Pediatrics

Pancreas disorders-Pancreatitis-acute, chronic, hereditary

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Pancreatitis? What are the typical findings for this disease?

The clinical definition of acute pancreatitis (AP) requires a minimum of TWO of the following THREE features:

1. Acute onset of abdominal pain or tenderness, epigastric in nature, with guarding, associated with nausea and/or vomiting; +/- radiation to the back

2. Elevated serum amylase or lipase activity at least 3 times the upper limit of normal or greater (international units/liter)

3. Characteristic findings on cross-sectional abdominal imaging, such as transabdominal ultrasonography, contrast-enhanced computed tomography (CT) scan, magnetic resonance imaging (MRI), MRCP, ERCP,or endoscopic ultrasound. Findings may include pancreatic edema, fluid collections, areas of pancreatic or peri-pancreatic necrosis, peripancreatic inflammation, acute fluid collections or pancreatic hemorrhage

What other disease/condition shares some of these symptoms?

Clinical symptoms of epigastric pain or tenderness can be seen with certain gastrointestinal conditions such as peptic ulcer disease or dyspepsia, cholelithiasis, cholecystitis, intestinal obstruction, or pancreatic malignancies. Non-GI conditions include renal colic.

Laboratory findings of an elevated amylase or lipase can be seen with enteritis or intestinal ischemia, sialadenitis, biliary tract disease, and renal insufficiency (due to decreased clearance).

What caused this disease to develop at this time?

Background: Understanding pathophysiology of the pancreas

The main parenchymal cell of the pancreas, the acinar cell, secretes pancreatic enzymes, notably pancreatic proteases in their inactive, or zymogen, form. These proteases are normally activated only when they reach the duodenum and are exposed to enterokinase along the intestinal brush border. In the physiologic state, these enzymes allow for proper digestion of nutrients.

In the pathologic state (e.g., due to a pancreatic insult), these enzymes are prematurely activated within the acinar cell, leading to an aberrant rise in cytosolic calcium as well as other downstream events. The pathologic cascade over-activates intra-acinar proteases and is followed by the generation of inflammatory mediators, varying degrees of ischemia, and, in severe cases, autolysis of the pancreas. Multi-organ dysfunction and/or pancreatic necrosis can occur.

Predisposing factors

Factors which can trigger pancreatitis include:

Biliary causes (gallstone impaction, sludge or microlithiasis), medications or toxins, systemic causes (e.g., sepsis), trauma to the mid-abdomen, infectious diseases, metabolic and hereditary conditions, post-ERCP, and acute or chronic alcohol ingestion (mostly in adults).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Serum amylase and lipase >3 times the upper limit of normal

  • Lipase is more sensitive than amylase for detecting acute pancreatitis, particularly among infants and toddlers

    • Elevated amylase may be found in other conditions, i.e., sialadenitis, nephrolithiasis, cholangitis, cholecystitis, peptic ulcer, intestinal obstruction, ischemia or perforation, ectopic pregnancy

    • Elevated lipase may also have non-pancreatitis causes, i.e., pancreatic cancer, non-pancreatic abdominal pain, macrolipasemia, renal insufficiency (due to decreased clearance), acute cholecystitis, esophagitis, hypertriglyceridemia

    • Lipase >10,000 suggestive of biliary pancreatitis

  • Liver functions test (LFT) elevations can be seen during biliary pancreatitis

    • Aminotransferase levels (AST, ALT) rise and fall rapidly with transient obstruction of the common bile duct (CBD) due to gallstones

    • Rising alkaline phosphatase seen with persistent CBD obstruction

    • Also can have hyperbilirubinemia and jaundice

  • Gold standard for diagnosis is pancreatic biopsy with histological analysis, but this is impractical and performed primarily during autopsy from severe, acute pancreatitis

    • Severe pancreatitis identified by intense inflammation and edema, fat necrosis, hemorrhage, vascular injury and loss of normal acinar architecture

    • Mild, interstitial pancreatitis defined by lower degree of inflammation, edema, acinar cell vacuolization and apoptosis

Would imaging studies be helpful? If so, which ones?

  • Ultrasound

    • Widely available, no radiation

    • Does not require sedation

    • High specificity but poor sensitivity

    • Pancreatic edema seen in less than 1/3 of children undergoing ultrasound with acute pancreatitis

    • Head and tail of pancreas can be obscured by bowel gas

    • Best for detecting gallbladder stones but only detects 1/3 of patients with choledocholithiasis

  • CT scan

    • Widely available, but significant radiation exposure

    • Does not usually require sedation

    • High specificity, moderate sensitivity of about 60% in detecting pancreatitis

    • Detects edema, fluid collections, necrosis

    • Preferably perform using a contrast-enhanced protocol

  • MRCP

    • Helpful in confirming distal common bile duct stone impaction causing biliary pancreatitis

    • Can be used to detect pancreas divisum in cases of recurrent acute pancreatitis

    • Majority of pediatric patients will require sedation, especially since study is sensitive to motion artifact

    • Pediatric radiologists not available at all centers

  • ERCP

    • Therapeutic as well as diagnostic test of choice in cases of suspected stone impaction

    • Can detect pancreas divisum

    • 5-10% risk of causing pancreatitis

    • Requires sedation

    • Smaller pediatric patients technically difficult

    • Not routinely available at pediatric centers; may require referral to adult gastroenterologist

  • EUS

    • Can delineate ductal and parenchymal changes associated with chronic pancreatitis

    • Potentially obtain biopsies

    • Can be used to drain pseudocysts

    • Requires sedation

    • Not routinely available at pediatric centers; may require referral to adult gastroenterologist

Confirming the diagnosis

There are no established clinical algorithms for diagnosing pediatric acute pancreatitis other than establishing 2 of the 3 criteria listed in the first question.

If you are able to confirm that the patient has Pancreatitis, what treatment should be initiated?

Are there some therapies that should be instituted immediately?

Appropriate setting to manage patient: Although some very mild cases can be managed as outpatients, acute pancreatitis usually requires inpatient admission for pediatric patients due to symptoms from abdominal pain and dehydration. The median length of stay for hospitalization is about 4 to 8 days in most large studies. Infants and toddlers spent a significantly greater number of days in the hospital than older children.

Immediate concerns: Therapeutic measures involve appropriate fluid and electrolyte replacement, acid suppression, and analgesia and pain control. Common practice has been to initially make patients NPO and give bowel rest, thus reducing stimulation of pancreatic secretions. Recently, there is increasing evidence from several large, randomized, controlled trials to support starting enteral feeds early during admission, mainly via nasojejunal tube, with one large study reporting equivalent outcomes with slow nasogastric feeds. Total parenteral nutrition is generally not recommended unless a patient proves intolerant to enteral feeding.

For predicted severe, acute pancreatitis, patients may need intensive monitoring in an ICU setting with aggressive fluid management and pain control. Patients may develop secondary multi-organ dysfunction, requiring multi-disciplinary management.

With persistent biliary pancreatitis, sphincterotomy and stone extraction should be pursued as soon as possible.

What about longer-term treatment?

Complications can develop: Pancreatic necrosis can be seen within 1-2 weeks after onset of acute pancreatitis. Antibiotics and surgical debridement for confirmed infective necrosis (usually by FNA) are used to manage severe cases. Pancreatic pseudocyts can also develop with chronic pancreatitis and may require drainage if symptomatic. Follow-up ultrasound(s) of the pancreas are indicated to assess for complications when the patient’s clinical course does not improve.

Interval cholecystectomy for biliary pancreatitis can be planned once the patient's inflammation has subsided.

Pain management: Pain control is one of the most important considerations for patients. Pain can persist beyond resolution of the acute pancreatitis event and may require on-going management.

What are the adverse effects associated with each treatment option?

Bowel Rest: Traditional teaching and practice for decades was to avoid stimulating the pancreas and eventually supplementing with parenteral nutrition after 3-5 days. The rationale was that feeding stimulates zymogen release and further worsens pancreatitis. However, recent studies now favor slow enteral nutrition over parenteral. Studies show improved outcomes with mortality, multi-organ failure, systemic infection, and surgery.

Enteral nutrition: Benefits have been shown when started early on in disease, although there are disparities between studies over the timing. Some studies suggest early start (less than 24 hrs) and some suggest later start (after 48 hrs). Most studies used NJ tube feeds, but a randomized study from Glasgow suggest slow NG tube feedings are equivalent to NJ tube feedings.

Choice of intravenous fluid management: Lactated Ringers is potentially better than normal saline, especially during acute resuscitation.

Pain control: There has been debate over choosing morphine sulfate versus meperidine in the acute setting. In theory, MSO4 can cause Sphincter of Oddi spasm, but clinically this has not been a significant problem. Additionally, meperidine metabolites can accumulate when given on a standing basis. Beyond the acute setting, pain can become a chronic problem. NSAIDS and acetaminophen should be tried first-line, but some patients will require narcotics to manage symptoms. Adequate pain control is important to improving quality of life for pancreatitis patients.

Empiric Antibiotics: Empiric antibiotics are not recommended if infection is not proven or not highly suspected.

ERCP: Patients with an obstructed stone will need ERCP to alleviate the impaction. Post-ERCP pancreatitis is a well-known and documented complication. Progressive pancreatitis and cholangitis with persistent stone impaction may outweigh the risk of ERCP-related pancreatitis.

What are the possible outcomes of Pancreatitis?

What will you tell the family about prognosis?

Most pediatric cases are mild and resolve spontaneously. The first episode of unexplained mild acute pancreatitis will likely resolve without sequelae. There is a 20-25% chance of recurrence.

For severe acute pancreatitis most published data comes from adult populations. 10-20% of all patients will develop complications, either local complications (e.g., necrosis or acute collection of fluid) or persistent multi-organ failure (e.g., shock, respiratory failure or renal insufficiency). Overall mortality has declined in the past several decades (range 1-5% of all patients), and pediatrics has significantly less mortality. The Atlanta criteria defines measure of severity (using adult criteria) and is the most established classification system for acute pancreatitis (AP).

Multiple clinical scoring models (using adult data) have been developed to predict outcomes in AP. Traditional scoring systems include Ranson’s, APACHE-II, and Modified Glasgow. Although validated in children, the recent BISAP (Bedside Index for Severity in AP) model is an accurate means for risk stratification in AP. BISAP measures blood urea nitrogen >25mg/dL, impaired mental status, systemic inflammatory response syndrome (SIRS), age >60 years, and pleural effusions.

Laboratory tests are also used to assess prognosis. These include:

1. Blood Urea Nitrogen - Level >7.14 nmol/L at admission or increase in level over 24 hrs. Accurate, inexpensive, widely available but it may reflect several disease processes.

2. Serum Creatinine - Increase during initial 48 hrs associated with necrosis. Routine test, widely available. Unclear if findings can be extrapolated to earlier time points.

3. C-reactive protein - Level > 143 nmol/L at 48hrs has high level of accuracy for prediction of severe outcome. Widely available. Peaks at 48 hrs.

What will you tell the family about risks/benefits of the available treatment options?

Treatment for acute pancreatitis focuses on providing supportive care and reducing complications. There are specific risks with each intervention:

CT scan - radiation risk

ERCP - pancreatitis risk

Enteral feeding - dislodgement of tube

Debridement - surgical risks and risk of worsening peritonitis

Antibiotics - antimicrobial resistance risk

What causes this disease and how frequent is it?

  • In adults, the most common etiologies are biliary pancreatitis and alcohol ingestion (both acute binge drinking and chronic consumption)

  • In children, the etiologies are more varied:

    • Biliary (25%)

      • Gallstone pancreatitis (~55% of all biliary causes)

      • Microlithiasis/Sludge (~20% of all biliary causes)

      • Structural (~25% of all biliary causes)

    • Medications or drug exposure (20%)

    • Idiopathic (19%)

    • Systemic (14%)

    • Trauma (8%)

    • Infections (7%)

    • Metabolic (3%)

    • Hereditary (4%)

  • Incidence of acute pancreatitis in children

    • 1 in 7,500 per year

    • 11,000 children present with acute pancreatitis in United States each year

    • Rising number of cases correlates with increased annual ED visits and increased awareness of pancreatitis among pediatricians

How do these pathogens/genes/exposures cause the disease?

Biliary pancreatitis (25% of cases)

Pancreatitis results when small gallstones or sludge migrate out of the gallbladder into the cystic duct, then into the common bile duct (CBD). When stones obstruct the Ampulla of Vater or the common channel, they can cause pancreatitis or cholangitis. The risk of a stone causing pancreatitis is inversely proportional to the size of the stone. Microlithiasis, or sludge, may also cause pancreatitis.

Obstruction can also result from structural causes. Pancreas divisum is an embryologic anomaly resulting from incomplete fusion of the ventral and dorsal pancreas during development. This occurs in 5-10% of the normal population and is the most common congenital anomaly of the pancreas. Most individuals are asymptomatic, but pancreas divisum can be of clinical relevance when obstruction of flow through the minor papilla causes high intrapancreatic dorsal ductal pressure and pancreatitis develops.

Medication or drug exposure can cause pancreatitis (20%)

Medication, drug, and toxin exposure account for the second most common cause of pancreatitis. Most commonly implicated are: valproic acid, azathioprine, 6-Mercaptopurine, furosemide, tetracycline, sulindac, L-asparaginase, corticosteroids, 5-aminosalicylic acid compounds, bactrim, and acetaminophen.

Idiopathic cases (19%)

Despite better detection modalities and increased awareness, there has not been a reduction in the proportion of idiopathic patients with pancreatitis over the past decade.

Systemic-associated (14%)

Pancreatitis can be seen in patients with systemic illnesses. The majority of these cases are related to sepsis and shock. Shock is associated with generalized or localized ischemia and hypoperfusion, causing ischemic pancreatitis.

Other associated diseases: Systemic Lupus erythematosus (SLE), Hemolytic Uremic Syndrome (HUS), Inflammatory bowel disease (IBD), acute liver failure, sarcoidosis.

Traumatic (8%)

Abdominal trauma causes an elevation of amylase and lipase levels in up to 20% of trauma cases and clinical pancreatitis in 5% of those cases. Pancreatic injury usually occurs in midline, where the body of the pancreas can be compressed against the vertebral column from external forces. Children are especially susceptible to this type of injury, which comes more from blunt trauma than from penetrating injuries. Blunt injury can crush the gland across the spine, disrupt the pancreatic duct and cause leakage. While usually seen in motor vehicle accidents, sports injuries, and accidental falls, a child presenting with this type of injury should also be considered for child abuse.

Post-ERCP procedure associated-pancreatitis is a rising cause of pancreatitis as ERCP has become more commonly performed in children. The risk is increased with an inexperienced endoscopist. No medications, other than aggressive pre-intervention intravenous hydration, have been shown to prevent post-ERCP pancreatitis.

Infections (7%)

Pancreatitis associated with infections commonly has a temporal association with a viral prodrome. These cases of acute pancreatitis tend to be milder when compared to biliary pancreatitis, resolve faster and are not prone to recurrent episodes.

Viral causes include mumps, Epstein-Barr virus, coxsackievirus, echovirus, varicella-zoster, Hepatitis A, rotavirus, Hepatitis E, adenovirus, moraxella catarrhalis and measles.

Bacterial causes include Mycoplasma pneumoniae, Salmonella, Campylobacter, and Mycobacterium tuberculosis.

Worldwide, ascariasis is a recognized cause of pancreatitis resulting from the migration of worms in and out of the duodenal papillae.

Metabolic (3%)

The most common metabolic condition associated with pancreatitis is diabetic ketoacidosis (DKA), which accounts for over half of these cases. Other important conditions include hypertriglyceridemia (serum triglycerides >1000 mg/dL), propionic academia, and hypercalcemia. Hypercalcemia can result from hyperparathyroidism. An aberrant rise in calcium is critical to the early phase of acute pancreatitis, since cytosolic calcium activates intra-acinar zymogens.

Hereditary (4%)

Hereditary pancreatitis is autosomal dominant condition with incomplete penetrance (about 80%) and is related to mutations in the cationic trypsinogen gene (PRSS1 gene mutations). Gain of function mutations in this gene cause premature activation of trypsinogen to trypsin. Most cases are of pediatric onset (under 19 years of age) and have an increased risk of pancreatic cancer.

Loss of function mutations in the serine protease inhibitor, Kazal type 1 (SPINK1), increase the risk of developing pancreatitis usually in the setting of another predisposing factor. Thus these mutations are gene modifiers.

Cystic fibrosis transmembrane regulator (CFTR gene mutations) can predispose patients to acute pancreatitis by causing abnormalities of ductal secretion. Classic CF (pancreatic insufficient) patients are not at-risk for pancreatitis. Heterozygous CFTR mutations (pancreatic sufficient) patients are at-risk for pancreatitis, both acute recurrent and chronic. There is wide phenotypic variability among these patients, and, with almost 1000 mutations, it is not entirely clear which variations confer the greatest risk.

Other clinical manifestations that might help with diagnosis and management

Recurrent acute pancreatitis - This is a clinical/phenotypic definition. There must be at least two distinct episodes of AP with complete resolution of symptoms and/or normalization of pancreatic enzyme levels between episodes. Recurrent AP may be an early stage of evolving chronic pancreatitis.

Chronic Pancreatitis - There are on-going consensus statements to define a classification system for chronic pancreatitis. Most describe a progressive inflammatory process with irreversible morphologic changes of the pancreatic parenchyma. Chronic abdominal pain (periodic or constant) is the main challenge for these patients. Exocrine, and rarely, endocrine dysfunction may develop due to destruction of the gland.

Pancreatitis due to cholelithiasis versus sludge - In adults, biliary obstruction is usually due to stones or tumors. In children, 30% of biliary cases are attributed to sludge (microlithiasis). In this setting, there is no clear indication for cholecystectomy in sludge-induced biliary pancreatitis unless the episodes become recurrent.

Autoimmune pancreatitis - This is a poorly defined and rare entity in pediatrics. Adult diagnostic criteria are newly evolving.

What complications might you expect from the disease or treatment of the disease?

Beyond the acute event, AP can lead to secondary multi-system organ dysfunction that persists even as biochemical and clinical resolution of AP occur. This includes ARDS, renal insufficiency, and other effects of cytokine upregulation.

Recurrent AP can also evolve into chronic pancreatitis, with early, intermediate and late complications. Early complications include recurrent bouts of apparent acute pancreatitis and pain. Intermediate complications include bile duct stricture, duodenal stricture, vascular stricture, portal hypertension, pseudocysts, pancreatic ascites, pancreatic fistula, and rarely, colonic stricture. Late complications involve pancreatic insufficiency or failure, including exocrine, endocrine or both.

Are additional laboratory studies available; even some that are not widely available?

  • Urine trypsinogen-activation peptide

    • Useful for determining prognosis

    • Urine spot measurement

    • High accuracy 24 hrs after symptom onset; validated for clinical use

    • Not commercially available

  • Procalcitonin, polymorphonuclear elastase, and interleukins 6 and 8

    • Inflammatory biomarkers

    • Higher levels associated with severe outcome

    • High degree of accuracy in early phase of disease

    • Not widely available

    • Peak early in course of disease

How can Pancreatitis be prevented?

The first episode of acute pancreatitis usually happens without warning. However, there are some important risk factors to be aware of, especially when counseling for prevention of recurrent episodes:

  1. Avoid medications that were associated with previous bouts of pancreatitis and other medications with known side-effects of pancreatitis

  2. Avoid heavy alcohol ingestion and smoking

  3. Genetic counseling, particularly in Hereditary Pancreatitis, since there is a high risk of pancreatic cancer

  4. No efficacy of empiric pancreatic enzyme therapy or antioxidants in preventing recurrence of AP

What is the evidence?

Bradley, EL. "A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992". Arch Surg. vol. 128. 1993. pp. 586-90.

(The classic paper for classification of acute pancreatitis, commonly referred to as "The Atlanta Criteria".)

Park, AJ, Latif, SU, Ahmad, MU, Bultron, G, Orabi, AI, Bhandari, V, Husain, SZ. "A comparison of presentation and management trends in acute pancreatitis between infants/toddlers and older children". J Pediatr Gastroenterol Nutr. vol. 51. 2010. pp. 167-70.

(Recent comparison of pediatric pancreatitis presentation and management.)

Bai, HX, Lowe, ME, Husain, SZ. "What have we learned about acute pancreatitis in children?". J Pediatr Gastroenterol Nutr. vol. 52. 2011.

(Comprehensive review on the current state of AP in children.)

Cornett, DD, Spier, BJ, Eggert, AA, Pfau, PR. "The Causes and Outcome of Acute Pancreatitis Associated with Serum Lipase >10,000 U/L". Dig Dis Sci. 2011.

Iqbal, CW, Baron, TH, Moir, CR, Ishitani, MB. "Post-ERCP pancreatitis in pediatric patients". J Pediatr Gastroenterol Nutr. vol. 49. 2009. pp. 430-4.

Spanier, BW, Bruno, MJ, Mathus-Vliegen, EM. "Enteral Nutrition and Acute Pancreatitis: A Review". Gastroenterol Res Pract. 2011.

Eatock, FC, Chong, P, Menezes, N, Murray, L, McKay, CJ, Carter, CR, Imrie, CW. "A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis". Am J Gastroenterol. vol. 100. 2005. pp. 432-9.

Wu, BU, Hwang, JQ, Gardner, TH, Repas, K, Delee, R, Yu, S, Smith, B, Banks, PA, Conwell, DL. "Lactated Ringer's Solution Reduces Systemic Inflammation Compared With Saline in Patients With Acute Pancreatitis". Clin Gastroenterol Hepatol. 2011.

Frossard, J-L, Steer, ML, Pastor, CM. "Acute pancreatitis". The Lancet. vol. 371. 2008. pp. 143-52.

Park, A, Husain, SZ. "Changing referral trends of acute pancreatitis in children: A 12-year single-center analysis". JPGN. 2009.

Wu, BU. "The prediction of mortality in acute pancreatitis: a large population-based study". Gut. vol. 57. 2008. pp. 1698-703.

Wu, BU. "Prognosis in acute pancreatitis". CMAJ. vol. 183. 2011. pp. 673-677.

Buchler, MW. "A proposal for a new clinical classification of chronic pancreatitis". BMC Gastroenterology. vol. 9. 2009. pp. 93.

Papachristou, GI. "Comparison of BISAP, Ranson, APACHE-II, and CTSI scores in predicting organ failure, complications and mortality in acute pancreatitis". Am J Gastroenterology. vol. 105. 2010. pp. 435-41.

Ongoing controversies regarding etiology, diagnosis, treatment

Enteral versus parenteral nutrition during AP - actual practice differs greatly from evidence in the literature.

Empiric antibiotics for moderate to severe pancreatic necrosis.

Pancreatic enzyme therapy and antioxidants.

Timing for genetic testing for hereditary pancreatitis in pediatrics - Not recommended unless AP evolves into recurrent or chronic pancreatitis. No current cancer survival benefit for screening for HP gene mutations at this time.

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