism in human organs commonly damaged by ethanol abuse. Science 231, 497–499 (1986).

    CAS  PubMed  Google Scholar 

  81. Pfutzer, R. H. et al. Pancreatic cholesterol esterase, ES-10, and fatty acid ethyl ester synthase III gene expression are increased in the pancreas and liver but not in the brain or heart with long-term ethanol feeding in rats. Pancreas 25, 101–106 (2002).

    PubMed  Google Scholar 

  82. Criddle, D. N. et al. Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology 130, 781–793 (2006).

    CAS  PubMed  Google Scholar 

  83. Fortunato, F. et al. Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis? Am. J. Physiol. Gastrointest. Liver Physiol. 290, G232–G241 (2005).

    PubMed  Google Scholar 

  84. Li, H. S. et al. Rat mitochondrial ATP synthase ATP5G3: cloning and upregulation in pancreas after chronic ethanol feeding. Physiol. Genomics 6, 91–98 (2001).

    CAS  PubMed  Google Scholar 

  85. Gullo, L., Pezzilli, R. & Ventrucci, M. Diagnostic value of the amino acid consumption test in pancreatic diseases. Pancreas 12, 64–67 (1996).

    CAS  PubMed  Google Scholar 

  86. Mariani, A. et al. Accuracy of the plasma amino acid-consumption test in detecting pancreatic diseases is due to different methods. Pancreas 18, 203–211 (1999).

    CAS  PubMed  Google Scholar 

  87. Kubisch, C. H. et al. Long-term ethanol consumption alters pancreatic gene expression in rats: a possible connection to pancreatic injury. Pancreas 33, 68–76 (2006).

    CAS  PubMed  Google Scholar 

  88. Yuan, J. et al. Protein kinase D1 mediates NF-kappaB activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G1190–G1201 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Gorelick, F. S. & Thrower, E. The acinar cell and early pancreatitis responses. Clin. Gastroenterol. Hepatol. 7, S10–S14 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Whitcomb, D. C. & Lowe, M. E. Human pancreatic digestive enzymes. Dig. Dis. Sci. 52, 1–17 (2007).

    CAS  PubMed  Google Scholar 

  91. Frick, T. W., Fernandez-del Castillo, C., Bimmler, D. & Warshaw, A. L. Elevated calcium and activation of trypsinogen in rat pancreatic acini. Gut 41, 339–343 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sutton, R. et al. Signal transduction, calcium and acute pancreatitis. Pancreatology 3, 497–505 (2003).

    CAS  PubMed  Google Scholar 

  93. Kruger, B., Albrecht, E. & Lerch, M. M. The role of intracellular calcium signaling in premature protease activation and the onset of pancreatitis. Am. J. Pathol. 157, 43–50 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Rao, R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 50, 638–644 (2009).

    CAS  PubMed  Google Scholar 

  95. Li, Y. Y. et al. Regulation of Hsp60 and the role of MK2 in a new model of severe experimental pancreatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G981–G989 (2009).

    CAS  PubMed  Google Scholar 

  96. Singh, M., LaSure, M. M. & Bockman, D. E. Pancreatic acinar cell function and morphology in rats chronically fed an ethanol diet. Gastroenterology 82, 425–434 (1982).

    CAS  PubMed  Google Scholar 

  97. Van Laethem, J., Robberecht, P., Resibois, A. & Deviere, J. Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice. Gastroenterology 110, 576–582 (1996).

    CAS  PubMed  Google Scholar 

  98. Muller-Pillasch, F. et al. TGFbeta and the extracellular matrix in pancreatitis. Hepatogastroenterology 46, 2751–2756 (1999).

    CAS  PubMed  Google Scholar 

  99. Perides, G., Tao, X., West, N., Sharma, A. & Steer, M. L. A mouse model of ethanol dependent pancreatic fibrosis. Gut 54, 1461–1467 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Buchholz, M. et al. Transcriptome analysis of human hepatic and pancreatic stellate cells: organ-specific variations of a common transcriptional phenotype. J. Mol. Med. 83, 795–805 (2005).

    CAS  PubMed  Google Scholar 

  101. Omary, M. B., Lugea, A., Lowe, A. W. & Pandol, S. J. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J. Clin. Invest. 117, 50–59 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Bachem, M. G., Zhou, Z., Zhou, S. & Siech, M. Role of stellate cells in pancreatic fibrogenesis associated with acute and chronic pancreatitis. J. Gastroenterol. Hepatol. 21 (Suppl. 3), S92–S96 (2006).

    CAS  PubMed  Google Scholar 

  103. Apte, M. V., Pirola, R. C. & Wilson, J. S. Battle-scarred pancreas: Role of alcohol and pancreatic stellate cells in pancreatic fibrosis. J. Gastroenterol. Hepatol. 21 (Suppl. 3), S97–S101 (2006).

    CAS  PubMed  Google Scholar 

  104. Apte, M. V. et al. Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology 118, 780–794 (2000).

    CAS  PubMed  Google Scholar 

  105. Li, J. et al. Does chronic ethanol intake cause chronic pancreatitis?: evidence and mechanism. Pancreas 37, 189–195 (2008).

    PubMed  Google Scholar 

  106. Wittel, U. A. et al. Chronic pancreatic inflammation induced by environmental tobacco smoke inhalation in rats. Am. J. Gastroenterol. 101, 148–159 (2006).

    CAS  PubMed  Google Scholar 

  107. Feick, P., Gerloff, A. & Singer, M. V. Effect of non-alcoholic compounds of alcoholic drinks on the pancreas. Pancreatology 7, 124–130 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Bode, C., Bode, J. C., Erhardt, J. G., French, B. A. & French, S. W. Effect of the type of beverage and meat consumed by alcoholics with alcoholic liver disease. Alcohol Clin. Exp. Res. 22, 1803–1805 (1998).

    CAS  PubMed  Google Scholar 

  109. Santhosh, S. et al. A loss of function polymorphism (G191R) of anionic trypsinogen (PRSS2) confers protection against chronic pancreatitis. Pancreas 36, 317–320 (2008).

    PubMed  Google Scholar 

  110. Witt, H. et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat. Genet. 38, 668–673 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Witt, H. et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat. Genet. 25, 213–216 (2000).

    CAS  PubMed  Google Scholar 

  112. Pfutzer, R. H. et al. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 119, 615–623 (2000).

    CAS  PubMed  Google Scholar 

  113. Sharer, N. et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N. Engl. J. Med. 339, 645–652 (1998).

    CAS  PubMed  Google Scholar 

  114. Cohn, J. A. et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N. Engl. J. Med. 339, 653–658 (1998).

    CAS  PubMed  Google Scholar 

  115. Masson, E., Chen, J. M., Scotet, V., Le Marechal, C. & Ferec, C. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum. Genet. 123, 83–91 (2008).

    CAS  PubMed  Google Scholar 

  116. Muddana, V. et al. Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1 type and alcohol. World J. Gastroenterol. 14, 4486–4491 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Felderbauer, P. et al. A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations. BMC Gastroenterol. 3, 34 (2003).

    PubMed  PubMed Central  Google Scholar 

  118. Rosendahl, J. et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat. Genet. 40, 78–82 (2008).

    CAS  PubMed  Google Scholar 

  119. Witt, H. et al. Mutation in the SPINK1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis. JAMA 285, 2716–2717 (2001).

    CAS  PubMed  Google Scholar 

  120. Schneider, A. et al. Limited contribution of the SPINK1 N34S mutation to the risk and severity of alcoholic chronic pancreatitis – a preliminary report from the United States. Dig. Dis. Sci. 48, 1110–1115 (2003).

    CAS  PubMed  Google Scholar 

  121. Aoun, E. et al. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS ONE 3, e2003 (2008).

    PubMed  PubMed Central  Google Scholar 

  122. Chen, J. M., Mercier, B., Audrezet, M. P. & Ferec, C. Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis. J. Med. Genet. 37, 67–69 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Pidasheva, S., D' Souza-Li, L., Canaff, L., Cole, D. E. & Hendy, G. N. CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum. Mutat. 24, 107–111 (2004).

    CAS  PubMed  Google Scholar 

  124. Yen, S., Hsieh, C. C. & MacMahon, B. Consumption of alcohol and tobacco and other risk factors for pancreatitis. Am. J. Epidemiol. 116, 407–414 (1982).

    CAS  PubMed  Google Scholar 

  125. Bourliere, M., Barthet, M., Berthezene, P., Durbec, J. P. & Sarles, H. Is tobacco a risk factor for chronic pancreatitis and alcoholic cirrhosis? Gut 32, 1392–1395 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Lin, Y., Tamakoshi, A., Hayakawa, T., Ogawa, M. & Ohno, Y. Cigarette smoking as a risk factor for chronic pancreatitis: a case-control study in Japan. Research Committee on Intractable Pancreatic Diseases. Pancreas 21, 109–114 (2000).

    CAS  PubMed  Google Scholar 

  127. Lowenfels, A. B., Zwemer, F. L., Jhangiani, S. & Pitchumoni, C. S. Pancreatitis in a native American Indian population. Pancreas 2, 694–697 (1987).

    CAS  PubMed  Google Scholar 

  128. Tolstrup, J. S., Kristiansen, L., Becker, U. & Gronbaek, M. Smoking and risk of acute and chronic pancreatitis among women and men: a population-based cohort study. Arch. Intern. Med. 169, 603–609 (2009).

    PubMed  Google Scholar 

  129. Lindkvist, B., Appelros, S., Manjer, J., Berglund, G. & Borgstrom, A. A prospective cohort study of smoking in acute pancreatitis. Pancreatology 8, 63–70 (2008).

    PubMed  Google Scholar 

  130. Maisonneuve, P. et al. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 54, 510–514 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Maisonneuve, P. et al. Impact of smoking on patients with idiopathic chronic pancreatitis. Pancreas 33, 163–168 (2006).

    PubMed  Google Scholar 

  132. Talamini, G. et al. Smoking cessation at the clinical onset of chronic pancreatitis and risk of pancreatic calcifications. Pancreas 35, 320–326 (2007).

    PubMed  Google Scholar 

  133. Szabo, G. & Mandrekar, P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin. Exp. Res. 33, 220–232 (2009).

    CAS  PubMed  Google Scholar 

  134. Angelini, G. et al. Association of chronic alcoholic liver and pancreatic disease: a prospective study. Am. J. Gastroenterol. 80, 998–1003 (1985).

    CAS  PubMed  Google Scholar 

  135. Pelli, H., Sand, J., Laippala, P. & Nordback, I. Long-term follow-up after the first episode of acute alcoholic pancreatitis: time course and risk factors for recurrence. Scand. J. Gastroenterol. 35, 552–555 (2000).

    CAS  PubMed  Google Scholar 

  136. Pelli, H., Lappalainen-Lehto, R., Piironen, A., Sand, J. & Nordback, I. Risk factors for recurrent acute alcohol-associated pancreatitis: a prospective analysis. Scand. J. Gastroenterol. 43, 614–621 (2008).

    PubMed  Google Scholar 

  137. Gorry, M. C. et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 113, 1063–1068 (1997).

    CAS  PubMed  Google Scholar 

  138. Ammann, R. W. & Muellhaupt, B. Progression of alcoholic acute to chronic pancreatitis. Gut 35, 552–556 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Nordback, I. et al. The recurrence of acute alcohol-associated pancreatitis can be reduced: a randomized controlled trial. Gastroenterology 136, 848–855 (2009).

    PubMed  Google Scholar 

  140. Singer, M. V., Pfutzer, R. H. & Kiefer, F. Striving for abstinence in alcoholic pancreatitis: act of humanity, economic necessity, or flogging a dead horse after all? Gastroenterology 136, 757–760 (2009).

    PubMed  Google Scholar 

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Yadav, D., Whitcomb, D. The role of alcohol and smoking in pancreatitis. Nat Rev Gastroenterol Hepatol 7, 131–145 (2010). https://doi.org/10.1038/nrgastro.2010.6

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