Observational Study
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2014; 20(48): 18432-18438
Published online Dec 28, 2014. doi: 10.3748/wjg.v20.i48.18432
Pancreatic exocrine insufficiency, diabetes mellitus and serum nutritional markers after acute pancreatitis
Miroslav Vujasinovic, Bojan Tepes, Jana Makuc, Sasa Rudolf, Jelka Zaletel, Tjasa Vidmar, Maja Seruga, Bostjan Birsa
Miroslav Vujasinovic, Jana Makuc, Tjasa Vidmar, Department of Internal Medicine, Slovenj Gradec General Hospital, Slovenj Gradec 2380, Slovenia
Bojan Tepes, Abakus Medico Diagnostic Centre, Rogaska Slatina 3250, Slovenia
Sasa Rudolf, Department of Radiology, University Medical Centre Maribor, Maribor 2000, Slovenia
Jelka Zaletel, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia
Maja Seruga, Department of Internal Medicine, Murska Sobota General Hospital, Murska Sobota 9001, Slovenia
Bostjan Birsa, Department of Internal Medicine, Celje General Hospital, Celje 3000, Slovenia
Author contributions: Vujasinovic M and Tepes B designed the study and drafted the manuscript; Vujasinovic M, Vidmar T, Seruga M and Birsa B recruited the patients; Rudolf S performed magnetic resonance imaging; Vujasinovic M, Tepes B, Makuc J, and Zaletel J wrote the manuscript.
Correspondence to: Miroslav Vujasinovic, MD, MSc, Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1, Slovenj Gradec 2380, Slovenia. mvujas@gmail.com
Telephone: +386-2-8823448 Fax: +386-2-8823505
Received: April 25, 2014
Revised: June 22, 2014
Accepted: August 13, 2014
Published online: December 28, 2014

Abstract

AIM: To investigate impairment and clinical significance of exocrine and endocrine pancreatic function in patients after acute pancreatitis (AP).

METHODS: Patients with AP were invited to participate in the study. Severity of AP was determined by the Atlanta classification and definitions revised in 2012. Pancreatic exocrine insufficiency (PEI) was diagnosed by the concentration of fecal elastase-1. An additional work-up, including laboratory testing of serum nutritional markers for determination of malnutrition, was offered to all patients with low levels of fecal elastase-1 FE. Hemoglobin A1c or oral glucose tolerance tests were also performed in patients without prior diabetes mellitus, and type 3c diabetes mellitus (T3cDM) was diagnosed according to American Diabetes Association criteria.

RESULTS: One hundred patients were included in the study: 75% (75/100) of patients had one attack of AP and 25% (25/100) had two or more attacks. The most common etiology was alcohol. Mild, moderately severe and severe AP were present in 67, 15 and 18% of patients, respectively. The mean time from attack of AP to inclusion in the study was 2.7 years. PEI was diagnosed in 21% (21/100) of patients and T3cDM in 14% (14/100) of patients. In all patients with PEI, at least one serologic nutritional marker was below the lower limit of normal. T3cDM was more frequently present in patients with severe AP (P = 0.031), but was also present in some patients with mild and moderately severe AP. PEI was present in all degrees of severity of AP. There were no statistically significantly differences according to gender, etiology and number of AP attacks.

CONCLUSION: As exocrine and endocrine pancreatic insufficiency can develop after AP, routine follow-up of patients is necessary, for which serum nutritional panel measurements can be useful.

Key Words: Acute pancreatitis, Diabetes mellitus, Pancreatic exocrine insufficiency, Serum nutritional markers

Core tip: Endocrine and exocrine pancreatic insufficiency can develop after acute pancreatitis regardless of the severity, etiology, age, gender and number of attacks. In all patients with pancreatic exocrine insufficiency (PEI), at least one serum nutritional marker was below the lower limit of normal regardless of the presence of classical clinical symptoms of PEI. Routine follow-up of patients with acute pancreatitis at least 24 mo after discharge from the hospital is necessary with special emphasis on diabetes detection. Measurement of serum nutritional markers regardless of the presence of other clinical symptoms of PEI can be of clinical importance.



INTRODUCTION

Pancreatic exocrine insufficiency (PEI) and type 3c diabetes mellitus (T3cDM) can occur in patients after acute pancreatitis (AP). The data on the incidence of PEI and T3cDM and the clinical significance of both are controversial, ranging from sporadic cases to 78% of all patients having abnormal values[1-8]. The reasons for such differences in the results are attributable to the different methods used (direct and indirect), inclusion of different groups of patients (severe and mild AP) and different follow-up periods (early and late). Over the last 15 years, the fecal elastase-1 (FE) test became a suitable method for noninvasive diagnosis of PEI with high specificity and sensitivity, especially for the severe form of PEI (< 100 μg/g), and is now recommended as the first step in exocrine pancreatic function diagnostics[9,10].

Pancreatogenic diabetes due to pancreatic disease is classified as type 3c in the current classification of diabetes mellitus (diseases of the exocrine pancreas) and accounts for 5%-10% of the Western diabetic population[11,12]. Clinical and laboratory features of T3cDM differ from other types of diabetes[12], and it is often termed “brittle diabetes” due to the combination of persistent hyperglycemia (due to persistent hepatic glucose production) and exaggerated peripheral sensitivity to insulin[13]. Typically, hepatic insulin resistance predominates as a consequence of pancreatic polypeptide deficiency, while peripheral insulin sensitivity is enhanced because of relative hypoinsulinemia, resulting in problems with hypoglycemia in T3cDM[14]. Although T3cDM is associated with various benign and malignant diseases of the exocrine pancreas, the most common cause is chronic pancreatitis (CP), found in 78.5% of T3cDM cases[15]. In addition, both CP and diabetes are risk factors for the development of pancreatic carcinoma. Also, new-onset T3cDM occurs in 30% of pancreatic cancer patients[12,14]. Because of these specific features, it is important to correctly diagnose T3cDM, especially in view of the evidence showing that nearly half of the T3cDM patients are misdiagnosed as type 1 or 2[15]. There is also a misconception that the treatment of T3cDM is the same as for other forms of diabetes. The use of insulin, insulin secretagogues and incretin-based treatment should be used with caution in these types of patients owing to the high risk of pancreatic carcinoma[12,16-19]. On the other hand, therapy with metformin is associated with a significant reduction in cancer risk and should be preferred as a drug of choice due to its anti-diabetic and anti-neoplastic actions[12,16,19,20].

In pancreatitis, the relationship between the extent of pancreatic necrosis and the severity of exocrine and endocrine pancreatic insufficiency has not been clearly demonstrated[2]. Clinical symptoms of PEI, such as abdominal pain, bloating, steatorrhea and weight loss, were traditionally the most important criteria for monitoring treatment success, but in recent years new studies have also demonstrated the importance of maldigestion, malnutrition and serum nutritional markers in PEI in the absence of the clinical symptoms[21,22].

The aims of the present study were: (1) to determine whether exocrine and endocrine pancreatic function are impaired in patients after AP; (2) to evaluate the relationship between exocrine and endocrine functions and the etiology and severity of AP; and (3) to assess the clinical significance of both exocrine and endocrine pancreatic insufficiency.

MATERIALS AND METHODS
Patients

Patients who experienced an AP attack were invited to participate in the study. All patients were Caucasians, over 18 years of age, and gave their informed consent prior to participating in the study. They were selected from the gastroenterology outpatient clinics of the general hospitals, which function as secondary level centers. Medical records of all patients were analyzed including demographics, laboratory tests, abdominal ultrasound, contrast-enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasound. FE and glycated hemoglobin or oral glucose tolerance tests were performed in patients without previous diabetic conditions.

Measurement of laboratory tests

FE measurements were performed using the enzyme-linked immunosorbent assay method and a commercial kit (ScheBo Biotech, Giessen, Germany). The results of FE are expressed in μg/g stool. FE levels > 200, 100-200 and < 100 μg/g were considered as normal exocrine pancreatic function, mild and severe PEI, respectively.

In patients with low FE (< 200 μg/g), further work-up was performed including the following laboratory serum measurements to determine malnutrition: iron, vitamin B12, folic acid, magnesium, and vitamins A, D, and E.

Definitions

Pancreatic endocrine function (the occurrence of T3cDM) was determined by the American Diabetes Association criteria: glycated hemoglobin ≥ 6.5% or two-hour plasma glucose ≥ 11.1 mmol/L during oral glucose tolerance test in patients without a history of diabetes[11]. Severity and morphology of AP were determined by the Atlanta classification and definitions revised in 2012[23]. Pancreatic necrosis was determined by contrast-enhanced computed tomography according to the Balthazar’s classification[24].

Ethics

The study was approved by the National Medical Ethics Committee number 133/01/11 on 28 January 2011.

Statistical analysis

Categorical data are presented as absolute numbers with relative frequencies. The normality of the numerical data distribution was checked using the Kolmogorov-Smirnov test and are described by mean ± SD. The χ2 test was performed to test the significance in the distribution of gender, etiology, number of attacks, pancreatitis severity and morphology in patients with or without exocrine and endocrine pancreatic insufficiency. The Student’s t-test was applied to test the difference in nutritional markers in patients with severe and mild to moderate PEI. A P < 0.05 was considered statistically significant. The statistical analyses were performed using the SPSS version 21 software package (IBM Corp., Armonk, NY, United States).

RESULTS

One hundred patients were included in the study: 65 male and 35 female, mean age 56.5 ± 13.9 years (range: 20-88 years). 75% (75/100) of the patients had one attack of AP and 25% (25/100) had two or more attacks. The most common etiology was alcohol (n = 42), followed by gallstones (n = 36), unexplained (n = 12), hypertriglyceridemia (n = 6), drug-induced (n = 3), and post-endoscopic retrograde cholangiopancreatography (n = 1). Mild, moderately severe and severe AP were present in 67, 15 and 18 patients, respectively. The mean time from the AP attack to inclusion in the study was 2.7 ± 4.3 years. In the majority (69/100) of patients, the time was one year, 2-5 years in 20% (20/100) of patients, and > 6 years in 11% (11/100). PEI was diagnosed in 21% (21/100) of patients and T3cDM in 14% (14/100) of patients.

The characteristics of patients with exocrine pancreatic insufficiency are summarized in Table 1. In the group with PEI, 17/21 (81%) were male and 4/21 (19%) were female, with a mean age of 57.2 ± 11.6 years (range: 30-83 years). The most common etiology was alcohol (13/21; 61.9%), followed by gallstones (5/21; 23.8%), unexplained (2/21; 9.5%) and drug-induced (1/21; 4.8%). Most patients with PEI had one attack of AP (14/21; 66.7%) and mild severity of AP (11/21; 52.4%). Imaging was performed in 14/21 (66.7%) patients with PEI; among them 71.4% (10/14) showed radiologic signs of CP. Laboratory testing was performed in 16/21 (76.2%) patients with PEI, and in all of them, at least one serologic nutritional marker was below the lower limit of normal (Table 2). In 6/21 (28.6%) patients with PEI, T3cDM was also found.

Table 1 Characteristics of patients with exocrine pancreatic insufficiency.
GenderAge (yr)EtiologyNo. of attacksSeverity of APFE (μg/g)T3cDM
Male30Alcohol1Moderately Severe7No
Male63Alcohol1Moderately Severe101No
Male59Gallstone1Severe19Yes
Female63Gallstone1Severe63No
Male52Alcohol1Mild46No
Male43Alcohol2Moderately Severe134No
Male66Gallstone2Mild5Yes
Female53Alcohol1Mild4No
Male47Alcohol2Mild156No
Male58Unknown8Mild176Yes
Male63Alcohol9Mild9No
Male59Alcohol2Mild37No
Female73Gallstone1Mild137No
Male64Alcohol1Severe151Yes
Male83Gallstone1Mild191Yes
Male63Alcohol2Mild163No
Female52Drug-induced1Mild94No
Male63Unknown1Severe89No
Male40Alcohol1Severe119No
Male53Alcohol1Severe198Yes
Male57Alcohol1Severe117No
Table 2 Nutritional parameters in patients with pancreatic exocrine insufficiency n (%).
ParameterValid cases (n)Below lower limit of normal
Vitamin D1611 (68.8)
Vitamin A161 (6.3)
Vitamin E160
Vitamin B12163 (18.8)
Folic acid163 (18.8)
Iron165 (31.2)
Magnesium160

Bivariate statistical analysis was performed to determine differences between two groups of patients (PEI vs non-PEI, and T3cDM vs non-T3cDM). There were no statistically significant differences according to gender (P = 0.085), etiology (P = 0.316), time from AP attack to inclusion in the study (P = 0.863) or number of AP attacks (P = 0.182). However, there was a statistically significant difference according to the severity of AP between patients with T3cDM and non-T3cDM (P = 0.031): patients with severe AP had a higher prevalence of T3cDM. There was no difference according to AP severity in patients with PEI (P = 0.115).

An enzyme replacement therapy was recommended for all patients with PEI. All patients with T3cDM were transferred to diabetic outpatient clinic.

DISCUSSION

The relationship between PEI and AP was a topic of many studies in the last 30 years. Mitchell et al[25] tested 30 patients with an N-benzoyl-l-tyrosyl-p-aminobenzoic acid test and showed that an attack of AP can impair exocrine pancreatic function for several months. Seidensticker et al[26] followed 38 patients for 34 mo after the first AP attack using endoscopic retrograde cholangiopancreatography, secretin-pancreozymin tests and fecal fat analysis, and found exocrine pancreatic impairment in half of the patients.

Other invasive and noninvasive methods were also used for the determination of PEI. Glasbrenner et al[27] used a fluorescein dilaurate test and fecal chymotrypsin in a group of 29 patients after the first episode of AP, and confirmed abnormal findings in 79% patients on days 2-3 and in 10% of patients on days 28-30 after the attack. Bozkurt et al[8] performed a follow-up study on 53 patients after the first attack of necrotizing pancreatitis using a Lundh test meal for diagnosis of PEI. In the first 4-12 wk after recovery, 26% of patients had a marked decrease in pancreatic function and 74% had a mild to moderate decrease. PEI persisted after 18 mo of follow-up in 13% of the patients. In studies with longer follow-ups (5-7 years), both exocrine and endocrine impairment were found in a high percentage of patients (Table 3) and a correlation with the extent of necrosis and PEI was found.

Table 3 Prevalence of exocrine and endocrine pancreatic insufficiency after acute pancreatitis.
Ref.YearFollow-upnEtiologyMethodsExocrine insufficiencyEndocrine insufficiency
Glasbrenner et al[27]1992Acute phase and after 1 mo29 oedematous APAlcohol, gallstoneFDL serum test, fecal chymotrypsinFDL abnormal: 79% in acute phase and 10% after 1 mochymotrypsin abnormal: 69% in acute phase and 3% after 1 moHas not been determined
Seidensticker et al[26]199534 mo38Alcohol, gallstone, unexplainedSPT, fecal fat analysis, ERCP50% had one or more abnormal testsHas not been determined
Bozkurt et al[8]19954 wk-18 mo53all severe APAlcohol, gallstoneLundh test meal with measurement of duodenal secretion and enzyme activity6%-84% of all patients; 6%-26% marked and 74%-81% moderateHas not been determined
Tsiotos et al[7]19985 yr44severe APAlcohol, gallstone, post-ERCP, hereditaryFecal fat excretion, fasting plasma glucose25%36.4%
Appelros et al[6]2001Mean 7 yr26all severe APAlcohol, gallstone, post-ERCP, hyperlipidemia, unexplainedTriolein test, fasting plasma glucose, HbA1c69.2% with pathologic triolein test43%
Boreham et al[2]2003Acute phase and after 3 mo2316 mild, 7 severe APAlcohol, gallstone, post-ERCP, hyperlipidemia, unexplainedFecal elastase-1, fasting plasma glucose34.8% of all patients; 26.1% after severe and 8.7% after mild AP17.4% of all patients; 13.0% after severe and 4.4% after mild AP
Connor et al[3]200529 mo63after necrosectomyAlcohol, gallstoneClinical symptoms of steatorrhea, OGTT25%33%
Symersky et al[1]20064.6 yr3422 mild, 12 severe APGallstone, post-ERCPPABA test, OGTT, PP secretion, fecal fat analysis64.7% of all patients; 29.4% after severe and 35.3% after mild AP35%
Pezzilli et al[4]2009Acute phase (on the day of refeeding)7560 mild, 15 severe APAlcohol, gallstone, hyperlipidemiaFecal elastase-112% of all patients; 2.7% after severe and 9.3% after mild APHas not been determined
Gupta et al[5]2009Mean 31 mo3021 with necrosisAlcohol, gallstone, unexplainedFecal fat excretion, urinary D-xylose excretion, OGTT40%40%
Present study2013Mean 2.7 yr10017 with necrosisAlchohol, gallstone, hyperlipidemia, unexplained, drug-induced,Fecal elastase-1, OGTT21%14%

In the last 25 years, noninvasive methods have become a gold standard for PEI detection[9,28-30]. In the largest study performed so far with FE as a diagnostic method, Pezzilli et al[4] included 75 patients with AP in the early recovery phase (on the day of re-feeding) and found 12% of patients had PEI (9.3% with mild and 2.7% with severe AP). The present study addresses the highest number of patients suffering from an AP attack so far and includes all etiologies and severities of AP. Based on the above-mentioned results, we expected to find PEI more often in patients with severe AP and in those recovering after alcohol-induced AP. Surprisingly, we found a significantly lower prevalence of PEI (21/100), which was frequently of mild severity and occurring after one attack of AP. On the other hand, PEI was also confirmed in patients with AP due to other etiologies, with one or more attacks of AP, and in those recovering from mild and moderately severe AP. There was no difference in gender, etiology, or time from, severity or number of AP attacks between patients with and without PEI. One explanation for the lower than expected PEI prevalence could be a decreased sensitivity of the FE test in mild and moderate PEI, which was predominant in our cohort. The 13C breath test is a useful diagnostic tool for PEI, but as with secretin magnetic retrograde cholangiopancreatography, is not currently widely available, and could be even more useful for a definitive determination of pancreatic morphology and exocrine function in this group of patients. However, these methods, along with the quantitative stool fat analysis, are not currently a part of a routine diagnostic procedure in Slovenia, leaving FE as the only diagnostic method for PEI.

The clinical significance of PEI was also assessed in this study by using a complete laboratory serum nutritional panel. At least one serologic nutritional marker was below the lower limit of normal in all of these patients, which also confirms the importance of maldigestion, malnutrition and serum nutritional markers in PEI in the absence of the clinical symptoms[21,22]. We performed a nutritional evaluation only in patients with low FE, which is a limitation of the study. It would be interesting to evaluate nutritional status in all patients, which could be even more accurate for than FE for PEI. The commonest findings were vitamin D, iron and folic acid deficiencies. Previous studies show the importance and clinical significance of serum nutritional status in patients with CP[21,22], which was observed in the majority of our patients with PEI. However, we have also demonstrated low serologic nutritional markers in patients without radiologic signs of CP, suggesting that late complications of AP could be present even in the absence of CP. In addition, the majority of patients with PEI had a mild episode of AP, which is an unexpected finding (it is generally accepted that the probability of PEI depends on extent of necrosis due to the loss of functional parenchyma). Unfortunately, data about smoking are lacking, which is another important limitation of the study. Nevertheless, the number of patients (four) in this group was too small for definite conclusions.

CP could also explain the occurrence of T3cDM, which was used to evaluate endocrine pancreatic function in patients who have suffered an AP attack. We found T3cDM after AP in 14% of the patients, and patients with severe AP had a higher prevalence of T3cDM, but there were no differences in gender, age, time from AP attack to inclusion in the study and number of AP attacks in patients with T3cDM. Due to specific features of T3cDM and a high risk of pancreatic cancer in patients with chronic pancreatitis and T3cDM, we transferred all our T3cDM patients to a diabetes outpatients clinic for further diagnostics and treatment.

In conclusion, our study confirmed that exocrine and endocrine pancreatic insufficiency can develop after AP regardless of its severity, etiology, age and gender, suggesting that routine follow-up of patients with AP after discharge from the hospital is necessary. Most of the patients with PEI had radiologic or endoscopic signs of CP, but PEI was also present in small amount of patients after the first attack of mild AP without signs of CP. Measurement of the serum nutritional panel regardless of the presence of clinical symptoms of PEI can be of clinical importance. Further studies on this topic are necessary, especially in patients after the first attack of AP with the use of more accurate diagnostic procedures in combination of serum nutritional markers.

ACKNOWLEDGMENTS

The authors thank Davorin Benko, MD, Head of the Department of Internal Medicine at the General Hospital Slovenj Gradec, for the organization and support during the study.

COMMENTS
Background

Pancreatic exocrine insufficiency (PEI) and type 3c diabetes mellitus (T3cDM) can occur in patients after acute pancreatitis (AP). The data on the incidence of PEI and T3cDM and the clinical significance of both are controversial.

Research frontiers

Although the relationship between PEI, T3cDM and AP has been a topic of many studies over the last 30 years, the results are limited due to small patient samples and the methodologies used.

Innovations and breakthroughs

Noninvasive methods, such as fecal elastase-1 concentrations, have currently become a gold standard for PEI detection. Combined with the results of the serum nutritional panel, they allow the timely detection of maldigestion and malnutrition in patients to prevent further complications even in the absence of clinical symptoms. Due to the specific features and a high risk of pancreatic cancer, it is also of great importance to diagnose and properly treat T3cDM.

Applications

The results of this study suggest that routine follow-up of patients with AP after discharge from the hospital is necessary to improve the final outcome after an attack of AP.

Terminology

Acute pancreatitis is a sudden inflammation of the pancreas. PEI is the lack of pancreatic digestive enzymes with the consequent inability to properly digest food. Fecal elastase-1 is a pancreatic digestive enzyme that breaks down elastin and other proteins. T3cDM is diabetes secondary to pancreatic diseases.

Peer review

This is an excellent paper in which exocrine and endocrine pancreatic insufficiency were observed after AP.

Footnotes

P- Reviewer: Chen Z, Gao RP S- Editor: Qi Y L- Editor: AmEditor E- Editor: Zhang DN

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