FRACP LECTURE PROGRAMFRACP LECTURE PROGRAM

PANCREATIC DISEASES IN CHILDREN PANCREATIC DISEASES IN CHILDREN

CHRONIC DIARRHOEACHRONIC DIARRHOEA

PRESENTATION PART TWOPRESENTATION PART TWO

CYSTIC FIBROSISCYSTIC FIBROSIS

!! Most common lethal genetic defect in the white Most common lethal genetic defect in the white population (AR, CFTR,chromosome7, 1200 mutations)population (AR, CFTR,chromosome7, 1200 mutations)

!! Molecular defects result in epithelial cell electrolyte Molecular defects result in epithelial cell electrolyte transport transport

!! Overall clinical picture depends on the nature of the Overall clinical picture depends on the nature of the combined combined CFTR CFTR mutations, modifier genes and mutations, modifier genes and environmental factorsenvironmental factors

!! Mutations affecting synthesis, maturation and activation Mutations affecting synthesis, maturation and activation lead to more severe phenotypes, whilst other deficits lead to more severe phenotypes, whilst other deficits cause less severe diseasecause less severe disease

Pancreatic Enzyme ReplacementPancreatic Enzyme Replacement

!! Enteric coated Enteric coated microspheresmicrospheres protects the protects the enzymes from gastric acidenzymes from gastric acid

!! Taken before mealsTaken before meals

!! Can increase bioCan increase bio--availability by decreasing availability by decreasing gastric acid and increasing duodenal gastric acid and increasing duodenal bicarbonate secretion; including H2 bicarbonate secretion; including H2 antagonist, PPI and antagonist, PPI and MisoprostilMisoprostil

Colonic StricturesColonic Strictures

!! Results from high doses of enzymesResults from high doses of enzymes

!! Ascending colon causing intestinal obstruction Ascending colon causing intestinal obstruction and appears pathologically as postand appears pathologically as post--ischaemic ischaemic ulceration followed by mucosal and subulceration followed by mucosal and sub--mucosal mucosal fibrosisfibrosis

!! Nearly all children <12 yrs, had prior Nearly all children <12 yrs, had prior gastrointestinal surgery or DIOSgastrointestinal surgery or DIOS

!! Limit dose to <10,000units lipase/KgLimit dose to <10,000units lipase/Kg

Meconium IleusMeconium Ileus

!! 1010--20% of infants born with CF and implies PI20% of infants born with CF and implies PI

!! Rarely occurs in children without CF but has been Rarely occurs in children without CF but has been reported in children with stenosis of the reported in children with stenosis of the pancreatic duct and partial pancreatic aplasiapancreatic duct and partial pancreatic aplasia

!! Presents as an intestinal obstruction within the Presents as an intestinal obstruction within the first 48 hrsfirst 48 hrs

!! Sweat tests or gene testing should be conducted Sweat tests or gene testing should be conducted an all children with an all children with MecMec ileus with jejunal ileus with jejunal orilealorilealatresia or with volvulusatresia or with volvulus

Meconium Ileus TreatmentMeconium Ileus Treatment

!! Bowel washouts: low mortality and 90% Bowel washouts: low mortality and 90% longlong--term survivalterm survival

!! Various irrigation solutions have been Various irrigation solutions have been used including Nused including N--acetylcysteine, acetylcysteine, TweenTween 80, 80, gastrografingastrografin enemas, however will need enemas, however will need careful fluid monitoringcareful fluid monitoring

DIOSDIOS

!! Incidence 3Incidence 3--10%10%

!! Presents as abdominal pain, palpable mass Presents as abdominal pain, palpable mass in the caecum or complete bowel in the caecum or complete bowel obstructionobstruction

!! Remember Remember DDxDDx of appendicitis (1.5% in CF) of appendicitis (1.5% in CF) and intussusception (1%)and intussusception (1%)

Liver DiseaseLiver Disease

!! Liver involvement varies from 15Liver involvement varies from 15--25%25%

!! Palpable liver (11%), elevated LFT (2.4%), abnormal Palpable liver (11%), elevated LFT (2.4%), abnormal albumin levels (7.4%), cirrhosis and PHT (2.5%), fatty liver albumin levels (7.4%), cirrhosis and PHT (2.5%), fatty liver (7%), neonatal liver disease(6%) and palpable spleen (7%), neonatal liver disease(6%) and palpable spleen (2.2%)(2.2%)

!! Fatty liver, focal biliary cirrhosis, multiFatty liver, focal biliary cirrhosis, multi--lobular biliary lobular biliary cirrhosis and CBD obstruction cirrhosis and CBD obstruction

!! Risk factors: neonatal disease, PI, meconium ileus and Risk factors: neonatal disease, PI, meconium ileus and possibly human leukocyte antigen classpossibly human leukocyte antigen class

Clinical Features of CFLDClinical Features of CFLD

!! Patients with hepatomegaly, abnormal Patients with hepatomegaly, abnormal LFTsLFTs and and abdominal pain (even if not RUQ) should undergo abdominal pain (even if not RUQ) should undergo evaluationevaluation

!! Often signs are noted only on clinical Often signs are noted only on clinical examination as liver failure examination as liver failure per se per se is unusualis unusual

!! Assessment includes exclusion of other causes Assessment includes exclusion of other causes of liver disease, checking synthetic function and of liver disease, checking synthetic function and US ; US ; scintigraphicscintigraphic studies, ERCP and liver biopsy studies, ERCP and liver biopsy are also performed according to clinical are also performed according to clinical indications indications

Treatment of CFLDTreatment of CFLD

!! UrsodeoxycholicUrsodeoxycholic acidacid

!! Nutritional support: macro and Nutritional support: macro and micronutrients (Fat soluble vitamins and micronutrients (Fat soluble vitamins and Iron)Iron)

!! GI bleeding and Liver failure would be GI bleeding and Liver failure would be treated using a standard approachtreated using a standard approach

Nutrition in CFNutrition in CF

!! Independent indicator of survivalIndependent indicator of survival

!! Important to assess both macro and Important to assess both macro and micronutrient requirementsmicronutrient requirements

!! Guidelines have been set down “Consensus Guidelines have been set down “Consensus report on Nutrition for Pediatric Patients report on Nutrition for Pediatric Patients with CF” with CF” BorowitzBorowitz D, Baker RD and Stallings D, Baker RD and Stallings V. JPGN 2002;35(3):246V. JPGN 2002;35(3):246--259 259

Acute PancreatitisAcute Pancreatitis

!! Incidence Incidence is thought to be increasing based on is thought to be increasing based on personal experience from many GI units world personal experience from many GI units world wide and it has been suggested by some that this wide and it has been suggested by some that this represents a real increase rather then represents a real increase rather then heightened clinical awarenessheightened clinical awareness

!! Diagnosis Diagnosis is based on 2is based on 2--3X elevation of 3X elevation of pancreatic enzymes associated with clinical pancreatic enzymes associated with clinical symptoms and/or radiological evidence of symptoms and/or radiological evidence of pancreatic inflammation pancreatic inflammation

Acute pancreatitis: AetiologyAcute pancreatitis: Aetiology

!! TraumaTrauma, usually blunt and accounts for 10, usually blunt and accounts for 10--30% of affected 30% of affected childrenchildren

!! DrugsDrugs: 10: 10--20% of cases with Azathioprine, Valproic acid 20% of cases with Azathioprine, Valproic acid and Land L--AspariginaseAspariginase being the most common culpritsbeing the most common culprits

!! InfectionInfection: Usually viral including Mumps, Enterovirus, EBV, : Usually viral including Mumps, Enterovirus, EBV, Echo and influenza A. Also bacterial and MycoplasmaEcho and influenza A. Also bacterial and Mycoplasma

!! Biliary tract diseaseBiliary tract disease

!! MetabolicMetabolic: CF, MMA, PCM: CF, MMA, PCM

!! FamilialFamilial

!! MultiMulti--system disease: system disease: HSP, HUS, SLE, Perforated DUHSP, HUS, SLE, Perforated DU

InvestigationsInvestigations

!! Lipase levelsLipase levels

!! Abdominal USAbdominal US

!! Biochemistry including electrolytes, calcium, Biochemistry including electrolytes, calcium, magnesium, phosphate, blood glucose and lipid magnesium, phosphate, blood glucose and lipid profileprofile

!! Careful drug history, including nonCareful drug history, including non--prescribed prescribed medicationsmedications

!! Viral studies if indicatedViral studies if indicated

TreatmentTreatment

!! SymptomaticSymptomatic

!! NasojejunalNasojejunal vsvs TPNTPN: Several controlled studies support : Several controlled studies support the use of the former, as it results in less complications, the use of the former, as it results in less complications, disease severity is decreased by NJ feeds and it is 4X disease severity is decreased by NJ feeds and it is 4X cheapercheaper

!! Decrease of oxidative stress: Decrease of oxidative stress: small trials of utilising a small trials of utilising a mixture of Selenium, Betamixture of Selenium, Beta-- carotene,Vitamin C, Vitamin E carotene,Vitamin C, Vitamin E and Methionine may decrease pain scores and length of and Methionine may decrease pain scores and length of admission in children with relapsing pancreatitisadmission in children with relapsing pancreatitis

Complications of Acute PancreatitisComplications of Acute Pancreatitis

!! DeathDeath: very uncommon and usually only following : very uncommon and usually only following haemorraghichaemorraghic pancreatitis (13% of all patients; pancreatitis (13% of all patients; DxDxsuggested by severe pain, peritoneal signs protracted suggested by severe pain, peritoneal signs protracted vomiting and circulatory compromise)vomiting and circulatory compromise)

!! PseudocystPseudocyst: 15% and symptoms include vomiting, fever, : 15% and symptoms include vomiting, fever, mass and elevated pancreatic enzymesmass and elevated pancreatic enzymes

!! Pancreatic Abscess: Pancreatic Abscess: unknown frequency in children but unknown frequency in children but should be considered if the patient has a fever and should be considered if the patient has a fever and prolonged clinical courseprolonged clinical course

!! Disseminated fat necrosis: Disseminated fat necrosis: SC nodules, SC nodules, polyartheritispolyartheritis, , fever, eosinophilia, soft tissue swelling and bone painfever, eosinophilia, soft tissue swelling and bone pain

Gene Mutations Associated with Acute Gene Mutations Associated with Acute and Chronic Pancreatitisand Chronic Pancreatitis

!! Gene mutations in Gene mutations in CFTR, CFTR, Pancreatic secretory trypsin Pancreatic secretory trypsin inhibitor (inhibitor (PSTIPSTI), and cationic trypsinogen), and cationic trypsinogen are all are all associated with both acute and chronic pancreatitisassociated with both acute and chronic pancreatitis

!! Hereditary pancreatitisHereditary pancreatitis is usually recognised as an AD is usually recognised as an AD disorder caused by a gene defect in all members of the disorder caused by a gene defect in all members of the family affected by pancreatitisfamily affected by pancreatitis

!! Experience from gene testing reveals that family history Experience from gene testing reveals that family history alone is not an accurate predictor of detecting or alone is not an accurate predictor of detecting or excluding gene mutations that predispose a person to excluding gene mutations that predispose a person to pancreatitispancreatitis

Cationic Trypsinogen Gene (CTG) Cationic Trypsinogen Gene (CTG) MutationsMutations

!! Trypsinogen activation within the pancreas Trypsinogen activation within the pancreas results in autodigestion and pancreatitisresults in autodigestion and pancreatitis

!! Abnormalities in CTG results in enhanced Abnormalities in CTG results in enhanced activity of trypsinogen and or prevents activity of trypsinogen and or prevents inactivation of trypsin by SPINK 1, a 56 AA inactivation of trypsin by SPINK 1, a 56 AA peptide that inhibits trypsin by peptide that inhibits trypsin by physiologically blocking its active sitephysiologically blocking its active site

CFTRCFTR abnormalitiesabnormalities

!! In 1998 a significant association between In 1998 a significant association between patients with idiopathic pancreatitis and various patients with idiopathic pancreatitis and various CFTR mutations was reportedCFTR mutations was reported

!! It is thought that these patients are It is thought that these patients are compound heterozygotes with one mild and compound heterozygotes with one mild and a severe mutation and may be at risk of a severe mutation and may be at risk of developing pancreatitis, sinusitis and developing pancreatitis, sinusitis and infertility (CBAVD)infertility (CBAVD)

Chronic PancreatitisChronic Pancreatitis

!! Recurring or persistent abdominal pain, Recurring or persistent abdominal pain, development of both exocrine and development of both exocrine and endocrine insufficiencyendocrine insufficiency

!! Increased incidence of pancreatic cancerIncreased incidence of pancreatic cancer

!! Treatment is supportive and includes Mx of Treatment is supportive and includes Mx of chronic pain, malabsorption, nutritional chronic pain, malabsorption, nutritional support and Diabetes Mellitussupport and Diabetes Mellitus