Overview
Definition:
Recurrent pancreatitis in children is defined as two or more distinct episodes of acute pancreatitis, or a persistent state of chronic pancreatitis, in the absence of a clear acquired cause such as trauma, infection, or biliary disease
Genetic factors play a significant role in a substantial proportion of these cases, often leading to hereditary pancreatitis syndromes.
Epidemiology:
The incidence of recurrent acute pancreatitis in children is estimated to be 0.3-1.3 per 100,000 children per year
A significant percentage, ranging from 10% to 50% depending on the study population and diagnostic criteria, have an identifiable genetic predisposition
Familial clustering is common, underscoring the hereditary component.
Clinical Significance:
Identifying a genetic cause is crucial for several reasons: it allows for accurate diagnosis and classification of pancreatitis subtypes, facilitates early detection and management of affected family members, informs prognosis, guides genetic counseling, and may influence long-term management strategies to prevent further episodes and complications like chronic pancreatitis or pancreatic cancer.
Clinical Presentation
Symptoms:
Epigastric pain, often severe and radiating to the back
Nausea and vomiting
Fever
Abdominal distension
Jaundice may be present in cases of common bile duct involvement
Older children may describe the pain as constant and worsening
Younger children may present with irritability and poor feeding.
Signs:
Tenderness in the epigastrium
Guarding and rigidity of the abdominal muscles
Tachycardia and hypotension can indicate severity
Fever
Signs of dehydration
Cullen's sign or Grey Turner's sign are rare but indicative of severe hemorrhagic pancreatitis.
Diagnostic Criteria:
Diagnosis of acute pancreatitis relies on the presence of at least two of the following three features: characteristic abdominal pain
Serum amylase or lipase levels at least three times the upper limit of normal
Characteristic findings of acute pancreatitis on cross-sectional imaging (CT or MRI)
Recurrence is defined by multiple such episodes or development of chronic pancreatitis features.
Diagnostic Approach
History Taking:
Detailed family history of pancreatitis or pancreatic diseases is paramount
History of recent trauma, infections (viral, bacterial), medications (e.g., valproate, azathioprine), metabolic disorders, and biliary tract abnormalities
Nutritional history and presence of congenital anomalies
Characterize the pain: onset, duration, severity, radiation, aggravating, and relieving factors.
Physical Examination:
Complete abdominal examination focusing on tenderness, distension, guarding, and rebound tenderness
Assess hydration status and vital signs
Examine for signs of jaundice or signs of retroperitoneal hemorrhage
Assess for any dysmorphic features or stigmata of underlying systemic diseases.
Investigations:
Serum amylase and lipase: elevated levels confirm pancreatic inflammation, with lipase being more specific and having a longer half-life
Complete blood count: leukocytosis may be present
Liver function tests: assess for cholestasis
Electrolytes, calcium, and triglycerides: hypocalcemia and hypertriglyceridemia can be causes or consequences
Imaging: Ultrasound to rule out gallstones
Contrast-enhanced CT scan is the gold standard for diagnosing acute pancreatitis, assessing severity, and identifying complications
MRI/MRCP is useful for evaluating the pancreatic ductal system and common bile duct, especially in recurrent cases or suspected chronic pancreatitis.
Differential Diagnosis:
Other causes of acute abdominal pain in children: appendicitis
Cholecystitis
Peptic ulcer disease
Mesenteric adenitis
Bowel obstruction
Diabetic ketoacidosis
Hemolytic uremic syndrome
Intussusception
Gastoenteritis
Vasculitis
Pancreatic pseudocyst
Pancreatic abscess.
Genetic Testing And Genes
Rationale For Testing:
Genetic testing is indicated in children with idiopathic recurrent acute pancreatitis, especially if there is a family history of pancreatitis or if pancreatitis occurs at a young age
It helps identify specific genetic syndromes and guides management and counseling.
Prss1 Mutations:
Mutations in the *PRSS1* gene, encoding cationic trypsinogen, are the most common cause of hereditary pancreatitis (HP)
These mutations lead to auto-activation of trypsinogen, causing premature and auto-digestion of the pancreas
Autosomal dominant inheritance with high penetrance
Examples: R122H, N29I
Individuals with *PRSS1* mutations have a significantly increased risk of developing chronic pancreatitis and pancreatic cancer.
Spink1 Mutations:
Mutations in the *SPINK1* gene (serine protease inhibitor Kazal type 1) are another significant cause, often associated with autosomal recessive or recessive with modifier inheritance patterns
SPINK1 is a pancreatic secretory trypsin inhibitor that protects the pancreas from premature trypsin activation
Heterozygous carriers are generally asymptomatic, but homozygous or compound heterozygous mutations can lead to pancreatitis
This is often seen in recurrent acute pancreatitis of unknown etiology and in tropical calcific pancreatitis.
Cftr Mutations:
Mutations in the *CFTR* (cystic fibrosis transmembrane conductance regulator) gene are primarily associated with cystic fibrosis (CF), but even in individuals without classic CF phenotype, certain *CFTR* mutations can predispose to pancreatic dysfunction, including pancreatitis
Pancreatitis in CF patients can be acute, chronic, or present as DIOS (Distal Intestinal Obstruction Syndrome)
Testing is considered in children with recurrent pancreatitis, especially if there are other subtle CF symptoms like recurrent sinopulmonary infections, male infertility, or reduced sweat chloride values
Pancreatic involvement in CF can be diverse, ranging from pancreatic insufficiency to pancreatitis.
Other Genes:
While *PRSS1*, *SPINK1*, and *CFTR* are the most commonly tested, other genes associated with pancreatitis include *CTRC*, *CASR*, *CCK-BR*, *LIPE*, and *CPA1*
Testing for these may be considered in complex cases or if initial testing is negative.
Management
Initial Management:
Aggressive fluid resuscitation with intravenous crystalloids (e.g., Lactated Ringer's solution) at 5-10 mL/kg/hour
Pain control with intravenous analgesics (e.g., morphine, hydromorphone)
Nasogastric decompression if significant vomiting or ileus
Nutritional support: Initially NPO (nil per os), followed by jejunal feeding distal to the ligament of Treitz once pain and nausea subside
Avoid oral intake until markers normalize and pain resolves.
Medical Management:
Pain management is critical
Opioids are typically used
Antiemetics for nausea and vomiting
Close monitoring of fluid balance and electrolytes
Antibiotics are reserved for documented infection or severe pancreatitis with signs of organ failure.
Surgical Management:
Surgery is generally not the primary treatment for acute pancreatitis
Indications include complications such as infected necrosis, pseudocyst requiring drainage, or biliary obstruction
ERCP (Endoscopic Retrograde Cholangiopancreatography) may be indicated for removal of bile duct stones causing pancreatitis
Pancreatic necrosectomy is reserved for severe infected necrosis.
Supportive Care:
Close monitoring of vital signs, urine output, and abdominal examination
Serial assessment of laboratory markers (amylase, lipase, CRP)
Management of complications like pseudocysts, abscesses, or organ failure
Genetic counseling for affected families.
Complications
Early Complications:
Systemic inflammatory response syndrome (SIRS)
Organ failure (respiratory, renal, cardiovascular)
Acute peripancreatic fluid collections
Pancreatic necrosis (necrotizing pancreatitis)
Hemorrhagic pancreatitis.
Late Complications:
Chronic pancreatitis leading to exocrine and endocrine insufficiency (diabetes mellitus)
Pancreatic pseudocysts
Pancreatic fistulas
Malnutrition
Increased risk of pancreatic cancer in *PRSS1* carriers.
Prevention Strategies:
For children with confirmed genetic mutations, preventing further episodes is key
This involves avoiding known triggers such as alcohol, certain medications, and high-triglyceride states
Close monitoring for signs of chronic pancreatitis and diabetes
Prophylactic screening for pancreatic cancer in *PRSS1* carriers may be considered in adulthood based on family history and genetic counseling.
Prognosis
Factors Affecting Prognosis:
Severity of initial attack
Presence of complications
Underlying genetic mutation (*PRSS1* mutations are associated with higher risk of chronic pancreatitis and cancer)
Timeliness and adequacy of supportive care
Age at onset.
Outcomes:
Most children with acute pancreatitis recover fully
However, recurrent episodes increase the risk of chronic pancreatitis, which can lead to significant long-term morbidity
For individuals with *PRSS1* mutations, the prognosis includes a lifelong increased risk of pancreatic malignancy.
Follow Up:
Children with recurrent pancreatitis, especially those with identified genetic mutations, require lifelong follow-up
This includes regular clinical assessments, monitoring for endocrine (diabetes) and exocrine (malabsorption) dysfunction, and imaging to detect structural changes
Genetic counseling for patients and families is essential.
Key Points
Exam Focus:
Understand the role of PRSS1, SPINK1, and CFTR genes in pediatric recurrent pancreatitis
Differentiate the inheritance patterns and clinical implications of mutations in these genes
Recognize when to suspect hereditary pancreatitis and the indications for genetic testing.
Clinical Pearls:
A strong family history of pancreatitis is a major red flag for hereditary pancreatitis
Always consider CFTR mutations even in the absence of classic CF symptoms when evaluating pediatric recurrent pancreatitis
Genetic counseling is an integral part of managing children with hereditary pancreatitis.
Common Mistakes:
Attributing all recurrent pancreatitis to gallstones or trauma and neglecting genetic causes, especially in young children
Underestimating the significance of CFTR mutations in non-classic CF patients presenting with pancreatitis
Failing to involve genetic counselors early in the management of suspected hereditary pancreatitis.