Pancreatitis in Children

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Pancreatitis in Children

• J. Antonio Quiros MD FAAP
• Director, Pediatric Gastroenterology
• California Pacific Medical Center
• Associate Clinical Professor
• University of California Davis

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Objectives

• Manage acute pancreatitis
• Review anatomic considerations and
  physiopathology of pancreatic disease
• Genetics of pancreatic disease
• Review diagnostic and therapeutic modalities
  available for management in these patients.

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• YOUR PANCREAS IS LIKE YOUR MOTHER IN LAW

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What is pancreatitis

• It is a primary necro-inflammatory process
  derived from auto-necrosis of pancreatic tissue
  due to abnormal activation of proteolytic and
  lipolytic enzymes within the pancreatic parenchyma

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Epidemiology of pancreatic disease

• Depends on who you ask?
• Recent review shows that incidence varies with
  levels of alcohol consumption
• Incidence of 1st attack 17.5 45.3 / 100,000
  (Europe)
• There has been a recent increase in the frequency
  of admissions for acute pancreatitis across the
  US.
• Hospitalization rate in the USA 0.7 per 1000
  hospital admissions (2001)

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Pancreatic disease progression

• Overall, European also data shows increase in
  rates of acute pancreatitis.
• Idiopathic pancreatitis comprise about 30 in
  large series.
• Recent studies show that rate of recurrent
  pancreatitis after 1st case of acute pancreatitis
  has declined to 4.2-14.4.
• Mortality rates with recurrent pancreatitis vary
  from lt1 - 3.2.

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Acute pancreatitis across the USA (N 210,000
admissions)

Adapted from Fagenholz et al. Ann Epidemiol 2007
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Pancreatitis in the young

• Alcohol plays less of a role.
• Causative factors include
• Biliary diseases
• Anatomic anomalies
• Metabolic disorders
• Trauma
• Cystic fibrosis
• Inflammatory bowel diseases
• Hereditary pancreatitis

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Definition

• Chronic pancreatitis a relapsing or continuing
  inflammatory disease of the pancreas
  characterized by irreversible morphologic changes
  leading to pain, pancreatic exocrine
  insufficiency, glucose intolerance (Diabetes
  Mellitus) or all of the above.

Sarles H, et al. Scan J Gastroenterol 1989
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• Biliary diseases
• Gallstones
• Sclerosing cholangits
• Choledocal cysts
• Carolis disease
• Anatomic anomalies
• Metabolic disorders
• Trauma
• Cystic fibrosis
• Inflammatory bowel diseases
• Hereditary pancreatitis

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Epidemiology of GS pancreatitis

• Prevalence of GS varies with geography and age.
• Increasing incidence in western countries noted
  to be increasing in the last 3 decades.
• 4 major types of GS
• Mixed cholesterol
• Pure cholesterol
• Black pigment
• Brown pigment
• 60 of cases of acute non-alcoholic pancreatitis
  episodes are felt to be biliary in origin.
• Known gallstones are cause of recurrent
  pancreatitis in 50-90 of un-operated cases

Kelly D. Diseases of the Liver and Biliary tree
2nd Ed. (textbook) Madhukar K, et al.
Gastrointestinal Endosc 2002
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Gallstone pancreatitis
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Choledocal cysts
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• Choledochal cysts are congenital dilatations of
  the intrahepatic and extrahepatic biliary tree.
• The Todani modification of the Alonso-Lej
  classification of choledochal cysts is the system
  most often used for diffentiating and planning
  management of these cysts.
• Clinical presentation pain, jaundice, palpable
  tumor.

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Carolis disease

• Involves congenital cystic dilatation of the
  intrahepatic biliary radicles of the liver.
• Autosomal-recessive inheritance pattern. It may
  be associated with autosomal-recessive polycystic
  kidney disease.
• Insufficient resorption of the primitive ductal
  plates leads to the formation of multiple
  primitive bile ducts surrounding the central
  portal vein.

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Primary Sclerosing Cholangitis

• 3 / 100,000 world wide prevalence
• 70 men, 75 have inflammatory bowel disease
  (mainly ulcerative colitis).
• About half will have anti neutrophil cytoplasmic
  antibodies and less anti-smooth mm or
  anti-nuclear antibodies.
• Median time from diagnosis to liver
  transplantation is 10 years.
• Diagnosis usually made by imaging or ERCP

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• Biliary diseases
• Anatomic anomalies
• Pancreas divisum
• Choledocal cyst
• Sphincter of Odi dysfunction
• Ectopic pancreas
• Metabolic disorders
• Trauma
• Cystic fibrosis
• Inflammatory bowel diseases
• Hereditary pancreatitis

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Pancreas development
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Pancreas divisum

• 30 of people have patent accessory duct.
• PD affects 10 of normal individuals.
• PD seen in 20-30 of cases of recurrent
  pancreatitis undergoing ERCP.
• CF mutations thought to play a role (22).
• Heterozygotes for a known CFTR mutation,
  pancreatitis and a PD have impaired nasal
  transepithelial potential difference testing.

Gelrud A, et al. Am j Gastroenterol 2004
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Pancreas divisum anatomy
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SOD dysfunction in children

• Limited available literature.
• SOD seen in 6/11 children evaluated. (age range 5
  -16y).
• 3 recurrent pancreatitis, 3 post cholecystectomy
  pain.
• Mean follow-up 583 days.
• 4/6 asymptomatic, 1 partial relief and 1
  recurrent symptoms.

Varadarajulu S, et al. J Pediatr Gastroenterol
Nutr 2006
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Sphincter of Oddi dysfunction

• 128 ERCP studies performed in Venezuelan
  children.
• 64 cases of recurrent pancreatitis
• 28 (18/64) had anomalous pancreatobiliary
  unions.
• 9/18 underwent manometry during ERCP and 100 of
  these patients had sphincter of Oddi dysfunction.

Guelrud M, et al. Gastrointest Endosc 1999
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Anomalous pancreato-biliary union
From Guelrud M, et al. Gastrointest Endosc 1999
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• Biliary diseases
• Anatomic anomalies
• Metabolic disorders
• Alpha1-antitrypsin deficiency
• Spink 1 mutations
• Drug induced pancreatitis
• Diabetes mellitus
• Trauma
• Cystic fibrosis
• Inflammatory bowel diseases
• Hereditary pancreatitis

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• Biliary diseases
• Anatomic anomalies
• Metabolic disorders
• Trauma
• Cystic fibrosis
• Inflammatory bowel diseases
• Hereditary pancreatitis

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• Biliary diseases
• Anatomic anomalies
• Metabolic disorders
• Trauma
• Cystic fibrosis
• Inflammatory bowel diseases
• Hereditary pancreatitis

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• Biliary diseases
• Anatomic anomalies
• Metabolic disorders
• Trauma
• Cystic fibrosis
• Inflammatory bowel diseases
• Celiac disease
• Crohns disease
• Hereditary pancreatitis

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Celiac disease and pancreatitis

• Postulated mechanisms include
• Impaired CCK production leading to bile stasis.
• Duodenal inflammation leading to papillary
  dysfunction.
• Case series 9/12 new onset celiac patients
  presented with pancreatitis.
• 100 (12/12) had papillary stenosis and
  periampullary inflammation.

Patel RS. Et al. Gastrointest Endosc 1999.
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Pancreatitis and Crohns disease

• Duodenal disease involvement and drug therapy
  account for gt30 of cases.
• Gallstones 21
• Alcohol 15
• Post-ERCP 10
• Post-operative complication 12
• Idiopathic 7
• Other medications 4

Source Mayo Clinic. Moolinstong P, et al.
Inflamm Bowel Dis 2005
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Pancreatitis and Crohns disease

• Duodenal disease involvement and drug therapy
  account for gt30 of cases.
• Gallstones 21
• Alcohol 15
• Post-ERCP 10
• Post-operative complication 12
• Idiopathic 7
• Other medications 4
• 21 developed recurrent disease

Source Mayo Clinic. Moolinstong P, et al.
Inlfamm Bowel Dis 2005
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• Biliary diseases
• Anatomic anomalies
• Metabolic disorders
• Trauma
• Cystic fibrosis
• Inflammatory bowel diseases
• Hereditary pancreatitis

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Role for genetic testing

• In most cases you can explain acute pancreatitis
  by looking at drug exposure, alcohol or biliary
  disease.
• Unexplained recurrent pancreatitis warrants
  further investigation.
• The age at symptom onset and family history might
  offer clues regarding the likelihood a
  susceptibility gene mutation.
• The cationic trypsinogen (PRSS1), serine protease
  inhibitor (SPINK1) and Cystic Fibrosis
  transmembrane regulator gene (CFTR) are the only
  known susceptibility genes worth testing for.

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Familiar pancreatitis

• Gain of function mutation that leads to decreased
  enzyme autolysis or premature inactivation.
• 20 mutations reported.
• For patients with R122H and N29I mutations,
  60-80 will develop pancreatitis. 30-40 will
  develop chronic pancreatitis.
• 40 of individuals with CP will develop
  pancreatic cancer.

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SPINK 1 and PRSS1

• Serine protease inhibitor kasal type 1
• Serine antiprotease naturally occurring in man,
  discovered by Kasal in 1948.
• Loss of function mutations in the SPINK1 gene
  noted in about 20 of children with CP in
  Germany.
• 15-40 of patients with idiopathic pancreatitis
  had SPINK1 mutations.
• Co-existence of SPINK1 and a gain of function
  lesion like PRSS1 lead to worse phenotype.

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Tropical Calcific Chronic Pancreatitis

• Idiopathic CP unique to tropic countries.
• Patients usually present young, with nutritional
  deficiencies and develop insulin-dependent
  diabetes along with pancreatic exocrine
  insufficiency.
• Environmental and dietary factors have been
  suggested.
• In cohort of unrelated patients (n66), 44 of
  SPINK1 mutations identified.
• NO PRSS1 identified.
• Severity of pancreatitis didnt differ between
  these homozygous and heterozygous for SPINK1
  mutations.

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Role for Genetic testing
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Mortality In Acute Pancreatitis

• Overall 6
• Interstitial Pancreatitis 3
• Necrotizing Pancreatitis 17
• Infected Necrosis 30
• Single Organ Failure 3
• Multisystem Organ Failure 47
• No Organ Failure 0

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Correction of Early Organ Failure Prevents
Mortality
At 48 hours
Johnson and Abu-Hilal. Gut 2004 53 1340-1344
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RISING HCT, FLUID SHIFTS AND PANCREATITIS
Extravasation of Fluid to Peritoneum Decreased
Intravascular Volume
HCT RISES
Decreased Pancreatic Perfusion
Increased Third Space Loss Increased TNF,
Trypsin, PLA2, Elastase, etc.
Increased Pancreatic Necrosis
HALT THE CYCLE WITH FLUID !!!
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How Much Fluid Should We Give?

• Titrate to HCT

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When should Early ERCP be applied?

• Severe acute pancreatitis Not Mild
  Pancreatitis.
• Neoptolemos et al. Lancet 1988 2979-983
• Benefits Patients with Biliary Sepsis
• Perform Urgently (lt24 hours may be better then 72
  hours)
• Fan et al. NEJM 1993 328228-232.
• Unclear benefit in patients without evidence of
  cholangitis despite severe acute pancreatitis.
• Folsch et al. NEJM 1997336237-242

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The Role of Antibiotics In Patients With Severe
Acute Pancreatitis

• Early studies with Ampicillin showed no benefit.
• Beger and Buchler, Ulm Penetration Studies
  Imipenem, Metronisazole, Quinolones
• (Gastroenterology 1986 91 433-438).
• Pederzoli and colleagues show imipenem effective
  in decreasing Morbidity within 72 hours.
• (Surg Gynecol Obset 1993 176 480-483)

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Early Antibiotic Treatment for Severe Acute
Necrotizing Pancreatitis Randomized, Double
Blind, Placebo-Controlled Study

• Double blinded, placebo controlled
• 100 patients enrolled from 32 Centers
• Meropenem vs Placebo
• Problems of other studies addressed!
• No Statistically Significant Benefit in
  Preventing Infection, Sepsis, Mortality.

Dellinger, et al. Surgery 2007
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Role of Antibiotics In Severe Acute
Pancreatitis

• No Longer Controversial
• Does Not Prevent Sterile Necrosis from Becoming
  Infected Necrosis.
• Does Not Decrease Incidence of Sepsis
• Does Not Decrease Morbidity or Mortality In
  Patients With Sterile Necrosis or Severe Disease
  in the Absence of Obvious Infection

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Practice GuidelinesBanks and FreemanAJG 2006
101 2379

• prophylactic antibiotics are not recommended in
  necrotizing pancreatitis

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Abstinence of feeding allows the pancreas to
rest and thus heal

• William Osler
• Principles and Practice of Medicine
• 1905

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Rethinking Enteral Nutrition

• More physiologic
• Maintains gut integrity
• Decreases intestinal permeability
• Maintain less pathogenic intestinal flora
• If nasojejunal feeding used, gastric phase of
  pancreatic stimulation not effected
• Thus, the pancreas remains at rest

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Enteral Nutrition (EN) vs Parenteral Nutrition
(PN)

• 9 prospective randomized trials EN vs PN
• 435 Patients
• Initiated 1-9 days
• Nasojejunal (typically elemental formula)

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Enteral Nutition (EN) vs Parenteral Nutrition
(PN)

• Less hyperglycemia
• Fewer septic complications
• Fewer days in hospital
• Decreased costs
• Decrease in morbidity
• Decrease mortality

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Treatment of Sterile Necrosis

• Organ failure seen in almost 50 patients
• Sterile necrosis is managed medically during the
  first 3-4 weeks
• After this time, if pain persists or prevents
  oral intake, surgical debridement should be
  considered
• Be cautious about early endoscopic, radiologic or
  surgical intervention

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Treatment of Infected Necrosis

• Begin pancreatic necrosis penetrating antibiotics
• Surgical debridement is treatment of choice
• If patients are not stable, early surgical
  intervention
• If stabledelay and consider alternative
  minimally invasive approaches

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Acute Pancreatitis Summary

• Avoid Labeling Patients Mild during the first
  48 hours
• Beware of Organ Failure Maximize Supportive
  Care ICU
• Prevent Necrosis Aggressive Hydration
• Remove Retained Stones Cholangitis? ERCP
• Prevent Infection of Necrosis (if present)
• Do not use prophylactic antibiotics
• Avoid TPN
• Provide nutrition with enteric feeding
• Sterile Necrosis conservative approach
  supportive gt4 weeks, if
  persistent pain, unable to eat, debridement.
  If no symptoms, feed and discharge f/u?
• Infected Necrosis begin antibiotics, attempt
  delay in debridement ? Timing and ?
  Antibiotics

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Role for Genetic testing
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When to do genetic testing

• Consensus recommendations.
• Adults can be tested at any time if RP or CP
  present.
• Children under 16 years of age
• Acute pancreatitis requiring hospitalization.
• gt 2 episodes of AP with unknown etiology
• Child with documented pancreatitis and family
  history of known genetic predisposition
• Child with recurrent abdominal pain and suspicion
  of familiar or hereditary pancreatitis.
• CP where hereditary pancreatitis is a distinct
  possibility.

Ellis I, et al. Pancreatology 2001
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Treatment options

• Endoscopy
• Upper endoscopy with biopsies
• EUS
• ERCP with focused endotherapy
• Surgery
• Transduodenal papilotomy
• Pancreatic resection with islet cell
  transplantation
• Open/laparoscopic biliary exploration
• Interventional Radiology

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Role of Endoscopic Ultrasound (EUS)

• ERCP is not recommended as a diagnostic tool.
• EUS offers advantages in respect of high quality
  of imaging and avoidance of ionizing radiation.
• Experience in children has found that EUS
  pre-ERCP affects management in 93 of children
  with pancreatobiliary disease.
• It offered a diagnosis in 60 and precluded ERCP
  evaluation in 50 of cases examined.

Varadajulu S, et al. Gastrointest Endosc 2005
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Questions?