1. Primary Care Approach to Celiac Disease

2. What Celiac Disease Is
Gluten-sensitive enteropathy/celiac disease/non-tropical sprue/celiac sprue – all refer to same condition
Genetically linked
HLA DQ2 or DQ8 – present in 35-40% of North Americans
Must have one of these genotypes to have sprue (only 2-5% of those with one of them get sprue)
Question: Why don’t the other 95-98% get sprue?

3. Modifiers of Incidence and Severity of Celiac Sprue
Increase risk or worsen course – children effected
Early exposure to gluten
Early enteropathic virus exposure (Rotavirus)
Change in bowel flora (? early antibiotics)
Short duration of or no breastfeeding

4. Modifiers of Incidence and Severity of Celiac Sprue
Decrease risk
Breastfeeding
Begin early and continue especially during ages 4-7 months
Do it while introducing gluten
Continue longer
Delay introduction of gluten
Beginning between 4-7 months when immune response is “tolerogenic”
Prevent infections rather than treating them - ? avoid antibiotics + immunize (?Rotavirus)

5. What Celiac Disease is (cont.)
Food “allergy” / autoimmune disease in those genetically susceptible
Gluten = one of commonest ingredients in human diet
Gliadin fraction incompletely cleaved in small bowel
Resultant peptides get into lamina propria through leaky intercellular junctions
Deamidated by tTG – negative charge
Affinity for HLA DQ2/8 molecules on APC’s which activates CD4 T lymphocytes – release of proinflammatory cytokines
B lymphocytes activated – gliadin and tTG antibodies

7. What Celiac Disease is Not
Uncommon – up to 1% of US population
Present only in Caucasians of Northern European extraction
Seen mostly in children
most common in age group and beyond
possibly related to longer breast feeding and later introduction of gluten

8. What Celiac Disease is Not (cont.)
Most often symptomatic in classic sense when diagnosed
atypical presentations
screening results – 7:1 previously unknown vs known
Stable in terms of prevalence – has increased 4X in past 45 years – possibly related to change in wheat and bread processing and early childhood infections
Benign if mild and therefore undiagnosed – 4x mortality

9. Diagnosis - Clinical Classic presentation
Tip of the Iceberg - diarrhea, weight loss, malabsorption
Awareness of different presentations
Silent/subclinical – few symptoms, +tTG aby, abnormal biopsy
Latent - no/few symptoms, + tTG aby, normal biopsy,
Refractory
Atypical

10. Atypical presentations (% risk)
GI – IBS symptoms (4-5%)
Extra intestinal
Abnormal LFT’s (1.5-9%)
Iron deficiency anemia (2-15%)
Osteoporosis (1-3%)
Arthritis
Neuropsychiatric diseases
Ataxia, depression, anxiety, epilepsy, headaches
Unexplained Infertility (2-4%)
Chronic fatigue syndrome (2%)
Pancreatitis – acute and chronic; macroamylasemia

11. Relationship between Celiac Disease (CD) and IBS
4-5% prevalence of CD in IBS patients
Gluten sensitivity (GS) – atypical abnormal immune response to gluten
tTG negative but HLA DQ2 or 8 +
May have mild biopsy change only – increased lymphocytes
IBS symptoms may happen in GS with only these mild changes

12. Relationship between Celiac Disease (CD) and IBS
GS may be a middle ground overlap between IBS and CD
May respond to gluten-free diet
“Between CD and IBS: The No Man’s Land of GS”

13. Associated Conditions (% risk)
Autoimmune endocrine disorders
Diabetes mellitus, type 1 (2-8% - highest in children)
Thyroid disease (3%)
Adrenal disease
Autoimmune connective tissue disorders
Sjogrens RA
Lupus
Liver diseases
PSC
PBC (0-6%)
Autoimmune hepatitis (3-6%)
Autoimmune cholangitis
Elevated AST/ALT

14. Associated Conditions - continued
Skin
Dermatitis herpetiformis
Other GI
Microscopic colitis (15-27%)
GI lymphomas and other cancers
3x risk of small bowel lymphomas in untreated CD
Risk falls to that of normal population after on gluten-free diet for 5 years
Miscellaneous
IgA deficiency
IgA nephropathy
Down’s (3-12%)
Turner’s

15. Diagnosis - Labs
tTG IgA antibody ***
Sensitive (95-98%)
Specific (90-98%)
Relatively less expensive ($11.20)
False negative – IgA deficiency
False positive – autoimmune diseases, liver disease, inflammatory bowel disease, CHF
DGP IgG (deaminated gliadin peptide) antibody – if IgA absent

16. Diagnosis – Labs (cont.)
Endomysial antibody
Sensitive (100%)
Specific (90-97%)
More expensive ($55.00)
Gliadin antibodies
Too non-specific and less sensitive
Genetic testing – HLA DQ2,8 ($187.45)

17. Diagnosis - Small Bowel Biopsy
Gold standard
Disease can be patchy
Findings not 100% specific
Especially true of mild changes – NSAIDS, H. pylori, Crohn’s, gluten sensitivity (GS)

18. Treatment Gluten free diet Encouragement
Don’t empirically try without diagnosis
IBS patients can feel some better off gluten too
Needs life long commitment to diet if has sprue
Strict diet can decrease and even eliminate increased risk of GI lymphomas and other GI cancers
Strict diet may help associated diseases as well
Nutrition consult very important
Encouragement

19. Difficulties of Diet $ Social/family Boring Tricky – additives,etc
Increase fat and calories to make interesting – weight gain
Nutrient and fiber deficient
Reduction of beneficial gut bacteria

20. Follow Up After Dietary Treatment
tTG in 6 months to see if normalizes – may not correlate with biopsies or symptoms
F/U small bowel biopsy done after 6 months of gluten-free diet if clinically not doing well. Not critical if asymptomatic and tTG is negative
DEXA scan
See someone on care team every year as well as nutritionist – more frequently if other related associated diseases or if not doing well.

21. Approach to Patients - Primary Care
High index of suspicion
Typical symptoms
Atypical presentations ***
Associated diseases ***
tTG blood test – check IgA level too
If + send to GI for EGD and small bowel biopsies
Screening – not general mass screening but family relatives of patients with sprue
1st degree relatives (10-15% risk)
2nd degree relatives ( % risk)

22. Challenging Scenarios
Patient already on a gluten-free diet
False + tTG
Abnormal small bowel biopsy with negative tTG

23. What about the Patient already on a Gluten-free Diet?
Accurate diagnosis of CD is important
Beneficial response to gluten-free diet does not make the diagnosis of CD – overlap with IBS and GS
What to challenge with?
Hopefully 4 slices of whole wheat bread/d
For how long?
6 weeks and recheck tTG to see if now +

24. Gluten Challenge Follow Up
If tTG negative at 6 weeks, recheck at 3 and 6 months and if no symptoms and tTG negative at 6 months likely does not have CD
When to do small bowel biopsy?
When tTG becomes +

25. False Positive tTG Autoimmune diseases Liver disease
Inflammatory bowel disease
CHF
Solution: small bowel biopsy, ?genetic testing

26. Abnormal Small Bowel Biopsy with Negative tTG
False negative tTG – really has celiac sprue (classic pathology)
IgA deficiency
Partially treated celiac sprue – takes proximal small bowel longer to heal than more distal parts
Other causes (non-classic pathology): NSAIDS, Crohn’s, H. pylori, gluten sensitivity (GS)

27. When to Consider Genetic Testing
tTG unreliable – IgA deficiency
Patient off gluten and won’t go back on or gets too sick if goes back on
To avoid unnecessary endoscopy
Children
+ family history of celiac sprue but negative tTG

28. Future Treatment
Alter gluten in wheat, barley, and rye to make it less immunogenic: enzymes, bacterial fermentation, genetic manipulation
Oral enzymes to break down gluten – less immunogenic
Complexing gliadins in gut – decreases gliadin digestion

29. Future Treatment Sealing tight junctions
Interfering with immune recognition
tTG/DQ2/DQ8 inhibitors
Restoring immune tolerance toward gluten
Vaccination with toxic gluten peptides
Dermal inoculation with hookworm antigen
Biologic agents/bone marrow transplants