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How to test for Celiac Disease?

The only way you can get a definite YES or a NO for Celiac Disease (CD) is by doing an intestinal biopsy. As this is an invasive and expensive procedure, many prefer measuring serum antibodies as an initial screening process. When someone decides to test for antibodies against gluten it is necessary to keep in mind:

a) that the gluten protein is fairly complex and thus all antibodies need to be tested

b) that the blood test is not a substitute for the biopsy.

Whichever assessment method one decides to use it is important to know that:

For CD, early diagnosis means early intervention with treatment and prevention of long-term complications, including the development of severe and irreversible phenotypes and of other autoimmune disorders.” (Ventura A et al., 2010)

 

Intestinal biopsy is the golden standard for diagnosing Celiac Disease.

 

An individual is classified as celiac when a biopsy of the duodenal mucosa is taken which detects:

a) a reduction or disappearance of intestinal villi &

b) intraepithelial lymphocytes (IELs) higher than 25/100 enterocytes (Sapone A. et al., 2012).

Individuals presenting with significant villous atrophy are classified as CD March stage III, whereas normal villi but increased number of intraepithelial lymphocytes are classified as Marsh I or II (Hill ID et al., 2005). Marsh type II may also suffer from CD but positive serological tests is needed to strengthen the diagnosis (Hill ID et al., 2005). When only elevated IELs are observed but no damage of the intestinal lining, it is difficult to diagnose CD (Kakar eta l., 200). In literature this state is usually referred to as latent CD (Dewar et al., 2005) and further testing is required.

 

Can elevated IELs be due to a different cause other than Celiac Disease?

The presence of IELs can be due to gastrointestinal inflammation caused by H. pylori (Memeo et al., 2005) or tropical sprue (Ross et al., 1981). Unexplained neurological or psychiatric disorders such as autism, schizophrenia, and cerebellar ataxia (Cascella N et al., 2009, Burk K et al., 2009, Genuis S and Bouchard T, 2010) are also linked with elevated IELs and no mucosal damage.

 

Can a blood test confirm Celiac Disease?

No. However, a lot of the time serum antibody testing is used in the screening process. The ones necessary are: anti-DGP IgG & anti-tTG IgA

 

Antibodies for the diagnosis of Celiac Disease

Antibodies

Accurate

Not affected by IgA deficiency

Not prone to interpretation

Cheap

Appropriate for children <2 years old

AGA IgA

AGA IgG

EMA IgA

tTG IgA

DGP IgG

Anti-Actin IgA

 

 

classic Anti-gliadin (AGA) antibody IgA

Pros:

1. relatively cheap

Cons:

1. found in healthy individuals (Bizzaro N et al., 2012)

2. May fluctuate within the first 2 years of age (Simell et al., 2007)

3. relatively insensitive (Fasano A, 2013)

 

AGA-IgG

Pros:

1. useful for pediatric patients with CD who test negative for anti-tTG (Carlsson A et al. 2001, Lagerqvist C et al., 2008).

2. useful in patients with IgA deficiency (Villalta D et al., 2007).

3. reasonably cheap

3. Same results where obtained with the DGP IgG test (Liu E et al., 2007, Agardh D 2007, Basso D et al., 2009, Naiyer A et al., 2009).

4. Remains constant the first 2 years of age (Simell et al., 2007)

Cons:

1. relatively insensitive (Fasano A, 2013)

 

EmA (Endomysial Antibodies – antigliadin) IgA (unless IgG requested)

Pros:

1. It is equally specific with the anti-tTG antibodies, meaning it recognizes the same antigens (Hill 2005)

Cons:

1. It is prone to subjective interpretation

2. It is less sensitive than the anti-tTG (Biagi F et al., 2001, Baudon J et al., 2004, Lock et al., 2004, Kaukinen K et al., 2007).

3. Not accurate in patients with selective IgA deficiency.

4. May fluctuate within the first 2 years of age (Simell et al., 2007)

5 *The IgG version has inferior sensitivity (Fasano A, 2013)

 

anti-tTG (antihuman tissue transglutaminase) IgA (unless IgG requested)

Pros:

1. As it is quantitative, automated and not prone to subjective interpretation

2. high diagnostic sensitivity (95%) specificity (97%) (Tozzoli et al., 2010)

Cons:

1. Anti-tTG IgA is not sensitive enough to be used alone and the addition of the anti-DGP IgG test would increase the accuracy for CD especially in children (Niveloni S et al., 2007, Villalta D et al., 2007, Volta U et al., 2010, Tonutti E et al., 2009, Villalta et al., 2010, Maglio M et al., 2010)

2. May fluctuate within the first 2 years of age (Simell et al., 2007)

3 *The IgG version has inferior sensitivity (Fasano A, 2013)

 

DGP antibodies IgG (deamidated gliadin peptide)

Pros:

1. antibodies comparable sensitivity and specificity to anti-tTG and EMA (Sugai E et al., 2006)

2. Remains constant the first 2 years of age (Simell et al., 2007)

3. DGP IgG test positive in 80% of cases of CD patients with IgA deficiency as compared to 40% for AGA IgG ( Villalta et al., 2010)

 

ANTI-ACTIN IgA

Pros: can evaluate the severity as it is related to the severity of intestinal damage (Granito A et al., 2004, Carroccio A et al., 2005)

Cons: limited usefulness for diagnosis

 

In monitoring of patients on a gluten-free diet, positivity with a low titer of anti-DGP antibodies suggests that the diet should be reassessed, even if the anti-tTG test is negative” (Tursi et al., 2006)

 

Interpretation of serological and biopsy test results

Biopsy

+

Serology

+

CD

Absence of CD and possible false-positive blood test. A negative genetic test can strengthen the negative diagnosis.

This result is treated as CD. However, inflammation in the lining can be due to other causes, including intolerances to other foods.

No CD. However, in the presence of other autoimmune conditions or genetic predisposition, future monitoring may be appropriate.

 

Which other blood biomarkers are available?

While the tests above are the ones most commonly done there is evidence that more thorough testing may be needed for those with negative results and positive symptoms. A complete antibody screening should include: Alpha gliadin, Omega gliadin, Gamma gliadin, Deamidated gliadin, TG2, TG3, TG6.

 

Deamidation is an acid or enzymatic treatment used by the food processing industry to make wheat, water-soluble so it mixes with other foods. It has been shown to cause severe immune responses to people (Leduc V et al., 2003).

Gliadin is broken down to alpha, omega and gamma fractions. If a lab tests only for alpha gliadin antibodies the results may be misleading (Quartesn H et al. 2001).

Elevated antibodies of TG2 indicated a reaction against the intestinal track (Thomas H et al., 2011). Transglutaminase 3 (TG3) is found in the skin. An autoimmune reaction to skin may lead to skin disorder known as dermatitis herpetidormis, which presents as itchy red blisters found usually in the knees, elbows, buttocks but can appear anywhere on the body (Stamnaes I et al., 2010). Elevated antibodies to transglutaminase 6 indicate an immune response against the nervous system (Alessio et al., 2012).

histamine intolerance

How do you fix histamine intolerance?

Histamine is a hormone involved in digestion, immune & nervous system function. Anti-histamine drugs for asthma, they are also prescribed to those with food allergies. Improving digestive health and in particular, the gut microbiome and intestinal integrity can help you fix histamine intolerance.

 

What is histamine intolerance?

Histamine intolerance results from an imbalance between accumulated histamine and the capacity to break it down. The symptoms are due to histamine’s relation with the immune system. Histamine activates immune cells (basophils & mast cells) while causing blood vessels to dilate so that immune cells can be quickly transferred to kill pathogens.

 

the symptoms of histamine intolerance

Histamine Intolerance is a fire alarm 🚨 turned on in the immune system, because of a breakdown in the endocrine system.

How is histamine broken down?

Like all hormones, histamine needs to be eliminated from the body when it has done its job. While it is broken down by a few different enzymes (HNMT, NAT1,2 & DAO), it is the DAO (ref) responsible for the breakdown of ingested histamine.

Histamine Breakdown pathway

 

Can histamine cause digestive problems?

Gastrointestinal problems are very common among those with histamine intolerance. While histamine is necessary for proper gut function excess levels can cause digestive complications. Below are a few findings, highlighting the link between histamine intolerance and gut health:

a. all 4 histamine receptors H1R-H4R are found in the digestive tract and they have excitatory actions there (ref).

b. In a study conducted in Italy, 13 out of 14 subjects (with food intolerances) reported benefits in at least 1 food after DAO supplementation (ref).

c. The capacity of both histamine breakdown pathways: HNMT and DAO have been reported to be reduced in those with food intolerances (ref).

histamine intolerance

d. Elevated levels of histamine in the brain have been shown to suppress appetite (ref).

e. 30-55% of individuals with digestive disorders, including IBS, IBD, and Chron’s Disease have histamine intolerance (ref).

Diet can help histamine intolerance in 2 ways: i. reduce histamine load ii. support histamine breakdown.

Histamine intolerance foods to avoid

Those with histamine intolerance will benefit by avoiding 2 categories of foods:

a. Those that contain histamine

b. those that can cause the release of histamine in the body, although they don’t contain histamine (ref)

 

Histamine intolerance diet

The fresher the food the lower it is in histamine.

Vitamin C supplementation has also been shown to reduce histamine levels (ref), while B6 supplementation is also beneficial as it acts as a co-factor in DAO production (ref).

 

Drugs that cause histamine intolerance

It should probably come as no surprise that medication can also mess up your levels of histamine. Drug intake, especially long-term, should be considered in the interpretation of histamine intolerance symptoms and DAO concentrations (ref).

 

Can hormonal imbalance cause histamine intolerance?

Histamine levels are positively correlated with estrogen, while progesterone and testosterone levels are negatively correlated in women and men respectively. Women are more likely than men (ref) to suffer from histamine intolerance possibly due to the fluctuations in sex hormones during the menstrual cycle and menopause.

Histamine and estrogen have a bidirectional relationship.

Histamine has been shown to stimulate, in a dose-dependent manner, the synthesis of estradiol (E2) (ref). As estradiol levels are responsible for painful uterine contractions of primary dysmenorrhea, through the increase of prostaglandin F2α, histamine can also be considered a contributing factor. Estrogen also influences histamine’s action. During the mid-cycle, when ovulation occurs and estrogen peaks, a significant increase in the occurrence of wheal and flare is observed due to histamine (ref). Progesterone on the other hand stabilizes histamine levels (ref).

During pregnancy, DAO concentrations in the body may increase by as much as 500%, due to the production of DAO by the placenta (ref), which may well explain the reduction in food intolerances women experience during this period (ref).

Histamine increases libido (ref), which is why antihistamine medication needs to be considered when treating sexual dysfunction.

Blood sugar regulation and histamine intolerance

The link between histamine and diabetes goes back to 1950 (ref). Plasma histamine was shown to reduce after insulin administration in diabetic rats (ref). Given the positive correlation between diabetes and histamine intolerance (ref), stabilizing sugar levels should be of high priority in those with histamine symptoms.

In pancreatic beta cells, the activation of histamine 3 receptors (H3R) was shown to:

a. inhibit insulin secretion (ref)

b. reduce glucagon production in a non-hyperglycemic state (ref).

 

Can histamine cause breathing problems?

Histamine release is involved in seasonal allergies. A recent novel clinical trial (ref) has shown that the inhalation of small dosages of COcan suppress the symptoms of seasonal allergies.

histamine intolerancehistamine intolerance

histamine intoleranceCOcan suppress histamine release in mast cells by increasing intracellular Calcium levels (ref). While no studies so far have tested the use of breathing exercises to suppress seasonal allergies, it is well documented and clinically confirmed that certain breathing exercises can increase the levels of COin the body. Based on that it is well worth considering using CO2 Breathing Therapy for histamine intolerance.

 

How to test for histamine intolerance?

Prior to treating any condition, it is wise to confirm its presence first. The symptoms of histamine intolerance overlap with those having intestinal permeability and gut dysbiosis. By measuring the levels of DAO enzyme in your blood you can assess your body’s capacity to break down histamine and thus indirectly the presence of histamine overload.

When DAO levels are below <10 U/mL (ref1, ref2) the probability of histamine intolerance is high.

 

Histamine Intolerance🚦 • Serum DAO: 🧨 <3U/mL, 👎🏻<10U/mL, 👍🏻>10U/mL

 

Labs that offer this service in 🇬🇧 UK are Smart Nutrition (link) and Invivo Clinical, and in 🇦🇺 AUS: ImmunoPro (link).

23andme results & histamine intolerance

23andme results can be useful in identifying potential blockages in the pathway of histamine. At the same time, it is dangerous to drive conclusions solely from one’s genetic makeup, let alone one gene. In many cases, a person may have no SNPs in the gene that produces the DAO enzyme (AOC1 gene) and at the same time experience histamine-like reactions after the consumption of red wine for instance. The case below is such an example.

The woman is in her mid-40s, vegetarian with a more or less healthy lifestyle. She carries only 1 homozygous polymorphism in the AOC1 gene which has been shown to be beneficial.

 

Source: Opus23

 

While there seems to be no burden on the production of DAO if you look at the entire pathway you will see that she carries SNPs in the HNMT and MAOB genes. Both of which can tax DAO’s function.

 

Source: Opus23

 

How can this information be useful? 

For this woman supporting the function of HNMT and MAOB can help with histamine symptoms. For HNMT methylation support as well Salacia Oblonga (ref)  can be used while for MAOB vit B2.

 

Source: Opus23

 

This Nutrigenomics analysis would not be possible without access to Opus23 analytics.

 

FAQ

Do Antihistamines reduce histamine?

Antihistamine tablets can be life-saving in times of crisis. At the same time if one doesn’t deal with what causes the reaction at 1st place she/he is trying to put off a fire by removing the battery from the fire alarm.

 

References

Breunig, E., Michel, K., Zeller, F., Seidl, S., Weyhern, C.W.H.V. and Schemann, M., 2007. Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors. The Journal of physiology583(2), pp.731-742.

 

Casale, T. B., Onder, R. F., Berkowitz, R. B., & Korenblat, P. E. (2018). Nasal Carbon Dioxide Used As Needed in the Symptomatic Treatment of Seasonal Allergic Rhinitis. The Journal of Allergy and Clinical Immunology: In Practice6(1), 183-189.

 

Hemilä, H., 2014. The effect of vitamin C on bronchoconstriction and respiratory symptoms caused by exercise: a review and statistical analysis. Allergy, Asthma & Clinical Immunology10(1), p.58.

 

Hollis, T.M., Kern, J.A., Enea, N.A. and Cosgarea, A.J., 1985. Changes in plasma histamine concentration in the streptozotocin-diabetic rat. Experimental and molecular pathology, 43(1), pp.90-96.

 

x Kuefner, M.A., Schwelberger, H.G., Weidenhiller, M., Hahn, E.G. and Raithel, M., 2004. Both catabolic pathways of histamine via histamine-N-methyltransferase and diamine oxidase are diminished in the colonic mucosa of patients with food allergy. Inflammation Research, 53, pp.S31-S32.

 

x Malmlöf, K., Zaragoza, F., Golozoubova, V., Refsgaard, H.H.F., Cremers, T., Raun, K., Wulff, B.S., Johansen, P.B., Westerink, B. and Rimvall, K., 2005. Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight. International journal of obesity, 29(12), pp.1402-1412.

 

x Manzotti, G., Breda, D., Di Gioacchino, M. and Burastero, S.E., 2015. Serum diamine oxidase activity in patients with histamine intolerance. International journal of immunopathology and pharmacology, p.0394632015617170.

x Maintz, L. and Novak, N., 2007. Histamine and histamine intolerance. The American journal of clinical nutrition, 85(5), pp.1185-1196.

 

Nakamura, T., Yoshikawa, T., Noguchi, N., Sugawara, A., Kasajima, A., Sasano, H. and Yanai, K., 2014. The expression and function of histamine H3 receptors in pancreatic beta cells. British journal of pharmacology, 171(1), pp.171-185.

 

Nakamura, T., Yoshikawa, T., Naganuma, F., Mohsen, A., Iida, T., Miura, Y., Sugawara, A. and Yanai, K., 2015. Role of histamine H 3 receptor in glucagon-secreting αTC1. 6 cells. FEBS open bio, 5, pp.36-41.

 

Oda, Y., Ueda, F., Utsuyama, M., Kamei, A., Kakinuma, C., Abe, K. and Hirokawa, K., 2015. Improvement in Human Immune Function with Changes in Intestinal Microbiota by Salacia reticulata Extract Ingestion: A Randomized Placebo-Controlled Trial. PloS one, 10(12), p.e0142909.

 

Pini, A., Obara, I., Battell, E., Chazot, P.L. and Rosa, A.C., 2016. Histamine in diabetes: is it time to reconsider?. Pharmacological research111, pp.316-324.

 

Strider, J. W., Masterson, C. G., & Durham, P. L. (2011). Treatment of mast cells with carbon dioxide suppresses degranulation via a novel mechanism involving repression of increased intracellular calcium levels. Allergy66(3), 341-350.