Clinical Practice Guideline

Chronic Pancreatitis

Definition, Etiology, Investigation and Treatment

Dtsch Arztebl Int 2013; 110(22): 387-93; DOI: 10.3238/arztebl.2013.0387

Mayerle, J; Hoffmeister, A; Witt, H; Lerch, M M; Mössner, J

Background: Chronic pancreatitis has an annual incidence of 23 per 100 000 population in Germany, where it accounts for about 10 000 hospital admissions per year. The disease shortens the life expectancy of its sufferers by an average of 23%. It most commonly affects men aged 20 to 40.

Methods: A systematic search for pertinent literature retrieved 19 569 publications, 485 of which were considered in the creation of this guideline, including 67 randomized controlled trials (RCTs). A consensus conference reached agreement on a total of 156 definitions and recommendations.

Results: The identification of genetic risk factors for pancreatitis is now well established. The diagnosis is made mainly with ultrasonography of the pancreas; if the findings are uncertain, further studies can be performed, including endosonography and endosonographically assisted fine-needle puncture for the examination of small foci of disease. Computed tomography and MRI/magnetic resonance cholangiopancreatography are supplementary diagnostic methods. Endoscopic retrograde cholangiopancreatography is now used almost exclusively for treatment, rather than for diagnosis. 30% to 60% of patients develop complications of chronic pancreatitis, including pseudocysts, bile-duct stenosis, or medically intractable pain, which can be treated with an endoscopic or surgical intervention. Patients with steatorrhea, a pathological pancreatic function test, or clinical evidence of malabsorption should be given pancreatin supplementation. The head of the pancreas should be resected if it contains an inflammatory pseudotumor.

Conclusion: The management of patients with chronic pancreatitis requires close interdisciplinary collaboration, as it can be treated medically and endoscopically as well as surgically.

LNSLNS

Most patients with chronic pancreatitis are treated on an outpatient basis, yet a large number are still hospitalized: There were 10 267 inpatient admissions for chronic pancreatitis (ICD-10 code K86) in Germany in 2008, according to the German Federal Statistical Office. The incidence of the disease is rising and has now reached 23 cases per 100 000 persons per year in Germany (1). One-third of patients can no longer work in their original profession, and 40% become temporarily or permanently disabled because of the disease (2). The mortality of persons with chronic pancreatitis exceeds that of the general population by a factor of 3.6 (3). Reported mortality figures over time periods of 6 to 10 years range from 13% to 20% (4). The 10-year survival rate is 70% and the 20-year survival rate is 45%, compared to 93% and 65% in age-matched controls (4).

The goal of this German, Austrian, and Swiss guideline is to summarize and evaluate current knowledge of the definition, etiology, diagnostic investigation, and treatment of chronic pancreatitis in adults and children and to derive evidence-based clinical recommendations.

Methods

After a systematic search of the literature, experts from 10 German, Swiss, and Austrian medical societies (eBoxes 1 and 2) analyzed 19 569 publications (1400 as whole text, including 67 randomized controlled trials [RCTs], eTable 1) and evaluated them according to the Oxford criteria for evidence-based medicine (eTable 2). After an internal consensus had been reached in each of 10 working groups (eBox 1), a joint consensus conference agreed on the 156 definitions and recommendations that were issued in this S3 guideline.

The sensitivity and speificity of pancreatic function tests
The sensitivity and speificity of pancreatic function tests
Table 1
The sensitivity and speificity of pancreatic function tests
The sensitivity and specificity of imaging studies for the diagnosis of chronic pancreatitis
The sensitivity and specificity of imaging studies for the diagnosis of chronic pancreatitis
Table 2
The sensitivity and specificity of imaging studies for the diagnosis of chronic pancreatitis
Specialist society representatives participating in the creation of this guideline
Specialist society representatives participating in the creation of this guideline
eBox 1
Specialist society representatives participating in the creation of this guideline
The S3 guideline was created under the aegis of the German Association of Digestive and Metabolic Diseases
The S3 guideline was created under the aegis of the German Association of Digestive and Metabolic Diseases
eBox 2
The S3 guideline was created under the aegis of the German Association of Digestive and Metabolic Diseases
Results of the literature search
Results of the literature search
eTable 1
Results of the literature search
Oxford Centre for Evidence-based Medicine—Levels of Evidence
Oxford Centre for Evidence-based Medicine—Levels of Evidence
eTable 2
Oxford Centre for Evidence-based Medicine—Levels of Evidence

A total of 485 pertinent publications were considered in the final evaluation and are cited in the complete version of the guideline, which has been published elsewhere with a detailed description of the method by which it was produced (5). The guideline can be downloaded at http://www.awmf.org/uploads/tx_szleitlinien/021–003l_S3_Chronische_Pankreatitis_08–2012.pdf and at www.dgvs.de/index_2444.php. It will be valid for the next five years.

Definition

Chronic pancreatitis is a disease of the pancreas in which recurrent episodes of inflammation lead to replacement of the pancreatic parenchyma with fibrotic connective tissue (6). Consequently, the exocrine and endocrine functions of the pancreas are progressively lost. Further characteristic complications include:

  • pseudocysts
  • stenosis of the pancreatic duct
  • duodenal stenosis
  • vascular complications
  • compression of the bile ducts
  • malnutrition
  • chronic pain.

Pain is the main symptom of patients with chronic pancreatitis. The disease raises the risk of developing pancreatic carcinoma by a factor of 16 and, in patients who also smoke, by a factor of 25 (7). Among patients with chronic pancreatitis, the lifetime risk of pancreatic carcinoma is 5% at most.

The relative risk of pancreatic carcinoma in patients with chronic pancreatitis is 13.1% (95% confidence interval [95% CI] 6.1%–28.9%); in patients with hereditary pancreatitis, it is 69% (95% CI 56.4%–84.4%) (8).

The causes of chronic pancreatitis

Alcohol has been identified as a definitive cause of chronic pancreatitis. Persons who drink 80 g or more of alcohol per day over a period of 6–12 years are at risk of developing chronic pancreatitis (9).

Patients with chronic pancreatitis who smoke should be urgently advised to enroll in a smoking-cessation program (level of evidence: 3b, recommendation grade: A, strong consensus). Large-scale cohort studies, some of them prospective, including as many as 695 patients have shown that smoking accelerates the progression of chronic pancreatitis (10).

Hereditary factors in chronic pancreatitis

Mutations of the cationic trypsinogen gene (PRSS1) lead with 80%–93% penetrance to autosomal dominant chronic pancreatitis (level of evidence: 1c, recommendation grade: A, strong consensus) (11, 12).

The prevalence of hereditary pancreatitis is 1/300 000 (7). 66%–68% of all patients with hereditary pancreatitis have a mutation in the PRSS1 gene (11, 12). Other genetic risk factors that are much more common in patients with sporadic pancreatitis are variants in the SPINK1 gene (7) and the CFTR gene (13).

Genetic testing for suspected hereditary pancreatitis

The PRSS1 gene should be analyzed for mutations in patients with a positive family history (one or two first-degree relatives with idiopathic pancreatitis), those with two or more episodes of acute pancreatitis of no identifiable cause before age 25, or those with idiopathic chronic pancreatitis with onset before age 25 (level of evidence: 3b, recommendation grade: B, consensus).

Testing for mutations in the SPINK1, CFTR, and CTRC genes and other associated genetic changes can be performed in a research setting or for further etiological investigation (level of evidence: 3b, recommendation grade C, consensus).

The development and clinical manifestations of exocrine pancreatic insufficiency

The characteristic manifestations of exocrine pancreatic insufficiency are abdominal discomfort, steatorrhea, and signs of malnutrition. Exocrine pancreatic insufficiency may arise even before chronic pancreatitis is diagnosed but becomes more common starting about 10 years after the onset of overt manifestations of chronic pancreatitis. Decompensation, with steatorrhea, occurs only when lipase secretion is reduced by more than 90% to 95% (14). Exocrine pancreatic insufficiency can cause malnutrition and weight loss even in the absence of symptomatic steatorrhea (15). Subclinical, mild, or moderate exocrine insufficiency markedly elevates the risk of osteoporosis, fractures, and vitamin deficiencies, particularly of vitamins D and E. The absence of morphological evidence of chronic pancreatitis is no guarantee of normal pancreatic function.

The clinical evaluation should include a noninvasive test of pancreatic function, e.g., a fecal elastase test (with specific antibodies). Alternatively, a breath test with 13C-marked lipids can be used (Table 1) (level of evidence: 5, recommendation grade: B, consensus, clinical consensus in favor of noninvasive testing).

Imaging studies in chronic pancreatitis

The diagnosis of chronic pancreatitis is based on clinical, morphological, and functional evidence. These three lines of evidence are not closely correlated with one another and therefore play complementary roles in the diagnosis of the disease.

After history-taking and physical examination, the initial imaging study is ultrasonography of the pancreas. If chronic pancreatitis is clinically suspected, but ultrasonography reveals less than definitive evidence (an inhomogeneous organ with a pancreatic duct of normal width), endosonography (EUS) should follow (16). Tissue can be obtained by endosonographically assisted fine-needle puncture (EUS-FNP) for the cytological or histological differentiation of foci of disease (and the ascertainment of autoimmune pancreatitis, if present). Computed tomography (CT) and MRI with magnetic resonance cholangiopancreatography (MRCP) are complementary diagnostic methods for the further evaluation of unclear pancreatic changes. In particular, MRCP should be performed to obtain detailed information about the pancreatic duct system (level of evidence: 2a, recommendation grade: B, consensus) (Table 2).

No prospective randomized studies have yet been performed to compare ultrasonography (US), EUS, and CT for the diagnostic evaluation of chronic pancreatitis. Prospective studies have only compared endoscopic retrograde cholangiopancreatography (ERCP) with EUS, MRCP with EUS, and US with ERCP. Endosonography is the most sensitive diagnostic test for chronic pancreatitis. Comparative studies have shown that EUS is superior to MRCP for the diagnosis of early forms of the disease. ERCP is associated with higher morbidity (5%–10% overall; 3.47% post-ERCP pancreatitis) and mortality (0.3‰) and therefore should no longer be performed as a solely diagnostic procedure (17).

Endoscopic retrograde pancreatography (ERP) is still indicated in rare cases, e.g., when both EUS and MRI/MRCP have been performed without yielding a definitive diagnosis. Diagnostic ERP can also be useful in suspected cases of autoimmune pancreatitis (18) (level of evidence: 4, recommendation grade: C, strong consensus).

The different criteria for the various imaging modalities in use should be modified and applied in accordance with the Cambridge classification (Table 3) (level of evidence: 2a, recommendation grade: B, strong consensus).

Evaluation criteria for various diagnostic techniques according to the Cambridge classification
Evaluation criteria for various diagnostic techniques according to the Cambridge classification
Table 3
Evaluation criteria for various diagnostic techniques according to the Cambridge classification

Indications for interventional or surgical treatment

30%–60% of patients with chronic pancreatitis develop complications of their disease requiring either interventional or surgical treatment. These include

  • strictures of the common bile duct,
  • inflammatory masses,
  • pancreatic pseudocysts, and
  • pancreatic duct stones.

In the following paragraphs, we discuss the indications for treatment. Persons who persistently need to take analgesic medication for pain should receive either interventional or surgical treatment (level of evidence: 2b, recommendation grade: B, consensus).

Pain relief can be achieved by endoscopic techniques in 66% of cases (19). Surgery is more likely to bring long-term relief compared to endoscopic techniques, but is associated with higher morbidity (30.6%–36% [20, 21]) and mortality for pancreatic resective techniques (6.1–6.4% [22]).

Only two studies have provided level 1b evidence from a direct comparison of surgery with endoscopy (23, 24). Both showed that surgical drainage yielded better results over the long term regarding pain reduction.

Pancreatic duct stones and stenoses that cause pain by blocking the outflow of pancreatic secretions, induce recurrent bouts of disease, maintain a pseudocyst or fistula, or cause other complications can be treated either endoscopically or surgically (level of evidence: 4, recommendation grade: D, strong consensus).

When resectable pancreatic carcinoma is suspected, the treatment should be surgical (level of evidence: 2b, recommendation grade: A, consensus).

Unoperated patients with pancreatic carcinoma have a life expectancy of less than one year; after successful resection, the likelihood of surviving five years is 20% to 25% (25). Symptomatic pseudocysts should be treated. The endoscopic or surgical treatment of a symptomatic pseudocyst is indicated regardless of size (level of evidence: 2a, recommendation grade: B, strong consensus).

Pseudocysts that cause complications such as gastric outlet obstruction, hemorrhage, pain, cholestasis, or vascular stenosis should be treated either endoscopically or surgically. Surgical methods of treating pseudocysts tend to have higher success rates than endoscopic pseudocyst drainage into the duodenum or the stomach but are associated with somewhat higher mortality. (Open surgery [156 cases]: success rate 90%–100%, complication rate 20%, recurrence rate 12%, mortality 5%–20%; laparoscopic surgery [253 cases]: success rate 92%, recurrence rate 3%, complication rate 9%, mortality 0%; endoscopic treatment [1312 cases]: success rate 92%, recurrence rate 8.5%, complication rate 14.4%, mortality <1%) (26).

Asymptomatic pancreatic pseudocysts measuring more than 5 cm in diameter that do not regress within six weeks can be treated (level of evidence: 2a, recommendation grade: C, majority agreement).

In a multivariate analysis, Gouyon showed that pseudocyst size less than 4 cm is the single favorable prognostic factor for spontaneous regression (27). Bradley et al. showed that untreated cysts larger than 5 cm cause complications in 41% of cases (rupture, infection, jaundice, or hemorrhage) (28).

If chronic pancreatitis causes distal bile duct stenosis with cholestasis or jaundice, surgery or endoscopic stenting should be performed. If there are intrapancreatic calcifications, surgery is preferable (level of evidence: 4, recommendation grade: B, consensus).

Cholestasis in chronic pancreatitis can be treated by endoscopic stenting with lasting efficacy over twelve months in only one-third of patients (and in only 9% of those with calcific pancreatitis) (29). If cholangiitis is present, endoscopic drainage should be performed without delay (30). If an indication for surgical treatment is present in a case of chronic pancreatitis with cholestasis, than preoperative endoscopic stenting of the bile duct should be performed only if:

  • surgery cannot be performed without delay, or
  • cholangiitis is present (level of evidence: 2a, recommendation grade: B, strong consensus).

A study of patients with pancreatic tumors showed that preoperative drainage markedly increases postoperative complications (31).

The treatment of pain

The causes of pain in chronic pancreatitis include inflammatory infiltration of the parenchyma and nerve sheaths as well as increased pressure in the pancreatic duct due to stenoses or stones.

The intensity of pain in chronic pancreatitis should be evaluated with a validated pain score such as that of Bloechle at al. or the Visual Analog Scale (VAS) (32) (level of evidence: 1b, recommendation grade: B, strong consensus). The pain of chronic pancreatitis can be treated according to the WHO stepwise algorithm (level of evidence: 5, recommendation grade: D, strong consensus). This is presented in Table 4. Surgical treatment is the most effective method of achieving long-term pain relief in chronic pancreatitis (level of evidence: 1a, recommendation grade: A, consensus).

Recommended analgesic dosages for patients with chronic pancreatitis, according to the gudeline of the Word Health Organization
Recommended analgesic dosages for patients with chronic pancreatitis, according to the gudeline of the Word Health Organization
Table 4
Recommended analgesic dosages for patients with chronic pancreatitis, according to the gudeline of the Word Health Organization

Two randomized controlled trials showed that pancreaticojejunostomy provides better pain relief than endoscopic treatment (Cahen et al.: Bloechle Score 25 [surgery] versus 51 [endoscopy] at 24 months, p<0.001; Dité et al.: pain-free state in 34% of patients after surgery, versus 15% after endoscopic treatment) (23, 24).

Enzyme supplementation in chronic pancreatitis

Patients who have, or are considered likely to have, steatorrhea (the pathological excretion of more than 15 grams of fat per day in the stool) should receive pancreatin supplementation, as should those with an abnormal pancreatic function test combined with clinical evidence of malabsorption.

Even if the excretion of fat in the stool is in the low abnormal range (7–15 g/d), pancreatin should be given if there is evidence of malassimilation, e.g., weight loss, or if the patient has abdominal manifestations attributable to maldigestion and malabsorption (level of evidence: 1b, recommendation grade: A, strong consensus). Empirical treatment for 4–6 weeks can be useful if symptoms are unclear or equivocal (33).

The dose of pancreatin preparations is expressed in terms of lipase activity. For each of the main meals of the day, 20 000 to 40 000 units (Ph. Eur.) should be given as an initial dose; for lesser amounts of food intake between meals, about 10 000 to 20 000 lipase units can be given (level of evidence: 1b, recommendation grade: B, strong consensus). In case of inadequate efficacy, the enzyme dose should be doubled or trebled (strong consensus, clinical consensus point). If the efficacy remains inadequate, pancreatin granules should be combined with an acid inhibitor (level of evidence: 2b, recommendation grade: B, strong consensus). If this still does not lead to the desired success of treatment, another cause for the persistent symptoms should be sought (strong consensus, clinical consensus point).

Nearly all pancreatic enzyme preparations now available in Germany contain porcine pancreatin. As this is a medication, rather than a food, it may be taken even by patients who choose not to eat pork for religious or ethical reasons (cf. Koran, sura 2, verse 173) (strong consensus, clinical consensus point). The patient should nonetheless be told of the origin of the preparation.

Surgical techniques and their indications

Surgery is an effective treatment for intractable pain and/or local complications in chronic pancreatitis (24, 34). In principle, endoscopic methods can also be used for these indications; thus, early interdisciplinary discussion is advisable to determine the most appropriate treatment for the individual patient (35). The standard operative technique in chronic pancreatitis with an inflammatory pseudotumor of the head of the pancreas is resection of the head of the pancreas. For this purpose, one of the variants of duodenum-preserving resection of the head of the pancreas (surgery according to Beger, Frey, Bern, Hamburg) or the Kausch-Whipple procedure (either the classic or the pylorus-preserving variant) should be performed (level of evidence: 1a, recommendation grade: A, strong consensus).

If the main problem is an obstructed pancreatic duct, pure drainage procedures such as lateral pancreaticojejunostomy (the Partington-Rochelle procedure) or the Frey operation, with only limited resection of the head of the pancreas, have a good primary success rate. The results are better than those of endoscopic treatment (24, 34), but the long-term success of treatment is still not as good as that obtainable with other techniques in which the head of the pancreas is resected. Moreover, these techniques are likely to succeed only if the ductal system is markedly enlarged (>7 mm) and in the absence of an inflammatory pseudotumor of the pancreatic head (36).

The monitoring and follow-up of patients with chronic pancreatitis

Chronic pancreatitis gives rise to treatable complications including endocrine and exocrine pancreatic insufficiency, acute episodes of inflammation, pseudocyst formation, cholestasis, and an increased risk of pancreatic carcinoma. Patients should, therefore, have further monitoring and follow-up once the diagnosis has been made (consensus, clinical consensus point).

Twenty years after diagnosis, the mortality of persons with chronic pancreatitis is 38.4% higher than in the general population (3). Clinical experience therefore suggests that follow-up studies should be performed annually (history, physical examination, transabdominal ultrasonography, and laboratory testing including HbA1c).

Tumor markers should not be measured as part of the follow-up of patients with chronic pancreatitis (Ca19.9, CEA, or others; level of evidence: 2a, recommendation grade: B, strong consensus).

The diagnosis and treatment of chronic pancreatitis in childhood

The diagnostic evaluation and treatment of chronic pancreatitis in children and adolescents should be performed under the direction of a pediatric gastroenterologist, in collaboration with an experienced pediatric surgeon or visceral surgeon, a pediatric radiologist, and, where appropriate, an interventional endoscopist (consensus, clinical consensus point).

A sweat test to rule out cystic fibrosis should be part of the etiological work-up of children with chronic pancreatitis (level of evidence: 1c, recommendation grade: A, strong consensus).

Patients with cystic fibrosis with preserved exocrine pancreatic function often suffer from recurrent pancreatitis. Thus, an episode of pancreatitis may, in fact, be the initial manifestation of cystic fibrosis. Moreover, patients with so-called idiopathic chronic pancreatitis often turn out to have mutated CFTR alleles.

Conflict of interest statement
Prof. Mayerle has served as a paid consultant for AstraZeneca and has been paid by the Falk Foundation for preparing continuing medical education presentations.

PD Dr. Hoffmeister has received lecture honoraria from the Falk Foundation.

Prof. Lerch has served as a paid consultant for Roche, Abbott, Falk, and Aptalis. He has received reimbursement of scientific meeting participation fees and travel expenses from Roche, Abbott, Menarini, and Falk. He has been paid by Roche, AstraZeneca, Reccordati, Menarini, Abbott, Falk, and Aptalis for preparing continuing medical education presentations. He has received financial support in an external-funding account for conducting clinical trials on behalf of AstraZeneca, Abbott, Menarini, Solvay, Roche, and Sanofi-Aventis. He has also received financial support in an external-funding account from AstraZeneca, Metanomics, Roche, Abbott, Solvay, and SanofiAventis for a research project that he initiated.

Prof. Werner and Prof. Witt state that they have no conflict of interest.

Prof. Mössner has received reimbursement of travel and accommodation expenses and of scientific meeting participation fees from Aptalis and Axcan and lecture honoraria from Abbott, AstraZeneca, Eisai, Essex, the Falk Foundation, Forthe, Norgine, Novartis, Roche, Solvay, and UCB.

Manuscript submitted on 14 November 2012, revised version accepted on 4 April 2013.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Markus M. Lerch
Klinik für Innere Medizin A
Universitätsmedizin
Ernst-Moritz-Arndt-Universität Greifswald
Ferdinand-Sauerbruch-Str.
17475 Greifswald, Germany
lerch@uni-greifswald.de

@eTables, eBoxes:
www.aerzteblatt-international.de/13m0387

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*1Professor Mayerle and Dr. Hoffmeister have equally contributed to the manuscript.
*2Professor Lerch and Professor Mössner are joint senior authors.
University Medicine Greifswald, Department of Internal Medicine A (on behalf of the German Society of Digestive and Metabolic Diseases, DGVS): Prof. Dr. med. Mayerle, Prof. Dr. med. Lerch
Department of Gastroenterology and Rheumatology, University Hospital of Leipzig
(Leitliniensekretariat): PD Dr. med. Hoffmeister, Prof. Dr. med. Mössner
Department of General, Visceral and Transplantation Surgery at Heidelberg University Hospital:
Prof. Dr. med. Werner
Children’s Hospital Munich-Schwabing, Department of Child and Adolescent Medicine: Prof. Dr. med. Witt
The sensitivity and speificity of pancreatic function tests
The sensitivity and speificity of pancreatic function tests
Table 1
The sensitivity and speificity of pancreatic function tests
The sensitivity and specificity of imaging studies for the diagnosis of chronic pancreatitis
The sensitivity and specificity of imaging studies for the diagnosis of chronic pancreatitis
Table 2
The sensitivity and specificity of imaging studies for the diagnosis of chronic pancreatitis
Evaluation criteria for various diagnostic techniques according to the Cambridge classification
Evaluation criteria for various diagnostic techniques according to the Cambridge classification
Table 3
Evaluation criteria for various diagnostic techniques according to the Cambridge classification
Recommended analgesic dosages for patients with chronic pancreatitis, according to the gudeline of the Word Health Organization
Recommended analgesic dosages for patients with chronic pancreatitis, according to the gudeline of the Word Health Organization
Table 4
Recommended analgesic dosages for patients with chronic pancreatitis, according to the gudeline of the Word Health Organization
Specialist society representatives participating in the creation of this guideline
Specialist society representatives participating in the creation of this guideline
eBox 1
Specialist society representatives participating in the creation of this guideline
The S3 guideline was created under the aegis of the German Association of Digestive and Metabolic Diseases
The S3 guideline was created under the aegis of the German Association of Digestive and Metabolic Diseases
eBox 2
The S3 guideline was created under the aegis of the German Association of Digestive and Metabolic Diseases
Results of the literature search
Results of the literature search
eTable 1
Results of the literature search
Oxford Centre for Evidence-based Medicine—Levels of Evidence
Oxford Centre for Evidence-based Medicine—Levels of Evidence
eTable 2
Oxford Centre for Evidence-based Medicine—Levels of Evidence
1.Dufour MC, Adamson MD: The epidemiology of alcohol-induced pancreatitis. Pancreas 2003; 27: 286–90. CrossRef MEDLINE
2.Gastard J, Joubaud F, Farbos T, et al.: Etiology and course of primary chronic pancreatitis in Western France. Digestion 1973; 9: 416–28. CrossRef MEDLINE
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4.Lankisch PG, Lohr-Happe A, Otto J, Creutzfeldt W: Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion 1993; 54: 148–55. CrossRef MEDLINE
5.Hoffmeister A, Mayerle J, Beglinger C, et al.: S3-Leitlinie Chronische Pankreatitis: Definition, Ätiologie, Diagnostik, konservative, interventionell endoskopische und operative Therapie der chronischen Pankreatitis. Leitlinie der Deutschen Gesellschaft für Verdauungs und Stoffwechselkrankheiten (DGVS). Z Gastroenterol 2012; 50: 1176–224. CrossRef MEDLINE
6.Gress TM, Muller-Pillasch F, Lerch MM, et al.: Balance of expression of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in chronic pancreatitis. Z Gastroenterol 1994; 32: 221–5. MEDLINE
7.Ellis I, Lerch MM, Whitcomb DC: Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology 2001; 1: 405–15. CrossRef MEDLINE
8.Lowenfels AB, Sullivan T, Fiorianti J, Maisonneuve P: The epidemiology and impact of pancreatic diseases in the United States. Curr Gastroenterol Rep 2005; 7: 90–5. CrossRef MEDLINE
9.Spicak J, Poulova P, Plucnarova J, et al.: Pancreas divisum does not modify the natural course of chronic pancreatitis. J Gastroenterol 2007; 42: 135–9. CrossRef MEDLINE
10.Maisonneuve P, Lowenfels AB, Mullhaupt B, et al.: Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005; 54: 510–4. CrossRef MEDLINE PubMed Central
11.Howes N, Lerch MM, Greenhalf W, et al.: Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004; 2: 252–61. CrossRef MEDLINE
12.Rebours V, Boutron-Ruault MC, Schnee M, et al.: The natural history of hereditary pancreatitis: a national series. Gut 2009; 58: 97–103. CrossRef MEDLINE
13.Weiss FU, Simon P, Bogdanova N, et al.: Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut 2005; 54: 1456–60. CrossRef MEDLINE PubMed Central
14.DiMagno EP, Go VL, Summerskill WH: Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973; 288: 813–5. CrossRef MEDLINE
15.Dumasy V, Delhaye M, Cotton F, Deviere J: Fat malabsorption screening in chronic pancreatitis. Am J Gastroenterol 2004; 99: 1350–4. CrossRef MEDLINE
16.Catalano MF, Sahai A, Levy M, et al.: EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc 2009; 69: 1251–61. CrossRef MEDLINE
17.Dumonceau JM, Andriulli A, Deviere J, et al.: European Society of Gastrointestinal Endoscopy (ESGE) Guideline: prophylaxis of post-ERCP pancreatitis. Endoscopy 2010; 42: 503–15. CrossRef MEDLINE
18.Chari ST, Kloeppel G, Zhang L, et al.: Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document. Pancreas 2010; 39: 549–54. CrossRef MEDLINE
19.Dumonceau JM, Delhaye M, Tringali A, et al.: Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 2012; 44: 784–800. CrossRef MEDLINE
20.Balcom JH4th, Rattner DW, Warshaw AL, Chang Y, Fernandez-del Castillo C: Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001; 136: 391–8. CrossRef MEDLINE
21.Buchler MW, Wagner M, Schmied BM, et al.: Changes in morbidity after pancreatic resection: toward the end of completion pancreatectomy. Arch Surg 2003; 138: 1310–4; discussion 1315. CrossRef MEDLINE
22.Finks JF, Osborne NH, Birkmeyer JD: Trends in hospital volume and operative mortality for high-risk surgery. N Engl J Med 2011; 364: 2128–37. CrossRef MEDLINE PubMed Central
23.Dite P, Ruzicka M, Zboril V, Novotny I: A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 2003; 35: 553–8. CrossRef MEDLINE
24.Cahen DL, Gouma DJ, Nio Y, et al.: Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med 2007; 356: 676–84. CrossRef MEDLINE
25.Neoptolemos JP, Stocken DD, Bassi C, et al.: Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010; 304: 1073–81. CrossRef MEDLINE
26.Lerch MM, Stier A, Wahnschaffe U, Mayerle J: Pancreatic pseudocysts: observation, endoscopic drainage, or resection? Dtsch Arztebl Int 2009; 106(38): 614–21. VOLLTEXT
27.Gouyon B, Levy P, Ruszniewski P, et al: Predictive factors in the outcome of pseudocysts complicating alcoholic chronic pancreatitis. Gut 1997; 41: 821–5. CrossRef MEDLINE PubMed Central
28.Bradley EL, Clements JL Jr., Gonzalez AC: The natural history of pancreatic pseudocysts: a unified concept of management. Am J Surg 1979; 137: 135–41. CrossRef MEDLINE
29.Kahl S, Zimmermann S, Genz I, et al.: Risk factors for failure of endoscopic stenting of biliary strictures in chronic pancreatitis: a prospective follow-up study. Am J Gastroenterol 2003; 98: 2448–53. CrossRef MEDLINE
30.Lawrence C, Romagnuolo J, Payne KM, Hawes RH, Cotton PB: Low symptomatic premature stent occlusion of multiple plastic stents for benign biliary strictures: comparing standard and prolonged stent change intervals. Gastrointest Endosc 2010; 72: 558–63. CrossRef MEDLINE
31.van der Gaag NA, Rauws EA, van Eijck CH, et al.: Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010; 362: 129–37. CrossRef MEDLINE
32.Bloechle C, Izbicki JR, Knoefel WT, Kuechler T, Broelsch CE: Quality of life in chronic pancreatitis--results after duodenum-preserving resection of the head of the pancreas. Pancreas 1995; 11: 77–85. CrossRef MEDLINE
33.Keller J, Layer P: Human pancreatic exocrine response to nutrients in health and disease. Gut 2005; 54 Suppl 6: vi1–28. CrossRef MEDLINE PubMed Central
34.Cahen DL, Gouma DJ, Laramee P, et al.: Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct in patients with chronic pancreatitis. Gastroenterology 2011; 141: 1690–5. CrossRef MEDLINE
35.Birkmeyer JD, Siewers AE, Finlayson EV, et al.: Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346: 1128–37. CrossRef MEDLINE
36.Buchler MW, Warshaw AL: Resection versus drainage in treatment of chronic pancreatitis. Gastroenterology 2008; 134: 1605–7. CrossRef MEDLINE
37.Siegmund E, Lohr JM, Schuff-Werner P: The diagnostic validity of non-invasive pancreatic function tests—a meta-analysis. Z Gastroenterol 2004; 42: 1117–28. CrossRef MEDLINE
38.Mayerle J, Stier A, Lerch MM, Heidecke CD: Chronic pancreatitis. Diagnosis and treatment. Chirurg 2004; 75: 731–47. MEDLINE