Addressing the Auto Immune Component of Thyroid Disease

Graves and Hashimoto’s Disease – Role of H.Pylori and other infections, Gluten Free Diet, Vitamin D, Selenium, Excess Iodine etc.

One of the errors of modern endocrinology is to ignore the auto-immune component of Hashimoto’s and Graves’ Disease.  The typical mainstream endocrinologist is concerned solely with managing thyroid function,  believing there is no known cause or treatment for the autoimmune component. In 2010, Dr. Jerome M. Hershman, makes this exact point in Clinical Thyroidology, expressing the hope a “rational therapy” for the autoimmune origin of thyroid disease can be found. Dr. Jerome M. Hershman writes:

It is difficult to predict how patients with Graves’ disease will be treated 20 years from now, but I hope that we will have some rational therapy that is directed at the autoimmune origin and that makes our entire current armamentarium obsolete. (7)

The reality is that we do know causes, origins and “rational therapy” of autoimmune thyroid disease. This is widely available information found in the medical literature.

Vitamin D and Auto-Immune Disease

I give credit and thanks to Abram Hoffer MD who alerted me to the importance of Vitamin D in preventing autoimmune disease. In April 2007, I attended the Orthomolecular Medical Society Annual Meeting in Toronto, and in the evening, we attended Dr. Abram Hoffer’s Lifetime Achievement Award, 90th birthday celebration and gala black-tie dinner.  During the daytime meeting program, a Canadian nurse sitting next to me confided that her son had been cured of M.S. (multiple sclerosis) by Dr. Hoffer with large doses of Vitamin D. After examining her son, Dr. Hoffer made the diagnosis of M.S., and then advised the young man to purchase Vitamin D at the local pharmacy over the counter, and start taking large doses. The young man did so, and his neurologic symptoms soon resolved.  Dr. Hoffer cured this young man’s autoimmune disease  with Vitamin D, a vitamin which plays a role in the prevention and treatment of most, if not all autoimmune diseases.(1-5)

Vitamin D reduces auto-immune disease by 22 per cent

In 2022, Dr Jill Hahn did a 5.3 year randomized clinical trial giving placebo or 2,000 iu of vitamin D/day to 25,871 people over age 50.  The Vitamin D group had a 22 per cent reduction in various auto-immune diseases, such as autoimmune thyroid disease, rheumatoid arthritis, psoriasis, and others. Dr.  Hahn concludes:

Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22% .(6)

Vitamin D is important for a functioning immune system. Vitamin D deficiency is associated with increased risk for various autoimmune diseases, cancer, and increased mortality from viral infection.  For example, in a 2021 study by Dr. Lorenz Borsche mortality from infection with the Sars Cov-2 virus was reduced to zero when the vitamin 25 hydroxy D3 level is raised above 50 ng/mL ! (8)

For these reasons, in my office, we routinely measure serum vitamin D levels and supplement to a target level over 50. Vitamin D supplements are available over the counter without a prescription. However, it is advisable to work with a knowledgeable physician who can monitor levels.(9-11)

Vitamin D and Autoimmune Thyroid Disease

In 2022, Dr. Dorina Galușca reviewed Vitamin D in autoimmune thyroid disorders, writing:

In Hashimoto’s disease, vitamin D deficiency appears to be correlated with a higher titer of anti-TPO antibodies and with thyroid volume, and supplementation was associated with reduction of antibodies in some studies. In other studies, supplementation appeared to reduce TSH levels. In Grave’s disease, there was a significant correlation regarding vitamin D levels and thyroid volume respective to the degree of exophthalmos…Vitamin D deficiency is highly prevalent in endocrine disorders and its supplementation appears to have numerous beneficial effects.(12-17)

Wheat Gluten and Leaky Gut

I give credit and thanks to Dr Jonathan Wright for alerting me to the link between gluten sensitivity and autoimmune disease. Here is a quote from Dr. Jonathan Wright’s newsletter (Nutrition & Healing newsletter; Vol. 8 Issue 12, February 2012.):

In 1989, my wife Holly and I visited the office of Christopher Reading in Dee Why, a suburb of Sydney, Australia. He showed us documentation of over 500 individuals who came to see him with a diagnosis of Lupus [erythematosus] … How did over 500 individuals eliminate all signs and symptoms of Lupus – and all patent medicines given for it, too – over 20 years ago? Reading had them totally eliminate all gluten, all milk and dairy products, and often other foods to which they were found to be allergic. The other major part of Reading’s treatment included repeated massive (but safe) doses of vitamins and minerals given intravenously. (27) Endquote Emphasis Mine.

Gluten, Autoimmune Disease, Alessio Fasano MD

How does eating wheat cause autoimmune disease? This remained a mystery for many years until the groundbreaking work on cholera by Dr. Alessio Fasano, a pediatric gastroenterologist at the University of Pennsylvania. Dr. Fasano discovered Zonulin, the hormone that controls the tight junctions in the gut epithelium. The tight junctions are normally closed. However, in certain people sensitive to wheat gluten, excess Zonulin is secreted, opening the tight junctions for prolonged periods of time.  This creates what is known as “leaky gut”, the leakage of bacteria, and partially digested food particles from the gut lumen into the blood stream. In a mechanism called “molecular mimicry,” these leaked particles may have amino acid sequences that mimic those of our own tissues and organs, triggering an autoimmune attack. If our immune system attacks the thyroid, then we may find elevation of the anti-TPO and anti-thyroglobulin antibodies. This is called Hashimoto’s Autoimmune  thyroiditis.  If we have elevation of the TSI and TRAb antibodies, then this defines Graves’ Disease, a hyperthyroid state. Note: a competing mechanism was described in the Chapter on Production of Thyroid Hormone in which excess hydrogen peroxide production damages TPO and Thyroglobulin, rendering them antigenic, thus leading to autoimmune disease. (18-26)

Anti-Gliadin Antibody Test

For this reason, routine testing for wheat gluten sensitivity using the anti-gliadin antibody test and TTG (transglutaminase antibody) would be prudent.  A gluten free diet is advised for all patients with auto-immune thyroid disease. A larger panel of food sensitivity testing is advised, since many will have additional food sensitivities, such as egg, dairy and soy. (28-29)

Iodine, Selenium and Autoimmune Thyroid Disease

As mentioned in the previous chapter, Selenium deficiency has been implicated in the etiology of autoimmune thyroid disease. Selenium is the only known mineral in which selenium insertion with selenocysteine is coded by our DNA.  In 2002,  Dr. Vadim N. Gladyshev at the University of Nebraska unraveled the mystery of selenium insertion into proteins by decoding the selenium insertion sequence.  Genetic code for proteins have a “start” and a “stop” codon, indicating the beginning and the end of the amino acid sequence. However, under some circumstances, the “stop” codon does not mean “stop”. Instead it means, insert a selenocysteine, the 21st naturally occurring amino acid, into the amino acid sequence. Dr. Vadim N. Gladyshev writes:

Selenium is …inserted into protein as the amino acid selenocysteine (Sec). The elucidation of how Sec is incorporated into protein has progressed at a rapid pace in the last decade and has revealed some surprising results. In fact, unraveling this mystery has altered our understanding of the genetic code, as the code has now been expanded to include Sec as the 21st naturally occurring amino acid. We now know that UGA serves as both a termination codon and a Sec codon.(101-102)

Selenium is incorporated into seleno-proteins involved in antioxidant function, immune function, wound healing and cancer prevention. A good Selenium intake is required for a functioning anti-oxidant system. The thyroid gland has the highest concentration of selenium in the body, useful for the intrathyroid glutathione peroxidases (GPx) and thioredoxin reductases (TrxR), used in neutralization of hydrogen peroxide generated by the production of thyroid hormones. Another seleno-protein is the iodothyronine deiodinase enzymes involved in conversion of T4 to T3.

Selenium deficiency is implicated in various thyroid and systemic diseases, such as autoimmune thyroid disease, muscle degeneration (White Marble Disease in Oregon Cattle), cardiomyopathy (Keshan’s Disease), cancer, and infection, etc.  All of which are directly related to deficiency of the seleno-protein antioxidant system, leading to cellular oxidative damage from ROS (reactive oxygen species) arising from cellular energy production (mitochondrial oxidative phosphorylation), or in the case of the thyroid gland, failure to neutralize excess hydrogen peroxide. (30-42)

Low Selenium in Hashimotos, Graves’

In 2020, Dr Kristian Hillert Winther reviewed selenium in thyroid disorders, writing low selenium status is linked to autoimmune thyroiditis:

Epidemiological studies have linked an increased risk of autoimmune thyroiditis, Graves’ disease and goitre to low selenium status. Trials of selenium supplementation in patients with chronic autoimmune thyroiditis have generally resulted in reduced thyroid autoantibody titre without apparent improvements in the clinical course of the disease. In Graves’ disease, selenium supplementation might lead to faster remission of hyperthyroidism and improved quality of life and eye involvement in patients with mild thyroid eye disease. Despite recommendations only extending to patients with Graves ophthalmopathy, selenium supplementation is widely used by clinicians for other thyroid phenotypes. (42)(107)

Selenium in Iodine Escape Phenomenon

In view of the above, one might wonder if selenium deficiency might explain the “iodine escape phenomenon” when using Iodine in Graves’ Disease. In Japan, treatment of Graves Disease with Potassium Iodine alone (KI) is widely accepted by thyroid specialists, and in 2015, Dr Yoshihara switched 260 women with Graves’ disease (GD)  from Methimazole to Potassium Iodide to control the hyperthyroidism in first trimester of pregnancy. For 88%, this switch was successful. However, for 11% (22 patients, Worsened Group), these remained hyperthyroid requiring a higher dose of Methimazole for control. This suggests “escape from anti-thyroid effect of Iodine phenomenon”. In a follow-up paper in 2020, Dr. Yoshihara reviewed this data, finding the TRAb level predicted continuation of thyroid suppressive medication. However, Dr Yoshihara had no parameter to predict iodine escape (worsened group), writing:

It was difficult to control the maternal thyrotoxicosis of 22 of the 107 patients with KI [potassium iodide] alone, and a higher dose of MMI [methimazole] compared with the dose at the time of conception was required (worsened group).…It must be kept in mind that a certain proportion of GD [Graves Disease] patients escape from the antithyroid effect of iodide and that careful follow-up is necessary after switching a pregnant patient’s medication to KI. Emphasis Mine (43-44)

One wonders if the parameter to explain the 11 per cent “escape phenomenon” is Selenium and Magnesium deficiency in this subgroup, unable to “alleviate the toxic effects of Iodine”. Unfortunately, selenium levels were not measured in this study, so this remains speculation. Perhaps this question could be answered in future studies which include measurement of selenium and magnesium levels in Graves’ disease patients before and during treatment with potassium iodide.(43-46)

NIS Auto-Antibodies and Iodine Escape

In 2010, Dr.  Anna-Maria Eleftheriadou found that about 12 per cent of Graves’ Disease patients have auto-antibodies to the NIS, sodium iodide symporter, the active transport for iodine. A second speculative explanation for Iodine “resistance or escape” in Graves’ disease is the presence of NIS antibodies in about 12 per cent of Graves’ disease patients. The NIS (sodium iodide symporter) is embedded in the basolateral membrane of the thyrocyte, and mediates active transport of iodine into the thyroid cell, concentrating iodine 100 times to that of plasma. NIS antibodies inhibit iodine uptake and concentration, thus explaining the iodine “escape” or “resistance” in a subset of Graves disease patients treated with iodine to control hyperthyroidism. If the NIS is inhibited by antibody deposition, then iodide concentration within the thyrocyte is insufficent to invoke the Wolf-Chaikoff Effect. (108-110)

Immune Complex Deposits at Basolateral Membrane of Follicles

In 1977, Dr. Kalderon identified immune complex deposits at the follicular basal lamina of the follicles in the thyroid glands of patients with Hashimotos’ and Grave’s autoimmune thyroid disease. Note this is the location of the NIS, sodium iodine symporter. Dr. Kalderon also identified this same finding in a hereditary model of autoimmune thyroid disease in obese chickens.  Perhaps these immune complexes of Dr. Kalderon are the same NIS antibdies discovered by Dr.  Anna-Maria Eleftheriadou (above). Deposition of immune complexes at the basolateral membrane interferes with NIS function and the ability of thyroid autoregulation.  This could be an explanation for “Iodine Escape” in 12 per cent of patients.(111-112)

Dr. Daniela Gallo – Adding Selenium and Vitamin D

Observational studies show that newly diagnosed Graves’ disease patients have low selenium and low vitamin D levels.  In 2022, Dr. Daniela Gallo did a randomized clinical trial in 42 patients, half treated with methimazole, and half treated with methimazole combined with Selenium and Vitamin D3. Dr. Daniela Gallo found the combination with Selenium and Vitamin D3 improved the efficacy of the Methimazole and improved quality of life, writing:

Low Se [selenium] levels might exacerbate oxidative stress by compromising the antioxidant machinery’s response to reactive oxygen species, and low Vitamin D levels might hamper the anti-inflammatory immune response… Our results suggest that reaching optimal Se and Vit D levels increases the early efficacy of MMI [methimazole] treatment when Se and Vit D levels are sub-optimal.(47)

Dr. Christine Hotz, Selenium and Iodine in Laboratory Mice

In 1997, Dr. Christine S. Hotz studied the effect of dietary iodine and selenium on thyroid function and antioxidant status in laboratory mice. Dr. Hotz found the combination of low selenium and high iodine intake causes low antioxidant status leading to thyroidal damage, writing:

Activity of thyroidal GSH-Px [Glutathione-peroxidase, selenoprotein antioxidant] was lowest in rats fed a diet containing high iodine and low selenium. The results suggest that high iodine intake, when selenium is deficient, may permit thyroid tissue damage as a result of low thyroidal GSH-Px activity during thyroid stimulation. (48)

Dr Xu, Iodine and Selenium in Mice

In 2006 and 2011, Dr. Jian Xu  studied mice given excess iodine, comparing them to laboratory mice fed both excess iodine and selenium combined. Dr. Jian Xu found selenium supplementation in mice alleviated the toxic effects of excess iodine.  Dr Jian Xu found iodine excess consumes the anti-oxidants and leads to decreased Glutathione peroxidase (the seleno-protein antioxidant system). This relative impairment of the anti-oxidant system results in increased H202 which depresses TPO activity. The excess iodine increased the iodine content in the thyroid gland, and altered thyroid gland histology with enlargement of colloid containing follicles leading to goiter. Excess iodine reduced Deiodinase type I activity by 30-40% in liver, kidneys and thyroid, causing higher plasma T4 and lower T3. This was restored to normal when selenium was added. TPO activity was significantly inhibited by excess iodine, however, selenium restored TPO activity, This was done by restoring the seleno-protein Glutathione Peroxidase which neutralizes H202.  Since excess H202 inhibits TPO, this neutralization restores TPO activity.  One might then conclude from Dr. Xu’s study, treating the selenium deficient Grave’s Disease patient with excess iodine to  control hyperthyroidism will increase H202 causing oxidative damage and thyroiditis. Thus, selenium deficiency could explain escape or resistance to iodine treatment in Graves’ Disease. Note: selenium levels must be maintained for good glutathione peroxidase (GSHPx) activity. Colloid is thyroglobulin, the precursor protein to thyroid hormone. Deiodinase Type I converts T4 to T3. In 2006, Dr. Xu writes:

The experimental results show that…hepatic selenium and the activity of GSHPx [glutathione peroxidase] in EI [excess iodine] group decrease compared with those in NI [normal iodine] group. So, the H2O2 from thyroid hormone biosynthesis could not be converted effectively neutralized [by GSHPx]; therefore, the thyroid hormone biosynthesis will be damaged. There was no significant difference in hepatic selenium and GSHPx between the NI [normal iodine] and IS [iodine/selenium combination] groups, which means that the oxidative/anti-oxidative balance has been maintained in IS groups…The activity of TPO [thyroperoxidase] was inhibited by excessive iodine significantly. Compared with the effect of iodine alone, iodine in combination with selenium increased the activity of TPO, indicating that selenium supplement alleviated the damage of TPO resulted from iodide excess… [in the excess iodine group] the excessive H2O2 in thyroid would depress the activity of TPO. Supplemental selenium could increase GSHPx activity and correct the unbalanced oxidative/anti-oxidative system. It is the ultimate reason for TPO activity recovery. Supplemental selenium could decrease the level of TPO antibody and the damage of thyroid in the patients with Graves’ disease…  We could draw the conclusion that supplemental selenium could alleviate toxic effect of excessive iodine on thyroid. (49) (113) Emphasis Mine

In 2020, Dr. Ioana Vasiliu confirmed the 2006 and 2011 studies of Dr. Jian Xu.  Dr. Ioana Vasiliu again studied the protective role of selenium in iodine induced auto-immune thyroiditis in laboratory mice. When the mice were fed excessive amounts of iodine, moderate to severe thyroiditis was observed in 83% of males and 50% of female rats. When mice were fed the combination of selenium with the iodine, none developed moderate to severe thyroiditis.  Dr. Ioana Vasiliu writes:

Excess iodine may induce and exacerbate autoimmune thyroiditis (AIT) in humans and animals…Thus, the administration of Se [selenium] was proven to have protective effects against thyroiditis cytology in both male and female Wistar rats. (50-51)

Iodine Deficiency- Toxic Effects of Iodine

In 2000, Dr Bernard Corvilain studied animal models showing under normal conditions, excess iodide will inhibit H202 generation. However, the opposite is found in an iodide depleted animal.  Instead of inhibiting hydrogen peroxide generation, acute iodide exposure activates H2O2 generation in the iodide depleted animal. This is thought to promote efficent oxidation of the iodide, and may explain the toxic effects of acute administration of iodide on iodine-depleted thyroids. This could represent another explanation for “iodine escape or iodine resistance” in the iodine treated Graves’ Disease patient who is also severely iodine deficient at the start of treatment. Dr. Bernard Corvilain writes:

In comparison with conditions in which an inhibitory effect of iodide on H2O2 generation is observed, the stimulating effect was observed for lower concentrations and for a shorter incubation time with iodide. Such a dual control of H2O2 generation by iodide has the physiological interest of promoting an efficient oxidation of iodide when the substrate is provided to a deficient gland and of avoiding excessive oxidation of iodide and thus synthesis of thyroid hormones when it is in excess. The activation of H2O2 generation may also explain the well described toxic effect of acute administration of iodide on iodine-depleted thyroids.(118)

Although the Graves’ Disease patient may have a normal dietary iodine intake, yet their thyroid gland behaves as if it is iodine depleted, similar to the iodine-depleted animals in the above study by Dr Bernard Corvilain. Remember, in GD, the thyroid gland is under massive stimulation of the TSH receptor from TSI and TRAb antibodies which increases the production of thyroid hormone creating a thyrotoxic state. This is a process requiring massive amounts of iodine.

Enlargement of thyroid gland, with increased 5 hour radio-iodine uptake related to TSH receptor stimulation is common to both entities, iodine deficiency and Graves Disease. The hyperactive thyroid gland in Graves disease is “starved ” of iodine. One might then consider the experiments of Dr. Bernard Corvilain using dog thyroid slices showing administering iodide to iodide depleted thyroid glands increases H202 production leading to thyroiditis, also applies to the Graves’ Disease thyroid gland which acts and behaves as if it is iodine depleted, a condition caused by massive TSH Recptpr stimulation.(118)

Antibodies to Selenium Transport Proteins

In 2021, Dr Qian Sun found that Hashimotos patients have antibodies to the blood Selenium transport protein called SELENOP.  These antibodies inhibit selenium uptake by the thyroid, and leads to low Glutathione peroxidase anti-oxidant status. One might speculate this same defect in Graves’ Disease. Dr Qian Sun writes:

Using a newly established quantitative immunoassay, SELENOP autoantibodies were particularly prevalent in Hashimoto’s thyroiditis as compared with healthy control subjects (6.6% versus 0.3%).… GPX3 activity was low and correlated inversely to SELENOP autoantibody concentrations. In renal cells in culture, antibodies to SELENOP inhibited Se uptake. Our results indicate an impairment of SELENOP-dependent Se transport by natural SELENOP autoantibodies, suggesting that the characterization of health risk from Se deficiency may need to include autoimmunity to SELENOP as additional biomarker of Se status.(52)

Note: the SELENOP antibody test is a research test and not comercially available as yet.

Magnesium Deficiency

We routinely test for Magnesium RBC on all patients in our office. Magnesium deficiency worsens the anti-oxidant status in selenium deficiency. In 1993, Dr Zongjian Zhu studied selenium and magnesium deficient mice, finding that combined magnesium and selenium deficiency made the anti-oxidant status worse than selenium deficiency alone, writing:

Magnesium deficiency had an influence on distribution of Se [selenium] , which was increased in muscle and decreased in other tissues. The changes in GSHPx [glutathione peroxidase] matched those in Se. The levels of Se and GSHPx in most tissues were lower in Se-Mg-deficient rats than in Se-deficient rats. Thus, selenium and Mg deficiencies would make oxidant lesion more serious than Se deficiency.(45)

The above studies highlight the importance of routine testing for serum selenium, RBC Magnesium, Vitamin D and spot urinary iodine levels in every auto-immune thyroid patient, as suggested in 2017 by Dr Liontiris, who also advises a Gluten Free Diet. Dr. Liontiris writes:

Serum levels of iodine, Se and vitamin D, in HT [Hashimoto thyroiditis] patients are necessary, and a careful supplementation in case of deficiency of these agents is recommended. Due to the increasing coexistence of HT with CD [celiac disease] and other autoimmune diseases, a low gluten diet is important. (54-55)

Iron Deficiency- Dr Margaret Rayman Explains Importance of Iron-TPO is a Heme Protein with Central Iron

As previously mentioned, thyroperoxidase (TPO) is directly responsible for organification of iodine into thyroglobulin using H202 as a substrate. TPO is a heme protein, meaning it contains a heme chemical structure, a porphyrin ring with a central iron atom. Thus, thyroid hormone production is dependent on adequate iron stores. In auto-immune thyroid patients, there may be co-existing auto-immune gastritis or gluten sensitivity with iron malabsorption, both associated with iron deficiency. Iron supplementation to a ferritin level of 100 μg/l is suggested by Dr Margaret Rayman who writes in 2019:

It is important to recognize that low iron stores may contribute to symptom persistence in patients treated for hypothyroidism…An example is afforded by a small study in twenty-five Finnish women with persistent symptoms of hypothyroidism, despite appropriate L-T4 [Levothyroxine] therapy, who became symptom-free when treated with oral iron supplements for 6–12 months… all had serum ferritin <60 μg/l. Restoration of serum ferritin above 100 μg/l ameliorated the symptoms in two-thirds of the women. At least 30–50 % of hypothyroid patients with persisting symptoms despite adequate L-T4 therapy may, in fact, have covert ID [iron deficiency]…Patients with AITD or hypothyroidism should be routinely screened for ID [iron deficiency]. If either ID or serum ferritin below 70 μg/l is found, coeliac disease or autoimmune gastritis may be the cause and should be treated.(100-101)

Graves’ Disease is an Autoimmune Disease

Graves’ disease is an autoimmune disease in which antibodies attack and stimulate the TSH receptor.  As such, based on the work of Alessio Fasano MD, gluten sensitivity and leaky gut has been implicated in the etiology Graves’ s Disease, and all other autoimmune diseases for that matter. This explains why a gluten free diet is recommended by Dr. Liontiris above for all auto-immune thyroid patients.(54)(28)

Wheat, Leaky Gut and Molecular Mimicry

Underlying gluten sensitivity is the common cause of leaky gut and auto-immune disease. The mechanism of molecular mimicry has been proposed with leakage of bacteria into the blood stream which invokes an immune response. Various infectious organisms have been implicated in molecular mimicry. One is Yersinia, a bacteria implicated in Graves’ Disease. Antibodies to Yersinia cross react with the TSH receptor, producing hyperthyroidism by stimulating the TSH receptors in the thyroid gland. Similarly, thyroid eye disease (TED) is the result of autoimmune attack on TSH receptors or other antigens in the extra-ocular muscles, peri-orbital adipose and connective tissue. (36-47)

Helicobacter Pylori and Graves’ Disease

In 2005, Drs. Robin Warren and Barry Marshall were awarded the Nobel prize in physiology or medicine for their 1982 discovery of Helicobacter pylori, a bacterial infection in the stomach wall, thought to cause gastritis, gastric ulcers, and gastric cancer.  H. Pylori is treatable with a protocol known as Triple Therapy consisting of a PPI proton pump inhibitor antacid, and two antibiotics over a ten-day course. The infection can be diagnosed easily with a breath test developed in 1991 by Dr. Barry Marshal. Infection with H. Pylori bacteria has been associated with Graves’ disease and other autoimmune conditions. It would be prudent to test for H. Pylori in all patients with autoimmune thyroid disease, and treat with Triple Therapy when found positive. Triple therapy may be more effective when combined with probiotics and bismuth.  A decrease in thyroid auto-antibodies has been reported after treatment for H. Pylori. One study found a more 2000 point reduction in TPO antibodies in Hashimotos’ patients affter H. Pylori eradication. (56-77)(83)

Use of Probiotics for Graves’ Disease

The connection between the gut microbiome and autoimmune thyroid disease has sparked interest, and was touched upon in the above discussion of wheat gluten sensitivity and leaky gut. Therefore, it is not surprising that restoring the microbiome with probiotics can be enormously beneficial in the Graves’ disease patient. (78-81)

In 2021, Dr Huo studied the effect of probiotic, Bifidobacterium longum supplied in addition to the usual Methimazole treatment in 9 Graves’ Disease (GD) Patients.  As expected, Methimazole alone (MMI) controlled the hyperthyroidism, effectively reducing Free T3 and Free T4 thyroid hormone levels, but had no effect on the auto-immune disease measured by the TRAb antibodies.  However, when probiotics were administered in combination with Methimazole, Dr. Huo found dramatic reduction in TRAb antibodies indicating improvement in the auto-immune component of the disease. Dr Huo writes:

Unsurprisingly, MI [Methimazole] intake significantly improved several thyroid indexes but not the most important thyrotropin receptor antibody (TRAb), which is an indicator of the GD [Graves Disease] recurrence rate…the clinical thyroid indexes of patients with GD in the probiotic supplied with MI treatment group continued to improve. Dramatically, the concentration of TRAb recovered to the healthy level. (78) Emphasis Mine.

Auto-Immune Thyroid Disease and GI Health

In 2022, Dr. Michael Ruscio made the bold statement that treating the GI (gastro-intestinal) tract directly reduces autoimmunity, and the health of the GI health may be a root cause in the pathogenesis of autoimmunity.  Dr. Michael Ruscio feels dysbiosis [altered microbiome] and intestinal permeability are directly related to thyroid autoimmunity,  both Hashimoto’s and Graves’ disease. Dr. Michael Ruscio writes:

The connection between GI health and autoimmunity may be mediated by increased intestinal permeability caused by various forms of GI imbalances (i.e., SIBO, dysbiosis, pathogens). One study found that increased GI permeability is found at higher rates in those with thyroid dysfunction and is associated with more thyroid symptoms…A small pilot study found that children with Hashimoto’s disease have increased markers of leaky GI when compared to controls. In this study, higher serum zonulin was associated with higher levothyroxine dose. In other words, more intestinal permeability was associated with more thyroid dysfunction…Similarly, higher GI permeability levels among Graves’ patients were associated with higher antibody levels, lower TSH, higher fT4/fT3, and more symptoms. This suggests that dysbiosis and intestinal permeability have a direct interaction and impact on thyroid autoimmunity (both Hashimoto’s and Graves’ disease) and can contribute to the autoimmune phenomenon as a whole. GI therapies directly reduce autoimmunity, suggesting that GI health may be a root cause behind the pathogenesis of autoimmunity. For example, a small study found an average of a 2000-point decrease in TPO antibodies after H. pylori eradication [154]. Probiotics have multiple lines of evidence showing that they lower inflammation and autoimmunity. (82)

Use of Berberine for Auto-Immune Thyroid Disease

Berberine is a botanical used for hundreds of years to prevent or reverse “leaky gut”, and to alter the gut microbiome in beneficial ways, increasing beneficial bacteria and decreasing pathogenic bacteria. Numerous studies in animals and humans have shown benefits of Berberine for improving intestinal barrier function (tight junctions) and the gut microbiome.(84-90)

Berberine for Graves’ Disease

In 2021, Dr. Zhe Han studied the use of berberine in Graves’ disease (GD).  Eight patients were given methimazole (MMI) alone, and 10 patients were given both MMI and Berberine over 6 months. Dr. Zhe Han notes that the Berberine had a beneficial effect on the gut microbiome, increasing beneficial Lactococcus lactis while decreasing pathogenic bacteria, writing:

The results showed that the addition of berberine [to the MMI] restored the patients’ TSH and FT3 [Free T3] indices to normal levels, whereas MMI alone restored only FT3. In addition, TRAb [TSH Receptor Antibodies] was closer to the healthy threshold at the end of treatment with the drug combination. MMI alone failed to modulate the gut microbiota of the patients. However, the combination of berberine with methimazole significantly altered the microbiota structure of the patients, increasing the abundance of the beneficial bacteria Lactococcus lactis while decreasing the abundance of the pathogenic bacteria … In conclusion, methimazole combined with berberine has better efficacy in patients with GD.(84)

Use of Berberine and Probiotics has been found beneficial for Graves’ Orbitopathy, the exophthalmos eye disease associated with Graves’.  (85)

A new drug for Graves Orbitopathy

A new drug for Graves Orbitopathy, the IGF-IR inhibitor, teprotumumab is given by intravenous infusions. In a controlled trial, at week 24, the percentage of patients with responding with improvement in proptosis was higher (83%) with teprotumumab than with placebo (10%). Note: IGF-IR  is insulin-like growth factor I receptor. There is overlap in activity between the TSH and IGF-1 (Marker for Growth Hormone) (91-93)

Low Dose Naltrexone (LDN)

Naltrexone is an opiate antagonist originally developed as a treatment for opiate addiction. Used in lower doses, usual 3-4.5 mg taken at night before sleep, the drug may have benefits in various auto-immune diseases, neuropathic pain and cancer. Although clinical trials for autoimmune thyroid disease are lacking, anecdotal reports have suggested a possible benefit in Hashimotos’ and Graves’ as well as Graves’ Orbitopathy. Other than its obvious withdrawal effects in opiate addicts, LDN has virtually no adverse side effects, a factor which has liberalized its use. (94-99)

Vitamin C is Protective of Toxic Effects of Excess Iodine

in 2022 Dr, Rong Sun studied Vitamin C in an animal model finding that Vitamin C counteracts the oxidative damage caused by excess iodine intake, writing:

additional supplements of vitamin C are a better method to counteract the oxidative damage caused by excess iodine exposure. Vitamin C represents one of the most prominent antioxidants both in plasma as well as intracellular regions; enables the quenching and scavenging of free radicals; and is required in the body for collagen formation in the bones, blood vessels, and muscles…In this study, it could be found that vitamin C can increase the activity of antioxidant enzymes, which decreased in the HI [Hi Iodine] group, and had a protective effect on oxidative stress caused by excessive iodine… Long-term chronic excessive iodine exposure caused oxidative damage in rats, such as decreasing the activity of antioxidant enzymes and increasing the content of lipid peroxides, and there was a difference between females and males. Vitamin C had a certain protective effect against oxidative damage induced by excess iodine exposure; a high-dose intake of vitamin C reduced the content of MDA [Malondialdehyde, a lipid peroxide], while a low-dose intake of it promoted oxidative damage.(114)

In 2019, Dr. Karimi studied patients with autoimmune thyroid disease, finding administration of Vitamin C, 500 mg/day over 3 months reduced anti-thyroid antibody (TPO-Ab) levels to the same degree as selenium 200 mcg/d supplementation. (115-116)

Combination of Antioxidants Beneficial in Graves Disease

A 2005 study by Dr. Vesna Bacic-Vrca from Croatia, evaluated the effects of supplementation with a combination of antioxidants (vitamins C and E, beta-carotene and selenium) in a group of patients with Graves’ Disease (GD) treated with methimazole.  The results show that patients receiving antioxidant supplementation along with methimazole therapy achieve euthyroidism at a faster rate than those treated with methimazole alone. (117)

How to Address Underlying Autoimmune Cause of Thyroid Disease

1) Gluten sensitivity testing with anti-gliadin antibody, and genetic testing. If positive, a Gluten Free Diet is advisable.

2) Testing and Supplementation for Serum Selenium, Vitamin C, Vitamin D3, Magnesium RBC and Iodine spot urine.

3) Extended Food Reactivity testing, and dietary modification to eliminate reactive foods.

4) H. Pylori Breath Test and if positive, Triple Therapy to eradicate H Pylori.

5) Healing the Gut with Probiotics and Berberine, etc.

6) Low Dose Naltrexone, an immune modulator, has been found useful in autoimmune disease patients. (94-99)

7) Iron and Ferritin testing and supplementation when found low.(100-101)

Conclusion: One of the errors of modern endocrinology is to ignore the autoimmune component  of Hashimotos’ and Graves’ disease. We have made the case that treating the auto-immune component can have a major beneficial impact on the course of disease.

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Articles with Related Interest

Wheat Gluten Leaky Gut  part one, Part Two , Part three.

Wheat Gluten Leaky Gut  Part Four

Berberine Antidote to a Modern Epirdemic

Hashimotos  Disease

Graves Disease

Vitamin D Articles

Header Image: Lactobacillus, a probiotic organism in the microbiome courtesy of wikimedia commons.

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314


1) Hoffer, A. “Adventures in Psychiatry: The Scientific Memoirs of Dr.” Abram Hoffer (2005)

2) Hayes, Colleen E. “Vitamin D: a natural inhibitor of multiple sclerosis.” Proceedings of the Nutrition Society 59.4 (2000): 531-535.

3) Mowry, Ellen M., et al. “Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis.” Annals of neurology 72.2 (2012): 234-240.

4) Pierrot-Deseilligny, Charles, and Jean-Claude Souberbielle. “Vitamin D and multiple sclerosis: An update.” Multiple sclerosis and related disorders 14 (2017): 35-45.

5) Sîrbe, Claudia, et al. “An update on the effects of vitamin D on the immune system and autoimmune diseases.” International Journal of Molecular Sciences 23.17 (2022): 9784.

6) Hahn, Jill, et al. “Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial.” bmj 376 (2022).

7) Hershman, Jerome M. “A Survey of Management of Uncomplicated Graves’ Disease Shows that Use of Methimazole Is Increasing and Use of Radioactive Iodine Is Decreasing.” children 95.3260 (2010).

8) Borsche, Lorenz, Bernd Glauner, and Julian von Mendel. “COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/mL 25 (OH) D3: results of a systematic review and meta-analysis.” Nutrients 13.10 (2021): 3596.

9) Gallo, Daniela, et al. “Add-on effect of selenium and vitamin D combined supplementation in early control of Graves’ disease hyperthyroidism during methimazole treatment.” Frontiers in endocrinology 13 (2022).

10) Keum, N., et al. “Cancer mortality reduced 40 pcnt by 2000 IU Vitamin D daily if normal weight–Meta-analysis June 2022.” Br J Cancer (2022).

11) Niedermaier, Tobias, et al. “Vitamin D food fortification in European countries: the underused potential to prevent cancer deaths.” European Journal of Epidemiology (2022): 1-12.

12) Galușca, Dorina, et al. “Vitamin D Implications and Effect of Supplementation in Endocrine Disorders: Autoimmune Thyroid Disorders (Hashimoto’s Disease and Grave’s Disease), Diabetes Mellitus and Obesity.” Medicina 58.2 (2022): 194.

13) Vieira, Inês Henriques, Dírcea Rodrigues, and Isabel Paiva. “Vitamin D and Autoimmune Thyroid Disease—Cause, Consequence, or a Vicious Cycle?.” Nutrients 12.9 (2020): 2791.

14) Miteva, Mariya Zh, et al. “Vitamin D and autoimmune thyroid diseases-a review.” Folia Medica 62.2 (2020): 223-229.

15) Płazińska, Maria Teresa, et al. “Vitamin D deficiency and thyroid autoantibody fluctuations in patients with Graves’ disease–A mere coincidence or a real relationship?.” Advances in Medical Sciences 65.1 (2020): 39-45.

16) Pratita, Winra, Karina Sugih Arto, and Nindia Sugih Arto. “Efficacy of vitamin-d supplement on thyroid profile in children with Graves’ disease.” Open Access Macedonian Journal of Medical Sciences 8.B (2020): 798-801.

17) Heisel, Curtis J., et al. “Serum vitamin D deficiency is an independent risk factor for thyroid eye disease.” Ophthalmic plastic and reconstructive surgery 36.1 (2020): 17-20.

18) Benvenga, Salvatore, and Fabrizio Guarneri. “Molecular mimicry and autoimmune thyroid disease.” Reviews in Endocrine and Metabolic Disorders 17.4 (2016): 485-498.

19) Rojas, Manuel, et al. “Molecular mimicry and autoimmunity.” Journal of autoimmunity 95 (2018): 100-123.

20) Fasano, Alessio. “All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases.” F1000Research 9 (2020).

21) Leonard, Maureen M., et al. “Celiac disease and nonceliac gluten sensitivity: a review.” Jama 318.7 (2017): 647-656.

22) Cascella, Nicola G., et al. “Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population.” Schizophrenia bulletin 37.1 (2011): 94-100.

23) Serena, Gloria, et al. “The role of gluten in celiac disease and type 1 diabetes.” Nutrients 7.9 (2015): 7143-7162.

24) Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011;91(1):151-175.

25) Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012;1258:25-33.

26) Sturgeon, Craig, and Alessio Fasano. “Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases.” Tissue barriers 4.4 (2016): e1251384.

27) Wright Jonathan V, “The Root Cause of Your Autoimmune Disease – and Why Treating It Can Be Easier Than You Think”, Nutrition & Healing newsletter; Vol. 8 Issue 12, February 2012.

28) Pinto-Sanchez, María Inés, et al. “Gluten-free diet reduces symptoms, particularly diarrhea, in patients with irritable bowel syndrome and antigliadin IgG.” Clinical Gastroenterology and Hepatology 19.11 (2021): 2343-2352.

29) Ch’ng, Chin Lye, et al. “Prospective screening for coeliac disease in patients with Graves’ hyperthyroidism using anti‐gliadin and tissue transglutaminase antibodies.” Clinical Endocrinology 62.3 (2005): 303-306.

30) Tsuji, Petra A., et al. “Historical roles of selenium and selenoproteins in health and development: The good, the bad and the ugly.” International Journal of Molecular Sciences 23.1 (2021): 5

31) Hariharan, Sneha, and Selvakumar Dharmaraj. “Selenium and selenoproteins: It’s role in regulation of inflammation.” Inflammopharmacology 28.3 (2020): 667-695.

32) Radomska, Dominika, et al. “Selenium as a Bioactive Micronutrient in the Human Diet and Its Cancer Chemopreventive Activity.” Nutrients 13.5 (2021): 1649.

33) Wu, Qian, et al. “Increased Incidence of Hashimoto Thyroiditis in Selenium Deficiency: A Prospective 6-Year Cohort Study.” The Journal of Clinical Endocrinology & Metabolism 107.9 (2022): e3603-e3611.

34) Davcheva, Delyana M., et al. “Serum selenium concentration in patients with autoimmune thyroid disease.” Folia Medica 64.3 (2022): 443-449.

35) Kryczyk‐Kozioł, Jadwiga, et al. “Positive effects of selenium supplementation in women with newly diagnosed Hashimoto’s thyroiditis in an area with low selenium status.” International Journal of Clinical Practice 75.9 (2021): e14484.

36) Wang, Lan-Feng, et al. “The effects of selenium supplementation on antibody titres in patients with Hashimoto’s thyroiditis.” Endokrynologia Polska 72.6 (2021): 666-667.

37) Davcheva, Delyana M., et al. “Serum selenium concentration in patients with autoimmune thyroid disease.” Folia Medica 64.3 (2022): 443-449.The s-Se concentrations in patients with hyperthyroidism were significantly lower than those in the control group (hyperthyroidism: 69±15.0 µg/L vs. controls: 84±13 µg/L, p<0.001).

38) Karimi, F., and G. R. Omrani. “Effects of selenium and vitamin C on the serum level of antithyroid peroxidase antibody in patients with autoimmune thyroiditis.” (2019): 481-487.

39) Krysiak, Robert, Karolina Kowalcze, and Bogusław Okopień. “Selenomethionine potentiates the impact of vitamin D on thyroid autoimmunity in euthyroid women with Hashimoto’s thyroiditis and low vitamin D status.” Pharmacological Reports 71.2 (2019): 367-373.

40) Pace, Cinzia, et al. “Role of selenium and myo-inositol supplementation on autoimmune thyroiditis progression.” Endocrine Journal (2020): EJ20-0062.

41) Rayman, Margaret P. “The importance of selenium to human health.” The lancet 356.9225 (2000): 233-241.

42) Winther, Kristian Hillert, et al. “Selenium in thyroid disorders—essential knowledge for clinicians.” Nature Reviews Endocrinology 16.3 (2020): 165-176.

43) Yoshihara, Ai, et al. “Characteristics of patients with Graves’ disease whose thyroid hormone levels increase after substituting potassium iodide for methimazole in the first trimester of pregnancy.” Thyroid 30.3 (2020): 451-456.

44) Yoshihara, Ai, et al. “Substituting potassium iodide for methimazole as the treatment for Graves’ disease during the first trimester may reduce the incidence of congenital anomalies: a retrospective study at a single medical institution in Japan.” Thyroid 25.10 (2015): 1155-1161.

45) Zhu, Zongjian, Mieko Kimura, and Yoshinori Itokawa. “Selenium concentration and glutathione peroxidase activity in selenium and magnesium deficient rats.” Biological trace element research 37.2 (1993): 209-217.

46) Moncayo, Roy, Helga Moncayo, and Juliana Reisenzahn. “Global view on the pathogenesis of benign thyroid disease based on historical, experimental, biochemical and genetic data, identifying the role of magnesium, selenium, coenzyme Q10 and iron in the context of the unfolded protein response and protein quality control of thyroglobulin.” Journal of Translational Genetics and Genomics 4.4 (2020): 356-383.

47) Gallo, Daniela, et al. “Add-on effect of selenium and vitamin D combined supplementation in early control of Graves’ disease hyperthyroidism during methimazole treatment.” Frontiers in endocrinology 13 (2022).

48) Hotz, Christine S., et al. “Dietary iodine and selenium interact to affect thyroid hormone metabolism of rats.” The Journal of nutrition 127.6 (1997): 1214-1218.

49) Xu, Jian, et al. “Supplemental selenium alleviates the toxic effects of excessive iodine on thyroid.” Biological trace element research 141.1 (2011): 110-118.

50) Vasiliu, Ioana, et al. “Protective role of selenium on thyroid morphology in iodine‑induced autoimmune thyroiditis in Wistar rats.” Experimental and therapeutic medicine 20.4 (2020): 3425-3437.

51) Vasiliu, Ioana, et al. “Experimental induced autoimmune thyroiditis in wistar rats: possible protective role of selenium.” Endocrine Abstracts. Vol. 70. Bioscientifica, 2020.

52) Sun, Qian, et al. “Natural autoimmunity to selenoprotein P impairs selenium transport in Hashimoto’s thyroiditis.” International Journal of Molecular Sciences 22.23 (2021): 13088.

53) Zhu, Zongjian, Mieko Kimura, and Yoshinori Itokawa. “Selenium concentration and glutathione peroxidase activity in selenium and magnesium deficient rats.” Biological trace element research 37.2 (1993): 209-217.

54) Liontiris, Michael I., and Elias E. Mazokopakis. “A concise review of Hashimoto thyroiditis (HT) and the importance of iodine, selenium, vitamin D and gluten on the autoimmunity and dietary management of HT patients. Points that need more investigation.” Hell J Nucl Med 20.1 (2017): 51-56.

55) Wang, Kunling, et al. “Severely low serum magnesium is associated with increased risks of positive anti-thyroglobulin antibody and hypothyroidism: A cross-sectional study.” Scientific reports 8.1 (2018): 1-9.

56) Marshall, Barry J., et al. “A 20-minute breath test for helicobacter pylori.” American Journal of Gastroenterology (Springer Nature) 86.4 (1991).

57) Hellström, Per M. “This year’s Nobel Prize to gastroenterology: Robin Warren and Barry Marshall awarded for their discovery of Helicobacter pylori as pathogen in the gastrointestinal tract.” World Journal of Gastroenterology: WJG 12.19 (2006): 3126.

58) Marshall, Barry. “A Brief History of the Discovery of Helicobacter pylori.” Helicobacter pylori. Springer, Tokyo, 2016. 3-15.

59) Marshall, Barry J. “One hundred years of discovery and rediscovery of Helicobacter pylori and its association with peptic ulcer disease.” Helicobacter pylori: physiology and genetics (2001): 19-24.

60) Thiyagarajan, Santhanamari, Anil MR Saini, and Jamal Alruwaili. “Helicobacter pylori-induced autoimmune thyroiditis: is the pathogenic link concluded or still a hypothesis?.” Reviews in Medical Microbiology 29.2 (2018): 64-72.

61) Youssefi, Masoud, et al. “Helicobacter pylori infection and autoimmune diseases; Is there an association with systemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis and autoimmune pancreatitis? A systematic review and meta-analysis study.” Journal of Microbiology, Immunology and Infection 54.3 (2021): 359-369.

62) Figura, Natale, et al. “Helicobacter pylori infection and autoimmune thyroid diseases: the role of virulent strains.” Antibiotics 9.1 (2019): 12.

63) Abdalla, Taghrid Mohamed, Fayrouz Othman Selim, and Thoraya Hosny. “The Association between Helicobacter pylori and Graves’ Disease.” Afro-Egyptian Journal of Infectious and Endemic Diseases 8.4 (2018): 196-201.

64) Gianoukakis, Andrew G., et al. “Graves’ disease patients with iron deficiency anemia: serologic evidence of co-existent autoimmune gastritis.” American journal of blood research 11.3 (2021): 238.

65) Raafat, Mohammed Nabil, et al. “Correlation between autoimmune thyroid diseases and helicobacter pylori infection.” The Egyptian Journal of Hospital Medicine 76.7 (2019): 4499-4505.

66) Oudah, Marwah Ali. “Relationship between H. Pylori Patients and Autoimmune Thyroid Disease.” Indian Journal of Forensic Medicine & Toxicology 14.3 (2020).

67) Thiyagarajan, Santhanamari, Anil MR Saini, and Jamal Alruwaili. “Helicobacter pylori-induced autoimmune thyroiditis: is the pathogenic link concluded or still a hypothesis?.” Reviews in Medical Microbiology 29.2 (2018): 64-72.

67) Elmahalawy, Mostafa Haseeb”Study Of Chronic Atrophic Gastritis In Patients With Autoimmune Thyroid Disease.” Al-Azhar International Medical Journal (2021).

68) Bassi, Vincenzo, Olimpia Fattoruso, and Crescenzo Santinelli. “Autoimmune Thyroid Diseases and Helicobacter Pylori.” Open Journal of Thyroid Research 1.1 (2017): 001-003.

69) Shmuely, Haim, Ilan Shimon, and Limor Azulay Gitter. “Helicobacter pylori infection in women with Hashimoto thyroiditis: A case-control study.” Medicine 95.29 (2016).

70) Choi, Yun Mi, et al. “Association between thyroid autoimmunity and Helicobacter pylori infection.” The Korean Journal of Internal Medicine 32.2 (2017): 309.

71) de Luis, Daniel A., et al. “Helicobacter pylori infection is markedly increased in patients with autoimmune atrophic thyroiditis.” Journal of clinical gastroenterology 26.4 (1998): 259-263.

72) Figura, N., et al. “The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders.” Journal of Physiology and Pharmacology 50.5 (1999): 817-826.

73) Choi, I. J., et al. “Efficacy of low‐dose clarithromycin triple therapy and tinidazole‐containing triple therapy for Helicobacter pylori eradication.” Alimentary pharmacology & therapeutics 16.1 (2002): 145-151.

74) McNicholl, Adrian G., et al. “Combination of bismuth and standard triple therapy eradicates Helicobacter pylori infection in more than 90% of patients.” Clinical Gastroenterology and Hepatology 18.1 (2020): 89-98.

75) Fang, Hao-Ran, et al. “Efficacy of Lactobacillus-supplemented triple therapy for Helicobacter pylori infection in children: a meta-analysis of randomized controlled trials.” European Journal of Pediatrics 178.1 (2019): 7-16.

76) Bertalot, Giovanni, et al. “Decrease in thyroid autoantibodies after eradication of Helicobacter pylori infection.” Clinical endocrinology 61.5 (2004): 650-652.

77) Wang, Li, et al. “Helicobacter Pylori and Autoimmune Diseases: Involving Multiple Systems.” Frontiers in Immunology 13 (2022).

78) Huo, Dongxue, et al. “Probiotic Bifidobacterium longum supplied with methimazole improved the thyroid function of Graves’ disease patients through the gut-thyroid axis.” Communications Biology 4 (2021).

79) Virili, Camilla, Ilaria Stramazzo, and Marco Centanni. “Gut microbiome and thyroid autoimmunity.” Best Practice & Research Clinical Endocrinology & Metabolism 35.3 (2021): 101506.

80) Hou, Jueyu, et al. “The Role of the Microbiota in Graves’ Disease and Graves’ Orbitopathy.” Frontiers in Cellular and Infection Microbiology (2021): 1301.

81) Jiang, Wen, et al. “Gut Microbiota May Play a Significant Role in the Pathogenesis of Graves’ Disease.” Thyroid 31.5 (2021): 810.

82) Ruscio, Michael, et al. “The Relationship between Gastrointestinal Health, Micronutrient Concentrations, and Autoimmunity: A Focus on the Thyroid.” Nutrients 14.17 (2022): 3572.

83) Bertalot, Giovanni, et al. “Decrease in thyroid autoantibodies after eradication of Helicobacter pylori infection.” Clinical endocrinology 61.5 (2004): 650-652.

84) Han, Zhe, et al. “The Potential Prebiotic Berberine Combined With Methimazole Improved the Therapeutic Effect of Graves’ Disease Patients Through Regulating the Intestinal Microbiome.” Frontiers in Immunology 12 (2021).

85) Diao, J., et al. “Potential Therapeutic Activity of Berberine in Thyroid-Associated Ophthalmopathy: Inhibitory Effects on Tissue Remodeling in Orbital Fibroblasts.” Investigative ophthalmology & visual science 63.10 (2022): 6-6.

86) Cheng, Hao, et al. “Interactions between gut microbiota and berberine, a necessary procedure to understand the mechanisms of berberine.” Journal of Pharmaceutical Analysis (2021).

87) Yang, Shengjie, et al. “Multi-Pharmacology of berberine in atherosclerosis and metabolic diseases: potential contribution of gut microbiota.” Frontiers in Pharmacology 12 (2021): 1774.

87) Tang, Min, Daixiu Yuan, and Peng Liao. “Berberine improves intestinal barrier function and reduces inflammation, immunosuppression, and oxidative stress by regulating the NF-κB/MAPK signaling pathway in deoxynivalenol-challenged piglets.” Environmental Pollution 289 (2021): 117865.

88) Li, Yanning, et al. “Berberine reduces gut-vascular barrier permeability via modulation of ApoM/S1P pathway in a model of polymicrobial sepsis.” Life Sciences 261 (2020): 118460.

89) Hou, Qiuke, et al. “Berberine improves intestinal epithelial tight junctions by upregulating A20 expression in IBS-D mice.” Biomedicine & Pharmacotherapy 118 (2019): 109206.

90) Wang, Yuzhen, et al. “Berberine ameliorates intestinal mucosal barrier dysfunction in nonalcoholic fatty liver disease (NAFLD) rats.” Journal of King Saud University-Science 32.5 (2020): 2534-2539.

91) Douglas, Raymond S., et al. “Teprotumumab efficacy, safety, and durability in Longer-Duration thyroid eye disease and Re-treatment: OPTIC-X study.” Ophthalmology 129.4 (2022): 438-449.

92) Douglas, Raymond S., et al. “Teprotumumab for the Treatment of Active Thyroid Eye Disease.” (2020): 341-352.

93) Kahaly, George J., et al. “Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials.” The Lancet Diabetes & Endocrinology 9.6 (2021): 360-372.

94) McDermott, Michael T. “Low-dose naltrexone treatment of Hashimoto’s thyroiditis.” Management of Patients with Pseudo-Endocrine Disorders. Springer, Cham, 2019. 317-326.

95) Kim, Yoon Hang John. “Case Report: Reversing Hypothyroidism with Low Dose Naltrexone (LDN).” Multiple sclerosis 3: 4.

96) How, L. D. N. “Low Dose Naltrexone And Hashimoto’s-Dr. Izabella Wentz (2022).”

97) Moore, Elaine A., and Lisa Marie Moore. Advances in Graves’ Disease and Other Hyperthyroid Disorders. McFarland, 2013.

98) Li, Zijian, et al. “Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy.” International immunopharmacology 61 (2018): 178-184.

99) Toljan, Karlo, and Bruce Vrooman. “Low-dose naltrexone (LDN)—review of therapeutic utilization.” Medical Sciences 6.4 (2018): 82.

100) Rayman, Margaret P. “Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease.” Proceedings of the Nutrition Society 78.1 (2019): 34-44.

101) Fayadat, Laurence, et al. “Role of heme in intracellular trafficking of thyroperoxidase and involvement of H2O2 generated at the apical surface of thyroid cells in autocatalytic covalent heme binding.” Journal of Biological Chemistry 274.15 (1999): 10533-10538.

102) Hatfield, Dolph L., and Vadim N. Gladyshev. “How selenium has altered our understanding of the genetic code.” Molecular and cellular biology 22.11 (2002): 3565-3576.

103) Korotkov, Konstantin V., et al. “Mammalian selenoprotein in which selenocysteine (Sec) incorporation is supported by a new form of Sec insertion sequence element.” Molecular and Cellular Biology 22.5 (2002): 1402-1411.

104) Eleftheriadou, Anna-Maria, et al. “Re-visiting autoimmunity to sodium-iodide symporter and pendrin in thyroid disease.” European Journal of Endocrinology 183.6 (2020): 571-580.

105) Czarnocka, Barbara. “Thyroperoxidase, thyroglobulin, Na (+)/I (-) symporter, pendrin in thyroid autoimmunity.” Frontiers in Bioscience-Landmark 16.2 (2011): 783-802.

106) Seissler, Jochen, et al. “Low frequency of autoantibodies to the human Na+/I− symporter in patients with autoimmune thyroid disease.” The Journal of Clinical Endocrinology & Metabolism 85.12 (2000): 4630-4634.

107) Skowrońska-Jóźwiak, Elżbieta. “The effect of Selenium on thyroid physiology and pathology.” (2015).

108) Eleftheriadou, Anna-Maria, et al. “Re-visiting autoimmunity to sodium-iodide symporter and pendrin in thyroid disease.” European Journal of Endocrinology 183.6 (2020): 571-580.

109) Czarnocka, Barbara. “Thyroperoxidase, thyroglobulin, Na (+)/I (-) symporter, pendrin in thyroid autoimmunity.” Frontiers in Bioscience-Landmark 16.2 (2011): 783-802.

110) Seissler, Jochen, et al. “Low frequency of autoantibodies to the human Na+/I− symporter in patients with autoimmune thyroid disease.” The Journal of Clinical Endocrinology & Metabolism 85.12 (2000): 4630-4634.

111) Kalderon, A. E., and H. A. Bogaars. “Immune complex deposits in Graves’ disease and Hashimoto’s thyroiditis.” The American journal of medicine 63.5 (1977): 729-734.

112) Kalderon, A. E., et al. “Electron-dense deposits in the follicular basal lamina of obese strain chickens with spontaneous hereditary autoimmune thyroiditis. An electron microscopic study.” Laboratory Investigation; a Journal of Technical Methods and Pathology 37.5 (1977): 487-496.

113) Xu, Jian, et al. “Selenium supplement alleviated the toxic effects of excessive iodine in mice.” Biological Trace Element Research 111 (2006): 229-238.

114) Sun, Rong, et al. “Protection of Vitamin C on Oxidative Damage Caused by Long-Term Excess Iodine Exposure in Wistar Rats.” Nutrients 14.24 (2022): 5245.

115) Karimi, F., and G. R. Omrani. “Effects of selenium and vitamin C on the serum level of antithyroid peroxidase antibody in patients with autoimmune thyroiditis.” Journal of Endocrinological Investigation 42.4 (2019): 481-487.

116) Abdul-Majeed, Abdullah F., Saeb Y. Abdul-Rahman, and Hassan A. Al-krad. “Effect of Vitamin C as Antioxidant on Stressed Quail Induced by Hydrogen Peroxide.” Euphrates Journal of Agriculture Science 13.4 (2021).

117) Bacic-Vrca, Vesna, et al. “The effect of antioxidant supplementation on superoxide dismutase activity, Cu and Zn levels, and total antioxidant status in erythrocytes of patients with Graves’ disease.” Clinical Chemistry and Laboratory Medicine (CCLM) 43.4 (2005): 383-388.

118) Corvilain, Bernard, et al. “Stimulation by iodide of H2O2 generation in thyroid slices from several species.” American Journal of Physiology-Endocrinology and Metabolism 278.4 (2000): E692-E699.


Extra References
Steinbrenner, Holger, Bodo Speckmann, and Lars-Oliver Klotz. “Selenoproteins: Antioxidant selenoenzymes and beyond.” Archives of Biochemistry and Biophysics 595 (2016): 113-119.

Wang, Li, et al. “Helicobacter Pylori and Autoimmune Diseases: Involving Multiple Systems.” Frontiers in Immunology 13 (2022).

The modern Gastroenterology have witnessed an essential stride since Helicobacter pylori was first found in the stomach and then its pathogenic effect was discovered. According to the researches conducted during the nearly 40 years, it has been found that this bacterium is associated with a natural history of many upper gastrointestinal diseases. Epidemiological data show an increased incidence of autoimmune disorders with or after infection with specific microorganisms. The researches have revealed that H. pylori is a potential trigger of gastric autoimmunity, and it may be associated with other autoimmune diseases, both innate and acquired. This paper reviews the current support or opposition about H. pylori as the role of potential triggers of autoimmune diseases, including inflammatory bowel disease, autoimmune thyroiditis, type 1 diabetes mellitus, autoimmune liver diseases, rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, as well as Sjogren’s syndrome, chronic urticaria and psoriasis, and tried to explain the possible mechanisms.

Lahner, Edith, et al. “Thyro-entero-gastric autoimmunity: Pathophysiology and implications for patient management.” Best Practice & Research Clinical Endocrinology & Metabolism 34.1 (2020): 101373.

The association between autoimmune atrophic gastritis and thyroid disorders has been observed since the early 1960s and the expression “thyrogastric syndrome” was coined to indicate the presence of thyroid autoantibodies or autoimmune thyroid disease in patients with pernicious anemia, a late clinical stage of autoimmune atrophic gastritis. More recently, it was confirmed that autoimmune thyroid disorders, in particular Hashimoto’s thyroiditis, may be frequently associated with other organ-specific, immune-mediated disorders, such as autoimmune atrophic gastritis or celiac disease. The association of Hashimoto’s thyroiditis with autoimmune atrophic gastritis or celiac disease in adult patients is currently considered part of the polyglandular autoimmune syndromes which include several autoimmune disorders associated with an autoaggressive impairment of endocrine glands. From a clinical point of view, the thyro-entero-gastric autoimmunity may lead to potentially serious consequences like anemia, micronutrients deficiencies, and drugs malabsorption, as well as to an increased risk for malignancies. These alterations may frequently present in an underhand manner, with consequent diagnostic and treatment delays. Many aspects of the association between thyroid, gastric and intestinal autoimmune diseases still await clarification. The present review focuses on the embryological, genetic and pathophysiological aspects of thyro-entero-gastric autoimmunity. In particular, the current diagnostic criteria of autoimmune thyroid disease, autoimmune atrophic gastritis, and celiac disease are reviewed, along with the evidences for their association in poly-autoimmunity syndromes. The benefits of proactive screening of autoimmune thyroid disorders in patients with autoimmune gastritis or enteropathy and viceversa are also discussed.

Triggiani, Vincenzo, et al. “Role of iodine, selenium and other micronutrients in thyroid function and disorders.” Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets-Immune, Endocrine & Metabolic Disorders) 9.3 (2009): 277-294.

Most people can be exposed to large amounts of iodine without apparent problems [106]. Iodine supplementation programs in iodine-deficient populations leading to iodine intakes of 150-200 mcg/day have been associated with an increased incidence of iodine-induced hyperthyroidism, mainly in older people with multinodular goiter. Iodine deficiency, in fact, increases the risk of developing autonomous thyroid nodules that are unresponsive to the normal thyroid  regulation system, resulting in hyperthyroidism after iodine supplementation [107, 108]. This is a complication of iodine profilaxis usually of short duration in a given population, but it can be a very serious health problem for a given patient, because of the high risk of atrial fibrillation [109].=\

An increased incidence of autoimmune thyroid disease frequently parallels an increased dietary iodine intake [113]. In iodine-sufficient populations (e.g., the U.S.), in fact, excess iodine intake is most commonly associated with elevated blood levels of thyroid stimulating hormone (TSH), hypothyroidism and goiter. Thyroid autoimmunity is depressed in iodine deficiency but it is “reset to normal” after its correction. Acute and massive excess of iodide can inhibit the process of synthesis of hormones by the thyroid gland through an inhibition of the process of iodide organification, the socalled Wolff-Chaikoff effect . Se deficiency increases the sensitivity of the thyroid gland to necrosis caused by iodide overload in iodine-deficient thyroid glands [209-214].

Several studies reported on the benefit of Se treatment both in Hashimoto’s thyroiditis and Graves’  disease. In two of these blind, placebo-controlled prospective studies, serum levels of thyroid anti-TPO autoantibody decreased, and patients’ self-assessment of the disease process improved, compared with a placebo group, after 3 to 6 months of treatment with 200 mcg/day sodium selenite or  selenomethionine. All patients were substituted with levotiroxine to maintain TSH within the normal range. Se substitution may improve the inflammatory status in patients with autoimmune thyroiditis, especially in those with high activity. These studies were performed in areas of Europe with limited nutritional Se supply. Se supplementation led to increased plasma Se and GPx activity [203, 204, 224].

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Hotz, Christine S., et al. “Dietary iodine and selenium interact to affect thyroid hormone metabolism of rats.” The Journal of nutrition 127.6 (1997): 1214-1218.

Vrca VB, Skreb F, Cepelak I, Romic Z, Mayer L (2004) Supplementation with antioxidants in the treatment of Graves disease; the effect on glutathione peroxidase activity and concentration of selenium. Clin Chim Acta 341(1–2):55–63

Zagrodzki P, Ratajczak R (2008) Selenium supplementation in autoimmune thyroiditis female patient—effects on thyroid and ovarian functions (case study). Biol Trace Elem Res 126(1–3):76–82

Dabbaghmanesh, Mohammad Hossein, et al. “Low serum selenium concentration as a possible factor for persistent goiter in Iranian school children.” Biofactors 29.2-3 (2007): 77-82.

Kucharzewski, M., et al. “Concentration of selenium in the whole blood and the thyroid tissue of patients with various thyroid diseases.” Biological trace element research 88.1 (2002): 25-30.

Lyons, Graham. “Biofortification of cereals with foliar selenium and iodine could reduce hypothyroidism.” Frontiers in Plant Science 9 (2018): 730.

Danailova, Yana, et al. “Nutritional Management of Thyroiditis of Hashimoto.” International Journal of Molecular Sciences 23.9 (2022): 5144.

Moncayo, Roy, Helga Moncayo, and Juliana Reisenzahn. “Global view on the pathogenesis of benign thyroid disease based on historical, experimental, biochemical and genetic data, identifying the role of magnesium, selenium, coenzyme Q10 and iron in the context of the unfolded protein response and protein quality control of thyroglobulin.” Journal of Translational Genetics and Genomics 4.4 (2020): 356-383.

Karbalaei, M., and M. Keikha. “Rescue effects of Lactobacillus-containing bismuth regimens after Helicobacter pylori treatment failure.” New Microbes and New Infections 42 (2021): 100904.

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