Congenital Enteropathies by dr. arun aggarwal gastroenterologist

Dr. Arun Aggarwal Gastroenterologist

Intractable Diarrhea
 Avery and colleagues (1968):
 diarrhea of >2 wks,
 age <3 mos and
 ≥3 negative stool culture for bacterial pathogens.
 Managed with IVF
 Mortality: infection, dehydration, malnutrition
 No specific etiology

Guarino and colleagues
Catassi and colleagues
 Protracted diarrhea of infancy (PDI): resolves with
time
 Intractable diarrhea of infancy (IDI): continues despite
treatment

Protracted diarrhea of infancy (PDI)
 Causes:
 specific immune deficiency,
 sensitization to a common food protein (eg, cow’s milk
and gluten),
 severe infection,
 lack of diagnosis where a specific treatment is available
(eg, celiac disease in developing country)

Intractable diarrhea of infancy (IDI)
 Diarrhea starts with in first 2 yr of life
 Diarrhea is abundant: ≥ 100 ml/kg/day
 Diarrhea persists despite bowel rest (PDI responds to
bowel rest)
 Long term TPN is required
 Continues for years despite various therapeutic trials
(PDI recovers eve nafter several wks/mos of
parenteral/ enteral nutrition)

Classification of IDI
 Histological analysis is most imp for the diagnosis of
IDI.
 Mononuclear cell infiltration of lamina propria and is
associated with activated T cells: autoimmune
enteropathy, IPEX syndrome
 Villous atrophy without mononuclear cell infiltration,
but with specific histologic abnormalities involving the
epithelium

MVA/ MVID
 Congenital and constitutive disorder of intestinal
epithelial cells
 Neonatal onset of abundant watery diarrhea
 Diarrhea persists despite bowel rest
 Diagnosis is based on typical morphological
abnormalities detected through light and electron
microscopic analysis of proximal small bowel biopsies.

 Histology: variable degree of villous atrophy without
marked crypt hyperplasia, abnormal accumulation of
PAS positive material in the apical cytoplasm of upper
crypt and mature enterocytes and absent neutral PAS
staining of the enterocyte brush border membrane
 EM: atrophic or completely absent microvilli on
mature enterocytes along with microvillous inclusions
and the finding of electron dense secretory granules in
the same distribution as the abnormal PAS positive
accumulation.

Epidemiology
 Extremely rare
 Higher in countries with high degree of consanguinity
 Autosomal recessive

Clinical Presentation
 Pregnancy and delivery are uneventful
 Severe watery diarrhea starts with in few days of life
 Profound metabolic acidosis and severe dehydration
 High mortality rate with in 1st yr of life
 Stool vol: 150-3—ml/kg/day
 Stool Na content: 100-130mmol/L

Clinical Presentation contd..
 Most children are at risk of developing cholestasis and
liver failure
 Pruritis secondary to elevated bile acid in blood
 Abdominal distention with fluid filled intestinal and
colonic loops

Histopathological presentation
 Gold standard in diagnosis is a combined light/
electron microscopic histological analysis of small
bowel biopsies.

Etiopathogenesis
 Unknown
 Defect in membrane trafficking in enterocyte has been
proposed

Management and outcome
 Hypovolemia → temporary ischemia → neurological
and psychological symptoms, developmental
retardation
 Impaired renal function, nephrocalcinosis
 TPN → cholestasis, liver failure
 Mortality: infection of central catheter, liver failure.
 Permanent intestinal failure
 Small bowel transplantation, liver transplantation

Genetic counseling
 As a genetic defect has not been identified, no genetic
counseling or prenatal diagnosis is possible.

 Characterized by clinical and histological
heterogeneity and association with malformations or
other epithelial diseases.
 Abnormal enterocyte development/ differentiation.

Epidemiology
 Very rare
 Higher in countries with high degree of consanguinity.
 ? Autosomal recessive

Clinical presentation
 Watery diarrhea with in first few days of life
 Stool vol: 100-200 ml/kg/day, electrolyte conc similar
to those seen in small intestine fluid.
 No past history of hydramnios suggesting congenital
chloride or sodium malabsorption diarrhea.
 May have dysmorphic features
 Malformations: esophageal atresia, choanal atresia,
imperforated anus, punctuated keratitis.

Histopathologic Presentation
 Villous atrophy, disorganization of surface epithelium
(include disorganization of surface enterocytes with
focal crowding, resembling tufts) and basement
membrane abnormalities.
 Repeated biopsies are reqd.

Differential Diagnosis
 Congenital chloride diarrhea:
 lifetime watery diarrhea with high chloride content and
low pH, causing dehydration and hypochloremic
metabolic alkalosis.
 Chloride is low in urine and very high in stools
(>150mmol/L)
 Congenital sodium diarrhea:
 defective sodium/ proton exchange.
 Patients have acidosis and hyponatremia and stools with
high conc oh bicarb and sodium

 Glucose- galactose malabsorption: autosomal
recessive, neonatal diarrhea which ceases with in 1 hr
of removing oral intake of lactose, glucose and
galactose.

Management and outcome of IED
 Continuous enteral feeds may worsen the diarrhea
 Parenteral nutrition and its complications
 Irreversible intestinal failure
 Liver cirrhosis: due to underlying digestive disease and
unadapted PN
 Intestinal transplantation/ liver transplantation.

 Early onset severe intractable diarrhea
 SGA baby
 Non specific villous atrophy with low or without
mononuclear cell infiltration of the lamina propria
 Facial dysmorphism + immune disorders + early onset
of severe liver cirrhosis

Epidemiology
 Much less common than MVA/ MVID or IED
 consanguinity

Clinical Presentation
 Diarrhea starting with in 6 mo of life
 Severe malabsorption→ protein energy malnutrition→
FTT
 Diarrhea persists with bowel rest
 Babies are SGA, have facial dysmorphism (prominent
forehead and cheeks, broad nasal root and hypertelorism)
 Difficulty with fine motor movement
 Mental retardation
 Hairs are woolly, easily removed and poorly pigmented.

Histopathologic Presentation
 Moderate or severe villous atrophy with variable
mononuclear cell infiltration of the lamina
propria and no epithelial abnormalities.
 In patients with liver disease→ macronodular
cirrhosis with normal extrahepatic ducts
 Perl’s staining shows iron depositions involving
the hepatocytes and to a lesser extent Kuppfer
cells→ consistent with Neonatal
Hemochromatosis.

Immune profile
 Functional T-cell immune deficiency with defective
antibody production
 Defective antibody responses despite normal serum
immunoglobulin levels
 Defective antigen specific skin tests despite positive
proliferative responses in vitro.

Management and outcome
 Prognosis is poor (>25% of currently reported patients
died b/w 2-5 yr of age)
 Growth velocity remains low and final stature very
short.

Etiopathogenesis
 The coexistence of morphological, trichological and
immunological abnormality with early onset
intractable diarrhea disproportionate to the mucosal
architectural abnormality (consistent with a primary
enterocyte abnormality) suggests either mutation
within several genes, inherited together by linkage
disequilibrium or more probably interference with a
higher level of control such as a patterning gene.

Conclusion
 List of congenital enteropathies is not exhaustive.
 Most of these diseases don't involve the digestive tract
alone but cause intestinal failure of variable intensity.
 Prognosis is poor.

Congenital Enteropathies by dr. arun aggarwal gastroenterologist

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