Gastro Flashcards

Question

Oesophageal obstruction - sx, aetiology

Answer 1

1. Four areas of anatomic narrowing at risk for FB a. Cricopharyngeus (upper esophageal sphincter) b. Aortic arch c. Left main stem bronchus d. Diaphragmatic hiatus 2. Clinical presentation a. Complete i. Unable to swallow ii. Drooling iii. Violent retching iv. Pain from neck to epigastrium b. Proximal i. Stridor ii. Sudden cyanosis 1. Compression of trachea by food in upper esophagus or oropharynx 3. Aetiology a. Foreign bodies – coins, food, batteries b. Anatomic anomalies i. Carcinoma ii. Stricture – peptic/ chemical c. Extrinsic compression i. Thyroid enlargement ii. Aortic arch iii. Anomalous right subclavian artery iv. Bronchogenic carcinoma

Answer 2

4. Investigations a. Endoscopy = gold standard for diagnosis and treatment b. Plain X-ray = AP/lateral i. If FB suspected – not seeing does not rule out c. Contrast studies i. Gastrograffin vs barium d. CT scan 5. Management a. Oropharyngeal = retrieve with Kelly/ McGill forceps b. Esophageal i. Endoscopic removal – rigid or flexible ii. Foley catheter c. Lower esophagus i. Often food impaction ii. Glucagon 1 mg IV (maximum 2 mg) 1. Relax sphincter enough to allow passage of food in 50% of patients 2. Affects only smooth muscles so not helpful for proximal obstructions or strictures iii. Flexible endoscopy 6. Specific objects a. Sharp objects i. Urgent intervention ii. Cause intestinal perforation in 15-35% iii. If reaches duodenum – watch and wait b. Batteries i. “Button batteries” urgent removal ii. Zn, Li, Hg – leakage causes toxicity – positive and negative sides in contact with esophagus  creates a current causing a thermal injury  rapid ulceration and perforation with resultant mediastinitis

Answer 3

1. Key points = rare, potentially life threatening 2. Aetiology a. Cause i. Iatrogenic – endoscopy ii. Foreign body ingestion iii. Trauma 1. Majority in children due to blunt trauma b. Spontaneous = Boerhaave syndrome (cough, childbirth) i. Less common in children ii. Associated with sudden increase in intra-oesophageal pressure eg. vomiting, coughing, straining iii. Children and adults with eosinophilic oesophagitis have been described with Boerhaave syndrome in the setting of forceful vomiting 3. Clinical manifestations a. Upper oesophagus: Neck/ chest pain, Dysphagia, Respiratory distress, Fever b. Lower oesophagus: Abdominal pain/ pain radiating to back, Pneumothorax, Pneumomediastinum, Subcutaneous emphysema c. Other i. Tachycardia ii. Cold water polydipsia in attempt to soothe pain in throat iii. Perforation in proximal thoracic oesophagus  pneumothorax, effusions LEFT side of chest iv. Signs of more distal tears manifest on the RIGHT

Answer 4

4. Investigations a. CXR/ upright AXR i. Subcutaneous emphysema ii. Pnuemo-mediastinum iii. Mediastinal widening iv. Pleural effusion b. Contrast studies = gastrograffin/barium c. CT i. Mediastinal air ii. Extra luminal contrast iii. Fluid collections 5. Treatment a. Aggressive treatment i. Unstable – NBM, NG tube (careful) ii. Contamination of mediastinum/pleura iii. Treat with broad spectrum antibiotics b. Conservative i. Stable, afebrile ii. Endoscopic injury iii. Delayed presentation

Answer 5

1. Key points a. Majority (80%) of FB occur in children 6 month to 3 years b. Older children and adolescents with developmental delays c. Presence of FB lodged in oesophagus = emergency  significant morbidity + mortality d. Coins and small objects most common e. Food impactions less common in children than in adults – associated with eosinophillic oesophagitis, repair of oesophageal atresia, and fundoplication f. Most lodge at the level of the cricopharyngeus (UES), the aortic arch, or just superior to the gastroesophageal junction (LES) 2. Clinical presentation a. 30% of children with oesophageal FB may be totally asymptomatic – any hx of foreign body should be taken seriously and investigated b. Initial bout of choking, gagging and coughing may be followed by excessive salivation, dysphagia, food refusal, emesis, pain in neck, throat or sternal notch c. Respiratory symptoms (stridor, wheezing, cyanosis, dyspnoea) may be encountered if FB impinges on larynx or membranous posterior tracheal wall d. Cervical swelling, erythema or SC crepitations suggest perforation 3. Investigations a. Plain AP of neck, chest and abdomen with lateral views of neck and chest i. Disc batteries look like coins – high risk of burns and necrosis ii. Materials such as plastic, wood, glass, aluminum  radiolucent b. CT = sometimes required to see FB 4. Treatment a. MUST ASSESS RISK OF AIRWAY COMPROMISE b. Endoscopy = required to remove object c. Sharp objects, disc button batteries or those associated with respiratory symptoms  urgent ETT and endoscopy d. Asymptomatic blunt objects and coins can be observed for 24 hours to see if they passage into the stomach e. Meat impactions can be observed for 12 hours

Answer 6

1. Key points a. Most cases are accidental ingestion of liquid alkali substances that produce severe, deep liquefaction necrosis the more that is ingested b. Acidic agents are bitter so less may be consumed  produce coagulation necrosis and a thick protective eschar 2. Complications a. Oesophagitis b. Necrosis c. Perforation d. Stricture formation 3. Clinical presentation a. Vomiting, drooling, refusal to drink, oral burns, dysphagia, dyspnoea, abdominal pain, haemtemesis, and stridor b. 20% develop strictures 4. Treatment a. Dilution by water or milk is recommended as acute treatment – neutralization, induced emesis and gastric lavage are contraindicated b. Strictures may require dilatation

Answer 7

1. Key points a. Along with FB most common cause of oesophageal obstruction b. Benign or malignant (rare in children) c. Oesophagitis/inflammation  scarring  stricture 2. Causes of oesophagitis which can result in stricture a. GORD b. Eosinophilic oesophagitis c. Infectious oesophagitis d. Pill oesophagitis = particularly tetracyclines e. Caustic ingestion f. Radiation g. Sclerotherapy 3. Treatment a. Dilatation i. Bougie dilators – done blindly, inserting increasing size calibers ii. Balloon dilators – done under radiological guidance

Answer 8

• Lump in the throat, globus sensation • Criteria: o Persistent or intermittent non-painful sensation of lump or foreign body in throat. o Occurrence of sensation between meals. o Absence of dysphagia and odynophagia. o Absence of evidence GOR causing symptoms. o Absence of histopathology based oesophageal motility disorders. o Criteria fulfilled for 3 months with symptoms onset at least 6 months before diagnosis.

Answer 9

a. Primitive gut recognized by the 4th week of gestation b. Composed of the foregut, midgut and hindgut i. Foregut  upper GI tract including oesophagus, stomach and duodenum to the level of bile duct insertion ii. Midgut  rest of small bowel and large bowel to the midtransverse colon iii. Hindgut  colon and upper anal canal c. Enteric nervous system is derived from neural crest cells that migrate in a cranial to caudal fashion d. Migration of the neural crest tissue is complete by the 24th week of gestation

Answer 10

Specialised pacemaker cells located in the wall of the stomach, small intestine and large intestine – responsible for migrating motor complex which result in waves in peristalsis

Answer 11

a. Cephalic phase (minutes) – stomach responds to sight, smell, taste or thought of food (olfactory and taste receptors – hypothalamus – PNS) – 20% secretion b. Gastric phase (3-4hours) – swallowed food and protein activate mechanoreceptors which stimulate short and long reflex action to increase gastric secretion – 70% secretion c. Intestinal phase (hours) – duodenum response to acidic chyme entering, activates hormonal and nervous reflexes - 10% gastric secretion

Answer 12

a. Oxyntic cells/ parietal cells = HCl, intrinsic acid i. Found mostly in upper half of gland ii. Body of stomach and pylorus b. Chief cells = pepsinogen i. Activated by acid in stomach, deactivated by high pH in duodenum ii. Dominate in lower half of gastric glands iii. Body (absent in fundus and pylorus) c. Enterochromaffin-like cells = histamine i. Concentrated in lower end of gland and secrete hormones and paracrine messengers that regulate digestion d. Mucous cells = mucous i. Thick and alkaline to protect from acid ii. Prominent in cardia and pyloric regions iii. Concentrated in the neck of the gland where it opens into pit e. G cells = gastrin i. Located in the antrum 2. Gastrin – stimulates secretion of acidic gastric juice by stomach glands AND motor functions of stomach

Answer 13

1. Key points a. Gastric glands produce 2-3L gastric juice per day, made of water, pepsin and HCl b. pH 1-4 (low as 0.8) 2. Parietal cell functions a. Secrete HCL acid b. Intrinsic factor for B12 absorption 3. Function of stomach acid a. Activates pepsin and lingual lipase b. Converts ferric iron 3+ to ferrous iron 2+ for absorption c. Breakdown of CT in plant cell walls d. Bactericidal 4. Physiology a. Stomach parietal cell produces HCl due to presence of carbonic anhydrase which converts CO2 into carbonic acid and then H+ b. H+ then pumped into the stomach by H-K antiporter c. K+ enters cell then exits again down concentration gradient i. Gradient maintained by Na-K+ ATPase on basal membrane d. Simultaneously bicarbonate is exchanged for chloride in the blood creating chloride shift and chloride is pumped into lumen to join H+ e. HCL accumulates in stomach, bicarbonate in blood (alkaline tide as pH blood leaving stomach has higher pH)

Answer 14

a. Gastrin – secreted from G cells i. Binds to G receptors ii. Increased intracellular calcium iii. Increase PKA activity iv. Stimulated H-K pump b. Ach – from PNS nerve endings i. Binds to M3 receptors ii. Increased intracellular calcium iii. Increase PKA activity iv. Stimulated H-K pump c. Histamine – released from mast cells or ECL (enterochromaffin like cells) i. Activates H2 histamine receptors ii. Activated adenylyl cyclase leading to cAMP production iii. cAMP activates PKA leading to activation of H-K pump Omeprazole/PPI blocks H/K/ATPase (antiporter) -> blocks acid secretion in response to all stimuli (vs H2 receptor antagonist e.g. ranitidine) - dose dependent irreversible inhibition, maximal effect at day 5 - >20mg inhibits all intragastric acidity in most individuals

Answer 15

1. Definition a. Histological diagnosis of inflammation of gastric mucosa 2. Aetiology a. H pylori b. NSAIDs c. Corrosive agents i. Bile ii. Ingested acids/ alkalis d. Ethanol, potassium, iron e. Malignancy, ulcer (eg. Crohn’s) f. Other infectious organisms – viral, mycobacteria 3. Clinical presentation a. Variable and non-specific b. Asymptomatic c. Abdominal pain d. N+V e. GI bleeding (rare) f. Shock (rare) 4. Complications a. Ulcer b. Perforation c. Gastric outlet obstruction 5. Diagnosis a. Often clinical b. Must rule out other causes of potential pain c. Endoscopy +/- biopsy useful if symptoms severe or persistent i. Ulcers – Crohn’s ii. Haemorrhage – viral iii. Nodular – H pylori 6. Treatment a. Antacids i. PPI ii. H2 antagonists b. Thermal/Argon Plasma (APC) – if bleeding c. Consider H Pylori eradication d. Immunosuppression for Crohn’s

Answer 16

1. Key points a. Erosion = superficial to muscularis mucosa, no scarring b. Ulcer = penetrates muscularis mucosa, scarring i. End result of inflammation c. Multifactorial – final common pathway is the action of acid and pepsin-laden contents of the stomach on the gastric and duodenal mucosa, and the inability of normal mucosal defenses to allay its effect d. Gastric ulcers = located on the lesser curvature (unclear if just applies to adults but greater curvature ulcers considered to be malignant, also just more common on lesser curvature) e. Duodenum = 90% found in the duodenal bulb f. Rates in childhood very low 2. Pathogenesis a. Acid production i. By age 3-4 years gastric acid secretion similar to adults ii. Acid secreted by oxyntic acid has a pH of 0.8, whereas pH of the stomach is 1-2 iii. Excessive acid secretion associated with large parietal cell mass, hypersecretion by antral G cells, and increased vagal tone iv. Gastric acid secretion promoted by = vagus nerve, histamine secreted by enterochromaffin cells, gastrin v. Gastric acid secretion reduced by = prostaglandins b. Mucosal defense i. Mucous gel = mucous production and secretion stimulated by prostaglandin E2 ii. Epithelium secrete bicarbonate into the mucous coat regulated by PG iii. If mucosal injury occurs, active proliferation of cells occurs to protect the area

Answer 17

``` Aetiology Duodenal Gastric H pylori 90% 60% NSAIDs 7% 35% Stress-induced <3% <5% Zollinger-Ellison <1% <1% ``` 4. Clinical manifestations a. Vary with age of patient b. Abdominal pain (95%) c. Gastric ulcer i. Generally epigastric ii. Usually worse 2-4 hours after meal iii. Often pain 2-3AM (HCl secretion highest) iv. Relieved with antacids d. Duodenal ulcer i. Pain worst before meal ii. Relieved by meal e. Other features i. Haematemesis or malaena – half of patients with PUD ii. School age children and adolescents – epigastric pain or fullness, nausea and dyspepsia iii. Infants and young children – feeding difficulty, vomiting, crying episodes, haematemesis or malaena iv. Pain often described as dull or aching v. Nocturnal pain waking the child common in older children

Answer 18

a. Endoscopy i. Clean, well demarcated, benign looking ii. All should be biopsied as risk of cancer (adults > children) b. Upper GI contrast c. Bloods = FBE, UEC, LFT, lipase d. Imaging = CXR/AXR if suspect perforation e. Diagnosis of H pylori i. Endoscopy – GOLD standard (gastric biopsy, urease testing, culture, histopathology); endoscopic findings range from normal to gastritis with prominent rugal folds, nodularity or ulcers; antrum often appears normal ii. Enzyme immunoassay on stool – highly sensitive/specific iii. Serology – NOT recommended; IgG may persist for years after resolution of the infection iv. Urea breath test

Answer 19

a. H pylori i. Almost all non-NSAID ulcers due to H pylori ii. GN rod – produces catalase and oxidase iii. Lives in upper GI tract between epithelial surface and mucous iv. Faecal-oral or oral-oral transmission v. Risk factors = socio-economic status, family members vi. All children infected with H. pylori develop histological chronic active gastritis but are often asymptomatic vii. Can result in abdominal pain or vomiting, less often iron deficiency or growth retardation viii. Rarely associated with autoimmune thrombocytopaenia ix. Increased risk of 1. Duodenal ulcer (DDx NSAIDs) 2. Gastric cancer (adenocarcinoma) 3. Mucosal associated lymphoid tissue lymphoma (MALT) b. Idiopathic ulcers i. H pylori duodenal ulcers in children with no Hx of NSAIDs represents 15-20% of paediatric duodenal ulcers ii. Patients do not have nodularity in the gastric antrum or histologic evidence of gastritis iii. In idiopathic ulcers, PPI suppression alone adequate iv. High rate of recurrence

Answer 20

a. Aspirin and NSAIDs i. Can result in bleeding ulcers or gastric perforation ii. More common in the stomach than the duodenum, more common in the antrum iii. Pathogenesis 1. Direct effect a. Diffuse into mucosal cells b. Become trapped and directly damage cell i. Inhibition of PG secretion ii. Reduce mucous production iii. Reduced cell turnover 2. Indirect effect a. Systemic inhibition of COX decreased production of PG b. ‘Stress’ ulceration i. Occurs within 24 hours of a critical illness ii. 25% of children in PICU have macroscopic evidence of gastric bleeding iii. Intracranial = Cushing ulcer iv. Severe burn = Curling ulcer

Answer 21

a. Upper GI bleed (15%) i. Posterior surface – gastroduodenal artery ii. Treatment – resuscitation, endoscopy, PPI, surgery b. Perforation (7%) i. Usually anterior duodenal ulcers ii. Sudden generalised peritonitis iii. Diagnosis = free air on CXR iv. Treatment = surgery – oversew ulcer and patch, antrectomy and vagotomy c. Gastric outlet obstruction (2%) i. Nausea/vomiting ii. Caused by edema and scarring iii. Treatment = surgery, gastrectomy d. Penetration i. Posterior duodenal ulcers can erode into pancreas ii. History of epigastric pain that worsens and radiates to back – becomes refractory to treatment iii. Investigations = elevated amylase

Answer 22

a. Lifestyle modification i. Stop NSAIDs ii. Reduce caffeine, EtOH, spicy foods, smoking cessation b. NSAID induced ulcer i. Stop NSAID ii. PPIs = more potent in ulcer healing 1. Block the gastric parietal cell H+/K+ ATPase in a dose dependent fashion 2. Reduce basal gastric acid secretion iii. H2 receptor antagonists 1. Competitively inhibit binding of histamine to the H2 subtype receptor of the gastric parietal cell c. Not taking NSAID i. PPI ii. Exclude Crohn’s, malignancy iii. Treat for H pylori 1. The goal of therapy is to eradicate H pylori on the first attempt 2. Triple therapy with two antibiotics and a proton pump inhibitor is recommended 3. Longer duration of therapy (up to 14 days) has been associated with higher eradication rates 4. Current first-line therapy (10 - 14 days) = amoxicillin + clarithromycin + omeprazole a. Multiple regimens and commercially packaged – Nexium HP7 (amoxicillin/ clarithromycin/ omeprazole) for 7 days 5. If more than one family member is affected, it is our practice to treat individuals concurrently, to minimise reinfection within the household 6. Increasing resistance 7. Difficult to eradicate a. Longer durations sometimes needed b. Back to back and triple vs quadruple therapy under investigation c. Biopsy for culture and sensitivity

Answer 23

Rare, characterised by severe, refractory PUD Neuroendocrine tumour - gastrinoma -> excessive/autonomous gastrin->gastric acid secretion Usually also diarrhoea 98% patients have elevated gastrin levels A/W MEN1, NF, TS

Answer 24

a. H pylori infection varies between the developed and developing world (40% vs 90% in adults aged 40 years) b. Commonest bacterial pathogen in humans – infecting >50% of world’s population c. Prevalence is higher in developing countries and older age groups d. Usually acquired during first 2 years of life, but disease consequences rarely arise in childhood e. Children i. 10% adolescents in developed world + 80% adolescents in developing countries ii. Neonatal infection rare f. Risk factors i. Socioeconomic differences are the most important predictor of H pylori ii. Household crowding iii. Ethnicity iv. Migration from high prevalence areas v. Infected parent, particularly mother vi. Contaminated water g. Route of transmission = faecal-oral, oral-oral or gastric-oral

Answer 25

2. Clinical manifestations a. Asymptomatic in absence of ulceration b. Commonest paediatric cause of chronic gastritis c. Gastritis always present – but can be microscopic d. Infection associated with gastritis, GU and DU e. Role in recurrent abdominal pain uncertain 3. H-pylori associated disease a. Gastric i. Asymptomatic ii. Chronic gastritis iii. Peptic ulcer – gastric, duodenal iv. Gastric adenocarcinoma v. B cell MALT lymphoma b. Extra-gastric i. GERD ii. Iron deficiency anaemia iii. Short stature

Answer 26

a. Endoscopy i. Involves antrum, occasionally body ii. Antral nodularity (specific, not in adults) iii. Gram negative rods in surface mucosal layer b. Summary i. Serology should NOT be used as does NOT test for active infection and 50% of positive is a false positive ii. Tests for active infection 1. H pylori stool antigen (good sens/spec 94-95%) 2. Urea breath test (95-96% sens/spec) 3. Endoscopy (invasive) iii. All patients with dyspepsia who do not have alarm symptoms, have not been using NSAIDs, should be tested for an active infection test before being prescribed PPIs iv. Stool antigen is the most cost effective means of detecting active infection – can be used to diagnosis, monitoring and eradication confirmation for patients of all ages

Answer 27

a. Triple therapy i. Ampicillin + clarithromycin + omeprazole 1. Metronidazole substituted for either antibiotic – but high resistance ii. Indications for Tx 1. Children with ulcers + proven infection 2. Children with histologically proven infection w/ gastro symptoms 3. Children with gastric lymphoma + proven infection 4. Children with atrophic gastritis w/ intestinal metaplasia + proven infection 5. Children with refractory IDA + proven infection

Answer 28

1. Aetiology a. Idiopathic b. Post-infectious – viral c. Anorexia – primary or secondary d. Diabetic e. Autoimmune f. Neurological g. Post-surgical – vagal damage 2. Pathophysiology a. Loss of pacemaker cells - due to deinnervation b. Gastric dysrhythmias -tachy/ bradygastrias or incoordinate c. Not responsive to usual emptying signals (hot meals, hypogylcaemia, ghrelin, motilin) 3. Pathophysiological classification a. Gastric dysrhythmia and gastroparesis i. Severe gastric myoelectrical disorder ii. Rx – N+V, prokinetic therapy, gastro/jejunostomy, TPN , gastric electrical stimulation, pacemaker b. Normal gastric rhythm and gastroparesis i. Due to pylorospasm/ obstruction at pylorus/ duodenum with electrocontractile dissociation ii. Rx – botox/ balloon dilatation, surgical relief of obstruction, prokinetics and antinausea c. Gastric dysrhythmia and normal emptying i. Gastric myoelectric disorder ii. Rx – N+V, prokinetic therapy d. Normal gastric rhythm and normal emptying i. Visceral hypersensitivity/ nongastric causes ii. Rx – N+V, antidepressant therapy, drugs for fundic/ antral relaxation. Further Ix for other causes

Answer 29

4. Symptoms a. Feed intolerance b. Bad breath c. Nausea d. Early satiety e. Reflux f. Vomiting 5. Diagnosis a. Clinical history b. Barium meal c. NM scintigraphy d. Antro-duodenal manometry 6. Treatment a. Re-feeding – slowly grading up b. Nizatidine – prokinetic c. PPIs d. Domperidone – dopamine receptor antagonist e. Erythromycin – acts on motilin receptors in stomach f. Botox – open sphincter and improve gastric emptying g. Jejunal feeding (PEJ)

Answer 30

1. Key points a. Can be fastened with button or balloon systems b. Once the PEG has been placed a tract forms between the stomach and the abdominal wall, this happens quite quickly c. Note however that the external bumper should be 1-2cm from the abdominal wall i. It is not the external bumper that prevents leakage 2. Complications a. Early i. Wound site infection and bleeding ii. Pneumoperitoneum post procedure iii. Ileus iv. Oesophageal and gastric perforation = rare b. Late i. Deterioration of gastrostomy site ii. Buried bumper syndrome 1. Long-term consequence of tight apposition of the external bolster of the gastrostomy tube against the abdominal wall 2. Internal bolster gradually erodes into the gastric wall – resulting in pain and inability to infuse feeding iii. Colocutaneous fistula iv. PEG tract c. Any time i. Tube dysfunction 1. Clogging = managed with irrigation of warm water (better than cola or juice) 2. Tube deterioration = can leak and break which makes tube feeding difficult or impossible 3. Early balloon deflation (internal bolster) ii. Infection iii. Bleeding = rare iv. Peristomal leakage = most common within first few days but can also be seen with mature gastrostomy tract 1. More likely in malnourished patients and those with diabetes v. Ulceration vi. Gastric outlet obstruction 1. Gastrostomy tubes can migrate forward into the duodenum and cause gastric outlet obstruction 2. Occurs if the external bolster on the gastrostomy tube is allowed to migrate away from the abdominal wall, allowing the gastrostomy tube to slide forward through the gastrostomy tract and into the duodenum vii. Inadvertent removal 1. If removed within 4 weeks of placement should NOT be replaced blindly at the bedside; tract may not have matured and gastric wall and abdominal wall may have separated viii. Leakage of gastric contents or tube contents into peritoneal cavity 1. Results in peritonitis 2. If contents include tube feeding – chemical peritonitis

Answer 31

Neonates • Swallowed blood • Haemorrhagic disease of newborn + other coagulopathies • Structural problems – intestinal duplications, vascular anomalies • Gastritis / ulcers(rare) • Milk protein allergy (rare – usually lower GI) ``` Children • Mallory Weiss tear • Oesophagitis • Oesophageal varices • Peptic ulcer disease/GI • Pill oesophagitis • Foreign body/ingestions ``` Stress (critically ill)

Answer 32

1. Anatomy a. 270 cm long at birth, increases to 450-550 cm by 4 years of age b. Major features i. Ileocecal valve: prevents backflow from colon to the small intestine ii. Ileocecal sphincter: remains mildly constricted, slows emptying of ileal contents into the cecum c. Microscopic features i. Mucosa composed of villi – finger like projections ii. Brush border contains digestive enzymes and transport mechanisms iii. Cells of villi originate in crypts, become more absorptive as they migrate up (crypts are secretory) iv. Villi present by 8 weeks of gestation in duodenum, by 11 weeks of age in the ileum v. Renewed every 4-5 days 2. Structure a. Permanent plicae circulates – involve mucosa and submucosa b. Mucosa lined with villi that increase SA for absorption i. Goblet cells – mucous secretion ii. Enterocytes – absorption iii. Core of villi – capillary network, smooth muscle, lymphatics iv. Form brush border – each villi consists of microvilli to increase SA for absorption, contains enzymes for contact digestion v. Between bases of villi are intestinal crypts – upper half goblet cells and enterocytes, lower half stem cells for replacement vi. Paneth cells – secrete lysozyme, phospholipase and defensins which protect against bacterial infection vii. Brunner glands – in duodenum secrete bicarbonate rich mucous to neutralize stomach acid and allow pancreatic enzyme action viii. Peyer patches – in ileum large lymphatic nodules with lymphocytes 3. Physiology a. Food entering the small intestine triggers i. Intestinal phase gastric secretion – vasovagal PNS ii. Enterogastric reflex – duodenum inhibits stomach – SNS iii. CCK release – gallbladder contraction and pancreatic secretion iv. Secretin release – bicarbonate release into pancreatic/hepatic secretions v. Enteroendocrine release of – secretin, cholecystokinin, gastric inhibitory peptide (suppress gastric activity, promote pancreatic/bile secretion)

Answer 33

1. Overview a. 75-100 cm tube, 3 strips of longitudinal muscle (taenia coli) b. Gross function i. Absorption of water and electrolytes (mostly proximal half) ii. Storage of fecal matter until expulsion 2. Key features a. Tinea coli – muscularis externa concentrated in three thickened strips b. Tinea coli contract to form haustra (non-permanent infoldings of mucosa and submucosa) c. Colonic crypts, no villi d. Caecum, ascending, transverse, descending, sigmoid colon e. Rectum and anal canal (simple columnar epithelium changes to non-keratinized stratified squamous) i. Arterial supply – superior 2/3 IMA, inferior 1/3 systemic circulation ii. Venous drainage – superior 2/3 portal, inferior 1/3 systemic iii. Sphincters – internal (smooth muscle- involuntary), external (skeletal muscle- voluntary) iv. Innervation – superior 2/3 ANS, inferior 1/3 somatic v. Mucosa – superior 2/3 endodermal columnar, inferior 1/3 ectodermal squamous f. Regulated by i. Gastrocolic + duodenocolic reflexes (stretch  movement of colon) ii. Irritation 3. Defecation a. Rectum is usually empty of faeces due to weak functional sphincter between sigmoid colon + rectum AND sharp angulation b. Presences of faeces in the rectum induces reflex contraction of rectum and relaxation of anal sphincter c. Prevention of faecal dribble prevented by i. Internal anal sphincter (immediately inside anus) ii. External anal sphincter – striated voluntary muscle that surrounds internal sphincter 1. Controlled by pudendal nerve d. Defecation reflex – consists of two nervous system actions: local enteric and parasympathetic i. Intrinsic reflex: local enteric nervous system  rectal wall, initiates peristaltic waves moving feces towards anus 1. This initiates internal anal sphincter relaxation through myenteric plexus inhibitory signals ii. Fortified by parasympathetic defecation reflex: PNS fibres via pelvic nerves intensify peristaltic waves and relax the internal anal sphincter e. Last step is conscious relaxation of the external anal sphincter 4. Bacterial flora a. Involved in digestion (bilirubin and bile acids) b. Provide body with vitamins (B and K) c. Trains immune system d. Elimination of pathogenic bacteria

Answer 34

1. Duodenum a. Iron b. Folic acid 2. Jejunum a. CHO b. Folic acid c. Water soluble vitamins 3. Duodenum + jejunum a. Calcium/Magnesium/Phosphate 4. Proximal 100-200cm of intestine a. CHO b. Protein c. FFA + TG (more distal) d. Water soluble vitamins 5. Throughout the small intestine a. Monoglycerides and fatty acids as micellar complexes b. MCT directly into portal circulation 6. Distal ileum a. Vitamin B12 b. Bile salts c. Fatty acids 7. Colon a. Water b. Electrolytes

Answer 35

1. Intake a. 200-300 gm/day (adult) b. 50% starch, 50% sugars (30% sucrose, 10% lactose) c. CHO provides 50% energy requirements 2. Dietary forms a. Polysaccharides = starch (glucose polymer) digested in human gut i. Glycogen = from animals in long chain (1:4 alpha), with branch (1:6 alpha) ii. Amylopectin (major diet) = from plants only (1:4 alpha), rare branches iii. Amylose = 1:4 alpha chain b. Disaccharides i. Sucrose = glucose + fructose ii. Lactose = glucose + galactose iii. Maltose = glucose + glucose c. Monosaccharides = glucose, galactose, fructose 3. Digestion a. Mouth i. Salivary amylase - inactive at acid pH ie. in stomach b. Intestinal lumen i. In duodenum, salivary amylase is reactivated when pH is returned to neutral by bicarbonate in pancreatic juice and secreted from duodenal epithelium ii. Pancreatic alpha-amylase secreted due to CCK release from duodenal mucosa iii. Both salivary and pancreatic alpha-amylase are effective against 1:4 alpha linkages but ineffective at 1:6 alpha linkages, thus leaving a variety of oligosaccharides intact iv. Glucose, disaccharides and oligosaccharides are brought up against brush border membranes of the mucosal enterocytes (especially tips of villi) v. Amylases can only break down polysaccharides to disaccharides c. Intestinal brush border i. Several different enzymes in brush border break up oligosaccharides and disaccharides ii. Glucoamylase + dextrinase = maltose iii. Sucrase-isomaltase 1. Sucrose  glucose + fructose 2. Maltose  glucose + glucose 3. Effective against 1:6 alpha linkages iv. Lactase 1. Lactose  glucose + galactose 2. Peak activity at birth 3. 50% of world population has drop – decline 5-7 years of age 4. Infectious gastroenteritis – monosaccharide malabsorption due to transient lactase deficiency; can also have transient sucrase deficiency 5. Lactase is NOT inducible; sucrase-isomaltase and brush border oligopeptidases CAN be inducible 4. Absorption a. Glucose and fructose are rapidly absorbed in duodenum and jejunum i. Glucose + galactose – Na+ dependent glucose transporter (SGLT1) [basis of ORS] ii. Fructose – facilitated diffusion via GLU5 b. All monosaccharides are transported across basal border by GLUT 2 transport

Answer 36

1. Requirements a. 0.75 g/kg/day high quality protein i. Maintenance of nitrogen balance ii. Adequate supply of essential amino acids iii. Higher intake for illness, growth pregnancy and lactation b. 20 amino acids = 9 essential, not synthesized by mammals i. Histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine c. Dietary proteins vary in composition - plant protein less digestible d. Protein absorption > 90% efficient e. Process = Intraluminal hydrolysis  brush border peptidases 2. Digestion a. Stomach i. Digestion begins in stomach with pepsin ii. Pepsin = hydrolyses bonds between aromatic amino acids (phenylalanine, tyrosine) and a second amino acid polypeptides of diverse sizes (as it only acts at limited places in a protein) 1. Secreted from chief cells as pepsinogen (A/C) (pro-enzyme) 2. Stimulus for secretion a. cAMP (secretin, VIP, adrenaline, PG) b. Intracellular Ca2+ (ACh, CCK, gastrin) 3. Activated/cleaved by gastric acid to pepsin (active form) (pH optimum 1.6-3.2) iii. Inactivated at neutral pH (not effective once it gets out of the stomach and into the duodenum) b. In duodenum and jejunum i. CCK release triggered by amino acids causes secretion of pancreatic proteases in form of inactive proenzymes ii. Pro-enzymes activated first by enterokinase in epithelial membrane 1. Trypsinogen to trypsin 2. Trypsin is an endopeptidases resulting in a cascade to activate other proenzymes 3. Producing chymotrypsin, elastase, carboxypeptidase A and B 4. Results in formation of oligopeptides iii. Pancreatic peptidases 1. Endopeptidases = trypsin, chymotrypsin, elastase a. Act at interior peptide bonds 2. Exopeptidases = pancreatic carboxypeptidases a. Act on terminal amino acids iv. Peptidases at the brush border break oligopeptides down into dipeptides, tripeptides and amino acids 1. Produces 40% free amino acids, 60% oligopeptides 3. Absorption a. Protein can enter the cell by separate non-competitive carriers that can transport individual amino acids or dipeptides and tripeptides b. Brush border i. Amino acids 1. Multiple transport systems ii. Peptides 1. Small peptide transport independent of amino acid uptake 2. Peptide transport often faster than free amino acid a. Absorption faster in jejunum (amino acid faster in ileum) 3. Active transport c. Basolateral membrane (to portal blood) i. Systems: Na independent (3), Na dependent (2)

Answer 37

1. Adult intake a. Consumption 120-150g b. Biliary lipid 40-50g c. 3 physical forms i. Fat or oil droplets ii. Membranes iii. Skin lipids (animal and vegetable) 2. Key events a. Emulsification = starts in stomach (peristalsis) b. Lipolysis = lingual, gastric + pancreatic c. Micelle formation = bile salts + lipids d. Absorption e. Fat absorption >95% efficient (85% in infants) f. 2-3% exocrine function allows normal fat absorption 7. NOTE: a. Fat absorption is less efficient in the neonate compared with adults b. Premature infants can lose up to 20% of their fat calories compared with 6% of an adult c. Decreased synthesis of bile acids and pancreatic lipase and decreased efficiency of ileal absorption are contributing factors d. Medium chain fatty acids (10C)  portal venous system e. 85% of CF patients have no pancreatic function when born – reasonable absorption up to 50% - due to lingual and gastric lipase

Answer 38

3. Fat digestion a. Lingual lipase = active in stomach, digests up to 10% TG b. Gastric lipases = less important – although if pancreatic insufficiency activity increases i. Greater role in infants c. Pancreatic lipases i. CCK release leads to secretion of pancreatic lipolytic enzymes (and bile) ii. Trypsin activates colipase  colipase activates lipase iii. Act on emulsified fats iv. Hydrolyses 1,3 bonds – products are FFA and 2MG d. Bile salt activated lipase i. Hydrolyses cholesterol esters ii. Fat soluble vitamins, phospholipids 4. Micelle formation a. Emulsified by bile acids  micelles with phospholipids and other fat soluble substances b. Micelles composed of 20-40 bile acids in circle with hydrophilic outwards and hydrophobic inward c. Bile cholesterol and phospholipids form core d. Function to absorb fat soluble vitamins, cholesterol, FFA and monoglycerides e. Transport to SI wall where fat absorbed into enterocyte (terminal ileum) 5. Fat absorption a. Lipids inside micelles brought to apical surface of epithelial cells, at tips of villi b. When in contact with membrane fat soluble lipids can dissolve in membrane and enter cells (as lipid soluble) c. Bile salts – poorly absorbed in proximal gut (absorbed in terminal ileum) d. Lipid absorption i. FA <12 C direct to portal system (ie. MCT) ii. FA >12 C re-esterified to TG 1. Leave cell with cholesterol esters 2. Coated with protein, cholesterol and phospholipid as chylomicrons via lymphatics e. NO active transport required 6. Chylomicron formation + transport a. In epithelial cells, fatty acids and monoglycerides reform triglycerides in smooth ER (membrane structure in which they can dissolve) b. Golgi processes them into chylomicrons by combining with phospholipids and cholesterol c. Secreted by exocytosis into extracellular space d. Chylomicrons exocytose at basal membrane and enter lacteals e. Lacteals enter the lymphatics and join blood supply as they go into the larger blood vessels where they can be transported to the liver

Answer 39

Fat globules = maldigestion eg. pancreatic insufficient, cholestatic liver disease Fat crystals = malabsorption (e.g. giardia)

Answer 40

``` • Na cotransport o Ascorbic acid  Actively transported, Na coupled  Simple diffusion if concentration high o Also riboflavin, thiamine, niacin, pyridoxine, biotin, pantothenate ``` • Na independent o Folate – hydrolysis before entry, jejunal absorption, saturable Vitamin B12 1. Intake a. From animal sources b. 10-20 ug ingested/day – only 1-2 ug needed 2. Digestion + Absorption a. Food bound B12 is released by gastric acid and pepsin and binds preferentially with salivary R protein in the stomach b. Proteolysis of R protein by trypsin release B12 for binding with IF c. This then binds specific ileal receptors and this is then released at an intracellular site – transported across the BL membrane – and taken up transcobalamin II for transport to portal circulation for distribution d. Absorption occurs in distal small intestine 3. NOTE: a. PPI may lead to B12 deficiency due to proximal effects with respect to B12 release

Answer 41

* All ingested with dietary fats * Absorbed in terminal ileum with micelles * Protein bound in plasma * Must be activated * Absorption of fat-soluble vitamins commonly impaired more than absorption of dietary fats

Answer 42

1. Functions and dietary sources a. Adult body 1200g of Ca (99% bone/teeth) b. 1% nerve conduction, muscle contraction, membrane permeability, protein kinases etc c. Dairy 55% , also leafy green vegetables, Ca fortified 2. Pathways of intestinal Ca absorption a. Small intestine and colon b. At high dietary intakes, passive diffusion (paracellular) c. At low intake, saturable energy dependent transcellular - depend on vitamin D 3- 1,25(OH)2D3 3. Absorption a. Efficiency 30-80% b. Activity in upper small intestine most important c. Diffuses through apical membrane then binds to calbindin cytoplasmic protein d. Exits basal membrane via calcium ATPase e. Vitamin D – increases calbindin and calcium-ATPase f. Factors affecting absorption i. 1,25 DHCC  Ca+ binding protein, Ca++-H+ATPAse (calbindin-D – alters rate not final amount) ii. Increased Ca2+  reduction in 1,25 DHCC iii. Low Ca2+  increased 1,25 DHCC g. Some passive diffusion

Answer 43

1. Role a. Cellular oxidative energy metabolism (redox enzymes) b. Oxygen transporting proteins (Hb, myoglobin) 2. Balance a. Losses generally small – 0.6-1.2 mg/day b. Intake 20 mg/day (haem and nonhaem iron) i. Fe2+ best absorbed (haem) ii. Dietary Fe3+ reduced in gastric acid to Fe2+ (vitamin C) iii. Diet affects iron availability (phytates, phosphate, oxalate inhibit) c. Stores regulated by intestinal absorption i. Amount absorbed = amount lost (usually) d. Deficiency = hypochromic microcytic anaemia i. Celiac most common cause of proximal small intestinal disease – therefore common cause of iron deficiency ii. Always think intake, absorption + losses e. Overload = oxidant damage (haemochromatosis) 3. Absorption a. Absorbed in duodenum b. 10% of dietary intake is absorbed and this depends on iron status c. Most is in the ferric form Fe3+ that is converted to the ferrous form Fe2+ at the apical membrane by ferroreductase which is induced by hypoxia and deficiency d. 3 pathways are proposed for absorption – divalent metal transporter, Para cellular, and a separate pathway from haem iron e. Within the cell one or more iron binding proteins take up the iron and transfer it to the BL membrane of transfer across this and binding to transferrin

Answer 44

• Water o Water balance – 2L/day ingested, 7L/day secreted, 98% absorbed o Water follows osmotic gradients set by Na+ o Active transport with Na-coupled transporters o Daily stool water loss about 200ml • Sodium absorption o Na+ actively absorbed down concentration gradient established BL Na-K-ATPase associated with Cl o Na coupled transport for glucose and amino acids enables solute transport o Coupled NaCl transport (uses 2 exchangers, Na-H, and Cl-HCo3) • Chloride transport o Chloride absorbed in the distal ileum in exchange for bicarbonate – active transport o Enters cells via basolateral Na-K-2 Cl cotransport o Secretion via Cl channels o Regulated by protein kinases o Regulated by PK-A and cAMP (cholera) • Potassium transport o K secretion partly down electrical gradient o Absorbed by concentration gradient o Active secretion of K increased by aldosterone (Chronic diarrhoea > low K)

Answer 45

* B1 (thiamine)  Beriberi (infantile form affects heart>nerves) * B2 (riboflavin) angular cheilitis, stomatitis, seborrheic dermatitis, eye problems * B3 (niacin) pellagra (3 D’s – dermatitis, diarrhoea, dementia) * B6 (pyridoxine) neuro, hypochromic anaemia * B12 (cobalamin)  neuro, megaloblastic anaemia Passive diffusion in upper small intestine - except for B12 which requires intrinsic factor and distal ileum

Answer 46

- pH: Alkaline < 6 suggests osmotic diarrhoea - Reducing substances: <0.25 g/dL = negative, 0.25-0.5 g/dL = suspicious, >0.5 g/dL = abnormal - Osmolality: Equal to serum ~300 mOsm/kg, < 220 suggests hypotonic dilution, >330 poorly stored specimen - Osmolar gap 290 – 2x (Na+K): 50-100, > 100 suggests osmotic diarrhoea ( eg laxatives), < 50 suggests secretory diarrhoea - Sodium: ~ 30, >70 suggests osmotic diarrhoea - Potassium: 75 - Chloride: 20-30, > 60 in infants/ > 100 in adults suggests congenital/ secondary chloridorrhoea , < 20 in laxative use

Answer 47

Osmotic - Caused by non-absorbed nutrients in the intestinal lumen dragging water out into gut with glucose (gut hyperosmolar to blood) - cease with fasting: Yes (as no more sugar) - volume: <200 ml/day - sodium: <70 meq/L - osmotic gap: High >100, > (Na + K) x 2 - reducing substances: Present - pH: <5 - explosive, excoriated: ++ - aetiology: • Osmotic laxatives (eg. lactulose, sorbitol, mannitol) • Mucosal injury – infective (eg. post-rotavirus), inflammation (IBD), immune mediated (celiac), vascular • Disaccharidase deficiency • Monosaccharide transport defect (eg. glucose-galactose deficiency) • Transport overload (increased sugar, fruits) Secretory - Drags water out into gut with sodium (due to reduced absorption of electrolytes or abnormal ion transport into intestinal epithelial cells) - fasting: No effect - volume: >200 ml/day - sodium: >70 meq/L - osmotic gap: Low <50, = (Na + K) x 2 - reducing substances: Absent - pH: >6 - explosive, excoriated: +/- - aetiology: • Congenital transport and mucosal defects eg. chloridorrhoea, microvillus inclusion, tufting enteropathy • Secretagogue o Toxigenic bacteria – cholera (turn on cAMP), E coli (toxigenic), Salmonella, C difficile, cryptosporidium, Yersinia o Bile acid malabsorption (bile acids turn on cAMP) • Tumours producing hormones (eg. VIP-5HIAA) • Short gut • Rapid transport

Answer 48

• Stool electrolytes and calculating an osmotic gap can help distinguish secretory and osmotic diarrhoea • Osmotic gap = subtracting the sum of the sodium and potassium concentration in stool multiplied by a factor of 2 from 290 mOsm/kg to account for unmeasured anions (ie, 290 - 2 ({Na+} + {K+}) o Osmotic gap of >100 mOsm/kg suggests an osmotic diarrhea  ie there is a low concentration of Na and K in the stool o Gap of <50 mOsm/kg suggests a secretory diarrhea ie there is a high concentration of Na and K in the stool driving the diarrhoea

Answer 49

Contrast 1. Barium swallow a. Fluoroscopic form of imaging b. Assess motility and anatomy c. Useful for – strictures, hiatal hernia, pyloric stenosis, external oesophageal compression 2. Modified barium swallow a. For H-type tracheoesophageal fistula b. Esophagus distended with barium via a nasogastric tube with patient lying prone c. Various consistencies of barium used Endoscopy 1. Endoscopy a. Direct visualisation of oesophageal mucosa b. Therapies – removal of foreign bodies, treatment of varices, biopsies 2. Fiberoptic endoscopic evaluation of swallowing a. Nasopharyngeal endoscopy used to visualize pharynx + larynx during swallowing b. Useful for – laryngeal penetration, aspiration

Answer 50

a. Breath samples every half hour post ingestion of lactose b. Hydrogen level will rise due to bacterial fermentation of lactose (as it is not absorbed ) c. BUT false negative may be obtained if relevant bacteria not present d. Negative test must be compared to lactulose test  not absorbed, looks for fermentation by bacteria e. Can also be used as test of gastric emptying

Answer 51

1. Key points a. All disorders of malabsorption are associated with diminished intestinal absorption of one or more nutrients b. Can result from a defect in nutrient digestion in the intestinal lumen or defective mucosal absorption c. Categorized into general mucosal abnormalities usually resulting in malabsorption of multiple nutrients, or malabsorption of specific nutrients d. Almost all malabsorption disorders are accompanied by chronic diarrhoea which worsens malabsorption ``` Types/Categories Mucosal disorders (coeliac, CMPA) Protein losing enteropathy (lymphangiectasia, Crohns) Congenital bowel mucosal defect Immunodeficiency disorders Autoimmune enteropathy (IPEX) Miscellaneous (short bowel syndrome) ```

Answer 52

a. Variation in clinical presentation based on age i. Nutritional consequences of malabsorption more dramatic in toddlers due to limited energy reserves and higher proportion of calorie intake being used for weight gain and linear growth ii. In older children, malnutrition more often results in growth retardation b. Common presenting symptoms i. Diarrhoea ii. Abdominal distension iii. Falling growth centiles iv. Failure to gain weight – particularly toddlers v. Anorexia vi. Specific to underlying condition 1. Diarrhoea a. Onset in infancy  congenital defect b. Secretory diarrhoea caused by disorders such as congenital chloride diarrhoea and microvillus inclusion disease  stool watery and voluminous can be mistaken for urine c. Explosive watery diarrhoea suggests  CHO malabsorption d. Loose, bulky stools are associated  celiac disease e. Pasty and yellowish offensive stools  exocrine pancreatic insufficiency f. ‘Peas and carrots’ with green stool  Toddler’s diarrhoea 2. Anorexia a. Many children have good appetite b. Exocrine pancreatic insufficiency – faecal losses of up to 40% of ingested protein and energy does not lead to malnutrition provided increased caloric intake c. In conditions associated with villous atrophy or inflammation (celiac disease, post-infectious enteropathy), fecal protein and energy losses are usually modest, but associated anorexia and reduced food  malnutrition 3. Onset of symptoms after food intake eg. sucrose in sucrase-isomaltase deficiency c. Examination findings i. Abdominal distension ii. Muscle wasting iii. Disappearance of SC fat  lose skin folds iv. Specific to underlying condition 1. Edema – usually associated with protein losing enteropathy 2. Digital clubbing – CF, celiac disease 3. Perianal excoriation and gaseous abdominal distension – CHO malabsorption 4. Perianal and circumoral rash – acroderma enteropathica 5. Abnormal hair – Menkes syndrome 6. Facial features typical of Johanson-Blizzard syndrome d. Nutritional assessment i. Calcium and vitamin D malabsorption  reduced BMD and metabolic bone disease, increasing risk of fractures ii. Vitamin K malabsorption  coagulopathy iii. Severe protein losing enteropathy (often associated with malabsorption syndromes celiac disease, intestinal lymphangiectasia)  hypoalbuminaemia and edema iv. Iron malabsorption  IDA and low reticulocyte count

Answer 53

a. Stool tests i. Microscopy/Culture  RBC/WBC associated with inflammatory conditions ii. Microscopy for ova/cysts/parasites  Giardia iii. Antibody tests for parasites iv. pH and reducing substrates  CHO malabsorption v. Quantitative stool fat  identify fat malabsorption vi. Alpha-1 antitrypsin  protein malabsorption vii. Elastase  exocrine pancreatic insufficiency viii. Calprotectin  IBD b. Blood tests i. FBE + film 1. Microcytic anaemia  Fe deficiency 2. Lymphopenia  Lymphangiectasia 3. Neutropenia  Shwachman syndrome 4. Acanthocytosis  Abetalipoproteinaemia ii. Serum IgA and tTG antibodies  celiac disease

Answer 54

a. CHO malabsorption i. Stool pH and reducing substrates – acidic stool with >2+ reducing substrates suggestive ii. Hydrogen breath tests – can identify specific CHO being Malabsorbed iii. Small bowel mucosal biopsies – can measure mucosal disaccharidase (lactase, sucrase, maltase, palatinase) concentrations 1. Primary enzyme deficiencies = low levels and normal morphology 2. Celiac disease or following rotavirus = partial or total villous atrophy with associated reduction in enzymes (return to normal after mucosal healing) b. Fat malabsorption i. Fat globules in stool – suggestive of fat malabsorption ii. Quantitative 3 day stool collection – allows you to calculate coefficient of fat absorption iii. Nutritional deficiencies (ADEK) – associated with fat malabsorption c. Protein-losing enteropathy i. Hypoalbuminaemia 1. Most common cause in children is renal disease – urine protein excretion must be determined 2. Other potential causes include liver disease + inadequate protein ii. Stool alpha1-antitrypsin 1. MW similar to albumin, however resistant to digestion in the GI tract 2. Excessive alpha-1 antitrypsin excretion in the stool should prompt further Ix to identify the specific cause of gut or stomach (Mentrier disease) protein loss d. Exocrine pancreatic function i. Cystic fibrosis most common cause of exocrine pancreatic insufficiency – needs to be excluded ii. Faecal elastase 1 – sensitive test to assess exocrine function 1. Cannot distinguish between primary exocrine pancreatic deficiency and exocrine dysfunction secondary to intestinal villous atrophy 2. Mucosal atrophy can lead to reduced CCK/pancreozymin secretion  reduced hormonal stimulation for exocrine enzyme secretion 3. False positives can occur in diarrhoea iii. Serum trypsinogen 1. Screening for exocrine pancreatic insufficiency 2. In CF – levels elevated in early life, then gradually fall 3. Shwachman syndrome – serum trypsinogen low e. Intestinal mucosal disorders i. Biopsy often required

Answer 55

1. Key points a. Immune-mediated systemic disorder elicited by gluten and related prolamines i. Wheat, rye and barley; oats appear to be safe (however reports of some reactivity) b. Characterised by the presence of a variable combination of gluten-dependent clinical manifestations, celiac-specific antibodies, HLA-DQ2 an DQ8 haplotypes, and enteropathy 2. Epidemiology a. Common – 1% prevalence b. Rare in Central Africa and East Asia c. Associated disorders - essentially autoimmunes (T1DM, thyroid, addison, Sjogren, cholangitis/hepatitis, PBC) 3. Genetics a. Genetic predisposition suggested by family aggregation + concordance in monozygotic twins – approaches 100% b. Risk in first degree relative 10% c. Strongest association is with HLA DQ2 and DQ8 i. 90-95% express HLA DQ2, 5-10% carries HLA DQ8 ii. 40% of the general white population are DQ2 +ve, 40% DQ8 +ve 4. Pathogenesis a. T cell mediated chronic inflammatory disorder with autoimmune component c. Immunodominant epitopes from gliadin are highly resistant to intraluminal and mucosal digestion d. Gliadin peptides stimulate the innate immunity (particularly IL-15) -> T cell activation f. Pattern of cytokines dominated towards IFN-g (Th1 type skewed); IL-21 also increased g. Downstream T cell activation, a complex remodeling of the mucosa h. Severe impairment of intra-epithelial lymphocytes (IELs) homeostasis is present

Answer 56

a. <2 years i. Intestinal symptoms ii. FTT iii. Chronic diarrhoea iv. Vomiting, abdo distension v. Muscle wasting vi. Anorexia and irritability vii. Occasionally rectal prolapse, intussusception or constipation b. >2 years i. Extraintestinal manifestations become more common ii. Most common – iron deficiency anaemia not responsive to iron iii. Other - short stature, arthritis and arthralgia, epilepsy with bilateral occipital calcifications, peripheral neuropathies, cardiomyopathy, isolated hypertransameinasemia, dental enamel hypoplasia, aphthous stomatitis, and alopecia c. Most common extra-intestinal manifestation is iron deficiency anaemia, not responsive to Fe supplements d. Silent celiac disease increasingly recognized – mainly in asymptomatic 1st degree relatives identified with screening -- small bowel biopsy can show severe mucosal damage e. Presentation in T1DM i. Unpredictable BGL ii. Recurrent hypoglycaemia iii. Poor glycaemic control iv. Growth failure (GIT symptoms less likely) Vit D/Ca malabsorption -> rickets Thiamine/B12 deficiency -> neuropathy, epilepsy, ataxia

Answer 57

6. Investigations a. Diagnosis is a combination of symptoms, antibodies, HLA and biopsy (MCH gastro team no interest in HLA) b. Can be confirmed by clinical response to gluten free diet and reducing antibody titre c. Serology i. Current serology 1. Tissue transglutaminase (IgA) 2. Deamidated gliadin peptide (DGP) IgG ii. In practice, both tests have >85% sensitivity and >90% specificity iii. Note the DGP assay has replaced the whole-protein anti-gliadin antibody (AGA) assay because of improved specificity; however, many labs will report the DGP result as the ‘anti-gliadin antibody’ iv. The anti-endomysial antibody (EMA) test measures tTG antibodies, but is labour-intensive, user-dependent and less widely performed v. The tTG assay has lower sensitivity in children under three years of age 1. Ensure DGP-IgG testing is performed alongside tTG-IgA to overcome this issue d. Genetic studies i. HLA DQ2, DQ8 1. If negative, it can be used to exclude coeliac disease 2. If positive, not useful as 30% of the population is DQ2 or DQ8 positive; 1% have coeliac disease 3. NOT useful as a screening tool e. Biopsy i. Gold standard for diagnosis ii. Duodenal biopsy iii. NEEDS to be while individual consuming gluten iv. Histological features 1. Increased intraepithelial lymphocytes 2. Loss of villi – partial to total villous atrophy 3. Elongated crypts 4. Increased mitotic index in crypts 5. Loss of brush border, abnormal flattened epithelial cell 7. Diagnostic guidelines a. New European guidelines, based on evidence that high-titre tTG is strongly predictive of coeliac disease in children, suggest small intestinal biopsies can be avoided if children meet the following criteria: i. Characteristic symptoms of coeliac disease ii. tTG-IgA levels >10× upper limit of normal iii. A positive endomysial antibody (EMA) on a different blood sample iv. Positive HLA susceptibility for coeliac disease

Answer 58

8. Treatment a. Lifelong strict adherence to gluten free die (wheat, barley and rye); usually exclude oats b. Wheat, Rye, Barley ‘oats’ (in Australia due to contamination) c. Note rice and maize are okay! d. Clinical improvement ~ 3 weeks e. Improvement in histology and serology may take 6-18 months 9. Complications a. Osteoporosis i. 70% of untreated adults have osteopenia, increases with age at diagnosis ii. Gluten free diet allows improvement within 1 year iii. Low bone density in 27-40% of CD b. Autoimmune diseases c. Increased risk of cancer i. 20X RR for small bowel lymphoma (EATL) ii. 30x RR for small bowel adenocarcinoma (uncommon generally, one of few conditions which causes) iii. 2-4X RR for esophageal cancer

Answer 59

1. IgE mediated wheat allergy a. May have overlapping symptoms with celiac disease b. More often presents without an enteropathy but with symptoms of atopy (urticaria, angioedema, eczema, asthma, rhinitis) c. Diagnosed by the presence of IgE antibodies to wheat (serum specific or skin prick test) d. Symptoms occur classically soon after ingestion 2. Gluten sensitivity a. Area of uncertainty in paediatrics

Answer 60

a. Microvillous inclusion disease (congenital microvillus atrophy) i. Key points 1. Autosomal recessive disorder 2. Manifests at birth with profuse watery secretory diarrhoea 3. Most severe cause of congenital diarrhoea 4. Polyhydramnios may be present antenatally 5. Many cases run in the same family in highly consanguineous union; suggests autosomal recessive ii. Pathogenesis 1. Light microscope shows thinning of the mucosa, with hypoplastic villous atrophy and no inflammatory infiltrate 2. Electron microscopy shows enterocytes with absent or sparse microvilli; hallmark is presence of microvilli within involutions of the apical membrane iii. Clinical manifestations 1. Very early onset of severe watery diarrhoea (up to 200-330 ml/kg/day)  dehydration + FTT 2. Disease fatal without long term TPN 3. Most children die in infancy or early childhood 4. Intestinal transplantation only definitive treatment b. Tufting enteropathy i. Manifests in the first few weeks of life with persistent watery diarrhoea; accounts for a small fraction of infants with intractable diarrhoea of infancy; persists despite bowel rest and TPN ii. Distinctive feature on small intestinal mucosal biopsy is focal epithelial ‘tufts’ involving 80-90% of the epithelial surface vi. No treatment effective; requires TPN +/- intestinal transplantation c. Enteric anendocrinosis i. Mutations in NEUROG3 gene ii. Generalised mucosal malabsorption, vomiting, diarrhoea, FTT, dehydration and hyperchloraemic acidosis iii. Oral alimentation with anything other than water produces diarrhoea iv. Staining for neuroendocrine cells demonstrate a complete absence of this cell lineage with preserved goblet and Panathe cells v. Treatment = TPN +/- transplantation

Answer 61

a. Autosomal recessive condition ; mutation in PCSK1 gene b. Chronic watery neonatal onset diarrhoea c. Hyperinsulinism, hypoglycaemia, hypogonadism and hypoadrenalism d. Small bowel biopsy shows non-specific enteropathy e. Siblings have marked obesity and Hyperphagia f. Elevated levels or proinsulin highly supportive

Answer 62

a. Usually occur AFTER the first 6 months life – present with chronic diarrhoea, protein-losing enteropathy, malabsorption and FTT b. Histology – partial or complete villous atrophy, crypt hyperplasia, and an increase in chronic inflammatory cells in lamina propria; cf. celiac disease NO increased number in intra-epithelial lymphocytes c. Immunologic shows presence of anti-enterocyte antibodies and anti-autoimmune enteropathy d. Extra-intestinal autoimmune disorders = arthritis, membranous GN, IDDM, thrombocytopenia, hepatitis, hypothyroidism, immune deficiency e. Must exclude primary immune deficiency – can be linked to IPEX syndrome f. Treatment options limited – based on immunosuppression

Answer 63

a. Mutation in the ileal sodium-bile acid cotransporter gene (SCL10A2) -> congenital diarrhoea, steatorrhoea, interruption of enterohepatic circulation of bile acids, and reduced plasma cholesterol levels b. Usually only 10% of bile acids escape reabsorption

Answer 64

a. AR disorder of lipoprotein metabolism -> severe fat malabsorption from birth b. Defect in chylomicron assembly c. Clinical features i. Steatorrhoea ii. Vitamin ADEK deficiency -> peripheral neuropathy (vit E deficiency) iii. ID iv. Ataxia with loss of position + vibration sense due to vit E deficiency v. Atypical retinitis d. Diagnosis i. Acanthocytes and fat inclusions on peripheral blood smear ii. Low plasma levels of cholesterol, triglycerides and LDL e. Treatment = supplementation 9. HOMOZYGOUS HYPOBETALIPOPROTEINAEMIA a. AD disorder similar to abetalipoproteinemia b. Differentiated on small bowel biopsies

Answer 65

a. Definition i. Small bowel bacterial overgrowth – meaning colonic bacteria found proximally in small bowel 1. Small bowel usually populated by aerobes- enterococci, gram positive, lactobacilli 2. Colon usually anaerobes – bacteroides, lactobacillus, clostridium b. Predisposing conditions i. Dysmotility – short bowel syndrome (due to adaptive changes in SI), pseudo-obstruction, malnutrition ii. Biliary obstruction – cirrhosis iii. Pancreatic insufficiency – chronic pancreatitis iv. Absent ileocaecal valve / communication – intestinal fistula, bowel strictures, short bowl v. Other – diabetes, prematurity c. Pathogenesis i. Bacteria usually only present in a small number in the stomach and small bowel – excessive numbers can be harmful ii. The role of enteric bacteria 1. CHO – salvage unabsorbed dietary sugars by fermentation to FA – absorption in colon 2. Produce vitamins folate and vitamin K 3. Prime immune response – preventing reaction to protein antigens in diet 4. Inhibit pathogenic bacterial population causing disease iii. Mechanisms protecting against excessive SI colonization 1. Motility – peristalsis, migrating motor complex 2. Gastric and bile acid destruction 3. Digestion by proteolytic enzymes from pancreas 4. Ileocaecal valve – inhibits colonic bacterial reflux 5. Immune system and secretory IgA 6. Mucosal defenses such as mucin and Ig d. Clinical manifestations i. Excessive fermentation (CHO malabsorption – abdominal distension, diarrhoea, flatulence) ii. Protein malabsorption (protein losing enteropathy) iii. Fat malabsorption iv. B12 deficiency (anaemia and neurological effects) v. Inflammation by unwelcome bacteria (immune dysregulation = arthritis) e. Diagnosis i. Culturing small bowel aspirate ii. Lactulose hydrogen breath test = not digested by mucosal brush border enzymes + fermented by bacteria high baseline hydrogen and a quick rise suggests bacterial overgrowth (false pos common) f. Treatment i. Correction of underlying disorders eg. partial obstruction ii. Antibiotics = 2-4 weeks of metronidazole, cycling of bactrim, azithromycin, ciprofloxacin, metronidazole 1. Other options – aminoglycosides, nitazonxaide, rifaximin

Answer 66

1. POST-INFECTIOUS DIARRHOEA a. In infants and very young toddlers chronic diarrhoea can appear following infectious enteritis b. Pathogenesis - unclear i. Secondary lactase deficiency ii. Food protein allergy iii. Antibiotic associated colitis c. Treatment = supportive; may include lactose free diet 2. BACTERIAL OVERGROWTH (SIBO) - separate flashcard 3. TROPICAL SPRUE a. Natives and expats of certain tropical regions can present with a diffuse lesion of the small intestinal mucosa – topical sprue – long after migration b. Etiology unclear; infectious etiology suspected c. Leading cause of malabsorption in India d. Diagnosis = small bowel biopsy, shows villous flattening, crypt hyperplasia and chronic inflammatory cell infiltrate e. Treatment = nutritional supplementation, including folate and vitamin B12 i. To prevent recurrence oral folic acid + 6/12 of tetracycline or sulfonamide ii. Relapse in 10-20% of patients who live in endemic tropical region 4. WHIPPLE DISEASE a. Chronic systemic infectious disorder b. Rare disease, especially in childhood c. Caused by infectious agent Tropheryma whipplei d. Treatment = bactrim for 1-2 years

Answer 67

1. IMMUNODEFICIENCY DISORDERS a. Malabsorption can occur with congenital immunodeficiency disorder, and chronic diarrhoea with FTT is often the mode of presentation b. Defects of humoral or cellular immunity, eg: i. IgA deficiency = usually asymptomatic, malabsorption may be caused by giardiasis or non-specific enteropathy in which bacterial overgrowth can occur ii. CVID = malabsorption in 60% of patients, usually non-infectious iii. Agammaglobulinaemia iv. SCID v. Wiskott-Aldrich syndrome vi. CGD = phagocytic function impaired and granulomas develop along the GI tract mimicking Crohn’s disease 2. IMMUNOSUPROLIFERATIVE SMALL INTESTINAL DISORDERS a. Malignant lymphomas of the small intestine (Burkitt most common and involves terminal ileum, NHL, Mediterranean lymphoma) 3. EOSINOPHILIC GASTROENTERITIS a. Eosinophilic digestive diseases are a group of rare and heterogenous conditions characterized by patchy or diffuse eosinophilic infiltration of GI tissue b. Eosinophilic gastroenteritis based on GI symptoms, GI eosinophilic infiltrates, and the absence of other infections c. Peripheral eosinophilia and elevated IgE variably present but not diagnostic d. Most patients have history of allergic disorders e. 10% of patients have immediately family member affected g. Diagnosis requires biopsies h. Symptoms = abdominal pain, vomiting, nausea, abdo distension; diarrhoea and weight loss occur due to malabsorption if small bowel involvement with villous blunting is extensive i. Nutritional exclusion (or elemental) diets + corticosteroids are mainstay of treatment 4. Autoimmune enteropathy/ immune enteropathy a. Protracted diarrhoea with severe enteropathy and villous atrophy b. Starts in first few weeks of diet c. Frequent episodes of dehydration, electrolyte imbalances and malnutrition d. PN dependent e. No response to exclusion diets f. Presence of circulating anti-enterocyte antibodies, anti-goblet cell antibodies, or evidence of other autoimmune disease g. Genotyping of suspected mutations based on clinical presentation h. Examples i. IPEX = chronic diarrhoea, dermatitis, autoimmune endocrinopathy (diabetes, thyroiditis) ii. APS1

Answer 68

1. CHO MALABSORPTION a. Symptoms = loose watery diarrhoea, flatulence, abdominal distension pain i. Some children symptoms depend on CHO load b. Pathogenesis = unabsorbed CHO enter large bowel and are fermented by intestinal bacteria -> organic acid and gases -> discomfort and osmotic diarrhoea c. Aetiology = disaccharidases are present on the brush border membrane -> genetic deficiency or secondarily by damage to epithelium (inflammatory, infectious) d. Diagnosis = hydrogen breath test 2. LACTASE DEFICIENCY a. Congenital lactase deficiency -> rare (50 cases worldwide) b. Primary adult-type hypolactasia i. Caused by a physiological decline in lactase activity that occurs following weaning in most mammals ii. Varies between ethnic groups (less common Caucasian) c. Secondary lactose intolerance i. Follows small bowel mucosal damage (celiac disease, rotavirus) ii. Diagnosed with hydrogen breath testing iii. Treatment avoidance of cow’s milk; live-culture yoghurt contains bacteria that produces lactase enzymes so usually well tolerated 3. FRUCTOSE MALABSORPTION a. Children consuming a large quantity of juice rich in fructose, corn syrup or natural fructose can present with diarrhoea abdominal distension and slow weight gain b. Restricting juice usually resolves sx without need for ix c. Fructose H2 breath testing can help diagnosis d. Caused by reduced abundance of GLUT-5 transporter on the surface of the intestinal brush border membrane, which occurs in 5% of the population 4. SUCRASE-ISOMALTASE DEFICIENCY a. Rare autosomal recessive with a complete absence of sucrase and reduced maltase digestive enzyme b. 2% of Europeans and Americans are heterozygous c. Clinical manifestations i. Symptoms begin when the infant is exposed to sucrose or glucose polymer diet ii. Diarrhoea, abdominal pain and poor growth are observed d. Diagnosis i. Stools are acidic and contain sugar – reducing substances NEGATIVE (sucrose + maltose are non-reducing sugars) ii. Hydrogen breath test e. Treatment i. Dietary restriction of sucrose-containing foods ii. Enzyme replacement 5. GLUCOSE-GALACTOSE MALABSORPTION a. >30 mutations in sodium/glucose co-transporter (SGLT1) identified b. Cause a rare autosomal recessive disorder of intestinal glucose and galactose/Na+ cotransport that leads to osmotic diarrhoea – present with severe acidosis and dehydration c. Most dietary sugars are polysaccharides or disaccharides with glucose or galactose, diarrhoea follows the ingestion of glucose, breast milk, or conventional lactose-containing formulas d. Diagnosis i. Stools are acidic and contain sugar – reducing substances +ve ii. Hydrogen breath test e. Treatment = rigorous restriction of glucose and galactose; fructose is the only sugar which can be given safely

Answer 69

1. ENTEROKINASE (ENTEROPEPTIDASE) DEFICIENCY a. Deficiency of enterokinase – a key enzyme produced in the proximal small bowel and is responsible for the activation of trypsinogen to trypsin, manifests clinically as exocrine pancreatic insufficiency b. Rare autosomal recessive disorder c. Treatment = pancreatic enzymes + protein hydroylsed formula + MCT oil in infancy 2. TRYPSINOGEN DEFICIENCY a. Rare syndrome similar to enterokinase deficiency b. Results in severe diarrhoea, malabsorption, FTT and hypoproteinaemic edema c. Treatment as above

Answer 70

a. Cystic fibrosis – most common congenital disorder associated with exocrine pancreatic deficiency b. Shwachman-Diamond syndrome – second most common congenital disorder d. Autoimmune polyendocrinopathy syndrome type 1 – rare autosomal recessive disorder caused by a mutation in AIRE i. Chronic mucocutaneous candidiasis is associated with failure of the parathyroid gland, adrenal cortex, pancreatic beta cells, gonads, gastric parietal cells and thyroid gland ii. Pancreatic insufficiency and steatorrhoea are common

Answer 71

Background - normally, lactose -> glucose/galactose -> absorbed - abnormally, lactose -> large intestine -> digested by microbiota -> short chain FA, hydrogen, methane - hydrogen + methane -> dx lactose intolerance - some individuals won't produce hydrogen -> test for methane instead Interpretation - late peak = malabsorption - early peak + late peak = SIBO (bacterial overgrowth)

Answer 72

Presentation - abdo pain, flatulence, bloating, vomiting - diarrhoea: bulky, watery, frothy - PERIANAL EXCORIATION due to acidic stool - note lactase NOT inducible -> at high enough intake everybody has lactose intolerance/malabsorption and positive stool reducing subtances Classification - ethnic: asian/african level decrease by 2-5 years, Caucasian typically persists - congenital: rare, decreased expression of lactase-phlorizin hydrolase, diarrhoea from birth + hypercalcaemia and nephrocalcinosis - congenital: sucrase-isomaltase deficiency, glucose-galactose malabsorption - developmental: premature infants have reduced lactase - secondary: bacterial overgrowth, bowel stasis, short gut syndrome, post infectious, coeliac, CMPA, microvillous inclusion disease, tufting enteropathy Diagnosis - symptoms + positive lactose tolerance (blood following lactose ingestion)/hydrogen breath test - stool reducing subtances - suggestive if >0.25% and pH <7.5 (CHO malabsorption)

Answer 73

1. Overview a. Some congenital (primary) malabsorption disorders originate from a defect of integral membrane proteins b. Histological examination of the small and large bowel is typically normal c. Most inherited in autosomal recessive pattern d. Most are rare, and patients present with broad phenotypic heterogeneity 2. Classification a. Disorders of CHO absorption - eg Fanconi-Bickel syndrome (GLUT2 mutation) b. Disorders of amino acid and peptide absorption - Hartnup disease - cystinuria - iminoglycincuria - dicarboxylic aminoaciduria c. Disorders of fat transport - Tangier disease - Sitosterolemia d. Disorders of vitamin absorption - B12/folate e. Disorders of electrolyte and mineral absorption - congenital chloride disorder - congenital sodium diarrhoea - Menke disease

Answer 74

1. Key points a. Characterized by excessive loss of serum proteins into GIT b. Hypoproteinaemia results in decreased intravascular oncotic pressure and leakage of fluid into third spaces c. Results in: i. Hypoproteinaemia/Hypoalbuminaemia ii. Oedema iii. Pleural or pericardial effusions d. Considered in patients in whom other causes of hypoproteinaemia have been excluded 2. Pathogenesis a. Inflammatory exudation i. Mucosal injury results in exudation of protein rich fluids across the eroded epithelium i. IBD, Coeliac, GI malignancies, Infections – shigella and salmonella (HUS), C Diff colitis, Eosinophilic gastroenteritis b. Increased mucosal permeability i. Altered integrity of the mucosa results in protein leakage into the lumen c. Intestinal loss of lymphatic fluid i. Lymphatic obstruction due to granulomatous or neoplastic involvement of the lymphatic system, congenital abnormalities, or disorders of venous stasis – increase lymphatic pressure ii. Results in: 1. Decreased absorption of chylomicrons and fat soluble vitamins (ADEK) 2. Reduced recirculation of intestinal lymphocytes into the peripheral circulation 3. Leakage of lymph into intestinal lumen EG: i. Primary intestinal lymphangiectasia ii. Secondary 1. Cardiac disease– CCF / restrictive pericarditis / Post-Fontan a. Post-Fontan in 4-15%, 5 year survival 50% 2. Retroperitoneal LN enlargement due to chemotherapy, infection or toxic substances

Answer 75

4. Clinical manifestations a. Manifestations of hypoalbuminaemia i. Oedema ii. Ascites iii. Pleural effusion iv. Pericardial effusion b. Manifestations of underlying disease i. Gastrointestinal symptoms = diarrhoea, steatorrhoea, abdominal pain, bloating, flatulence 5. DDx = Other causes of hypoproteinaemia a. Decreased production – protein malnutrition, liver synthetic failure b. Increase loss – protein losing enteropathy, nephrotic syndrome, burns c. Redistribution - inflammation of vasculature, haemodilution

Answer 76

6. Investigations a. Hypoalbuminaemia b. Reduced plasma concentration of gamma globulins, cholesterol, alpha-1 antitrypsin, fibrinogen, ceruloplasmin c. Lymphopaenia – if due to loss of LYMPH (other causes of protein-losing enteropathy will NOT result in low lymphocytes) d. Malabsorption of fat soluble vitamins e. Stool alpha 1 anti-trypsin increased = paired serum and 24hour collection stool i. Non-dietary, resistant to intestinal digestion, excreted intact in stool, stable levels f. Nuclear medicine scan 99m technetium can help determine site of protein loss 7. Treatment a. Diet i. Low-fat, MCT supplemented diet – MCT bypass enteric lymphatics straight into portal system, and prevents rupture of lymphatics by exclusion of LCT ii. High-protein – for replacement of losses iii. +/- supplementation with calcium and water soluble forms of vitamins ADEK b. Medical according to underlying cause c. Surgical in refractory cases

Answer 77

1. Key points a. Diffuse or localised ectasia of enteric lymphatics b. Often associated with lymphatic abnormalities elsewhere in the body (mucosa, submucosa or subserosa) c. Affects children and young adults (mean age of onset 11yo) d. Most cases sporadic 2. Associations a. Turner’s b. Noonan’s c. Klippel-Trenaunay (hemiangiectatic hypertrophy - port-wine stain, lymphatic and venous malformations and soft-tissue hypertrophy of affected limb) 3. Clinical manifestations a. Intermittent diarrhoea b. Nausea, vomiting c. +/- steatorrhoea d. Peripheral oedema e. Chylothorax and chylous ascites f. Pleural effusions and ascites (from hypoproteinaemia) 4. Diagnosis a. Hypoalbuminaemia b. Decreased plasma proteins – gamma globulins, ceruloplasmin c. Stool alpha 1 anti-trypsin increased d. Lymphopenia (differentiates from other causes PLE) e. Clotting factors frequently deficient (no clinical consequence) f. Contrast study may show thickened, nodular mucosal folds (‘stacked coins’) g. Endoscopy – macroscopic white spots on mucosa i. Small bowel biopsy: Markedly dilated lymphatics most apparent at the tip of the villi in mucosa/submucosa 5. Treatment a. Low-fat, high-protein, MCT supplemented diet +/- supplementation with calcium and water soluble forms of vitamins ADEK b. May require intestinal resection or anastamosis of abnormal lymphatics to venous channels in refractory cases

Answer 78

a. Intestinal failure = significant amount of malabsorption of macro and micronutrients, not necessarily due to loss of bowel or length of bowel, usually due to SI malfunction due to; resection, congenital defect, or disease associated malabsorption i. One pubmed definition: “the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth” b. Short bowel = loss of >50% of the small intestine, with or without a portion of the large intestine  generalised malabsorption OR specific nutrient deficiencies, depending on region of bowel affected i. IF = reduced gut function as above due to any cause, but most frequently due to SBS ii. SBS = specific definition related to loss of length/amount of bowel c. Length of bowel i. At birth length of the bowel = 200-250cm ii. Adulthood = 300-800cm iii. Bowel resection in an infant has a better prognosis than in an adult due to the potential for intestinal growth iv. An infant with as little as 15cm of bowel with an ileocaecal valve, or 20cm without, has the potential to survive and eventually be weaned from TPN d. Site of bowel i. The proximal 100-200cm of jejunum is the main site for CHO, protein, iron and water soluble absorption; whereas fat absorption occurs over the length of the intestine ii. Depending on the region of bowel resected, specific nutrient malabsorption can result iii. Vitamin B12 and bile salts are ONLY absorbed in distal ileum iv. Net sodium and water absorption is relatively much higher in the ileum  ileal resection has a profound effect on fluid and electrolyte absorption due to malabsorption of sodium and water by the remaining ileum 1. Ileal malabsorption of bile salts stimulates increased colonic secretion of fluid and electrolytes e. Adaptation i. Occurs in response to short gut ii. Involves hypertrophy of villi to increase surface area for absorption iii. Ileum can compensate for lack of jejunum (site of protein, CHO and fat), however jejunum cannot compensate for loss of ileum

Answer 79

a. Congenital i. Congenital short bowel syndrome ii. Multiple atresias iii. Gastroschisis b. Acquired i. Necrotising enterocolitis ii. Volvulus +/- malrotation iii. Long segment Hirschsprung disease iv. Meconium periostitis v. Crohn’s disease vi. Trauma Most-least common: NEC, meconium ileus, abdo wall defect, atresia, volvulus

Answer 80

a. Maintain fluid, electrolyte and nutritional state i. Nutritional support via TPN b. Bowel rehabilitation i. Gradual reintroduction of enteral feeds – also reduces the complications of line ii. Small volume trophic enteral feeds initiated with hydrolysed protein and MCT-enriched formula to stimulate gut hormones and promote mucosal growth iii. Need to avoid oral aversion – offer breastmilk in neonatal period, introduce solids at appropriate age (avoid fruit) iv. 50% of patients with short bowel syndrome achieve enteral autonomy within 5 years of bowel resection c. Management of specific micronutrient and vitamin deficiencies i. Monitor vitamins – C/M/P, Zinc, selenium, ADEK, Fe, Vit D – especially when weaning PN – B12 if they have no terminal ileum d. Management of large stool output i. Addition of soluble fibre and Antidiarrhoeal agents and anticholinergics can be used ii. Cholestyramine beneficial for patients with distal ileal resection, but can deplete bile acid pool and cause increased steatorrhoea iii. Bacterial overgrowth is common in infants with short bowel – empirical treatment with antibiotics often useful iv. Diets high in fat and lower in CHO may be helpful 5. Surgery a. STEP procedure (serial transverse enteroplasty) to lengthen the bowel b. Small bowel transplantation – for those who have repeated hospitalisations, or recurrent line sepsis c. Liver and small intestine transplant – for those with PNALD

Answer 81

a. TPN associated complications i. CVL infection ii. CVL thrombosis iii. Hepatic cholestasis and cirrhosis – causes multifactorial: 1. Toxic defects of TPN on hepatocytes 2. Disruption of bile flow and bile acid metabolism 3. Frequent occurrence of bacterial translocation and sepsis with endotoxin release in portal circulation iv. Gallstones b. Other complications i. Ileal resection -> B12 deficiency ii. Other vitamin deficiency iii. Renal stones – result of hyperoxaluria secondary to steatorrhoea (calcium binds to the excess fat and not to oxalate, so more oxalate is absorbed and excreted in the urine) iv. Venous thrombosis and vitamin deficiency associated with hypohomocystinaemia in short bowel syndrome c. Other points i. Sepsis is a leading cause of death ii. Lack of central line access is potential life-threatening

Answer 82

1. Key points a. Intestinal failure describes a patient who has lost the ability to maintain nutritional support and adequate fluid requirements needed so sustain growth - dependent on TPN 2. Causes of intestinal failure in children requiring transplantation a. Short bowel b. Intestinal dysmotility = intestinal pseudoobstruction, intestinal aganglionosis (Hirschsprung disease) c. Enterocyte dysfunction = microvillus inclusion disease, tufting enteropathy, autoimmune disorders, Crohn’s d. Tumours = familial polyposis, inflammatory pseudotumour 3. Indications for transplantation a. Paucity of venous access = 6 readily accessible sites (bilateral IJ, bilateral subclavian, iliac) i. Usually occurs in the setting of recurrent catheter sepsis and thrombosis b. Life-threatening infections = usually catheter related c. Liver disease = cholestatic liver disease most serious complication of intestinal failure 4. Transplant operation a. Donor selection i. Usually procured from haemodynamically stable ABO identical brain dead donors who have minimal clinical or laboratory evidence suggesting ischaemia ii. HLA antigen has been random, an cross matching not been a determinant of graft acceptance b. Types of intestinal grafts i. Isolated graft or composite graft (liver-intestine) c. Recipient operation i. Can be challenging due to multiple previous abdominal surgeries 5. Post-operative management a. Immunosuppression b. Allograft assessment i. Gold standard for diagnosis is serial endoscopic surveillance ii. Signs and symptoms of rejection or infection overlap and mimic each other iii. Any change in clinical status should warrant evaluation for rejection c. Rejection vs GVHD i. Acute rejection rates for intestinal allograft are significantly higher than with any other organ – range of 80 to 90% ii. Severe rejection may require treatment of anti-lymphocyte antibody rejection; as high as 30% iii. Vascular rejection uncommon, chronic rejection 15% iv. GVHD is infrequent but life threatening (80% mortality) d. Infections i. Infectious complications most significant cause of morbidity after intestinal transplant e. Outcomes i. Poor outcomes compared with other transplants

Answer 83

c. Age of onset i. 25-30% of all cases of CD and 20% of all causes of UC occur in individuals <18 years ii. Onset most often in adolescent and young adulthood iii. Bimodal pattern of distribution – onset 10-20 years and second smaller peak at 50-80 years 2. Classification based on age a. Paediatric onset = <17 years b. Early onset = <10 years c. Very early onset = <6 years d. Infant/toddler = 0-2 years b. 4 factors involved i. Genetic susceptibility ii. Environmental triggers iii. Luminal microbial antigens and adjuvants 1. Changes in gut microbiota influenced by other environmental factors 2. Dysbiosis = definitive change of gut microbiota  probably defining event in development in IBD; shift from symbiote microbes (friendly) to pathobiome microbes (harmful) iv. Immune response c. In susceptible individuals - dysregulated or inappropriate immune response to environmental factors in genetically susceptible host d. Abnormality in intestinal mucosal immunoregulation a. Believed to be a polygenic disease – NOT Mendelian c. The younger age of onset the more likely a family history of IBD d. Genetic influence lower in UC than CD f. Inheritance = highly heritable i. Sibling of affected individual – relative risk of CD 30 and UC 10 ii. Affected relatives likely 15-20% (usually first or second degree) in both UC/CD iii. Child whose parents both have IBD >35% risk iv. Concordance rates in twins is higher in CD (35-50%) than in UC (16%) g. Genetic disorders associated with IBD = Turner syndrome, glycogen storage disease, immunodeficiency

Answer 84

a. 1st line investigations i. FBE – looking for anaemia and thrombocytosis 1. Usually due to iron deficiency ii. ESR, CRP, albumin – red flags 1. HypoAlb from malabsorption or blood loss 2. ESR/CRP elevated in inflammation iii. LFT – raised ALT, GGT iv. Celiac serology v. Stool MCS – to exclude infection, look for WBC, RBC, C diff vi. Stool calprotectin vii. Serology 1. Antibodies present in serum of patients with IBD 2. Examples = pANCA, ASCA, antiOmpC a. CD – tends to be ASCA positive b. UC – tends to be pANCA positive 3. Low sensitivity (40-65%) – poor screening tool b. 2nd line investigations = endoscopy – gastroscopy + colonoscopy 7. Infections that can mimic IBD a. Mimic colitis i. Salmonella, Shigella, Yersinia, Campylobacter ii. C Diff iii. E coli iv. Entamoeba Histolytica b. Mimic ileitis i. Tuberculosis – major issue in Asia and Africa  must ALWAYS CONSIDER ii. Yersinia

Answer 85

• May be cause by variety of genetic defects • Collectively known as ‘monogenic IBD’ • Likelihood of these disorders is greatest in children <6 years of age, and higher in those in infancy • Disorders include = IL-10 mutation, atypical SCID, CVID, CGD, neutrophil defects, Wiskott-Aldrich syndrome, agammaglobulinaemia, hypergammaglobulinemia M syndrome, familial HLH, IPEX • Features which raise suspicion of VEO IBD o Young age of onset (eg, younger than six years) o Family history of IBD and/or immunodeficiency in multiple family members, particularly with male predominance, or consanguinity o Recurrent infections or unexplained fever o Associated features of autoimmunity (eg, arthritis, primary sclerosing cholangitis, anemia, or endocrine dysfunction) o Very severe IBD and/or resistance to conventional therapies for IBD o Symptoms or signs suggesting hemophagocytic lymphiohistiocytosis (hepatomegaly, fever, cytopenias, high ferritin) o Lesions of the skin, nails, or hair o Tumors

Answer 86

* Extraintestinal manifestations slightly more common with Crohn’s disease than UC * 10% of patients at diagnosis; 30% of patients within a few years of diagnosis * Most common skin manifestation = erythema nodosum ``` Correlate with disease activity • Peripheral arthritis • Erythema nodosum • Anaemia No correlation • Pyoderma gangrenosum • Sclerosing cholangitis • Ankylosing spondylitis • Sacroilitis ``` ``` More common in CD • Oral aphthous ulcers • Fevers • Erythema nodosum • Digital clubbing • Arthritis More common in UC • Pyoderma gangrenosum • Sclerosing cholangitis • Chronic active hepatitis • Ankylosing spondylitis ``` • Rare in children o Glomerulonephritis o Uveitis o Hypercoagulable state • Arthritis o Arthritis occurs in 3 patterns and tends to be non-destructive  Migratory peripheral arthritis involving primarily large joints  Ankylosing spondylitis = begins in 3rd decade and occurs most commonly in patients with UC have HLA-B27 • Symptoms include low back pain and morning stiffness • Back, hips, shoulders and sacroiliac joints are typically affected  Sacroilitis • Miscellaneous o Patients with erythema nodosum or pyoderma gangrenosum have a high likelihood of having arthritis as well

Answer 87

Presenting features - more consistent with UC: rectal bleeding (90%) and diarrhoea - more consistent with CD: abdo pain, weight loss, growth failure, perianal disease, EOI (erythema nodosum, anaemia, arthritis, mouth ulcers, fever) ``` UC • Colon only • Continuous • No rectal sparing • No granulomas • Mucosal inflammation • Abscesses very rare • Strictures rare • Cx: Toxic megacolon ``` ``` CD • Any part of GIT • Discontinuous • Rectal sparing • Non-caseating granulomas • Transmural inflammation • Fistulae and abscesses • Strictures common • Ileum commonly involved • Perianal disease ```

Answer 88

Iron Deficiency Anaemia • Most common systemic complication (up to 75%) • Causes: blood loss, reduced iron absorption • Ferritin will be high due to chronic inflammation Growth Failure 1. Key points a. Height velocity is most sensitive parameter to recognize impaired linear growth b. More common in CD than UC 3. Pathogenesis a. Multifactorial (malnutrition, inflammation, steroids) 4. Timing a. Decreased height velocity has been reported in ~50% patients BEFORE onset of GI symptoms d. Growth failure may be the ONLY feature of CD h. Interventions should be initiated before completion of puberty 5. Consequences a. Short stature can have significant impact on QOL/psychological function Bone Disease 1. Key points a. Bone mineral density is often reduced in childhood with IBD 2. Therapy a. Control underlying disease b. Optimise nutrition i. Calories/ protein ii. Calcium/vitamin D c. Promote physical activity d. Should be managed in conjunction with a specialist in bone health Psychosocial Issues + QOL • 25-30% of children with IBD have symptoms of depression and/or anxiety • Similar to rates in children with other chronic illness Malignancy • 2% at 10 years 8% at 20 years, 18% after 30 years • Risk related to time of disease + length of colon + presence of sclerosing cholangitis • FHX of colorectal CA • Screening – begins at 8 years of widespread colitis

Answer 89

- Leukocyte derived protein, accounts for 60% of neutrophil cytosolic protein - Stable in stool for >7 days, resistant to degradation Increased in: infection, inflammation, malignancy - False positives: NSAIDs, chest infection, bleeding into bowel - Sensitivity 96%, specificity 87%, elevated in >95% of patients with IBD - Cut off levels vary with age (?from MCH rotation needs to be >100 to be convincing) - Indications: lower GI symptoms, chronic GI symptoms, to monitor IBD (correlates with activity) - Do NOT use: young <4 years, where infection is likely/established, GI red flags / rectal bleeding

Answer 90

1. Key points a. Affects GIT from mouth to anus b. Paediatric Crohn’s disease more likely to have extensive anatomic involvement c. Bimodal age distribution – first peak beginning in teenage years d. Diagnosis often delayed until 1-2 years after symptom onset e. Only 20% present with diarrhoea, weight loss and abdominal pain i. Most do NOT have diarrhoea; only 25% have GI bleeding 2. Classifying CD a. Gastroduodenal (30%) b. Jejunoileal (20%) c. Ileal (30%) d. Ileocolonic (50%) e. Colonic (20%) f. Perianal (20%) 3. Phenotypes a. Types i. Inflammatory ii. Stenotic iii. Fistulizing b. Change over time i. Most patients start with inflammatory disease ii. Over time inflammation decreases but complications of stricturing/penetrating(=fistulizing) iii. The longer time without treatment the higher chance of complication

Answer 91

a. Systemic signs and symptoms = fever, malaise and easy fatigability b. Growth i. Growth failure with delayed bone maturation and delayed sexual development 1. Can precede other symptoms by 1-2 years and is twice as likely in Crohn’s than UC 2. Decreased height velocity occurs in 90% of children with Crohn’s disease – often precedes GI symptoms 3. Can present with growth failure as only symptom c. Sexual development = primary or secondary amenorrhoea and pubertal delay are common d. Extra-intestinal i. More common in Crohn’s disease than UC ii. Particularly associated with Crohn’s disease 1. Oral aphthous ulcers, arthritis, erythema nodosum, clubbing, episcleritis, renal stones, gall stones e. Intestinal i. Spectrum of disease 1. At initial presentation >50% have disease that involves the ileum and colon (ileocolitis), 20% have exclusively colonic disease, and upper GI involvement (esophagus, stomach, duodenum) 30% 2. Isolated small bowel disease much less common in paediatric population 3. Isolated colonic involvement more common in children <8 y, difficult to distinguish from UC 4. Anatomic location of disease spreads over time 5. Perianal disease common (contrasting UC) (tag, fistula, deep fissure, abscess) 6. NOTE: orofacial and perianal inflammation can occur in the ABSENCE of bowel disease 5. Examination a. Often appear chronically ill b. Growth failure – decreased height velocity (earliest sign) c. Pale, decreased energy level d. Abdominal tenderness – diffuse or localised to RLQ e. Tender mass or fullness may be present f. Perianal disease may be characteristic g. Extra-intestinal manifestations i. Oral aphthous ulcers ii. Peripheral arthritis = non-deforming iii. Erythema nodosum iv. Digital clubbing

Answer 92

1. Stricture = can result in partial bowel obstruction 2. Penetrating disease = demonstrated by fistula formation a. Enterohepatic or enterocutaneous fistulas = often asymptomatic but can contribute to malabsorption if they have high output or result in bacterial overgrowth b. Enterovesical fistula (bowel and bladder) = originate from ileum or sigmoid colon and appear as UTI, pneumaturia, or faecaluria c. Enterovaginal fistula (rectum and vagina) = cause faeculant vaginal discharge; difficult to manage d. Enterocutaneous fistulas (bowel and skin) = often caused by prior surgical anastomoses with leakage e. Perianal fistula = usually produce fewer symptoms than anticipated 3. Abscesses a. Intra-abdominal abscesses = may be associated with fever and pain but might have few symptoms b. Hepatic or splenic abscesses = can occur with or without a local fistula c. Anorectal abscesses = often originate immediately above the anus at the crypts of Morgagni d. Perianal abscess = usually extremely painful 4. Short bowel = extensive involvement, especially with surgical resection can lead to small bowel syndrome 5. Terminal ileum dysfunction a. Bile acid malabsorption with secondary diarrhoea and vitamin B12 malabsorption b. Chronic steatorrhoea can lead to oxaluria with secondary renal stones c. Increasing calcium intake can decrease the risk of renal stones secondary to ileal inflammation d. Choledocholithiasis increased secondary to bile acid depletion

Answer 93

a. Peripheral blood tests i. Anaemia, often iron deficiency ii. Thrombocytosis iii. CRP and ESR often elevated – but can be normal iv. Alb – low, indicating small bowel inflammation and protein losing enteropathy, also acute phase reaction b. Stool = faecal calprotectin c. Investigations to map disease and distribution i. Small bowel follow-through + CT scan – extremely high radiation load so avoided 1. Specific indications eg. abscess formation requiring drainage ii. MRI = most commonly used imaging modality 1. Usually >7 years due to requirement for GA iii. USS – in well-trained hands iv. Capsule endoscopy – not standard v. Double balloon endoscopy – not standard d. Endoscopy i. Macroscopic = patchy, unspecific inflammatory changes, aphthous ulcers, linear ulcers, nodularity, strictures ii. Microscopic = non-caseating granulomas, transmural inflammation (surgical specimen)

Answer 94

i. Mild-moderate 1. Aminosalicylates – topical and oral (?more commonly UC) 2. Antibiotics 3. Enteral feeds 4. Corticosteroids – budesonide, prednisolone (oral or rectal) ii. Moderate to severe 1. Induction a. Enteral feeds = FIRST line b. Corticosteroids - NOT for maintenance as does not alter disease course i. Budesonide vs prednisolone 2. Maintenance = immunomodulators a. 6MP b. Azathioprine c. Methotrexate 3. Biologics (induction + maintenance) a. Infliximab (UC + CD) b. Adalimumab (UC + CD) c. Certolizumab - not available for children in AUS

Answer 95

i. Exclusive enteral nutrition (EEN) – all patient’s calories delivered by formula 1. Elemental vs polymeric no difference - tend to use polymeric as more palatable 2. Usually administered via NG/PEG 3. Considered first line for inducing remission in children ii. Effectiveness 1. Effectiveness in children 50-80% 2. Effective primary as well as adjunctive treatment 3. Rapid onset and as effective as other treatments including steroids as inducing remission iii. Benefits 1. Avoids AE of steroids 2. Allows window to give vaccinations prior to biologics 3. Addresses nutritional concerns 4. No side effects iv. Paediatric studies suggest similar efficacy to prednisolone for improvement in clinical symptoms, but EEN is superior to steroids for actual healing of mucosa v. Controversy regarding influence of anatomic location (colon vs small intestine) – recent studies suggest no difference

Answer 96

a. Dose i. 6MP = 1.0-1.5 mg/kg/day ii. AZA = 2-2.5 mg/kg/day b. Beneficial effect can be delayed by 3-4 months; not helpful acutely i. Earlier use of these agents can decrease cumulative use of prednisolone c. Variants in thiopurine methyltransferase  must be tested first d. TPMT genotype (thiopurine methyltransferase) – genetically controlled enzyme activity; may identify patients at risk of drug-induced neutropenia e. Common toxicities i. Gastrointestinal symptoms ii. Hepatitis – monitor iii. Decreased cell counts – monitor iv. Pancreatitis f. Less common i. Risk of malignancy = HL, NHL, NMSC 1. Slight increased risk of EBV associated lymphoma 2. Minimal if any risk of NHL 3. Benefit in maintaining remission lymphoma risk 4. No increased risk of colorectal malignancy ii. Risk of skin infections = HSV, HPV * HSTCL = hepatosplenic T cell lymphoma (>30 reported cases in paediatrics, usually if used with AZA) * TB and increased risk of infections (histoplasma) – highlights importance of differentiating intestinal TB from CD  at RCH screen with CXR and QFG

Answer 97

1. Anti-TNF-alpha a. Infliximab = chimeric (must have other immunusuppression on board to avoid making antibodies!) monoclonal antibody to TNF-a i. IV administration ii. Rapid onset iii. Usually given as 3 infusions over a 6 week (0, 2 and 6 weeks) period followed by maintenance therapy every 8 weeks b. Adalimumab = full humanized antibody to TNF-alpha i. S/C administration ii. Usually administered once every 2 weeks iii. High dose induction followed by maintenance iv. 80% respond to infliximab – 50% remission after 1 year v. Monitoring = infliximab trough levels and antibodies 1. Trough levels > 3 associated with higher likelihood of remission 2. Newer agents a. Vedoluzimab = anti-integrin A4B7 molecule i. Gut selective anti-inflammatory ii. Blocks trafficking of T lymphocytes out of vascular endothelium involving MAdCAM-1 use in UC b. Usteikinumab = human MAb to IL-12/23 i. Involved in activation of T cells

Answer 98

i. 90% develop complication over 20 year period – in one study 70% of patients required surgical intervention within 15 years of diagnosis ii. Recurrence after bowel resection is very high (>50% by 5 years) iii. Complications of surgery = development of fistula or stricture, anastomotic leak, post-operative partial small bowel obstruction secondary to adhesions, short bowel syndrome iv. Must remove as limited length of bowel as possible – no evidence that removing bowel to margins that are free of histological disease improves outcome v. Indication for surgery 1. Failure of medical therapy 2. Recurrent obstruction 3. Perforation 4. Fistula or abscesses a. Often surgeon places seton through the fistula to keep the tract open and actively draining while medical therapy is administered b. Only severe symptomatic perianal fistula fistulotomy 5. Haemorrhage 6. Growth retardation (if disease limited to terminal ileum) 7. Carcinoma

Answer 99

9. Long term complications a. Osteopenia – particularly common in chronic poor nutrition and high dose corticosteroids b. Permanent decrease in linear growth c. Extra-intestinal manifestations can be a great cause of morbidity = sclerosing cholangitis, chronic active hepatitis, pyoderma gangrenosum, ankylosing spondylitis d. Colon cancer = risk of colon cancer in patients with long-standing Crohn colitis approaches that associated with UC and screening for colonoscopy after 10 years of colonic disease is indicated 10. Prognosis a. High morbidity but low mortality b. Region of bowel involved and complications of inflammatory process increases with time c. Majority of patients eventually require surgery – unlikely to be curative and should be avoided if possible

Answer 100

1. Clinical manifestations a. Intestinal i. Disease usually begins in the rectum and extends proximally for a variable distance ii. When confined to the rectum = ulcerative proctocolitis; when involving entire colon = pancolitis iii. 50-80% of paediatric patents have extensive colitis (adults more likely to have distal colitis) iv. 30% of children who present with ulcerative proctitis experience proximal disease spread v. Rarely noted to be present in infancy vi. Symptoms 1. Blood, mucous and pus in the stool with diarrhoea 2. Tenesmus, urgency, cramping, abdominal pain (especially with bowel movement), nocturnal bowel movements 3. Constipation possible in those with proctitis b. Extra-intestinal manifestations i. More common in UC 1. Pyoderma gangrenosum 2. Sclerosing cholangitis 3. Chronic active hepatitis 4. Ankylosing spondylitis c. Other i. Secondary amenorrhoea 2. Clinical course a. Marked by remission and relapse, often without explanation b. After treatment of initial symptoms, approximately 5% of children with UC have prolonged remission (>3 years) c. 25% of children presenting with severe colitis require colectomy within 5 years of diagnosis, compared with only 5% of those with only mild disease d. NSAIDs + intercurrent infection known to provoke disease 3. Fulminant colitis a. Fever, severe anaemia, hypoAlb, leukocytosis and >5 stools per day b. Colonoscopy should NOT be performed due to the risk of provoking toxic megacolon or causing perforation

Answer 101

4. Differential diagnosis a. Infectious colitis i. Bacterial, Parasites iii. AIDS associated = cryptosporidium b. Allergic colitis c. Crohn colitis 5. Investigations (to diagnose and exclude other DDx) a. Bloods i. Anaemia - from chronic blood loss, decreased intake +/- anaemia of chronic disease ii. Iron deficiency iii. Hypoalbuminaemia iv. CRP and ESR – often elevated, can be normal even with fulminant colitis v. Elevated WBC – only seen with severe colitis vi. Folate deficiency unusual vii. Microangiopathic haemolysis + thrombocytopenia + renal impairment – indicates HUS b. Stool i. MCS, ova parasites, C diff – to exclude infectious etiology c. Endoscopy i. Macroscopic = rectum with erythema, edema, loss of vascular pattern, granularity ,and friability 1. With severe disease pseudopolyps are seen ii. Microscopic = acute and chronic mucosal inflammation; typical findings are of cryptitis, crypt abscesses, separation of crypts by inflammatory cells, foci of acute inflammatory cells, edema, mucous depletion, branching of crypts 1. Granulomas, or full thickness involvement suggests Crohn’s d. X-ray i. X-ray = may show loss of haustral markings in an air filled colon or marked dilatation in toxic megacolon (in an adult diameter > 6cm)

Answer 102

6. Treatment a. Therapy based on disease severity i. Mild-moderate 1. Induction AND maintenance = aminosalicylates e.g. sulphasalazine, mesalazine (better tolerated) - tend to use colonic release formulations for UC - hypersensitivity common, 10-20% - PO, PR ii. Moderate-severe 1. Induction = corticosteroids - NOT effective for maintenance 2. Maintenance = 6MP/AZA - not indicated for acute treatment of fulminant colitis Infliximab, adalimumab Surgery 2. Colectomy + Endorectal pull-through a. Segment of distal rectum is retained + the mucosa is stripped down from this region b. Distal ileum is pulled down and sutured at the internal anus with a J pouch created from ileum immediately above the rectal cuff c. Allows child to maintain continence d. Temporary ileostomy often created to protect the delicate anastomosis e. Major complication = Pouchitis i. Chronic inflammatory reaction to the pouch ii. Cause is unknown, more common when the ileal pouch has been constructed for ulcerative colitis than for other indications (eg. familial adenosis polyposis coli) iii. Pouchitis seen in 30-40% of patients iv. Responds to treatment with oral metronidazole or ciprofloxacin

Answer 103

7. Long-term complications a. Colon cancer = begins to increase 8-10 years after diagnosis i. Risk is delayed by approximately 10 years in patients with colitis limited to descending colon ii. Proctitis alone not associated with colon cancer iii. Those with UC >10 years need screening iv. If cancer detected: total colectomy 8. Prognosis a. Most children with this disorder initially respond to medical treatment b. Many child with mild manifestations continue to respond well to medical management and may stay in remission on prophylactic 5-ASA for long periods c. Occasional child with mild onset disease experience intractable symptoms at a later time

Answer 104

= an uncommon, neutrophilic dermatosis Neither infectious nor gangrenous Most commonly a/w IBD (also cancers, arthritis, PAPA syndrome) Rx - local wound care - local corticosteroids - topical tacrolimus - systemic steroids/CNI - infliximab

Answer 105

Potentially lethal cx IBD or infectious colitis, highest risk early in disease Total/segmental non-obstructive colonic dilatation + systemic toxicity Sx - severe bloody diarrhoea (improvement may herald the onset of TMC) - toxic (tachycardia, fever, hypotension) - lower abdo distension and tenderness without evidence of peritonitis Ix - AXR: dilation of right colon >6cm, loss of haustral markings - send stool for C. diff Rx - IV fluids, broad spectrum abx, corticosteroids, bowel rest, bowel decompression - surgery

Answer 106

``` • Adverse effects of 6MP/AZA o Pancytopenia/ myelosuppression o Infection and lymphoma o Pancreatitis o Elevated aminotransferases/ hepatotoxicity • Monitoring = FBE, LFT ``` • Therapeutic efficacy, bone marrow toxicity + liver toxicity of AZA and 6MP related to metabolites • Enzymes responsible for catalyzing reaction o Thiopurine methyltransferase (TPMT) o Hypoxanthine phosphoribosyl transferase • Metabolites o 6-thioguanine (6-TG)  Correlate with response and remission of IBD  Levels >400 result in bone marrow suppression o 6-methylmercaptopurine (6-MMP)  Levels >5700 result in liver toxicity • TPMT genotype + activity (phenotype) recommended in all patients o 90% homozygous for wild type TPMT = rapid metabolism of thiopurines, higher doses for clinical effect o 10% heterozygous for wild type TMPT = metabolise slowly and respond to much lower doses o 0.3% absent TPMT metabolism = negligible activity therefore 6MP preferentially metabolised to produce high levels of 6-TG resulting in bone marrow suppression o Shunters = use the XO pathway resulting in limited effect, therefore can give allopurinol to increase efficacy • Allopurinol o Low or absent 6TG levels may indicate poor compliance, subtherapeutic dose or preferential metabolism to 6MMP instead of 6TG (ie. 6MP resistance) o Allopurinol has been used to cause shunting of 6-MMP metabolites towards 6TG o Inhibits xanthine oxidase

Answer 107

1. Definition a. Increase in frequency, volume or fluidity of stool b. WHO = passage of lose or watery stools at least 3 times in 24 hour period c. Stool volume >10 ml/kg/day d. Normal adult = 200 grams daily 2. Stool pattern in children a. Breastfed can stool 10x per day to once every 10 days b. 12 months of age – passing 2-3 stools/day c. Adult pattern of stools age 2-3 years 3. Epidemiology a. Second most common cause of morbidity and mortality worldwide b. Leading cause of malnutrition in children <5 years c. Second leading cause of death in children <5 years d. Significant proportion of diarrheal disease can be prevented through sanitation and hygiene 4. Pathophysiology a. Diarrhoea is usually due to an excess of stool water resulting from abnormal water and electrolyte transport b. Normally the small intestine and colon absorb 99% of both oral intake and endogenous secretions = total fluid load of 8-10 L per day c. Water is not actively transported i. Moves across intestinal mucosa via paracellular and transcellular pathways ii. Movement secondary to osmotic forces generated by the transport of solutes – particularly Na

Answer 108

5. Absorption of water and solutes in intestine a. Sodium coupled transport i. Provides absorption of glucose, galactose, amino acids, oligopeptides ii. Absorbed Na+ is pumped by sodium pumps out of the cell iii. Establishes a high osmolarity between the small intercellular spaces between adjacent enterocytes and water follows iv. Remains intact during enteritis = basis for ORS b. Na+/H+ exchange i. Absorption of electrolytes ii. Not associated with other solutes c. Paracellular transport i. Energy-independent ii. Passive pathway iii. Tight junction 6. Factors affecting absorption + secretion a. Absorption in the villus = associated with Na+ i. Electrolyte state ii. Blood and lymph flow iii. Nutrient intake iv. Gastric motility v. Intestinal motility b. Secretion in the crypt = dependent on Cl- secretion i. Luminal factors ii. Irritants iii. Bacterial toxin iv. Bowel c. Colon = short chain fatty acids i. Cl/HCO3 exchange and Na/H ii. Some HCO3 secretion is linked to short chain fatty acids iii. SCFA – energy source of colonocytes iv. Can absorb up to 5L per day

Answer 109

a. Time course i. Acute = abrupt, increase fluid content > 10 ml/kg/day ii. Chronic = > 2 weeks (adults 4 weeks) b. Volume i. Small = usually colon ii. Large = usually small intestine c. Pathophysiology i. Osmotic = passive, responds to fasting, low electrolytes, high osmotic gap, associated with CHO malabsorption (acidic with reducing sugars) ii. Secretary = not affected by fasting, high load of sodium, low osmotic gap d. Stool exam i. Watery ii. Steatorrhoea iii. Inflammatory

Answer 110

OSMOTIC Caused by non-absorbed nutrients in the intestinal lumen dragging water out into gut with glucose (gut hyperosmolar to blood) Responds to fasting (as no more sugar) Volume: <200 ml/ay Na: <70 meq/L Osmotic gap (290 - 2x stool(Na+K)): High >100 Reducing substances present pH<5 Explosive/excoriated ++ Aetiology: • Osmotic laxatives (eg. lactulose, sorbitol, mannitol) • Mucosal injury – infective (eg. post-rotavirus), inflammation (IBD), immune mediated (celiac), vascular • Disaccharidase deficiency • Monosaccharide transport defect (eg. glucose-galactose deficiency) • Transport overload (increased sugar, fruits) • Bacterial overgrowth SECRETORY Drags water out into gut with sodium (due to reduced absorption of electrolytes or abnormal ion transport into intestinal epithelial cells) No effect with fasting Volume: >200 ml/day Na: >70 meq/L Osmotic gap: Low <50 Reducing substances: Absent pH>6 Explosive/excoriated: +/- (as mostly due to acidity) Aetiology: • Congenital transport and mucosal defects eg. chloridorrhoea, microvillus inclusion, tufting enteropathy • Secretagogue o Toxigenic bacteria – cholera (turn on cAMP), E coli (toxigenic), Salmonella, C difficile, cryptosporidium, Yersinia o Bile acid malabsorption (bile acids turn on cAMP) • Tumours producing hormones (eg. VIP-5HIAA) • Short gut • Rapid transport Complex diarrhoea can exist with both osmotic and secretory effects, e.g. IBD: a. Destruction to the mucosa  exudate into lumen b. Intestinal immune cells, bacterial toxins  secretory release c. Down-regulation of sodium channels and pumps  anti-absorptive effect d. Bacterial proteins – stimulate the production of inflammatory mediators  cytokines (Il-1, TNF alpha, chemokines such as IL-8, attract inflammatory cells + prostaglandins induce intestinal secretion e. Cytokines and immune cells directly influence tight junction barrier function and enterocyte secretory and absorptive pathways f. Epithelial cells may secrete cytokines (IL6) which enhance neutrophil function

Answer 111

1. Key points a. Abnormal ion transport in intestinal cells b. Decreased absorption of electrolytes c. Most common cause = infection d. Results in profound fluid and electrolyte loss 2. Aetiology a. Exogenous secretagogues = enterotoxins (eg. cholera) b. Endogenous secretagogues = neuroendocrine tumours (eg. carcinoid syndrome) c. Absence of ion transporter = congenital chloridorrhoea d. Loss of intestinal surface area = intestinal resection, diffuse intestinal mucosal disease e. Intestinal ischaemia = diffuse mesenteric atherosclerosis f. Rapid intestinal transit = intestinal hurry following vagotomy 3. Example = cholera a. Chorea toxin is released from bacteria in the lumen b. Toxin binds via the B subunit to GM1 receptors on enterocytes triggering endocytosis c. Following activation in the cytosol of an infected cell, the A subunit enzymatically activates a G protein and leads to activation of adenylyl cyclase and increased cAMP d. High cAMP levels activate membrane bound CFR protein  efflux of chloride, sodium and water from intestinal epithelium e. Regulatory system in intestine = ALPINES – regulatory system in intestine i. Autocrine Luminal Paracrine immune Neural and Endocrine System f. Other i. Stimulate endocrine cell and neural elements ii. Causes changes in intestinal motility iii. Target the tight junctions and alter permeability

Answer 112

1. Infection (viral, bacteria, parasite e.g. amoeba) 2. Medications a. Antibiotic associated (erythromycin, augmentin) b. Laxatives c. Opiate withdrawal d. Oral Mg 3. Vitamin deficiency 4. Dietary a. Sorbitol, fructose, lactulose b. Intolerance to specific foods Systemic illness Hirschprungs Toxins

Answer 113

1. Key points a. Gastroenteritis = characterised by GI symptoms including nausea, vomiting, diarrhoea and abdominal discomfort b. Diarrhoea = abnormal faecal discharge characterised by frequent and/or fluid stool; usually resulting from disease of the small intestine + involving increased fluid + electrolyte loss c. Dysentery = inflammatory disorder of the GIT often associated with blood and pus in the faeces and accompanied by symptoms of fever, pain, abdo cramps; usually from disease of the large intestine d. Enterocolitis = inflammation involving the mucosa of both the small and large intestine (signs of inflammation – blood or pus in stool, fever) i. Examples = shigella (highly contagious, person to person spread), campylobacter (most common bacterial cause, poultry, meat, dairy production and contaminated water) 2. Epidemiology a. Account for a large (9%) of childhood deaths b. Decline in diarrhoeal mortality is the result of preventative rotavirus vaccine 5. Aetiology a. Viral i. Rotavirus = seasonal peak in Autumn and Winter ii. Adenovirus = 7-17% of cases requiring hospital admission iii. Norovirus iv. CMV enteritis = consider in immunocomprimised patients b. Bacterial = 5-10% of all cases i. Salmonella spp. ii. Campylobacter jejuni vi. C. difficile – follows antibiotic therapy c. Parasites i. Cryptosporidium - another rare cause of acute diarrhoea; consider in immunocomprimised patients ii. Giardia – rare cause of acute dehydrating diarrhoea, commonly a cause of persistent diarrhoea with flatulence and bloating 1. Common in toddlers and young children, also in their parents and caregivers 2. Also common in people who have traveled overseas

Answer 114

a. Preformed toxins = S aures, Bacillus cerus b. Secretory toxins = Cholera, E. coli, Salmonella, Shigella c. Cytotoxic toxins = Shigella, S aureus, vibrio parahaemolyticus, C difficile, E coli, Campylobacter jejuni

Answer 115

7. Clinical manifestations a. Poor feeding b. Vomiting and fever, followed by diarrhoea c. Stools are frequent and watery in consistency d. Bacterial gastroenteritis = suggested by history of small-volume stools with passage of blood and mucous, and abdominal pain e. Blood, mucous and the passage of small frequent bowel actions + abdo pain = colitis d/t bacteria (bacterial dysentery), amoebic dysentery, or potentially IBD f. Signs of dehydration – only present if 4% of body weight lost g. Be wary of diagnosing gastroenteritis in the child with vomiting alone who is dehydrated or unwell 8. Diagnosis a. Clinical diagnosis - In most children with gastroenteritis no investigations are required i. Note some viruses (eg. enterovirus) and other organisms (eg. Dientamoeba fragilis, Blastocystis hominis) can be found in stools of healthy individuals and detection does not change management b. Stool MCS = consider if: i. Child appears septic ii. Blood or mucous in the stools iii. Child is immunocomprimised iv. Following overseas travel v. Has not improved by day 7 c. Bloods indicated for i. History of prolonged diarrhoea with severe dehydration ii. Altered conscious state iii. Convulsions iv. Short bowel syndrome, ileostomy, chronic cardiac, renal or metabolic disorders v. Infants <6 months who are judged as being dehydrated vi. Home therapy with excessively hypertonic fluids (eg homemade solutions with added salt) or excessively hypotonic solutions (eg prolonged plain water or diluted formula) vii. 'Doughy' skin (suggesting hypernatraemia)

Answer 116

i. Clinical signs of dehydration give only an approximation of the deficit ii. Other 'signs of dehydration' (such as sunken eyes, lethargy & dry mucous membranes) may be considered in the assessment of dehydration, although their significance has not been validated in studies, and they are less reliable than the signs listed below iii. Weight = gold standard Mild (<4%) No clinical signs May have thirst ``` Moderate dehydration (4-6%) Delayed CRT (Central Capillary Refill Time) > 2 secs Increased respiratory rate Mild decreased tissue turgor ``` ``` Severe dehydration (>/= 7%) Very delayed CRT > 3 secs, mottled skin Other signs of shock (tachycardia, irritable or reduced conscious level, hypotension) Deep, acidotic breathing Decreased tissue turgor ```

Answer 117

a. Oral rehydration therapy = preferable i. ORS = standard of care ii. Contains sodium, chloride, potassium and glucose iii. SGLT1 protein = cotransport of glucose and sodium into the cell  water follows iv. NG rehydration = safe and effective, even if the child is vomiting 1. Most children stop vomiting after NG fluids are started; if continues slow NG fluids temporarily 2. Rapid NG rehydration (25 ml/kg/hour over 4 hours) suitable patients with moderate dehydration 3. Slow NG rehydration = infants <6 months, comorbidities present, significant abdominal pain 4. If ongoing profuse vomiting during NG rehydration = consider DDx; slow NG or consider IV fluids b. Intravenous rehydration i. NG rehydration safer and more effective than IV rehydration ii. Indications: 1. Severe dehydration 2. NG rehydration fails 3. Children who already have an IV in situ 4. Certain comorbidities particularly GIT conditions (eg. short gut, previous surgery) c. Antibiotics i. Indications: 1. Cholera 2. Systemic infection eg. typhoid fever 3. Immunocomprimised patients 4. Severe infection with Shigella 5. Protozoal infection = metronidazole, tinidazole 6. Severe pseudomembranous colitis d. Other i. Zinc supplementation in developing countries - reduces duration and severity of illness e. Nutrition i. Early re-feeding (after dehydration) – enhance mucosal recovery in children/ infants + reduces the duration of diarrhoea ii. Breast-feeding should continue through the rehydration and maintenance phases of treatment iii. Formula-fed infants and children should re-start oral age appropriate formula or food intake after completion of rehydration iv. Children can have complex CHO (eg. rice, wheat, bread and cereals), yoghurt, fruit and vegetables once rehydration is complete v. Transient lactase deficiency = with acute gastroenteritis may occur but is not common in infants <6 months 1. Lactose free diets are infrequently required after acute gastroenteritis 2. If there is persistent diarrhoea after re-introduction of feeds, evidence for lactose intolerance should be sought (pH <5 and >9.75% reducing substance) -> lactose free formula

Answer 118

a. Hypernatraemic dehydration (sodium >150mmol/L) i. Results from severe water + sodium depletion with greater loss of water ii. Consequence = severe neurological sequelae iii. Management = oral rehydration therapy preferred to IV rehydration 1. If shocked – bolus of normal saline 20ml/kg IV, repeat until organ perfusion restored 2. Slow ORT – aiming to complete rehydration over 12 hours, followed by maintenance fluids iv. Serum electrolytes should be monitored on a 4 hourly basis v. Serum sodium should NOT fall by >0.5 mmol/L per hour b. Hyponatraemic dehydration (sodium <130mmol/L) i. Can cause seizures and coma ii. Be aware of iatrogenic hyponatreamia due to fluid (hypotonic) overload Extra intestinal - reactive arthritis • Salmonella, Shigella, Yersinia, Campylobacter, Cryptosporidium, C difficile • Typically 1-3 weeks after infection • Relapse after re-infection can develop in 15-50% of people, most children fully recover within 2-6 months - Guillain barre • Campylobacter • Usually occurs a few weeks after the original infection • Prognosis is good although 15-20% may have sequelae - glomerulonephritis • Shigella, Campylobacter, Yersinia • Sudden onset in acute, or chronic which comes on gradually • In most cases gradual recovery - IgA nephropathy • Campylobacter • Characterised by recurrent episodes of haematuria • IgA nephropathy can progress with no noticeable symptoms • Men > women - erythema nodosum • Yersinia, Campylobacter, Salmonella • Although painful, usually benign and more commonly seen in adolescents • Resolves in 4-6 weeks - HUS • Shigella dysenteriae 1 • EHEC O157:h7

Answer 119

``` Hypo-osmolar (200-310 - normal serum 275-295) Sodium 60-90mmol Glucose Potassium Chloride Citrate Starch ``` Na/Glucose - SGLT1 - 1 Na + 1 glucose, Na then actively transported across basolateral membrane by Na/K/ATP pump - water follows sodium/solutes Starch - fermented in colon -> short chain fatty acide - SCFA absorbed which promotes Na and fluid absorption

Answer 120

1. Overview a. Incubation period = 12h-4 days b. Infectious period = shed virus in stool for up to 10 days; however 1/3 with severe primary rotavirus continue shedding for >21 days c. Responsible for 40-50% of cases requiring hospital admission d. Peak incidence between 6-24 months e. Peaks in winter-spring 2. Vaccination a. Since the introduction of the rotavirus vaccine there has been a 60-70% decline in rotavirus hospitalisations in children <5 years – 7000 children/year 3. Pathophysiology a. Day 1: virus infects enterocytes within villous epithelium of jejunum and ileum → destruction of cells of this layer → transudation of fluid into lumen with loss of fluid and salt b. Day2-5: adjacent villi fuse, reducing surface area of injury c. Day 6-10: normal villous architecture d. Intestinal injuries lead to a loss of the ability to digest food (especially complex sugars) and to absorb digested food across the intestinal mucosa → inability to absorb CHO manifests as transient lactose intolerance e. Rotavirus may also cause secretory diarrhoea via the non-structural glycoprotein- (NSP4) enterotoxin, which induces age- and calcium ion dependent chloride secretion, disrupts reabsorption of water 4. Clinical presentation a. Vomiting (may precede diarrhoea) b. Diarrhoea c. Fever d. Resp symptoms e. Complications – dehydration, electrolyte imbalance, acidosis 5. Investigations a. Enzyme immunoassay + latex agglutination assay 6. Treatment – supportive, hydration 7. Prevention - Vaccine now available (since 2007)

Answer 121

* Commonly infects older children + adults * Acute onset vomiting, cramps, diarrhoea; symptoms only last 1-2 days * Infections occur all year round * Also called ‘Winter vomiting bug’ (in children vomiting predominates, in adults diarrhoea does) * Major cause in epidemic viral gastroenteritis; 2/3 of food-related illnesses due to norovirus

Answer 122

* Common >5 years of age * Causes diarrhoea with visible or occult blood, abdo pain, malaise + fever * Antibiotic Tx usually not necessary • Pathogenesis o Attach and invade the intestinal epithelium via fimbriae-like filaments o Following attachment, colonize and then invade the intestinal epithelial cells o Histologic picture is that of acute mucosal inflammation with edema, cellular infiltration of the lamina propria, and crypt abscess formation  These findings are indistinguishable from those seen in salmonellosis and shigellosis.

Answer 123

1. Overview a. Age specific attack rates highest in children (<5 years of age, peak at <1 year of age) and elderly b. Invasive infections + mortality more common in infants + elderly c. Food = contaminated raw or undercooked egg 2. Pathogenesis a. Intestinal mucosal response to nontyphoidal Salmonella infection is an enterocolitis with diffuse mucosal inflammation and edema, sometimes with erosions and microabscesses b. Salmonella attaches ot epithelial cells via fimbriae and invades cells by process of bacterial-mediated endocytosis c. Remain inside phagosome d. Induce inflammatory response→ induce secretion of IL 8, recruit neutrophils and phagocytes and pro-inflammatory mediators 3. Clinical presentation a. Asymptomatic carriage b. Gastroenteritis c. Bacteraemia d. Focal infections (eg. bone + joint) 4. Investigations = does not alter Mx; serology + PCR available 5. Treatment a. Antibiotic treatment NOT usually indicated for uncomplicated GE as it may prolong excretion b. Indicated for i. Bacteraemia ii. Systemic involvement iii. Infants <3 months of age iv. Underlying disease (eg. immunocomprimised), elderly people

Answer 124

1. Contaminated food or water 2. Classification a. EHEC = haemolytic uraemic syndrome (HUS), haemorrhagic colitis b. EPEC = watery diarrhoea in children <2 years of age in developing countries c. ETEC = major cause of travelers’ diarrhoea (self-limiting) d. EIEC = watery diarrhoea, may cause dysentery e. EAEC = chronic diarrhoea in infants and young children 3. Treatment = antibiotics not usually indicated for diarrhoea caused by E. coli and may be associated with increased rates of HUS in EHEC infection

Answer 125

1. Transmission a. Most common parasite identified in stool specimens from children b. More common in children (and staff) in childcare centres and returned travellers c. Major reservoir + means of spread is contaminated water, and to a lesser extent, food d. Person-to-person spread also occurs 2. Clinical presentation a. Diarrhoea (persistent) b. Abdo distension, flatulence, cramps c. Weight loss d. FTT 3. Investigations = microscopy of stool specimens a. Do NOT usually contain blood, mucous or leukocytes 4. Treatment = metronidazole or tinidazole

Answer 126

* Causes watery diarrhoea, cramps, nausea, vomiting * Can survive chlorination * Usually self-limiting, lasting 2 weeks * The diarrhoea may be acute or chronic; transient, intermittent, or continuous * Secretory type diarrhoea * Acquired from contaminated water; common cause of recreational water-borne illness

Answer 127

* Common in subtropical + tropical countries * Infection occurs when food or drink is contaminated either by infected food handlers or as a result of inadequate sanitation * Commonly asymptomatic * Clinical amoebiasis generally has a subacute onset, usually over 1 to 3 weeks * Symptoms range from mild diarrhoea to severe dysentery, producing abdominal pain, diarrhoea, and bloody stools * Complications = perforation of intestine (peritonitis), Extraintestinal invasion (liver forming abscess, lung)

Answer 128

* Gram negative bacillus * Usually acquired through undercooked pork or contaminated water, meat or milk. * Mild-self-limiting enterocolitis or terminal ileitis * Watery/bloody diarrhoea and fever resembling salmonella or shigella * Can cause pseudoappendicitis as in the terminal ileum it invades Peyer’s patches  lymphadenopathy * Infection is sometimes followed with arthritis, erythema nodosum or reactive arthritis * Typically develops 4-7 days post exposure

Answer 129

1. Overview a. Rare cause of diarrhoea in those <12 months of age b. Only clinically significant diarrhoea or colitis should be considered to be caused by C diff c. Occurs in patients on antibiotics – penicillins, clindamycin and cephalosporins d. Up to 50% of healthy neonates and infants <2 years of age are colonised (cf. 5% of those >2 years) e. Asymptomatic carriage in 1-3% of healthy adults, 40-60% of neonates (esp if born in hospital) 3. Pathogenesis a. Infection requires disruption of normal flora, and an exogenous source b. Associated with prolonged hospital stay and antibiotic treatment c. Only toxin producing strains cause disease 4. Transmission a. Faecal- oral transmission from colonised host 5. Treatment a. Cessation of antibiotics b. Oral metronidazole c. Consider probiotics d. Failure of treatment or recurrence i. Re-infection ii. Non-compliance iii. Continued antibiotic use iv. Metronidazole-resistance (rare) v. Tx = oral vancomycin (NOT IV), repeat metronidazole, probiotics

Answer 130

* Brief illness caused by toxins produced by bacteria * Causes abdominal pain + vomiting * Usually high volume watery diarrhoea * Some bacteria produce toxin in food before intake or in the intestine after food * Symptoms usually appear within several hours • Staphylococcus aureus o Produces toxins in food before it is eaten o Usually food contaminated left unrefrigerated overnight, e.g. meat, potato, egg salad, ham - toxigenic strains, 5 serotypes, A most common - onset 1-6 hours after ingestion, lasts 1-2 days • Clostridium perfringens o Multiplies in food o Produces toxins in small intestine after contaminated food is eaten ``` • Bacillus cereus o Spore forming (survives boiling) o Causes vomiting or diarrheal illness - Gram positive rod - present in soil/vegetation - vomiting: 1-5 hours after ingestion - diarrhoea: 8-16 hours - rice and cereals ``` Campylobacter, Salmonella, E coli - all in the realms of 1-8 days after ingestion, slower onset than above

Answer 131

1. Pathophysiology a. Usually mixed and complex b. Cases of pure secretory or osmotic diarrhoea uncommon c. Combination of i. Osmotic ii. Malabsorption/ maldigestion/ steatorrhoea iii. Inflammation iv. Secretory v. Altered motility 2. Aetiology a. Common i. Toddler’s diarrhoea ii. Constipation with overflow iii. Post infectious / irretractable diarrhoea of infancy b. Congenital (carbohydrate, protein/AA, lipid, electrolytes, other e.g. tufting, microvillus inclusion) c. GIT (coeliac, IBD, Hirschprungs, pancreatic insufficiency, anatomical e.g. short bowel, small bowel overgrowth) d. Immunological/ Allergic (allergic, AI, immun deficiency) e. Other (IBS, laxatives, drugs, neuroendocrine tumours) 3. Common causes a. Infants/Children i. Post-infectious = villous atrophy secondary to mucosal injury by infectious agent ii. Coeliac disease iii. Toddler’s diarrhoea iv. Carbohydrate intolerance v. Allergy b. Adolescents i. IBS – diarrhoea ii. IBD

Answer 132

``` 0-3 months GI infection Disaccharidase deficiency Cow’s milk intolerance Cystic fibrosis ``` 3 months – 3 years Toddler’s diarrhoea GI infection Celiac disease 3 years – 18 years GI infection Celiac disease IBD ``` Other Constipation w/ overflow Diarrhoea Drug induced UTI Short bowel syndrome ```

Answer 133

4. History a. Travel b. Diet c. Family history d. Stool pattern, consistency, frequency i. Small, frequent, painful and mucoid stools with tenesmus may be suggestive of colitis ii. Large, watery and relatively painless stools indicative of small bowel origin 5. Alarm signals a. History i. Involuntary weight loss ii. Growth retardation iii. Persistent abdominal distension (variable IBS) iv. Significant vomiting v. Significant diarrhoea vi. GI blood loss vii. RUQ or RLQ abdominal pain viii. Associated fever, arthritis, rash, amenorrhoea ix. Symptoms of psychiatric disorder x. Family history of IBD b. Abnormal physical findings i. Localised tenderness in RUQ or RLQ ii. Localised fullness or mass iii. Hepatomegaly/ splenomegaly iv. Perianal fissure or fistula

Answer 134

a. Bloods i. Inflammation = ESR, CPR, LFT ii. Allergy= IgE, RAST iii. Nutrition = FBE, UEC, PT, vitamins ADE, B12, CMP, ferritin, folate, Tg, cholesterol iv. Celiac = TTG IgA, DPG IgG, (EMA IgA) v. Toxicology vi. Thyroid function b. Stool i. pH, reducing sugars, fat, faecal calprotectin ii. Stool culture 1. Microscopy a. WBC, RBC, mucous – colitis b. Cysts – giardia c. Fatty acid crystals – mucosal damage d. Fat globules – pancreatic insufficiency/gall bladder 2. Chemistry a. pH <7.0 b. CLINITEST i. Positive = reducing sugars >0.5 g/dL ii. Modified pos = non-reducing sugar (eg. sucrose) c. TRYPTIC ACTIVITY – elastase 1 i. Low = pancreatic insufficiency d. STOOL ELECTS i. Na > 70 = active secretion 3. Faecal calprotectin c. Invasive i. Include 1. Esophagogastroduodenoscopy with small bowel biopsy 2. Sigmoidoscopy with biopsy 3. Ileocolonoscopy with biopsy 4. Anorectal manometry 5. Deep rectal biopsy ii. Indications 1. To rule out allergic or inflammatory colitis 2. To rule out villous atrophy, celiac disease, histological abnormalities, to perform enzyme activist 3. To rule out IBD 4. To rule out exocrine pancreatic insufficiency 5. To rule out Hirschsprung’s disease d. Further investigations i. Elastase 72 hour faecal fat collection ii. Alpha-1 antitrypsin (?protein losing enteropathy) iii. Osmotic gap iv. Breath test evaluating absorption v. Sweat test vi. Plain abnormal x-ray vii. Small bowel follow-through viii. White blood cell scan

Answer 135

UNDERLYING a. Fasting decreases secretion (bowel rest) b. Hydroylsed/ elemental formulas if mucosal disease c. Lactose elimination d. Medium-chain TG (MCTs) i. More readily absorbed and oxidized than most lipids ii. Absorbed without the need for bile or pancreatic enzymes iii. Bypass lymphatic systems e. Long chain TG = osmotically inert, calorie dense i. Absorbed to a variable extent in biliary obstruction, pancreatic insufficiency f. NG feeds = enteral nutrition is essential for mucosal healing i. Oral or enteral feeding is essential to stimulate mucosal recovery ii. Prolonged exclusive IV support lead into a vicious cycle 1. Parenteral nutrition should be avoided

Answer 136

* Rare tumours of the neuroendocrine cells of the gastroenteropancreatic axis and adrenal and extra-adrenal sites * Characterised by an excessive production of 1 or several peptides  exert endocrine effects * Tumour resection treatment of choice ``` Carcinoid - Serotonin (5HT), urine 5-HIAA Gastrinoma = Zollinger-Ellison syndrome - gastrin Mastocytoma - histamine, VIP (vasoactive intestinal peptide) Medullary carcinoma - calcitonin, VIP, PG ```

Answer 137

• Defect of digestion, absorption + transport o Disaccharidase deficiency  Congenital lactase deficiency  Sucrase-isomaltase deficiency  Maltase-glucoamylase deficiency o Ion and nutrient transport defects  Glucose-galactose malabsorption  Fructose malabsorption  Fanconi-Bickel syndrome – basolateral glucose transporter  Cystic fibrosis  Acrodermatitis enteropathica – Zn transporter  Congenital chloride diarrhoea – Cl/base exchanger  Congenital sodium diarrhoea – serine-protease inhibitor  Familial diarrhoea syndrome  Lysinuric protein intolerance  Congenital bile acid diarrhoea – ileal Na/bile salt transporter o Lipid trafficking  Abetalipoproteinaemia  Hypobetalipoproteinemia  Chylomicron retention disease • Defects of enterocyte differentiation + polarization o Microvillous inclusion disease o Congenital tufting enteropathy o Syndromic diarrhoea • Defects in enteroendocrine cell differentiation • Defects of modulation of intestinal immune system o IPEX o Immunodeficiency-associated autoimmune enteropathy o APS1

Answer 138

Pathogenesis • Abnormal anion exchanger (genetic mutation SLC26A3) Secretory Features • Excessive faecal salt/fluid loss • Hyponatremia, hypochloremia, metabolic alkalosis. • +/- polyhydramnios * Stool diagnosis – Cl > cations * Normal biopsy

Answer 139

Pathogenesis • Abnormal sodium in stool (genetic mutation SPINT2) Secretory Features • Some syndromic (choanal/anal atresia) • Hyponatremia, metabolic acidosis Diagnosis • Stool – alkaline, sodium HIGH • Normal biopsy

Answer 140

Pathogenesis • Type 5b myosin motor protein defect MYO5B Secretory Features • Intractable secretory diarrhoea after birth • Rapid shock and metabolic acidosis • Milder form presents few months Diagnosis • EM – characteristic microvillus inclusions + partial/total atrophy of microvilli in enterocytes Treatment • Transplant

Answer 141

Pathogenesis • Mutation EpCAM (epithelial cell adhesion molecule) gene Secretory ``` Features • Secretory diarrhoea after birth • Partial response to fasting • +/- chronic arthritis • Ophthalmologic – punctate keratitis or conjunctival erosions ``` Diagnosis • Villous atrophy + crypt hyperplasia + disorganization of surface enterocytes with crowding, resembling tufts. Treatment Transplant

Answer 142

Pathogenesis • Mutation neurogenin3 with paucity enteroendocrine cells in pancreas and intestine Secretory Features • Diarrhoea • IDDM (antibody negative) Diagnosis • Staining demonstrates absent enteroendocrine cells

Answer 143

Pathogenesis • ARs • Deficiency in intestinal sodium/glucose transporter – SGLT1 transporter (SLC5A1 gene) Osmotic Features • Severe life-threatening diarrhoea in neonatal period. • Symptoms with lactose (glucose + galactose) • Diarrhoea resolves when sugars eliminated, E.g. when giving water. • Metabolic acidosis ``` Diagnosis • Stool – osmotic, acidic, reducing substances. • Glycosuria – same defect in kidney • Positive glucose breath hydrogen test • Normal intestinal biopsy ``` • Treatment – fructose based formula and lifelong dietary restriction

Answer 144

Pathogenesis • Transporter defect Osmotic Features • Rare unless Eskimo / Canadian • Asymptomatic if diet only lactose (breast fed) • Develop chronic diarrhoea after sucrose introduced (fruits, juices, grains)

Answer 145

1. Key points a. Most common cause of chronic diarrhoea in infancy b. Onset between 6-36 months of age (can be older), ceases spontaneously between 2-4 years (can be older) c. Diarrhoea as the sole symptom of malabsorption in a normally thriving child is rare d. A trial of lactose and fruit-juice free diet done separately is practical and diagnostic e. Small bowel biopsy is rarely indicated unless strong evidence suggests another cause f. Diagnosis of exclusion in thriving child (no weight loss, FTT, no fluid or electrolyte abnormalities) 2. Clinical presentation a. Diet history – excess juice intake overwhelms small bowel resulting in disaccharide malabsorption b. Stool may contain undigested food particles, 4-6 bowel movements per day c. Excoriated diaper rash 3. Pathophysiology a. CHO malabsorption i. Excessive consumption of sorbitol ii. High fructose/glucose ratio b. Disturbed motility i. Short mouth to anus transit time ii. Persistence of immature bowel motility pattern iii. Failure of initiation of normal postprandial delayed gastric emptying 1. Low fat meals 2. Excess fluid intake 3. Low fiber diet 4. Excessive faecal bile acids 4. Rome criteria (revised 2016) a. Daily painless, recurrent passage of 4 or more large, unformed stools b. Symptoms last more than 4 weeks c. Onset between 6 and 60 months of age d. No failure to thrive if caloric intake is adequate 6. Tests a. Sweat test, stool for pancreatic enzymes, genetic testing b. Celiac disease c. FBE, Fe studies, vitamin levels, serum albumin d. Inflammatory markers 7. Management a. Daily diet and defaecation diary b. Diet i. Feeding pattern should normalize ii. Reduce consumption of fruit juice – especially high fructose/glucose ratio (apple juice, pear nectar) iii. Fiber intake normalized iv. Dietary fat to 35-40% total energy intake v. Reduce fluid intake to <90 ml/kg/day if fluid consumption >150 ml/kg/day c. Improvement occurs within few days to weeks

Answer 146

• Usually frequent, large volume diarrhoea associated with cramping abdominal pain • Investigations o Blood tests  Hypokalemia  Metabolic alkalosis - hypokalemia impairs reabsorption of chloride + bicarbonate secretion into the intestinal lumen  Magnesium/ phosphate may be elevated depending on type of laxative used o Stool osmolality  < 250 suggests ‘watered down’ – colon cannot dilute stool beyond this level  > 400 – poor storage , concentrated urine o Osmotic gap > 75 ( if the laxative is osmotic, some can be secretory) o Laxative screen o Endoscopy – melanosis coli  Dark brown discolouration with lymph follicles shining through pale patches  Can affect proximal -> whole colon  Not specific, can be also found in patients with chronic colitis • Abuse leads to melanosis coli – identified as pigmentation macroscopically on colonoscopy (pigment is lipofuschin in macrophages which engulf damaged epithelium from laxative use)

Answer 147

• Diagnosis o Chronic abdominal pain o Altered bowel habits o In the absence of any organic cause ``` • Pathogenesis o Altered motility o Visceral hypersensitivity o Inflammation o Alterations in faecal flora o Bacterial overgrowth o Food sensitivity o Genetic predisposition ``` • Treatment o Diet o Medication o CBT

Answer 148

• After acute bacterial gastroenteritis up to 1/3 will have prolonged GI complications o Portion will meet criteria for IBS • After resolution of the acute infection o Chronic mucosal immunologic dysregulation o Altered intestinal permeability o Dysmotility • Both host- and pathogen- related factors, such as pre-existing psychological disorders and duration of initial infection, have been associated with increased risk for post-infectious diarrhoea

Answer 149

1. Key points a. Incidence – 0.3% ED presentations b. 4% life threatening – intussusception and Meckel’s diverticulum c. Defined as – bleeding distal to the ligament of Trietz (junction of duodenum and jejunum) 2. Diagnostic approach a. Is it blood? Examine directly and test b. Is it haematochezia (indicating lower GI bleed – colon or anus) or melena (indicating upper GI bleed) c. What is the cause? 3. Tests for blood in stool a. Bedside guaiac based paper that turns blue if in contact with blood i. False positive with red meat, some veg (turnips, broccoli, cauliflower, cantaloupe) b. Faecal occult blood test – measuring haemoglobin in stool or alpha-1-antitrypsin

Answer 150

Neonatal - Well: swallowed maternal blood, anal fissure - Unwell: NEC, malrotation+volvulus, Hirschprungs, coagulopathy, severe enteritis ``` Infants + Toddlers Anal fissure Food protein induced colitis Intussusception Meckel’s diverticulum Lymph nodular hyperplasia GI duplication cyst Infantile and VEO IBD ``` ``` Preschool Infectious colitis HUS IgA vasculitis (HSP) Juvenile polyps Solitary rectal ulcer syndrome ``` School age + Adolescent IBD

Answer 151

Inspect stool - ?melaena vs haematochezia Melaena - oesophageal or gastric losses - varices, PUD Haematochezia -> stool MCS Not blood - bile pigment, food colouring Blood, no WBCs - vigorous upper GI bleed - Meckels - polyp - fissure RBC+WBC+pathogen - infectious (bacteria, viral) RBC+WBC+no pathogen - IBD

Answer 152

1. Key points a. Common cause for rectal bleeding in children b. 6-12% children with colorectal bleeding 2. Clinical manifestations a. Rectal bleeding b. Painless c. +/- Prolapsed rectal mass d. +/- Mucopurulent stools 3. Aetiology a. Isolated juvenile polyps i. Most common ii. First 10 years of life (peak 2-5years) iii. Usually left sided, 50% >1 iv. If solitary no risk of cancer, >5 polyps increased risk CRC v. Management = colonoscopy with polypectomy b. Juvenile polyposis syndrome i. AD inheritance (multiple mutations) ii. Late childhood/adolescents iii. Characterised by >5 juvenile polyps iv. Painless rectal bleeding vi. Increased risk CRC – approx 50% vii. Management – colonoscopy 3-5years c. Familial adenomatous polyposis i. AD inheritance ii. 80% family history iii. Mutation in APC gene (chromosome 5) – gain of function iv. Presents in young adults approx 30years, usually asymptomatic v. Characterised by >100 adenomatous colorectal polyps vi. Can present in young children with haematochezia in severe phenotype (>1000 polyps) vii. Associated – hepatoblastoma, hypertrophy of retinal pigment epithelium viii. Risk of CRC – 100%, adenoma appear adolescence, cancer 30-40 years ix. Management – prophylactic colectomy d. Attenuated FAP i. AD inheritance ii. Heterogenous genetic mutations on APC iii. Fewer colorectal polyps (usually <100), later onset, extracolic manifestations iv. Increased risk CRC – 80% v. Management – regular surveillance and snare excision, colectomy later e. Peutz-Jegher syndrome - separate

Answer 153

i. AD inheritance ii. 1/8,000-200,000 live births, M=F iii. 10-20% no family history (de novo) iv. Most commonly germline mutation STK11 chromosome 19q13.3 – tumor suppressor gene predisposes to mucosal prolapse and cancer + acquired mutation in second allele v. Clinical features 1. Mucocutaneous pigmentation >95% patients – 1-5mm flat blue/grey/brown spots; lips and perioral region (95%), palms of hand (75%), buccal mucosa (65%), soles of feet (60%), also nose, perianal, genitals, intestines (occur 1-2years then fade after puberty) 2. Hamartomatous polyps – small bowel (60-90%, most jejunal), stomach (15-30%), colon (50-65%) – develop in first decade, symptomatic 10-30years (bleeding, intussusception 70%) 3. Cancer- colorectal, breast, stomach, small bowel, pancreas, biliary tree, GB, oesophagus (lung, breast, ovary, uterus, Sertoli cells); Lifetime cancer risk 40-90%, average age 42years vi. Diagnosis = 2 of 3 - histology of polyp + FHx + mucocutaneous pigmentation

Answer 154

* Failure to pass meconium in first 24 hours of life = Hirschsprung disease * FTT/ growth failure = hypothyroidism, celiac disease, other * Gross abdo distension = Hirschsprung disease, other gastrointestinal dysmotility * Abnormal lower limb neurology or deformity (eg. talipes or secondary urinary incontinence) = lumbosacral pathology * Sacral dimple above natal clef, over the spine – naevus, hairy patch, central pit, discoloured skin = spina bifida occulta * Abnormal appearance/ position/ patency of anus = abnormal anorectal anatomy * Perianal bruising or fissures = sexual abuse * Perianal fistulae, abscesses or fissures = perianal Crohn’s disease

Answer 155

1. Definition a. At last 2 of the following problems in the previous 8 weeks i. <3 bowel motions/ week ii. >1 episode of faecal incontinence per week iii. Large stools in the rectum or palpable on abdominal examination iv. Passing of stools so large they obstruct the toilet v. Retentive posturing and withholding behavior vi. Painful defaecation 2. Aetiology a. Functional faecal retention = withholding of stool i. Painful or fear of painful defaecation are the most common triggers, leading to apprehension about defaecation and a cycle of withholding and passage of hard retained stool ii. Majority of cases of constipation caused by functional faecal retention b. Organic causes i. Cow’s milk protein intolerance – manifest as constipation in the first 3 years of life ii. Hirschsprung’s disease – failure to pass meconium in the first 48 hours of life, and virtually never causes faecal soiling iii. Slow colonic transit and motility (including neuronal intestinal dysplasia) iv. Celiac disease v. Hypothyroidism vi. Hypercalcaemia vii. Drugs (codeine, antacids) viii. Spinal cord lesions ix. Anorectal malformations c. Lack of dietary fibre and poor fluid intake rarely contribute to childhood CC d. Inappropriate emphasis on diet and fluid serve to lay blame on the parents 3. Infants a. Constipation of infancy is not well understood b. Dyschezia (a healthy infant, straining and crying before passing soft stool) is normal but can be mistaken for constipation c. Common organic causes include i. Anal fissures ii. Weaning iii. Cow’s milk protein intolerance d. Treatment with laxative and stool softeners should be undertaken with great caution

Answer 156

1. Definition = passage of stool in an inappropriate place; supersedes the terms encopresis and faecal soiling 2. Aetiology a. Functional and associated with constipation b. Other i. Functional non-retentive (ie. not constipation) ii. Organic causes – from neurological damage or anal sphincter anomalies 3. Associations with faecal incontinence a. Nocturnal enuresis + daytime detrusor overactivity = when all 3 occur together it is known as ‘dysfunctional elimination syndrome’ – perhaps linked through pelvic floor dysfunction i. About 30% of children with FI also have nocturnal enuresis ii. May have family history of nocturnal enuresis b. Behavioral problems are common but most are secondary to FI rather than the cause c. Genetics – a family history of FI is common 4. Pathophysiology a. The majority of children with FI have significant faecal retention causing in turn, chronic rectal dilatation, hypersensitivity to stretching of the rectal ampulla, loss of normal urge to pass stool and further retention b. When the external anal sphincter relaxes, the stool accumulated in the rectal ampulla leaks c. Unaware of the full rectum, the child may only sense the passage of stool by its contact with external skin, initiating an urgent rush to the toilet and a false impression that the child has ‘waited until the last minute’ leading to inappropriate blame

Answer 157

a. Empty the bowel, keep it empty and provide soft lubricated stools b. Needs to be done for a long period in order for the child to overcome the apprehension about defaecation c. Disimpaction = for severe symptoms or to kick-start long-term Mx i. Rectally instilled medication (suppositories or enemas) may add to the child’s fearfulness ii. If using medications per rectum, consider sedation with nitrous oxide or midazolam iii. Suggested medications (singly or combination) 1. Stool softener = paraffin oil 2. Osmotic laxative 3. Microlax enema 4. Gut stimulant eg. Senokot granules d. Follow-on treatment i. A long-term approach is needed, often spanning months to years ii. The physician, child and family need to work together and design an individualised treatment plan iii. Behaviour modification is the mainstay of treatment iv. This involves regular sitting on the toilet and pushing, three times a day for 3–5 min 1. Use of a timer can be helpful to avoid arguments v. Attention to the sitting position: feet supported, hips flexed and encourage ‘bulging’ of the abdomen vi. Reinforce desired behaviour with stickers on an age-appropriate chart vii. Reward achievable goals such as good compliance with sitting programme rather than clean pants. viii. Medications are an adjunct to a toileting regimen ix. Paediatricians usually start with a single agent, most commonly paraffin oil or movicol x. Long-term use of most of these medications is safe and does not render the bowel ‘lazy’ or make the child ‘dependent.’ xi. Only when defecation has been effortless for many months and toileting behaviour is consistent should one try to gradually withdraw adjunct medications

Answer 158

1. Primary functions of the liver a. Metabolism i. Lipid metabolism: synthesis of cholesterol, triglycerides, phospholipids ii. Glucose regulation (storage as glycogen) b. Absorption of fats = bile made in the liver is secreted and collected into gall bladder, stored for release to duodenum to emulsify fats and aid their digestion i. Secretion of bile contributes to digestion- secretes 500-1000mL per day c. Protein synthesis = plasma proteins (bind and carry compounds in the blood), lipoproteins, albumin, clotting factors (except FVIII), apolipoproteins, bile, angiotensin d. Storage = iron, some vitamins (eg. vitamin A) i. Vitamin A stores last ~ 10 months ii. Vitamin D stores 3-4 months iii. Vitamin B12 – 1 year e. Detoxification = inactivates many peptide hormones, steroids, catecholamines, toxins/drugs, alcohol i. Endogenous and exogenous toxins f. Immune = Kupffer cells 3. Anatomy – SUMMARY a. 4 lobes- left, right, quadrate and caudate b. On inferior surface, at the junction of all 4 lobes, the porta hepatis is evident - point of entry for the hepatic portal vein, hepatic artery, and exit of bile c. Cellular content i. Hepatocytes 60% ii. Mesenchyme 30% - Kupffer, Ito, sinusoidal endothelial, bile duct epithelia iii. Highly polarised - Basolateral = bile formation + secretion d. Lobule is structural unit i. Centered on central hepatic vein (CHV) ii. Bordered by 6 portal tracts PV, HA, BD iii. Linear arrays of hepatocytes radiate out from CHV iv. Sinusoids carry blood from portal triad to CHV v. Zones of reducing oxygenation 4. Primary tissue types in the liver a. Hepatocytes (≈80% of total weight) - lifespan 150 days b. Connective tissue (stroma) c. Blood vessels, lymphatics  sinusoids (capillaries) d. Fibrous connective tissue capsule e. Serous external surface

Answer 159

a. Portal triads i. Two blood vessels and a bile duct (and lymphatic) 1. Branch of hepatic artery (oxygenated blood) 2. Branch of hepatic portal vein (deoxygenated blood from gut, spleen) ii. Supplies multiple lobules b. Central vein i. Sinusoids (specialized capillaries) converge on central vein ii. Central vein carries blood to hepatic vein and out of liver then into the systemic venous system iii. Direction of blood flow in lobule “outside in” c. Liver sinusoids i. Both vein and artery give rise to network of capillaries (sinusoids) ii. Sinusoids run between cells and expose blood (from artery and vein) to every hepatocyte iii. Blood in sinusoids flows towards middle of lobule (central vein) iv. Sinusoids carry mixture of oxygenated (20%) and deoxygenated (80%) blood v. Features of sinusoids 1. Larger than other capillaries, discontinuous lining 2. Gap between endothelium and adjacent hepatocyte = space of Disse 3. Hepatocytes have microvilli on this surface to enhance surface area so that 2 way communication is maximized 4. Macrophages on inner walls of sinusoids (Kupfer cells)

Answer 160

a. Synthesis = cholesterol precursor to cholic and chenodeoxycholic acids - first noticed at 12 weeks gestation - at term, cholesterol and phospholipid is LOW and bile acid concentration is LOW b. Conjugation i. Primary bile acids conjugated with AA or CHO to glycocholic and glycochenodeoxycholic acids = water soluble ii. Secretion – into biliary system (gallbladder) then duodenum vii. The gall bladder concentrates the bile, removing water and salts (≈90% resorbed) i. Fat in duodenum stimulates specialized cells of duodenum mucosa to release hormone (CCK) into blood ii. CCK causes gall bladder to contract and sphincter of Oddi to relax iii. Bile released into duodenum c. Function = bile acids form micelles with phospholipids (lecithin) to aid absorption of dietary fat d. Metabolism in GIT i. Secondary bile acids – formed in intestine by bacterial enzymes (only some primary go on to be secondary) ii. Deconjugation – most primary or secondary bile acids also deconjugated e. Reabsorption /enterohepatic circulation i. Deconjugated and conjugated bile acids then reabsorbed mainly in ileum via active transport ii. Conjugated more permeable to plasma membrane therefore likely to be reabsorbed iii. Enter blood and travel back to liver via portal vein bound to albumin iv. 90% bile acids recycled f. Excretion i. Removal of cholesterol dependent on excretion of bile acids in faeces ii. 10% not reabsorbed in enterohepatic circulation

Answer 161

1. Conjugated vs unconjugated a. Conjugated = water soluble  CANNOT CROSS BBB b. Unconjugated = fat soluble 2. Key points a. Bilirubin is a normal breakdown product of haemoglobin i. Produced intra- and extra-vascularly from haemolysis b. Transported to the liver bound to albumin c. Conjugation = glucuronide (sugar) attached to bilirubin by bilirubin UDP-glucuronyl transferase (BUGT) enzyme i. Reaction takes place in endoplasmic reticulum (donor of glucuronyl is uridine diophosphoglucuronic acid) ii. Need >50% activity to maintain normal serum conjugated bilirubin d. Excretion into gastrointestinal tract e. Converted to urobilinogen by bacterial proteases f. Two options i. Reabsorption in terminal ileum - enterohepatic circulation (portal vein) – 90-95% of circulating bile acid pool is within enterohepatic circulation 1. Recycles back to liver 2. Oxidized in kidney  urobilen ii. Converted to stercobilinogen  oxidized to stercobilen – brown colour

Answer 162

3. BUGT enzyme (bilirubin UDP-glucuronyl transferase) a. 5 exons and upstream TATA box b. Mutations at various points will produce a reduction in function (affinity) or enzyme c. Hence variation in function depending on the mutation d. Extra TATA repeat – Gilberts syndrome  reduce translation of the enzymes and slightly reduced activity Gilberts BUGT activity: 5-52% Serum unconjugated bilirubin: 15-75 CN2 BUGT activity: 2-23% Unconj bili: 135-425 CN1 BUGT activity: severely reduced Serum unconj bili: 255-765

Answer 163

1. General points a. Aminotransferases increase with hepatocellular damage b. Normal AST/ALT levels do not preclude the diagnosis of cirrhosis c. In most acute hepatitis, the rise in ALT may be greater than the rise in AST d. Alcohol-induced liver injury, fulminant echovirus and various metabolic causes, AST rise may be greater e. In most chronic liver diseases (EXCEPT ALD) ALT > AST but as disease progresses there may be reversion of this finding f. Cholestasis (from PSC or PBC) causes increased ALP and GGT with minimal derangement of AST/ALT

Answer 164

a. Intracellular enzymes, catalyse transfer of an amino acid group from aa to alpha ketoglutarate b. Found in liver cells, elevation suggests ‘leakage of hepatocellular cells” c. Location inside cell i. AST = cytosol and mitochondria - also liver, skeletal muscle, kidney, pancreas, lungs and WBC, RBC ii. ALT = cytosol - highest concentration in liver, less so in muscle and other tissues d. ALT more liver specific, but longer half-life than AST e. Ratio of AST/ALT i. AST/ALT > 2 in alcohol ii. AST/ALT < 1 in fatty liver iii. If AST/ALT > 20x and isolated, ?extra-hepatic source -> muscle, myopathy, coeliac, RBC f. Differentials for elevated transaminases – viral hepatitis, autoimmune, drugs g. Further investigation – viral serology, abdominal USS i. Isolated AST: check CK, AST, LDH, coeliac screen

Answer 165

a. GGT i. Predominantly in biliary tree and hepatocytes – but also present in many tissues (kidney, pancreas, spleen, brain, breast, small intestine, T lymphocytes) ii. Single transmembrane ectoenzyme iii. Inducible – carbamazepine, frusemide, heparin, isotretinoin, MTX, oral contraceptives, phenobarbital, phenytoin and valproic acid iv. Interpreting elevated levels 1. If obstruction ALP usually raised 2. If induced, rest of LFTs usually normal v. Recently identified as an independent predictor of cardiac failure, atherosclerosis, diabetes vi. Why does it rise in biliary obstruction? 1. GGT is an ectoenzyme -> when obstruction occurs, bile acids destabilize membrane and GGT is leached out and enters the serum 2. Special cases – rare disorders of bile acid synthesis or excretion have cholestasis with a LOW GGT (no bile acids in biliary tree, so no rise in GGT) – need to be picked up early and treated b. ALP i. Found in liver and bone (intestine 10-20%) ii. Adolescents have higher values during growth iii. Iso-enzymes – liver vs bone iv. Transient hyperphosphatasemia 1. Usually >5x ULN 2. Child <5 years 3. Usually follows viral infection 4. Resolves in 3 months v. Low in fulminant Wilsons disease

Answer 166

4. Bilirubin a. Isolated hyperbilirubinemia (unconjugated) i. Gilbert, Criggler Najjar ii. Exclude haemolysis + check conjugation iii. Genetic testing for diagnosis b. Unconjugated hyperbilirubinaemia in the neonate i. Breast milk jaundice, haemolysis, other rare syndromes as above c. Conjugated hyperbilirubinemia (conjugated should be < 20%) i. Infection – TORCH/ sepsis ii. Structural – EHBA, choledochal cyst iii. Bile duct paucity – eg Alagille, non-syndromic iv. Metabolic – A1AT, CF, galactosemia, tyrosinemia, hereditary fructose intolerance, Nieman Pick A and C, bile acid transport and synthetic disorders v. Endocrine; hypothyroid and hyperpituitarism vi. Differentials: sludge, gallstones, choledochal cyst vii. Must be fasting – gallbladder contracts if fed 5. Tests of synthetic function a. Prothrombin time and INR = prolongation is a marker of hepatic synthetic function i. NOTE: unresponsiveness to vitamin K suggests severe hepatic disease b. Albumin level = decrease is a marker of hepatic synthetic function 6. Other tests a. Serum sodium = hyponatraemia is a common finding, worsens as disease progresses b. Platelet count = thrombocytopenia is a marker of cirrhosis in the setting of CLD and results from PHT with hypersplenism and platelet sequestration

Answer 167

1. Ultrasound a. Provides information about size/ composition / blood flow of liver b. Can detect stones/ dilatation of biliary tract c. Biliary atresia: triangular cord sign – echogenic density in bifurcation of portal vein, representing fibrous remnants at the porta hepatis 2. CT/ MRI a. Alone do not add to much to USS b. CTs may be more useful for hepatic tumour , infiltration c. MRCP – can provide more detailed information about the biliary tract 3. HIDA scan a. Nuclear medicine test b. Radiolabeled isotope that is treated like bilirubin - provides information about uptake and secretion 4. ERCP = papilla of Vater cannulated under endoscopic vision with dye injected into the biliary and pancreatic ducts

Answer 168

1. Background a. Jaundice occurs in 60% of full term neonates (80% of pre-term babies) within first week of life b. Visual assessment NOT reliable c. Kernicterus is a rare complication of unconjugated hyperbilirubinaemia that can lead to major long-term sequelae d. Jaundice before 48 hrs of age suggests haemolysis e. Onset of jaundice after 3 days of age more likely to be physiological 2. Pathological if: a. Conjugated / direct b. <24hours c. >2 weeks (>3 weeks in premature infant) 3. Neonates predisposed to jaundice due to a. Increase production – shorter RBC survival (Fetal Hb) and higher RBC mass (high Hb) b. Decreased metabolism i. Deficiency of UGT1A1 does not reach adult levels until 14 weeks of age ii. Ethnic variation in conjugation ability 1. East Asian: mutation in UGT1A1 increased risk of severe jaundice c. Increase enterohepatic circulation – decreased gut motility, less conversion to stercobilinogen (sterile gut) 4. Definitions a. Unconjugated – total bilirubin raised and conjugated fraction <20% b. Conjugated – total bilirubin is raised and conjugated fraction >20%

Answer 169

a. SBR with fractions b. LFT +/- synthetic function (albumin / coagulation) c. Unconjugated i. FBE + film + blood group + DCT (+/- LDH / retic count) ii. G6PD iii. TFT iv. Septic screen d. Conjugated i. TORCH infection screen, CMV PCR ii. Metabolic screen (Serum AA + urine organic acids + galactoscreen) iii. Alpha 1 antitrypsin iv. CF testing v. Thyroid function tests vi. MUST RULE OUT biliary atresia 1. Liver US 2. HIDA scan 99m technetium (scintigraphy) 3. Intraoperative cholangiogram e. Liver biopsy i. Expanded portal tracts with bile duct proliferation, portal tract edema, fibrosis + inflammation, canalicular and bile duct plugs  biliary atresia ii. Bile duct paucity  Alagille iii. RAS positive diastase resistant granules  a1 antitrypsin deficiency iv. MRD3 staining  PFIC3

Answer 170

a. Hydration and support of feeding b. Phototherapy i. 450-460nm ii. Conversion of bilirubin in blood to extractible form – soluble in urine - structural isomerisation to lumirubin is main mechanism (more soluble, excreted without conjugation), plus photo-oxidation to polar molecules and photoisomerisation to less toxic bilirubin iii. Indications – Rh disease, haemolysis, small sick infants 1. Guided by risk group: low, moderate, high 2. Threshold for therapy on nomogram iv. Effective and safe – monitor for side effects: 1. Hypo/hyperthermia 2. Dehydration 3. Change in skin color 4. Eye damage 5. Diarrhoea 6. Rash v. Ceased once SBR levels fall 25-50mmol/L below threshold c. Exchange transfusion i. Indications – rapid rise, rise despite phototherapy, above threshold ii. Acts to remove unconjugated bilirubin and antibodies Conjugated - depends on cause, surgery

Answer 171

a. Goal of treatment is to prevent this complication b. Bilirubin staining and neuronal necrosis affecting basal ganglia, hippocampus and subthalamic nuclei c. Free unconjugated bilirubin crosses the blood brain barrier d. Clinical presentation i. Acute 1. Hypotonia, stupor, poor suck 2. Hypertonia of extensor muscles, fever, seizures ii. Chronic 1. Hypotonia in first year of life 2. High pitched cry 3. Hearing and visual impairment (upward gaze palsy) 4. Extrapyramidal abnormalities – choreoathetoid cerebral palsy, deafness, cognitive defects e. Risk factors i. Prematurity ii. Low albumin – free able to cross BBB iii. Rapid rise in bilirubin iv. Hypoxia, acidosis, hypoglycaemia, sepsis f. Outcomes = 10% mortality, 70% morbidity

Answer 172

1. Increased production a. Haemolysis i. Isoimmune mediated haemolysis (ABO/ RH D incompatibility) ii. Red blood cell membrane defects iii. G6PD deficiency, PK deficiency iv. Sepsis induced haemolysis b. Excessive non-haemolytic breakdown i. Polycythaemia ii. Bruising, cephalohaematoma 2. Decreased clearance due to abnormalities of UGT1A1 a. Crigler Najjar b. Gilbert syndrome 3. Increased enterohepatic circulation/ reduced excretion a. Breast milk jaundice = common, jaundice may continue for many weeks b. GIT obstruction or ileus (eg. pyloric stenosis) 4. Other a. Breast milk jaundice b. Physiological jaundice = exaggerated physiological response, should resolve within 2 weeks (term) or 3 weeks (pre-term) c. Prematurity d. Hypothyroidism (TSH included in newborn screening tests)

Answer 173

Pale stools, dark urine, raised conjugated bilirubin (>15% total or >15umol/L) 3 main: neonatal hepatitis, biliary atresia, alpha 1 antitrypsin deficiency 1. Congenital infection = TORCH, sepsis 2. Structural/ obstruction a. Extra-hepatic i. Biliary atresia ii. Choledochal cyst b. Intra-hepatic i. Alagille syndrome (intrahepatic biliary hypoplasia) ii. ARPCKD, ADPCKD, Caroli disease (bile duct ectasia and fibrosis) iii. Primary sclerosing cholangitis/ Primary biliary cirrhosis c. Functional obstruction i. Idiopathic neonatal hepatitis (giant cell hepatitis) ii. Disorders of bile acid synthesis and conjugation iii. Disorders of membrane transport and secretion 3. Metabolic a. CHO disorders – galactosaemia, hereditary fructose intolerance, glycogen storage disease 4 b. AA disorder – tyrosinaemia c. Peroxisomal – Zellweger d. Lysosomal – Niemann-Pick, Gaucher’s e. Alpha - 1 antitrypsin f. CF g. Wilson’s disease h. Bile acid transport and synthetic disorders 4. Endocrine a. Hypothyroid b. Hypopituitarism 5. Other a. Neonatal hepatitis (‘idiopathic’) b. Complication of TPN c. Gestational alloimmune liver disease (neonatal haemochromatosis)

Answer 174

1. Definitions a. Prolonged elevation of the serum levels of conjugated bilirubin beyond the first 14 days of life b. Jaundice that appears after week 2 of age, continues to progress, or does not resolve should be evaluated c. Differentiation between biliary atresia and idiopathic neonatal hepatitis is difficult d. Cholestasis i. Impairment in the excretion of bile ii. Caused by defects in intrahepatic production of bile, transmembrane transport of bile, or mechanical obstruction of bile flow iii. Elevated conjugated bilirubin is a predominant characteristic in most cases of neonatal cholestasis 3. Classification a. Intrahepatic i. Hepatocyte injury = metabolic disease, viral disease, idiopathic neonatal hepatitis ii. Bile duct injury = intrahepatic bile duct paucity b. Extrahepatic disease 4. Clinical manifestations a. ALL very similar b. Affected infants have icterus, dark urine, light or acholic stools, and hepatomegaly – all result from decreased bile flow as a result of either hepatocyte injury or bile duct obstruction c. Hepatocyte synthetic dysfunction can results in bleeding 5. Investigations a. In contrast to unconjugated hyperbilirubinaemia, cholestasis (conjugated bilirubin elevation of any degree) in a neonate is ALWAYS PATHOLOGICAL b. Serum bilirubin fractionation -> suggests cholestasis c. Assessment of stool colour -> indicates bile flow into intestine d. Urine and serum bile acid measurement -> confirms cholestasis; might indicate inborn error of bile acid biosynthesis e. Hepatic synthetic function (albumin, coagulation profile) -> indicates severity of hepatic dysfunction f. Alpha-1 anti-trypsin phenotype -> diagnose PiZZ g. Thyroxine and TSH -> endocrinopathy h. Sweat chloride and mutation analysis -> CF i. Urine and serum amino acids and urine reducing -> metabolic liver j. USS -> Choledochal cyst, triangular cord sign suggestive of biliary atresia k. Hepatobiliary cintigraphy -> bile patency or obstruction l. Liver biopsy -> distinguishes biliary atresia

Answer 175

1. Key points a. With any form of neonatal cholestasis, affected patients are at risks of progression and complications of chronic cholestasis b. Any substance normally excreted into the bowel is retained in the liver – with accumulation in the tissue and in serum c. Decreased delivery of bile acids to the proximal intestine leads to inadequate digestion and absorption of dietary long-chain TG and fat soluble vitamins d. Impairment of hepatic metabolic function can alter hormonal balance and utilization of nutrients 2. Consequences a. Growth failure i. Major concern ii. Related to malabsorption and malnutrition iii. Use of medium chain TG containing formula can improve nutrition b. Fat soluble vitamin deficiency (ADEK) iv. Degenerative neuromuscular syndrome 1. Found in patients with chronic cholestasis – caused by chronic malabsorption and vitamin E deficiency 2. Affected children experience progressive areflexia, cerebellar ataxia, ophthalmoplegia, and decreased vibratory sensation 3. Lesions found in the CNS, peripheral nerves and muscles 4. Not commonly seen today 5. Can be prevented with oral administration of large doses c. Pruritis i. Often appears with xanthomas ii. Both features are related to the accumulation of cholesterol and bile acids in serum and tissues iii. Elimination of these retained compounds is difficult when bile ducts are obstructed, if there is any degree of bile duct patency, administration of ursodeoxycholic acid can increase bile flow or interrupt the enterohepatic circulation of bile acids and decrease the xanthomas and ameliorate pruritis d. Biliary cirrhosis + portal hypertension i. Progressive fibrosis and cirrhosis lead to the development of portal hypertension ii. Ascites iii. Upper GI bleeding e. End stage liver disease i. Hepatic transplantation has a success rate of >85% ii. Prolongs life and may correct the metabolic error such as alpha-1 antitrypsin, tyrosinaemia and Wilsons disease

Answer 176

1. Key points a. The term neonatal hepatitis implies intrahepatic cholestasis 2. Classification a. Idiopathic neonatal hepatitis i. Occur as sporadic or familial ii. After all the investigations – up to 25% still have no diagnosis 1. Unknown cause 2. Presumably viral or metabolic cause if sporadic iii. Prognosis generally good iv. Predictors of poor prognosis 1. Jaundice >6 months of age 2. Acholic stools 3. Persistent hepatomegaly 4. Severe inflammation on biopsy 5. Familial occurrence 6. Low GGT v. If OK at 12 months – long term outcome good with little evidence of liver disease b. Aagenaes syndrome i. Intrahepatic cholestasis associated with lymphoedema of the lower extremities ii. Affected patients present with episodic cholestasis with elevation of serum aminotransferases, ALP, and bile acids iii. Between episodes patients asymptomatic iv. Good prognosis – 50% have normal lifespan c. Zellweger (cerebrohepatorenal syndrome) i. Rare autosomal recessive genetic disorder ii. Progressive degeneration of liver and kidneys iii. Fatal by 6-12 months iv. Affected patients have severe, generalised hypotonia and markedly impaired neurologic function with psychomotor retardation v. Abnormal head shape and unusual facies, hepatomegaly, renal cortical cysts, stippled calcifications of the patellas and greater trochanter, ocular abnormalities vi. Hepatic cells on ultrastructural examination show an absence of peroxisomes d. Neonatal iron storage disease (neonatal haemochromatosis) 3. Prognosis a. Sporadic i. 60-70% recover with no evidence of hepatic structural or functional impairment ii. 5-10% have persistent fibrosis or inflammation iii. Small percent have more sever liver disease b. Familial i. 20-30% recover ii. 10-15% acquire chronic liver disease – may require liver transplantation

Answer 177

* Heterogenous group of disorders * Characterised by defective secretion of bile acids or other components of bile * Usually present during infancy or childhood * Associated with growth failure + progressive liver disease * Many patients present with coagulopathy due to vitamin K malabsorption * Intractable pruritis is a dominant feature of PFIC and PFICII Type 1 and 2 - LOW GGT Type 3 - HIGH GGT Type 4 - normal or mildly raised GGT

Answer 178

= Byler Disease a. Severe form of intra-hepatic cholestasis b. Affected patients present with steatorrhoea, pruritis, vitamin D deficient rickets, gradually develop cirrhosis, and have LOW GGT c. Absence of bile duct paucity and extra-hepatic features differentiate from Alagille syndrome d. Genetics i. Mutation in F1C1 on 18q21

Answer 179

a. Cholestasis, progressive liver disease b. Low GGT c. Occurs in Middle East, Europe d. BSEP 2q24 – homozygotes, mainly compound heterozygotes e. Major ATP dependent canalicular bile acid transporter, expressed only in the liver f. Most PFIC II – SPGP absent, decreased BA excretion

Answer 180

a. Can present at any age b. Biliary cirrhosis, portal hypertension, cholestasis of pregnancy, early onset gallstones, cholestasis with OC c. HIGH levels of GGT (contrasting type 1 and 2) d. Mutations in MDR3 gene causing inactivated truncated protein (homozygote or compound heterozygote) e. MDR 3 – phosphatidyl translocation absence of micelle formation, causing bile duct damage f. UDCA

Answer 181

a. TJIP deficiency b. Protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localisation and disruption of tight-junction structure, leading to severe cholestatic liver disease c. GGT normal or mildly raised, risk of HCC

Answer 182

a. Characterised by intermittent cholestatic episodes i. Range from several episode per year to one episode in a decade b. During attacks present with conjugated hyperbilirubinaemia, malaise, anorexia, pruritis, weight loss + malabsorption c. Investigations show cholestasis without severe hepatocellular injury d. Associated with mutations of PFICI and PFICII – unsure why less pathogenic e. No specific treatment

Answer 183

1. Key points a. Inherited defects in enzymes that are necessary for two main bile acids (cholic acid + chenodeoxycholic acid) b. Cholestasis results from i. Inadequate production of bile acids essential for bile flow ii. Increased production of aberrant bile acids – hepatotoxic c. Cholesterol substrate – rate limiting step is 7 alpha hydroxylase, changes to ABCD ring nucleus, side chain oxidation 2. Clinical manifestation a. Severe cholestatic jaundice from birth b. Progressive liver failure c. May have steatorrhoea or acholic stools 3. Investigations a. Conjugated hyperbilirubinaemia b. Elevated transaminases – paradoxically normal GGT 4. Types a. Bile acid synthesis defect type 1-5 b. Sterol 27-hydroxylase defect c. Amidation defects i. Amino acid n-acyltransferase deficiency ii. Bile acid CoA ligase deficiency 5. Treatment a. Primary bile acids (cholic acid, not ursodeoxycholic acid) normalizes LFTs in most patients i. If you provide normal bile acids produces negative feedback to 7 alpha hydroxylase reducing production of abnormal bile acids

Answer 184

1. Key points a. Most common syndrome with intra-hepatic bile duct paucity = absence or marked reduction in number of interlobular bile ducts in portal triads, with NORMAL branches of portal vein and hepatic arteriole b. Serial biopsy shows progressive destruction of bile ducts 2. Genetics a. Linked to mutations in Jagged1 gene (JAG1) 3. Clinical manifestations a. Unusual facial characteristics (broad forehead, deep set widely spaced eyes, long straight nose, underdeveloped mandible) b. Hepatic i. Cholestasis ii. Bile duct paucity on liver biopsy c. Ocular abnormalities i. Posterior embryotoxon ii. Other = microcornea, optic disc drusen, shallow anterior chamber d. CV abnormalities i. Peripheral pulmonic stenosis ii. Other = Tetralogy of Fallot, pulmonary atresia, VSD, ASD, aortic coarctation e. Vertebral defects = butterfly vertebrae, fused vertebrae, spina bifid occulta, rib anomalies f. Tubulointerstitial nephropathy 4. Treatment a. MDT management b. Ursodeoxycholic acid c. Other medications for pruritis – cholestyramine, rifampicin 5. Prognosis a. Good prognosis = 10% mortality – vascular accident, cardiac disease + liver disease result in death b. Patients likely to have pruritis, xanthomas with markedly elevated serum cholesterol, neurological complications of vitamin E deficiency if untreated

Answer 185

1. Key points a. 1/14,000 live births – unknown cause b. More accurately called non-cystic obliterative cholangiopathy c. Obliterative cholangiopathy may be divided into 2 major types = cystic and non-cystic i. Cystic disorder = incorporate the different types of choledochal cysts ii. Non-cystic forms = 2 types of BA (fetal and perinatal) in additional to neonatal sclerosing cholangitis d. Commonly characterised by obliteration of the entire extra-hepatic biliary tree at or above the porta hepatis e. Usually normal at birth and have postnatal progressive obliteration of bile ducts 2. Clinical manifestations a. Hepatomegaly b. Conjugated hyperbilirubinaemia c. Pale stools 3. DDx – neonatal hepatitis a. Difficult to distinguish between biliary atresia and idiopathic neonatal hepatitis

Answer 186

i. Idiopathic neonatal hepatitis has a familial incidence of 20%; BA is unlikely to recur within same family ii. A few infants with fetal onset BA have increased incidence of other abnormalities – polysplenia syndrome with abdominal heterotaxia, malrotation, levocardia + intra-abdominal vascular anomalies iii. Neonatal hepatitis appears to be more common in infants who are premature or SGA iv. Persistently acholic stools suggests BA, but patients with severe idiopathic neonatal hepatitis can have transient severe impairment of bile excretion v. Consistently pigmented stools rules against biliary atresia vi. Bile-stained fluid on duodenal intubation also excludes biliary atresia vii. Palpation of the liver might find an abnormal size or consistency inpatients with biliary atresia; this less common with intrahepatic hepatitis

Answer 187

a. Liver function tests b. Abdominal USS i. Must be done fasting – looking for a contracted small or absent gallbladder; should maximally fill ii. Identifies choledocholithiasis, perforation of the bile duct, or other structural abnormalities of the biliary tree such as a Choledochal cyst iii. Biliary atresia 1. Identify associated anomalies such as abdominal polysplenia and vascular malformation; 2. Gall bladder is either not visualized or is a microgallbladder 3. Triangular cord sign = represents cone-shaped fibrotic mass cranial to the bifurcation of the portal vein (echogenic cord at the bifurcation of the portal vein) iv. Idiopathic hepatitis, CF or TPN = similar USS findings to BA c. Hepatobiliary scintigraphy (HIDA scan) - technetium-labeled iminodiacetic acid i. Sensitive but not specific test for BA ii. Fails to identify other structural abnormalities of the biliary tree or vascular anomalies iii. Failure of tracer excretion suggests BA, but does not exclude other diseases 1. Strong suspicion for BA (acholic stools), excretion of tracer unlikely and it is acceptable to proceed directly to liver biopsy iv. Definite excretion: patency is established, BA unlikely d. Liver biopsy = most important in evaluation of liver disease i. Biliary atresia = bile ductular proliferation, the presence of bile plugs, and portal or perilobular edema and fibrosis, with the basic hepatic lobular architecture intact ii. Neonatal hepatitis = severe, diffuse hepatocellular disease, with distortion of the lobular architecture, marked infiltration with inflammatory cells, + focal hepatocellular necrosis; the bile ductules unchanged iii. Alagille = bile duct paucity iv. Alpha 1 AT = PAS positive diastase resistant granules v. PFIC3 = loss of MRD3 staining

Answer 188

a. Surgery = further confirm cause of disease i. Exploratory laparotomy and direct cholangiography to determine the presence and site of obstruction ii. Direct drainage can be accompanied in few patients with a correctable lesion iii. When no correctable lesion is found, frozen section from the transected porta hepatis can detect the presence of biliary epithelium and determine the size and patency of the residual bile ducts iv. In some cases the biliary tree is patent but has diminished calibre, suggesting not due to biliary tract obliteration but due to bile duct paucity or markedly diminished flow due to intrahepatic disease b. Hepatoportoenterostomy (Kasai) i. Minute bile duct remnants, representing residual channels, may be present in the fibrous tissue of the porta hepatis  transection of the porta hepatis with anastomosis of bowel to the proximal surface of the transection may allow bile to drain into the bowel ii. If flow is not rapidly established in the first month of life, progressive obliteration and cirrhosis ensue iii. If microscopic channels of patency >150 um, post-operative establishment of bile flow is likely iv. Timing is critical – Kasai <30 days of age has BEST outcome v. Success rate for establishing good flow is much higher (90%) if performed before the 8th week of life vi. Some patients have ‘non-correctable type’ – still derive benefits from Kasai 1. Allows decompression and drainage of the biliary tree sufficient to await liver transplantation c. Liver transplantation i. Required if Kasai does not result in adequate bile drainage ii. Most require transplantation

Answer 189

= COMPLETE GLUCURONYL TRANSFERASE DEFICIENCY 1. Key points a. Complete lack of BUGT -> unconjugated hyperbilirubinaemia b. Risk of kernicterus/ death without phototherapy 2. Genetics and aetiology a. Autosomal recessive trait b. Secondary to mutations that cause a premature stop codon or frameshift mutation and therefore completely abolish UGT1A1 activity c. Parents of affected children have partial defects in conjugation; serum unconjugated bilirubin concentrations are NORMAL 3. Clinical manifestations a. Severe unconjugated hyperbilirubinaemia occurs in homozygous infants in the 1st 3 days of life b. Without treatment unconjugated bilirubin reaches 25-35 mg/dL in the first month c. Kernicterus – universal complication of this disorder – noted early in the neonatal period d. Treated infants survive to childhood without clinical sequelae e. Stools are pale yellow 4. Diagnosis a. Persistence of unconjugated hyperbilirubinaemia after the 1st week of life without haemolysis b. Definitive diagnosis established by measuring hepatic glucuronyl transferase activity in a liver specimen; note often avoid as surgery can precipitate kernicterus c. Genetic testing available 5. Treatment a. Exchange transfusion b. Phototherapy i. Continued through early years of life; usually continued during sleep ii. Photo-isomerises the bilirubin in the skin to make it water soluble so it can be excreted via the kidneys iii. Bilirubin usually less responsive to phototherapy with age – SA: BW decreases c. Medical therapy i. Oral calcium phosphate supplementation = phototherapy more effective as it forms complexes with bilirubin in the gut ii. Phenobarbital therapy (CYP450 enzyme induction) = can be considered to determine responsiveness and differentiate between type I and II (NO response in type I) iii. Cholestyramine + agar = Additional adjuvant therapy using agents that bind photobilirubin products such as cholestyramine and agar can be used to interfere with the enterohepatic recirculation of bilirubin d. Transplant = orthotropic liver transplantation cures the disease and has been successfully used in a number of patients – ‘eventually will require a liver transplant’ 6. Prognosis a. Risk of kernicterus persists into adult life – higher levels of bilirubin required to produce brain injury b. All patients with CN type 1 have eventually experienced severe kernicterus by young adulthood c. Prompt treatment of intercurrent infections, febrile episodes and other types of illness can help prevent later development of bilirubin

Answer 190

= PARTIAL GLUCURONYL TRANSFERASE DEFICIENCY 1. Genetics and aetiology a. Autosomal recessive b. Homozygous missense mutation in UGT1A1 resulting in reduced enzymatic activity c. Distinguished from type I by the marked decline in serum bilirubin that occurs in type II disease after treatment with phenobarbital secondary to inducible phenobarbital response element on the UGT1A1 promoter 2. Clinical manifestations a. When this disorder appears in the neonatal period, unconjugated hyperbilirubinaemia usually occurs in the first 3 days of life b. Serum bilirubin concentrations can be in a range compatible with physiological jaundice OR at pathological levels c. Concentrations characteristically remain elevated into and after the third week of life d. Development of kernicterus is unusual e. Stool colour is normal and infants are without signs and symptoms of the disease f. No evidence of haemolysis g. Liver enzymes and synthetic function normal 3. Diagnosis a. Concentrations of bilirubin in the bile is nearly completely normal in patients with CN type II b. Jaundiced infants and young children with type II syndrome respond readily to 5 mg/kg/24 hour of oral phenobarbital with a decrease in serum bilirubin in 7-10 days 4. Treatment a. Long term reduction can be achieved with phenobarbital b. Cosmetic and psychosocial benefit weighed against the risks of an effective dose of the drug as there is a small long-term risk of kernicterus even in the absence of haemolytic disease c. Orlistat (irreversible inhibitor of intestinal lipase) increases faecal fat excretion and decreases plasma unconjugated bilirubin concentrations in patients with CN type I and II

Answer 191

1. Key points a. NOT associated with chronic liver disease b. Occurs 5-10% of the white population 2. Genetics and aetiology a. Autosomal recessive – 30% carriers b. Common polymorphism – TA insertion into the promoter region of UGT1A1 c. Results in decreased binding of the TATA binding protein and decreases normal gene activation but only to approximately 30% 3. Clinical manifestations a. Usually manifests after puberty may be triggered by, among other things, dehydration, fasting, intercurrent illness, menstruation and overexertion b. Results in asymptomatic jaundice - elevated unconjugated bilirubin c. Often triggered by viral infections 4. Investigations = usually clinical diagnosis 5. Cancer risk a. As UGT1A1 is involved in glucuronidation of multiple other substances (pharmaceutical drugs, endogenous hormones, toxins, aromatic hydrocarbons) and glucuronidation leads to inactivation of these substances b. Mutations in UGt1A1 gene -> CANCER RISK and predisposition of drug toxicity in cancer chemotherapy

Answer 192

* Caused by a small number of rare autosomal recessive conditions characterised by mild jaundice * Transfer of bilirubin and other organic anions from the liver cell to bile is defective * Chronic mild conjugated hyperbilirubinaemia is usually detected during adolescence or early adulthood * Routine LFT are normal * Jaundice can be exacerbated by infection, pregnancy, oral contraceptives, alcohol and surgery

Answer 193

1. Genetics and aetiology a. Autosomal recessive b. Inherited defect with variable penetrance in hepatocyte secretion of bilirubin glucuronide c. Defect in hepatic excretory function is not limited to conjugated bilirubin excretion but also involves several organic anions normally excreted from the liver into bile d. Absent function of MPR2 – ATP dependent canalicular transporter e. >10 different mutations identified 2. Clinical manifestations a. Bile acid excretion and serum bile acid levels are normal b. Total urinary coproporphyrin excretion is normal in quantity i. Coproporphyrin I excretion increases to approximately 80% with concomitant decrease in coproporphyrin III excretion ii. Normally coproporphyrin III is >75% of normal c. Cholangiography fails to visualise the biliary tract and X-ray of the GB is abnormal d. Liver histology = normal architecture, but hepatocytes contain black pigment similar to melanin e. Liver function is normal and prognosis excellent f. Most commonly reported symptoms = jaundice, fatigue, dark urine and slight enlargement of the liver

Answer 194

* Additional deficiency in organic anion uptake * Inactivating mutations in linked genes in SLCO1B1 and SCLO1B3  functional deficiencies of both protein products (OAT1B1 ad OATP1B) * These mutations may confer significant drug toxicity risk * Unlike Dubin-Jonson syndrome, total urinary coproporphyrin excretion is elevated, with relative increase in the amount of coproporphyrin I isomer * Gall bladder is normal * Liver contains no black pigment

Answer 195

1. Genetics + pathogenesis a. Rare AR disorder b. Results from deficiency in one of three enzymes i. Galactose-1-phosphate uridyl transferase (GALT) deficiency 1. Classic galactosaemia – complete deficiency of GALT; most common and severe ii. Galactokinase (GALK) deficiency iii. Uridine diphosphate (UDP) galactose-4-epimerase (GALE) deficiency 2. Clinical manifestations a. Untreated infant i. Mixed hyperbilirubinaemia (conjugated + unconjugated) following introduction of galactose containing feeds (human or cow’s milk) ii. Sepsis common at presentation (E coli) iii. Vomiting iv. Failure to thrive v. Renal tubular acidosis vi. Cataracts (uncommon in infancy) vii. Coagulopathy b. Long-term i. Development delay ii. Speech problems = verbal dyspraxia iii. Abnormalities of motor function iv. Cataracts v. Liver failure/ cirrhosis vi. Premature ovarian failure 3. Investigations a. Increased plasma galactose + RBC galactose 1P b. Liver dysfunction i. Conjugated and/or unconjugated hyperbilirubinaemia ii. Elevated transaminases iii. Coagulopathy iv. Elevated plasma amino acids (phenylalanine, tyrosine, methionine) c. Renal tubular acidosis – metabolic acidosis, galacatosuria, glycosuria, aminoaciduria, albuminuria d. Reducing substances in urine e. GALT activity in erythrocytes f. Newborn screening – not screened in VIC 4. Treatment a. Elimination of galactose – soy formula, lactose/galactose free formula b. Monitoring i. Regular reviews ii. Biochemical status – RBC galactose-1-phosphate iii. Developmental status – referral for speech therapy/OT/physio if required iv. Cataract detection v. Growth monitoring vi. Ovarian failure – occurs in most individuals

Answer 196

1. Genetics + pathogenesis a. Deficiency of fumarylacetoacetate hydrolase b. Results in buildup of FAA causing oxidative cell damage 2. Clinical manifestations a. Presents in infancy b. Progressive liver disease i. Cholestasis + coagulopathy disproprionate to degree of liver disease c. Renal tubular acidosis d. Neurological impairment 3. Investigations a. Increased urinary excretion of succinylacetone b. Increased blood concentration of tyrosine concentration

Answer 197

1. Key points a. Autosomal recessive disorder b. Key features = BRAIN, LIVER, EYES c. Progressive and potentially fatal if untreated d. Specific effective treatment available 2. Genetics and pathogenesis a. Autosomal recessive b. Abnormal gene localised on long arm of chromosome 13 (13q14.3) c. Wilson disease gene encodes a copper transporting ATPase – ATP7B d. AP7B gene = transmembrane copper-transporting ATPase, expressed on hepatocyte membrane e. Spectrum i. Mutations that completely knock out gene function -> onset of disease as early as 2-3 years ii. Milder mutations associated with neurological symptoms or liver disease as late as 70 years of age 3. Pathogenesis a. Normal i. 40-60% of ingested copper (2-5mg) absorbed in duodenum -> portal circulation bound to albumin ii. Free copper dissociates and is taken up by hepatocytes and binds to apoceruloplasmin (alpha2-globulin) to form caeroplasmin -> secreted into the blood (90-95% of plasma copper) iii. Circulating ceruloplasmin is eventually endocytosed by the liver, degraded in lysosomes and copper is released into bile = primary mechanism for copper excretion iv. Total body copper 50-150mg b. Wilson’s Disease i. Deficiency in ATP7B protein causes 1. Decrease in copper transport into bile 2. Impairs its incorporation into ceruloplasmin 3. Inhibits ceruloplasmin secretion into blood ii. Copper accumulates in the liver  production of ROS by Fenton reaction  cirrhosis iii. Hepatic capacity for incorporating copper into ceruloplasmin exceeded  sudden onset of critical systemic illness as non-ceruloplasmin-bound copper spills over from the liver into the circulation  accumulates in other organs iv. Consequences = haemolysis, brain (BG particularly), corneas, kidney, bone, joints, parathyroid v. Most patients are compound heterozygotes

Answer 198

4. Natural history a. Disease presentations are variable, with a tendency to familial patterns b. The younger the patient, the more likely hepatic involvement is the predominant manifestation c. Girls are 3x more likely to present with acute hepatic failure d. Clinically evident liver disease may precede neurological manifestations by as much as 10 years e. After 20 years, neurological symptoms predominate 5. Clinical manifestations a. HEPATIC DISEASE i. Asymptomatic hepatomegaly (with or without splenomegaly) ii. Subacute or chronic hepatitis iii. Acute hepatic failure (with or without haemolytic anaemia) iv. Cryptogenic cirrhosis, portal hypertension, ascites, edema, variceal bleeding, or other effects of hepatic dysfunction (delayed puberty, amenorrhoea, coagulation defects) b. NEUROLOGICAL DISEASE i. Insidiously or precipitously with intention tremor, dysarthria, rigid dystonia, Parkinsonism, choreiform movements, lack of motor coordination, deterioration in school performance, or behavioural change ii. Kayser-Fleischer rings are absent in young patients with hepatic Wilson disease up to 50% of the time, but are present in 95% of patients with neurological symptoms c. PSYCHIATRIC MANIFESTATIONS i. Depression, personality change, anxiety, psychosis d. HAEMOLYTIC ANAEMIA i. Coombs-negative haemolytic anaemia may be an initial manifestation, possibly related to the release of a large amount of copper from damaged hepatocytes ii. This form of Wilsons disease is usually fatal without transplantation iii. During haemolytic episodes, urinary copper excretion and serum copper levels (NOT ceruloplasmin bound) are markedly elevated iv. Manifestations of renal Faconi syndrome and progressive renal failure with alterations in tubular transport of amino acids, glucose and uric acid may be present

Answer 199

a. Ceruloplasmin levels = reduced i. Failure of copper to be incorporated into ceruloplasmin leads to a plasma protein with shorter half life ii. Reduced steady state circulation b. Serum copper level = may be elevated in early Wilson disease c. Urinary copper level = increased i. In equivocal cases, the response of urinary copper output to chelation may be diagnostic help ii. During 24 hour urine collection patients are given 2 doses of D-penicillamine – affected patients excrete >1600 ug/24 hour d. Kayser Fleischer rings = may not be present in young children; seen with slit-lamp i. After treatment rings resolve e. Liver biopsy = extent and severity of liver disease and measuring the hepatic copper content i. Only required if diagnosis confirmed with other investigations f. Family members should have screening – serum ceruloplasmin level, urinary copper excretion i. If abnormal or equivocal -> liver biopsy g. Genetic screening is possible

Answer 200

8. Treatment a. Dietary restriction – liver, shellfish, nuts, chocolate b. Initial treatment in symptomatic patients = copper chelating agents i. Oral D penicillamine 1. Results in marked increase in urinary copper levels 2. Marked improvement in liver and neurological function and disappearance of KF rings 3. Approximately 10-15% of patients treated with penicillamine have worsening of neurological condition – toxic effects of penicillamine occur in 10-20% and consisted of hypersensitivity reactions (eg. Goodpasture, SLE, polymyositis) 4. As penicillamine is an antimetabolite of vitamin B6 additional amounts of this vitamin are used ii. Triethylene tetramine dihydrochloride (Trientine) iii. Ammonium tetrhiomolybdate c. Adjuvant therapy with zinc i. Impaires the gastrointestinal absorption of copper ii. AE = gastric irritation, reduced leukocyte chemotaxis and elevation in serum lipase and/or amylase d. Liver transplant 9. Prognosis a. Untreated -> death due to hepatic, neurologic, renal or hematological complications b. Medical therapy rarely effective in those presenting with acute liver failure c. Liver transplantation can be required – curative with survival rate of 85-90%

Answer 201

1. Key points a. Small percentage of patients homozygous for deficiency in major serum protease inhibitor alpha1 antitrypsin manifest as neonatal cholestasis or later-onset childhood cirrhosis b. Alpha1 antitrypsin protects alveolar tissue from destruction by neutrophil elastase 2. Genetics a. Caused by a mutation in SERPINA1 gene and is an autosomal recessive disorder b. Most common allele of the protease inhibitor (Pi) system is M – normal phenotype PiMM c. Z allele predisposes to clinical deficiency i. Patients with liver disease usually PiZZ homozygotes and have alpha1 antitrypsin levels <10-20% of normal (<2 mg/ml) d. Compound heterozygotes – PiZ-, PiSZ, PiZI are not a cause of liver disease alone, but act as modifier gene -> increased risk of liver disease such as non-alcohol fatty liver disease and hepatitis C 3. Pathogenesis a. In affected patients with PiZZ the rate at which the alpha- antitrypsin peptide folds is decreased, and this delay allows the formation of polymers that are retained in the endoplasmic reticulum b. How polymers cause liver damage is unclear 4. Prognosis a. Liver disease highly variable b. Infants with liver disease are indistinguishable from other infants with ‘idiopathic’ neonatal hepatitis – alpha-1 antitrypsin constitutes 10% of these neonates c. Complete resolution, persistent liver disease, or development of cirrhosis can follow d. Older children can present with asymptomatic hepatomegaly or manifestations of chronic liver disease or cirrhosis with evidence of portal hypertension e. Emphysema is not typically observed in children but an increased risk for developing asthma is reported

Answer 202

* Neonatal intrahepatic cholestasis caused by citrin deficiency presents in the first few months of life with manifestations that initially may be indistinguishable from other causes of neonatal cholestasis, particularly biliary atresia * Patients may have jaundice, hepatomegaly, liver dysfunction with coagulopathy, fatty liver infiltration, hyperammonaemia with or without hypoglycemia * Presymptomatic patients may be identified from newborn metabolic screen with hypergalactosaemia, hypermethioninemia, and hyperphenylalanaemia – not all identified * Caused by mutation in SCL25A13 gene which encodes citrin – mitochondrial carrier protein * Common among East Asian populations * Treatment includes that for neonatal cholestasis * Many patients progress to hepatic failure requiring transplantation in the first year of life

Answer 203

1. Key points a. Hepatic failure due to hepatic and extrahepatic accumulation of iron (haemosiderosis) during the neonatal period - unrelated to hereditary haemochromatosis b. Also known as neonatal haemochromatosis – but UNRELATED to familial haemochromatosis c. Alloimmune disorder with maternal antibodies directed against the fetal liver d. High rate of recurrence in families 2. Pathogenesis a. Result of maternal alloimmune injury (analogous to erythroblastosis fetalis) c. Iron deposition is a consequence rather than a cause of liver injury 3. Clinical manifestations a. Manifests in first few days – onset intrauterine b. Newborns present with severe liver failure including coagulopathy, ascites, hypoalbuminaemia, mixed hyperbilirubinaemia and cirrhosis c. Rapidly progressive disease characterised by iron deposition in the liver, heart, and endocrine organs WITHOUT increased iron stores in the reticuloendothelial system d. Patients have multi-organ failure and shortened survival 4. Diagnosis a. Very high ferritin 2-3000 b. Liver biopsy - characteristic immuno-staining with anti-human C5b-9 complex (terminal complement cascade), acute inflammation and cirrhosis c. Confirmation by demonstrating extrahepatic siderosis (buccal mucosal glands laden with iron) 5. Treatment a. Iron chelating agents – E.g. desferioxamine b. Exchange transfusion and IVIg (increased survival without liver transplant from 15-20%) c. Liver transplant curative but difficult due to lack of donors and vascular and infective complications 6. Prognosis a. Generally poor b. 90% recurrence rate in future pregnancies (reduced risk with antenatal IVIg from week 18 of pregnancy)

Answer 204

* Cholestasis with onset after the neonatal period is most often cause by acute viral hepatitis or drugs * Many of the conditions causing neonatal cholestasis can also cause chronic cholestasis in older children • Aetiology o Gilbert syndrome o Infections – EBV, HAV, HBV, HCV, non-AE o Drug induced liver disease – paracetamol, erythromycin, flucloxacillin, NSAIDs o Autoimmune AIH, sclerosing cholangitis o Metabolic A1AT, Wilsons disease, cystic fibrosis o Structural-choledochal cyst, PSC * Older children should be evaluated for = viral hepatitis, alpha-1 antitrypsin deficiency, Wilson disease, associated with IBD, autoimmune hepatitis, drug induced injury, and syndromes of intrahepatic cholestasis * Other causes = obstruction caused by cholelithiasis, abdominal tumours, enlarged LN or hepatic inflammation resulting from drug ingestion

Answer 205

1. Key points a. Pyogenic liver abscesses rare in children b. Aetiology i. Bacteria entering the liver via the portal circulation in cases of omphalitis, portal vein pylephlebitis or intra-abdo infection, or abscess secondary to appendicitis or IBD ii. Ascending cholangitis iii. Penetrating trauma iv. Cryptogenic biliary tract infections v. Rarely following percutaneous biopsy c. 50% seen in children <6 years d. Liver transplantation is a significant risk factor 2. Microbiology a. Bacterial = Staphylococcus aureus, Streptococcus, E coli, Klebsiella pneumoniae, Salmonella b. Amoebic disease = Entamoeba histolytica i. Rare in developed countries ii. Recovery from stool is pathogenic and h highly suggestive of amebic abscess 3. Clinical manifestations a. Fever, chills, night sweats, malaise, fatigue, nausea, abdominal pain with RUQ tenderness, and hepatomegaly b. Jaundice uncommon 4. Investigations a. Elevated liver enzymes – AST > ALP b. ESR elevated with leukocytosis c. CXR – may show elevation of right hemidiaphragm with pleural effusion d. USS or CT – confirms diagnosis i. Solitary liver abscesses (70%) In right lobe more common than multiple or solitary 5. Treatment a. Percutaneous or CT guided drainage b. Antibiotics c. Amoebic abscesses – metronidazole or tinidazole plus paromomycin

Answer 206

• Lots of viruses implicated – hepatitis A, B, C, D and E, HSV, CMV, EBV etc - HBV/HCV longer incubation period (1-6mo) cf other (2-6 weeks), roughly • Common features: o Usually present with icterus o Damage involves acute cytopathic and immune mediated injury:  Necrosis usually most marked in centrilobular areas  Lobular architecture remains intact  Fatty change is rare  Bile duct damage is uncommon  Neonates often respond to injury by forming giant cells • Morphology returns to normal within 3 months of an acute infection • Investigative findings o Elevated transaminases + bilirubin (bilirubin usually normalizes first) o Markers of cholestasis can be elevated due to abnormal bile flow at canalicular / cellular level o Synthetic function must be assessed

Answer 207

1. Epidemiology a. Most common viral hepatitis worldwide, often occurs in epidemics - affects children and young adults b. Contagious from 2 weeks prior – 7 days after onset of jaundice 2. Risk factors a. Living in endemic region, close personal contact with an infected person c. MSM d. Known food-borne outbreak 3. Transmission = faecal-oral route; arises from the ingestion of contaminated food or water (eg. shellfish) [or close contact with an infected person] 4. Incubation = 1 month 5. Clinical presentation/ Outcome of infection a. Most infections in adults are symptomatic b. Majority of infections in children <6 years are asymptomatic (key reservoirs for infection) c. Different presentations i. Prodromal stage (VIRAEMIA) = unwell with non-specific symptoms (nausea, anorexia) ii. Icteric stage/ classic hepatitis (IMMUNE RESPONSE) = 1-2 weeks later, jaundice iii. Hepatitis A relapse after initial improvement = symptoms as for classic hepatitis 1. Two or more occasions within 6-10 weeks iv. Cholestatic hepatitis = initial symptoms as in classic hepatitis A, prolonged pruritis v. Fulminant hepatitis (1-5%) = initial presentation as in classic hepatitis A -> rapid deterioration with confusion and decreased LOC d. Extra-hepatic manifestations = arthritis, vasculitis, myocarditis, AKI

Answer 208

6. Investigations a. LFTs = elevated transaminases (may reach 10,0000), ALT > AST; PRECEEDS JAUNDICE (prodromal stage) b. Bilirubin = elevated; usually occurs AFTER a rise in transaminases (icteric stage) c. Urea + creatinine = rise indicates renal failure (fulminant hepatitis) d. Prothrombin time = may be mildly prolonged; more marked prolongation with fulminant hepatitis e. FBC = leukopenia with a relative lymphocytosis f. ESR = raised g. Diagnosis of HAV i. Serology = IgM, IgG 1. IgM can be detected 5-10 days before symptoms and remains elevated for 4-6 months 2. IgG levels begin to rise soon after IgM and stay elevated through a person’s lifetime ii. Viral particles in stool 7. Course and prognosis a. Mortality in young adults is 0.1% and increases with age b. Death occurs due to fulminant hepatic necrosis, occurs in <1% of patients i. Characterised by worsening jaundice + encephalopathy c. During convalescence 5-15% of patients have relapse of hepatitis but this settles spontaneously d. Occasionally, a more severe jaundice with cholestasis will run a prolonged course of 7-20 weeks (‘cholestatic viral hepatitis’) 8. Treatment a. Both active + passive vaccination available b. Unvaccinated people with recent exposure (<2 weeks) = hepatitis A vaccine or immune globulin c. Confirmed hepatitis A with worsening jaundice/ encephalopathy i. Supportive care = rest, avoid XS paracetamol + alcohol ii. Liver transplant = those with fulminant hepatis d. Cholestyramine = symptomatic relief of pruritis 9. Prevention a. Immunoglobulin therapy can be given if i. < 1 year of age pre travel ii. Prior to travel if exposure going to be in < 2 weeks iii. Post exposure prophylaxis < 2 weeks if < 1 year of age (otherwise give HAV vaccine) b. Vaccination for: i. Children > 1 ii. 2 dose schedule – 6-12 months apart iii. Seroconversion > 90% after first dose, up to 100% after 2nd dose iv. Antibody titre persists for ~ 10 years

Answer 209

1. Key points a. 25-40% of CHB die prematurely of liver disease or HCC b. Up to 1/3 may have severe disease with significant cirrhosis, even decompensated cirrhosis and HCC reported in childhood 2. Epidemiology a. 2 billion people have been infected by HBV, of whom 400 million have chronic HBV b. Nearly half of all infections are in South East Asia, China and Africa (endemic regions) c. Can be clinically silent so must look in high risk groups – migrants, children of HBV positive mothers, IVDU 3. Risk factors = IVDU, chronic Haemodialysis patients, MSM, those born in endemic countries, multiple sexual partners, prisoners, household/sexual contacts of HBsAg positive person, Hx of HIV/HCV 4. Transmission a. Vertical i. Greatest risk if mother is HBeAg +ve (90% become chronic if untreated, 2.5% intrauterine infection) ii. Breast feeding not thought to confer risk of hepatitis b. Horizontal – children in endemic country c. Blood-borne d. Sexual 5. Incubation = 1-5 months 6. Microbiology a. Double stranded DNA virus b. Circular structure has 4 genes: surface, core, X and polymer genes c. HBsAg – surface of virus d. HBcAg – nucleocapsid that encodes the viral DNA in portion of virion e. HBeAg – nonstructural Ag derived from HBcAg by proteolytic self-cleavage i. Marker of active viral replication ii. Usually correlated with HBV DNA levels 7. Pathogenesis a. HBV is a predominantly noncytopathogenic virus, which causes injury mostly by immune mediated processes b. Severity of hepatocyte damage reflects the degree of immune response i. Most complete immune response  greatest likelihood of viral clearance but also the most severe injury to hepatocytes.

Answer 210

8. Phases of infection a. Immune tolerant i. Extremely high HBV-DNA (>20,000 IU/ml), HBeAG +ve ii. Normal AST/ALT – body’s immune system is not responding (immune response = liver damage) iii. Characteristic of perinatal infection (or ‘incubation period’ in adult with newly acquired HBV) iv. Most children are in the ‘immune tolerant’ phase – lasts for months, years or decades b. Immune clearance i. Falling but elevated HBV-DNA (>20,000 IU/ml), HBeAg +ve, high ALT/AST ii. Immune attack on the virus and immune-mediated liver damage iii. While there is active viral replication – HBeAg is positive c. Immune control = inactive carrier i. Lower HBV-DNA (<20,000 IU/ml), HBeAg –ve, anti-HBe positive, ALT/AST normal ii. Seroconversion occurs; HBeAg –ve + anti-HBe positive iv. Risk of reactivation to immune-activation (resembles acute hepatitis B), especially with immunosuppression d. Immune escape (‘core or precore mutant’) i. Virus can mutate – levels start to rise again and immune system starts to flare again iii. HBeAg –ve because of pre-core or core promoter gene mutation iv. Anti-HBe positive v. ALT/AST high 9. Outcome of infection a. NOT curable b. Host immune response to the virus is the main determinant of the outcome of infection c. Neonates with immature immune system = 95% become asymptomatic chronic HBV carriers d. Children >6 years = 30% become asymptomatic chronic carriers e. Adults i. 70% of infections are asymptomatic + self-limiting ii. 30% of adults have symptomatic icteric hepatitis iii. <5% develop chronic hepatitis f. Of those with chronic hepatitis = 10-20% risk of cirrhosis -> risk of hepatocellular carcinoma

Answer 211

1. Clinical presentation a. Usually clinically silent b. Fatigue, anorexia, malaise (occur 6-7 weeks post exposure) c. Jaundice – 25% of acutely infected patients i. Usually begins 8 weeks after exposure and lasts 4 weeks d. Extra-hepatic manifestations (serum sickness like reaction with rash, arthritis; GN) 2. Investigations a. Determine phase of CHB = 1) LFT 2) E serology 3) HBV DNA b. Any patient with risk factors = HBsAg, anti-HBs, anti-HBc c. Patients with chronic hepatitis B = LFTs, HBeAg, HBeAb, HBV-DNA, FBE, INR, AFP (marker for HCC) d. Determine extent of cirrhosis = 1) biopsy 2) fibroscan e. Other investigations i. AFP = screening for HCC ii. U/S of liver = screening for HCC Serology - HBsAg Indicates active viral infection (appears first) - HBsAb Immunity to HBV – vaccination or infection - HBcAb Infection with HBV – either past or current - HBeAg Indicates activate viral infection, marker of infectivity - HBeAb Seroconversion, goal of treatment

Answer 212

12. Management a. Education = alcohol minimization, weight loss, smoking cessation, IDU harm reduction b. Surveillance = hepatoma with ultrasound every 6 months +/- AFP c. Pharmacological management = immune clearance + immune escape phase i. Goal = normal ALT, undetected HBV DNA, reversal of fibrosis, prevention of cancer ii. The only children that are treated are those with ALT, high levels of virus, no other liver disease and significant inflammation + fibrosis iii. Usually life-long treatment iv. Aim for HBSAg loss – best at reducing HBSAg results is IFN-alpha (but most side effects) v. Treatment options 1. Pegylated interferon 2. Antivirals = entecavir + tenofovir a. Oral tablets 1/daily b. Well tolerated, taken long term but cannot be given with pregnancy c. 90% drop viral load to undetectable at 12 mo, E seroconversion at 15%/year, <1% loss of surface Ag d. Other antivirals licensed for children are lamivudine and adefovir 13. Prevention a. Avoid risk factors = not sharing needles, safe sex b. Passive immunisation with HBIG = given to accidental exposure, newborn babies with +ve mother, regular sexual partners of +ve patients c. Active immunisation 14. Summary of complications a. Fulminant hepatic failure = associated with acute hepatitis B infection b. Cirrhosis = occurs in about 20% of patients with chronic HBV and is thought to be due to ongoing immune attack of infected cells in the liver, resulting in development of fibrosis and regenerative nodules i. Risk factors = age, co-infection (hep C, A, HIV), high levels of HBV DNA, alcohol intake c. HCC = thought to result from chronic inflammation and cellular regeneration i. Cirrhosis is the greatest risk factor d. Hepatitis B associated GN e. Complications in children i. 1/3 children have severe disease with fibrosis, cirrhosis and HCC ii. 25-40% of chronic disease die from liver disease/ HCC

Answer 213

1. Key points a. In children most newly acquired infection is vertical from HCV positive b. Transmission from mother to baby is relatively uncommon i. <5% of infants born to HCV + mothers will acquire HCV infection ii. Almost restricted to viraemic mothers (particularly during 3rd trimester) iii. Increased risk with concomitant HIV (up to 20%) and higher maternal viral load 2. Natural history a. Perinatal infection i. 20% clear HCV ii. 30% have chronic active infection iii. 50% chronic asymptomatic infection d. Increased fibrosis/cirrhosis with time – 11% to 20% over 5 years 3. Virology a. Single stranded RNA c. Transmission = via IVUD/ sexual contact d. Perinatal transmission = 5% of viraemic mothers e. Incubation period 7-9 weeks 4. Epidemiology a. 1.15% of population – more common than Hep B in Australia (cf. worldwide) b. 90% acquire via IDU, 15% born OS, 5% tattoo, 5% transfusion 5. Transmission = blood-borne (sexual transmission very unlikely) 7. Pathophysiology a. Following an acute infection, almost all patients develop a vigorous antibody and cell-mediated immune response that fails to clear the infection but may contribute to progressive liver damage i. HCV has a high mutation rate so is able to avoid the immune response b. Persistent viraemia is accompanied by variable degrees of hepatic inflammation and fibrosis over time c. When chronic infection is established, HCV may not be cytopathic i. Liver damage probably results from locally driven immune responses, which are mainly non-specific.

Answer 214

8. Outcome of infection a. Acute infection = almost always subclinical i. Those who develop an acute HCV infection are less likely to develop chronic infection b. Chronic infection = 80% of infected individuals c. Cirrhosis = 20% develop cirrhosis in 20-25 years i. Risk factors = alcohol, coinfection with HBV or HIV d. Hepatic failure = 20% of patients who develop cirrhosis e. Hepatocellular carcinoma = develops in patients with cirrhosis at a rate of 0-3% per year 9. Clinical presentation a. Acute hepatitis C is rarely diagnosed, as infected patients are usually asymptomatic b. If clinical features occur they are 6-8 weeks after exposure = mild and vague (fatigue, malaise, nausea) d. HCV infection is often only diagnosed after routine blood testing or blood donor screening 10. Diagnosis a. LFTs = elevated ALT/AST (particularly ALT); episodic elevations in serum aminotransferases is characteristic in hepatitis C b. Serology = anti-HCV (despite this the virus persists) c. HCV-RNA = confirm viraemia in patient with positive EIA, confirm early infection, or assess the effectiveness of antiviral therapy i. Loss of, or reduction in, hepatis C virus RNA can mean that a patient has cleared the virus after acute exposure + is the primary indicator to antiviral therapy d. Genotyping = predicts response to antiviral therapy f. Screen = ex and current IDU, previous tattoo, transfusion before 1990, patients born overseas, history of incarceration, children of mothers with HCV g. Monitoring = biopsy, fibroscan (elastography)

Answer 215

11. Treatment a. Goal of treatment = sustained virological response (SVR) undetected virus > 6 months = cure b. HCV can be cured c. Antivirals i. Currently approved is PEG IFN and ribavirin ii. Response guided therapy depends on 1. Genotype of virus 2. IL28B genotype of the patient indicates likelihood of response to therapy iii. Oral only therapies currently trialed in children for G1-6 and G2,3 1. Not currently available 2. Over 95% sustained virological response (SVR), younger age groups still under trial d. Lifestyle i. Blood-borne precautions ii. Vaccinate against Hep A and B (if serology negative) iii. Avoid alcohol e. Transplant i. Commonest indication for liver transplant ii. Accounts for 1/3 in AUS 12. Complications a. Cirrhosis = 5-10% develop cirrhosis at 25-30 years b. Hepatoma = seen in those with chronic infection and cirrhosis c. Other (rheum, skin, GN, eye) e. Cryoglobulinaemia = single or mixed immunoglobulins that undergo reversible precipitation at low temperatures i. Cryoglobulins deposit in the skin, kidney, and joints ii. Patients may present with fatigue, arthralgias, peripheral neuropathy, palpable purpura, or glomerulonephritis 13. Prognosis a. Patients who have attained sustained virological response (SVR) have <5% relapse rate at 4 years b. Null responders have the same risk of developing cirrhosis as those who have not been treated

Answer 216

1. Overview a. Hepatitis D is a dependent virus – requires HBV to provide an envelope b. Smallest animal virus c. Should be considered in anyone who has hepatitis B 2. Types of infection a. Coinfection = presents with acute hepatitis but rarely becomes chronic b. Superinfection = almost always leads to chronic infection with both HBV and HDV, may present as a severe acute hepatitis in a previously unrecognized HBV carrier or as an exacerbation of chronic hepatitis B 3. Outcome of infection a. Cirrhosis = occurs in 70-80% of HBV carriers with HDV superinfection, 5% in coinfection, compared to 15-30% of HBV alone 4. Diagnosis a. HDV RNA b. IgM and IgG Ab 5. Treatment a. Acute = supportive b. Chronic = drug therapy (low dose interferon-alpha) 6. Prevention = vaccination for hepatitis B prevents hepatitis D

Answer 217

1. Epidemiology a. Epidemics in developing countries and sporadically in developed countries, in patients who have had contact with farm animals or travel abroad (Middle East, SE Asia, Mexico) b. Occurs primarily in young to middle aged adults c. Sporadic infection and overt illness in children are rare 2. Transmission a. Faecal-oral; usually due to contaminated water b. 30% of dogs, pigs and rodents carry the virus -> zoonotic disease 3. Outcome of infection a. Acute hepatitis = similar to hepatitis A i. Symptoms usually resolve in 2-4 weeks b. Fulminant hepatic failure = 1-2% , rises to 20% in pregnant women c. NO risk of chronic disease 4. Diagnosis a. IgG and IgM Ab b. HEV RNA (serum + stool) 5. Prevention a. Good sanitation and hygiene b. No passive or active immune prophylaxis is available

Answer 218

1. Key points a. Clinical syndrome resulting from massive necrosis of hepatocytes or from severe functional impairment of hepatocytes b. Synthetic, excretory and detoxifying functions of the liver are all severely impaired c. Fulminant hepatic failure can be the presenting feature of liver disease OR it can complicate previously known liver disease (acute on chronic) d. Definition 1. Acute liver related illness (jaundice, elevated transaminases) with no history of known chronic disease (<8 weeks), PLUS 2. Coagulopathy – not corrected by vitamin K a. INR >1.5 or PT >15s with encephalopathy b. INR >2.0 or PT >20s with or without encephalopathy 2. Epidemiology a. Neonatal peak b. Smaller peak in adolescence – usually related to paracetamol overdose 3. Aetiology a. Viral i. Cx of viral hep A, B, D, (C and E uncommon) ii. Unusual high risk of fulminant hepatic failure occurs in individuals with hepatitis B and D iii. Mutations in the precore and/or promoter HBV DNA associated with fulminant failure v. Co-infection with other hepatitis inducing viruses b. Autoimmune hepatitis – 5% of cases c. Haemophagocytic lymphiohistiocytosis d. Idiopathic i. Occurs sporadically ii. Accounts for 40-50% of liver failure in children e. Drugs and chemicals f. Ischaemic and hypoxia from hepatic vascular occlusion, severe heart failure, cyanotic congenital metabolic diseases, or circulatory chock g. Metabolic disorders i. Wilsons disease ii. Acute fatty liver of pregnancy iii. Galactosaemia iv. Hereditary fructose intolerance v. Neonatal iron storage defects vi. Defects in beta oxidation of fatty aids vii. Deficiencies of mitochondrial electron transplant

Answer 219

5. Clinical manifestations a. Progressive jaundice, fetor hepaticus, fever, anorexia, vomiting and abdominal pain b. Rapid decrease in liver size without clinical improvement is an ominous sign c. Haemorrhagic diatheses and ascites can develop d. Hepatic encephalopathy i. Initially characterised by minor disturbance of consciousness and motor function ii. Irritability, poor feeding and change in sleep rhythm may be only finding in infants iii. Asterixis may be demonstrable in older children iv. Often somnolent, confused or combative on arousal and can eventually be responsive to only painful stimuli v. Can progress to coma with extensor responses and decerebrate and decorticate posturing appear vi. Respiratory failure can occur in stage IV 7. Investigations a. Blood tests - LFTS iii. Blood ammonia iv. Coags – PT and INR are prolonged and often do NOT improve with vitamin K v. Hypoglycaemia vi. Hypokalaemia, hyponatraemia, metabolic acidosis, or respiratory acidosis b. Liver biopsy i. Zonal pattern of necrosis may be observed with certain insults ii. Centrilobular damage is associated with paracetamol or circulatory shock iii. Occasionally reveals severe dysfunction rather than necrosis v. Metabolic screening 1. CHO 2. FAO defects 3. Urea cycle disorders and organic acidaemias 4. Mitochondrial disorders

Answer 220

10. Treatment a. Specific therapies i. N acetyl cysteine – paracetamol ii. Aciclovir – HSV iii. Penicillin – Amanita mushroom iv. Nucleos(t)ide analogues (entecavir, lamivudine) – HBV v. Prednisolone – autoimmune hepatitis b. Supportive care v. Coagulopathy – Vitamin K + FFP + cryoprecipitate + platelets; sometimes plasmapheresis 2. Usually only corrected if INR >4.0 or PC <20,000 and oozing or invasive procedure 1. PPI for GI bleeding viii. Dietary – protein intake should be restricted or eliminated ix. Gut purging with enemas/lactulose 1. Lactulose is metabolized to organic acids by colonic bacteria; probably lowers ammonia production through trapping of ammonia in acidic intestinal contents x. Rifaximin or neomycin – can reduce enteric bacteria responsible for ammonia xi. Cerebral edema – complication of hepatic encephalopathy that needs steroids and osmotic diuresis 1. QuadH therapy (hyperventilation to lower CO2, hypernatraemia 148-152, hypothermia, haemofiltration to reduce ammonia) c. Transplantation iii. Orthotopic liver transplantation should NOT be done in patients with mitochondrial or neuromuscular dysfunction as neurological deterioration will continue post transplantation 11. Prognosis a. Improved survival cf adults b. Prognosis varies considerably with the cause of liver failure and stage of hepatic encephalopathy c. In patients who progress to stage IV coma, the prognosis is extremely poor d. Major complications = brainstem herniation (commonest cause of death), sepsis, severe haemorrhage or renal failure e. Poor prognosis = age <1 year, stage 4 encephalopathy, INR >4 and need for dialysis before transplantation f. Children with acute hepatic failure are more likely to die waiting for transplant than other organs g. 6 month post-transplant survival = 75% (compared with 90% for chronic liver disease)

Answer 221

• Cholestasis = extrahepatic or intrahepatic obstruction to bile flow o Substances that are usually excrete in the bile accumulate in the liver • Cirrhosis = defined histologically by the presence of bands of fibrous tissue that link central and portal areas and form parenchymal nodules o Macronodular = nodules of various sizes (up to 5cm) o Micronodular = nodules of uniform size (<1cm) Management • Liver transplantation routine hence aggressive management of chronic liver disease and its complications • Nutrition o NG tube feeding o MCT formulas – do not require bile acids for digestion or absorption • Fat soluble vitamin deficiencies - oral/ parenteral • Bleeding – banding/ sclerotherapy/ B blockers/ TIPS o TIPS = transjugular intrahepatic portosystemic shunt (TIPS)  Portal blood is under pressure resulting in collaterals including varices and other manifestations of PHT  Stent placed to join portal vein to systemic vein – relieves pressure  Reduces spleen size and risk of bleeding from varices  However blood bypasses the liver – detoxication, handling of drugs and ammonia is compromised  Used in life-threatening bleeding • Ascites – diuretics, albumin, drainage • Bone health – densitometry, vitamins (D, K, Ca) bisphosphonates

Answer 222

1. HEPATOMEGALY a. Underlying mechanism - increased number or size of cells, infiltration, increased vessels b. Normal liver edge can be felt up to 2cm below the right costal margin, ?or up to 3.5cm in neonate 2. JAUNDICE b. Clinically apparent when serum concentration reaches 34-50 umol/L – neonate may not appear icteric until bilirubin reaches >85 umol/L c. May be the earliest and only sign of hepatic dysfunction 3. PRURITIS a. Generalised itching can occur in patients with chronic liver disease and is often associated with cholestasis b. Symptoms can be generalised or localised (commonly to palms and soles), usually worse at night, exacerbated with stress and heat, relieved by cool temperatures c. Unrelated to the degree of hyperbilirubinaemia d. Multifactorial cause e. Therapeutic agents: bile-acid binding agents (cholestyramine), choleretic agents (ursodeoxycholic acid), opiate antagonists, antihistamines, rifampicin 4. SPIDER ANGIOMAS a. Characterised by central pulsating arterioles from which wiry venules radiate b. More common in SVC distribution (face and chest) d. Result from altered estrogen metabolism e. >3 suggests liver disease (in adults) 5. PALMAR ERYTHEMA a. Blotchy erythema most noticeable over the thenar and hypothenar eminence, d/t abnormal serum estradiol levels and alterations in peripheral circulation 6. XANTHOMAS a. Marked elevation of serum cholesterol can be associated with some forms of chronic cholestasis b. Deposition of lipid in the dermis and SC tissue c. Brown nodules can develop first over the extensor surfaces 7. PORTAL HYPERTENSION b. Normal pressure = 3-6mmHg; Portal HTN = >10mmHg d. Responsible for 2 major complications of cirrhosis: - Ascites (can be cx by SBP) - Variceal haemorrhage (GIT bleeding) 10. ENCEPHALOPATHY a. Can involve any neurological function – can be prominent or present in subtle forms such as deterioration of school performance, sleep disturbance, depression, emotional outbursts 11. ENDCORINE ABNORMALITIES a. More common in adults than children c. Proteins that bind hormones in plasma are synthesized in the liver; and steroid hormones are conjugated in the liver 12. RENAL DYSFUNCTION 13. PULMONARY INVOLVEMENT 14. RECURRENT CHOLANGITIS a. Often seen in paediatric cholestatic disorders b. Most commonly caused by GN enteric organisms – E. coli, Klebsiella, Pseudomonas and Enterococcus c. Liver transplantation is the definitive treatment for recurrent cholangitis 15. MISCELANEOUS a. Anorexia b. Abdominal pain or distension c. Spontaneous peritonitis d. Malnutrition and growth failure e. Bleeding f. Hypersplenism

Answer 223

a. Systemic disease or toxins can affect the liver and kidney simultaneously, or parenchymal liver disease can produce secondary impairment of renal function b. Renal alterations in sodium and water balance and potassium metabolism c. Ascites in patients may be related to inappropriate retention of sodium and expansion of plasma volume, or it may be related to sodium retention mediated by diminished effective plasma volume d. Hepatorenal syndrome = defined as functional renal failure in patients with end stage liver disease i. Pathophysiology is related to splanchnic vasodilation, mesenteric angiogenesis, an decreased effective blood volume with resulting decreased renal perfusion ii. Hallmark is intense renal vasoconstriction (mediated by haemodynamic, humoral and neurogenic mechansims) with coexistant systemic vasodilation iii. Diagnosis supported by oliguria, urine electrolyte abnormalities (urine sodium <10meq/L, fractional excretion <1%, normal sediment), absence of hypovolaemia and exclusion of other causes

Answer 224

Hepatopulmonary syndrome = triad of 1) hypoxaemia 2) intrapulmonary vascular dilatation 3) liver disease i. Intrapulmonic R to L shunting of blood resulting from enlarged pulmonary vessels that prevents RBC traveling through the center of the vessel allowing adequate exposure to oxygen-rich alveoli ii. Shunting of vasodilatory mediators from the mesentery away from the liver is thought to contribute iii. Should be suspected and investigated in the child with chronic liver disease with a history of dyspnoea or exercise intolerance, and clinical examination findings of cyanosis, digital clubbing, oxygen saturations, particularly in upright position iv. Treatment requires liver transplantation b. Portopulmonary hypertension = characterised by increase in the resistance to pulmonary arterial flow in the setting of portal hypertension i. Defined as pulmonary arterial pressure > 25 mmHg at rest and above 30 mmHg with exercise, elevated pulmonary vascular resistance with pulmonary arterial occlusion pressure, or LVEDP of <15 mmHg

Answer 225

Hands • Leukonychia = secondary to hypoalbuminaemia • Palmar erythema = redness of thenar + hypothenar eminences d/t raised estrogen levels • Pale palmar creases = anaemia d/t 1) blood loss from GI bleeding 2) hypersplenism 3) malnutrition 4) chronic disease • Metabolic flap (asterixis) = d/t hepatic encephalopathy Arms • Excoriations on skin d/t pruritis = secondary to impaired bile secretion • Bruising = haematological disorder o Hepatocellular damage  interfere with protein synthesis + therefore the production of all the clotting factors (except factor VII which is made elsewhere) o Obstructive jaundice  shortage of bile acids  reduced absorption of vitamin K (fat soluble vitamin)  reduced synthesis of factor II, VII, IX, X • Petichiae o Alcoholism bone marrow suppression o Cirrhosis  portal HT  splenomegaly • Muscle wasting Face • Jaundice = d/t reduced hepatic excretion of conjugated bile • Pale conjunctiva = d/t anaemia • Hepatic fetor = d/t reduced breakdown of toxins caused by portosystemic shunting Chest • Spider naevi = >2 abnormal [chest + arms] • Gynacomastia = d/t raised estrogen levels OR drugs (eg. spironolactone) • Loss of chest/axillary hair Abdomen • Distension (particularly flanks) + shifting dullness = ascites • Caput medusae or dilated abdominal veins = d/t portal hypertension • Splenomegaly = d/t portal hypertension • Hepatomegaly (shrinks later in cirrhosis) Legs • Swelling = peripheral edema d/t hypoalbuminaemia Testicles • Testicular atrophy Mental • Altered = hepatic encephalopathy

Answer 226

``` Stage 1 Alert and awake Agitated, irritable, fussy Tremor, poor handwriting Obeys command ``` ``` Stage 2 Confused, lethargic Combative or inappropriate Hyperactive reflexes, asterixis Purposeful movement doesn’t obey commands ``` ``` Stage 3 Stuporose but rousable Incoherent speech Hyperreflexia, hyperventilation, asterixis Motor response to pain ``` ``` Stage 4 Unconscious Pupils sluggish Reflexes hyperactive, irregular respiration Responds non-purposefully to pain ``` ``` Stage 5 Unconscious Pupils fixed Hypoactive reflexes, no tone Apneic ``` Precipitants • Alcohol • Bleeding – GIT protein load increase • Constipation – slows transit time and allows increase absorption ammonia • Drugs/diet – high protein diet, alcohol • Electrolyte disturbance • Infection/intervention – TIPPS procedure Management • Remove precipitants • Monitor mental state, EEG, Avoid sedatives • Low protein diet, lactulose with NGT • Cerebral oedema management – elevate head, mannitol, hyperventilation • Ventilation if stage ¾

Answer 227

1. Key points a. Portal hypertension defined as elevation of portal pressure >10-12 mmHg b. Major cause of morbidity and mortality in patients with liver disease c. Normal venous pressure approximately 7 mmHg 2. Classification a. Post sinusoidal = blockages of the hepatic vein b. Sinusoidal or intrahepatic = cirrhosis c. Presinusoidal = blockage of the portal vein (portal vein thrombosis) f. 3 KEY CLINICAL CONSEQUENCES of portal hypertension i. Splenic enlargement (splenomegaly) ii. Ascites (accumulation of fluid in the peritoneal cavity) iii. Varices at sites of porto-systemic anastomoses - oesophagus/stomach (congestive gastropathy), anorectal, abdomen (caput medusae) - bleeding (oesophageal most common -> haematemesis, malaena) d. Hepatopulmonary syndrome i. Develops in >10% of patients with portal hypertension ii. Defined as an arterial oxygenation defect induced by intra-pulmonary microvascular dilatation, resulting from release of a number of endogenous vasoactive molecules e. NOTE: if there are no signs of CLD portal vein obstruction is most likely 6. Diagnosis - USS + doppler ("hepatofugal" = reversal of flow) - TTE for hepatopulmonary syndrome - endoscopy for varices/bleeding 7. Treatment - resuscitate as indicated - correct coagulopathy (vit K, plts, FFP) - +/- PPI, vasopressin, GTN, octreotide - endoscopy -> sclerotherapy, +/- shunts - liver transplant - beta blockers for prophylaxis (limited evidence in children) 8. Prognosis a. Portal hypertension secondary to intrahepatic disease has a poor prognosis - usually progressive HTN and liver dysfunction, usually require transplant d. Liver transplantation is the ONLY effective therapy for Hepatopulmonary syndrome

Answer 228

1. Indications a. Obstructive biliary tract disease = biliary atresia, PSC, traumatic or post-surgical injury i. Biliary atresia most common (50%) ii. Note Kasai procedure may be initially successful however can still develop cirrhosis and portal hypertension iii. Children with biliary atresia (Or any obstructive biliary disorder) who do not achieve successful drainage require liver transplantation within the first year of life b. Metabolic = alpha1 antitrypsin, tyrosinaemia type I, glycogen storage disease type IV, Wilson disease, neonatal haemochromatosis, CN type I, familial hypercholesterolaemia, primary oxalosis organic acidemia, urea cycle defects c. Acute hepatitis = fulminant hepatic failure, viral, toxin or drug induced d. Chronic hepatitis with cirrhosis = hepatitis B or C, autoimmune e. Intrahepatic cholestasis = idiopathic neonatal hepatitis, Alagille syndrome, progressive familial intrahepatic cholestasis f. Miscellaneous = cryptogenic cirrhosis, congenital hepatic fibrosis, Caroli disease, CF, PCKD and liver disease cirrhosis induced by TPN g. Primary liver tumours = benign tumours (hamartomas, Hemangioendothelioma), unresectable hepatoblastoma (75% of primary liver tumours in childhood), HCC h. Emerging indication = GVHD, haemophilia, and portosystemic shunt 2. Contraindications a. Uncontrolled infection of extra-hepatic origin b. Uncontrolled extra-hepatic malignancy c. Severely disabling and uncorrectable disease in other organ systems

Answer 229

a. Primary non-function i. First few hours – due to hypotension/hypoxia, direct tissue injury, hyperacute rejection ii. High lactate, increase PT and TT (?APTT) iii. Failure of patient to wake iv. Management – infusion prostaglandin E1, prevention cerebral oedema (mannitol and hyperventilation), supportive v. Re-transplant if symptoms more than a few hours b. Vascular complications i. Hepatic artery thrombosis 1. Most frequent and early vascular complications (5-10%) - Devastating consequences ii. Portal vein thrombosis 1. 5-10%, can be early or late c. Biliary complications i. Biliary strictures most frequent surgical complication (10-30%) ii. Bile leak also common iv. Elevated ALP/GGT vi. Management – stenting, reconstruction d. Rejection i. Acute 1. Usually w/i 2w of transplantation, highest incidence (30-60%) in first 90 days 2. 20-50% at least one episode of acute rejection in first week after transplant 3. Suspected based on abnormal liver function tests and rarely are there systemic signs 4. Diagnosis requires biopsy confirmation ii. Chronic rejection 1. Less common (5-10%) and is characterised by progressive damage and loss of bile ductules with consequent cholestasis e. Transplant related infections i. Most common cause morbidity/mortality post-transplant iii. Bacterial infection – usually gram negative enteric, enterococci, staph iv. Fungal infection – if high risk then liposomal amphotericin B post op v. Viral infection – EBV, CMV, HSV (EBV/CMV risk dictated by serological status compared with donor) f. Post-transplant lymphoproliferative disorder i. Most frequent tumor in children following transplantation ii. Heterogenous group ranging from benign lymphatic hyperplasia to lymphoma - majority of cases <2years post-transplant iii. RF – higher dose immunosuppression, absence of prior EBV, intensity of vital load iv. Management – decrease immunosuppression, if CD20 expressed can use anti-CD20 rituximab + cyclophosphamide + prednisolone

Answer 230

8. Outcomes a. Outcomes depend on disease, weight at time of transplant***, type of graft, ABO compatibility i. 70% year 30 year survival ii. Children >8kg best survival*** iii. Worst survival – malignancy iv. Split grafts do the same or slightly better than whole grafts v. Cut down grafts do the worst 9. Recurrence following transplant a. Diseases that do not recur following liver transplant i. Congenital anatomical anomalies 1. Biliary atresia 2. Polycystic liver 3. Caroli disease 4. Alagille syndrome 5. Congenital hepatic fibrosis ii. Metabolic disease 1. Wilsons disease 2. Alpha-1 antitrypsin deficiency iii. Acute drug induced liver failure b. Diseases that recur following transplant – i. Hepatitis B + C viral infection ii. Primary biliary cirrhosis iii. Primary sclerosing cholangitis iv. Autoimmune hepatitis v. NAFLD vi. Alcohol associated liver disease vii. Haemochromatosis viii. Hepatocellular carcinoma

Answer 231

1. Key points a. Non-alcohol fatty liver disease (NAFLD) = spectrum of liver disease strongly associated with obesity and is the most common liver disease in children b. Note that fat in liver does NOT mean NAFLD – many conditions result in fat in the liver 2. Spectrum of disease a. Fatty liver alone (NAFLD) b. Non-alcoholic steatohepatitis (NASH) = fatty infiltration + inflammation i. Tends to be associated with ‘metabolic syndrome’ ii. Closely resembles alcohol disease iii. Two subtypes: NASH type 1 = adult histological findings, NASH type 2 = steatosis and portal inflam c. Cirrhosis 3. Epidemiology a. 12% in Australian children b. More prevalent in females c. Central obesity is much more common in females than males, but metabolic syndrome is more common in males 4. Clinical manifestations a. Many patients asymptomatic 5. Risk factors a. Obesity b. Male gender c. White or Hispanic ethnicity d. HyperTG e. Insulin resistance 6. Investigations a. Liver enzymes are not reliably elevated b. No biomarkers can be used as alternative to biopsy reliably c. USS = echogenic (fatty) liver; cannot distinguish NASH from NAFLD d. Liver biopsy = required to determine NAFLD vs NASH 7. Treatment a. No definitive treatment b. Lifestyle changes BIGGEST treatment: LOW, diet 8. Prognosis: long-term prognosis unknown

Answer 232

1. Key points a. Chronic hepatic inflammatory process manifested with elevated serum aminotransaminase concentrations, liver associated serum autoantibodies, and/or hypergammaglobulinemia b. Target of inflammatory process can include hepatocytes and to a lesser extent bile duct epithelium c. Chronicity determined either by duration of liver disease (typically 3-6 months) or by evidence of chronic hepatic decompensation (hypoalbuminaemia, thrombocytopenia) or physical stigmata of chronic liver disease d. Refers to a primarily hepatocyte specific process, whereas autoimmune cholangiopathy and sclerosing cholangitis are predominated by intra- and extrahepatic bile duct injury 2. Definitions a. Autoimmune hepatitis = hepatocyte specific process b. Cholangiopathy/ sclerosing cholangitis = intra and extrahepatic bile duct injury 3. Epidemiology a. Triggers: infections, drugs, toxins b. Genetics – HLA DR3 isoforms appear predisposed

Answer 233

TYPE 1 - Autoantibodies: Antinuclear antibody (ANA), Smooth muscle antibody (SMA), Anti-actin antibody (AAA), Autoantibodies against soluble liver antigen and liver-pancreas antigen (Anti-SLA/LP), Atypical perinuclear ANCA - Age: Any age - Severity: Broad rage, variable - Histopath: Broad; mild to cirrhosis - Rx failure: Infrequent - Relapse: Variable - Need for long term rx: Variable TYPE 2 - Autoantibodies: Anti-liver kidney microsome type 1 (LKM1), Anti-liver cytosol type 1 (ACL-1), Anti-liver kidney microsomal type 3 - Age: Predominantly childhood and young adults - Severity: Generally severe - Histopath: Generally advanced - Rx failure: Frequent - Relapse: Common - Need for long term rx: 100% Both worldwide, mostly female, a/w other AI

Answer 234

Clinical manifestations a. Highly variable – insidious or fulminant onset b. Viral-hepatitis like illness in 25-30% c. Vague symptoms – fatigue, malaise, behavioral change, anorexia, amenorrhoea d. Extra-hepatic manifestations: arthritis, vasculitis, nephritis, thyroiditis, anaemia, rash e. Some patients initial clinical features represent cirrhosis (ascites, bleeding varies, encephalopathy) 8. Investigations a. LFTs i. Aminotransferase ranges between 100-300 (asymptomatic) or >1000 (symptomatic) ii. ALP/GGT usually normal to slightly increased – may be significantly elevated in autoimmune cholangiopathy or in the setting of overlap with sclerosing cholangitis b. Serum bilirubin = may be normal, or elevated in more severe cases c. Gamma globulin = marked polyclonal elevations d. Albumin = hypoalbuminaemia common e. Coags = prolonged prothrombin time; due to vitamin K deficiency/reflection of impaired hepatocellular function f. FBE = anaemia of chronic disease, leukopenia, thrombocytopenia – become more severe with portal hypertension and hypersplenism g. Autoantibodies i. Serum IgG usually >16 g/L ii. Autoantibodies are rare in children; titres as low as 1:40 may be significant iii. 20% of patients have no autoantibodies 9. Diagnosis a. Diagnostic criteria used as no single test will make diagnostic b. Positive features i. Female gender ii. Primary elevation in transaminases and not ALP/GGT iii. Presence of autoantibodies: most common anti-nuclear and SMA (Type 1) and LKM (type 2) iv. Histological findings c. Negative features i. Absence of viral markers ii. Absence of drug or blood product exposure iii. Negligible alcohol consumption

Answer 235

10. Treatment b. High rate of relapse after discontinuation of therapy c. Usual treatment regimen = prednisolone +/- azathioprine or 6-MP e. Azathioprine i. Used in patients with severe side effects or who cannot be maintained on low dose steroids ii. Note need to measure thiopurine methyltransferase before starting 6-MP or AZT – patients with low activity (10%) at risk of myelotoxicity from accumulation of unmetabolized drug iii. Need monitoring for myelosuppression f. Cyclosporine, tacrolimus, MMF and sirolimus = used in patients refractory to usual treatments 11. Prognosis a. > 75% chance of remission i. Transaminases and bilirubin fall to near-normal levels often within 1-3 months b. Following tapering and withdrawal: 50% relapse c. Relapse usually responds to treatment d. Ongoing immunosuppression i. Many children will not meet the criteria for an attempt at discontinuation of immunosuppression – continued on the lowest dose of prednisolone possible ii. Require continual screening for complications (growth, eyes, bones, BP, sugar) e. Some children have steroid-resistant form of hepatitis – need to ensure not actually PSC or Wilsons disease f. Progression to cirrhosis can occur in autoimmune hepatitis despite a good response to drug therapy g. Liver transplantation has been successful i. Disease recurs after transplant in 30% of patients

Answer 236

1. Classification of mitochondrial disorders a. Primary = mutations affecting mitochondrial DNA or by nuclear genes that encode mitochondrial proteins or cofactors b. Secondary = include diseases with uncertain aetiology such as Reye syndrome, disorders caused by endogenous or exogenous toxins, drugs or metals etc 2. Primary mitochondrial hepatopathies a. Neonatal liver failure b. Alpers syndrome (Alpers-Huttenlocher Syndrome or Alpers Hepatopathic Poliodystrophy) c. Mitochondrial DNA depletion syndrome d. Navajo neurohepatopathy e. Pearson syndrome f. Villous atrophy syndrome g. GRACILE syndrome h. Mutations in nuclear translation and elongation factors 3. Secondary mitochondrial hepatopathies a. Reye syndrome i. Reye syndrome is precipitated in a genetically susceptible person by the interaction of a viral infection (influenza, varicella) and salicyclate and or antiemetic use ii. Clinically it is preceded by a preceding viral illness that appears to be resolving and the acute onset of vomiting and encephalopathy iii. Neurological symptoms can rapidly progress to seizures, coma and death iv. Liver dysfunction is invariably present v. Death usually secondary to increased ICP and herniation b. Many other secondary mitochondrial hepatopathies c. Other causes – valproate, Bacillus cereus, nucleoside analogs, valproic acid , reverse transcriptase inhibitors 4. Treatment a. No effective therapy for most patients with mitochondrial hepatopathies b. Neurologic involvement often precludes orthotopic liver transplantation c. Several drug mixtures including antioxidants, vitamins, and electron acceptors have been proposed but no evidence

Answer 237

a. Congenital dilatation of the CBD that can cause progressive biliary obstruction and biliary cirrhosis i. Segmental or diffuse dilatation is observed ii. Diverticulum of the CBD or dilatation of the intraduodenal portion of the common duct (choledochoceles) is a variant iii. Cystic dilatation of the intrahepatic bile ducts may be associated with a choledochal cyst or Caroli disease b. Pathogenesis uncertain c. 75% of cases appear during childhood d. Clinical manifestation i. Infant presents with cholestatic jaundice, severe liver dysfunction including ascites and coagulopathy ii. Rapidly evolve if biliary obstruction is no relieved iii. Abdominal mass rarely palpable iv. Classic triad of abdo pain, jaundice and mass occurs in <33% v. Features of acute cholangitis may be present e. Investigations = USS makes diagnosis; MRCP can also be done i. Need to identify all of the biliary tree (not obscured by gas) ii. Look for connections to bile ducts proximally iii. Repeat if uncertain f. Treatment = excision of the cyst and Roux-en-Y choledochojejunosomty i. Simple drainage into the small bowel less satisfactory due to risk of developing carcinoma in the residual cystic tissue ii. Require resection – confer a risk of cholangiocarcinoma

Answer 238

* Cystic renal disease is usually associated with cystic liver disease and often determines the clinical presentation and prognosis * Virtually all proteins encoded by genes mutated in combined cystic diseases of the liver and kidney are at least partially localised to primary cilia in renal tubular cells and cholangiocytes 2. AUTOSOMAL RECESSIVE PCKD a. ARPKD manifests predominantly in childhood b. Disorder invariably associated with congenital hepatic fibrosis and various degrees of biliary ductal ectasia c. Cysts arise as ectatic expansion of collecting tubules and bile ducts d. Liver disease related to congenital malformation of the liver with varying degrees of periportal fibrosis, bile ductular hyperplasia, ectasia and dysgenesis e. Initial symptoms are liver related in 25% of patients 5. AUTOSOMAL DOMINANT PCKD a. Dilated, non-communicating cysts are most commonly observed b. Other hepatic lesions i. Ductal plate malformation ii. Congenital hepatic fibrosis iii. Biliary microhamartomas c. 50% of patients with renal failure have demonstrable hepatic cysts d. Hepatic cysts increase with age e. Often asymptomatic but can cause pain and are occasionally complicated by haemorrhage, infection, jaundice from bile duct compression, portal hypertension with variceal bleeding, or hepatic venous outflow obstruction from mechanical compression of hepatic veins, resulting in tender hepatomegaly and exudative ascites f. Cholangiocarcinoma can occur g. Selected patients may benefit from liver-kidney transplantation

Answer 239

= CYSTIC DILATATION OF THE INTRA-HEPATIC BILE DUCTS a. Features i. Congenital saccular dilatation can affect several segments of the intra-hepatic bile ducts ii. Choledochal cysts also associated b. Genetics i. Most cases are transmitted AR c. Pathogenesis i. Caroli disease = bile ductal ectasia without other hepatic abnormalities ii. Caroli syndrome = bile duct dilatation associated with congenital hepatic fibrosis iii. Stagnation of bile leads to formation of biliary sludge and intraductal lithiasis iv. Stagnation leads to increase risk infection / cholangitis v. Progression to cirrhosis and complications (lithiasis, infection) e. Clinical manifestations i. ARPKD frequently presents in neonates ii. Neonatal jaundice due to cholestasis iii. Pruritus and hepatomegaly are common iv. Bacterial cholangitis +/- sepsis +/- hepatic abscess formation v. Secondary biliary cirrhosis can occur due to obstruction vi. Caroli syndrome – can present with portal HTN and its consequences f. Diagnosis i. USS = dilated intrahepatic ducts ii. Definitive diagnosis requires percutaneous transhepatic, endoscopic or MRCP – show bile duct ectasia iii. Liver biopsy shows fibrosis g. Treatment i. Cholangitis and sepsis – Abx, and biliary stone extraction ii. Fat soluble vitamin supplements iii. Oesophageal varies – beta blockers iv. Look out for cholangiocarcinoma v. Liver transplant for refractory disease vi. 25% risk brain damage in type 1

Answer 240

a. Key features i. Characterised by diffuse periportal and perilobular fibrosis in broad bands that contain distorted bile duct like structures that often compress or incorporate central or sublobular veins ii. Irregularly shaped islands of liver parenchyma contain normal appearing hepatocytes b. Associated conditions i. Caroli disease and Choledochal cysts ii. Most have ARCKD and rarely nephronophthisis iii. Also occurs as part of COACH syndrome C - cerebellar vermis defect (Joubert syndrome) O - oligophrenia A - ataxia C - coloboma H - hepatic fibrosis d. Clinical manifestations i. Usually has onset in childhood, with hepatosplenomegaly or bleeding secondary to portal hypertension ii. Cholangitis can occur in patients e. Investigations i. Serum aminotransverase and bilirubin usually normal ii. ALP may be slightly elevated iii. Alb and prothrombin time normal iv. Liver biopsy rarely required f. Treatment i. Control of bleeding from oesophageal varices ii. Aggressive treatment of cholangitis iii. Portocaval anastomosis can relieve portal hypertension

Answer 241

a. Distinct clinical and genetic identify in which multiple cysts develop and are unassociated with cystic kidney disease b. Liver cysts arise from but are not in continuity with the biliary tract c. Girls > boys d. Cysts often enlarge during pregnancy e. Rarely identified in children f. Cyst complications – compression, infection, haemorrhage, rupture g. Genes = PRKCSH and SEC63 h. Solitary cyst (non-parasitic) rarely occurs in children

Answer 242

1. Definition = bacterial infection of biliary tree in a patient with biliary obstruction 2. Risk factor – biliary obstruction a. Caroli disease / Alagille’s b. Biliary Atresia c. Biliary calculi d. Benign stasis e. Malignancy 3. Clinical features a. Charcot’s triad of RUQ pain, fever and jaundice – 50-75% b. Reynold’s pentad – RUQ pain, fever, jaundice, hypotension & confusion c. Fever and RUQ are more common than jaundice 4. Investigations a. Elevated WCC, neutrophils ++ b. Blood cultures c. Cholestatic pattern with ALP, GGT and bilirubin d. Can have AST up if has an hepatic abscess 5. Diagnosis a. Suspect it in a patient with history of biliary disease, fever or rigors, jaundice & abdo pain b. Lab tests and Charcot’s triad, or Charcot’s triad alone c. Dx by ERCP – is also treatment with biliary drainage d. USS to look for dilatation if not convinced 6. Management a. Manage sepsis – may develop septic shock, needs Abx and IVT (gram negative and anaerobic cover – E.g. Tazocin or ceftriaxone + metronidazole) b. Biliary drainage – ERCP +/- sphincterectomy +/- stent insertion c. Surgery if ERCP fails d. Prevent recurrence – cholecystectomy generally recommended, and biliary atresia kids go on prophylaxis

Answer 243

a. Key points i. Acute non-calculous inflammatory distension of the gall bladder can occur in infants and children ii. Defined by the absence of calculi , bacterial infection or congenital anomalies of the biliary system iii. Hydrops is distinguished from acalculous cholecystitis by the presence of a significant inflammatory process and generally benign prognosis b. Clinical manifestations i. Affected patients usually have RUQ pain with palpable mass ii. Fever, vomiting illness and jaundice may be present and are associated with a systemic illness c. Investigations = USS shows a markedly distended, echo free GB without dilatation d. Treatment = Usually treated conservatively e. Conditions associated with hydrops i. Kawasaki disease ii. Streptococcal pharyngitis iii. Staphylococcal infection iv. Other infections – leptospirosis, ascaris, threadworm, typhoid, viral hepatitis, sepsis v. Sickle cell crisis vi. Thalassaemia vii. TPN viii. Prolonged fasting ix. HSP x. Mesenteric adenitis xi. NEC

Answer 244

i. Acute acalculous cholecystitis is uncommon in children 1. Usually caused by infection – streptococci, GN organisms (salmonella, Leptospira), parasitic infections (Ascaris or Giardia) ii. Calculous cholecystitis may rarely follow abdominal trauma or burn injury, or is associated with systemic vasculitis such as periarteritis nodosa iii. Clinical features = RUQ pain, nausea, vomiting, fever, jaundice iv. Investigations 1. USS = enlarged, thick-walled gall bladder, without calculi 2. ALP and conjugated bilirubin elevated 3. Leukocytosis v. Treatment = conservative, cholecystectomy if fail to improve

Answer 245

i. Rare in otherwise healthy children ii. Many predisposing conditions = biliary dyskinesia, chronic haemolytic disease, ileal resection or disease, CF, cirrhosis, cholestasis, Crohn’s, obesity, prolonged TPN, prematurity, prolonged fasting, treatment of childhood cancer, abdo surgery pregnancy, sepsis iii. >70% are pigment, 15-20% cholesterol, remainder a mix 1. Black pigment gallstones (calcium bilirubinate and glycoprotein) a. Frequent in chronic haemolytic anaemia and Wilson disease b. IN sickle cell disease pigment gallstones can develop before 4 years of age c. Gilbert syndrome risk factor for pigment gallstone formation in sickle cell 2. Brown pigment stones – form in infants as a result of biliary tract infection iv. Acute or chronic cholecystitis is often associated with gallstones v. Clinical manifestations 1. >50% of patients with gallstones have symptoms 2. 18% present with a complication as the first indication of cholelithiasis – pancreatitis, choledocholithiasis or acute calculous cholecystitis 3. Most important clinical feature of cholelithiasis is recurrent upper abdominal pain 4. Older children may have intolerance for fatty foods 5. Jaundice occurs more commonly in children than adults 6. Pain may radiate to right scapula vi. Investigations 1. USS = investigation of choice vii. Treatment 1. Cholecystectomy = curative b. Controversy regarding asymptomatic cholelithiasis

Answer 246

a. Motility disorder of the biliary tract that may cause acalculous biliary colic in children  nausea and fatty food intolerance b. Usually no gall stones c. Sphincter of Oddi dysfunction may be a variant that can present with chronic abdominal pain and recurrent pancreatitis d. Diagnosis based on CCK-diisoproyl iminodiacetic acid scan demonstrating GB ejection fraction of <35% e. Cholecystectomy – provides short and long term relief

Answer 247

1. Liver processing of drugs a. Phase 1: activation i. Enzymatic activation of substrate to reactive intermediates ii. Ie drug made to contain a carboxyl/ pheno/epoxide/ hydroxyl group iii. This involves CYP system, cytochrome-c reductase, hydrolases and mono-oxygenase b. Phase 2: conjugation i. Conjugation with glucuronic acid, sulfate, acetate, glycine, glutathione ii. Can be overwhelmed if there is enhanced production of toxic metabolites c. Phase 3: excretion i. Excretion of drug metabolites by transporters – eg multiple drug resistant protein 1 (MDR-1) 2. CYP system a. CYP3A4: the primary hepatic CYP b. Poorly expressed in the fetus, increases after birth to 30% of adult values (50% by 6-12 months) c. Induced by: phenytoin, phenobarbital, rifampin d. Inhibited by: erythromycin, cimetidine 3. Differences in neonates a. Many phase 1 and 2 enzymes are immature in the neonate - Drug metabolism is impaired, improves w age c. EG: UDP-GT1A6 i. Phase 2 enzymes ii. Glucuronidises paracetamol iii. ABSENT in the human fetus, increase in the neonate iv. Does not reach adult levels until 10 years of age c. N-Acetyl cysteine = stimulates glutathione synthesis and is effective in preventing or attenuating hepatotoxicity when administered within 16 hours of a paracetamol overdose

Answer 248

a. Associated liver disease i. Sclerosing cholangitis, autoimmune hepatitis ii. Drug toxicity – thiopurine, MTX, 5-ASA, biologics iii. Malnutrition and disordered physiology – fatty liver, cholelithiasis iv. Infection v. Hypercoagulability – infarction, Budd Chiari vi. Long-term complications of these diseases – cirrhosis, ascending cholangitis, PHT b. Sclerosing cholangitis (UC!) i. Most common hepatobiliary disease associated with IBD 1. 2-8% of patients of UC and less often with Crohn’s disease 2. Of those with PSC, 70-90% have UC iii. Characterised by progressive inflammation and fibrosis of segments of the intra- and extra-hepatic bile ducts and can progress to complete obliteration iv. Many patients asymptomatic and disease is detected on screening with ALP or GGT v. Investigations 1. pANCA or anti—SMA antibodies may be present 2. MRCP = beading and irregularity of intra-hepatic and extra-hepatic bile ducts 3. Liver biopsy = periductal fibrosis and inflammation, fibro-obliterative cholangitis, and portal fibrosis vi. Associations 1. Strongly associated with hepatobiliary malignancies = cholangiocarcinoma, HCC, gall bladder carcinoma 2. Incidence of 9-14% 3. Tumour serology (CA 19-9) and imaging useful for screening vii. Treatment 1. No definitive treatment 2. Ursodeoxycholic acid improves bile flow and laboratory parameters but has not been shown to improve clinical outcome 3. Stenting = dominant extrahepatic biliary strictures can be dilated 4. Immunosuppressive therapy = has been trialed but no evidence 5. Supportive therapy c. Autoimmune hepatitis i. IBD-associated autoimmune hepatitis (AIH) can closely resemble IBD-associated sclerosing cholangitis, a condition often referred to as overlap syndrome or autoimmune sclerosing cholangitis (ASC) ii. Typically have hyperglobulinemia iii. In some children, disease thought to be AIH is later found to be sclerosing cholangitis after cholangiography; in other cases AIH manifests years after diagnosis of IBD-associated sclerosing cholangitis iv. Biopsy = interface hepatitis, in addition to bile duct injury associated with sclerosing cholangitis v. Treatment = immunosuppressive therapy

Answer 249

Can cause a variety of liver diseases i. Hepatic steatosis ii. Gall bladder and bile duct damage iii. Cholestasis b. Cholestasis i. Cholestasis is the most severe complication and can lead to progressive fibrosis and cirrhosis ii. MAJOR limiting factor of long-term TPN use iii. Risk factors for TPN associated cholestasis = duration, prem/LBW, sepsis, NEC, SBS iv. Pathogenesis is multifactorial – excess calories, high amounts of protein, fat or CHO, specific AA toxicities, nutritional deficiencies, toxicities related to trace elements v. Typically marked by gradual onset of cholestasis, developing > 2 weeks after onset of TPN vi. Treatment 1. Limit duration of TPN whenever possible 2. Enteral feeding initiated as soon as possible 3. Improved TPN solutions that meet specific needs of neonates 4. Ursodeoxycholic acid may be beneficial in improving jaundice and hepatosplenomegaly c. Biliary complications i. Cholelithiasis and development of biliary sludge, associated with thick, gall stones ii. May be asymptomatic

Answer 250

a. Hepatobiliary complications account for 2.5% of overall mortality b. Onset of liver disease occurs at a median age of 10 years, >90% occurs by age 20 c. Focal biliary cirrhosis is the pathognomic liver lesion of CF i. Impaired secretory function of the bile duct epithelium + blocked biliary ductules secondary to viscid acid secretions  periductal inflammation, bile duct proliferation + increased fibrosis within focal portal tracts d. Gradual progression to multilobular cirrhosis can occur and result in portal hypertension and end stage liver disease in 1-8% of patients e. Risk factors = male gender, increasing age, pancreatic insufficiency, possible meconium ileus f. Treatment = oral ursodeoxycholic acid i. May be beneficial in improving liver function, presumably by improving bile flow ii. Further research necessary to determine whether a true long term benefit exists iii. May require liver transplantation

Answer 251

Patients with sickle cell or thalassaemia can have liver disease caused by i. Acute or chronic viral hepatitis ii. Haemosiderosis from frequent transfusions iii. Hepatic crises related to severe intrahepatic cholestasis, sequestration or ischaemic necrosis b. Hepatic sickle cell crisis i. Occurs in 10% of patients ii. Manifests with RUQ pain and tenderness, fever, leukocytosis and jaundice iii. Bilirubin levels may be markedly elevated, serum ALP levels may be only moderately elevated iv. Difficult to distinguish from viral hepatitis, acute cholecystitis or gall stones c. Sickle cell intrahepatic crisis i. Manifests as hepatomegaly, abdominal pain, hyperbilirubinaemia, coagulopathy and progresses to liver failure ii. Transplantation carries a high risk of graft loss from vascular complications

Answer 252

Definition a. Liver palpable – MCL i. Newborns >3.5cm from costal margin ii. Children >2cm b. Liver span (percussion upper edge, and palpable lower edge) i. Newborn >4.5-5cm ii. Boys >7-8, girls >6-6.5 c. Other things that might mimic hepatomegaly i. Ptosis – inferior displacement due to thoracic pathology ii. Retroperitoneal mass, choledochal cyst, perihepatic abscess iii. MSK abnormalities of chest wall iv. Riedel lobe – variant of right lobe extending below right costal margin DDX: - malaria - leishmaniasis - myelofibrosis - CML/CLL - Gaucher's

Answer 253

a. Inflammation i. Infections ii. Hepatitis / viral – TORCH, EBV, CMV, HSV, HIV, syphilis iii. Toxin/drug – Aspirin (Reye), NSAID, PTU, isoniazid, sulphonamides, valproate iv. Autoimmune hepatitis v. Primary sclerosing cholangitis, primary biliary cirrhosis b. Storage disease i. Glycogen – storage disease, gangliosidoses, galactosaemia ii. Lipids – e.g. Gaucher iii. Fat – FA oxidation defects, mucopolysaccharidosis iv. Sarcoid, Amyloid vi. DM (build up glycogen and fat) vii. TPN (build up glycogen and fat) viii. Protein (alpha-1 antitrypsin) ix. Copper (Wilson’s) x. Iron (haemochromatosis) c. Haemolysis / CT disorder i. Haemophagocytic syndromes ii. Extramedullary haematopoeisis iii. SLE, JIA iv. Serum sickness d. Infiltration i. Primary neoplastic tumors ii. Primary benign tumors iii. Cysts – parasitic, choledochal, polycystic liver disease iv. Metastases – leukaemia, lymphoma, neuroblastoma, histiocytosis e. Congestion i. Suprahepatic – CCF, restrictive pericarditis, hepatic vein thrombosis (Budd-Chiari) ii. Intrahepatic veno-occlusive disease f. Obstruction i. Cholelithiasis ii. Choledochal cyst iii. Biliary atresia iv. Tumors – hepatic, biliary, pancreatic, duodenal v. Alagille

Answer 254

Investigations a. FBE and film – haemolysis b. UEC / LFT i. AST / ALT indicate hepatocellular injury (ALT more liver specific) 1. Doesn’t correlate with prognosis as declining levels may indicate decrease functioning hepatocytes from ongoing necrosis ii. ALP / GGT indicate cholestasis c. Synthetic function i. Albumin ii. INR / PT time (rapidly reflects synthetic function due to short half-life (of factor 7)) d. Metabolic screen (glucose, ketons, lactic acid, pyruvic acid, AA, uric acid, organic acids) e. Urine MCS / metabolic screen 4. Imaging a. Liver US i. Parenchymal disease ii. Biliary tree, stones, sludge iii. Hepatic and portal vein flow via Doppler studies b. CT / MRI = Superior for small focal lesions; tumors, cysts, abscesses c. Radionuclide HIDA scan in neonates to differentiate biliary atresia from hepatitis d. Cholangiography – usually intraoperative to rule out biliary atresia, endoscopic/MRCP is alternative for older children 5. Liver biopsy a. Used to differentiate biliary atresia from neonatal hepatitis and diagnostic for other conditions

Answer 255

a. Primitive gut recognisable by the 4th week of gestation, made up of the following sections i. Foregut - upper GIT: oesophagus, stomach, duodenum (to insertion of common bile duct), trachea, buds form liver and pancreas ii. Midgut - rest of small bowel, mid transverse colon (grows rapidly and protrudes out of the abdominal cavity and rotates counterclockwise until cecum lies in the RLQ) iii. Hindgut - remainder of colon + anal canal b. The general process i. GIT starts out as a flat, embryonic disc – this folds inward longitudinally and transversely to form the eventual tube structure of the GIT ii. Endoderm becomes epithelium, mesoderm becomes the gut muscle iii. Neuroblasts migrate from the oesophagus  colon to form the neural ectoderm Vitelline duct to umbilical artery = remnant of stalk connection with yolk sac Meckel's diverticulum = results from incomplete obliteration of the vitelline duct leading to the formation of a true diverticulum of the small intestine Liver e. Peak size at 9th week (10% of fetal weight), at birth 5% BW, as an adult 2% f. Hematopoiesis early in development (week 7 – 2 months postnatally) v. Vasculature 1. Fetal hepatic blood flow is from hepatic artery + portal/ umbilical veins a. Portal venous: R lobe of liver b. Umbilical flow: L lobe of liver 2. Ductus venosus: shunts blood from portal -> umbilical vein, bypassing sinusoidal network 3. Enteric nervous system a. Derived from neural crest cells that migrate from cranial -> caudal b. Migration of neural crest cells complete by 24th week of gestation c. Abnormality of this process = Hirschsprung disease

Answer 256

a. Mucosa i. Lines the lumen and consists of inner epithelium (squamous in the oesophagus and stomach and columnar in the rest) ii. Loose CT layer called the lamina propria iii. Thin layer of smooth muscle called muscularis mucosa. b. Submucosa i. Thicker layer of loose CT containing blood vessels, lymphatic vessels ii. Submucosal nerve plexus and glands in some areas c. Muscularis externa i. Usually consists of 2 layers 1. Inner circular (constricts tube) 2. Outer longitudinal (shortens tube) - responsible for GI tract motility ii. Circular layer thickens along GIT to form sphincters (prevent backflow) iii. Smooth muscle is electrically coupled by gap junctions so that each muscle layer is a syncytium d. Serosa i. Composed of thin areolar tissue with lining simple squamous mesothelium (begins in lower oesophagus and ends in rectum). ii. The rest of the digestive tract is surrounded by fibrous CT adventitia.

Answer 257

a. Enteric nervous system = myenteric plexus + submucosal plexus i. Lies entirely in the wall of the gut from oesophagus  anus ii. Consists of the outer myenteric plexus + inner submucosal plexus iii. Both have sympathetic + parasympathetic nervous inputs b. Myenteric plexus = OUTER i. Controls GI movements e.g. peristalsis ii. Has both excitatory and inhibitory neurons e.g. sphincters c. Submucosal plexus = INNER i. Controls GI secretion + local blood flow (AND HENCE ABSORPTION) ii. Contraction of submucosal muscle causes various degrees of infoldings of GI mucosa a. Parasympathetic supply = STIMULATORY (ACh) i. Divided into cranial and sacral divisions ii. Cranial = mostly vagus -> oesophagus, pancreas, stomach iii. Sacral (S2-4) via pelvic nerves -> distal half of large intestine to anus iv. Postganglionic neurons mainly in the myenteric and submucosal plexuses b. Sympathetic supply = INHIBITORY (NA) i. Mostly from T5-L2 ii. Main action from noradrenalin inhibits intestinal tract smooth muscle c. Afferent sensory nerve fibres i. Activated by irritation, excessive distension or chemical substances ii. Feed back to brain and spinal cord (eg vagus = 80% afferent)

Answer 258

Secreted by: G cells of antrum, Duodenum , Jejunum Stimuli: Protein load, Distension , Nerve (vagal stimulation), GRP Inhibition: Acid Functions • Gastric acid secretion • Mucosal growth

Answer 259

Secreted by: Small intestinal mucosa -> I cells of duodenum, Jejunum, Ileum Stimuli: Protein, Fat, Acid CCK results in more enzyme secretion than secretin ``` Functions • Pancreatic enzyme secretion • Pancreatic bicarbonate secretion • Exocrine pancreas growth • Gallbladder contraction • Inhibits gastric emptying ``` o Enhances enterokinase secretion

Answer 260

Secreted by: S cells of duodenum, Jejunum, Ileum Stimuli: Fat, Acid Secretin important for bicarb and water secretion ``` Functions • Stimulates pepsin secretion • Pancreatic bicarbonate secretion • Biliary bicarbonate secretion • Growth of exocrine pancreas • INHIBITS gastric acid secretion ```

Answer 261

Secreted by: K cells of duodenum, Jejunum Stimuli: Protein, Fat, (Carbohydrate) Functions • Stimulates insulin release • Inhibits gastric acid secretion

Answer 262

Secreted by: M cells of duodenum and jejunum Stimuli: Fat, Acid, Nerve Function • Stimulates gastric + intestinal motility

Answer 263

``` • Non-immunological o Gastric acid o Bile acids o Hepatic filtration o Pancreatic enzymes ``` • Innate immune system o Neutrophils, macrophages, NK cells and large lymphocytes that are cytotoxic and not T cells o TLR bind fungal Ag and then trigger activation of genes coding for antifungal protein and switch on innate immunity o TLR respond to lipid and CHO sequences in cancer cells, infectious agents and transplanted organs • Local immunisation o B and T cells prime • Microbiome o Bacteria outnumber somatic cells by one order of magnitude o Gut population 100 trillion with 500-1000 species and 60% of faecal biomass is bacteria – variation in diet o Microflora exert important effect on  Structure, physiology, biochemistry, immunology and gene expression in GIT  Bidirectional effects on gut neuromotor function  Role in C difficile, IBD, SIBO, IBS and other diseases including CF o Relatively stable by about 3 years of age o Dysbiosis = less variation in microbiome

Answer 264

1. Indications a. Neurological – CP (impaired swallowing, oesophagitis, GOR, aspiration, constipation) i. Most common in children with development delay ii. Problems – feeding difficulties, choking, prolonged time spent feeding iii. Note difficult to assess linear growth - trial tibial length + knee height (correlates well with linear growth + approximate height) b. High caloric requirement – CF, cardiac 3. Complications a. Mechanical – infection, blockage, tube displacement, migration, intestinal perforation b. Refeeding syndrome c. Dumping syndrome and diarrhoea d. GOR and aspiration 4. Other aspects of management a. Motility agents – erythromycin (more general GI) , domperidone, metoclopramide (gastric phase) b. Antireflux medications – antacids, Ranitidine, Omeprazole

Answer 265

a. NG i. Suitable for short term enteral feeding ii. Contraindication – altered conscious state iii. Risk of aspiration iv. Frequent dislodgement b. PEG i. Usually changed after 6 months ii. Mickey tubes – two dimensions, width and length 1. Balloon device connects to feeding tube, less prone to leakage and can be easily replaced in clinic 2. Risk of accidental dislodgement if balloon pops iii. Button gastrostomy 1. Connects to feeding tube 2. Prone to leakage 3. Needs to be forced into stomach using introducer, can cause peritoneal placement iv. General complications – infection, granulation tissue, leakage, skin breakdown, dislodgement and tube migration v. No difference to rates of GOR vi. Improves weight gain, ease of care c. Jejunal i. Indications 1. Delayed gastric emptying 2. Reduce risk of aspiration 3. Acute pancreatitis ii. Can be nasajejunal/ gastrojejunal or surgical jejunostomy iii. Difficult to place – needs to be endoscopic/ radiological iv. Reduces risk of aspiration v. Requires slow pump infusion vi. Bypasses pancreatic phase vii. Not practical long term, requires frequent replacement

Answer 266

a. Bolus i. Usually over 15-30minutes with breaks between ii. Preferred over continuous feeds iii. Greater physiological response – thermogenesis, gastrin secretion (response to AA content), intestinal motility, enterohepatic circulation of bile acids, gall bladder contraction, and hormonal response (insulin to CHO) • Increased thermogenesis • Increased gastrin secretion • Increased intestinal motility • Increased enterohepatic circulation of bile acids • Increased gall bladder contraction • Increased hormonal response b. Continuous i. Maximizes tolerance in the setting of limited gut functional capacity • Maximises tolerance • Decreased risk of aspiration • Increases gastric emptying rate

Answer 267

a. Micronutrient deficiencies and excess - zinc, selenium, iron, copper, vitamins A + E b. Thrombosis and line related complications i. Sepsis – gram negative (translocation), gram positive and fungal ii. Line occlusion – fibrin + calcium deposits iii. Extravasation – causes bad burns c. PN associated cholestasis i. Affects 40-60% of patients on long term TPN ii. Clinical spectrum: cholestasis, cholelithiasis, hepatic fibrosis, biliary cirrhosis, portal HT, chronic liver failure iii. Risk factors = premature infants/ neonates, recurrent sepsis, previous GI surgery, no oral intake, lipid / manganese toxicity iv. Prevention / treatment 1. Early ‘minimal’ enteral feeding 2. Cycling of PN v. Avoid energy overload vi. ?ursodeoxycholic acid, ?cholecystokinin vii. Liver transplantation d. Metabolic complications i. Hyperglycaemia / hypoglycaemia ii. Hyperammonaemia iii. Hypertriglyceridaemia iv. Metabolic acidosis v. Fluid imbalance e. Refeeding i. Low phosphate, magnesium, potassium ii. Monitor with UEC/CMP if high risk iii. Management – stop PN, correct electrolytes

Answer 268

• Migrainous type syndrome – recurrent severe episodes of vomiting +/- abdominal pain Severe, associated with dehydration < 2 x a week Always stereotypic Early morning with lethargy, nausea, abdominal pain ``` • Investigations: o Upper GI series o Metabolic profile Ammonia Lactate Carnitine Urinalysis + metabolic screen o If not responding  cranial MRI, Gastroscopy, vestibular function UGI/ SBFT Endoscopy with biopsies Abdominal USS CT sinuses/ head MRI ``` • Treatment o Migraine prophylaxis: cyproheptadine, amitriptyline, propranolol o Abortive treatment: lorazepam, ondansetron, triptan o Sedation – chlorpromazine

Answer 269

Anti-emetic options: • Antihistamines • Antidopaminergic – prochlorperazine: metabolic, toxin, medication associated • 5-HT3 antagonist – ondansetron • NK1 antagonist - aprepitant • TCA – Amitriptyline: chronic idiopathic nausea, functional vomiting, cyclic vomiting syndrome Prokinetic agents • Erythromycin – motilin agonist – for gastroparesis, intestinal pseudoobstruction • Metoclopramide – 5-HT4 agonist + antidopaminergic – gastroparesis • Domperidone – peripheral antidopaminergic – gastroparesis

Answer 270

NEONATAL PERIOD • Systemic infection • Bowel obstruction 1. Malrotation of the intestine 2. Hirschsprung’s disease 3. Duodenal atresia 4. Strangulated inguinal hernia • Hypoglycaemia – more common in ‘small for dates’ babies and infants of diabetic mothers • Renal disease – UTI, renal insufficiency p/w vomiting + poor weight gain • Adrenal insufficiency o CAH = deficiency of enzyme 21-hydoxylase o P/w ambiguous genitalia in the female + if unrecognized (male) it may lead to vomiting, dehydration + collapse in the second week of life; if of the salt-losing type results in low Na+ and high K+ • Inborn metabolic errors =rare ``` INFANCY • Infection – tonsillitis, otitis media, pneumonia, meningitis and UTI • Volvulus • GORD • Pyloric stenosis • Gastroenteritis • Malabsorption • Intussusception • Strangulated inguinal hernia ``` ``` OLDER CHILDREN • Migraine • Poisoning • Psychological causes of vomiting • Cyclical vomiting syndrome ``` Hints to underlying cause • Bile stained vomit = intestinal obstruction • Haematemesis = oesophagitis, peptic ulceration, oral/nasal bleeding • Projectile vomiting, first few weeks of life = pyloric stenosis • Vomiting at the end of paroxysmal coughing = pertussis • Abdo tenderness/ abdo pain on movement = surgical abdo • Abdo distension = intestinal obstruction, including strangulated inguinal hernia • Hepatosplenomegaly = CLD • Blood in stool = intussusception, gastroenteritis – salmonella or campylobacter • Severe dehydration, shock = severe gastroenteritis, systemic infection (UTI, meningitis), DKA • Bulging fontanelle or seizure = raised ICP • Failure to thrive = GERD, celiac disease and other chronic GI conditions

Answer 271

ii. Functional abdominal pain is very common but is a diagnosis of exclusion. ``` NEONATES Hirschprung’s enterocolitis Incarcerated hernia Intussuception Irritable/unsettled infant Meckel’s diverticulum UTI Volvulus ``` ``` INFANT/PRESCHOOL Appendicitis Gastroenteritis Intussusception Pneumonia UTI Volvulus Constipation ``` ``` SCHOOL AGE Appendicitis DKA Gastroenteritis Henoch Schonlein Purpura Mesenteric adenitis Migraine Ovarian Pathology Pneumonia Constipation Testicular torsion UTI Viral Illness ``` ``` ADOLESCENT Appendicitis DKA Ectopic pregnancy Cholecystitis/ Cholelithiasis Gastroenteritis Inflammatory Bowel disease Ovarian cyst-torsion or rupture Pancreatitis Pelvic Inflammatory Disease Renal calculi Testicular torsion UTI Viral illness ```

Answer 272

d. Retroperitoneal = lies transversely in the upper abdomen between the duodenum + spleen e. Important relationships: i. Duodenum – pancreatic head adherent to C loop of duodenum ii. Vena cava + renal vein – pancreatic head rests above these vessels iii. Splenic hilum/ L kidney: tail reaches splenic hilum, sit above left kidney 2. Structural unit = acinus iii. Acinar cell synthesizes, stores and secretes >20 enzymes – stored in zymogen granules – some in inactive forms a. Endocrine – secretion of insulin, glucagon etc i. Beta-islets of Langerhans- insulin ii. Alpha cells – glucagon iii. Delta cells – somatostatin b. Exocrine – secretion of hormones responsible for fat absorption i. Secretes 1.2-1.5L of pancreatic juice per day ii. Exocrine acini open into the pancreatic duct that joins the bile duct at the hepatopancreatic ampulla iii. Release controlled by the hepatopancreatic sphincter iv. Normal fat absorption = 95% of intake, requires 2% of total exocrine function for this to occur

Answer 273

a. Components of pancreatic secretions i. Water, Electrolytes, Sodium bicarbonate- to neutralise acidic chyme from stomach: HCl + NaHCO3 = NaCl +H2CO3 - acinus produces proenzymes - ductule produces water and bicarb iv. Active enzymes = LARD 1. Pancreatic amylase (starch digestion) 2. Pancreatic lipase (digests fat) 3. Ribonuclease 4. Deoxyribonuclease (digest RNA and DNA) 5. These enzymes are not altered after secretion but become active when exposed to bile and ions in intestinal lumen v. Inactive enzymes = Zymogens = PECT 1. Trypsinogen (converted to trypsin by enterokinase - intestinal brush border enzyme- contact digestion) 2. Chymotrypsinogen (converted to chymotrypsin by trypsin) 3. Procarboxypeptidase (converted to carboxypeptidase by trypsin) 4. Elastase (activated by trypsin) - DEACTIVATED by alpha-1 antitrypsin 5. All function to break peptide bonds and breakdown protein but are inactive to avoid autodigestion b. Main enzymes involved in digestion i. Amylase = starch ii. Trypsin and chymotrypsin = peptidases iii. Lipase = fatty acids from the 1 and 3 positions of TG -> monoglycerides 1. Requires colipase found in pancreatic fluid for activity 2. Pro-colipase -> colipase -> activates lipase

Answer 274

a. USS = sensitivity of 30% for acute pancreatitis b. Endoscopic USS - more detailed c. CT = good at looking at parenchyma d. MCRCP = good at looking at ducts e. ERCP i. Good at looking for structural problems ii. Associated with 5% risk of pancreatitis 2. Function a. Indirect testing i. Microscopy - fat globules/crystals ii. 72 hour stool collection = quantitative analysis of fat content GOLD standard for malabsorption 3. Normal fat absorption is >93% of intake - impairment doesn't differentiate cause iii. Faecal elastase 2. Standard screening test for pancreatic insufficiency 3. Compared with direct tests – sensitivity of 93-98% and specificity of 96-100% in severe pancreatic exocrine insufficiency 4. Very doubtful use in mild and moderate exocrine insufficiency b. Direct testing i. Measure CCK and secretin to stimulate pancreas ii. Measure pancreatic enzyme and bicarbonate iii. INVASIVE iv. Correlates with 3 day faecal fat balance

Answer 275

Agenesis - rare - a/w severe neonatal diabetes and early death - partial is usually asymptomatic 2. Annular pancreas a. Results from incomplete rotation of the left (ventral) pancreatic anlage c. Usually present in infancy with symptoms of complete or partial bowel obstruction, or in the 4th or 5th decade f. Treatment of choice is a duodenojejunostomy 3. Ectopic pancreas a. Ectopic pancreatic crests in the stomach or small intestine occur in 3% of the population b. Most cases (70%) found in the upper intestinal tract c. Rarely of clinical significance 4. Pancreas divisum a. Occurs in 5-15% of the population b. Most common pancreatic developmental anomaly c. Dorsal and ventral pancreatic analgen fail to fuse, the tail, boy and part of the head of the pancreas drain through the small accessory duct, rather than the main duct d. Mostly asymptomatic 5. Choledochal cysts a. Dilatations of the biliary tract and usually cause biliary tract symptoms – jaundice, pain and fever b. On occasion, may present with pancreatitis

Answer 276

1. Key points a. Uncommon but may presence in infancy b. Early diagnosis important to avoid malnutrition in infancy c. 30% of fat digestion is due to action of gastric lipase so will still have some absorption despite pancreatic insufficiency e. Pancreas has large functional reserve – malabsorption doesn’t occur until pancreatic exocrine function <2% normal values therefore if symptomatic = vital organ failure 3. Clinical manifestations a. Failure to thrive despite very large appetite b. Wasting c. Steatorrhoea (normal to have 10% dietary fat in stool, infants PI 30-50%, children <2years 15%) – often oil droplets visible, pale, bulky, greasy, odourous d. Hypoproteinaemia with oedema e. Rarely, coagulopathy from vitamin K deficiency, haemolytic anaemia from vitamin E deficiency (i.e. fat soluble vitamin deficiencies) 4. Aetiology a. Cystic fibrosis – most common b. Chronic pancreatitis 5. Diagnosis a. Stool examination – fat globules b. 72 hour faecal fat c. Faecal elastase = low - other: fat soluble vitamins/coags, FBE/LFT (Shwachman), sweat test (CF) 6. Treatment a. Pancreatic enzyme replacement therapy i. Enzymes enterically coated to protect from degradation by gastric acid and autodigestion in the small intestine iii. Can increase bio-availability by decreasing gastric acid and increasing duodenal bicarbonate secretion; usually a PPI iii. Adequate dose allows normal growth and stools with normal fat content iv. As no elastase in creon faecal elastase can be used to measure appropriateness of dosage v. Should be given at the beginning of the meal vi. Must be swallowed whole viii. Most preparations contain more protease than lipase b. Adverse effects i. Fibrosing colonopathy and colonic strictures (RARE) 5. Limit dose to <10,000 units lipase/ kg ii. Allergic reactions iii. Increased uric acid levels iv. Kidney stones (fat malabsorption = more fat in GIT = binds calcium = less calcium available to bind oxalate, phosphate = more absorbed = more excreted in kidneys = stones)

Answer 277

2. Epidemiology a. 85-90% of children pancreatic insufficient at birth b. 10-15% of children pancreatic sufficient – 50% become pancreatic insufficient over the next 5 years c. Of those who are pancreatic sufficient 25% have recurrent pancreatitis a. I-III associated with more severe pancreatic dysfunction Best correlation with CFTR abnormalities is exocrine pancreatic insufficiency a. Treatment of the associated pancreatic insufficiency leads to improvement in absorption, better growth, and more normal stools b. General principles i. Allow a normal diet; stress high protein intake ii. Pancreatic supplements +/- gastric acid suppression iii. Vitamins iv. Medium chain TG (directly absorbed)

Answer 278

``` Pancreas • Total achylia at birth (85-90%) • Partial or normal function (10-15%) • Pancreatitis (1%) • Abnormal glucose tolerance (20-30%) • Diabetes (4-7%) Intestine • Meconium ileus (10-15%) (but most mec ileus babies have CF) • Rectal prolapse (1-2%) • DIOS (3%) • Intussusception (1%) • Pneumatosis intestinalis Liver • Fatty liver (7%) • Focal biliary cirrhosis (2-3%) • Portal hypertension (2-3%) Biliary tract • Gallbladder abnormal, non-functional or small (25%) • Gallstones (8%) • Cholecystitis • Bile duct strictures Esophagus • GERD • Esophagitis ``` 6. Nutrition a. If pancreatic insufficiency left untreated results in malnutrition b. Nutrition is the second most important single factor which is an independent predictor of outcome in CF

Answer 279

1. Pancreatic insufficiency a. 2nd most common cause b. Patients typically present in early infancy with poor growth and steatorrhoea c. Differentiated from CF by i. Normal sweat chloride levels ii. Lack of mutation in CF gene iii. Characteristic metaphyseal lesions iv. Fatty pancreas characterised by a hypodense appearance on CT and MRI 2. Haematological 3. Skeletal defects 4. Failure to thrive, short stature

Answer 280

• Definitions o Acute pancreatitis  Typical abdominal pain  Elevated amylase or lipase to 3x the normal range  And/or confirmatory findings on cross-sectional imaging o Acute recurrent/relapsing pancreatitis  2 or more distinct episodes of AP o Chronic pancreatitis  Typical abdominal plain, plus characteristics of imaging  +/- endocrine and exocrine insufficiency • Key points o Acute pancreatitis is common with varied causes o Acute recurrent accounts for 15-35% of acute pancreatitis o Chronic pancreatitis is rare (<0.5%) of all cases o Both acute recurrent and chronic pancreatitis can be associated with a genetic cause o Chronic pancreatitis has a high lifetime risk of exocrine failure, endocrine failure and malignancy

Answer 281

1. Key points a. Most common pancreatic disorder in children More severe in children Most of the mortality is related to trauma 2. Aetiology a. Blunt abdominal trauma b. Idiopathic c. Systemic eg. HUS, IBD d. Biliary stones and microlithiasis (sludging) e. Drug toxicity = valproic acid, asparaginase, 6-MP and AZA (2-4%) f. Infections 3. Pathogenesis a. After initial insult/ acinar injury where there is release of calcium b. Results in premature activation of trypsinogen to trypsin within the acinar cells c. Trypsin then activates other pancreatic pro-enzymes leading to autodigestion  viscous cycle

Answer 282

4. Diagnostic criteria = 2/3 of a. Abdominal pain b. Serum amylase and/or lipase at least 3x ULN ii. Lipase rises by 4—8 hours, peaks at 24-48 hours and remains elevated 8-14 days c. Imaging findings characteristic/compatible with pancreatitis (would start with USS although not sensitive) iii. CT = major role in diagnosis and follow-up 1. Pancreatic enlargement, a hypoechoic, sonolucent, edematous pancreas, pancreatic masses, fluid collections and abscesses 2. 20% or more of children with acute pancreatitis initially have normal imaging studies 5. Clinical manifestations a. Mild acute i. Severe abdominal pain, persistent vomiting and possibly fever ii. Pain is epigastric or either upper quadrant iii. Very uncomfortable and irritable, appears acutely ill v. Pain intensity can increase over 24-48 hours vi. Excellent prognosis b. Severe acute i. Rare in children ii. Life-threatening condition – patient is acutely ill with sever nausea, vomiting and abdominal pain iii. Shock, high fever, jaundice, ascites, hypocalcaemia and pleural effusions can occur iv. Cullen sign = bluish discolouration around the umbilicus v. Grey turner sign = as above but around the flanks vi. Pancreas is necrotic and can be transformed into an inflammatory haemorrhagic mass vii. Mortality rate approximately 20% related to SIRS, multi-organ dysfunction, shock, renal failure, ARDS, DIC, massive GI bleeding, infections

Answer 283

7. Investigations + treatment depending on etiology a. Trauma  USS/CT i. Intact pancreatic duct = conservative therapy ii. Pancreatic duct damaged = ERCP, stent or surgery b. Infection  viral serology, bacterial cultures c. Evidence of biliary obstruction  USS/CT, or MCRP i. Gallstone = cholecystectomy vs sphincterotomy +/- ursodeoxycholic acid d. Medication related  cease medication e. Uncertain  LFT, calcium, lipids, USS i. Positive tests = treat cause ii. Recurrent attacks (negative tests) = consider more extensive investigations 8. Treatment a. Analgesia b. Supportive = fluid, electrolyte management c. Specific treatment as above e. Nutrition = studies favour enteral nutrition NOT TPN i. Using gut protects against SIRS, infection and multi-organ failure by maintaining mucosal integrity ii. NG works just as well as NJ iii. Majority of patients unless very nauseas or sick – can feed enterally iv. Should NEVER use TPN

Answer 284

9. Complications a. Death i. Very uncommon in children ii. Ranges from 0-11%  usually due to trauma iii. Higher end due to underlying disease b. Pseudocyst i. Occurs in 15% ii. Symptoms include vomiting, fever, mass and elevated pancreatic enzymes c. Pancreatic abscesses i. Unknown in children ii. Should be considered if the patient has a fever and prolonged clinical course 10. Prognosis a. Children with uncomplicated acute pancreatitis do well and recover within 4-5 days b. When pancreatitis is associated with trauma or systemic disease prognosis related to underlying condition

Answer 285

* Much greater genetic component  2/3 have genetic mutation * Increased incidence of exocrine (50%) and endocrine insufficiency (30-50%) over 20-30 years after diagnosis * Increased incidence of pancreatic cancer * Treatment supportive - management of chronic pain, malabsorption, nutritional support and diabetes mellitus Genetics • 5 genetic variations that result in pancreatitis (CFTR, other 4 genes prematurely activate trypsinogen) 1. Aetiology a. Genetic mutation b. Congenital anomalies of the pancreatic or biliary ductal system c. Hyperlipidaemia (types I, IV and V) d. Hyperparathyroidism e. Ascariasis 4. Complications a. Pseudocyst b. Malignancy

Answer 286

i. Typically manifests with jaundice, abdominal pain and weight loss ii. Pathogenesis is unknown iii. Type 1 = systemic disease and is associated with high serum IgG4 iv. Type 2 = IgG levels are normal and disease limited to the pancreas v. Both respond to steroids vi. Few cases in children

Answer 287

i. Most common form of chronic pancreatitis in developing equatorial countries ii. Highest prevalence in Kerala iii. Occurs during late childhood or early adulthood iv. Pancreatic ducts are obstructed by inspissated secretions which later calcify v. Associated with mutations in SPINK gene in 50% of cases

Answer 288

1. Key points a. Uncommon sequelae to acute or chronic pancreatitis b. Sacs delineated by a fibrous wall in the lesser peritoneal sac c. Suggested when an episode of pancreatitis fails to resolve or when a mass develops after an episode of pancreatitis 2. Clinical features a. Symptoms i. Abdominal pain ii. Nausea and vomiting iii. Can be asymptomatic b. Signs i. Palpable mass 50% ii. Jaundice 10% iii. Ascites and pleural effusions 3. Investigations a. CT, MRCP or MRI 4. Treatment a. Percutaneous and endoscopic draining

Answer 289

1. Non-endocrine a. Pancreatoblastoma, pancreatic adenocarcinoma, cystadenoomas, rhabdomyoscaromas = RARE b. Pancreatoblastoma = malignant embryonal tumour that secretes AFP i. Most common pancreatic neoplasm in children c. Carcinoma = very rare; no definitive cases known 2. Endocrine tumours a. Functioning tumours occur in autosomal dominant multiple endocrine neoplasia (MEN-1) b. Types i. Gastrinoma = gastrin  refractory gastric ulcers (Zollinger-Ellison syndrome) 1. Most are NOT in the pancreas ii. Insulinoma = insulin  hypoglycaemia accompanied by high levels of insulin 2. May require subtotal/ total pancreatectomy iii. VIP-oma = VIP  diarrhoea + hypokalaemia + acidosis c. Treatment of choice = removal i. If not possible 1. Gastrinoma – PPI 2. VIPoma analogue of somatostatin