Publications by authors named "Søren S Olesen"

57 Publications

Time trends in incidence and prevalence of chronic pancreatitis: A 25-year population-based nationwide study.

United European Gastroenterol J 2021 Feb 22;9(1):82-90. Epub 2021 Feb 22.

National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.

Background: Updated population-based estimates on incidence and prevalence of chronic pancreatitis are scarce.

Methods: We used nationwide healthcare registries to identify all Danish patients diagnosed with chronic pancreatitis and computed crude and standardised incidence rates and prevalence estimates in 1994-2018. Incidence and prevalence were evaluated in relation to patients age and gender, aetiology (alcoholic vs. non-alcoholic) and smoking and alcohol consumption in the general Danish population.

Results: The mean incidence rate of chronic pancreatitis during the study period was 12.6 per 100,000 person years for the total population, for women it was 8.6 per 100,000 person years and for men it was 16.7 per 100,000 person years. The standardised incidence rate was stable from 1994 to 2018, remaining at 12.5 per 100,000 person years in the last observation period (2014-2018). The point prevalence of chronic pancreatitis in 2016 was 153.9 per 100,000 persons. A gradual increase in standardised prevalence estimates was observed during the study period from 126.6 in 1996 to 153.9 in 2016. The mean age at chronic pancreatitis diagnosis increased from 52.1 to 60.0 years during the study period.

Conclusion: The prevalence of chronic pancreatitis is increasing in the Danish population despite a stable incidence level. Improved management strategies and changes in the underlying patient population may explain these observations.
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http://dx.doi.org/10.1177/2050640620966513DOI Listing
February 2021

Extragastrointestinal Symptoms and Sensory Responses During Breath Tests Distinguish Patients With Functional Gastrointestinal Disorders.

Clin Transl Gastroenterol 2020 08;11(8):e00192

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Introduction: Patients with functional gastrointestinal disorders (FGIDs) are classified based on their gastrointestinal (GI) symptoms, without considering their frequent extra-GI symptoms. This study defined subgroups of patients using both GI and extra-GI symptoms and examined underlying mechanisms with fructose and lactose breath tests.

Methods: Latent class analysis defined distinct clusters of patients with FGID based on their long-term GI and extra-GI symptoms. Sensory and breath gas responses after fructose and lactose ingestion were compared across symptom clusters to investigate differences in sensory function and fermentation by intestinal microbiota.

Results: Six symptom clusters were identified in 2,083 patients with FGID. Clusters were characterized mainly by GI fermentation-type (cluster 1), allergy-like (cluster 2), intense pain-accentuated GI symptoms (cluster 3), central nervous system (cluster 4), musculoskeletal (cluster 5), and generalized extra-GI (cluster 6) symptoms. In the 68% of patients with complete breath tests, the areas under the curve of GI and central nervous system symptoms after fructose and lactose ingestion differed across the clusters (P < 0.001). The clusters with extensive long-term extra-GI symptoms had greater symptoms after the sugars and were predominantly women, with family or childhood allergy histories. Importantly, the areas under the curves of hydrogen and methane breath concentrations were similar (P > 0.05) across all symptom clusters. Rome III criteria did not distinguish between the symptom clusters.

Discussion: Patients with FGID fall into clusters defined extensively by extra-GI symptoms. Greater extra-GI symptoms are associated with evidence of generalized sensory hypersensitivity to sugar ingestion, unrelated to intestinal gas production. Possible underlying mechanisms include metabolites originating from the intestinal microbiota and somatization.
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http://dx.doi.org/10.14309/ctg.0000000000000192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431249PMC
August 2020

Pain and aetiological risk factors determine quality of life in patients with chronic pancreatitis, but a brick in the puzzle is missing.

Pancreatology 2020 Oct 10;20(7):1347-1353. Epub 2020 Sep 10.

Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Clinical Institute, Aalborg University, Aalborg, Denmark.

Background And Objectives: Chronic pancreatitis (CP) is a debilitating fibro-inflammatory disease with a profound impact on patients' quality of life (QOL). We investigated determinants of QOL in a large cohort of CP patients.

Methods: This was a multicentre study including 517 patients with CP. All patients fulfilled the EORTC QLQ-C30 questionnaire. Questionnaire responses were compared to results obtained from a general reference population (n = 11,343). Demographic characteristics, risk factors (smoking and alcohol consumption), pain symptoms, disease phenotype (complications) and treatments were recorded. A multivariable regression model was used to identify factors independently associated with QOL scores.

Results: Included patients had a mean age of 56.3 ± 12.8 years, 355 (69%) were men and 309 (60%) had alcohol aetiology. Compared to the reference population, patients with CP had lower global health status (50.5 vs. 66.1; p < 0.001) as well as reduced scores for all functional scales (all p < 0.001). Additionally, CP patients reported a higher burden for all symptom items, with pain being the most prominent complaint (all p < 0.001). Constant pain (coefficient -11.3; p = 0.02), opioid based pain treatment (coefficient -19.7; p < 0.001) and alcoholic aetiology (coefficient -5.1; p = 0.03) were independently associated with lowered global health status. The final multivariable model explained 18% of the variance in global health status.

Conclusions: Patients with CP have significantly lower QOL compared to a population-based reference population. Factors independently associated with a lowered QOL are constant pain, opioid based pain treatment and alcohol aetiology. However, these factors only explain a fraction of QOL and additional factors need identification.
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http://dx.doi.org/10.1016/j.pan.2020.09.004DOI Listing
October 2020

Is Preoperative Quantitative Sensory Testing Related to Persistent Postsurgical Pain? A Systematic Literature Review.

Anesth Analg 2020 10;131(4):1146-1155

From the Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

Persistent postsurgical pain (PPSP) is a common complication of surgery that significantly affects quality of life. A better understanding of which patients are likely to develop PPSP would help to identify when perioperative and postoperative pain management may require specific attention. Quantitative sensory testing (QST) of a patient's preoperative pain perception is associated with acute postoperative pain, and acute postoperative pain is a risk factor for PPSP. The direct association between preoperative QST and PPSP has not been reviewed to date. In this systematic review, we assessed the relationship of preoperative QST to PPSP. We searched databases with components related to (1) preoperative QST; (2) association testing; and (3) PPSP. Two authors reviewed all titles and abstracts for inclusion. Inclusion criteria were as follows: (1) QST performed before surgery; (2) PPSP assessed ≥3 months postoperatively; and (3) the association between QST measures and PPSP is investigated. The search retrieved 905 articles; 24 studies with 2732 subjects met inclusion criteria. Most studies (22/24) had moderate to high risk of bias in multiple quality domains. Fourteen (58%) studies reported a significant association between preoperative QST and PPSP. Preoperative temporal summation of pain (4 studies), conditioned pain modulation (3 studies), and pressure pain threshold (3 studies) showed the most frequent association with PPSP. The strength of the association between preoperative QST and PPSP varied from weak to strong. Preoperative QST is variably associated with PPSP. Measurements related to central processing of pain may be most consistently associated with PPSP.
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http://dx.doi.org/10.1213/ANE.0000000000004871DOI Listing
October 2020

Combined extracorporeal shock wave lithotripsy and endoscopic treatment for pain in chronic pancreatitis (SCHOKE trial): study protocol for a randomized, sham-controlled trial.

Trials 2020 Apr 16;21(1):338. Epub 2020 Apr 16.

Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India.

Background: Pain is the primary symptom of chronic pancreatitis (CP) and remains a considerable therapeutic challenge. In patients with obstruction of the pancreatic duct, including stones and strictures, endoscopic treatment with or without preceding extracorporeal shock wave lithotripsy (ESWL) has been used for pancreatic duct decompression. The rationale for these procedures is based on the assumption that obstruction of the pancreatic duct leads to ductal hypertension and pain. However, clinical pain symptoms correlate poorly with pancreatic duct morphology, and the evidence for pancreatic duct decompression as an effective treatment for pain is based on case series and comparison between different procedures. No randomized, prospective, sham-controlled trials are currently available. The SCHOKE (Extracorporeal Shock Wave Lithotripsy and Endotherapy for Pain in Chronic Pancreatitis) trial is a randomized, sham-controlled trial designed to determine if pancreatic duct decompression is an effective treatment for pain in patients with CP.

Methods: The SCHOKE trial is a randomized, single-blind, parallel-group, sham-controlled trial designed to evaluate the effect of combined ESWL and endoscopic treatment for pain in patients with CP. In total, 106 adult patients with painful CP and pancreatic duct obstruction will be randomized to combined ESWL and subsequent endoscopic treatment or corresponding sham procedures. The primary outcome is pain relief during the 3-month postrandomization period as documented in a pain diary. Secondary outcomes include quality of life and functional scores, patient global impression of change, change in use of analgesics, frequency of hospitalization, and complications. Standard follow-up is at 3 and 6 months after randomization. In an experimental substudy, quantitative sensory testing obtained before and after intervention will be used to obtain information on central pain processing and to develop models for prediction of treatment outcome.

Discussion: The SCHOKE trial investigates if pancreatic duct decompression, obtained by combined ESWL and endoscopic treatment, is effective for pain treatment in patients with CP.

Trial Registration: ClinicalTrials.gov, NCT03966781. Registered on May 25, 2019. Protocol date and version identifier: March 1, 2020; version 3.0.

Sponsor: Rupjyoti Talukdar, Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India.
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http://dx.doi.org/10.1186/s13063-020-04296-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164272PMC
April 2020

Multiple risk factors for diabetes mellitus in patients with chronic pancreatitis: A multicentre study of 1117 cases.

United European Gastroenterol J 2020 05 17;8(4):453-461. Epub 2020 Jan 17.

Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Background: Diabetes mellitus is a common complication of chronic pancreatitis. It is traditionally considered to develop as a consequence of beta cell loss, but there might be additional factors. Recent studies have highlighted the importance of type 2 diabetes-related risk factors in this context and population-based studies show increased risk of diabetes following acute pancreatitis. The aim of this study was to explore multiple risk factors for diabetes in patients with chronic pancreatitis.

Methods: We conducted a multicentre, cross-sectional study of patients with definitive chronic pancreatitis according to the M-ANNHEIM criteria. We used multivariable logistic regression models to determine risk factors independently associated with diabetes.

Results: The study included 1117 patients of whom 457 (40.9 %) had diabetes. The mean age was 52.8 ± 14.2 years and 67% were men. On multivariate analysis, parameters indicative of beta cell loss (pancreatic calcification, exocrine insufficiency, pancreatic resection) were confirmed as independent risk factors for diabetes (all  ≤ 0.02). In addition, type 2 diabetes-related risk factors (dyslipidaemia and overweight/obesity) were associated with the presence of diabetes (all  ≤ 0.002). Patients with a history of pancreatic fluid collections (indicative of previous attacks of acute pancreatitis) had a marginally increased risk of diabetes ( = 0.07).

Conclusion: In patients with chronic pancreatitis the presence of diabetes is associated with multiple risk factors including type 2 diabetes-related factors. Our observations attest to the understanding of this entity and may have implications for treatment.
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http://dx.doi.org/10.1177/2050640620901973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226693PMC
May 2020

Bias towards surgery for pain in chronic pancreatitis.

Pancreatology 2020 04 10;20(3):305-306. Epub 2020 Mar 10.

Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

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http://dx.doi.org/10.1016/j.pan.2020.03.003DOI Listing
April 2020

Gastrointestinal pain.

Nat Rev Dis Primers 2020 01 6;6(1). Epub 2020 Jan 6.

Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

Gastrointestinal (GI) pain - a form of visceral pain - is common in some disorders, such as irritable bowel syndrome, Crohn's disease and pancreatitis. However, identifying the cause of GI pain frequently represents a diagnostic challenge as the clinical presentation is often blurred by concomitant autonomic and somatic symptoms. In addition, GI pain can be nociceptive, neuropathic and associated with cancer, but in many cases multiple aetiologies coexist in an individual patient. Mechanisms of GI pain are complex and include both peripheral and central sensitization and the involvement of the autonomic nervous system, which has a role in generating the symptoms that frequently accompany pain. Treatment of GI pain depends on the precise type of pain and the primary disorder in the patient but can include, for example, pharmacological therapy, cognitive behavioural therapies, invasive surgical procedures, endoscopic procedures and lifestyle alterations. Owing to the major differences between organ involvement, disease mechanisms and individual factors, treatment always needs to be personalized and some data suggest that phenotyping and subsequent individual management of GI pain might be options in the future.
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http://dx.doi.org/10.1038/s41572-019-0135-7DOI Listing
January 2020

Symptoms of mast cell activation syndrome in functional gastrointestinal disorders.

Scand J Gastroenterol 2019 Nov 5;54(11):1322-1325. Epub 2019 Nov 5.

Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Mast cell involvement is evident in functional gastrointestinal disorders (FGID). FGID and mast cell activation syndrome (MCAS) are associated with multi-organ symptoms. An overlap has not been assessed. MCAS symptoms were determined by questionnaires in 2083 FGID patients. The median number of MCAS symptoms ([IQR] (range 0-16)) was 6 [4-8] in all FGID, and in functional dyspepsia (FD) patients, 7 [5-9] in overlapping irritable bowel syndrome and FD (IBS+FD), 5 [3-8] in IBS and 5 [3-6] in non-IBS/non-FD ( < .001 FD and IBS + FD) patients. MCAS symptoms in ≥2 organ-systems existed in 1773 (85%) of all patients. MCAS symptoms are common in FGID warranting further mechanistic investigation.
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http://dx.doi.org/10.1080/00365521.2019.1686059DOI Listing
November 2019

Pancreatic calcifications associate with diverse aetiological risk factors in patients with chronic pancreatitis: A multicentre study of 1500 cases.

Pancreatology 2019 Oct 21;19(7):922-928. Epub 2019 Aug 21.

Clinical Institute, Aalborg University, Aalborg, Denmark; Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.

Background: Pancreatic calcifications is a common finding in patients with chronic pancreatitis (CP), but the underlying pathophysiology is incompletely understood. Past studies for risk factors of calcifications have generally been focused on single parameters or limited by small sample sizes. The aim of this study was to explore several patient and disease characteristics and their associations with pancreatic calcifications in a large cohort of CP patients with diverse aetiological risk factors.

Methods: This was a multicentre, cross-sectional study including 1509 patients with CP. Patient and disease characteristics were compared for patients with calcifications (n = 912) vs. without calcifications (n = 597). Multivariable logistic regression was performed to assess the parameters independently associated with calcifications.

Results: The mean age of patients was 53.9 ± 14.5 years and 1006 (67%) were men. The prevalence of calcifications was 60.4% in the overall patient cohort, but highly variable between patients with different aetiological risk factors (range: 2-69%). On multivariate analysis, alcoholic aetiology (OR 1.76 [95% CI, 1.39-2.24]; p < 0.001) and smoking aetiology (OR 1.77 [95% CI, 1.39-2.26], p < 0.001) were positively associated with the presence of calcifications, while an autoimmune aetiology was negatively associated with calcifications (OR 0.15 [95% CI, 0.08-0.27], p < 0.001). Patients with pancreatic calcifications were more likely to have undergone pancreatic duct stenting (OR 1.59 [95%CI, 1.16-2.19], p = 0.004).

Conclusion: The presence of pancreatic calcifications is associated with diverse aetiological risk factors in patients with CP. This observation attest to the understanding of CP as a complex disease and may have implications for disease classification.
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http://dx.doi.org/10.1016/j.pan.2019.08.009DOI Listing
October 2019

Association of multiple patient and disease characteristics with the presence and type of pain in chronic pancreatitis.

J Gastroenterol Hepatol 2020 Feb 31;35(2):326-333. Epub 2019 Jul 31.

Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Background And Aim: Pain is the primary symptom of chronic pancreatitis (CP) and associates with a number of patient and disease characteristics. However, the complex interrelations of these parameters are incompletely understood, and pain treatment remains unsatisfactory in a large proportion of patients. The aim of this study is to investigate multiple pain risk factors in a large population of CP patients, with a special emphasis on patients' patterns of smoking and alcohol use.

Methods: This was a multicenter, cross-sectional study including 1384 patients with CP. Patient demographics and disease characteristics, as well as current patterns of smoking and alcohol use, were compared for patients with pain (n = 801) versus without pain (n = 583). Multivariate logistic regression models were performed to assess the variables associated with the presence and type of pain (constant vs intermittent pain).

Results: The mean age of participants was 52.1 ± 14.6 years, and 914 (66%) were men. Active smoking (odds ratio 1.6 [95% confidence interval 1.1-2.2], P = 0.005) and alcohol consumption (odds ratio 1.8 [95% confidence interval 1.1-3.0], P = 0.03) were independently associated with the presence of pain. In addition, patients' age at diagnosis, pancreatic duct pathology, and the presence of pseudocysts, duodenal stenosis, and exocrine pancreatic insufficiency were confirmed as pain risk factors (all P ≤ 0.01). Constant pain, as opposed to intermittent pain, was more frequently reported by smokers (P = 0.03), while alcohol consumption was associated with intermittent pain (P = 0.006).

Conclusion: Multiple patient and disease characteristics, including patterns of smoking and alcohol consumption, associate with the presence and type of pain in patients with CP.
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http://dx.doi.org/10.1111/jgh.14783DOI Listing
February 2020

Patient and Disease Characteristics Associate With Sensory Testing Results in Chronic Pancreatitis.

Clin J Pain 2019 09;35(9):786-793

Department of Gastroenterology and Hepatology, Centre for Pancreatic Diseases.

Background: Abdominal pain is the most common symptom in chronic pancreatitis (CP) and has an extensive impact on patients' lives. Quantitative sensory testing (QST) provides information on sensitivity to pain and mechanisms that can help quantify pain and guide treatment. The aims of this study were (1) to explore sensitivity to pain in patients with CP using QST and (2) to associate patient and disease characteristics with QST results.

Methods: Ninety-one patients with painful CP and 28 healthy control participants completed a QST paradigm using static tests (muscle pressure stimulation and electrical skin stimulations) to unravel segmental and widespread hyperalgesia as a consequence of visceral pain. A dynamic conditioned pain modulation (CPM) paradigm was used as a proxy of pain modulation from the brainstem to inhibit incoming nociceptive barrage, and questionnaires were used to gather information on pain experience and quality of life.

Results: Patients had impaired CPM compared with controls (18.0±29.3% vs. 30.9±29.3%, P=0.04) and were hypersensitive to pressure stimulation, specifically in the pancreatic (Th10) dermatome (P<0.001). The capacity of CPM was associated with clinical pain intensity (P=0.01) and (in the univariate analysis only) the use of opioids was associated with hyperalgesia to pressure stimulation (P<0.05).

Conclusions: Sensitivity to pain in CP patients can be characterized by a simple bedside QST. Severe clinical pain in CP was associated with reduced CPM function and should be targeted in management.
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http://dx.doi.org/10.1097/AJP.0000000000000740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693925PMC
September 2019

Complications to Chronic Pancreatitis and Etiological Risk Factors: A Continental Divide?

Am J Gastroenterol 2019 08;114(8):1353

Department of Gastroenterology and Hepatology, Centre for Pancreatic Diseases and Mech-Sense, Aalborg University Hospital, Aalborg, Denmark.

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http://dx.doi.org/10.14309/ajg.0000000000000302DOI Listing
August 2019

Altered brain morphology in chronic pancreatitis patients and its association with pain and other disease characteristics.

Eur J Gastroenterol Hepatol 2019 Sep;31(9):1092-1098

Mech-Sense, Department of Radiology.

Objective: Abnormal pain processing in the central nervous system is a hallmark of chronic pancreatitis (CP). We characterized brain structure in CP patients and identified disease characteristics that impact the brain structure in CP patients.

Patients And Methods: Thirty-three CP patients and 23 matched healthy controls underwent brain MRI. Total and regional gray matter volume (GMV) and cortical thickness analyses were carried out. Multivariate linear regression models were used to determine the independent predictors of total GMV.

Results: CP patients had 31.9 ± 9.3 ml (mean ± SE) (5.1%) reduced total GMV compared with the healthy controls (587.1 ± 5.8 vs. 619.0 ± 7.0 cm, P < 0.001). Alcoholic etiology was associated independently with a decreased total GMV (P < 0.001), whereas no association was observed for pain or other disease characteristics (all P > 0.05). Similarly, regional GMV loss and cortical thinning were observed for several cortical areas in patients with alcoholic etiology compared with their nonalcoholic counterparts (P < 0.05). These regional differences were particularly evident for pain-related cortical areas; however, no significant differences in regional GMV or cortical thickness were observed between patients with and without pain (all P > 0.05).

Conclusion: Patients with CP have GMV loss that is associated with alcoholic disease etiology. No associations were detected between pain and GMV loss, likely because the potential effect of long-lasting pain on brain structure is masked by the effects of previous alcohol use. The findings imply that alcoholic etiology is the most prominent contributing factor for structural brain alterations in CP patients.
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http://dx.doi.org/10.1097/MEG.0000000000001470DOI Listing
September 2019

Reply.

Gastroenterology 2019 03 18;156(4):1221-1222. Epub 2019 Feb 18.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

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http://dx.doi.org/10.1053/j.gastro.2019.02.025DOI Listing
March 2019

Chronic Pancreatitis Is Characterized by Distinct Complication Clusters That Associate With Etiological Risk Factors.

Am J Gastroenterol 2019 04;114(4):656-664

Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Objectives: Chronic pancreatitis (CP) is characterized by several disease-related complications and multiple etiological risk factors. Past studies of associations between complications and risk factors have mostly been limited to single complications or highly focused on single etiologies. Using an objective data-driven approach (cluster analysis), we characterized complication clusters and their associations with etiological risk factors in a large cohort of patients with CP.

Methods: This was a multicenter, cross-sectional study including 1,071 patients with CP from the Scandinavian and Baltic countries. Complications to CP were classified according to the M-ANNHEIM system, and treelet transform was used to derive complication clusters. Cluster complication frequencies were analyzed for their association with main etiological risk factors (smoking and alcohol).

Results: The mean age of participants was 57 years and 66% were men. Alcohol (55%) and smoking (53%) were the most common etiological risk factors and seen in combination in 36% of patients. Cluster analysis identified 3 distinct complication clusters characterized by inflammation, fibrosis, and pancreatic insufficiencies. An independent association between inflammatory complications and alcoholic etiology was seen (odds ratio [OR] 2.00 [95% CI [confidence interval], 1.38-2.90], P < 0.001), whereas smoking was associated with fibrosis-related complications (OR 2.23 [95% CI, 1.56-2.3.20], P < 0.001) and pancreatic insufficiencies (OR 1.42 [95% CI, 1.00-2.01], P = 0.046).

Discussion: Three distinctive clusters of complications to CP were identified. Their differing associations with alcoholic and smoking etiology indicate distinct underlying disease mechanisms.
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http://dx.doi.org/10.14309/ajg.0000000000000147DOI Listing
April 2019

Sarcopenia associates with increased hospitalization rates and reduced survival in patients with chronic pancreatitis.

Pancreatology 2019 Mar 14;19(2):245-251. Epub 2019 Jan 14.

Centre for Pancreatic Diseases & Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

Background: Objectives: Malnutrition is a well-known complication of chronic pancreatitis and alterations in body composition are common in this context. We investigated the prevalence of sarcopenia in patients with chronic pancreatitis, its associated risk factors and health-related outcome.

Methods: This was a prospective cohort study of chronic pancreatitis outpatients. Bioelectric impedance was used to measure body composition, and a handheld dynamometer and the timed-up-and-go test characterized muscle function. Several demographic and disease characteristics, including exocrine pancreatic insufficiency (EPI), were analyzed for their association with sarcopenia. The EORCT QLQ-C30 questionnaire was used to document life quality, and associations between sarcopenia and the number of hospital admissions, the number of in-hospital days and survival over the next 12 months were analyzed.

Results: A total of 182 patients were enrolled in the study. The prevalence of sarcopenia was 17.0% (95% CI; 11.9-23.3) and 74% of sarcopenic patients had a BMI in the normal or overweight range (BMI >18.5 kg/m). EPI was an independent risk factor for sarcopenia (OR 3.8 95% CI [1.2-12.5]; p = 0.03). Several QLQ-C30 scales and items were associated with sarcopenia including physical functioning (p < 0.001) and global health (p = 0.003). During follow-up, sarcopenia was associated with an increased risk of hospitalization (OR 2.2 95% CI [0.9-5.0]; p = 0.07), increased number of in-hospital days (p < 0.001), and reduced survival (HR 6.7 [95% CI; 1.8-25.0]; p = 0.005).

Conclusion: Sarcopenia is a common complication of chronic pancreatitis and associates with adverse health-related outcomes. As sarcopenia is not recognized by conventional anthropometric parameters in the majority of patients, systematic nutritional assessment should be prioritized.
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http://dx.doi.org/10.1016/j.pan.2019.01.006DOI Listing
March 2019

Mechanism-based pain management in chronic pancreatitis - is it time for a paradigm shift?

Expert Rev Clin Pharmacol 2019 Mar 5;12(3):249-258. Epub 2019 Feb 5.

a Centre for Pancreatic Diseases and Mech-Sense, Department of Gastroenterology and Hepatology , Aalborg University Hospital , Aalborg , Denmark.

Introduction: Pain is the most common symptom in chronic pancreatitis and treatment remains a challenge. Management of visceral pain, in general, is only sparsely documented, and treatment in the clinic is typically based on empirical knowledge from somatic pain conditions. This may be problematic, as many aspects of the neurobiology differ significantly from somatic pain, and organs such as the gut and liver play a major role in tolerability to analgesics. On the other hand, clinical awareness and new methods for quantitative assessment of pain mechanisms, will likely increase our understanding of the visceral pain system and guide more individualized pain management. Areas covered: This review includes an overview of known pain mechanisms in chronic pancreatitis and how to characterize them using quantitative sensory testing. The aim is to provide a mechanism-oriented approach to analgesic treatment, including treatment of psychological factors affecting pain perception and consideration of side effects in the management plan. Expert opinion: A mechanism-based examination and profiling of pain in chronic pancreatitis will enable investigators to provide a well-substantiated approach to effective management. This mechanism-based, individualized regime will pave the road to better pain relief and spare the patient from unnecessary trial-and-error approaches and unwanted side effects.
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http://dx.doi.org/10.1080/17512433.2019.1571409DOI Listing
March 2019

Cortical networks are disturbed in people with cirrhosis even in the absence of neuropsychometric impairment.

Clin Neurophysiol 2019 03 26;130(3):419-427. Epub 2018 Nov 26.

UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, Hampstead, London, UK. Electronic address:

Objective: Hepatic encephalopathy is a common complication of cirrhosis; it is characterised by neuropsychometric/neurophysiological abnormalities. Its pathophysiology is complex but glial neuronal communication is likely to be disrupted and to impact on oscillatory networks and cortical connectivity. The aim of this study was to use multichannel electroencephalography (EEG) to investigate functional connectivity, as a surrogate for cortical networks, in patients with cirrhosis.

Methods: Resting EEGs were recorded in 98 healthy controls and in 264 patients with cirrhosis characterised psychometrically using the Psychometric Hepatic Encephalopathy Score (PHES). Functional connectivity was calculated using the phase-lag index with stratification into standard EEG frequency bands. The findings were validated in a further cohort of 39 healthy controls and 106 patients with cirrhosis.

Results: Widespread disruption in functional connectivity was observed in the patients compared with the controls; connectivity was increased in the theta (4-8 Hz) band and decreased in the delta (1-3.5 Hz), alpha (8.5-13 Hz) and beta (13.5-26.5 Hz) bands. Changes were apparent even in patients who were psychometrically unimpaired compared with healthy controls viz mean ± SEM theta 0.107 ± 0.001 vs. 0.103 ± 0.002 (p < 0.05) and alpha 0.139 ± 0.003 vs. 0.154 ± 0.003 (p < 0.01); more pronounced changes were observed with increasing neuropsychometric impairment. The findings were replicated in the second cohort.

Conclusions: Cortical networks are disturbed in patients with cirrhosis even in the absence of psychometric impairment.

Significance: These findings will facilitate further exploration of the pathophysiology of this condition and provide a robust means for assessing treatment effects in research settings.
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http://dx.doi.org/10.1016/j.clinph.2018.11.011DOI Listing
March 2019

A Pragmatic Utility Function to Describe the Risk-Benefit Composite of Opioid and Nonopioid Analgesic Medication.

J Pharmacol Exp Ther 2019 11 15;371(2):416-421. Epub 2018 Nov 15.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark (A.E.O., S.S.O., A.M.D.); Department of Clinical Medicine, School of Medicine and Health, Aalborg University, Aalborg, Denmark (A.E.O., S.S.O., A.M.D.); and Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands (S.B., M.N., M.v.V., A.D., E.O.).

It is not straightforward to simultaneously evaluate the beneficial and harmful effects of pain management, since different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived from the pharmacokinetics and pharmacodynamics of individual outcome parameters, have been constructed to address this problem. Here, we construct "pragmatic" utility functions based on measurements of benefit and harm, but without making assumptions about the underlying pharmacokinetics and pharmacodynamics. Using data from two previous studies, utility functions were designed by estimating the probability of occurrence of benefit and harm and combining these into one function. Study 1 was a clinical trial on the effect of oral pregabalin on pain relief in chronic pancreatitis patients, with endpoint analgesia and dizziness monitored for 21 days. Study 2 was an experimental study on the effect of intravenous fentanyl on antinociception and respiratory depression in healthy volunteers. From study 1, the utility function was negative the first week of treatment, indicative of the greater probability of dizziness than analgesia, but positive thereafter. From study 2, the utility function showed a nadir 30 minutes after dosing, after which the probability function slowly increased toward zero. A pragmatic utility function based on the probability of two binary outcomes, analgesia and adverse effect, was successfully constructed using data from the two previous studies. The results yielded valuable insights into the utility of treatment and may be highly educative for physicians and potentially used in development of potent analgesics without serious side effects.
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http://dx.doi.org/10.1124/jpet.118.253716DOI Listing
November 2019

Repeatability and effect of blinding of fructose breath tests in patients with functional gastrointestinal disorders.

Neurogastroenterol Motil 2019 02 4;31(2):e13497. Epub 2018 Nov 4.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Background: Breath tests are used as measures of sugar intolerance or malabsorption in patients with functional gastrointestinal disorders (FGID), although the repeatability or anticipatory bias have not been adequately studied. We examined the repeatability and anticipatory bias during fructose breath testing using a nocebo-controlled, randomized, cross-over, and double-blind study design.

Methods: Gastrointestinal symptoms and breath concentrations of hydrogen and methane were documented during breath tests with fructose (given open twice and blinded once), water (blind neutral nocebo) and a cyclamate/saccharine sweetener (blind sweet nocebo) on 5 days in patients with FGID. Repeatability of fructose breath tests (16 patients) and differences between open and blinded substrate groups (31 patients) was assessed using thresholds for intolerance and malabsorption, and areas-under-the-curve (AUC) of symptoms and breath gas concentrations.

Key Results: Fructose breath tests showed moderate repeatability for intolerance status (absolute agreement 87%, kappa 0.72), but limited repeatability for malabsorber status (absolute agreement 53%, kappa 0.05). Repeatability of AUCs of GI symptoms, hydrogen and methane breath concentrations was moderate (intraclass correlation coefficients 0.70, 0.57, and 0.57, respectively). There were no significant differences between open and blinded fructose breath tests in intolerance or malabsorber status, or in AUCs of GI symptoms, hydrogen and methane concentrations.

Conclusions & Inferences: Fructose breath tests showed moderate repeatability for intolerance status and for AUCs of symptoms and gas concentrations, lying within the range of accepted gastrointestinal sensory and transit tests. Repeatability for malabsorption status was inadequate and requires revisiting. The fructose breath test can be used unblinded in FGID.
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http://dx.doi.org/10.1111/nmo.13497DOI Listing
February 2019

Fermentable Sugar Ingestion, Gas Production, and Gastrointestinal and Central Nervous System Symptoms in Patients With Functional Disorders.

Gastroenterology 2018 10 3;155(4):1034-1044.e6. Epub 2018 Sep 3.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Background & Aims: Functional gastrointestinal disorders (FGID) are defined by broad phenotypic descriptions and exclusion of recognizable disease. FGIDs cause multi-organ symptoms and abnormal results in a wide range of laboratory tests, indicating broad mechanisms of pathogenesis. Many patients with FGID develop symptoms following ingestion of fermentable sugars; we investigated the associations between symptoms and intestinal gas production following sugar provocation tests to elucidate mechanisms of FGID.

Methods: We performed fructose and lactose breath tests in 2042 patients with a diagnosis of FGID (based on Rome III criteria), referred to a gastroenterology practice from January 2008 through December 2011. Medical and diet histories were collected from all subjects. Breath samples were collected before and each hour after, for 5 hours, subjects ingested fructose (35 g) and lactose (50 g) dissolved in 300 mL water. Hydrogen and methane gas concentrations were measured and GI and non-GI symptoms were registered for 5 hours following sugar ingestion. Symptom and gas time profiles were compared, treelet transforms were used to derive data-related symptom clusters, and the symptom severity of the clusters were analyzed for their association with breath gas characteristics.

Results: We identified 11 GI and central nervous system (CNS) symptom profiles and hydrogen and methane breath concentrations that changed significantly with time following sugar ingestion. Treelet transform analysis identified 2 distinct clusters, based on GI and CNS symptoms. The severity scores for the GI and CNS symptoms correlated following ingestion of sugars (all, P < .0001). However, only the GI symptoms associated with hydrogen and methane gas production (all, P < .0001).

Conclusions: In an analysis of breath test results from more than 2000 patients with FGIDs, we identified clusters of GI and CNS symptoms in response to fructose of lactose ingestion. The association between specific symptoms and breath gas concentrations indicate distinct mechanisms of FGID pathogenesis, such as changes in the microbiome or mechanical and chemical sensitization. ClinicalTrials.gov ID: NCT02085889.
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http://dx.doi.org/10.1053/j.gastro.2018.07.013DOI Listing
October 2018

Breath methane concentrations and markers of obesity in patients with functional gastrointestinal disorders.

United European Gastroenterol J 2018 May 15;6(4):595-603. Epub 2017 Nov 15.

Mech-Sense, Department of Gastroenterology and Hepatology, Clinical Institute, Aalborg University Hospital, Aalborg, Denmark.

Background: Obesity is associated with changes in the intestinal microbiome and methane-producing archaea may be involved in energy homeostasis.

Objective: The objective of this article is to investigate the associations between intestinal methane production, waist circumference and body mass index (BMI) as biomarkers for obesity.

Methods: Breath methane and hydrogen concentrations were measured over five hours following fructose or lactose ingestion in 1647 patients with functional gastrointestinal disorders. The relationships between gas concentrations and measures of obesity were investigated by stratifying gas concentration-time profiles by BMI and waist circumference, and, conversely, BMI and waist circumference by peak breath hydrogen and methane concentrations.

Results: Following fructose ingestion, patients with lower BMI and lesser waist circumference had greater breath methane concentrations (all  < 0.003). Conversely, patients with increased methane concentrations had lower BMI ( < 0.001) and waist circumference ( = 0.02). After lactose ingestion, BMI and waist circumference were not associated with significant differences in methane. However, greater methane concentrations were associated with a lower BMI ( < 0.002), but not with waist circumference.

Conclusion: In this large group of patients mainly negative associations between breath methane concentrations and anthropometric biomarkers of obesity were evident. Studies investigating microbial methane production and energy homoeostasis in different populations are of substantial interest to distinguish epiphenomena from true causality.A follow-up study was registered at Clinical trials.gov NCT02085889.
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http://dx.doi.org/10.1177/2050640617744457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987281PMC
May 2018

A pilot-study of hypnotherapy as complementary treatment for pain in chronic pancreatitis.

J Complement Integr Med 2018 May 10;15(4). Epub 2018 May 10.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

BackgroundChronic pain is the hallmark symptom of chronic pancreatitis (CP). Its treatment is complicated, and often the patients have side-effects notwithstanding that pain is not ameliorated in many cases. Hypnotherapy has been shown to improve symptoms of irritable bowel syndrome including abdominal pain and, as such, may serve as a remedy to relive pain. The aim of this open-label pilot-study was to test the effect of hypnotherapy for pain in patients with CP. MethodsFour patients with CP and chronic abdominal pain were included and followed for four consecutive weeks. The primary efficacy parameter was pain relief. After 1 week of baseline patients received a 1-h session of hypnotherapy. This was repeated at day 15 and day 23 and supplemented by self-administered hypnotherapy. ResultsThree of four participants completed the trial and experienced short lasting pain reduction during the trial. The reported pain relief was in the range of 20%-39% compared to baseline. Hypnotherapy improved self-reported sleep, vitality, and social life. ConclusionsThe results suggest that hypnotherapy may reduce pain related to CP. Furthermore, no adverse effects were reported and the majority of participants completed the trial. Further prospective controlled trials are warranted to examine the potential of hypnotherapy.
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http://dx.doi.org/10.1515/jcim-2017-0084DOI Listing
May 2018

Pain in pancreatic ductal adenocarcinoma: A multidisciplinary, International guideline for optimized management.

Pancreatology 2018 Jun 22;18(4):446-457. Epub 2018 Apr 22.

Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.

Abdominal pain is an important symptom in most patients with pancreatic ductal adenocarcinoma (PDAC). Adequate control of pain is often unsatisfactory due to limited treatment options and significant variation in local practice, emphasizing the need for a multidisciplinary approach. This review contends that improvement in the management of PDAC pain will result from a synthesis of best practice and evidence around the world in a multidisciplinary way. To improve clinical utility and evaluation, the evidence was rated according to the GRADE guidelines by a group of international experts. An algorithm is presented, which brings together all currently available treatment options. Pain is best treated early on with analgesics with most patients requiring opioids, but neurolytic procedures are often required later in the disease course. Celiac plexus neurolysis offers medium term relief in a substantial number of patients, but other procedures such as splanchnicectomy are also available. Palliative chemotherapy also provides pain relief as a collateral benefit. It is stressed that the assessment of pain must take into account the broader context of other physical and psychological symptoms. Adjunctive treatments for pain, depression and anxiety as well as radiotherapy, endoscopic therapy and neuromodulation may be required in selected patients. There are few comparative studies to help define which combination and order of these treatment options should be applied. New pain therapies are emerging and could for example target neural transmitters. However, until better methods are available, management of pain should be individualized in a multidisciplinary setting to ensure optimal care.
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http://dx.doi.org/10.1016/j.pan.2018.04.008DOI Listing
June 2018

Predicting Persistent Pain After Surgery: Can Predicting the Weather Serve as an Example?

Anesth Analg 2018 11;127(5):1264-1267

From the Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1213/ANE.0000000000003318DOI Listing
November 2018

A Quantitative Sensory Testing Paradigm to Obtain Measures of Pain Processing in Patients Undergoing Breast Cancer Surgery.

J Vis Exp 2018 01 18(131). Epub 2018 Jan 18.

Department of Anesthesiology, Pain, and Palliative Medicine, Radboud University Medical Center.

Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and lower quality of life. Persistent postsurgical pain is relatively refractory to treatment hence generating a high need for preventive strategies and treatments. Therefore, the identification of patients at risk of developing persistent pain is an area of active ongoing research. Recently it was demonstrated that peri-operative disruptions in central pain processing may be able to predict persistent postsurgical pain at long term follow-up in breast cancer patients. The aim of the current report is to present a short protocol to obtain pain thresholds to different stimuli at multiple sites and a measure of endogenous analgesia in breast cancer patients. We have used this method successfully in a clinical context and detail some representative results from a clinical study.
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http://dx.doi.org/10.3791/56918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908658PMC
January 2018

Towards a neurobiological understanding of pain in chronic pancreatitis: mechanisms and implications for treatment.

Pain Rep 2017 Nov 25;2(6):e625. Epub 2017 Oct 25.

Department of Gastroenterology and Hepatology, Centre for Pancreatic Diseases & Mech-Sense, Aalborg University Hospital, Aalborg, Denmark.

Introduction: Chronic pancreatitis (CP) is a disease characterized by inflammation of the pancreas resulting in replacement of the normal functioning parenchyma by fibrotic connective tissue. This process leads to progressively impairment of exocrine and endocrine function and many patients develop a chronic pain syndrome.

Objectives: We aimed to characterize the neurobiological signature of pain associated with CP and to discuss its implications for treatment strategies.

Methods: Relevant basic and clinical articles were selected for review following an extensive search of the literature.

Results: Pathophysiological changes in the peripheral (pancreatic gland) and central nervous system characterize the pain syndrome associated with CP; involved mechanisms can be broken down to 3 main branches: (1) peripheral sensitization, (2) pancreatic neuropathy, and (3) neuroplastic changes in the central pain pathways. Disease flares (recurrent pancreatitis) may accelerate the pathophysiological process and further sensitize the pain system, which ultimately results in an autonomous and self-perpetuating pain state that may become independent of the peripheral nociceptive drive. These findings share many similarities with those observed in neuropathic pain disorders and have important implications for treatment; adjuvant analgesics are effective in a subset of patients, and neuromodulation and neuropsychological interventions may prove useful in the future.

Conclusion: Chronic pancreatitis is associated with abnormal processing of pain at the peripheral and central level of the pain system. This neurobiological understanding of pain has important clinical implications for treatment and prevention of pain chronification.
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http://dx.doi.org/10.1097/PR9.0000000000000625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741325PMC
November 2017

The cortical responses to evoked clinical pain in patients with hip osteoarthritis.

PLoS One 2017 30;12(10):e0186400. Epub 2017 Oct 30.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Background: Experimental models have been used extensively to evaluate pain using e.g., visual analogue scales or electroencephalography (EEG). Stimulation using tonic pain has been shown to better mimic the unpleasantness of chronic pain, but has mainly been evoked by non-clinical stimuli. This study aims to, evaluate the EEG during clinical pain in patients scheduled for total hip replacement with control and resting conditions.

Methods: The hip scheduled for replacement was moved by the examiner to evoke pain for 30 seconds while recording EEG. The control condition entailed movement of the opposite hip in a similar fashion and holding it for 30 seconds. In addition, EEG was recorded during the resting condition with open eyes. The relative spectral content was calculated from the EEG as well as functional connectivity using phase-lag index for frequency bands delta (1-4Hz), theta (4-8Hz), alpha (8-12Hz) and beta (12-32Hz). A mixed model was used for statistical comparison between the three recording conditions.

Results: Spectral content differed between conditions in all bands. Functional connectivity differed in delta and theta frequency bands. Post-hoc analysis revealed differences between the painful and control condition in delta, theta and beta for spectral content. Pain during the hip rotation was correlated to the theta (r = -0.24 P = 0.03) and beta (r = 0.25 P = 0.02) content in the EEG.

Conclusion: EEG differences during hip movements in the affected and unaffected hip appeared in the spectral beta and theta content. This was correlated to the reported pain perceived, pointing towards pain specific brain activity related to clinical pain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662082PMC
November 2017

The prevalence of underweight is increased in chronic pancreatitis outpatients and associates with reduced life quality.

Nutrition 2017 Nov - Dec;43-44:1-7. Epub 2017 Jul 6.

Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

Background: Underweight is a well-known complication of chronic pancreatitis (CP), but little is known about its prevalence in the outpatient setting. We investigated the prevalence of underweight in outpatients with CP and its association with quality of life (QOL) and various risk factors.

Methods: This was a cross-sectional study of 166 outpatients with CP that was conducted at a tertiary referral center. The primary outcome was the prevalence of underweight (body mass index [BMI] <20 kg/m) in patients with CP compared with 160 age- and sex-matched controls. Clinical and demographic parameters including QOL, exocrine pancreatic insufficiency (EPI), pain severity, pain pattern (constant versus intermittent), opioid use, and smoking and drinking habits were analyzed for their association with BMI.

Results: Patients with CP had a decreased mean BMI compared with controls (22.9 ± 4.2 kg/m versus 26.8 ± 5.2 kg/m; P < 0.0001). Of 166 patients with CP, 43 (26.0% [95% confidence interval: 19.8-33.1%]) were underweight compared with 15 of 160 controls (9.4% [95% confidence interval: 5.8-14.9%]; odds ratio: 3.38 [95% confidence interval: 1.79-6.38]; P = 0.0001). Several QOL scales and items were associated with underweight, including physical functioning (P = 0.024). Alcoholic etiology (P = 0.002), EPI (P = 0.004), and constant pain (P = 0.026) were independently associated with low BMI.

Conclusions: One quarter of outpatients with CP are underweight and report reduced life quality compared with their normal-weight counterparts. EPI, alcoholic etiology, and pain-related symptoms are independent risk factors. Our findings emphasize the need for a multidisciplinary approach in the handling of patients with CP that focuses on alcohol cessation and the appropriate treatment of pain and EPI.
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http://dx.doi.org/10.1016/j.nut.2017.06.019DOI Listing
May 2018