Acute recurrent pancreatitis and chronic pancreatitis – retrospective data from a Czech tertiary pediatric center

Summary

Summary: Introduction: Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) do not frequently occur in the pediatric population. Data on Czech pediatric patients have not been published yet. Methods: We collected retrospective single-center data on patients diagnosed with ARP and CP at the Department of Pediatrics, University Hospital Brno, from 2010 through 2021. Results: We identified 6 patients (3 boys; 50%) with ARP and 5 patients (4 boys; 80%) with CP. Genetic predisposition to chronic pancreatic disease was more frequent among children with ARP (5 out of 6; 83.3%) in contrast to CP (2 out of 5; 40%). Ultrasound was the predominant radiologic method to visualize the structural changes of the pancreatic tissue. The number of hospital admissions between ARP and CP groups did not differ: ARP median (IQR; min–max) 2 (1–3; 1–6) and 2 (1–6; 1–7) in CP, respectively. Pediatric patients with ARP in our cohort require a median (IQR; max) of 9.63 (7.00–11.88; 15.83) years in pediatric medical follow-up and CP patients require 3.83 (3.50–4.91; 5.17) years. Conclusion: We assume pediatric patients presenting with ARP or CP need multidisciplinary specialized care in pediatric gastroenterology centers.

Keywords:

pancreatitis – chronic pancreatitis – pediatric

Introduction

Recurrent pancreatitis (ARP) and chronic pancreatitis (CP) represent rare conditions in childhood. Nevertheless, they are associated with a high disease burden and health care costs. Children with ARP or CP experience frequent abdominal pain, emergency room visits, and hospitalisations [1]. Over time, there is an increased risk of developing complications, including pancreatic fibrosis, pancreatic exocrine insufficiency, diabetes mellitus, chronic pain syndromes, and pancreatic ductal adenocarcinoma.

Pediatric ARP is represented as at least two distinct episodes of acute pancreatitis (AP) as defined by the INSPIRE criteria in the absence of evidence of irreversible structural changes in the pancreas. The patient must fail to meet the criteria for AP for a period longer than 3 months after the first episode. The INSPIRE Criteria [2] for AP is the presence of at least two of the following:

1. characteristic abdominal pain;

2. imaging consistent with AP;

3. lipase or amylase ≥ 3-times the upper limit of normal (3× ULN).

 

Pediatric CP is the presence of at least one of the following:

1. irreversible, structural changes in the pancreas such as diffuse or focal destruction, sclerosis, pancreatic duct abnormalities/obstruction with some periods of consistent abdominal pain, or lipase or amylase ≥ 3× ULN;

2. irreversible structural changes in the pancreas such as diffuse or focal destruction, sclerosis, and pancreatic duct abnormalities/obstruction with endocrine pancreatic insufficiency [3].

 

Both ARP and CP in children are caused by genetic mutations, autoimmune disease, congenital pancreatic abnormalities, and other conditions [4]. Among genetic risk factors, crucial roles are variants in the cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane regulator (CFTR), chymotrypsin C (CTRC), and carboxypeptidase A1 (CPA1) genes. Possibly associated are genes for the calcium-sensing receptor (CaSR), carboxyl ester lipase (CEL), chymotrypsinogen B1 and B2 (CTRB1–CTRB2), pancreatic lipase (PNLIP), and chymotrypsin-like elastase (CELA3B). Several genetic variants are associated with early onset disease (PRSS1, CTRC, CPA1) [5]. Genetic testing is recommended in the 2^nd episode of idiopathic AP or the first one while there is a family history of pancreatitis [6].

 

Aim and methods

The aim of this study was to collect and analyse retrospective data on patients diagnosed with ARP and CP. This study was approved by the University Hospital Brno ethical committee (approval No 01-080223/EK). It was performed according to the ethical standards laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards. The study inclusion criteria were diagnoses of ARP (ICD 11 code K85.0) and CP (ICD code K86.1) during 2010–2021 and age at diagnosis below 19 years. The criterion of exclusion was the diagnosis of cystic fibrosis (CF). We searched within the digital University Hospital Brno documentation system for patients diagnosed with ARP or CP and collected data on age at diag- nosis, gender, (presumed) duration of pediatric care, types and numbers of diag- nostic assessments, laboratory results, treatment, genetics, underlying disease, surgical interventions, and number of hospitalisations.

 

Results

We identified 14 patients with chronic pancreatic disease other than CF. Six children diagnosed with ARP (3 boys; 50%), median age (IQR; min–max) 9.38 (7.12–11.94; 3.17–15.58) in years at diagnosis and five children with CP (4 boys; 80%), median age (IQR; min–max) 15.50 (14.83–15.91; 13.83–16.00) in years at diagnosis. Furthermore, there were three patients requiring long-term follow-up despite different reasons (one with a pancreatic cyst, one with lipoid degeneration of the pancreas, and one with pancreatic lithiasis). The expected period in years under pediatric medical supervision was the median (IQR; min–max) 9.38 (7.12–11.94; 3.17–15.58) for ARP and 15.50 (14.83–15.91; 13.83–16) for CP, respectively. Ultrasonography was the most frequently used method to assess structural pancreatic changes during the disease course. A summary of radiologic assessments is displayed in Tab. 1.

Genetic determinants of the disease are summarized in Tab. 2.

In addition to SPINK and PRSS mutations, we identified one patient with a mutation of the LPL gene (variant c. (953A-G)), causing lipase activity decrease and thus the increase of serum TAG level with clinical consequences including pancreatitis [7]. Regarding first-degree relatives in ARP, we found one positive with PRSS1 and two with SPINK1. There was no positivity nor negativity proven in CP patients’ first relatives, as those were not genetically tested. Among patients with ARP, there was no positive autoantibody detection (ANA, ENA, ASMA, rheumatic factor, antibodies against pancreatic ducts, and IgG4). Among CP patients, there was one with a positive serum level of IgG4 antibodies diagnosed with autoimmune pancreatitis Type I AIP (lymphoplasmacytic sclerosing pancreatitis type). This patient did not develop IBD during the observed period. The median of acute pancreatic attacks among our cohort was 2, with a minimum of 1 and a maximum of 7.

Other findings of possible causative factors are summarized in Tab. 3.

Elastase in stools was not routinely tested in patients with ARP. One patient with CP had a low level of elastase.

Pancreatic secretion using a secretin test was not explored in our patients.

Discussion

This is the first report on ARP and CP, except for those with CF among children in the Czech Republic originating from a tertiary pediatric center. Our data show that pediatric ARP and CP are not frequent (ARP = 6 patients, CP 5 = patients during 12 years). However, they may occur early in childhood, as documented by the youngest patient diagnosed at 3.17 years of age with ARP. All affected individuals will require repeated assessment during the recurrence of the disease and long-term follow-up, including US, MRI, MRCP, ERCP, and/or EUS. The most frequent method for imaging the pancreas in our cohort was US, which is easy to perform, and in contrast to the latter mentioned, does not require anaesthesia even in young children. MRCP was the preferred method to assess pancreatic duct involvement. Invasive ERCP procedures were limited to CP patients who needed obstruction relief. Due to possibly incomplete data, we do not consider this a rationale to determine the prevalence of ARP and CP in our region. We presume some patients were treated in other healthcare settings and could not be included in our cohort. Furthermore, ARP can be considered for acute gastroenteritis and thus be misdiagnosed. CP meets the same bias if not considered a possible diagnosis and not explored by imaging methods. We expected more pronounced toxic aetiology (alcohol) of ARP and CP among teenagers. However, there was only one positive patient in each group. It is questionable whether the history given by parents and the affected individuals is relevant, since alcohol consumption is prohibited under 18 years of age. Defining the impact of smoking on ARP and CP incidence in pediatric cases would be speculative as well. Providing our results to healthcare professionals may increase awareness of ARP, also known as the risk factor for CP [8].

Among rare diseases, cystic fibrosis (CF) is the most common cause of ARP and CP. The cumulative incidence of CF in our country (2012–2022) was 1: 6,283 births. The prevalence of CF in the country in 2022 was 6.6 per 100,000 people [9]. Almost half of the cases are adults. CF in the Czech Republic is manifested by pancreatic insufficiency in 84.2%. Then, 15.8% of cases are pancreatic suficient, and these are prone to both ARP and CP [10]. The regional pediatric CF center of University Hospital Brno registers 10 such pediatric patients.

An equilibrated diet with an age-appropriate content of proteins, fibres, poly- saccharides, and fats is recommended in AR and CP during the period free from acute flare-ups of the disease. Pancreatic substitution to support digestion is dedicated to patients with pancreatic insufficiency; thus, being pancreatic sufficient, most of our patients did not require enzymatic support. The risk of inadequate resorption of macro- and micronutrients is more pronounced in patients suffering from CF. Furthermore, CF patients require a different dietary approach than those with ARP and CP.

Our ARP and CP patients were tested for the most common genetic determinants: CFTR, SPINK, PRSS 1, and in the case of hypertriglyceridemia, for LPL. However, recent research identified other loci responsible for the ARP and CP burdens. Patients with ARP and CP should undergo more comprehensive genetic testing, also including mutations of CTCR, PRSS 2, CASR, CEL, CTRB1–CTRB2, CPA 1, PNLIP, and CELA3B. The coincidence of more mutations in the same individual might be the key to different clinical presentations in healthy individuals with an inherited predisposition to chronic pancreatic disease and those with active disease [11,12]. Testing patients with ARP and CP and their first/second relatives is necessary to prove this presumption.

Our study may have biases due to retrospective data collection, origin from a single tertiary centre, and a relatively long period of retrospection, which may lead to insufficient exploration in some fields (e. g., genetic testing). A prospective multicentric study is an option to evaluate pediatric patients‘ clinical conditions. Further exploration of the topic in Czech conditions is needed.

 

Conclusions

From 2010 to 2021, we diagnosed 14 pediatric patients with chronic pancreatic disease other than cystic fibrosis. Median age at disease onset was lower in patients with ARP. The maximal duration of presumed pediatric care in our cohort was 15.8 years. ARP patients presented a genetic predisposition to pancreatic inflammation in 83% and CP in 40%. However, there is a risk of CP development in patients with ARP. Our findings suggest that although ARP and CP are not frequent in children, affected patients require long-term pediatric professional care.

 

Author contribution

KB and PD designed the study. KB collected and analyzed the data. KB, EH, and LH wrote the first draft of the manuscript. All authors critically revised it for important intellectual content and provided final approval of the version to be submitted for publication.

 

Abbreviations

ARP      acute recurrent pancreatitis

CP         chronic pancreatitis

CF         cystic fibrosis

ERCP   
endoscopic retrograde cholangiopancreatography

EUS      endoscopic ultrasound

ICD 11 
International Classification of Diseases, version 11

MRCP  
magnetic resonance cholangiopancreatography

MRI      magnetic resonance imaging

US        ultrasonography