Undifferentiated Gut Symptoms

Prof Tony Catto-Smith

Director of Gastroenterology

Lady Cilento Children’s Hospital

Undifferentiated gut symptoms

– The screaming baby and PPI’s

– How to dose with PPI’s

– Abdominal pain, diarrhoea

and lactose intolerance

– Treating Dientamoeba – or not?

– Coeliac disease, serology and HLA

testing

– 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

0

1

2

3

4

2 3 4 5 6 7 8 9 10 11 12

Age in weeks

Hou

rs o

f cry

ing

/ 24

hrs

Crying in infancy

Median

Upper quartile

Lower quartile

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

Drug therapy

• Prokinetics

– Cisapride

• Antiacid drugs

– H2 receptor antagonists

(ranitidine)

– PPI’s

The screaming baby and PPI’s

• PPI’s ineffective

Gieruszczak-Bialek J Pediatr 2015

No Effect of Proton Pump Inhibitors on Crying and Irritability in Infants: Systematic Review of Randomized Controlled Trials

How to dose PPI’s

– Proton Pump Inhibitors

broken down in acid -

best absorbed from alkaline

intestine (enteric coating)

– T ½ 1.5hr

– Tmax 1-3hr

– Concentrated in acid

compartments (parietal cell)

– HAS TO BE ACTIVELY

SECRETING ACID

• Covalently bind to proton pump

(H+, K + ATPase) in canaliculus

• Acid inhibition lasts up to 24hr

• Takes 18hr for synthesis of new

proton pumps

Katzung 2009

How to dose PPI’s • Bioavailability

– decreased 50% by food

– need to be given on empty stomach

– In fasting state only 10% proton

pumps are actively secreting acid and

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

• PPIs best taken approx 1hr before

a meal (usually breakfast) so peak

serum concentration coincides

with maximal activity of proton

pump secretion

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 disinfectant

• Strong evolutionary biological correlation between gastric acidity and “bacterial risk” of diet (eg carnivores vs herbivores) Beasley PlosOne 2015

• Less acid neonatal stomach may allow easier microbial entry to gut – a good thing

• Long term PPI use – Has variable effects on

bacterial diversity

– Specifically influences 3 bacterial strains which have metabolic products which:-

– Upregulate bacterial genes associated with epithelial invasion 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

and 4 days of loose

stools

• PCR showed

Dientamoeba fragilis

• Dientamoeba linked to

intermittent diarrhoea, abdo

pain, nausea, anorexia, malaise,

fatigue, eosinophilia

• 2013 – detection changed from

microscopy to multiplex PCR

(Giardia lamblia,

Cryptosporidium spp, Entamoeba

histolytica, Dientamoeba fragilis,

Blastocystis spp)

Bowen 2016

Roser 2014

Garcia 2016

Treating Dientamoeba – or not?

• Significant concerns regarding D

fragilis and Blastocystis – role as

putative GI pathogens

controversial and possibly

unproven.

• Both may be colonising flora –

prevalence rates about 17% esp

in children under age 10yr – 2nd

peak at 30-40 yr of age

• Best evidence in children – – double blind randomised

controlled trial showed no

difference in symptoms between

treatment and placebo for

dientamoebiasis

– though did partially eradicate

(62% at 2 wk, 25% 8wk)

– 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

and Blastocystis controversial and

unproven

• Testing leads to inappropriate

medical consultations,

unnecessary use of

antimicrobials, anxiety for

families

• ASID and RCPA recommend to practitioners

– Do not request stool pathogen assessment (including

multiplex faecal PCR) on formed stool samples;

– do not request specific testing for D.

fragilis or Blastocystis spp.;

– should consider the markedly increased sensitivity with

unclear significance in their clinical interpretation of

pathology laboratory reports of detection of these

parasites;

– adhere to comments appended to the laboratory report

regarding the significance of D. fragilis and Blastocystis spp.

and avoid specific treatment and further testing;

– discuss with a paediatric or adult infectious diseases

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 testing

– IgA tissue translutaminase 6 (NR<7)

– IgG deamidated antigliadin 5 (NR<7)

– Total IgA 0.9 (normal range)

– HLA DQ2 present

– HLA DQ8 not present

• What does this mean?

• Coeliac prevalence approx 1/80

• HLA DQ2/8 status of coeliacs

– 90% coeliacs have HLA DQ2

– 5% HLA DQ8, 5% variations on HLA DQ2

• HLA DQ2/8 genes in general population

– 65% of first degree relatives of CD

– 30-40% Western population (56% Vic)

• Predictive value of HLA testing

– PPV 3.4% general population (CD prev 1%)

– 28% high risk population (CD prev 10%)

– 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

or equivocal HLA useful to triage

(lymphocytic duodenitis, inadequate

sampling or gluten,

immunosuppressants)

– Failure to improve on gluten free diet

(?incorrect diagnosis)

– Gluten free diet commenced before

serology/biopsy – patient unwilling to

challenge – negative HLA excludes CD

– At risk groups but not all (type 1 DM,

autoimmune thyroid or liver disease,

Down’s, Turner’s and William’s

syndrome

– Family members of individuals with

confirmed CD (affects 10% FDR)- may

justify biopsy even if sero-negative.

Identifies patients for screening 1-3 yr?

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)

– Soluble protein – 60% of soluble

protein content of neutrophil

cytoplasm

– Bacteriostatic and fungistatic

(sequesters Mg and Zn)

– Resistant to enzymatic degradation –

measured in faeces

– Increased faecal secretion in

intestinal inflammation

• Inflammatory bowel disease

during treatment and as marker

• Coeliac disease (untreated)

• Allergic colitis (infant)

• NEC, Cystic fibrosis, Colorectal

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

Fiona Davidson, and Robert J Lock Ann Clin Biochem 2016;0004563216639335

Copyright © by Association for Clinical Biochemistry

Normal levels of stool calprotectin vary with age –

increased in young

Fiona Davidson, and Robert J Lock Ann Clin Biochem 2016;0004563216639335

Copyright © by Association for Clinical Biochemistry

Calprotectin higher in infancy

Faecal calprotectin

• Higher values below age 1 yr

• Above age of 1 yr

– Extremely useful to identify

intestinal mucosal inflammation

• In presence of rectal bleeding or

CHRONIC diarrhoea

– Normal excludes IBD

• Useful test but no MBS

rebate at present

• Out of pocket varies $50-

100

Undifferentiated gut symptoms

The take-home messages – The screaming baby and PPI’s

• THEY DON’T WORK

– How to dose with PPI’s

• BEST DOSED BEFORE BREAKFAST

– Abdominal pain, diarrhoea

and lactose intolerance

• PRIMARY AND SECONDARY

LACTASE DEFICIENCY

– Treating Dientamoeba – or not?

• TRY NOT TO

– Coeliac disease, serology and HLA

testing

• HLA DQ2/8 IS A USEFUL NEGATIVE

TEST

– Abdominal pain, rectal bleeding,

diarrhoea and calprotectin

• CALPROTECTIN – A REALLY GOOD

TEST TO IDENTIFY INFLAMMATION