Gluten Sensitivity

Problems of an Emerging Condition Separate From Celiac Disease

Amy C Brown

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

Delayed Diagnosis

A major problem for people with gluten sensitivity is that physicians using tests for celiac disease simply state that the client does not have celiac disease, leaving uniformed patients to fend for themselves. Symptoms continue, but the yet unanswered question remains: 'Are people with gluten sensitivity at risk for the same long-term, serious systematic side-effects of celiac disease (Box 2)?'

It is suggested that the debate on whether or not gluten sensitivity even exists is interfering with the very real need of it being recognized, treated and researched. It is time to recognize the numerous clinical cases of gluten sensitivities in adults and the need to formally confirm this through research. In addition, a renewed recognition needs to occur of the already medically established fact that a second bimodal wave of celiac disease can occur in adults, and not just in infants and children under 3 years of age with the classic symptoms of stunted growth, emaciation, anemia, pot-belly, diarrhea and foul smelling, pale stools. The failure to recognize that celiac disease can also occur later in life, results in a time to diagnosis that is often up to a decade. Is the same scenario occurring for patients with gluten sensitivity?

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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