The Johns Hopkins Hospital

Baltimore MD.

C. CUFFARI, MD, FRCPC, FACG, AGAF

Presentation and Evaluation of

Celiac Disease

Main Points

• Celiac disease is not rare (1 in 100-300)

• It can present in many ways:

– IBS or non-specific GI symptoms, iron deficiency

anemia, depression, osteopenic bone disease, abnormal

LFTs, dyspepsia, DH, recurrent miscarriages, microscopic

colitis

• Associated with autoimmune diseases

• Screening with tTG IgA is best

• Confirm diagnosis with duodenal biopsy

• Cornerstone of treatment is avoidance of gluten

• Prognosis overall appears very good

Celiac Disease: Overview

Gluten Induced Enteropathy

AKA: Celiac Sprue, Non-tropical sprue

Permanent, genetically determined auto-immune illness initiated by cereal prolamines (gluten/gliadin); anti-body to tTg (screening)

Mucosal Lesion causes intestinal malabsorption. Biopsy of small Intestine is gold standard for diagnosis

Histologic and clinical improvement on gluten withdrawal.

Celiac Disease: Prevalence

• USA (OLMSTEAD Co) 1/4,600

• N. IRELAND 1/122

• ARGENTINA 1/170

• EUROPE 1/200-300

• USA (BALTIMORE) 1/250

Genetic Factors: HLA + Other Genes

Plus Environmental Factors

• Increased frequency of

HLA haplotypes

– DR3-DQ2

– DR5/7-DQ2

– DR4-DQ8

• 70% concordance in MZ twins

• 10-15% prevalence in first degree relatives

• Other factors involved since most with these haplotypes do not get celiac sprue

• Other genetic factors - genes on chromosomes 5, 16, ?6

• Environmental factors - Infectious agents– Cytokines released during infection -

Affecting APCs (e.g., dendritic cells)

– Cross-reactive amino acid sequences - Adenovirus, H. pylori

SC

Celiac Disease

Pathogenesis

Gluten: albumin

globulin

gliadin

glutinin

Prolamin: rye, barley, oats*

Olsen. Gastroenterology 1999;A914

Celiac Disease

Genetic basis (DQ2/DQ8)

Abnormal Permeability

Gluten ingestion

T-cell mediated

Antibodies

Kagnoff, J Clin Invest, 117:41, 2007

Pathogenesis of Celiac Disease

PRESENTATION OF CELIAC DISEASE

Diarrhea

Incidental Endoscopy

Screening

Bone Disease

Anemia

Other

Diarrhea

(36%)

Incidental at EGD

(4%)

Screening

(8%)

Bone disease

(5%)

Anemia

(13%)

PG

CAUSES OF SCALLOPING OF

DUODENAL MUCOSA

Tropical sprue

HIV enteropathy

Opportunistic infections

Giardiasis

Amyloid

Crohn’s disease

Systemic mastocytosis

Changing Picture of Celiac Disease

• Classical form less prevalent now

• Other presentations are being increasingly recognized:

– Irritable Bowel Syndrome

– Anemia

– Osteoporosis

– Obstetrical problems

– Neuropsychiatric manifestations

– Related autoimmune conditions

– Microscopic colitis

Celiac Disease: Asymptomatic and Latent Forms

Asymptomatic:

No apparent symptoms or associated diseases

May be first or second degree relatives of

Patients with biopsy proven celiac disease

“picked up” at mass screenings

Latent:

Positive serology

Negative small bowel biopsies

Positive biopsies later in life.

–

– -

–

Celiac Disease: Prevalence of

Autoimmune DiseaseN (909)

• Type I Diabetes 3.9%

• Dermatitis Herpet. 3.5%

• Epilepsy 1.5%

• Alopecia 1.3%

• CTD 1.3%

• Thyroiditis 1.2%

• AIH 1.1%

• psoriasis 0.9%

Ventura et al. Gastroenterology 2009;117:297

12 year old female with Type 1

diabetes, no GI symptoms and a

positive serology for celiac disease:

Endoscopy: Duodenitis

Scalloping of the folds

Biopsy: To confirm the diagnosis of

celiac disease in patients with co-

morbid conditions and nonspecific

duodenitis.

Case: Silent Celiac Disease in Patients

with Co-morbid Conditions

Case: Associated Illnesses

20 year old patient with

Diabetes:

bone pain

muscle weakness

Osteomalacia

Pseudofractures

High alk. phosphatase

Low Vitamin D

Clinical Presentations:

Musculoskeletal

• Enamel defects of permanent teeth

• Osteopenia/Osteoporosis

• Osteomalacia, rickets

• Related autoimmune conditions– RA, SLE, Sjogren’s syndrome, psoriasis

• Idiopathic short stature

• Delayed bone age

• ClubbingSC

Associated Hepatobiliary

Conditions

• Primary sclerosing cholangitis

• Autoimmune cholangitis

• Primary biliary cirrhosis

• Elevated transaminases

(aminotransferases)

– Evaluation of unexplained elevated AST,

ALT should include celiac screening

Ludvugsson et al, Clin Gastroenterol Hepatol, 5:63, 2007SC

Clinical Presentations:

Neuropsychiatric

• Hyperactivity -

attention deficit

disorder

• Irritability

• Cognitive deficits

• Cerebral calcifications

• Fatigue

• Seizures

• Peripheral neuropathy

• Ataxia

• Myelopathy

• Schizophrenia

• Depression

• Migraines

SC

Other Associated Conditions

• Oral aphthae

• Microscopic colitis

• Down’s syndrome

• Turner’s syndrome

• IgA deficiency

• IgA nephropathy

• Many others postulated, ? realSC

ROLE OF SEROLOGICAL

TESTING IN CELIAC DISEASE

• Triage patients for biopsy

• Monitoring adherence to diet

• Screening high risk groups

Serologic Tests

Test Sensitivity Specificity

AGA IgA < 80% in 50% > 80% in most

AGA IgG variable non-specific

EMA IgA 96-97% ME, 90% HUV

100% ME, HUV

tTG IgA 90% GP, 98%HR

95% GP, 98% HR

tTG IgG 40% 98%

Rostom et al, Gastroenterology, 128:S38, 2005

SC

SELECTIVE IgA

DEFICIENCY

• Occurs in 1.5%-2.5% of celiac patients

• 10 – 16 X general population

• Lack EMA, anti-tTG, IgA AGA

• Elevated IgG antibodies (AGA, EMA,

anti-tTG)

• Identical clinically

Relatives: Who and How to

Screen?

• Index case has proven celiac disease

• Relative is interested in being screened

• Relative is willing to undergo diagnostic

testing and treatment

• Relative will derive benefit from

treatment

• If relative is symptomatic, approach is

diagnostic not screening SC

CELIAC DISEASE

• Common (high risk groups)

• Increased rate of diagnosis (use of serologies

IgA, EMA, ttg (IgA, IgG)

IgA deficient- ttg, anti-gliadins (IgG)

DQ2DQ8

• Easy to treat ?

surveillance: compliance

nutritional

co-morbidities

REASONS FOR CASE SEEKING

AND STRICT ADHERENCE TO

THE DIET

• Prevention of ill health – anemia, osteoporosis

• Elderly with CD are often extremely ill

• Increased mortality Vs general population

• Increased incidence of malignancy

• Occurrence of autoimmune disorders

Refractory Celiac Disease

• 80-90% ingesting gluten or wrong Dx

• Type 1 refractory: Respond to oral or topical steroids (budesonide or beclamethasone)

• Type 2: Pre-malignant condition:50% develop Enteropathy Associated T-cell Lymphoma (ETAL) within 5 yrs of Dx– 3X Rel Risk in un-Rxed CD for ETAL

• CD on GFD >5yrs:No incr. risk ETAL or GI Cancer

• Ulcerative Jejuno-Ileitis (? Relation to ETAL)(Bayless, et al. NEJM 1967)

ML

Prognosis

• Generally good prognosis

• Small increase in death rate returns to

baseline in first few years after

diagnosis

• Increased mortality in malabsorptive

presentations, if diagnosis delayed, and

in those poorly compliant with diet

• Main cause of excess death is

lymphoma

• Ulcerative jejuno-ileitis, can be fatal

Summary

• Celiac disease is not rare (1 in 100-300)

• It can present in many ways:

– Iron deficiency anemia, depression, osteopenic bone

disease, abnormal LFTs, non-specific or IBS-like GI

symptoms, dyspepsia, DH, recurrent miscarriages,

microscopic colitis

• Associated with autoimmune diseases

• Screening with tTG IgA is best

• Confirm diagnosis with duodenal biopsy

• Cornerstone of treatment is avoidance of gluten

• Prognosis overall appears very good