RECURRENT ACUTE PANCREATITIS

 

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Acute pancreatitis (AP) and chronic pancreatitis (CP) were originally described as two well defined entities on the opposite end of a disease spectrum. We now think that recurrent acute pancreatitis (RAP) is a transition stage between acute and chronic pancreatitis.

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Acute pancreatitis is defined as an acute inflammatory condition characterized by epigastric pain, elevated amylase and lipase and imaging consistent with pancreatitis. There is currently no consensus definition of chronic pancreatitis. One consistent requirement is that there is documentation of irreversible changes either histologically (i.e., fibrosis, atrophy) or morphologically (i.e., calcifications, ductal abnormalities with or without other accompanying features (e.g., pain, AP, or RAP), organ dysfunction (diabetes, exocrine deficiency), and impaired quality of life.  

Recurrent acute pancreatitis is defined as two or more distinct episodes of acute pancreatitis with near complete resolution of symptoms between episodes with no evidence of chronic pancreatitis. The difference between RAP and CP is based on morphology and histology of the pancreas. The difference is based on whether or not there are definitive changes of CP in cross sectional studies, like a CT scan or a MRI.  

In the United States, acute pancreatitis is one of the most common gastrointestinal causes of hospitalization. Although most cases of acute pancreatitis are self-limited, studies have shown that up to one quarter of patients can have a reoccurrence of acute pancreatitis and up to ten percent of patients go on to develop chronic pancreatitis.

Recurrent acute pancreatitis by definition occurs when a patient has two or more episodes of acute pancreatitis. A challenge in the diagnosis acute recurrent pancreatitis is that there is often symptom overlap with chronic pancreatitis. Patients may present with an acute attack, a recurrence or may have an acute on chronic flare with minimal imaging findings consistent with chronic pancreatitis. In addition, sometimes determining the etiology of RAP remains challenging. Alcohol and gallstones are by far the most common causes of RAP and together they account for 70% of the cases. Other common etiologies include toxins, metabolic, idiopathic, genetic, autoimmune and obstructive causes. Patients with RAP also are younger with a higher incidence in patients (<40 years old).  

The risk of developing acute recurrent pancreatitis can be reduced by encouraging alcohol abstinence and by performing a cholecystectomy after the first episode of acute pancreatitis in patients diagnosed with biliary disease. It is also important to note that because up to thirty percent of patients have no defined etiology of recurrent acute pancreatitis on routine lab work and imaging treatment options are limited. Etiologies such as pancreas divisum, occult stone disease and sphincter of Oddi dysfunction and genetic causes are overrepresented in idiopathic RAP patients.

A patient’s history and standard tests such as blood chemistry, trans-abdominal ultrasound, MRCP, and CT scan generally detect the causes of recurrent episodes in about 70% of cases. When no cause is found at the initial diagnostic work-up, these patients should have a more advanced diagnostic work-up, that includes specific pancreatic tests, genetic testing, MRCP with secretin stimulation, sphincter of Oddi motility evaluation, EUS, and in selected cases ERCP. Genetic and autoimmune pancreatitis can be diagnosed by testing respectively for CFTR or SPINK1/PRSS1 gene mutations and IgG 4.

In patients with idiopathic RAP, endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy with or without pancreatic duct stent placement have been suggested to offer some benefit however the long term benefit and outcomes have not been adequately defined in the literature.  Laparoscopic cholecystectomy is curative when gallbladder stones or sludge are detected; however, the clinical benefit for sludge is less evident. In documented SOD endoscopic sphincterotomy is currently the standard therapy.
Amit H. Sachdev

Clinical Instructor of Medicine, Interventional Gastroenterology, Columbia University College of Physicians and Surgeons

John M. Poneros M.D.

Associate Professor of Medicine, Associate Director of Endoscopy, Columbia University College of Physicians and Surgeons

 

REFERENCES:

Amann, S.T., Yadav, D., Barmada, M.M., O’Connell, M., Kennard, E.D., Anderson, M., Baillie, J., Sherman, S., Romagnuolo, J., Hawes, R.H., et al. (2013). Physical and mental quality of life in chronic pancreatitis: a case-control study from the North American Pancreatitis Study 2 cohort. Pancreas 42, 293–300.

Attwell, A., Borak, G., Hawes, R., Cotton, P., and Romagnuolo, J. (2006). Endoscopic pancreatic sphincterotomy for pancreas divisum by using a needle-knife or standard pull-type technique: safety and reintervention rates. Gastrointest. Endosc. 64, 705–711.

Bertin, C., Pelletier, A.-L., Vullierme, M.P., Bienvenu, T., Rebours, V., Hentic, O., Maire, F., Hammel, P., Vilgrain, V., Ruszniewski, P., et al. (2012). Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations. Am. J. Gastroenterol. 107, 311–317.

Chacko, L.N., Chen, Y.K., and Shah, R.J. (2008). Clinical outcomes and nonendoscopic interventions after minor papilla endotherapy in patients with symptomatic pancreas divisum. Gastrointest. Endosc. 68, 667–673.

Das, R., Clarke, B., Tang, G., Papachristou, G.I., Whitcomb, D.C., Slivka, A., and Yadav, D. (2016). Endoscopic sphincterotomy (ES) may not alter the natural history of idiopathic recurrent acute pancreatitis (IRAP). Pancreatol. Off. J. Int. Assoc. Pancreatol. IAP Al 16, 770–777.

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

Gardner, T.B., Kennedy, A.T., Gelrud, A., Banks, P.A., Vege, S.S., Gordon, S.R., and Lacy, B.E. (2010). Chronic pancreatitis and its effect on employment and health care experience: results of a prospective American multicenter study. Pancreas 39, 498–501.

Garg, P.K., Tandon, R.K., and Madan, K. (2007). Is Biliary Microlithiasis a Significant Cause of Idiopathic Recurrent Acute Pancreatitis? A Long-term Follow-up Study. Clin. Gastroenterol. Hepatol. 5, 75–79.

van Geenen, E.J.M., van der Peet, D.L., Mulder, C.J.J., Cuesta, M.A., and Bruno, M.J. (2009). Recurrent acute biliary pancreatitis: the protective role of cholecystectomy and endoscopic sphincterotomy. Surg. Endosc. 23, 950–956.

Hall, T.C., Dennison, A.R., and Garcea, G. (2012). The diagnosis and management of Sphincter of Oddi dysfunction: a systematic review. Langenbecks Arch. Surg. 397, 889–898.

Heetun, Z.S., Zeb, F., Cullen, G., Courtney, G., and Aftab, A.R. (2011). Biliary sphincter of Oddi dysfunction: response rates after ERCP and sphincterotomy in a 5-year ERCP series and proposal for new practical guidelines. Eur. J. Gastroenterol. Hepatol. 23, 327–333.

Jacob, L., Geenen, J.E., Catalano, M.F., and Geenen, D.J. (2001). Prevention of pancreatitis in patients with idiopathic recurrent pancreatitis: a prospective nonblinded randomized study using endoscopic stents. Endoscopy 33, 559–562.

Lans, J.I., Geenen, J.E., Johanson, J.F., and Hogan, W.J. (1992). Endoscopic therapy in patients with pancreas divisum and acute pancreatitis: a prospective, randomized, controlled clinical trial. Gastrointest. Endosc. 38, 430–434.

Machicado, J.D., and Yadav, D. (2017). Epidemiology of Recurrent Acute and Chronic Pancreatitis: Similarities and Differences. Dig. Dis. Sci. 62, 1683–1691.

Mariani, A. (2014). Outcome of endotherapy for pancreas divisum in patients with acute recurrent pancreatitis. World J. Gastroenterol. 20, 17468.

Michailidis, L. (2017). The efficacy of endoscopic therapy for pancreas divisum: a meta-analysis. Ann. Gastroenterol.

Nøjgaard, C., Becker, U., Matzen, P., Andersen, J.R., Holst, C., and Bendtsen, F. (2011). Progression from acute to chronic pancreatitis: prognostic factors, mortality, and natural course. Pancreas 40, 1195–1200.

Nordback, I., Pelli, H., Lappalainen-Lehto, R., Järvinen, S., Räty, S., and Sand, J. (2009). The recurrence of acute alcohol-associated pancreatitis can be reduced: a randomized controlled trial. Gastroenterology 136, 848–855.

Park, S.-H., Watkins, J.L., Fogel, E.L., Sherman, S., Lazzell, L., Bucksot, L., and Lehman, G.A. (2003). Long-term outcome of endoscopic dual pancreatobiliary sphincterotomy in patients with manometry-documented sphincter of Oddi dysfunction and normal pancreatogram. Gastrointest. Endosc. 57, 483–491.

Rebours, V., Boutron-Ruault, M.-C., Schnee, M., Férec, C., Le Maréchal, C., Hentic, O., Maire, F., Hammel, P., Ruszniewski, P., and Lévy, P. (2009). The natural history of hereditary pancreatitis: a national series. Gut 58, 97–103.

Roberts, J.R., and Romagnuolo, J. (2013). Endoscopic Therapy for Acute Recurrent Pancreatitis. Gastrointest. Endosc. Clin. N. Am. 23, 803–819.

Romagnuolo, J., Durkalski, V., Fogel, E.L., Freeman, M.L., Tarnasky, P.R., Wilcox, C.M., Cotton, P.B., Warth, S., Orrell, K., and Williams, A.W. (2013). Mo1427 Outcomes After Minor Papilla Endoscopic Sphincterotomy (MPES) for Unexplained Acute Pancreatitis and Pancreas Divisum: Final Results of the Multicenter Prospective FRAMES (Frequency of Recurrent Acute Pancreatitis After Minor Papilla Endoscopic Sphincterotomy) Study. Gastrointest. Endosc. 77, AB379.

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

Yadav, D., and Lowenfels, A.B. (2013). The Epidemiology of Pancreatitis and Pancreatic Cancer. Gastroenterology 144, 1252–1261.

Yaghoobi, M., and Romagnuolo, J. (2015). Sphincter of Oddi Dysfunction: Updates from the Recent Literature. Curr. Gastroenterol. Rep. 17, 31.

Genes Behind Pancreatic Cancer

Pancreatic cancer is the third most common cause of cancer-related deaths in the United States, with over 43,000 deaths expected in 2017.1 While most pancreatic cancers are sporadic, approximately 10% of pancreatic cancers appear to have a familial component.2

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Familial Pancreatic Cancer (FPC) is defined as families that have > 2 affected individuals who are first-degree relatives of each other. FPC can also include families with > 3 affected individuals on the same side of the family, even if they are not first-degree relatives of each other.

Germline mutations in BRCA1, BRCA2, PALB2, ATM, p16, PRSS1, STK11, and the mismatch repair genes (Lynch syndrome) are associated with a significantly increased risk of pancreatic cancer; however, these genes have a low penetrance for pancreatic cancer, and often the family history is more notable for other cancers.

Despite what appears to be an autosomal dominant mechanism for inheritance, a genetic mutation leading to pancreatic cancer is found only 10% of seemingly hereditary cases.

Several large-volume centers have begun to study screening for pancreatic cancer in high-risk patients, and consensus-based guidelines have been published.3  Candidates for screening may include:

1) First-degree relative of an affected individual in a FPC family

2) First-degree relative of an affected individual in a family with > 2 pancreatic cancers

3) BRCA2, PALB2, p16, ATM, and mismatch repair gene mutation carriers with affected first-degree relatives

4)  BRCA2 mutation carriers with 2 affected relatives, even if no first-degree relative is affected

5) All Peutz-Jegher’s syndrome (STK11 mutation) patients regardless of their family history

6) All PRSS1 mutation carriers

Consensus guidelines recommend pancreatic cancer screening in high-risk individuals at age 50, with the exception being PRSS1 mutation carriers who start screening at age 40.

The goals of pancreatic cancer screening include:

1)  Detection and treatment of precancerous lesions (i.e., high grade multifocal pancreatic intraepithelial neoplasms, or high-grade dysplasia within an intraductal papillary mucinous neoplasm).

2) The detection and treatment of a T1N0M0 cancer.

3) Detection of any resectable pancreatic carcinoma.

Detection of these early pancreatic cancers or pre-malignant lesions is dependent on our ability to identify and screen high-risk individuals before the onset of symptoms.  Current tools for pancreatic cancer screening include Magnetic Resonance Imaging (MRI) with MR Cholangiography (MRCP) and endoscopic ultrasound (EUS.)

MRI has the benefit of being a non-invasive test, but is sometimes limited by the patient’s ability to lie still for the duration of the study. 

EUS is a more invasive examination which requires anesthesia, but offers an opportunity to sample any abnormalities that may be detected on examination.

Emerging data suggest that MRCP may be more effective in detecting cystic lesions of the pancreas, while EUS may be more sensitive to detect small solid lesions.4 Computer tomography (CT scan), abdominal ultrasound, and endoscopic retrograde cholangiopancreatography are not generally used in pancreatic cancer screening.

For further information on pancreatic cancer screening studies, or to arrange a consultation please visit  http://www.mountsinai.org/profiles/aimee-lucas or  http://labs.icahn.mssm.edu/lucas

Amiee Lucas, MD  Professor of Medicine – Gastroenterology  Mt. Sinai Hospital

References

1. Society AC. Cancer Facts & Figures 2017. Atlanta: American Cancer Society 2017.

2. Klein AP, Hruban RH, Brune KA, et al. Familial pancreatic cancer. Cancer J 2001;7:266-73.

3. Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2012.

4. Harinck F, Konings IC, Kluijt I, et al. A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals. Gut 2015.