What is celiac disease?

What is Celiac Disease

Celiac disease is an immune-mediated disorder triggered by gluten ingestion in genetically susceptible individuals, characterized by small intestinal villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia that improves with strict gluten-free diet. 1

Pathophysiology

Celiac disease results from a complex interplay between genetic predisposition, immune dysregulation, and environmental triggers. 1

Genetic Component:

• Nearly 100% of patients with celiac disease carry HLA-DQ2 and/or HLA-DQ8 molecules, with approximately 75% concordance in monozygotic twins. 1
• First-degree relatives have a 10% prevalence, indicating strong familial clustering. 1

Immunologic Mechanism:

• Gluten proteins from wheat, rye, and barley are incompletely digested by gastric, pancreatic, and brush border peptidases due to their high proline and glutamine content, leaving large peptides of 10-50 amino acids. 1
• Tissue transglutaminase (tTG) deamidates glutamine residues to glutamic acid, increasing peptide binding affinity to HLA-DQ2/DQ8 molecules on antigen-presenting cells. 1
• This triggers CD4+ T cell activation in the intestinal mucosa, leading to both adaptive and innate immune responses. 1
• The humoral response produces antibodies against both gluten (the exogenous antigen) and tTG (the autoantigen). 1

Epidemiology

• Worldwide prevalence is approximately 1% in the general population, with a female-to-male ratio of 2:1. 1
• Only about 24% of those with celiac disease are diagnosed, creating a substantial "celiac iceberg" of undiagnosed cases. 2
• Prevalence is significantly higher in high-risk groups: 5.4% in patients with type 1 diabetes and 1-16% overall in diabetic populations compared to 0.3-1% in the general population. 1

Clinical Manifestations

Classic Gastrointestinal Presentation:

• Diarrhea with or without steatorrhea, frequently accompanied by abdominal pain. 2, 3
• Weight loss or poor weight gain (particularly critical in children). 2
• Bloating, flatulence, nausea, and vomiting. 2
• Malabsorption leading to nutritional deficiencies. 2, 4

Non-Classical and Extraintestinal Manifestations:

• Iron deficiency anemia resistant to oral supplementation. 2, 3
• Decreased bone mineral density, osteomalacia, and osteoporosis. 1, 5
• Fatigue, weakness, irritability, and inability to concentrate. 2
• Growth failure in children. 2
• Reproductive issues including infertility and recurrent miscarriages. 2, 6
• Neurologic manifestations including neuropathy and ataxia. 1, 5
• Elevated transaminases (liver enzyme abnormalities). 6
• Dermatitis herpetiformis (pathognomonic for celiac disease). 3

Special Considerations in Type 1 Diabetes:

• Unpredictable blood glucose levels despite insulin adherence. 2
• Unexplained hypoglycemia episodes. 2
• Deterioration in glycemic control without obvious cause. 2

Diagnostic Approach

Initial Serological Testing (Must Be Done While on Gluten-Containing Diet):

• IgA tissue transglutaminase antibody (tTG-IgA) is the preferred first-line test with 90-96% sensitivity and >95% specificity. 7
• Total IgA levels must be measured simultaneously to identify IgA deficiency (present in 1-3% of celiac patients vs. 1 in 500 in general population), which causes false-negative results. 1, 7
• Patients must consume at least 10g of gluten daily for 6-8 weeks before testing to avoid false negatives. 7

Confirmatory Testing:

• Upper endoscopy with small bowel biopsy remains the gold standard for diagnosis in adults. 7
• Multiple biopsies are required: 1-2 samples from the duodenal bulb and at least 4 samples from the distal duodenum. 7
• Characteristic histologic findings include villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. 1, 7

Genetic Testing:

• HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value and is useful when celiac disease is suspected despite negative serology, in patients with equivocal histology, or in those already on a gluten-free diet without prior testing. 7

Treatment

The cornerstone and only effective treatment is a strict, lifelong gluten-free diet, which eliminates wheat, rye, and barley from all food sources. 1, 4, 3

• In most patients, a strict gluten-free diet results in complete symptomatic and histologic resolution and reduces risk of complications including lymphoma, osteoporosis, and other autoimmune disorders. 4, 5
• Noncompliance with diet is the leading cause of treatment failure. 4
• Approximately 5% of patients have refractory celiac disease despite strict gluten-free diet adherence for at least 12 months and require gastroenterology referral for corticosteroids and immunomodulators. 2, 3

Critical Clinical Pitfalls

• Many patients present with non-specific or extraintestinal symptoms rather than classic gastrointestinal complaints, leading to delayed diagnosis. 2
• Initiating a gluten-free diet before completing diagnostic testing leads to false-negative serological and histologic results. 7
• Symptom improvement on a gluten-free diet has low positive predictive value and should not be used for diagnosis without supportive serological and histologic evidence. 7
• Lymphocytic infiltration without villous atrophy is not specific for celiac disease and requires consideration of other causes. 7