Gluten sensitivity has been best recognized and understood in the context of two conditions, celiac disease and wheat allergy. However, some individuals complain of symptoms in response to ingestion of “gluten,” without histologic or serologic evidence of celiac disease or wheat allergy. The term non-celiac gluten sensitivity (NCGS) has been suggested for this condition, although a role for gluten proteins as the sole trigger of the associated symptoms remains to be established. This article reviews the available information regarding symptomatology, epidemiology and genetics, serology and histology, and in vitro and in vivo experimental data on the pathophysiology of NCGS.
- •
Nonceliac gluten sensitivity (NCGS) has emerged as a frequently encountered entity in the clinical setting. Individuals with self-reported NCGS appear to far outnumber those with celiac disease, and may be increasing.
- •
A better understanding of NCGS is hampered by the lack of objective clinical diagnostic criteria and absence of specific biomarkers.
- •
The financial burden on patients is considerable.
- •
In countries where reimbursement or prescription for gluten-free diet exists, the clinician must be aware of the condition and carefully consider the health economic aspects.
Introduction
Celiac disease (CD) is an autoimmune enteropathy triggered by ingestion of wheat gluten and related cereal proteins in genetically predisposed individuals. The ensuing inflammatory response in the small intestine leads to villous atrophy, crypt hyperplasia, and lymphocytic infiltration. Elimination of the gluten proteins from diet generally leads to clinical and histologic improvement. CD is a multigenic disorder, with genes for specific class II human leukocyte antigens (HLA) conferring about 40% of the genetic susceptibility. The primary HLA association is with DQ2 (DQA1 *05/DQB1 02) and DQ8 (DQA1 *0301/DQB1 *0302). The HLA-DQ2 and HLA-DQ8 molecules confer susceptibility for CD by having the important role of presenting specific immunogenic gluten peptides to gluten-specific T cells in the small intestine. The major antibody responses in CD are targeted at (1) gluten proteins, (2) deamidated gluten sequences, and (3) the transglutaminase 2 (TG2) enzyme autoantigen. Among these antibodies, the immunoglobulin A (IgA) anti-TG2 antibody is currently considered the most sensitive and specific serologic marker of CD. Immunoglobulin G (IgG) and IgA antibodies to deamidated gliadin have also been shown to have high sensitivity and specificity for CD. Antibodies to native gliadin proteins have low specificity for CD, and have been reported to be elevated in several other conditions. The presence of these antibodies has been suggested in some studies to be a marker of immune sensitivity to gluten, even in the absence of CD. CD is now understood to have a wide range of clinical manifestations, both intestinal and extraintestinal.
Some of the CD-associated symptoms experienced in response to ingestion of wheat are also reported by individuals who do not have the typical serologic, histologic, or genetic markers of CD, and who also do not experience the immunoglobulin E (IgE) serologic response associated with wheat allergy. The term nonceliac gluten sensitivity (NCGS) has been proposed to refer to the spectrum of conditions reported by these patients. The term nonceliac gluten intolerance has also been used in the past, but is not recommended.
Definition of NCGS
A precise and widely agreed definition of NCGS does not yet exist. NCGS is currently understood as a condition associated with the experiencing of various symptoms in response to ingestion of foods containing wheat, rye, and barley, and the resolution of symptoms on removal of those foods from diet in individuals in whom CD and wheat allergy have been ruled out. The symptoms may be accompanied with an increase in levels of antibody to gluten. The majority of symptoms associated with NCGS are subjective, including abdominal pain, headache, “brain fog,” tingling and/or numbness in hands and feet, fatigue, and musculoskeletal pain. However, other symptoms such as rash and diarrhea, as well as more severe neurologic and psychiatric conditions including schizophrenia and cerebellar ataxia, have also been reported to be associated with NCGS. Table 1 lists the most commonly reported symptoms associated with NCGS in comparison with those of CD and wheat allergy.
| CD | Wheat Allergy | NCGS | |
|---|---|---|---|
| Gastrointestinal | Abdominal pain Diarrhea Constipation | Abdominal pain Vomiting Diarrhea | Abdominal pain Diarrhea Constipation Nausea Vomiting |
| Neurologic/psychiatric | Headache Musculoskeletal pain Brain fog Tingling and/or numbness in hands and feet Fatigue Ataxia | Dizziness Headache | Headache Musculoskeletal pain Brain fog Tingling and/or numbness in hands and feet Fatigue Other neurologic and psychiatric conditions |
| Other | Dermatitis herpetiformis Weight loss | Eczema Asthma Rhinitis Nausea Itchiness | Rash Nausea Weight loss |
Definition of NCGS
A precise and widely agreed definition of NCGS does not yet exist. NCGS is currently understood as a condition associated with the experiencing of various symptoms in response to ingestion of foods containing wheat, rye, and barley, and the resolution of symptoms on removal of those foods from diet in individuals in whom CD and wheat allergy have been ruled out. The symptoms may be accompanied with an increase in levels of antibody to gluten. The majority of symptoms associated with NCGS are subjective, including abdominal pain, headache, “brain fog,” tingling and/or numbness in hands and feet, fatigue, and musculoskeletal pain. However, other symptoms such as rash and diarrhea, as well as more severe neurologic and psychiatric conditions including schizophrenia and cerebellar ataxia, have also been reported to be associated with NCGS. Table 1 lists the most commonly reported symptoms associated with NCGS in comparison with those of CD and wheat allergy.
| CD | Wheat Allergy | NCGS | |
|---|---|---|---|
| Gastrointestinal | Abdominal pain Diarrhea Constipation | Abdominal pain Vomiting Diarrhea | Abdominal pain Diarrhea Constipation Nausea Vomiting |
| Neurologic/psychiatric | Headache Musculoskeletal pain Brain fog Tingling and/or numbness in hands and feet Fatigue Ataxia | Dizziness Headache | Headache Musculoskeletal pain Brain fog Tingling and/or numbness in hands and feet Fatigue Other neurologic and psychiatric conditions |
| Other | Dermatitis herpetiformis Weight loss | Eczema Asthma Rhinitis Nausea Itchiness | Rash Nausea Weight loss |
Past studies of NCGS
Although NCGS has garnered increased attention during the last few years, there have been earlier reports suggesting that the condition is a distinct clinical entity. A study in 1980 described 8 female subjects with abdominal pain and chronic diarrhea who had dramatic relief on a gluten-free diet and a return of symptoms on gluten challenge. CD was ruled out by lack of villous atrophy on a gluten-containing diet, but it was noted that the gluten challenge induced a jejunal cellular infiltrate. The clinical description of these patients is similar to that for patients who are now frequently found in clinical practice and are thought to have NCGS.
In a study using rectal challenge of gluten for investigation of CD, it was shown that about half of nonceliac siblings of CD patients respond to gluten, with epithelial changes and an increase in intraepithelial lymphocyte numbers. It is interesting that this rectal response was not dependent on the presence of HLA-DQ2. The observation suggests that an immune response to gluten can happen in the absence of the HLA-DQ2–restricted, gluten-specific T cells that are central to the development of CD.
Kaukinen and colleagues observed further that intolerance to cereals is not specific for overt or latent CD. Ninety-three adults reporting symptoms in response to ingestion of gluten were recruited. Only 8 patients were found to have CD, 7 could be said to have latent CD, and 19 were positive for allergy tests. Similar data were reported from Campanella and colleagues. One hundred eighty patients on a gluten-free diet because of a diagnosis of CD not based on proper diagnostic criteria were reanalyzed in a tertiary referral setting. In 112 patients gluten was reintroduced to their diet. A definite diagnosis of CD was made in 51 of these patients. Gluten exposure induced clinical symptoms in 71% of the CD patients and in 54% of the nonceliac subjects. The investigators concluded that a clinical response to either withdrawal or reintroduction has no role in the diagnosis of CD. These data correlate well with a recent publication from the Oslo group. Thirty-five patients on a strict, self-introduced, gluten-free diet were recruited after newspaper advertisement and from gastroenterological outpatient clinics. These patients were selected from more than 100 responders based on positivity for HLA-DQ2. Subjects were challenged with gluten-containing sandwich bread for 3 days, and examined with gastroscopy and a newly developed HLA-DQ2–deamidated gliadin peptide tetramer test on the sixth day of challenge. Only 3 of the 35 HLA-DQ2 + patients were diagnosed with CD. The nonceliac patients reported more symptoms than the CD patients.
Gluten sensitivity and neuropsychiatric disease
A connection between CD and certain specific neurologic and psychiatric disorders has been proposed in the last few decades, based primarily only on findings of elevated antibodies to gliadin in affected patients. Some of the most discussed and debated among these include schizophrenia, peripheral neuropathy, cerebellar ataxia, and autism. Recently published reports by two independent groups in the United States using large patient cohorts demonstrate increased circulating levels of antibody to gluten in about a quarter of individuals with schizophrenia. However, new data indicate that the antigluten immune response in these patients differs significantly from that in CD, displaying a unique antigenic specificity that is apparently independent of the action of transglutaminase enzyme and presentation by HLA-DQ2 and HLA-DQ8 molecules. As such, the majority of such patients may belong to the NCGS category rather than the CD category. Case reports and small studies indicate improvement in response to gluten-free diet in some patients with schizophrenia, although double-blinded and placebo-controlled trials are still lacking.
Similarly, elevated antibody reactivity to gluten has been reported in up to 40% of patients with idiopathic sporadic ataxia. Other investigators have shown similarly higher prevalence of increased antibody reactivity to gliadin in both sporadic and hereditary ataxias. Most of these patients do not appear to have the specific serologic markers of CD and may again fit more appropriately within the NCGS spectrum. A study with a cohort of patients with ataxia and elevated antigliadin antibodies has shown a positive response to gluten-free diet in some individuals. However, the pathogenic relevance of the increased antibody response to gliadin in the different forms of ataxia and the potential effect of gluten-free diet on disease remain subjects of debate.
A possible association between autism and CD was first discussed by Dohan more than 40 years ago. In both the scientific and lay literature, dietary gluten proteins have been suggested to be associated with or to play a role in the etiopathogenesis of autism, either directly as circulating partially digested peptides with opioid-like properties, or through the body’s immune response to them. Whereas some studies have pointed to an increase in the prevalence of CD, family history of CD, or antibodies to gluten among autistic children, others have ruled out an association. The inconsistency in results has been attributed to methodological differences in assaying, variation in patient diagnostic instruments, and the lack or incompleteness of controls. In addition, the effect of gluten-free diet on autism-spectrum disorders has received considerable attention. Diets that exclude gluten are becoming increasingly popular in the autism community, although their effectiveness has not been shown in controlled studies. A Cochrane database systematic review in 2008 reported that the evidence for a gluten- and casein-free diet in autism was weak, calling for large-scale, good-quality randomized controlled trials.
It is becoming increasingly clear that at least some of the neurologic and psychiatric deficits previously thought to be associated with CD may be more aptly attributed to NCGS. Substantial additional work is needed to understand whether and how gluten may contribute to the pathogenesis of certain neuropsychiatric conditions.
Epidemiology and genetics
Reliable epidemiologic studies of NCGS have not been published. According to an article in The Wall Street Journal , some experts think as many as 1 in 20 Americans may have some form of NCGS. The data behind such an estimate remain elusive. It is also estimated that the market for gluten-free food, as of 2010, was $2.6 billion. This figure would suggest that a considerable proportion of the United States population is consuming gluten-free foods. Data from both scientific and lay literature suggest that there is greater public recognition of gluten sensitivity than of CD. Whereas the “low-carb diet” was widely adopted in the years after 2000, this diet has shown a steady decline since 2005. On the other hand, the popularity of the gluten-free diet has shown a steady increase since 2008 and is expected to increase further. Although the prevalence of CD in the United States is around 1%, most of these patients are undiagnosed and the known celiacs make up a relatively small fraction of the consumers of gluten-free products. High-quality genetic studies on the NCGS population have not been performed as yet. There are no data suggesting that the condition follows the same HLA-DQ2/-DQ8 association as CD.
Diagnosis of NCGS
In clinical practice, it is typical to meet patients who have commenced a gluten-free diet without formal evaluation for food sensitivity. There are many reasons as to why they have started the diet. Some receive suggestions from family members and relatives who may have CD. Others have received advice from dieticians or “alternatively orientated doctors.” In many cases, their diet has resolved their symptoms. In other cases, the patients continue their diet although the symptoms remain uncontrolled. In the authors’ experience, NCGS patients usually maintain a strict gluten-free diet, even though they might not have received professional advice. In addition, there is a high rate of misdiagnosis among patients with a formal diagnosis of CD, shown to be as much as 20% in one study.
The clinical workup for diagnosis of NCGS usually focuses initially on the exclusion of CD and wheat allergy. Serologic testing is particularly useful in this regard, including testing for IgA antibodies to TG2, as well as IgG and IgA antibodies to deamidated gliadin for CD, and IgE antibodies to wheat proteins for wheat allergy. HLA typing may also be particularly useful, as negativity for HLA-DQ2 and HLA-DQ8 has an excellent negative predictive value for CD. Skin-prick testing is an additional tool for ruling out wheat allergy. The task of exclusion is difficult in the case of a patient already on a strict gluten-free diet. If the patient in fact has CD, the mucosa may have recovered and the serology could also be negative. However, in many cases the mucosal damage persists for a definite diagnosis, so a small intestinal biopsy can be taken and serologic tests performed, even if the patient is on a gluten-free diet already. In other cases, a short gluten challenge may be necessary.
The definitive diagnosis of NCGS can so far only be made through gluten challenge. It is reasonable to demand that the patients’ symptoms be under good control before initiation of a gluten challenge. The clinical response after gluten challenge might be variable but usually overlaps with symptoms of CD to a large degree. The need for performing a double-blinded, placebo-controlled food challenge (DBPCFC) is a controversial issue. A single-day DBPCFC with capsules containing wheat flour has been used and is recommended, but has been disappointing in the authors’ hands (Rudihaugen J, unpublished results, 2006). The American Gastroenterological Association technical review from 2001 recommended a DBPCFC, and this was also recommended in a recent review and a workgroup report. Others have emphasized the limitations and impracticality of the DBPCFC and consider the procedure not suitable in a normal clinical setting. Virtually none of these publications have addressed the investigation of NCGS as the clinical entity encountered today.
The authors generally perform an open challenge with 4 slices of white sandwich bread (approximately 4 g gluten per slice). As this challenge is not blinded, one could expect a substantial placebo effect. However, the clinical responses picked up by this method seem to overlap with those seen after blinded challenge. There is no clear agreement on how to perform symptom evaluation after challenge. The authors have used symptom scoring with the following questionnaires: Short Form (36) Health Survey (SF-36), Scoring System for Subjective Health Complaints (SHC), and Gastrointestinal Symptom Rating Scale for IBS (GSRS-IBS). None of the validated CD-specific symptom questionnaires have been applied to NCGS investigation. A consensus among clinicians on how to diagnose NCGS is urgently needed. Fig. 1 shows a proposed algorithm for the diagnosis of NCGS.
