Clinical manifestations and diagnosis of chronic and acute recurrent pancreatitis in children

INTRODUCTION — Chronic pancreatitis is a progressive inflammatory disease of the pancreas. It often begins as acute pancreatitis and variably progresses to chronic pancreatitis over months to years, depending on etiology and modifying factors. The severity of clinical signs and symptoms vary between patients, and more advanced disease is characterized by pancreatic atrophy, fibrosis, pain syndromes, and sometimes pancreatic exocrine or endocrine dysfunction.

This topic review will provide an overview of the clinical manifestations, diagnosis, and prognosis in children with chronic and acute recurrent pancreatitis. Related information is available in the following topic reviews:

●(See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents".)

●(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".)

DEFINITIONS — Chronic and acute recurrent pancreatitis are distinguished by frequency of symptoms and presence or absence of irreversible changes in the pancreas or pancreatic function (table 1) [1].

●Chronic pancreatitis – Chronic pancreatitis is defined by the presence of compatible symptoms or pancreatic exocrine or endocrine insufficiency, with evidence of chronic pancreatic damage on imaging or histology.

It can also be defined mechanistically as "a pathologic fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental, or other risk factors who develop persistent pathologic responses to parenchymal injury or stress" [2].

●Acute recurrent pancreatitis – Defined as at least two distinct episodes of acute pancreatitis with complete resolution of pain or normalization of serum pancreatic enzyme levels between episodes. The term acute recurrent pancreatitis (ARP) is typically used in pediatrics rather than recurrent acute pancreatitis (RAP) to avoid confusion with the acronym for recurrent abdominal pain.

CLINICAL MANIFESTATIONS — The clinical manifestations of chronic and acute recurrent pancreatitis are similar regardless of the etiology. The child may have had a recognized episode of pancreatitis or may present with what appears to be the initial episode of pancreatitis but with a history of unexplained abdominal pain. The most common presenting symptoms include abdominal pain, nausea and vomiting, and poor growth. Less commonly, patients may be asymptomatic or present only after developing signs of pancreatic failure (eg, malabsorption, diabetes), which occur late in the course [3-6]. The age of onset, rate of disease progression, and prognosis depend upon the specific etiology and severity of the underlying condition or process. (See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents".)

Abdominal pain — Abdominal pain is the cardinal feature of chronic pancreatitis. The pain typically is epigastric, often radiates to the back, is often associated with nausea and vomiting, and may be relieved by sitting upright or leaning forward. The pain may sometimes be poorly localized and recognized in retrospect as a symptom of chronic pancreatitis.

The pain pattern varies among patients and may change during the course of the disease. Early in the course of chronic pancreatitis, the pain may occur in discrete attacks; as the condition progresses, pain tends to become more continuous. In some patients, with the loss of pancreatic tissue and fibrosis, the pain eventually improves [7]. However, in a long-term study of the natural history of chronic pancreatitis in 335 adults, the majority did not experience pain relief (so-called "burnout") over more than 10 years of clinical follow-up [8].

Chronic pain, similar to other visceral pain syndromes, may evolve and lead to both peripheral and central sensitization. Patients may experience hyperalgesia or neuropathic pain or both. Symptoms at sites inconsistent with pancreatic pain are legitimate symptoms of chronic pain, although this pattern is sometimes misinterpreted as falsified pain or malingering [9,10]. Hyperalgesia is generally recognized as severe pain in response to light touch or brushing of the abdomen. Neuropathic pain is defined as pain in the absence of a clear nociceptive stimulus (eg, phantom limb pain). Neuropathic pain may be difficult to confirm in chronic pancreatitis because it can be difficult or impossible to demonstrate the absence of inflammation in the pancreas, yet studies suggest it is a component of pain in chronic pancreatitis. (See 'Pain management' below.)

Age and maturity may also affect a child's experience or expression of pain. Very young children may be irritable rather than complaining specifically of pain. Some children may develop depression and/or anxiety associated with chronic abdominal pain but complain of pain rather than expressing these psychological symptoms. Other children may deny pain because of fear of "shots" for pain relief.

The differential diagnosis of abdominal pain in children is broad and includes physiologic and functional disorders. Functional abdominal pain is the most common cause of chronic or recurrent abdominal pain in children. Functional abdominal pain usually is not related to meals, is rarely associated with vomiting, and does not affect the child's growth. The clinician must attempt to distinguish between possible causes of abdominal pain based on the clinical pattern of symptoms, supported by carefully selected laboratory testing. (See "Causes of acute abdominal pain in children and adolescents" and "Chronic abdominal pain in children and adolescents: Approach to the evaluation", section on 'Etiology'.)

Malabsorption — Patients with chronic pancreatitis may develop malabsorption of protein and fat due to exocrine pancreatic dysfunction. However, clinically significant protein and fat deficiencies do not occur until more than 70 to 90 percent of pancreatic exocrine function is lost [5]. In a national series of 200 patients with hereditary pancreatitis in France, exocrine pancreatic insufficiency eventually developed in 34 percent and presented at a mean age of 29 years [11]. In a study of 324 children with chronic pancreatitis, 33.1 percent had exocrine pancreatic insufficiency by a mean age of 12 years [12]. Clinically important nutrient deficiencies may occur in the absence of steatorrhea [13].

The clinical manifestations of fat malabsorption include loose, greasy, foul-smelling stools that are difficult to flush. Untreated malabsorption can cause some of the pain experienced by patients with chronic pancreatitis. It should be noted that these stool characteristics are not consistently found in patients with fat malabsorption, and growth failure may be the main finding. Malabsorption of the fat-soluble vitamins (A, D, E, K) and vitamin B12 also may occur, although clinically symptomatic vitamin deficiency is rare [13,14]. Malabsorption may also affect levels of other micronutrients, including magnesium, iron, zinc, and selenium [15,16].

Pancreatic diabetes — Patients with chronic pancreatitis may develop endocrine pancreatic insufficiency, manifested by glucose intolerance. Routine screening for diabetes is appropriate in patients with advanced pancreatic disease. (See 'Monitoring' below.)

Overt diabetes mellitus is common late in the course of chronic pancreatitis [8,17]. In a national series of 200 patients with hereditary pancreatitis in France, diabetes mellitus was reported in 26 percent and presented at a mean age of 38 years [11]. However, there is evidence of increased risk for diabetes early in the disease course of acute recurrent pancreatitis and chronic pancreatitis. In an international registry of pediatric patients (mean age about 12 years) with chronic pancreatitis, 8.7 percent were reported to have diabetes mellitus [12]; this is approximately 30 times higher than the prevalence of diabetes in the general pediatric population [18]. At least one-quarter of the patients with diabetes had beta cell autoantibodies, suggesting that an autoimmune mechanism may contribute to diabetes in this population.

Diabetes caused by chronic pancreatitis is known as pancreatic diabetes, or type 3c diabetes [19]. The primary abnormality is decreased insulin secretion, similar to type 1 diabetes. However, pancreatic diabetes is also characterized by impaired secretion of glucagon, which leads to hypoglycemia due to loss of the pancreatic counterregulatory mechanism. The problem of glucose control in patients with pancreatic diabetes is exacerbated by diminished pancreatic digestive enzyme secretion with maldigestion and delayed nutrient absorption as well as altered gut hormone secretion. As a result, patients with this disorder are at increased risk for hypoglycemia. Ketoacidosis is relatively rare. However, some individuals with diabetes and chronic or acute recurrent pancreatitis have characteristics of types 1 or 2 diabetes; understanding this variation and how it impacts management is a goal of future study [18].

Disease progression — The pace and severity of disease progression varies among patients. More advanced disease is characterized by pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, calcifications, pancreatic exocrine dysfunction, pancreatic endocrine dysfunction, and dysplasia, typically with symptoms of chronic pain, weight loss, and malnutrition. In advanced disease, the structural changes, pain syndromes, and exocrine and/or endocrine pancreatic insufficiency appear to be irreversible [3,4,20]. The structural changes include irregular sclerotic and diffuse or focal destruction, acinar cell loss, islet cell loss, inflammatory cell infiltrate, and pancreatic duct abnormalities. Intraductal obstruction may be caused by protein plugs and/or calculi.

Complications — In addition to the manifestations described above, chronic and acute recurrent pancreatitis may present with or later develop signs or symptoms related to various complications. These include:

●Pseudocysts, which are usually asymptomatic but may be associated with fever and/or epigastric mass. Depending on the location and extent of the fluid collection, pseudocysts may cause a variety of problems, including each of the complications listed here.

●Splenic vein thrombosis, which may result in gastric and esophageal varices. Arterial pseudoaneurysm, which may lead to gastrointestinal hemorrhage. A retrospective study of 1363 adults with chronic pancreatitis found vascular complications in 12.2 percent [21]; similar data are not available for children.

●Pancreatic insufficiency, either exocrine or endocrine (diabetes).

●Nutritional deficiencies; the most common deficiencies described in adults with chronic pancreatitis are of vitamin D, zinc, magnesium, vitamin A, and vitamin E [22]. Children with severe chronic pancreatitis have been shown to have deficiencies of vitamins A, E, and D [23].

Less common complications include bile duct obstruction (which may cause abdominal pain and abnormal liver enzyme tests), duodenal obstruction (which may cause postprandial pain and early satiety), and pancreatic ascites and pleural effusion (which may cause abdominal distension, early satiety, and/or shortness of breath).

These complications are discussed in greater detail separately. (See "Overview of the complications of chronic pancreatitis".)

INITIAL EVALUATION FOR SUSPECTED CHRONIC OR ACUTE RECURRENT PANCREATITIS — Chronic or acute recurrent pancreatitis should be suspected in any child presenting with severe chronic or recurrent abdominal pain. The first step is a focused history and physical examination to help to distinguish this disorder from other causes of abdominal pain. If this evaluation is consistent with pancreatitis, further steps include laboratory testing and imaging, which are necessary to make the diagnosis (table 1) [1,24]. The initial steps in the evaluation can be taken by the primary care provider; referral to a pediatric gastroenterologist or other clinician with special expertise is valuable as soon as there is a strong suspicion for pancreatitis. (See "Chronic abdominal pain in children and adolescents: Approach to the evaluation".)

History — The history should include each of the following:

●Characterize the painful episodes:

•The initial onset, location, nature, duration, and progression of epigastric pain episodes should be established, as well as whether the episodes are triggered by food or exercise and whether there is associated vomiting (with or without flu-like symptoms). The pain associated with pancreatitis often radiates, particularly into the back. These characteristics can help to distinguish the pain of pancreatitis from the many other physiologic and functional causes of abdominal pain. A standardized pain Likert score may be useful, either a numeric system for older children or a FACES scale for younger children (figure 1). It is important that the clinician acknowledge that the child's pain is real; children with a history of recurrent or chronic abdominal pain may have experienced disbelief on the part of family members or previous clinicians. (See 'Abdominal pain' above.)

•History of pain management, including non-medication approaches (visual imaging, distraction, and formal training in these techniques), use of opioids (frequency and dose, who in the household controls the opioids), and use of non-opioids (acetaminophen, nonsteroidal antiinflammatory drugs [NSAIDs], gabapentin, or pregabalin). This information may be useful in designing a treatment program in the future.

●Inquire about psychosocial problems, such as absences from school, inability to participate in sports, and withdrawal from social situations. Such problems are common in children with chronic pancreatitis and may represent direct consequences of the painful episodes and/or manifestations of associated anxiety or depression.

●Evaluate for symptoms suggesting complications of chronic pancreatitis, including poor appetite, excessive flatulence, growth failure, diarrhea, and symptoms of diabetes.

●Inquire about clues to the cause of the chronic pancreatitis, including a history of acute pancreatitis, abdominal trauma (including sports-related trauma, as might occur in gymnastics), severe illness, toxic-metabolic risk factors including medications, and previous evaluation including endoscopic retrograde cholangiopancreatogram (ERCP). Risk factors for chronic pancreatitis are outlined in the table (table 2) and discussed in more detail in a separate topic review. (See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents".)

The family history should include questions about pancreatitis, pancreatic cancer, and cystic fibrosis in family members. Of note, chronic pancreatitis in adults is often erroneously ascribed to alcohol, although alcohol may not be the only mechanism for the pancreatitis. Families may not volunteer information about family members with alcoholic pancreatitis, believing that this history does not pertain to their child's problem.

Physical examination — The physical examination should include:

●Abdominal examination – This provides information to support or rule out the diagnosis and also helps to identify options for pain management. In patients with pancreatitis, the site(s) of maximal tenderness are generally the mid-epigastric but may also be right and left upper quadrants. The spleen should be evaluated; splenomegaly suggests the possibility of splenic vein thrombosis, which can be a complication of chronic pancreatitis. Signs of constipation may be present and can be triggered by opioid use or poor fluid intake.

●General physical examination – The general physical examination should evaluate for growth failure, weight loss, or other signs of malnutrition. Other sites where the patient experiences pain should also be evaluated. Chest wall musculoskeletal pain is common in patients with chronic pancreatitis, perhaps as a result of tension and positioning to relieve abdominal pain.

Laboratory testing — If the history and physical examination suggest a high index of suspicion for chronic or acute recurrent pancreatitis, the next steps are laboratory testing and imaging to provide further evidence of the diagnosis and to evaluate for complications of chronic or acute recurrent pancreatitis.

Laboratory tests provide important biomarker evidence of pancreatic dysfunction but cannot be used to confirm or exclude the diagnosis of chronic or acute recurrent pancreatitis outside of the clinical context (table 1). Other laboratory tests are targeted to evaluate for risk factors for chronic or acute recurrent pancreatitis, to exclude other causes of chronic abdominal pain, and to evaluate the child's general condition and nutritional state.

In children with previously confirmed or highly suspected chronic or acute recurrent pancreatitis, laboratory testing includes:

●Serum amylase and lipase – Elevation of amylase and/or lipase at least three times the upper limit of normal on several occasions, coupled with a characteristic episode of pain, supports a diagnosis of acute recurrent pancreatitis. However, lipase and amylase are made by tissues other than the pancreas and elevations do not always represent pancreatitis. Conversely, normal results for amylase and lipase do not exclude the diagnosis of chronic or acute recurrent pancreatitis.

●Complete blood count (CBC), electrolytes, albumin, glucose, and calcium – These results are usually normal in chronic or acute recurrent pancreatitis. A severe flare of the pancreatitis may cause temporary hyperglycemia; a diagnosis of diabetes cannot be made during an episode of pancreatitis.

●Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transferase (GGT), and total bilirubin – Elevations in these tests suggest concomitant liver disease and/or bile duct obstruction.

●Fecal elastase – This is performed as a screening test for exocrine pancreatic insufficiency. Fecal elastase <100 mcg/g stool suggests exocrine pancreatic insufficiency (although higher thresholds are sometimes used for patients with a high risk for exocrine pancreatic insufficiency, such as cystic fibrosis). The test should not be performed during an episode of acute pancreatitis, because results may be temporarily low. Similarly, the test should not be performed in a patient with diarrhea, because levels will be falsely low due to dilution.

Pancreatic insufficiency develops only after a substantial portion of the pancreas is destroyed. Exocrine pancreatic insufficiency does not perfectly correlate with pain or fibrosis, and it sometimes occurs in patients with otherwise limited signs and symptoms of chronic pancreatitis. (See 'Malabsorption' above.)

●Fat-soluble vitamins – Fat-soluble vitamin status should be assessed by measuring vitamin A, vitamin E, and 25-hydroxyvitamin D levels. Vitamin K adequacy is assessed indirectly by measuring international normalized ratio (INR) or prothrombin time (PT). (See "Overview of vitamin K" and "Overview of vitamin D" and "Overview of vitamin A" and "Overview of vitamin E".)

Initial imaging — The evaluation typically starts with abdominal ultrasonography, followed in most cases by magnetic resonance cholangiopancreatogram (MRCP) [25]. MRCP may not be necessary if the ultrasonography clearly demonstrates a cause of the pancreatitis that can be treated by proceeding directly to therapeutic ERCP. (See 'Therapeutic endoscopic retrograde pancreatography' below.)

●Ultrasonography with Doppler – The primary purpose of this test is to evaluate for evidence of biliary pathology such as gallstones, which may trigger episodes of acute pancreatitis [24]. In patients with more advanced disease, ultrasound also evaluates for complications of acute or chronic pancreatitis, including pseudocyst as well as thrombosis of the portal or splenic veins.

●MRCP – MRCP is the imaging study of choice in the evaluation for chronic pancreatitis (image 1) [25,26]. It provides anatomic detail of the pancreas and its ducts, without radiation. Findings suggestive of chronic pancreatitis or chronic pancreatic damage include ductal changes (irregular contour of the main pancreatic duct or its radicles; intraductal filling defects; calculi, stricture, or dilation) and parenchymal changes (generalized or focal enlargement, irregular contour [accentuated lobular architecture], cavities, calcifications, heterogeneous echotexture) and atrophy [1,25,27-32]. In addition to providing evidence to support the diagnosis, MRCP findings may help to determine whether a therapeutic intervention with ERCP would be helpful to reduce pain and recurrent episodes.

Secretin is sometimes administered during the procedure to stimulate pancreatic fluid secretion, resulting in dilation of the pancreatic ducts and enhancing their visualization [26,27,33]. The value of the secretin test in children is somewhat controversial [34,35], and consultation with a pediatric radiologist may be helpful. Secretin-stimulated MRCP may also provide indirect evidence of pancreatic exocrine function based on the volume of fluid in the proximal intestine after secretin stimulation [35,36].

Sedation or general anesthesia may be required to perform MRCP in a young child. This may need to be considered when planning multiple procedures requiring anesthesia.

Other tests — The following approaches may be used to evaluate the pancreas if the diagnosis remains unclear after the initial imaging or if MRCP is not available.

●Endoscopic ultrasound (EUS) – EUS can be helpful in establishing a diagnosis of chronic pancreatitis in children if expertise in this technique is available [37,38]. The technique permits high-resolution ultrasound imaging of the pancreas without interference from bowel gas. Conventional and Rosemont criteria used for diagnosis in adults have been applied in pediatric EUS [1] but have not been validated in children. MRCP is the first choice since it is more readily available at most centers and can be done with sedation in most children, whereas EUS requires anesthesia. However, both EUS and MRCP may be valuable if a tumor is present in the pancreas, if there is ambiguity about the diagnosis after ERCP, or if an intervention is planned to biopsy the pancreas or drain a cyst. (See "Endoscopic ultrasound in chronic pancreatitis".)

●Magnetic resonance imaging (MRI) and computed tomography (CT) – MRI is generally preferred for most situations because it is somewhat superior to CT for capturing biliary abnormalities and avoids radiation exposure.

A CT scan is also reasonably sensitive in identifying moderate to severe chronic pancreatitis. In the critically ill patient, CT has the advantage of being a quick study that generally does not require sedation. CT may also provide information about intrabdominal complications of chronic pancreatitis [39]. CT is more sensitive than ultrasound in demonstrating the extent of disease and detecting pancreatic calcifications and permits characterization of the tissue injury [40].

Typical MRI or CT findings in chronic pancreatitis include:

•Calcification within the pancreatic ducts or parenchyma (image 2)

•Dilatation of the main pancreatic ducts

•Pancreatic atrophy

•Fibrosis

Other abnormalities that may be seen include pancreatic enlargement, cystic lesions, and fatty replacement (particularly in cystic fibrosis and Shwachman-Diamond syndrome).

●ERCP – ERCP is generally not used as a diagnostic modality but may be useful for therapeutic interventions, such as sphincterotomy, stent placement, and stone removal. (See "Endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic disease in children".)

●Pancreatic biopsy – There is a limited role for pancreatic biopsy in pediatric patients. The most common indications are for the diagnosis of autoimmune pancreatitis and the evaluation of pancreatic masses. If indicated, a biopsy may be performed by a skilled interventional radiologist, surgeon, or skilled EUS operator. The choice of biopsy technique depends on the information sought and the availability of skilled providers.

DIAGNOSIS — Chronic pancreatitis is a syndrome, so isolated features are not diagnostic. The diagnosis of acute recurrent or chronic pancreatitis is made from a combination of clinical, laboratory, and imaging findings, as outlined in a consensus statement (table 1) [1].

Chronic pancreatitis in advanced stages is typically diagnosed by the combination of functional and structural features:

●Abdominal pain and tenderness consistent with pancreatic origin (particularly if exacerbated by meals), with or without elevations in amylase and lipase

●Imaging findings demonstrating pancreatic atrophy, calcifications, increased diameter of the pancreatic duct or other ductal abnormalities

Other supporting evidence may include episodes of severe exacerbation with amylase or lipase elevations, evidence of exocrine pancreatic insufficiency (low fecal elastase or high fecal fat), or endocrine pancreatic insufficiency (diabetes mellitus). Imaging studies alone are not diagnostic, especially in early stages of the syndrome. If chronic pancreatitis is suspected but initial imaging is normal, it may be necessary to follow the child for a time to confirm the diagnosis.

FURTHER EVALUATION FOR THE CAUSE — Further evaluation to determine the cause or contributing risk factors for the chronic pancreatitis is directed by the results of the initial evaluation. The main considerations are listed in the table (table 2). Pathogenic genetic variants in multiple susceptibility genes are common in children with unexplained acute recurrent and chronic pancreatitis. Genetic testing should be performed in children with early chronic pancreatitis to define the etiology, classify the patients by syndrome and disease mechanisms, and guide future management. Other tests listed below are selected based upon suspicion for specific risk factors.

Genetic testing — Testing for genetic risk factors is important because these are found in a high proportion of children with chronic pancreatitis [26,32,41]. Genetic factors may interact with other risk factors (for example, pancreas divisum, trauma, or toxic/metabolic causes) in the development of chronic pancreatitis [26].

Genetic counseling is useful before testing to counsel the patient and family, assure that the correct testing is performed, and interpret the results for the patent and family. Genetic testing may be helpful in predicting the future course of the disease, counseling family members and, in some cases, increasing confidence in the diagnosis. It should be noted that some of the genetic risk factors occur at high frequency in the general population, so the finding of these mutations in the absence of clinical and radiographic abnormalities should not be construed as confirming the diagnosis of acute or chronic pancreatitis. Counseling can include discussion about the risk of smoking or alcohol use, which can trigger or exacerbate the pancreatitis. The counseling may include information about the complications of chronic pancreatitis, including development of diabetes and increased risk of pancreatic cancer. (See "Overview of the complications of chronic pancreatitis".)

Candidates for testing should be evaluated for mutations in each of the following genes, noting that the number of genes associated with acute recurrent and chronic pancreatitis continues to grow. Evaluation of each gene is valuable, even for patients whose family is known to have a mutation in genes contributing to the risk of chronic pancreatitis, since the genetic model is often compound-complex with modifying factors and does not follow classic Mendelian patterns [32]. An updated list of laboratories that perform this testing is available at the Genetic Testing Registry. (See "Pancreatitis associated with genetic risk factors", section on 'Genetic testing'.)

●PRSS1 – Mutations are identified in the PRSS1 gene (serine protease 1) that encodes cationic trypsinogen in up to 80 percent of families with autosomal dominant hereditary pancreatitis. The most common pancreatitis-associated mutations in PRSS1 are the R122H and N29I mutations. (See "Pancreatitis associated with genetic risk factors", section on 'PRSS1 gene'.)

●SPINK1 – There is a weaker association between chronic pancreatitis and mutations in the SPINK1 gene (serine protease inhibitor Kazal type 1). SPINK1 mutations are fairly common in the general population (2 percent of healthy individuals carry a "high-risk" mutation) [42], but less than 1 percent of carriers develop pancreatitis [43]. Therefore, SPINK1 mutations probably act as disease modifiers, lowering the threshold for pancreatitis caused by other genetic or environmental factors (eg, a second gene mutation, pancreas divisum, alcohol, or other insult). (See "Pancreatitis associated with genetic risk factors", section on 'SPINK1 gene'.)

●CFTR – Mutations in the CFTR gene (cystic fibrosis transmembrane conductance regulator) can cause pancreatitis with or without associated manifestations of cystic fibrosis. Chronic or acute recurrent pancreatitis is usually seen in pancreatic-sufficient cystic fibrosis [44] or occasionally with the carrier state. In the latter condition, environmental or other modifiers likely contribute to the pathogenesis of the disease. Most diagnostic laboratories in the United States screen for 20 to 30 of the most common gene mutations causing cystic fibrosis in the United States population. These panels may not capture less common mutations of CFTR and may not reflect common mutations in other populations. Therefore, complete CFTR gene sequencing is used when assessing this as a risk factor for chronic or acute recurrent pancreatitis [26]. Sweat chloride testing is necessary to diagnose cystic fibrosis (table 3). Children diagnosed with cystic fibrosis and chronic pancreatitis should be evaluated at a cystic fibrosis center for other complications of cystic fibrosis and should also be offered genetic counseling. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Diagnostic criteria' and "Pancreatitis associated with genetic risk factors", section on 'CFTR gene'.)

●CTRC – Chymotrypsin C (CTRC) is an enzyme that protects the pancreas by eliminating prematurely activated trypsin. Mutations in the CTRC gene are more common among patients with chronic pancreatitis (12 percent) as compared with the general population (1 percent) [45].

●CPA1 – Carboxypeptidase A1, a digestive enzyme encoded by the CPA1 gene, is associated with autosomal dominant hereditary pancreatitis presenting in early childhood [46,47].

Several other genes have been identified in patients with acute recurrent and chronic pancreatitis [48]. The clinical significance and management options are being evaluated in expert centers. Broader panels that include more than a dozen genes associated with pancreatic disorders are now available for evaluation of complex or idiopathic cases.

Obstructive risk factors — Obstruction of the pancreatic ducts is the second most common risk factor for acute recurrent pancreatitis and chronic pancreatitis in children [26,32]. In one large cohort study, pancreas divisum was found in approximately 15 percent of children with chronic pancreatitis or acute recurrent pancreatitis, which is a higher proportion than in the general population [49]. Evidence of obstruction may be found or suspected on magnetic resonance cholangiopancreatogram (MRCP); however, endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatogram (ERCP) may be required for confirmation. Detection of an obstructive risk factor should not preclude genetic testing, because of the complex etiology of acute recurrent pancreatitis and chronic pancreatitis. (See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents", section on 'Obstructive'.)

Toxic-metabolic risk factors — Most toxic-metabolic factors associated with pancreatitis are either diagnosed by history or have become apparent during prior episodes of acute pancreatitis. These include:

●Medications – Medications that are associated with acute pancreatitis include metronidazole, mercaptopurine, azathioprine, mesalamine, chemotherapy (particularly L-asparaginase), valproate, and isoniazid. (See "Etiology of acute pancreatitis", section on 'Medications'.)

●Alcohol and tobacco smoking – Children may abuse alcohol or tobacco at an early age. Adolescents and preadolescents should be asked about these risk factors without the parent in the room to encourage disclosure. (See "Substance use disorder in adolescents: Epidemiology, clinical features, assessment, and diagnosis".)

●Cannabis – There is some evidence that cannabis may be a risk factor for acute pancreatitis [50]. Given the increasing availability of cannabis and its use in managing chronic pain, providers should be aware of this association, and consider whether a patient's cannabis use is relieving or exacerbating his or her pain. (See "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects".)

●Hyperlipidemia – Triglycerides are associated with acute pancreatitis only at very high levels (serum triglyceride levels >1000 mg/dL). In a study of 521 adult patients with chronic pancreatitis in the United States, 13 percent of cases were associated with hyperlipidemia [51]. (See "Hypertriglyceridemia-induced acute pancreatitis".)

●Inborn errors of metabolism – Organic acidemias are associated with pancreatitis. In most cases, affected patients will have been identified by other symptoms or laboratory abnormalities before presenting with pancreatitis. (See "Organic acidemias: An overview and specific defects".)

Autoimmune pancreatitis — Autoimmune pancreatitis may present with only classic symptoms of chronic pancreatitis or acute recurrent pancreatitis but should particularly be suspected in the following situations:

●When the patient has an underlying autoimmune disease, especially sclerosing cholangitis or Sjögren's disease [52]. There is also an association with inflammatory bowel disease affecting the colon, although an autoimmune mechanism has not been established.

●When the pancreatitis is characterized by obstructive jaundice and an enlarged pancreas in the absence of a stone or tumor.

Adults with autoimmune pancreatitis often have elevated gamma globulin (immunoglobulin G4 [IgG4]), which characterizes type 1 autoimmune pancreatitis. Autoimmune pancreatitis is rare in children, and, when it does develop, it has features of type 2 [26,53]. As a result, IgG4 levels usually are normal in children and do not exclude autoimmune pancreatitis. The diagnosis of autoimmune pancreatitis is controversial, with some authors proposing a trial of steroids and others a pancreas biopsy prior to therapeutic trial [53,54]. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis".)

OVERVIEW OF MANAGEMENT — Early referral to an expert in acute recurrent or chronic pancreatitis is important to management. Management involves treating pain, ensuring adequate nutrition to preserve normal function and growth, and monitoring for complications of the disease. Patients experience exacerbations of disease that may resemble episodes of acute pancreatitis. Creating a specific plan for managing exacerbations helps to avoid unnecessary imaging studies and delay in pain management by other clinicians who may be unfamiliar with chronic and acute recurrent pancreatitis. Treatment of chronic pancreatitis is detailed in a separate topic review (see "Chronic pancreatitis: Management"); the main considerations for children are outlined below.

Therapeutic endoscopic retrograde pancreatography — Patients with abdominal pain due to chronic pancreatitis and dilated main pancreatic duct may benefit from endoscopic retrograde pancreatography (ERCP) or other surgical procedures to relieve the obstruction. The role of endoscopic versus surgical intervention has not been well established in either adults or children; however, most practitioners would perform ERCP to relieve obstruction before considering surgical drainage. Management in children is based on expert opinion, guided by indirect evidence from adults with chronic pancreatitis and a few small case series in children. Therapeutic ERCP in children requires special expertise and is generally available only at major medical centers. Therapeutic ERCP for pancreas divisum is particularly difficult and controversial; consultation with an expert interventional pancreatologist is important before considering this option. (See "Endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic disease in children", section on 'Chronic pancreatitis'.)

Monitoring — Most experts in pediatric pancreatitis see patients in follow-up at least once yearly. Routine monitoring should include:

●Assessment of growth and nutritional status with serial plotting of height, weight, and body mass index on growth charts as well as tracking of pubertal development. (See "Measurement of growth in children".)

●Assessment of psychosocial function, including school attendance.

●Screening for exocrine pancreatic insufficiency. Measurement of fecal elastase is the simplest test for this purpose. The use of pancreatic enzyme replacement therapy (PERT) does not interfere with fecal elastase testing, since PERT is porcine and the fecal elastase test measures human elastase. (See 'Malabsorption' above.)

●Measurement of fat-soluble vitamin levels (vitamins A and E, 25-hydroxyvitamin D, and prothrombin time [PT]/partial thromboplastin time [PTT]).

●Screening for endocrine pancreatic insufficiency (impaired glucose tolerance or diabetes mellitus). An oral glucose tolerance test is the best test for endocrine insufficiency but may be too invasive or time consuming early in the course of chronic or acute recurrent pancreatitis. Hemoglobin A1c, with or without a fasting glucose, is used as a screening test by some. This may not be the most sensitive test but may be acceptable, particularly in patients with preserved exocrine function.

Pain management — Pain is by far the greatest burden in chronic pancreatitis, responsible for loss of school and social time and for many hospitalizations. Pain relief is crucial to both management and the goal of maintaining as normal a life as possible.

Patients with chronic pain should ideally be evaluated by a skilled pediatric pain team and/or psychologist to develop an integrated pain management program. The plan would include a tiered program of management strategies, typically including:

●Non-medication therapies (distraction, visual imaging)

●Integrative pain strategies (eg, aromatherapy, acupuncture)

●Non-opioid medications (acetaminophen, nonsteroidal antiinflammatory medications [NSAIDS], or gabapentinoids)

●Opioids (with a clear protocol for inpatient and outpatient use and careful monitoring)

●Hospitalization with inpatient pain management (eg, patient-controlled analgesia)

The tiered program should be clearly communicated to the family and managed by the parents/caregivers. Children should not control their own home medications, regardless of age. It is helpful to develop a specific plan for pain management in the event of hospitalization and include it in the medical record to facilitate early relief of pain during an exacerbation. The pain team can also develop treatment plans for hyperalgesia and neuropathic pain and educate families on these symptoms.

Other factors may contribute to the child's distress and should be evaluated and specifically addressed. These include nonpancreatic sources of pain, such as constipation and musculoskeletal pain. Depression and anxiety are common among children with chronic pain, and treatment may improve the child's quality of life and ability to cope with the illness. Social engagement, a regular daytime schedule, and distraction are often beneficial; for this reason, it is often helpful to keep the child in school as much as possible rather than changing to homeschooling, although individual families' decisions must be respected.

Evidence for other agents improving pain in chronic pancreatitis, including pancreatic enzymes in a pancreatic-sufficient patient and antioxidant therapy, is controversial. A trial of non-enteric-coated PERT is reasonable, but its efficacy is unproven.

Nutrition — Children with chronic pancreatitis should be routinely monitored for growth and development, as well as for fat-soluble vitamin deficiencies. (See 'Monitoring' above.)

Children who develop significant weight loss, reduced body mass index, or stunting of linear growth or who have severe disease and many hospital admissions may benefit from nasogastric or nasojejunal feedings. This strategy helps to improve weight gain and weight maintenance and may also improve pain.

Patients with advanced chronic pancreatitis may develop exocrine pancreatic insufficiency, which may contribute to growth failure and is identified by low levels of fecal elastase, as described above (see 'Laboratory testing' above). Such patients should be treated with PERT, as well as close monitoring and replacement of fat-soluble vitamins. Management and initial dosing of PERT are similar to that for patients with cystic fibrosis (although patients without cystic fibrosis may require lower final doses than do those with cystic fibrosis) and is detailed in a separate topic review. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

Dual-energy x-ray absorptiometry (DXA) may be of value in assessing bone mineralization in children with chronic pancreatitis since they may be at risk for osteopenia [55].

Children with advanced chronic pancreatitis are also at risk for endocrine pancreatic insufficiency (see 'Pancreatic diabetes' above); patients with pancreatic diabetes should be referred to an experienced pediatric endocrinologist for management.

Surgery — A crucial decision in the care of a child with acute recurrent or chronic pancreatitis is referral for surgery. Children with intractable pain, particularly when it interferes with school or other activities, and children with evidence of pancreatic duct obstruction unresponsive to ERCP may be considered for pancreatic drainage procedures (eg, Peustow, Frye, etc) or total pancreatectomy with islet autotransplantation. Because of the long life expected for children, and the potential complications of either procedure, referral to a center experienced in the care of children with pancreatitis is warranted. (See "Chronic pancreatitis: Management", section on 'Surgical resection'.)

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 AND RECOMMENDATIONS

●Definitions – Acute recurrent pancreatitis and chronic pancreatitis are progressive inflammatory disorders of the pancreas, characterized by irreversible structural changes that often result in pain syndromes. They are distinguished by frequency of symptoms and presence or absence of irreversible changes in the pancreas or pancreatic function (table 1). (See 'Definitions' above.)

●Clinical manifestations – The most common presenting symptoms include abdominal pain, nausea and vomiting, and poor growth. Less commonly, patients may be asymptomatic or present only after developing signs of pancreatic exocrine or endocrine insufficiency (eg, malabsorption, particularly of fat and fat-soluble vitamins, or diabetes), which occurs late in the course. (See 'Clinical manifestations' above.)

●Initial evaluation – The first step in evaluating a child with suspected chronic pancreatitis is a focused history and physical examination to help distinguish this disorder from other causes of abdominal pain. If this evaluation is consistent with pancreatitis, further steps include laboratory testing and imaging. Early referral to a pediatric gastroenterologist is valuable in guiding the evaluation and management.

•Laboratory tests – Initial laboratory testing includes a complete blood count (CBC), liver enzymes, amylase, and lipase. Normal results for amylase and lipase do not exclude the diagnosis of chronic or acute recurrent pancreatitis. Elevation of amylase and/or lipase at least three times the upper limit of normal supports a diagnosis of acute recurrent pancreatitis if it coincides with a characteristic episode of pain. The patient should also be evaluated for exocrine pancreatic insufficiency by measuring fecal elastase and for fat-soluble vitamin deficiencies. (See 'Laboratory testing' above.)

Patients with advanced pancreatic disease are at risk for pancreatic diabetes and should be monitored. (See 'Monitoring' above.)

•Imaging – Imaging typically starts with abdominal ultrasonography, followed in most cases by magnetic resonance cholangiopancreatography (MRCP). MRCP may not be necessary if the ultrasonography clearly demonstrates stigmata of chronic pancreatitis and a cause of the pancreatitis that can be treated by proceeding directly to therapeutic endoscopic retrograde cholangiopancreatogram (ERCP). (See 'Initial imaging' above.)

●Diagnosis – Chronic pancreatitis is most commonly diagnosed by the combination of abdominal pain consistent with pancreatic origin (particularly if exacerbated by meals) and imaging findings demonstrating pancreatic atrophy, calcifications, increased diameter of the pancreatic duct, or other ductal abnormalities. Combinations of findings that can be used to make the diagnosis of chronic or acute recurrent pancreatitis are outlined in the table (table 1). (See 'Diagnosis' above.)

●Further evaluation for cause – Further evaluation to determine the cause or contributing risk factors for the chronic pancreatitis is directed by the results of the initial evaluation. The main considerations are listed in the table (table 2). Genetic testing should be performed for most children with chronic pancreatitis and ideally should include, at minimum, testing for mutations in PRSS1, SPINK1, CFTR, CTRC, and CPA1. Broader panels that include more than a dozen genes associated with pancreatic disorders are now available for evaluation of complex or idiopathic cases. Testing for toxic-metabolic risk factors or autoimmune disease is appropriate for selected patients. (See 'Further evaluation for the cause' above and 'Genetic testing' above.)

●Management – Management of chronic or acute recurrent pancreatitis involves managing pain and nutrition to preserve normal function and growth as well as monitoring for complications of the disease, including psychosocial stress. Pain should be managed with a tiered program that includes nonmedication strategies, nonopioid medications, and carefully planned use of opioids. (See 'Nutrition' above and 'Monitoring' above and 'Pain management' above.)

Patients with abdominal pain due to chronic pancreatitis and dilated main pancreatic duct may benefit from ERCP to relieve the obstruction. Surgical options may be indicated in select cases. (See 'Therapeutic endoscopic retrograde pancreatography' above and "Endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic disease in children" and 'Surgery' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mohamad Miqdady, MD, and Seiji Kitagawa, MD, who contributed to earlier versions of this topic review.