Gluten Sensitivity

Problems of an Emerging Condition Separate From Celiac Disease

Amy C Brown

Expert Rev Gastroenterol Hepatol. 2012;6(1):43-55.

Lack of Diagnostic Criteria

Both celiac disease and gluten sensitivity are non-IgE-mediated immune-mediated food reactions,^[6] but differ in how they are diagnosed.

Biopsy Criteria

The gold standard for celiac disease is detection of flat villi through an upper endoscopy biopsy of the small intestine. However, according to the classification proposed by Marsh in 1992, the spectrum of gluten enteropathy is wide and can range from only intraepithelial increased lymphocytes to complete villous atrophy.^[6] The four Marsh stages reflect a series of mucosal changes presented as a continuous spectrum of mucosal deterioration due to gluten exposure.

According to the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) current criteria, duodenal villous atrophy (Marsh stage III and onwards) is the necessary criteria for diagnosing celiac disease and recommending a gluten-free diet. This now obsolete assumption was based on the traditional misinterpretation that Marsh I infiltrative lesions (also known as lymphocytic enteritis) were not associated with any symptom or sign of malabsorption. Multiple findings have since suggested that villous intraepithelial lymphocytosis can now serve as histological index for many untreated adult celiac disease patients.^[7–11] Moreover, the majority of patients with dermatitis herpetiformis only exhibit duodenal biopsies consistent with the Marsh I stage.^[12–14] Tortora and Colleagues in Italy suggested that an in vitro response of mucosal HLA-DR to gliadin is an accurate tool for the diagnosis of celiac disease and also in patients with difficult diagnosis.^[15]

Despite these observations, caution is still necessary before diagnosing celiac disease in patients with Marsh I lesions. Intraepithelial lymphocytic infiltration can be a common, nonspecific inflammatory response of the epithelium to a number of noxious or inflammatory signals. A new committee of experts is currently working on new revised ESPGHAN guidelines, in which Marsh I will be considered as a part of the celiac disease diagnostic spectrum, as well as avoiding biopsies in cases of very high antitransglutaminase antibodies.^[16]

Gluten Sensitivity

People with gluten sensitivity test negative for celiac disease and wheat allergy, but experience resolution of symptoms on a gluten-free diet. Confirmation is obtained by following the gluten-free diet with a monitored reintroduction of gluten. The possibility of a placebo effect exists, unless blinded capsules containing gluten or nongluten material are offered during the challenge. The American Dietetic Association has published guidelines for the dietary treatment of celiac disease. Referrals to a registered dietitian for dietary instruction would best benefit these patients.^[202]

Laboratory Tests

A primary serological test is the current diagnosis of celiac disease – that is, antitransglutaminase IgA. Although controversial, others suggest that deamidated gliadin peptide IgA, IgG^[17] and anti-endomysial antibodies (EMAs) can also be ordered.^[18] Unlike a classic allergy, which involves an IgE response, celiac disease involves an IgA and/or IgG immune system response to dietary gluten. Sapone et al. suggested that the big difference between celiac disease and gluten sensitivity is that the latter is negative for autoantibodies against tissue transglutaminase and EMAs or autoimmune comorbidities.^[19]

Table 2 shows that this leaves few, if any, laboratory tests in the detection of gluten sensitivity. The field continues to wax and wane as other experimental tests surface to aid in the detection of celiac disease (Box 1).

Testing Problems

Serological tests for celiac disease can be problematic. Transglutaminase IgA titers correlate linearly with the stage of the histological lesion, with a higher sensitivity for celiac disease diagnosis in patients with villous atrophy.^[20–22] As such, transglutaminase IgA sensitivity approximates 90% in pediatric cases, but only 15–30% in adults. In addition, transglutaminase IgA is very low in children in whom only lymphocytic enteritis is observed. On the other hand, Marsh I can represent >50% of cases in adults. This well-known low sensitivity of transglutaminase IgA in diagnosing adult-onset celiac disease also limits its use in population screening.

Unfortunately, prior gluten ingestion by celiac disease patients is required to make the above biopsy or serological tests accurate. This may not be an option for some patients experiencing abdominal pain and or other symptoms following gluten ingestion. It is additionally difficult for patients who have already eliminated gluten from their diet. The duration of gluten exposure is debated because histological changes occur in some cases within as little as 1 day, while others suggest 3 or more months.^[23] Catassi and Fasano suggested that 50 mg of daily gluten for at least 3 months was necessary to deteriorate intestinal villous height and crypt depth ratio.^[24] One slice of bread contains approximately 4500 mg of gluten, so 50 mg is a 90th of a slice. Gluten exposure is just one of the possible factors contributing to negative or inconclusive tests.

Another problem in testing people for celiac disease or gluten sensitivity is that the biopsy procedure can be invasive and expensive. Serologically positive patients in China preferred the simpler gluten-free diet over the invasive procedure of a duodenal biopsy.^[25]

Unfortunately, people seeking relief of symptoms may be subjected to advertised nonstandard and expensive 'stool, saliva or allergy' tests with limited reliability.

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Next Section

Abstract and Introduction
Lack of a Standard Definition for Gluten Sensitivity
Lack of Diagnostic Criteria
Delayed Diagnosis
Are Gluten Sensitivity Rates Rising?
What is Causing the Gluten Sensitivity Problem?
Treatment: Gluten-free Diet
Expert Commentary
Five-year View
References
Sidebar

Table 1. Subgroups of celiac disease.
Subgroups	Approximate percentage	Symptoms	Diagnostic tests
Classical	<50	Gastrointestinal Malabsorption	Positive serology Biopsy evidence of villous atrophy Gluten-free diet improves symptoms
Atypical	>50	Lacks gastrointestinal symptoms Extraintestinal manifestations predominate	Same as above
Silent	20	Asymptomatic	Positive serology Biopsy evidence of villous atrophy
Latent	Unknown	Usually asymptomatic at first, but may eventually develop symptoms and/or villous atrophy	Positive serology No biopsy evidence of villous atrophy
Refractory	1	Clinical and serological abnormalities nonresponsive to gluten-free diet (~1%)	Persistent symptoms after 6 months on strict gluten-free diet

Adapted from [92,93]

Table 2. Serological testing for celiac disease versus gluten sensitivity.
Test^†	Celiac disease	Gluten sensitivity
ATA or anti-tTG^‡ – IgA^§/IgG	Positive	Negative
EMAs^§ – IgA/IgG	Positive	Negative
DGPs AGAs^¶	Positive	Positive?
AGAs^# – IgA/IgG	Not recommended	Not recommended
Wheat allergy	Negative	Negative
Genetic testing for HLA-DQ and HLA-DQ8^††	Supports diagnosis	Unknown
Biopsy (flattened villi)^‡‡	Positive	Negative
Lactulose/mannitol	Positive	Negative
Albumin, cholesterol, complete blood count	Possibly low	Unknown
Alkaline phosphatase (bone loss indicator), prothrombin time	Possibly high	Unknown
Clotting factors, liver enzymes (transaminases)	Possibly abnormal	Unknown
Gluten-free diet response	Positive	Positive

†Antibody testing is only accurate if the person's diet contains gluten for at least 1–6 months (varies by source) prior to testing. The amount of time is based on current practice and has not been firmly established through evidenced-based research.
‡ATA or anti-tTG released from damaged intestine during active disease. The intestinal T-cell response to a-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase.
§EMAs detect antibodies to tissue transglutaminase. Replaced by ATA or anti-tTG.
¶Tests for deamidated gliadin antibodies are considered experimental by Aetna. IgG DPGs and AGAs appear to have specificity for celiac disease and gluten sensitivity, as well as for cerebellar ataxia without intestinal involvement.
#IgG AGAs no longer routinely recommended because of their lower sensitivity and specificity: approximately 50% for both celiac disease and gluten sensitivity. Recommended that this test be abandoned and replaced by ATAs or anti-tTG. However, ATA or anti-tTG and EMA are inaccurate in infants, so AGA are ordered.
††Most patients with celiac disease are HLA-DQ2(+), with the remaining few expressing HLA-DQ8. These two class II molecules present gluten peptides to the gluten-specific T cells found only in the gut of celiac disease patients, but not controls. Karell et al. noted that approximately 6% of adult celiac patients with villous atrophy did not express a DQ2 or DQ8 haplotype [94].
‡‡Celiac disease is patchy so at least four to five biopsy specimens should be obtained, including samples from the duodenum's more distal segments and bulb area. Pathologists experienced in celiac disease detection are recommended.
Approximately 10% of celiac disease patients are IgA deficient, so both IgA and IgG should be used along with total IgA to determine whether there is an IgA deficiency.
AGA: Antigliadin antibody; Anti-tTG: Autoantibodies against the transglutaminase protein; ATA: Antitissue transglutaminase antibodies; DGP: Deamidated gliadin antibody; EMA: Anti-endomysial antibody.
Adapted from [92,95]. © 2011 Amy Brown.

Box 1. Experimental tests available.
Tissue tG2 IgA antibodies to tG2 in the intestine can be another tool to relate gluten sensitivity to neurological impairment. IgA intestinal deposits may reflect villous atrophy [96].
Epidermal tG3 Antibodies to tG3 may be markers for dermatitis herpetiformis.
Brain tG6 Antibodies to tG6 are markers for neurological disorders.
Plasma citrulline A nonprotein amino acid produced by enterocytes that reflect their functional mass so levels are lower in celiac disease patients [97].
Urinary nitric oxide
Intestinal inflammation has been reported to increase levels of urinary nitric oxide metabolites, nitrite and nitrate in people with celiac disease [98].

Box 2. Selected possible symptoms of celiac disease.
Gastrointestinal^† Nausea Gas Bloating Abdominal pain Diarrhea Constipation Vomiting Increased risk of cancer of the intestine (adenocarcinoma), pharynx and esophagus, as well as non-Hodgkin lymphoma
Malabsorption Fatigue or weakness Anemia Muscle cramps Bone or joint pain Arthritis Easy bruising Aphthous ulcers Dental enamel defects Weight loss Failure to thrive in infants/children Osteopenia/osteoporosis
Reproductive Late menarche/early menopause Infertility Miscarriages
Skin & joint Irritation Dermatitis herpetiformis Arthritis
Neurological
Concentration and memory problems Headaches or migraine (may be due to cerebral calcifications; reverses with gluten-free diet) Mood swings or depression Seizures Cerebral ataxia (damage or degeneration of nerve cells in the part of the brain controlling muscle coordination resulting in lack of coordination; 60% have MRI evidence of cerebellar atrophy) Peripheral neuropathy

^†Less than half of newly diagnosed celiac patients exhibit classic gastrointestinal symptoms.
Adapted from [64,92,93,99–103].
© 2011 Amy Brown.

Box 3. Selected conditions that may warrant celiac disease screening.
Addison's disease [104] Allergic disease [89] Autism (controversial) Autoimmune liver disease Diabetes Type 1 Down's syndrome Eosinophilic esophagitis [105] Infertility [106] Psoriasis [107] Rheumatoid arthritis Schizophrenia (subset) [108] Selective IgA deficiency Sjögren's syndrome [109] Systemic lupus erythematosus [110] Thyroid diseases – Autoimmune thyroiditis – Graves's disease – Primary hypothyroidism
Turner syndrome William's syndrome