What are the common symptoms of celiac disease in a patient with a genetic predisposition and normal laboratory results?

Symptoms of Celiac Disease

Celiac disease presents with a broad spectrum of both gastrointestinal and extraintestinal manifestations, and critically, many patients—particularly adults—present with non-classic or extraintestinal symptoms rather than typical GI complaints, which frequently leads to diagnostic delay. 1, 2

Gastrointestinal Symptoms

The classic intestinal presentation includes:

• Diarrhea is the most common classic symptom, frequently accompanied by abdominal pain 1, 2
• Weight loss or poor weight gain, particularly critical in pediatric patients 2
• Bloating and flatulence are common complaints 2
• Nausea and vomiting may occur 2
• Malabsorption leading to nutritional deficiencies 2
• Steatorrhea (fatty stools) 3

However, it is essential to recognize that gastrointestinal symptoms alone cannot accurately differentiate celiac disease from other GI disorders such as irritable bowel syndrome, lactose intolerance, or microscopic colitis. 1, 4

Extraintestinal Manifestations

Many adult patients present primarily or exclusively with extraintestinal symptoms without any gastrointestinal complaints, which is a major diagnostic pitfall. 5, 4 These include:

Hematological

• Iron deficiency anemia affects 48% of adults at presentation and may be resistant to oral iron supplementation 5, 4
• Anemia can occur even in the complete absence of GI symptoms 5

Musculoskeletal

• Osteopenia and osteoporosis occur frequently, with prevalence ranging from 1.7% to 42% depending on sex, geography, age at diagnosis, and clinical phenotype 5, 4
• Increased fracture risk shows 60-100% excess compared to the general population before diagnosis 5, 4

Neurological and Psychiatric

• Fatigue and weakness related to anemia or general malnutrition 2, 4
• Irritability and inability to concentrate, particularly noted in children 2, 4
• Depression and psychiatric disorders affect approximately 24% of adults 5, 4
• Peripheral neuropathy 5, 4
• Cerebellar ataxia 5, 4
• Epilepsy and seizures in both children and adults 5, 4

Reproductive

• Infertility and recurrent miscarriages 2, 5, 4
• Adverse pregnancy outcomes in undiagnosed disease 5, 4

Pediatric-Specific

• Growth failure and short stature is the most common extraintestinal manifestation in children (33% of pediatric cases) 5, 4
• Failure to thrive 1, 2

Hepatic

• Abnormal liver function tests (transaminitis) 3, 6

Dermatological

• Dermatitis herpetiformis 1

Clinical Presentation Patterns

Understanding the presentation patterns is crucial for diagnosis:

• Classic presentation: Primarily gastrointestinal symptoms such as diarrhea, weight loss, and abdominal pain 2
• Non-classic presentation: Less specific GI symptoms or predominantly extraintestinal manifestations 6
• Silent/asymptomatic celiac disease: Diagnosed through screening of high-risk groups despite absence of symptoms 2

Special Considerations in Type 1 Diabetes

Patients with concurrent type 1 diabetes and celiac disease may present with:

• Unpredictable blood glucose levels despite adherence to insulin regimen 2, 4
• Unexplained hypoglycemia episodes 2, 4
• Deterioration in glycemic control without obvious cause 2, 4

High-Risk Groups Requiring Heightened Suspicion

The following populations warrant increased clinical suspicion and screening:

• First-degree relatives of people with celiac disease (7.5% risk) 1, 2, 4
• Type 1 diabetes patients (5-10% prevalence of celiac disease) 1, 2, 5, 4
• Autoimmune thyroid disease (3% prevalence) 1, 5, 4
• Down syndrome (5.5% confirmed prevalence) 1, 5, 4
• Turner syndrome (6.3% prevalence) 5, 4
• Patients with autoimmune liver disease 5

Critical Clinical Pitfalls

Only approximately 24% of those with celiac disease are diagnosed, creating a "celiac iceberg" of undiagnosed cases. 2, 5, 4 Key pitfalls include:

• Many patients present with non-specific or extraintestinal symptoms rather than classic GI complaints, leading to significant diagnostic delay 2, 5, 4
• Symptoms overlap substantially with irritable bowel syndrome, lactose intolerance, and microscopic colitis 1, 4
• Patients on a gluten-free diet before testing may have false negative serological results, making diagnosis impossible without gluten challenge 1, 4
• Symptom response to a gluten-free diet alone has very low positive predictive value and should not be used for diagnosis without supportive serological and histological evidence 1
• Even asymptomatic celiac disease, if left undiagnosed and untreated, leads to higher risk of complications including osteoporosis, infertility, and small bowel lymphoma 5

Diagnostic Approach in Patients with Normal Laboratory Results

In patients with genetic predisposition (HLA-DQ2/DQ8 positive) but normal serology, celiac disease cannot be definitively excluded if clinical suspicion remains high. 1 The approach should include:

• Ensure the patient is consuming adequate gluten (gluten-containing diet) at the time of testing, as serological and histological features normalize after initiating a gluten-free diet 1
• If suspicion remains high despite negative serology, upper endoscopy with duodenal biopsy should be pursued 1
• Consider that symptoms may represent the initial presentation of celiac disease before antibody development 1
• HLA-DQ2/DQ8 testing has a negative predictive value of more than 99% when both are negative, effectively ruling out celiac disease 1