Primary Care Approach to Celiac Disease

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?

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

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)

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

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 10-40 age group and beyond possibly related to longer breast feeding and later introduction of gluten

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

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

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

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

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”

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

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

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

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)

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)

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

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

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.

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 (2.6-5.5% risk)

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

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 +

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 +

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

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)

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

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

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