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Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus
Pancreatology 13 (2013) 343e346
Contents lists available at SciVerse ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Original article
Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus Miroslav Vujasinovic a, *, Jelka Zaletel b, Bojan Tepes c, Betka Popic a, Jana Makuc a, Metka Epsek Lenart a, Marjana Predikaka a, Sasa Rudolf d a
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1, 2380 Slovenj Gradec, Slovenia Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Zaloska 7, 1000 Ljubljana, Slovenia Abakus Medico Diagnostic Centre Rogaska, Prvomajska 29A, 3250 Rogaska Slatina, Slovenia d Department of Radiology, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 March 2013 Received in revised form 30 May 2013 Accepted 31 May 2013
Introduction: Exocrine pancreatic insufficiency (EPI) can occur in patients with diabetes mellitus (DM). Incidence of EPI and its clinical significance remain poorly defined. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with DM. Patients and methods: One hundred and fifty consecutive patients, mean age 59.0 (12.0 years), with DM lasting at least 5 years were included in the study. We included 50 patients with type 1 DM (DM1), 50 insulin-treated patients DM type 2 (DM2-insulin) and 50 non-insulin treated patients with DM type 2 (DM2 no-insulin). Diagnosis of DM was established from health records, lasting 15.0 9.9 years on average. EPI was diagnosed with a fecal elastase-1 concentration (FE1) of less than 200 mg/g (ELISA). Results: FE1 was reduced in 8 (5.4%) patients: mildly reduced (100e200 mg/g) in 4 patients (2.7%) and markedly reduced (<100 mg/g) in 4 patients (2.7%). Frequency of EPI was 3 in DM1, 5 in DM2(insulin) and none in DM2 (no-insulin) groups. Conclusions: EPI in DM occurred less frequently than in previous studies, probably due to our strict exclusion criteria (age, alcohol intake). Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Exocrine Pancreatic Insufficiency Diabetes mellitus Fecal elastase-1
1. Introduction Gastrointestinal symptoms are more prevalent in patients with diabetes mellitus (DM) than in healthy population. In a populationbased survey of 15,000 adults Bytzer et al. reported an increased prevalence rate of symptoms in patients with diabetes and poor glycemic control [1]. There have been numerous reports on exocrine pancreatic insufficiency (EPI) in patients with diabetes mellitus in the last fifty years. In the beginning, pancreatic secretion was assessed after the injection of cholecystokinin-pancreozymin and secretin. The prevalence rate of EPI in those studies ranged from 43 to 80% [2e5]. The studies were limited due to a small number of patients and invasiveness of diagnostic methods. In the last 20 years non-invasive methods have become a gold standard for EPI detection, which improved our understanding of exocrine pancreatic function. Fecal elastase-1 (FE1) and chymotrypsin were used in recent studies. Using direct pancreatic function tests as a
* Corresponding author. Tel.: þ386 2 8823 400; fax: þ386 2 8823 505. E-mail address: [email protected] (M. Vujasinovic).
reference standard, FE1 has approximately 100% sensitivity for severe, 77e100% for moderate and 0e63% for mild EPI with approximately 93% of specificity [6e9]. These studies also suggest higher sensitivity and specificity of FE1 in comparison with fecal chymotrypsin. In the last ten years there have been numerous reports of impaired EPI in patients with DM using FE1 as a diagnostic method, which implicated high prevalence [10e16]. The aim of the present study was to determine the prevalence of EPI in patients with DM in the Slovene population (Caucasians).
2. Patients and methods 2.1. Patients One hundred and fifty patients with diabetes mellitus were invited to participate in a single centre prospective study and gave their written informed consent. The study was approved by the National Medical Ethics Committee of the Republic of Slovenia. We included 50 patients with type 1 DM (DM1), 50 insulin-treated patients with DM type 2 (DM2 insulin) and 50 non-insulin treated
1424-3903/$ e see front matter Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2013.05.010
344
M. Vujasinovic et al. / Pancreatology 13 (2013) 343e346
patients with DM type 2 (DM2 no-insulin). Patients were enrolled at the Department of Internal Medicine of the Slovenj Gradec General Hospital and referred from outpatient departments in the Carinthian region in the north-east of Slovenia, with the population of about 100,000 people. Seventy-eight (52%) patients were female and 72 (48%) were male, mean age of 59.0 (12.0) years. Mean duration of DM was 15.0 (9.9) years (Table 1).
Detailed medical history and physical examination were performed, including history of alcohol consumption, smoking, gastrointestinal disease, surgery, duration of DM, DM complications (retinopathy, neuropathy, nephropathy, vasculopathy) and current gastrointestinal symptoms. We excluded patients with any of the following: DM lasting <5 years, younger than 18 and older than 75 years, alcohol consumption over 20 g per day, medical history of abdominal surgery, any other known reason for malabsorption, previous pancreatic disease, abnormal liver function tests, malignant disease, inflammatory bowel disease, short bowel syndrome and autoimmune diseases.
Systems) with a torso phased-array coil with standard protocol, which consisted of T1-weighted gradient-echo in-phase and opposed-phase sequence, T2-weighted fast recovery fast spin-echo and an axial and coronal T1-weighted fast spoiled gradient-echo sequence with fat suppression. All images were obtained in the axial plane with 6-mm slice thickness and matrix 192 320 and coronal with matrix 192 384. MRCP images were obtained using 2D breath-hold thick slab and 3D respiratory-triggered images. All images were loaded to an ADW 4.4 workstation for evaluation of MRCP images and quantitative image analysis. For assessing the morphologic features of the pancreatic gland, we analysed the size, fatty infiltration and the signal intensity (SI) in all three segments: head, body and tail of the pancreas, and mean values were calculated. Pancreas was considered atrophic according to measured AP diameter in each segment in millimeters below the age-related mean size [18,19]. For fatty infiltration we looked for a decrease in the signal intensity on the opposed-phase T1-weighted gradientecho image and for the SI the signal of the pancreas was compared to the signal of the spleen on axial T1-weighted fat saturated images. The pancreatic duct was evaluated on MRCP images and classified either as normal or showing signs of chronic pancreatitis.
2.3. Laboratory
2.5. Statistics
Patients sampled a probe of their morning stool into a labeled stool tube that was collected from our laboratory stuff and was transported to central laboratory. FE1 measurements were performed at the Institute of Clinical Chemistry and Biochemistry of the University Medical Centre Ljubljana using enzyme-linked immunosorbent assay (ELISA) and a commercial kit ScheBo Biotech, Giessen, Germany. The results of FE1 were presented in mg/ g of stool. Levels of >200 mg/g, 100e200 mg/g and <100 mg/g were considered as normal exocrine pancreatic function, mild exocrine pancreatic insufficiency and severe pancreatic insufficiency, respectively. FE 1 was measured in duplicate (in all patients with first positive result laboratory test was repeated). Hemoglobin A1c concentration was measured using boronate affinity chromatography. In all patients with low FE-1 further work-up was performed using the following laboratory tests: serum iron, ferritin, transferrin, vitamin B12, folic acid, calcium, phosphates, magnesium, potassium, sodium chloride, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, bilirubin, amylase, lipase, carbohydrate deficient transferrin (CDT), CA19-9, alpha-1-antitripsyn, tissue transglutaminase antibodies, vitamin D, HEp-2 antibodies, immunoglobulin G4, protein, albumin, total cholesterol, HDL cholesterol, triglycerides and LDL cholesterol (LDL was calculated using Friedewald’s formula).
Statistical analysis was performed using SPSS version 17.0 software (SPSS Inc., Chicago, Illinois, ZDA). Qualitative (descriptive) variables are given as frequency of categories and the percentage. Distribution of frequencies of two variables is given in twodimensional contingency tables. Relationships between variables were tested by ChieSquare test. In the event that the frequencies were too low for the chi-square test, Fisher’s exact test was used instead. For numeric variables, average value, median, standard deviation, minimum and maximum value were calculated. For all statistical tests a significance level of 0.05 was used (p < 0.05).
2.2. Methods
2.4. MRI Patients with confirmed EPI underwent combined MRI of the upper abdomen and magnetic resonance cholangiopancreatography (MRCP) using a 3.0T MR scanner (Signa HDxt, GE Medical
3. Results Descriptive statistics of clinical and metabolic characteristics of the enrolled patients is shown in Tables 1e3. FE1 was reduced in 8 (5.4%) patients, their characteristics are shown in Table 3. FE1 was mildly reduced (100e200 mg/g) in 4 patients (2.7%) and markedly reduced. (<100 mg/g) in 4 patients (2.7%). Frequency of EPI was 3 in DM1, 5 in DM2 (insulin) and none in DM2 (no-insulin). In this group of patients, no statistically significant relationship between DM duration and EPI was found (Fisher’s exact test, p ¼ 1000). Three patients out of eight with EPI had one or more symptoms in the past. In five out of eight patients with EPI a vitamin D deficiency was found. In one patient (No 2 in Table 3) tissue transglutaminase antibody levels were higher than normal (23.2 AU), suggesting celiac disease, but multiple duodenal biopsy showed normal histopathology finding. In 5 out of 8 patients (3 patients declined) with EPI a MRI/MRCP was performed for morphologic evaluation of the pancreatic parenchyma and pancreatic duct. Two of them were male and 3 female: 3 patients had DM1 and 2 patients DM2 (insulin). Image
Table 1 Characteristics of all included patients. Age (years) FE-1 (mg/g) DM duration HbA1c (years) (%) Mean 59.0 SD 12.004 RANGE 19e75
449.3 140.7 7e746
15.0 9.9 5e54
DM COMPLICATIONS (%)
7.5 Neuropathy 15.3 1.2 Retinopathy 27.3 5.2e11.7 Nephropathy 14.0 Vasculopathy 10.0
Abbreviations: FE ¼ fecal elastase; DM ¼ diabetes mellitus; SD ¼ standard deviation; HbA1c ¼ hemoglobin A1c.
Table 2 Prevalence of pancreatic exocrine insufficiency according to diabetes duration. Diabetes duration (years)
Pancreatic exocrine insufficiency (number of patients)
Total number of patients
5e10 11e20 >20 Total
2 2 4 8
45 56 49 150
M. Vujasinovic et al. / Pancreatology 13 (2013) 343e346
345
Table 3 Characteristics of patients with exocrine pancreatic insufficiency. No.
Gender
Age (years)
FE-1 (mg/g)
HbA1c (%)
DM group
DM dur. (years)
DM complications
1 2 3
Male Female Female
60 38 44
89 7 174
8.7 7.6 7.1
DM2-ins DM-1 DM-1
10 24 30
4
Female
55
143
8.5
DM-1
37
5 6 7 8
Male Male Male Female
61 46 75 75
36 162 177 82
8.6 9.6 7.2 8.5
DM2-ins DM2-ins DM2-ins DM2-ins
16 5 26 16
None None Retinopathy Nephropathy Retinopathy Neuropathy Retinopathy, nephropathy,neuropathy, vasculopathy Retinopathy, nephropathy None Nephropathy, vasculopathy
Abbreviations: No ¼ number of patients; FE-1 ¼ level of fecal elastase-1; HbA1c ¼ hemoglobin A1c; DM group ¼ diabetes mellitus group; DM2-ins ¼ insulin treated diabetes mellitus type 2; DM-1 ¼ type 1 diabetes mellitus; DM dur. ¼ duration of diabetes mellitus; DM compl. ¼ complications of diabetes mellitus.
analysis showed atrophy of the pancreatic parenchyma according to age-related mean size in 4 patients (1 with DM2 insulin and 3 with DM1). Fatty infiltration was present in 2 patients (both with DM2 insulin) aged 47 years and 78 years, respectively. In 3 patients lower signal intensity was found on T1-weighted fat saturated images compared to the spleen (2 with DM2 insulin and 1 with DM1). In all patients pancreatic duct was of normal diameter with no signs of chronic pancreatitis. 4. Discussion EPI is a well-known clinical feature in patients with DM and has been a topic of many studies in the last decades, suggesting high prevalence but controversial clinical significance [10e16]. Our goal was to determine EPI prevalence and its clinical relevance in DM patients from our region. We found reduced FE1 serum concentrations in 5.4% patients, of these 4 were markedly and 4 mildly reduced. Our prevalence of EPI is lower than in other studies (Table 4). We speculate that lower prevalence as expected is mostly due to our strict exclusion criteria, especially excessive alcohol consumption and other known reason for malabsorption. EPI was found in 3 DM1 patients and 5 DM2 (insulin) patients, but none in the DM2 (no-insulin) group. In our study, pancreatic atrophy was found on MRI in 4 patients out of 5 that had MRI performed: in 3 patients with DM1, possibly related to acinar cell atrophy as found in diabetes mellitus type 1, and more likely agerelated in the one 78-year old patient with DM2. All findings are similar to the morphological changes seen on MRI in patients with DM and EPI described in previous studies [20,21]. Additionally, we
Table 4 Prevalence of PEI in diabetics in different studies. Author
Number of patients and type of diabetes mellitus
Incidence of EPI
Nunes, 2003
42 patients; all DM-2
Hardt, 2000 Cavalot, 2004
114 patients; DM-1 and DM-2 37 patients; all DM-1
Icks, 2001
112 patients; all DM-1
Yilmaztepe, 2003
32 patients; all DM2-ins
Hardt, 2003
1021 patients; DM-1 and DM2 150 patients; DM-1 and DM-2
36.0% total (14.0% mild and 22.0% severe) 40.4% total (20.2% mild and 20.2% severe) 56.7% total (45.9% mild and 10.8% severe) 45.5% total (19.6% mild and 25.9% severe) 28.1% total (25% mild and 3.1% severe) 40.7% total (17.8% mild and 22.9% severe) 5.4% total (2.7% mild and 2.7% severe)
Present study, 2012
Abbreviations: DM2-ins ¼ insulin treated diabetes mellitus type 2; DM-1 ¼ type 1 diabetes mellitus.
found no signs of chronic pancreatitis on MRI imaging, thus excluding secondary pancreatogenic diabetes, which was also suggested as a more frequent cause of DM as presently believed. Hardt et al. performed a retrospective evaluation of ERCP in 156 diabetic patients and found sings of chronic pancreatitis in 76.7% of patients [22]. Three of our patients showed decreased signal intensity in T-1 weighted fat saturated images, which was found to be associated with the loss of acinar cell integrity. Fatty infiltration of the pancreas was present in 2 patients (both with DM2 insulin), suggesting fatty infiltration of the pancreas within metabolic syndrome as a possible cause of EPI in patients with DM2. Finally, the clinical relevance of EPI in DM patients is also controversial. Three out of our 8 patients with EPI had one or more gastrointestinal symptoms in the past, and 5 out of 8 had vitamin D deficiency. Since none had any other clinical or laboratory sign of malabsorption, this suggests EPI as a primary cause. Malnutrition is a well known and important complication in patients with EPI and chronic pancreatitis. The usefulness of serum nutritional markers as surrogate markers for EPI was investigated and serum magnesium was found as most reliable in one study by Lindkvist et al. [17] They concluded that chronic pancreatitis patients with a magnesium value above 2.05 mg/dL (0.84 mmol/L) were very unlikely to suffer from EPI. In the present study, there were no signs of chronic pancreatitis on MRI imaging. Additionally, it has been suggested that EPI correlates with earlier onset and longer duration of DM18, but we found no statistically significant relationship between diabetes duration and symptoms of EPI or FE1 level. The strengths of the study are the number of patients included, non-invasive diagnostic method, strong exclusion criteria and additional MRI morphology. There are also limitations of the study, relating particularly to the use of FE1 as a diagnostic method due to its low sensitivity in cases of mild to moderate EPI, which is a general problem with all indirect pancreatic function tests [17]. On the other hand, it is easy and simple to use, which is its main advantage in comparison to other direct and indirect diagnostic methods. In our country, quantitative stool fat analysis and 13C breath test are not routinely used and the determination of FE1 can be recommended as a standard in exocrine pancreatic function diagnostics. Nevertheless, EPI is still of high clinical importance. Further multi-centric studies on this topic, using non-invasive methods for EPI detection with high sensitivity and specificity, allowing a greater number of patients to be enrolled, and with stringent exclusion criteria should be encouraged. 5. Conclusions In conclusion, our study confirms that EPI has a prevalence of 5.4% in patients with DM (2.7% of the patients had severe and 2.7%
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M. Vujasinovic et al. / Pancreatology 13 (2013) 343e346
had mild EPI). Three out of eight patients had type 1 diabetes and five had type 2 diabetes, treated with insulin. No EPI was found in type 2 diabetes patients not using insulin. EPI was not associated with diabetes duration, as frequently speculated. The lower prevalence as expected is probably related to stringent exclusion criteria (i.e. alcohol consumption and other known reason for malabsorption). The results of our study suggest that routine screening for PEI may not be recommended in patients with diabetes in the absence of overt malnutrition. Disclosure VM Consultant: Takeda Nycomed. Lecture fee: Falk Pharma, Krka, Abbott, Lek (a Sandoz company), Takeda Nycomed. ZJ: Nothing to disclose. TB: Consultant: Takeda Nycomed. Lecture fee: Krka, Astra Zeneca, Novartis, Falk Pharma. Research grant: Krka, Astra Zeneca. PB: Nothing to disclose. MJ: Nothing to disclose. LEM: Nothing to disclose. PM: Nothing to disclose. RS: Nothing to disclose. Acknowledgments The authors thank Davorin Benko, MD (Head of the Department) and Martin Tretjak, MD, PhD from Department of Internal Medicine in Slovenj Gradec General Hospital, for support during the study, valid comments and assistance in manuscript editing. We also thank Alenka Sesek Briski, MSc, Head of laboratory department University Medical Centre Ljubljana Institute of Clinical Chemistry and Biochemistry for cooperation and useful comments. References [1] Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus. Arch Intern Med 2001;161:1989e96. [2] Chey WY, Shay H, Shuman CR. External pancreatic secretion in diabetes mellitus. Ann Intern Med 1963;59:812e21. [3] Frier BM, Saunders JHB, Wormsley KG, Bouchier IAD. Exocrine pancreatic function in juvenile-onset diabetes mellitus. Gut 1976;17:685e91.
[4] Lankisch PG, Manthey G, Otto J, Koop H, Talaulicar M, Willms B, et al. Exocrine pancreatic function in insulin dependent diabetes mellitus. Digestion 1982;25:211e6. [5] Ewald N, Raspe A, Kaufmann C, Bretzel RG, Kloer HU, Hardt PD. Determinants of exocrine pancreatic function as measured by fecal elastase-1 concentracions (FEC) in patients with diabetes mellitus. Eur J Med Res 2009;14:118e22. [6] Domínguez-Munoz JE, Hieronymus C, Sauerbruch T, Malfertheiner P. Fecal elastase test: evaluation of a new noninvasive pancreatic function test. Am J Gastroenterol 1995;90:1834e7. [7] Gullo L, Ventrucci M, Tomassetti P, Migliori M, Pezzili R. Fecal elastase 1 determination in chronic pancreatitis. Dig Dis Sci 1999;44:210e3. [8] Behhary S, Ellis L, Corey M, Marcon M, Durie P. How useful is fecal pancreatic elastase 1 as a marker of exocrine pancreatic disease? J Pediatr 2002;141:84e90. [9] Löser C, Möllgaard, Fölsch UR. Faecal elastase 1: a novel, highly sensitive and specific tubeless pancreatic function test. Gut 1996;39:580e6. [10] Hardt PD, Krauss A, Bretz L, Pörsch-Özcürümez M, Schnell-Kretschmer H, Mäser E, et al. Pancreatic exocrine function in patients with type 1 and type 2 diabets mellitus. Acta Diabetol 2000;37:105e10. [11] Icks A, Haastert B, Giani G, Rathmann W. Low fecal elastase-1 in type I diabetes mellitus. Z Gastroenterol 2001;39:823e30. [12] Nunes ACR, Pontes JM, Rosa A, Gomes L, Carvalheiro M, Freitas D. Screening for pancreatic exocrine insufficiency in patients with diabetes mellitus. Am J Gastroenterol 2003;98:2672e5. [13] Hardt PD, Hauenschild A, Nalop J, Marzeion AM, Jaeger C, Teichmann J, et al. High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase-1 concentrations in 1,021 diabetic patients. Pancreatology 2003;3:395e402. [14] Cavalot F, Bonomo K, Perna P, Bacillo E, Salacone P, Gallo M, et al. Pancreatic elastase-1 in stools, a marker of exocrine pancreas function, correlates with both residual b-cell secretion and metabolic control in type 1 diabetic subjects. Diabetes Care 2004;27:2052e4. [15] Yilmaztepe A, Ulukaya E, Ersoy C, Yilmaz M, Tokullugil HA. Investigation of fecal pancreatic elastase-1 levels in type 2 diabetic patients. Turk J Gastroenterol 2005;16:75e80. [16] Löhr JM. Exocrine pancreatic insufficiency. 2nd ed. Bremen: UNI-MED; 2010. [17] Lindkvist B, Domínguez-Munoz JE, Luaces-Regueira M, Castineiras-Alvarino M, Nieto-Garcia L, Iglesias-Garcia J. [18] Ewald N, Raspe A, Kaufmann C, Bretzel RG, Kloer HU, Hardt PD. Determinants of exocrine pancreatic function as measured by fecal elastase-1 concentrations (FEC) in patients with diabetes mellitus. Eur J Med Res 2009;14:118e22. [19] Baert AL, Delorme G, Van Hoe L. Radiology of the pancreas. 2nd ed. Springer; 1999. [20] Bilgin M, Balci NC, Momtahem AJ, Bilgin Y, Klör HU, Rau WS. MRI and MRCP findings of the pancreas in patients with diabetes mellitus. Compared analysis with exocrine function determined by fecal elastase 1. J Clin Gastroenterol 2009;43:165e70. [21] Alkaade S, Balci NC, Momtahen AJ, Burton F. Normal pancreatic function does not exclude MRI/MRCP chronic pancreatitis findings. J Clin Gastroenterol 2008;42:950e5. [22] Hardt PD, Killinger A, Nalop J, Schnell-Kretschmer H, Zekorn T, Klör HU. Chronic pancreatitis and diabetes mellitus. A retrospective analysis of 156 ERCP investigations in patients with insulin-dependent and non-insulindependent diabetes mellitus. Pancreatology 2002;2:30e3.
Contents lists available at SciVerse ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Original article
Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus Miroslav Vujasinovic a, *, Jelka Zaletel b, Bojan Tepes c, Betka Popic a, Jana Makuc a, Metka Epsek Lenart a, Marjana Predikaka a, Sasa Rudolf d a
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1, 2380 Slovenj Gradec, Slovenia Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Zaloska 7, 1000 Ljubljana, Slovenia Abakus Medico Diagnostic Centre Rogaska, Prvomajska 29A, 3250 Rogaska Slatina, Slovenia d Department of Radiology, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 March 2013 Received in revised form 30 May 2013 Accepted 31 May 2013
Introduction: Exocrine pancreatic insufficiency (EPI) can occur in patients with diabetes mellitus (DM). Incidence of EPI and its clinical significance remain poorly defined. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with DM. Patients and methods: One hundred and fifty consecutive patients, mean age 59.0 (12.0 years), with DM lasting at least 5 years were included in the study. We included 50 patients with type 1 DM (DM1), 50 insulin-treated patients DM type 2 (DM2-insulin) and 50 non-insulin treated patients with DM type 2 (DM2 no-insulin). Diagnosis of DM was established from health records, lasting 15.0 9.9 years on average. EPI was diagnosed with a fecal elastase-1 concentration (FE1) of less than 200 mg/g (ELISA). Results: FE1 was reduced in 8 (5.4%) patients: mildly reduced (100e200 mg/g) in 4 patients (2.7%) and markedly reduced (<100 mg/g) in 4 patients (2.7%). Frequency of EPI was 3 in DM1, 5 in DM2(insulin) and none in DM2 (no-insulin) groups. Conclusions: EPI in DM occurred less frequently than in previous studies, probably due to our strict exclusion criteria (age, alcohol intake). Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Exocrine Pancreatic Insufficiency Diabetes mellitus Fecal elastase-1
1. Introduction Gastrointestinal symptoms are more prevalent in patients with diabetes mellitus (DM) than in healthy population. In a populationbased survey of 15,000 adults Bytzer et al. reported an increased prevalence rate of symptoms in patients with diabetes and poor glycemic control [1]. There have been numerous reports on exocrine pancreatic insufficiency (EPI) in patients with diabetes mellitus in the last fifty years. In the beginning, pancreatic secretion was assessed after the injection of cholecystokinin-pancreozymin and secretin. The prevalence rate of EPI in those studies ranged from 43 to 80% [2e5]. The studies were limited due to a small number of patients and invasiveness of diagnostic methods. In the last 20 years non-invasive methods have become a gold standard for EPI detection, which improved our understanding of exocrine pancreatic function. Fecal elastase-1 (FE1) and chymotrypsin were used in recent studies. Using direct pancreatic function tests as a
* Corresponding author. Tel.: þ386 2 8823 400; fax: þ386 2 8823 505. E-mail address: [email protected] (M. Vujasinovic).
reference standard, FE1 has approximately 100% sensitivity for severe, 77e100% for moderate and 0e63% for mild EPI with approximately 93% of specificity [6e9]. These studies also suggest higher sensitivity and specificity of FE1 in comparison with fecal chymotrypsin. In the last ten years there have been numerous reports of impaired EPI in patients with DM using FE1 as a diagnostic method, which implicated high prevalence [10e16]. The aim of the present study was to determine the prevalence of EPI in patients with DM in the Slovene population (Caucasians).
2. Patients and methods 2.1. Patients One hundred and fifty patients with diabetes mellitus were invited to participate in a single centre prospective study and gave their written informed consent. The study was approved by the National Medical Ethics Committee of the Republic of Slovenia. We included 50 patients with type 1 DM (DM1), 50 insulin-treated patients with DM type 2 (DM2 insulin) and 50 non-insulin treated
1424-3903/$ e see front matter Copyright Ó 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2013.05.010
344
M. Vujasinovic et al. / Pancreatology 13 (2013) 343e346
patients with DM type 2 (DM2 no-insulin). Patients were enrolled at the Department of Internal Medicine of the Slovenj Gradec General Hospital and referred from outpatient departments in the Carinthian region in the north-east of Slovenia, with the population of about 100,000 people. Seventy-eight (52%) patients were female and 72 (48%) were male, mean age of 59.0 (12.0) years. Mean duration of DM was 15.0 (9.9) years (Table 1).
Detailed medical history and physical examination were performed, including history of alcohol consumption, smoking, gastrointestinal disease, surgery, duration of DM, DM complications (retinopathy, neuropathy, nephropathy, vasculopathy) and current gastrointestinal symptoms. We excluded patients with any of the following: DM lasting <5 years, younger than 18 and older than 75 years, alcohol consumption over 20 g per day, medical history of abdominal surgery, any other known reason for malabsorption, previous pancreatic disease, abnormal liver function tests, malignant disease, inflammatory bowel disease, short bowel syndrome and autoimmune diseases.
Systems) with a torso phased-array coil with standard protocol, which consisted of T1-weighted gradient-echo in-phase and opposed-phase sequence, T2-weighted fast recovery fast spin-echo and an axial and coronal T1-weighted fast spoiled gradient-echo sequence with fat suppression. All images were obtained in the axial plane with 6-mm slice thickness and matrix 192 320 and coronal with matrix 192 384. MRCP images were obtained using 2D breath-hold thick slab and 3D respiratory-triggered images. All images were loaded to an ADW 4.4 workstation for evaluation of MRCP images and quantitative image analysis. For assessing the morphologic features of the pancreatic gland, we analysed the size, fatty infiltration and the signal intensity (SI) in all three segments: head, body and tail of the pancreas, and mean values were calculated. Pancreas was considered atrophic according to measured AP diameter in each segment in millimeters below the age-related mean size [18,19]. For fatty infiltration we looked for a decrease in the signal intensity on the opposed-phase T1-weighted gradientecho image and for the SI the signal of the pancreas was compared to the signal of the spleen on axial T1-weighted fat saturated images. The pancreatic duct was evaluated on MRCP images and classified either as normal or showing signs of chronic pancreatitis.
2.3. Laboratory
2.5. Statistics
Patients sampled a probe of their morning stool into a labeled stool tube that was collected from our laboratory stuff and was transported to central laboratory. FE1 measurements were performed at the Institute of Clinical Chemistry and Biochemistry of the University Medical Centre Ljubljana using enzyme-linked immunosorbent assay (ELISA) and a commercial kit ScheBo Biotech, Giessen, Germany. The results of FE1 were presented in mg/ g of stool. Levels of >200 mg/g, 100e200 mg/g and <100 mg/g were considered as normal exocrine pancreatic function, mild exocrine pancreatic insufficiency and severe pancreatic insufficiency, respectively. FE 1 was measured in duplicate (in all patients with first positive result laboratory test was repeated). Hemoglobin A1c concentration was measured using boronate affinity chromatography. In all patients with low FE-1 further work-up was performed using the following laboratory tests: serum iron, ferritin, transferrin, vitamin B12, folic acid, calcium, phosphates, magnesium, potassium, sodium chloride, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, bilirubin, amylase, lipase, carbohydrate deficient transferrin (CDT), CA19-9, alpha-1-antitripsyn, tissue transglutaminase antibodies, vitamin D, HEp-2 antibodies, immunoglobulin G4, protein, albumin, total cholesterol, HDL cholesterol, triglycerides and LDL cholesterol (LDL was calculated using Friedewald’s formula).
Statistical analysis was performed using SPSS version 17.0 software (SPSS Inc., Chicago, Illinois, ZDA). Qualitative (descriptive) variables are given as frequency of categories and the percentage. Distribution of frequencies of two variables is given in twodimensional contingency tables. Relationships between variables were tested by ChieSquare test. In the event that the frequencies were too low for the chi-square test, Fisher’s exact test was used instead. For numeric variables, average value, median, standard deviation, minimum and maximum value were calculated. For all statistical tests a significance level of 0.05 was used (p < 0.05).
2.2. Methods
2.4. MRI Patients with confirmed EPI underwent combined MRI of the upper abdomen and magnetic resonance cholangiopancreatography (MRCP) using a 3.0T MR scanner (Signa HDxt, GE Medical
3. Results Descriptive statistics of clinical and metabolic characteristics of the enrolled patients is shown in Tables 1e3. FE1 was reduced in 8 (5.4%) patients, their characteristics are shown in Table 3. FE1 was mildly reduced (100e200 mg/g) in 4 patients (2.7%) and markedly reduced. (<100 mg/g) in 4 patients (2.7%). Frequency of EPI was 3 in DM1, 5 in DM2 (insulin) and none in DM2 (no-insulin). In this group of patients, no statistically significant relationship between DM duration and EPI was found (Fisher’s exact test, p ¼ 1000). Three patients out of eight with EPI had one or more symptoms in the past. In five out of eight patients with EPI a vitamin D deficiency was found. In one patient (No 2 in Table 3) tissue transglutaminase antibody levels were higher than normal (23.2 AU), suggesting celiac disease, but multiple duodenal biopsy showed normal histopathology finding. In 5 out of 8 patients (3 patients declined) with EPI a MRI/MRCP was performed for morphologic evaluation of the pancreatic parenchyma and pancreatic duct. Two of them were male and 3 female: 3 patients had DM1 and 2 patients DM2 (insulin). Image
Table 1 Characteristics of all included patients. Age (years) FE-1 (mg/g) DM duration HbA1c (years) (%) Mean 59.0 SD 12.004 RANGE 19e75
449.3 140.7 7e746
15.0 9.9 5e54
DM COMPLICATIONS (%)
7.5 Neuropathy 15.3 1.2 Retinopathy 27.3 5.2e11.7 Nephropathy 14.0 Vasculopathy 10.0
Abbreviations: FE ¼ fecal elastase; DM ¼ diabetes mellitus; SD ¼ standard deviation; HbA1c ¼ hemoglobin A1c.
Table 2 Prevalence of pancreatic exocrine insufficiency according to diabetes duration. Diabetes duration (years)
Pancreatic exocrine insufficiency (number of patients)
Total number of patients
5e10 11e20 >20 Total
2 2 4 8
45 56 49 150
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Table 3 Characteristics of patients with exocrine pancreatic insufficiency. No.
Gender
Age (years)
FE-1 (mg/g)
HbA1c (%)
DM group
DM dur. (years)
DM complications
1 2 3
Male Female Female
60 38 44
89 7 174
8.7 7.6 7.1
DM2-ins DM-1 DM-1
10 24 30
4
Female
55
143
8.5
DM-1
37
5 6 7 8
Male Male Male Female
61 46 75 75
36 162 177 82
8.6 9.6 7.2 8.5
DM2-ins DM2-ins DM2-ins DM2-ins
16 5 26 16
None None Retinopathy Nephropathy Retinopathy Neuropathy Retinopathy, nephropathy,neuropathy, vasculopathy Retinopathy, nephropathy None Nephropathy, vasculopathy
Abbreviations: No ¼ number of patients; FE-1 ¼ level of fecal elastase-1; HbA1c ¼ hemoglobin A1c; DM group ¼ diabetes mellitus group; DM2-ins ¼ insulin treated diabetes mellitus type 2; DM-1 ¼ type 1 diabetes mellitus; DM dur. ¼ duration of diabetes mellitus; DM compl. ¼ complications of diabetes mellitus.
analysis showed atrophy of the pancreatic parenchyma according to age-related mean size in 4 patients (1 with DM2 insulin and 3 with DM1). Fatty infiltration was present in 2 patients (both with DM2 insulin) aged 47 years and 78 years, respectively. In 3 patients lower signal intensity was found on T1-weighted fat saturated images compared to the spleen (2 with DM2 insulin and 1 with DM1). In all patients pancreatic duct was of normal diameter with no signs of chronic pancreatitis. 4. Discussion EPI is a well-known clinical feature in patients with DM and has been a topic of many studies in the last decades, suggesting high prevalence but controversial clinical significance [10e16]. Our goal was to determine EPI prevalence and its clinical relevance in DM patients from our region. We found reduced FE1 serum concentrations in 5.4% patients, of these 4 were markedly and 4 mildly reduced. Our prevalence of EPI is lower than in other studies (Table 4). We speculate that lower prevalence as expected is mostly due to our strict exclusion criteria, especially excessive alcohol consumption and other known reason for malabsorption. EPI was found in 3 DM1 patients and 5 DM2 (insulin) patients, but none in the DM2 (no-insulin) group. In our study, pancreatic atrophy was found on MRI in 4 patients out of 5 that had MRI performed: in 3 patients with DM1, possibly related to acinar cell atrophy as found in diabetes mellitus type 1, and more likely agerelated in the one 78-year old patient with DM2. All findings are similar to the morphological changes seen on MRI in patients with DM and EPI described in previous studies [20,21]. Additionally, we
Table 4 Prevalence of PEI in diabetics in different studies. Author
Number of patients and type of diabetes mellitus
Incidence of EPI
Nunes, 2003
42 patients; all DM-2
Hardt, 2000 Cavalot, 2004
114 patients; DM-1 and DM-2 37 patients; all DM-1
Icks, 2001
112 patients; all DM-1
Yilmaztepe, 2003
32 patients; all DM2-ins
Hardt, 2003
1021 patients; DM-1 and DM2 150 patients; DM-1 and DM-2
36.0% total (14.0% mild and 22.0% severe) 40.4% total (20.2% mild and 20.2% severe) 56.7% total (45.9% mild and 10.8% severe) 45.5% total (19.6% mild and 25.9% severe) 28.1% total (25% mild and 3.1% severe) 40.7% total (17.8% mild and 22.9% severe) 5.4% total (2.7% mild and 2.7% severe)
Present study, 2012
Abbreviations: DM2-ins ¼ insulin treated diabetes mellitus type 2; DM-1 ¼ type 1 diabetes mellitus.
found no signs of chronic pancreatitis on MRI imaging, thus excluding secondary pancreatogenic diabetes, which was also suggested as a more frequent cause of DM as presently believed. Hardt et al. performed a retrospective evaluation of ERCP in 156 diabetic patients and found sings of chronic pancreatitis in 76.7% of patients [22]. Three of our patients showed decreased signal intensity in T-1 weighted fat saturated images, which was found to be associated with the loss of acinar cell integrity. Fatty infiltration of the pancreas was present in 2 patients (both with DM2 insulin), suggesting fatty infiltration of the pancreas within metabolic syndrome as a possible cause of EPI in patients with DM2. Finally, the clinical relevance of EPI in DM patients is also controversial. Three out of our 8 patients with EPI had one or more gastrointestinal symptoms in the past, and 5 out of 8 had vitamin D deficiency. Since none had any other clinical or laboratory sign of malabsorption, this suggests EPI as a primary cause. Malnutrition is a well known and important complication in patients with EPI and chronic pancreatitis. The usefulness of serum nutritional markers as surrogate markers for EPI was investigated and serum magnesium was found as most reliable in one study by Lindkvist et al. [17] They concluded that chronic pancreatitis patients with a magnesium value above 2.05 mg/dL (0.84 mmol/L) were very unlikely to suffer from EPI. In the present study, there were no signs of chronic pancreatitis on MRI imaging. Additionally, it has been suggested that EPI correlates with earlier onset and longer duration of DM18, but we found no statistically significant relationship between diabetes duration and symptoms of EPI or FE1 level. The strengths of the study are the number of patients included, non-invasive diagnostic method, strong exclusion criteria and additional MRI morphology. There are also limitations of the study, relating particularly to the use of FE1 as a diagnostic method due to its low sensitivity in cases of mild to moderate EPI, which is a general problem with all indirect pancreatic function tests [17]. On the other hand, it is easy and simple to use, which is its main advantage in comparison to other direct and indirect diagnostic methods. In our country, quantitative stool fat analysis and 13C breath test are not routinely used and the determination of FE1 can be recommended as a standard in exocrine pancreatic function diagnostics. Nevertheless, EPI is still of high clinical importance. Further multi-centric studies on this topic, using non-invasive methods for EPI detection with high sensitivity and specificity, allowing a greater number of patients to be enrolled, and with stringent exclusion criteria should be encouraged. 5. Conclusions In conclusion, our study confirms that EPI has a prevalence of 5.4% in patients with DM (2.7% of the patients had severe and 2.7%
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had mild EPI). Three out of eight patients had type 1 diabetes and five had type 2 diabetes, treated with insulin. No EPI was found in type 2 diabetes patients not using insulin. EPI was not associated with diabetes duration, as frequently speculated. The lower prevalence as expected is probably related to stringent exclusion criteria (i.e. alcohol consumption and other known reason for malabsorption). The results of our study suggest that routine screening for PEI may not be recommended in patients with diabetes in the absence of overt malnutrition. Disclosure VM Consultant: Takeda Nycomed. Lecture fee: Falk Pharma, Krka, Abbott, Lek (a Sandoz company), Takeda Nycomed. ZJ: Nothing to disclose. TB: Consultant: Takeda Nycomed. Lecture fee: Krka, Astra Zeneca, Novartis, Falk Pharma. Research grant: Krka, Astra Zeneca. PB: Nothing to disclose. MJ: Nothing to disclose. LEM: Nothing to disclose. PM: Nothing to disclose. RS: Nothing to disclose. Acknowledgments The authors thank Davorin Benko, MD (Head of the Department) and Martin Tretjak, MD, PhD from Department of Internal Medicine in Slovenj Gradec General Hospital, for support during the study, valid comments and assistance in manuscript editing. We also thank Alenka Sesek Briski, MSc, Head of laboratory department University Medical Centre Ljubljana Institute of Clinical Chemistry and Biochemistry for cooperation and useful comments. References [1] Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus. Arch Intern Med 2001;161:1989e96. [2] Chey WY, Shay H, Shuman CR. External pancreatic secretion in diabetes mellitus. Ann Intern Med 1963;59:812e21. [3] Frier BM, Saunders JHB, Wormsley KG, Bouchier IAD. Exocrine pancreatic function in juvenile-onset diabetes mellitus. Gut 1976;17:685e91.
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