Celiac Disease SYED A. SADIQ, MD GASTROENTEROLOGY ASSOCIATE OF NORTH TEXAS .

Celiac Disease

SYED A. SADIQ, MDGASTROENTEROLOGY ASSOCIATE OF NORTH TEXAS

WWW.GANTGI.COM

CELIAC DISEASE

Issues for consideration

• What clinical presentation suggest CD

• How to screen and diagnose CD

• How to evaluate someone already on GFD

• Do we need to screen family members

• Follow up of patients with CD

• What to do with “Non responsive” CD

• Managing complications

• Potential new therapies

PREVALENCE OF CELIAC DISEASE

• Traditionally, highest in western Ireland (1:300), with lower in other European countries (1:1000) and even lower in USA (1:5000)

• Higher prevalence (1:100 – 1:300) in genetically susceptible population

• In USA less then 10 – 15 % of current cases of CD have been diagnosed as compere to over 50% in some other countries

SUSCEPTIBILITY FOR CELIAC DISEASE

General population of USA

Expression of HLA DR3-DQ2 or HAL

DR4-DQ*

Patient with Celiac disease

SUSCEPTIBILITY FOR CELIAC DISEASE

• Increased frequency of HLA haplotypes ( DR3-DQ2, DR4-DQ8)

• Other Factors involved:

• Other genetic influences (GWAS), Gene on chromosome 5, 16 and ? 6…

• Environmental factors: Drugs, Infections, Cross reactivity H. P

(Cytokines released during infection altering immunity)

PATHOPHYSIOLOGY OF CELIAC DISEASE

IBS CD

PATHOPHYSIOLOGY OF CELIAC DISEASE • The toxic component of the gluten molecule lies in the “PROLAMIN” portion ( Proline +

Glutamine)

• Prolamine containing food causing “CD” is present in

Wheat (Gliadin)

Rye (Secalin)

Barley (Hordien)

• Prolamine Containing food that DOES NOT causes “CD”

Oat (Avenine) ??? (Wheat cross reactivity)

Rice

Corn

PATHOPHYSIOLOGY OF CELIAC DISEASE

PATHOPHYSIOLOGY OF CELIAC DISEASE

PATHOPHYSIOLOGY OF CELIAC DISEASE

PATHOPHYSIOLOGY OF CELIAC DISEASE

CLINICAL PRESENTATION OF CELIAC DISEASE

• Classic “CD” of childhood

• Late onset : Non specific symptoms

• Dermatitis Herpetiformis

• Extra intestinal presentation ( Multiple, e.g undefined iron deficiency Anemia)

• Silent / Asymptomatic disease

• Latent or Potential “CD”

CLINICAL PRESENTATION OF CELIAC DISEASECLASSICAL PRESENTATION

PRESENT IN PEDIATRIC POPULATION

• Failure to thrive

• Weight loss

• Protuberant abdomen

• Bloating

• Diarrhea- steatorrhea

• Abdominal pain

• Dramatic response to gluten free diet

CLINICAL PRESENTATION OF CELIAC DISEASEVARYING FORMS

• Classical presentation is less common

• Average age of diagnosis is 5 th decade

• Seroprevalance M=F, Diagnosis F > M

• Other presentation are more common

Unexplained Iron deficiency Anemia

Osteoporosis

Obstetrical problems

Neuropsychiatric manifestation

Related autoimmune conditions

CLINICAL PRESENTATION OF CELIAC DISEASEADULTS : IBS V/S “CD”

• Altered bowel habit ( Diarrhea, constipation, combination)

• Bloating

• Dyspepsia

• Abdominal discomfort

• Heartburn

CLINICAL PRESENTATION OF CELIAC DISEASEDERMATITIS HERPETIFORMIS

Pruritic Papulovesicular leions ( IgA deposit at he dermal-Epidermal level)

Almost all patient have GI symptoms

Topical treatment does not help. GFD resolve all skin lesions

CLINICAL PRESENTATION OF CELIAC DISEASEOBSTETRIC/GYNECOLOGICAL

• Delayed Menarche

• Earlier Menopause

• Increased prevalence of early amenorrhea

• Infertility

• Higher miscarriage rate

• Increased IUGR

• Lower birth weights

• Premature birth

CLINICAL PRESENTATION OF CELIAC DISEASENEUROPSYCHIATRIC & BEHAVIORAL

Folate and Vit-B12 deficiency

• Ataxia

• Peripheral neuropathy

• Schizophrenia

• ADHD

• Irritability / cognitive disorder

• Depression

• Migraine

• Cerebral calcifications

CLINICAL PRESENTATION OF CELIAC DISEASEASSOCIATED CONDITIONS

• Primary sclerosing cholangitis

• Autoimmune cholangitis

• Primary biliary cirrhosis

• Non specific “Transaminases” (LFT) elevation ( up to x 5)

• Progressive systemic sclerosis (Scleroderma) / Sjogren’s syndrome / RA

• Hashimoto thyroiditis (Autoimmune thyroid disorder)

• Type I Diabetes

• Microscopic colitis

CELIAC DISEASEDIAGNOSIS

CELIAC DISEASEDIAGNOSIS

• Intestinal histology “GOLD STANADARD” in diagnosing Celiac Disease (Characteristic histological changes)

• Serology

• Clinical: some cases histological response to a “GFD”

• Rarely necessary to observe clinical and histological response to “Gluten Challenge”

• Dermatitis Herpetiformis: a classical skin biopsy is sufficient to make diagnosis

CELIAC DISEASEDIAGNOSIS

Marsh Classification

CELIAC DISEASEDIAGNOSIS

NORMAL

Celiac disease

CELIAC DISEASESEROLOGY DIAGNOSIS

Test Sensitivity Specificity

AGA IgA < 80 % ( 50 % range) > 80 % in most

AGA IgG Variable Non specific

EMA IgA 96-97 % 100 %

tTG IgA 90-98 % 95-98%

tTG IgM 40% (Useful in IgA def) 98%

Important to check serum total IgA level in all patients

CELIAC DISEASEDIAGNOSIS

What are the best serological test for screening:

Overall, tTG IgA remain the best recommended test

EMA IgA is helpful if positive

Anti Glidan Ab, no longer used as first line.

Always check total IgA, to avoid false negative results

CELIAC DISEASE DIAGNOSIS GENETICS

• HLA DQ screening test: PCR of RNA extracted from cells.

• DR3-DQ2 or DR5/7-DQ2---90-95 %

• DR4-DQ8 – 5-10 %

Only HLA DQ2 or DQ8 are at risk for CD

CELIAC DISEASE DIAGNOSIS GENETICS

WHO TO TEST:

• Close relative of patients with confirmed CD (Wishing to know if they are at risk)

• Patient on Gluten free diet who are candidate to undergo a gluten challenge to confirm CD

• Equivocal histology and serology, Suspect CD

How often to test: Once in life time

CELIAC DISEASE PROPOSED NEW CRITERIA FOR DIAGNOSIS

Four out of Five are sufficient to diagnose CD:

• Typical symptoms of CD

• High titers of serum CD IgA class autoantibodies ( tTG > 10 X UL, option to diagnose without biopsy)

• HLA DQ2/DQ8 genotype

• Celiac enteropathy by small bowel biopsy (GOLD STANDARD)

• Response to CFD

CELIAC DISEASEDIAGNOSIS ALGORITHM

CELIAC DISEASE MANAGEMENT

• Goal: Return of normal health and prevent complications

Life long GFD

Low lactose diet

Nutritional supplement (Calcium, Vit-D, Iron, Folate and other micronutrients)

Utilize registered dietician

Encourage patient to gain self knowledge, by joining local chapter of various Celiac organization

CELIAC DISEASE MANAGEMENT

TREATMENT = GLUTEN FREE DIET • Non compliance is the biggest issue

• Eating out of home

• Peer pressure in children

• Less acceptable taste

• Accidental ingestion of Gluten

• Cost 1-3 times higher

• GFD ameliorate complication of CD

• Unclear how much if any is safe ( New FDA guideline 20 PPM (up to 10 mg/day is safe)

• Labeling in USA for wheat since 2008 (Gluten free product since 2008)

CELIAC DISEASE UNTREATED

• Manifestation of malabsorption ( Anemia , Osteoporosis, neurological symptoms)

• Decrease QOL

• Infertility, Miscarriage, IUGR

• Malignancy ( ~ 4 times general population)

• Slight increase in mortality

• May progress to refractory disease

CELIAC DISEASE RESPONSE TO TREATMENT

• Clinical improvement in 2 weeks in 70 %, and by 6 weeks > 90 %

• Serologic improvement by 4-6 weeks

• Weight restoration

• Constipation is quite common ( Diarrhea in disease state)

• Histological improvement is last ( May take up to 2 years or more)

CELIAC DISEASE FOLLOW-UP

• Correct nutritional deficiencies

• Follow tTG IgA initially until normalize, Then Check tTG IgA every year or two thereafter

• Repeat DEXA scan ever 2 year if abnormal

• In persistent symptoms for over a year or so check radiological studies and +/- repeat EGD ( For lymphoma surveillance)

• Promote general good health ( Exercise, maintain BMI and adhere to screening)

CELIAC DISEASE NON RESPONDER

• Celiac disease and Microscopic colitis:

• 4-5 % have coexisting MC

• Older group of patient

• More severe CD ( Severe mucosal atrophy)

• High morbidity

• Coincident disorder:

• Lactose deficiency

• Pancreatic insufficiency

• Small intestinal bacterial overgrowth (SIBO)

• IBS

CELIAC DISEASE REFRACTORY CELIAC DISEASE

• Despite strict GFD for 6-12 months: Severe villous atrophy with persistent malabsorption

• Rare with low prevalence

• Primary form – No initial response to GFD

• Secondary form ( More common): After initial response to GFD

• tTG IgA remain normal if patient is on GFD

• Risk for RCD: old age, Two DQ2 alleles

• Poor prognosis: 40-50 % mortality rate ( 50 % patient dies within 3-5 years of diagnosis)

• Higher incidences of intestinal lymphomas

CELIAC DISEASE REFRACTORY CELIAC DISEASE

CELIAC DISEASE REFRACTORY CELIAC DISEASE

Treatment options: • Anti-Inflammatory agents: Mesalamine

• Immune modulating therapies: e.g. Corticosteroid therapy, Anti TNF

• Nutritional support: TPN, Hypoallergenic-elemental formula

• Hematopoietic Stem cell transplantation

• Anti IL-15

CELIAC DISEASE PREVENTION AND FUTURE

• Prevention: • Affective screening

• Different times of introduction of “Gluten” in to the infant diet

• Modify Gluten molecules: • Endopepetidases: “KUMAMOLISIN-AS” ( KUMA-MAX) break the gluten

molecule, so it is no longer immunogenic

• Immunotherapy: • Block: tTG expression, HLA or T cell response

CELIAC DISEASE TAKE HOME MESSAGE

• CD is not rare ( 1 in 100-300)

• It present in many different ways and is associated with various autoimmune diseases

• Increase reporting of Gluten sensitivity or Gluten Intolerance

• Diagnostic test perform well but have some limitations

• Gluten free diet remain the main stay of successful treatment

• Potential new therapies are being investigated

• Multiple causes of nonresponsive celiac disease