Gastrointestinal System

Gastrointestinal System Embryology Gut forms as tube from mouth to cloaca at 4/40 Fully differentitated by 20/40 Foregut – As far as ampulla of vater Lips fuse by 5/40 (beyond = cleft) Palate fuses by 8-9/40 Liver buds off distal foregut (D2) Midgut – Distal duodenum à proximal 2/3 of transverse colon Gut rotates 90 degrees & returns to abdo, during return rotates a further 180 degrees clockwise = total 270 degrees Failure to return à exomphalos Hindgut – Distal 2/3 transverse colon à end of gut At 6/40 septum forms to separate rectum from urogenital tract Motility Starts from 16/40 Fully functional by 36/40 therefore motility probs in prems is common Meconium < 34/40 is rare Swallowing Starts during 2nd trimester Hydramnios by 20/40 if gut not patent Low sphincter pressures puts prems at high risk of reflux Carb absorption Disaccharide activity not fully estabilished until 10months Maltase ready 1st, then sucrase, then lactase Total lactase deficiency is common < 30/40 à intolerance Fat Absorption Decreased bile salts in prems Cope best with polyunsaturated & medium chain fatty acids (rather than long) Steatorrhoea is normal in prems Secretions Gastric acid is insignificant until 32/40 Lipase should be adequate by term Low trypsin often à poor protein absorption Investigations Liver biopsy If Plts > 60, PT no more than 3 secs above normal, G&S, US to exclude vascular malformations Complications include bleeding, perf, pneumothorax, haemopneumothorax and infection If likely to bleed can do transjugular Jejunal biopsy via endoscopy Recal biopsy if suspected hischsprungs / neonatal intestinal dysplasia Breath Test Undigested sugar à bowel bacteria à fermented to H2 à excreted on breath Plot time from ingestion to peak H2 levels Normal transit time = 2hrs If peak < 2hrs = small bowel overgrowth If peak after 2hrs = malabsorption/ delayed digestion Test control levels at -30mins and 0 mins (fasted) Then give oral bolus à measure every 30 mins for 3 hrs Rise in H2 à small bowel overgrowth Larger rise = intolerance NB: times vary if short gut syndrome Stool pH – reducing substances & chromatography for poor sugar absorption Calprotectin – white cell protein = ELISA assay Normal in IBS, raised in IBD / polyps / Ca / Infection Pancreatic function Stool trypsin/chymotrypsin/elastase, faecal fat and lipase IRT on blood for CF H.Pylori Histology - H&E stain CLO – “campylobacter like organism” from biopsy Urea Breath Test H.Pylori has urease à urea à ammonia + bicarb à CO2 Use stable C13 isotope & detect C13O2 >90% sensitive, 95% specific Decreased sensitivity if had antibiotics / PPI in last month Serology IgG/IgA Ab 90-100% sensitive, 76-96% specific -ve test in UK is likely true result +ve can be false therefore combine with breath test Serology will take 1 yr to become negative after infection Stool antigen 94% sensitive, 90% specific False –ves if Abx / PPI FU to check eradication = breath test / stool Motility & pH probes – if ? achalasia & to prove reflux Oesophageal pH monitoring Usually 24 hrs Often also include HR + Sats to correlate with apnoea’s Parents record events diary Only monitors reflux of acid (if food buffers then no acid so won’t be detected) Reflux index = % of time with pH < 4.0. Usually up-to 12% at < 1yr old, <6% at >1yr old Helpful if ? Sandifer’s syndrome/efficacy of PPI Rx Radiology – plain films for perf/dilation / loading, Contrast for malformations US for pyloric stenosis, CT for virtual colography Pancreatic function tests Direct – cannulate duodenum à inject CCK à aspirate secretions Indirect – faecal chymotrypsin (low sens & spec & invalid if on creon) / elastase (93% spec, 93% sens & valid on creon) Fat malabsorption Causes of Clubbing Quantitative estimation of stool fat Resp – CF, mesothelioma, Standard diet for 3/7 then 3/7 collection bronchiectasis, fibrosis, Ca OR diet diary & spot tests GI – Lymphoma, IBD, Cirrhosis Steatorrhoea if > 7% of ingested fat is excreted (15% in Cardiac – Cyanotic lesions, infants) myxoma, endocarditis OR use steatocrit = spot check Enteral / parenteral nutrition Oral – compliant child who likes tastes NG – bolus / continuous, tube visible on face & easily displaced. Used if feeding difficulties/increased requirements NJ – check site using XR. Used if vomits ++ / severe reflux. Also decreases pancreatic simulation Gastrostomy – needs GA to site. Local infection risk. Can be used for medium / long term support Jejunostomy – as above but for severe reflux Peripheral parenteral – peripheral cannula = short life. Phlebitis is common (limit concentration of feed) = short term solution Central parenteral – full requirements – difficult initial line placement + high infection risk. Can be used as long term solution Vomiting Nausea = feeling of wanting to vomit. + autonomic features e.g. hypersalivation, pallor, sweating, decreased gastric motility, duodenal contents à stomach Retching = strong involuntary efforts to vomit with diaphragm & abdo muscles contracting Vomiting = expulsion of gastric contents Regurgitation / Posseting = relatively effortless Physiology - Drugs, toxins, hormones & metabolic effects à CTZ (floor of 4th ventricle) à vomiting centre (also receives input from vestibulo-occulo stimulation and higher cortical centres) If assoc. with neck movements = Sandifer’s syndrome If severe can à Oesophagitis & stricture with bleeding Rx – positional, thickener, pro-kinetic agents, RARELY surgery Anti-emetics Antihistamine – motion sickness/mild chemo induced. Acts by labyrinth suppression by anticholinergic H1 receptor antagonism Metoclopramide – chemotherapy/gastroparesis. Acts by D2 receptor blockade in CTZ. High doses also have 5HT3 activity Ondansetron – chemotherapy and PONV. 5HT3 receptor antagonism in gut and CTZ and vomiting centre Benzodiazepines – chemotherapy. Central gaba inhibition à sedation & anxiolysis Phenothiazides – DON’T use in children due to EPSE à D2 receptor blockade in CTZ Butyrophenones (e.g. domperidone) – chemotherapy, gastroparesis and GOR à D2 receptor blockade in enteric NS Acute Infection (gastritis, tonsillitis, UTI, meningitis, appendicitis) Ingestion (accidental / intentional / poisoning) Obstruction (webs, malformations, volvulus, stenosis) Raised ICP (space occupying lesion, meningitis) Chronic Recurrent Reflux Peptic inflammation Infection (recurrent UTI) Menetrier disease = increased gastric folds due to CMV / H.pylori Diet intolerance (e.g. wheat, CMPI) Achalasia Obstruction SMA syndrome (compression of D3 by Aorta & SMA) Malignancy (inc. cranial) Cyclical Vomiting Syndrome Recurrent episodes of N&V lasting hrs / days Complete wellbeing between episodes, usually early am / late evening onset, Can have prodrome 2-7 yrs at onset Assoc with family Hx of migraine, travel sickness, or other functional bowel probs Pallor, abdo pain, headache, intolerance to smells, light or sound, diarrhoea, rash, HTN Rx is difficult – try ondansetron, ibuprofen, erythromycin (for prokinetic effect) 80% have emotional trigger (e.g. upset / pressure) Others Behavioural – rumination, cyclical vomiting, bulimia Neuro - abdominal migraine Endocrine (phaeochromocytoma) Metabolic (MCAD, porphyria) Pyloric Stenosis 1/1000-3000 Boys : girls = 4 : 1 Multi-factorial inheritance, commonest in first born male, high twin concordance, 7% risk if previous affected sibling Due to hypertrophy & hyperplasia of pyloric muscle (circular fibres) Assoc with CMPI - ? hypertrophy linked to immune response Timing – Birth to 15 weeks (most common 4-6 weeks old, 5weeks after full feeds in prems) Hx & O/E: persistant projectile vomit but still hungry, NEVER bilious vomit, olive sized mass (2cm), visible peristalsis on test feed à undernourished & dehydrates USS: if mass not found Capillary blood gas: Hypochloraemic metabolic alkalosis (due to loss of HCl) + Hypokalaemia (2o hyperaldosteronism due to low volume à try to retain Na à loss of K+) + low Na ΔΔ: basic reflux, overfeeding, gastroenteritis (accompanied by diarrhoea) Rx: IV fluid to correct blood gas abnormalities over 24 - 48hrs (0.45% NS + Dextrose + K+) Then surgery – Ramsteadt Pyloromyotomy Achalasia Absent / decreased relaxation of lower oesophageal sphincter à dysphagia & vomiting (@ night) Sx - Wt loss, retrosternal pain chest infections. Diagnosis – CXR (air fluid level with widened mediastinum, barium, manometry Rx – dilatation (temp) / Heller myotomy (definitive) Reflux Posseting (winding à air + some milk) is normal Some babies enjoy ruminating (eases as diet changes) Excess regurgitation Contents reach mouth Faltering growth à Ix for other causes FBC, UE, LFT, Ammonia, Glucose, MSU, Urine ketones & reducing substances. Stool reducing substances + barium studies. Rx – thickening, hypoallergenic formula, increased calories, pro-kinetic agents, continuous NG feeds Reflux Involuntary retrograde flow into oesophagus Effortless – no nausea / retching Normal resting sphincter pressures but intermittent spontaneous lower oesophagus sphincter relaxation Intra-gastric pressure doesn’t change Common in infancy (due to incompetent sphincters) – 11% on pH studies (6% by 2y) 50% at 0-3m Peak at 4m 5% at 10-12m – improves with growth, weaning, more time upright & improved tone Physiological GOR = improves with age/weaning & upright position. 80% resolve by 18m, 9095% by 2 yrs. Reassure & can offer thickener If excess reflux – Calm child b4 feeds prevents swallowing air Thicken feeds (cornflour /carob seed) Upright after feeds Pathological if… Oesophagitis Irritable with feeds / food refusal Arching, hematemesis / anaemia, Sandifer’s syndrome (= abnormal posturing), Biopsy & endoscopy Rx – neutralise acid & thicken & pro-kinetic agents Respiratory disorders (apnoea, aspiration) Can à apnoea, stridor & aspiration pneumonia + hoarse voice Assoc. with ALTES and SUDI Rx with maximal therapy In older children (Typical): Heartburn, positional / post prandial, acid regurg, epigastric pain If recurrent then biopsy Atypical sx: vomiting, dental enamel erosion, ENT sx, Resp Sx (asthma, cough), atypical chest pain, dystonic movements (sandifer complex) GOR & Neuro-disability 1/3 of children with neuro-disability Increased if hiatus hernia / foregut dysmotility Can à faltering growth, dental erosion etc. SE are more severe than in normal children Often get oesophagitis à H2 antagonist/PPI May need fundoplication à increased rate of complications If assoc. with spasms & dystonia = Sandifer’s Syndrome Increased incidence / severity in oesophageal surgery, chronic chest problems & neurological conditions Investigate by… Barium swallow, pH monitor, endoscopy & biopsy pH study will give “Reflux index” = time with pH < 4 5-10% = mild 10-12% = mod 20% = severe 30% = consider surgery Differentials Malrotation / congenital malformation Metabolic problem Neurological problem Food allergy Rx: Simple measures as above Thickener (gaviscon) – NB gaviscon is activated by reacting with acid – no benefit to use with PPI Antacid (PPI/H2 receptor antagonist) Prokinetic (domperidone, metoclopromide, erythromycin, cisapride) May be due to intolerance – therefore in infants try formula change If very severe à nissens fundoplication If not responding to basic treatment then consider Lactose intolerance (check stool reducing substances) Pyloric stenosis (check blood gas and US abdo) Urine infection Stricture / mass / achalasia Eosinophilic oesophagits IBD (usually crohns) Caustic ingestion (in older children) GvHD / Lymphoma / Drug induced / Connective tissue disease Prognosis – Reflux in 1st few weeks usually resolves Reflux in older children will continue into adults in 50% Oesophageal in-coordination Sx - Dribbling, aspiration, choking, regurg Should exclude in all cases of cerebral palsy Investigate with cine radiography 3-Month Colic Breast & bottle fed = same incidence Screaming, draw knees up, red in face – usually in afternoon/eve/night Most commonly around 6pm Sometimes improves with passing stool / flatus NOT pathological, reassure parents Diarrhoea Physiology GI immune system = increased Lymphocytes in lamina propria/peyers patches & follicles GALT = gut assoc. lymphoid tissue 40% of total body lymphocytes are in gut These produce IgA Gut immune maturity occurs around 2 yrs. Gut water 99% of water is absorbed in small & large intestine Dehydration <5% = mild = dry mouth & lips 5-10% = moderate = dry tongue, sunken eyes / fontanelle, decreased skin turgor, decreased UO & increased HR >10% = severe – poor perfusion with drowsy & NO UO for 12 hours. Sunken eyes & fontanelle. Increased HR, decreased BP Can be increase in frequency, decreased consistency, increased water or increased vol (>10g/kg/day in toddlers, > 200g/day in 3yrs +) Increased fluid content in stool (normal fluid = 10mls/kg/day)/ Acute <3/52 = acute Acute diarrhoea = abrupt onset Acute diarrhoea can à metabolic acidosis Osmotic = malabsorption à raised osmotic pressure à water into gut. Usually carbohydrate. Stops quickly if the child is fasted Large osmotic gap (i.e.) 2 x (Na + K) = measured faecal osmolality. If difference >50mmol/l = likely osmotic Often stool pH < 5.5 due to carbohydrate fermentation by bacteria further down gut Secretory induced by enterocytes = continues despite fasting. High faecal Na+, balanced equation NB – infections are usually osmotic AND secretory Dietary Watery diarrhoea + abdominal pain Likely to be diet problem e.g. fruit juice, squash, fizzy, sugar free, boiled sweets Infective Can result in 2o lactose intolerance Low Na > High Na in gastroenteritis 1/50 children are admitted due to GE in childhood (>95% are < 5yrs) 6-24m then viral = most common – otherwise bacteria more common Watery diarrhoea with vomiting, dehydration & 2o lactose intolerance = rota, adeno, calci, noro, enteropathic e.coli or giardia Watery diarrhoea alone – cholera, enterotoxic e.coli, crypto Dysentery (cramps + bloods diarrhoea & fever) – salmonella, shigella, Yersinia, campylobacter, invasive e.coli, amoeba) Bacterial Commonly with fever & blood if invasive NB: don’t cause chronic infection E.coli - (3-5%) 0157 à verotoxin à endothelial damage & HUS E.coli – is also invasive à inflammation & ulceration Campylobacter (6-8%) (from uncooked meats) – most common in children & young people (rather than adults). Rx with cipro. Common pathogen in domestic animals & poultry. Stool culture needs special conditions (42o, micro-aerobic, blood agar with antimicrobial added). Can cause colitis Shigella (0-3%) neurotoxin à pyrexial convulsions & marked meningism, also invasive Salmonella (3-7%) – invasive Yersinia (1-2%) – invasive C.diff (0-2%) - toxin Virus 50-60% of acute gastroenteritis < 5yrs Rotavirus (25-40%) – double stranded RNA for winter epidemics Calcivirus (1-20%) Astrovirus (4-9%) Adenovirus (2-4%) Norovirus (unknown) Often co-exist with UTRI symptoms Parasites Cryptosporidium (1-3%) Giardia (1-3%) Management – Assess dehydration (3-4% = mild, mod = 5%, sev = 10%) Give dioralyte (90mmol/l of Na) Hyponatraemic dehydration more common than hyper Chronic > 3/52 = chronic Can be due to • Enteropathy = loss of SA due to inflammation • Defect in transport mechanism • Or deficiency of enzyme Lactase deficiency Can be congenital enzyme deficiency Or seen post infection due to loss of cells from brush border Low pH stool = acidic & burns perianal area +ve for reducing substances à faecal sugars by chromatography Cow’s Milk Protein Intolerance 2-7.5% of ppn Usually present in 1st 3m 50% have other food allergy (8-14% soya) Clinical diagnosis based on Hx. Sx - Crying, D&V – loose blood stained stool, colic, irritable, urticaria, lip swelling, stridor, bronchospasm, FTT, rectal bleed, anaemia, hepatosplenomegaly, Ix – RAST is Unreliable à exclusion diet Rx: usually temporary, substitute with soy protein (25% will develop soy intolerance too) Usually outgrow. NB. If breast fed then mum needs milk free diet too Toddler’s Diarrhoea 6m - 3y m>f ALWAYS thriving 3+ stools / day – smelly with undigested food (peas & carrots), Due to increased transit time (triggered by small snacks and cold drinks) No weight loss / failure to thrive Rx: restrict fluids to meal times, no drugs needed Acrodermatitis enteropathica Rare AR due to defect in Zn metabolism. Sx - Severe Diarrhoea, FTT & rash over mucocutaenous junctions & pressure areas. Also alopecia & nail dystrophy. Rx - Fatal without supplementation Congenital Chloridorrhoea Rare AR – defect in ileal Cl transport è Polyhydramnios, Watery diarrhoea from birth, Dehydration, Hypokalaemic, hypochloraemic, alkalosis Stool Cl- > K+ + Na+ No Rx available Can be compatible with normal lifespan Pseudomembranous colitis Caused by toxogenic C.diff (Gr +ve, obligate anaerobe, bascillus) Toxin A à diarrhoea Toxin B à increased vascular permeability (detectable on lab test) Increased risk if Abx, antivirals, diet change, hirschsprungs, uraemia & anaesthesia C.diff infection can cause mild, non bloody diarrhoea OR Haemorrhagic colitis with protein losing enteropathy à Shock, fever, leucocytosis (in some cases), toxic megacolon, perforation & peritonitis On colonoscopy (high risk for perf!) see lesions of grey/white exudate which are poorly adherent (pseudomembranes). Surrounded by oedema & erythematous inflammation Constipation Constipation = Passage of difficult / painful stool for > 3wks – often assoc with soiling Soiling – leakage of liquid stool around impaction OR no faecal continence after 4 yrs Encopresis – involuntary leakage / soiling in inappropriate places 90% is functional à decreased appetite, wt loss, poor behaviour, UTIs / urine incontinence Hx & OE ALWAYS examine spine & legs inc reflexes Check for delayed passage of meconium (can present late) Causes Infants Commonly – inadequate food / fluid (esp if vomiting) Rarely – Hirchsprungs Toddlers / Children Common – 2o to minor illness, anal fissure à pain passing à withholding stool, functional / psych, no cause Rarer – anal stenosis, hirschsprungs, hypothyroid, hypercalcaemia, neurological problems/ hypotonia Organic Anatomical – structural / nerve (e.g. Hirschsprungs) Neuropathic – spinal cord Gastrointestinal – CF, Coeliac, CMPI Metabolic – Hypothyroid, hypocalcaemia, hypokalaemia, DM, MEN Connective Tissue Drugs Non organic Development – e.g. ADHD, cognitive Depression Constituitional – genetic predisposition Situational – school avoidance, sexual Dietary – inadequate fluid / fibre Infants – inadequate milk, hunger stools, overstrength bottle formula Weaning to cows milk à hard less freq stools, à anal irritation à withhold à harder Rx: Behavioural methods – star charts etc Fluid & fibre – adequate hydration & fibre in diet Prompt use of gentle laxatives & increase fluids May require disimpaction regime (picosulphate) Long term Prolonged constipation à acquired megacolon & failing of sphincters à soiling Increased risk of diverticular disease as adults Crohns Disease (regional ileitis) Antigen driven abnormal inflammatory cascade via mucosal immune system. ¼ of cases present before 18yrs (increased if smoking, decreased if breast fed). 10-20% lifetime risk if 1st degree relative) 75% have ileocolic disease (histologically) = 25% DONT Sx: Abdo pain (increased by eating, decreased by soiling), Diarrhoea (with blood & mucus) Anorexia, early satiety, FTT, fever, Oral & perianal ulcers (consider in anorexia nervosa) Also Systemic features e.g. arthropathy, erythema nodosum, pyoderma gangrenosum, renal stones, fistulae, HPB stones, cholangitis, pancreatitis, hepatitis, DVT. Osteoporosis is common Ix: ESR, CRP, platelets, Hb, Endoscopy – mucosal thickening, loss of vascular pattern, apthous ulcers, skip lesions, lesions, fissures & fitulae, cobblestones, transmural oedema à Stricture + obstruction, perianal skin tag. Barium study White cell scan à areas of inflammation in gut Biopsy à crypt abscesses, non-caseating granuloma Rx: 1. Elemental diets (e.g. modulin) 2. Steroids may be required 3. Ciclosporin / azathioprine 4. TPN then use ASA, Abx, probiotics 5. Immune modulators and biological agents (e.g. anti TNF alpha) to maintain remission 6. Surgery as last option Crohns V UC Ca Risk is equal Apthous ulcers, gallstones, perianal abscess & skin tags & non-caseating granuloma are ALL MORE COMMON IN CROHNS Ulcerative Colitis Sx: diarrhoea with visible blood & mucus (early episodes can be brief) GI changes ONLY affects colon (except backwash ileitis) Urge, tenesmus, pain, fever FTT, arthritis, liver probs & Skin signs Erythema nodosum = top = mpst common (red lumps, tender, usually on shins) Pyoderma gangrenosum =nxt pg (necrotic areas to legs) Also increased risk of psoriasis (2-3x ppn risk) 10-35% have growth delay Can get glomerulonephritis & hypercoagulable state à cerebral thromboembolism Ix: Exclude infection Raised inflammatory markers Colonoscopy & multiple biopsy àMucosal thickening, loss of vascular pattern, ulceration Rx: Steroids for acute attacks (enemas / foam suppositories if local, otherwise systemic) to avoid Toxic MegaColon Sulfasalazine (asacol, pentasa) for inducing & maintaining remission If extensive disease à immune suppression with azathioprine / cyclosporine Final option = colectomy = curative Toxic megacolon – transverse colon > 6cm + fever + Neutrophilia + tachycardia = MEDICAL EMERGENCY – NG / IV antibiotics / early surgical involvement Malabsorption Carb digestion 50-60% starch à add amylase à maltose & maltotriose à sucrose –isomaltase (80%) & glucoamylase (20%) à glucose 30-40% sucrose à sucroisomaltase à glucose + fructose Lactose (0.20% in adult, 40-100% in infants) à lactose à glucose + galactose Sugar Malabsorption Osmotic diarrhoea (stops on fasting) + waters + acidic (pH < 5.5) +++ Flatus à explosive nature e.g. – lactose malabsorption can be 1o = congenital hypolactosaemia in some ethinic groups 2o = more common = after infective GE e.g. congenital glucose-galactose malabsorption Rare AR = absent glucose/galactose/Na transporter in membranes Therefore can’t tolerate lactose / glucose based feeds Rx –fructose based formula e.g. sucroisomaltase deficiency AR Watery diarrhoea after sucrose / starch Present after weaning Ix – sucrose: hydrogen breath test / sucrose challenge à diarrhoea +ve for sucrose. Rx – exclude from diet Protein malabsorption Proteins digested by Pepsin & other pancreatic enzymes Can get protein loosing enteropathy due to: Abnormal / inflamed mucosa OR abnormal lymphatics à low albumin & increased stool A-1 antitrypsin e.g. Coeliac, CMPI, Crohns, Giardiasis, Tropical Sprue, GvHD Fat malabsorption Digestion in duodenum / jejunum Most dietary fat = insoluble long chain TGs Digestion in stomach with lipase from fundus Bile salts emulsify Then lipase splits TGs to MGs& FFAs Then pancreatic bicarb à maintains pH for hydrolysis Micelle formation à mucosal cells à reforms to TGs à Chylomicrons à lymphatic system à blood Steatorrhoea Exocrine pancrease insufficieny e.g. CF /Schwachmann-Diamond Syn Shwachmann-Diamond Syndrome Rare AR (1/20-200,000) 2nd most common cause of pancreatic insufficiency + cyclical neutropenia + other haem abnormalities (low plts) Developmental delay Enlarged liver with abnormal LFTs Short stature Risk of sepsis, skeletal anomalies (inc syndactly) & increased risk of haematological malignancies Rx – pancreatic supplements Lack of bile salts 1o = Byler’s disease 2o = Obstruction / ileal resection / bacterial overgrowth Mucosal pathology Enteropathy e.g. coeliac/CMPI etc Co-lipase deficiency Failure of Chylomicron formation = abetalipoproteinaemia Abetalipoproteinaemia Rare autosomal recessive disorder à Deficiency of apolipoprotein B-48 and B-100 à Failure to transport chylomicrons and VLDL from gut Causes malabsorption of lipds & fat soluble vitamins à steatorrhoea & osteopenia Can cause ataxia & retinitis pigmentosa NORMAL IQ On X-ray – thickening of mucosal folds in duodenum & jejunum On blood film – acanthocytes (speculated RBCs) NOT assoc with atherosclerosis as failure to absorb so low fat Damage to lymphatics = intestinal lymphangectasia Coeliac Disease (gluten intolerance) 1/2000 (1/300 in west Ireland) Usually present before age 2 Higher risk if breast fed for longer Pathophysiology Immune mediated Multisystem Reversible gluten sensitive small intestine enteropathy in a genetically susceptible individual (HLA-DQ2 in 90%+, rest – HLA DQ8 – If not +ve for either then CANT be coeliac) Can be triggered by viral infection à exposure of microvilli to gliadin à cascade by T lymphocytes. More common if FH / DM / other autoimmune condition / IgA deficiency / T21 / Turners / Williams syndrome, Linked with prems & low birth wt 1/3 of population are at genetic risk – but many are asymptomatic / non-manifesting S&S: Ix: FTT – due to malabsorption (of glucose & lactose), muscle wasting, delayed puberty Pale offensive watery “porridge-oat” stools (can also be constipated) D+V, abdo distension, irritable, Anorexia, Fe def anaemia (& due to bleeding tendency due to Vit K deficiency) Osteopenia & delayed bone age, can à rickets (will improve after 1 year on gluten free diet) Can be assoc with behavioural changes, unexplained epilepsy, peripheral neuropathy & hypotonia, Can see Clubbing Can get dermatitis herpetiformis (right) Dental hypoplasia/osteoporosis Exclude Giardia infection IgA & IgG antigliadin antibodies (now less used) Modern tests use antiendomysial Ab & tTG Can get selective IgA deficiency (= x10 likely of celiac) à test total IgA IgA Endomysial Ab – 85-98% sensitive, 97-100% specific. Ab against connective tissue around smooth muscle IgA TTG Ab – 90-98% specific, 95-97% specific IgA and IgG antigliadin Ab being phased out NB – coeliac patients can be IgA deficient à not valid test if low total IgA levels. Levels decrease with treatment can therefore be used to check compliance Duodenal / jejunal biopsy = gold standard. Shows total/subtotal villous atrophy (shortened), crypts lengthened & intraepithelial lymphocytes (in lamina propria). Differential is tropical sprue NB: Villi also flattened in milk protein intolerance, & giardiasis Raised transaminases (AST/ALT) (resolves on diet). NB if present <2yrs then challenge later as may be transient (either pre/post pubertal growth spurt New diagnostic criteria: • If serum Ab are 10x upper limit of normal AND HLA +ve then don’t need biopsy • If in at rick group (e.g. T21) the HLA screen – if –ve then don’t need further yearly checks Increased risk GI malignancy (T cell lymphoma & oesophageal Ca) – decreased to ppn risk after 5 yrs on diet. & non GI malignancy – melanoma & NHL Rx – Gluten free diet (symptoms start to resolve within 2 weeks) – rice & potatoes are safe Ulcers IBS Duodenal more common than gastric in children H pylori (gr –ve) à 10% lifetime risk of ulcers. Chronic gastritis & duodenal metaplasia à increased gastrin levels, decreased HCO3- à ulceration. Grade 1 carcinogen (gastric Ca / B-cell lymphoma) Others 10-20% of ulcers are H.Pylori negative (usually assoc with NSAIDs or consider IBD/ zollingerellison syn/hyperparathyroidism, short bowel syn) Ix – Biopsy à CLO / histology Serology C13/14 breath test Rx: Eradicate H.Pylori with PPI, Clarithromycin + amoxicillin / metronidazole Antacids – Mg, Ca or Al Omeprazole / ranitidine Sucralfate à local coating of ulcer Avoid steroids & NSAIDS Rome II criteria 10% of school children experience regular abdo pain Pain + normal physiology & growth = IBS Can be triggered by foods (e.g. lactose, sorbitol, fizzy drinks) Can be linked to stress (psych rv can help) Intestinal Lymphangectasia Persistent diarrhoea with FTT Low albumin, low lymphocytes, low Ig, low Ca Abdo distension Swollen feet Nausea & vomiting Can get steatorrhoea Increased enteric lymphocytes & infiltrates elsewhere Rx: low fat formula & hydrolysed Microvilus inclusion disease AR Very rare Microvilli turned inwards on cells Diarrhoea from birth Need TPN but often have liver problems Cure = small bowel transplant Upper GI Bleed Red = active process Coffee ground = older blood ? portal hypertension / gastritis / ulcer Causes of PR bleeding Consider Fresh V Malena Anal fissure – bright red on stool / dripped. H/O constipation. Usually posterior. Rx stool softener Food allergy à colitis Infection – salmonella, shigella, campylobacter, E.coli 0157, C.diff Meckle’s – usually <2yrs, large volume of dark red blood b:g = 2:1, usually painless Intussusception – redcurrant jelly stool Polyps – usually < 2yrs. Painless – usually hamartomatous polyps in left colon = benign. Rx colonoscopy & remove Haemorrhoids – rare in children. Usually due to portal HTN/constipation. Aching pain with protruding out Neonate – swallowed maternal blood (Apt’s test), NEC, Haemorrhagic disease of the newborn, mudgut volvulus, anal fissure Well child with bright blood – anal fissure, polyp, rectal prolapse, milk allergy Well child with large amount of blood – meckles, peptic ulcers, varices Sick child - gastroenteritis, intussusception, HSP, Crohns, US Recurrent Abdo Pain 10-15% of school age children. Only 10% of those have organic problem Episodic pain, >3month duration, disrupts family & school life Functional abdominal pain = 90% Occurs in approx. 10% of 5yr olds Periumbilical (T10), assoc. with vomiting NO weight loss Good health between episodes. High achievers with colic as a baby Childhood migraine – pain + vomit, nausea, can have aura, FH of migraine, Rx. Pizotifen / trial of food exclusion Renal Tract infection – must be excluded (MSU M+C), loin pain should have USS in case hydronephrosis Peptic Ulcers – waking due to epigastric pain, FH, if H.pylori à triple therapy Chronic Recurrent Pancreatitis – pain à back + vomit, high blood amylase GI – IBS, constipation, oesophagitis, peptic ulcer, IBD, Malabsorption Renal – UTI / Stones Hepatic – Hepatitis Gynae – dysmenorrhoea, PID, ovarian cysts, haematocolpos Others – lead poisoning, sickle cell, migraine IBS – constipation & diarrhoea with bloating. Colic as infant Ix – FBC, UE, LFT, CRP, Amylase. MSU. Stool for Micro & FOB, US abdo + X-ray Acute Abdomen Acute Appendicitis Commonest childhood surgical emergency (3-4/1000 each yr) Most over 5 yrs Young children = RTI à anorexia, vomiting, irritable & high fever Older children = abdo pain, fever, tenderness Mesenteric Adenitis Non-specific abdo pain, inflammation of mesenteric LN, ­ motility Often assoc with viral URTI Dx of exclusion (DD for appendicitis so often have laparotomy) Rx - self-limiting Primary Peritonitis Usually pneumococcus, assoc with nephrotic syn, liver disease & immune def Malrotation Normal embryology Herniates into cord from 6-14/40 Apex of midgut loop communicates with yolk sac by vitelline duct If residual connection = Meckles 2% ppn Whilst extraembryonic à 270o anticlockwise rotation 14/40 gut starts to return to abdo, proximal jejunum 1st, caecum last (initially rests in subhapatic before descending to RIF) Arrested Caecal descent Caecum stays subhepatic Bile stained vomiting due to duodenal obstruction by Ladd’s bands Partial recurrent volvulus in older children due to narrow mesentery between caecum & DJ flexure Often asymptomatic, severe problem if appendicitis! Incomplete rotation Rotation only 90o anticlockwise Colon & caecum return to abdo 1st à left side, small bowel to RHS Whole small bowel on very narrow mesentry àhigh risk volvulus True malrotation 90o clockwise Duodenum results anterior to transverse colon Clinical problems are rare Volvulus Twisting around mesentery Midgut most common in infants Can be intermittent/permanent (à ischaemia) Abdo pain, bilious vomits, distension & fullness Double bubble on XR Confirm with upper GI contrast = abnormal site for ligament of treitz à surgery Meckel Diverticulum Remnant of vitello-intestinal duct Arises from antimesenteric border of terminal ileum Can contain gastric mucosa / pancreatic tissue Mimics acute appendicitis Can à intussussception, volvulus or peptic ulcer Can occur in Lettre’s hernia Ix – technecium scan to find ectopic mucosa Intussussception 3m – 6y (peak < 3yrs) following URTI/GE @ introduction of solids. 2/1000 births, most common cause of obstruction under 2 yrs M : F = 3:1 Pathophysiology – Invagination into adjacent lower section of bowel (usually at ileo-caecal valve) Usually terminal ileum into caecum Meckles / enlarged peyers patches = lead point therefore more common if viral infection, food allergy or immune deficiency Leading segment can be polyposis as in Peutz-Jagher syndrome or ppt by adenovirus with mesenteric LN Sx - colicy abdominal pain (cycles of crying with knees drawn up à pale à normal). Recurrant jelly stool is a late sign due to strangulation O/E – can have sausage shped mass in abdomen Ix – AXR can show, US also - Doughnut sign on USS. Barium enema can show and treat Rx - air / barium enema with reduce 75%, others need urgent surgery Pancreatitis Sx – pain (upper abdo, sudden onset, continuous & intense à back & flanks) due to haemorrhage & enzymes. +vomiting (bilious/feculent) due to paralytic ileus. + CVS collapse if severe Causes Usually trauma, viral infection or other congenital problems with duct Mumps, Zoster, EBV Drugs Biliary Sludging (e.g. CF) Blunt abdominal trauma, including abuse Less commonly – HUS, Kawasaki, Re-feeding syndrome, Pancreas Divisium, Bone marrow transplant, brain tumour, heat trauma, increased triglyceride & methylmalonic aciduria, hereditary (AD, incomplete penetrance) Mx – NBM, IVI, NG, Analgesia, Abx, TPN if required Chronic pancreatitis – atrophy & fibrosis à Obstructed ducts + cysts à exocrine insufficiency. In rare cases à fistulae à pleural effusion with high amylase Short bowel syndrome Malabsorption, fluid loss and electrolyte loss following major bowel surgery Term baby small bowel = 200-300cm (adult = 600-800cm) If ileocaecal valve in present can loose upto 75% of length (without valve backwash à complications). Commest cause = NEC (others = gastroschisis, jejuna/intestinal atresia, volvulus, intussusceptions. Congential short gut, long segment hischsprungs, crohns, SMA thrombosis, trauma) Mx Optimise nutrition – elemental formula (e.g. neocate +/- ) TPN (à cholestasis / sepsis / electrolyte disturbance) Small volume trophic feeds aid adaption (non-feeding à atrophy) Supplements (ADEK, folate, B12, Ca, Mg, Fe, Zn) Probiotics – protect against bacterial overgrowth (worsened if no valve à increased Dlactate) Ranitidine/PPI to protect against acid (high gastrin levels) Urso –malabsorbed fat à increased oxalate à gall stones. Also protects against TPN cholestasis Careful hydration – prone to dehydration and electrolyte imbalance Loperamide/codeine/bile salt resins à slow GI transit (unabsorbed bile salts à diarrhoea) Prognosis: Need 40-60cm of non-dilated upper small bowel + competent ileocaecal valve + colon to cope without PN à Will gradually adapt over 1-2 years to cope Death due to infection / liver failure / imbalance. 90% with 40-80cm survive, 66% if < 40cm Some centres do small intestine transplant (risk of EBV, CMV, fungal infection and graft rejection) Food allergies 5-30% of infants Type I or IV reaction Usually IgE mediated to milk / eggs / fish / peanuts Ix – remove from diet / Specific IgE in blood tests / skin prick test Commonest foods = cows milk, soy and wheat Egg – 1.6% of all children. Present approx. 6m. Rash within 1 hr, stridor, angioedema. Outgrow by 3yrs Peanuts – 0.5%. Urticaria, angioedema. Tends to be life long Cow’s milk protein intolerance Usually transient Can be just Gut or other atopy (rash etc) 30-35% cross react to soya Can be normal biopsy or subtotal villous atrophy Cow’s milk colitis = < 2yrs à bloody diarrhoea with FH of atopy & colitis on biopsy with eosinophils in lamina propria Bloods can be normal or can have raised eosinophils, raised IgE and +ve RAST to SMP +/- +ve skin prick GI Sx – D & V, FFT, Acute colitis, constipation Non GI – migraine, eczema, asthma, anaphylaxis Gradual reintroduction @ 12 months will show some tolerance 85% will lose sensitivity by 3-5 yrs Polyps Juvenile (inflammatory) polyps 90% of all childhood polyps Usually cause painless, intermittent PR bleed between 2-10yrs 1/3 will present with anaemia Peutz-Jeghers Syndrome (a.k.a hereditary intestinal polyposis syndrome) AD inheritance Benign Hamartoma Polyps in small intestine AND hyperpigmented macules on lips & oral mucosa (circumoral) Can à iron deficiency anaemia High risk of intussusception with polyp as lead point Low risk pre-malignant condition 50% malignancy by 50 years Familial adenomatous polyposis (FAP) AD – mutation to APC gene on chr 5 1st – 2nd decade High risk progression to Ca – start screening endoscopy at 12yrs Assoc with retinal hyperpigmentation Cowden Syndrome Multiple hamartomas, papillomas of lips, tongue & nose. Polyps throughout gut esp. stomach & colon Present 2nd – 3rd decade Assoc with breast lesions, ductal Ca & thyroid disease Turcot Syndrome FAP + neurological problems & tumours (glioblastoma, medulloblastoma) Presents in adolescence Gardner Syndrome Triad of: • small GI polyps (stomach, duodenum & colon) • soft tissue tumours (usually epidermoid cysts to head/neck/trunk, or desmoids tumours to abdo) • osteomas Appear in 2nd decade, AD inheritance. Aim for colectomy by end of 2nd decade HPB problems Anatomy R&L lobes Each has 8 segments With lobules that drain to a central vein Function Form & secrete bile Glycogen storage & metabolism Ketone formation Detox of toxins & drugs Manufacture of plasma proteins & coagulation factors LFTS AST/ALT = aminotransferases Increased levels in hepatocyte damage Also found in skeletal & cardiac muscle Can increase with hyperphosphataemia and growth spurts ALP In liver, kidney, bone, placenta, intestine Increased = biliary epithelial damage / cirrhosis / rejection OR osteopenia due to low Vit D GGT In biliary epithelium & hepatocytes Synthetic functions Albumin – decreased in chronic disease Clotting factors – acute/chronic Hypoglycaemia = acute failure Jaundice Conjugated = direct, un-conj = indirect Hb/Haem à biliverdin after 120d (adult) or 90d (neonate) Biliverdin à bound to albumin à liver à Taken up by liver cells à conjugated with glucaronic acid by glucaronyl transferase à water soluble form Excreted in bile as bilirubin diglucaronides (70-90%) or monoglucaronides (upto 30%) Secretion is increased by choleretic agents (e.g. Phenobarbital) and decreased by hormones (e.g. oestrogen) Bilirubin in bowel à converted by gut bacteria to stercobilinogen à excreted in faeces (but can re broken down & reabsorbed) Unconjugated Increased production = haemolysis Transport failure to site of conjugation e.g. Gilberts = AD with mild jaundice – increases with illness, dehydration or exercise, Vague abdo pain & malaise Defective glucaronyl transferase e.g. Crigler Najjar 1 = no UDRGT = risk of kernicterus. Treat with phototherapy / transplant 2 = partial decrease. No transplant needed Conjugated Failure of transport of bile e.g. Dubin-Johnson/ Rotor syndrome = both AR Intra/extrahepatic obstruction Intrahepatic = drugs, viral, autoimmune Extrahepatic = mechanical obstruction e.g. gallstones, atresia or choledochal cysts Neonatal Jaundice Affects 50% healthy neonates & 85% of prems will be jaundice within 1st week Risk factors: Asian race (independent of risk of G6PD) Oxytocin in pregnancy Breast Fed Premature baby Bruising Increasing maternal age Previous child requiring PT Polycythaemia (e.g. delayed cord clamping / twin-twin transfusion) In fetus: placenta & maternal liver metabolise bilirubin. If excess (e.g. rhesus disease) à amniotic fluid & cord stain yellow & haemopoetic tissue cannot cope with turnover à hydrops (generalised oedema, effusions, ascites, hepatosplenomegaly) due to combination of hypoxia, hypoproteinaemia, low colloid osmotic pressure & congestive heart failure In newborn: most bilirubin comes from RBCs (short lifespan = 70-90d v 120d in adult), & is jaundice is due to initial enzyme deficiency UDPGT (rate limiting step in conjugation). 1gm Hb à 600µmol/l of unconjugated bili Unconjugated bilirubin: Is lipid soluble & carried bound to albumin. Binding decreased by low albumin, asphyxia, acidosis, infection, prem & hypoglycaemia. Some substances such as sulphonamides, cephalosporins, sodium benzoate (in diazepam), furosemide & thiazides & free fatty acids produces by starvation, cold & TPN. When bound cannot cross barrier but if unbound = free can cross BBB à basal ganglia à neurological problems = kernicterus (increased risk if birth asphyxia) Step 1 – poor suck, hypotonia, lethargy = transient if treated Step 2 – fever, hypertonia, opistotonus (back & neck arched) Step 3 – high pitched cry & athetosis with seizures (50% mortality) à survivors à Chorioathetoid cerebral palsy & mental handicap, high tone hearing loss Treat with phototherapy to increase conjugated bili = water soluble = can’t cross BBB Kramers Zones: 1. Head & neck <100µmol/l 2. Upper trunk 150µmol/l 3. Lower trunk & thighs 200µmol/l 4. Arms & legs below knees 250µmol/l 5. Hands & feet >300µmol/l + Jaundice is pathological if: <24hrs old Total > 250µmol/l on day 2 Rising at > 100µmol/l in 24 hrs Prolonged jaundice (>14d in term, >21d in prems) Pale stools & dark urine Jaundice in the child of a Rh-ve mother with antibodies Investigation Examination: inc bruising, purpura, pallor, hepatosplenomegaly, neuro signs Infection screen Bloods including bili (with split), U&Es, FBC and G+C Urine dip = only detects conjugated Coombs Test Rh- mother initially has no antibodies to Rh At 1st exposure mother develops Rh antibodies Before / at birth these cross the placenta à attack baby’s Rh+ve red cells à destruction of red cells by baby’s immune system Can also occur with Group O mothers who pass A & B antibodies (less severe) Indirect Coombs test = tests mother’s blood for antibodies Direct Combs test = Baby’s blood + coomb’s reagent (Anti Hu-IgG). Baby’s sample is +ve if cells have mothers antibodies on surface Treatment levels After day 2 “gestational age x 10” = baseline Well baby: +50µmol/l = exchange, -50µmol/l = phototherapy Baby on SCBU: baseline = exchange, -100µmol/l = phototherapy For sick baby: baseline -50µmol/l = exchange, -150µmol/l = phototherapy Draw line between 50 (PT) and 80 (exchange) and treatment lines for days 0-2 Phototherapy: Blue light (450nm) Works in 3 ways: Photo-oxidation, configurational isomerisation & structural isomerisation = most important because à lumirubin = excreted in bile & urine Common side effects are skin rashes, fluid loss, diarrhoea (PT decreases transit time & induces lactose intolerance) & poor temp control Serious side effects include DNA damage & retinal damage (no evidence but wear eye shades & nappy) Bronze baby = occurs when infant with obstructive jaundice receives PT Exchange transfusion Consider if hydrops, rapid rising bili despite PT (>17µmol/l per hr) Will correct anaemia, remove antibodies & reduce bili Required whole blood Usually exchange “double volume” = 180mls/kg Risks / complications Electrolyte disturbance – Low Ca, high K+ Glucose disturbance – initially high, then rebound low Infection – from contaminated blood Thromboembolism – air / clot NEC Fluid overload (or sometimes hypovolaemia) Acidosis, hypoxia, bradycardia & arrest Benign intrahepatic cholestasis (if severe IUGR) Haemorrhage Adjunct Therapy Albumin - 1g/kg IV before exchange transfusion or added to donor blood increases binding Metalloporphyrins – haem-oxygenase is rate limiting step in bili production. Inhibiting this step à reduces production of bili. Can be used (usually as IM tin protoporphyrin in G6PD IVIG – limited evidence that will reduce antibody induced haemolytic cases, still need PT Phenobarbitone – improved conjugation, but NOT recommended for neonatal hyperbilirubinaemia Timing Day1 1 - 5d Unconjugated Haemolytic disease of newborn (until proven otherwise), Usually RhD à lysis of baby’s cells Physiological – technically a diagnosis of exclusion Jaundice of prematurity Conjugated Neonatal hepatitis Rubella, CMV, Syphylis 5 - 10d 10d + Haemolysis Sepsis – TORCH screen Polycythaemia G6PD - common in afro-carribean / Mediterranean, oriental Puyruvate Kinase Spherocytosis Breast feeding jaundice – poor oral intake à bowel stasis à increases enterohepatic recycling Sepsis – TORCH screen Galactosaemia - Due to enzyme def to process milk, Improves on stopping feeds, worsens again on starting Hypothyroid - Mixed jaundice, assoc with umbilical hernia & constipation Drugs Sepsis UTI Breast milk jaundice – thriving baby, enzymes (beta-glucaronidase) in breast milk increase enterohepatic recirculation Biliary atresia Neonatal hepatitis Choledochoal cyst Pyloric stenosis Jaundice over 2 weeks = PROLONGED JAUNDICE Neonates all tend towards cholestasis (takes little abnormality to make it clinically significant) Bile acid is toxic to the liver. Cholestasis à inflammation à fibrosis / cirrhosis 70% of cases are idiopathic neonatal cholestasis or biliary atresia Can allow conjungated bili upto 20 (or< 20% of total) GGT & ALP = inflammation, AST/ALT = hepatocyte damage Biliary Atresia (conjugated) 1/15000 Acquired condition Idiopathic sclerosis of a previously patent biliary tree Without drainage à cirrhosis à death (so investigate any prolonged jaundice or pale stools. NB – also low ADEK) Ix: conjugated hyperbilirubinaemia, ­ transaminase, USS (absent gall bladder) à liver biopsy Exclude by radiolabled bile acid on scan (HIDA) Rx: Kasai procedure to reconnect portahepatis to duodenum but high risk of ascending cholangitis Before 60 days has 60-70% of jaundice free After 60d has 25-35% of jaundice free 2/3 of survivors will require liver transplant by age 10 Neonatal Hepatitis Conjugated jaundice, liver cell damage, patent bile duct Many causes inc virus, alpha-1-antitrypsin, etc Hepatic Infections Hep A – RNA Virus 15-50 days incubation Oro-faecal transmission Usually mild / subclinical à immunity after 1st infection Sx: anorexia, fever, vomit, abdo pain before jaundice (can last up to 2 weeks) Ix: ­ serum transaminase (remain for several weeks) IgM is best marked of recent infection, IgG = immunity Hep B – DNA Virus 50-180 days incubation Vertical transmission / body fluids Antenatal screening can alert to risk Acute self limited (majority) – recovery after jaundice, malaise & anorexia à immune. Incubation 6-8 weeks à rise in HbsAg (peaks before clinical disease & undetectable in 6 months). Serum transaminase will be elevated during symptomatic illness Fulminant acute – very rare à massive necrosis of liver cells Chronic hepatitis – may à cirrhosis / recovery. Arises if failure to eliminate virus from liver Asymptomatic carrier state à may later develop chronic hepatitis Clinically unapparent asymptomatic – may à recover / chronic / carrier ­ risk of cirrhosis & hepatocellular CA Rx - C-sect, immunise at birth if vertical transmission Serological markers – HBsAg – Surface antigen – appears 6 wks after infection, gone by 3 months HBeAg – Internal component antigen – occurs similar to HBsAg & = high infectivity HBcAg – Core antigen = immunity (if not present = carrier) Hep C – RNA Virus Blood/vertical transmission 2 month incubation à acute hepatitis with fever, malaise, anorexia & jaundice. Some recover within 2 months, others à chronic à remission & relapses. NB: Risk of hepatocellular CA. Extra hepatic manifestations common (arthritis, agranularcytosis) Serological markers – Anti HCV antibody, HCV RNA Hep D – RNA Virus Requires infection by hep B. Common in drug users & dialysis patients. If chronic then seldom resolves & 60% à cirrhosis Serological markers – IgM anti D, with IgM anti HBc Hep E – RNA virus Causing acute illness. No carrier state Spread by water (faeco-oral). Similar to Hep A. Causes self limiting epidemics. Incubation 1 month à mild jaundice. Can à fulminant hepatitis if pregnant Other viruses CMV, infectious mononucleosis (EBV), Varicella, HSV, Measles, Rubella, Parvovirus B19, Adenovirus, EBV, HHV6, Yellow fever Non viral leptospirosis, listeria, toxo, hydatid Hydatids Echinococcus (tapeworm)from sheep/dogs Ingest ova à embryo develops à penetrates stomach wall à portal vein à liver & lungs à Asymptomatic hepatomegaly (slow growing) Rx – excise & 3/12 mebendazole Alpha1-antitrypsin def Autosomal co-dominant PiZZ or PiNulNul phenotypes of protease inhibitor Can be assoc with cANCA à Liver damage Produced in hepatocytes Acute phase protein Abnormal protein structure à cannot be transported out of liver à Accumulates in hepatocytes (in endoplasmic reticulum) à Hepatomegaly, conjugated jaundice, rise in LFTs Spectrum of liver disease (mild – severe) Transported to lungs Decreased serum alpha-1-antitrypsin levels At lungs Inactivates neutrophil elastase (normally released during phagocytosis) Therefore deficiency reaching lungs à alveolar destruction à respiratory problems Can also get Panniculitis = nodular far necrosis (also occurs in SLE, scleroderma, lymphoma, histiocytosis or pancreatic disease) Rx - limit effects by ADEK supplements. Alcohol à hepatocyte damage à increased cirrhosis. High risk of liver Ca Smoking à increased neutrophils à faster damage à COPD Tyrosinaemia Uncommon Missing enzyme (FAH) à difficulty in processing tyrosine (amino acid) à Increased succinylacetone (can be detected in urine) and raised AFP Leads to Progressive liver dysfunction Renal fanconi syndrome & hypophosphateamic rickets Enlarged liver & kidneys Mildly deranged LFTs but severely deranged COAG Increased risk of liver Ca Galactosaemia (Galactose-1-Phosphate Uridyltransferase Deficiency = GAL-1-PUT) Carbohydrate metabolism disorder GALPUT enzyme converts galactose-1-phosphate to galactose & glucose-1-phosphate Presents in 1st week with severe illness (vomiting, encephalopathy, jaundice, FTT, cataracts, hepatomegaly, coag defects) Diagnosis – urine for reducing substances. If +ve for reducing substances AND neg for glucose (+ve clinitest, -ve clinistix) à GAL1-PUT screen Treatment Galactose free milk Outcome Most have significant developmental delay despite dietary management (damage done pre diagnosis) Outcome NOT improved with early screening (yet still on Guthrie) Copper & Wilsons disease Needed for production of RBCs, transferring, Hb, Fe absorption, & enzyme activation Absorbed with sulphur rich proteins Transported bound to Alpha-g globulin Present in RBCs in labile & stable form (haemocuprine) Highest concentration in liver & CNS Extreted via intestinal wall & bile Deranged metabolism in Wilsons & Menkes Deficiency Refractory anaemia, Neutropenia Osteoporosis, delayed bone age & bone infarcts Depigmentation Excess Pseudo-paralysis Ataxia Cirrhosis Gastritis Haemolysis Dietary sources Liver, oysters, meat, fish, wholegrain, nuts, legumes Wilson Disease Rare, AR (Chr 13q) Decreased synthesis of Cu binding protein ceruloplasmin à Decreased Cu in bile Excess Cu à free radical formation à oxidation of lipids & proteins Onsets in teens: Increased copped in… Liver (hepatitis) Brain (extrapyramidal & decreased behaviour) Cornea (Kayser Fleisher rings, sun flower cataracts) Kidneys (tubular problems with vitamin D resistant rickets) Joint pains, tics, haemolytic anemia, proteinuria, arthralgia, Ix: high urine copper, liver biopsy shows deposits, elevated LFTs Dx: serum Cu, decreased ceruloplasmin , increased 24 hr urine Cu (after D-penicillamine) & increased liver copper on biopsy Rx: penicillamine (promotes urinary excretion of Copper) Zn to reduce absorption Liver transplant Check siblings Can use serial INRs to monitor wilsons Gilbert Syndrome Autosomal dominant Hereditary unconjugated hyperbilirubinaemia (decreased amounts of glucaronyl transferase (UDPGT) to approx 50%) Can present early as neonatal jaundice – rarely above 85micromol/l Bilirubin levels rise during stress, ill health, prolonged fasting and menstruation Often re-presents at onset of puberty with fatigue, nausea, diarrhoea & headache but general ill health is unusual Linked with pyloric stenosis Crigler-Najjar (1 & 2) Rare AR Mutations of UGT gene à very low activity levels of glucaronyl-transferase Marked unconjugated hyperbilirubinaemia in neonatal period (levels > 350) Type 2 will respond (with 48 hrs) to Phenobarbital Type 1 will need prolonged phototherapy to avoid kernicterus (may need exchange transfusion) and usually require liver transplant Rotor Syndrome Mixed jaundice – over 50% conjugated Levels upto 200 but LFTs normal Normal histology and no treatment required Dubin-Johnson Syndrome Mixed jaundice with normal LFTs Presents in pubertal phase, worsens during pregnancy / on pill Liver is macroscopically black (increased pigmentation) but with normal histology No treatment available Alagille Syndrome Syndromic bile duct paucity AD, variable expression, low penetrance (often subclinical in other family members) Present at 3 months with cholestatic jaundice, itch (out of proportion for jaundice) and fat soluble vitamin deficiencies. Also bossed forehead, hypertelorism, small pointed chin, poor growth (< 3rd centile) & delayed development. 90% have posterior embryotoxin in eyes, butterfly vertebrae, cysts and stones. High cholesterol and triglycerides à xanthomas and corneal arcus Assoc with branch pulmonary stenosis and Fallots 25% will develop chronic liver disease Reye Syndrome Presents similar to acute hepatic failure Biopsy shows fatty infiltration not necrosis Combination of genetic susceptibility & environmental insults Can be triggered by viral illness or aspirin (no longer licenced in children) Congenital Hepatic Fibrosis Assoc with AR polycycstic kidney disease Arrest in development of portal and duct system à hepatomegally, portal hypertension, cystic kidneys, increased risk ascending cholangitis st 1 presentation is often bleeding (between 5 yrs & 12-14 yrs) OE – firm hepatomegaly, signs of hypersplenism, prominent varices. Not always visible jaundice Ix - US to image portal flow, Biopsy for extent of fibrosis, Transplant if failure (+/- renal Tx) Autoimmune Chronic Hepatitis F 70%, M 30%, usually older children Genetic susceptibility linked to HLA B8 DR3, but trigger unknown Sx - Can present as acute hepatitis or gradual onset of fever, rash, colitis, hepatosplenomegally etc. Ix - ­ transaminase Hypergammaglobulinaemia +ve autoantibodies (ANA & Smooth mm Ab (Type 1) & LKM Ab (type 2)) Prolonged PT Liver biopsy shows widened tract with necrosis & mononuclear cells Rx: immunosuppression to ¯ cirrhosis (steroids, azathioprine, ciclosporin) NB: links with primary sclerosing cholangitis Gall stones Rare but increasing with childhood obesity Prepubertal tend to be pigment, older children cholesterol Assoc with sickle cell, spherocytosis or thallasaemia Ceftriaxone can increase stones risk Non-Alcoholic Steato-hepatitis (NAFLD) Increased risk in obesity Free-radical damage à liver inflammation à fibrosis Moderately raised aminotransferases with increased echogenicity on US Assoc with insulin resistance, DMII, Turners and PCOS Osler-Weber-Rendu syndrome (a.k.a hereditary haemorrhagic telangectasia) Genetic – AD inheritance 1/5000 Telangectasia in skin, mucous membranes (e.g. lips) & organs (lungs, liver & brain) Can present as nosebleed / GI bleed Chronic bleeding therefore often need Fe supplements to prevent anaemia Acute Hepatic Failure Rare in childhood, high mortality Follows idiopathic hepatocellular necrosis (may be paracetamol etc) Encephalopathy & coagulopathy within 8/52 of onset of liver disease è Jaundice, low BMs, encephalopathy (drowsy & irritable with poor sleep patterns) Increased transaminases but can initially be normal Prolonged COAG & increased ammonia Management 10% dextrose to maintain BM> 4 – until proven not metabolic error Treat coagulopathy with Vit K & FFP Treat cerebral oedema with 60% fluids & head up, vent if needs be NAC to protect liver Good nutrition with vitamin supplements Regular monitoring of growth Modulae feeds may help Can require upto 150% of expected calories URSO improves bile flow Rifampicin / Phenobarbital improved flow through hepatocytes Cholestyramine prevents enterohepatic recycling Naltrexone, Antihistamine, Ranitidine to reduce itch Lactulose and Abx to decontaminate bowel to reduce encephalopathy Cirrhosis Fibrosis & regeneration nodules à portal HTN Ascites (low albumin, Na retention) à Rx with diuretics + albumin Hypersplenism – low WCC & plts Varices – bleeds à transfuse, PPI/H2, Octreotide, Endoscopy, shunt Encephalopathy Causes Genetic (metabolic / storage) Wilsons Haemachromatosis Galactosaemia Indian familial childhood cirrhosis Alpha 1 antitrypsin deficiency (also causes varices) Post necrotic Neonatal hepatitis Drugs, poisons, toxins Biliary cirrhosis Extra/intrahepatic billiary atresia Choledochal cyst Portal Hypertension Consequence of increased pressure in liver Normal pressure = 5mmHg. If > 6 à varices & splenomegally, if > 12 = risk of bleeds Can present as haematemnesis, malena, ascites, protein losing enteropathy (due to small bowel congestion), prominent abdo veins, haemorrhoids etc Rx: Octreotide à decreases splanchnic blood flow (or Terlipressin), Propranolol à decreases pressure. Sclerotherapy / Banding for varices, TIPSS (transjugular Intrahepatic Portosystemic shunting. Avoid aspirin and NSAIDs as high risk of bleeding If actively bleeding from varices à sengstaken tube Ascites High pressure à increased lymph formation High albumin (>11g/l) = portal HTN, heart failure, Budd-Chairi, liver mets, portal vein thrombosis Low Albumin (< 11g/l) = TB / Pancreatitis High risk of spontaneous bacterial peritonitis (strep pneumoniae, Klebsiella pneumonia or H. Influenza) Hepatic enzyme inducers Phenytoin Rifampicin Carbemazepine Splenomegally A thin palpable spleen in normal in 10% neonates, 10% children & 5% adolescents For spleen to be palpable has to be 2-3x larger than normal Infection Bacteria – typhoid, endocarditis, septicaemia, abscess Viral – CMV, EBV Protozoa – malaria, toxo Haem Haemolysis, extramedullatry haematopoesis, thalassamia, osteopetrosis, myelofibrosis Oncology Malignant – leukaemia, lymphoma, metastasis Benign – haemangioma, hamartoma Infiltration / storage Lipidoses – Neimann-Pick, Gaucher Mucopolysaccharidosis – infiltration histiocytosis Congestion Cirrhosis / hepatic fibrosis Venous obstruction Congestive cardiac failure Cysts Congenital (true) or acquired (pseudocysts) Other SLE, sarcoid, Rheumatoid Arthritis