요오드와 하시모토병

저자: Paul Jaminet

http://perfecthealthdiet.com/2011/05/iodine-and-hashimotos-thyroiditis-part-i/

대부분의 의사들은 요오드 보충제가 자가면역 갑상선염을 악화시킬 것이라 믿고 있다. 이러한 견해는 요오드 섭취량이 증가한 집단에서 하시모토병(Hashimoto's hypothyroidism) 발병률이 증가하는 경향이 있다는 관찰이 지지해준다. (하지만 갑상선 기능 저하증의 발병률은 요오드 섭취량이 감소할 수록 증가한다.) 그러나 모든 역학연구들이 이러한 상관관계를 보여주지는 않는다.  [1][2][3][4].

2010년 저서 "Why Do I Still Have Thyroid Symptoms?"로 하시모토병 환자들 사이에서 유명한 Datis Kharrazian 박사(Dr. K)는 하시모토병에 요오드 사용하는 것을 격렬히 반대한다 [5][6][7]. The Healthy Skeptic의 Chris Kresser는 "갑상선 기능 저하증에 요오드를 사용하는 것은 마치 불이난 곳에 기름을 붓는 것과 같다"고 주장한다 [8]. 그리고 실제로 일부 환자들은 고용량 요오드로부터 안좋은 결과를 얻기도 하였다.

하지만 Guy E. Abraham [9], David Brownstein[10] , Jorge D. Flechas [11], David Derry [12] 박사는 고용량의 요오드를 하시모토병과 유방암 및 갑상선암 환자에게 성공적으로 사용할 수 있다고 주장한다.

배경 이론

갑상선과산화효소(TPO)는 주로 갑상선에서 발현되는 효소로 유리시킨 요오드를 티로글로빈(TG)의 티로신 잔기에 결합시켜 갑상선 호르몬인 thyroxine(T4)나 triiodothyronine (T3)을 생성한다.

체내 TG와 TPO에 대한 자가항체 수치는 평상시 낮게 유지된다. 하지만 자가면역 갑상선염은 이들 자가항체 수치가 높게 나타나며, 면역체계는 갑상선을 공격하게 된다.

높은 갑상선 자가항체 수치는 갑상선 기능 저하증과 관련이 있다[13][14]. TPO 항체와 TSH 수치는 무증상 갑상선기능저하증에서 명백한 갑상선기능저하증으로 진행되는 것과 밀접한 관련이 있다[3].

셀레늄이 요오드 과잉을 치료할 수 있다.

닥터 K는 그의 저서에서 "요오드가 과산화효소(TPO)의 생성 및 활성을 촉진시킨다"고 말한다[5][7]. 하시모토병 환자에서 TPO는 자가면역이 공격하는 대상이므로 질병을 악화시킬 수 있다 [5][6][7]. 또한 그는 과잉 요오드가 TPO 활성을 차단한다고 주장하였지만 그의 주장에 대한 출처나 얼만큼의 요오드가 TPO 활성을 차단하는지는 전혀 언급하지 않았다. [5]

사실 과잉 요오드가 셀레늄 결핍과 동반될 경우에만 TPO 활성이 감소할 것이다. (증가하거나 완전히 차단하는 것이 아니다)[15]. 이를 뒷받침하는 실험은 대상자를 다음 7개의 그룹으로 나뉘어 실험을 진행하였다: 적당한 요오드와 실험식이 셀레늄 (NI), 과잉 요오드와 실험식이 셀레늄 (EI), 나머지 다섯개그룹은 과잉 요오드를 투여한 뒤 점차적으로 셀레늄 첨가량을 늘렸다. 과잉 요오드는 TPO 활성을 감소시키지만 셀레늄이 존재하는 경우 control 레벨로 돌아온다. 과잉 요오드와 과잉 셀레늄 투여한 경우도 TPO 활성이 감소하였다.

고용량 요오드 섭취가 TPO 활성을 감소시킨다는 것을 입증시킨 다른 실험도 존재한다[23][24].

실험은 서로 다른 쥐에게 요오드 적정량(NI), 과잉 요오드(EI), 과잉 요오드와 0.2 mg/L의 셀레늄 (IS2)을 투여한 뒤 갑상선 여포를 관찰하였다[15]. 과잉 요오드를 투여한 경우 갑상선 여포는 비대해졌다. 그러나 첫번째와 마지막 사진은 차이를 나타내지 않았다! 만약 셀레늄과 요오드를 함께 증량시킨다면 갑상선 종은 발생하지 않는다는 것을 확인시켜 준다.

셀레늄은 자가면역질환을 고칠 수 있다.

요오드로 유발된 자가면역 갑상선염을 지닌 동물 모델에게 셀레늄이 주는 효과를 관찰한 중국 연구팀이 있다[16]. 연구팀은 쥐를 세그룹으로 나누었다: 건강한 대조군, 요오드가 유발한 자가면역 갑상선염 (AIT)에 셀레늄을 투여하거나 (AIT+Se) 투여하지 않은 그룹 (AIT). AIT+Se 그룹은 8주간 고용량의 요오드를 투여하여 질병을 유발하였고 그 후 8주간 요오드와 셀레늄을 같이 투여하였다. 불구하고 셀레늄을 8주간 보충하자 (고용량 요오드를 계속 투여했음에도) 그들의 갑상선 여포는 거의 완벽히 회복되었다.

AIT 그룹은 갑상선종의 특징인 비대해진 세포와 죽은 조직이 관찰되었다; AIT-Se 그룹의 갑상선은 정상 갑상선을 닮았다. 갑상선의 무게는 AIT 그룹에서 두배였는데, 셀레늄을 보충해주자 정상 무게로 돌아왔다. AIT+Se 그룹에 셀레늄을 투여하기 전 혈청 TgAb 항체가 상승되었지만, 셀레늄을 보충하자 정상 수치로 돌아왔다.

이 실험에서 흥미로운 점은 면역 세포의 변화이다. negative regulatory T cells or Tregs는 자가항원 반응을 억제하고 과도한 면역반응을 억제함으로써 self-tolerance를 유지시켜준다. 만약 Treg 세포수가 부족하거나 기능이상이 발생하면 자가면역질환이 초래된다[17].

이 실험에서 고용량의 요오드로 인해 CD4+CD25+Foxp3+ Treg Cells 수가 줄어들지만 (요오드 용량을 유지시킨 상태로) 8주동안 셀레늄을 보충하자 정상 수치로 돌아왔다. 따라서 Treg 세포수를 적절히 유지시키기 위해서는 셀레늄-요오드의 균형을 맞춰주어야 하며, 셀레늄 보충은 자가면역의 정상적인 조절을 복구시켜준다.

요오드가 자가면역을 유발하는 경우는?

지난 실험에서 고용량의 요오드가 자가면역 갑상선염을 유발시키기 위해 사용되었다. 어떤 상황에서 유발되는지 자세히 살펴보도록 하자.

하시모토병 환자에게 과잉 요오드는 T 림프구의 증식과 Th1/Th2 axis 및 CD4/CD8 수치에 영향을 미친다. 자가면역 질환의 발병은 자가공격(autoagression)의 활성으로부터 시작되는 것으로 알려져 있다.

셀레늄이 결핍된 경우에만 과잉 요오드가 자가면역 질환을 유발할 수 있다는 중국 연구 결과가 있다[18].

쥐를 다섯 그룹으로 나눈뒤 각 그룹의 요오드와 셀레늄 양을 달리하여 30일간 경구 투여하였다. 4개 그룹은 셀레늄 없이 서로 다른 요오드 량을 투여하였다:  0 μg/L (group I), 1500 μg/L (group II), 3000 μg/L (group III), and 6000 μg/L (group IV). 다섯번째 그룹은 6000 μg/L 요오드와 0.3 mg/L 셀레늄을 투여하였다 (group V).

그룹 IV에서 고용량의 요오드 (6000 ug/L)는 림프구의 증식을 유발하였다. 하지만 셀레늄이 보충된 경우 완전히 사라졌다 (그룹 V):

T세포는 면역 기능에 이상이 생기지 않는다면 상대적으로 일정한 농도로 존재한다. 요오드가 증가하면 그룹 IV에서와 같이 T 림프구의 증식이 증가된다. (그림 1) 그러나 동일하게 셀레늄을 투여한 그룹 V는 대조군과 같은 수치를 보였다.

하시모토병 환자는 CD4+/CD8+ 비가 대조군에 비해 낮다[19][20]. 하시모토병 환자는 CD4+/CD8+ 비가 대조군에 비해 낮다. 그러나 가장 많은 양의 요오드와 함께 셀레늄을 투여한 그룹 V는 전체를 통틀어 CD4+/CD8+의 비가 가장 컸다. 그러나 가장 많은 양의 요오드와 함께 셀레늄을 투여한 그룹 V는 전체를 통틀어 CD4+/CD8+의 비가 가장 컸다.

자가면역 갑상선염의 또 다른 마커는 Th1과 Th2 반응 강도를 비교하는 것으로 각각의 마커는 interferon-gamma과 interleukin-4이다. 하시모토병 환자에서 Th1(IFN-γ)/Th2(IL-4) 비가 증가하며[21][22], 질환의 중증도와 관련있다[22].

셀레늄 없이 고용량의 요오드만 섭취한 그룹 IV은 Th1/Th2 비가 명확히 높게 나타났다. 고농도 요오드와 셀레늄을 투여한 그룹 V의 Th1/Th2 비는 대조군과 비슷하였다.

"실험 결과, 중재그룹 (group V)과 대조군 (group I)의 면역독성은 큰 차이가 없었는데, 이는 셀레늄이 과잉 요오드 섭취에 이로운 효과를 나타내는 것을 시사한다."

결론

고용량의 요오드 섭취는 자가면역 갑상선염을 유발할 수 있다. 그러나 동물실험에서 그런 상황은 셀레늄이 너무 많거나 결핍된 상황에서만 일어났다.

요오드 섭취량과 상관없이 셀레늄 수치가 적절할때는 갑상선 여포가 건강하고 갑상선 종은 사라졌으며 자가면역의 마커인 Th1/Th2 와 CD4+/CD8+의 비가 정상으로 나타났다. 셀레늄 보충이 자가면역 갑상선 질환에 대한 강력한 보호역할을 하고 다양한 요오드 섭취량에 대한 내성을 제공하는 것으로 보인다.

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Iodine and Hashimoto’s Thyroiditis

Dr. Datis Kharrazian (“Dr. K”), whose 2010 book “Why Do I Still Have Thyroid Symptoms?”[5] is popular among Hashimoto’s patients, vehemently opposes the use of iodine in Hashimoto’s [5][6][7]. Chris Kresser of The Healthy Skeptic [8] has argued this point of view in his post “Iodine for hypothyroidism: like gasoline on a fire?”. And there’s little doubt that some patients have experienced bad consequences from high-dose iodine.

On the other side, doctors such as Dr. Guy E. Abraham [9], Dr. David Brownstein [10], Jorge D. Flechas [11] and Dr. David Derry [12] have claimed success prescribing high doses of iodine for Hashimoto’s and for breast and thyroid cancers.

Can these experiences by reconciled? What we will try to do is demonstrate that iodine acts synergistically with selenium, and that it is imbalances between the two that damage the thyroid.

First, Some Background

Thyroid peroxidase or thyroperoxidase (TPO) is an enzyme expressed mainly in the thyroid that liberates iodine for addition onto tyrosine residues on thyroglobulin (TG) for the production of the thyroid hormones thyroxine (T4) or triiodothyronine (T3).

The human body normally has low levels of auto-antibodies against both TG and TPO, which serve some physiological function. Autoimmune thyroiditis features high levels of these auto-antibodies, leading to immune attacks on the thyroid.

High levels of thyroid auto-antibodies are positively associated with hypothyroidism symptoms [13][14]. TPO antibodies and TSH levels are strongly associated with progression of subclinical hypothyroidism to overt hypothyroidism [3], as can be see in Table 3 below:

Selenium Can Cure An Iodine Excess

Dr. K said in his book and site that “iodine stimulates the production and activity of the thyroid peroxidase (TPO) enzyme” [5][7]. Since TPO is a target of autoimmune attack in Hashimoto’s patients, this might worsen the disease [5][6][7]. In his book he also states that excessive iodine will shut down TPO activity [5], but he neither cites a reference nor states what level of iodine intake will cause this to happen.

In fact, excess iodine combined with selenium insufficiency will reduce (not increase, not shut down) TPO activity [15]. Let’s look at a study that had seven groups: normal iodine and lab-chow selenium only (NI), excess iodine and lab-chow selenium only (EI), and five groups with excess iodine and steadily increasing levels of selenium added to water (IS1 to IS5). TPO activity was reduced by excess iodine (EI), but returned to control levels (NI) with moderate selenium (IS1 and IS2). With excess iodine and excessive selenium (IS3 to IS5), TPO activity was also decreased, as we can see from table 2 below.

Some other studies have also demonstrated this reduced TPO activity at high iodine intakes [23][24].

This study [15] also showed a picture (fig. 1) of thyroid follicles from rats receiving normal iodine diet (NI), excessive iodine (EI) and excessive iodine plus 0.2 mg/L selenium (IS2). Thyroid follicles from the excessive iodine group (EI) are enlarged, a characteristic of goiter. But, there is virtually no difference between the first and last picture! If selenium and iodine are increased together, no goiter occurred.

Note that the IS2 level of selenium, which protects against iodine toxicity, corresponds in a person who drinks 1-2 liters per day to a selenium dose of 200 to 400 mcg per day – which happens to be the Perfect Health Diet “plateau range” for selenium.

Selenium Can Cure Autoimmunity

Another paper, also from China, looked at the effects of selenium in an animal model of iodine induced autoimmune thyroiditis [16].

There were three groups of mice, a healthy control group, and groups with iodine induced autoimmune thyroiditis without (AIT) and with (AIT+Se) selenium. The AIT+Se group was given high iodine (AIT only) for 8 weeks to induce the disease, and then, for 8 weeks more, they were given iodine plus selenium. After 8 weeks of selenium supplementation their thyroid follicles were almost fully recovered, as we can see below, even though high-dose iodine had continued:

The AIT group has enlarged cells characteristic of goiter and dead tissue; the AIT-Se group thyroid section resembles a normal thyroid. Thyroid weight doubled in the AIT group, proof of goiter, but returned to normal after selenium supplementation.

Before selenium was given to the AIT+Se group, serum TgAb antibodies were elevated, but they returned to normal after selenium supplementation:

An interesting aspect of this study was the changing population of immune cells. A specialized subpopulation of T cells, negative regulatory T cells or Tregs, helps establish and maintain self-tolerance by suppressing response to self-antigens and suppressing excessive immune responses deleterious to the host. Deficits in Treg cell numbers or function lead to autoimmune diseases [17].

In this study, CD4⁺CD25⁺Foxp3⁺ Treg Cells were reduced by high iodine, but returned much of the way toward normal after 8 weeks of selenium even though high iodine intake continued. The implication is that selenium-iodine balance may be needed to maintain proper Treg cell populations, and that selenium supplementation may restore normal regulation of autoimmunity.

The researchers concluded:

“In the present study, we observed that Se supplementation increased the frequency  of CD4+CD25+Foxp3+ T cells and enhanced expression of Foxp3 in vivo. These changes were accompanied by suppressed TgAb titers and reduced thyroiditis. Thus the benefit of Se treatment may be due to the increase of CD4+CD25+ regulatory T cells.”

Under What Circumstances Does Excess Iodine Induce Autoimmunity?

In the previous study high doses of iodine were used to induce autoimmune thyroiditis. Let’s look more closely into the circumstances in which that happens.

It’s often said that excessive iodine in Hashimoto’s triggers an immune response characterized by proliferation of T lymphocytes, a disrupted Th1/Th2 axis, and altered CD4/CD8 levels. Pathogenesis of autoimmune disease is believed to begin with the activation of T cell autoaggression (turning them into “allergized T cells”).

Our next study, also from China, showed that excess iodine can indeed cause such an autoimmune pathology, but only if there is a deficiency in selenium [18].

Mice in 5 groups were orally administrated different combinations of iodine and selenium for 30 days. Four groups had no selenium but varying amounts of iodine in their water: 0 μg/L (group I), 1500 μg/L (group II), 3000 μg/L (group III), and 6000 μg/L (group IV). The fifth group had 6000 μg/L iodine plus 0.3 mg/L selenium (group V).

In Group IV, high-dose iodine at 6000 μg/L caused a proliferation of lymphocytes. But this was completely abolished by the addition of selenium to water in Group V:

Normally there are relatively stable population of T cells and their subgroups in tissue till immune function is in disorder. As we can see from Fig. 1, increasing iodine increased T lymphocytic reproductive activity, and was clearly high in group IV. But group V, which also received selenium, had the same values as the control group (I).

Subjects with Hashimoto’s also have a lower ratio of CD4⁺ to CD8⁺ lymphocytes than controls [19][20]. From fig. 2, we can see that iodine supplementation in groups II and III actually increased the CD4⁺ to CD8⁺ ratio, until the onset of autoimmune symptoms at very high doses in Group IV when the ratio decreased. However, group V, which had the highest iodine intake but with selenium as well, had the highest CD4⁺ to CD8⁺ ratio of all groups.  This suggests that high-dose iodine and selenium together may actually diminish the autoimmune syndrome compared to the low levels in the controls.

Another marker of autoimmune thyroiditis is the relative strength of the Th1 and Th2 responses, as indicated by the markers interferon-gamma and interleukin-4 (Th2). Th1(IFN-γ)/Th2(IL-4) ratios are increased in Hashimoto patients [21][22], and related with severity of Hashimoto’s disease [22].

As we can see from Fig. 3, the group with the highest iodine intake but no selenium (IV) was the only group that had clearly higher Th1/Th2 ratio. High iodine plus selenium in group V had similar Th1/Th2 ratios than control group (I).

The researchers concluded:

“The results revealed that there was no significant difference in the immunotoxicity between interventional group (group V) and control group (group I), indicating that adequate selenium has a favorable interventional effect on excessive iodine intake.”

Conclusion

Excess iodine intake can cause an autoimmune thyroiditis that bears all the characteristics of Hashimoto’s. However, in animal studies this occurs only if selenium is deficient or in excess. Similarly, in animal studies very high iodine intake can exacerbate a pre-existing autoimmune thyroiditis, but only if selenium is deficient or in excess.

With optimal selenium status, thyroid follicles are healthy, goiter is eliminated, and autoimmune markers like Th1/Th2 ratio and CD4+/CD8+ ratio are normalized over a wide range of iodine intake. It seems that optimizing selenium intake provides powerful protection against autoimmune thyroid disease, and provides tolerance of a wide range of iodine intakes.

In the next post in this series (Iodine and Hashimoto’s Thyroiditis, Part 2, May 26, 2011), we’ll transition from animals to humans. Does epidemiological evidence suggest that these animal findings are transferable to humans?

References:

[1] F. Aghini-Lombardi et al. The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano Survey. J. Clin. Endocrinol. Metab. 84, 561–566 (1999). http://pmid.us/10022416.

[2] Marino MA et al. Urinary iodine in patients with auto-immune thyroid disorders in Santo André, SP, is comparable to normal controls and has been steady for the last 10 years. Arq Bras Endocrinol Metabol. 2009 Feb;53(1):55-63. http://pmid.us/19347186.

[3] Strieder TG et al. Prediction of progression to overt hypothyroidism or hyperthyroidism in female relatives of patients with autoimmune thyroid disease using the Thyroid Events Amsterdam (THEA) score. Arch Intern Med. 2008 Aug 11;168(15):1657-63. http://pmid.us/18695079.

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