Undifferentiated Gut Symptoms

Prof Tony Catto-Smith Director of Gastroenterology Lady Cilento Children’s Hospital Undifferentiated gut symptoms

– The screaming baby and PPI’s – Treating Dientamoeba – or not?

– How to dose with PPI’s – Coeliac disease, serology and HLA testing – Abdominal pain, diarrhoea and lactose intolerance – Abdominal pain, rectal bleeding, diarrhoea and calprotectin

The screaming baby

• ‘A vicious circle is set in motion; the screaming infant, the harried mother and the helpless father all fervently wishing they were someone or somewhere else. The parental anxiety reinforces the symptoms and by the time of consultation the physician is faced by an array of distraught and dishevelled human beings.’

• Des Gurry after Ziai Crying in infancy

4 From: TB Brazelton (1990) Infant Mental Health Journal 11:349-356

2 Upper quartile 1 Median Hours crying of / 24 hrs

0 Lower quartile 2 3 4 5 6 7 8 9 10 11 12

Age in weeks Drug therapy

• Prokinetics • Antiacid drugs – Cisapride – H2 receptor antagonists (ranitidine) – PPI’s The screaming baby and PPI’s

• PPI’s ineffective

No Effect of Proton Pump Inhibitors on Crying and Irritability in Infants: Systematic Review of Randomized Controlled Trials Gieruszczak-Bialek J Pediatr 2015 How to dose PPI’s

– Proton Pump Inhibitors • Covalently bind to proton pump broken down in acid - (H+, K + ATPase) in canaliculus best absorbed from alkaline • Acid inhibition lasts up to 24hr intestine (enteric coating) • Takes 18hr for synthesis of new – T ½ 1.5hr proton pumps

– Tmax 1-3hr – Concentrated in acid compartments (parietal cell) – HAS TO BE ACTIVELY SECRETING ACID

Katzung 2009

How to dose PPI’s

• Bioavailability • PPIs best taken approx 1hr before – decreased 50% by food a meal (usually breakfast) so peak – need to be given on empty stomach serum concentration coincides – In fasting state only 10% proton with maximal activity of proton pumps are actively secreting acid and pump secretion susceptible to inhibition – Going to bed dosing not effective • Up to 3-4 days of daily medication before full acid inhibition potential is achieved • IV PPI same principles but short half life and acid secretion returns in hours – IV has to be given as continuous secretion or repeated boluses Table 1 Reported associations with PPI use and adverse events

Kia, L. & Kahrilas, P. J. (2016) Risks associated with chronic PPI use — signal or noise? Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2016.44 Stomach acid, PPI’s and C difficile

• Stomach acid is a microbial • Long term PPI use disinfectant – Has variable effects on • Strong evolutionary biological bacterial diversity correlation between gastric – Specifically influences 3 acidity and “bacterial risk” of bacterial strains which have diet metabolic products which:- (eg carnivores vs herbivores) Beasley PlosOne 2015 – Upregulate bacterial genes • Less acid neonatal stomach associated with epithelial may allow easier microbial invasion entry to gut – a good thing Freedberg Gastroenterology 2015

Abdo pain, diarrhoea and lactose intolerance • 9yr old boy of Vietnamese background with abdo pain and diarrhoea whenever he drinks milk – well in himself • Neither parent drinks milk

Genetic variation in Primary Lactase Deficiency

• POPULATION ADULT DECLINE IN LACTASE ACTIVITY (%) • Asian 90 - 100 • African Black 85 - 100 • Mediterranean 60 - 85 • Native American 50 - 95 • American Black 45 - 80 • Mexican American 40 - 75 • Northern European 5 - 15 • American Caucasian 10 - 25 Simoons FJ. The geographical hypothesis and lactose malabsorption: a weighing of the evidence. Am J Dig Dis 1978;23:963 BEFORE post-weaning decline, lactase activity can be lost by: • Infection • Malnutrition • Inflammatory processes (eg Crohn’s) • Loss of luminal nutrients • Small bowel bacterial overgrowth

=Secondary Lactase Deficiency

Treating Dientamoeba – or not?

• 7 yr old boy – abdo pain • Dientamoeba linked to intermittent diarrhoea, abdo and 4 days of loose pain, nausea, anorexia, malaise, stools fatigue, eosinophilia • 2013 – detection changed from • PCR showed microscopy to multiplex PCR Dientamoeba fragilis (Giardia lamblia, Cryptosporidium spp, Entamoeba histolytica, Dientamoeba fragilis, Blastocystis spp) Bowen 2016 Roser 2014 Garcia 2016 Treating Dientamoeba – or not?

• Significant concerns regarding D • Best evidence in children – fragilis and Blastocystis – role as – double blind randomised putative GI pathogens controlled trial showed no controversial and possibly difference in symptoms between unproven. treatment and placebo for • Both may be colonising flora – dientamoebiasis prevalence rates about 17% esp – though did partially eradicate in children under age 10yr – 2nd (62% at 2 wk, 25% 8wk) peak at 30-40 yr of age – n=96, metronidazole – Denmark

Bowen MJA 2016 Garcia Clin Infect Dis 2016 Dientamoeba and Blastocystis recommendations from Australian Society of Infectious Diseases and Royal College of Pathologists of Australasia • Putative roles of Dientamoeba • ASID and RCPA recommend to practitioners – Do not request stool pathogen assessment (including and Blastocystis controversial and multiplex faecal PCR) on formed stool samples; – do not request specific testing for D. unproven fragilis or Blastocystis spp.; – should consider the markedly increased sensitivity with • Testing leads to inappropriate unclear significance in their clinical interpretation of pathology laboratory reports of detection of these medical consultations, parasites; unnecessary use of – adhere to comments appended to the laboratory report regarding the significance of D. fragilis and Blastocystis spp. antimicrobials, anxiety for and avoid specific treatment and further testing; – discuss with a paediatric or adult infectious diseases families specialist or medical microbiologist, if clarification is required. • Recommends that laboratories do not include D fragilis and Blastocystis spp within enteric multiplex testing. If still tested and reported, recommend including a cautionary note. http://www.rcpa.edu.au/Library/College-Policies/Guidelines/Faecal-pathogen-testing-by-PCR.aspx Coeliac disease, serology and HLA testing

• 4 yr old – loose stools for 1 yr • Coeliac prevalence approx 1/80 • HLA DQ2/8 status of coeliacs • Coeliac testing – 90% coeliacs have HLA DQ2 – IgA tissue translutaminase 6 (NR<7) – 5% HLA DQ8, 5% variations on HLA DQ2 • HLA DQ2/8 genes in general population – IgG deamidated antigliadin 5 (NR<7) – 65% of first degree relatives of CD – Total IgA 0.9 (normal range) – 30-40% Western population (56% Vic) • Predictive value of HLA testing HLA DQ2 present – – PPV 3.4% general population (CD prev 1%) – HLA DQ8 not present – 28% high risk population (CD prev 10%) • What does this mean? – Negative predictive value >99% • HLA DQ2/8 testing in coeliac – 10 fold increase from 2003-2014 (2,826-32,039 services) – Concern regarding • HLA testing in inappropriate clinical situations • Overly complicated/ambiguous HLA results • Inappropriate medical decisions based on results (eg starting gluten free diets) Tye-Din Int Med J 2015 Blood tests for coeliac disease

• CD Serology – First line in symptomatic children • TTG (IgA), DAG (IgG) • High PPV (>90%) pop prev 1%

– HLA DQ2/8 if Asymptomatic at risk • HLA typing – if positive→ • Serology (absence of HLA excludes CD) • HLA negative EXCLUDES CD

Appropriate use of HLA typing

– CD serology or biopsies inconclusive – At risk groups but not all (type 1 DM, or equivocal HLA useful to triage autoimmune thyroid or liver disease, (lymphocytic duodenitis, inadequate Down’s, Turner’s and William’s sampling or gluten, syndrome immunosuppressants) – Family members of individuals with confirmed CD (affects 10% FDR)- may – Failure to improve on gluten free diet justify biopsy even if sero-negative. (?incorrect diagnosis) Identifies patients for screening 1-3 yr?

– Gluten free diet commenced before serology/biopsy – patient unwilling to challenge – negative HLA excludes CD

Abdominal pain, rectal bleeding, diarrhoea and calprotectin • 14 yr old boy with 4 mo rectal bleeding, on toilet paper • FH of UC • Lots of anxiety in family • DDX – IBD, POLYPS, FISSURE

Joshi Ann Clin Biochem 2010 Davidson Ann Clin Biochem 2016 Duman Am J Emerg Med 2015 Wikipedia 2016 Abdominal pain, rectal bleeding, diarrhoea and calprotectin • Calprotectin (no MBS item) – Increased faecal secretion in – Soluble protein – 60% of soluble intestinal inflammation protein content of neutrophil • Inflammatory bowel disease cytoplasm during treatment and as marker – Bacteriostatic and fungistatic • Coeliac disease (untreated) (sequesters Mg and Zn) • Allergic colitis (infant) – Resistant to enzymatic degradation – • NEC, Cystic fibrosis, Colorectal measured in faeces cancer • NSAIDS • Bacterial (but not viral) gastroenteritis

Joshi Ann Clin Biochem 2010 Davidson Ann Clin Biochem 2016 Duman Am J Emerg Med 2015 Wikipedia 2016 Normal levels of stool calprotectin vary with age – increased in young

• Higher values below age 1 yr • Useful test but no MBS rebate at present • Above age of 1 yr • Out of pocket varies $50- – Extremely useful to identify intestinal mucosal inflammation 100

• In presence of rectal bleeding or CHRONIC diarrhoea – Normal excludes IBD Undifferentiated gut symptoms The take-home messages – The screaming baby and PPI’s – Treating Dientamoeba – or not? • THEY DON’T WORK • TRY NOT TO

– How to dose with PPI’s – Coeliac disease, serology and HLA • BEST DOSED BEFORE BREAKFAST testing • HLA DQ2/8 IS A USEFUL NEGATIVE – Abdominal pain, diarrhoea TEST and lactose intolerance • PRIMARY AND SECONDARY – Abdominal pain, rectal bleeding, LACTASE DEFICIENCY diarrhoea and calprotectin • CALPROTECTIN – A REALLY GOOD TEST TO IDENTIFY INFLAMMATION