Integrating Novel Diagnostic Strategies

into Practice: Key Points

Stanley Cohen, MD

Emory University

Atlanta, Georgia

Disclosure

Luminal fluid

Research: Janssen, Covidien/Medtronics, AbbVie,

AstraZeneca and QOL

Speaker: Janssen, Prometheus, AbbVie, Nestles Institute,

Nutricia and Lupin

Consultant: Janssen, Covidien/Medtronics, AbbVie,

AstraZeneca and QOL

Shareholder: Nutrition 4 Kids

Advisor: Nutrition 4 Kids

MEDICATION LABS PROGRESS

NOTES

OTHER

Patient Case

HISTORY

& PE

17 year-old female

HPI

• Originally had issues with

GERD, responded to a PPI

• Periumbilical pain

intermittently, often waking her

and often with diarrhea, can

last for days

• Increased with stress at school

• Somewhat better with an

anticholinergic prn

PMH

• On BCP, gabapentin,

and iron

Labs

• CBC, ESR, CMP, RAST,

tTG, thyroid, lipids –all wnl

• Stool studies requested,

but not performed

• GD / colon 2 yrs prior --nl

Searching for IBS: Differential Diagnoses

Carbohydrate maldigestion

Celiac disease

Food allergy

Bile acid diarrhea

Non-celiac gluten sensitivity

Microscopic colitis

MEDICATION HISTORY LABS OTHER

Patient Follow-Up

• EGD/colonoscopy visually and histologically normal

• Disaccharidases

Lactase 0.0 (abnormal < 15)

Sucrase 19.4 (abnormal <25)

Maltase 71.0 (abnormal < 100)

Palatinase 4.0 (abnormal < 5)

Patient diagnosed with pan-disaccharidase deficiency

with hypolactasia

PROGRESS

NOTES

Understanding Carbohydrate Malabsorption

Amylase

Sucrase Lactase Maltase

Polysaccharides Disaccharides Monosaccharides

lactose ● isomaltose ●

maltose ● sucrose fructose ● glucose ●

galactose

starch ● glycogen

Palatinase

(isomaltase)

1. Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S13. 2. Canani RB et al. Nutrients. 2016;8:157.

Clinical Consequences of Carbohydrate

Malabsorption

Luminal fluid

Diarrhea

Pain

Gas

Bloating

1. Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S13. 2. Canani RB et al. Nutrients. 2016;8:157.

Maltase

• Used to approximate glucoamylase

• Not explicit to maltase, more related to SI

(75%) than MGAM (only 25%)

Palatinase

• Used to approximate isomaltase

• SI responsible for most isomaltase

activity (>70%)

Lactase

• Specific to lactose, but lactase deficiency

can be as high as 50% after 5 years

of age

Sucrase • ≥85% specific to sucrose

Key Intestinal Disaccharidases

MGAM, maltase-glucoamylase; SI, sucrase-isomaltase.

Quezada-Calvillo R et al. J Nutr. 2008;138:685-692.

Digests table sugar

Digests milk sugar

Digests starch

Potential Etiologies of Key

Disaccharidase Deficiencies

Secondary causes2

Genetic Sucrase-Isomaltase

Deficiency (GSID)

Congenital

lactase

deficiency

Autosomal

recessive (CSID)

Symptomatic

heterozygous carriers

Celiac disease

Bacterial overgrowth

IBD

Allergic enteropathy

Genetic1,2

Other (eg, mucositis)

Acute gastroenteritis

Giardiasis

Compound

heterozygotes

CSID, congenital sucrase isomaltase deficiency; IBD, inflammatory bowel disease.

1. Cohen S. Molecular Cellular Pediatr. 2016;3:5. 2. Naim HY et al. J Pediatr Gastroenterol Nutr. 2012; 55(Suppl 2):S13-S20.

The Spectrum of GSID Phenotypes

Phenotypes Enzymatic activity

IV, VI Active sucrase, active isomaltase

V Active isomaltase, absent sucrase

VII Decreased sucrase, absent

isomaltase

I, II, III Completely inactive

Naim HY et al. J Pediatr Gastroenterol Nutr. 2012; 55(Suppl 2):S13-S20.

Presenting Symptoms of GSID

95

85

66 66 62 60

34

18

0

10

20

30

40

50

60

70

80

90

100

Diarrhea Bloating/

gas

Abdominal

pain

Irritability Diaper

rash

Failure to

thrive

Nausea/

vomiting

IBS

Pa

tie

nts

, %

Presenting Symptoms in GSID (N=65)

Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S13.

Symptoms of GSID: Infants vs. Adults

Shorter length of GI tract

Increased consumption of high-carbohydrate diet (juices, baby food

fruits/vegetables, cereals)

More rapid intestinal and colonic transit

↓ time available for alternative carbohydrate digestion pathways

Changes in bowel flora may

alleviate symptoms

Diet control

Carrier status, milder variants

Ileal hyperproliferation

May be misdiagnosed as IBS, lactose

intolerance

Symptom severity more severe less severe

1. Treem WR. J Pediatr Gastroenterol Nutr. 1995;21:137-42.

2. Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S13.

Methods to Diagnose GSID

Small bowel

biopsy1,2

Genetic

test2

Sacrosidase

response dose2,3

Breath

tests2

Stool

tests1,2

• Definitive

diagnosis

• Often sent to

specialty lab

• Buccal or saliva

• Detects 37

polymorphisms in

SI gene

• Determined by

decrease in GI

symptoms

Sucrose

hydrogen or 13C-sucrose

• pH, osmolality,

reducing sugars

• Not specific for

sucrose

malabsorption

z

SI, sucrase isomaltase

1. Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S13.

2. Cohen S. Molecular Cellular Pediatr. 2016;3:5.

3. Puntis JW and Zamvar V. Arch Dis Child. 2015;100(9):869-871.

Hydrogen-Methane Breath Test for GSID

• Indirect test for CHO

malabsorption (not specific for

GSID)1-3

• Reduced CHO diet 24 hours

before test and 12 hours of

fasting4

• Catch breath into 6 tubes over

3 hours after ingesting sucrose

solution4

• May produce symptoms in GSID

patients due to consumption of

sucrose1,2

Sucrose

load

Colonic

fermentation

H2 &/or

methane

CHO, carbohydrate; GSID, genetic sucrase-isomaltase deficiency.

1. Ghoshal UC. J Neurogastroenterol Motil. 2011;17(3):312-317.

2. de Lacy Costello BPJ et al. J Breath Res. 2013;7:024001.

3. Simren M and Stotzer P. Gut. 2006;55:297-303. 4. Sucrose tolerance/malabsorption breath test. Commonwealth Laboratories Inc. Salem, MA.

How Common Is

Disaccharidase Deficiency?

55% No

disaccharidase

deficiency

45% ≥1 disaccharidase

deficiency

75%

21%

4% Other

Sucrase deficiency

(9.4% of biopsies)

Lactase deficiency

(34.7% of biopsies)

Analysis of Mucosal Biopsies (N=27,875)

Nichols BL et al. J Pediatr Gastroenterol Nutr. 2012;(Suppl 2):S28-S30.

Primary Results

44 (60%) Pan-disaccharidase

25 (34%) with lactase deficiency

4 (5%) isolated

73 (7.6%) Sucrase deficiency

430 (45%) Lactase deficiency only

963 (18%) Disaccharidase testing

5,362 EGDs

Pertinent Indications

62

10 5 4

0.1 0

10

20

30

40

50

60

70

n=3,344 n=529 n=266 n=235 n=4

Abdominal

pain

Diarrhea Nausea Weight loss Bloating

Most Patients With SD Had

Multiple Symptoms

Symptoms n (%)

Abdominal pain 49 (78%)

Diarrhea 27 (43%)

Constipation 21 (33%)

Nausea 19 (30%)

Vomiting 15 (24%)

Weight loss/failure to thrive 15 (24%)

Most Common Presenting Symptom

Note: Excludes patients with blood in stool (n=8) and missing (n=2).

Normal vs Abnormal Biopsies

Normal Abnormal P-Value *

N 30 33

Age 13.0 ± 4.9 10.8 ± 4.0 < 0.05

BMI 63 + 34 46 + 32 < 0.05

Diarrhea week 20 13 < 0.05

Isolated sucrase deficiency 3 1

Sucrase/lactase deficiencies 25 4 0.08

Pan-deficiency (sucrase, lactase,

maltase, palatinase) 19 15

*P values similar when all patients included.

Sucrase Deficiency By Type

Pan-Disaccharidase

Deficiency

Lactase/ Sucrase

Deficiency

Isolated Sucrase

Deficiency P-Value

N 44 15 4 63

M/F 31/13 9/6 2/2 –––

Age 12.5 + 4.2 12.2 + 4.2 4.7 + 6.1 0.1

BMI, % 52.8 + 33.5 53.1 + 34.3 98.5 + 0.7 ≤ 0.0001

Sucrase activity 15.8 + 5.5 16.9 + 4.3 5.5 + 6.0 0.08

Abdominal pain 35 13 1 –––

Diarrhea 16 8 3 0.07

Nausea 11 7 1 0.28

Constipation 10 5 0 –––

FTT / Weight loss 12 3 0 –––

Normal histology 19 11 3 0.08

Most Common Presenting Symptom

–––, unable to calculate significance value. FTT, failure to thrive.

Disaccharidase Test Results

51.4 47.5

44.4

21.4

37.5 36.8 37.2

25

75

47.4 54.5

42.5

33.3

12.5 5.5

0 7.1

12.5 6.6 7

0

50

7.2 13.6

10.4 11.1

0

10

20

30

40

50

60

70

80

Treating

MD 1 2 3 4 5 6 7 8 9 10 11 12 13

N 148 645 557 164 212 205 203 181 27 449 92 213 248

% Tested 48.6 64.5 1.6 8.5 3.8 51.7 21.2 4.4 14.8 21.6 23.9 62.9 10.9

Disaccharidase Deficiency Among Patients with Abdominal Pain

Lactase deficient Sucrase deficient

Pa

tie

nts

, %

Sucrase Deficiency

P=0.09

P=0.001

Integrating Novel Diagnostic Strategies into Practice

Key Points

• Symptoms of disaccharidase deficiency can mimic IBS

• Sucrase deficiency is a genetic condition

• The different symptom patterns may be related to the

different genotypes

• Testing for diasaccharidase deficiencies is best

accomplished by breath testing or duodenal biopsies