Why Celiac Disease is So Easy to Miss

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Less than half of patients present with GI symptoms. Here’s what to look for, who to test, and how to manage patients once they’ve gone gluten-free.




› Do not rely on symptoms or symptom response to 
a gluten-free diet alone 
to diagnose celiac disease (CD); this approach does not differentiate CD from non-celiac gluten sensitivity. B
› Use HLA-DQ2 and -DQ8 genotype testing to effectively rule out the disease in selected clinical situations. B
› Test for CD in any
 patient who has unexplained elevated serum aminotransferase levels, even in the absence of CD symptoms. A
› Screen all first-degree relatives of patients with
 CD by testing for immunoglobulin A (IgA) tissue transglutaminase antibodies and serum IgA levels. A

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

CASE › It was a clinical conundrum. A 2011 case study1 described a 33-year-old woman with a 10-year history of progressive, debilitating pain and weakness. The patient had not received a unifying diagnosis or effective treatment despite multiple diagnostic tests and different recommendations from multiple specialists. The diagnosis remained elusive until a rheumatologist agreed to reexamine the case.

While reviewing the woman’s thick chart, the rheumatologist noted a series of negative results from upper and lower endoscopies and abdominal scans. Further investigation revealed an almost obfuscated clue—blood tests performed 2 years earlier that were positive for celiac disease (CD). However, a small intestine biopsy, which normally is done to confirm the diagnosis, was never performed.

The rheumatologist made a tentative diagnosis of CD and referred her to a nutritionist, who recommended the patient adhere to a strict gluten-free diet. Within 3 months, the patient experienced marked improvement and returned to work.

CD is an often-missed diagnosis. According to a study based on National Health and Nutrition Examination Survey data, only 17% of patients with CD are aware they have the disease.2 As such, it is imperative that primary care physicians familiarize themselves with CD’s myriad clinical presentations, diagnosis, and treatment.3-6

Gluten triggers an immune response
 in genetically susceptible patients

CD initially was known as “celiac sprue” because it shares characteristics with tropical sprue—diarrhea, malabsorption, and emaciation. It is a unique T-cell autoimmune enteropathy that is precipitated in genetically susceptible individuals by the ingestion of gluten, the major storage protein of wheat, barley, and rye.3,7

Upon ingestion, gluten breaks down to gliadin, which provokes an immune response in the intestinal mucosa of patients with CD. This response results in an inflammatory reaction, primarily in the upper small intestine, that destroys the absorption surface and causes villous atrophy, leading to nutrient malabsorption and chronic diarrhea.8 CD is associated with significant morbidity due to an abnormal excretion of fat (steatorrhea) and varying degrees of malabsorption of vitamins A, D, and K, as well as B complex vitamins including B12 and folate; carbohydrates; protein; water; and minerals such as magnesium, calcium, and iron.9

CD develops only in individuals who possess alleles that encode for HLA-DQ2 or HLA-DQ8 proteins, products of 2 of the HLA genes. And while 30% of Caucasians carry the HLA-DQ2 allele and virtually 100% consume wheat, only 1 in 100 will develop CD.3,10,11 Although the genes are necessary, it is the interplay between genes (both HLA and non-HLA associated) and environment (ie, gluten) that leads to the intestinal mucosa damage typical of the disease. The HLA-DQ region also is associated with increased risk of type 1 diabetes, which might explain the correlation of CD to a host of other autoimmune disorders, including Graves’ disease and rheumatoid arthritis.8,10,11

Increased prevalence reflects 
better recognition of celiac disease

CD affects .6% to 1% of the population worldwide, with wide regional variation.3 Before the development of serologic assays in the 1970s, CD was a clinical diagnosis based on classic symptoms. With the advent of assays for immunoglobulin A (IgA) antibodies, the prevalence of CD has drastically increased to the current estimates of 1:250 to 1:500.4,5 The prevalence will continue to increase as clinicians become more aware of the different presentations of the disease, which are described below.

CD runs in families. Most patients with CD have a family history of the disease based on inheritance of the HLA alleles. A US study determined that the prevalence of CD was 1:22 in first-degree relatives and 1:39 in second-degree relatives of patients with biopsy-proven CD.12

Less than half of patients 
have GI symptoms

The classic presentation of CD involves a constellation of signs and symptoms of malabsorption: diarrhea, muscle wasting, and weight loss. Other typical gastrointestinal (GI) symptoms include bloating, flatulence, and abdominal pain.

It is the interplay between genes and the environment that leads to the intestinal mucosa damage typical of the disease. Recognizing CD can be challenging, however, because <50% of patients diagnosed with CD present with these classic GI symptoms.3 About 50% of CD patients present with extra-intestinal symptoms, such as iron deficiency anemia, aphthous stomatitis, chronic fatigue, osteopenia, and dental enamel hypoplasia.3,8,13 Other possible non-GI symptoms include abnormal liver function test results and skin disorders such as dermatitis herpetiformis, a pruritic rash with cutaneous IgA deposits.3,8 In addition, many patients are asymptomatic.14 This highly variable clinical picture is due to the genetic and immunologic basis of the disease, extent of mucosal injury, and patients’ dietary habits, gender, and age of onset.15 A common clue that suggests a patient may have CD is unexplained iron deficiency anemia that does not improve with oral iron supplementation.4,13


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