Celiac disease

How can I be sure that the patient has celiac disease?

Celiac disease can present a diagnostic challenge because of its highly diverse mode of presentation. Patients can have overt gastrointestinal symptoms, such as diarrhea and weight loss, but these are the presenting features in fewer than 50% of all cases.

More commonly, patients present with so-called atypical (extra-intestinal) manifestations, such as fatigue related to iron deficiency anemia, metabolic bone disease, and peripheral neuropathy, or have incidentally noted abnormalities in the duodenum during endoscopy performed for indications such as heartburn.

Some patients present with no symptoms but have laboratory abnormalities such as elevated transaminase levels on liver profile tests or a depressed HDL on a lipid panel. Still others have truly “silent” celiac disease, lacking any clinical or laboratory abnormalities. Such patients may be diagnosed as part of a screening program, such as first-degree relatives of patients with celiac disease.

A tabular or chart listing of features and signs and symptoms

Classical presentation
  • Diarrhea
  • Weight loss
  • Malabsorption
  • Abdominal bloating/distension
  • Growth or developmental retardation (children)
Atypical presentation
  • Iron deficiency
  • Vitamin B12 or folate deficiency
  • Metabolic bone disease (osteopenia or osteoporosis)
  • Peripheral neuropathy
  • Migraine headaches
  • Arthralgia
  • Esophageal reflux

Due to associated conditions

  • Type 1 diabetes
  • Turner’s syndrome
  • Down’s syndrome
  • Autoimmune hepatitis
  • Primary biliary cirrhosis
  • Autoimmune thyroid disease
  • Due to family history

How can I confirm the diagnosis?

The diagnosis of celiac disease is made by small intestinal biopsy. Although current serologic tests are accurate in most scenarios, the presence of false positive results, and the fact that the gluten-free diet is a lifelong prescription, mandates biopsy confirmation. As the pathologic abnormalities in the small intestine can be patchy, at least four specimens from the descending duodenum and two specimens from the duodenal bulb should be submitted during biopsy.

In patients with low to moderate suspicion for celiac disease, the diagnostic work-up begins with serologic testing, followed by small intestinal biopsy in positive cases. Ordering IgA antibodies to tissue transglutaminase (TTG) in combination with total IgA levels is an effective initial screening strategy. Total IgA levels are checked because of the increased prevalence of IgA deficiency/insufficiency in patients with celiac disease, which may yield a false-negative TTG. Another effective strategy is to check TTG IgA together with antibodies to the deamidated gliadin peptide, both IgA and IgG. This latter strategy does not require checking a total IgA level because it includes an IgG serology that appears to be highly sensitive and specific.

Certain patient groups should undergo biopsy regardless of serologic results. This includes patients in whom the suspicion for celiac disease is high; patients with IgA deficiency with a moderate suspicion for celiac disease; and patients who are already on a gluten-free diet at the time of diagnostic testing. Biopsy is useful in this last scenario because histologic abnormalities resolve significantly slower than serological abnormalities.

In certain scenarios, genetic testing for the HLA DQ2 or DQ8 alleles can be a useful diagnostic tool. These alleles are necessary for the development of celiac disease, and so celiac disease can be ruled out when these alleles are absent. Situations in which gene testing is particularly useful include (1) family members of affected individuals (to obviate the need for repeat testing every few years; (2) patients already adhering to a gluten-free diet at the time of diagnostic testing; and (3) patients with inconclusive biopsy results.

What other diseases, conditions, or complications should I look for in patients with celiac disease?

There is ongoing controversy in the field of gastroenterology regarding the entity of Non-Celiac gluten Sensitivity. Despite negative testing for celiac disease, some subjects note sensitivity to gluten with resolution of symptoms after withdrawal from their diet, and the return of symptoms after resuming gluten. There is conflicting evidence about this entity, and these symptoms may be secondary to alternative diagnoses such as small intestinal bacterial overgrowth or lactose intolerance

At the time of diagnosis, patients with celiac disease should be checked for common clinical sequelae, including anemia, low iron stores, and vitamin D deficiency (often accompanied by secondary hyperparathyroidism). Levels of vitamin B12 and folate as well as thyroid stimulating hormone should also be checked. Patients with neuropathic symptoms should be screened for deficiencies of vitamins B1 and B6. Patients should undergo bone mineral density testing at the time of diagnosis.

The majority of symptomatic patients improve significantly within days to weeks of the adoption of the gluten-free diet. For patients with persistent or recurrent symptoms, the first step should be to confirm the correct diagnosis; this should include a review of prior serologic records and, if there is doubt about the diagnosis, a review of the initial biopsy by a pathologist with expertise in celiac disease. Inadvertent gluten ingestion is common, and thorough evaluation by a dietician with specialization in celiac disease is indicated. Coexisting diseases including microscopic colitis, small intestinal bacterial overgrowth, and pancreatic insufficiency should be excluded.

A small proportion of patients (<5%) have persistent symptoms due to refractory celiac disease (RCD). This diagnosis is confirmed histologically during follow-up biopsy and is further classified via immunohistochemistry and flow cytometry as well as PCR of the intraepithelial T cell receptor. RCD type 1 features persistent villous atrophy with a polyclonal population of intraepithelial lymphocytes. RCD type 2, which carries a poor prognosis, features a monoclonal T cell population characterized as the loss of the T cell surface markers CD3 and CD8. RCD type 2 can transform into enteropathy-associated T cell lymphoma, a rare consequence of celiac disease that currently lacks effective therapeutic regimens and has a low 5-year survival rate.

Causes of nonresponsive celiac disease

Most Common

  • Incorrect diagnosis
  • Ongoing (often inadvertent) gluten ingestion


  • Microscopic colitis
  • Small intestinal bacterial overgrowth
  • Pancreatic exocrine insufficiency
  • Lactose intolerance
  • Irritable bowel syndrome


  • Refractory celiac disease types 1 and 2
  • Enteropathy-associated T cell lymphoma

What is the right therapy for the patient with celiac disease?

The only proven therapy for celiac disease at this time is life-long adherence to a gluten-free diet. Upon diagnosis, patients should meet with a dietician with specialized expertise in the intricacies of the gluten-free diet. Obstacles to adherence to the diet include expense, limited availability and palatability, inconsistent food labeling practices, social pressures, and lack of knowledge regarding gluten at food establishments.

In addition to education regarding gluten avoidance, the dietician plays a crucial role in guiding healthy food choices in the transition to this diet, including attaining adequate fiber intake and appropriate caloric balance to prevent excessive weight gain. After initial consultation, patients often benefit from follow-up visits with a dietician and regular meetings with regional support groups.

In a small percentage of patients who present with severe malabsorption or develop refractory celiac disease, budesonide may result in rapid clinical improvement. Small intestinal release mesalamine may also be effective in RCD type 1.

CELIAC acronym for management of celiac disease (NIH Consensus Conference 2004)

C: Consultation with a dietician

E: Education about the disease

L: Lifelong adherence to the gluten-free diet

I: Identification and treatment of nutritional deficiencies

A: Access to an advocacy group

C: Continuous long-term follow-up

What additional therapy is indicated for this condition?

We recommend that patients on a long-term gluten-free diet take a daily multivitamin so as to prevent the development of micronutrient deficiencies. Given the small increased risk of community-acquired pneumonia and influenza, patients should be offered vaccination against pneumococcus and seasonal influenza virus.

What is the most effective initial therapy?


Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

What potential pharmacologic therapy will be available in the future?

Although the only therapy for celiac disease is the gluten-free diet, investigation of possible nondietary pharmacologic therapy is ongoing.

Potential therapeutic targets include the detoxification of gluten via congested synthetic polymers or recombinant enzymes that digest gluten, blockers of intestinal permeability, and modulation of the adaptive immune response to gluten via inhibiting tissue transglutaminase, blocking the activity of HLA DQ2/DQ8, or inducing tolerance via vaccine.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies


Listing of these, including any guidelines for monitoring side effects.


How should I monitor the patient with celiac disease?

With strict adherence to the gluten-free diet, elevated serologies typically normalize within 6 to 12 months. Patients whose serologies are not declining after that time should have a thorough reassessment with a dietician to rule out inadvertent gluten ingestion. Mucosal healing occurs more slowly than clinical improvement, and so a follow-up biopsy to confirm healing may be performed at least 2 years after diagnosis. This may be done at a shorter interval in clinical scenarios suggestive of refractory celiac disease (older age, ongoing diarrhea/weight loss).

After confirmation of serological normalization, patients should be seen annually for a physical examination and laboratory evaluation, including blood count, iron stores, vitamins B12 and folate, and vitamin D, as well as any micronutrients that were deficient on initial examination.

What’s the evidence?

Green, PH, Cellier, C. “Celiac disease”. N Eng J Med. vol. 357. 2007. pp. 1731-43. (A general overview of the epidemiology, pathogenesis, diagnosis, and management of celiac disease.)

Lo, W, Sano, K, Lebwohl. “Changing presentation of adult celiac disease”. Dig Dis Sci. vol. 46. 2003. pp. 395-6. (Describes the evolution of celiac disease symptoms from a predominantly classical presentation [during the preserology era] to more varied and atypical symptoms today.)

Catassi, C, Bai, JC, Bonaz, B. ” Non-celiac gluten sensitivity: The new frontier of gluten related disorders”. Nutrients. vol. 5. 20113. pp. 3829-3853. (Review discussing the entity of non-celiac gluten sensitivity)

Lebwohl, B, Ludvigsson, JF, Green, PH. ” The unfolding story of celiac risk factors”. Clin Gastroenterol Hepatol. vol. 12. 2014. pp. 632-635. (discusses ongoing debate regarding the gene-environment risk factors for celiac disease)

Latoree, M, Lagana, SM, Freedberg, DE. ” Endoscopic biopsy technique in the diagnosis of celiac disease: one bite or two?”. Gastrointest Endosc. vol. 81. 2015. pp. 1228-1233. (Discusses endoscopic technique for biopsies for diagnosis of celiac)

Fasano, A, Berti, I, Gerarduzzi, T. “Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study”. Arch Intern Med. vol. 163. 2003. pp. 286-92. (Screening study of celiac disease in the United States that determined a prevalence of 0.8%.)

Rubio-Tapia, A, Kyle, RA, Kaplan, EL. “Increased prevalence and mortality in undiagnosed celiac disease”. Gastroenterology. vol. 137. 2009. pp. 88-93. Prevalence study determining that celiac disease has increased four-fold in the United States since the mid-twentieth century.)

Lebwohl, B, Kapel, RC, Neugut, AI. “Adherence to biopsy guidelines increases celiac disease diagnosis”. Gastrointest Endosc. vol. 74. 2011. pp. 103-9. (Quantifies the yield of submitting an adequate number of specimens when performing small intestinal biopsy to diagnose celiac disease.)

Brar, P, Lee, S, Lewis, S. “Budesonide in the treatment of refractory celiac disease”. Am J Gastroenterol. vol. 102. 2007. pp. 2265-9. (Describes the use of budesonide in the management of refractory celiac disease types 1 and 2.)

Jamma, S, Leffler, DA, Dennis, M. “Small intestinal release mesalamine for the treatment of refractory celiac disease type 1”. J Clin Gastroenterol. vol. 45. 2011. pp. 30-3. (Describes the use of small intestinal release mesalamine in the management of refractory celiac disease type 1.)

Leffler, DA, Dennis, M, Hyett, B. “Etiologies and predictors of diagnosis in nonresponsive celiac disease”. Clin Gastroenterol Hepatol. vol. 5. 2007. pp. 445-50. (Quantifies the relative frequency of etiology of persistent symptoms after the diagnosis of celiac disease.)

Meyer, D, Stavropolous, S, Diamond, B. ” Osteoporosis in a North American adult population with celiac disease”. Am J Gastroenterol. vol. 96. 2001. pp. 112-9. Describes a high frequency of osteoporosis in patients with celiac disease.)