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Prospective evaluation of the aetiological profile of acute pancreatitis in young adult patients
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Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Liver, Pancreas and Biliary Tract
Prospective evaluation of the aetiological profile of acute pancreatitis in young adult patients Adrian Culetto a , Barbara Bournet a , Audrey Haennig a , Laurent Alric b , Jean-Marie Peron c , Louis Buscail a,∗ a
Department of Gastroenterology, University Hospital Centre Rangueil-Larrey, University of Toulouse, Toulouse, France Department of Internal Medicine, University Hospital Centre Purpan, University of Toulouse, Toulouse, France c Department of Gastroenterology, University Hospital Centre Purpan, University of Toulouse, Toulouse, France b
a r t i c l e
i n f o
Article history: Received 29 October 2014 Accepted 10 March 2015 Available online xxx Keywords: Acute pancreatitis Cannabis consumption Hereditary pancreatitis Magnetic-resonance cholangiopancreatography
a b s t r a c t Background: The aetiologies of acute pancreatitis in young adult patients are poorly known. Aims: To prospectively evaluate the causes of acute pancreatitis in patients aged less than 35 years. Methods: Overall, 309 consecutive patients admitted to our centre for acute pancreatitis received first-line investigations, including medical history, standard laboratory tests, abdominal ultrasound and computed tomography. If no aetiology was found, second-line investigations were performed, including endoscopic ultrasound, magnetic-resonance cholangiopancreatography and genetic testing in cases of idiopathic pancreatitis. Results: Overall, 66 patients aged between 16 and 35 years were included. After first-line investigations, 49% of cases of acute pancreatitis remained idiopathic. Second-line investigations reduced this rate to 21%. The frequency of aetiologies for acute pancreatitis significantly differed in adults aged ≤35 compared to those aged >35 years: biliary aetiology was less frequent (23% versus 43%, p = 0.003) as well as alcoholrelated (8% versus 24%, p = 0.01); drug-induced was more common (16% versus 4%, p = 0.0007), as well as cannabis-related (13% versus 1%, p < 0.0001), or genetic (10% versus 1.5%, p = 0.003). Conclusions: The aetiologies of acute pancreatitis significantly differed in adults aged less than 35 years when compared to older patients. Thus, use of medications, exposure to cannabis, and genetic mutations should be actively sought in these patients. © 2015 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
1. Introduction In adults, most cases of acute pancreatitis (AP) are closely linked to gallstones and chronic alcohol consumption, accounting for 70–80% of the cases. Other aetiologies (non-alcoholic, non-biliary AP) are less frequent; among these, the proportion of idiopathic AP has declined due to advances in radiological investigations and more detailed searches for autoimmune, drug-induced, or genetic causes [1–5]. The age of patients with biliary and alcoholic AP is usually between 40 and 60 years [1–4], while genetic causes are generally diagnosed at a younger age [6]. Candidate genes and geneticlinkage studies have identified mutations or polymorphisms in
∗ Corresponding author at: Department of Gastroenterology, University Hospital Centre Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France. Tel.: +33 5 61 32 30 55; fax: +33 5 61 32 22 29. E-mail address: [email protected] (L. Buscail).
the following genes: cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), chymotrypsinogen C (CTRC), cystic fibrosis trans-membrane conductance regulator (CFTR), cathepsin B, calcium-sensing receptor, proinflammatory cytokines (tumour necrosis factor, interleukin-1 and -10, monocyte chemoattractant protein 1), claudin-2, and carboxypeptidase A1 [6–11]. Among these, PRSS1 (gain-of-function mutations), SPINK1, and CFTR (lossof-function mutations) have been predominantly involved in a syndrome characterised by recurrent acute and late chronic pancreatitis [10,12]. It is now recognised that autoimmune pancreatitis is a heterogeneous disorder that has significant variations in its pathophysiology and extra-pancreatic manifestations. The systemic IgG4-related sclerosing syndrome, with high levels of serum IgG4, characterises type-1 autoimmune pancreatitis. The average age at first onset of type-1 autoimmune pancreatitis is 60–65 years [13]. Conversely, type-2 autoimmune pancreatitis has a lack of IgG4-positive cells and the patients are usually younger, with an average age of 40 years at the first signs (including AP). This latter form is more
http://dx.doi.org/10.1016/j.dld.2015.03.009 1590-8658/© 2015 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
Please cite this article in press as: Culetto A, et al. Prospective evaluation of the aetiological profile of acute pancreatitis in young adult patients. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.03.009
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frequent in Western countries, while type-1 autoimmune pancreatitis is more common in Asian series. Reports from many countries underline the alarming increase of alcohol and drug consumption in young adults, especially teenagers. We and others have previously described cases of cannabis-related AP, but their frequency could be underestimated for many reasons [5,14–19]: (i) the cases of toxic-induced AP being often difficult to prove; (ii) the difficulty in monitoring cannabinoids in the body and determining its pathophysiology as a cause of AP; (iii) the illegality of cannabis use and, consequently, patients not admitting usage. The aim of this prospective study was to investigate the aetiological profile of AP in a population of young adults.
2. Patients and methods 2.1. Inclusion criteria and study design All patients admitted to the emergency ward at the University Hospital Centre of Toulouse, (France) between September 2012 and December 2013 for AP were prospectively included in this study. AP was defined as an evocative painful abdominal syndrome associated with a serum-lipase level of >3 N [3,5]. Patients with acute pancreatitis that had been initially managed in another centre were excluded from the study. In the present work, we defined young adult patients as being aged between 16 and 35 years. Being aged ≥16 years is the minimum age for admission into the adult clinical department, while 35 years is the upper limit for the first symptoms of hereditary pancreatitis [6] and the lower limit for the first symptoms of alcoholic chronic pancreatitis [3]. All patients aged between 16 and 35 years were included in the aetiological investigation according to three phases (as previously described with minor corrections) [5]: (i) assessment during the acute phase of AP as a first-line investigation; (ii) second-line investigations; and (iii) follow-up of all idiopathic AP patients. The following first-line investigations for aetiological diagnoses were performed at our centre during initial hospitalisation for AP: clinical history that included medication, pharmaceutical-drug use, toxic substances and alcohol consumption, as well as standard biology (including lipids, phosphorus, calcium), abdominal ultrasound, computerised tomographic examination (CT scan 48–72 h after admission), and investigations for infections, if there was doubt. At this stage, the causes of AP were considered as biliary, alcoholic, with another recognised aetiology (i.e. non-alcoholic, non-biliary AP), or idiopathic. Cases of idiopathic AP were defined as AP with no cholelithiasis or choledocolithiasis at the initial examination, no chronic alcohol intake (<40 g per day), no recent serious alcohol consumption, absence of metabolic disorders, no recent consumption of toxic substances (including cocaine, cannabis, amphetamine) or medications known to induce AP (a systematic research using the http://www.mediquick.net website was performed combined with a request to the national pharmacovigilance database), no previous history of pancreatobiliary surgery, and no family history of pancreatitis or mucoviscidosis. Second-line investigations were conducted on idiopathic AP patients as well as when non-alcoholic or non-biliary AP was not clearly proven after the first-line investigations. These investigations were performed after a minimum delay of 2 months, although this delay could be increased in cases of severe necrotic AP. In these latter cases, a subsequent CT-scan was proposed, if necessary, to verify that necrotic pancreatic and peri-pancreatic inflammatory patterns had disappeared. The second-line investigations included examination and clinical history (especially consumption of toxic substances, including cannabis), standard laboratory testing (including serum lipids,
calcium, phosphorus, and parathormone), immunology (including anti-DNA and IgG4 serum levels), endoscopic ultrasound (EUS), and magnetic-resonance cholangiopancreatography (MRCP). Genetic investigations were systematically proposed at this step. The third step of this study was to follow up all patients who presented with idiopathic AP after the first and second phases of the study. For patients aged >35 years, an aetiological diagnosis was made according to the same three phases except for genetic testing, which was proposed during the follow-up period depending on the results of the previous investigations and the context [5]. Genetic testing mutations of PRSS1 (exons 1–3), SPINK1 (exons 1–4), CTRC (exons 3, 5, 7 and 7) and intronic flanking sequences were analysed by high-resolution melting and sequencing in cases when there was an abnormal profile. Genomic rearrangements at locus 7q34 were analysed by semi-quantitative fluorescent PCR and capillary electrophoresis (at the laboratory of molecular genetic and histocompatibility, Pr C. Ferec, CHU of Brest, France) [20]. The 50 most frequent mutations and the c.1210-12T polymorphism [5] (IVS8-5T polymorphism) in the CFTR gene (Locus CF (7q31.2) – ABCC7 gene) were searched for using multiplex PCR, capillary electrophoresis, and a Gene Mapper (ELUCIGENE Kit, Manchester, UK). Written informed consent for these investigations was obtained from each patient or from their parents (for patients aged <18 years; according to the rules of the French Society of Gastroenterology [SNFGE] and Endoscopy [SFED]). Written informed consent was also obtained for the genetic analyses (one consent for PRSS1, SPINK1, and CTRC, and one consent for CFTR). The study conformed to the ethical guidelines of the 1975 declaration of Helsinki (6th revision, 2008) as reflected by the a priori approval from the institution’s human research committee. 2.2. Recorded data and follow-up assessments All standard medical data were prospectively recorded at inclusion: i.e. patient’s age, gender, Ranson and Balthazar scores, clinical examinations and biological tests, local and/or general complications, aetiology after first-line investigations, time delay until a second-line investigation for patients with idiopathic AP, and results from EUS and MRCP. The follow-up included the results after surgery in cases of biliary AP and a minimum of one clinical examination every 6 months. In patients in whom AP remained idiopathic after the second phase, repeat abdominal ultrasounds (every 6 months) and a repeat EUS or MRCP, were performed if necessary. 2.3. Radiological and EUS investigations MRCP was performed with a 1-T superconducting MR unit (Magnetom Impact; Siemens, Erlangen, Germany) using a half-Fourier single-shot turbo spin-echo (HASTE) sequence, as previously described [5,21]. EUS was performed before MRCP, as previously described [21,22], using an Olympus EUM-160 or GF-UC140T echoendoscope (Olympus, Hamburg, Germany). The EUS examination included systematic high-frequency visualisation of the gallbladder (10–12 MHz). We applied the EUS criteria as defined by others, and we met to discuss a diagnosis of lithiasis of the gallbladder and/or the common bile duct. A diagnosis of chronic pancreatitis was defined by either the presence of major criteria (hyperechoic foci with shadowing and main pancreatic-duct calculi and lobularity with honeycombing), or the association of minor criteria, such as lobularity and dilated main pancreatic ducts ≥3.5 mm in size with a hyperechoic and moniliform wall, and dilated side branches of ≥1 mm, with non-shadowing hyperechoic foci [22,23]. More
Please cite this article in press as: Culetto A, et al. Prospective evaluation of the aetiological profile of acute pancreatitis in young adult patients. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.03.009
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Table 1 Characteristics of 66 young patients aged ≤35 years with acute pancreatitis. n (%) Men Mean age (years ± SD) (range) Previous attack Previous cholecystectomy Balthazar score A Balthazar score B Balthazar score C Balthazar score D Balthazar score E Admission into an ICU Mortality Atlanta Classification Mild or moderate Atlanta Classification Severe
36 (54.5) 26.1 ± 5.3 (16–35) 21 (31.5) 0 31 (47) 5 (7.5) 9 (13.5) 12 (18.5) 9 (13.5) 2 (3) 0 62 (94) 4 (6)
ICU, Intensive Care Unit.
precisely, biliary microlithiasis referred to the presence of gallbladder or common bile-duct calculi of ≤4 mm in size [5,24,25]. 2.4. Statistical analyses The data are presented as mean ± standard deviation (SD). Comparisons between the groups of patients and the results of the investigations were made using the Fisher’s exact test, Student’s t-test, and chi-squared test (as appropriate), plus Yates correction. Analyses were performed using the InStat 3.1a software (GraphPad, La Jolla, CA, USA). 3. Results 3.1. Baseline characteristics and first-line investigations At the end of the inclusion period, 309 adult patients were included: 243 patients were aged >35 years (mean age 60.3 ± 16.4 years; range: 36–92 years) and, of these, 157 were males (64.6%). The remaining 66 patients were aged ≤35 years, and their characteristics are detailed in Table 1. During the acute phase, the first-line clinical, laboratory, and imaging investigations allowed us to recognise or highly suspect an aetiology for 34 cases of AP (52%). The remaining 32 patients with idiopathic AP (49%), as well as patients for whom an aetiology was not totally confirmed, were enrolled in the second phase of the study. Table 2 (upper panel) details the investigations that were performed at this first stage as well as the aetiologies that were retained.
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Table 2 Detailed aetiologies found after first- and second-line investigations in 66 young adults (≤35 years old) with acute pancreatitis. n (%) First-line investigations (n = 66 patients) Abdominal US 57 (86.4) 63 (95.5)a CT-scan Aetiologies after first-line investigations (n = 66 patients) 12 (18.5) Biliary 5 (7.5) Alcohol Non-alcoholic, non-biliary Pharmaceutical/drugs 10 (15) Cannabis 4 (6) Miscellaneousb 3 (4.5) Idiopathic 32 (48.5) Second-line investigations and aetiology (n = 43 patients) MRCP 37 (86) EUS 32 (74.5) 30 (70) Both EUS and MRCP 21 (49) Genetic testing Final distribution of aetiologies (n = 62 patients)c Biliary 14 (22.5) Alcohol 5 (8) Non-alcoholic, non-biliary 10 (16.5) Pharmaceutical/drugs 8 (13) Cannabis 6 (9.5) Geneticd Miscellaneousb 6 (9.5) 13 (21) Idiopathic Abdominal US, abdominal ultrasound; EUS, endoscopic ultrasound; CT, computed tomography; MRCP, magnetic-resonance cholangiopancreatography. a Not performed in three cases because of pregnancy. b Hyperlipidaemia, autoimmune pancreatitis, intraductal papillary mucinous neoplasm, trauma. c Excluding four patients lost to follow-up after the first-line investigations. d Chronic cannabis consumption associated in one case.
of cannabis was regular (mostly daily); in addition, a recent increase in consumption was noted in two-thirds of the cases before the AP attack. None of these patients presented with cannabinoid hyperemesis syndrome, and two of them also displayed a psychiatric complication following initial hospitalisation (which required subsequent admission into a psychiatric department). Six cases had a genetic aetiology: a heterozygous pN34S mutation in the SPINK1 gene occurred in three cases and a mutation of the CFTR (ABCC7) gene occurred in the other three cases (heterozygous p.Phe508del, polymorphism c.1210-12T [5], with association of heterozygous p.Phe508del and polymorphism c.1210-12T [5]). It is noteworthy that in one of these cases a SPINK-1 heterozygous mutation was also associated with daily cannabis consumption.
3.2. Second-line investigations 3.3. Follow-up of younger patients Second-line investigations were conducted on 43 patients (65%), including 28 with idiopathic AP after the first-line investigations and 15 patients for whom a non-alcoholic or non-biliary AP was not clearly proven after the first-line investigations. Four patients definitively refused the subsequent follow-up or did not attend the successive appointments (6% of all young patients were lost to follow-up). Table 2 (lower panel) details the investigations performed in the second phase and the retained aetiologies. After the second-line investigations, two additional cases of biliary AP were diagnosed (mini-lithiasis assessed by EUS, CPRM, or an abdominal ultrasound) and pharmaceutical drug-induced AP was confirmed: i.e. azathioprine, NSAIDs, oral contraceptives, codeine, association of codeine plus NSAIDs, liraglutide. Also, four additional cannabis-induced cases of AP were diagnosed. All eight cases of cannabis-induced AP occurred in patients aged <30 years (median age: 26 years; males n = 7); of these, only one patient also consumed excess alcohol, while the other seven had not consumed any other known toxic substance. In these 8 patients the consumption
Mean follow-up time was 9.5 ± 3.6 months (median 8.5 months, range: 6–20 months). Ten patients (15%) had subsequent recurrence of AP (none of these patients experienced signs of chronic pancreatitis during follow-up). Patients with biliary lithiasis were surgically treated, and in all cases a diagnosis was confirmed by visualising either a macro- or microlithiasis at surgery. One patient with an intraductal papillary mucinous neoplasm, which only involved the branch ducts, was included in the clinical- and imaging-survey programme because the cystic lesions showed no signs of malignancy (<2 cm diameter). This patient had been followed up biannually and, up until then, the lesion had not increased in size or aspect. The eight patients with cannabis-induced AP stopped consumption (all were included in a drug-addiction programme) and no recurrence was recorded. In addition, none of the druginduced APs recurred after stopping or changing medication. In one patient, the follow-up allowed us to confirm type-2 autoimmune
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Table 3 Aetiologies of acute pancreatitis after the two investigations and the follow-up in 66 patients aged ≤35 years compared with 243 patients aged >35 years who were prospectively investigated during the same period. Aetiology
Patients aged ≤35 yearsa
Biliary 14 (22.5) 5 (8) Alcohol Non-alcoholic, non-biliary 10 (16) Drug 8 (13) Cannabis Genetic 6 (9.5) Tumour 2 (3) Autoimmune 1 (1.5) 3 (5)b Miscellaneous 13 (21) Idiopathic
Patients aged >35 years
Pd
104 (43) 55 (23.5)
0.003 0.011
8 (3.5) 2 (1) 3 (1.5) 8 (3.5) 1 (0.5) 12 (5)c 50 (20.5)
0.0007 <0.0001 0.003 1.00 0.38 1.00 1.00
a
Over 62 patients and excluding 4 patients with a lost of follow-up. Hyperlipidaemia, trauma. c Trauma, endoscopic retrograde cholangiopancreatography, and idiopathic chronic pancreatitis. d Fisher’s exact test and the chi-squared test with Yates’ correction. b
pancreatitis, which was successfully treated with corticosteroids. In the 13 remaining patients with idiopathic AP that were followed up, no aetiologies were found despite repeated radiological investigations and biological tests. 3.4. Comparison with patients aged >35 years After the three phases were completed, an aetiological diagnosis was achieved in a total of 48 cases (77.5% excluding the four patients who were lost to follow-up). EUS, MRCP, or a combination of EUS and MRCP, enabled an aetiological diagnosis in five of the 37 patients who underwent at least one of the two radiological examinations (13.5%, i.e. 7.5% of the entire series of young patients). The results from MRCP were concordant with EUS in these five cases (intraductal papillary mucinous neoplasm, biliary lithiasis, and autoimmune pancreatitis). Overall, genetic testing and the search for drug-induced and cannabis-induced AP enabled us to aetiologically diagnose 39% of these patients. Table 3 shows the frequency of the different aetiologies at the end of the three phases in patients aged ≤35 years compared to patients aged >35 years. The aetiologies significantly differed between the two subgroups: biliary- and alcohol-induced AP were significantly more frequent in older patients, whereas drug- and/or cannabis-induced and genetic-related AP were significantly more frequent in patients aged ≤35 years. In addition, in young patients, biliary AP was significantly more frequent in females than in males (p < 0.01), but gender did not affect any other aetiology (data not shown). A flow chart of the study is shown in Fig. 1. 4. Discussion This prospective study has demonstrated that the aetiologies of AP in young adults significantly varied from those observed in adults aged >35 years. In younger patients, biliary and alcohol aetiologies were less frequent, whereas use of drugs, toxic compounds, and presence of genetic anomalies were more often involved. Heterozygous mutations of the SPINK1 and CFTR genes conferred susceptibility to recurrent AP, either in the absence of other aetiologies or in association with chronic alcohol intake [10–12,26]. About 80% of patients with SPINK1 mutations can show at least one sign of chronic pancreatitis after a follow-up time of 15–20 years [10–12]. In the present study, however, the follow-up of our patients was too short to detect signs of chronic pancreatitis. In patients referred for recurrent AP and idiopathic chronic pancreatitis, a strong association is found between mutation in the CFTR genotypes and AP. These mutations can either be a combination of
Fig. 1. Flow chart of the study showing the frequency of the aetiologies at the different steps during the investigation of young adult patients with acute pancreatitis (Non-A: non-alcoholic, Non-B: non-biliary acute pancreatitis; Abdominal US: abdominal ultrasound; EUS: endoscopic ultrasound; CT: computed tomography; MRCP: magnetic-resonance cholangiopancreatography).
severe and mild mutations, or the 5T allele within intron 8 of the gene that is associated or not to a mutation, as was observed in our patients [27–29]. The recent consensus on idiopathic AP is that genetic counselling should be considered only after recurrent attacks of AP [2]. Although only 10% of AP cases were of genetic origin in our study, it would seem appropriate to perform genetic testing after a first attack of idiopathic AP in young patients. In addition, a multicentre study should be performed to confirm the real frequency of genetic susceptibility to AP in young patients, with the goal of revising the role of genetic testing in cases of idiopathic AP, if necessary. Medication-induced AP is common in young adults [30,31]. However, complete radiological investigations are required to confirm the causal relationship of different medications in AP attacks. Before 2000, drug-induced AP was considered to cause <2% of AP cases [32]; however, a French national registry on druginduced AP reported that the incidence of this condition has now increased [33]. Nowadays, the most frequent drugs incriminated are immunosuppressors, antivirals, antibiotics, NSAIDs, statins, and the association between paracetamol and codeine. Besides drug-induced and genetic mutations, cannabis consumption represented the third cause of AP in our population of young patients. Until now, no more than 12 observations of cannabis-induced AP have been published [14–19]. In France, among illicit substances, cannabis is the most common regardless of age or gender: the estimated daily consumers are 550,000, representing around 1% of the French adult population. From the OFDT 2010 report (Observatoire Franc¸ais des Drogues et des Toxicomanies – www.ofdt.com), among regular consumers of cannabis, the highest rates are seen in students and unemployed persons. The relative consumption among various age groups is estimated as follows: 23% among 15 to 25-year-olds, 14% among 26 to 34-year-olds, 5% among 35 to 44-year-olds, and 1% among 45 to 55-year-olds.
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to accurately detect pancreatic-duct abnormalities and, thus, can be complementary to EUS, which more frequently detects small biliary stones [5]. However, in the present work, in the subgroup of young adult patients the yield from these two investigations was lower (i.e. about 13% of idiopathic AP cases): thus, the use of both MRCP and EUS was ineffective. Consequently, in young patients, MRCP should be solely proposed for this indication to avoid unnecessary costs and anaesthesia. An aetiological algorithm is proposed in Fig. 2, which could be applied to young adult patients with AP and validated during a multicentre study. In conclusion, the aetiological profile for AP significantly differs in adults aged <35 years when compared to older adults. Consequently, a search for drug-related causes, chronic exposure to cannabis, and genetic mutations should be proposed in this subgroup of patients.
Conflict of interest None declared.
References
Fig. 2. Aetiological algorithm and investigations that could be proposed for young adults with acute pancreatitis.
Demonstrating the causal relationship of cannabis to AP means that other causes have to be eliminated and chronic consumption has to be detected. The common profile of patients with cannabis-induced AP in our series was as follows: they were aged <30 years, were chronic consumers of cannabis (i.e. for >3 years and often daily), and had recently increased intake. Some pre-clinical work, performed in rats and mice, has investigated the effects of endogenous and exogenous cannabinoids on the severity of AP. These studies concluded that endocannabinoids and exogenous cannabinoids may be implicated in the severity of AP, despite a dual effect (protection vs worsening) was also observed, depending of the phase of the disease. The mechanisms remain unclear and may involve sensory nerves or visceral arterial pressure, as well as pro-inflammatory processes [34–39]. Overall, this is the first time that such a large proportion of cannabis-induced cases of AP has been observed. Further studies are required not only to confirm whether special attention to cannabis consumption should become mandatory, but also to assess if the occurrence of AP, when induced by cannabis consumption, is over- or underestimated. This requires a larger prospective study, that would include specific quantification of cannabinoids in the blood of patients suspected of having cannabis-related AP compared to a control group with no cannabis consumption and AP. We and others have previously demonstrated that the combination of EUS and MRCP, when performed later after idiopathic AP, reveals ∼50% of the aetiologies in adult patients [5]. The association of these two procedures and the subsequent follow-up reduces the rate of idiopathic pancreatitis by approximately 66%. Even though EUS is more efficient than MRCP for this indication, we consider that the use of both methodologies is valid. Indeed, MRCP appears
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Liver, Pancreas and Biliary Tract
Prospective evaluation of the aetiological profile of acute pancreatitis in young adult patients Adrian Culetto a , Barbara Bournet a , Audrey Haennig a , Laurent Alric b , Jean-Marie Peron c , Louis Buscail a,∗ a
Department of Gastroenterology, University Hospital Centre Rangueil-Larrey, University of Toulouse, Toulouse, France Department of Internal Medicine, University Hospital Centre Purpan, University of Toulouse, Toulouse, France c Department of Gastroenterology, University Hospital Centre Purpan, University of Toulouse, Toulouse, France b
a r t i c l e
i n f o
Article history: Received 29 October 2014 Accepted 10 March 2015 Available online xxx Keywords: Acute pancreatitis Cannabis consumption Hereditary pancreatitis Magnetic-resonance cholangiopancreatography
a b s t r a c t Background: The aetiologies of acute pancreatitis in young adult patients are poorly known. Aims: To prospectively evaluate the causes of acute pancreatitis in patients aged less than 35 years. Methods: Overall, 309 consecutive patients admitted to our centre for acute pancreatitis received first-line investigations, including medical history, standard laboratory tests, abdominal ultrasound and computed tomography. If no aetiology was found, second-line investigations were performed, including endoscopic ultrasound, magnetic-resonance cholangiopancreatography and genetic testing in cases of idiopathic pancreatitis. Results: Overall, 66 patients aged between 16 and 35 years were included. After first-line investigations, 49% of cases of acute pancreatitis remained idiopathic. Second-line investigations reduced this rate to 21%. The frequency of aetiologies for acute pancreatitis significantly differed in adults aged ≤35 compared to those aged >35 years: biliary aetiology was less frequent (23% versus 43%, p = 0.003) as well as alcoholrelated (8% versus 24%, p = 0.01); drug-induced was more common (16% versus 4%, p = 0.0007), as well as cannabis-related (13% versus 1%, p < 0.0001), or genetic (10% versus 1.5%, p = 0.003). Conclusions: The aetiologies of acute pancreatitis significantly differed in adults aged less than 35 years when compared to older patients. Thus, use of medications, exposure to cannabis, and genetic mutations should be actively sought in these patients. © 2015 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
1. Introduction In adults, most cases of acute pancreatitis (AP) are closely linked to gallstones and chronic alcohol consumption, accounting for 70–80% of the cases. Other aetiologies (non-alcoholic, non-biliary AP) are less frequent; among these, the proportion of idiopathic AP has declined due to advances in radiological investigations and more detailed searches for autoimmune, drug-induced, or genetic causes [1–5]. The age of patients with biliary and alcoholic AP is usually between 40 and 60 years [1–4], while genetic causes are generally diagnosed at a younger age [6]. Candidate genes and geneticlinkage studies have identified mutations or polymorphisms in
∗ Corresponding author at: Department of Gastroenterology, University Hospital Centre Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France. Tel.: +33 5 61 32 30 55; fax: +33 5 61 32 22 29. E-mail address: [email protected] (L. Buscail).
the following genes: cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), chymotrypsinogen C (CTRC), cystic fibrosis trans-membrane conductance regulator (CFTR), cathepsin B, calcium-sensing receptor, proinflammatory cytokines (tumour necrosis factor, interleukin-1 and -10, monocyte chemoattractant protein 1), claudin-2, and carboxypeptidase A1 [6–11]. Among these, PRSS1 (gain-of-function mutations), SPINK1, and CFTR (lossof-function mutations) have been predominantly involved in a syndrome characterised by recurrent acute and late chronic pancreatitis [10,12]. It is now recognised that autoimmune pancreatitis is a heterogeneous disorder that has significant variations in its pathophysiology and extra-pancreatic manifestations. The systemic IgG4-related sclerosing syndrome, with high levels of serum IgG4, characterises type-1 autoimmune pancreatitis. The average age at first onset of type-1 autoimmune pancreatitis is 60–65 years [13]. Conversely, type-2 autoimmune pancreatitis has a lack of IgG4-positive cells and the patients are usually younger, with an average age of 40 years at the first signs (including AP). This latter form is more
http://dx.doi.org/10.1016/j.dld.2015.03.009 1590-8658/© 2015 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
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frequent in Western countries, while type-1 autoimmune pancreatitis is more common in Asian series. Reports from many countries underline the alarming increase of alcohol and drug consumption in young adults, especially teenagers. We and others have previously described cases of cannabis-related AP, but their frequency could be underestimated for many reasons [5,14–19]: (i) the cases of toxic-induced AP being often difficult to prove; (ii) the difficulty in monitoring cannabinoids in the body and determining its pathophysiology as a cause of AP; (iii) the illegality of cannabis use and, consequently, patients not admitting usage. The aim of this prospective study was to investigate the aetiological profile of AP in a population of young adults.
2. Patients and methods 2.1. Inclusion criteria and study design All patients admitted to the emergency ward at the University Hospital Centre of Toulouse, (France) between September 2012 and December 2013 for AP were prospectively included in this study. AP was defined as an evocative painful abdominal syndrome associated with a serum-lipase level of >3 N [3,5]. Patients with acute pancreatitis that had been initially managed in another centre were excluded from the study. In the present work, we defined young adult patients as being aged between 16 and 35 years. Being aged ≥16 years is the minimum age for admission into the adult clinical department, while 35 years is the upper limit for the first symptoms of hereditary pancreatitis [6] and the lower limit for the first symptoms of alcoholic chronic pancreatitis [3]. All patients aged between 16 and 35 years were included in the aetiological investigation according to three phases (as previously described with minor corrections) [5]: (i) assessment during the acute phase of AP as a first-line investigation; (ii) second-line investigations; and (iii) follow-up of all idiopathic AP patients. The following first-line investigations for aetiological diagnoses were performed at our centre during initial hospitalisation for AP: clinical history that included medication, pharmaceutical-drug use, toxic substances and alcohol consumption, as well as standard biology (including lipids, phosphorus, calcium), abdominal ultrasound, computerised tomographic examination (CT scan 48–72 h after admission), and investigations for infections, if there was doubt. At this stage, the causes of AP were considered as biliary, alcoholic, with another recognised aetiology (i.e. non-alcoholic, non-biliary AP), or idiopathic. Cases of idiopathic AP were defined as AP with no cholelithiasis or choledocolithiasis at the initial examination, no chronic alcohol intake (<40 g per day), no recent serious alcohol consumption, absence of metabolic disorders, no recent consumption of toxic substances (including cocaine, cannabis, amphetamine) or medications known to induce AP (a systematic research using the http://www.mediquick.net website was performed combined with a request to the national pharmacovigilance database), no previous history of pancreatobiliary surgery, and no family history of pancreatitis or mucoviscidosis. Second-line investigations were conducted on idiopathic AP patients as well as when non-alcoholic or non-biliary AP was not clearly proven after the first-line investigations. These investigations were performed after a minimum delay of 2 months, although this delay could be increased in cases of severe necrotic AP. In these latter cases, a subsequent CT-scan was proposed, if necessary, to verify that necrotic pancreatic and peri-pancreatic inflammatory patterns had disappeared. The second-line investigations included examination and clinical history (especially consumption of toxic substances, including cannabis), standard laboratory testing (including serum lipids,
calcium, phosphorus, and parathormone), immunology (including anti-DNA and IgG4 serum levels), endoscopic ultrasound (EUS), and magnetic-resonance cholangiopancreatography (MRCP). Genetic investigations were systematically proposed at this step. The third step of this study was to follow up all patients who presented with idiopathic AP after the first and second phases of the study. For patients aged >35 years, an aetiological diagnosis was made according to the same three phases except for genetic testing, which was proposed during the follow-up period depending on the results of the previous investigations and the context [5]. Genetic testing mutations of PRSS1 (exons 1–3), SPINK1 (exons 1–4), CTRC (exons 3, 5, 7 and 7) and intronic flanking sequences were analysed by high-resolution melting and sequencing in cases when there was an abnormal profile. Genomic rearrangements at locus 7q34 were analysed by semi-quantitative fluorescent PCR and capillary electrophoresis (at the laboratory of molecular genetic and histocompatibility, Pr C. Ferec, CHU of Brest, France) [20]. The 50 most frequent mutations and the c.1210-12T polymorphism [5] (IVS8-5T polymorphism) in the CFTR gene (Locus CF (7q31.2) – ABCC7 gene) were searched for using multiplex PCR, capillary electrophoresis, and a Gene Mapper (ELUCIGENE Kit, Manchester, UK). Written informed consent for these investigations was obtained from each patient or from their parents (for patients aged <18 years; according to the rules of the French Society of Gastroenterology [SNFGE] and Endoscopy [SFED]). Written informed consent was also obtained for the genetic analyses (one consent for PRSS1, SPINK1, and CTRC, and one consent for CFTR). The study conformed to the ethical guidelines of the 1975 declaration of Helsinki (6th revision, 2008) as reflected by the a priori approval from the institution’s human research committee. 2.2. Recorded data and follow-up assessments All standard medical data were prospectively recorded at inclusion: i.e. patient’s age, gender, Ranson and Balthazar scores, clinical examinations and biological tests, local and/or general complications, aetiology after first-line investigations, time delay until a second-line investigation for patients with idiopathic AP, and results from EUS and MRCP. The follow-up included the results after surgery in cases of biliary AP and a minimum of one clinical examination every 6 months. In patients in whom AP remained idiopathic after the second phase, repeat abdominal ultrasounds (every 6 months) and a repeat EUS or MRCP, were performed if necessary. 2.3. Radiological and EUS investigations MRCP was performed with a 1-T superconducting MR unit (Magnetom Impact; Siemens, Erlangen, Germany) using a half-Fourier single-shot turbo spin-echo (HASTE) sequence, as previously described [5,21]. EUS was performed before MRCP, as previously described [21,22], using an Olympus EUM-160 or GF-UC140T echoendoscope (Olympus, Hamburg, Germany). The EUS examination included systematic high-frequency visualisation of the gallbladder (10–12 MHz). We applied the EUS criteria as defined by others, and we met to discuss a diagnosis of lithiasis of the gallbladder and/or the common bile duct. A diagnosis of chronic pancreatitis was defined by either the presence of major criteria (hyperechoic foci with shadowing and main pancreatic-duct calculi and lobularity with honeycombing), or the association of minor criteria, such as lobularity and dilated main pancreatic ducts ≥3.5 mm in size with a hyperechoic and moniliform wall, and dilated side branches of ≥1 mm, with non-shadowing hyperechoic foci [22,23]. More
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Table 1 Characteristics of 66 young patients aged ≤35 years with acute pancreatitis. n (%) Men Mean age (years ± SD) (range) Previous attack Previous cholecystectomy Balthazar score A Balthazar score B Balthazar score C Balthazar score D Balthazar score E Admission into an ICU Mortality Atlanta Classification Mild or moderate Atlanta Classification Severe
36 (54.5) 26.1 ± 5.3 (16–35) 21 (31.5) 0 31 (47) 5 (7.5) 9 (13.5) 12 (18.5) 9 (13.5) 2 (3) 0 62 (94) 4 (6)
ICU, Intensive Care Unit.
precisely, biliary microlithiasis referred to the presence of gallbladder or common bile-duct calculi of ≤4 mm in size [5,24,25]. 2.4. Statistical analyses The data are presented as mean ± standard deviation (SD). Comparisons between the groups of patients and the results of the investigations were made using the Fisher’s exact test, Student’s t-test, and chi-squared test (as appropriate), plus Yates correction. Analyses were performed using the InStat 3.1a software (GraphPad, La Jolla, CA, USA). 3. Results 3.1. Baseline characteristics and first-line investigations At the end of the inclusion period, 309 adult patients were included: 243 patients were aged >35 years (mean age 60.3 ± 16.4 years; range: 36–92 years) and, of these, 157 were males (64.6%). The remaining 66 patients were aged ≤35 years, and their characteristics are detailed in Table 1. During the acute phase, the first-line clinical, laboratory, and imaging investigations allowed us to recognise or highly suspect an aetiology for 34 cases of AP (52%). The remaining 32 patients with idiopathic AP (49%), as well as patients for whom an aetiology was not totally confirmed, were enrolled in the second phase of the study. Table 2 (upper panel) details the investigations that were performed at this first stage as well as the aetiologies that were retained.
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Table 2 Detailed aetiologies found after first- and second-line investigations in 66 young adults (≤35 years old) with acute pancreatitis. n (%) First-line investigations (n = 66 patients) Abdominal US 57 (86.4) 63 (95.5)a CT-scan Aetiologies after first-line investigations (n = 66 patients) 12 (18.5) Biliary 5 (7.5) Alcohol Non-alcoholic, non-biliary Pharmaceutical/drugs 10 (15) Cannabis 4 (6) Miscellaneousb 3 (4.5) Idiopathic 32 (48.5) Second-line investigations and aetiology (n = 43 patients) MRCP 37 (86) EUS 32 (74.5) 30 (70) Both EUS and MRCP 21 (49) Genetic testing Final distribution of aetiologies (n = 62 patients)c Biliary 14 (22.5) Alcohol 5 (8) Non-alcoholic, non-biliary 10 (16.5) Pharmaceutical/drugs 8 (13) Cannabis 6 (9.5) Geneticd Miscellaneousb 6 (9.5) 13 (21) Idiopathic Abdominal US, abdominal ultrasound; EUS, endoscopic ultrasound; CT, computed tomography; MRCP, magnetic-resonance cholangiopancreatography. a Not performed in three cases because of pregnancy. b Hyperlipidaemia, autoimmune pancreatitis, intraductal papillary mucinous neoplasm, trauma. c Excluding four patients lost to follow-up after the first-line investigations. d Chronic cannabis consumption associated in one case.
of cannabis was regular (mostly daily); in addition, a recent increase in consumption was noted in two-thirds of the cases before the AP attack. None of these patients presented with cannabinoid hyperemesis syndrome, and two of them also displayed a psychiatric complication following initial hospitalisation (which required subsequent admission into a psychiatric department). Six cases had a genetic aetiology: a heterozygous pN34S mutation in the SPINK1 gene occurred in three cases and a mutation of the CFTR (ABCC7) gene occurred in the other three cases (heterozygous p.Phe508del, polymorphism c.1210-12T [5], with association of heterozygous p.Phe508del and polymorphism c.1210-12T [5]). It is noteworthy that in one of these cases a SPINK-1 heterozygous mutation was also associated with daily cannabis consumption.
3.2. Second-line investigations 3.3. Follow-up of younger patients Second-line investigations were conducted on 43 patients (65%), including 28 with idiopathic AP after the first-line investigations and 15 patients for whom a non-alcoholic or non-biliary AP was not clearly proven after the first-line investigations. Four patients definitively refused the subsequent follow-up or did not attend the successive appointments (6% of all young patients were lost to follow-up). Table 2 (lower panel) details the investigations performed in the second phase and the retained aetiologies. After the second-line investigations, two additional cases of biliary AP were diagnosed (mini-lithiasis assessed by EUS, CPRM, or an abdominal ultrasound) and pharmaceutical drug-induced AP was confirmed: i.e. azathioprine, NSAIDs, oral contraceptives, codeine, association of codeine plus NSAIDs, liraglutide. Also, four additional cannabis-induced cases of AP were diagnosed. All eight cases of cannabis-induced AP occurred in patients aged <30 years (median age: 26 years; males n = 7); of these, only one patient also consumed excess alcohol, while the other seven had not consumed any other known toxic substance. In these 8 patients the consumption
Mean follow-up time was 9.5 ± 3.6 months (median 8.5 months, range: 6–20 months). Ten patients (15%) had subsequent recurrence of AP (none of these patients experienced signs of chronic pancreatitis during follow-up). Patients with biliary lithiasis were surgically treated, and in all cases a diagnosis was confirmed by visualising either a macro- or microlithiasis at surgery. One patient with an intraductal papillary mucinous neoplasm, which only involved the branch ducts, was included in the clinical- and imaging-survey programme because the cystic lesions showed no signs of malignancy (<2 cm diameter). This patient had been followed up biannually and, up until then, the lesion had not increased in size or aspect. The eight patients with cannabis-induced AP stopped consumption (all were included in a drug-addiction programme) and no recurrence was recorded. In addition, none of the druginduced APs recurred after stopping or changing medication. In one patient, the follow-up allowed us to confirm type-2 autoimmune
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Table 3 Aetiologies of acute pancreatitis after the two investigations and the follow-up in 66 patients aged ≤35 years compared with 243 patients aged >35 years who were prospectively investigated during the same period. Aetiology
Patients aged ≤35 yearsa
Biliary 14 (22.5) 5 (8) Alcohol Non-alcoholic, non-biliary 10 (16) Drug 8 (13) Cannabis Genetic 6 (9.5) Tumour 2 (3) Autoimmune 1 (1.5) 3 (5)b Miscellaneous 13 (21) Idiopathic
Patients aged >35 years
Pd
104 (43) 55 (23.5)
0.003 0.011
8 (3.5) 2 (1) 3 (1.5) 8 (3.5) 1 (0.5) 12 (5)c 50 (20.5)
0.0007 <0.0001 0.003 1.00 0.38 1.00 1.00
a
Over 62 patients and excluding 4 patients with a lost of follow-up. Hyperlipidaemia, trauma. c Trauma, endoscopic retrograde cholangiopancreatography, and idiopathic chronic pancreatitis. d Fisher’s exact test and the chi-squared test with Yates’ correction. b
pancreatitis, which was successfully treated with corticosteroids. In the 13 remaining patients with idiopathic AP that were followed up, no aetiologies were found despite repeated radiological investigations and biological tests. 3.4. Comparison with patients aged >35 years After the three phases were completed, an aetiological diagnosis was achieved in a total of 48 cases (77.5% excluding the four patients who were lost to follow-up). EUS, MRCP, or a combination of EUS and MRCP, enabled an aetiological diagnosis in five of the 37 patients who underwent at least one of the two radiological examinations (13.5%, i.e. 7.5% of the entire series of young patients). The results from MRCP were concordant with EUS in these five cases (intraductal papillary mucinous neoplasm, biliary lithiasis, and autoimmune pancreatitis). Overall, genetic testing and the search for drug-induced and cannabis-induced AP enabled us to aetiologically diagnose 39% of these patients. Table 3 shows the frequency of the different aetiologies at the end of the three phases in patients aged ≤35 years compared to patients aged >35 years. The aetiologies significantly differed between the two subgroups: biliary- and alcohol-induced AP were significantly more frequent in older patients, whereas drug- and/or cannabis-induced and genetic-related AP were significantly more frequent in patients aged ≤35 years. In addition, in young patients, biliary AP was significantly more frequent in females than in males (p < 0.01), but gender did not affect any other aetiology (data not shown). A flow chart of the study is shown in Fig. 1. 4. Discussion This prospective study has demonstrated that the aetiologies of AP in young adults significantly varied from those observed in adults aged >35 years. In younger patients, biliary and alcohol aetiologies were less frequent, whereas use of drugs, toxic compounds, and presence of genetic anomalies were more often involved. Heterozygous mutations of the SPINK1 and CFTR genes conferred susceptibility to recurrent AP, either in the absence of other aetiologies or in association with chronic alcohol intake [10–12,26]. About 80% of patients with SPINK1 mutations can show at least one sign of chronic pancreatitis after a follow-up time of 15–20 years [10–12]. In the present study, however, the follow-up of our patients was too short to detect signs of chronic pancreatitis. In patients referred for recurrent AP and idiopathic chronic pancreatitis, a strong association is found between mutation in the CFTR genotypes and AP. These mutations can either be a combination of
Fig. 1. Flow chart of the study showing the frequency of the aetiologies at the different steps during the investigation of young adult patients with acute pancreatitis (Non-A: non-alcoholic, Non-B: non-biliary acute pancreatitis; Abdominal US: abdominal ultrasound; EUS: endoscopic ultrasound; CT: computed tomography; MRCP: magnetic-resonance cholangiopancreatography).
severe and mild mutations, or the 5T allele within intron 8 of the gene that is associated or not to a mutation, as was observed in our patients [27–29]. The recent consensus on idiopathic AP is that genetic counselling should be considered only after recurrent attacks of AP [2]. Although only 10% of AP cases were of genetic origin in our study, it would seem appropriate to perform genetic testing after a first attack of idiopathic AP in young patients. In addition, a multicentre study should be performed to confirm the real frequency of genetic susceptibility to AP in young patients, with the goal of revising the role of genetic testing in cases of idiopathic AP, if necessary. Medication-induced AP is common in young adults [30,31]. However, complete radiological investigations are required to confirm the causal relationship of different medications in AP attacks. Before 2000, drug-induced AP was considered to cause <2% of AP cases [32]; however, a French national registry on druginduced AP reported that the incidence of this condition has now increased [33]. Nowadays, the most frequent drugs incriminated are immunosuppressors, antivirals, antibiotics, NSAIDs, statins, and the association between paracetamol and codeine. Besides drug-induced and genetic mutations, cannabis consumption represented the third cause of AP in our population of young patients. Until now, no more than 12 observations of cannabis-induced AP have been published [14–19]. In France, among illicit substances, cannabis is the most common regardless of age or gender: the estimated daily consumers are 550,000, representing around 1% of the French adult population. From the OFDT 2010 report (Observatoire Franc¸ais des Drogues et des Toxicomanies – www.ofdt.com), among regular consumers of cannabis, the highest rates are seen in students and unemployed persons. The relative consumption among various age groups is estimated as follows: 23% among 15 to 25-year-olds, 14% among 26 to 34-year-olds, 5% among 35 to 44-year-olds, and 1% among 45 to 55-year-olds.
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to accurately detect pancreatic-duct abnormalities and, thus, can be complementary to EUS, which more frequently detects small biliary stones [5]. However, in the present work, in the subgroup of young adult patients the yield from these two investigations was lower (i.e. about 13% of idiopathic AP cases): thus, the use of both MRCP and EUS was ineffective. Consequently, in young patients, MRCP should be solely proposed for this indication to avoid unnecessary costs and anaesthesia. An aetiological algorithm is proposed in Fig. 2, which could be applied to young adult patients with AP and validated during a multicentre study. In conclusion, the aetiological profile for AP significantly differs in adults aged <35 years when compared to older adults. Consequently, a search for drug-related causes, chronic exposure to cannabis, and genetic mutations should be proposed in this subgroup of patients.
Conflict of interest None declared.
References
Fig. 2. Aetiological algorithm and investigations that could be proposed for young adults with acute pancreatitis.
Demonstrating the causal relationship of cannabis to AP means that other causes have to be eliminated and chronic consumption has to be detected. The common profile of patients with cannabis-induced AP in our series was as follows: they were aged <30 years, were chronic consumers of cannabis (i.e. for >3 years and often daily), and had recently increased intake. Some pre-clinical work, performed in rats and mice, has investigated the effects of endogenous and exogenous cannabinoids on the severity of AP. These studies concluded that endocannabinoids and exogenous cannabinoids may be implicated in the severity of AP, despite a dual effect (protection vs worsening) was also observed, depending of the phase of the disease. The mechanisms remain unclear and may involve sensory nerves or visceral arterial pressure, as well as pro-inflammatory processes [34–39]. Overall, this is the first time that such a large proportion of cannabis-induced cases of AP has been observed. Further studies are required not only to confirm whether special attention to cannabis consumption should become mandatory, but also to assess if the occurrence of AP, when induced by cannabis consumption, is over- or underestimated. This requires a larger prospective study, that would include specific quantification of cannabinoids in the blood of patients suspected of having cannabis-related AP compared to a control group with no cannabis consumption and AP. We and others have previously demonstrated that the combination of EUS and MRCP, when performed later after idiopathic AP, reveals ∼50% of the aetiologies in adult patients [5]. The association of these two procedures and the subsequent follow-up reduces the rate of idiopathic pancreatitis by approximately 66%. Even though EUS is more efficient than MRCP for this indication, we consider that the use of both methodologies is valid. Indeed, MRCP appears
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Please cite this article in press as: Culetto A, et al. Prospective evaluation of the aetiological profile of acute pancreatitis in young adult patients. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.03.009