English language version of the S3-consensus guidelines on chronic pancreatitis: Definition, aetiology, diagnostic examinations, medical, endoscopic and surgical management of chronic pancreatitis^[1]

Abstract

Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganisation of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients. These guidelines were researched and compiled by 74 representatives from 11 learned societies and their intention is to serve evidence-based professional training as well as continuing education. On this basis they shall improve the medical care of affected patients in both the inpatient and outpatient sector. Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy.

Zusammenfassung

Die chronische Pankreatitis ist eine Erkrankung der Bauchspeicheldrüse, bei der rezidivierende Entzündungsschübe zu einem Ersatz des Pankreasparenchyms durch narbiges Bindegewebe führen. Diese Narbenbildung des Pankreas führt zu einem fortschreitenden Verlust der exokrinen und endokrinen Pankreasfunktion. Darüber hinaus treten typische Komplikationen auf zu denen die Bildung von Pseudozysten, Stenosen im Pankreasgang, Obstruktionen des Zwölffingerdarms, Gefäßkomplikationen, einer Obstruktion des Gallengangs, eine Mangel- und Fehlernährung sowie ein Schmerzsyndrom gehören. Das wichtigste Symptom der chronischen Pankreatitis sind abdominelle Schmerzen. Die chronische Pankreatitis stellt einen Risikofaktor für die Entstehung des Pankreaskarzinoms dar. Die chronische Pankreatitis reduziert sowohl die Lebensqualität als auch die Lebenserwartung betroffener Patienten deutlich. Die hier vorgelegte Leitlinie wurde von 74 Vertretern aus 11 Fachgesellschaften als Basis für eine evidenzbasierte Fort- und Weiterbildung zusammengestellt. Ihr Ziel ist es, die medizinische Versorgung betroffener Patienten sowohl im ambulanten als auch im stationären Bereich zu verbessern. Wegen ihrer Krankheitsschwere, ihrer Häufigkeit, ihres chronischen Verlaufs und ihres deutlich negativen Einflusses auf die Lebensqualität und die Lebenserwartung, bedürfen Patienten mit chronischer Pankreatitis einer angemessenen Diagnostik und systematischen Therapie.

Key words

pancreas - chronic pancreatitis - guideline

Schlüsselwörter

pankreas - chronische Pankreatitis - leitlinie

The present guidelines were compiled by the German Society of Gastroengerology, Digestive and Metabolic Diseases (Guideline coordinators: Prof. Dr. M. M. Lerch MD, Department of Medicine A, University Medicine Greifswald; Prof. Dr. J. Mössner MD, Department of Gastroenterology and Rheumatology, University Hospital Leipzig).

The following Professional Associations/Organisations participated in compiling these guidelines:

• German Society for General and Visceral Surgery (DGAV)

• German Society for Internal Medicine (DGIM)

• German Society of Pathology (DGP)

• German Society for Paediatric Gastroenterology (DPGE)

• Austrian Society for Gastroenterology and Hepatology (ÖGGH)

• Swiss Society of Gastroenterology (SGG)

• Swiss Society of Visceral Surgery (SGVC)

• Working Group of Pancreatectomy Patients

• German Pancreas Aid

• German Radiology Society (DRG)

• bng German Association of Private-practice Gastroenterologists

Scope and validity of the guidelines

The recommendations of these guidelines are intended primarily for specialists involved in the diagnostics and treatment of pancreatitis patients in hospital and outpatient settings. The guidelines are intended to impart knowledge in the context of continuing education and shall serve to achieve optimal medical care of patients. Further, the guidelines provide those suffering from chronic pancreatitis with information about their disease. The guidelines are intended to facilitate decision making regarding diagnostic and therapeutic measures. Nevertheless, disease severity and manifestation must always be assessed individually for each patient, and the patients’ general health status shall be considered in any further steps taken. Deviations from the recommendations of the guidelines are possible and may be required in individual cases. The guidelines are valid for five years and were originally published in German (Z Gastroenterol. 2012;50:1176 – 224, reference 486).

Working group members

The compilation of the different topics was undertaken in various working groups. The individual working groups and their members are listed in [Table 1]. The heads of the working groups are highlighted in bold letters.

Table 1 Members of the Working Groups.

working group 1 “Function Tests”

head: Jutta Keller, Hamburg

head: Matthias Löhr, Stockholm/Sweden

Philip Hardt, Gießen

Joachim Mössner, Leipzig

working group 2 “Imaging Techniques”

head: Jürgen Riemann, Ludwigshafen

head: Andreas Schreyer, Regensburg

Christoph F. Dietrich, Bad Mergentheim

Michael Gebel, Hannover

Michael Jung, Mainz

Uwe Will, Gera

working group 3 “Aetiology and Follow-up/Monitoring”

head: Helmut Michael Friess, Munich

head: Julia Mayerle, Greifswald

Jürgen Kleeberg, Berlin

Jörg Kleeff, Munich

Niels Teich, Leipzig

working group 4 “Management of acute episodes”

head: Ulrich R. Fölsch, Kiel

head: Michael Rünzi, Essen

Jürgen Freise, Mülheim an der Ruhr

Bernhard Glasbrenner, Münster

Peter Malfertheiner, Magdeburg

Claus Niederau, Oberhausen

Alexander Schneider, Mannheim

Emre F. Yekebas, Hamburg

working group 5 “Indications for surgery and interventional endoscopic treatment & treatment of recurrence”

head: Ernst Klar, Rostock

head: Markus Lerch MD, Greifswald

Beat Gloor, Bern/Switzerland

Stefan Kahl, Berlin

Steffen Klabunde, Otterberg

Jutta Lüttges, Hamburg

Horst Neuhaus, Dusseldorf

Bettina Rau, Rostock

working group 6 “Surgical management of chronic pancreatitis”

head: Jakob Izbicki, Hamburg

head: Jens Werner, Heidelberg

Ulrich Adam, Berlin

Markus Büchler, Heidelberg

Thilo Hackert, Heidelberg

Claus-Dieter Heidecke, Greifswald

Ulrich Hopt, Freiburg

Michael Schoenberg, Munich

Christian Wittekind, Leipzig

Helmut Witzigmann, Dresden

working group 7 “Endoscopic and interventional management of chronic pancreatitis”

head: Albrecht Hoffmeister, Leipzig

head: Okka Hamer, Regensburg

Hans-Joachim Schulz, Berlin

Jörg Emmrich, Rostock

Hans Seifert, Oldenburg

working group 8 “Pain management”

head: Wolfram Trudo Knoefel, Dusseldorf

head: Roland Schmid, Munich

Andrea Alexander, Dusseldorf

Roland Pfützer, Cologne

Tim Strate, Reinbek

Matthias Treiber, Munich

working group 9 “Enzyme replacement, nutrition”

head: Peter Layer, Hamburg

Christian Löser, Kassel

Paul Georg Lankisch, Lüneburg

Jutta Keller, Hamburg

Remy Meier, Liestal, Switzerland

Johann Ockenga, Bremen

working group 10 “Paediatrics”

head: Philip Bufler, Munich

Dirk Grothues, Regensburg

Jobst Henker, Dresden

Klaus-Michael Keller, Wiesbaden

Dietrich von Schweinitz, Munich

Heiko Witt, Munich

Methodology

In these guidelines, the level-of-evidence grades are presented according to the Oxford Classification ([Table 2]). The recommendations are expressed to reflect the strength of the recommendations ([Fig. 1]). Exceptions are recommendations which represent a “clinical consensus point” (CCP) and describe good clinical practice for treatment where a higher degree of published evidence is lacking.

Table 2 Classification of evidence according to the Oxford grading system.[1]

level of evidence grade	description
Ia	“evidence” from a systematic review of randomised controlled trials (RCT)
Ib	“evidence” from suitably planned RCTs
Ic	all-or-none principle studies
IIa	“evidence” from a systematic review of well-planned cohort studies
IIb	“evidence” from a well-planned cohort study/low-quality RCT (e. g., < 80 % follow-up)
IIc	“evidence” from outcome research studies
IIIa	“evidence” from a systematic review of well-planned case-control studies
IIIb	“evidence” from an individual case-control study
IV	“evidence” from case series / poor quality cohort and moderate case-control studies
V	expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”

¹ According to the “Oxford Centre of Evidence Based Medicine“, www.cebm.net.

Fig. 1 Conversion of level of evidence into recommendation grades (modified illustration from “Lehrbuch Evidenzbasierte Medizin in Klinik und Praxis” (Text book of evidence-based medicine in clinic and practice), Ed. Kunz et al., Deutscher Ärzte-Verlag 2008, page 367).

The definition of consensus strength was reached by the percentage approval of the consensus conference participants: Strong consensus > 95 %, consensus 75 – 95 %, majority approval 50 – 75 %, no consensus < 50 %.

Further, extensive details regarding the organisational process and the methodological principles of the S3-consensus guideline development process (literature research, classification of evidence and recommendation grades, consensus process, etc.) are referred to in the methodological guideline report.

Basic principles

Chapter 1 – Definition and Epidemiology

1 – 1: Definition (WG1-WG10)

Explanatory note

For centuries the pancreas was a “terra incognita”, hidden behind the stomach, and therefore the pathophysiological role of this organ remained unknown. As recently as 1761, Jean-Baptista Morgagni reported the first autopsy case of chronic pancreatitis and it took another 60 years until Kuntzmann made the connection between fatty stools (steatorrhoea) and a disease of the pancreas. Even in the 21st century, the time period between onset of symptoms and establishing the diagnosis of chronic pancreatitis is disproportionately long. The reason for this is the absence of specific laboratory parameters and the unspecific clinical symptoms which characterise its clinical presentation. The first modern method of establishing the diagnosis of pancreatic disorders in general originated in 1929, when Elman introduced measuring amylase (diastase) levels in serum into routine clinical practise. Following this discovery, Comfort and co-workers succeeded in describing the natural course of chronic pancreatitis from clinical observations, knowledge gained from surgical procedures, and autopsy studies. They reported for the first time an association with long-term alcohol consumption, the frequent occurrence of the disease in the third and fourth decades of life, and typical complications such as loss of the endocrine or exocrine function of the pancreas.

The incidence of chronic pancreatitis increases proportionally with the amount of alcohol consumed in the general population. The incidence worldwide is reported to be between 1.6 to 23 per 100 000 with an increasing prevalence [1]. Although most patients with chronic pancreatitis are treated as outpatients, in 2008 there were 10 267 (ICD-10: K86) hospital admissions for chronic pancreatitis in Germany alone (Federal Statistics Office). This does not include those patients who were coded as having acute pancreatitis including those due to an acute episode of chronic pancreatitis (50 673 cases). This substantiates the high socio-economic significance of the disease. Mortality from chronic pancreatitis is reported to be 12.8 – 19.8 %, with a mean observation period of 6.3 – 9.8 years [2] [3] [4]. Total mortality in the same studies was reported to be 28.8 – 35 %. Continued alcohol consumption results in a significantly reduced survival rate. Thirty-three percent of patients suffering from chronic pancreatitis are no longer able to pursue their profession [5]. The number of patients who leave the workforce and gainful employment due to prolonged illness or continued alcohol consumption, or become who disabled and are forced to retire prematurely during the course of the disease amounts to 40 % [3]. Mortality is increased 3.6 fold in comparison with the normal population. The ten-year survival rate is 70 % and the 20-year survival rate is 45 % in comparison with 93 % and 65 %, respectively, for an age-adjusted cohort. Continued alcohol abuse has a negative effect on the prognosis of the disease with a hazard ratio (HR) of 1.6, continued smoking with an HR of 1.4, and liver cirrhosis with an HR of 2.5 [6].

Many aspects of the pathogenesis of chronic pancreatitis are still unclear. Alcohol is the most important risk factor and the most common cause during adulthood. When children are affected by chronic pancreatitis, a genetic component is often involved. Smoking in itself appears to be an important factor in the onset and progression of chronic pancreatitis [7] [8].

Since the formulation of the first German consensus recommendations [9], understanding of chronic pancreatitis has improved considerably, from its basic principles to its management. This can be attributed to significant advances in the clarification of the pathomechanisms of the disease and a larger number of valid epidemiological observations as well as prospective, in some cases randomised, therapy trials.

The aim of these guidelines is to summarise and evaluate the current level of knowledge with respect to definition, aetiology, diagnostics and management of all types of chronic pancreatitis in adults and children, and to provide this information in a practice-relevant form. The intention of the guidelines is to serve evidence-based professional training and continuing education and on this basis to improve the medical care of affected patients in both the inpatient and outpatient sector.

To do this, a fundamental prerequisite was to confine the guidelines to the clinical presentation of chronic pancreatitis only (acute pancreatitis was excluded). Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy.

Chapter 2 – Aetiology (WG3)

2 – 1: Causes of chronic pancreatitis

Comments

Retrospective case-control studies with sufficient case numbers are available which suggest a causal relationship between alcohol abuse and chronic pancreatitis [10] [11] [12] [13] [14] [15] [16]. In a study from Marseille in 1995, Levy et al. substantiated a logarithmic relationship between the relative risk of developing pancreatitis and the quantity of consumed alcohol and protein. A minimum of 80 g alcohol per day over a period of 6 – 12 years is assumed to be a risk for the development of chronic pancreatitis. It is currently not possible to specify a threshold value. The type of consumed alcohol has no influence on the increased risk. Patients with chronic pancreatitis or cirrhosis of the liver do not differ significantly with regard to the amount of consumed alcohol. An average of 18 ± 11 years elapses between the start of excessive alcohol consumption and the development of pancreatitis. The prevalence of chronic pancreatitis correlates with the amount of alcohol consumed in the general population [12] [17] [18].

Chronic pancreatitis is not caused by cholecystolithiasis or choledocholithiasis. Neither clinical studies nor data from animal studies substantiate a causal relationship for a biliary origin of chronic pancreatitis (however, evidence does exist for acute pancreatitis or, when gallstone disease remains untreated, also for recurrent acute pancreatitis) [level of evidence grade 4]. According to national and international guidelines, there is an indication for cholecystectomy in patients with cholecystolithiasis after an episode of acute pancreatitis [19] [20]. For pathophysiological reasons, it is possible that the disease chronifies after recurrent acute episodes, but this should not occur if the bile duct is cleared of gallstones in a timely fashion. Untreated, microlithiasis/sludge in the common bile duct (CBD) can result in recurrent episodes of pancreatitis. Signs of chronic pancreatitis, such as calcifications or higher-grade ductal changes, have not been reported to date in this context [21] [22].

Primary hyperparathyroidism can lead to chronic pancreatitis, with or without calcifications [level of evidence grade 4]. Case series are available of patients with primary hyperparathyroidism (pHTP) which substantiate an increased rate of pancreatitis (acute and chronic). A causal connection is assumed to exist with elevated serum calcium levels [23]. About 1 % of patients with pancreatitis also have pHTP, and 12 % of patients with pHTP also have pancreatitis [24]. Consequently, patients with pHPT have a 28-fold increased risk of developing pancreatitis. No controlled studies are presently available [23] [24].

Diabetes mellitus type 1 or 2 is not an independent risk factor for chronic pancreatitis. Diabetes mellitus type 3c (pancreoprivic) can be a consequence of chronic pancreatitis [level of evidence grade 4]. Individual case series are available which exclude an association between diabetes mellitus and chronic pancreatitis. The association between chronic pancreatitis and diabetes mellitus type 3c is undisputed. Destruction of the islets of Langerhans by the progressive inflammatory reaction results in the loss of expression and secretion of insulin, glucagon and somatostatin. Thus, diabetes in this case is the result of chronic pancreatitis, not its cause [25].

The discussion about whether pancreas divisum is a risk factor for the development of chronic pancreatitis continues to be contentious. During the consensus conference, a statement was agreed upon with the following wording: The presence of pancreas divisum without any further risk factors tends not to lead to chronic pancreatitis [level of evidence grade 3b]. Pancreas divisum develops from an incomplete fusion of the dorsal (duct of Santorini) with the ventral (duct of Wirsung) excretory duct of the pancreas during embryonic development. As a result, both ducts drain into the duodenum via separate papillae (major and minor duodenal papillae). Pancreas divisum is the most common congenital malformation of the pancreas.

Autopsy studies report the frequency of pancreas divisum to be between 5 and 10 %; it is found in 6 – 26 % of patients with idiopathic chronic pancreatitis [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]. If a further risk factor is present (e. g., alcohol, SPINK-1 mutations) chronic pancreatitis can develop. Cohorts reported in support of an increased risk for chronic pancreatitis in the presence of pancreas divisum were often not examined for other risk factors (e. g., genetic factors). Endoscopic intervention may be appropriate in individual cases. The occurrence of acute idiopathic pancreatitis during childhood should prompt an aetiological search for anomalies of the hepatopancreaticobiliary system [30].

There is no good evidence that a papillary tumour can result in chronic pancreatitis [level of evidence grade 4]. Individual case reports show an association between a papillary tumour and recurrent episodes of pancreatitis; chronification, however, has not been reported. Resection of papillary tumours which trigger pancreatitis episodes normally prevents chronification [36].

Comments

Smoking accelerates the progression of chronic pancreatitis and maybe regarded as a cause of the pathogenesis. Larger, in part prospective, cohort studies involving up to 695 patients show that smoking leads to exacerbation of the pancreatic pain and to calcifications [2] [6] [7] [16] [37] [38] [39] [40] [41] [42]. Even with alcohol abstinence, continued smoking results in a more rapid progression of chronic pancreatitis [39] [40]. The study by Yadav et al. [38] shows that patients without a history of alcohol but with 21 – 35 pack years have an increased risk of chronic pancreatitis (p < 0.05, odds ratio, OR, 3.26) [38]. It is highly probable that future studies will establish smoking as an independent risk factor.

Comments

The three linkage analyses published in 1996 demonstrated a linkage with a locus on chromosome 7q35 for hereditary pancreatitis [43] [44]. Further genetic analyses revealed an association of the disease with mutations in the trypsinogen gene (PRSS1) (initially p.N29I and p.R112H) [43]. Clinical data from the EUROPAC collaborative register substantiate an association between trypsinogen mutations and the occurrence of the disease in patients [45]. Trypsinogen is a key molecule in the pathogenesis of pancreatitis. As many as 66 % of patients with hereditary pancreatitis have a mutation of the PRSS1 gene. The prevalence of hereditary pancreatitis is 0.3 per 100.000 (selection: [43] [44] [45] [46] [47] [48] [49] [50] [51] [52]).

Comments

The meta-analysis of 2431 patients and 4857 controls published in 2008 substantiated with an odds ratio (OR) of 11.0 that the N34S mutation in the gene encoding the serine protease inhibitor Kazal type 1 (SPINK1) is associated with chronic pancreatitis. The OR for idiopathic pancreatitis is reported as 14.97. Further, rarer mutations in the SPINK1 gene are also associated with the development of chronic pancreatitis. An OR of 4.98 for the N34S mutation is calculated for the group of alcohol-induced pancreatitis. Altogether, mutations of the SPINK1 gene occur in as many as 30 % of patients with idiopathic chronic pancreatitis [53] [54], but only in 1 – 2 % of the general population.

Comments

In all case series published to date, there is evidence of an increased risk for idiopathic pancreatitis if a mutation exists in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, yet without clinical signs of cystic fibrosis. Cystic fibrosis (mucoviscidosis), a disease with an autosomal recessive inheritance pattern and an estimated incidence of 1:2500, is characterised (amongst other things) by pancreatic insufficiency and chronic lung disease. Pancreas involvement varies from a complete loss of exocrine and endocrine function to almost normal pancreatic function. Recurrent episodes of pancreatitis are observed in 1 – 2 % patients with unimpaired exocrine pancreatic function but extremely rarely in patients with exocrine insufficiency [55]. In comparison with the normal population, patients with idiopathic pancreatitis have about twice as many molecular changes in their CFTR gene [56] [57] [58] [59] [60].

Comments

Since the first report of mutations of the chymotrypsin C (CTRC) gene in the year 2008 [61], the association of this mutation with idiopathic chronic pancreatitis, alcoholic chronic pancreatitis and hereditary pancreatitis has been reproduced in at least three independent cohorts [62] [63]. Mutations of the CTRC gene occur in 3.3 % of patients with idiopathic pancreatitis. Under experimental conditions, CTRC gene mutations lead to endoplasmatic reticulum stress (ER stress) in acinar cells, which is considered the cause of the cell damage [61] [62] [63] [64].

Summary of the aetiology of chronic pancreatitis

There are no population-based data from Europe on the aetiology of chronic pancreatitis. Alcohol abuse is the predominant predisposing cause during adulthood in 50 – 84 % of the cases, depending on where the study was carried out. The second most common group is idiopathic pancreatitis, accounting for up to 28 % of the cases. Here, genetic susceptibility factors play a role in up to 45 % of cases. Using Comfort and Steinberg’s definition, hereditary pancreatitis is present in up to 1 – 4 % of patients. Anatomical variations do not lead to chronic pancreatitis with any certainty. Primary hyperparathyroidism can lead to chronic pancreatitis. The available figures on the incidence and prevalence are not reliable [level of evidence grade 4].

In addition to the above-mentioned aetiologies, autoimmune pancreatitis was most recently characterized. This is a systemic fibroinflammatory disease in which the pancreas is one of the affected organs. Autoimmune pancreatitis was first reported by Henri Sarles in 1961 [65]; the concept of the clinical entity “autoimmune pancreatitis” was mentioned for the first time by Yoshida et al. in 1995 [66]. The largest comparative study recruited 731 cases [67]. Men are affected more commonly than women (2:1) [68]. In Asia, the prevalence of autoimmune pancreatitis is considered to be 5 – 6 % in a cohort of patients with chronic pancreatitis. About 5 % of patients who underwent surgery for suspected pancreatic carcinoma had histological confirmation of autoimmune pancreatitis [69]. Clinical symptoms include discrete abdominal pain, jaundice (50 %) and recurrent episodes of pancreatitis. Radiological findings include a diffuse or segmental stenosis of the pancreatic duct, frequently without prestenotic dilation, “sausage-shaped pancreas” and, rarely, calcifications. In the Asian patients in particular, increased serum levels of immunoglobulin (Ig) G and IgG4 were found. Lactoferrin and carboanhydrase-II antibodies were also found, albeit rarely and of questionable diagnostic relevance. Increased IgG-4 levels are found in only about 50 % of those affected with auto-immune pancreatitis in the European population. Autoimmune pancreatitis is characterised histologically by a dense periductal lymphoplasmacytic infiltration with obliterative phlebitis and periductal fibrosis (type 1 autoimmune pancreatitis) or granulocytic epithelial lesion (GELSs) in ~45 % of patients (type 2 autoimmune pancreatitis, mostly female, associated with chronic inflammatory bowel disease, no IgG4, rarely recurrent), with similar alterations in other organs. The diagnosis of autoimmune pancreatitis is reached according to the HiSORT criteria, a combination of criteria which include histology, serology, other organ involvement and response to steroid therapy [68] [70]. The diagnosis is confirmed by a rapid response to steroids. As autoimmune pancreatitis is not part of these guidelines, please refer to the literature listed below [65] [66] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78].

2 – 2: Genetic testing in chronic pancreatitis

Comments

As early as 1952, Comfort and Steinberg reported a hereditary form of pancreatitis with an autosomal dominant inheritance pattern [79]. These patients are now recruited to the patient registers EUROPAC and CAPER. An increased risk of developing pancreatic carcinoma is substantiated for patients with trypsinogen (PRSS1) mutations [80]. Work is currently being done to develop efficient tumour prevention strategies for this patient group. An increased cancer risk has so far not been substantiated for mutations in the SPINK1, CFTR and CTRC genes. Knowledge of the genetic cause has currently no clinical consequences for the treatment of the patient. Health-insurance coverage should be discussed with the patient or her/his relatives prior to performing the genetic test. Genetic testing of non-affected family members should not be conducted outside of research projects [79] [81].

Comments

Carriers of a PRSS1 mutation have a cumulative risk of up to 49 % of developing pancreatic carcinoma by age 75 when they suffer from chronic pancreatitis. This risk is significantly higher than for all other known aetiologies of chronic pancreatitis. Despite its reduced penetrance, the autosomal dominant inheritance pattern suggests a causal relationship between PRSS1 mutations and the development of chronic pancreatitis [45] [46] [48] [49] [80] [81] [82]. Which procedure for tumour screening is best suited for this high-risk group is currently being examined.

Comments

There is no provable increased risk of tumour development in patients with mutations in these susceptibility genes compared to other aetiologies of chronic pancreatitis. It may be assumed that these are susceptibility factors which predispose to the disease, but do not trigger it on their own. Even the detection of mutations in these genes does not allow a definite aetiological classification of chronic pancreatitis and does not generally provide any alternative therapeutic options [45] [46] [53] [60] [61].

Chapter 3 – Diagnostic procedures for exocrine insufficiency (WG1)

3 – 1: Definition of exocrine insufficiency

Exocrine pancreatic insufficiency is defined as the functional impairment of pancreatic enzyme and bicarbonate secretion – regardless of the cause. The main causes of exocrine pancreatic insufficiency in adults are chronic pancreatitis, pancreatic carcinoma and previous pancreas resection [83]. Impaired pancreatic function is also expected after (sub-) total gastrectomy as well as in patients with marked protein deficiency or progression of cystic fibrosis (mucoviscidosis). Rare causes include Shwachman-Diamond syndrome, Johanson-Blizzard syndrome and congenital enzyme deficiency, such as trypsinogen, enteropeptidase (enterokinase) or α1-antitrypsin deficiencies, as well as amylase, lipase or other protease deficiencies. Typical symptoms of exocrine insufficiency are abdominal symptoms, steatorrhoea and signs of malnutrition.

Development and clinical features of exocrine pancreatic insufficiency

In principle, the development of steatorrhoea and other symptoms of exocrine pancreatic insufficiency is already to be expected at the time of diagnosis of chronic pancreatitis, becoming more marked from about ten years after appearance of the symptoms of chronic pancreatitis [level of evidence grade 1b–2b].

The moment when exocrine pancreatic insufficiency due to chronic pancreatitis will appear depends on the cause of the disease, among other things. In patients with alcoholic chronic pancreatitis, clinically manifest exocrine pancreatic insufficiency usually appears about 10 – 15 years after development of the first symptoms. In patients with an early onset of idiopathic chronic pancreatitis or a hereditary form of the disease, exocrine insufficiency often does not manifest until after an even longer period [84] [level of evidence grade 2b]. The usually late manifestation of exocrine insufficiency, despite destruction of pancreatic tissue already in the early stages of the disease, is due to the large functional reserve capacity of the pancreas. It is widely agreed that decompensation associated with steatorrhoea and creatorrhoea does not occur until secretion of the corresponding enzymes has been reduced by more than 90 – 95 % [85] [86] [level of evidence grade 1b/2b]. However, there are patients who primarily present with signs and symptoms of exocrine insufficiency, such as malnutrition and/or abdominal symptoms (diarrhoea/steatorrhoea, abdominal distension/meteorism, pain).

Steatorrhoea is a typical symptom of high-grade exocrine pancreatic insufficiency. This may, however, also be missing or have other causes. On the whole, there is no clinical symptom which unequivocally confirms or excludes exocrine pancreatic insufficiency [level of evidence grade 1b-2b]. Clinically, steatorrhoea cannot be reliably detected. Inspection of the stools is also unreliable, even when done by an experienced practitioner [87] [88] [level of evidence grade 2b]. Absence of clinical symptoms of steatorrhoea is even much less reliable; the negative predictive value is only 31 % [89] [level of evidence grade 2b].

Moreover, the possible causes of diarrhoea and other abdominal symptoms are manifold, even in patients with chronic pancreatitis, and exocrine pancreatic insufficiency in patients with chronic pancreatitis is not the only cause of malnutrition; rather, these may for instance be due to a pain-related reduction of nutrition or continued alcohol consumption as well as an increased basal metabolic rate [90].

On the other hand, exocrine pancreatic insufficiency which is not associated with symptomatic steatorrhoea can also have a negative effect on nutritional parameters such as body weight [89] [level of evidence grade 2b]. Moreover, some studies substantiate reduced absorption of fat-soluble vitamins in patients with mild to moderate exocrine insufficiency ([91], 1b/2b, [92] 2b, [93]), and some recent data have documented significantly reduced faecal elastase levels in patients with osteoporotic fracture, which correlates with low vitamin D3 levels [94] [level of evidence grade 3b]. Patients with steatorrhoea were excluded from this study. Hence, there appears to be a clearly increased risk of osteoporosis and fracture even with subclinical, i. e., mild to moderate, exocrine insufficiency.

Relationship between exocrine insufficiency and morphological changes in patients with chronic pancreatitis

Exocrine pancreatic function and morphological signs of chronic pancreatitis usually, but not always, run parallel. Exocrine pancreatic insufficiency is also possible even in the absence of morphological evidence of chronic pancreatitis [level of evidence grade 1b–2b].

Isolated older studies have shown a virtually complete correlation between normal morphology and normal exocrine function, but also severe changes with regard to both parameters [95] [level of evidence grade 1b]. It is also well substantiated that in the majority of patients with chronic pancreatitis, a correlation exists between the extent of morphological and functional disturbances. According to the results of several other studies, discordant findings with varying degrees of morphological and functional changes are found in about one-fourth of patients [87] [level of evidence grade 2b] [96] [97] [level of evidence grade 1b–2b], [98] [level of evidence grade 1b–2b], and the absence of morphological signs of chronic pancreatitis is not to be equated with normal pancreatic function. This is also true even after using highly sensitive examination techniques, such as endoscopic ultrasound, as several recent studies have shown [98] [level of evidence grade 1b–2b], [97] [level of evidence grade 1b–2b], [99] [level of evidence grade 2b]. Even in the presence of normal morphological findings, 28 % of patients examined had exocrine pancreatic insufficiency as verified by measuring enzymatic activity in duodenal contents [100] [101] [level of evidence grade 2b]. In another study, in which endoscopic ultrasound and the secretin test were compared with histological findings as a reference, the sensitivity of endoscopic ultrasound for the diagnosis “chronic pancreatitis” was 84 %, and that of the secretin test 86 %. The specificity of endoscopic ultrasound was higher than that of the secretin test (100 % vs. 67 %), but a combination of the two examination methods produced a sensitivity level of 100 % [102] [level of evidence grade 2b]. Exocrine pancreatic insufficiency despite normal morphological findings appears to exist particularly in patients with the “small duct disease” type of chronic pancreatitis [97] [level of evidence grade 1b-2b].

Comments regarding statements 3 -1- 1 and 3 -1- 2

Measuring faecal elastase levels in a random stool sample is currently the best clinically available and most widely used pancreatic function test in Germany. The following pancreatic function tests are also clinically available: measurement of faecal fat excretion, measurement of chymotrypsin activity in stool, breath test with ¹³C-labelled substrates (preferentially ¹³C-labelled mixed triglycerides), secretin test.

Measuring the quantitative amount of fat secreted in the faeces is rarely performed in Germany nowadays because of the effort involved and the unpleasant procedure of collecting and processing large quantities of stool. The qualitative faecal fat test, on the other hand, is routinely performed in most large laboratories. Breath tests with ¹³C-labelled substrates (preferentially ¹³C-labelled mixed triglycerides) are also available but less well established.

Chymotrypsin activity in stool is rarely used at present.

The Pancreolauryl^® test is no longer available in Germany. As the most exact technique for quantifying exocrine pancreatic function, the secretin-pancreozymin test (or the secretin-caerulein test) is no longer practicable in this form because the only available cholecystokinin analogue Takus^® has been taken off the market. The remaining option, therefore, is to perform a tube test, stimulating only secretin. This normally results in a sharp rise in pancreatic bicarbonate secretion, which is regarded as the most important parameter measured, but enzyme secretion is also somewhat stimulated. However, this examination is not only labor-intensive, requiring insertion of a nasoduodenal tube, it is also expensive. It is therefore confined to specialist centres and strictly selected indications. The endoscopic variation of the secretin test, with repeated endoscopic aspiration of duodenal juices after secretin stimulation, is increasingly favoured in the USA and can in principle be carried out in any endoscopy department with standard equipment. The technique is rarely used, however, because of the long examination time (up to 60 min).

To date, MRI-based techniques are used in an increasing number of studies measuring exocrine pancreatic function. However, an additional, semi-quantitative parameter for assessing exocrine pancreatic function can now be obtained, for example, by determining fluid secretion into the duodenum during secretin-enhanced MRCP (magnetic resonance cholangiopancreatography) to image the pancreaticobiliary ductal system [103] [104] [level of evidence grade 2b], [105].

Sensitivity and specificity of the available pancreatic function tests are listed in [Table 3] [level of evidence grade [Table 3]] see [106].

Table 3 Sensitivity and specificity of the available pancreatic function tests.[1]

test	mild exocrine insufficiency	moderate exocrine insufficiency	severe exocrine insufficiency		level of evidence grade
	sensitivity (%)	sensitivity (%)	sensitivity (%)	specificity (%)
faecal elastase 1	54 %	75 %	95 %	85 % (96 % / 79 %)[2]	1a/b
qualitative faecal fat test	0 %	0 %	78 %3	70 %[3]
chymotrypsin activity in stool	< 50 %	approx. 60 %	80 – 90 %	80 – 90 %	1a/b
13C (mixed triglyceride) breath test	62 – 100 %		90 – 100 %	80 – 90 %	1b/2b

¹ The direct invasive pancreatic function tests (secretin and secretin-pancreozymin tests) were used as reference methods. Sensitivity and specificity are therefore not stated for these.

² Average specificity, in brackets: Specificity for various controls (healthy volunteers/patients).

³ In relation to quantitative faecal fat test.

Comments

The statement is founded on the following (see also Sections 3 – 2 and 3 – 3):

1. In a given case, the initial pancreatic function test provides a basis for a diagnosis because it is rare for patients with chronic pancreatitis to have no pathological findings in their morphological investigations.

2. Even with unequivocal morphological findings which justify the diagnosis of chronic pancreatitis, clinical symptoms (history and inspection of the stools) are unreliable for recognising exocrine insufficiency, even if it is severe and associated with steatorrhoea. These severe forms, however, are reliably detected by all clinically available function tests. The initial exclusion of severe exocrine insufficiency is therefore appropriate.

3. Conversely, the possible causes of diarrhoea and other abdominal symptoms are manifold, even in patients with chronic pancreatitis, and exocrine pancreatic insufficiency in patients with chronic pancreatitis is not the only cause of malnutrition. Rather, this can be due for instance to a pain-related reduction of food intake or continued alcohol consumption as well as an increased basal metabolic rate [90].

Comments

The development of symptoms of exocrine pancreatic insufficiency in a patient with known chronic pancreatitis is possible at any time, even if steatorrhoea usually only develops several years after the appearance of initial symptoms. Mild impairment of exocrine pancreatic function may have clinical significance; this becomes evident from the clinical context [level of evidence grade 2b].

Comments

A significant proportion of patients with type 1 and type 2 diabetes mellitus suffer from exocrine pancreatic insufficiency [107] [108] [109] [110]. This is explained by a deficient insulo-acinar axis [111] and significant exocrine atrophy [112], among other factors. Thus, if relevant signs and symptoms are present, a pancreatic function test is appropriate.

Chapter 4 – Diagnostic imaging (WG2)

The diagnosis of chronic pancreatitis is based on clinical, morphological and functional parameters. Due to the insufficient correlation of the three diagnostic pillars with clinical signs and symptoms, they should be used in a complementary way. Transabdominal ultrasound is regarded as the basic morphological diagnostic technique.

Comments

In the diagnostics of chronic pancreatitis, endoscopic ultrasound has the highest accuracy [113] [114] [115] [116]. In comparative studies with endoscopic retrograde cholangiography (ERC), endoscopic ultrasound achieved comparable results [117] [118]. In a prospective study comparing MRCP with endoscopic retrograde cholangiopancreatography (ERCP) to diagnose malignant tumours, MRCP demonstrated a higher sensitivity (84 %) than did ERCP (70 %), with equal specificity (94 %). Purely diagnostic ERCP should no longer be used because of its higher morbidity and mortality rates. Comparative studies between MRCP and EUS showed a better discriminatory power for endoscopic ultrasound, especially with early forms of chronic pancreatitis [119]. Diagnostic ERCP should only be used in exceptional cases [120] [121] [122] [123] which include unclear cases of suspected autoimmune pancreatitis.

Table 4 Sensitivity and specificity for the individual imaging techniques.

examination	sensitivity	specificity	level of evidence	references
CT	n/a	n/a	2b	[124]
ERCP	70 – 80 %	80 – 100 %	2a	[98] [120] [124] [125] [126] [127]
MRCP	88 %	98 %	2b	[121] [122]
US	60 – 81 %	70 – 97 %	2a	[124] [128] [129]
EUS	80 – 100 %	80 – 100 %	2a	[113] [120] [130] [131] [132]

Comments

There are no prospective randomised studies comparing endoscopic ultrasound (EUS), ultrasound (US) and CT for diagnosing chronic pancreatitis. Prospective comparative studies are only available comparing ERCP with EUS and MRCP with EUS [120] [124] and US with ERCP [133]. It has been shown that EUS is superior to ERCP, especially for assessing early forms of pancreatitis. The only ultrasound study available demonstrated a sensitivity of 81 % for US in comparison with 53 % for ERCP. Some studies substantiate that patients with changes on EUS, but an initially unremarkable ductography in their ERP, demonstrate pathological changes in their ductal system in the form of chronic pancreatitis or demonstrate histological changes of chronic pancreatitis as the disease progresses [131] [134]. In a comparative study with secretin stimulation, EUS vs. ERP revealed similar results (sensitivity 72 % vs. 68 %, specificity 76 % vs. 79 %) [125] [126]. In the first instance, ultrasound should be performed for suspected chronic pancreatitis and, if the result is normal, the higher spatial resolution of EUS will be able to detect any early parenchymal changes indicative of chronic pancreatitis. CT scanning still has an essential role in pre-operative planning [113] [128] [129] [131] [132] [133] [134].

ERCP

Cambridge 0: no pathological alterations on good visualization of pancreatic duct system

Cambridge 1: less than 3 abnormal side branches, main duct normal

Cambridge 2: more than 3 abnormal side branches, main duct normal

Cambridge 3: 3 or more abnormal side branches plus abnormal main pancreatic duct

Cambridge 4: as in 3, plus cysts, duct calculi, duct obstruction (stricture), involvement of adjacent organs

Transabdominal ultrasound:

Cambridge 0: normal organ, duct < 2 mm, regular contour

Cambridge 1: echo-dense gland contour, gland enlarged (up to 1.5-fold), duct < 3 mm, lobular honeycomb appearance

Cambridge 2: contour irregularities, irregular hyperechoic main pancreatic duct > 3 mm, lobular texture with echo-dense septations

Cambridge 3: as in 2, plus cysts, focal calcifications

Cambridge 4: as in 3, plus duct stones, duct obstruction, tumorous enlargement of the gland > 2-fold, splenic vein thrombosis

Endoscopic ultrasound:

Cambridge 0: none

Cambridge 1: lobular honeycomb appearance – duct < 3 m

Cambridge 2: hyperechogenic duct, hyperechogenic foci, hyperechoic contour, duct < 3 mm

Cambridge 3: lobular honeycomb appearance, septated, hyperechogenic foci, duct > 3 mm, irregular duct, no duct calculi

Cambridge 4: as in 3, plus calcifications, duct calculi, cysts

CT/MRCP:

Cambridge 0: none

Cambridge 1: not possible to demarcate duct system on CT/MRCP using current methods

Cambridge 2: Two or more of the following pathological changes:

• pancreatic duct between 2 and 4 mm in the pancreatic body

• mild pancreatic enlargement

• heterogeneous parenchymal structure

• small cystic changes (< 10 mm)

• duct irregularities

• pathological side branches > 3

Cambridge 3: All changes named under 2 plus pathological main duct (> 4 mm)

Cambridge 4: One of the changes named under 2 or 3 plus one or more of the following:

• cystic structures > 10 mm

• parenchymal calcifications

• intraductal filling defects (calcifications)

• duct obstruction (strictures)

• major duct irregularities

Comments

The gold standard for assessing chronic pancreatitis was, until now, ERP using the Cambridge classification [135]. The Cambridge classification and its adaptation for cross-sectional imaging (US, EUS, CT/MRCP) should be used for diagnosing chronic pancreatitis in adults. It still corresponds to the state of the art [level of evidence grade 3a].

The Cambridge criteria for assessing the pancreatic ductal system is still used for ERCP, but only for patients referred for interventional ERP. Non-invasive techniques (ultrasound, CT, MRCP, EUS) are employed for patients with suspected chronic pancreatitis. Whereas the Cambridge criteria only describe the pancreatic ductal system, it is possible to include both the ductal system and the adjacent parenchymal structures with the above-mentioned imaging techniques. These methods employ the criteria of the Cambridge classification to describe the ductal system. MRCP in particular implements the nomenclature of the Cambridge classification [113] [117] [135] [136].

Due to its higher morbidity, ERP, as an invasive diagnostic technique, should be replaced by alternative imaging techniques with identical validity [115] [117] [137] [188]. Randomised comparative studies using ERP and the imaging techniques are only available for EUS and MRCP. Based on comparisons of the individual imaging techniques, it is appropriate to adopt the Cambridge classification for ultrasound, CT and MRCP in order to achieve standardisation of nomenclature [121] [122].

Early changes of chronic pancreatitis are only detectable using EUS. Pathognomonic reporting criteria from comparative studies involving chronic pancreatitis have been compiled which correlate directly with the probability of the disease [113]. Prospective histopathological studies have shown with a specificity of 100 % that EUS is more sensitive than MRCP when more than four criteria are present [113] [114] [116] [117] [118] [119] [120] [121] [122].

Comments

To date, monocentric studies involving elastography have examined patients with space-occupying lesions of the pancreas [138]. So far, two studies have shown that elastography can differentiate well between malignant and benign focal lesions (sensitivity 91.4 %, specificity 87.9 % [139]; sensitivity 100 %, specificity 92.9 % [140]). The study by Saftiou et al. involving 68 patients, however, included only 11 patients with chronic pancreatitis. The study by Iglesia et al. reported 27 patients with inflammatory pancreatic changes, but did not distinguish between acute and chronic pancreatitis. A study by Janssen et al. demonstrated that for chronic pancreatitis, elastography generated images comparable with those for ductal carcinoma. EUS elastography currently has no significance for diagnosing chronic pancreatitis. Patients with chronic calcifying pancreatitis should be prospectively examined by elastography in order to verify the value of this technique in differentiating between focal chronic pancreatitis and pancreatic carcinoma in chronic pancreatitis. There are initial indications that elastography may be helpful in diagnosing autoimmune pancreatitis [141].

The morphological findings of chronic pancreatitis (CP) can be assessed using the following classification systems:

1. Manchester Classification [142]:

* Mild CP: ERP, CT, US, EUS – evidence of chronic pancreatitis, no peripancreatic complications, preserved endocrine and exocrine function; abdominal pain; no regular analgesia

* Moderate CP: ERP, MRT, CT, US, EUS – evidence of chronic pancreatitis, pain despite analgesics, defective endocrine or exocrine function

* Severe CP: as for moderate (with or without abdominal pain), plus: biliary stricture, portal hypertension, duodenal stenosis, as well as exocrine or endocrine insufficiency

2. ABC System (Ramesh, modified according to Büchler) [143] [144]:

* Stage A: Pain, positive imaging on US, ERP, MRT, EUS, no exocrine or endocrine insufficiency

* Stage B: Pain, positive imaging, no exocrine or endocrine insufficiency, plus complications (obstruction CBD, duodenum, pseudocyst, fistula, etc.), but without exocrine and endocrine insufficiency

* Stage C: Pain, positive imaging, with exocrine (C1) or endocrine dysfunction (C2), with or without complications

3. Rosemont Classification based on endoscopic ultrasound [113]:

* In addition to parenchymal changes (hyperechoic foci with and without shadowing, honeycomb-type lobularity, cysts, hyperechoic strands), ductal changes (main pancreatic duct calculi, irregular duct, dilated side branches, hyperechoic duct wall) are also described. Prospective histopathological studies demonstrated that EUS was more sensitive than MRP with a specificity of 100 % if more than four criteria were present [116] [119].

4. M-ANNHEIM Classification [145]:

* Pain, pain control, need of surgery, exocrine insufficiency, endocrine insufficiency, morphology (according to Cambridge criteria), gland complications and imaging based on CT or US or MRT or EUS.

Comments

The Manchester classification conclusively combines imaging findings of chronic pancreatitis with clinical findings and converts them into a simple classification table for chronic pancreatitis [142]. In this system, the dominating criterion for the severity of pancreatitis is evidence of exocrine or endocrine insufficiency and/or evidence of complications. The various imaging findings tend to play a subordinate role with regard to severity. The ABC system of Ramesh and Büchler represents a comparable form of classification [143] [144]. It requires positive imaging for all stages, while the presence of exocrine or endocrine insufficiency and/or complications alone determines the severity of chronic pancreatitis. The Rosemont classification describes the presence of chronic pancreatitis using EUS criteria [113]. The number of presenting parameters correlates with the severity of the chronic pancreatitis. This has been confirmed in histopathological studies. This system does not include clinical findings for evaluation. The M-ANNHEIM classification attempts to characterise patients according to aetiology, clinical stage and severity [145]. The severity of the inflammatory reaction is evaluated using clinical symptoms and therapeutic interventions. At the end of a complex classification system, there is a point system (0 – 25 points) which describes the severity of chronic pancreatitis [145].

All classification systems should be tested in prospective randomised studies for their validity. The target criterion must be the calculation of morbidity and mortality in order to measure the effects of treatment.

The choice of imaging technique depends on the expected complication [level of evidence grades: ultrasound 3a; EUS 2a, CT 4, MRI 3a].

Necroses

Contrast-enhanced ultrasound (CEUS) is capable of detecting necroses to the same degree as contrast-enhanced CT. This is particularly advantageous in patients with impaired kidney function. However, quantification as demanded by Balthazar und Moertele for evaluating the degree of severity is not possible [146] [147]. A US- or CT-guided fine needle biopsy can follow if infected necrosis is suspected. Contrast-enhanced MRT can also detect necrotic pancreatic tissue [148] [149].

Cysts

Larger cysts are easily detectable using transabdominal ultrasound [150] [151]; their criteria are clearly defined (echo-free, tangential artefact, dorsal acoustic enhancement). Findings which deviate from this are referred to as atypical cysts. In this context, cystic neoplasms should be considered in the differential diagnostics and other imaging techniques used.

The highest detection rates for the differentiation of cystic pancreatic lesions are achieved by EUS and MRT/MRCP. Cystic neoplasms can be well differentiated from pseudocysts or peri-intestinal fluid accumulations using EUS und MRT/MRCP. In case of doubt, a EUS-FNA with the asservation of cyst fluid (cytology, lipase and carcinoembryonic antigen [CEA] determination) may follow. There is no comparative literature available.

Pseudoaneurysms

Upon detection of cystic changes within the pancreas, ultrasound should be performed in combination with colour Doppler ultrasonography in order to reliably detect perfusions in the lesion as an indication of a pseudoaneurysm. This should be obligatory before any interventions.

CT angiography and MR angiography are very well suited for identifying pseudoaneurysms. There are no comparative imaging studies available.

Carcinoma

Once chronic pancreatitis has been diagnosed, transabdominal ultrasound and endoscopic ultrasound can only distinguish between carcinoma and inflammation only to a limited degree. In case of doubt, an EUS-FNA should follow; this can raise sensitivity to over 85 % with good specificity [152] [153]. The probability of false negative findings is reported to be between 5 and 10 %, so that given operable findings on images and a suspected tumour, surgery is recommended even without prior cytological confirmation (see Adler et al. [154]).

A sensitivity of 84 % and a specificity of 97 % have been reported for MRT combined with MRCP. A sensitivity of 93 % and a specificity of 75 % have been calculated for differentiating between chronic pancreatitis and pancreatic carcinoma [155]. This does not apply when a carcinoma develops in the presence of chronic pancreatitis. In this case, even after exhausting all diagnostic techniques, sensitivity for detecting a tumour is 67 %, with a specificity of 45 %.

Explanatory note

More recent studies involving CE-US and endoscopic ultrasound show [156] that both necroses and pancreatic carcinoma appear as demarcated hypoperfused focal lesions [139] [140] [157] [158] [159]. In the presence of acute pancreatitis, necrosis may be assumed if positive clinical presentation and laboratory findings are taken into account. In the presence of chronic pancreatitis, imaging may suggest focal necrosis or carcinoma [160] of relevance for the decision for surgery, an EUS-FNA of the focal lesion is appropriate, although a considerable rate of false negative findings is to be expected [161].

Comments

Forty percent of patients with autoimmune pancreatitis present with a focal lesion. The diagnostic accuracy of endoscopic ultrasound for diagnostic classification of a pancreatic lesion using endoscopic ultrasound-guided fine needle aspiration is reported to be 95 % for lesions < 10 mm and 100 % for lesions > 3 cm. According to HiSORt criteria, the cytological/histological diagnosis is the gold standard for establishing autoimmune pancreatitis. If autoimmune pancreatitis is suspected based on imageing or clinical findings, endoscopic ultrasound-guided FNA may be performed [68] [162] [163].

Comments

Either EUS or MRCO, or the combination of both examinations is usually sufficient for diagnosing chronic pancreatitis. ERP carries too high a risk of developing post-ERCP pancreatitis, especially in the early stages of chronic pancreatitis. The rate of post-ERCP pancreatitis is 3.5 % in an unselected patient population. In the majority of cases, post-ERCP pancreatitis assumes a mild course; however, in 10 % of cases, a severe course develops with the possibility of a fatal outcome. Therefore, as a rule, its use for purely diagnostic purposes is not justified.

Four criteria with high sensitivity and specificity were developed for diagnosing autoimmune pancreatitis and for differentiating it from pancreatic carcinoma using ERP: (1) Long stenotic segment > 1/3 of the length of the pancreatic duct, (2) without downstream dilatation of the pancreatic duct, (3) dilatation of the side branches, (4) multifocal strictures along the pancreatic duct all indicate the presence of autoimmune pancreatitis. Japanese guidelines [164] require ERCP for diagnostics; comparative examinations for MRCP are not yet available. Since serological parameters (IgG4, IgG) are of limited informative value in the Western population, diagnostic ERP for establishing autoimmune pancreatitis plays a larger role in Europe than in Japan [165] and remains one of the last indications for Diagnostic ERP in cases where the diagnosis of autoimmune pancreatitis annot be confirmed by other means.

Chapter 5 – Management of acute episodes

Introduction

Especially for the management of acute episodes of recurrent pancreatitis, the same principles are valid as for acute pancreatitis, and less so for typical chronic calcifying pancreatitis. For this reason, the clinically important aspects in the management of acute pancreatitis and its complications will be addressed in the following passage. The acute episode of chronic pancreatitis is one of the most common gastroenterological disorders. The incidence of new cases of acute pancreatitis lies between 10 and 79 per 100 000 inhabitants. There were 50 673 hospital discharges for acute pancreatitis in Germany in the year 2008. Therefore, approx. 1.2 % of the clinical patient population is affected [19]. An increasing incidence has been observed in recent years. Clinical symptoms such as band-like upper abdominal pain and vomiting, together with a rise in serum amylase or lipase levels more than 3-fold above normal, lead to the diagnosis of acute pancreatitis. With serum lipase values below the threefold normal value, the revised criteria of the Atlanta Classification of 1994 (publication pending) suggest the use of an imaging technique to establish the diagnosis (e. g., contrast-enhanced CT). The most common cause of an acute episode of chronic pancreatitis is continued alcohol abuse or dietary factors. In terms of severaty, two forms of acute episodes of chronic pancreatitis can be distinguished, the development of which is independent of the aetiology of the disease: acute interstitial oedematous pancreatitis (75 – 85 %) with a mortality rate below 1 % and acute haemorrhagic necrotising pancreatitis (15 – 25 %) with mortality between 10 and 24 %. It is essential that patients with acute pancreatitis be treated in the hospital on an in-patient basis to ensure adequate care. Frequent requirement for follow-up assessments of the clinical findings, of laboratory parameters and the imaging results make optimal out-patient care virtually impossible. At the time of admission to the hospital, it is usually difficult to differentiate between the majority of patients with a mild and uncomplicated course (about 80 %) and those patients with a severe course, which is usually burdened by multiple organ complications (about 20 %). Apart from the physical examination by an experienced physician, various parameters have been identified to allow an assessment of the prognosis: A complicated course can usually be expected in patients with three or more signs of organ complication, e. g., in the Ranson or Imrie score, or with clinical signs of a systemic complication (e. g., respiratory or renal failure), or with the identification of pancreatic necrosis on the contrast-enhanced CT scan. Currently, C-reactive protein (CRP), haematocrit and persistent (> 48 hours) organ failure are considered to be parameters of high prognostic significance for predicting the degree of severity of acute pancreatitis.

Treatment

Comments

The crucial therapeutic measure in the treatment of acute pancreatitis (and the most common treatment error if not undertaken) is adequate fluid replacement. A Japanese retrospective analysis demonstrated that mortality in a patient group with acute pancreatitis was 61.2 % if less than 3.5 litres of fluid had been infused in the first 24 hours of hospitalisation [166] [167] [168]. Acute prerenal kidney failure within the first 48 hours after admittance to hospital correlated with increased mortality. Every increase of serum urea levels by 5 mg/dl raises mortality by a factor of 2.2 [169] [170]. However, the excessive administration of fluid results in local complications and global respiratory failure. In order to establish adequate fluid replacement, the clinical course using two regimens of fluid replacement were examined in a prospective randomised study involving patients with severe acute pancreatitis (APACHE-II score > 14). One group received 10 s–15 ml/kg/h until the fluid deficit was corrected, measured by fulfilling two or more of the following criteria: heart rate < 120/min, mean arterial pressure 65 – 85 mmHg, urine output > 1 ml/kg/h, haematocrit < 35 %. The second group received less fluid replacement with 5 – 10 ml/kg/h. In the group receiving 10 – 15 ml/kg/h, 94.4 % of the patients had to be artificially ventilated in comparison with 65 % in the group with 5 – 10 ml/kg/h. Mortality in the group which received the greater volume was significantly increased, as were local complications such as abdominal compartment syndrome or sepsis [164]. If invasive monitoring of fluid deficit is not possible, then treatment with 5 – 10 ml/kg/h can be recommended [level of evidence grade 1b, recommendation grade A]. Volume administration should, if possible, be regulated by a thermodilution system. Neither haematocrit nor CVP have proven adequate for assessing volume deficit. Based on the findings of the VISEP study on sepsis management, crystalloid solutions – not colloids such as hydroxyl ethyl starch (HES) – should be used for fluid replacement [171]. There is a general consensus (international guidelines) that rapid and adequate fluid replacement is important for the prognosis [19] [166] [167] [172] [173].

Comments

The insertion of a nasogastric tube is indicated as prophylaxis and therapy for a paralytic ileus. However, today the idea of ‘resting the pancreas’ by nasogastric suction of gastric juices is obsolete [174] [175] [176] [177].

Comments

Controlled studies on stress ulcer prophylaxis are not available. Prophylaxis is generally recommended.

Comments

Patients with an acute episode of pancreatitis often suffer from extreme visceral pain. Adequate analgesia is therefore one of the most important and often most urgent aims of treatment. The argument that morphine possibly causes contraction of the duodenal papilla, thus creating an additional obstruction for pancreas secretion, is obsolete according to the current state of knowledge [level of evidence grade 2b]. Today, we know that this effect either does not occur with the majority of analgesics of this group or is so insignificant that it plays no clinical role. Some morphine-analogue analgesics are successfully used for pain control in acute pancreatitis. Tramadol, which is very popular for reasons of controlled-substance legislation, often causes nausea and vomiting in patients with acute pancreatitis, so that its use in this disease is not to be recommended. Some centres have meanwhile achieved good results with the use of thoracic epidural analgesia (EPA). This often not only results in rapid analgesia in the patients, but in addition prevents or treats paralytic ileus. The prerequisite for the use of EPA is that the patient is alert and responsive and that no manifest coagulopathy is present [178] [179] [180] [181] [182].

Comments

Fasting has a positive effect on the course of paralytic ileus, which can occur as a consequence of acute pancreatitis. In addition, many patients subjectively experience fasting as a relief from their nausea, vomiting and pain. According to more recent studies, fasting has no positive effect on the clinical course or prognosis of acute pancreatitis itself. Above all, the notion that the pancreas needs to be “rested” by fasting is now regarded as obsolete. Both experimental and clinical studies have convincingly substantiated that exocrine secretion is blocked during the course of pancreatitis, making the suppression of secretion as a therapeutic principle pointless [183]. Therapeutic reversal of the secretion block in pancreatitis would be, at least in terms of pathophysiology, a more promising treatment approach. Enteral tube feeding is superior to parenteral nutrition in acute pancreatitis.

Ten prospective randomised clinical studies [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] have meanwhile demonstrated that enteral nutrition is superior to parenteral nutrition in acute pancreatitis. The reasons for this not only lie in the cost of parenteral nutrition (six times more expensive than enteral tube feeding), but above all in the complications of parenteral nutrition. Apart from the risk of an additional source of infection from the central venous catheter, animal studies have shown the development of intestinal villous atrophy within a few days of exclusively parenteral nutrition, which then facilitates bacterial translocation into the adjacent parenchymatous organs. In patients with necrotising pancreatitis, the translocated bacteria preferentially colonise pancreatic necrosis and can cause one of the most feared complications of pancreatitis: infected necrosis or pancreatic abscess. Enteral nutrition administered via a nasojejunal tube oralternatively via a nasogastric tube (shown by most recent studies to be equally effective) counteracts translocation and has proven itself as an alternative to parenteral nutrition [194] [195] [196] [197]. The administration of the total caloric requirement via an enteral nutrition tube is not possible in all patients with necrotising pancreatitis and additional intravenous supplementation is occasionally required to prevent catabolism. Nevertheless, enteral calories should be administered whenever possible to prevent intestinal villous atrophy. All those who question this paradigm shift in the treatment of acute pancreatitis should note that in none of the studies on enteral nutrition in patients with acute pancreatitis was a clinically relevant disadvantage associated with this treatment method as opposed to full parenteral nutrition. Imrie et al. demonstrated that the rate of pulmonary complications is significantly reduced by enteral nutrition [195].

Comments

New prospective studies on the use of intensive-care procedures specific to pancreatitis do not exist. A multicentre study on the role of the PiCCO thermodilution method for monitoring volume in acute pancreatitis has already begun [198].

Comments

More recent studies indicate that eating can have a positive effect on the course of mild acute pancreatitis in comparison with fasting. Resuming eating, which should begin as early as possible in the pain-free patient, can start with easily digestible food. In a multicentre cohort study on symptom relapse in acute pancreatitis, Lévy et al. were able to show that about 20 % of patients suffer recurrence upon resuming eating, and that the probability of recurrence depends on the extent of necrosis, i. e., the severity of the pancreatitis [199]. A meta-analysis, which includes all three of the studies published on this topic (274 patients), confirms this result [200]. The value of so-called pancreas diets or bland diet for pancreas patients is not only completely unproven – they are also hardy palatable for normal taste buds. A recently published randomised trial suggests not to prescribe complete fasting for mild acute pancreatitis [201]. This produced a reduction in the length of hospital stay and a more rapid reconvalescence. The work by Teich et al. confirms this therapeutic approach [202].

Comments

Studies were unable to show that nasojejunal tube feeding is superior to nasogastric tube feeding [193] [194] [201] [203] [204]. The two methods are therefore to be regarded as equally applicable, and the choice depends on local and patient-related circumstances. The superiority of enteral over parenteral nutrition has already been elucidated above.

Comments

The significance of immunonutrition is currently unclear, although its cost is clearly higher. Studies have not been able to substantiate an unequivocal or favourable effect on the disease course [205] [206] [207] [208].

Comments

A mild course of the disease does not require antibiotic prophylaxis. The attitude toward treating acute pancreatitis with antibiotics has changed several times over the past years. More recent studies have convincingly shown that a blanket approach to antibiotic prophylaxis does not offer any advantages and only contributes to the selection of resistant organisms. On the other hand, patients with proven infected pancreatic necrosis profit considerably from antibiotic treatment. The most recent meta-analysis of prophylactic antibiotic administration, which also includes the data of the most recent “Meropenem Study” by Dellinger et al. [209] and thus incorporates seven studies with a total of 467 patients in the analysis, found no change in the rate of infected necrosis [210]. Total mortality was also not significantly reduced in the antibiotic therapy group.

In the severe forms of the disease, numerous studies and meta-analyses were unable to substantiate a significant advantage of antibiotic prophylaxis as a matter of principle with regard to extrapancreatic infection, infected pancreatic necrosis and mortality. A significant advantage with regard to infected necrosis was demonstrated for the beta-lactam antibiotic imipenem, but not, however, with regard to mortality. All studies had methodological weaknesses, the foremost of which was inadequate study power. Given the high mortality rate of the severe necrotising form of the disease, the administration of antibiotics which penetrate infected necrotic tissue in the pancreas (e. g. beta-lactams, chinolones, amongst others) is assumed to be beneficial in this subgroup due to their ability to reduce mortality [209] [210] [211] [212] [213] [214] [215] [216].

Comments

Probiotics are living microorganisms said to have a number of positive effects on health. Olah and colleagues conducted two randomised controlled studies on the prophylaxis of infected necrosis in patients with acute pancreatitis. Both studies substantiated that the use of probiotics lowers the incidence of infectious complications [186] [217]. All the more surprising, therefore, were the results of the PROPATRIA study of the Dutch Pancreatitis Study Group. In a double-blind placebo-controlled study involving 298 patients with severe acute pancreatitis, the authors observed that the administration of a probiotic preparation (Ecologic 641: Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus salivarius, Lactococccus lactis, Bifidobacterium bifidum and Bifidobacterium lactis) did not result in a significant reduction of infectious complications, but rather in a significant increase in mortality, caused predominantly by intestinal necrosis in the verum group [218] [219]. The administration of probiotics for the treatment of acute pancreatitis should therefore cease until further studies have clarified the reasons behind this finding [218] [220] [221].

Comments

Laboratory parameters alone, such as procalcitonin, cannot confirm necrotic infection. Physical examination, laboratory parameters and contrast-enhanced CT together can usually provide sufficient evidence for assuming infected necrosis and to initiate appropriate (mostly antibiotic) treatment. Confirmation by fine needle aspiration is possible, but usually not required and not overly sensitive [19] [173] [222].

Comments

A surgical approach for acute necrotising pancreatitis is only indicated for confirmed infected necrosis and not for sterile necrosis. Over the last two decades, the therapeutic concept has changed from an aggressive surgical approach to conservative interventional management. Originally, the indication for necrosectomy was established once multiple organ failure had occurred. This approach was associated with a mortality of 65 %, which cast doubt on the benefit of the surgical approach in this situation. Even in the year 2003, the mortality rate of open necrosectomy was 47 % [223]. Open necrosectomy should therefore be avoided whenever possible because the surgical trauma induces a SIRS, which is difficult to contain [224]. A study by Mier et al. substantiates that a surgical approach within two weeks after onset of disease is associated with significantly higher mortality [225]. A combined conservative and interventional approach is at least equal to the surgical approach, even in the presence of infected necrosis [226]. Over the past few years, a number of studies have shown that minimally invasive therapeutic approaches such as percutaneous drainage or laparoscopically assisted necrosectomy provide very promising results [227] [228]. The minimally invasive “step-up approach” results in a significantly better clinical course, as shown in the PANTER study (combined endpoint: mortality and severe complications) [229]. Transgastric or transduodenal endoscopic necrosectomy can be regarded as a new and much less invasive therapeutic approach. To date, approximately 250 treatment cases have been reported in the literature. The indication was either confirmed infected necrosis or pancreatic abscess. The technical success rate in these highly selected patients was 92.1 %, with complications such as colonic fistula, haemorrhage, prosthesis dislocation, pain after more than 24 hours, perforation or gravitation abscess being reported in 19.6 % of cases. Mortality in this patient group was 5.6 %, long-term treatment success was 81.2 % and the median number of interventions was 2.3 [230] [231] [232] [233]. On the whole, this procedure is a very promising therapeutic approach given the correct indication and ideally 4 weeks after onset of disease [221] [226] [229] [234] [235] [236] [237] [238] [239] [240] [241].

Chapter 6 – Indications for interventional or surgical treatment

The band-like upper abdominal pain is the cardinal symptom of chronic pancreatitis, together with weight loss, steatorrhoea and diabetes mellitus. In the absence of causal therapeutic approaches, treatment is restricted to symptom control by means of enzyme replacement, pain therapy and optimal control of endocrine insufficiency. 30 % to 60 % of patients develop complications such as strictures of the common bile duct, inflammatory space-occupying lesions, pancreatic pseudocysts, or pancreatic ductal stones, which require interventional or surgical treatment. The following deals with the indications for treatment.

Comments

The severe pain of chronic pancreatitis requiring opiate analgesics can be effectively treated by both endoscopic and surgical procedures [level of evidence grade 2b/3b from several studies] [242]. Surgical procedures (drainage) are superior to endoscopic procedures with regard to long-term pain reduction; they are, however, associated with higher mortality but lower morbidity. There are 25 studies with a level of evidence grade 2b or 3a available dealing with the treatment of pain from chronic pancreatitis by endoscopy, ESWL, thoracoscopic splanchnicectomy, surgical resection and draining procedures [242]. A direct comparison between surgery and endoscopy was carried out in only two studies with level of evidence grade 1b [243] [244]. Both studies demonstrated an advantage for the surgical procedure in the long term.

Comments

If a space-occupying lesion of the pancreas is present and suspected (resectable) pancreatic carcinoma cannot be excluded, surgical resection should then be performed. Explanatory statement: Without surgery, the life expectancy of patients with pancreatic carcinoma is less than one year; after successful resection the median five-year-survival rate is 20 – 25 % [Level of evidence grade 1a] [245] [246].

Comments

Since exocrine pancreatic insufficiency is usually well treatable with drugs and there are no consistent studies available showing that exocrine pancreatic function is lastingly improved by endoscopic intervention or surgery, surgical or interventional procedures cannot be recommended for the treatment of exocrine pancreatic function.

Virtually no studies on endoscopy exist in this context. The final results of exocrine pancreatic function after a Beger, Kausch-Whipple or Frey procedure are very heterogeneous [247].

Comments

Occasional positive case series exist which demonstrate an improvement of the endocrine metabolic state after resection of a pancreatic carcinoma. Randomised studies showing a positive effect on the endocrine metabolic state after resection for chronic pancreatitis are not available [248]. There was strong consensus that the existing case series do not justify the recommendation for surgery solely to improve endocrine insufficiency. The recommendation was therefore ranked as a clinical consensus point despite the formal level of evidence grade 4.

Comments

Gastric outlet obstruction or duodenal stenosis due to chronic pancreatitis should be corrected by interventional or surgical means [strong recommendation, but only consensus of expert clinical opinion]. Comparative studies are not available addressing whether resection surgery, bypass surgery or endoscopic insertion of self-expanding metal stents offer greater advantages [249] (see Surgical Treatment).

Comments

Endoscopy or surgery should be performed on pseudocysts which have resulted in complications such as gastric outlet obstruction, haemorrhage, pain, cholestasis or vascular stenosis. The surgical procedures to treat pseudocysts tend to have higher success rates, but have the disadvantage of a somewhat higher mortality rate than endoscopic pseudocyst drainage into the duodenum or stomach [recommendation grade B] [151].

Comments

A retrospective analysis of all patients treated with an average observation period of 45 months demonstrated that stent therapy for bile duct obstruction due to chronic pancreatitis does not produce a long-term effect beyond one year [250].

A prospective study showed a much poorer long-term effect of insertion for distal bile duct obstruction when calcifications were present in chronic pancreatitis [251].

Chapter 7: Endoscopic and interventional management of chronic pancreatitis

The natural course of chronic pancreatitis shows that between 30 and 60 % of all patients ultimately require intervention. In at least 30 % of cases, conservative management, supplemented by endoscopic therapeutic interventions, appears to be sufficient. In 10 to 40 % of cases, stenosis of the common bile duct (CBD) developed, which required intervention. A further complication is the development of stenosis of the pancreatic duct. For the latter case, the indication for insertion of an endoprosthesis (stent) has to date not been adequately elucidated. No prospective controlled studies are available which demonstrate a positive effect of stent drainage of a dominant stenosis in the duct of Wirsung. Some studies found that the insertion of a prosthesis into the pancreatic duct can induce secondary changes due to the stent with subsequent fibrosis and stricture [252] [253]. Removal of the obstruction of the pancreatic duct is often effective for pain management in the shorter term, and success rates of between 37 and 94 % have been reported [254]. Metabolic side effects of stent therapy in the pancreatic duct have not yet been studied in the long term. Pancreatic pseudocysts develop as a frequent complication of acute or chronic pancreatitis. A further endoscopic/interventional procedure for treating chronic pancreatitis is extracorporeal shock wave lithotripsy (ESWL) for stones of the pancreatic duct. Before the introduction of ESWL in 1989, surgery was often the only option for removing pancreatic duct stones which could not be removed endoscopically. Several retrospective studies have addressed the question of the clinical benefit of ESWL for pancreatic duct stones (see Statement 7 – 2-5). Endoscopic and interventional treatment of pseudocysts is a procedure commonly used in clinical practice.

7 – 1: Treatment of pseudocysts in chronic pancreatitis

The decision on whom, when and by which procedure pancreatic pseudocysts should be treated has been very controversial in the past. Pancreatic pseudocysts develop as a frequent complication of acute or chronic pancreatitis. The prevalence of pancreatic pseudocysts in chronic pancreatitis lies between 20 and 40 % [255]. Pancreatic pseudocysts occur most often in patients with alcoholic chronic pancreatitis (70 – 78 %) [2]. The second most common cause is idiopathic chronic pancreatitis (6 – 16 %), followed by biliary pancreatitis (6 – 8 %) [256]. Within the first six weeks after an acute episode of pancreatitis, 40 % of the pseudocysts resolve spontaneously, while in 20 % of cases, complications such as infection, displacement of adjacent tissue or adjacent organs, rupture of the cyst or persistent pancreatitis render an intervention necessary. Spontaneous remission of pseudocysts after 12 weeks is very rare, and complications are observed in up to 2/3 of cases. The increase in size of pseudocysts to over 5 cm is associated with the development of complications. If pseudocyst formation becomes symptomatic, either surgery or percutaneous or endoscopic drainage can be performed. All of these procedures demonstrate comparable results regarding technical success and recurrence rate. Thus, endoscopic drainage should be performed, given its lower morbidity [151].

Comments

The literature available on interventional therapy of pancreatic pseudocysts as a form of pain management is very limited, as currently no single randomised study is available. Most of the data is based on retrospective case series [257] [258] [259] [260] [261] [262]. Based on the poor data situation, there are three systematic reviews of the evidence at hand [151] [263] [264]. Compiled studies reported that pain relief was achieved in a large number of patients through surgical, endoscopic or percutaneous drainage techniques. Given that a high rate of pain relief was achieved in these retrospective series (about 80 %), all three systematic reviews came to the conclusion that, although conservative management of chronic pancreatitis also results in pain relief in a certain percentage of patients, percutaneous, endoscopic or surgical drainage is still a more effective form of pain management. It is not possible to derive a significant difference in the comparison of the three procedures from the published data. In summary, however, it may be assumed from what little data there is that pseudocyst drainage improves the pain of the patients. Appropriate randomised controlled studies are urgently needed. The literature currently available on the suitable therapeutic intervention for other complications caused by pancreatic pseudocysts is even more scant. If pancreatic pseudocysts result in obstruction of the bile duct or pancreatic duct, then the pseudocyst should be treated. If cholestasis does not improve after drainage of the pseudocyst alone, then stent placement into the bile duct or a resection procedure may be indicated. This is presented in the relevant sections on the treatment of obstruction of the CBD and pancreatic duct in patients with chronic pancreatitis (see Sections 7 – 2 and 7 – 3).

Further complications which make endoscopic or surgical treatment of the pseudocyst necessary include the following: compression of large abdominal vessels; clinically relevant gastric outlet obstruction or duodenal stenosis; infection of the pancreatic pseudocyst; pancreaticopleural fistula formation, abdominal distension, nausea and vomiting due to the pancreatic pseudocyst.

Endoscopic interventional therapy of a haemorrhagic pseudocyst is associated with a high risk of bleeding. It should therefore be treated surgically.

Comments

Endoscopic procedures of draining a pancreatic pseudocyst are less prone to complications than surgical procedures. Not all pseudocysts are successfully and lastingly treatable by endoscopic pseudocyst drainage alone and therefore require surgery. Studies comparing the two procedures are not available. Efforts should be made to establish an interdisciplinary therapeutic concept [151] [265].

Comments

Pancreatic pseudocysts shown by imaging to be enclosed by a more than 5-mm wall of connective tissue are particularly suited for endoscopic or surgical drainage. In a multivariate analysis, Gouyon showed that a pseudocyst size < 4 cm is the only prognostically favourable factor for spontaneous involution [266]. Bradley et al. demonstrated that untreated cysts larger than 5 cm result in complications (rupture, infection, jaundice, or haemorrhage) in 41 % of cases [267].

Comments

The examiner should select the access route for endoscopic transmural drainage of pseudocysts which, upon endoscopic ultrasound assessment, appears to be the safest. This depends on the size, vessels in the vicinity and location of the pseudocyst. Comparative studies showing the superiority of one endoscopic access route over the other (either through the stomach or duodenal wall) are not available. Experience has shown that transcutaneous drainage carries the risk of persistent cutaneous fistula formation. Furthermore, an existing transcutaneous drain can adversely affect the patient’s quality of life. Hence, if drainage of pseudocysts is indicated, endoscopic transmural drainage is preferred [151] [265].

Comments

Endoscopic ultrasound is a procedure which can best assess the nature of the pseudocyst its wall, content, location and relationship to adjacent blood vessels. Endoscopic transmural drainage should therefore be performed under endoscopic ultrasound guidance to reduce the rate of failed puncture attempts and complications [268]. A direct comparison of the complication rate for transmural needle drainage without ultrasound guidance is not available. However, a higher complication rate must be assumed. For this reason, the recommendation was upgraded to “B”. The success rate for the 1126 published cases of patients with transmural drainage of a pancreatic pseudocyst is reported to be 79.2 %, with the more recent studies reporting success rates well over 85 %, which corresponds to surgical results. The mortality rate in larger series involving over 30 patients was 0.2 %. The recurrence rate is reported to be 7.6 % and the complication rate 12.8 % [151].

Comments

If diagnostic needle aspiration of the cyst confirms an infection of the contents, then drainage of the pseudocyst is indicated. Surgical treatment should be carried out if malignancy is detected. Diagnostic needle aspiration of a pseudocyst with the aid of EUS helps in differentiating between cystic malignancies and pseudocysts. In summary: If EUS-guided needle aspiration of a cyst reveals a CEA > 400 ng/ml, a variably increased or low amylase (lipase) level, high viscosity, mucin or epithelial cells in the cyst contents, then the presence of a mucinous neoplasm must be assumed. It is then usually a mucinous cystic neoplasm (MCN), which is more prevalent in women aged between 30 and 50 years of age, is located usually in the pancreatic tail and demonstrates mural nodules on imaging. The so-called eggshell pattern of calcification is typical. Prognosis after surgery is good, given non-invasive growth. If, however, invasive growth is confirmed, then average survival is 45 months. A malignant lesion may be assumed with a CEA value > 6000 ng/ml. Aspiration biopsy of an MCN differs only slightly from an intraductal papillary mucinous neoplasm (IPMN). IPMN is regarded as a precancerous lesion. Its malignant potential depends on location (main duct or side branch duct) and the size of the lesion as well as its solid parts. An IPMN originating from the main pancreatic duct should always be resected, because in 52 – 92 % of cases, a carcinoma develops from this lesion within eight years. For lesions of the side branch duct, this occurs in 6 – 46 % [269]. Lesions less than 1 cm on MRI or EUS and originating from a side branch duct may be followed-up by imaging after one year. Side-branch lesions which are between 1 and 3 cm in size and exhibit no solid components should be followed up after six months. However, lesions which are larger than 3 cm or exhibit mural nodules or cytology with higher-grade dysplasia must be resected. IPMN can occur as multifocal lesions; in this case, they behave in a more aggressive manner [270]. Without a positive case history, a serous cystadenoma is diagnosed as pancreatitis in 30 % of cystic lesions and virtually never becomes malignant. In this case, aspiration of the cyst is negative for mucin, CEA and amylase. Cytology reveals glycogen-rich epithelium.

Comments

In 1 % of all CT scans of the abdomen, a cystic lesion of the pancreas is discovered as an incidental finding [271]. More than two-thirds of these lesions are dysontogenetic cysts or pancreatic pseudocysts. The prevalence of pancreatic pseudocysts in chronic pancreatitis lies between 20 and 40 %. Of the cystic lesions which are not pancreatic pseudocysts but genuine cystic neoplasms, 30 % are benign serous cystadenomas, 45 % of the resected lesions are mucinous-cystic neoplasms and 25 % intraductal papillary mucinous neoplasms. Solid pseudopapillary tumours or cystic acinic cell carcinoma are less frequently encountered. For classification of the differential diagnosis of cystic tumours in asymptomatic patients, the question of connection to the pancreatic duct (IPMN and pancreatic pseudocysts) and the size of the cystic lesion (indication for resection in the case of IPMN or therapeutic indication for pseudocyst) is essential. Diagnostic needle aspiration of a pseudocyst with the aid of EUS helps in differentiating between premalignant cystic neoplasms, cystic malignancies and pseudocysts.

Surgery is always urgently indicated if malignancy or a precursor of a malignant lesion is suspected, given that a cure can be achieved with a five-year survival rate of 63 % after resection of a malignant cystic tumour [151] [272] [273] [274].

Comments

Whether an ERCP with the attempt of draining the pseudocyst via the papilla should be performed before transgastric or transduodenal pseudocyst drainage is still a matter of controversy. On the one hand, drainage of the pseudocyst via a stent in the pancreatic duct is the “most physiological” form of drainage. Depending on the study, 22 – 57 % of pancreatic pseudocysts have a connection with the pancreatic ductal system [259]. Based on current information, an ERP can precede endoscopic transmural drainage in order to detect a connection with the duct or to exclude rupture of the pancreatic duct (8 % after acute necrotising pancreatitis). Transmural drainage with undetected rupture of the pancreatic duct or a connection of the pancreatic pseudocyst with an obstructed pancreatic duct is less promising with regard to long-term treatment outcome. On the other hand, the success rate of attempted transpapillary drainage lies at a maximum of 60 %. Such an attempt puts the patient at risk of an ERCP-induced pancreatitis, whereas direct transgastric or transduodenal cyst drainage is very effective and is associated with few complications [151] [265]. Peri-interventional antibiotic prophylaxis before ERCP is a requirement if pancreatic pseudocysts are suspected or if they are the indication for ERCP or ERP. Otherwise, the risk of retention of infected contrast medium rises if there is a communication with the pancreatic ductal system. Without antibiotic prophylaxis, the examination-related incidence of infected pseudocysts and pancreas abscesses after ERCP increases [275].

Comments

A relative indication to treat pancreatic cysts is the presence of chronic pancreatitis with pancreatic duct anomalies or pancreatic ductal stones, because in such cases, the rate of spontaneous involutions, even for small cysts, is only a maximum of 10 – 26 % due to the constant inflammatory irritation [151] [265].

Comments

Pancreatic pseudocysts are maintained by pancreatic duct obstruction in the presence of prestenotic duct dilatations or fistulae, if these stenoses block drainage. In these cases, treatment of pancreatic duct obstruction is therefore recommended.

Comments

There are no comparative studies available which compare active treatment of vascular pseudoaneurysms with mere watchful waiting. Nor are there studies examining the best moment for treatment of vascular pseudoaneurysms at different points in time.

Surgical or radiological interventional treatment of pseudoaneurysms is in accordance with current clinical practice.

Comments

A systematic review of case series and case reports exist on this topic [276]. In this study, the success rate of angiographic treatment was 66 %. The complication rate is less than that for surgical treatment and is associated with a shorter hospital stay. The operation should be restricted to patients in good general condition, in whom an operation is also indicated for other complications of chronic pancreatitis.

7 – 2: Treatment of pancreatic duct alterations and pancreatic ductal stones in patients with chronic pancreatitis

In patients with chronic pancreatitis, the pressure in the pancreatic duct is initially increased, regardless of aetiology and dilatation of the duct of Wirsung [277]. An important role in the pathogenesis of pain is ascribed to ductal and interstitial hypertension and possible relative pancreatic ischaemia. The aim of endoscopic and surgical decompression therapy in patients with chronic pancreatitis and pain and/or clinical episodes of acute pancreatitis is to remove the obstruction to the flow of exocrine pancreatic juice. Techniques such as sphincterotomy, dilatation, ESWL and stent insertion have been modified for the pancreatic duct. The endoscopic procedure can precede the surgical procedure. It is an alternative to surgery and is associated with low morbidity and low mortality. Endoscopic interventions do not impair surgery that might be necessary at a later date. Furthermore, clinical success after endoscopic reduction of the intraductal pressure does provide some indication of the later result of surgical drainage or a resection procedure.

Comments

Pancreatic ductal stones are the result and not the cause of chronic pancreatitis or pancreatic duct obstruction. They can, however, lead to a consecutive obstruction of the flow of pancreatic juicefrom the duct and thus maintain pseudocysts or fistulae. They can also cause recurrent episodes of inclammation or contribute to the pain of patients with chronic pancreatitis if the flow of pancreatic juice is obstructed. Under these conditions, treatment of pancreatic ductal stones appears appropriate. There are, however, no studies available which have compared the treatment of pancreatic ductal stones with a sham intervention.

Case series and one meta-analysis are available which show an alleviation of pain after treatment of pancreatic ductal stones; comparative studies involving the spontaneous course or randomised studies, however, do not exist.

Endoscopic treatment appears particularly suited for treating solitary stones and proximal obstructions, but surgical drainage procedures have been shown to be superior for distal obstructions.

The literature contains no comparative studies on endoscopic or surgical procedures vs untreated cohorts or in direct comparison with the natural progression of the disease. In two studies in which endoscopic treatment was compared with surgical operations (drainage), surgical treatment was significantly better with respect to long-term pain reduction [243] [244].

Comments

If there is an indication for treatment according to the conditions named under 7 -2- 1, endoscopic management using dilatation and placement of a stent can be performed. The literature contains no studies involving dilatation of pancreatic duct obstruction in comparison with a sham intervention. In a prospective non-randomised study, rapid improvement of symptoms was achieved by insertion of a pancreatic stent in inoperable patients, although further interventions were frequently necessary [278]. Some studies substantiate that the insertion of a prosthesis into the pancreatic duct can induce secondary alterations due to the stent with subsequent fibrosis and stricture [252] [253]. Removal of the obstruction of the pancreatic duct is effective for the treatment of pain in the short term. Success rates between 37 % and 94 % have been reported. In the largest hitherto examined cohort of 1021 patients, a long-term reduction of pancreas-related pain was achieved in 84 % of cases [279]. However, in 79 % of the patients, stent therapy for pain management had to be repeated within one year and in 97 % of the patients within two years. Metabolic side-effects have not been examined over the long term.

Comments

Benign strictures of the duct of Wirsung can develop as a complication of an impacted stone or as a result of acute inflammatory parenchymal changes with compression or stricture of the duct of Wirsung [280]. The success rate of stent insertion was examined taking the rise in pressure due to the stone into consideration as a cause of pain development and recurrent episodes of chronic pancreatitis [280] [281] [282] [283] [284] [285] [286] [287] [288] [289]. Pancreatic stent placement was technically successful in 308 of 328 patients, and in 66 %, an improvement of symptoms after stent management of a dominant obstruction was reported at follow-up (follow-up observation period: 8 – 39 months). On the whole, those patients profited in whom stones or obstruction had maintained a pancreatic fistula or pseudocyst, or had induced an obstruction or episodes of pancreatitis. Endoscopic drainage with stone extraction and stent therapy is an effective measure to control pain in some patients with dilated duct of Wirsung [261]; it can delay the need for surgery or make it superfluous, and can also provide an indication of the potential effectiveness of a drainage operation [290]. Better pain management, however, was achieved by pancreaticojejunostomy in two randomised controlled studies [242] [243] [244]. Thus, endoscopic therapy reduced pain or provided complete pain relief in 32 % [244] and 65 % [243], respectively, whereas this was achieved in 75 % [244] and 86 % [243], respectively, by pancreaticojejunostomy. The different success rates of endoscopic therapy in the two studies are possibly due to the longer duration of the stent therapy adopted by Dite et al [243].

There are currently no reliable data available regarding the necessary duration of stent therapy [243] [244] [261]. Some authors recommend treatment over one year with an exchange of the stent at least every three months; however, there are no comparative data available on this.

Comments

Individual case reports and small case series suggest that coated self-expanding metal stents may be inserted into the pancreatic duct to treat the pain of chronic pancreatitis. Their advantage over plastic stents lies in their longer period of patency. Long-term results of their benefit are lacking. It is advised not to use uncoated self-expanding metal stents in the pancreatic duct due to the rapid proliferation of duct epithelium as a reaction to the metal mesh [291] [292].

Comments

ESWL can be employed to remove obstructing stones. A meta-analysis demonstrated a significant effect on pain reduction, albeit with a strong heterogeneity of the results [293]. All the studies included in the meta-analysis were case series without untreated or sham-operated control groups.

In a cohort study [294], a better result was reported regarding the technical freedom from stones by using ESWL with subsequent endoscopic stone retrieval, in comparison with ESWL alone. Only one randomised controlled study has been published to date comparing ESWL of pancreatic ductal stones with and without subsequent ERP to remove fragments from the main pancreatic duct. In that study, the subsequent endoscopic stone extraction had no influence on pain relief after two years [295].

Both endoscopic treatment and ESWL alone enable good pain control in some patients [243] [244] [261] [296] [297].

7 – 3 Endoscopic treatment of bile duct obstruction in patients with chronic pancreatitis

In 10 to 44.6 % of cases, obstruction of the common bile duct (CBD) requiring intervention develops in patients with chronic pancreatitis. Indications for endoscopic intervention include significant cholestasis, episodes of cholangitis, prevention of secondary biliary cirrhosis, and differentiation of the cause of pain (obstruction of the CBD vs. chronic pancreatitis). Several studies have assessed the efficacy and cost efficiency of endoscopic drainage of the CBD. Because only 1/3 of the endoscopically treated patients profited long term, endoscopic therapy is only indicated as a transient approach until definitive surgery, as an acute intervention in septic patients, or in inoperable patients or those unwilling to undergo surgery. In principle, there is a risk of developing cholangitis after endoscopic stent placement. The administration of prophylactic long-term antibiotics together with ursodeoxycholic acid to prolong stent patency has not been proven effective in various clinical studies [298] [299] [300] [301] [302]. The commonly occurring complications include stent occlusion by cellular detritus, microcolonies of bacteria, or extracellular, fibrillar material [303].

Comments

Published studies in which endoscopic therapy of cholangitis resulting from mechanical cholestasis is compared with expectant observation are lacking. Treatment of mechanical cholestasis as part of the therapy for cholangitis is important and well substantiated by clinical experience.

Comments

There are no published studies available comparing active treatment of mechanical cholestasis in the context of chronic pancreatitis with expectant observation. The recommendation grade was classified as “grade B” because treatment of mechanical cholestasis appears to be substantiated by clinical experience.

Cholestasis in patients with chronic pancreatitis may be remedied by endoscopic or surgical means, although endoscopic stent therapy is of lasting success for more than 12 months in only one-third of patients. A prospective study showed an even poorer long-term effect of stent management of distal bile duct obstruction in patients with calcifying pancreatitis (long-term effect 9 %) [251]. In these cases, therefore, surgical treatment is clearly preferred. A retrospective analysis of all treated patients observed for an average of 45 months demonstrated that stent therapy for obstruction of the CBD in patients with chronic pancreatitis has no additional effect beyond one year [250]. Surgical treatment should therefore be planned if CBD obstruction reoccurs after one year of stent therapy.

Comments

The placement of multiple plastic stents into the bile duct to treat bile duct obstruction in patients with chronic pancreatitis is superior to both insertion of solitary plastic stents and that of uncoated metal mesh stents. In a prospective, non-randomised monocentric study, the long-term success rate after insertion of 4 to 5 stents into the CBD was higher than after one single stent [304].

Comments

The insertion of coated metallic stents has demonstrated good results in case series. Randomised studies comparing coated metallic stents with single or multiple plastic stents are still lacking [305] [306].

Comments

The insertion of stents into the bile duct is suitable for treating obstruction of the bile duct in patients with chronic pancreatitis and extrahepatic cholestasis. Long-term success, defined as no further need to change the stent every three months without recurrence of cholestasis, is only achieved in about one-third of patients [289] [307] [308] [309] [310]. Stents should be exchanged at least every three months; otherwise, occlusion of the stent could cause cholangitis. The change interval is less critical with the insertion of multiple stents [311].

Comments

Resecting surgical procedures to treat bile duct obstruction in patients with chronic pancreatitis are effective and sustainably successful. The long-term results of the Beger, Büchler, Kausch-Whipple and Frey surgical procedures do not differ from each other with regard to quality of life, exocrine pancreatic insufficiency, endocrine pancreatic insufficiency, pain or recurrence rate [312] [313] [314].

Comments

A multicentre prospective randomised study examined the effect of preoperative endoscopic stent insertion into the CBD for mechanical cholestasis resulting from chronic pancreatitis or carcinoma of the pancreatic head before pancreas resection. A study involving patients with a postoperative pancreatic tumour showed that preoperative drainage significantly increased the rate of complications [315]. Similar data are available from the Heidelberg working group, but have so far only been published as an abstract.

Chapter 8: Pain management

Pain is the leading clinical symptom for 80 – 95 % of patients. Studies on the natural course of the disease show that the intensity of the pain often declines with duration of the disorder (“burn-out of pain”) [40]. In the majority of cases, the reduction of pain intensity correlates with the development of calcifications and the loss of exocrine and endocrine function. In America, the annual cost caused by pain due to chronic pancreatitis amounts to 638 million dollars [316]. The cause of the pain is multifactorial. Pancreas-related causes of pain include inflammatory infiltrates of the parenchyma and nerve sheaths, especially of the sensory nerves. Obstructed flow of pancreatic juice by duct obstruction and stones can produce a rise in pressure. Nevertheless, drainage of the duct or reduction of secretion with the aid of drugs (somatostatin analogues) does not usually result in adequate pain reduction. Increased pancreatic parenchymal pressure causes pain due to tension in the pancreas capsule, similar to the development of pancreatic pseudocysts. Extrapancreatic causes of pain include concomitant and secondary disorders, such as gastric or duodenal ulcers and meteorism, caused by abnormal bacterial colonisation of the intestine in maldigestion.

Comments

There are altogether only two studies [317] [318] available which present validation of a pain scale. The older study [317] assesses a pancreatitis-specific pain score. The following are rated on a scale of 0 – 100: frequency of the pain attacks (0 never, 100 daily), the intensity of the pain on the VAS (1 – 100), the analgesic (100 morphine, 1 acetylsalicyclic acid) and the pain-related absence from work (100: permanent, 0: not in the last year).

The more recent study [318] compares the SF-12 with the SF-36 Quality of Life Questionnaire. Both studies also include aspects of pain which have an effect on the quality of life. An explicit pain score, assessed independently of the quality of life data, is not included in the evaluation. Nevertheless, both the SF-12 and the SF-36 in this study have been assessed as valid, albeit only for the assessment of the quality of life. The pain score published in 1995 is therefore the only validated score explicitly for pain in patients with chronic pancreatitis. Its wider dissemination and above all its use in therapy studies should be pursued.

Comments

The literature contains four randomised controlled studies involving 10 to 40 patients. Unfortunately, the WHO pain management plan was not consistently used in any of these studies. Only the effectiveness of various morphine derivatives was examined. The question regarding the effectiveness of the WHO pain management plan cannot therefore be answered using available literature. Nevertheless, analgesics are clinically indicated to treat patients with pain from chronic pancreatitis in order to achieve pain relief or reduction of pain until definitive treatment (e. g., endoscopic or surgical).

Comments

How long pain therapy can be performed using conservative means and when endoscopic or surgical treatment is indicated cannot be answered from the literature available today.

In general, the majority of authors regard obstruction of the duct of Wirsung as an indication for endoscopic or surgical intervention. However, a retrospective cohort study demonstrated good pain control after pancreaticojejunostomy even in patients without obstruction of the duct of Wirsung [319].

Comments

Conservative pain management of chronic pancreatitis on the whole follows the WHO three-step analgesic ladder, although this was not specifically designed for patients with chronic pancreatitis.

The literature lacks studies showing how this analgesic plan might be de-escalated, for example, after an endoscopic intervention or surgery. It seems logical to follow the WHO three-step analgesic ladder in reverse order, re-assessing the patient’s pain relief at each step. Superiority or inferiority to another graduated plan or to simply discontinuing the pain medication has not, however, been examined.

Comments

Assessing the success of pain therapy is determined by the reduction of pain during therapy. For this purpose, pain quantification is necessary. This has already been addressed in Statement 8 – 1-1. The pain score according to Bloechle et al. [317] is the best validated, precisely because it is able to demonstrate pain reduction achieved by successful therapy.

Comments

Since the pain in patients with chronic pancreatitis is also caused by increased pancreatic parenchymal and ductal pressure, the approach of reducing the amount of pancreatic juice and thus lowering the pressure is pathophysiologically coherent. Apart from numerous single case reports and retrospective case series, a double-blind crossover study [320] and an unblinded crossover study exist comparing octreotide with octreotide long-acting release (LAR) [321]. In both studies, pain was largely measured with the VAS. The double-blind crossover study comparing octreotide with saline administration [320] was unable to detect reduction in pain or analgesic requirement while effectively blocking pancreatic secretion. The unblinded crossover study showed no difference between octreotide and octreotide LAR with regard to pain reduction.

In summary, it may be said that the only study comparing octreotide with saline administration was unable to show a significant reduction in pain, while at the same time a further study showed no advantage of octreotide LAR over octreotide. Thus, the value of octreotide in the treatment of pain associated with chronic pancreatitis remains unproven by studies.

Comments

The rationale behind pancreatic enzyme therapy for pain relief is based on the assumption of a negative feedback mechanism for the release of the cholecystokinin releasing peptide. This in turn leads to a reduced release of cholecystokinin and so to reduced exocrine pancreas secretion. In a Systematic Review of the Cochrane Collaboration published in 2009, ten RCTs with a total of 361 patients were identified which examined the various aspects of the effectiveness of pancreatic enzyme supplements [322]. Six of the studies compared enteric encapsulated preparations with placebo, one compared an unencapsulated preparation with placebo, two examined different preparations, and one study examined different dosage regimens. The heterogeneity of the selected dependent variables and the lack of statistical parameters do not allow the data to be pooled. Three of five studies using a pain score showed a significant reduction in pain; two on the other hand did not. One of four studies which quantified analgesic usage reported a reduction in the consumption of analgesics. Not one single study examined long-term effects of the various types of treatment. The authors reach the conclusion that the use of pancreatic enzyme supplements had no proven positive effect on the symptom of pain or, due to an absence of data, improvement in the quality of life [322]. A randomised controlled study published since then (25 patients verum, 29 placebo) showed no significant effect on pain reduction [323].

Due to the different inclusion criteria, which are in part not clearly explained in the studies, it is not possible to deduce whether the cause of the pancreatitis, the presence of exocrine pancreatic insufficiency or a certain formulation of the preparations used was responsible for the lack of therapeutic success.

Comments

Oxidative stress is a possible factor in the development of chronic pancreatitis. Increased levels of free oxygen radicals have been detected in the serum and pancreatic juice of patients with chronic pancreatitis. Based on this knowledge, treatment using antioxidants could help to reduce cellular damage from pancreatitis and thus prevent pain. One initial study involving patients with recurrent acute and chronic pancreatitis demonstrated a significant improvement in the number of acute episodes as well as in chronic pain, but particularly the latter was only included in the per protocol analysis. In fact, only 20 of the initial 28 patients were assessed [324]. In a further study involving 36 patients, an improvement regarding pain as well as the quality of life was also demonstrated, but here too only 19 patients completed the study [325]. Evaluation of the study leaves important questions open, since a one-sided p-value was employed and the items of the SF-36 questionnaire used were evaluated individually without correcting for multiple testing. In a double-blind placebo-controlled study from India, 71 patients were treated with antioxidants and 56 with placebo over a period of six months. Over the study period, there was a significant reduction in the number of days with pain arising from the pancreas in the verum arm [326]. The study was discontinued before the recruitment target was reached and also demonstrated further methodological flaws. Evidence that antioxidants have a role in the treatment of pain from chronic pancreatitis is therefore still lacking.

Viewed altogether, antioxidants may possibly have a role in pain therapy of CP. However, since in all of the studies mentioned, preparations were used which contain beta-carotene – the administration of which is associated with the development of bronchial carcinoma in smokers when given in combination with retinol or alpha tocopherol, and taking into consideration that the majority of all patients with chronic pancreatitis also smoke – a general recommendation for treatment with antioxidants cannot be made at present [327] [328].

Comments

Information regarding complementary or other new forms of treatment is often only available as case reports. Altogether, only three studies have been identified in which a sufficient number of patients were examined in a standardised manner.

In a randomised study, electro-acupuncture and transcutaneous electrical nerve stimulation (TENS) were each compared with placebo, demonstrating no effectiveness with regard to pain reduction or use of analgesics [329].

Comments

A three-month treatment with the leukotriene receptor antagonist montelukast also showed no significant reduction in pain [330].

Comments

In a pilot study, significant reduction in pain and reduction of acute episodes were achieved with one session of radiotherapy in 12 of 15 patients [331]. Given the increased risk of developing a malignant tumour with chronic pancreatitis, its use appears fraught with risk and thus cannot be recommended.

Comments

The literature contains no randomised controlled trials comparing coeliac plexus block with placebo. On the other hand, meta-analyses exist [332] [333] which examined the efficacy of coeliac plexus block in a large patient population and showed reduction in pain in about 50 % of patients. This pain reduction, however, did not last for more than a few weeks. If pain is the only principal symptom and no significant secondary complications of chronic pancreatitis are detected by imaging, thoracoscopic splanchnicectomy may be undertaken to control the pain. The concept of pancreatic denervation was mentioned for the first time in 1943 by Mallet-Guy. The procedure was rediscovered in 1993 and modified into a minimally invasive procedure by the introduction of video-assisted thoracoscopy. A prospective long-term study was able to demonstrate that adequate pain control was achieved with a perioperative morbidity of 7 % by bilateral splanchnicectomy in patients who respond well to epidural anaesthesia [334]. This study was not randomised and therefore has only a very low level of evidence grade.

A case-control study [335] showed that the results of splanchnicectomy after previous use of opioids are worse than in treatment-naive patients, although thoracoscopic splanchnicectomy showed significantly better results vs. control patients who received purely symptomatic treatment.

In conclusion, it may be said that coeliac plexus block for pain associated with chronic pancreatitis is only effective in the short term (a few months) and is clearly inferior to surgical management. Splanchnicectomy is, to a certain extent, a modification of coeliac plexus block, which can be performed by thoracoscopy. Although there is a paucity of data, it showed good results in individual cases. The indication for coeliac plexus block can only be pursued in patients who cannot be given reliable, effective, long-term pain control. This means that in patients who are in an inoperable state for pancreatic surgery or have an unfavourable prognosis due to their general condition, coeliac plexus block may be undertaken. Nevertheless, the coeliac plexus block is only effective for a few weeks to months.

Comments

Randomised controlled studies are available comparing endoscopically guided with CT-guided plexus block indicating superiority of the endoscopic ultrasound guidance [336].

Studies also exist on the question of an endoscopic ultrasound-guided plexus block with one or two injections (no significant difference) [337], as well as the comparison of a coeliac plexus block vs. pancreaticogastrostomy (superiority of the surgical procedure) [338] and endoscopic ultrasound guidance vs fluoroscopy for coeliac plexus block (superiority of the endoscopic ultrasound guidance) [339]. Endoscopic ultrasound guidance appears to be better suited for coeliac plexus block than CT-guided plexus block, with 30 % of patients still profiting from it after 24 weeks as opposed to 12 % after CT-guided injection [336]. Whether one or two injections should be given appears irrelevant in terms of pain relief [337]. As the oldest technique for coeliac plexus block, fluoroscopy on the other hand is clearly inferior to endoscopic ultrasound guidance [339].

Furthermore, a cohort study examined the central single endoscopic ultrasound-assisted plexus block in comparison with the bilateral approach [340]. This showed that pain reduction after bilateral injection was better after seven days than after the central single injection (70 vs. 46 %). With more institutional experience with CT-guided coeliac plexus block, this may be regarded as an alternative technique.

Comments

Two randomised controlled studies achieved better pain management by surgical treatment involving a pancreaticojejunostomy than by endoscopic treatment [243] [244] [341]. Thus, endoscopic therapy yielded pain reduction or complete pain relief in 32 % [244] and 65 % [243], respectively, whereas this was achieved by pancreaticojejunostomy in 75 % [244] and by resection in 86 % [243].

Chapter 9 – Enzyme replacement for chronic pancreatitis

The indication for pancreatic enzyme replacement therapy is clinically given by the weight loss of more than 10 % of the body, weight, steatorrhoea with faecal fat excretion of more than 15 g/d, dyspeptic symptoms with severe meteorism or diarrhoea. The majority of enzyme supplements contain pancreatin, a pulverised extract from porcine pancreas, with the main components being lipase, amylase, trypsin and chymotrypsin. Pancreatin is not absorbed from the gastrointestinal tract, but is inactivated by enteric bacteria and digestive secretions, and eliminated in the faeces. The option of a gastric-acid-protected administration as encapsulated microsphere formulations has clearly improved efficacy of pancreatic enzyme replacement. The measure of success of treatment is improvement of the disease symptoms.

Chapter 9 – 1: Enzyme replacement for chronic pancreatitis

Comments 9 -1- 1 and 9 -1- 2

The indication for pancreatic enzyme replacement is established for steatorrhoea with faecal fat excretion of more than 15 g/day. Since the quantitative measurement of faecal fats is often no longer performed, the indication for replacement is also present with a pathological pancreatic function test in combination with clinical signs of malabsorption [90] [342] [343] [344]. This includes weight loss and abdominal pain with dyspepsia, severe meteorism or diarrhoea. Conversely, pancreatin is also to be supplemented if faecal fat excretion is pathological (> 7 g/day) without reaching the critical value of 15 g/day, yet the above-mentioned clinical signs of malabsorption are present [90]. Therapy with pancreatin purely as a trial for 4 – 6 weeks may also be beneficial if symptoms are unclear.

Comments

Untreated severe exocrine pancreatic insufficiency results in a severe malabsorption syndrome, which in the long term is not compatible with life. Clinically, this manifests itself mainly in the form of steatorrhoea, deficiency of fat-soluble vitamins together with its sequelae, and weight loss, even to the extent of cachexia [85] [86] [92] [93] [345]. Malabsorption can also lead to abdominal complaints such as diarrhoea/steatorrhoea, abdominal distension/meteorism and pain.

Among other things, these may be due to intestinal motility disorders caused by maldigestion and malabsorption [343].

Comments 9 -1- 4 and 9 -1- 5

The disappearance of clinical signs of malabsorption is the most important criterion for the success of pancreatic enzyme therapy and is associated with an improvement of the quality of life [346]. If the symptoms do not, or only partially, respond, this may also be due to other pathomechanisms. Several studies have shown that breath tests with ¹³C-labelled lipids provide a good measure of fat digestion and faecal fat excretion and are therefore suitable for monitoring the effectiveness of pancreatin therapy [347] [348] [349]. Success of replacement therapy cannot be assessed by measuring the faecal concentration of elastase, because only the natural human enzyme and not the therapeutically administered enzyme contained in pancreatin are measured. Faecal chymotrypsin excretion does not provide any information about the effect enzyme replacement therapy has on nutrient digestion and nutrient absorption; it can, however, be used to test for compliance (low values correspond to inconsistent intake).

Comments

The effectiveness of pancreatic enzyme supplements presupposes the mixing of pancreatin and chyme. If more than one capsule/tablet per meal must be taken, it may be beneficial to take one part of the dose immediately at the beginning of and the rest distributed during the meal [86] [350].

Comments

Lipase activity in particular is irreversibly destroyed at pH values below 4 [351]. Such low values are present in the stomach during most of the postprandial period and, in patients with exocrine insufficiency, also in the duodenum due to limited bicarbonate secretion [86]. Without concomitant acid suppression, preparations with acid protection lower faecal fat excretion more than those without [352].

Comments

This critical value is in principle only relevant for patients with a preserved pylorus [353]. However, small particle sizes can facilitate and/or accelerate gastric emptying and/or release of enzymes, even after distal gastric resection.

Comments 9 – 1-9 to 9–1-13

The clinical efficacy of pancreatin preparations is determined by the administered dose, the time of intake, acid protection and size of the pancreatin particles, specific biochemical properties of the preparation (which depend on its origin), as well as past and concomitant disorders of the patient to be treated. The latter refers to, for example, postoperative conditions with alterations of the gastrointestinal anatomy (e. g., after gastric resection) as well as complementary therapy with certain medications (e. g., treatment with proton pump inhibitors in patients taking non-steroidal antirheumatic agents) [323] [342] [348] [350] [352] [353] [354] [355] [356] [357] [358] [359]. The recommended initial dose is about 5 – 10 % of the cumulatively secreted lipase activity into the duodenum after a normal meal [360] and should therefore suffice to prevent malabsorption and steatorrhoea [85]. Clinical experience shows, however, that a doubling or tripling of this dose is necessary and helpful in some patients. If secretion of gastric acid is suppressed, then unprotected pancreatin can be administered. This is often particularly beneficial because it immediately takes effect once the protective coating has dissolved.

Patients with chronic pancreatitis frequently have an abnormal bacterial colonisation [361]. This may be considered a possible cause of persistent symptoms and other disturbances, if the above-mentioned measures are not successful.

Comments

Pancreatic enzyme products from cattle are a theoretical alternative, but in practice this is irrelevant due to their low lipase activity. Preparations with fungal (Rhizopus oryzae, Aspergillus oryzae) enzymes have less favourable biochemical properties (higher acid stability, but rapid deactivation in the presence of low bile acid concentrations) and are therefore of only limited clinical applicability. Bacterial enzymes and human lipase produced using gene technology are not yet relevant in the treatment of exocrine pancreatic insufficiency. Even in religions which reject the consumption of pork, the use of porcine pancreatic enzymes is permitted as a medical therapy (e. g., Koran, Sura 5, Verse 1). The patient should, however, be made aware of the origin of the preparations.

Comments 9 – 1-15 and 9 – 1-16

Primarily one working group has reported the very rare (< 0.1‰) development of fibrosing colonopathy with the risk of ileus after the administration of extremely high doses of pancreatin in children with cystic fibrosis [362]. A causality has not been established and is considered improbable [363] [364] [365] [366]. On the whole, such high doses are not necessary anyway in patients with exocrine pancreatic insufficiency based on chronic pancreatitis (see above). In particular, adjuvant acid suppression and/or treatment with alternative or additional means (if necessary) should be considered in the event of patients becoming refractory to the above standard doses.

Comments

Patients with chronic pancreatitis and associated diabetes mellitus may encounter more significant problems with controlling their blood sugar levels if pancreatin therapy is initiated or discontinued. This includes emergency situations requiring treatment: In a study by O’Keefe et al. symptomatic hypoglycaemia developed during placebo treatment and ketoacidosis after recommencing pancreatin therapy [367].

Chapter 9 – 2: Nutrition for patients with chronic pancreatitis

Comments on 9 - 2-1 to 9 – 2-3

Malnutrition and underweight in patients with chronic pancreatitis are associated with increased mortality [368] and are therefore to be avoided as far as possible. For this purpose, patients with exocrine insufficiency usually require a combination of enzyme replacement therapy (see above) and adequate medical nutritional treatment. It should be noted that some of the patients have an increased basal metabolic rate [369]. Given the grave sequelae from malnutrition in patients with chronic pancreatitis, a recommendation grade A was given with strong consensus.

Comments

A normal balanced, sufficiently isocaloric diet according to the patient’s preferences is recommended; there is no established specific pancreas diet [90]. Provided it is well tolerated, adequate fat intake should be ensured. Data from animal studies indicate that diets with a high fat and protein content plus adequate enzyme replacement can improve the effectiveness of fat absorption [370].

Comments

Fat is important as a central source of energy for avoiding and treating catabolism. If fat consumption must to be reduced for reasons of intolerability despite adequate enzyme replacement therapy, it is necessary to ensure that the subsequent compensatory oral intake of other sources of energy (carbohydrates, proteins) is increased to maintain isocaloric nutrition.

Comments

In conjunction with enzyme administration, medium-chain triglycerides appear to result in a further increase of fat absorption. They should therefore not be recommended under these conditions [371].

Comments

Drinking supplementary liquid meals is required by about 10 – 15 % of all patients, enteral tube feeding is necessary in approximately 5 %, and parenteral nutrition in less than 1 % of cases [90]. They are not usually intended for the treatment of exocrine pancreatic insufficiency, but rather for patients with complications of the disease, namely gastric outlet obstruction or complex fistula systems. This is usually a temporary measure, e. g., before definitive surgical management.

Comments

Alcohol consumption is an important pathogenetic factor for the progression of exocrine pancreatic insufficiency in patients with chronic pancreatitis [372]. As there are currently no data on whether in the presence of chronic pancreatitis the consumption of small amounts of alcohol (e. g., < 20 g/day) is damaging, it is appropriate to recommend general abstinence from alcohol.

Comments

Patients with chronic pancreatitis and exocrine pancreatic insufficiency take in less than the recommended daily allowance of vitamins and trace elements. Thus, deficiencies of the fat-soluble vitamins A, D, E and K as well as of calcium, magnesium, zinc, thiamine and folic acid often occur. A reduced intake has also been reported for riboflavin, choline, copper, manganese and sulphur. Although the ingestion of vitamin C and selenium was within the recommended daily values, it was less than in healthy controls [92] [93] [373].

Comments

A routine control of these parameters in adults cannot be recommended due a lack of data.

Comments

In children, subclinical deficiency states can develop and cause a failure to thrive over time.

Chapter 10 – Surgical procedures and their indications

Surgery of chronic pancreatitis effectively treats intractable pain and/or local complications [244] [374]. Since endoscopic techniques can, in principle, also be used for these indications, an early interdisciplinary discussion is essential to determine the therapeutic concept best suited to the individual patient.

Above all, the long-term prospects of success of endoscopic therapy should be considered. The correct moment for surgery is difficult to determine and remains a contentious issue. Evidence is mounting, however, that timely surgical intervention can at least delay progressive pancreatic insufficiency.

Apart from the success rate, complications and in particular mortality of the therapeutic procedures should be included in the decision-making process. Historically, pancreatic surgery is associated with a high morbidity rate, but has made dramatic improvements in recent decades by advances in surgical techniques, perioperative management and the foundation of pancreas centres [374] [375] [376] [377] [378].

10.1: Surgical procedures and their indications

Comments

There is no therapeutic, potentially curative alternative to surgical resection for suspected malignancy. Whereas the median overall survival rate in the presence of pancreatic carcinoma is only 6 months, a five-year survival rate of over 20 % and a median survival rate of approx. 24 months can be achieved by surgical resection [246] [379].

Resection of the head of pancreas is also the most effective therapeutic option for treating pain associated with pancreatitis and local complications [374] [380]. The individual risk of surgery should be weighed against the therapeutic benefit in any given case.

Comments

Pancreatic head resection is the most effective surgical procedure for an inflammatory mass of the pancreatic head and is superior to pure drainage surgery and endoscopic interventions. Duodenum-preserving pancreatic head resections (DPPHR) are superior to the Kausch-Whipple procedure in the short and medium term over a follow-up observation period of up to two years [377] [378] [381] [382]. The treatment efficacy of the three variations of duodenum-preserving pancreatic head resection is equivalent [383]. The surgical procedure according to the Bern modification is technically the least sophisticated. The long-term outcome after the Kausch-Whipple procedure and after duodenum-preserving pancreatic head resection is comparable. A randomised multicentre study, funded by the German Research Foundation (DFG), is currently recruiting [248] [384] [385] [386] [387] [388] [389] [390] [391] [392] [393] [394].

Comments

Whereas in the classical and pylorus-preserving Kausch-Whipple procedure a biliodigestive anastomosis is always constructed to drain the bile duct, this is not performed routinely during DPPHR. By resecting the pancreatic head, the bile duct is freed of pancreatic tissue in all DPPHR variations (Beger, Frey, Bern, Hamburg); the bile duct is usually opened within the pancreatic head only in patients with preoperative cholestasis and reinserted into the resection cavity. This internal bile duct drainage may be performed in all modifications of DPPHR. A T-tube to divert bile in the postoperative phase until the anastomosis has healed can, but does not have to, be placed.

Conditions under which a deviation from the recommendation Statement 10 – 1-1 should/can be made:

If congestion of the pancreatic duct is predominant, pure drainage procedures such as the lateral pancreaticojejunostomy (Partington-Rochelle procedure) or Frey’s procedure with limited pancreatic head resection [395] [396] have good primary success rates. The results are indeed better than after endoscopic therapy [244], but demonstrate a poorer long-term outcome in comparison with pancreatic head resection procedures [374] [397]. Furthermore, these procedures only promise success given a very wide ductal system (> 7 mm) without inflammatory tumour of the pancreatic head. They are therefore an option in less than 10 % of cases [398].

The majority (> 85 %) of patients, however, present an inflammed, enlarged head of pancreas and a secondary obstruction of the pancreatic duct. These patients rarely experience improvement of their clinical symptoms from a drainage procedure, and so resection procedures are preferable.

Comments

Beger procedure: In the duodenum-preserving pancreatic head resection procedure by Beger et al. [399], the pancreas is transected above the portal vein and the inflammatory space-occupying lesion in the pancreatic head resected, leaving behind a 5- to 8-mm-wide parenchymal collar on the wall of the duodenum. In some cases, this may result in restoration of portal venous flow, which also applies to the Kausch-Whipple procedure, although this usually does not succeed due to the chronic blood flow obstruction. However, the work by Blöchle et al. has shown that in segmental non-occlusive portal hypertension caused by chronic pancreatitis, portal venous flow can indeed be restored by a decompressing removal of the obstruction [400].

Reconstruction is achieved with a Roux-en-Y diversion using a jejunal loop and end-to-side anastomosis to the pancreatic corpus and side-to-side anastomosis to the enucleated pancreatic head. The prerequisite for the long-term success of this technique is a pancreatic duct to the left which allows probe insertion without obstruction. If the bile duct obstruction is impassable, the bile duct may be opened and connected to the head of pancreas as an internal bile duct anastomosis.

Frey’s procedure: In the USA, Beger’s technically more complex duodenum-preserving pancreatic head resection did not establish itself. Frey et al. subsequently developed a modification, in which a circumscribed enucleation of the pancreatic head is combined with a longitudinal pancreaticojejunostomy, corresponding to the Partington-Rochelle drainage operation [401] [402]. This procedure seems appropriate in the presence of an inflammatory space-occupying lesion of limited size in the pancreatic head combined with ductal obstruction of the pancreatic duct. The Hamburg and Berne variations are technical simplifications of Beger’s duodenum-preserving pancreatic head resection [388] [403].

In patients with portal venous thrombosis and cavernous transformation of the portal vein, procedures which do not transect the mesenterico-portal axis are preferred (Hamburg, Bern). The indication for surgery in this difficult patient population requires extensive interdisciplinary communication because fatality and mortality are significantly increased. Nevertheless, complete pain relief and return to work can also be achieved in this patient population [244] [313] [390] [392] [401] [403] [404] [405] [406] [407] [408] [409] [410] [411].

Comments

Indications for segmental pancreatic resection include segmental inflammatory alterations located in the transition area between pancreatic corpus and head or in the pancreatic corpus. The main argument for segmental pancreatic resection to remove inflammatory alterations in the pancreatic corpus lies in the lower postoperative morbidity in comparison with partial pancreaticoduodenectomy and left-sided pancreatic resection, as shown in numerous publications [412]. Because considerably less viable pancreatic parenchyma is removed during segmental resection, the development of postoperative diabetes mellitus or exocrine pancreatic insufficiency is less frequent [413] [414] [415] [416] [417] [418] [419]. Only two fatalities have been reported amongst the more than 350 segmental pancreatic resections documented in the literature [420] [421]. The postoperative surgical morbidity of approx. 20 – 30 % is acceptable. Also, satisfaction and quality of life of the patients is very good at 97.4 %. If clinically indicated, segmental resection of the pathologically and morphologically identifiable finding can be performed [420] [421] [422].

Comments

Very rarely, cases of chronic pancreatitis are also seen in which the pancreatic duct is discovered not to be dilated, contrary to the high-pressure theory. These cases are defined as “small-duct disease”. The frequency of this disease manifestation is very controversial. In recent years, an increasing number of patients have been diagnosed with autoimmune pancreatitis, which is characterised morphologically by an inflammation of the parenchyma without dilatation of the duct. Therefore, it is important today to differentially diagnostically exclude autoimmune pancreatitis in patients with small-duct disease.

Because surgical therapy of small-duct disease by pancreatic head resection or a pure duct drainage procedure did not produce satisfactory results [423] [424], the V-shape excision technique was developed for this clinical situation [388] [403]. In a prospective study, this technique achieved long-term pain relief, together with a significant improvement in the quality of life in more than 85 % of patients [403]. The low postoperative morbidity and mortality rates also show that this procedure can be safely performed in centres specialized in pancreatic surgery.

Comments

For further explanation, see Comments on Statement 10 – 1-6.

Comments

A Kausch-Whipple procedure or a Beger DPPHR procedure can achieve improvement of portal venous flow in cases of obstruction of the portal vein and superior mesenteric vein. Among other things, the success rate depends on the degree and duration of obstruction. The technical operability depends on the formation of collaterals and inflammatory adhesions [248].

Comments

A thorough pre-operative medical history should be obtained and any new symptoms such as weight loss, fever, or night sweats (B symptoms) noted. Tomographic imaging (CT or MRI) and the results of previous examinations should be at hand. Laboratory parameters should include baseline CA19 – 9 for postoperative follow-up reviews. Endoscopic ultrasound should be performed for its better local resolution.

Bearing in mind that the indication for surgery for suspected pancreatic carcinoma in chronic pancreatitis is absolute and the surgical technique is predetermined, preoperative diagnostics should not be prolonged. The Kausch-Whipple procedure or a pylorus-preserving pancreatic head resection is indicated [407] [408] [409].

10.2. Treatment of postoperative complications

Pancreas surgery has progressed from high-risk operations, which in years past were often regarded as heroic interventions, to operations with a manageable perioperative risk [425] [426]. Mortality has also been clearly reduced in recent years at highly specialised centres. This is especially the case for surgery of chronic pancreatitis, because a fibrotic, hard pancreas is less vulnerable and reconstructions tend to heal better. A standardised surgical technique and improved perioperative management of the patients have contributed significantly to this.

Comments

The critical operative steps during a pancreaticoduodenectomy and left-sided pancreatic resection are pancreatic anastomosis and pancreatic stump closure [385] [386]. The consensus definition for POPF (postoperative pancreatic fistula) of the International Study Group for Pancreatic Fistula (ISGPF) is oriented on the amylase concentration in the drainage fluid: POPF is defined as an amylase content in the drain output greater than three times the serum amylase level on or after the third postoperative day. Three grades – A to C – reflect the clinical impact on the patient after development of a POPF ([Table 5]). An initial validation and a multi-centre study made a retrospective calculation that the prevalence of POPF as defined by the ISGPF is approximately 30 %, with Grade A fistula without clinical relevance being the predominant case [427] [428] [429]. Unlike fistulae after left-sided pancreatic resection which do not result in activation of pancreatic juice by the intestinal enzyme enterokinase, the pancreatic fistulae which develop in rare cases after pancreatic head resection in patients with chronic pancreatitis are potentially more dangerous. Diagnostic examinations for fistulae are performed by determining amylase and lipase levels via an intra-abdominal drain, CRP measurements, as well as ultrasound and tomographic imaging [430] [431] [432] [433].

Table 5 ISGPF consensus definition of postoperative pancreatic fistulae (adapted from [430]).[1]

grade	clinical status, CT result	adjustment of management, intervention	hospital stay
A	good, no fluid accumulation	no, consider CT diagnostics	not prolonged
B	often good, peripancreatic fluid	yes, no invasive intervention	usually prolonged
C	critical, peripancreatic fluid	yes, percutaneous drainage or revision laparotomy	prolonged
definition	drain output of any measurable volume of fluid on or after postoperative day 3 with an amylase content greater than 3 times the serum amylase activity.

¹ ISGPF: International Study Group for Pancreatic Fistula.

10.3: Follow-up after surgical management

Comments

CBD obstruction after a Kausch-Whipple procedure is defined as renewed cholestasis and is usually the result of a bile duct leak which has healed with scar formation. Whereas initially an endoscopic or interventional dilatation and/or stent therapy might be appropriate, revision surgery is necessary if the problem persists [434].

Comments

Postoperatively, pain is significantly reduced in approx. 90 % of all patients after pancreatic head resection. Just as for pre-operative pain, postoperatively persistent pain is treated with analgesics according to WHO pain plan. Cause of persistent pain can be unrelated to the pancreas following established chronification of the pain. However, recurrence of pain after initial pain relief can also develop as a result of a recurrence of the inflammatory pancreatic tumour and renewed pancreatic duct obstruction. In these cases, revision surgery is possibly indicated, involving renewed duodenum-preserving pancreatic head resection or Whipple’s procedure [435] [436].

Comments

Residual pancreatectomy is not indicated for persistent pain or completely atrophic or calcified pancreas [426] [437]. Residual pancreatectomy is only indicated as a last resort for postoperative septic complications after unsuccessful interventional therapy [438].

Comments

Revision operations are among the most difficult abdominal operations. If pain persists or recurrent cholestasis cannot be successfully treated by medication, interventional or endoscopic means, however, then the most promising therapy is resection surgery, as in the primary situation. Today, revision surgery is no longer associated with increased mortality, but should nevertheless be performed in experienced centres [279] [434].

Chapter 11 – Monitoring and follow-up of chronic pancreatitis

Comments

Prospective studies which substantiate the benefits of follow-up reviews do not exist. Twenty years after diagnosis, mortality in patients with chronic pancreatitis is 38.4 % higher than in an age-adjusted control cohort [439].

The risk of developing pancreatic carcinoma is increased 16-fold in patients with chronic pancreatitis and by 25-fold in those who also smoke. As calculated in a recent meta-analysis, the relative risk of developing pancreatic carcinoma for chronic pancreatitis is 13.3 % (95 % CI 6.1 – 28.9 %) and 69 % for hereditary pancreatitis (95 % CI 56.4 – 84.4 %) [440]. The lifetime risk for developing pancreatic carcinoma in patients with chronic pancreatitis is a maximum of 5 % [level of evidence grade 2b] [439] [440] [441] [442]. Clinical experience therefore calls for a yearly follow-up (clinical findings, transabdominal ultrasound, laboratory tests including HbA_1c).

Comments

Eight years after diagnosing chronic pancreatitis, 50 % of patients suffer from diabetes mellitus requiring therapy. Episodic hypoglycaemia occurs in up to 79 % of patients and severe hypoglycaemia in up to 41 %. Mortality in patients with diabetes mellitus is significantly increased. Median survival is 8.7 years after establishing the diagnosis of pancreoprivic diabetes. Diagnosis and follow-up monitoring of diabetes mellitus should be performed according to the guidelines of the German Diabetes Society [http://www.uni-duesseldorf.de/AWMF/ll/ll_057.html] [443] [444] [445] [446] [447] [448] [449].

Comments

Exocrine pancreatic insufficiency results in cachexia and secondary complications such as vitamin deficiency and osteoporosis. Diagnostic tests and treatment for osteoporosis should therefore be carried out in patients with chronic pancreatitis according to the guidelines of the German Umbrella Association of Osteoporosis (DVO). Individually tailored nutritional intervention should be carried out to prevent deterioration of the nutritional state. Follow-up monitoring is indicated according to the guidelines of the German Society for Nutritional Medicine [89] [450] [451].

Comments

Carriers of PRSS1 mutations have a cumulative risk up to 49 % of developing a pancreatic carcinoma by age 75 in the presence of chronic pancreatitis. This risk is significantly higher than for all other known aetiologies of chronic pancreatitis. Rapid progression of the disease in patients who smoke is well substantiated, together with an associated increased risk for developing pancreatic carcinoma [2] [6] [7] [37] [38] [39] [41] [42] [45] [46] [48] [49] [80] [452] [453] [454].

Comments

The moment of diagnosis does not correspond to the duration of the disease, and already eight years after diagnosis, 50 % of patients with chronic pancreatitis develop diabetes mellitus. Since complications such as exocrine or endocrine insufficiency are associated with a considerable degree of morbidity and an increased mortality rate if untreated, follow-up examinations appear appropriate. The aim of follow-up monitoring includes diagnosis and treatment of exocrine or endocrine insufficiency, intervention for patients with cachexia or pain, as well as the treatment of local complications (gastric outlet obstruction, pseudoaneurysms, complicated pseudocysts). Follow-up examinations should not only be performed after developing warning signs (pain, diabetic metabolic state, weight loss, jaundice, vomiting, loss of appetite, recurrent episodes), as all relevant complications of chronic pancreatitis have usually already caused irreversible damage once warning signs appear [2] [6] [7] [37] [38] [39] [41] [42] [45] [46] [48] [49] [80] [89] [443] [444] [445] [446] [447] [448] [449] [450] [451] [452] [453] [454] [455].

Comments

The sensitivity of diagnosing pancreatic disease with transabdominal ultrasound is 94 %; however, specificity is only 35 %. The sensitivity of the case history, physical examination and transabdominal ultrasound reaches 94 %. Specificity can be increased by subsequent examination techniques such as EUS, ERCP or CT, but not sensitivity. Transabdominal ultrasound therefore appears suitable as an initial examination. An additional imaging modality might be necessary to confirm the diagnosis [456].

Comments

This is in line with clinical practice. The gold standard for detecting complications of chronic pancreatitis is contrast-enhanced CT. However, it must be pointed out that CT is not well suited for diagnosing early pancreatic cancer. In fact, none of the above-mentioned techniques can exclude operable cancer with reasonable certainty against the background of chronic pancreatitis. A combination of imaging techniques may be necessary if there is clinical suspicion. At the moment, at least, endoscopic ultrasound appears to be superior to the other imaging techniques, not least due to the option of taking a biopsy. See topic area “Imaging techniques in patients with chronic pancreatitis” (selection: [152] [157]).

Comments

Tumour markers are unsuitable as screening tests for pancreatic carcinoma, even in patients with chronic pancreatitis. Falsely high values must be expected in patients with cholestasis. To date, no cost-benefit analyses exist which substantiate the use of tumour markers in patients with chronic pancreatitis.

The diagnostic sensitivity and, above all, specificity of tumour markers for differentiating a space-occupying lesion in the pancreas are not adequate [457].

Comments

All known complications of chronic pancreatitis are curable, reversible or at least amenable to treatment during the asymptomatic early stage. Thus, it must be the goal of the attending physician to make a diagnosis before warning signs develop. A consensus exists that, for the above-named reasons, diagnostic examinations should be performed. Controlled studies examining the value of early diagnosis of complications of chronic pancreatitis and early intervention are urgently needed. Patients with chronic alcoholic pancreatitis die more frequently of cancer of the hypopharynx, oesophagus or stomach. This should be borne in mind during follow-up monitoring [458] [459].

Comments

Up to 52 % of cases develop impaired glucose tolerance after resection of the pancreas. 22 % develop insulin-dependent diabetes mellitus. A postoperative follow-up is therefore indicated. For this reason, the classification is recommendation grade A [313] [382] [389] [390] [460].

Comments

No prospective studies on total pancreatectomy are available. A general recommendation for total pancreatectomy cannot be expressed due to high morbidity and considerable mortality. Median survival following total pancreatectomy in patients with benign disease is 8.2 years. The average 5-year survival rate was 50 % in a recently published Japanese cohort. Professor Büchler’s group reports an identical mortality over a follow-up observation period of 23.5 months in comparison with patients after Whipple’s procedure for chronic pancreatitis. The decision for total pancreatectomy should always be reached by an interdisciplinary team. After-care in specialist centres should be arranged to reduce morbidity [461] [462] [463] [464]. The guidelines group classified this recommendation as being of high clinical relevance. For this reason, the classification is recommendation grade B.

Chapter 12 – Diagnostics and treatment of chronic pancreatitis in childhood

Acute and acute recurrent pancreatitis in childhood is far more common than previously assumed and, depending on its cause, can lead to chronic pancreatitis. The most common causes are trauma, infections, systemic disorders, medications and structural bile duct lesions; a large proportion is idiopathic. During childhood, pancreatitis usually has a mild course and the prognosis is good. In a retrospective 10-year analysis (1991 – 2000) by the University Hospital Dresden, a total of 156 children were treated as in-patients for acute pancreatitis. That corresponds to 0.29 % of the total patient population. Only one child, a four-year-old girl, had severe haemorrhagic necrotising pancreatitis with a complicated, but not fatal, course. Another child with multiple recurrences was diagnosed with hereditary pancreatitis. All the other 154 children with mild acute pancreatitis made a full recovery. An analysis of literature data involving 589 children with acute pancreatitis and an average age of 9.2 ± 2.4 years (1 week–21 years) revealed the following causes of pancreatitis: idiopathic 23 %, trauma 22 %, structural anomalies 15 %, multiple system disorders 14 %, medications 12 %, infections 10 %, hereditary and metabolic disorders 2 % each [465]. There appear to be regional differences, however, in the frequency of the individual causes, as evident from an article from Japan published in 1994 [466]. In this analysis, 204 cases which had been published in the Japanese literature were compared with 304 cases published in Western countries. Almost half of the Japanese cases were due to a congenital abnormal biliary tract, while traumatic causes dominated in the children affected in the Western countries, alongside a large number of idiopathic cases.

12.2: Imaging in children with chronic pancreatitis

Comments

Transabdominal ultrasound is the primary imaging technique for investigating chronic pancreatitis in children because the examination is simple to perform and does not involve radiation exposure. However, there are no comparative studies on the validity of ultrasound imaging in children. The benefit of ultrasound contrast agents in children has not been evaluated [467].

Comments

Endoscopic ultrasound is technically possible in children from about age 5 and is primarily performed for fine-needle aspiration or to investigate calcifications [468] [469] [470]. X-ray and CT of the abdomen should only be performed in exceptional cases to diagnose chronic pancreatitis in children.

Comments

MRCP is the tomographic imaging technique of choice to demonstrate the bile ducts and the pancreatic duct in children because the examination is hardly invasive and does not involve radiation exposure. One study showed that the intravenous application of secretin resulted in a better demonstration of pancreatic side branches [467] [471]. In children < 6 years, it is usually only possible to perform MRCP under general anaesthesia.

Comments

ERCP is technically difficult to perform in children < 5 years of age and is exclusively employed for planned interventions [472]. Endoscopic ultrasound is only used for special indications in children and has a higher sensitivity than MRCP in the diagnostics of CP.

Comments

In an older study involving 300 children and adolescents between the ages of 0 and 19 years, normal standard values for pancreatic size were determined by ultrasound. The pancreatic head has a diameter of 1.0 ± 0.4 to 2.0 ± 0.5 cm in the anterior-posterior plane (infant to young adulthood), the body of the pancreas a diameter of 0.6 ± 0.2 to 1.1 ± 0.3 cm, and the pancreatic tail a diameter of 1.0 ± 0.4 to 2.0 ± 0.4 cm. The main growth of the pancreas takes place in the first years and is subject to high variation. Determining the size of the pancreas, therefore, does not allow any conclusion to be drawn on the presence of chronic pancreatitis [473].

12.3: Summary of chronic pancreatitis in childhood

Comments

Epidemiological data for chronic pancreatitis in childhood are sparse. There are, however, a number of case reports for the following causes, which must therefore be clarified in children and adolescents.

• Chronic inflammatory bowel diseases: Several case reports exist on this in childhood [474].

• Coeliac disease: Epidemiological data (Swedish register).

• No increased incidence in childhood, but in adult patients [475].

• Haemolytic-uraemic syndrome: common association with acute pancreatitis, rarely with chronic pancreatitis. Other autoimmune diseases: Case reports exist on lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis and chronic pancreatitis in childhood.

• Hypertriglyceridaemia: Case reports exist of patients with lipoprotein lipase deficiency and apolipoprotein CII deficiency and very high triglyceride levels. There does not appear to be an association between chronic pancreatitis and hypercholesterolaemia in childhood.

• Two percent of patients with cystic fibrosis present symptoms of chronic pancreatitis [55].

• Children with organoacidopathies can present as recurrent acute pancreatitis. Hypercalcaemia is also a risk factor for pancreatitis in childhood. There is no association with alpha-1 antitrypsin deficiency [476].

• Data available in the literature on parasitic infections and chronic pancreatitis in childhood are inconclusive.

• There is a proven association between medications and chronic pancreatitis for cytostatic agents, e. g., asparaginase or immune modulators (azathioprine) and valproate, although the data available for childhood is sparse [477] [478].

• A connection between abdominal trauma and chronic pancreatitis in childhood has not been proven. A precise statement cannot be made about the frequency distribution of the various aetiologies for chronic pancreatitis in childhood.

Comments

Pancreatic-sufficient patients with cystic fibrosis often suffer from recurrent pancreatitis [55]. Furthermore, mutations on the CFTR alleles are commonly found in patients with so-called idiopathic chronic pancreatitis [479] [480].

12.4: Acute episodes of chronic pancreatitis in childhood

Comments

No controlled studies exist on nutrition during an acute episode of chronic pancreatitis in childhood. In principle, early enteral nutrition should be pursued, as for adults, in order to maintain the intestinal barrier function. Oral nutrition is possible in almost all cases due to the usually milder course in childhood. There are no studies available comparing oral nutrition with gastric or jejunal administration in childhood. Complete parenteral nutrition in children with chronic pancreatitis is indicated only in severe cases of an acute episode associated with vomiting and (sub-)ileus.

Comments

There are no studies on the controlled use of antibiotics during an acute episode of CP in childhood; treatment analogous to that of acute pancreatitis in adulthood, however, appears acceptable.

Comments

Using the literature available, it is not possible to answer the question regarding the indication for surgery of the pancreas in paediatric patients with chronic pancreatitis, timing of an operation or the choice of surgical technique.

12.5: Endoscopic, interventional and surgical treatment of chronic pancreatitis in childhood

Comments

There are individual retrospective case series [470] [472] [481] and one prospective case series [468], which not only describe the diagnostic use of ERCP and EUS, but also their application as interventional therapy in paediatric patients with chronic pancreatitis. Sphincterotomy, stent insertion, stone removal and balloon dilation have been described for ERCP, and the endoscopic ultrasound-guided internal drainage of symptomatic pancreatic pseudocyst for EUS.

This kind of interventional therapy in children demands appropriate staff and facilities and is usually performed under general anaesthesia.

Comments

The literature does not provide any guidelines for the surgical approach for chronic pancreatitis in childhood. In principle, particular emphasis is placed on organ preservation of pancreas and spleen in children, but there is no evidence for this, given the extremely small number of patients.

Comments

Given the extremely low number of surgical interventions for chronic pancreatitis in childhood, there are on the whole no valid results on the outcome of specific surgical procedures. In a retrospective study, data on 25 patients were collected over 34 years, in whom six different surgical procedures were employed. It therefore not possible to provide a statement on the validity of an individual surgical procedure in children [481].

12.6: Pain therapy of chronic pancreatitis in childhood

Comments

Pain management in children follows the experience gained in adults. Studies on pain management in children are lacking. The general principles of pain management in children can also be applied to abdominal pain due to pancreatitis.

12.7: Enzyme replacement for chronic pancreatitis in childhood

Particularly in childhood, replacement therapy should be undertaken for exocrine insufficiency. Although secretion of all enzymes is affected in exocrine pancreatic insufficiency, it is fat maldigestion that plays the decisive pathophysiological role. The following mechanisms interact: earlier and greater reduction of lipase secretion in comparison with other enzymes; acid denaturation of lipase due to duodenal pH (bicarbonate deficiency!); associated fat malabsorption due to denaturation of bile acid by low intraduodenal pH levels; more rapid proteolytic breakdown of lipase; absence of effectively compensatory enzymatic systems. The digestion of protein and starch is not usually disturbed to a significant degree or is taken over by other enzymes of saliva, the stomach and the duodenal mucosal brush border. Flatulence is possible in certain cases.

Comments

Allergic sensitisation, oral mucosal excoriation and fibrosing colonopathy may develop in children and adolescents during oral pancreatic enzyme replacement therapy.

Only individual case reports exist on this, however, from which no details regarding frequency may be inferred. Sensitisation as diagnosed in the skin-prick test is not observed more often in patients with cystic fibrosis than in healthy controls [482] [483] [484]. Fibrosing colonopathy or oral mucosal excoriation has so far only been reported in patients with cystic fibrosis.

Comments

Frequent voluminous stools, fatty stools, increased flatulence, excessive appetite and reduced growth rate are indications of inadequate pancreatic enzyme replacement therapy and should therefore receive special attention during childhood and adolescence. The substitution of a pancreatic lipase preparation by a delayed-release formulation is effective and may be advantageous given poor compliance [484].

Comments

Various trials have shown that children and adolescents who have signs of maldigestion with steatorrhoea, despite regular replacement with non-encapsulated or microencapsulated pancreatic enzymes, thrive better under acid-suppressive therapy [359] [484] [485]. This English language version of the guidelines represents a translation of the original version in German [486].

Appendix: Participating authors ([Table  6])

Table 6 Participating authors.

Prof. Dr. Ulrich Adam, Berlin

Dr. Andrea Alexander, Dusseldorf

Prof. Dr. Dr. Åke Andrén-Sandberg, Stockholm

Prof. Dr. Christoph Beglinger, Basel

Assistant Professor Dr. Philip Bufler, Munich

Prof. Dr. Markus W. Büchler, Heidelberg

Dr. Güllü Cataldegirmen, Hamburg

Assistant Professor Dr. Katarina Dathe, DGVS

Prof. Dr. Christoph F. Dietrich, Bad Mergentheim

Prof. Dr. Jörg Emmrich († 25.6.2011), Rostock

Prof. Dr. Jürgen Freise, Mülheim an der Ruhr

Prof. Dr. Helmut Michael Friess, Munich

Prof. Dr. Ulrich R. Fölsch, Kiel

Prof. Dr. Michael Gebel, Hannover

Prof. Dr. Bernhard Glasbrenner, Münster

Prof. Dr. Beat Gloor, Bern

Dr. Dirk Grothues, Regensburg

Assistant Professor Dr. Thilo Hackert, Heidelberg

Prof. Dr. Okka Hamer, Regensburg

Prof. Dr. Philip D. Hardt, Giessen

Prof. Dr. Claus-Dieter Heidecke, Greifswald

Prof. Dr. Jobst Henker, Dresden

Assistant Professor Dr. Albrecht Hoffmeister, Leipzig

Prof. Dr. Ulrich Hopt, Freiburg

Prof. Dr. Jakob Izbicki, Hamburg

Prof. Dr. Michael Jung, Mainz

Assistant Professor Dr. Stefan Kahl, Berlin

Assistant Professor Dr. Jutta Keller, Hamburg

Prof. Dr. Klaus-Michael Keller, Wiesbaden

Dr. rer. nat. Steffen Klabunde, Otterberg

Prof. Dr. Ernst Klar, Rostock

Jürgen Kleeberg, Berlin

Prof. Dr. Jörg Kleeff, Munich

Prof. Dr. Wolfram Trudo Knoefel, Dusseldorf

Prof. Dr. Paul Georg Lankisch, Lüneburg

Prof. Dr. Peter Layer, Hamburg

Prof. Dr. Markus M. Lerch, Greifswald

Prof. Dr. Matthias Löhr, Stockholm

Prof. Dr. Christian Löser, Kassel

Prof. Dr. Jutta Lüttges, Hamburg

Prof. Dr. Peter Malfertheiner, Magdeburg

Prof. Dr. Julia Mayerle, Greifswald

Prof. Dr. Rémy Meier, Liestal

Prof. Dr. Joachim Mössner, Leipzig

Prof. Dr. Horst Neuhaus, Dusseldorf

Prof. Dr. Claus Niederau, Oberhausen

Prof. Dr. Johann Ockenga, Bremen

Assistant Professor Dr. Roland Pfützer, Cologne

Prof. Dr. Bettina Rau, Rostock

Prof. Dr. Jürgen Riemann, Ludwigshafen

Prof. Dr. Michael Rünzi, Essen

Prof. Dr. Roland Schmid, Munich

Assistant Professor Dr. Alexander Schneider, Aschaffenburg

Prof. Dr. Michael Schoenberg, Munich

Assistant Professor Dr. Andreas Schreyer, Regensburg

Prof. Dr. Hans-Joachim Schulz, Berlin

Prof. Dr. Dietrich von Schweinitz, Munich

Prof. Dr. Hans Seifert, Oldenburg

Dr. Peter Simon, Greifswald

Prof. Dr. Tim Strate, Reinbek

Assistant Professor Dr. Niels Teich, Leipzig

Dr. Matthias Treiber, Munich

Prof. Dr. Barbara Tribl, Vienna

Prof. Dr. Jens Werner, Heidelberg

Prof. Dr. Uwe Will, Gera

Prof. Dr. Heiko Witt, Munich

Prof. Dr. Christian Wittekind, Leipzig

Prof. Dr. Helmut Witzigmann, Dresden

Prof. Dr. Emre F. Yekebas, Darmstadt

Conflict of interest

All potential conflict of interest of all participant authors have been registered with DGVS and AWMF and can be obtained on request.

¹ Guidelines of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS)

¹ In co-operation with the German Society of Internal Medicine (DGIM), German Association of Private-practice Gastroenterologists (bng), Society for Paediatric Gastroenterology and Nutrition (GPGE), German Society for Nutritional Medicine (DGEM), German Society of General and Visceral Surgery (DGAV), Austrian Society for Gastroenterology and Hepatology (ÖGGH), Swiss Society of Gastroenterology (SGG), Swiss Society of Visceral Surgery (SGVC), German Radiology Society, German Pancreas Aid, Working Group of Pancreatectomy Patients, German Society for Pathology (DGP) (DRG).

^* Equally contributing first author.

^** Equally contributing senior author.

• References

• 1 Dufour MC, Adamson MD. The epidemiology of alcohol-induced pancreatitis. Pancreas 2003; 27: 286-290
• 2 Ammann RW, Akovbiantz A, Largiader F. et al. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984; 86: 820-828
• 3 Miyake H, Harada H, Kunichika K. et al. Clinical course and prognosis of chronic pancreatitis. Pancreas 1987; 2: 378-385
• 4 Lankisch PG, Lohr-Happe A, Otto J. et al. Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion 1993; 54: 148-155
• 5 Gastard J, Joubaud F, Farbos T. et al. Etiology and course of primary chronic pancreatitis in Western France. Digestion 1973; 9: 416-428
• 6 Lowenfels AB, Maisonneuve P, Cavallini G. et al. Prognosis of chronic pancreatitis: an international multicenter study. International Pancreatitis Study Group. Am J Gastroenterol 1994; 89: 1467-1471
• 7 Maisonneuve P, Lowenfels AB, Mullhaupt B. et al. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005; 54: 510-514
• 8 van Geenen EJ, Smits MM, Schreuder TC. et al. Smoking is related to pancreatic fibrosis in humans. Am J Gastroenterol 2011; 106: 1161-1166; quiz 1167
• 9 Mossner J, Keim V, Niederau C. et al. Guidelines for therapy of chronic pancreatitis. Consensus Conference of the German Society of Digestive and Metabolic Diseases. Halle 21-23 November 1996. Z Gastroenterol 1998; 36: 359-367
• 10 Durbec JP, Sarles H. Multicenter survey of the etiology of pancreatic diseases. Relationship between the relative risk of developing chronic pancreaitis and alcohol, protein and lipid consumption. Digestion 1978; 18: 337-350
• 11 Johnson CD, Hosking S. National statistics for diet, alcohol consumption, and chronic pancreatitis in England and Wales, 1960-88. Gut 1991; 32: 1401-1405
• 12 Lin Y, Tamakoshi A, Hayakawa T. et al. Associations of alcohol drinking and nutrient intake with chronic pancreatitis: findings from a case-control study in Japan. Am J Gastroenterol 2001; 96: 2622-2627
• 13 Maruyama K, Otsuki M. Incidence of alcoholic pancreatitis in Japanese alcoholics: survey of male sobriety association members in Japan. Pancreas 2007; 34: 63-65
• 14 Sarles H, Cros RC, Bidart JM. A multicenter inquiry into the etiology of pancreatic diseases. Digestion 1979; 19: 110-125
• 15 Stigendal L, Olsson R. Alcohol consumption pattern and serum lipids in alcoholic cirrhosis and pancreatitis. A comparative study. Scand J Gastroenterol 1984; 19: 582-587
• 16 Talamini G, Bassi C, Falconi M. et al. Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer. Dig Dis Sci 1999; 44: 1303-1311
• 17 Levy P, Mathurin P, Roqueplo A. et al. A multidimensional case-control study of dietary, alcohol, and tobacco habits in alcoholic men with chronic pancreatitis. Pancreas 1995; 10: 231-238
• 18 Suda K, Shiotsu H, Nakamura T. et al. Pancreatic fibrosis in patients with chronic alcohol abuse: correlation with alcoholic pancreatitis. Am J Gastroenterol 1994; 89: 2060-2062
• 19 UK guidelines for the management of acute pancreatitis. Gut 2005; 54 (Suppl. 03) iii1-9
• 20 Bakker OJ, van Santvoort HC, Hagenaars JC. et al. Timing of cholecystectomy after mild biliary pancreatitis. Br J Surg 2011; 98: 1446-1454
• 21 Yan MX, Li YQ. Gall stones and chronic pancreatitis: the black box in between. Postgrad Med J 2006; 82: 254-258
• 22 Garg PK, Tandon RK. Survey on chronic pancreatitis in the Asia-Pacific region. J Gastroenterol Hepatol 2004; 19: 998-1004
• 23 Jacob JJ, John M, Thomas N. et al. Does hyperparathyroidism cause pancreatitis? A South Indian experience and a review of published work. ANZ J Surg 2006; 76: 740-744
• 24 Carnaille B, Oudar C, Pattou F. et al. Pancreatitis and primary hyperparathyroidism: forty cases. Aust N Z J Surg 1998; 68: 117-119
• 25 Talamini G, Falconi M, Bassi C. et al. Previous cholecystectomy, gastrectomy, and diabetes mellitus are not crucial risk factors for pancreatic cancer in patients with chronic pancreatitis. Pancreas 2001; 23: 364-367
• 26 Burtin P, Person B, Charneau J. et al. Pancreas divisum and pancreatitis: a coincidental association?. Endoscopy 1991; 23: 55-58
• 27 Kamisawa T, Tu Y, Egawa N. et al. Clinical implications of incomplete pancreas divisum. JOP 2006; 7: 625-630
• 28 Kim MH, Lee SS, Kim CD. et al. Incomplete pancreas divisum: is it merely a normal anatomic variant without clinical implications?. Endoscopy 2001; 33: 778-785
• 29 Spicak J, Poulova P, Plucnarova J. et al. Pancreas divisum does not modify the natural course of chronic pancreatitis. J Gastroenterol 2007; 42: 135-139
• 30 Su WJ, Chen HL, Lai HS. et al. Pancreaticobiliary anomalies is the leading cause of childhood recurrent pancreatitis. J Formos Med Assoc 2007; 106: 119-125
• 31 Yatto RP, Siegel JH. The role of pancreatobiliary duct anatomy in the etiology of alcoholic pancreatitis. J Clin Gastroenterol 1984; 6: 419-423
• 32 Agha FP, Williams KD. Pancreas divisum: incidence, detection, and clinical significance. Am J Gastroenterol 1987; 82: 315-320
• 33 Dhar A, Goenka MK, Kochhar R. et al. Pancrease divisum: five years' experience in a teaching hospital. Indian J Gastroenterol 1996; 15: 7-9
• 34 Quest L, Lombard M. Pancreas divisum: opinio divisa. Gut 2000; 47: 317-319
• 35 Buhler H, Seefeld U, Deyhle P. et al. [Clinical significance of pancreas divisum]. Schweiz Med Wochenschr 1983; 113: 320-324
• 36 Akatsu T, Aiura K, Takahashi S. et al. Recurrent pancreatitis caused by ampullary carcinoma and minor papilla adenoma in familial polyposis: report of a case. Surg Today 2008; 38: 440-444
• 37 Maisonneuve P, Frulloni L, Mullhaupt B. et al. Impact of smoking on patients with idiopathic chronic pancreatitis. Pancreas 2006; 33: 163-168
• 38 Yadav D, Hawes RH, Brand RE. et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med 2009; 169: 1035-1045
• 39 Ammann RW, Knoblauch M, Mohr P. et al. High incidence of extrapancreatic carcinoma in chronic pancreatitis. Scand J Gastroenterol 1980; 15: 395-399
• 40 Ammann RW, Muellhaupt B. The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999; 116: 1132-1140
• 41 Cavallini G, Talamini G, Vaona B. et al. Effect of alcohol and smoking on pancreatic lithogenesis in the course of chronic pancreatitis. Pancreas 1994; 9: 42-46
• 42 Talamini G, Bassi C, Falconi M. et al. Pain relapses in the first 10 years of chronic pancreatitis. Am J Surg 1996; 171: 565-569
• 43 Whitcomb DC, Gorry MC, Preston RA. et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996; 14: 141-145
• 44 Whitcomb DC, Preston RA, Aston CE. et al. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 1996; 110: 1975-1980
• 45 Howes N, Lerch MM, Greenhalf W. et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004; 2: 252-261
• 46 Applebaum-Shapiro SE, Finch R, Pfutzer RH. et al. Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study. Pancreatology 2001; 1: 439-443
• 47 Simon P, Weiss FU, Sahin-Toth M. et al. Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 → Cys) that alters autoactivation and autodegradation of cationic trypsinogen. J Biol Chem 2002; 277: 5404-5410
• 48 Rebours V, Boutron-Ruault MC, Jooste V. et al. Mortality rate and risk factors in patients with hereditary pancreatitis: uni- and multidimensional analyses. Am J Gastroenterol 2009; 104: 2312-2317
• 49 Rebours V, Boutron-Ruault MC, Schnee M. et al. The natural history of hereditary pancreatitis: a national series. Gut 2009; 58: 97-103
• 50 Elitsur Y, Chertow BC, Jewell RD. et al. Identification of a hereditary pancreatitis mutation in four West Virginia families. Pediatr Res 1998; 44: 927-930
• 51 Le Bodic L, Bignon JD, Raguenes O. et al. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum Mol Genet 1996; 5: 549-554
• 52 Le Bodic L, Schnee M, Georgelin T. et al. An exceptional genealogy for hereditary chronic pancreatitis. Dig Dis Sci 1996; 41: 1504-1510
• 53 Aoun E, Chang CC, Greer JB. et al. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS One 2008; 3: e2003
• 54 Witt H, Luck W, Hennies HC. et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000; 25: 213-216
• 55 Durno C, Corey M, Zielenski J. et al. Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology 2002; 123: 1857-1864
• 56 Cohn JA, Neoptolemos JP, Feng J. et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat 2005; 26: 303-307
• 57 Choudari CP, Imperiale TF, Sherman S. et al. Risk of pancreatitis with mutation of the cystic fibrosis gene. Am J Gastroenterol 2004; 99: 1358-1363
• 58 Sharer N, Schwarz M, Malone G. et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998; 339: 645-652
• 59 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: 1456-1460
• 60 De Boeck K, Weren M, Proesmans M. et al. Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype. Pediatrics 2005; 115: e463-469
• 61 Rosendahl J, Witt H, Szmola R. et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 2008; 40: 78-82
• 62 Masson E, Chen JM, Scotet V. et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet 2008; 123: 83-91
• 63 Masson E, Le MarechalC, Delcenserie R. et al. Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation. Hum Genet 2008; 123: 521-529
• 64 Chang MC, Chang YT, Wei SC. et al. Association of novel chymotrypsin C gene variations and haplotypes in patients with chronic pancreatitis in Chinese in Taiwan. Pancreatology 2009; 9: 287-292
• 65 Sarles H, Sarles JC, Muratore R. et al. Chronic inflammatory sclerosis of the pancreas--an autonomous pancreatic disease?. Am J Dig Dis 1961; 6: 688-698
• 66 Yoshida K, Toki F, Takeuchi T. et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 1995; 40: 1561-1568
• 67 Kamisawa T, Chari ST, Giday SA. et al. Clinical profile of autoimmune pancreatitis and its histological subtypes: an international multicenter survey. Pancreas 40: 809-814
• 68 Chari ST, Smyrk TC, Levy MJ. et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006; 4: 1010-1016; quiz 1934
• 69 Kamisawa T, Egawa N, Nakajima H. et al. Clinical difficulties in the differentiation of autoimmune pancreatitis and pancreatic carcinoma. Am J Gastroenterol 2003; 98: 2694-2699
• 70 Chari ST, Kloeppel G, Zhang L. et al. Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document. Pancreas 39: 549-554
• 71 Frulloni L, Gabbrielli A, Pezzilli R. et al. Chronic pancreatitis: report from a multicenter Italian survey (PanCroInfAISP) on 893 patients. Dig Liver Dis 2009; 41: 311-317
• 72 Lankisch PG, Assmus C, Maisonneuve P. et al. Epidemiology of pancreatic diseases in Luneburg County. A study in a defined german population. Pancreatology 2002; 2: 469-477
• 73 Levy P, Barthet M, Mollard BR. et al. Estimation of the prevalence and incidence of chronic pancreatitis and its complications. Gastroenterol Clin Biol 2006; 30: 838-844
• 74 Kloppel G, Sipos B, Zamboni G. et al. Autoimmune pancreatitis: histo- and immunopathological features. J Gastroenterol 2007; 42 (Suppl. 18) 28-31
• 75 Church NI, Pereira SP, Deheragoda MG. et al. Autoimmune pancreatitis: clinical and radiological features and objective response to steroid therapy in a UK series. Am J Gastroenterol 2007; 102: 2417-2425
• 76 Deheragoda MG, Church NI, Rodriguez-Justo M. et al. The use of immunoglobulin g4 immunostaining in diagnosing pancreatic and extrapancreatic involvement in autoimmune pancreatitis. Clin Gastroenterol Hepatol 2007; 5: 1229-1234
• 77 Okazaki K, Kawa S, Kamisawa T. et al. Japanese clinical guidelines for autoimmune pancreatitis. Pancreas 2009; 38: 849-866
• 78 Kamisawa T, Shimosegawa T, Okazaki K. et al. Standard steroid treatment for autoimmune pancreatitis. Gut 2009; 58: 1504-1507
• 79 Comfort MW, Steinberg AG. Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology 1952; 21: 54-63
• 80 Lowenfels AB, Maisonneuve P, Whitcomb DC. et al. Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. JAMA 2001; 286: 169-170
• 81 Ellis I, Lerch MM, Whitcomb DC. Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology 2001; 1: 405-415
• 82 Rebours V, Boutron-Ruault MC, Schnee M. et al. Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series. Am J Gastroenterol 2008; 103: 111-119
• 83 Löhr J. Exokrine Pankreasinsuffizienz. 3rd Edition. Bremen: UNI-MED Verlag; 2010
• 84 Layer P, Holtmann G. Pancreatic enzymes in chronic pancreatitis. Int J Pancreatol 1994; 15: 1-11
• 85 DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973; 288: 813-815
• 86 DiMagno EP, Malagelada JR, Go VL. et al. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med 1977; 296: 1318-1322
• 87 Lankisch PG, Seidensticker F, Otto J. et al. Secretin-pancreozymin test (SPT) and endoscopic retrograde cholangiopancreatography (ERCP): both are necessary for diagnosing or excluding chronic pancreatitis. Pancreas 1996; 12: 149-152
• 88 Lankisch PG, Droge M, Hofses S. et al. Steatorrhoea: you cannot trust your eyes when it comes to diagnosis. Lancet 1996; 347: 1620-1621
• 89 Dumasy V, Delhaye M, Cotton F. et al. Fat malabsorption screening in chronic pancreatitis. Am J Gastroenterol 2004; 99: 1350-1354
• 90 Meier R, Ockenga J, Pertkiewicz M. et al. ESPEN Guidelines on Enteral Nutrition: Pancreas. Clin Nutr 2006; 25: 275-284
• 91 Haaber AB, Rosenfalck AM, Hansen B. et al. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency. Int J Pancreatol 2000; 27: 21-27
• 92 Kalvaria I, Labadarios D, Shephard GS. et al. Biochemical vitamin E deficiency in chronic pancreatitis. Int J Pancreatol 1986; 1: 119-128
• 93 Mann ST, Stracke H, Lange U. et al. Vitamin D3 in patients with various grades of chronic pancreatitis, according to morphological and functional criteria of the pancreas. Dig Dis Sci 2003; 48: 533-538
• 94 Mann ST, Mann V, Stracke H. et al. Fecal elastase 1 and vitamin D3 in patients with osteoporotic bone fractures. Eur J Med Res 2008; 13: 68-72
• 95 Bozkurt T, Braun U, Leferink S. et al. Comparison of pancreatic morphology and exocrine functional impairment in patients with chronic pancreatitis. Gut 1994; 35: 1132-1136
• 96 Chowdhury RS, Forsmark CE. Review article: Pancreatic function testing. Aliment Pharmacol Ther 2003; 17: 733-750
• 97 Chowdhury R, Bhutani MS, Mishra G. et al. Comparative analysis of direct pancreatic function testing versus morphological assessment by endoscopic ultrasonography for the evaluation of chronic unexplained abdominal pain of presumed pancreatic origin. Pancreas 2005; 31: 63-68
• 98 Stevens T, Lopez R, Adler DG. et al. Multicenter comparison of the interobserver agreement of standard EUS scoring and Rosemont classification scoring for diagnosis of chronic pancreatitis. Gastrointest Endosc 71: 519-526
• 99 Conwell DL, Zuccaro G, Purich E. et al. Comparison of endoscopic ultrasound chronic pancreatitis criteria to the endoscopic secretin-stimulated pancreatic function test. Dig Dis Sci 2007; 52: 1206-1210
• 100 Conwell DL, Zuccaro G, Purich E. et al. Comparison of endoscopic ultrasound chronic pancreatitis criteria to the endoscopic secretin-stimulated pancreatic function test. Dig Dis Sci 2007; 52: 1206-1210
• 101 Conwell DL, Zuccaro Jr G, Vargo JJ. et al. Comparison of the secretin stimulated endoscopic pancreatic function test to retrograde pancreatogram. Dig Dis Sci 2007; 52: 1076-1081
• 102 Albashir S, Bronner MP, Parsi MA. et al. Endoscopic ultrasound, secretin endoscopic pancreatic function test, and histology: correlation in chronic pancreatitis. Am J Gastroenterol 105: 2498-2503
• 103 Bali MA, Sztantics A, Metens T. et al. Quantification of pancreatic exocrine function with secretin-enhanced magnetic resonance cholangiopancreatography: normal values and short-term effects of pancreatic duct drainage procedures in chronic pancreatitis. Initial results. Eur Radiol 2005; 15: 2110-2121
• 104 Bali MA, Golstein P, Deviere J. et al. Evaluation of somatostatin inhibitory effect on pancreatic exocrine function using secretin-enhanced dynamic magnetic resonance cholangiopancreatography: a crossover, randomized, double blind, placebo-controlled study. Pancreas 2006; 32: 346-350
• 105 Donati F, Boraschi P, Gigoni R. et al. Secretin-stimulated MR cholangio-pancreatography in the evaluation of asymptomatic patients with non-specific pancreatic hyperenzymemia. Eur J Radiol 75: e38-e44
• 106 Siegmund E, Lohr JM, Schuff-Werner P. The diagnostic validity of non-invasive pancreatic function tests--a meta-analysis. Z Gastroenterol 2004; 42: 1117-1128
• 107 Rathmann W, Haastert B, Icks A. et al. High prevalence of undiagnosed diabetes mellitus in Southern Germany: target populations for efficient screening. The KORA survey 2000. Diabetologia 2003; 46: 182-189
• 108 Hardt PD, Hauenschild A, Jaeger C. et al. High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations: a prospective multicenter study. Dig Dis Sci 2003; 48: 1688-1692
• 109 Hardt PD, Hauenschild A, Nalop J. et al. The commercially available ELISA for pancreatic elastase 1 based on polyclonal antibodies does measure an as yet unknown antigen different from purified elastase 1. Binding studies and clinical use in patients with exocrine pancreatic insufficiency. Z Gastroenterol 2003; 41: 903-906
• 110 Ewald N, Bretzel RG, Fantus IG. et al. Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-centre trial. Diabetes Metab Res Rev 2007; 23: 386-391
• 111 Creutzfeldt W, Arnold R. Somatostatin and the stomach: exocrine and endocrine aspects. Metabolism 1978; 27: 1309-1315
• 112 Lohr M, Kloppel G. Pathology of the pancreas in chronic type 1 diabetes mellitus: B-cell content, exocrine atrophy and angiopathy. Verh Dtsch Ges Pathol 1987; 71: 114-119
• 113 Catalano MF, Sahai A, Levy M. et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc 2009; 69: 1251-1261
• 114 Catalano MF, Lahoti S, Geenen JE. et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998; 48: 11-17
• 115 Catalano MF, Geenen JE. Diagnosis of chronic pancreatitis by endoscopic ultrasonography. Endoscopy 1998; 30 (Suppl. 01) A111-A115
• 116 Chong AK, Hawes RH, Hoffman BJ. et al. Diagnostic performance of EUS for chronic pancreatitis: a comparison with histopathology. Gastrointest Endosc 2007; 65: 808-814
• 117 Nattermann C, Goldschmidt AJ, Dancygier H. Endosonography in chronic pancreatitis. A comparative study of endoscopic retrograde pancreatography and endoscopic sonography. Ultraschall Med 1992; 13: 263-270
• 118 Nattermann C, Goldschmidt AJ, Dancygier H. Endosonography in chronic pancreatitis--a comparison between endoscopic retrograde pancreatography and endoscopic ultrasonography. Endoscopy 1993; 25: 565-570
• 119 Pungpapong S, Wallace MB, Woodward TA. et al. Accuracy of endoscopic ultrasonography and magnetic resonance cholangiopancreatography for the diagnosis of chronic pancreatitis: a prospective comparison study. J Clin Gastroenterol 2007; 41: 88-93
• 120 Wiersema MJ, Hawes RH, Lehman GA. et al. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 1993; 25: 555-564
• 121 Tamura R, Ishibashi T, Takahashi S. Chronic pancreatitis: MRCP versus ERCP for quantitative caliber measurement and qualitative evaluation. Radiology 2006; 238: 920-928
• 122 Testoni PA, Mariani A, Curioni S. et al. MRCP-secretin test-guided management of idiopathic recurrent pancreatitis: long-term outcomes. Gastrointest Endosc 2008; 67: 1028-1034
• 123 Adamek HE, Albert J, Breer H. et al. Pancreatic cancer detection with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography: a prospective controlled study. Lancet 2000; 356: 190-193
• 124 Buscail L, Escourrou J, Moreau J. et al. Endoscopic ultrasonography in chronic pancreatitis: a comparative prospective study with conventional ultrasonography, computed tomography, and ERCP. Pancreas 1995; 10: 251-257
• 125 Stevens T, Conwell DL, Zuccaro GJr. et al. A prospective crossover study comparing secretin-stimulated endoscopic and Dreiling tube pancreatic function testing in patients evaluated for chronic pancreatitis. Gastrointest Endosc 2008; 67: 458-466
• 126 Stevens T, Conwell DL, Zuccaro Jr G. et al. Comparison of endoscopic ultrasound and endoscopic retrograde pancreatography for the prediction of pancreatic exocrine insufficiency. Dig Dis Sci 2008; 53: 1146-1151
• 127 Stevens T, Zuccaro Jr G. et al. Prospective comparison of radial and linear endoscopic ultrasound for diagnosis of chronic pancreatitis. Endoscopy 2009; 41: 836-841
• 128 Glasbrenner B, Kahl S, Malfertheiner P. Modern diagnostics of chronic pancreatitis. Eur J Gastroenterol Hepatol 2002; 14: 935-941
• 129 Hollerbach S, Ruser J, Ochs A. et al. Current status of abdominal pancreatic ultrasound. A retrospective analysis of 585 pancreatic ultrasound examinations. Med Klin (Munich) 1994; 89: 7-13
• 130 Kahl S, Glasbrenner B, Leodolter A. et al. EUS in the diagnosis of early chronic pancreatitis: a prospective follow-up study. Gastrointest Endosc 2002; 55: 507-511
• 131 Kahl S, Glasbrenner B, Zimmermann S. et al. Endoscopic ultrasound in pancreatic diseases. Dig Dis 2002; 20: 120-126
• 132 Sahai AV, Zimmerman M, Aabakken L. et al. Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc 1998; 48: 18-25
• 133 Gebel M, Stiehl M, Freise J. Value of sonographic imaging of the pancreatic duct for the diagnosis of chronic pancreatitis and pancreatic cancer compared to ERCP. Ultraschall Med 1985; 6: 127-130
• 134 Kahl S, Glasbrenner B, Leodolter A. et al. EUS in the diagnosis of early chronic pancreatitis: a prospective follow-up study. Gastrointest Endosc 2002; 55: 507-511
• 135 Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984; 25: 756-759
• 136 Sai JK, Suyama M, Kubokawa Y. et al. Diagnosis of mild chronic pancreatitis (Cambridge classification): comparative study using secretin injection-magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography. World J Gastroenterol 2008; 14: 1218-1221
• 137 Catalano MF, Lahoti S, Geenen JE. et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998; 48: 11-17
• 138 Janssen J, Schlorer E, Greiner L. EUS elastography of the pancreas: feasibility and pattern description of the normal pancreas, chronic pancreatitis, and focal pancreatic lesions. Gastrointest Endosc 2007; 65: 971-978
• 139 Saftoiu A, Vilmann P, Gorunescu F. et al. Neural network analysis of dynamic sequences of EUS elastography used for the differential diagnosis of chronic pancreatitis and pancreatic cancer. Gastrointest Endosc 2008; 68: 1086-1094
• 140 Iglesias-Garcia J, Larino-Noia J, Abdulkader I. et al. Quantitative endoscopic ultrasound elastography: an accurate method for the differentiation of solid pancreatic masses. Gastroenterology 139: 1172-1180
• 141 Dietrich CF, Hirche TO, Ott M. et al. Real-time tissue elastography in the diagnosis of autoimmune pancreatitis. Endoscopy 2009; 41: 718-720
• 142 Bagul A, Siriwardena AK. Evaluation of the Manchester classification system for chronic pancreatitis. JOP 2006; 7: 390-396
• 143 Buchler MW, Martignoni ME, Friess H. et al. A proposal for a new clinical classification of chronic pancreatitis. BMC Gastroenterol 2009; 9: 93
• 144 Ramesh H. Proposal for a new grading system for chronic pancreatitis: the ABC system. J Clin Gastroenterol 2002; 35: 67-70
• 145 Schneider A, Lohr JM, Singer MV. The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying classification system based on a review of previous classifications of the disease. J Gastroenterol 2007; 42: 101-119
• 146 Balthazar EJ, Robinson DL, Megibow AJ. et al. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990; 174: 331-336
• 147 Balthazar EJ, Freeny PC, vanSonnenberg E. Imaging and intervention in acute pancreatitis. Radiology 1994; 193: 297-306
• 148 Arvanitakis M, Delhaye M, De Maertelaere V. et al. Computed tomography and magnetic resonance imaging in the assessment of acute pancreatitis. Gastroenterology 2004; 126: 715-723
• 149 Rickes S, Uhle C, Kahl S. et al. Echo enhanced ultrasound: a new valid initial imaging approach for severe acute pancreatitis. Gut 2006; 55: 74-78
• 150 Brugge WR. Role of endoscopic ultrasound in the diagnosis of cystic lesions of the pancreas. Pancreatology 2001; 1: 637-640
• 151 Lerch MM, Stier A, Wahnschaffe U. et al. Pancreatic pseudocysts: observation, endoscopic drainage, or resection?. Dtsch Arztebl Int 2009; 106: 614-621
• 152 Will U, Mueller A, Topalidis T. et al. Value of endoscopic ultrasonography-guided fine needle aspiration (FNA) in the diagnosis of neoplastic tumor(-like) pancreatic lesions in daily clinical practice. Ultraschall Med 31: 169-174
• 153 Fritscher-Ravens A, Brand L, Knofel WT. et al. Comparison of endoscopic ultrasound-guided fine needle aspiration for focal pancreatic lesions in patients with normal parenchyma and chronic pancreatitis. Am J Gastroenterol 2002; 97: 2768-2775
• 154 Adler G, Seufferlein T. ZfG 2007: A successful interim result. Z Gastroenterol 2007; 45: 943
• 155 Kim JK, Altun E, Elias J. et al. Focal pancreatic mass: distinction of pancreatic cancer from chronic pancreatitis using gadolinium-enhanced 3D-gradient-echo MRI. J Magn Reson Imaging 2007; 26: 313-322
• 156 Hocke M, Schmidt C, Zimmer B. et al. Contrast enhanced endosonography for improving differential diagnosis between chronic pancreatitis and pancreatic cancer. Dtsch Med Wochenschr 2008; 133: 1888-1892
• 157 Krishna NB, Mehra M, Reddy AV. et al. EUS/EUS-FNA for suspected pancreatic cancer: influence of chronic pancreatitis and clinical presentation with or without obstructive jaundice on performance characteristics. Gastrointest Endosc 2009; 70: 70-79
• 158 Saftoiu A, Popescu C, Cazacu S. et al. Power Doppler endoscopic ultrasonography for the differential diagnosis between pancreatic cancer and pseudotumoral chronic pancreatitis. J Ultrasound Med 2006; 25: 363-372
• 159 Napoleon B, Alvarez-Sanchez MV, Gincoul R. et al. Contrast-enhanced harmonic endoscopic ultrasound in solid lesions of the pancreas: results of a pilot study. Endoscopy 42: 564-570
• 160 Ardengh JC, Paulo GA, Nakao FS. et al. Endoscopic ultrasound guided fine-needle aspiration core biopsy: comparison between an automatic biopsy device and two conventional needle systems. Acta Gastroenterol Latinoam 2008; 38: 105-115
• 161 Horwhat JD, Paulson EK, McGrath K. et al. A randomized comparison of EUS-guided FNA versus CT or US-guided FNA for the evaluation of pancreatic mass lesions. Gastrointest Endosc 2006; 63: 966-975
• 162 Chari ST. Diagnosis of autoimmune pancreatitis using its five cardinal features: introducing the Mayo Clinic's HISORt criteria. J Gastroenterol 2007; 42 (Suppl. 18) 39-41
• 163 Choi EK, Kim MH, Kim JC. et al. The Japanese diagnostic criteria for autoimmune chronic pancreatitis: is it completely satisfactory?. Pancreas 2006; 33: 13-19
• 164 Lerch MM, Mayerle J. The benefits of diagnostic ERCP in autoimmune pancreatitis. Gut 60: 565-566
• 165 Sugumar A, Levy MJ, Kamisawa T. et al. Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study. Gut 60: 666-670
• 166 Hirota M, Takada T, Kawarada Y. et al. JPN Guidelines for the management of acute pancreatitis: severity assessment of acute pancreatitis. J Hepatobiliary Pancreat Surg 2006; 13: 33-41
• 167 Hirota M, Takada T, Kitamura N. et al. Fundamental and intensive care of acute pancreatitis. J Hepatobiliary Pancreat Sci 17: 45-52
• 168 Gardner TB, Vege SS, Chari ST. et al. Faster rate of initial fluid resuscitation in severe acute pancreatitis diminishes in-hospital mortality. Pancreatology 2009; 9: 770-776
• 169 Wu BU, Johannes RS, Conwell DL. et al. Early hemoconcentration predicts increased mortality only among transferred patients with acute pancreatitis. Pancreatology 2009; 9: 639-643
• 170 Wu BU, Johannes RS, Sun X. et al. Early changes in blood urea nitrogen predict mortality in acute pancreatitis. Gastroenterology 2009; 137: 129-135
• 171 Brunkhorst FM, Engel C, Bloos F. et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 125-139
• 172 Lankisch PG, Mahlke R, Blum T. et al. Hemoconcentration: an early marker of severe and/or necrotizing pancreatitis? A critical appraisal. Am J Gastroenterol 2001; 96: 2081-2085
• 173 Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006; 101: 2379-2400
• 174 Field BE, Hepner GW, Shabot MM. et al. Nasogastric suction in alcoholic pancreatitis. Dig Dis Sci 1979; 24: 339-344
• 175 Fuller RK, Loveland JP, Frankel MH. An evaluation of the efficacy of nasogastric suction treatment in alcoholic pancreatitis. Am J Gastroenterol 1981; 75: 349-353
• 176 Naeije R, Salingret E, Clumeck N. et al. Is nasogastric suction necessary in acute pancreatitis?. Br Med J 1978; 2: 659-660
• 177 Sarr MG, Sanfey H, Cameron JL. Prospective, randomized trial of nasogastric suction in patients with acute pancreatitis. Surgery 1986; 100: 500-504
• 178 Jakobs R, Adamek MU, von Bubnoff AC. et al. Buprenorphine or procaine for pain relief in acute pancreatitis. A prospective randomized study. Scand J Gastroenterol 2000; 35: 1319-1323
• 179 Staritz M. Pharmacology of the sphincter of Oddi. Endoscopy 1988; 20 (Suppl. 01) 171-174
• 180 Niesel HC, Klimpel L, Kaiser H. et al. Epidural blockade for analgesia and treatment of acute pancreatitis. Reg Anaesth 1991; 14: 97-100
• 181 Bernhardt A, Kortgen A, Niesel H. et al. Using epidural anesthesia in patients with acute pancreatitis – prospective study of 121 patients. Anaesthesiol Reanim 2002; 27: 16-22
• 182 Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis. Am J Gastroenterol 2001; 96: 1266-1272
• 183 Niederau C, Niederau M, Luthen R. et al. Pancreatic exocrine secretion in acute experimental pancreatitis. Gastroenterology 1990; 99: 1120-1127
• 184 Eatock FC, Brombacher GD, Steven A. et al. Nasogastric feeding in severe acute pancreatitis may be practical and safe. Int J Pancreatol 2000; 28: 23-29
• 185 McClave SA, Greene LM, Snider HL. et al. Comparison of the safety of early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN J Parenter Enteral Nutr 1997; 21: 14-20
• 186 Olah A, Belagyi T, Issekutz A. et al. Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis. Br J Surg 2002; 89: 1103-1107
• 187 Powell JJ, Murchison JT, Fearon KC. et al. Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg 2000; 87: 1375-1381
• 188 Pupelis G, Selga G, Austrums E. et al. Jejunal feeding, even when instituted late, improves outcomes in patients with severe pancreatitis and peritonitis. Nutrition 2001; 17: 91-94
• 189 Sax HC, Warner BW, Talamini MA. et al. Early total parenteral nutrition in acute pancreatitis: lack of beneficial effects. Am J Surg 1987; 153: 117-124
• 190 Windsor AC, Kanwar S, Li AG. et al. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 1998; 42: 431-435
• 191 Karamitsios N, Saltzman JR. Enteral nutrition in acute pancreatitis. Nutr Rev 1997; 55: 279-282
• 192 Petrov MS, Kukosh MV, Emelyanov NV. A randomized controlled trial of enteral versus parenteral feeding in patients with predicted severe acute pancreatitis shows a significant reduction in mortality and in infected pancreatic complications with total enteral nutrition. Dig Surg 2006; 23: 336-344 ; discussion 344-335
• 193 Eckerwall GE, Axelsson JB, Andersson RG. Early nasogastric feeding in predicted severe acute pancreatitis: A clinical, randomized study. Ann Surg 2006; 244: 959-965 ; discussion 965-957
• 194 Eatock FC, Chong P, Menezes N. et al. A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gastroenterol 2005; 100: 432-439
• 195 Imrie CW, Carter CR, McKay CJ. Enteral and parenteral nutrition in acute pancreatitis. Best Pract Res Clin Gastroenterol 2002; 16: 391-397
• 196 Kumar A, Singh N, Prakash S. et al. Early enteral nutrition in severe acute pancreatitis: a prospective randomized controlled trial comparing nasojejunal and nasogastric routes. J Clin Gastroenterol 2006; 40: 431-434
• 197 Lecleire S, Antonietti M, Ben-Soussan E. et al. Nasojejunal feeding in patients with severe acute pancreatitis: comparison of endoscopic and self-migration tube placement. Pancreas 2007; 35: 376-378
• 198 Huber W, Umgelter A, Reindl W. et al. Volume assessment in patients with necrotizing pancreatitis: a comparison of intrathoracic blood volume index, central venous pressure, and hematocrit, and their correlation to cardiac index and extravascular lung water index. Crit Care Med 2008; 36: 2348-2354
• 199 Levy P, Heresbach D, Pariente EA. et al. Frequency and risk factors of recurrent pain during refeeding in patients with acute pancreatitis: a multivariate multicentre prospective study of 116 patients. Gut 1997; 40: 262-266
• 200 Petrov MS, van Santvoort HC, Besselink MG. et al. Oral refeeding after onset of acute pancreatitis: a review of literature. Am J Gastroenterol 2007; 102: 2079-2084
• 201 Eckerwall GE, Tingstedt BB, Bergenzaun PE. et al. Immediate oral feeding in patients with mild acute pancreatitis is safe and may accelerate recovery--a randomized clinical study. Clin Nutr 2007; 26: 758-763
• 202 Teich N, Aghdassi A, Fischer J. et al. Optimal timing of oral refeeding in mild acute pancreatitis: results of an open randomized multicenter trial. Pancreas 39: 1088-1092
• 203 Weimann A, Braunert M, Muller T. et al. Feasibility and safety of needle catheter jejunostomy for enteral nutrition in surgically treated severe acute pancreatitis. JPEN J Parenter Enteral Nutr 2004; 28: 324-327
• 204 Zhihui T, Wenkui Y, Weiqin L. et al. A randomised clinical trial of transnasal endoscopy versus fluoroscopy for the placement of nasojejunal feeding tubes in patients with severe acute pancreatitis. Postgrad Med J 2009; 85: 59-63
• 205 Sahin H, Mercanligil SM, Inanc N. et al. Effects of glutamine-enriched total parenteral nutrition on acute pancreatitis. Eur J Clin Nutr 2007; 61: 1429-1434
• 206 Fuentes-Orozco C, Cervantes-Guevara G, Mucino-Hernandez I. et al. L-alanyl-L-glutamine-supplemented parenteral nutrition decreases infectious morbidity rate in patients with severe acute pancreatitis. JPEN J Parenter Enteral Nutr 2008; 32: 403-411
• 207 Wang X, Li W, Zhang F. et al. Fish oil-supplemented parenteral nutrition in severe acute pancreatitis patients and effects on immune function and infectious risk: a randomized controlled trial. Inflammation 2009; 32: 304-309
• 208 Petrov MS, Loveday BP, Pylypchuk RD. et al. Systematic review and meta-analysis of enteral nutrition formulations in acute pancreatitis. Br J Surg 2009; 96: 1243-1252
• 209 Dellinger EP, Tellado JM, Soto NE. et al. Early antibiotic treatment for severe acute necrotizing pancreatitis: a randomized, double-blind, placebo-controlled study. Ann Surg 2007; 245: 674-683
• 210 Xu T, Cai Q. Prophylactic antibiotic treatment in acute necrotizing pancreatitis: results from a meta-analysis. Scand J Gastroenterol 2008; 43: 1249-1258
• 211 Villatoro E, Mulla M, Larvin M. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev: CD002941
• 212 Hart PA, Bechtold ML, Marshall JB. et al. Prophylactic antibiotics in necrotizing pancreatitis: a meta-analysis. South Med J 2008; 101: 1126-1131
• 213 Xue P, Deng LH, Zhang ZD. et al. Effect of antibiotic prophylaxis on acute necrotizing pancreatitis: results of a randomized controlled trial. J Gastroenterol Hepatol 2009; 24: 736-742
• 214 Isenmann R, Runzi M, Kron M. et al. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology 2004; 126: 997-1004
• 215 Rokke O, Harbitz TB, Liljedal J. et al. Early treatment of severe pancreatitis with imipenem: a prospective randomized clinical trial. Scand J Gastroenterol 2007; 42: 771-776
• 216 de Vries AC, Besselink MG, Buskens E. et al. Randomized controlled trials of antibiotic prophylaxis in severe acute pancreatitis: relationship between methodological quality and outcome. Pancreatology 2007; 7: 531-538
• 217 Olah A, Belagyi T, Issekutz A. et al. Combination of early nasojejunal feeding with modern synbiotic therapy in the treatment of severe acute pancreatitis (prospective, randomized, double-blind study). Magy Seb 2005; 58: 173-178
• 218 Besselink MG, van Santvoort HC, Buskens E. et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371: 651-659
• 219 Sand J, Nordback I. Probiotics in severe acute pancreatitis. Lancet 2008; 371: 634-635
• 220 Zhang MM, Cheng JQ, Lu YR. et al. Use of pre-, pro- and synbiotics in patients with acute pancreatitis: a meta-analysis. World J Gastroenterol 16: 3970-3978
• 221 Besselink MG, van Santvoort HC, Boermeester MA. et al. Timing and impact of infections in acute pancreatitis. Br J Surg 2009; 96: 267-273
• 222 Sharma M, Banerjee D, Garg PK. Characterization of newer subgroups of fulminant and subfulminant pancreatitis associated with a high early mortality. Am J Gastroenterol 2007; 102: 2688-2695
• 223 Nieuwenhuijs VB, Besselink MG, van Minnen LP. et al. Surgical management of acute necrotizing pancreatitis: a 13-year experience and a systematic review. Scand J Gastroenterol Suppl 2003; 111-116
• 224 Connor S, Alexakis N, Raraty MG. et al. Early and late complications after pancreatic necrosectomy. Surgery 2005; 137: 499-505
• 225 Mier J, Leon EL, Castillo A. et al. Early versus late necrosectomy in severe necrotizing pancreatitis. Am J Surg 1997; 173: 71-75
• 226 Runzi M, Niebel W, Goebell H. et al. Severe acute pancreatitis: nonsurgical treatment of infected necroses. Pancreas 2005; 30: 195-199
• 227 Shankar S, vanSonnenberg E, Silverman SG. et al. Imaging and percutaneous management of acute complicated pancreatitis. Cardiovasc Intervent Radiol 2004; 27: 567-580
• 228 Werner J, Feuerbach S, Uhl W. et al. Management of acute pancreatitis: from surgery to interventional intensive care. Gut 2005; 54: 426-436
• 229 van Santvoort HC, Besselink MG, Bakker OJ. et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med 362: 1491-1502
• 230 Raczynski S, Teich N, Borte G. et al. Percutaneous transgastric irrigation drainage in combination with endoscopic necrosectomy in necrotizing pancreatitis (with videos). Gastrointest Endosc 2006; 64: 420-424
• 231 Seewald S, Groth S, Omar S. et al. Aggressive endoscopic therapy for pancreatic necrosis and pancreatic abscess: a new safe and effective treatment algorithm (videos). Gastrointest Endosc 2005; 62: 92-100
• 232 Seifert H, Wehrmann T, Schmitt T. et al. Retroperitoneal endoscopic debridement for infected peripancreatic necrosis. Lancet 2000; 356: 653-655
• 233 Hocke M, Will U, Gottschalk P, Settmacher U, Stallmach A. Transgastral retroperitoneal endoscopy in septic patients with pancreatic necrosis or infected pancreatic pseudocysts. Z Gastroenterol 2008; 46: 1363-1368
• 234 Niederau C, Hippenstiel J. Conservative management of acute pancreatitis: complications and outcome in a community-based hospital. Pancreas 2006; 32: 67-79
• 235 Ramesh H, Prakash K, Lekha V. et al. Are some cases of infected pancreatic necrosis treatable without intervention?. Dig Surg 2003; 20: 296-299 ; discussion 300
• 236 Besselink MG, van Santvoort HC, Nieuwenhuijs VB. et al. Minimally invasive “step-up approach” versus maximal necrosectomy in patients with acute necrotising pancreatitis (PANTER trial): design and rationale of a randomised controlled multicenter trial [ISRCTN38327949]. BMC Surg 2006; 6: 6
• 237 Besselink MG, van Santvoort HC, Schaapherder AF. et al. Feasibility of minimally invasive approaches in patients with infected necrotizing pancreatitis. Br J Surg 2007; 94: 604-608
• 238 Besselink MG, van Santvoort HC, Witteman BJ. et al. Management of severe acute pancreatitis: it's all about timing. Curr Opin Crit Care 2007; 13: 200-206
• 239 van Santvoort HC, Besselink MG, Bollen TL. et al. Case-matched comparison of the retroperitoneal approach with laparotomy for necrotizing pancreatitis. World J Surg 2007; 31: 1635-1642
• 240 van Santvoort HC, Besselink MG, Horvath KD. et al. Videoscopic assisted retroperitoneal debridement in infected necrotizing pancreatitis. HPB (Oxford) 2007; 9: 156-159
• 241 Seifert H, Biermer M, Schmitt W. et al. Transluminal endoscopic necrosectomy after acute pancreatitis: a multicentre study with long-term follow-up (the GEPARD Study). Gut 2009; 58: 1260-1266
• 242 Chauhan S, Forsmark CE. Pain management in chronic pancreatitis: A treatment algorithm. Best Pract Res Clin Gastroenterol 24: 323-335
• 243 Dite P, Ruzicka M, Zboril V. et al. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 2003; 35: 553-558
• 244 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: 676-684
• 245 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 304: 1073-1081
• 246 Burris 3rd HA, Moore MJ. et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403-2413
• 247 Izbicki JR, Yekebas EF, Strate T. et al. Extrahepatic portal hypertension in chronic pancreatitis: an old problem revisited. Ann Surg 2002; 236: 82-89
• 248 Beger HG, Schlosser W, Friess HM. et al. Duodenum-preserving head resection in chronic pancreatitis changes the natural course of the disease: a single-center 26-year experience. Ann Surg 1999; 230: 512-519 ; discussion 519-523
• 249 Vijungco JD, Prinz RA. Management of biliary and duodenal complications of chronic pancreatitis. World J Surg 2003; 27: 1258-1270
• 250 Cahen DL, van Berkel AM, Oskam D. et al. Long-term results of endoscopic drainage of common bile duct strictures in chronic pancreatitis. Eur J Gastroenterol Hepatol 2005; 17: 103-108
• 251 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: 2448-2453
• 252 Smith MT, Sherman S, Ikenberry SO, Hawes RH, Lehman GA. Alterations in pancreatic ductal morphology following polyethylene pancreatic stent therapy. Gastrointest Endosc 1996; 44: 268-275
• 253 Kozarek RA. Pancreatic stents can induce ductal changes consistent with chronic pancreatitis. Gastrointest Endosc 1990; 36: 93-95
• 254 Nguyen-Tang T, Dumonceau JM. Endoscopic treatment in chronic pancreatitis, timing, duration and type of intervention. Best Pract Res Clin Gastroenterol 24: 281-298
• 255 Barthet M, Bugallo M, Moreira LS. et al. Management of cysts and pseudocysts complicating chronic pancreatitis. A retrospective study of 143 patients. Gastroenterol Clin Biol 1993; 17: 270-276
• 256 Andren-Sandberg A, Dervenis C. Surgical treatment of pancreatic pseudocysts in the 2000's--laparoscopic approach. Acta Chir Iugosl 2003; 50: 21-26
• 257 Traverso LW, Tompkins RK, Urrea PT. et al. Surgical treatment of chronic pancreatitis. Twenty-two years' experience. Ann Surg 1979; 190: 312-319
• 258 Usatoff V, Brancatisano R, Williamson RC. Operative treatment of pseudocysts in patients with chronic pancreatitis. Br J Surg 2000; 87: 1494-1499
• 259 Nealon WH, Walser E. Duct drainage alone is sufficient in the operative management of pancreatic pseudocyst in patients with chronic pancreatitis. Ann Surg 2003; 237: 614-620 ; discussion 620-612
• 260 Cheruvu CV, Clarke MG, Prentice M. et al. Conservative treatment as an option in the management of pancreatic pseudocyst. Ann R Coll Surg Engl 2003; 85: 313-316
• 261 Bartoli E, Delcenserie R, Yzet T. et al. Endoscopic treatment of chronic pancreatitis. Gastroenterol Clin Biol 2005; 29: 515-521
• 262 Johnson MD, Walsh RM, Henderson JM. et al. Surgical versus nonsurgical management of pancreatic pseudocysts. J Clin Gastroenterol 2009; 43: 586-590
• 263 Aghdassi A, Mayerle J, Kraft M. et al. Diagnosis and treatment of pancreatic pseudocysts in chronic pancreatitis. Pancreas 2008; 36: 105-112
• 264 NIH state-of-the-science statement on endoscopic retrograde cholangiopancreatography (ERCP) for diagnosis and therapy. NIH Consens State Sci Statements 2002; 19: 1-26
• 265 Barthet M, Lamblin G, Gasmi M. et al. Clinical usefulness of a treatment algorithm for pancreatic pseudocysts. Gastrointest Endosc 2008; 67: 245-252
• 266 Gouyon B, Levy P, Ruszniewski P. et al. Predictive factors in the outcome of pseudocysts complicating alcoholic chronic pancreatitis. Gut 1997; 41: 821-825
• 267 Bradley EL, Clements Jr JL , Gonzalez AC. The natural history of pancreatic pseudocysts: a unified concept of management. Am J Surg 1979; 137: 135-141
• 268 Varadarajulu S, Christein JD, Tamhane A. et al. Prospective randomized trial comparing EUS and EGD for transmural drainage of pancreatic pseudocysts (with videos). Gastrointest Endosc 2008; 68: 1102-1111
• 269 Tanaka M, Chari S, Adsay V. et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006; 6: 17-32
• 270 Brugge WR, Lewandrowski K, Lee-Lewandrowski E. et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004; 126: 1330-1336
• 271 Spinelli KS, Fromwiller TE, Daniel RA. et al. Cystic pancreatic neoplasms: observe or operate. Ann Surg 2004; 239: 651-657 ; discussion 657-659
• 272 Grutzmann R, Niedergethmann M, Pilarsky C. et al. Intraductal papillary mucinous tumors of the pancreas: biology, diagnosis, and treatment. Oncologist 15: 1294-1309
• 273 Megibow AJ, Baker ME, Gore RM. et al. The incidental pancreatic cyst. Radiol Clin North Am 49: 349-359
• 274 Werner J, Bartosch HRA, Andersson R. Cystic pancreatic lesions: Current evidence for diagnosis and treatment. Scand J Gastroenterol 2011; 46: 773-788
• 275 Barthet M, Sahel J, Bodiou-Bertei C. et al. Endoscopic transpapillary drainage of pancreatic pseudocysts. Gastrointest Endosc 1995; 42: 208-213
• 276 Udd M, Leppaniemi AK, Bidel S. et al. Treatment of bleeding pseudoaneurysms in patients with chronic pancreatitis. World J Surg 2007; 31: 504-510
• 277 Widdison AL, Alvarez C, Karanjia ND. et al. Experimental evidence of beneficial effects of ductal decompression in chronic pancreatitis. Endoscopy 1991; 23: 151-154
• 278 Treacy PJ, Worthley CS. Pancreatic stents in the management of chronic pancreatitis. Aust N Z J Surg 1996; 66: 210-213
• 279 Rosch T, Daniel S, Scholz M. et al. Endoscopic treatment of chronic pancreatitis: a multicenter study of 1000 patients with long-term follow-up. Endoscopy 2002; 34: 765-771
• 280 Cremer M, Deviere J, Delhaye M. et al. Stenting in severe chronic pancreatitis: results of medium-term follow-up in seventy-six patients. Endoscopy 1991; 23: 171-176
• 281 McCarthy J, Geenen JE, Hogan WJ. Preliminary experience with endoscopic stent placement in benign pancreatic diseases. Gastrointest Endosc 1988; 34: 16-18
• 282 Binmoeller KF, Jue P, Seifert H. et al. Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: long-term results. Endoscopy 1995; 27: 638-644
• 283 Huibregtse K, Schneider B, Vrij AA. et al. Endoscopic pancreatic drainage in chronic pancreatitis. Gastrointest Endosc 1988; 34: 9-15
• 284 Kozarek RA. Endoscopic treatment of chronic pancreatitis. Indian J Gastroenterol 2002; 21: 67-73
• 285 Kozarek RA, Ball TJ, Patterson DJ. et al. Endoscopic transpapillary therapy for disrupted pancreatic duct and peripancreatic fluid collections. Gastroenterology 1991; 100: 1362-1370
• 286 Kozarek RA, Patterson DJ, Ball TJ. et al. Endoscopic placement of pancreatic stents and drains in the management of pancreatitis. Ann Surg 1989; 209: 261-266
• 287 Kozarek RA, Traverso LW. Endotherapy for chronic pancreatitis. Int J Pancreatol 1996; 19: 93-102
• 288 Ponchon T, Bory RM, Hedelius F. et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointest Endosc 1995; 42: 452-456
• 289 Smits ME, Rauws EA, van Gulik TM. et al. Long-term results of endoscopic stenting and surgical drainage for biliary stricture due to chronic pancreatitis. Br J Surg 1996; 83: 764-768
• 290 Boerma D, van Gulik TM, Rauws EA. et al. Outcome of pancreaticojejunostomy after previous endoscopic stenting in patients with chronic pancreatitis. Eur J Surg 2002; 168: 223-228
• 291 Sauer B, Talreja J, Ellen K. et al. Temporary placement of a fully covered self-expandable metal stent in the pancreatic duct for management of symptomatic refractory chronic pancreatitis: preliminary data (with videos). Gastrointest Endosc 2008; 68: 1173-1178
• 292 Kahl S, Zimmermann S, Glasbrenner B. et al. Treatment of benign biliary strictures in chronic pancreatitis by self-expandable metal stents. Dig Dis 2002; 20: 199-203
• 293 Guda NM, Partington S, Freeman ML. Extracorporeal shock wave lithotripsy in the management of chronic calcific pancreatitis: a meta-analysis. JOP 2005; 6: 6-12
• 294 Schneider HT, May A, Benninger J. et al. Piezoelectric shock wave lithotripsy of pancreatic duct stones. Am J Gastroenterol 1994; 89: 2042-2048
• 295 Dumonceau JM, Costamagna G, Tringali A. et al. Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy versus endoscopic treatment: a randomised controlled trial. Gut 2007; 56: 545-552
• 296 Adamek HE, Jakobs R, Buttmann A. et al. Long term follow up of patients with chronic pancreatitis and pancreatic stones treated with extracorporeal shock wave lithotripsy. Gut 1999; 45: 402-405
• 297 Brand B, Kahl M, Sidhu S. et al. Prospective evaluation of morphology, function, and quality of life after extracorporeal shockwave lithotripsy and endoscopic treatment of chronic calcific pancreatitis. Am J Gastroenterol 2000; 95: 3428-3438
• 298 Barrioz T, Ingrand P, Besson I. et al. Randomised trial of prevention of biliary stent occlusion by ursodeoxycholic acid plus norfloxacin. Lancet 1994; 344: 581-582
• 299 Ghosh S, Palmer KR. Prevention of biliary stent occlusion using cyclical antibiotics and ursodeoxycholic acid. Gut 1994; 35: 1757-1759
• 300 Ghosh S, Palmer KR. Preventing biliary stent occlusion. Lancet 1994; 344: 1087-1088 ; author reply 1088-1089
• 301 Groen AK, Out T, Huibregtse K. et al. Characterization of the content of occluded biliary endoprostheses. Endoscopy 1987; 19: 57-59
• 302 Smit JM, Out MM, Groen AK. et al. A placebo-controlled study on the efficacy of aspirin and doxycycline in preventing clogging of biliary endoprostheses. Gastrointest Endosc 1989; 35: 485-489
• 303 Mayerle J, Stier A, Lerch MM. et al. [Chronic pancreatitis. Diagnosis and treatment]. Chirurg 2004; 75: 731-747 ; quiz 748
• 304 Catalano MF, Linder JD, George S. et al. Treatment of symptomatic distal common bile duct stenosis secondary to chronic pancreatitis: comparison of single vs. multiple simultaneous stents. Gastrointest Endosc 2004; 60: 945-952
• 305 van Boeckel PG, Vleggaar FP, Siersema PD. Plastic or metal stents for benign extrahepatic biliary strictures: a systematic review. BMC Gastroenterol 2009; 9: 96
• 306 Behm B, Brock A, Clarke BW. et al. Partially covered self-expandable metallic stents for benign biliary strictures due to chronic pancreatitis. Endoscopy 2009; 41: 547-551
• 307 Wilcox CM, Varadarajulu S. Endoscopic therapy for chronic pancreatitis: an evidence-based review. Curr Gastroenterol Rep 2006; 8: 104-110
• 308 Smits ME, Rauws EA, Tytgat GN. et al. Endoscopic treatment of pancreatic stones in patients with chronic pancreatitis. Gastrointest Endosc 1996; 43: 556-560
• 309 Cahen D, Rauws E, Fockens P. et al. Endoscopic drainage of pancreatic pseudocysts: long-term outcome and procedural factors associated with safe and successful treatment. Endoscopy 2005; 37: 977-983
• 310 Farnbacher MJ, Rabenstein T, Ell C. et al. Is endoscopic drainage of common bile duct stenoses in chronic pancreatitis up-to-date?. Am J Gastroenterol 2000; 95: 1466-1471
• 311 Lawrence C, Romagnuolo J, Payne KM. et al. Low symptomatic premature stent occlusion of multiple plastic stents for benign biliary strictures: comparing standard and prolonged stent change intervals. Gastrointest Endosc 72: 558-563
• 312 McClaine RJ, Lowy AM, Matthews JB. et al. A comparison of pancreaticoduodenectomy and duodenum-preserving head resection for the treatment of chronic pancreatitis. HPB (Oxford) 2009; 11: 677-683
• 313 Muller MW, Friess H, Martin DJ. et al. Long-term follow-up of a randomized clinical trial comparing Beger with pylorus-preserving Whipple procedure for chronic pancreatitis. Br J Surg 2008; 95: 350-356
• 314 Riediger H, Adam U, Fischer E. et al. Long-term outcome after resection for chronic pancreatitis in 224 patients. J Gastrointest Surg 2007; 11: 949-959 ; discussion 959-960
• 315 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: 129-137
• 316 Mullady DK, Yadav D, Amann ST. et al. Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study. Gut 60: 77-84
• 317 Bloechle C, Izbicki JR, Knoefel WT. et al. Quality of life in chronic pancreatitis--results after duodenum-preserving resection of the head of the pancreas. Pancreas 1995; 11: 77-85
• 318 Pezzilli R, Fantini L, Calculli L. et al. The quality of life in chronic pancreatitis: the clinical point of view. JOP 2006; 7: 113-116
• 319 Delcore R, Rodriguez FJ, Thomas JH. et al. The role of pancreatojejunostomy in patients without dilated pancreatic ducts. Am J Surg 1994; 168: 598-601 ; discussion 601-592
• 320 Malfertheiner P, Mayer D, Buchler M. et al. Treatment of pain in chronic pancreatitis by inhibition of pancreatic secretion with octreotide. Gut 1995; 36: 450-454
• 321 Lieb 2nd JG, Shuster JJ. et al. A pilot study of Octreotide LAR vs. octreotide tid for pain and quality of life in chronic pancreatitis. JOP 2009; 10: 518-522
• 322 Shafiq N, Rana S, Bhasin D. et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst Rev 2009 CD0063022nd
• 323 Whitcomb DC, Lehman GA, Vasileva G. et al. Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A double-blind randomized trial. Am J Gastroenterol 2010; 105: 2276-2286
• 324 Uden S, Bilton D, Nathan L. et al. Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial. Aliment Pharmacol Ther 1990; 4: 357-371
• 325 Kirk GR, White JS, McKie L. et al. Combined antioxidant therapy reduces pain and improves quality of life in chronic pancreatitis. J Gastrointest Surg 2006; 10: 499-503
• 326 Bhardwaj P, Garg PK, Maulik SK. et al. A randomized controlled trial of antiioxidant supplementation for pain relief in patients with chronic pancreatitis. Gastroenterology 2009; 136: 149-159 e142
• 327 Omenn GS, Goodman GE, Thornquist MD. et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996; 334: 1150-1155
• 328 The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330: 1029-1035
• 329 Ballegaard S, Christophersen SJ, Dawids SG. et al. Acupuncture and transcutaneous electric nerve stimulation in the treatment of pain associated with chronic pancreatitis. A randomized study. Scand J Gastroenterol 1985; 20: 1249-1254
• 330 Cartmell MT, O'Reilly DA, Porter C. et al. A double-blind placebo-controlled trial of a leukotriene receptor antagonist in chronic pancreatitis in humans. J Hepatobiliary Pancreat Surg 2004; 11: 255-259
• 331 Guarner L, Navalpotro B, Molero X. et al. Management of painful chronic pancreatitis with single-dose radiotherapy. Am J Gastroenterol 2009; 104: 349-355
• 332 Kaufman M, Singh G, Das S. et al. Efficacy of endoscopic ultrasound-guided celiac plexus block and celiac plexus neurolysis for managing abdominal pain associated with chronic pancreatitis and pancreatic cancer. J Clin Gastroenterol 2010; 44: 127-134
• 333 Puli SR, Reddy JB, Bechtold ML. et al. EUS-guided celiac plexus neurolysis for pain due to chronic pancreatitis or pancreatic cancer pain: a meta-analysis and systematic review. Dig Dis Sci 2009; 54: 2330-2337
• 334 Howard TJ, Swofford JB, Wagner DL. et al. Quality of life after bilateral thoracoscopic splanchnicectomy: long-term evaluation in patients with chronic pancreatitis. J Gastrointest Surg 2002; 6: 845-852 ; discussion 853-844
• 335 Stefaniak T, Vingerhoets A, Makarewicz W. et al. Opioid use determines success of videothoracoscopic splanchnicectomy in chronic pancreatic pain patients. Langenbecks Arch Surg 2008; 393: 213-218
• 336 Gress F, Schmitt C, Sherman S. et al. A prospective randomized comparison of endoscopic ultrasound- and computed tomography-guided celiac plexus block for managing chronic pancreatitis pain. Am J Gastroenterol 1999; 94: 900-905
• 337 LeBlanc JK, DeWitt J, Johnson C. et al. A prospective randomized trial of 1 versus 2 injections during EUS-guided celiac plexus block for chronic pancreatitis pain. Gastrointest Endosc 2009; 69: 835-842
• 338 Madsen P, Hansen E. Coeliac plexus block versus pancreaticogastrostomy for pain in chronic pancreatitis. A controlled randomized trial. Scand J Gastroenterol 1985; 20: 1217-1220
• 339 Santosh D, Lakhtakia S, Gupta R. et al. Clinical trial: a randomized trial comparing fluoroscopy guided percutaneous technique vs. endoscopic ultrasound guided technique of coeliac plexus block for treatment of pain in chronic pancreatitis. Aliment Pharmacol Ther 2009; 29: 979-984
• 340 Sahai AV, Lemelin V, Lam E. et al. Central vs. bilateral endoscopic ultrasound-guided celiac plexus block or neurolysis: a comparative study of short-term effectiveness. Am J Gastroenterol 2009; 104: 326-329
• 341 Deviere J, Bell Jr RH , Beger HG. et al. Treatment of chronic pancreatitis with endotherapy or surgery: critical review of randomized control trials. J Gastrointest Surg 2008; 12: 640-644
• 342 Regan PT, Malagelada JR, DiMagno EP. et al. Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 1977; 297: 854-858
• 343 Layer P, von der Ohe MR, Holst JJ. et al. Altered postprandial motility in chronic pancreatitis: role of malabsorption. Gastroenterology 1997; 112: 1624-1634
• 344 Wooldridge JL, Heubi JE, Amaro-Galvez R. et al. EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency. J Cyst Fibros 2009; 8: 405-417
• 345 Layer P, Yamamoto H, Kalthoff L. et al. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994; 107: 1481-1487
• 346 Czako L, Takacs T, Hegyi P. et al. Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis. Can J Gastroenterol 2003; 17: 597-603
• 347 Dominguez-Munoz JE, Iglesias-Garcia J, Vilarino-Insua M. et al. 13C-mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2007; 5: 484-488
• 348 Dominguez-Munoz JE, Iglesias-Garcia J. Oral pancreatic enzyme substitution therapy in chronic pancreatitis: is clinical response an appropriate marker for evaluation of therapeutic efficacy?. JOP 2010; 11: 158-162
• 349 Ritz MA, Fraser RJ, Di Matteo AC. et al. Evaluation of the 13C-triolein breath test for fat malabsorption in adult patients with cystic fibrosis. J Gastroenterol Hepatol 2004; 19: 448-453
• 350 Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M. et al. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther 2005; 21: 993-1000
• 351 Heizer WD, Cleaveland CR, Iber FL. Gastric Inactivation of Pancreatic Supplements. Bull Johns Hopkins Hosp 1965; 116: 261-270
• 352 Delchier JC, Vidon N, Saint-Marc Girardin MF. et al. Fate of orally ingested enzymes in pancreatic insufficiency: comparison of two pancreatic enzyme preparations. Aliment Pharmacol Ther 1991; 5: 365-378
• 353 Meyer JH, Elashoff J, Porter-Fink V. et al. Human postprandial gastric emptying of 1-3-millimeter spheres. Gastroenterology 1988; 94: 1315-1325
• 354 Borowitz D, Goss CH, Limauro S. et al. Study of a novel pancreatic enzyme replacement therapy in pancreatic insufficient subjects with cystic fibrosis. J Pediatr 2006; 149: 658-662
• 355 Bruno MJ, Rauws EA, Hoek FJ. et al. Comparative effects of adjuvant cimetidine and omeprazole during pancreatic enzyme replacement therapy. Dig Dis Sci 1994; 39: 988-992
• 356 Bruno MJ, Borm JJ, Hoek FJ. et al. Comparative effects of enteric-coated pancreatin microsphere therapy after conventional and pylorus-preserving pancreatoduodenectomy. Br J Surg 1997; 84: 952-956
• 357 Durie PR, Bell L, Linton W. et al. Effect of cimetidine and sodium bicarbonate on pancreatic replacement therapy in cystic fibrosis. Gut 1980; 21: 778-786
• 358 Lankisch PG, Lembcke B, Kirchhoff S. et al. Therapy of pancreatogenic steatorrhea. Comparison of 2 acid-protected enzyme preparations. Dtsch Med Wochenschr 1988; 113: 15-17
• 359 Carroccio A, Pardo F, Montalto G. et al. Use of famotidine in severe exocrine pancreatic insufficiency with persistent maldigestion on enzymatic replacement therapy. A long-term study in cystic fibrosis. Dig Dis Sci 1992; 37: 1441-1446
• 360 Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut 2005; 54 (Suppl. 06) vi1-28
• 361 Casellas F, Guarner L, Vaquero E. et al. Hydrogen breath test with glucose in exocrine pancreatic insufficiency. Pancreas 1998; 16: 481-486
• 362 Smyth RL, Ashby D, O'Hea U. et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet 1995; 346: 1247-1251
• 363 Serban DE, Florescu P, Miu N. Fibrosing colonopathy revealing cystic fibrosis in a neonate before any pancreatic enzyme supplementation. J Pediatr Gastroenterol Nutr 2002; 35: 356-359
• 364 Taylor CJ. Fibrosing colonopathy unrelated to pancreatic enzyme supplementation. J Pediatr Gastroenterol Nutr 2002; 35: 268-269
• 365 Waters BL. Cystic fibrosis with fibrosing colonopathy in the absence of pancreatic enzymes. Pediatr Dev Pathol 1998; 1: 74-78
• 366 Connett GJ, Lucas JS, Atchley JT. et al. Colonic wall thickening is related to age and not dose of high strength pancreatin microspheres in children with cystic fibrosis. Eur J Gastroenterol Hepatol 1999; 11: 181-183
• 367 O'Keefe SJ, Stevens S, Lee R. et al. Physiological evaluation of the severity of pancreatic exocrine dysfunction during endoscopy. Pancreas 2007; 35: 30-36
• 368 Nojgaard C. Prognosis of acute and chronic pancreatitis – a 30-year follow-up of a Danish cohort. Dan Med Bull 2010; 57: B4228
• 369 Hebuterne X, Hastier P, Peroux JL. et al. Resting energy expenditure in patients with alcoholic chronic pancreatitis. Dig Dis Sci 1996; 41: 533-539
• 370 Suzuki A, Mizumoto A, Sarr MG. et al. Bacterial lipase and high-fat diets in canine exocrine pancreatic insufficiency: a new therapy of steatorrhea?. Gastroenterology 1997; 112: 2048-2055
• 371 Caliari S, Benini L, Sembenini C. et al. Medium-chain triglyceride absorption in patients with pancreatic insufficiency. Scand J Gastroenterol 1996; 31: 90-94
• 372 Gullo L, Barbara L, Labo G. Effect of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology 1988; 95: 1063-1068
• 373 Marotta F, Labadarios D, Frazer L. et al. Fat-soluble vitamin concentration in chronic alcohol-induced pancreatitis. Relationship with steatorrhea. Dig Dis Sci 1994; 39: 993-998
• 374 American Gastroenterological Association Medical Position Statement: treatment of pain in chronic pancreatitis. Gastroenterology 1998; 115: 763-764
• 375 Birkmeyer JD, Siewers AE, Finlayson EV. et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346: 1128-1137
• 376 Fong Y, Gonen M, Rubin D. et al. Long-term survival is superior after resection for cancer in high-volume centers. Ann Surg 2005; 242: 540-544 ; discussion 544-547
• 377 Belina F, Fronek J, Ryska M. Duodenopancreatectomy versus duodenum-preserving pancreatic head excision for chronic pancreatitis. Pancreatology 2005; 5: 547-552
• 378 Witzigmann H, Max D, Uhlmann D. et al. Quality of life in chronic pancreatitis: a prospective trial comparing classical whipple procedure and duodenum-preserving pancreatic head resection. J Gastrointest Surg 2002; 6: 173-179 ; discussion 179-180
• 379 Hartwig W, Hackert T, Hinz U. et al. Pancreatic cancer surgery in the new millennium: better prediction of outcome. Ann Surg 2011; 254: 311-319
• 380 Strobel O, Buchler MW, Werner J. Duodenum-preserving pancreatic head resection: technique according to Beger, technique according to Frey and Berne modifications. Chirurg 2009; 80: 22-27
• 381 Witzigmann H, Max D, Uhlmann D. et al. Outcome after duodenum-preserving pancreatic head resection is improved compared with classic Whipple procedure in the treatment of chronic pancreatitis. Surgery 2003; 134: 53-62
• 382 Mobius C, Max D, Uhlmann D. et al. Five-year follow-up of a prospective non-randomised study comparing duodenum-preserving pancreatic head resection with classic Whipple procedure in the treatment of chronic pancreatitis. Langenbecks Arch Surg 2007; 392: 359-364
• 383 Izbicki JR, Bloechle C, Knoefel WT. et al. Drainage versus resection in surgical therapy of chronic pancreatitis of the head of the pancreas: a randomized study. Chirurg 1997; 68: 369-377
• 384 Diener MK, Bruckner T, Contin P. et al. ChroPac-trial: duodenum-preserving pancreatic head resection versus pancreatoduodenectomy for chronic pancreatitis. Trial protocol of a randomised controlled multicentre trial. Trials 11: 47
• 385 Diener MK, Knaebel HP, Witte ST. et al. DISPACT trial: a randomized controlled trial to compare two different surgical techniques of DIStal PAnCreaTectomy – study rationale and design. Clin Trials 2008; 5: 534-545
• 386 Diener MK, Rahbari NN, Fischer L. et al. Duodenum-preserving pancreatic head resection versus pancreatoduodenectomy for surgical treatment of chronic pancreatitis: a systematic review and meta-analysis. Ann Surg 2008; 247: 950-961
• 387 Izbicki JR, Bloechle C, Broering DC. et al. Extended drainage versus resection in surgery for chronic pancreatitis: a prospective randomized trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg 1998; 228: 771-779
• 388 Izbicki JR, Bloechle C, Broering DC. et al. Longitudinal V-shaped excision of the ventral pancreas for small duct disease in severe chronic pancreatitis: prospective evaluation of a new surgical procedure. Ann Surg 1998; 227: 213-219
• 389 Koninger J, Seiler CM, Sauerland S. et al. Duodenum-preserving pancreatic head resection--a randomized controlled trial comparing the original Beger procedure with the Berne modification (ISRCTN No. 50638764). Surgery 2008; 143: 490-498
• 390 Muller MW, Friess H, Leitzbach S. et al. Perioperative and follow-up results after central pancreatic head resection (Berne technique) in a consecutive series of patients with chronic pancreatitis. Am J Surg 2008; 196: 364-372
• 391 Strate T, Bachmann K, Busch P. et al. Resection vs drainage in treatment of chronic pancreatitis: long-term results of a randomized trial. Gastroenterology 2008; 134: 1406-1411
• 392 Gloor B, Friess H, Uhl W. et al. A modified technique of the Beger and Frey procedure in patients with chronic pancreatitis. Dig Surg 2001; 18: 21-25
• 393 Buchler MW, Friess H, Muller MW. et al. Randomized trial of duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis. Am J Surg 1995; 169: 65-69 ; discussion 69-70
• 394 Strate T, Taherpour Z, Bloechle C. et al. Long-term follow-up of a randomized trial comparing the beger and frey procedures for patients suffering from chronic pancreatitis. Ann Surg 2005; 241: 591-598
• 395 Duval Jr MK . Caudal pancreaticojejunostomy for chronic pancreatitis; operative criteria and technique. Surg Clin North Am 1956; 831-839
• 396 Partington PF. Chronic pancreatitis treated by Roux type jejunal anastomosis to the biliary tract. AMA Arch Surg 1952; 65: 532-542
• 397 Jimenez RE, Fernandez-Del Castillo C, Rattner DW. et al. Pylorus-preserving pancreaticoduodenectomy in the treatment of chronic pancreatitis. World J Surg 2003; 27: 1211-1216
• 398 Buchler MW, Warshaw AL. Resection versus drainage in treatment of chronic pancreatitis. Gastroenterology 2008; 134: 1605-1607
• 399 Beger HG, Witte C, Krautzberger W. et al. Experiences with duodenum-sparing pancreas head resection in chronic pancreatitis. Chirurg 1980; 51: 303-307
• 400 Bloechle C, Busch C, Tesch C. et al. Prospective randomized study of drainage and resection on non-occlusive segmental portal hypertension in chronic pancreatitis. Br J Surg 1997; 84: 477-482
• 401 Frey CF, Amikura K. Local resection of the head of the pancreas combined with longitudinal pancreaticojejunostomy in the management of patients with chronic pancreatitis. Ann Surg 1994; 220: 492-504 ; discussion 504-497
• 402 Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas 1987; 2: 701-707
• 403 Yekebas EF, Bogoevski D, Honarpisheh H. et al. Long-term follow-up in small duct chronic pancreatitis: A plea for extended drainage by "V-shaped excision" of the anterior aspect of the pancreas. Ann Surg 2006; 244: 940-946 ; discussion 946-948
• 404 Bockhorn M, Gebauer F, Bogoevski D. et al. Chronic pancreatitis complicated by cavernous transformation of the portal vein: contraindication to surgery?. Surgery 2011; 149: 321-328
• 405 Shrikhande SV, Kleeff J, Friess H. et al. Management of pain in small duct chronic pancreatitis. J Gastrointest Surg 2006; 10: 227-233
• 406 Whipple AO, Parsons WB, Mullins CR. Treatment of Carcinoma of the Ampulla of Vater. Ann Surg 1935; 102: 763-779
• 407 Yeo CJ, Cameron JL, Sohn TA. et al. Pancreaticoduodenectomy with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: comparison of morbidity and mortality and short-term outcome. Ann Surg 1999; 229: 613-622; discussion 622-614
• 408 Warshaw AL, Thayer SP. Pancreaticoduodenectomy. J Gastrointest Surg 2004; 8: 733-741
• 409 Cameron JL, Riall TS, Coleman J. et al. One thousand consecutive pancreaticoduodenectomies. Ann Surg 2006; 244: 10-15
• 410 Beger HG, Kunz R, Poch B. The Beger procedure--duodenum-preserving pancreatic head resection. J Gastrointest Surg 2004; 8: 1090-1097
• 411 Izbicki JR, Bloechle C, Knoefel WT. et al. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized trial. Ann Surg 1995; 221: 350-358
• 412 Cataldegirmen G, Schneider CG, Bogoevski D. et al. Extended central pancreatic resection as an alternative for extended left or extended right resection for appropriate pancreatic neoplasms. Surgery 2010; 147: 331-338
• 413 Asanuma Y, Koyama K, Saito K. et al. An appraisal of segmental pancreatectomy for benign tumors of the pancreatic body: a report of two cases. Surg Today 1993; 23: 733-736
• 414 Christein JD, Kim AW, Golshan MA. et al. Central pancreatectomy for the resection of benign or low malignant potential neoplasms. World J Surg 2003; 27: 595-598
• 415 Iacono C, Bortolasi L, Serio G. Is there a place for central pancreatectomy in pancreatic surgery?. J Gastrointest Surg 1998; 2: 509-516 ; discussion 516-507
• 416 Ikeda S, Matsumoto S, Maeshiro K. et al. Segmental pancreatectomy for the diagnosis and treatment of small lesions in the neck or body of the pancreas. Hepatogastroenterology 1995; 42: 730-733
• 417 Rotman N, Sastre B, Fagniez PL. Medial pancreatectomy for tumors of the neck of the pancreas. Surgery 1993; 113: 532-535
• 418 Sperti C, Pasquali C, Ferronato A. et al. Median pancreatectomy for tumors of the neck and body of the pancreas. J Am Coll Surg 2000; 190: 711-716
• 419 Warshaw AL, Rattner DW, Fernandez-del CastilloC. et al. Middle segment pancreatectomy: a novel technique for conserving pancreatic tissue. Arch Surg 1998; 133: 327-331
• 420 Muller MW, Friess H, Kleeff J. et al. Middle segmental pancreatic resection: An option to treat benign pancreatic body lesions. Ann Surg 2006; 244: 909-918 ; discussion 918-920
• 421 Sauvanet A, Partensky C, Sastre B. et al. Medial pancreatectomy: a multi-institutional retrospective study of 53 patients by the French Pancreas Club. Surgery 2002; 132: 836-843
• 422 Partelli S, Boninsegna L, Salvia R. et al. Middle-preserving pancreatectomy for multicentric body-sparing lesions of the pancreas. Am J Surg 2009; 198: e49-53
• 423 Braasch JW, Vito L, Nugent FW. Total pancreatectomy of end-stage chronic pancreatitis. Ann Surg 1978; 188: 317-322
• 424 Rossi RL, Rothschild J, Braasch JW. et al. Pancreatoduodenectomy in the management of chronic pancreatitis. Arch Surg 1987; 122: 416-420
• 425 Balcom JHt, Rattner DW, Warshaw AL. et al. Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001; 136: 391-398
• 426 Buchler MW, Wagner M, Schmied BM. et al. Changes in morbidity after pancreatic resection: toward the end of completion pancreatectomy. Arch Surg 2003; 138: 1310-1314 ; discussion 1315
• 427 Pratt WB, Maithel SK, Vanounou T. et al. Clinical and economic validation of the International Study Group of Pancreatic Fistula (ISGPF) classification scheme. Ann Surg 2007; 245: 443-451
• 428 Reid-Lombardo KM, Farnell MB, Crippa S. et al. Pancreatic anastomotic leakage after pancreaticoduodenectomy in 1 507 patients: a report from the Pancreatic Anastomotic Leak Study Group. J Gastrointest Surg 2007; 11: 1451-1458 ; discussion 1459
• 429 Reid-Lombardo KM, Ramos-De la Medina A, Thomsen K. et al. Long-term anastomotic complications after pancreaticoduodenectomy for benign diseases. J Gastrointest Surg 2007; 11: 1704-1711
• 430 Bassi C, Dervenis C, Butturini G. et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 2005; 138: 8-13
• 431 Welsch T, Borm M, Degrate L. et al. Evaluation of the International Study Group of Pancreatic Surgery definition of delayed gastric emptying after pancreatoduodenectomy in a high-volume centre. Br J Surg 2010; 97: 1043-1050
• 432 Welsch T, Frommhold K, Hinz U. et al. Persisting elevation of C-reactive protein after pancreatic resections can indicate developing inflammatory complications. Surgery 2008; 143: 20-28
• 433 Molinari E, Bassi C, Salvia R. et al. Amylase value in drains after pancreatic resection as predictive factor of postoperative pancreatic fistula: results of a prospective study in 137 patients. Ann Surg 2007; 246: 281-287
• 434 Seelig MH, Chromik AM, Weyhe D. et al. Pancreatic redo procedures: to do or not to do -- this is the question. J Gastrointest Surg 2007; 11: 1175-1182
• 435 Cruciani RA, Jain S. Pancreatic pain: a mini review. Pancreatology 2008; 8: 230-235
• 436 Laubenthal H, Becker M, Neugebauer E. Guideline: "Treatment of acute perioperative and posttraumatic pain". Updating from the S2- to the S3-level: a preliminary report. Anasthesiol Intensivmed Notfallmed Schmerzther 2006; 41: 470-472
• 437 Gueroult S, Parc Y, Duron F. et al. Completion pancreatectomy for postoperative peritonitis after pancreaticoduodenectomy: early and late outcome. Arch Surg 2004; 139: 16-19
• 438 de Castro SM, Busch OR, van Gulik TM. et al. Incidence and management of pancreatic leakage after pancreatoduodenectomy. Br J Surg 2005; 92: 1117-1123
• 439 Lowenfels AB, Maisonneuve P, Cavallini G. et al. Prognosis of chronic pancreatitis: an international multicenter study. International Pancreatitis Study Group. Am J Gastroenterol 1994; 89: 1467-1471
• 440 Lowenfels AB, Sullivan T, Fiorianti J. et al. The epidemiology and impact of pancreatic diseases in the United States. Curr Gastroenterol Rep 2005; 7: 90-95
• 441 Levy P, Milan C, Pignon JP. et al. Mortality factors associated with chronic pancreatitis. Unidimensional and multidimensional analysis of a medical-surgical series of 240 patients. Gastroenterology 1989; 96: 1165-1172
• 442 Seicean A, Tantau M, Grigorescu M. et al. Mortality risk factors in chronic pancreatitis. J Gastrointestin Liver Dis 2006; 15: 21-26
• 443 Gullo L, Parenti M, Monti L. et al. Diabetic retinopathy in chronic pancreatitis. Gastroenterology 1990; 98: 1577-1581
• 444 Billings BJ, Christein JD, Harmsen WS. et al. Quality-of-life after total pancreatectomy: is it really that bad on long-term follow-up?. J Gastrointest Surg 2005; 9: 1059-1066 ; discussion 1066-1057
• 445 Nakamura T, Imamura K, Takebe K. et al. Diabetic retinopathy in Japanese patients with long-standing pancreatic diabetes due to calcifying pancreatitis. Tohoku J Exp Med 1994; 174: 49-58
• 446 Rosa ESL, Troncon LE, Gallo LJr. et al. Factors associated with abnormal gastric emptying in alcohol-related chronic pancreatitis. J Clin Gastroenterol 2007; 41: 306-311
• 447 Tiengo A, Segato T, Briani G. et al. The presence of retinopathy in patients with secondary diabetes following pancreatectomy or chronic pancreatitis. Diabetes Care 1983; 6: 570-574
• 448 Malka D, Levy P, Bernades P. Thrombotic thrombocytopenic purpura caused by acute pancreatitis in a woman with a pancreas divisum: a case report. Pancreas 1996; 12: 414-416
• 449 Parsaik AK, Murad MH, Sathananthan A. et al. Metabolic and target organ outcomes after total pancreatectomy: Mayo Clinic experience and meta-analysis of the literature. Clin Endocrinol (Oxf) 73: 723-731
• 450 Moran CE, Sosa EG, Martinez SM. et al. Bone mineral density in patients with pancreatic insufficiency and steatorrhea. Am J Gastroenterol 1997; 92: 867-871
• 451 Teichmann J, Mann ST, Stracke H. et al. Alterations of vitamin D3 metabolism in young women with various grades of chronic pancreatitis. Eur J Med Res 2007; 12: 347-350
• 452 Lowenfels AB. Chronic pancreatitis, pancreatic cancer, alcohol, and smoking. Gastroenterology 1984; 87: 744-745
• 453 Ammann RW, Heitz PU, Kloppel G. The "two-hit" pathogenetic concept of chronic pancreatitis. Int J Pancreatol 1999; 25: 251
• 454 Talamini G, Bassi C, Falconi M. et al. Early detection of pancreatic cancer following the diagnosis of chronic pancreatitis. Digestion 1999; 60: 554-561
• 455 Mohan V, Premalatha G, Padma A. et al. Fibrocalculous pancreatic diabetes. Long-term survival analysis. Diabetes Care 1996; 19: 1274-1278
• 456 Rosch T, Schusdziarra V, Born P. et al. Modern imaging methods versus clinical assessment in the evaluation of hospital in-patients with suspected pancreatic disease. Am J Gastroenterol 2000; 95: 2261-2270
• 457 Adler G, Seufferlein T, Bischoff SC. et al. S3-Guidelines "Exocrine pancreatic cancer" 2007. Z Gastroenterol 2007; 45: 487-523
• 458 Tuyns AJ, Pequignot G, Jensen OM. [Esophageal cancer in Ille-et-Vilaine in relation to levels of alcohol and tobacco consumption. Risks are multiplying]. Bull Cancer 1977; 64: 45-60
• 459 Salaspuro MP. Alcohol consumption and cancer of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 2003; 17: 679-694
• 460 Menge BA, Schrader H, Breuer TG. et al. Metabolic consequences of a 50% partial pancreatectomy in humans. Diabetologia 2009; 52: 306-317
• 461 Ozturk E, Can MF, Yagci G. et al. Management and mid- to long-term results of early referred bile duct injuries during laparoscopic cholecystectomy. Hepatogastroenterology 2009; 56: 17-25
• 462 Muller MW, Friess H, Kleeff J. et al. Is there still a role for total pancreatectomy?. Ann Surg 2007; 246: 966-974 ; discussion 974-965
• 463 Linehan IP, Lambert MA, Brown DC. et al. Total pancreatectomy for chronic pancreatitis. Gut 1988; 29: 358-365
• 464 Cooperman AM, Herter FP, Marboe CA. et al. Pancreatoduodenal resection and total pnacreatectomy--an institutional review. Surgery 1981; 90: 707-712
• 465 Benifla M, Weizman Z. Acute pancreatitis in childhood: analysis of literature data. J Clin Gastroenterol 2003; 37: 169-172
• 466 Tomomasa T, Tabata M, Miyashita M. et al. Acute pancreatitis in Japanese and Western children: etiologic comparisons. J Pediatr Gastroenterol Nutr 1994; 19: 109-110
• 467 Darge K, Anupindi S. Pancreatitis and the role of US, MRCP and ERCP. Pediatr Radiol 2009; 39 (Suppl. 02) S153-S157
• 468 Varadarajulu S, Tamhane A, Eloubeidi MA. Yield of EUS-guided FNA of pancreatic masses in the presence or the absence of chronic pancreatitis. Gastrointest Endosc 2005; 62: 728-736 ; quiz 751, 753
• 469 Varadarajulu S, Wilcox CM, Eloubeidi MA. Impact of EUS in the evaluation of pancreaticobiliary disorders in children. Gastrointest Endosc 2005; 62: 239-244
• 470 Attila T, Adler DG, Hilden K. et al. EUS in pediatric patients. Gastrointest Endosc 2009; 70: 892-898
• 471 Manfredi R, Lucidi V, Gui B. et al. Idiopathic chronic pancreatitis in children: MR cholangiopancreatography after secretin administration. Radiology 2002; 224: 675-682
• 472 Hsu RK, Draganov P, Leung JW. et al. Therapeutic ERCP in the management of pancreatitis in children. Gastrointest Endosc 2000; 51: 396-400
• 473 Siegel MJ, Martin KW, Worthington JL. Normal and abnormal pancreas in children: US studies. Radiology 1987; 165: 15-18
• 474 Kugathasan S, Halabi I, Telega G. et al. Pancreatitis as a presenting manifestation of pediatric Crohn's disease: a report of three cases. J Pediatr Gastroenterol Nutr 2002; 35: 96-98
• 475 Ludvigsson JF, Montgomery SM, Ekbom A. Risk of pancreatitis in 14 000 individuals with celiac disease. Clin Gastroenterol Hepatol 2007; 5: 1347-1353
• 476 Witt H, Kage A, Luck W. et al. Alpha1-antitrypsin genotypes in patients with chronic pancreatitis. Scand J Gastroenterol 2002; 37: 356-359
• 477 Gerstner T, Bell N, Konig S. Oral valproic acid for epilepsy--long-term experience in therapy and side effects. Expert Opin Pharmacother 2008; 9: 285-292
• 478 Earl M. Incidence and management of asparaginase-associated adverse events in patients with acute lymphoblastic leukemia. Clin Adv Hematol Oncol 2009; 7: 600-606
• 479 Noone PG, Zhou Z, Silverman LM. et al. Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 2001; 121: 1310-1319
• 480 Audrezet MP, Chen JM, Le Marechal C. et al. Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. Eur J Hum Genet 2002; 10: 100-106
• 481 Iqbal CW, Baron TH, Moir CR. et al. Post-ERCP pancreatitis in pediatric patients. J Pediatr Gastroenterol Nutr 2009; 49: 430-434
• 482 Griese M, Dokupil K, Latzin P. Skin prick test reactivity to supplemental enzymes in cystic fibrosis and pancreatic insufficiency. J Pediatr Gastroenterol Nutr 2005; 40: 194-198
• 483 Stallings VA, Stark LJ, Robinson KA. et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc 2008; 108: 832-839
• 484 Graff GR, Maguiness K, McNamara J. et al. Efficacy and tolerability of a new formulation of pancrelipase delayed-release capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double-blind, placebo-controlled, two-period crossover, superiority study. Clin Ther 2010; 32: 89-103
• 485 DiMagno EP. Gastric acid suppression and treatment of severe exocrine pancreatic insufficiency. Best Pract Res Clin Gastroenterol 2001; 15: 477-486
• 486 Hoffmeister A, Mayerle J, Beglinger C. et al. S3-consensus guidelines on definition, etiology, diagnosis and medical, ensocopic and surgical menagment of chronic pancreatitis; german society of digestive and metabolic diseases (DGVS). Z Gastroenterol 2012; 50: 1176-1224