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 CW admitted 29/11/2010  7 week old female  Brought by mother – 18 year old  6 day history diarrhoea  No vomiting, tolerating feeds  Dry cough,

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Presentation on theme: " CW admitted 29/11/2010  7 week old female  Brought by mother – 18 year old  6 day history diarrhoea  No vomiting, tolerating feeds  Dry cough,"— Presentation transcript:

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2  CW admitted 29/11/2010  7 week old female  Brought by mother – 18 year old  6 day history diarrhoea  No vomiting, tolerating feeds  Dry cough, blocked nose  No traditional or other medicines taken  No TB contacts

3  Birth history:  Caesarean section at 43 weeks for failed induction for post-dates  Birthweight - 2.8kg  Mother Rh positive, RPR negative, HIV negative  Feeding:  Breastmilk, supplementing with Nan, Pelargon  Formula incorrectly mixed – too dilute, possibly not enough given  6 week vaccine up to date. Had weighed 3.2kg at clinic  Stays with mother and maternal grandparents

4  Ill-looking baby  Weight – 2.7kg  Blood sugar 5.3mmol/l  Oxygen saturation 90% on room air  Afebrile  Pink  Capillary refill 3 seconds, dry mucous membranes, decreased skin turgor. Fontanelle not sunken  Blocked nose  Chest - acidotic breathing. Chest clear  CVS - normal

5  Abdomen – soft, no masses felt  Excoriated nappy rash  CNS – lethargic, but moving limbs equally  Blood gas – metabolic acidosis with respiratory compensation ◦ pH – 7,166 Bicarb – 5.0mmol/l PaCO₂ – 14,3mmHg BE - -21mmol/l  Assessed as 7 week old infant with gastroenteritis complicated by >10% dehydration and acidosis. Possibly also septic.

6 FBCU&ECRPCSFCMP WCC 25.1Na P 13Ca corrected 2.09 Hb 11.4K 4.1L 2Mag 1.03 MCV 92Cl 121RBC 3Phos 1.76 Plts 289Co2 5Prot 1.26Albumin 38 Urea 10.6Glucose 3.8 Creat 63Cl 140 AG 15No bacteria Urine dipstickUricult Nil abnormalNo growth

7  Intravenous fluids  Cefotaxime  Zinc sulphate orally and zinc topically to nappy rash  Mother continued to breastfeed and also gave Isomil

8  Post-intake ward round ◦ still looked quite lethargic, grey and mottled ◦ still acidotic ◦ Skin looked dry, and as if peeling superficially ◦ Profuse diarrhoea still noted  Stools gradually settled, still quite frequent  Blood sugars normal, afebrile  Blood gases initially took time to improve  U&E improved

9  Day 4 - looked hypothyroid ◦ Dry skin ◦ Yellowish tinge ◦ Small umbilical hernia ◦ TSH – mIU/l ◦ FT₄ – 10.1 pmol/l  Weight on discharge – 3.64kg (almost 1kg more than on admission) ◦ Approximately 25% dehydrated on admission  Discharged after 6 days, on Eltroxin  For follow up at Unit Follow-up clinic

10  23/12/2010 (18 days after discharge)  Age 2 ½ months  3 day history of sleeping a lot  Mother said no diarrhoea but loose stools noted in nappy  No vomiting  No cough  Apparently still feeding well  Now taking breastmilk and Lactogen (soy formula not available)  Also started porridge

11  Ill-looking  Afebrile – actually hypothermic (35°c)  Blood sugar – 7.5mmol/l  Heart rate 111/min  Oxygen saturation 99% in room air  Signs of severe dehydration ◦ Markedly decreased skin turgor ◦ Sunken eyes ◦ Capillary refill >3 seconds ◦ Dry mucous membranes ◦ Acidotic breathing ◦ lethargic

12  Required 3 fluid boluses  Slow rehydration ( ½ Darrow’s dextrose)  Cefotaxime  Metabolic screen considered  Not kept NPO – continued breast and restarted Isomil  Post intake ward round ◦ not dysmorphic ◦ sclerematous ◦ Slightly distended abdomen, soft, having ++ watery stools ◦ Scissoring of legs, brisk (3/4 reflexes) ◦ Blood culture positive already

13  Assessed as ◦ 2 ½ month old female ◦ HIV negative ◦ Recurrent admissions (2) for severe gastroenteritis complicated by acidosis ◦ Now with hyponatraemia, hypocalcaemia (on gas) ◦ Clinically septic with positive blood culture ◦ ??other metabolic condition

14 Blood gasFBCCRPU&ECSFStool red subst Urine red subst pH 6.985WCC Na 119P 0Neg (?)Neg* CO₂ 17.3Hb 11.4K 3.5L 4 Bicarb 4Plts 478Cl 102E 0 BE -25.8CO₂ <5Prot 1.65 Ca 1.268Urea 9.8Gluc 5.5 Lac 2.4Creat 72Cl 131*on Isomil AG 15

15 TFT’SBlood cultures FT₄ <5.1 pmol/l1) E. Coli sensitive to Ampicillin, Cefotaxime TSH mIU/l2) Coag. neg Staph (43.9hrs) - contaminant Urine – no dipstick results, no Uricult done

16  Acidosis improved over next 2 days  U&E improved (sodium increased without additional sodium replacement). Oral potassium given - corrected  Blood sugars generally normal – no hypoglycaemia recorded, 2 hyperglycaemia’s noted on day of admission, also on blood gas  Temperature improved, no spikes  Passed frequent (up to 8) soft stools a day  Weight improved to 3,52kg within a week  Discharged 01/01/2011 (8 days after admission)  T.T.O. - Eltroxin

17  Readmitted 15/01/2011 (2 weeks after d/c)  Now 3 months of age  3 day history fever, “face yellowish”, cough, diarrhoea, also vomiting  Been drinking Lactogen at home. Mother had stopped breastfeeding on previous admission

18  Appeared lethargic, pale, coughing  Temperature below 35°c  Bullous lesion on chin, pustules in neck flexure, scalp  Acidotic breathing  Capillary refill 4 seconds  (other signs of dehydration not mentioned)  Chest - decreased air entry on right  CVS - normal  Abdomen – slightly distended

19 ◦ Umbilical hernia, blue-grey discolouration around it ◦ Nappy rash  CNS – increased tone, brisk reflexes ◦ Fontanelle not bulging  Assessed as a 3 month old female infant with ◦ Recurrent admissions for acute gastroenteritis ◦ Hypothyroidism ◦ Presenting with sepsis complicated by severe metabolic acidosis ◦ ?bronchopneumonia, ?meningitis

20  Fluid bolus x 2  Cefotaxime  Initially kept nil per os  Nursed in incubator  Blood gas ◦ Ph – 6.9 PaCO₂ HCO₃ BE Lac – 1.7  Only results – FBC, CSF, Blood culture  WCC – 34.4 Hb – 10.4 MCV – 91.6 Plts  CSF – NAD  Blood culture – no growth after 7 day s

21  Despite fluids, gas no better. Bolus repeated  Post intake ward round ◦ Mild dysmorphism – small chin, low set ears, small upturned nose ◦ Chest – crackles bilaterally ◦ Assessed as sepsis, bronchopneumonia ◦ Cloxacillin added for ? Staph skin lesions

22 UrineU&E (18/01)PyruvateLFTTFTCMPMetabolic screen Dipstick NAD Na (N)Bili 2/1FT₄ 11.2Ca 1.38Abn org acids Uricult no growth K 5.4Prot/ Alb 43/24 TSH 17.7Mg 0.43Abn amino acids Cl 118ALP 270Po₄ 1.75Low B₁₂ CO₂ 7GGT <5 Urea 11ALT 25 Creat 84AST 52 Stat dose calcium gluconate, MgSO₄ given

23 U&E19/0120/0125/01 Na K Cl CO₂ Urea Creat AG131714

24 FBC (19/01) CRPFBC (20/01) FBC (22/01) CMP (20/01) CMP (22/01) CMP (31/01) WCC 149WCC 20WCC 24Ca 1.43Ca 1.63Ca 2.17 Hb 7.8Hb 7.7Hb 8.8Mg 0.39 Mg 0.73 Plts 31Plts 29Plts 54PO₄ 1.13PO₄ 1.28PO₄ 1.38 Started Fluconazole. No growth on blood cultures Titralac, oral PO₄ enema, Vit D commenced Stool MC&S (28/01)Yellow, soft, yeast, N flora, no parasites

25 Cytogenetic studies (FISH) FOR 22q11 deletion Negative - no deletion detected Chromosome analysis46, XX

26  During admission ◦ Weaned off oxygen by day 2 ◦ Only 1 temp spike whilst in incubator (day 2) ◦ Blood sugars normal (2 high on admission) ◦ Only 2 stools whilst NPO ◦ Restarted feeds day 2-3 ◦ Stools charted as normal, on Isomil ◦ Nan given (?accidentally) – profuse watery diarrhoea followed ◦ Loose stools persisted on Isomil, changed to Alfare after 8 days ◦ Fewer stools charted, but loose stools persisted ◦ Zinc sulphate given

27  Cholestyramine, Reuteri drops started whilst on Alfare as loose stools persisting. Not much improvement  ??Phosphate enema orally exacerbating diarrhoea – stopped  Clinically remained stable, did not require intravenous fluids despite loose stools  Took Sorol after loose stools. Always drank very eagerly!  Weight unchanged for 2 weeks. Slowly improved to 3.9kg by discharge  Discharged 08/02/2011 (3 weeks after admission), on Alfare, Vit D, Titralac, Zinc, Eltroxin

28  Came to Unit follow-up clinic 21/ (2 weeks after d/c)  4 ½ months of age  Mother said had been coughing for a few days  Feeding Alfare, correctly mixed, 100ml 3 hourly. Feeding well apparently  No vomiting  8 normal stools per day

29  Weight 3.6kg – lost 300 g since discharge  Looked tachypnoeic and lethargic  Afebrile (in ward 17 – 38.8°C)  Oxygen saturation 90% in room air  Heart rate 125/min  5% dehydrated  For first time noticed white area on left iris  Systems not remarkable, chest clear

30  Decided to admit ◦ IV fluids ◦ To monitor condition, avoid antibiotics so sweat test could be done ◦ Step down to Isomil, monitor response ◦ CXR  Course in ward ◦ numerous loose stools on Isomil ◦ Became very dehydrated within hours ◦ Rehydrated, changed back to Alfare ◦ Required Ampicillin for bronchopneumonia ◦ Responded well to above management ◦ Rebooked sweat test

31 U&E21/0222/0224/02FBCTFT’s CMP Na WCC 4.43FT₄ <5.1FT₄ 15.8Ca 2.04 K Hb 10.4TSH 9.75TSH 14.04Mg 0.99 Cl MCV 87.8Po₄ 0.95 CO₂91223Plts 383 Urea Creat AG Blood culturesCoag neg staph (57 hours)

32 AmylaseAmmoniaLFTVit DPTH 1384TP/Alb 57/37 Not processed ALP 352 GGT 10 ALT 38 AST 46

33  Given Vit B₁₂ IM, zinc sulphate in ward  Discharged after 1 week  Weight on discharge – 4.06kg  Vit D, Eltroxin, Alfare  Called back for weight check 10/03  Weight 4.3kg  Still having intermittent loose stools  Looking well!  For sweat test 18/03/2011

34 Lymphocyte subset analysis (11/03) WCC6.08 Lymphocytes2.81 (N – ) CD32012 CD41299 CD8606 IgA, IgM, IgG levelsNormal

35  Frequent passage of loose stools or passage of an increased volume of stool water  >200ml/m²/day or > g/m²/day  Difficult to measure in children  Increase in stool frequency + change to loose/watery stools  NB breastfed infants pass frequent stools normally  Some say >3 loose stools/day  Acute diarrhoea - <2weeks’ duration  Chronic diarrhoea - >2 weeks’ duration  Persistent diarrhoea - >2 weeks’ duration with dehydration  Protracted diarrhoea – severe enough to require nutritional support (parenteral alimentation)

36  Normally stool output dictated by balance between absorption and secretion by intestinal lining – absorption usually > secretion  Proportion of water absorption coupled with absorption of nutrients, electrolytes ◦ Requires adequate digestion of nutrients ◦ Prevent unabsorbable, osmotically active substrates in lumen  Diarrhoea occurs if net secretion of water due to ◦ ↓ absorption from lumen or ◦ ↑ secretion/ water loss

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38 ↓ absorption of water and electrolytes ↑ secretion/ loss of water and electrolytes into lumen  ↑ in secretory cells  Stimulation of secretory pathways ◦ Enterotoxins activate intracellular signal transduction – Cl⁻ secretion  ‘Leaky ‘ epithelium  Osmotic shift into lumen  Effects on enteric nervous system  ↑ in secretory cells  Stimulation of secretory pathways ◦ Enterotoxins activate intracellular signal transduction – Cl⁻ secretion  ‘Leaky ‘ epithelium  Osmotic shift into lumen  Effects on enteric nervous system  ↓ functional absorptive area  Decreased intraluminal digestion  ↓enterocyte cellular absorptive function  ↓intestinal transit  ↓ functional absorptive area  Decreased intraluminal digestion  ↓enterocyte cellular absorptive function  ↓intestinal transit

39  Symptom not disease  Various underlying causes  Previously – term ‘Intractable Diarrhoea of Infancy’ applied to chronic unexplained diarrhoea in children ◦ Out of favour – not a discrete disease entity; defined disorders have recently been characterised ◦ TPN - better survival of these children  Causes of chronic diarrhoea in children can be divided into ◦ Diseases having normal villus-crypt architecture ◦ Diseases having villus atrophy

40  Transport defects ◦ Chloride-bicarbonate exchanger – Chloride-losing diarrhoea ◦ Sodium-hydrogen exchanger – Congenital sodium diarrhoea ◦ Ileal bile-salt receptor deficiency ◦ Sodium-glucose co-transporter – glucose-galactose malabsorption ◦ Abetalipoproteinaemia – fat and fat-soluble vitamin malabsorption ◦ Acrodermatitis enteropathica – defect in zinc transport  Enzyme defects ◦ Enterokinase deficiency – protein malabsorption ◦ Primary lactase deficiency – congenital form very rare ◦ Pancreatic malabsorption – cystic fibrosis, Shwachman Diamond Syndrome

41  Surgical ◦ congenital/acquired short bowel ◦ Malrotation with bacterial overgrowth ◦ Dysmotility causing pseudo-obstruction and bacterial overgrowth ◦ Blind-loop syndrome with bacterial overgrowth  Transport defects and enzyme deficiencies may cause diarrhoea in early neonatal period  May even be history of polyhydramnios during pregnancy  If consider diagnosis – send stool electrolyte concentrations

42  Primary epithelial causes ◦ Microvillus inclusion disease neonatal ◦ Tufting enteropathy enteropathies  Associated with immune system abnormalities ◦ Autoimmune enteropathy ◦ IPEX syndrome ◦ Primary immune deficiencies – SCID, thymic hypoplasia, CD40 ligand deficiency  chronic pathogen infection, propensity to autoimmunity ◦ Acquired immunodeficiency  Recurrent episodes of infection ◦ Intestinal lymphangiectasia – PLE, dilated lacteals, decreased circulating lymphocytes

43  Food-sensitive enteropathy ◦ Post-enteritis enteropathy – lactase, sucrase deficiency ◦ Cow’s milk protein sensitivity ◦ Coeliac disease – after introduction of gluten into diet, PLE  Infective enteropathy ◦ Post-enteritis enteropathy ◦ EPEC ◦ Cryptosporidiosis ◦ Rotavirus – always associated with disturbed immune function  Metabolic conditions ◦ Mitochondrial cytopathies (MELAS)  Bacterial overgrowth syndrome

44  Inflammatory bowel disease ◦ Very rare in infancy  Cryptogenic ◦ Syndromatic intractable diarrhoea – dysmorphic features including hypertelorism, broad midface and nose, trichorrhexis nodosa, subtle immunodeficiency, occ cirrhosis

45  Severe enteropathy  Watery diarrhoea from day 1 of life  Stools even mistaken for urine  Faecal sodium and chloride concentrations similar to plasma  Volume of stool loss greater than cholera  Secretory diarrhoea  2 nd most common cause of severe protracted diarrhoea starting during 1 st week of life (after infection)  Genetic aetiology  Intractable diarrhoea, requires parenteral nutrition  Fatal without TPN/ intestinal transplant

46  Villus atrophy  Intracytoplasmic microvillus inclusions  Inclusions thought to be due to a genetic defect in trafficking of membrane proteins to apical surface

47 Histopathologic features of classic microvillus inclusion disease. A: Low magnification view of a jejunal biopsy showing total villus atrophy and relatively short crypts. B: Higher magnification of surface enterocytes with vacuolated apical cytoplasm and focal piling-up of cells.

48  Similar to MVID but initially less aggressive  Presents in first few months life  Chronic watery diarrhoea  Impaired growth  Prognosis variable  Molecular basis unknown – thought to be due to genetic defect  Characteristic feature presence of focal epithelial tufts – closely packed enterocytes, rounding of apical plasma membrane

49 Stained sections from a child with tufting enteropathy showing severe villus atrophy and moderate crypt hyperplasia without a marked inflammatory cell component in the lamina propria

50  Protracted diarrhoea – unresponsive to all dietary exclusions, often requiring TPN  Often initially misdiagnosed as post-enteritis/ food- sensitive enteropathy in early stages  First few months of life – often only after first 8 weeks, may be perinatal  Usually period of good growth prior to onset of symptoms  Frequently associated with extra-intestinal manifestations of auto-immunity ◦ Most commonly renal disease, polyendocrinopathy (esp. pancreas)  Rarely family history of unexplained infant diarrhoea  Clinical response to potent immunosuppression

51  Males > females (often X-linked)  Consanguinity  Can have aggressive or insidious onset  May be unmasked by enteric pathogens – often consider infective gastroenteritis/ post-enteritis syndrome/ cow’s milk sensitive enteropathy first  Initial management – milk exclusion – lactose-free/ oligoallergenic formula ◦ May induce slight improvement because often 2°lactase deficiency ◦ Loose stools, weight loss tend to continue

52 Histopathologic features of autoimmune enteropathy. Jejunal biopsy obtained from a child with autoimmune enteropathy showing total villus atrophy, crypt hyperplasia and a marked mononuclear cell inflammatory infiltrate in the lamina propria.

53  Similar to Coeliac disease but no history of gluten ingestion prior to onset  Pathogenesis – circulating systemic antibodies against enterocytes  Levels decline/ disappear on immunosuppressive treatment  Titre not proportional to volume of stool losses  Pathological findings due to uncontrolled activation of T cells within intestinal mucosa  Associated B cell response – enterocyte auto- antibodies  Outcome poor ◦ Death due to complications of TPN, involvement of other organs by AI process, complications of immunosuppressive treatment

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55  Only described in males  Usually lethal in infancy/ childhood  Growth retardation and cachexia prominent feature ◦ May even begin prenatally ◦ Not simply due to diarrhoea, malnutrition ◦ Possibly also due to excessive cytokines/ TNF  Hypocalcamia can occur – in presence of high PTH, possibly due to PTH resistance  Also prone to sepsis ◦ Enterococcus, staphylococcus ◦ Immune dysregulation, drugs, autoimmune neutropenia, loss of skin and gut integrity, malnutrition

56  Mutation in Foxp3 gene  Foxp3 encodes transcription factor – Scurfin  Scurfin involved in T cell signalling, proliferation of CD₄⁺ T cells  State of immune hyperreactivity – organ destruction, eczema, lymphadenopathy, cachexia  Lack of functional regulatory T cells  Many intestinal manifestations similar to AI enteropathy ◦ Villus atrophy, marked infiltrate in lamina propria of activated T cells

57  Nutritional support, adequate hydration most important for growth, development  Severe cases – parenteral nutrition early  Await nutritional rehabilitation prior to diagnosing exact aetiology  Less severe cases – elemental/ low carbohydrate- containing formulae ◦ Improve enteral delivery of calories, nutrients ◦ Avoid complications associated with TPN

58  Antisecretory agents (somatostatin analogues) variable  Trophic factors (GH, ?colostrum) success  Autoimmune enteropathy, IPEX ◦ Corticosteroids, cyclosporine, tacrolimus, infliximab, cyclophosphamide ◦ Allogeneic bone marrow transplant  Microvillus inclusion disease, Tufting enteropathy – poor prognoses ◦ Small bowel transplantation, with/ without concomitant liver transplant has been successful

59  Clinicopathological condition in which small intestinal mucosal damage persists following acute gastroenteritis  Sensitization to food antigens classically considered  Secondary disaccharidase deficiency to be responsible  Both above actually occur to much lesser extent than previously thought  Another mechanism thought to be infection/ re-infection with enteric pathogen  Pathophysiology remains to be fully clarified

60  Symptoms occurring due to increased number bacteria stomach, duodenum, jejunum, proximal ileum  stem from increased bacterial burden on normal functions of upper GIT  Occurs when normal mechanisms which keep numbers low disrupted ◦ Structural abnormalities of GIT (congenital/ post-surgery) ◦ Decreased acidity ◦ Decreased peristalsis ◦ Mucosal damage/ atrophy ◦ Immunodeficiency ◦ Disruption of normal flora

61  Normally Gram positive organisms, anaerobes, aerobes, fungi in colon > ileum > duodenum, jejunum  BOS – increased numbers anaerobes, normal flora  Vicious cycle follows (pics)  Risk factors ◦ Malnutrition in neonates/ infants ◦ Immunocompromise ◦ Intestinal surgery/ congenital GI abnormalities ◦ Hypothyroidism - ↓motility  Clinically – signs & symptoms of malabsorption ◦ Anaemia, steatorrhoea, Vit A deficiency, dermatitis, weight loss/ FTT

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64 ◦ Treatment  Antibiotics rebalance enteric florae  Try to prevent total eradication of protective organisms  Broad spectrum antibiotics (aerobes, anaerobes, particularly Bacteroides fragilis)  Augmentin, Clindamycin, Metronidazole  Gentamicin – significant improvement <1yr olds  Cholestyramine, Flagyl/ Gentamicin been shown to reduce diarrhoea within 4-5 days, infants with idiopathic chronic diarrhoea  ?length of treatment

65  Nutrient/ vitamin replacement ◦ Especially important in population who are already deficient ◦ Zinc – NB in immunity, wound healing  ↓incidence, frequency, severity, persistence of diarrhoea ◦ Vit A – NB for maintenance of epithelium  Address underlying conditions ◦ Infectious diarrhoea ◦ Malnutrition ◦ Hypothroidism ◦ Immunodeficiency

66  History ◦ Age of onset ◦ ?Preceded by episode of acute gastroenteritis ◦ Diet – foods which exacerbate diarrhoea ◦ Gender (IPEX, AI enteropathy) ◦ Drugs, toxins – thyroid hormone ◦ Previous bowel surgery ◦ Underlying immunodeficiency ◦ Other conditions – diabetes, hypothyroidism ◦ Family history – males on mother’s side

67  Stool examination ◦ Look at it – watery, bulky, pasty, oily, blood/mucus ◦ Look at perineum – excoriation suggest acidic stools ◦ Reducing substances  need liquid component  nappies very absorptive  may need to repeat  must be on lactose-containing diet  >1% abnormal  Also check stool pH  Not useful beyond infancy ◦ Stool electrolytes – intractable diarrhoeas

68 ◦ Faecal elastase – pancreatic exocrine function ◦ Faecal α₁ Antitrypsin – protein-losing enteropathy  Endogenous protein, not secreted, absorbed, digested by GIT ◦ Leucocytes, occult blood, lactoferrin – suggestive of infectious diarrhoea ◦ Chromatography – identifies malabsorbed sugar  Microbiology & microscopy (fresh stool) ◦ Fat globules ◦ Leucocytes, blood - colitis ◦ Should repeat several times ◦ Culture for bacterial pathogens ◦ Cysts, ova, parasites (cryptosporidia) ◦ Viruses ◦ Giardia lamblia – duodenal juice, can do faecal antigen test

69  Sweat test – sodium test, exclude CF ◦ ΔF508 – commonest mutation, DNA analysis ◦ Must be well-hydrated, off antibiotics  Sugar hydrogen breath test – bacterial overgrowth ◦ Use of different sugars can help distinguish between CHO malabsorptions ◦ Stool reducing substances more useful in infants  Exclusion diets ◦ NPO – if diarrhoea continues – secretory ◦ Restrict carbohydrates (lactose) – if improves, likely disaccharidase deficiency ◦ Eliminate cow’s milk protein – if improves, possible food- sensitive enteropathy

70  Immunological studies ◦ Immune deficiency predisposes to chronic diarrhoea ◦ T cell subsets, immunoglobulins, IgG subsets ◦ Anti-tissue transglutaminase-IgA, serum IgA – coeliac disease  Radiological studies ◦ Barium studies – malrotation, blind loops, strictures  Small intestinal biopsy ◦ Endoscopically usually ◦ NB in diarrhoea in children ◦ Only way to diagnose coeliac disease

71  Isoelectric focussing of transferrin – congenital disorders of glycosylation ◦ Rare, rapidly expanding group of clinically heterogeneous disorders ◦ Most assoc with psychomotor retardation, dysmorphism ◦ CDG type 1b – normal neurodevelopment, predominant symptom diarrhoea  CW has genetics clinic appointment 25/03/2011

72  Look for complications of diarrhoea, malabsorption  May point to aetiology also  FBC ◦ Anaemia, WCC, platelets  U&E  Inflammatory markers  Albumin  Serum iron, ferritin, B12, folate  Vit D, calcium, ALP  INR

73  1) General supportive measures ◦ Early fluid, electrolyte replacement ◦ Oral rehydration therapy superior to IV – safer, more efficacious ◦ Additional amino acids/ substitution of rice gruel/ cereal for glucose been proposed ◦ Increase caloric intake

74 ◦ Though disaccharide deficiency not thought to be major cause of persistent diarrhoea, hypolactasia often 2° to intestinal damage, malnutrition  Lactose-free diet recommended (part of WHO treatment algorithm)  Lactose replaced by maltodextrins/ other CHO  May need sucrose-free formula also ◦ Exclusion diets instituted to overcome food intolerance which may be cause or effect of diarrhoea  Cow’s milk hydrolysate  If not tolerated, amino acid-based formula

75  Continuous enteral nutrition beneficial for ↓absorptive function ◦ Rationale - ↑time:absorptive surface ratio → increase daily nutrient absorption  Parenteral nutrition may be necessary (early)  2) Nutritional rehabilitation ◦ Micronutrient, vitamin supplementation

76  3) Drugs ◦ Antibiotics/ probiotics ◦ Modification of intestinal microflra ◦ Antibiotics – BOS, bacterial diarrhoea ◦ ‘Bowel cocktail’ – Metronidazole, Cholestyramine, Oral Gentamicin  Proposed for severe, protracted diarrhoea of suspected infectious aetiology  Lacking conclusive proof of efficacy ◦ Specific therapy  Immunosuppressives for AI enteropathy

77 ◦ Drugs to decrease fluid loss  Abnormal ion channels – enkephalinase inhibitor – racecadotril - ↓breakdown of endogenous opiates  Somatostatin/ octreotide – severe secretory diarrhoea  Loperamide – side effects unacceptable in children ◦ Trophic factors (increase cell growth) ◦ Growth hormone – used in short gut syndrome ◦ Inhibits chloride secretion, improves sodium absorption

78  Mono- or mixed cultures which must ◦ be live organisms ◦ be of human origin ◦ be non-pathogenic ◦ be viable in delivery vehicles ◦ be stable in acid and bile ◦ adhere to target epithelial cells ◦ persist within GIT ◦ produce antimicrobial substances ◦ modulate the immune system ◦ influence metabolic activities – bile acids, nutrients

79  Beneficially affect host by ◦ Improving properties of indigenous microflora ◦ Hampering growth of diarrhoeal pathogens ◦ Boost cellular and humoral immunity  Evidence for benefit in viral and antibiotic- associated diarrhoea ( ↓severity, duration)  Lactobacillus rhamnosus, L acidophilus, Bifidobacterium bifidum, yeast Saccharomyces boulardi (not human origin)  May also help in food-allergies – partial hydrolysis of antigens  Prebiotics – fructan, galactan – ferment in bowel → promote growth of beneficial bacteria ◦ Given together, enhance efficacy of probiotics  Problem – many ‘wannabe’ products – doubtful effectiveness

80  Is the hypothyroidism related to the cause of the diarrhoea?  Unlikely 2° to diarrhoea ◦ already had hypothyroidism on 1 st admission ◦ Monovalent ions absorbed easily in GIT  Hypothyroidism can cause diarrhoea due to ↓motility, BOS ◦ but ?should have settled on thyroxin replacement  Excessive exogenous thyroxin could cause diarrhoea, but diarrhoea came first…..  Recurrent infections ◦ Pneumonia, E. coli sepsis, skin lesions and ? Fungal sepsis – never proven ◦ HIV negative, lymphocytes slightly low (?significant) ◦ Considered CATCH 22 as dysmorphic, recurrent infections, hypocalcaemic, but FISH negative, PTH high, heart normal…..

81  Infections possibly due to immunocompromise 2° to malnutrition, decreased gut mucosal integrity  Hypocalcaemia, ↑PTH level, ?Vit D level, but responded to Vit D ◦ Why would Vit D have been low? Was on formula and breast, not prem, didn’t look clinically like fat malabsorption ◦ Did the diarrhoea just interfere with Ca²⁺ absorption?

82  CW had persistent diarrhoea  Began late neonatal period (7 weeks)  Was not ‘intractable’  Female infant  ?dysmorphic  Hypothyroid  Hypocalcaemia – possibly effect of malabsorption  No protein losing enteropathy  Recurrent infections, no eczema  UNLIKELY transport defect, epithelial enteropathies

83  Patient seems to have finally turned the corner and stabilised on Alfare (semi-elemental formula) ◦ Could be due to post-enteritis enteropathy, disaccharidase deficiency and/or cow’s milk protein intolerance ◦ Maybe just needed longer for bowel to recover ◦ Problem – accessing formula. When to step down? ◦ If relapses again, for SB biopsy  ?AI enteropathy  ?sucrase-isomaltase deficiency  ?CDG  ?Cystic fibrosis – but stools seemed watery, not typical – sweat test => negative 

84  Mucosal atrophy can result in an 80% reduction of intestinal surface area in infants  Once the offending agent is removed, repair of the small bowel progresses slowly  After 2 months, the villi surface area is 63% normal but the microvillous surface area is only 38% normal.


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