Neurological disease with GAD antibodies and gluten sensitivity

Posted on September 2, 2010 by Dr. Jonathan

GAD (glutamic acid decarboxylase) antibodies are expressed in type 1 (autoimmune) diabetes, adrenal failure (Addison disease), autoimmune thyroid diseases, premature ovarian failure, myasthenia gravis, pernicious anemia, Stiff-man syndrome and a number of other disorders. An informative study recently published in Acta Neurologica Scandinavica documents the link between these conditions and gluten sensitivity. The authors state:

“The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases.”

They used ELISA assays for GAD antibodies and serological markers of gluten sensitivity that generated compelling data:

“”Six of seven (86%) patients with SPS were positive for anti-GAD…This compared with 9/90 (11%) patients with idiopathic sporadic ataxia…16/40 (40%) patients with gluten ataxia…and 6/10 patients with type 1 diabetes only…”

Note that the serological tests for gluten sensitivity are a blunt instrument—only 40% of confirmed cases of gluten ataxia were recognized. The abundance of false negatives is why the gluten gene sensitivity test is so valuable.

Additionally, the authors found that…

“The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity.”

Their conclusion is simply stated:

“These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.“

This study is especially interesting in connection with earlier research published in the journal Psychiatry. The authors set out to investigate the role of GAD antibodies in schizophrenia and related disorders:

“We hypothesized that GAD antibodies are increased in patients with chronic psychotic disorders. The aim of this pilot study was to compare the level of GAD antibodies in patients with chronic psychotic disorders with normal controls.”

By way of background they note that:

“The role of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, and premenstrual dysphoric disorder has been a subject of some recent investigations. Absence of structural abnormalities in the brains of most patients with chronic psychotic disorders has always raised suspicion for an alternative pathogenesis and a possible functional disturbance at the neuronal/cellular level. Glutamic acid decarboxylase (GAD)…is involved in the formation of gamma aminobutyric acid (GABA) a central inhibitory neurotransmitter of the nervous system. Antibodies to GAD may impair GABA formation or inhibitory function.“

What did the data show?

“Serum levels of GAD antibodies in 12 patients with chronic psychotic disorders (schizophrenia and schizoaffective disorders) and 10 age-matched healthy control subjects were evaluated… Antibodies to GAD in patients with chronic psychotic disorders have a higher mean than nonpatient control individuals.”

The authors’ conclusion alerts the practitioner to be on the lookout:

“Antibodies to GAD65 are peripherally present in patients with chronic psychotic disorders (schizophrenia/schizoaffective disorders)... The presence of such antibodies also suggests a possible role for autoimmune mechanism in the pathogenesis of these disorders. In summary, from a practicing psychiatrist’s point of view, measurements of antibodies to GAD65 could potentially be used to screen for chronic psychotic disorders and for diabetes mellitus very early on in the disease process.”

GAD (glutamic acid decarboxylase) produces GABA, the most abundant inhibitory (calming) neurotransmitter in the body. Suboptimal levels can manifest as anxiety, insomnia, hyperarousal, panic, feeling overwhelmed, disorganized attention, restlessness, worry, tension, inner excitability, inability to relax, etc.

Feeling uncoordinated? Gluten sensitivity and ataxia

Posted on August 25, 2010 by Dr. Jonathan

A paper published a while back in the prestigious medical journal The Lancet is a useful reminder of a common neurological disorder resulting from gluten sensitivity that manifests as problems with coordination and balance. The authors state:

“Ataxia is the commonest neurological manifestation of coeliac disease. Some individuals with genetic susceptibility to the disease have serological evidence of gluten sensitivity without overt gastrointestinal symptoms or evidence of small-bowel inflammation. The sole manifestation of disease in such patients may be ataxia.”

The authors carried out clinical, neurophysiological, neuroradiological, and neuropathological examinations patients with antibodies to gliadin (the immunoreactive component of gluten):

“28 patients with gluten ataxia were identified. All had gait ataxia and most had limb ataxia….16 patients had no gastrointestinal symptoms…Six patients had evidence of cerebellar atrophy on magnetic-resonance imaging. Necropsy was done on two patients who died; there was lymphocytic infiltration of the cerebellum, damage to the posterior columns of the spinal cord, and sparse infiltration of the peripheral nerves.”

A key point is that most of the patients whose gluten sensitivity caused severe neurological damage had no gastrointestinal symptoms.

The authors conclude:

“Gluten sensitivity is an important cause of apparently idiopathic ataxia and may be progressive. The ataxia is a result of immunological damage to the cerebellum, to the posterior columns of the spinal cord, and to peripheral nerves.“

Children with constipation: cow’s milk intolerance in more than one third

Posted on August 4, 2010 by Dr. Jonathan

A study recently published in the Journal of Pediatric Gastroenterology and Nutrition reminds us that bovine (cow’s) milk allergy or intolerance can cause childhood constipation even though the laboratory tests are negative. The authors first note:

“It has been reported that a number of children with constipation respond to a diet free of cow’s-milk (CM) proteins, although evidence is lacking to support an immunoglobulin E-mediated mechanism.”

They found that thirty-five of 69 children (51%) improved during an initial CM-free diet phase with a significant increase in bowel movements per week; 39% developed constipation during the CM challenge and improved during the second CM-free phase. Interestingly…

“Seventy-eight percent of the children with developmental delay responded to the CM-free diet.”

The authors conclude:

“A clear association between CM consumption and constipation has been found in more than one third of children. However, analytical parameters do not demonstrate an immunoglobulin E-mediated immunologic mechanism.”

I want to draw your attention to the final comment about the absence of IgE antibodies. I have found any kind of antibody test (IgE, IgG, IgA) to be unreliable for the diagnosis of food allergy or intolerance due to numerous factors that can prevent their expression, resulting in false negatives (the allergy is present but undetected by the test). The immunological ‘gold standard’ is the elimination-provocation protocol (as conducted in this study).

There is a broad range of neurologic disorders in children with gluten sensitivity

Posted on July 26, 2010 by Dr. Jonathan

This paper recently published in the journal Pediatrics draws attention to our concern for the non-celiac manifestations of gluten sensitivity, especially the neurological dimension. The authors note importantly that:

“During the past 2 decades, celiac disease (CD) has been recognized as a multisystem autoimmune disorder. A growing body of distinct neurologic conditions such as cerebellar ataxia, epilepsy, myoclonic ataxia, chronic neuropathies, and dementia have been reported, mainly in middle-aged adults…The aim of the present study is to look for a broader spectrum of neurologic disorders in CD patients, most of them children or young adults.”

They found a much greater prevalence of neurological disorders in children with CD compared to normal controls: 51.4% to 19.9%, including hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia.

The authors conclude:

“This study suggests that the variability of neurologic disorders that occur in CD is broader than previously reported and includes “softer” and more common neurologic disorders, such as chronic headache, developmental delay, hypotonia, and learning disorders or ADHD.”

Bear in mind that we are equally concerned with the neurologic manifestations of gluten sensitivity in the absence of celiac disease.

Gluten-free diet can improve depression and behavioral problems in adolescents

Posted on May 28, 2010 by Dr. Jonathan

As the authors of this study published in the journal BMC Psychiatry observe:

“Coeliac disease in adolescents has been associated with an increased prevalence of depressive and disruptive behavioural disorders, particularly in the phase before diet treatment.”

We are equally concerned with the ‘non-celiac’ aspects of gluten sensitivity. Gluten related inflammation in the brain can manifest as a host of cognitive, emotional and neurodegenerative disorders in the absence of intestinal manifestations. This is often referred to as “silent celiac disease”:

“Coeliac disease is an under-diagnosed autoimmune type of gastrointestinal disorder resulting from gluten ingestion in genetically susceptible individuals. Non-specific symptoms such as fatigue and dyspepsia are common, but the disease may also be clinically silent.”

They further note that:

“”Depressive symptoms and disorders are common among adult patients with coeliac disease, and depressive and disruptive behavioural disorders are highly common also among adolescents, particularly in the phase before diet treatment. Recently 73% of patients with untreated coeliac disease – but only 7% of patients adhering to a gluten-free diet – were reported to have cerebral blood flow abnormalities similar to those among patients with depressive disorders.”

Their data revealed abnormalities in tryptophan assimilation (tryptophan is the amino acid precursor to serotonin) and prolactin levels in adolescents with celiac disease and depression prior to treatment. Consequently…

“A significant decrease in psychiatric symptoms was found at 3 months on a gluten-free diet compared to patients’ baseline condition, coinciding with significantly decreased coeliac disease activity…”

They also make a fascinating observation that links gluten sensitivity, inflammation, and the serotonergic aspect of depression unrelated to malabsorption:

“…increased production of interferon-γ (IFN-γ), known to be the predominant cytokine produced by gluten-specific T-cells in active coeliac disease, can suppress serotonin function both directly and indirectly by enhancing tryptophan and serotonin turnover…even without malabsorption.”

To diagnose gluten sensitivity in the absence of celiac disease the gluten gene sensitivity test is the most reliable method for a number of reasons.

Female reproductive disorders and gluten sensitivity

Posted on April 30, 2010 by Dr. Jonathan

Minverva Ginecologica As the authors of this paper published in the journal Minerva Ginecologica state:

“In the past coeliac disease, or intolerance to gluten, has been considered a rare disease in infancy, whose most important signs were chronic diarrhea with malabsorption and reduced growth. However, besides this classical form, there are a number of other clinical and subclinical forms which may appear even in the adult life and without any overt intestinal sign.”

The authors defined their objective:

“The aim of the present paper is to describe and evaluate the effects of coeliac disease on female reproduction. Such effects include delayed menarche, amenorrhea, infertility and early menopause.”

In addition, they noted that…

“Epidemiological studies show that besides reduced fertility, affected women are at higher risk of reproductive problems such as pregnancy loss, low birthweight of offspring and reduced duration of breastfeeding…the possible prevention or treatment of the reproductive effects is only the lifelong maintenance of a gluten-free diet.”

Another paper published in the Journal of Reproductive Medicine reports on a case that highlights the link between gluten sensitivity and amenorrhea. The authors’ conclusion:

“Celiac disease should be considered in patients presenting with malnutrition and primary amenorrhea.”

This was followed by a much more extensive study published recently in the same journal. The authors summarize an extensive body of literature on the subject:

“In women, this disease (celiac, gluten sensitivity) may have implications on menstrual and reproductive health. The symptom complex includes delayed menarche, early menopause, secondary amenorrhea, infertility, recurrent miscarriages and intrauterine growth restriction. These women benefit from early diagnosis and treatment. Therefore, celiac disease should be considered and screening tests performed on women presenting with menstrual and reproductive problems and treated accordingly.”

They offer an exhortation to doctors in their conclusion:

“Evidence in the literature suggests that celiac disease should be suspected in females with menstrual abnormalities, infertility and adverse pregnancy outcome. All health care providers should be aware of these diverse manifestations of the disease. Treating the disease has a benefit and may lead to prevention of symptoms and improvement in the quality of life…It is challenging to identify women with silent celiac disease and treat them with a gluten-free diet and nutrient supplements, which may lead to prevention of menstrual and other reproductive dysfunction.”

Another paper published in the journal Gynecologic and Obstetric Investigation focuses on the impact of gluten sensitivity on the reproductive cycle, fertility, pregnancy, and menopause. The authors explain that…

“Celiac disease (gluten-sensitive enteropathy) may manifest clinically with an array of nongastrointestinal symptoms among which are: dermatitis herpetiformis; dementia; depression; various neurological symptoms; osteoporosis; osteomalacia; dental enamel defects, and anemia of various types. Important data have accumulated in recent years regarding the association between celiac disease, fertility and pregnancy. Many primary care obstetricians and gynecologists and perinatologists are not aware of these important relationships.”

What does the scientific evidence establish?

“Review of the literature reveals that patients with untreated celiac disease sustain a significantly delayed menarche, earlier menopause, and an increased prevalence of secondary amenorrhea. Patients with untreated celiac disease incur higher miscarriage rates, increased fetal growth restriction, and lower birth weights.”

An interesting paper that dramatically shows the difference between adhering and not adhering to a gluten free diet for female reproductive health was published in the Journal of Clinical Gastroenterology:

“This study shows a broad analysis of gynaecological and obstetrical disturbances in patients with celiac disease in relation to their nutritional status and adherence to a gluten-free diet.”

In their investigation the authors analyzed data on adults and children/adolescents with gluten sensitivity, taking into consideration nutritional status and gluten-free diet adherence, and compared them to adults and adolescents with irritable bowel syndrome (not due to gluten) as a control group. What did the data show?

“…adult celiac patients, irrespective of the nutritional status…presented delayed menarche, secondary amenorrhea, a higher percentage of spontaneous abortions, anemia and hypoalbuminemia…After treatment, patients presented with normal pregnancies and one patient presented spontaneous abortion. The adolescents who were not adherent to gluten-free diet presented delayed menarche and secondary amenorrhea.”

They state what should by now be obvious in their conclusion:

“Therefore, celiac disease should be included in the screening of reproductive disorders.”

Important: gluten sensitivity without celiac manifestations (1) must be treated the same way as celiac disease and (2) cannot be diagnosed by the usual celiac tests for tissue transglutaminase antibodies, etc. Antibody levels, including anti-gliadin (gluten) antibodies, can fluctuate for a number of reasons resulting in false negatives. The gluten gene sensitivity test can be relied on for a dependable result. This post could go on at great length but the message is clear: for female reproductive disorders gluten sensitivity must be considered as a possible contributing cause.

Men: you are not immune. I am finding gluten sensitivity to be a common cause of low testosterone levels (hypogonadia).

If I’m sensitive to gluten, can I eat corn or oats?

Posted on March 11, 2010 by Dr. Jonathan

This becomes an important question when someone realizes how much they benefit from avoiding gluten due to celiac disease or non-celiac gluten sensitivity. The evidence suggests that corn (maize) has to be considered on an individual basis. It is possible, but not certain, that you may react to corn when you are sensitive to wheat gluten.

GUT Consider this study that was published in the journal GUT, An International Journal of Gastroenterology and Hepatology. The authors investigated how nitric oxide is part of the intestinal inflammatory reaction reaction to gluten, and how it relates to the white blood cell response. They noted this in their conclusion:

“Mucosal activation of neutrophils and eosinophils [white blood cells] precedes pronounced enhancement of mucosal NO [nitric oxide] production after rectal wheat gluten challenge in patients with coeliac disease. Some of our coeliac patients displayed signs of an inflammatory reaction, as measured by NO and granulocyte markers, after rectal corn gluten challenge.”

So it depends on the individual. The more serious your condition the more important it is to check yourself for corn sensitivity with the immunological ‘gold standard’—a properly managed elimination-provocation protocol.

We are also bereft of a perfectly decisive indication for oats because rare individuals can react, though this study published in the Scandinavian Journal of Gastroenterology indicates that most celiac patients can tolerate them. First the authors note that…

“We have…identified three adult coeliac disease patients who developed a flare of active coeliac disease after ingestion of oats, which suggests that oats might not be entirely innocent in coeliac disease.”

They set out to compare the immune response to oats and wheat by comparing production of the main intestinal antibody (IgA) that participates in the reaction. Although other immune activity was observed,…

“No significant differences were found in IgA against oats in oats-eating and non-oats-eating coeliac disease patients.”

Their conclusion:

“Ingestion of oats does not cause increased levels of IgA against oats in adult coeliac disease patients on a gluten-free diet. The findings support the notion that most adult coeliac disease patients can tolerate oats.”

Note the “most”. And even if you are not sensitive to oats, it is important to be sure that they are certified gluten-free. Otherwise they can be contaminated with gluten during storage, transport, processing and packaging.

What about blood tests for food allergies? Too many variables influence antibody tests for them to give a reliable indication. If you have a serious condition with an autoimmune basis, it’s best to consult with a functional medicine practitioner who can help you through an elimination-provocation protocol (eliminating and re-introducing foods), and who knows how to use objective lab tests to profile your immune imbalance.

Gluten sensitivity and brain disease: neuronal transglutaminase

Posted on March 8, 2010 by Dr. Jonathan

The authors of this paper published in Annals of Neurology make an important statement:

“Gluten sensitivity typically presents as celiac disease, a chronic, autoimmune-mediated, small-intestinal disorder. Neurological disorders occur with a frequency of up to 10% in these patients. However, neurological dysfunction can also be the sole presenting feature of gluten sensitivity.”

Antibodies directed toward transglutaminase in the gut are a well-known diagnostic feature of celiac disease. These investigators have identified another member of the transglutaminase family:

“…a novel neuronal transglutaminase isozyme and investigated whether this enzyme is the target of the immune response in patients with neurological dysfunction.” They found that “Whereas the development of anti-transglutaminase 2 IgA is linked with gastrointestinal disease, an anti-transglutaminase 6 IgG and IgA response is prevalent in gluten ataxia, independent of intestinal involvement.”

(Ataxia is loss of the ability to coordinate muscle movement, especially as it appears with difficulty walking.) Their conclusion:

“Antibodies against transglutaminase 6 can serve as a marker…to identify a subgroup of patients with gluten sensitivity who may be at risk for development of neurological disease.“

If you are gluten sensitive, you can have neurological disease without celiac involvement.

Increase in death risk from gluten-related gut inflammation

Posted on February 2, 2010 by Dr. Jonathan

This paper published in JAMA (The Journal of the American Medical Association) recently examined the risk of death associated with celiac disease. The investigators found a modest but significant increase in risk of death not only with celiac, but also with latent celiac disease and small intestine inflammation. They note that “This risk increase was also seen in children.” The take home message here is that even in the absence of gastrointestinal symptoms (“latent celiac disease”), there is an overall negative impact. The authors’ conclusion: “Risk of death among patients with celiac disease, inflammation, or latent celiac disease is modestly increased.”

Vitiligo must be treated as an autoimmune disorder

Posted on January 7, 2010 by Dr. Jonathan

It has come to my attention that many are still not aware that vitiligo, a condition that causes skin to lose its normal pigmentation, is an autoimmune disorder and must be treated as such. A cursory review of the literature turns up an abundance of evidence:

Experimental Dermatology Frontiers and controversies in the pathobiology of vitiligo: separating the wheat from the chaff

“There is a body of interlocking, compelling evidence supporting an autoimmune basis for most or all cases of generalized vitiligo. The development of an autoimmune disease generally involves three components; the immune system, environmental triggers and other exogenous precipitating factors, and the target tissue. In vitiligo, precipitating factors could induce melanocyte damage in genetically susceptible individuals and consequent cell death, loss of tolerance, and induction of melanocyte-directed autoimmunity.”

Immunological pathomechanisms in vitiligo Expert Reviews in Molecular Medicine

“Briefly, circulating autoantibodies and autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. In addition, vitiligo is often associated with other disorders that have an autoimmune origin, including Hashimoto’s thyroiditis, Graves’ disease, type 1 insulin-dependent diabetes mellitus and Addison’s disease.”

Current Directions in Autoimmunity-Dermatologic Autoimmune Etiology of Generalized Vitiligo

“Vitiligo is characterized by progressive skin depigmentation resulting from an autoimmune response targeting epidermal melanocytes…Type I cytokine-mediated immunity to melanocytes in vitiligo involves T cells reactive with melanosomal antigens…”

Journal of Investigative Dermatology Autoimmune Destruction of Skin Melanocytes by Perilesional T Cells from Vitiligo Patients

“Our data show that perilesional cytotoxic T cells eradicate pigment cells, the characteristic hallmark of vitiligo, thereby providing evidence of T cells being able to mediate targeted autoimmune tissue destruction.”

Archives of Dermatological Research Prediction and prevention of autoimmune skin disorders

“Autoimmune diseases can be preceded by a symptom-free phase which is defined by the presence of autoantibodies, and may last for many years…Characteristic autoantibodies and susceptible genes have been identified in many autoimmune systemic and mucocutaneous diseases such as systemic lupus erythematosus, pemphigus, vitiligo, dermatitis hepretiformis and even psoriasis…Prevention of overt disease may be achieved once high-risk individuals are identified and triggering factors are avoided. Numerous environmental factors, such as vitamin D deficiency, ultraviolet light, smoking, drugs, etc., that may trigger autoimmunity have been found.”

Moreover, an interesting and important connection with conditions such as autoimmune thyroiditis and type 1 diabetes has been observed:

Autoimmune Aspects of Vitiligo Autoimmunity

“In brief, the disease is frequently associated with other disorders which have an autoimmune origin such as autoimmune thyroiditis and insulin-dependent diabetes mellitus. Furthermore, circulating antibodies and T lymphocytes which react against melanocyte antigens are present in the sera of a significant proportion of vitiligo patients compared with healthy individuals.”

Acta Dermato-Venerologica High frequency of thyroid dysfunction in patients with vitiligo

“An association between vitiligo and autoimmune thyroid disease has previously been suspected…There appears to be an increased frequency of clinical as well as subclinical thyroid disease in patients with vitiligo. Our findings support the theory of vitiligo being an autoimmune disease and indicate a need for screening vitiligo patients for thyroid disease.”

Of keen interest and significance is the overlap with genes involved in gluten sensitivity:

HLA-DQA1*0301-Associated Susceptibility for Autoimmune Polyglandular Syndrome Type II and III Thieme eJournals

“We determined the HLA-DR and HLA-DQA1 association in 112 unrelated patients with APS II (n = 29), APS III (n = 83) and 184 unrelated patients with single-component diseases without further manifestations of APS: Graves’ disease, Hashimoto’s thyroiditis, autoimmune Addison’s disease, vitiligo and alopecia…”

Due to its prevalence, treating the causes of autoimmunity is a major part of a functional medicine practice.