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