Iodine Study #11


Evidence that the administration of Vitamin C improves a defective cellular transport mechanism for iodine: A Case Report

Guy E. Abraham, M.D. (1)and David Brownstein, M.D.(2)


Introduction

Orthoiodosupplementation is the daily amount of the essential element iodine needed for whole body sufficiency (1). Whole body sufficiency for iodine is assessed by an iodine/iodide loading test (2). The test consists of ingesting 4 tablets of a solid dosage form of Lugol (Iodoral®), containing a total of 50 mg iodine/iodide. Then urinary iodide levels are measured in the following 24 hr collection. The iodine/iodide loading test is based on the concept that the normally functioning human body has a mechanism to retain ingested iodine until whole body sufficiency for iodine is achieved. During orthoiodosupplementation, a negative feedback mechanism is triggered that progressively adjusts the excretion of iodine to balance the intake. As the body iodine content increases, the percent of the iodine load retained decreases with a concomitant increase in the amount of iodide excreted in the 24 hr urine collection. When whole body sufficiency for iodine is achieved, the absorbed iodine/iodide is quantitatively excreted as iodide in the urine (1-3).

In the first study of the loading test in 6 normal subjects, the percent of loading dose of iodine excreted in the 24 hr urine collection was 39 ± 17.2 (mean ± SD) with a range of 14.2 to 66% (2). In 8 patients not receiving iodine supplementation, a mean value of 40% was reported (4). Recently, more than 4,000 loading tests were performed in the U.S. population by the Flechas Family Practice Laboratory using our procedure (2). The amount of the iodine load excreted in the 24 hr collection averages 40%, covering a wide range of ages of both sexes (5).

After 3 months of supplementation with 50 mg iodine/iodide/day, most non-obese subjects not exposed to excess goitrogens achieved whole body iodine sufficiency, arbitrarily defined as 90% or more of the iodine load excreted in the 24 hr urine collections (2-6). Adult subjects retained approximately 1.5 gm of iodine when they reach sufficiency (3). Baseline serum inorganic iodide levels 24 hrs after last dose of iodine in 8 normal subjects with normal body weight who achieved whole body iodine sufficiency had a mean ± SD of 1.1 ± 0.18 mg/L (3,7). We have arbitrarily defined as a normally functioning iodine retention mechanism, baseline serum inorganic iodide levels between 0.65 and 1.3 mg/L 24 hrs after the last dose of iodine in a subject who excretes 90% or more of the ingested iodine (7).

In patients with a normal gastrointestinal absorption of iodine but with a very defective iodine retention system, the absorbed iodine is quantitatively excreted in the urine with little or no retention. In these rare cases, the loading test will suggest whole body iodine sufficiency (90% or more excreted) but the serum inorganic iodide levels 24 hrs after the iodine load will remain low (less than 0.13 mg/L). The inefficient iodine retention mechanism could be due to either a defective cellular iodine transport system, or due to blockage of this iodine cellular transport by goitrogens that compete with iodide for the halide binding site of the symporter system. The defective iodine cellular transport mechanism could be due to genetic defects or oxidative damage to the halide binding site of the symporter (6).

We previously reported a defective cellular transport system for iodine in two obese female subjects not responding to orthoiodosupplementation (6). These individuals had low serum iodide levels (0.011 mg/L and less than 0.006 mg/L) combined with high urinary excretion of iodide following the loading test (96% and 102%). We would like to report a third case of cellular iodide transport damage in a non-obese female subject with a past history of hyperthyroidism followed by hypothyroidism treated with Synthroid 50 µg/day over the last 4 years. The other treatment modalities were added to the thyroid hormone therapy which served as baseline. The patient developed symptoms of hyperthyroidism following implementation of orthoiodosupplementation with 50 mg iodine/day. She titrated her iodine dose down to 12.5 mg every other day (6.25 mg average daily dose). She tolerated a daily average dose of 6.25 mg iodine well with increased energy. The iodine transport damage was corrected as least partially by administration of the antioxidant Vitamin C in a sustained released form at 3 gm/day for three months.

Elevated bromide levels were observed in urine and serum samples, twenty times the levels reported in the literature in normal subjects(8,9). Mild bromism may have been the cause of the oxidative damage to the iodine transport system and the side effects to orthoiodosupplementation. Chloride competes with bromide at the renal level and increases the renal clearance of bromide (10,11). Sodium chloride at 10 gm/day for one week resulted in marked increase in urine bromide levels, and a sharp drop in serum bromide. While on the chloride load, urinary frequency improves for the first time in 5 years, but fatigue worsened and she experienced facial and body acne. No significant change in symptomatology was observed while on Vitamin C. The responses of her symptoms to various treatments modalities by self-assessment are summarized in Table I. The treatment modalities are cumulative and added sequentially in the patient's management. Measurements of serum and urine bromide and iodide levels reported in this manuscript were performed by ion-selective electrode assay, following chromatography on strong anion exchanger cartridges, as previously described (3,7).

Case Report

The patient is a 52 year old white female nurse (height = 64 inches; weight = 140 pounds) with a past history of hyperthyroidism. Her medical history was unremarkable until 5 years ago when she presented with tachycardia, tremors, exopthalmos and urinary frequency. Thyroid blood tests revealed slightly elevated total T3 and elevated T4 along with a suppressed TSH (TSH <0.02 IU/L; T4 = 17.1 µg %; T3 = 187 ng %). Her endocrinologist recommended treatment with radioiodide. After doing some research on this subject, the patient chose not to proceed with this treatment. She did not pursue any course of therapy at this point as she felt her symptoms were not severe enough to justify radioablation of the thyroid. She was followed with thyroid function tests. Her clinical history is summarized in Table II.

Four years ago, she developed severe fatigue. Thyroid function tests revealed elevated TSH and with slightly lowered T3 and T4 levels (TSH = 28.1 IU/L; T4 = 3.4 µg %; T3 = 114 ng %). She was placed on Synthroid 50mcg/day. After two months on Synthroid, her fatigue improved markedly. Follow-up blood tests revealed a euthyroid state with normal TSH (TSH = 1.2 IU/L; T4 = 8.7 µg %; T3 = 128 ng %). However, urinary frequency was still present. During the next 4 years while on Synthroid, exopthalmos followed a relapsing/remitting course with symptomatic periods alternating with asymptomatic periods. The exopthalmos would be her guide to how her illness was progressing.

One year ago, orthoiodosupplementation was implemented following the iodine/iodide loading test with evidence of whole body sufficiency for iodine (90% of the load recovered in the 24 hr urine collection) but with a very low basal serum iodide level (0.016 mg/L). The patient experienced an exacerbation of all of her symptoms including exopthalmos following the loading test. However, she did feel an increase in energy and warmth after the first dose of iodine. Over the next few months, she titrated the iodine down from 50 mg to 12.5 mg every other day (average daily dose 6.25 mg/day). Although she felt better on orthoiodosupplementation, the relapsing/remitting course of exopthalmos was still present. However, the patient felt her exopthalmos was overall improving following orthoiodosupplementation. She was able to tolerate a daily average of 6.25 mg iodine during the year, while on Synthroid.

Approximately 4 months ago, she was placed on Vitamin C sustained release (Optimox C-500) at 3 gm/day. She continued the every other day iodine 12.5 mg. Prior to Vitamin C administration and 3 months after, the serum profile of inorganic iodide levels was obtained following a load of 50 mg iodine/iodide. The pattern of serum inorganic iodide levels prior to supplementation with Vitamin C is displayed in Fig. 1. The profile of serum inorganic iodide levels obtained in 6 normal female subjects is superimposed for comparison. The sharp peak of serum iodide at 32 mg/L at 1 hr post load, followed by a rapid drop suggests that the gastrointestinal absorption of iodine was very efficient but she was unable to transfer efficiently the serum iodide into the target cells. Following 3 months on Vitamin C, the same test was repeated. The data presented in Fig. 2 revealed a normal profile of serum inorganic iodide levels. Her baseline serum inorganic iodide increased from 0.016 mg/L to 0.42 mg/L and she retained 50% of the iodine load (49.2% recovered in 24 hr urine collection), compared to 10% of the load prior to supplementation with Vitamin C.

During the post Vitamin C loading test, serum bromide was measured in the serum samples collected for the iodide profile displayed in Fig 2. Serum bromide levels were markedly elevated with a pre load level of 143 mg/L and values increased up to 202 mg/L post load (Fig. 3). The 24 hr urine collection contained 192 mg bromide. Serum bromide levels reported in normal subjects 20 years ago ranged from 3-12 mg/L (8.9). Since chloride increases renal clearance of bromide (10,11), the patient was told to ingest 10 gm of sodium chloride/day (in the form of Celtic Sea Salt) for 7 days. This resulted in a bromide detoxification reaction. The patient became very fatigued. In addition, she developed facial and body acne, most likely due to mild bromism. However, one positive response to the chloride load was that urinary frequency decreased significantly during that week. This was the first time that frequency of urination became normal since the onset of Graves’ disease five years ago.

Discussion

To our knowledge, this is the first case report of a patient with evidence of a very defective retention mechanism for iodine who was studied with serial serum iodide levels prior to and following intervention. A combination of orthoiodosupplementation in amounts of iodine the patients could tolerate and administration of the antioxydant Vitamin C via the oral route improved the performance of the iodine retention mechanism. Repair of a defective iodine cellular transport mechanism following orthoiodosupplementation combined with a complete nutritional program may explain our observation that in some cases a repeat loading test 3 months after orthoiodosupplementation resulted in a decreased percent load excreted instead of the expected increase. This explains why in some cases patients feel better on orthoiodosupplementation although the repeat loading test 3 months following orthoiodosupplementation reveals a greater retention of iodine and a drop in percent load excreted. The milder forms of iodine retention defect will probably be overlooked until a more refined procedure is worked out to assess accurately the efficiency of the iodine transport mechanism. To be discussed later, the salivary/serum iodide ratio may be the test that will detect various levels of iodine transport defect, the greater the ratio, the more efficient the transport system.

We have previously observed that some patients who experienced side effects while on orthoiodosupplementation excreted large amounts of bromide in the urine. Orthoiodosupplementation induced and increased mobilization of bromine from storage sites with increased urinary excretion of bromide (4,6,12). The halide bromide was measured in the serum and urine samples of the second loading test. Bromide levels were markedly elevated in the 24 hr urine collections, at 192 mg/24 hr, compared to 3-12 mg/24 hr reported in normal subjects (8,9). Serum bromide levels were markedly elevated with a baseline of 141 mg/L, with post-iodine load values as high as 202 mg/L (Fig. 3). The renal clearance of bromide in adult subjects not ingesting large amount of chloride is around 1 L/24 hr. Therefore, the 24 hr urine bromide levels at steady state conditions should be equal to the amount of bromide in one liter of serum. The levels of bromide in serum and urine were some 20 times higher than expected in normal subjects. Since chloride increases renal clearance of bromide (10,11), she was placed on sodium chloride (Celtic Sea Salt) at 10 gms per day for one week. After one day on chloride, urine bromide levels increased to 530 mg/24 hr and after the seventh day to 760 mg/24 hr. With a daily average excretion of 530 + 760 / 2 = 645 mg, she excreted 645 x 7 = 4515 mg of bromide during that week. Her serum bromide level after seven days on the chloride load decreased markedly to 43.2 mg/L, from a pre-chloride load of 141 mg/L. Since orthoiodosupplementation increases markedly urine excretion of bromide (4,6,12), it is likely that the patient's total body bromine content was much higher prior to starting the iodine supplementation. This patient was not taking a bromide-containing medication. Her elevated serum and urine bromide levels are most likely from a dietary source.

Some patients require up to 2 years of orthoiodosupplementation to bring post loading urine bromide levels below 10 mg/24 hr, if chloride load is not included in the bromine detoxification program. Rapid mobilization of bromine from storage sites with orthoiodosupplementation combined with increased renal clearance of bromide with a chloride load often causes side effects. Increasing fluid intake and adding a complete nutritional program to orthoiodosupplementation minimizes these side effects. In this patient, rapid mobilization of bromine from storage sites with iodine and increased excretion of bromide from chloride loading resulted in side effects of severe fatigue, facial and body acne, but urinary frequency improved significantly for the first time in 5 years. The patient was asked to score the effect of treatment modalities on her overall wellbeing, with a score of 1 being the worse and 10 being best. She gave a score of 3 while on Syntroid compared to a score of 5 following one year on orthoiodosupplementation at a daily average of 6.25 mg iodine; 3 months on Vitamin C at 3 gm/day; and 7 days on the chloride load.

We are currently preparing a protocol for the evaluation of patients not responding to orthoiodosupplementation and with evidence of a defective whole body iodine retention mechanism: The results of the loading test showing 90% or greater excretion of the iodine load combined with baseline serum iodide levels below 10-6M (<0.13 mg/L). The evaluation of such patients ideally should include antibody titer to the sodium iodide symporter. Several organs in the human body beside the thyroid gland are capable of concentrating 20 to 40 fold peripheral iodide levels against a gradient (13). The salivary glands have this capability, possessing a sodium iodide symporter system similar to the thyroidal iodide symporter (13). The least invasive way to assess response to interventions in these patients would be to measure iodide levels in saliva and serum and to calculate the ratio of saliva iodide/serum iodide. A ratio near unity would indicate a severe defect/damage of the symporter function. An increase in the ratio following intervention would reflect an improvement in the symporter function. We are planning to measure this ratio in normal subjects in order to establish a normal range.

References:

  1. Abraham, G.E., Flechas, J.D., Hakala, J.C., Orthoiodosupplementation: Iodine Sufficiency of the Whole Human Body. The Original Internist, 9:30-41, 2002.
  2. Abraham, G.E., The safe and effective implementation of orthoiodosupplementation in medical practice. The Original Internist, 11:17-36, 2004.
  3. Abraham, G.E., The concept of orthoiodosupplementation and its clinical implications. The Original Internist, 11:29-38, 2004.
  4. Brownstein, D., Iodine: Why You Need It, Why You Can't Live Without It. Medical Alternative Press, West Bloomfield, MI, 2004.
  5. Flechas, J.D., Personal communication, 7/22/05.
  6. Abraham, G.E., The historical background of the iodine project. The Original Internist, 12(2):57-66, 2005.
  7. Abraham, G.E., Serum inorganic iodide levels following ingestion of a tablet form of Lugol solution: Evidence for an enterohepatic circulation of iodine. The Original Internist, 11(3):29-34, 2004.
  8. Miller, M.E., Cappon, C.J., Anion-Exchange Chromatographic Determination of Bromide in Serum. Clin. Chem. 30(5):781-783, 1984.
  9. Sangster, B., Blom, J.L., Sekhuis, V.M., et al, The Influence of Sodium Bromide in Man: A Study in Human Volunteers with Special Emphasis on the Endocrine and the Central Nervous System. Fd. Chem. Toxic., 21:409-419, 1983.
  10. Rauws, A.G., Pharmacokinetics of Bromide Ion-An Overview. Fd. Chem. Toxic., 21:379-382, 1983.
  11. Sticht, G., Käferstein, H., Bromine. In Handbook on Toxicity of Inorganic Compounds - Seiler HG and Sigel, H Editors, Marcel Dekker Inc, 143-151, 1988.
  12. Abraham, G.E., Iodine Supplementation Markedly Increases Urinary Excretion of Fluoride and Bromide. Townsend Letter, 238:108-109, 2003.
  13. Brown-Grant K., Extrathyroidal Iodide Concentrating Mechanisms. Physiol. Rev. 41:189-213, 1961.