Causes and contributing risk factors for chronic pancreatitis in children and adolescents

INTRODUCTION — The contemporary international definition of chronic pancreatitis is "a pathologic fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental, and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress." The definition includes a description of the common characteristics of chronic pancreatitis, including structural changes that result in pain syndromes, sometimes progressing to irreversible exocrine, and/or endocrine pancreatic insufficiency [1-3]. The structural changes include diffuse or focal destruction, sclerosis, acinar cell loss, fatty replacement, islet cell loss, inflammatory cell infiltrate, and pancreatic duct abnormalities. Intraductal obstruction may be caused by protein plugs and/or calculi. Extraductal lesions such as trauma, pancreatic or hepatobiliary tumors, or surgical procedures may also lead to chronic inflammatory responses in the pancreas.

Chronic pancreatitis represents the end stages of a pathologic process that often includes acute pancreatitis and/or acute recurrent pancreatitis. In most patients, there are multiple factors that together confer susceptibility and drive progressive gland destruction. Finally, the clinical features are variable, such that the rate and extent of fibrosis, calcifications, atrophy, pain, exocrine pancreatic insufficiency, and diabetes mellitus differ markedly among patients.

Because the pancreas has a large reserve capacity, symptoms of pancreatic failure do not develop until there is a loss of over 90 percent of pancreatic exocrine function [4]. Most patients with chronic pancreatitis initially experience recurrent abdominal pain, which may progress to persistent pain. Less commonly, patients are asymptomatic or have minimal symptoms until developing signs of advanced disease, such as diabetes mellitus or fat and protein malabsorption. With advances in diagnostic methods, the diagnosis of chronic pancreatitis is becoming more common in children. (See "Clinical manifestations and diagnosis of chronic and acute recurrent pancreatitis in children".)

This topic review will outline the risk factors for chronic pancreatitis in children, which become contributing etiologic factors once the disease is established. Related information is available in the following topic reviews:

●(See "Clinical manifestations and diagnosis of chronic and acute recurrent pancreatitis in children".)

●(See "Pancreatitis associated with genetic risk factors".)

●(See "Endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic disease in children".)

●(See "Overview of the complications of chronic pancreatitis".)

●(See "Chronic pancreatitis: Management".)

OVERVIEW OF RISK FACTORS — Contributors to chronic pancreatitis in children are termed "risk factors" rather than "causes" because chronic pancreatitis may be the result of more than one pathophysiologic event. Some risk factors are seen in individuals without pancreatitis, suggesting that, in most cases, a single risk factor is not independently responsible for the pancreatitis or that another risk factor such as a viral infection, gallstone, or trauma may be needed to initiate any inflammatory processes. Once pancreatitis has developed, it is understood that the risk factors likely contribute to the disease progression and that attention should be directed at mitigating or modifying the risk factors if possible. Thus, a careful evaluation of potential risks and etiologies is indicated in children, especially in the earlier stages of disease where appropriate interventions are most likely to be effective.

Risk factors for chronic pancreatitis can be grouped according to their pathophysiologic mechanism (table 1):

●Genetic

●Obstructive

●Toxic/metabolic

●Idiopathic

●Autoimmune

The most common risk factors in children with chronic pancreatitis are genetic variants associated with pancreatitis, followed by anatomic abnormalities of the pancreatic ducts. As in adults, children may have more than one identifiable risk factor (eg, two genetic variants or a genetic variant and an anatomic abnormality). In one registry report, 21 percent of children with chronic pancreatitis had multiple risk factors [5]. Idiopathic chronic pancreatitis, indicating that no risk factors can be identified, is now diagnosed in a small minority of children when a full investigation has been performed [5]. By contrast, in adults, toxic/metabolic causes (particularly alcohol and smoking) predominate in those with etiologies defined [6].

In adults, chronic pancreatitis is sometimes categorized by morphology into calcific or noncalcific phenotypes. Calcific pancreatitis is usually associated with alcohol abuse and smoking, although the true etiology is more likely a combination of risk factors [7] (see 'Idiopathic' below). In children, pancreatic calcifications are less common (12 percent in a multicenter study of 76 children with chronic pancreatitis [5]). It is not common to classify pediatric pancreatitis by morphology.

GENETIC — Mutations in genes associated with increased risk of developing chronic pancreatitis are generally grouped into three categories [8,9]:

●Variants that increase trypsinogen activation and pancreatic autodigestion

●Variants that increase ductal calcium concentration

●Variants that lead to protein misfolding and acinar cell stress

The degree of risk varies with the mutated genes. Retrospective studies of children with chronic pancreatitis have demonstrated genetic risk factors in 30 to 79 percent of children, depending on the number of genes tested and the ethnicity of the population [5,10-14]. As in adults, children may have more than one genetic risk factor, so testing for a panel of genes is indicated. Chronic pancreatitis has been associated with mutations in each of the following genes:

Increased trypsinogen activation

●PRSS1 – Mutations in the cationic trypsinogen (serine protease 1) gene, called PRSS1, are present in up to 80 percent of cases of autosomal dominant hereditary pancreatitis. Prior to the identification of other genetic risk factors for chronic pancreatitis, this was called "hereditary pancreatitis," a term which may now be confusing. Compared with other causes of chronic pancreatitis, patients with this disorder tend to present at a young age. The majority of affected individuals develop symptoms before the age of 20 years, typically at age 10 to 12 years, but often before the age of five [15]. In a study of chronic pancreatitis in children <6 years of age, PRSS1 and chymotrypsin C (CTRC) mutations were more common than in older children [16]. The most common presentation is severe acute pancreatitis [17-21]. The disorder is associated with an increased risk of pancreatic cancer later in life, although this risk is reduced by lifestyle modifications such as avoidance of smoking [22]. (See "Pancreatitis associated with genetic risk factors", section on 'PRSS1 gene'.)

Mutations in PRSS1 may also be important in some patients with presumed idiopathic pancreatitis [23,24] and in patients with acute pancreatitis. (See 'Idiopathic' below and "Pathogenesis of acute pancreatitis", section on 'Genetic mutations in hereditary pancreatitis' and "Etiology and pathogenesis of chronic pancreatitis in adults", section on 'Idiopathic'.)

●SPINK1 – Mutations in serine protease inhibitor Kazal type 1 (SPINK1, also called pancreatic secretory trypsin inhibitor gene) are associated with chronic pancreatitis. They also occur in the general population (2 percent of healthy individuals carry a "high-risk" mutation) [25], but less than 1 percent of carriers develop pancreatitis [26]. Thus, these mutations probably act as a disease modifier, lowering the threshold for pancreatitis from other genetic, environmental, or anatomic factors (eg, pancreas divisum) [5,27,28] (see 'Congenital anomalies' below). The majority of patients with SPINK1 mutations and chronic pancreatitis are heterozygotes and display complex multigenerational inheritance patterns. (See "Pancreatitis associated with genetic risk factors", section on 'SPINK1 gene'.)

●CTRC – Chymotrypsin C (CTRC) is an enzyme that protects the pancreas by eliminating prematurely activated trypsin. Mutations in the CTRC gene and regulatory elements are more common among patients with early-onset chronic pancreatitis (14 percent) compared with the general population (1 percent) [16,29].

Increased ductal calcium concentration

●CFTR – Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) can increase risk for pancreatitis with or without associated manifestations of cystic fibrosis. As many as 20 to 30 percent of patients with pancreatic sufficient cystic fibrosis develop chronic pancreatitis [30]. The risk is higher for those with mild compared with severe CFTR mutations. Heterozygotes for CFTR mutations may also be at risk of chronic pancreatitis. A class of CFTR mutations associated with bicarbonate, but not chloride, channel abnormalities have been linked to chronic pancreatitis but not cystic fibrosis [31]. (See "Pancreatitis associated with genetic risk factors", section on 'CFTR gene' and "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'.)

Protein misfolding

●CPA1 – Carboxypeptidase A1 (CPA1), a digestive enzyme, is associated with autosomal dominant hereditary pancreatitis presenting in early childhood [32,33].

●PRSS1 – Protein misfolding is a second potential mechanism of action for this genetic mutation.

●CEL-HYB1 – A hybrid allele of the carboxyl-ester lipase gene and its pseudogene. The resultant protein is misfolded, causing toxic stress in the acinar cell [9,34].

A diagnosis of celiac disease is associated with a small increased risk for both acute pancreatitis and chronic pancreatitis [35]. Substantial variation in frequency of these gene variants relates to regional origin. Other genetic risk factors are being identified that will soon be available for clinical testing and further inform our understanding of the causes of chronic pancreatitis [36].

Many pancreatitis risk factor genes have been shown to have multiple mutations (for example, CFTR has >1000 mutations described), and not all mutations increase pancreatitis risk. A large web-based database can assist the clinician in determining if a reported CFTR mutation is important in chronic pancreatitis, available at the CFTR2 database, maintained by the Cystic Fibrosis Foundation, Johns Hopkins Medicine, and Sequenom Laboratories [37]. This database is not a substitute for professional genetic counseling.

OBSTRUCTIVE — Obstructive (noncalcific) chronic pancreatitis occurs after obstruction of the pancreatic duct by a congenital anomaly, injury, or tumors and other mass lesions. As examples, diseases that affect the proximal intestine, including Crohn disease, celiac disease, or eosinophilic gastroenteropathy, may cause chronic pancreatitis because of inflammation and obstruction of the ampulla. The parenchyma of the pancreas is characterized by diffuse or focal infiltration or replacement by fibrotic tissue, as in chronic fibrosing pancreatitis [38,39]. Obstructive risk factors are found in as many as 33 percent of children with chronic pancreatitis [5]. These problems can be demonstrated with appropriate testing and may be amenable to endoscopic intervention.

Congenital anomalies — Pancreas divisum (a condition in which the head and body of the pancreas are separate glands) is the second most common risk factor found in children with chronic pancreatitis, but its role in the pathogenesis of the pancreatitis remains unclear. The anomaly is found in 15 to 45 percent of children with chronic pancreatitis but is also present in approximately 7 percent of healthy children [5]. Of note, approximately one-half of patients with chronic pancreatitis and pancreas divisum also have a genetic polymorphism in SPINK1 or CFTR, as discussed above, suggesting that the genes act as cofactors. Rarely, annular pancreas with pancreaticobiliary malformation may be a cause of pancreatitis [40]. (See 'Genetic' above.)

Chronic pancreatitis has been described in association with biliary cysts (choledochal cysts), polycystic disease (which typically involves the kidney and liver but may affect the pancreas), or duplications of the pancreatic duct, stomach, or duodenum [41-44]. In one series, 16 percent of children with choledochal cyst had pancreatitis at the time of presentation [45]. The patients with pancreatitis were more likely to have choledochal cysts with a long common pancreaticobiliary channel, although a long channel was seen in some children who did not present with pancreatitis. Evaluation of these anomalies using magnetic resonance imaging cholangiopancreatography (MRCP) and treatment with endoscopic retrograde cholangiopancreatography (ERCP) is discussed in a separate topic review. (See "Endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic disease in children", section on 'Congenital anomalies'.)

Trauma — Pancreatic injury from trauma usually is acute and self-limited. However, chronic pancreatitis caused by disruption of the pancreatic ducts has been described, manifested by focal chronic changes and strictures, compression, and obstruction of the pancreatic duct. (See "Endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic disease in children", section on 'Pancreatic trauma'.)

Idiopathic fibrosing pancreatitis — Idiopathic fibrosing pancreatitis (IFP) has been described as a rare cause of chronic pancreatitis and obstructive jaundice in children and adolescents [46-48]. Unlike most other forms of chronic pancreatitis in children, fibrosing pancreatitis is characterized by extrinsic compression of the distal common bile duct, with resulting biliary obstruction. Imaging findings often resemble a mass in the pancreatic head [49]. The prominent obstructive features of IFP closely resemble the form of autoimmune pancreatitis that presents with jaundice. One comprehensive literature review, accompanied by a single-center review of historic cases of IFP in children, suggested that IFP has many of the same clinical characteristics as AIP presenting with jaundice and that these may be variants of a single condition [48]. It was noted that 16 percent of children with IFP had associated autoimmune disease (often inflammatory bowel disease) and 35 percent had an immune-mediated disease in a first- or second-degree relative. (See 'Autoimmune' below.)

IFP tends to present with symptoms of jaundice and abdominal pain developing over the course of days or weeks. Many patients eventually develop marked exocrine pancreatic insufficiency, while endocrine insufficiency (diabetes mellitus) is unusual [50,51]. The diagnosis can be established by endoscopic ultrasound or MRCP. The biliary obstruction tends to improve as the pancreas atrophies and has been successfully managed by placement of stents during ERCP [48-51]. However, consultation from a pediatric pancreatotomies' may be useful to guide management of IFP as an autoimmune process.

TOXIC/METABOLIC — While several toxic/metabolic risk factors contribute to acute pancreatitis in children, their role is less clear for chronic pancreatitis. The following factors have been described in small numbers as contributing to chronic pancreatitis in children [52]:

●Alcohol and tobacco smoking – These are the most common environmental risk factors for chronic pancreatitis in adults. The possibility of alcohol abuse or smoking also should be considered in adolescents presenting with acute recurrent pancreatitis. Patients with a history of alcohol or tobacco use should be evaluated for other contributing risk factors (genetic, obstructive). It is unknown whether secondhand smoke exposure contributes to the risk for chronic pancreatitis. (See "Etiology and pathogenesis of chronic pancreatitis in adults", section on 'Smoking' and "Etiology and pathogenesis of chronic pancreatitis in adults", section on 'Alcohol'.)

●Organic acidurias – The branched-chain organic acidurias, including methylmalonic, propionic, and isovaleric aciduria and maple syrup urine disease, are rare causes of chronic pancreatitis but should be considered in children with these disorders [53]. (See "Organic acidemias: An overview and specific defects".)

●Drugs – Medications (including metronidazole, mercaptopurine, azathioprine, mesalamine, L-asparaginase [54], valproate, and isoniazid) are associated with acute pancreatitis more frequently than chronic pancreatitis. If these drugs are the cause of an episode of acute pancreatitis and are not stopped, or if the acute pancreatitis is severe enough, chronic pancreatitis may result. (See "Etiology of acute pancreatitis", section on 'Medications'.)

●Chronic renal failure – Pancreatic disease, including pancreatitis, was found in more than 50 percent of adults with end-stage kidney disease undergoing autopsy [55,56]. Acute, rather than chronic, pancreatitis is more commonly seen and is more common in those on dialysis [52]. Of note, mild or moderate elevations in serum amylase and lipase (eg, one to three times the upper limits of normal) are common in patients with renal failure in the absence of pancreatitis, due to decreased clearance of these enzymes. (See "Approach to the patient with elevated serum amylase or lipase", section on 'Extrapancreatic disease'.)

●Hypertriglyceridemia – Hypertriglyceridemia is a relatively rare cause of acute pancreatitis in children. It generally occurs only at very high triglyceride concentrations (eg, >1000 mg/dL), which are typically associated with familial hyper triglyceridemic disorders. Its role in chronic pancreatitis is unclear [52], although it was linked to 13 percent of chronic pancreatitis cases in American adults [57]. (See "Hypertriglyceridemia-induced acute pancreatitis".)

●Hypercalcemia – Hypercalcemia (serum calcium >10.7 mg/dL) is an uncommon risk factor for chronic pancreatitis in adults. In most reported cases the hypercalcemia was caused by primary hyperparathyroidism, but other cases were associated with parenteral nutrition or other diseases [52].

AUTOIMMUNE — Autoimmune pancreatitis (AIP) is rarely reported in children; a large, international, multicenter cohort of >300 children with chronic pancreatitis found AIP in only 3.9 percent [58-63]. AIP is categorized into two types: type 1, previously lymphoplasmacytic sclerosing pancreatitis, and type 2, or idiopathic duct-centric chronic pancreatitis. Type 1 is more common in adults, and children are more likely to have type 2 AIP. Clinical features of these two forms of AIP overlap [61,64]. Establishing the diagnosis of AIP is important because the disease responds to glucocorticoids or immunomodulatory drugs. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis".)

AIP can occur as a primary pancreatic disorder or as part of multiorgan autoimmune disorders (immunoglobulin G4 [IgG4]-related disease). It is usually characterized by relatively mild symptoms, with an enlarged pancreas on abdominal imaging studies, often with obstructive jaundice. Affected children may report abdominal pain, back pain, jaundice, fatigue, and/or weight loss [65]. The pancreatic duct usually is irregularly narrowed, although a variety of morphologies have been described [66]. Adult patients with type 1 AIP often have elevated serum levels of gamma globulin (especially IgG4) [67]. In children, serum IgG4 may not be elevated [68,69]. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis".)

Consensus recommendations for diagnosis of AIP in children have been published [65]. This disorder (often with characteristics of type 2) can be seen in association with other diseases of presumed autoimmune etiology, including sclerosing cholangitis, primary biliary cholangitis, and Sjögren's disease [70]. Acute and chronic pancreatitis have been described in adults and children with inflammatory bowel disease (either Crohn disease or ulcerative colitis) and may precede the diagnosis of the bowel disease [71,72]. A common feature of these reports is the presence of colonic disease. In the setting of these diseases, the pathogenesis of the pancreatitis probably is multifactorial, including side effects of medications, but an autoimmune mechanism is also possible.

IDIOPATHIC — If a thorough evaluation fails to identify risk factors for chronic pancreatitis, the disorder is termed "idiopathic." As genetic testing has become more common, fewer cases of chronic pancreatitis fall into this category. In a large international registry, 11 percent of cases were considered idiopathic but some of these cases did not have genetic testing [5]. Further elucidation of gene mutations associated with chronic pancreatitis may reduce the number of children diagnosed with idiopathic chronic pancreatitis. (See 'Genetic' above.)

Two types of pancreatitis are considered "idiopathic" because their cause is unknown, but they are distinguished by their unique clinical features:

●Idiopathic fibrosing pancreatitis (IFP) – This type is characterized by fibrotic replacement of the pancreatic tissue, causing biliary obstruction and jaundice. (See 'Idiopathic fibrosing pancreatitis' above.)

●Tropical pancreatitis – Tropical pancreatitis (also known as tropical calcific pancreatitis) is a phenotypic description of a form of chronic pancreatitis seen in southern India and other parts of the tropics. Classically, it described chronic pancreatitis with an age of onset most commonly in childhood in which patients typically developed fibrocalculous pancreatic diabetes and malnutrition, often culminating in early death [73]. The histologic changes in the pancreas are similar to those of alcoholic pancreatitis, with fatty infiltration and often calculi [74]. This classical presentation of tropical pancreatitis has become less frequent in the last few decades.

It was initially thought that tropical pancreatitis was the result of severe malnutrition or cassava (tapioca) ingestion [75]. Mutations in SPINK1, CFTR, PRSS1, and CLDN2-MORC4 (claudin 2-MORC family CW-type zinc finger protein 4) variants and other genes associated with chronic pancreatitis in other geographic regions have been identified in some patients with tropical pancreatitis [76-78] (see 'Genetic' above). Some investigators have suggested that tropical pancreatitis may occur through the same pathways as chronic pancreatitis in other regions or that there may be factors particular to the tropical environment that trigger the disease [79,80].

ACUTE RECURRENT PANCREATITIS — Acute recurrent pancreatitis is a phenotypic description rather than a disease classification. It is likely that acute recurrent pancreatitis represents an early step in the progression to chronic pancreatitis. In adults, approximately 70 percent of chronic pancreatitis patients had acute recurrent pancreatitis prior to receiving a diagnosis of chronic pancreatitis [81]. Some patients with severe acute pancreatitis with widespread necrosis are left with scarring and duct destruction that becomes a chronic pancreatitis. (See "Etiology and pathogenesis of chronic pancreatitis in adults".)

There is not a clear distinction between diseases that cause recurrent attacks of acute pancreatitis and severe acute pancreatitis and those causing chronic pancreatitis, although the distribution of risk factors is somewhat different. In a multicenter study of 689 children (365 with acute recurrent pancreatitis and 324 with chronic pancreatitis), acute recurrent pancreatitis was more commonly associated with mutations in CFTR; Crohn disease; or risks such as specific medications, toxic-metabolic factors, or hypertriglyceridemia. In contrast, chronic pancreatitis was more commonly associated with female sex, younger age at first acute pancreatitis attack, Asian race, family history of pancreatitis, lower body mass index percentile, PRSS1 mutations, and pancreas divisum [82].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic pancreatitis and pancreatic exocrine insufficiency".)

SUMMARY

●Mechanisms and risk factors – Chronic pancreatitis can be associated with a variety of pathophysiologic mechanisms (table 1). In children, genetic and obstructive risk factors predominate. (See 'Overview of risk factors' above.)

•Genetic – The most common genetic risk factors for chronic pancreatitis in children include mutations in the genes encoding cationic trypsinogen (serine protease 1, or PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), carboxypeptidase A1 (CPA1), and cystic fibrosis transmembrane conductance regulator (CFTR). (See 'Genetic' above and "Pancreatitis associated with genetic risk factors".)

•Obstructive – Obstructive chronic pancreatitis occurs after obstruction of the pancreatic duct by a congenital anomaly, traumatic injury, or mass lesions. Magnetic resonance imaging cholangiopancreatography (MRCP) is a valuable tool for diagnosis; endoscopic retrograde cholangiopancreatography (ERCP) may be valuable for treatment. (See 'Obstructive' above and "Endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic disease in children".)

Idiopathic fibrosing pancreatitis (IFP) is a rare cause of chronic pancreatitis characterized by extrinsic compression of the distal common bile duct with resulting biliary obstruction, jaundice, and abdominal pain. Imaging findings often resemble a mass in the pancreatic head. The biliary obstruction has been successfully managed by placements of stents during ERCP. (See 'Idiopathic fibrosing pancreatitis' above.)

•Toxic/metabolic – Alcohol and tobacco are the most common risk factors for chronic pancreatitis in adults, and the possibility of alcohol abuse or tobacco use also should be considered in adolescents presenting with recurrent pancreatitis. Other toxic/metabolic causes of chronic pancreatitis include hypercalcemia and hyperlipidemia. (See 'Toxic/metabolic' above.)

•Autoimmune – Autoimmune pancreatitis (AIP) is more common in adults than children and can be associated with a multiorgan autoimmune disorder. In children, the immunoglobulin G4 (IgG4) elevations typical of AIP may not be present. (See 'Autoimmune' above and "Autoimmune pancreatitis: Clinical manifestations and diagnosis".)

•Idiopathic – If a thorough evaluation fails to identify risk factors for chronic pancreatitis, the disorder is considered idiopathic. (See 'Idiopathic' above.)

●Acute recurrent pancreatitis – There is not a clear distinction between diseases associated with acute recurrent pancreatitis and those associated with chronic pancreatitis. Patients with obstructive and genetic risk factors may have either acute recurrent or chronic pancreatitis. (See 'Acute recurrent pancreatitis' above.)