Anti-tissue Transglutaminase Antibodies (tTG) Present In Blood

What Are Anti-tissue Transglutaminase Antibodies?

[dropcap]A[/dropcap]nti-tissue transglutaminase antibodies (anti-tTG) are connective tissue autoantibodies and can be detected in blood samples from affected persons who are reacting to gluten in the diet.

Autoantibodies are abnormal because they attack the body’s own tissue, which in the case of these antibodies is tissue transglutaminase 2 (TG2).

Q: What is tissue transglutaminase 2 (TG2)?

A: Tissue transglutaminase 2 (TG2) is an enzyme that appears in many cell locations and is particularly abundant in endothelial cells that line the small intestine. It has been implicated in a variety of cellular processes, such as differentiation, cell death, inflammation, cell migration and wound healing.

The cell appears to adapt the dynamics of this enzyme to meet specific sub-cellular needs or to respond to stress or other stimuli. Substantial evidence indicates that the location of TG2 within cells is critical for the regulation of its various biochemical activities, which subsequently trigger diverse downstream events,¹

Although initially studied as an enzyme within cells, TG2 is now known to be secreted also into the extracellular space (between cells) or onto the cell surface.¹

Abnormal activation of TG2 or deregulation of its function(s) is involved in a variety of human diseases, such as celiac disease, diabetes, neurodegenerative diseases, multiple sclerosis and rheumatoid arthritis. A role in inflammatory disorders and septic shock has also been shown. Moreover, multiple studies have revealed elevated TG2 expression in many types of cancer cells.¹

What Are Anti-tissue Transglutaminase Antibodies In Celiac Disease and/or Gluten Sensitivity?

• Relationship between anti-tissue transglutaminase antibodies and celiac disease. The presence of anti-tissue transglutaminase antibodies in serology testing is a classic finding of untreated active celiac disease. Their abnormal presence in the blood is useful for identifying celiac disease and allow making a probable, but not definitive, diagnosis.
• Relationship between anti-tissue transglutaminase antibodies and gluten. Confocal and immunoelectron microscopy techniques showing the ultrastructural immunolocalization of TG2 in the intestinal epithelium of celiac patients clearly demonstrated an abundant presence of the enzyme at the level of the enterocyte surface, especially on microvilli. In samples from celiac patients after a gluten-free diet, the intestinal mucosa displayed remission of the intestinal epithelial damage. Quantification of TG2 revealed that the expression of the enzyme on the surface of the enterocytes of these patients was strongly reduced.¹
• Relationship between anti-tissue transglutaminase antibodies and mass screening. A large study screening 7208 sixth graders for celiac disease found that tTG-IgA is a robust marker when used in celiac disease mass screening and its performance can be enhanced by sequential testing for EMA (endomysial antibodies) or HLA-DQ genotyping.²
• Relationship between anti-tissue transglutaminase antibodies and negative results. A negative test result does not rule out the possibility of celiac disease, meaning the test fails to detect presence of antibodies in the blood although the patient has celiac disease that is established by other means.³ For example, patients will test negative for IgA-tTG if they cannot make IgA antibodies such as those who have hyposplenism, those who have the condition known as IgA deficiency, and persons on immunosupressant therapy.
• Relationship between anti-tissue transglutaminase antibodies and monitoring diet compliance. A study of  82 adult celiac disease patients designed to assess serologic antibody testing for diet compliance after diagnosis found at 3 months that most antibody assays showed significant decrease in mean concentrations and the percentage of positive samples with further improvement in subsequent determinations.  At 1 year, anti-tissue transglutaminase (p<0.02) predicted the degree of compliance as did IgA endomysial (p<0.02) and IgA antiactin antibodies (p<0.05).⁴,⁵

How Prevalent Are Anti-tissue Transglutaminase Antibodies In Celiac Disease and/or Gluten Sensitivity?

Celiac disease occurs in 1% of the general population. Anti-tissue transglutaminase antibodies are highly sensitive and specific to celiac disease.⁶

What Are The Symptoms Of Anti-tissue Transglutaminase Antibodies?

• The presence of  anti-tissue transglutaminase antibodies in blood is marked by positivity to tTG antibody assay, with or without abdominal symptoms.

How Do Anti-tissue Transglutaminase Antibodies Develop In Celiac Disease and/or Gluten Sensitivity?

• Anti-tissue transglutaminase antibodies are produced in response to exposure to gluten in genetically susceptible persons who are sensitized.
• Before antibodies are initially formed, there requires also an environmental trigger which activates the immune response. Thereafter, these antibodies will be produced within 2 hours whenever gluten is consumed, provided there is the ability to produce antibodies.

Do Anti-tissue Transglutaminase Antibodies Respond To Gluten-Free Diet?

Yes. A strict gluten free diet results in disappearance of these antibodies, usually diminishing within weeks.³

6 Steps To Improve Anti-tissue Transglutaminase Antibodies In Celiac Disease and/or Gluten Sensitivity:

• [dropcap]1[/dropcap]Remove the Trigger. Maintain a Strict, Nutritious Gluten Free Diet:

[box type=”shadow” ]Treatment. This condition responds to the complete elimination of gluten, which is the required treatment that improves both tTG antibodies and gut health.

• Gut health is the foundation to restore ALL health. Restored health will enable you to maintain a strict gluten free diet, just as other life tasks will be easier.
• A strict gluten free diet means removing 100% of wheat, barley, rye and oats from the diet.
• Cutting out bread and other obvious sources of gluten is not good enough for recovery. Even 1/8th teaspoon of flour or bread crumb is enough to sustain the inflammation that is damaging your small intestine, causing increased permeability (leaky gut) and allowing undigested gluten to enter your body where it can damage structures and function, and instigate immune inflammatory responses.

Correct Your Individual Nutritional Needs.

• Eat foods that can replenish missing nutrients. Find them under NUTRIENT DEFICIENCIES.
• Take nutritional supplements as needed. Find them under NUTRIENT DEFICIENCIES.

Recovery. You should begin to feel better within a week and notice more energy as inflammation subsides and the  absorbing cells that make up the surface lining of your small intestine are better able to function.

• Intestinal lining cells are replaced every 5 days. The healing process is like sunburn where the damaged surface layer of skin sloughs off and is replaced with new normal cells.
• Leaky gut normally resolves in two month after starting a gluten free diet and brings about a big improvement in health. Improvement in intestinal permeability precedes morphometric recovery (cell appearance and structure) of the small intestine in celiac disease.⁷
• The intestinal lining may take up to a year to heal.[/box]

• [dropcap]2[/dropcap] Reduce Inflammation. Foods to Eat and Foods Not to Eat:

Because gluten is inflammatory, eliminate OTHER inflammatory foods from your diet to reduce an additive effect to gluten. At the same time, try to eat foods that reduce inflammation (anti-inflammatory).

[box type=”shadow” ]Here Are Major Inflammatory Food Types That Reduce Healing:

• Damaging Foods. In susceptible persons, includes corn, dairy (cow), and soy. Lactose, the sugar in any animal milk disrupts intestinal permeability causing leaky gut.⁸
• Allergenic Foods. Includes foods that trigger the immune sytem to produce IgE antibodies. Allergy testing is the usual way to discover these offending foods.
• Shelf Stable Processed Foods. Includes any that contain additives and preservatives. Look for them on the nutrition label of the box or package. Additives and preservatives also disrupt intestinal permeability causing leaky gut.⁸
• Fats. Limit deep fried foods, trans-fats, saturated fats (animal fat/butter), and EXCESSIVE omega-6 fatty acid oils like corn oil. Rancid fats, sodium caprate (a medium chain fat), and sucrose monester fatty acid (a food grade surfactant) induce significant disruption of the intestinal barrier that causes leaky gut.⁸.
• Excessive Refined White Flours (bran layer removed). Includes products made from them such as cookies, bread, cakes, pies. Bran contains the vitamins and minerals that metabolize grains and slows the otherwise rapid entry of sugar from their digestion into the bloodstream. Also disrupt intestinal permeability causing leaky gut.⁸
• Refined Sugars.  Includes white sugar, corn fructose and high fructose corn syrup.
• Certain Spices. Includes paprika and cayenne pepper which disrupt intestinal permeability causing leaky gut.⁸
• Alcohol and Caffeine. Disrupt intestinal permeability causing leaky gut.⁸
• Cocoa and Black Tea increase blood sugar.
• Rosemary. Increases blood sugar levels and should not be used by persons with insulin resistance or diabetes. [/box]

[box type=”shadow” ]Here Are Important Anti-Inflammatory Food Types to Promote Health:

• Fruits. Contain ample amounts of vitamins, minerals and phytochemicals which are naturally occuring components in plants that detoxify toxins, carcinogens (reducing the risk by 50%) and mutagens.
• Non-Starchy Vegetables. Support intestinal integrity and provide ample amounts of vitamins, minerals and phytochemicals. Includes green leafy vegetables such as lettuce and kale, also onion, broccoli, garlic, and others.
• High Quality Complex Carbohydrates. Provide vitamins, minerals, and fiber while boosting serotonin levels to help you relax and feel calm. Includes whole grains, legumes, and root vegetables such as carrots, parsnips, sweet potatoes, turnips, red beets, and others.
• Antioxidants. Protect the body from inflammatory oxidant molecules that continually occur and help us handle stress and reduce irritability. Includes vitamin C-containing foods such as lemon, grapefruit, apricot, Brussels sprouts and strawberries, and others. Also, includes vitamin E-containing foods such as nuts, seeds, avocado, olive oil, and others. Cocoa is good, too.
• Omega-3 Fatty Acids. Balance opposing omega-6 fatty acids and bad fats. Fish sources includes tuna, salmon, cod, and others. Plants sources include flax, chia seeds, canola oil, and others.
• Probiotics. Supply normal microbes needed for colon health and health of the body such as these fermented foods: yogurt, kefir, and unpasteurized apple cider vinegar.
• Prebiotics/ High Fiber Foods.  Food with fiber keeps our population of colonic microbes healthy.
• Protective Herbs and Spices.  See below #6 below for examples.[/box]

• [dropcap]3[/dropcap] Information Sheet You Can Take to Your Doctor or Other Health Professional:

Click here.

• [dropcap]4[/dropcap] Manage Your Medications Safely:

[box type=”shadow” ]

Certain medications cause nutritional deficiencies that affect the health of persons with celiac disease. Some drugs suppress the immune system which prevents antibody production thereby producing false negative testing for celiac disease. Ask your doctor or pharmacist about this possible adverse effect if you are taking medications. Do not stop prescribed medications without supervision.

Examples of immunosupressants:

• Corticosteroids.
• Interferon.
• Some Cancer Therapies.
• Certain antibiotics.
• Drugs and Biologics used in Crohn’s disease/ Ulcerative Colitis (azathioprine, mercaptopurine, methotrexate, anti-TNF-α and anti-integrin antibodies).

 [/box]

• [dropcap]5[/dropcap]Nutritional Supplements To Help Correct Deficiencies:

[box type=”shadow” ]

The type and quantity of nutritional supplements that may be needed depend on which nutrients are deficient.

• Multivitamin/mineral combination that provides 100% once a day is useful to improve overall nutrient levels. This is a safe dose, but always check with your doctor to avoid interactions with medications.

Storage Note: Store container tightly sealed, away from heat, moisture and direct light to avoid loss of potency. That is, in a safe kitchen cabinet – not in the bathroom or on the kitchen table.[/box]

• [dropcap]6[/dropcap]Manage Natural Remedies: 

[box type=”shadow” ]Hydration:

• Eight glasses of water are recommended per day unless there is a contraindication such as kidney or heart disease. The Institute of Medicine recommends approximately 2.7 liters (91 ounces) of total water, from all beverages and foods, each day for women and 3.7 liters (125 ounces) daily of total water for men.
• If you are thirsty, drink water. Add fresh, squeezed lemon to water. Lemon is anti-inflammatory, alkalizing and provides vitamin C.
• Hydration Test: Urine should be pale yellow. Fingertips should be plump, without pruning but this may not be reliable when fingers are swollen with edema. Lips should be plump, without puckering. The feeling of thirst can be unreliable.
• What is wrong with soda, coffee, tea, and alcohol? These drinks are dehydrating, increase acid, and deplete nutrients.[/box]

[box type=”shadow” ]Carminatives. The following  anti-inflammatory plant sources called carminitives help heal the digestive tract. They also tone the digestive muscles which improves peristalsis, thus aiding in the expulsion of gas from the stomach and intestine to relieve digestive colic and gastric discomfort.

Carminative Food Remedies:

• Raspberry.
• Carrot is also a cleansing digestive tonic.
• Grape is also bile stimulating and a cleansing remedy for sluggish digestion and laxative.
• Redbeets also stimulate and improve digestion and are easily digested.
• Cabbage also stimulates and improves digestion and is also a liver decongestant.
• Lettuce also stimulates and improves digestion and is also an alterative, meaning it improves the function of organs involved with the digestion and excretion of waste products to bring about a gradual change.
• Potatoes are antispasmodic (due to atropine like properties) and a liver remedy.

Carminative Herb Remedies:

• Sage is also a digestive, astringent, bile stimulant and energy tonic that heals the mucosa.  Drink as tea or use in cooking.
• Chamomile, lemon balm, and fennel, (as a tea) also help relieve nervous tension.
• Parsley also relieves indigestion.
• Rosemary as a tea and in cooking also is a nervous system tonic for stress and fatigue, bile stimulant, and can relieve headaches and indigestion. However, because it increases blood sugar levels, it should not be used by persons with insulin resistance or diabete.
• Thyme is also soothing remedy useful for stimulating digestion of rich, fatty foods.

Carminative Spice Remedies:

• Cloves are also antispasmodic.
• Nutmeg is also useful for indigestion.
• Ginger.[/box]

[box type=”shadow” ]Exercise Helps:

Exercise improves circulation and rids the body of toxins.

• Walking is aerobic exercise that reconditions the whole body to improve stamina. Read more about Exercise and Fitness.
• Weight training builds muscle. Read more about Exercise and Fitness.
• Stretching improves flexibilty. Read more about Exercise and Fitness.

Note: Exercise is important, but the amount and type of exercise undertaken depends on your health. Your first priority is to heal. [/box]

What Do Medical Research Studies Tell About Anti-tissue Transglutaminase Antibodies In Celiac Disease and/or Gluten Sensitivity?

RESEARCH STUDY SUMMARIES

“Celiac disease in adult patients: specific autoantibodies in the diagnosis, monitoring, and screening.” This study investigating anti-endomysium (EmA) and anti-tissue transglutaminase IgA (tTG-A) antibodies in celiac disease diagnosis, gluten free diet monitoring, and first degree relatives screening in celiac disease adult patients found that EmA predictive ability for celiac disease diagnosis was slightly better compared to tTG-A (P = 0.043). EmA could assess compliance with gluten free diet already from the beginning of the diet, while both EmA and tTG-A had an equal ability to discriminate between strictly and partially compliant patients after the first semester and so on. Screening of first degree relatives resulted in the identification of 2 undiagnosed celiac disease cases.

70 newly diagnosed Greek adult patients, 70 controls, and 47 first degree relatives were tested for the presence of EmA and tTG-A. The celiac disease  patients were monitored during a 3-year period. Both EmA and tTG-A were found to be suitable markers in the celiac disease  diagnosis, in the screening of celiac disease  among first degree relatives, having also an equal performance in the long term monitoring.⁵

“Assessment of a Test for the Screening and Diagnosis of Celiac Disease.” This study investigating the performance of an ELISA test that uses the purified cross-linked complex of tissue transglutaminase and gliadin, referred as the “neoepitope” (AESKULISA® tTG New Generation), as antigen showed this assay has an excellent performance. ELISA-based serological tests help to decide if further duodenal biopsy is necessary, for this the diagnostic kits have to be accurate, specific, and sensible.

Due to the high level of diagnostic accuracy of the “neoepitope, this assay constitutes a new approach for the screening of celiac patients not only for the diagnosis of CD, but also for monitoring patients on gluten-free diet and their compliance.

Moreover, cases of neoepitope-positive subjects who were tested negative with “classical” serological markers could have a predictive value for this pathology. This aspect will require further studies of elaboration.

41 newly diagnosed celiac patients were evaluated, 18 celiac patients on gluten-free diet, and 169 controls, comprising healthy subjects, patients affected by other autoimmune diseases, and patients affected by several non-autoimmune diseases.⁹

“Transglutaminase IgA antibodies in a celiac disease mass screening and the role of HLA-DQ genotyping and endomysial antibodies in sequential testing.” This study designed to evaluate hypothetical screening strategies in a Swedish celiac disease mass screening found that tTG-IgA is a robust marker when used in celiac disease mass screening and its performance can be enhanced by sequential testing for EMA (endomysial antibodies) or HLA-DQ genotyping.

Of 10,041 Swedish sixth graders born in 1993 invited to a population-based celiac disease mass screening, 7208 participated. Anti-tissue transglutaminase (tTG) immunoglobulin (Ig) A were analyzed in all children and total serum IgA in 7161 children. Additional analyses of tTG-IgG, endomysial antibodies (EMA) IgA and IgG, and human leukocyte antigen (HLA) alleles were performed according to a standardized protocol. Children with elevated levels of serological markers were recommended to undergo a small intestinal biopsy to verify diagnosis, and 153 children with celiac disease were thus identified. Sensitivity, specificity, positive predictive values (PPVs) and negative predictive values (NPVs) were calculated and receiver operating characteristic curves were plotted.

By lowering the cutoff for tTG-IgA, 17 additional cases of celiac disease were identified at the cost of 32 biopsies. All children with tTG-IgA more than 50 U/mL (10 times the recommended upper limit of normal) had gluten enteropathy. Area under the receiver operating characteristic curve for tTG-IgA was 0.988. All cases carried HLA-DQ2 or HLA-DQ8, as did 53% of the controls. For different hypothetical screening strategies, sensitivity, specificity, PPV, and NPV ranged between 87.6% and 100%, 99.5% and 99.9%, 79.7% and 89.7%, and 99.7% and 100%, respectively.

Efforts to increase sensitivity by lowering tTG-IgA cutoff would result in increased number of small intestinal biopsies and lower PPV. Sequential testing for both EMA and HLA-DQ genotyping would reduce the number of negative small intestinal biopsies.¹⁰

“Dynamics of celiac disease-specific serology after initiation of a gluten-free diet and use in the assessment of compliance with treatment.” This study investigating serologic changes over time in patients on a gluten free diet and assessing whether serology tests can predict compliance with the gluten-free diet demonstrated that gluten-free diet treatment produced rapid and significant qualitative and quantitative changes in celiac disease-related antibodies which may be useful for monitoring dietary compliance.

Sera obtained at baseline and every 3 months thereafter for 1 year in 82 adult celiac disease patients were assayed for: (1) IgA anti-gliadin, (2) IgA anti-tissue transglutaminase, (3) IgA endomysial, (4) IgA, and (5) IgG anti-deamidated gliadin peptides, (6) dual detection of IgA and IgG anti-deamidated gliadin peptides, (7) a single assay for IgA and IgG of both anti-deamidated gliadin peptide and anti-tissue transglutaminase, and (8) IgA antiactin antibodies.

At 3 months after diagnosis, most antibody assays showed significant decrease in mean concentrations (p<0.0001) and the percentage of positive samples (p<0.0001) with further improvement in subsequent determinations. Strictly adherents had significantly lower concentrations of antibodies (p<0.01 to p<0.00001) and smaller proportion of positive samples for IgA endomysial, IgA antiactin antibodies and IgA antigliadin (15.6%, 17.4% and 23.9%, respectively) than partially compliant. At 1 year, IgA endomysial (p<0.02), IgA antiactin antibodies (p<0.05) and anti-tissue transglutaminase (p<0.02) predicted the degree of compliance.⁴

“Mass screening for coeliac disease using antihuman transglutaminase antibody assay.” This study investigating the diagnostic performance of serologic tests for the diagnosis and screening of Celiac Disease demonstrated the pooled specificity of transglutaminase antibody (tTG)-guinea pig (GP) and tTG-human recombinant (HR) were between 95% and 99%. The pooled sensitivity of tTG-GP in adults and children was 90% and 93%, respectively. The sensitivity of tTG-HR was 98% and 96%, respectively. The sensitivity of these tests appears to be lower than reported when milder histologic grades are used to define Celiac Disease (below 90%).¹¹

CASE REPORT SUMMARIES

“Pericardial effusion in celiac disease.” This case report describes diagnosis of celiac disease in a 40-year-old woman with progressive fatigue and pitting edema in her lower extremities. Iron deficiency anemia and celiac disease were diagnosed on the basis of low serum ferritin, elevated serum level of IgA endomysial and tissue transglutaminase anti-bodies and histologic findings in small bowel biopsies. Pericardial effusion in her evaluation was detected incidentally. Asymptomatic pericardial effusion in this patient was only detectable with imaging.

After starting of gluten free diet and iron supplement fatigue, peripheral edema and pericardial effusion on echocardiography decreased. It should be noted that asymptomatic pericardial effusion may be seen in adults with celiac disease.¹²

“Celiac disease manifested by polyneuropathy and swollen ankles.” This is a case study revealing celiac disease in a 27-year-old male who started to have his ankles swollen during his military service. He was examined at a military hospital where electromyoneurography showed the signs of distal sensory-motor polyneuropathy with axon demyelinization and weak myopathic changes, whereas histopathological examination of gastrocnemius muscle biopsy revealed some mild and nonspecific myopathy. Besides, he was found to have subcutaneous ankle tissue edemas and hypertransaminasemia. Due to these reasons, he was dismissed from the military service and examined at another hospital where bone osteodensitometry revealed low bone mineral density of the spine. However, his medical problems were not resolved and after the second discharge from hospital he was desperately seeing doctors from time to time.

Finally, at this institution he was shown to have celiac disease by positive serology (antitissue transglutaminase and antiendomysial antibodies) and small bowel mucosal histopathological examination, which showed total small bowel villous atrophy. Three months after the initiation of gluten-free diet, his ankle edema disappeared, electromyoneurographic signs of polyneuropathy improved and liver aminotransferases normalized. Good knowledge of celiac disease extraintestinal signs and serologic screening are essential for early recognition and therapy.¹³

“Carpopedal spasm in an elderly man: an unusual presentation of celiac disease.” This case report describes diagnosis of celiac disease in a 68-year-old single Caucasian man admitted to the hospital with a 24-hour history of carpopedal spasm of both hands. Apart from generalized weakness, he reported no other symptoms. Physical examination revealed carpopedal spasm, clubbing of fingers and cachexia (body mass index 14 kg/m2). This patient was found to have several unusual features of celiac disease, including negative tTG-antibodies despite  partial and subtotal villous atrophy of the,duodenum, severe hypocalcemia and electrolyte disturbances, and minimal gastrointestinal symptoms.

Blood tests showed severe hypocalcemia, with a total serum calcium of 1.06 mmol/L (normal range [NR] 2.05-2.55 mmol/L). He also had low serum potassium (2.8 mmol/L; NR 3.5-5.5 mmol/L) and magnesium (0.36 mmol/L; NR 0.65-1.05 mmol/L). Other significant results included hemoglobin 10.6 g/dL (NR 13-18 g/dL), mean corpuscular volume 98.1 fl (NR 82-98 fl), vitamin B12 157 ng/L (NR > 165 ng/L), folate 2.8 g/L (NR 3.1-17.5 μg/L), ferritin 252 μg/L (NR 30-250 μg/L), prothrombin time 20 s (NR 11-14 s), thyroid stimulating hormone 0.87 mu/L (NR 0.35-4.5 mu/L), phosphate 0.57 mmol/L (NR 0.8-1.45 mmol/L), albumin 32 g/L (NR 34-48 g/L) and alkaline phosphatase 313 IU/L (NR 47-141 IU/L).  Subsequent results revealed vitamin D deficiency with a low serum 25-OH vitamin D of < 7 μg/L (NR 7-40 μg/L), a low 24-hour urinary calcium excretion of 0.9 mmol (NR 2.5-7.5 mmol) and a raised serum parathyroid hormone of 22.7 pmol/L (NR 1.6-6.9 pmol/L).

Serology for tissue transglutaminase (tTG) antibodies was negative, and a serum IgA level of 4.95 g/L (NR 0.8-4.0 g/L) excluded selective IgA deficiency.

Barium meal and follow through showed dilated proximal bowel loops and absence of normal feathery pattern of the jejunum, features suggestive of a malabsorptive state. Upper gastroscopic examination was normal; however, the duodenal biopsy showed partial and subtotal villous atrophy with increased intra-epithelial lymphocyte infiltration, consistent with the diagnosis of celiac disease.¹⁴

Sources:

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