WHY SO MANY PEOPLE ARE GLUTEN INTOLERANT

Homo Sapiens did not appear on the earth, just because evolutionary theory predicts such an outcome based on themes of progress and increasing neural complexity.  Humans arose, rather, as a fortuitous and contingent outcome from thousands of linked events, any one of which could have occurred chaotically and sent history on an alternative pathway that would not have led to consciousness.  Since there is order in chaos this story of disease is given from predictable ecological rules, which not only governed, but also structured communities by principles of energy flow and thermodynamics.

Certain genetic mutations that often cause human disease is enabling scientists to trace the migration and growth of specific human populations over thousands of years.  Geneticists have discovered thousands of mutations responsible for disease in humans, but founder mutations stand apart.  Many carriers of genetic disease die before reproducing, stopping the mutant genes from reaching future generations.  Founder mutations often spare their carriers and therefore can spread from the original founder to his or her descendants.  Why does evolution preserve rather than weed out such seemingly detrimental mutations?  Researchers study disease mutations to identify at risk groups, to provide prevention and treatment. This study also gives anthropologists a powerful tool to trace the history of human populations and their migrations.  In this ecological mutation of natural grasses by our ancestors we have created a staff of life into a staff of disease, suffering and death.  If the original grasses had been left with the genetics unaltered the gluten intolerance we see today may not exist.  In gluten intolerance founder mutation is a direct result of genetic alteration in the gluten content of wheat, barley, rye, and spelt.

·      Founder mutations are a special class of genetic mutations embedded in stretches of DNA that are identical in all people who have the mutation.  Everyone with a founder mutation has a common ancestor, the founder in whom the mutation first appeared.

·      By measuring the length of the stretch of DNA that includes the founder mutation and by determining who currently carries the founder mutation, scientists can calculate the approximate date at which that mutation first appeared and its route of dispersion.   Both pieces of data provide information about the migrations of specific groups of people through history.

·      As discrete populations mix, disease-causing mutations now associated with specific ethnic groups will be found more randomly.  Future medicine will turn to DNA analysis to determine risks of disease currently associated with ethnicity.

Most traditional archaeologists divided Western prehistory into several periods.  The periods were based on the basis of technology developed in the different periods.  The Paleolithic period sometimes referred to as The Old Stone Age 2.5 million B.P., to about 10,000 B.P.  The Mesolithic period referred to as the Middle Stone Age lasting until the emergence of agriculture and further improvement of tools such as fine flint blades.  The Neolithic period, or New Stone Age is hall marked by the introduction of agriculture.  The Eneolithic period known as the Copper Age was the beginning of metallurgy.  Approximately 2,000 B.C.E. noted in Central Europe as the Bronze Age marking the returning of the humans to Alps.  Humans have been on Planet Earth for 3 to 4 million years. Homo Sapiens our nearest relatives have been here only close to 100,000 years.  The last great Ice Age peaked 21,000 years ago.  Half of North America and Europe were blanketed with ice sheets miles thick.  Ever encroaching sheets of ice swallowed all fertile land with the climatic temperature change averaging 70 degrees colder than it is today.   Nomadic hunter gathers have been here for 90,000 years and with Ice Age science indicates that evolution may be fueled less by competition and ecology, and more by climate.  Approximately 10,000 years ago the end of the last ice age a portion of the hunter gathers started what we refer to as settlements to cultivate and store wild seeds.  This was the beginning of the end of the Glacial Ice Age and the start of the Neo-Thermal Period.  This marked the passage from the Paleolithic to the Neolithic age.  Melting started from the equator to the poles over thousands of years.  This phase brought about the humid lands, which were fertile.  The cultivation of the wild plants and grasses endemic to the Tigris-Euphrates river basin land encompassed Southern Turkey, Palestine, Lebanon and North Iraq.  The highlands of these areas received abundant rainfall caused by the neo-thermal change.  Europe and other northern areas would take another 4,000 years to be slowly moved out of the frozen environment. This cultivation of wild plants and grasses was the greatest revolution of mankind.  The consolidation and fortification of property developed from the collecting of seeds, herbs, roots and tubers.  New plants and the connection between fallen seeds and new cultivation of plants had its beginning.  The male who was a hunter and warrior does not have credit for this change, but intelligent observations made by the woman who carried the daily burden of collecting the grass seeds, herbs, roots, and tubers.  Thus wheat, barley, rye and spelt are genetic derivatives of wild grass, and therefore pose the possibility that eating a wild plant may possess some toxicity.  The nature of toxicity, to gluten stems directly from the chemical nature of gluten, in relation to the immune system of individuals in possession of certain genes that recognize gluten as a foreign protein and is therefore toxic.

Agrarian civilizations of Mesopotamia and Egypt flourished with the genetic varieties of wheat, barley, rye, and spelt all developed from the wild grasses.  The agrarian culture expanded lasting from 9000 BC up to 4000 BC when they reached Ireland, Denmark and Sweden.  The expansions followed the waterways of Mediterranean and Danube across the time of Egyptians, Phoenicians, Greeks and Romans.  This demic expansion replaced the local dwellers, the Mesolithic populations of Europe, by the Neolithic.  More the 2/3 of our actual genetic inheritance originated in this new population, while the native genetic background has been progressively lost or confined to isolated geographical areas.

Genetic replacement of the native European population is marked by the B8 specificity of the HLA system following the migration of farmers is paralleled by the diffusion of HLA B8.  The frequency of B8 appears to be less frequent in populations that have lived on wheat for a longer time, as it is caused by a negative genetic selection in wheat cultivators.  Areas where wheat cultivation came later there is noted a very high frequency of gluten intolerance.  Wheat cultivation in Ireland came 3000 years BC and there is a high frequency of gluten intolerance.

The early wild Triticum (wheat) and Hordeum (barley) species were genetically diploid and carried few seeds.  Chromosomes in single diploidicity allowed for a wide genetic and phenotypic heterogeneity with remarkable variations in protein and starch content.  Poliploid plants occasionally originated in nature, but they had few chances to survive, without artificial cultivation.  With the use of irrigation an expansion of poliploid grains survived.  The new poliploid grains had reduced genetic variations since each gene is represented in several copies and frequently autoimpollinate themselves, causing increase in the genetic uniformity.  Poliploid grains dated around 6000 years BC had greater genetic uniformity which produced a rise in stability and yield giving the farmer rapid replacement of the wild species. 

Triticum Turgide Dicoccoides was crossed with Triticum Fanschii to originate the Triticum Aestivum, which is the progenitor of all our actual wheat.  Aestivum is esaploid wheat with 42 chromosomes, versus the 14 of the T. Monococcum.  This grain replaced all existing varieties to the point where genetic variability today is lost.  The world over there is 20,000 cultivated species of the same T. Aestivum wheat.  The rise of intolerance to gluten was a lack of adaptation.  The Mesolithic European dwellers that lived on hunting and gathering persisted beside the agrarian invaders.  The change in food was not well tolerated.  These pre-Neolithic age people could not recognize gluten as a tolerable protein available for digestion and absorption.  The intolerance increased as the gluten content increased with industrial quantities of gluten introduced by selection of wheat in order to improve bread making.  This produced unbearable quantities of intolerance to gluten proteins demonstrating progress does not always rule. 

SILENT DISEASE

Celiac disease is far from a modern term, but is not even a term that should be used in today’s terminology.  Diseases of gluten intolerance is much more appropriate.  We note that the symptom complex was first noted and described by Galen a Roman physician in 250 A.D.  Samuel Gee first named the present term celiac in 1888.  Celiac also known as coellac the adjective of or relating to the abdomen.  The noun is one who has celiac disease.  Abdomen n. 1601, borrowed from Latin abdomen; also known in 1541 in a translation from French.  Perhaps the original meaning is concealment (of viscera) and derived from Latin abdere conceal (ab- away + -dere combining form meaning to put, place perform.  Abdominal Adjective 1746, borrowed from New Latin abdominalis, from Latin abdominis (genitive of abdomen).  Britain term is probably from celtic which was part of Britain Ireland and Scotland where gluten sensitivity is extremely present.  The areas to receive wheat barley rye and spelt last have the highest percentage of gluten intolerance related diseases.  The above areas of Britain are such areas.

In 1950 wheat was hypothesized as the cause or one of the causes of celiac disease.  It was also noted that countries, which were not supplied with wheat and other grains after the Second World War had an improvement in health providing other sources of adequate nutrition, were available.  This was noted in children who had previously had a failure to thrive, experiencing improved health first reported by a Dutch physician Dicke.  He also noted that when pre-war conditions returned the prevalence of celiac disease returned.  Paulley in 1954 described the intestinal lesion (Villous atrophy) in celiac patients.  In 1958 Cyrus l. Rubin and his co-workers demonstrated that celiac disease in children and adults were identical diseases.  In the 1980’s Marsh and colleagues identified the relationship between the immune system and the intestinal lesion of  (Villous atrophy).  They discovered that lymphocyte infiltration in the small bowel was the first recognizable event in gluten sensitive enteropathy.

Patients with celiac disease produce a T-cell mediated autoimmune response to the ingestion of gluten related proteins.  The specific proteins are the gliadins and glutenins in wheat, the hordeins in barley, and the secalins found in rye.  These dietary proteins (poisons) are genetically altered through thousands of years of cultivation to be rich in praline and glutamine, which produce the gluten intolerance.  The wheat, barley and rye belong to the Titraceae family.  Oats contain avenins which taken in moderate amounts unless contaminated by the above grains should be tolerated. The damage to the intestinal tract is caused by T cell cross reactivity against these insoluble proteins.  The intake of food usually does not elicit a local or systemic reaction because the body is able to down regulate the immune response to ingested proteins called oral tolerance.  In celiac disease the proteins from wheat barley and rye activated the T cell mediated immune system.  This immune response not only causes damage to the small bowel but also creates many disease processes in the body.  Because these proteins gliadins, glutenins, hordeins and secalins are poorly digested by our enzyme system of proteases they are able to migrate intact through the intestinal epithelium.  Once these dietary protein peptides have passed through the epithelium into the lamina propria of the gut enteropathy is developing.  This mechanism of translocation through the gut wall of intact protein peptides is not completely understood.  We know that gliadins stimulate the human protein zonulin.  Zonulin opens the tight junctions between the enterocytes increasing intestinal permeability.  The active disease is produced be gluten dependent autoantibodies against endomysium (EMA), a complex connective tissue structure surrounding smooth muscle cells, and more precisely, against the protein type 2 (‘tissue’) Antibodies develop against human tissue IgA, IgG, IgM against human tissue transglutaminase (tTG) or TG2 and IgA against gliadins.  The celiac autoantigen anchored to endomysial collagen by fibronectin.  The glutamine rich intact peptides translocate entering the lamina propria, and are converted by a deamitzation process to glutamic acid by the small intestinal enzyme tissue transglutaminase.  This form of gliadins peptides can bind more effectively to the human leukocyte antigen (HLA) receptors, HLA DQ2 and HLADQ8.  When these receptors are attached to the surface of the gliadins peptide, the T cells recognize the delaminated peptides and stimulate an inflammatory cytokine response.  This intense inflammatory response produces the villous fattening characteristic of the intestinal tract of gluten sensitive enteropathy. 

Physicians Problems in Diagnosis

The problem is poor statistics on the number of North and South American, European and world population suffering from classical celiac disease.  This does not count the unbearable numbers of people suffering from silent or latent gluten intolerance.  These silent and none silent gluten intolerant peoples may at any stage of life develop a full-blown celiac disease, bowel cancer or other serious autoimmune disease.  The list of silent diseases, autoimmune diseases and malignances will be listed and talked about later.  The need for a new gold standard is needed for diagnosis.  The new gold standard should have a combination approach.  This should consist of serology, biopsy, and human leukocyte antigen testing. 

Symptoms of celiac can present at any age, and are highly variable.  Even though traditionally defined as a gastrointestinal (GI) malabsorptive disorder.  Celiac disease is a multi-system, multi symptom autoimmune disease due to proteins form wheat, barley, rye and spelt.

Demystifying Celiac Disease May Improve Your Life Quality or Even Save Your Life     

Celiac disease is currently classified into four sub phenotypes:

Classical celiac disease- manifests with classical GI symptoms of diarrhea and weight loss from malabsorption.  Serological and biopsy results confirm the diagnosis, and symptoms and improve on a gluten free diet.

Celiac disease with atypical symptoms- has a predominance of extra intestinal manifestations with few or no GI symptoms.  With classical celiac disease, diagnosis is made with positive serology and biopsy samples and amelioration from a gluten free diet.

Silent celiac disease- individuals being completely asymptomatic, but testing positive with serology and biopsy categorize silent celiac disease.  Detection is usually from screening of high-risk groups, or when biopsies and endoscopies are performed for other reasons.

Latent celiac disease- is associated with positive serological tests, but negative biopsy results.  While asymptomatic at the time of diagnosis, in the future symptoms usually develop and or histological changes are evident upon repeat biopsy.

Summarizes the symptoms and underlying causes of celiac disease.

Signs and symptoms Associated with Celiac Disease| Possible Underlying Causes  

Weight loss | Nutrient malabsorption

Diarrhea, abdominal pain | Accelerated gastrointestinal tract transit time, steatorrhea, malabsorption

Anemia | Most commonly iron deficiency and B12, Folate

Bone pain | Osteoporosis

Aphthous oral ulcers, glossitis stomatitis | Vitamin deficiency, ”oral” celiac disease

Male impotence, decreased libido | Peripheral insensitivity to circulating testosterone

Alopecia areata | Immunological attack on hair follicles

Dental enamel defects | Demineralization during tooth bud development in children

Hypoglycemia | Delayed absorption of glucose

Gas, flatus, borborygmus | Secondary digestion of sugars by intestinal flora

Seizures, gluten ataxia, central nervous system symptoms  | Increased affinity of celiac antibodies for brain vasculature

AUTO-IMMUNE DISORDERS ASSOCIATED WITH CELIAC DISEASE

Autoimmune disorders

Research has demonstrated a clear association between celiac disease and

Type 1 diabetes.  The prevalence of celiac disease in American children with Type 1 diabetes is now estimated to be between 4-6%.  European studies suggest a higher percentage still, and many patients exhibit no overt GI signs and symptoms.  Autoantibodies directed against the islet cells in the pancreas have been found in diabetics with untreated celiac disease.  After adhering to a gluten free diet, these autoantibodies disappear.  For this reason, it is speculated that a delayed diagnosis of celiac disease may actually increase the risk of developing diabetes.

Type1 diabetes is often associated with other autoimmune disease, of which Hashimoto’s thyroiditis is the most prevalent.  The incidence of celiac disease in patients with autoimmune thyroiditis is roughly 3% and appears to increase with advancing age.  In persons with chronic thyroiditis and Grave’s disease, latent celiac disease may impair the absorption of medications such as levothyroxine and calcium.

Type 1 diabetes mellitus

Autoimmune thyroid disease (Hashimoto’s thyroiditis)

Rheumatoid arthritis

Systemic Lupus erythematosus

Autoimmune disease

Addison’s disease

Recurrent aphthous ulcerations

Sjogren’s syndrome

Sarcoidosis

Vitiligo

IgA deficiency

Osteoporosis

Osteoporosis in both adults and children is a common finding with newly diagnosed celiac disease.  The severity of reduced bone density appears to be more pronounced in symptomatic individuals and in men.  To date, studies are mixed with regard to increased risk of fractures, though they clearly demonstrate increased bone mineral density on a gluten free diet.

Neurological Complications

A number of neurological syndromes have been associated syndromes have been associated with gluten sensitivity; Peripheral neuropathies and ataxia appear to be the most common.  While the pathogenesis is uncertain, it is thought that anti-ganglioside antibodies might mediate neurological symptoms.  Chin et al screened 400 neuropathy patients and found 5% with antibodies to gliadins and/or tissue transglutaminase.  Biopsies confirmed the diagnosis of celiac disease.  The authors concluded that there was an increased prevalence of celiac disease in these patients when compared with normal controls.  In one study of patients with sporadic ataxia, there was a 32% prevalence of anti-gliadin antibodies.

The association of neurological disorders and celiac disease is present in all age groups.  Zelnik et al. demonstrated an increased prevalence of neurological disorders in celiac infants and young adults versus controls (51.4% vs. 19.9% respectively).  The types of neurological disorders included: headaches, developmental delay, learning disorders, attention deficit, hyperactive disorder and cerebellar ataxia.  Implementation of a gluten free diet was found to markedly improve symptoms in patients with head headaches and hypotonia.  Similarly in adults, Cicarelli et al. found that neurological manifestations associated with gluten enteropathy improved on a wheat free diet.

Despite an estimated 10% prevalence of neurological disorders in celiac patients, the association appears to be causative to a high degree along with other factors.  Certainly there are other neurological components, which are due to other well-known etiologies, which are involved in gluten intolerant individuals. 

Irritable Bowel Syndrome (IBS) and Celiac Disease

Celiac disease in IBS patients is reported to be 7-fold higher when compared with general population.  When differentiating I BS into diarrhea- or constipation predominant subcategories, celiac disease was found to be more common in diarrhea predominant IBS individuals Recent article from the Netherlands postulated that the yeast Candida albicans may be involved.  This organism contains a cell wall component called hyphal wall protein 1 (HWP1) that has identical amino acid sequences as the gliadins found in wheat.  It is thought that an overgrowth of Candida albicans in the GI tract disrupts the intestinal barrier, which results in increased concentrations of transglutaminase in the intestine.  The HWP1 becomes the bridge that links transglutaminase to the yeast.  Because of the damaged mucosa, the now conjugated Candida albicans-tissue transglutaminase is able to cross the gut wall and stimulate the immune system.  This, in turn, results in the formation of auto-reactive antibodies against tissue transglutaminase.  Molecular mimicry between gliadins, bacteria and or viruses has also been proposed as trigger for the development of celiac disease.  One study demonstrated the presence of anti-ganglioside antibodies in patients with peripheral neuropathies following Campylobacter enteritis.

In a cost effective analysis study by Spiegel et al., the authors concluded the that routine testing for celiac disease in IBS patients is warranted even when no organic disease has been detected through radiographic investigation.

DISEASES AND DISORDERS ASSOCIATED WITH CELIAC DISEASE

Addison’s Disease

Anemia- Iron, B12 and folate deficiency

Ataxia Gait

Autism

Alopecia

Anxiety and Depression

Attention Deficit Disorder/ADHD

Arthritis

Autoimmune hepatitis/Chronic Active Hepatitis

Autoimmune thyroid disease

Brain White-Matter Lesions

Cardiac arrhythmia

Cerebellar Atrophy

Chronic Fatigue Syndrome

Congenital Heart Disease

Crohn’s disease

Cystic Fibrosis

Chronic Sinusitis

Carcinomas Small bowel

Dental Enamel Hypoplasia

Dermatitis Herpetiformis

Diabetes mellitus Type 1

Down Syndrome

Dyspepsia and Gerds

Epilepsy

Esophageal Cancer

Farmers Lung Fibromyalgia

Fibrosing Alveolitis

Follicular Keratosis

Gastro paresis

Headaches of many different classifications

Hashimoto’s disease Thyroiditis

Irritable Bowel Syndrome (IBS)

Inflammatory Bowel Disease (IBD)

Impotency

IgA deficiency

Infertility

Intestinal Cancers

Lymphoma of Colon

Myocarditis

Multiple Sclerosis

Myasthenia Gravis

Osteopenia

Osteoporosis

Oropharyngeal Cancer

Pancreatic Cancer

Pancreatitis

Pancreatic disorders/Exocrine pancreatic insufficiency

Peripheral Neuropathy

Polyneuropathy

Polymyositis

Primary Biliary Cirrhosis

Pulmonary Hemosiderosis

Recurrent aphthous ulcerations

Recurrent Pericarditis

Rheumatoid arthritis

Sarcoidosis

Schizophrenia

Scleroderma

Short Stature/delayed puberty

Sjogren’s syndrome

Small intestinal adenocarcinomas

Spontaneous Abortion and Fetal growth retardation

Systemic Lupus Erythematosus

T-Cell and B-Cell Leukemia/Lymphomas non-Hodgkin

T-Cell Lymphoma (Red man syndrome)

Thrombocytosis (Hyposplenism)

Thrombocytopenic Purpura (ITP)

Thyrotoxicosis

Vasculitis Vitamin K deficiency

Vitiligo

The long-term complications of celiac disease relate to the increased risk of malignancy and mortality.  Large cohort studies in Sweden, the United Kingdom and Italy have all demonstrated a 2-fold increase in mortality when compared with the general population which probably has some associated form to some degree which has not been connected as of yet in the general population.  Celiac disease has been associated with malignant gastrointestinal neoplasm’s, liver cancer, and non-Hodgkin’s Lymphoma.  Mortality analysis in celiac patients reveals an 18% prevalence of lymphoma as a cause of death.  The most frequent malignancy associated with celiac disease is an enteropathy-associated T-cell lymphoma of the upper small intestine.  This is a rare form of non-Hodgkin lymphoma, accounting for 0.5% of all new cases, but is unique to patients with celiac disease.  The risk of lymphoma increases significantly when celiac disease is diagnosed after the age of 60, and is related to the continued consumption of gluten.

Note:  All statistics quoted in this Book are not correct and are given in different percentages due to the studies performed.  The diagnostic testing is improving as well as physician awareness with each year.  All physicians do not know the connections related to celiac disease.  Testing is limited by the patients insurance and the physician’s knowledge of the disease.  One test is not able to rule out celiac disease or let the patient know if he or she has other markers for carrier, silent, or associated diseases.  

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