Practice Points: State of the Art Diagnostic Workup of Gluten Spectrum Disorders by Todd A. Born, ND

Dr. Todd A. Born, is a naturopathic doctor, co-owner and medical director of Born Naturopathic Associates, Inc., in Alameda, California. Dr. Born is also the Product Manager, Head of New Product Development, Scientific Advisor for Allergy Research Group, LLC and is Editor-in-Chief of their science Focus Newsletter. He is a Thought Leader for the UK-based Clinical Education, a free peer-to-peer service that offers clinicians a closed forum to ask clinical questions and receive evidence-based responses by experts in their fields.

To start: In 2011, my wife, naturopathic doctor Lindsay Born, adopted a gluten-free lifestyle. Lindsay has ankylosing spondylitis and is gluten sensitive. All of her coeliac serology, along with genetic tests were negative. Over time, she has noticed a cause and effect when she consumes gluten, or is accidentally cross-contaminated. When gluten-free, her back and joint pain improves, along with headaches and sinus pain. This personal experience served to highlight for me the possible associated symptoms in my patients.

One of the more dramatic and interesting cases of gluten sensitivity I have come across in my practice is a patient who was diagnosed with primary lateral sclerosis (PLS).  He was tested by his neurologist and myself for a number of other conditions.  Since I am aware of the neurological manifestations that can happen with gluten enteropathies, I thoroughly tested him for coeliac disease via serology and genetic testing.  Everything was negative.  These tests don’t show gluten sensitivities, so we applied the gold standard.  He removed gluten from his diet for a month and then challenged gluten by eating organic whole wheat bread three times in one day.  He kept a journal I gave him of his physical, mental and emotional symptoms. No change.

My own family’s experience, along with a few surprising patients, have convinced me it’s imperative to test chronically ill patients for coeliac disease and gluten sensitivity.

His wife and two daughters (all of whom are also patients of mine) are very sensitive to gluten.  Flash forward two years (by now he had worsened and was “upgraded” to a diagnosis of amyotrophic lateral sclerosis, (ALS) or Lou Gehrig’s disease) and he decided out of solidarity to go gluten free.  After six months on a gluten free diet, he returned to his neurologist with significant improvement.  So much so, there were discussions of “down-grading” his diagnosis to PLS!

My own family’s experience, along with surprising patients like Bob, have convinced me it’s imperative to test chronically ill patients for coeliac disease and gluten sensitivity. Here are the highlights from my presentations to physicians and medical students on how I approach testing and treating gluten spectrum disorders (GSD).

When To Test:

Understand GSD as genetic susceptibility acted on by environmental factors. For coeliac, there is more frequent occurrence among family members, and 98% of sufferers carry the genetic haplotypes HLA-DQ2 and/or DQ8.¹

Test the following subsets of patients:

• Those with gastrointestinal symptoms such as frequent diarrhoea, bloating, abdominal distension, symptoms of IBS or severe lactose intolerance, and unexplained weight loss.
• Those with unexplained iron deficiency anaemia, folate or vitamin B12 deficiency, short stature, delayed puberty, issues with fertility, miscarriage, or low birthweight infants, dental enamel defects, peripheral neuropathy, ataxia, recurrent migraines and early osteoporosis. In addition, chronically high aminotransferases, a largely silent chronic liver abnormality, may be a sign of untreated coeliac.
• Individuals with Type 1 diabetes mellitus and first degree relatives with celiac disease—if they have any signs of possible coeliac disease. Also test in asymptomatic first-degree relatives of patients with a confirmed diagnosis of celiac.
• Those of Northern European Ancestry and Italians, I also keep on my radar.
• One of the largest studies in the United States included 13,145 subjects (4,508 first-degree relatives of patients with coeliac disease, 1,275 second-degree relatives, 3,236 symptomatic patients, and 4,126 not-at-risk individuals) who underwent screening. In the at-risk groups, the prevalence of coeliac disease was 1:22 in first-degree relatives, 1:39 in second-degree relatives, 1:56 in symptomatic patients, and 1:133 in the not-at-risk groups.²

How to Test:

The most sensitive and specific blood testing for coeliac disease include the following: HLA DQ2/DQ8 and subtypes, tissue transglutaminase IgA/IgG (anti-tTG), total IgA, total IgG, endomysial IgA and deamidated gliadin peptide (DGP) IgA/IgG. The antibody testing is only useful in those that are actively consuming gluten, while the genetic test will not be affected.^3,4,5,6 Find out if your patient is on a low-gluten or gluten free diet before testing. Keep in mind that interpretation of serology is an art. Sensitivity of serology varies depending upon the severity of the disease. In 101 patients with biopsy-proven coeliac disease the sensitivity of IgA endomysial antibodies (antibodies against gluten) varied from 31% to 100%.⁷ These autoantibodies cause intestinal swelling and, if undetected, can damage the intestinal walls, including the lining of your small intestine.

Below is derived from the 2013 American College of Gastroenterology⁸

• Immunoglobulin A (IgA) anti-tissue transglutaminase (TTG) antibody, (together read as tTG IgA or IgA tTG) is the preferred screening test for detection of celiac disease in individuals over the age of two years.
• Total IgA should be measured, especially if IgA based serology is negative. Alternatively, include both IgA and IgG-based testing. For IgG-based testing, measure IgG-deamidated gliadin peptides (DGPs). In patients in whom low IgA or selective IgA deficiency is identified, IgG-based testing (preferably IgG DGP) is warranted.
• If your patient is on a gluten free diet, first do baseline anti-tTG or IgA endomysial and anti-DGP testing. If your patient tests positive, you may also refer them for a small bowel biopsy. If they test negative, test them for HLA DQ2/DG8. If they test negative on all these, they do not suffer from coeliac disease. If they test positive, encourage them to go on a gluten challenge diet (3 grams of gluten a day for eight weeks) followed by a biopsy and the above blood tests.
• If your patient refuses to go on a gluten challenge diet, or cannot tolerate it, then manage them as you would a coeliac patient. At the same time, consider other diagnoses such as Non-Celiac Gluten Sensitivity (NCGS), wheat allergy, and IBS.^9,10 Patients with a wheat allergy test positive on an IgE serology and skin prick test to wheat. Patients with NCGS test negative for celiac, usually have normal intestinal biopsies, and no wheat allergy. The above are ACG clinical guidelines, but in my clinical reality, I just go ahead and test total IgA, total IgG, tTG IgA/IgG, endomysial IgA and DGP IgG/IgA in a panel.  If they are gluten free, I use the genetic testing and obtain sub-typing without serology (except total IgA).

Why do I practice somewhat differently than the ACG’s 2013 guidelines? I typically see very sick people in my practice and I see a lot of children.  I don’t want to keep having them get their blood drawn and going to multiple appointments, when I can just do the workup all at once.

The most sensitive and specific blood testing for coeliac disease includes the following: HLA DQ2/DQ8 and subtypes, tissue transglutaminase IgA/IgG (anti-tTG), total IgA, total IgG, endomysial IgA and deamidated gliadin peptide (DGP) IgA/IgG.

For NCGS, I go by clinical signs and symptoms.  Unless they already know for sure gluten is an issue, I place them on a gluten free diet for 3 weeks and then have them challenge gluten (keeping the aforementioned journal).  I then have them consume gluten, typically as organic whole wheat bread, three times in one day, waiting up to 72 hours for a reaction (delayed sensitivity).  That reaction can be as flagrant as abdominal pain, headache or rash, or as nebulous as brain fog or irritability.  If there is a positive reaction, one can say with high certainty that that individual has NCGS and they need to avoid gluten.

How to Treat:

Adherence to a gluten-free diet is essential for coeliac patients, and yet studies show that through either deliberate or inadvertent ingestion of gluten, many coeliacs do not have full mucosal healing. Most experts agree there is a difference between the first-year, close follow-up of a newly diagnosed patient and the easier, long-term follow-up of an adherent patient who has recovered on a gluten-free diet.¹¹ To assess and encourage adherence, the following are recommended:

• Always inquire about your patient’s symptoms. IBS symptoms are more common in non-adherent patients.¹²
• Carefully assess your patient’s diet. There are several questionnaires that can be useful.¹³
• Consider repeat biopsy, if symptomatic while on a gluten free diet.
• To improve adherence to a gluten free diet, I provide my patients with a list of gluten containing foods, gluten free resources (fortunately the gluten free market has exploded with more delectable options), including a link to gluten free medications.  I also employ gastrointestinal healing “protocols” that I’ve devised to heal the gut, as well as widen their margin of error, so if they are inadvertently exposed, they don’t become as ill as they once did.
• For extra insurance, I give gluten degrading enzymes to the patient for use if they get cross-contaminated, but this doesn’t allow them to go ad libitum on gluten consumption. None of the enzymes currently available promise total efficacy, although I am optimistic that evolving research will render them more and more efficacious.
• In NCGS, also consider fructose intolerance, lactose intolerance, and FODMAPS (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyol) related symptomology.

References:

1. National Institutes of Health Consensus Development Conference Statement. Celiac Disease 2004. Available at: http://consensus.nih.gov/ (Accessed on October 25, 2004). Look at PMID: 15825115 Published in Gastroenterology. 2005 Apr; 128(4 Suppl 1):S1-9.
2. Fasano A, 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(3):286-92. PMID: 12578508. View Abstract
3. Niveloni S, et al. Antibodies against Synthetic Deamidated Gliadin Peptides as Predictors of Celiac Disease: Prospective Assessment in an Adult Population with a High Pretest Probability of Disease. Clin Chem. 2007 Dec;53(12):2186-92. PMID: 17901114 View Abstract
4. Vermeersch P, et al. Use of likelihood ratios improves clinical interpretation of IgG and IgA anti-DGP antibody testing for celiac disease in adults and children. Clin Biochem. 2011 Feb;44(2-3):248-50. PMID: 20920497 View Abstract
5. Celiac Disease Comprehensive Cascade. Mayo Clinic. 2012
6. Dieterich W, et al. Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology. 1998;115(6):1317-21. PMID: 9834256 View Abstract
7. Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ.Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice.Am J Gastroenterol. 1999;94(4):888-94. PMID: 10201452 View Abstract
8. Rubio-Tapia, et al. ACG clinical guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2013 May;108(5):656-76; quiz 677. PMID: 23609613 View Abstract
9. Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012;107(12):1898-906. PMID: 22825366 View Abstract
10. Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, Gibson PR. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;106(3):508-514. PMID: 21224837 View Abstract
11. Ludvigsson JF, Bai JC, Biagi F, Card TR, Ciacci C, Ciclitira PJ, Green PH, Hadjivassiliou M, Holdoway A, van Heel DA, Kaukinen K, Leffler DA, Leonard JN, Lundin KE, McGough N, Davidson M, Murray JA, Swift GL, Walker MM, Zingone F, Sanders DS. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014 Aug;63(8). PMID: 24917550 View Abstract
12. Sainsbury A, Sanders DS, Ford AC. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: a meta-analysis. Clin Gastroenterol Hepatol 2013;11:359–65.e1. PMID: 23246645 View Abstract
13. Leffler DA, Dennis M, Edwards George JB, et al. A simple validated gluten-free diet adherence survey for adults with celiac disease. Clin Gastroenterol Hepatol 2009;7:530–6, 536 e1–2. PMID: 19268725 View Abstract