Gluten Free Diets – A Challenge for the Practicing Physician (2024)

Introduction

In recent years, gluten free diets have become commonplace. Nearly one-third of all Americans report that they have either tried to reduce the amount of gluten in their diet or tried to eliminate it altogether.¹ In 2016, the sales on gluten free products sold in the U.S. were over $15.5 billion.² The proportion or prevalence of people attempting to follow a gluten free diet is highest in Latin America. The Middle East is second highest, and the United States has the third highest prevalence.³ Fueled by a confluence of testimonials by celebrities and other well-known public figures and relentless marketing, many people are of the opinion that a gluten-free diet is useful for better health, is more nutritious, will help in a variety of non-gastrointestinal illnesses, and will aid in weight loss and in improved athletic performance. However, these claims, for the most part, are without any scientific basis.

There are abundant data that prove that gluten free diets are life-saving for those with celiac disease and are a lifelong necessity. Yet, less than 1% of the population has celiac disease (CG), and only about 6% of the population carry the diagnosis of gluten sensitivity but not celiac disease (non-celiac gluten sensitivity - NCGS). However, when tested rigorously with a double-blind study, only 16–30% of the NCGS population show signs that it is the gluten to which they are sensitive.² IgE mediated allergy to gluten is quite rare, less than 0.4–0.9% of the population, and usually found in young children. Yet, the percentage of those in the U.S. who are on a gluten free diet has risen steadily in recent years. A 2014 CDC report showed that 72% of persons on a gluten free diet had neither gluten sensitivity nor celiac disease, an increase from 2009, when it was 44%.^2,4

So why should a practicing physician care that people are wasting their money buying gluten free products that will not add to their health or longevity? Surely we should be spending our valuable time spent with our patients on other more pressing and less contentious matters. After all, when a patient tells us that since they started on a gluten free diet they sleep better at night, have lost 10 pounds, and have a better tennis game, should we not just acquiesce and move on to another topic? Yet, the more well-informed we are regarding the benefits and hazards of these diets, the more compelling is the case that we should at the very least inform the patients that these diets have some very real long term hazards for most patients, and for some patients, warn them that their choice to begin on a largely gluten free diet may put them at very high risk for a bad outcome.

Risks of a Gluten-Free Diet – Undiagnosed Celiac Disease

So, what are the facts? What are the serious risks the patients may be inadvertently taking? Probably the most common severe risk comes with patients who are at high risk for celiac disease and do not know it. Celiac disease is a severe autoimmune disease which can destroy the small intestinal lining and cause a multitude of problems, some related to the intestinal malabsorption and inflammation and others that are extraintestinal in nature. A sizeable number of patients may have no symptoms and there is a small, but not insignificant, risk of intestinal lymphoma, or even adenocarcinoma of the small intestine in the long term. The keys to diagnosis of celiac disease are the presence of a specific genetic genotype (HLA-DQ2 and/or HLA-DQ8 genes) and the presences of highly specific autoantibodies, the IgA tissue transglutaminase antibodies (IgAt), antiendomysial antibodies (IgA EMA), and/or deamidated gliadin peptide (IgG) antibodies. Usually the IgAt antibody is used for screening, and confirmation is by the IgA EMA antibody. The disease is triggered by exposure to the environmental antigen, gluten.⁵ Gluten is a protein found in wheat, barley, rye, and spelt, and contains a mixture of prolamins and glutenins. These proteins are rich in prolines and glutamines and are incompletely digestible by intestinal enzymes. These indigestible proteins are potentially immunogenic and in patients with the genetic predisposition of the HLA antigens DQ2 or DQ8, a cascade of immunomodulated events are triggered that begin with disruption of the epithelial barrier of the small intestine, an immediate transient increase in gut permeability, followed by a cascading sequence of recruitment of multiple components of the immune system, and eventually causing the destruction of the intestinal villae. This sequence is accompanied by rising titers of both IgAt antibodies and IgA EMA antibodies.

Malabsorption of food may follow, leading to failure to thrive in children, widespread vitamin and protein deficiencies, pain and disability. The key to early diagnosis and avoidance of the pathological immunological cascade is early detection of the specific serum antibodies, particularly the IgAt. It is important to also recognize that this sequence is triggered by exposure to gluten and, in some patients, the amount of gluten required can be very small. Unfortunately, if the patient is already on a strictly gluten free diet, the titer of the antibody, which is at least two times higher than the upper limit of normal, begins decreasing and may become undetectable, delaying the diagnosis. If either avoidance of gluten is incomplete or the patient is very sensitive to very small amounts of gluten, long-term damage and risk of other extraintestinal complications may ensue.

Unfortunately, a strict gluten free diet in a patient with established celiac disease does not guarantee that healing will result, and medical evaluation and follow-up by a gastroenterologist is needed. There is a consensus among experts in celiac disease that if your patient is desirous to be on a gluten free diet, if there is any risk at all that they have a form of celiac disease, it is wise to ask them to first undergo a challenge with gluten and obtain the antibody titer after the challenge in order to rule out missed celiac disease. Unfortunately, if a person with undiagnosed celiac disease chooses to be on a gluten free diet before they are diagnosed, a gluten challenge of at least three months or more may be needed in adults before elevated levels of antibodies occur. There are reports that in children it may take up to a year for them to redevelop diagnostic antibody levels. If that person with celiac disease becomes symptomatic with a rechallenge of gluten after only a day or two, since the duodenal biopsy may not be diagnostic after being on a gluten free diet, it creates a dilemma for the patient and the physician, as to how to prove whether they have underlying celiac disease or not.

One option, albeit an imperfect one, is to do genetic testing, for if the patient does not have genes for the HLA-DQ2/DQ8, it would be improbable that their symptoms are due to celiac disease. Unfortunately, these genes are common in the general population, in some ethnic groups as high as 40%, and while a negative test for HLA DQ2/DQ8 genes makes celiac disease very unlikely, if the test is positive it does not prove they have celiac disease, since most people with the HLA DQ2/DQ8 genes do not have celiac disease. If IgA deficiency is present, since IgA antibody titers are no longer useful, IgG deamidated gliadin peptide antibodies may be used to screen for celiac disease. If the antibody titer is now elevated, the next step is a duodenal biopsy, which is considered to be the gold standard for the diagnosis of celiac disease. However, there are European guidelines which recommend that in children a biopsy can be avoided, (but not in adults), if the patient has an IgAt antibody titer greater than 10x the upper limit of normal of the assay, and the presence of the HLA DQ2/DQ8 genes, and a positive IgA EMA obtained at a time that is different from the time of the screening IgAt antibody test, and a family history that suggests high risk. The IgA EMA measurement is primarily used only as a confirmatory test. Although in clinical practice testing for HLA-DQ2/DQ8 genes is less often performed, when biopsy results and antibodies are discordant, checking for the HLA DQ2/DQ8 genes is indicated, because only very rarely can a patient have celiac disease without the presence of the genes.

It is important to check the family history carefully, since there is a very high concordance of celiac disease in families, particularly in first order relatives, and highest in monozygomatic twins (75–80%).⁶ Also, there are numerous disorders with an autoimmune basis that are much more likely to be found in patients with celiac disease, such as Addison’s disease, type 1 diabetes, Hashimoto’s thyroiditis, Graves’ disease, dermatitis herpetiformis, autoimmune hepatitis, primary sclerosing cholangitis, rheumatoid arthritis, Sjogrens syndrome, systemic lupus, as well as other disorders such as IgA deficiency, idiopathic dilated cardiomyopathy, cerebellar ataxia, and chromosomal diseases such as Downs syndrome, Turner syndrome, and Williams syndrome. The presence of one of these conditions should also trigger a search for celiac disease.

Cost and Social Issues with Gluten Free Diets

One of the many challenges patients with celiac disease face is that a lifelong pattern of being on a strict gluten free diet is difficult, socially isolating, extremely expensive, and the diet itself increases the risk for nutritional deficiencies. The public is largely unaware of the expense of the diet. A recently reported study by Lee et al. shows that in the U.S., the cost of a well-balanced gluten free diet is about 240% or more than a comparable well-balanced diet. Certain types of gluten-free foods are often over 300% higher in cost, and the prices vary considerably in different parts of the U.S.⁷

Gluten Free Diets May be Nutritionally Inferior

Because of the physical and chemical characteristics of gluten – it is viscoelastic, rich in nutrition, and can easily be made into bread and baked – it is difficult to substitute for, and many of the commonly used substitutes are not fortified with the nutrients commonly found in gluten containing products. Numerous studies have shown that diets that are gluten free tend to be deficient in protein, folate, iron, niacin, riboflavin, thiamin, B12, zinc, selenium, and fiber. In addition, they are more apt to have higher levels of nickel, which is highly allergenic to some patients.^1,2 These diets may also contain higher levels of arsenic, mercury, cadmium, lead, and higher levels of fat, saturated fats, and cholesterol.⁸ It can be quite challenging to obtain the correct nutritional balance with a strict gluten free diet, and the list of foods to avoid when eating out is sufficiently daunting that it tends to encourage patients to avoid restaurants and become obsessive about their food choices.

Social Costs

Several researchers have carefully evaluated the degree to which a gluten free diet has a negative social impact on patients who do not have celiac disease but are choosing a gluten free diet in hope of other benefits. In one study, 11% of respondents reported that following a gluten free diet led to high levels of interference with social leisure activities.² The respondents noted that they spent more money on the diet, spent more time on the food preparation, and wound up eating more at home, and enjoying their time eating much less than if they had not been following this diet. There are even reports of some patients developing an obsessive disorder, which is termed orthorexia nervosa, and obsession about healthy eating which can become very destructive.²

Long-Term Cardiovascular Risks of Gluten Free Diets

Other documented problems that persons on a gluten free diet face is weight gain. In general, unless the diet is constructed by a skilled professional, gluten free diets tend to have increases in the fat content of the foods. Although weight gain in an underweight patient with celiac disease is often welcome initially, in patients who do not have an indication for a gluten free diet, weight gain is often an unwelcome surprise and it may be accompanied by abnormal lipids and a higher risk for coronary heart disease. Hyperglycemia and an increase in insulin resistance and obesity has been reported as well.² These diets are also not recommended for a pregnant woman.

Non-Celiac Gluten Sensitivity (NCGS)

Patients who have been tested and do not have either celiac disease or IgE mediated wheat allergy, but have demonstrated sensitivity to gluten are initially considered to have non-celiac gluten sensitivity (NCGS). As many as 6% of the population in the United States may have this condition. These patients often experience intestinal or extraintestinal symptoms related to the ingestion of gluten. The intestinal symptoms may include diarrhea, constipation, bloating, and abdominal pain, and the extraintestinal symptoms include fatigue, anxiety, fibromyalgia, headaches, and mental “fogginess”. These patients have negative serologic markers for celiac disease and no evidence of duodenal villous atrophy.

In controlled, randomized, blinded studies, patients without celiac disease, but with a HLA DQ2 or DQ8 haplotype tended to be more likely to be sensitive to gluten. However, careful testing on many patients who tested negative for celiac disease and were negative for HLA DQ2/DQ8 genes, but who had been on a gluten free diet and considered themselves to have gluten sensitivity, did well on a low FODMAP diet. FODMAP diets are diets that contain low levels of fermentable oligosaccharides, di-and monosaccharides, and polyols that are poorly absorbed in the small intestine. While in the gut, these saccharides are often fermented by intestinal bacteria, leading to production of short chain fatty acids which are very active metabolically, and also increase bowel osmolality, increasing gut motility and gas formation.⁹ When gluten was then reintroduced to the diet of these patients, there was no specific effect, suggesting that although a gluten free diet shares some features with low FODMAP diets, it is the low FODMAP diet that is therapeutic.¹⁰ Other items may also masquerade as gluten sensitivity, such as amylase trypsin inhibitors, commonly found in wheat. Also, fructans, which are common among the FODMAPS that are common in diets,¹¹ nickel allergy, small intestinal bacterial overgrowth, or lactose intolerance may also be confused with NCGS.¹²

One effort to establish objective criteria for the diagnosis of NCGS, which does not have any unique diagnostic feature, is the Salerno Expert’s Criteria (2015), a consensus strategy of an initial six-week observation period of a gluten free diet, followed by a reintroduction of gluten.¹³ This should be blinded, ideally double blinded, but in a clinical practice a single blinded method is used. Most authorities recommend the blinded studies should not use gluten capsules added to a gluten free diet, but instead prefer foods that are very similar, but one group of meals contains gluten, and the others do not. This is not easy to do, as the texture of non-gluten foods is often quite different. Clearly this testing procedure has several shortcomings. Nevertheless, for the patient who firmly believes they have NCGS, a blinded trial may be an appropriate choice before committing a patient to a lifetime of a regiment of a gluten free diet.

Overlap of Symptoms of NCGS or CD with IBS

Many patients who have symptoms of irritable bowel syndrome (IBS) will try a gluten free diet and some patients report that they have improved on a gluten free diet. Yet, a number of medical societies, in their guidelines and systematic reviews, are very careful to recommend against using a gluten free diet in the treatment of IBS.^14,15 The reasoning behind these recommendations is relevant to our discussion, as the study of patients who are categorized as having IBS illustrates some of the complexities that we face when we counsel patents regarding gluten free diets.

Many clinicians consider diet to be a key factor in the treatment of the heterogeneous group of patients who initially may present as possibly having an IBS. Perhaps the first order of business is to be sure that the diagnosis is correct, for many different GI conditions may have features of IBS. Each of these patients should also be checked for IgAt antibodies, and, if they are IgA deficient, deamidated IgG gliadin antibodies would be an alternative. After other diseases, such as inflammatory bowel disease, small intestinal bacterial overgrowth, etc., have been ruled out, and the diagnosis of IBS has been established, treatment of IBS can begin. Some of the research regarding treatment of IBS discusses FODMAP diets. Gluten free diets also tend to be somewhat lower in FODMAPS, but when patients without celiac disease but with symptoms that are compatible with IBS are put on low FODMAP diets, may of these patients have a reduction in symptoms, and are surprised when reintroduction of gluten later does not cause symptoms. Because the evidence supporting gluten free diets in IBS is lacking, both the Canadian Association of Gastroenterology guideline and the Italian Pediatric Gastroenterological Association systematic reviews, in their dietary treatment recommendations, include a trial on FODMAPS, but not on a gluten free diet.^14,15 It is important to note that the FODMAP diet is considered to be a temporary diet, as it is widely recognized that long-term the FODMAP diet, as is the gluten free diet, is not usually nutritionally sound and long-term use is to be avoided if possible.¹⁴ Many patients who have had IBS-like symptoms and have chosen to start a gluten free diet would be better served to be evaluated first for celiac disease and a number of other causes of IBS-like symptoms and then, after a careful workup, if a dietary change is suggested, to first consider FODMAP diets as part of a careful evaluation. It is important to reemphasize that neither a low FODMAP diet nor a gluten free diet are prescribed for healthy patients, but are reserved for those who have a diagnosis that indicates that such a diet will have a benefit that outweighs the risks.

Conclusion

Americans spend more than $30 billion dollars annually on health foods, herbal preparations, anti-aging potions of various sources and a wide variety of diets, of which low-gluten diets are just one option. It is unlikely that physicians, even armed with the facts, are likely to prevail in all discussions with patients about which diets should not be used. Food is so central to most people that by the time they reach adult age, they often have many strong opinions about how best to eat. However, the gluten free diets are more frequently used as a choice for diets today throughout much of the world. Those persons who do so without a clear medical indication often have very limited knowledge about the risks and benefits of gluten free diets, and often are quite grateful when a physician provides evidence-based advice,¹⁶ allowing them to decide whether this popular diet is right for them, or rather a mistake that should be corrected.

Footnotes

References