congenital and acquired enteropathies
TRANSCRIPT
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Congenital and Acquired Enteropathies
Jon A. Vanderhoof M.D.Boston Children’s Hospital
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Disclosures
• Medical consultant, Mead Johnson Nutrition, Evansville, IN
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Purpose Of Presentation
• Briefly reviewed the various congenital and acquired enteropathies
• Establish differential diagnosis• Discussed practical approaches to diagnosis
and treatment
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Causes Of Protracted Diarrhea Beginning During The First Six Months Of Life
• Normal villus-crypt architecture:– Transport defects
• chloride-bicarbonate exchanger (chloride-losing diarrhea)
• sodium-hydrogen exchanger (congenital sodium diarrhea)
• ileal bile acid receptor defect• sodium-glucose
cotransporter (glucose-galactose malabsorption)
– Micronutrient deficiency• acrodermatitis enteropathica
(zinc deficiency)– Enzyme deficiency
• enterokinase deficiency– Congenital short bowel
• Villus atrophy:– microvillus inclusion disease– tufting enteropathy– autoimmune enteropathy– IPEX syndrome– infectious enteropathy– post-infectious enteropathy– allergic enteropathy– idiopathic
Philip M. Sherman, David J. Mitchell, and Ernest Cutz Journal of Pediatric Gastroenterology and Nutrition38:16–26 © January 2004
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Classification Of Congenital Diarrheal Disorders
• Defects in digestion, absorption, and transport• Disorders of enterocyte differentiation and
polarization• Dysregulation of the intestinal immune
response
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Defects In Transport, Digestion, And Absorption
• Congenital sucrase-isomaltase deficiency• Enterokinase deficiency• Glucose galactose-malabsorption• Congenital chloride diarrhea• Congenital sodium diarrhea• Acrodermatitis enteropathica• Cystic fibrosis• A-betalipoproteinemia• Chylomicron retention disease• Shwachman-Diamond syndrome
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Defects In Enterocyte Differentiation And Polarization
• Microvillus inclusion disease• Congenital tufting enteropathy• Tricho- hepato- enteric syndrome• Enteroendocrine cell dysgenesis
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Immunological Disorders
• Autoimmune polyglandular syndrome• Autoimmune dysfunction polyendocrinopathy
X-linked (IPEX)• IPEX Like Syndrome• Common variable immunodeficiency
syndrome• Food protein induced enterocolitis syndrome
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Genes have been identified for many disorders
Disorder MIM Number GeneOsmotic
Congenital lactase deficiency
223000 LCT
Congenital sucrase-isomaltase deficiency
222900 SI
Congenital maltase-glucoamylasedeficiency Glucose-galactosemalabsorption
606824 SLC5A1
Fructose malabsorption*
138230 SLC2A5
Fanconi-Bickel syndrome
227810 SLC2A2
Lysinuric protein intolerance
603593 SLC7A7
SecretoryCongenital chloride diarrhea
214700 SLC26A3
Congenital sodium diarrhea
270420
Primary bile acid malabsorption
613291 SLC10A2
Unregulated Bile acid production disorder
Microvillus inclusion disease 251850 MYO5B
Congential tufting enteropathy 613217 EPCAM
Tricho-hepato-enteric syndrome 1 222470 TTC37
Tricho-hepato-enteric syndrome 2 614602 SKIV2L
Enteric Anendocrinosis 610370 NEUROG3
Proprotein convertase 1/3 deficiency 600955 PCSK1
Autosomal Dominant Familial Diarrhea 614616 GUCY2C
Homozygous 11p15-p14 Deletion syndrome 606528
Autoimmune polyglandular syndrome type 1 240300 AIRE
Immune dysfunction, polyendocrinopathy, x-linked 304790 FOXP3
IPEX-like syndromeInflammatory
FattyCystic fibrosisShwachman-Diamond syndrome 260400 SBDS
Pancreatic lipase deficiency 614338
Pancreatic co-lipase deficiency
Abetalipoproteinemia 200100 ApoBHypobetalipoproteinemia 107730
Chylomicron retention disease 246700 SAR1B
MixedEnterokinase deficiency 226200 PRSS7
Courtesy of Daniel S. Kamin, MDStaff GastroenterologistBoston Children’s Hospital
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Disorders for discussion
• Infectious enteropathies• Celiac disease and inflammatory bowel disease• Hirschsprung’s disease• Food protein induced enterocolitis syndrome• Microvillus inclusion disease and tufting
enteropathy, enteroendocrine dysgenesis, syndromic diarrhea, acrodermatitis enteropathica
• Autoimmune enteropathy
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Food Protein Induced Enterocolitis Syndrome (FPIES)
• Presents during infancy most commonly due to milk or soy protein
• Chronic diarrhea, vomiting, failure to thrive• Rice is single most common solid food • Probably T-cell mediated but immunology is poorly
understood• Eosinophils may be present but not specific for this disorder• Most children outgrow the allergy by 2 to 5 years of age• Syndrome has been reported in older children and adults
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Food Protein Induced Enterocolitis Syndrome (FPIES)
• T-cell mediated disease accounts for 40% of cow’s milk protein sensitivity in infants and young children
• 30% go on to develop other forms of atopic disease
• 40 to 80% have a positive family history of allergy
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Autoimmune Enteropathy
• Protracted diarrhea beginning during the first year of life but often after the first 2-3 months
• Extraintestinal manifestations of autoimmunity
• Marked inflammation in lamina propria with polys and crypt abscesses
• Respond to some degree to immunosuppression
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Autoimmune Enteropathy
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IPEX Syndrome(Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked)
• Several FOXP3 mutations (key transcription factor for T regcells)
• Severe early enteropathy, type 1 diabetes, other endocrinopathies, liver and kidney involvement may develop
• Variety of autoantibodies may be present• Chronic immunosuppression required• Stem cell transplant may be effective• Prognosis poor
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Congenital Diarrheal Disorders
• Rare enteropathies related to specific genetic defects
• Normally inherited as autosomal recessive traits
• Some present with severe diarrhea from birth, others more subtle and persists undiagnosed into adulthood
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Disorders Of Electrolyte Transport
• Congenital chloride diarrhea-alkalosis, hypokalemia,hypochloremia
• Congenital sodium malabsorption-acidosis, hyponatremia
• Acrodermatitis enteropathica• Disorders of copper, calcium, magnesium
transport• Congenital cobalamine ( vitamin B12)
malabsorption• Congenital folate malabsorption
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Acrodermatitis Enteropathica
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Microvillus Inclusion Disease
• Severe secretory watery diarrhea from early infancy with high sodium losses
• Severity is somewhat variable• Variable degrees of Villous atrophy without
hyperplasia or inflammation on light microscopy
• Classic findings on electron microscopy
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Microvillus Inclusion Disease
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Tufting Enteropathy(Intestinal Epithelial Dysplasia)
• Watery diarrhea beginning in the first few months of life
• Poor growth• Classic histologic findings
– Partial villous atrophy– Crypt hyperplasia– Mild inflammation– Tufts of densely packed enterocytes
• Dysmorphic features reported• May not be parenteral nutrition dependent• Variable prognosis
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Courtesy of Lisa A. Teot, MDStaff Pathologist and Director of CytologyBoston Children's Hospital
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Entero-endocrine Cell Dysgenesis
• Profound malabsorption of all nutrients, except water, from birth
• No histologic abnormalities other than absence enteral endocrine cells
• NEUROG3 point mutations result in arrest of endocrine cell development in small bowel and colon
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Syndromic DiarrheaTricho-hepato-enteric syndrome
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Findings on Biopsy
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History
• Positive family history of chronic diarrhea• Epidemiological history• Polyhydramnios• Dilated bowel loops during ultrasound• Family history of allergy• Infectious exposure
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Clinical Evaluation
• Assess effect of n.p.o., diet• Blood tests: electrolytes, inflammatory markers,
celiac serology• Stool examination: electrolytes, pathogens, occult
blood, white cells, reducing substances, calprotectin
• Multiple small bowel and colon biopsies, possibly including electron microscopy and examination for ganglion cells
• Specific genetic testing when indicated
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Initial Evaluation
• Osmotic versus secretory• Stool anion gap• Basic laboratory studies• Fecal studies for pathogens, reducing
substances, fat• Sweat test• Small bowel and rectal biopsies (with EM)
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Diarrhea From Birth
• Polyhydramnios?• Diarrhea when receiving nothing by mouth• Consider congenital electrolyte transport
disorders, congenital absorptive defects, microvillus inclusion disease
• Check serum electrolytes and stool studies including white cells, reducing substances, electrolytes
• Small bowel and rectal biopsies including electron microscopy if possible and indicated and tissue enzymes as indicated
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Diarrhea From Early In The First Year
• Look for inflammatory disease in small bowel and colon
• Consider food protein induced enterocolitis syndrome and infectious neuropathies
• Tufting enteropathy• Autoimmune enteropathy• Celiac disease if dietary history compatible• Appropriate screening studies and biopsies as
indicated
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Steaorrhea, Hypoproteinemia, Edema
• Consider cystic fibrosis and other causes of pancreatic insufficiency
• Consider intestinal lymphangiectasia• Look for defects and protein digestion and
absorption• Consider diffuse small bowel injury disorders
including food protein induced enterocolitis syndrome and celiac disease
• Appropriate stool and serum screening studies and biopsies are indicated
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Summary
• We now can identify a specific cause for most cases of intractable diarrhea
• Biopsy with EM and enzyme analysis are useful tools
• Genetic analysis looks promising• Remember, uncommon presentations of
common disorders are more common than common presentations of uncommon disorders (ie FPIES, Hirschprungs, IBD, Etc.)