Congenital and Acquired Enteropathies

Jon A. Vanderhoof M.D.Boston Children’s Hospital

Disclosures

• Medical consultant, Mead Johnson Nutrition, Evansville, IN

Purpose Of Presentation

• Briefly reviewed the various congenital and acquired enteropathies

• Establish differential diagnosis• Discussed practical approaches to diagnosis

and treatment

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

Classification Of Congenital Diarrheal Disorders

• Defects in digestion, absorption, and transport• Disorders of enterocyte differentiation and

polarization• Dysregulation of the intestinal immune

response

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

Defects In Enterocyte Differentiation And Polarization

• Microvillus inclusion disease• Congenital tufting enteropathy• Tricho- hepato- enteric syndrome• Enteroendocrine cell dysgenesis

Immunological Disorders

• Autoimmune polyglandular syndrome• Autoimmune dysfunction polyendocrinopathy

X-linked (IPEX)• IPEX Like Syndrome• Common variable immunodeficiency

syndrome• Food protein induced enterocolitis syndrome

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

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

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

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

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

Autoimmune Enteropathy

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

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

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

Acrodermatitis Enteropathica

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

Microvillus Inclusion Disease

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

Courtesy of Lisa A. Teot, MDStaff Pathologist and Director of CytologyBoston Children's Hospital

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

Syndromic DiarrheaTricho-hepato-enteric syndrome

Findings on Biopsy

History

• Positive family history of chronic diarrhea• Epidemiological history• Polyhydramnios• Dilated bowel loops during ultrasound• Family history of allergy• Infectious exposure

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

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)

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

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

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

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.)