Presentation and Evaluation of Celiac Disease C. CUFFARI, MD, FRCPC, FACG, AGAF The Johns Hopkins Hospital Baltimore MD. 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 • 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 • Increased frequency of • Environmental factors - Infectious agents HLA haplotypes – Cytokines released during infection - – DR3-DQ2 Affecting APCs (e.g., dendritic cells) – DR5/7-DQ2 – Cross-reactive amino acid sequences - Adenovirus, H. pylori – DR4-DQ8 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 Pathogenesis of Celiac Disease Kagnoff, J Clin Invest, 117:41, 2007 PRESENTATION OF CELIAC DISEASE Diarrhea Diarrhea (36%) Incidental Endoscopy Anemia Screening (13%) Bone Disease Anemia Other Bone disease (5%) Screening Incidental at EGD (8%) (4%) 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 Disease N (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 Case: Silent Celiac Disease in Patients with Co-morbid Conditions 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: 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 • Clubbing SC 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, 2007 SC Clinical Presentations: Neuropsychiatric • Hyperactivity - • Seizures attention deficit • Peripheral neuropathy disorder • Ataxia • Irritability • Myelopathy • Cognitive deficits • Schizophrenia • Cerebral calcifications • Depression • Fatigue • Migraines SC Other Associated Conditions • Oral aphthae • Microscopic colitis • Down’s syndrome • Turner’s syndrome • IgA deficiency • IgA nephropathy • Many others postulated, ? real SC 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, 100% ME, 90% HUV HUV tTG IgA 90% GP, 95% GP, 98% 98%HR HR tTG IgG 40% 98% SC Rostom et al, Gastroenterology, 128:S38, 2005 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 .