As is often the case, I was digging around on something else and stumbled onto a more interesting topic.
In this case, it was that gluten intolerance not only causes folks to have bowel issues, but that there is a more subtle cluster of symptoms that folks might have, and never “make the connection” to wheat. For one, a friend has fibromyalgia and it is one of the possible causes.
In particular, the complex is called “Gluten-sensitive enteropathy-associated conditions” and yes, there’s a wiki on it (and the obligatory three letter acronym of GSE):
Gluten-sensitive enteropathy-associated conditions
Gluten-sensitive enteropathy (GSE) has key symptoms typically restricted to the bowel and associated tissues; however, there are a wide variety of associated conditions. These include bowel disorders (diarrhoea, constipation, irritable bowel), eosinophilic gastroenteritis and increase with coeliac disease (CD) severity. With some early onset and a large percentage of late onset disease, other disorders appear prior to the celiac diagnosis or allergic-like responses (IgE or IgA, IgG) markedly increased in GSE. Many of these disorders persist on a strict gluten-free (GF) diet, and are thus independent of coeliac disease after triggering. For example, autoimmune thyroiditis is a common finding with GSE.
However, GSEs’ association with disease is not limited to common autoimmune diseases. Coeliac disease has been found at increased frequency on followup to many autoimmune diseases, some rare. Complex causes of autoimmune diseases often demonstrates only weak association with celiac disease. The frequency of GSE is typically around 0.3 to 1% and lifelong risk of this form of gluten sensitivity increases in age, possibly as high as 2% for people over 60 years of age. This coincides with the period in life when late-onset autoimmune diseases also rise in frequency.
Genetic studies indicate that coeliac disease genetically links to loci shared by linkage with other autoimmune diseases. These linkages may be coincidental with how symptomatic disease is selected from a largely assymptomatic population.
So the basic point of that is simply that there’s a load of autoimmune related stuff going on, and wheat may have an involvement. It gets worth with age (and length of exposure?) and can rise as high as 1 in 50.
I’m not going to quote the whole thing, you can hit the link for that, but just to give the flavor of it, here’s the table of contents:
1 Associated blood disorders
1.3 Clotting abnormalities
2.1 Dermatitis herpetiformis
2.2 Atopy, urticaria, eczema
2.3 Rare dermatitis
2.4 Alopecia areata
3 Endocrine disorders
3.1 Autoimmune thyroidosis
3.3 Addison’s disease
4 Gastrointestinal diseases
4.1 Irritable bowel (IBS)
4.2 Inflammatory bowel disease (IBD)
4.3 Gastroesophageal reflux disease
4.4 Eosinophilic oesophagitis
4.5 Diseases of the pancreas, gall bladder, bile duct
5 Neurological disorders
5.1 Peripheral neuropathies
5.3 Dementia and epilepsy
5.4 Visual and auditory disturbances
5.5 White matter lesions
5.9 Chronic fatigue
6 Connective tissue disorders
6.2 Still’s disease
8 GSEA Nephritis
9 Precancerous states
10.1 Esophageal cancer
That’s one heck of a load of “associated” stuff. Anyone with any of those might benefit from trying a gluten free diet. That isn’t as easy as you might think, since just skipping toast and cereal in the morning is not enough. Wheat is all over the place in all sorts of things. Even Cherios Oat Cereal had it until recently ( one supposes enough folks complained so they swapped to corn starch…) You simply MUST read labels for this to work. For example, a great many “cream soups” have wheat flour as the thickener as do many (most?) gravies.
I’m going to focus in on just a couple on the list that have a particular ‘connection’ for me. Friends or family with similar symptoms.
First up, the general tendency for anything that screws around with the bowel to cause all sorts of malnutrition symptoms. (This ought to apply as well to folks with other food sensitivities / immune reactions, like my reaction to corn and the general tendency for BT toxin in GMO foods to cause bowel irritation issues). Any bold bits are my doing.
Avitaminosis. Avitaminosis caused by malabsorption in GSE can result in decline of fat soluble vitamins and vitamin B, as well as malabsorption of essential fatty acids. This can cause a wide variety of secondary problems. Hypocalcinemia is also associated with GSE. In treated GSE, the restrictions on diet as well as reduced absorption as a result of prolonged damage may result in post treatment deficiencies.
Vitamin A – Poor absorption of vitamin A has been seen in coeliac disease. and it has been suggested that GSE-associated cancers of the esophagus may be related to vitamin A deficiency 
Folate deficiency – Folate deficiency is believed to be primary to the following secondary conditions:
Calcification of brain channels – Epilepsy, Dementia, Visual Manifestations.
B6 deficiency. Vitamin B6 deficiency can result in neuropathies and increases in pain sensitivity. may explain some of the peripheral neuropathies, pain and depression associated with GSE.
Vitamin D deficiency. Vitamin D deficiency can result in osteopenia and osteoporosis
Vitamin K – Coeliac disease has been identified in patients with a pattern of bleeding that treatment of vitamin K increased levels of prothrombin.
Vitamin E – deficiency of vitamin E can lead to CNS problems  and possibly associated with myopathy
Mineral deficiencies. GSE is associated with the following mineral deficiencies:
Calcium – Hypocalcemia  causing Oesteopenia
Magnesium – hypomagnesemia, may lead to parathyroid abnormalities.
Iron – Iron deficiency anemia
Phosphorus – hypophosphatemia, causing Oesteopenia
Zinc – Zinc deficiencies  are believed to be associated with increased risk of Esophagus Carcinoma
Copper – deficiency 
Selenium – deficiency  – Selenium and Zinc deficiencies may play a role increasing risk of cancer. Selenium deficiency may also be an aggravating factor for autoimmune hyperthyroidism (Graves disease).
Carnitine – deficiency.
Prolactin – deficiency (childhood).
homocysteine – excess.
Megaloblastic anemia (MA) is associated with GSE and is believed to be the result of B12 and folate deficiency. In GSE, is appears to be associated with the IgA-less phenotype. Unlike other forms of megaloblastic anemia, GSEA MA is not a form of autoimmune gastritis.
Pernicious anemia (PA). Pernicious anemia is associated with GSE and is believed and results primarily from malabsorption phenomena.
Iron-deficiency anemia. Iron-deficiency anemia (IDA) may be the only symptom for CD, detected in subclinical CD and is accompanied by a decrease in serum ferritin levels. This can cause addition problems (see:symptoms of IDA and certain conditions like such as Paterson-Brown Kelly (Plummer-Vinson). Whereas IDA is corrected on GF diet, refractory disease or gluten-sensitive malignancies can cause persistent IDA.
The point? IFF you are wheat reactive, it might be showing up as all sorts of things that are entirely unrelated to bowel irritation, or the typical symptoms associated with wheat problems. That laundry list of nutrient impacts can have symptoms all over the place.
One friend has had asthma. No, it’s not on the TOC above, but buried under “dermatitis”:
A study of patients with dermatitis herpetiformis or coeliac disease revealed significantly more gluten in the blood than controls. This increases the risk of asthma, anaphylaxis and dermatological conditions.
Triticeae glutens are the primary cause of dermatitis herpetiformis(DH). Epidermal transglutaminase (eTG) is related to tTG and is the autoantigen of DH. It appears that all DH patients have or are susceptible on wheat ingestion to CD. Within CD DH is relatively rare or underdiagnosed with about 5% of patients having DH. Aphthous stomatitis is a common mouth lesion found with celiac disease.
So you ought to read the whole list in the wiki to see if you have some unexplained or hard to cure symptoms that are listed in an unexpected place in that parade of “issues”. I’m not going to quote it all here, and there are many such bits of “what the?” in it.
Several family and friends have migraine headache issues. One has fibromyalgia. She also just LOVES to start the day with a big bowl of wheat based cereals…
Neuropathies tend to be associated with late-onset celiac disease. Dementia and ataxia appear to be more common. A recent study of children with neuropathies revealed no increase of CD in early-onset neuropathies. Although many studies link CD to various neuropathies such as migraine, encephalopathy, chorea, brain stem dysfunction, myelopathy, mononeuritis multiplex, Guillain-Barre-like syndrome, and antiganglioside-positive neuropathy with antibodies, strong associations remain largely unconfirmed in epidemiologic studies. A recent study looking for changes in the physiology of the brain found regional cerebral hypoperfusion in 73% of untreated CD. The calcification of channels at the surface of the brain appears to be a leading phenomenon associated with migraine, visual, auditory, schizophrenia, epilepsy, dementia. The problem is that while these are found increased in GSE, the cause of these calcifications is unclear and this may extend beyond GSE to other immunological or allergic phenomena. A 2007 study in Sweden of 14,000 GSE patients revealed no association of CD with multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, hereditary ataxia, ataxia(the symptom), Huntington’s disease, myasthenia gravis, or spinal muscular atrophy, but prior polyneuropathy was associated with subsequent CD. However, a 2009 study of myasthenics revealed that 1 in 23 had high levels of anti-transglutaminase.
Peripheral neuropathies are greatly increased in people who have GSE. In clinical CD there is on obvious reason; avitaminosis and the inability to adsorb essential fatty acids and vitamins can lead to nervous system problems, including sensitivity of the peripheral nervous system. In addition to these problems there are a number or rare autoimmune conditions, secondary autoimmunities, such as fibromyalgia that are more frequent in GSE than in the normal population. Gulliane-Barre syndrome is associated with peripheral neuropathies, and it has been found that anti-ganglioside autoantibodies take part in the binding to axons and schwann cells. Antibodies to these gangliosides have been found elevated in coeliac disease
While this is hardly a “smoking gun”, anyone with migraines will know that you will give anything a try to make them stop, or even get just a little better. And folks with fibromyalgia basically get a migraine like feeling all over their bodies sometimes, and just plain hurt much of the rest of the time. For folks dealing with that, going gluten free for a month or two is a small price to pay for an assessment of the impact on pain.
Or maybe you just generally feel upset and like crap.
Anxiety is a common feature of GSE; treatment on a gluten-free diet is effective at reducing anxiety, some aspect of which may be due to malabsorption phenomena and cytokine activity (i.e. constant stress).
Fibromyalgia was found in 9% of adult patients relative to 0.03% in the general population with a link common to IBD. Concurrent IBS is found in 30% to 70%. Small intestinal bacterial overgrowth is associated is common with a transient response to antimicrobial therapy.
Chronic fatigue associated with GSE is a systemic disorder, however there are neurological components that are especially manifest in blood deficiencies like avitaminosis, amineralosis and anemia. Reduced iron and the lack of vitamins folate, B6, B12 and malabsorption of essential fatty acids can cause depression and chronic fatigue. Anti-gliadin antibodies correlate with higher risk for chronic-fatique when no clinical finding of CD is present. While fatigue is reduced on gluten-free diet, bouts of depression can become worse. 
So about a 1:10 chance of cutting wheat helping the fibromyalgia. For me, that’s in the “worth a shot” range.
Then there is the “biggie” for me:
Connective tissue disorders
Some instance of arthritis with small bowel villous atrophy have been found to resolve on gluten free diet, and anti-connective tissue antibodies have been found in increased levels in celiac disease. Anti-rheumatoid factor antibodies are also increased. In addition, cross-reactive anti-beef-collagen antibodies (IgG) may explain some rheumatoid arthritis (RA) incidences. Although the presence of anti-beef collagen antibodies does not necessarily lead to RA, the RA association with Triticeae consumption is secondary to GSE and involves DRB1*0401/4 linkages to DQ8 and is debatable. In one instance rhuematoid arthritis was tied directly to refractory disease.
As I’ve noted several times, eating beef more than once / week causes my joints to get ‘creaky’, i.e. arthritis symptoms start. That there is a wheat angle too interests me a great deal. A preliminary reduction of wheat seems to have had some benefit, and “falling off the wagon” seemed to have a return of mild discomfort. I have a cake to finish before I try the wheat free trial again, and a few more “on/off” cycles to prove a connection; but early indications are that it has some impact.
It goes on into a nephritis that correlates with calcium oxalate levels (spouse had an oxalate kidney stone) and then into ‘precancerous states’ that look to be correlated.
Clin Med Res. 2004 Feb; 2(1): 71–72.
Celiac Disease: Celiac Sprue, Gluten-sensitive Enteropathy
Anita I. Gheller-Rigoni, DO, Steven H. Yale, MD, and Ahmad S. Abdulkarim, MD
WHAT IS CELIAC DISEASE?
Celiac Disease (CD) or gluten-sensitive enteropathy is a T-cell mediated disease occurring in genetically susceptible individuals induced by the ingestion of one of several proteins found in wheat (gliadins), barley (hordeins) and rye (secalinin). Symptoms classically include episodic diarrhea, abdominal pain and distention and weight loss. Approximately one half of adults develop clinically significant diarrhea. Interestingly, only one half of all patients with CD have symptoms referable to the gastrointestinal tract.
So there is a genetic component, and you can have “issues” without having G.I. “issues”… The good news is you can have a blood test for it.
Serologic markers are used to screen patients with suspected CD and/or monitor their response and adherence to treatment with a gluten-free diet. Serological studies currently in clinical use include IgA endomysial antibody (IgA-EMA) and IgA tissue transglutaminase antibody (IgA-tTG). Antigliadin antibodies IgA and IgG (AGA) have moderate sensitivity but are less specific compared to IgA-EMA and -tTG antibodies (table 1). Antigliadin antibodies are generally not useful clinically due to the emergence of the more sensitive and specific EMA and tTG antibodies, and therefore their use as a screening test is no longer recommended (table 2).
If you dig into it more, you find (eventually) that HLA-DQ2 is one of the key bits.
HLA-DQ2 (DQ2) is a serotype group within HLA-DQ (DQ) serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles, DQB1*0201 and DQB1*0202. HLA-DQ2 and HLA-DQB1*02 are almost synonymous in meaning. DQ2 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1 alleles, to form the cis-haplotype isoforms. These isoforms, nicknamed DQ2.2 and DQ2.5, are also encoded by the DQA1*0201 and DQA1*0501 genes, respectively.
DQ2 is most common in Western Europe, North Africa and East Africa. Highest frequencies are observed in parts of Spain and Ireland; this distribution correlates with the frequency of two of the most prevalent autoimmune diseases. There is also an increase in DQB1*0201 in Central Asia, peaking in Kazakhstan and declining slowly west to east into China and finally Southeast Asia. DQA1*0501 : DQB1*0201. DQ2.5 is one of the most predisposing factors for autoimmune disease. DQ2.5 is encoded, often, by a haplotype associated with a large number of diseases. This haplotype, HLA A1-B8-DR3-DQ2, is associated with diseases in which HLA-DQ2 has suspect involvement. Direct involvement of DQ2 is certain in coeliac disease.
They then start looking at the particular variations on that gene.
DQ2.5 refers to either a protein isoform and a genetic (chromosomal) haplotype. DQ2.5 isoform or heterodimer is shorthand for the cell surface receptor HLA-DQ α5β2. Frequently called ‘the DQ2 heterodimer’, the DQ2.5 isoform is actually one of two common DQ heterodimers, the other being DQ2.2. DQ2.5 haplotype is created by close genetic linkage of two alleles, written as a haplotype, DQA1*0501:DQB1*0201. The haplotype encodes DQ2.5cis isoform, referring to the cis arrangement of the DQA1*0501 and DQB1*0201 on the same variant of chromosome 6. The isoform can also be encoded trans-haplotype (between two sister chromosomes) forming the DQ2.5trans isoform. This isoform occurs when a person has the DQ7.5/DQ2.2 phenotype.
DQ2.5 and the linked DR3 are associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotypes. The haplotype is positively associated with coeliac disease, dermatitis herpetiformis, juvenile diabetes, Lambert-Eaton myasthenic syndrome (LEMS), Sjögren’s syndrome, and autoimmune hepatitis (although significant proportion of the risk is secondary to coeliac disease). DR3 and/or DQ2.5 are linked to the following diseases: Moreen’s ulceration, “bout onset” multiple sclerosis, Grave’s disease and systemic lupus erythematosus.
In celiac disease
DQ2 represents the second highest risk factor for coeliac disease, the highest risk is a close family member with disease. Due to its link to coeliac disease, DQ2 has the highest association of any HLA serotype with autoimmune disease, close to 95% of all coeliacs have DQ2, of that 30% have 2 copies of DQ2. Of the DQ2 homozygotes who eat wheat, lifelong risk is between 20 and 40% for coeliac disease.
So folks with ANY autoimmune disease are more likely to have the particular genetics that make wheat sensitivity an issue. Oh, and if you have Irish ancestors, well… it gets worse:
DQ2.5 and gluten
As mentioned the DQA1*0501:DQB1*0201 haplotype produces DQ2.5cis which by frequency and efficiency in alpha-gliadin presentation is the major factor in adaptive immunity. The isoform, referred to frequently as the DQ2 heterodimer or DQ2 (DQA1*05:DQB1*02) and more recently DQ2.5 can be differentiated from responses from other DQ isoforms, including other DQ2. Specifically, that this DQ2 heterodimer is responsible for presenting the α2-gliadin that most effectively stimulates pathogenic T-cells.
The highest risk for coeliac disease is in Western Ireland and overlaps one of three global nodes of the DQ2.5 haplotype in Western Europe. The DQ2.5 haplotype is linked to DR3 and DR3 is not linked to DQ2.2. Therefore, using either serotyping or genotyping, DQ2.5 can be distinguished from DQ2.2 or DQ2.3. The refined studies of risk and immunology suggest that all DQ2 can mediate coeliac disease, but that DQ2.5 is the primary genetic risk factor. A genome wide survey of markers linked to CD, reveals that highest linkage is for a marker within the DQA1*0501 allele of the DQ2.5 haplotype. The association of DQB1*0201 is almost as high. Greatly elevating risk is the ability of the DQ2.5 haplotype encoded isoforms to increase abundance on the cell surface in DQ2.5 double homozygotes. While most people can form two or four different isoforms of DQ. Double homozygotes (of DQA1 and DQB1) can only form DQ2.5cis. This occurs when a person inherits a DQ2.5cis bearing chromosome from each parent. While the frequency of DQ2.5 haplotype is only 4 times higher than the general population, the number of DQ2.5 homozygotes is 10 to 20 times higher than the general population. Multiple copies of the DQ2.5 haplotype do not cause apparent increases of severity, DQ2.5/DQ2 increases risk of life threatening complications and more severe histological findings. Of the approximately 90% of coeliacs that bear the DQ2.5 isoform only 4% produce DQ2.5 by pair alleles from different haplotypes, this isoform is called DQ2.5trans and differs slightly, one amino acid, from DQ2.5cis.
So those of us with ancestry from “western Ireland” are pretty highly likely to have “an issue” of this form. (Though there are two other locations I’ve not mentioned that are hot spots for those genetics).
Anyone with Irish ancestors, and one of the autoimmune diseases, has a pretty good reason to try a wheat / gluten free diet for a while and see what happens. That, as it turns out, includes me and many in my family.
There are other variations, it isn’t all just DQ2.5:
The DQ isoform has a complex genetic involvement in coeliac disease. And these involvements explain the majority of disease. One other haplotype exists that is associated with disease, although not as common in Europe, DQ8 is found to be involved in coeliac disease in peoples where DQ2 is not present. DQ8.1 haplotype encodes the DQA1*0301:DQB1*0302 haplotype and represents the overwhelming majority of all DQ8. DQ2.5 is generally highest in northern, islandic Europe, and the Basque of Northern Spain. Phenotype frequency exceeds 50% in certain parts of Ireland. DQ8 is extremely high in Native Americans of Central America and tribes of Eastern American origin, fortunately most of these peoples have retained a maize-based diet.
So folks of Basque or North Spain ancestry have reason to take a special look (due to DQ2.5) while Native Americans may also have wheat issues (but due to DQ8).
So there you have it. Your genetics can predispose you to “autoimmune” reactions, and in particular to wheat induced “issues” that may or may not manifest with obvious gut symptoms. For some of those autoimmune reactions, and for some of the malabsorption related results, ditching wheat can help things. For some others, it doesn’t. ( I have a tendency to just ‘kill off’ all sorts of bacteria and viruses that take my workmates down, so I suspect that the ‘benefit’ of the genes is just a general “when in doubt, kill it fast” immune system… useful in pre-antibiotic days, not so much now that we have tons of wheat based foods everywhere all the year round…)
For me, that means a fairly long ‘trial’ of the gluten free diet is in my future. I can already modulate arthritic symptoms with beef, now we’ll see is the residual moderates when wheat is left out. (Oh, and tomatoes set off the spouse… so beef lasagna is a ‘triple threat’ for us, dang it… I make a mean lasagna…)
It isn’t hard (well, it IS annoying…) to do a gluten free trial. The hard part comes in with full avoidance longer term. The old college roomie has full on wheat allergies, so we have lots of practice making wheat free bread, pizza, etc. One can also get rice noodles for that lasagna and use pork or lamb for the meat. That just leaves a non-tomato marinara to develop… Sigh.
But for folks not reacting to beef and tomatoes, just swap in the rice noodles and go.
Swap over to non-wheat breakfast cereals. Have some buckwheat or millet cakes instead of wheat based pancakes. Pick up some gluten free bread at Whole Foods. It’s all doable. Then we get to see what happens. It will likely be a couple of weeks as I slowly run down the inventory of wheat stuff in the house, but eventually I’ll have a clear trial / report to make. The hardest part will be that I really like to make home made bread and have about 20 lbs of flour… Maybe I can make “gift loaves” for others ;-)