Why celiac disease is so easy to miss

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Applied Evidence

Why celiac disease is so easy to miss

J Fam Pract. 2014 September;63(9):508-513

Maureen A. Mavrinac, MD

Arthur Ohannessian, MD

Erin P. Dowling, MD

Patrick T. Dowling, MD, MPH

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.

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References

1. Sanders L. Hurt all over. New York Times Sunday Magazine. November 11, 2011:MM22.

2. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107:1538-1544.

3. Fasano A, Catassi C. Clinical practice. Celiac disease. N Engl J Med. 2012;367:2419-2426.

4. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357: 1731-1743.

5. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163:286-292.

6. Mustalahti K, Catassi C, Reunanen A, et al; Coeliac EU Cluster, Project Epidemiology. The prevalence of celiac disease in Europe: results of centralized, international mass screening project. Ann Med. 2010;42:587-595.

7. Farrel R, Kelly C. Celiac disease and refractory celiac disease. In: Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 9th ed. Philadelphia, PA: Saunders; 2010: 1797-1820.

8. Gujral N, Freeman HJ, Thomson Ab. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol. 2012;18:6036-6059.

9. Sleisenger MH. Diseases of malabsorption. In: Beeson PB, McDermott W. Cecil-Loeb Textbook of Medicine. 13th ed. Philadelphia, PA: WB Saunders Company; 1971:1285-1291.

10. Reilly NR, Green PH. Epidemiology and clinical presentations of celiac disease. Sem Immunopathol. 2012;34:473-478.

11. Kagnoff MF. Celiac disease. A gastrointestinal disease with environmental, genetic, and immunologic components. Gastroenterol Clin North Am. 1992;21:405-425.

12. Riddle MS, Murray JA, Porter CK. The incidence and risk of celiac disease in a healthy US adult population. Am J Gastroenterol. 2012;107:1248-1255.

13. Rampertab SD, Pooran N, Brar P, et al. Trends in the presentation of celiac disease. Am J Med. 2006;119:355.e9-355.e14.

14. Pietzak M. Celiac disease, wheat allergy, and gluten sensitivity: when gluten free is not a fad. JPEN J Parenter Enteral Nutr. 2012;36(1 suppl):68S-75S.

15. Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10:13.

16. Rubio-Tapia A, Hill ID, Kelly CP, et al; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management celiac disease. Am J Gastroenterol. 2013;108:656-676.

17. Hill ID, Dirks MH, Liptak GS, et al; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guidelines for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroentertol Nutr. 2005;40:1-19.

18. Husby S, Koletsko S, Korponay-Szabó IR, et al; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastoenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology and Nutrition Guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54:136-160.

19. Catassi C, Fasano A. Celiac disease diagnosis: simple rules are better than complicated algorithms. Am J Med. 2010;123:691-693.

20. US Food and Drug Administration. Foods labeled gluten-free must now meet FDA's definition. Available at: http://www.fda. gov/Food/NewsEvents/ConstituentUpdates/ucm407867.htm. Accessed August 13, 2014.

21. National Institutes of Health Consensus Development Conference on Celiac Disease. National Institutes of Health Consensus Development Conference Statement. Available at: http://consensus.nih.gov/2004/2004celiacdisease118html.htm. Accessed August 13, 2014.

22. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA. 2005;293:2343-2351. 

23. Pozo-Rubio T, Olivares M, Nova E, et al. Immune development and intestinal microbiota in celiac disease. Clin Dev Immunol. 2012;2012:654143

24. Ivarsson A, Myléus A, Norström F, et al. Prevalence of childhood celiac disease and changes in infant feeding. Pediatrics. 2013;131:687-694. 

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PRACTICE RECOMMENDATIONS

› 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