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Canadian Celiac Association Annual Conference

May 25-26, 2012 Delta Grand Okanagan Resort

Kelowna BC

Dentistry and Celiac Disease Prof. Hardy Limeback PhD DDS

University of Toronto

http://www.celiac.org/images/stories/PDF/are-you-the-one.pdf

Celiac Disease prevalence = 0.75% of the population OR 8 people out of 1000

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Great Source of Information

Only 3% to 5% of individuals with Celiac Disease are diagnosed Conditions that tend to mask or divert a diagnosis of celiac disease include dyspepsia, IBS, inflammatory bowel disease (IBD), tropical sprue, constipation, chronic fatigue, and various neurologic syndromes Source

Celiac Disease Coeliac Disease, Celiac Sprue, Nontropical Sprue, Gluten-Sensitive Enteropathy Cara L Snyder, MS, CGC, Danielle O Young, MS, CGC, Peter HR Green, MD, and Annette K Taylor, MS, PhD, FACMG.

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J Clin Gastroenterol. 2010 Mar;44(3):191-4.

Dr. Ted Malahias

www.celiacdiseasecenter.org

Celiac Enamel Hypocalcification looks like dental fluorosis..... How can you tell the difference?

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Kaukinen K, Collin P, Mäki M. 2007. Latent coeliac disease or coeliac disease beyond villous atrophy? Gut 56: 1339-1340

Enamel 96% mineral

Dentin 70% mineral

Cellular Cementum ~ 65% mineral

The Tooth

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Mechanical and chemical destruction dental hard tissues

Physical properties of Dental hard tissues

-dentin has proteins, tubular spaces, small crystals and can flex

-enamel is crystalline, has very large crystals and cracks easily… but is very hard

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Meckel et al., Arch. Oral Biol. 1965

Ultrastructure of Enamel

• Enamel is the hardest, most highly mineralized biomaterial •>95% inorganic carbonated hydroxyapatite matrix • more resistant to fracture than geological apatite crystals (indicating how important biomineralization is) • Meshwork of interwoven crystal prisms that grow as ribbons/rods • Inter-rod space contains organic components

Fincham et al., J.Struct. Biol. 1999

How enamel forms The developing tooth

http://www.youtube.com/watch?v=5kRTtTYhtCU

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Enamel Formation: where things can go wrong

• Lack of calcium (hypocalcemia, Vitamin D deficiency)

• Enamel protein matrix malfunction

(e.g. defective amelogenin)

• Defective enzymes that remove enamel proteins (MMP20, kallikrein)

• Injury to the developing tooth bud follicle

Formation of Enamel

Injury here = hypoplasia Injury here = hypocalcification

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Fincham AG, et al (1994) J Struct Biol, 112, 103-109.

Du et al., Science 2005

Proteases in the Enamel Matrix

• Kallikrein-4 (KLK4, EMSP-1, prostase) – Serine proteinase family (i.e. trypsin, chymotrypsin) – Expressed during maturation stage – Gene located on chromosome 19q13 – Mutations linked with AI in humans

Degradation of enamel proteins is required for crystal growth (mineralization) and is achieved by 2 enzymes

• Enamelysin (matrix metalloproteinase-20; MMP-20) a Zinc-dependent metalloproteinase

– MMP family (i.e. collagenase, gelatinase, stromelysin) – Expressed during late secretory and early maturation stage – Localized on chromosome 11q22 – KO mice show AI phenotype – Substrate specificity for amelogenins

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Are CD patients deficient in zinc?

• Tran CD, Katsikeros R, Manton N, Krebs NF, Hambidge KM, Butler RN, Davidson GP. Zinc homeostasis and gut function in children with celiac disease. Am J Clin Nutr. 2011 Oct;94(4):1026-32.

NO

• Botero-López JE, Araya M, Parada A, Méndez MA, Pizarro F, Espinosa N, Canales P, Alarcón T. Micronutrient deficiencies in patients with typical and atypical celiac disease. J Pediatr Gastroenterol Nutr. 2011 Sep;53(3):265-70.

YES

pH Oscillations During Enamel Maturation

Smith (1998) Crit Rev Oral Biol Med 9:128-161

Smooth-

ended Ruffle-

ended

Carbonic anhydrase is also essential for controlled mineralization

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What Do Celiac Teeth Look Like?

Hypocalcification

vs

Hypoplasia

Aguirre et al. (1997) Dental enamel defects in celiac patients. Oral Surg Oral Med Oral Path Oral Radiol Endod 87:646-650.

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Enamel defect classification in Celiacs (according to Aine et al, 1990)

Hypocalcification

Hypoplasia Hypoplasia

Hypoplasia

GRADE I

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GRADE II

GRADE III

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GRADE IV

Nikiforuk G, Fraser D. (1981)

The etiology of enamel hypoplasia:

a unifying concept.

J Pediatr. Jun;98(6):888-93.

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http://www.smilemichigan.com/Portals/1/Journal%20Flash/October%202011/index.html

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Differential Diagnosis of Enamel Lesions

Systemic and Local Factors

Systemic -genetic problems amelogenesis imperfecta,

epidermolysis bullosa pseudohypoparathyroidism taurodontism

heart disorders, unilateral facial hypoplasia hypertrophy

-infectious diseases, -neurological disturbances, -endocrinopathies, -nutritional deficiencies, -nephropathies, -enteropathies, -liver diseases

DEVELOPMENTAL ENAMEL DEFECTS NOT RELATED TO CELIAC ENAMEL PROBLEMS

Source: Pindborg JJ. Int Dent J. 1982 Jun;32(2):123-34.

-inborn errors of metabolism, galactosaemia,

phenylketonuria, alkaptonuria, erythropoietic porphyria primary hyperoxaluria

-neonatal disturbances, premature birth

hypocalcaemia Haemolytic anaemia

Local -trauma -periapical osteitis (infected baby teeth)

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Mulberry molars This is a congenital defect caused by syphilis. The occlusal surface of the molar has many small globules of enamel, not cusps.

http://www.cbstraining.com/student/Dental/OralPathology/M.html

Infection

http://oralpatho.blogspot.ca/2010/03/mulberry-molar-and-mulberryand-custard.html

An unusual disorder that creates the appearance of bluish green teeth. The congenital defect occurs during infancy whereby biliary atresia occurs, disrupting the draining of bile from the liver to the small intestine. Numerous developmental events can occur, depending on the extent of the condition. Not hereditary and not contagious.

Biliary Atresia

http://www.dental--health.com/bad_teeth_congenital.html

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Individuals affected with TDO that have very thin enamel can benefit from covering the teeth with a bonded filled composite resin to help prevent exposure of pulp horns through wear. The enamel that is present is typically well mineralized and generally retains bonded materials adequately.

http://www.dentistry.unc.edu/research/defects/pages/tdo.htm

Systemic insults are easy to detect: 1. Pairs of teeth are affected

(both sides) 2. Teeth that erupt together, suffer together (e.g. Incisor-molar hypoplasia)

It’s fun to play ‘Dr. House’ in the dental office. Doc: ‘You certainly had your hands full with your son being so sick at birth.’ Mom: ‘How did you know? I forgot to mention that on the medical questionnaire.’ http://www.youtube.com/watch?v=5H40I25xR1w&feature=related

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Sequence of tooth formation and eruption

http://www.youtube.com/watch?v=5H40I25xR1w&feature=related

Linear Enamel Hypoplasia (LEH) (the primary incisors were affected during development right after birth)

Return to normal enamel after birth

Neonatal Hypoplasia

Enamel development protected in utero

LEH indicates severe hypocalcemia at birth

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Ash, Major M.; Nelson, Stanley J. (2003). Wheeler's dental anatomy, physiology, and occlusion. Philadelphia: W.B. Saunders. pp. 32, 45, and 53.

Primary teeth

Central incisor

Lateral incisor

Canine

First molar

Second molar

Initial calcification

14 wk I.U. 16 wk I.U. 17 wk I.U. 15.5 wk I.U.

19 wk I.U.

Crown completed

1.5 mo 2.5 mo 9 mo 6 mo 11 mo

Root completed

1.5 yr 2 yr 3.25 yr 2.5 yr 3 yr

Birth

Lagerqvist C, Dahlbom I, Hansson T, et al. (2008) Antigliadin immunoglobulin A best in

finding celiac disease in children younger than 18 months of age. J Pediatr Gastroenterol Nutr. 2008 Oct;47(4):428-35.

Is breast feeding protective?

•Does CD cause enamel hypoplasia in primary teeth? •When is gluten usually introduced into the infant’s diet? •Does a wheat-based porridge cause enamel hypoplasia in the second primary molars in infants with CD?

Possible scenario: Gluten was introduced into the diet at age 1.5 years (which caused the enamel defect) then a gluten-free diet was introduced a month later after it was discovered that the diet containing gluten was making the child sick.

Liversidge HM. Crown formation times of human permanent anterior teeth.

Arch Oral Biol. 2000 Sep;45(9):713-21.

Fig. 3 (Rashid et al)

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If this were a child with Celiac Disease, could he avoid dental defects in his anterior teeth by continuing to drink breast milk????

Differential Diagnosis of Enamel Lesions

Ameogenesis Imperfecta

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Enamelin Translation Termination at Codon 53

Autosomal Dominant Local Hypoplastic AI

Mårdh et al., (2002) Hum Mol Gen 11:1069-74

APECED: Autoimmune

Polyendocrinopathy-

Candidiasis-Ectodermal

Dystrophy

APECED causes multiple endocrine

deficiencies, oral candidiasis and

different forms of ectodermal dystrophy

including enamel hypoplasia.

Mutations in autoimmune

regulator (AIRE, 21q22.3)

Pavlic & Waltimo-Siren (2009) Arch Oral Biol 54:658-65

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Amelogenesis Imperfecta

• Prevalence is estimated to be 1 in10,000 (Chosack 1979; Witkop 1989; Chan 2011)

• Half are caused by defects in the genes coding for secreted enamel proteins (AMELX, ENAM, AMBN, MMP20, KLK4)

• Could also be defects in membrane protein amino acid sequences

This one looks like dental fluorosis

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Differential Diagnosis

Premature Birth

Aine L, Backström MC, Mäki R, Kuusela AL, Koivisto AM, Ikonen RS, Mäki M.

Enamel defects in primary and permanent teeth of children born prematurely.

J Oral Pathol Med. 2000 Sep;29(8):403-9.

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Differential Diagnosis

AmoxycillinTherapy

1 in every 6th child treated with antibiotics (0 - 4 yrs.) shows damage to the enamel. -the damage is worse with higher frequency exposure and with multiple antibiotic protocols.

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When Amoxicillin was used to treat otitis media, between 3 to 6 mo., there was a 2.5 times greater chance of producing fluorosis-like enamel lesions Hong L, Levy SM, Warren JJ, Dawson DV, Bergus GR, Wefel JS. Association of amoxicillin use during early childhood with developmental tooth enamel defects.

Arch Pediatr Adolesc Med. 2005 Oct;159(10):943-8.

Differential Diagnosis

Environmental toxins

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http://www.helsinki.fi/science/dentenv/

Dioxin Polycyclic Aromatic Hydrocarbons (PAHs) Tributyltin (TBT)

Differential Diagnosis

Fluorosis

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0-20 mo 0-38 mo 0- 7.5 yr 34 mo – 14 yr 45 mo – 16 yr

Ishii T, Suckling G. The severity of dental fluorosis in children exposed to water with a high fluoride content for various periods of time.

J Dent Res. 1991 Jun;70(6):952-6.

Timing of Exposure: fluoride excess

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the upper front incisor takes 3 years to mineralize

Excessive fluoride exposure windows

birth to 1 yr. birth to 3 yrs.

1 yr. to 3 yrs.

> 2 yrs. fluorosis

Fluoride exposure birth to first year Crown development: maturation phase:

incisor tips 1st molar tips

Brothwell DR. (1981) Digging Up Bones. The Excavation, Treatment and Study of Human Skeletal Remains. Cornell University Press, Ithica NY, pp.64.

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Fluoride exposure 3rd to 4th year Crown development: maturation phase:

premolar and canine tips 2nd molar tips

Fluoride exposure birth to 8 years Crown development: maturation phase:

all teeth affected

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Mild to moderate fluorosis

Moderate to severe fluorosis

How Celiac Disease causes enamel defects

“The exact mechanism leading to these defects is not clear, but immune-mediated damage is suspected to be the primary cause. Nutritional disturbances, including hypocalcemia, may also play a role. Stimulation of naïve lymphocytes by gluten in the oral cavity has also been hypothesized.” Rashid et al

References: •Pastore L, Carroccio A, Compilato D, Panzarella V, Serpico R, Lo Muzio L. Oral manifestations of celiac disease. J Clin Gastroenterol. 2008;42(3):224-32. •Pastore L, Campisi G, Compilato D, Lo Muzio L. Orally based diagnosis of celiac disease: current perspectives. J Dent Res. 2008;87(12):1100-7. •Fraser D, Nikiforuk G. The etiology of enamel hypoplasia in children — a unifying concept. J Int Assoc Dent Child. 1982;13(1):1-11.

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This 13-year old boy has been recently diagnosed with celiac disease (severe reaction to gluten). He is a patient of mine. There are NO oral lesions.

Celiac Disease without oral symptoms

Enamel pitting

First molar fractured -complained of irritable bowels & abdominal cramps for years -she asked for the CD test -no anti-gliadin IgG , so no biopsy -she started to avoid gluten anyway -now symptom free

Female Patient- now retired

Anti-gliadin IgG is only found in 80% of patients with CD. Volta U et al (1985) Gut 26 (7): 667–71.

Was she misdiagnosed????

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What if disturbances of calcium intake results in more ‘free fluoride’ in developing teeth? Or what if localized calcium is deficient and this allows local ‘normal levels’ of fluoride to become toxic?

!!!!

gliadin [ˈglaɪədɪn], gliadine [ˈglaɪəˌdiːn -dɪn]n(Cookery) a protein of cereals, esp wheat, with a high PROLINE content: forms a sticky mass with water that binds flour into dough Compare glutelin [from

Italian gliadina, from Greek glia glue]

http://www.thefreedictionary.com/gliadin

http://food52.com/contests/112_your_best_porridge http://rinasrecipes.blogspot.ca/2009/04/bulgur-or-cracked-wheat-porridge.html

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CD patients have antibodies that react to gliadin that also react with enamel protein

Muñoz F, Del Río N, Sóñora C, Tiscornia I,

Marco A, Hernández A.

Enamel defects associated with coeliac

disease: putative role of antibodies against

gliadin in pathogenesis.

Eur J Oral Sci. 2012 Apr;120(2):104-12.

Antibody binding to enamel proteins during tooth formation could interfere with amelogenesis

anti-Enamel Matrix Derivative protein

Aphthous Ulcers:

http://www.drpaulose.com/general/apthous-ulcers-mouth-ulcers

Other Oral Signs of CD

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Diagnosis Potential differentiating features

Infection

Viral

Herpesvirus Vesicular lesions, Tzank stain

positive for inclusion-bearing giant

cells

Cytomegalovirus Immunocompromised patient, biopsy

positive for multinucleated giant cells

Varicella Characteristic skin lesions

Coxsackievirus Hand/foot/buttock lesions, typically in

children

Treponemal

Syphilis Risk factors, other skin lesions,

RPR/FTA test is positive

Fungal

Cryptosporidium,

mucormycosis,

histoplasma

Immunocompromised patient,

chronicity, biopsy and culture positive

TABLE 1

Differential Diagnosis of Aphthous Ulcers http://www.aafp.org/afp/2000/0701/p149.html

Autoimmune

Behçet's syndrome Genital ulceration, uveitis, retinitis

Reiter's syndrome Uveitis, conjunctivitis, HLA B27

arthritis

Inflammatory bowel disease Recurrent bloody or mucous

diarrhea, other GI ulcerations

Lupus erythematosus Malar rash, ANA-positive

Bullous pemphigoid Diffuse skin involvement

Pemphigus vulgaris Diffuse skin involvement

Hematologic

Cyclic neutropenia Periodic fever, neutropenia

Neoplasm

Squamous cell carcinoma Chronicity, head/neck adenopathy,

biopsy positive

TABLE 1

Differential Diagnosis of Aphthous Ulcers

Cont’d

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9% Recurrent Aphthous Stomatitis patients had CD

Baccaglini et al, 2011

27 out of 100 CD patients presented with Recurrent Aphthous Stomatitis

Baccaglini et al, 2011

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(1) Complex aphthosis is not a mild form of Behcet’s disease in North America or Western Europe; (2) Diagnostic criteria for periodic fever, aphthous stomatitis, pharyngitis, and adenitis have low specificity and the characteristics of the oral ulcers warrant further studies; (3) Oral ulcers may be associated with CD; however, these ulcers may not be Recurrent Aphthous Sotomatitis (RAS); (4) RAS is rarely associated with B12 deficiency; 33 controlled trials published in the past 6 years reported some effectiveness (of B12 administration), although potential for bias was high.

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Other Oral Signs of CD Angular cheilosis (cheilitis) -candida albicans infection -treated with nystatin, fluconazole or ketakonazole

Cheilosis.net

Mayoclinic.com

Oral Lichen Planus -unknown etiology (stress?) -treated with topical corticosteroids and immunosuppressants

doctorsgates.blogspot.ca

Atrophic Glossitis -Vitamin B12 deficiency? -treat with Vitamin B12

Interesting! I didn’t know that!

Certain dental plaque bacteria degrade gliadin!

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Zamakhchari M, Wei G, Dewhirst F, Lee J, Schuppan D, Oppenheim FG, Helmerhorst EJ.

Identification of Rothia bacteria as gluten-degrading natural colonizers of the upper

gastro-intestinal tract. PLoS One. 2011;6(9):e24455.

Strains with high activity towards gluten were typed as Rothia mucilaginosa and Rothia aeria. Gliadins added to Rothia cell suspensions were degraded by 50% after ∼30 min of incubation.

Maybe celiac patients could benefit by colonizing their oral cavities with probiotics enriched in R. mucilaginosa and R. aeria !!

Probiotics are gaining acceptance for good oral health

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‘Friendly’ Streptococcus Salivarius.

“Rothia mucilaginosa is an opportunistic pathogen in the human oral cavity and pharynx. We found that R. mucilaginosa DY-18, a clinical isolate from a persistent apical periodontitis lesion, had biofilm-like structures.”

Kazuyoshi Yamane,1 Takayuki Nambu,1 Takeshi Yamanaka,1 Chiho Mashimo,1 Chieko

Sugimori,1 Kai-Poon Leung,2 and Hisanori Fukushima1

Complete Genome Sequence of Rothia mucilaginosa DY-18: A Clinical Isolate with Dense Meshwork-Like Structures from a Persistent Apical Periodontitis Lesion. Sequencing, 2010 (2010), Article ID 457236, 6 pages

Maybe it’s not such a good idea to encourage gum disease !

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Interesting! I didn’t know that!

Celiac patients have fewer dental cavities. References:

Perez-Davidi M. (2011) [The relationship between celiac disease (CD) and dental problems]. Refuat Hapeh Vehashinayim. Oct;28(4):12-8, 37. Avşar A, Kalayci AG. (2008) The presence and distribution of dental enamel defects and caries in children with celiac disease. Turk J Pediatr. Jan-Feb;50(1):45-50 Priovolou CH, Vanderas AP, Papagiannoulis L. (2004) A comparative study on the prevalence of enamel defects and dental caries in children and adolescents with and without coeliac disease. Eur J Paediatr Dent. Jun;5(2):102-6.

Celiac patients have fewer dental cavities.

WHY???

1. Delayed tooth eruption 2. Bloated stomach, cramps, loss of appetite = less frequent snacking 3. Less exposure to wheat-based processed foods with sugar 4. Supplementation with Ca++ and Vit. D = reduced risk for caries 5. Education: dietary awareness = less consumption of junk food

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Celiac patients can present with severely eroded teeth

WHY?

...because there might be uncontrolled nausea and

vomiting, sometimes 2X/day for weeks until the

diagnosis is made (that’s like bullemia)

References: -Yucel B, Ozbey N, Demir K, Polat A, Yager J. Eating disorders and celiac disease: a case report. Int J Eat Disord. 2006 Sep;39(6):530-2. -Assiri AM, El Mouzan MI, Al Sanie A, Al Jurayyan N, Al Herbish AS, Bakr AA.

Pattern of celiac disease in infants and children. Trop Gastroenterol. 2008 Oct-Dec;29(4):217-20

-it’s enough to cause severe dental erosion

Describes most CD sufferers, right?

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http://www.hesslewoodlodge.com/Acid-in-Food-and-Drinks(2371390).htm

Holbrook, W. P., Ganss, C. Is diagnosing exposed dentine a suitable tool for grading erosive loss? Clinical Oral Investigations Vol. 12 Issue 1

Severe erosion in the primary dentition

Diagnostic ‘cupping’ of the molar cusp tips (I call them ‘potholes’)

Take home points

•Celiac patients MAY or MAY NOT have oral signs of celiac disease •Mild enamel defects from Celiac Disease look like dental fluorosis •Celiac patients are unique dental patients

•less dental decay, •more soft tissue problems •enamel damage from erosion