Risk factor for steatorrhea in pediatric chronic pancreatitis patients

The subjects of this study were CP patients hospitalized in Shanghai Changhai Hospital from January 2000 to December 2013. From January 2000 to December 2004, a retrospective collection of patient data was made according to the medical record system, telephone, mail and e-mail follow-up. In order to follow up the patients with CP and facilitate the study of CP. The database system of CP (version 2.1, YINMA Information Technology Company, Shanghai, China) has been established in the Department of Gastroenterology of Changhai Hospital since January 2005 to collect the medical records of patients with CP. Data collected from January 2005 to December 2013 were prospectively collected [12, 14‐23]. All patient information is first recorded in a paper-based case report form and then entered into an electronic document. The information collected includes basic information of patients, etiological characteristics (drinking, smoking, anatomic abnormalities, family history), natural course of CP (onset date, onset symptoms, diagnosis date, onset date of pain, pain classification, diagnosis date and treatment history of stones, diabetes mellitus, fatty diarrhea, pseudocysts, common bile duct stenosis); treatment strategy (conservative treatment, endoscopic treatment, surgical treatment).

The database system will remind researchers to notify patients for examination. Except for the examination when patients feel unwell, all patients were checked regularly (at least once a year). Ultrasound, magnetic resonance imaging (MRI), or computed tomography (CT) examination was performed to assess the condition. Patients who did not return to our hospital were followed up by telephone and recorded in the database. The end point of the study was December 2013. In December 2013, we followed up all patients with CP in the database, with the exception of some lost visits and deaths [12]. Follow-up was defined from the onset of CP to the time of the last follow-up, death, or end of follow-up (December 2013), whichever came earliest.

The exclusion criteria for this study were as follows (Figure 1): CP patients diagnosed with pancreatic cancer within 2 years of CP diagnosis [24], grooved pancreatitis (GP) [25], and autoimmune pancreatitis (AIP). Patients were assigned into pediatric group (onset before 18 years of age) and adult group (onset after 18 years of age).

In the study of steatorrhea, patients with steatorrhea diagnosed before CP were excluded in both groups.

The CP database establishing was as mentioned in our previous study [12]. The study was approved by the Ethics Committee of Changhai Hospital. Written informed consent was obtained from all participating patients. All of the diagnostic and therapeutic modalities were carried out in accordance with the approved guidelines.

The diagnosis of CP is based on the 2002 version of Asia Pacific consensus [26]. In the definition of etiologies, men with alcoholic intake of more than 80 g/d or women with alcoholic intake of more than 60 g/d for more than 2 years, excluding other causes, alcoholic CP could be diagnosed [27]. At least 2 first-degree relatives, or at least 3 s-degree relatives with CP and/or recurrent AP, excluding other causes, patients can be diagnosed as hereditary CP [28]. Patients with pancreatic divisum and abnormal pancreaticobiliary drainage are defined as abnormal anatomy of the pancreatic duct (although controversial) [29]. Patients with a clear history of pancreatic trauma and imaging findings suggesting secondary dilatation of the pancreatic duct may be diagnosed as traumatic CP. Hyperlipidemic CP was diagnosed in CP patients with plasma triglyceride > 1000 mg/dL [30]. When all the above causes are excluded, the patient can be diagnosed as idiopathic CP. The definition of severe acute pancreatitis (SAP) was based on the 1992 version of Atlanta classification [31].

Steatorrhea was diagnosed when one of the following two conditions was met: (1) stench, oily chronic diarrhea [32]; (2) positive result in quantification of fecal fat determination (fecal fat quantitation was performed within three days; patients with stool fat excretion over 14 g/day was diagnosed as steatorrhea).

Endoscopic interventional therapy was the first choice for CP patients. Extracorporeal shock wave lithotripsy (ESWL) and endoscopic retrograde cholangiopancreatography (ERCP) were used to remove pancreatic duct stones and drain the main pancreatic duct successfully [15, 33‐36]. The indications of surgery in CP patients include: endoscopic interventional therapy can not treat symptoms, combined with CBD stenosis but endoscopic treatment failed, cannot exclude malignant lesions or malignant diagnosed through biopsy, complex conditions and so on [37]. Surgical methods include surgical drainage, pancreaticoduodenectomy and distal pancreatectomy. In painless CP patients, endoscopic intervention or surgical treatment is indicated in patients with CBD stenosis or pancreatic portal hypertension [38]. Indications for endoscopic or surgical treatment did not include simple DM or steatorrhea. The treatment strategies of CP patients were as mentioned in our previous study [12].

In this study, continuous variables are represented in the form of mean ± standard deviation (SD) and compared with an unpaired, 2-tailed t test or the Mann-Whitney test. Categorical variables were expressed in the form of counting (percentage) and χ² test or the Fisher exact test were used to compare. CP patients who onset before 18 years of age were assigned into pediatric group and after 18 years of age were assigned into adult groups. The cumulative rates of steatorrhea in both groups after the onset of CP were calculated by Kaplan-Meier method [39]. The statistical analysis were as mentioned in our previous study [12].

Patients who had steatorrhea at/before the diagnosis of CP in pediatric and adult groups were excluded respectively. SPSS (version 21.0) was used to calculate the significance of each variable by multivariate Cox regression analysis in both groups.

As shown in Figure 1, from January 2000 to December 2013, a total of 2287 CP patients were entered into the Changhai CP Database. After the exclusion of 134 patients, including 10 patients diagnosed with GP, 108 patients diagnosed with AIP, and 16 patients diagnosed with pancreatic cancer within 2 years after the diagnosis of CP, a cohort of 2153 patients with CP was established. The median duration of follow-up was 7.6 years (range 0.0–52.7 years), with 10.4 years (range 0.0–52.7 years) in the pediatrics and 7.0 years (range 0.0–50.0 years) in the adults.

The general characteristics of the patients with CP are presented in Table 1. The mean age at the onset and the diagnosis of CP were 11.622 and 19.727, respectively. The male-to-female ratio in pediatrics was approximately 1:1, while in adults was 3:1. Patients with smoking or drinking history were significantly less in pediatrics (both P < 0.001). DM, steatorrhea, pancreatic pseudocyst, and biliary stricture were significantly common in adults (all P < 0.05). The etiology and type of pain were also significantly different between the pediatric and the adult groups (both P < 0.001).

Steatorrhea was found in 22.9% (493/2153) of patients after the onset of CP. The proportions were 15.8% (46/291) in pediatric patients and 24.0% (447/1862) in adult patients. The cumulative proportions of steatorrhea in pediatric patients were 2.1% (95% confidence interval [CI], 0.5–3.7%), 4.1% (95% CI, 1.6–6.6%) and 7.2% (95% CI, 3.5%-10.9) at 3, 5 and 10 years after the diagnosis of CP, respectively. The cumulative proportions of steatorrhea in adult patients were 12.8% (95% CI, 11.2–14.4%), 14.6% (95% CI, 12.8–16.4%) and 18.3% (95% CI, 16.1–20.5%) at 3, 5 and 10 years after the diagnosis of CP, respectively. Pediatric and adult patients showed significant difference in the rate of steatorrhea (P = 0.002, Figure 2).

After the exclusion of 35 patients diagnosed with steatorrhea before the diagnosis of CP in the pediatric patients, a total of 256 patients with CP were finally enrolled in the pediatric group. A univariate analysis for steatorrhea development among the 256 pediatric patients included in the study is shown in Table 2. Three variables showed a P value of less than 0.15: age at the onset of CP, DM, and SAP.

For the multivariate analysis, the 3 predictors above were included in the Cox proportional hazards regression model. Finally, 1 predictor for steatorrhea development in pediatric patients was identified. The risk of developing steatorrhea was significantly higher in pediatric patients with a history of SAP before the diagnosis of CP (Hazard ratio [HR], 13.946, 95% CI, 1.442–134.909).

After the exclusion of 262 patients diagnosed with steatorrhea before the diagnosis of CP in the adult patients, a total of 1600 patients with CP were finally enrolled in the adult group. A univariate analysis for steatorrhea development among the 1600 adult patients included in the study is shown in Table 3. Five variables showed a P value of less than 0.05: gender, age at the diagnosis of CP, etiology, initial manifestations, and DM.

For the multivariate analysis, the 5 predictors above were included in the Cox proportional hazards regression model. Finally, 4 predictors for steatorrhea development in adult patients were identified. The risk of developing steatorrhea was significantly higher in male patients (HR, 2.694, 95% CI, 1.756–4.133) and patients with a history of DM before the diagnosis of CP (HR, 1.558, 95% CI, 1.047–2.319). Adult patients with an older age at the diagnosis of CP (HR, 0.966, 95% CI, 0.953–0.978) were associated with decreased risk of developing steatorrhea. Initial manifestations were also identified risk factors for steatorrhea development in adult patients.