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Optimum Levels of Iodine for Greatest Mental and Physical Health

part 1

Guy. E. Abraham M.D.1, Jorge D. Flechas M.D.2 and John C. Hakala R.Ph.3

I. Introduction

For the sake of clarity, the element iodine in all its forms will be identified in this manuscript with the letter I, whereas the name iodine will be reserved for the oxidized state I2. According to a recent editorial of the Journal of Clinical Endocrinology and Metabolism (1), one third of the world’s population lives in areas of I deficiency, which is the world’ leading cause of intellectual deficiency (2). I is an essential element and its essentiality is believed to be due to its requirement for the synthesis of the thyroid hormones thyroxine (T4) and triodothyronine (T3). The recommended daily intake of I for adults of both sexes in North America and Western Europe varies from 150 to 300 ug (1). I deficiency results in goiter (enlarged thyroid gland) and hypothyroidism. The recommended levels for daily I intake were chosen with the goal of preventing and correcting endemic goiter and hypothyroidism, assuming that the only role of I in health maintenance is in its essentiality for the synthesis of T4 and T3.

Considering the importance of this element for overall wellbeing, it is most amazing that no study so far has attempted to answer the very important question: What is the optimal amount of daily I intake that will result in the greatest mental and physical levels of wellbeing in the majority of a population with a minimal degree of negative effects? In the studies designed to answer this question, consideration should be given to the possibility that I, at levels higher than those required to achieve normal thyroid function tests and absence of simple goiter, may have some very important thyroidal and extrathyroidal non T3-T4 related roles in overall wellbeing.

Some eighty years ago, D. Marine reported the results of his landmark study on the effect of I supplementation in the prevention and treatment of iodine-deficiency goiter. Based on extensive studies of goiter in farm animals, he estimated the amount of I that would be required for human subjects. He chose a population of adolescent school girls from the 5th to 12th grade between the ages of 10 and 18 years residing in Akron, Ohio, a city with a 56% incidence of goiter (3). His choice was based on the observation that the incidence of goiter was highest at puberty, and 6 times more common in girls than in boys (4). He studied two groups of pupils devoid of goiter (thyroid enlargement by palpation) at the beginning of the project. The control group consisted of 2305 pupils who did not receive I supplementation; and 2190 pupils received a total of 4 gm of sodium iodide per year for a period of 2 &½ years. The amount of I was spread out in 2 doses of 2 gm each during the spring and during the fall. This 2 gm dose was administered in daily amounts of 0.2 gm of sodium iodide over 10 days. At 4000 mg of sodium iodide per 365 days, the daily amount is 12 mg, equivalent to 9 mg I. After 2 &½ years of observation, 495 pupils in the control group developed thyroid enlargement (22%). Only 5 cases of goiter occurred in the I-supplementation group (0.2%). Iodism was observed in 0.5% of the pupils receiving I supplementation. In an area of Switzerland with an extremely high incidence of goiter (82 to 95%), Klinger, as reported by Marine (3), administered 10-15 mg of iodine weekly to 760 pupils of the same age group. The daily I intake in this group was 1.4-2 mg. The initial examination revealed 90% of them had enlarged thyroid. After 15 months of this program, only 28.3% of them still had an enlarged gland. None experienced iodism. In response to these studies, the Swiss Goiter Commission advised the use of I supplementation in all cantons. Iodized fat in tablet form containing 3 to 5 mg I per tablet was used for I supplementation.

Due to the large consumption of seaweeds in the Japanese diet, this population ingests several milligrams of I daily without ill effects and in fact with some very good results evidenced by the very low incidence of fibrocystic disease of breast (5) and of the low mortality rates for cancers of the female reproductive organs (6). According to the Japanese Ministry of Health and Welfare, the average daily intake of seaweed is 4.6 gm. At an average of 0.3% I content (range = 0.08-0.45%), that is an estimated daily I intake of 13.8 mg (7). Japanese living in the coastal areas consume more than 13.8 mg (7). Studies performed in some of the subjects living in the coastal areas, revealed that the thyroid glands exposed to those levels of I, organify more I than they secrete as T3 and T4 and the levels of T3 and T4 are maintained within a narrow range. The excess I is secreted as non hormonal I of unknown chemical composition, mostly as inorganic I (7). The intake of I in the non-coastal areas of Japan is less. A recent study of 2956 men and 1182 women residing in the non-coastal city of Sapporo, Japan (8), revealed a urine concentration of I in spot urine samples, with a mean value of 3.4 mg/L, corresponding to an estimated daily intake averaging 5.3 mg (5). This relatively low I intake by Japanese standard, is more than 30 times the recommended daily amount of I in North America and Europe (1).

B.V. Stadel, from the National Institute of Health, proposed in 1976 to test the hypothesis that the lower incidence and prevalence of breast dysfunctions and breast Ca; and the lower mortality rate from breast, endometrial and ovarian cancers observed in Japanese women living in Japan versus those women living in Hawaii and the continental US, was due their I intake (6). He suggested a prospective study with 2 groups of subjects recruited from the same population with a high incidence of the above pathologies: one control group on intakes of I from a Western diet at RDA levels, and the other intervention group, receiving I in amounts equivalent to that consumed by Japanese women living in Japan. So far, data from this type of prospective epidemiological research are not available in the published literature, regarding the incidence of cancer of the female reproductive organs in women receiving several mg of I daily as the only know variable, compared to women whose diet supplies RDA levels of I.

Data are available, however, regarding the effects of I, ingested in daily amounts of several mg on subjective and objective improvements of fibrocystic disease of the breast (FDB). In 1966, two Russian scientists (9) published their results regarding the effect of oral administration of potassium iodide in daily amounts equivalent to 10-20 mg I, on 200 patients with "dyshormonal hyperphasia of mammary glands". They postulated that this form of mastopathy was due to excess estrogens from ovarian follicular cysts which were caused by insufficient consumption of I. The duration of I supplementation of their patients varied from 6 months to 3 years. Within 3 months, there was significant reduction of swelling, pain, diffuse induration and nodularity of the breast. Out of 167 patients who completed the program, a positive therapeutic effect was observed in 72% of them. In five patients with ovarian follicular cysts, there was a regression of the cystic ovaries following 5 months to one year of I supplementation. No side effects of I supplementation was reported in those patients.

Ghent et al (10) extended the Russian study further, using different amounts of different forms of I in women with FDB. Beginning in 1975, these Canadian investigators tested various amounts of various forms of I in three open trials. Lugol 5% solution was used in 233 patients for 2 years in daily amounts ranging from 31 to 62 mg I. They achieved clinical improvement in 70% of the patients. Thyroid function tests were affected in 4% of the patients and iodism was present in 3% of them. In 588 patients, using iodine caseinate at 10 mg/day for 5 years, only 40% success rate was achieved. In 1365 patients, using an aqueous saturated solution of iodine in daily amount based on body weight, estimated at 3-6 mg I/day, 74% of the patients had clinical improvements both subjectively from breast pain and objectively, form breast induration and nodularity. Iodism was present in only 0.1% in this last group. In a double blind study of 23 patients ingesting aqueous solution of iodine in amounts of 3 to 6 mg/day for a mean of 191 days, 65% showed objective and subjective improvement whereas in 33 patients on a placebo, 3% experienced worsening of objective signs and 35% experienced improvement in subjective breast pain. These data are summarized in Table I. Although the percent of subjects reporting side effects in Ghent’s studies appear high ranging from 7% to 10.9%, the authors stated that the incidence of iodism was relatively low and most complaints were minor such as increased breast pain at the onset of I supplementation, and complaint about the unpleasant taste of iodine.

When the data from Marine’s, Klinger’s and Ghent’s studies (3,10) were evaluated regarding the incidence of iodism in relation to the daily amount of I ingested, a positive correlation was found between those 2 parameters: zero percent iodism at a daily amount of 1.4-2 mg; 0.1% iodism with 3-6 mg daily; 0.5% with 9 mg and 3% with 31-62 mg (Table II).

In the 19th Edition of Remington’s Science and Practice of Pharmacy, published in 1995 (11), the recommended daily oral intake of Lugol 5% solution for I supplementation was between 0.1 and 0.3 ml. This time-tested Lugol solution has been available since 1829, when it was introduced by French physician Jean Lugol. The 5% Lugol solution contains 50 mg iodine and 100 mg potassium iodide per ml, with a total of 125 mg I/ml. The suggested daily amount of 0.1 ml is equivalent to 12.5 mg of I, with 5 mg iodine and 7.5 mg of iodide as the potassium salt. This amount of I is very close to 13.8 mg, the estimated daily intake of I in Japanese subjects living in Japan, based on seaweed consumption (7). Obviously, this quantity of I present in 4.6 gm of seaweed would have to be consumed daily to maintain the I intake at this level. As quoted by Ghent et al (10), in 1928 an autopsy series reported a 3% incidence of FDB, whereas in a 1973 autopsy report, the incidence of FDB increased markedly to 89% (10,12,13). Is it possible that the very low 3% incidence of FDB reported in the pre-RDA early 1900’s (12) was due to the widespread use of the Lugol solution available then from local apothecaries; and the recently reported 89% incidence of FDB (13) is due to a trend of decreasing I consumption (2) with such decreased levels still within RDA limits for I, therefore giving a false sense of I sufficiency?

This lengthy introduction could be justified in the present context by stating that this background information was necessary to set the stage for the present study. If indeed, as suggested by Ghent et al, the amount of I required for breast normality is much higher than the RDA for I which is based on thyroid function tests and thyroid volume (10), then the next question is: What is the optimal amount of I that will restore and maintain normal breast function and histology, without any significant side effects and negative impact on thyroid functions? From the studies referred to (9,10) and Table I, the range of daily I intake in the management of FDB was between 3 and 62 mg. From Table II, we observe that the incidence of iodism increased progressively from zero % at 2 mg to 3% at 31-62 mg.

Our goal was to assess the effect of a standardized fixed amount of I within the range of daily amount of I previously used in FDB, on blood chemistry, hematology, thyroid volume and function tests in clinically euthyroid women with normal thyroid volume by ultrasonometry; and subsequently trying the same in women with FDB if there was no evidence of toxicity and adverse effects on the thyroid gland. The equivalent of 0.1 ml of a 5% Lugol solution, that is 12.5 mg I was chosen, a value close to the average intake of 13.8 mg consumed in Japan (7), a country with a very low incidence of FDB (5); slightly higher than the 9 mg amount used in Marine’s original study (3) of adolescents, with a very low 0.5% incidence of iodism following this level of I supplementation; also within the range of the 10 to 20 mg amount used in the Russian study of FDB, without any side effects reported (8); and five times less than the largest amount of 62 mg used in Ghent’s studies with a 3% iodism reported (10).

Because administration of I in liquid solution is not very accurate, may stain clothing, has an unpleasant taste and causes gastric irritation, we decided to use a precisely quantified tablet form containing 5 mg iodine and 7.5 mg iodide as the potassium salt. To prevent gastric irritation, the iodine/iodide preparation was absorbed unto a colloidal silica excipient; and to eliminate the unpleasant taste of iodine, the tablets were coated with a thin film of pharmaceutical glaze. Ten clinically euthyroid caucasian women were evaluated before and 3 months after ingesting a tablet daily. The evaluation included thyroid function tests and assessments of thyroid volume by ultrasonometry. The results suggest that this form and amount of I administered daily for 3 months to euthyroid women had no detrimental effect on thyroid volume and functions. Some statistically significant changes were observed in the mean values of certain tests of urine analysis, thyroid function, hematology and blood chemistry following I supplementation. These mean values were within the reference range, except for mean platelet volume (MPV) with a mean value below the reference range prior to supplementation, but the mean MPV value increased to reach a level within the normal range following I supplementation. In 2 subjects, baseline TSH levels were above 5.6 mIU/L, the upper limit for the reference range of the clinical laboratory used in this study. In both subjects, I supplementation markedly suppressed TSH levels.

II. Subjects and Methods

The female subjects were recruited from the private patients of one of us (JDF) and staff members of a medical clinic. They were ambulatory, without any serious medical problem, clinically euthyroid and on no medication known to affect thyroid functions. Informed consent was obtained on all subjects. Of 12 subjects recruited, 2 subjects were dropped from the data analyzed. One subject had a diffusely enlarged thyroid with a volume of 43 ml by ultrasonometry (14), significantly higher than the upper normal of 18 ml (14,15). Even though the thyroid function tests were within the normal limits for this subject, we decided to exclude her from this study, but she was placed on the same I supplementation and reevaluated every 3 months. The other subject did not return for follow-up. The clinical information on the 10 women selected are displayed in Table III. Mastodynia (breast pain) was initially the only symptom evaluated pre- and post-I supplementation. However, some of the subjects volunteered information regarding improvement of restless leg and tremor while on the program, so we included these 2 symptoms also.

The tablets containing 5 mg iodine and 7.5 mg of iodide as the potassium salt were prepared by one of us (JCH). A 5% Lugol solution prepared with USP grade iodine crystals and potassium iodide powder in purified water, was added to a colloidal silica excipient under mixing and the preparation was calibrated to contain the above amounts per tablet. The excess water was evaporated under low heat and the resulting dried preparation compressed into tablets which were coated with a thin film of pharmaceutical glaze. There was no loss of I due to evaporation since triplicate analysis by a commercial laboratory (Weber Laboratories, New Port Beach, CA) of tablets taken from the batch used in the present study, revealed quantitative recovery, with I concentrations of 12.5, 12.5 and12.6 mg per tablet. After initial evaluation, each subject was supplied with a bottle of 90 tablets*, with instruction to ingest one tablet a day for 90 days and to report any adverse effects.

The following laboratory evaluations were performed prior to and after 3 months of I supplementation: Complete blood count (CBC), was obtained from a Abbott Cell-DynÒ 1200; the metabolic panel and thyroid profile were performed by Lab Corporation of America; urine analysis was processed at the clinic with Multistix 10SG Reagent Strips, read on a Clinitek 100 that was calibrated daily. Measurement of thyroid volume by ultrasonometry was performed at the clinic by a registered sonographer using a portable Biosound Esaote Megas System unit with a frequency of 7.5 megaHerts, according to the procedure described by Brunn et al (14). The volume of each lobe of the thyroid gland was calculated according to the formula: V (mL) = W(cm) x D(cm) x L(cm) x 0.479 (14). The thyroid volume was the sum of the volumes of both lobes, taking 18 ml as the upper limit for normal thyroid volume in women living in a non-endemic goiter area (16). Body compositional analysis was performed at the clinic by near infrared technology (17), using a Futrex 5000: muscle mass, fat mass, % fat and total body water. The body mass index (BMI) is the ratio of body weight divided by height squared, using the metric units of kilogram (kg) for weight and meter (m) for height (18). Based on the classification of overweight and obesity by BMI, the normal range is 18.5-24.9 kg/m2, with less than 18.5 as underweight; between 25-29.9 as overweight, and 30 and above as obesity. The latest NHANES III study (1988-1994) revealed that 25% of American women are overweight and 25% obese (18). Based on this classification, 5 subjects were within the normal range, 2 were overweight; and 3 were obese (Table III). Therefore these subjects are a good representation of our "normal" population. Statistical analysis of the data, comparing pre- and post-I supplementation values within patients, was done by paired data analysis (19).

III. Results

Clinically, (Table III) there were significant improvements of mastodynia (p = 0.004), tremor (p = 0.048) and restless leg (0.009). There was no statistical significant effect of I supplementation on blood pressure, body temperature and body composition (Table IV). Percent body fat reached a near significant drop (p = 0.075).

Regarding laboratory evaluation of the subjects, results of urine analysis were normal in all subjects pre- and post-I supplementation. The only statistically significant effect of I was on urine pH (p = 0.012) with pre- and post-I values (mean ± S.D.) respectively of 6.05 ± 0.69 and 7.00 ± 0.85. (Reference Range: 5.0-8.5). Out of 17 different measurements performed on blood chemistry, 9 were affected significantly by I supplementation: a drop in creatinine (p less than0.01), calcium (p = 0.04), albumin (p less than 0.01), A/G ratio (p less than 0.01), alkaline phosphatase (p less than0.01); and a rise in sodium (p = 0.01), carbon dioxide (p = 0.02), globulin (p = 0.01), and SGPT levels (p less than0.01). However, all those values remained well within the reference ranges for these parameters (Table V). Three hematological measurements out of 13 assessed were significantly altered by the intervention: a drop in mean corpuscular volume (MCV) (p less than0.01), mean corpuscular hemoglobin (MCH) (p less than0.01) and a rise in mean platelet volume (MPV)

(p = 0.04). Although the above differences were statistically significant, they represented a small percentage of the mean values compared. (Table VI). The values for MCH and MCV were within the reference ranges both pre- and post-I supplementation. However, the mean value for MPV (± SD) was below the normal range of 8.2-10.3 ¦ l prior to intervention (7.5 ± 1.3 ¦ l) and increased to reach the normal range following I supplementation (8.2 ± 1.3 ¦ l). Although MPV below 4 ¦ l is an indication of a compromised immune system, this slightly low mean value prior to I supplementation may not be of clinical significance. Nevertheless, the effect of I supplementation was beneficial on this parameter.

The data on thyroid function tests and thyroid volume are displayed in Table VII. Thyroid volume in all the subjects were below 18 ml, the upper limit of normal values reported (14,15), suggesting that their intake of I prior to this study was adequate to prevent enlargement of the thyroid gland, and to maintain normal thyroid hormones, since all these values were within normal limits. Serum T4 levels dropped significantly (p less than0.01) from a mean of 8.8 (SD = 1.3) to 7.2 ug/dL (SD = 1.1). However, all individual values remained within the reference range (Table VII). Mean serum TSH levels decreased following I intake from 4.4 mIU/L to 3.2 mIU/L. This non significant decrease was due to the marked fall in subjects #1 and #10, with 16 mIU/L decrease between these 2 subjects contributing 1.6 mIU/ml less to the mean value. Using the classification of subclinical hypothyrodism as clinical euthyroidism with normal levels of thyroid hormones but elevated TSH above 6 mIU/L (20-22), subjects #1 and #10 would be classified as subclinical hypothyroid before I supplementation.

Please see Part 2

Edited by: _JULEE_ at: 1/3/2009 (10:02)
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