1
Q
Physiologic effects of Fibre
A
i. Bulking agent, absorb water which softens stool
ii. Degraded by colonic bacteria => flatus, bloating
iii. Stimulant of motility (SCFA stimulate SB and, to lesser extent, colonic motility)
iv. Bind colonic toxins / dilute carcinogens, minimizes duration of contact with intestinal mucosa
v. Binds bile acids: ↑fecal bile acid concentration (lower serum cholesterol, TG)
vi. Curtails insulin response to CHO meal
vii. Change pH in colon (↓pH)
viii. ↓intraluminal colonic pressures in diverticulosis
2
Q
Histological features of PJS polyps
A
- frond-like elongated epithelial component
- cystic gland dilation
- smooth muscle arborization
3
Q
Extra-intestinal sites of PJS polyps
A
- gallbladder
- bronchi
- bladder
- ureter
4
Q
How to make clinical dx of PJS
A
-any one of the following is present:
- two or more histologically confirmed PJS polyps
- Any number of PJS polyps detected in 1 individual who has a family history of PJS in close relatives
- Characteristic mucocutaneous pigmentation of an individual who has a family history of PJS in close relatives
- Any number of PJS polyps in an individual who has characteristic mucocutaneous pigmentation
5
Q
Where are the mucocutaneous lesions seen in PJS
A
- seen in 95% of patients
- tend to arise in infancy
- mouth, nostril, perianal area, fingers and toes, dorsal and volar aspects of hands and feet
- may face after puberty but tend to persist in the buccal mucosal
6
Q
What is the gene for PJS and where is it located
A
- STK11 (LKB1)
- Chromsome 19
- Autosomal dominant
-STK11 - tumor suppressor gene, role in regulation of cellular proliferation, apoptosis, cell polarity, regulation of the Wnt signalling pathway, cell metabolism and energy hemostasis
7
Q
What age should predictive genetic testing be undertaken in at risk children for PJS
A
- 3 yrs
- earlier if symptomatic
8
Q
Most significant risk in childhood for PJS
A
- small bowel intussusception
- approximately 95% of intussusceptions occur in the small bowel
- 5% in colon
- generally caused by harmatomas > 15 mm
- polyp size being most important risk factor
-cumulative intussusception risk is 50-68%, 15-30% requiring surgery before age 10 yrs
9
Q
What is the risk of PJS in children with mucosal freckling? What investigations should be preformed in a child with mucosal freckling suggestive of PJS
A
- Lip and mucosal freckling is not diagnostic of PJS alone
- pts with lip and mucosal freckling suggesting PJS should be referred to a geneticist fro diagnostic genetic testing
- investigations of the GI tract is recommended to start no later than 8 yrs unless symptoms arise earlier - if they are symptomatic should test early given risk of small bowel intussusception
- preferred imaging: gastroscopy, colonoscopy, VCE or MRE
10
Q
Syndromes that have mucosal freckling
A
-PJS
-Carney complex
LEOPARD syndrome
11
Q
Where are GI polyps most likely to be found in PJS
A
-most likely found in small bowel then followed by colon
12
Q
What age should GI surveillance commence in pts with PJS and what investigations should be performed
A
- GI surveillance by upper GI endoscopy, colonoscopy and VCE should commence no later than 8 yrs in an asymptomatic individual with PJS, earlier if symptomatic
- investigations should be repeated q3yr
13
Q
What is the preferred method of managing a symptomatic child with PJS presenting with intussusception and intestinal obstruction
A
- Symptomatic intussusception should be urgently referred for surgical reduction
- no role for radiologic or endoscopic reduction of intussusception in this picture
- at laparotomy - patient should ideally undergo an intraoperative enteroscopy to clear the small bowel of other PJS polyps
14
Q
What is the role of endoscopic polypectomy in the asympatomatic child and adolescent found to have PJS polyps at surveillance
A
- should do polypectomy to prevent polyp-related complications
- should remove polyps > 15-20 mm to prevent intussusception. can consider removing smaller polyps in a small <25 kg child
- PJS polyps do not undergo malignant change - done to avoid intussusception
- *Risk of perforation from polypectomy in PJS may be higher than in other GI polyps
- muscularis mucosa commonly invaginates into the large pedunculated stalk increasing the risk of perforation at electrocautery
15
Q
What is the appropriate investigation pathway for boys with Sertoli cell tumors and PJS
A
Large cell calcifying sertoli cell tumor sof the testes (LCCSCTs) leading to feminizing manifestations including gynaecomastia are associated with PJS
- males should be assessed for this at clinical assessment
- referral to peds endo in those with LCCSCTs
16
Q
Cancer in PJS
A
- cancer in children with PJS is extremely rare
- breast, pancreas, sex cord tumors,
17
Q
What does the diagnosis of PIPO require
A
At least 2/4
- objective measure of small intestinal neuromuscular involvement (manometry, histopathology, transit)
- recurrent and/or persistently dilated loops of small intestine with air fluid levels
- genetic and/or metabolic abnormalities definitively associated with PIPO
- inability to maintain adequate nutrition and/or growth on oral feeding (needing specialized eneteral nutrition and/or parental nutrition support)
18
Q
Causes of Primary PIPO
A
- sporadic or familial forms of myopathy and/or neuropathy and/or mesenchymopathy (abnormal ICC development) that relate to disordered development, degeneration or inflammation. Inflammatory (including autoimmune) conditions including lymphocytic and eosinophilic ganglionitis and/or leiomyositis
- Mitochondrial neuro-gastrointestinal-encephalomyopathy (MNGIE) and other mitochondrial diseases
- neuropathy associated with multiple endocrine neoplasia type IIB
- Hirschsprung disease - total intestinal aganglionosis
19
Q
Causes of Secondary PIPO
A
- Conditions affection GI smooth muscle:
- rheumatological conditions (dermatomyositis/polymyositis, scleroderma, SLE, Ehlers Danlos
- other (duchenne muscular dystrophy, myotonic dystrophy, amyloidosis, ceroidosis (brown bowel syndrome) - Pathologies affecting the enteric nervous system (familial dysautonomia, primary dysfunction of the autonomic nervous system, NF, diabetic neuropathy, FAS, post-viral related inflammatory neruopathy (CMV, EBV, Varicella, JC virus)
- Endocrinological disorders (hypothyroidism, diabetes, hypoparathyroidism, pheochromocytoma)
- Metabolic conditions (uraemia, porphyria, electrolyte imbalances (K, Mg, Ca))
- Gastroschisis
- Neuropathy post neonatal NEC
- Other (celiac, eosinophilic gastroenteritis, Crohn, radiation injury, Chagas, Kawasaki disease, angio-edema, drugs (opiates, anthraquinone laxatives, CCB, Anti-depressants, anti-neoplastic agents) paraneoplastic CIPO, major trauma/surgery, chromosome abnormalities
- Idiopathic
20
Q
When should you suspect a dx of PIPO
A
- In all children presenting with symptoms of intestinal obstruction without an occluding lesion
- In neonates with:
- prenatal dx of megacystis/enlarged bladder
- persistent or recurrent obstructive symptoms after exclusion of Hirschsprungs and hypothyroid
- persistent vomiting after Ladd procedure for malrotation
- symptoms of intestinal obstruction associated with bladder dysmotility - infant/children with:
- persistent or recurrent obstructive symptoms after exclusion of Hirschsprung disease
- persistent vomiting/intestinal obstruction after correction of malrotation
- symptoms of intestinal obstruction associated with: ptosis, deafness, abnormal cardiac rhythm/function
21
Q
What are features of normal neuromuscular function on Antral-Duodenal Manometry
A
-ADM is most discriminating test for PIPO b/c small intestine is almost always affected
Normal pattern:
-identification of normal fasting pattern with the presence of normal phase III of the MMC and the replacement of MMC cycle by a fed pattern following the ingestion of a test meal
22
Q
How does manometry differentiate between enteric neuropathy and enteric myopathy
A
Enteric neuropathy:
-motor activity is typically disorganized and/or uncoordinated
Enteric myopathy:
- normal manometric patterns usually preserved but the amplitude of contractions do not exceed 20 mmHg
- however lower amplitude contractions may also reflect presence of gut dilation, confident diagnosis of enteric myopathy should be made only in absence of dilated loops
23
Q
ADM features associated with PIPO
A
Interdigestive or fasting period:
- absence of phase III
- short intervals btw phase III
- abnormal phase III: simulatenous or retrograde
- non migrating burst of contractions
- sustained simultaneous cluster of contractions
- lower amplitude contractions
Postprandial or fed period
- failure to switch to postprandial period
- postprandial hypomotility: low frequency of contractions, low amplitude of contractions
- non migrating cluster of contractions
24
Q
What are features of normal neuromuscular function on Colonic Manometry
A
- normal high amplitude propagating contractions spontaneous or after drug stimulation
- increased colonic motor activity following test meal
25
What are features suggestive of PIPO on Colonic Manometry
- absent or abnormal high amplitude propagating contractions
- impaired gastrocolic reflex
- total absence of colonic contractions
26
How should tissues samples for PIPO be taken
-must be derived from full-thickness or near full thickness bx taken with deliberate diagnostic intent or alternatively as by-product of emergency or planned surgical intervention
-in general minimum tissue specimen six of 0.5 x 0.5 cm is required for adequate histopathological analysis
adult literature suggests 1.5 x 0.5 cm
27
How does the midgut rotate in utero
- midgut loop herniates through the primitive umbilical ring at 6 weeks GA
- loop rotates counterclockwise 270 degrees around SMA
- returns to abdominal cavity at 11 weeks GA
28
What is a meckel diverticulum
- remnant of vitelline duct persists, forming blind pouch on antimesenteric border of TI
- may contain ectopic gastric, thyroid or endodermal tissue
- usually 20cm from ileocecal junction
- persistent omphalomesenteric duct
29
Where is the myenteric plexu
- also known as auerbach plexus
- located between circular and longitudinal muscles
- primary controls motility of the GI tract
30
Where is the submucosal plexus
- also known as Meissner plexus
- lies in the submucosal coat
- contains ganglia from which nerve fibers pass to the muscularis mucosae and musosal layer
- primarily controls secretion and blood flow
31
What are peyer patches
- Peyer patches: lymphoid follicles located mostly in ileum and extending from mucosa to submucosa
- contain zinc and lysozyme which can kill some bacteria
- mostly prominent in ileum
- increase in size and number until puberty
- Hyperplastic Peyer patches found in TI during childhood (focal lymphoid hyperplasia) - linked to idiopathic intussuception
32
Causes of increase IELs
-normally 1 lymphocyte for every 5 epithelial cells
- celiac disease
- CMPA
- autoimmune enteropathy
- giardiasis
- bacterial overgrowth
33
What cell are must abundant in Lamina Propria
-plasma cells
- also contains, lymphocytes, eosinophils, histiocytes and mast cells
- neutrophils usually NOT present
34
What is the submucosa composed of
- collagenous and elastic fibers
- scattered migratory cells and adipose tissue
- major focus of vascular and lymphatic flow
- meissners plexus
35
What is the muscularis externa composed of
2 distinct muscular layers perpendicular to one another
- inner circular and outer longitudinal
- blood vessels, lymphatics
- Auerbach plexus
36
What are Brunner glands
- glands specifically in the duodenum
- most concentrated just distal to gastroduodenal junction and grandually decrease along duodenum
- collection of tubuloalveolar glands predominantly w/n the submucosa and extending through muscularis mucosa
- function not fully understood: possible protection of duodenal mucosa from acidic gastric contents: contributes to increase luminal pH
- hyperplasia of brunner's glands- coarse nodularity in the duodenum or discrete or solitary nodules in proximal duodenum
37
What are M cells
M cells: located in peyer patches and isolated lymphoid follicles
- pick up particles from lumen and funnel them to hematopoietic cells in lymphoid tissue on basolateral side
- allow luminal antigens to be sampled in a controlled manner and an appropriate immune response mounted
- defining M cell characteristic= ability to pick up and transcytose particles from gut lumen to LP where they are processed by hemotopoietic cells
38
Histological finding in microvillous inclusion disease
- microvillous inclusion and increased secretory granules on electron microscopy
- abnormal periodic acid-shiff-positive cells and villous flattening without crypt hyperplasia
39
What are the main findings of Congenital Chloride Diarrhea
-most common cause of severe congenital secretory diarrhea
- AR
- severe polyhydramnios, dilated small loops of bowel, US - resembling distal small bowel obstruction
- severe life threatening secretory diarrhea in first few weeks of life
- severe exacerbation of diarrhea with most febrile illness
- Fecal lyte abnormalities:
- increased fecal Cl conc and decrease fecal HCO3-
- Serum lyte abnormalities: hypochloremia, METABOLIC ALKALOSIS (unlike metabolic acidosis of other congenital diarrhea) , hyponatremia, hypokalemia
- involved receptor: DRA/SCL26A3- main role as Cl-/HCO3- exchanger
- Impaired Cl-/HCO3- exchanger function disrupts the neutralization of gastric acid normal exchanger for HCO3- for reabsorbed Cl- in proximal small bowel
- impairs luminal Cl- reabsorption in distal small bowel and colon
40
What are the main findings of Congenital Sodium Diarrhea
-exceedingly rare
- AR SPINT2 gene
- polyhydramnios
- very alkaline, high volume; secretory diarrhea with high conc of Na+
- mild proximal tubular acidosis secondary to role of NH3 in renal Na+ and HCO3 reabsorption
Fecal lyte abnormalities: increased fecal Na and HCO3 losses
Serum lyte abnormalties: hyponatremia, metabolic acidosis
low or normal urinary Na excretion
involved receptor: NHE3 exchanger
impaired NHE function - alkaline stools unique to CSD
41
Management of Congenital Chloride Diarrhea
-lifelong enteral KCl and NaCl supplementation
-Cholestyramine with oral electrolytes and oral butyrate: help decrease stool volume are still experimental
luminal butyrate can increase NaCl absorption by Cl-/butyrate exchanger and by decreasing basal and cAMP-mediated Cl- secretion
42
Management of Congenital Sodium Diarrhea
Lifelong use of oral fluids and salt supplements to maintain fluid electrolyte balance
43
Where does secretin come from
Source; S cells duodenum
| Action: Pancreatic HCO3- secretion, biliary HCO3- secretion, inhibits gastric H+ secretion
44
Where does Gastric inhibitory peptide come from
Source: GIP cells in duodenum and jejunum
Action: increase insulin secretion, decrease gastric H+ secretion
45
Where does Motilin come from
Source: Mo cells in the stomach
Action: motility
46
Where is somatostatin found
Source: D cells in pancreas, stomach and SI/LI
Action: decrease release of all GI hormones, decrease gastric H+ secretion
47
Where is Vasoactive Intestinal Polypeptide found
Source: Neurons in smooth muscle and mucosa
Action: relaxation of GI smooth muscles, vasodilation, increase pancreatic HCO3-, decrease gastric H+
increase intestinal secretion
48
What do Substance P and Substance K as well as Dynorphim do
From neurons in the nerves of the mucosa and smooth muscle in the GI tract
- increase contraction of GI smooth muscle especialy LES, pyloric and ileocecal
- decrease intestinal secretion of fluids and electrolytes
49
What are causes of false positive for the 99mTc-pertechnetate scintigraphy looking for meckles
- intestinal duplication w/n heterotopic mucosa
- obstructed loops of bowel
- intussusception
- AVM
- ulcers
50
What are causes of false negatives for the 99mTc-pertechnetate scintigraphy looking for meckles
- inadequate amounts of gastric mucosa w/n diverticulum
- dilution of radiotracer from high bleeding rate
- poor blood supply to diverticulum
51
What are the different types of duodenal atresia
1. Membranous - thin membrane/web occluding the lumen
a. 90% of DA
b. commonly near ampulla of Vater
c. Windsock abnormality - obstructing membrane distends distally
2. Fibrous cord - connection between proximal and distal lumens
3. Discontinuous gap between 2 blind ends of the duodenum w/o continuoity
4. Stenosis
52
Long term complications of Duodenal Atresia
- GERD
- Gastroparesis
- PUD
- pancreatitis
- intestinal obstruction (due to adhesions)
- megaduodenum (common when DA combined with annular pancreas
53
Associated Anomalies of Jejunoileal atresia
GI:
- omphalocele
- gastroschisis
- malrotation
- malrotation
- meckel diverticulum
- biliar atresia
- situs inversus
- ectopic pancreas
- abnormal gallbladder
Extraintestinal
-cardiac, renal skeletal and central nervous system
CF
54
What is the Louw classification with Grosfeld modification of Jejunoileol atresia
Type I - internal membrane, serosa in continuity and no mesenteric defect
Type II- serosal discontinuity and fibrous cord between proximal and distal ends
Type III - serosal discontinuity with mesenteric defect
Type IIIa- mesenteric defect only
Type IIIb - apple peel deformity
Type IV - multiple sites (string of sausages)
55
Potential etiologies of NEC
- ischemia/reperfusion injury
- immunologic immaturity/dyfunction
- exaggerated proinfalmmatory intracellular response
- translocation of intestinal flora across an immature intestinal mucosal wall
- genetic predisposition
56
Risk factors for NEC
| Protective Factors for NEC
Risk= longer volumes of hyperosmolar formula
Protective= breast milk feeding (IgAs), standard slow advancement of enteral feeds
57
Pathological Lead points for intussception?
- meckels
- polyps
- lymphoma
- duplication cyst
- massive lymphoid hyperplasia
- Henoch-schonlein purpura
- CF
- appendicitis/periappendictis
58
What is the definition of Abx associated diarrhea
-unexplained diarrhea defined by 3 soft or liquid stools for >/ 2 consecutive days occurring btw 2 hr and 2 months following abx
59
How do you diagnose Microvillous inclusion disease
- intractable diarrhea that presents either at birth (early onset) or 3-4 months of life (late onset)
- primary secretory diarrhea with osmotic component after eating
Dx with transmission EM
Light Microscopy
- villous atrophy
- NO crypt hyperplasia
- PAS positive material in upper crypt and villous epithelium with absent staining in brush border
EM
- intracellular inclusions and secretory granules
- microvilli depletion on apical epithelial surface
- microvilli present in intracellular inclusion bodies
- crypt epithelium shows secretory granules
60
Pathology of Tufting enteropathy
-Presents with moderate-to-severe watery diarrhea in neonatal period -4 days to 4 weeks after birth
Pathology:
- tufts of extruded epithelial cells that are teardrop shaped and appear to shed into lumen
- total or partial villous atrophy and crypt hyperplasia
- mild increase in lamina propria inflammatory cells, but typically no change in IELs
- tufting may be due to abnormal adhesion of enterocytes to basement membrane
61
What happens in sucrase-isomaltase deficiency
- sucrase hydrolyzes sucrose -> glucose and fructose
- isomaltase hydrolyzes alpha 1,6, branch points in alpha-limit dextrins
- Defect in SI gene autosomal recessive
- N/V/D, distension/gas
- H2 breath test - isolated sucrase deficiency on duodenal biopsies
- distinguish from GGM by tolerating glucose challenge
- Stool pH low and may be positive or neg for stool-reducing substances
62
What is the treatment in sucrase-isomaltase deficiency
- low-sucrose/low-starch diet
| - liquid yeast sucrase: sacrosidase
63
What happens in maltase-glucoamylase deficiency
-maltase glucoamylase hydrolyzes maltose to glucose and glucose
-deficiency leads to starch malabsorption
defect in MGAM gene (AR)
-diagnosis: decrease enzyme activity on intestinal biopsy
Treatment: avoid dietary starches and short glucose polymers
64
What happens in glucose-galactose malabsorption
- very rare defect of Na+/glucose/galactose cotransporter (SGLT1) coded by gene SLC5A1
- AR
- metabolic acidosis and dehydration
- decrease stool pH, increased osmolarity, increased osmotic gap, evidence of glycosuria
- glucose and/or galactose breath H2 test very abnormal
- treat with glucose and galactose elimination (use fructose containing formula)
65
How does fructose malabsorption occur
-rare defect of GLUT5 facilitated transporter
encoded by SLC2A5
-AR
-presents with osmotic diarrhea following introduction of fructose containing foods (fruits and juices) to diet (typically 3-6 months)
-dx with fructose breath H2 testing or observation on fructose free diet
66
What occurs in Enterokinase deficiency
- deficiency in enterocyte production of enterokinase due to mutation of PRSS7 gene
- AR
- diarrhea, FTT, on a protein-.polypeptide diet, does better on an elemental diet hypoproteinemia, vomiting
Treatment:
-enteric-coated pancreatic enzyme replacement therapy, generally only required for first 2 years as diarrhea improves without therapy
67
Primary Bile acid malabsorption
- caused by defect in apical Na+ codependent transporter (ASBT) of ileal enterocyte and cholangiocytes
- SLC10A2 gene
- AR
- secretory diarrhea caused by fat and bile acid malabsroption
- FTT and steatorrhea
- decrease serum LDL caused by cholesterol loss with bile acids
- 75SE-homocholic acid-taurine test value < 15%
Treatment
- Cholestyramine binds bile acids and decreases diarrhea - may worsen fat malabsorption
- low-fat diet with MCT oil supplementation
68
What happens in Abetalipoproteinemia
- defective microsomal triglyceride transfer protein
- AR
- FTT, steatorrhea, emesis
- Vit E deficiency -> neurologic deterioration, retinitis pigmentosa, ataxia and opthalmopolegia
69
How do you diagnosis and treat Abetalipoproteinemia
Diagnosis
- very low serum cholesterol levels
- very low or absent serum lipoprotein electrophoresis
- very low serum triglycerides
- RBC acanthosis or spiculation due to membrane defects of structural lipids
- Bx shows fat-laden enterocytes and cytoplasmic fat droplets on EM
- small bowel surface is yellow/white from fat
Treatment:
- low LCT and cholesterol diet--> decreased steatorrhea
- MCT and FSV supp
70
What occurs in IPEX
- immunodysregulation polyendocrinopathy enteropathy X-linked
- FOXP3
- X-linked
- severe diarrhea
- villous atrophy with mononuclear cell infiltrates in lamina propria
- severe eczematous dermatitis, neonatal diabetes, autimmune thryoid disease
- hypereosinophilia and elevated IgE levels
- Coombs+ anemia, thrombocytopenia and neutropenia
- decrease Treg
- increased Auto-Abs
-Treatment - immunosuppresion and BMT
71
What happens in Neonatal Inflammatory skin and bowel disease
- ADAM 17
- AR
diarrhea secretory and osmotic/malabsorptive, occasionally bloody
- mononuclear infiltration - villous blunting and crypt hyperplasia
- decreased ADAM17 staining in bowel and skin samples
- Gut bx improves with age
- skin rash at birth and recurrent sepsis/fevers- focal neutrophilic infiltrate and spongiotic dermatitis
- hepatitis with apoptosis
72
Pathogenesis of Neonatal Inflammatory skin and bowel disease
- ADAM17 encodes TNF alpha-converting enzyme
- ADAM17 cleaves membrane-bond TNFalpha to form its active soluble form
- ADAM17 also important for NOTCH and epidermal growth factor signalling
- lipopolysaccharide-induced production of TNF-alpha is impaired
73
Features of IL-10 or IL-10R deficiency
- AR
- infancy (usually first 3 months of life)
- perianal disease, enterocolitis, FTT and enterocutaneous fistulas often requiring multiple surgical interventions
- follicullitis, abscesses, arthritis and recurrent resp infections
- refractory to multiple immunosuppressant therapies
Treatment - HSCT
74
What is the pathogenesis of IL-10/IL-10R deficiency
- IL-10 receptor expressed in many adaptive/innate immunse cells
- simulation of receptor --> STAT3 phosphorylation in normal immune cells
- in healthy host - IL-10 mediated signaling abrogates inflammatory response
- Loss of IL-10 = abnormal hyperinflammatory response associated with tissue damage
Functional assay: stimulation of peripheral blood mononuclear cells from IL-10R deficient patients do not show IL-10 induced phosphorylation of STAT 3
-then confirm with gene sequencing
75
CD25/IL2RA deficiency
-AR
-present in infancy similar to IPEX
but more susceptible to infections - chronic CMV, recurrent resp infections, eczema, dermatitis and lymphoid hypertrophy
histology - severe villous atrophy
Mutation in IL-2 receptor subunit CD25--> loss of function
normal numbers of Fox3pT cells but cells do not respond to IL-2
76
STAT 1 deficiency
-AD
-enteropathy and mucocutaneous candidiasis presenting with diarrhea
-villous atrophy and lymphocyte/eosinophilic infiltrates
-recurrent bacterial, fungal and viral infections
Autoimmune diseases
cardiac or vascular defects
- increased STAT1 phsophorylation, resulting in gain of function mutation
- leads to inhibition of TH17 differentiation
77
What cytokines are involved in Celiac disease
- IL-15
- INF-gamma
Combo of:
-increased inflammatory cytokines, infiltration of CD8 converted IELs and direct gliadin cytotoxicity = loss of epithelial cells, proliferation of crypt cells and mucosal flattening/villous atrophy
78
Marsh Criteria
0: < 30 IEL, no crypt hyperplasia, normal vili
1: > 30 IEL, no crypt hyperplasia, normal vili
2: > 30 IEL, crypt hyperplasia, normal vili
3a: > 30 IEL, crypt hyperplasia, mild atrophy
3b: > 30 IEL, crypt hyperplasia, marked atrophy
3c: > 30 IEL, crypt hyperplasia, complete atrophy
79
What are the cancers associated with celiac disease
- non-Hodgkins lymphoma
- Enteropathy-associated T cell lymphoma
- small intestinal adenocarcinoma
80
Pathophysiology of tropical sprue
- gut dysbiosis and exaggerated fat-induced ileal break
- > slow intestinal transit time and bacterial proliferation/colonization
- > SIBO, dysregulated host immune response, inflammatory and reduced gut defense
- abnormal intestinal permeability, villous atrophy, mucosal disaccharide deficiency, bile acid deconjugation, neurohormonal dysregulation
- B12 and folate deficiency
- megaloblastosis and colonic dysfunction
81
DDX of villous blunting/atrophy
- SIBO
- Tropical sprue
- Celiac
- Cow's milk/soy protein enteropathy
- eosinophilic gastroenteritis
- autoimmune enteropathy
- infections: giardia, crypto, intestinal TB
- Immunodeficiency disorders (acquired immune deficiency syndrome and CVID)
- malnutrition
- whipple disease
82
Treatment for Topical Sprue
- Tetracycline + folic acid for 3-6 months
| - replace Vit B12 deficiency and iron deficiency
83
Pathophysiology of PLE
- mucosal ulceration
- decreased intravascular oncotic pressure
- increased hydrostatic pressure
- increased lymphatic pressure
- dysfunctional tight junctions = increased GI epithelial permeablity
- loss of heparin surface proteoglycans along the basolateral membrane = increased tight junction permeability
84
Serological findings in PLE
Decreased:
- albumin
- transferrin
- gamma globulins
- ceruloplasmin
- fibrinogen
85
Options for PLE treatment secondary to Fontan
- surgical correction of small hemodynamic lesions and alteration of primary hemodynamic derangement
- heart transplant
- anticoagulation can improve hemodynamics
- stabilization of intestinal epithelium wiht high dose steroids or subcutaneous high molecular weight heparin
86
Options for Primarily Intestinal Lymphangiectasia
- high protein, low fat diet supplemented with MCTs
- octreotide
- Antiplasmin therapy
- surgery
87
What is the hallmark of Aspergillosis infectino
- vascular invasion causing significant GI bleeding
88
Where is the target of autoimmune enteropathy
- Epithelium
| - T cell mediated disorder resulting in profuse diarrhea and PLE
89
What are the 3 forms of AIE
1. IPEX in boys
2. IPEX-like in boys and girls- without FOXP3 mutation
3. Autoimmune mannifestations limited to GI tract - presents with secretory diarrhea, has Anitenterocyte/anticolonocyte and Anti-75-AIE Ab, no extraintestinal manifestation
90
What is the clinical presentation of IPEX
1. Typical triad: AIE, autoimmune endocrinopathy, eczema
2. DM due to islet cell destruction usually before intestinal inflammation
3. GI: severe secretory diarrhea/bloody diarrhea, hypoalbuminemia and lyte distrubrances, require TPN, FTT
4. Eczema like dermatitis
5. High IgE, eriperhal eosionphiia, food allergies
Other:
- thyroiditis
- hematological abnormaltiies - coombs+ anemia, neutropenia, thrombocytopenia
- liver, kidney and pulm disease, lymphadenopathy, splenomegaly
91
Histology in IPEX
- villous atropy
| - massive T cell inflitration of LP
92
Immune work up for IPEX
- Antienterocyte/anticolonocyte abs highly sensitive for AIE
- Anti-75-AIE (ab against gut and kidney Ag 75kDA) highly specific for IPEX and AIE
- Abnormal T cell activation studies
93
What is Autoimmune polygandular syndrome
-AKA polyendocrinopathy-candidasis-ectodermal dysplasia syndrome
-polyendocrinopathy
-mucocutaneous candidasis
-ectodermal dysplasia
-AIRE gene on 21q22.3
usually milder course b/c immune target is enteroendocrine cells rather r than absorptive cells
Txt- bowel rest, TPN, chronic immune suppression, BMT
94
What are GI manifestations of IgA deficiency
-rare, most pts asymptomatic and do not require therapy
-infections- recurrent sinopulmon infections and chronic giardiasis
-celiac disease
nodular lymphoid hyperplasia, autoimmunity, IBD
95
GI manifestations of CVID
- infections; chronic or recurrent diarrhea
- atrophic gastritis and pernicious anemia - stomach bodies show apoptosis
- celiac-like manifestations
- IBD, GI malignancy, PSC, AIH
96
GI manifestations of X-linked agammaglobulinemia
- chronic diarrhea
- recurrent infections
- SIBO
- nodular hyperplasia
- Crohns like picture
treat with Ig replacement
97
Features of CGD
- mutation in NADPH oxidase pathway
- impaired production of reactive oxygen metabolites
- most X-linked
Risk of infections - catalase-positive organism: S. aureus, Burkholderia cepacia, Serratia, Aspergillous, Nocardia
GI: Granulomatous lesions in any portion of the GI tract, indistinguishable from Crohns, fistulizing disease, VEOIBD
Treatment: TMP SMX, itraconazole, HSCT
98
Features of IL-10/IL-10R
- < 3 -6 months with
- Severe intractable colitis
- perianal abscesses
- enterocutaneous fistulas
- chronic folliculitis
- occasionally arthritis
99
What is a deceleration injury
- rapid deceleration in MVA
- tearing of bowel wall and shearing of mesentery
- sites prone:
a) retroperitoneal bowel
b) fixed bowel: duodenojejenal junction at the LoT, ileocecal junction
100
Complications of duodenal injury
- duodenal cutaenous fistula (2-14%)
| - abscess (10-20%)
101
What is intestinal failure
- clinical description that refers to the loss of intestinal function (length or competence) below the minimal amount necessary to maintain normal digestion and absorption of nutrition and fluids required for growth in children
- also defined as need for PN for > 90 days
102
What is the result of intestinal adaption
- functional increase in absorptive area via:
- mucosal hypertrophy
- villus hyperplasia
- increased crypt depth and muscle thickness
- dilation of small bowel lumen
- increased number of absorptive transporters per cell: subsequent increase in enzyme activity that results in increased absorption of nutrients and lytes per unit of bowel length
103
What type of nutrient is better for intestinal cell hyperplasia for adapation
- most potent stimulus for intestinal adaptation is enteral feeds - primary fuel for enterocytes
- stimulate peristalsis and normal physiologic flow of intestinal secretion
-more complex nutrients (intact proteins and LCTs) more effective for intestinal cell hyperplasia than more modular nutrients (free AA and MCTs)
104
What are you at risk for with proximal small bowel loss
- small bowel hyperacidity secondary to decreased bicarb secretion
- impaired biliary and pancreatic secretions
- decrease iron and folate absorption
105
What is the effect of distal small bowel loss
- distal small bowel = greater role in nutrient absorption and salt/water reabsorption
- loss of distal ileum more impact on nutrient absorption than loss of proximal jejunum
- active reabsorption of bile salts
- increase in BA production by hepatocytes inadequate to make up for loss by stools
- leads to fat malabsorption, FSV deficiency, increase LCFA in colonic lumen
-loss of colonic fluids from: LCFA and BA in colon - scretagogues
digestion of LCFA by colonic bacteria stimulates further colonic lyte losses
- loss of ICV = loss of "ileal break" - overall decrease in exposure time to luminal content by absorptive mucosal surface of the distal ileum
- Vit B12 deficiency
106
What is the use of soluble fiber for short-gut pts
- increase the viscosity of the enteral material and to help slow gastric emptying
- serve as source of SCFA caloric salvage in the colon
107
What lyte/vit/trace elements considerations do you need for:
1) pt with a colon
2) pt without a colon
3) pt without TI
1) K and Bicarb
2) Zinc, Mg and Na
3) FSV and B12
108
What is the point of acid blocking in short gut
- decrease H20 and Na losses related to secretory diarrhea associated with gastric hypersecretion
- acidic duodenal pH interferes with pancreatic enzyme activity and micelle formation
- may increase risk for SIBO
109
Conditions that may be considered for intestinal transplant
1. Loss of intestinal length
2. Disorders of intestinal function (MVID, secretory diarrhea, autoimmune enteropathy, extensive radiation enteritis)
3. Motility disorders (pseudo-obstruction, total intestinal aganglionosis)
4. Malignant/premalignant disorders (desmoid tumors of the intestine/multiple polyposis syndromes with malignant potential)
110
Indications for small bowel transplant
1. anatomic or functional disease that preclude enteral feeding plus failure of PN resulting from:
a. lack of vascular access
b. life-threatening complication of PN
1) IFALD
2) recurrent infections>/2 episodes sepsis/year
3) frequent severe dehydration despite supplementing PN with extra fluid
2. High risk of death
a. severe SBS- residual bowel < 10 cm in infants, < 20 cm in adults
b. intestinal failure with frequent hospitalizations, narcotic dependency or pseuodoobstruction
c. pt unwillingness to accept long-term PN
111
Contraindications to intestinal transplant
- active infection
- significant coexistent condition with no potential for improvement post transplant
- uncontrolled infection or malignancy not eliminated by transplant
- psych factors: lack of capcity to assume management post TXT, absence of family support
112
What is involved in a multivisceral transplant
- intestine, liver stomach
| - pancreas and duodenum included to facilitate en bloc engraftment and obviate biliary reconstruction
113
What are the features of graft rejection in intestinal transplant
1) clinical course: increase stoma output, blood stoma output, congested ileal stoma, abdo pain, cramping, obstruction, fever, acidosis
2) endoscopic appearance of allograft- inflammation and ulcers but can be normal if early rejection
3) histology: mucosal necrosis and loss of villous architecture with transmural cellular infltrate, crypt cell apoptosis, cryptitis or crypt loss, necrosis and endothelitis
114
How do you treat PTLD in intestinal transplantation
a. decrease immunosuppression by 50% treats PTLD in 1/3 of cases
b. if improvement not evident after 2 weeks - discontinue all immunosuppression and consider additional therapies
1) chemo
2) monoclonal ab administration
3) adoptive immunotherapy
4) intestine only graft can be removed
115
How do you prevent PTLD in intestinal transplantation
1. proph with ganciclovir of IV Ig for 3-12 months
| 2. proph x -6 weeks follow by surveillance and pre-emptive therapy should surveillance identify increase EBV repl
116
What is the definition of SIBO
An increased number of bacteria in the small bowel (typically > 10^5 CFU of bacteria/mL of luminal aspirate
117
Causes and disorders associated with SIBO
Causes:
- loss of ICV
- poor motility
- obstruction
- immune dysfunction
Disorders:
- SIBO
- Pseudo obstruction
- Cystic fibrosis
- Chronic pancreatitis
SIBO often caused by disruption in >/ 1 of the following:
a. immune defense: hypochlorhydria related to prolong proton pump use and immunodeficiencies
b. proteolytic enzymes: decreased in chronic pancreatitis
c. Anatomy: SBS, diverticula, fistulae, SI dilation and blind intestinal loops, resection of ICV, SI obstruction
d. Motility: pseudo-obstruction, scleroderma, high dose antidiarrheal meds
118
Common bacteria identified in SIBO
- Streptococci
- Bacteroides
- E. coli
- Lactobacillus
119
How many bacterial normaly in the:
Stomach
TI
Colon
Stomach: < 10^4 (strep, staph, lactobacilli)
TI: 10^8-10^10
Colon: 10^11-10^12 (bacteroides, bifidobacterium, clostridium, enterococci)
120
How does liver damage occur in SIBO
-G neg org produce endotoxin that trigger cytokines that alter hepatocyte transporter function
121
How can SIBO cause malabsorption
1. Fat malabsorption:
- bacteria deconjugate bile acids -> less available to from micelles
- unabsorbed bile acids can be secretagogues for coloncytes
- leads to FSV deficiency
2. CHO malabsorption
- decrease brush border disaccharides and hydrolase activity -> can mucosal damage from luminal bacteria and poorly absorbed bile acids
- bacteria ferment CHO-> excess amounts of D-lactate, expired CO2, H2 and CH4. Gas production contributes to symptoms
3. Protein malabsorption
- decreased absorption of AA
- bacteria degrade protein and produce NH3 - encephalopathy
4. B12 deficiency
- SIBO may cause ileal inflammation that decreases B12 transport
- Anerobic bacteria compete from absroption and utilization of luminal Vit B12 as growth factor
122
What are the findings of a positive H2 breath test for SIBO
-All H2 present in body results from prokaryotic metabolism
1) Baseline fasting amount of exhaled H2 is >/ 20 ppm
2) Peak is >/10 ppm over the fasting level w/n 1 hour of CHO administration
123
What's the most common small intestinal lymphoma
- Non-hodgkin lymphoma (NHL) B type
- 75% w/n GI tract
Common sites (can be anywhere)
- Distal TI
- cecum
- Appendix
124
What is a carcinoid tumor
neuroendocrine cell within the GI tract
found in GI tract, lungs, mediastinum, thymus, liver kidney and gonads
-in kids - mostly in GI tract, appendix followed by stomach, SI and rectum
Carcinoid crisis
- from secretion of serotonin, histamine and catecholamines
- flushing, diarrhea, abdo pain, tachycardia, bp liability and heart failure
- octreotide effective in controlling this compliation
Dx: urinary 5-hydroxyindoleacetic acid
Txt: surgical resection
125
How does hypoparathyroidism result in steatorrhea
-hypocalcemia = insufficient CCK release = decrease gallbladder contraction and pancreatic enzyme secretion
126
How do NSAIDs cause injury
- bowel inflammation due to increase gut permeability and inflammation
1. acid-independent mechanism
2. inhibits COX-1 and COX-2 --> prevents PG synthesis = local mucosal ischemia and decreased mucosal integrity
3. Lysis of phospholipids on mucosal surfaces injures mitochondria of intestinal epithelial cells
a. cytosolic Ca2+ efflux, free radical formation, cellular apoptosis, decreased intracellular connections and increased mucosal permeability
b. intrusion of bile acids, proteases, intestinal bacteria, and toxins into paracellular space ultimately --> injury
c. inflammation and ulcer formation likely due to recruitment of activated neutrophils
4. exacerbates IBD
127
What is the mechanism of injury with chemotherapeutics
- disruption of mucosal barrier (mucositis)
- induce release of pro-inflammatory cytokines from cells of mucosal immune system
- inflammation is driving force for chemotherapy-induced GI toxicity
- diarrhea common - commonly seen with 5-FU +/- irinotecan
128
What happens in typhlitis
-also known as neutropenic enterocolitis
-hemorrhagic, necrotizing process involving the TI and cecum due to profound drug-induced leukopenia and neutropenia = mural bacterial invasion
-common Gi complicaiton in leukemia induction therapy of following stem cell supported high-dose chemo
associated with cytosine arabinoside, cisplatin, vincristine, 5-FU, mercaptopurine and thiguanine
pathologica examination = bacterial overgrowth and attenuated inflammatory response
129
Microscopic colitis associated with which medications
- NSAIDs
- lansoprazole
- ranitidine
- flutamide
130
Ischemic colitis associated with which medications
- cocaine
- amphetamine
- estrogen
Peds GI RC
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