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hours after last dose of iodine in eight normal subjects with normal body weight who achieved whole body io- Evidence that the
dine sufficiency had a mean ± SD of 1.1±0.18 mg/L.3,7 We have arbitrarily defined as a normally functioning Administration of Vitamin C
iodine retention mechanism, baseline serum inorganic iodide levels between 0.65 and 1.3 mg/L 24 hours after Improves a Defective Cellular
the last dose of iodine in a subject who excretes 90% or more of the ingested iodine.7 Transport Mechanism for
Iodine: A Case Report
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 by Guy E. Abraham, MD, and David Brownstein, MD urine with little or no retention. In these rare cases, the loading test will suggest whole body iodine sufficiency Introduction
(90% or more excreted), but the serum inorganic iodide Orthoiodosupplementation is the daily amount of the levels 24 hours after the iodine load will remain low essential element iodine needed for whole body suffi- (less than 0.13 mg/L). The inefficient iodine retention ciency.1 Whole body sufficiency for iodine is assessed mechanism could be due to either a defective cellular by an iodine/iodide loading test.2 The test consists of iodine transport system or blockage of this iodine cellu- ingesting four tablets of a solid dosage form of Lugol lar transport by goitrogens that compete with iodide for (Iodoral®), containing a total of 50 mg iodine/iodide. the halide binding site of the symporter system. The Then urinary iodide levels are measured in the following defective iodine cellular transport mechanism could be 24-hour collection. The iodine/iodide loading test is due to genetic defects or oxidative damage to the halide based on the concept that the normally functioning hu- man body has a mechanism to retain ingested iodine un- til whole body sufficiency for iodine is achieved. Dur- We previously reported a defective cellular transport sys- ing orthoiodosupplementation, a negative feedback tem for iodine in two obese female subjects not respond- mechanism is triggered that progressively adjusts the ing to orthoiodosupplementation.6 These individuals had excretion of iodine to balance the intake. As the body low serum iodide levels (0.11 mg/L and less than 0.06 iodine content increases, the percentage of the iodine mg/L) combined with high urinary excretion of iodide fol- load retained decreases with a concomitant increase in lowing the loading test (96% and 102%). We would like the amount of iodide excreted in the 24-hour urine col- to report a third case of cellular iodide transport damage lection. When whole body sufficiency for iodine is in a non-obese female subject with a past history of hy- achieved, the absorbed iodine/iodide is quantitatively perthyroidism followed by hypothyroidism treated with Synthroid 50 µg/day over the last four years. The other treatment modalities were added to the thyroid hormone In the first study of the loading test in six normal subjects, therapy which served as baseline. The patient developed the percent of loading dose of iodine excreted in the 24- symptoms of hyperthyroidism following implementation hour urine collection was 39±17.2 (mean ± SD) with a of orthoiodosupplementation with 50 mg iodine/day. range of 14.2-66%.2 In eight patients not receiving iodine She titrated her iodine dose down to 12.5 mg every other supplementation, a mean value of 40% was reported.4 day (6.25 mg average daily dose). She tolerated a daily Recently, more than 4,000 loading tests were performed average dose of 6.25 mg iodine well with increased en- in the US population by the Flechas Family Practice ergy. The iodine transport damage was corrected at least Laboratory using our procedure.2 The amount of the partially by administration of the antioxidant vitamin C in iodine load excreted in the 24-hour collection averages a sustained released form at 3 gm/day for three months. 40%, covering a wide range of ages of both sexes.5 Elevated bromide levels were observed in urine and se- After three months of supplementation with 50 mg io- rum samples, 20 times the levels reported in the literature dine/iodide per day, most non-obese subjects not exposed in normal subjects.8,9 Mild bromism may have been the to excess goitrogens achieved whole body iodine suffi- cause of the oxidative damage to the iodine transport ciency, arbitrarily defined as 90% or more of the iodine load system and the side effects to orthoiodosupplementation. excreted in the 24-hour urine collections.2,6 Adult subjects Chloride competes with bromide at the renal level and retained approximately 1.5 gm of iodine when they reach increases the renal clearance of bromide.10,11 Sodium sufficiency.3 Baseline serum inorganic iodide levels 24 Self-Assessed Effect of Treatment Modalities on Patient's Symptomatology
Synthroid
Vitamin C
Chloride load
(50 µg/day)
(6.25 mg/day)
(3 gm/day)
(10 gm/day)
Symptoms
0 = No effect; +1 = Some improvement; +2 = Marked improvement -1 = Worse; -2 = Much worse * Temporary improvement with alternating recurrence chloride at 10 gm/day for one week resulted in a marked lowered T3 and T4 levels (TSH = 28.1 IU/L; T4 = 3.4 µg increase in urine bromide levels and a sharp drop in serum %; T3 = 114 ng %). She was placed on 50 mcg/day of bromide. While on the chloride load, urinary frequency Synthroid. After two months on Synthroid, her fatigue improves for the first time in five years, but fatigue wors- improved markedly. Follow-up blood tests revealed a ened, and she experienced facial and body acne. No sig- euthyroid state with normal TSH (TSH = 1.2 IU/L; T4 = nificant change in symptomatology was observed while 8.7 µg %; T3 = 128 ng %). However, urinary frequency on vitamin C. The responses of her symptoms to various was still present. During the next four years while on treatments modalities by self-assessment are summa- Synthroid, exopthalmos followed a relapsing/remitting rized in Table 1. The treatment modalities are cumula- course with symptomatic periods alternating with as- tive and added sequentially in the patient's management. ymptomatic periods. The exopthalmos would be her Measurements of serum and urine bromide and iodide guide to how her illness was progressing. levels reported in this manuscript were performed by ion-selective electrode assay, following chromatography One year ago, orthoiodosupplementation was imple- on strong anion exchanger cartridges.3,7 mented following the iodine/iodide loading test with evi- dence of whole body sufficiency for iodine (90% of the Case Report
load recovered in the 24-hour urine collection) but with a The patient is a 52-year-old, white, female nurse (height very low basal serum iodide level (0.016 mg/L). The = 64 inches; weight = 140 pounds) with a past history of patient experienced an exacerbation of all of her symp- hyperthyroidism. Her medical history was unremarkable toms including exopthalmos following the loading test. until five years ago when she presented with tachycardia, However, she did feel an increase in energy and warmth tremors, exopthalmos, and urinary frequency. Thyroid after the first dose of iodine. Over the next few months, blood tests revealed slightly elevated total T3 and ele- she titrated the iodine down from 50 mg to 12.5 mg vated T4 along with a suppressed TSH (TSH <0.02 IU/L; every other day (average daily dose 6.25 mg/day). Al- T4 = 17.1 µg %; T3 = 187 ng %). Her endocrinologist though she felt better on orthoiodosupplementation, the recommended treatment with radioiodide. After doing relapsing/remitting course of exopthalmos was still pre- some research on this subject, the patient chose not to sent. However, the patient felt her exopthalmos was proceed with this treatment. She did not pursue any overall improving following orthoiodosupplementation. course of therapy at this point as she felt her symptoms She was able to tolerate a daily average of 6.25 mg io- were not severe enough to justify radioablation of the thy- dine during the year, while on Synthroid. roid. She was followed with thyroid function tests. Her clinical history is summarized in Table 2. Approximately four months ago, she was placed on vita- min C sustained release (Optimox C-500) at 3 gm/day. Four years ago, she developed severe fatigue. Thyroid She continued the every other day iodine 12.5 mg. Prior function tests revealed elevated TSH and with slightly THE ORIGINAL INTERNIST Fall 2005 to vitamin C administration and three months after, the the iodine load (49.2% recovered in 24-hour urine col- serum profile of inorganic iodide levels was obtained lection), compared to 10% of the load prior to supple- following a load of 50 mg iodine/iodide. The pattern of serum inorganic iodide levels prior to supplementation with vitamin C is displayed in Figure 1. The profile of During the post vitamin C loading test, serum bromide serum inorganic iodide levels obtained in six normal was measured in the serum samples collected for the female subjects is superimposed for comparison. The iodide profile displayed in Figure 2. Serum bromide sharp peak of serum iodide at 32 mg/L at one hour post levels were markedly elevated with a pre load level of load, followed by a rapid drop suggests that the gastroin- 143 mg/L and values increased up to 202 mg/L post testinal absorption of iodine was very efficient but she load (Figure 3). The 24-hour urine collection contained was unable to transfer efficiently the serum iodide into 192 mg bromide. Serum bromide levels reported in nor- the target cells. Following three months on vitamin C, mal subjects 20 years ago ranged from 3-12 mg/L.8,9 the same test was repeated. The data presented in Figure Since chloride increases renal clearance of bromide,10,11 2 revealed a normal profile of serum inorganic iodide the patient was told to ingest 10 gm of sodium chlo- levels. Her baseline serum inorganic iodide increased ride/day (in the form of Celtic Sea Salt) for seven days. from 0.016 mg/L to 0.42 mg/L, and she retained 50% of Chronology of Patient's Medical History
Signs, Symptoms, Blood Work, Diagnosis, Treatment, and Response
Signs and symptoms = tachycardia + tremors + exopthalmus + urinary frequency TSH = <0.02 IU/L T4 = 17.1 µg% T3 = 187 ng% Diagnosis - Hyperthyroidism with exopthalmus Treatment - Endocrinologist proposed radioablation of the thyroid gland. Patient refused, since she felt symptoms did not interfere with her performance at home and at work to justify such drastic measures. TSH = 28.1 IU/L T4 = 3.4 µg% T3 = 114 ng% Response - Fatigue improved. Euthyroid - TSH = 1.2 IU/L T4 = 8.7 µg% T3 = 128 ng% Response - Patient exopthalmus fluctuated between periods of remission and periods of relapse con-comitant with symptoms of urinary frequency Iodine/iodide loading test - 90% of oral load excreted in 24-hour urine collection but baseline serum iodide = 0.016 mg/L. Evidence of a defective iodine transport mechanism. - Orthoiodosupplementation implemented at 50 mg iodine/day (4 tablets Iodoral®). Exopthalmus, tremors and urinary frequency worsened. - Patient titrated intake down to 1 tablet every other day (daily average of 6.25 mg). - Average daily intake of 6.25 mg iodine was tolerated well during the year while in Synthroid. - Increased energy level. Some improvement in tremors and exopthalmus. Loading test was performed before and after three months on vitamin C Serum profile pre-vitamin C was indicative of iodine transport defect (Figure 1) Serum profile after three months on vitamin C revealed a normal pattern (Figure 2) Serum Profile of Inorganic Iodide Levels Following Iodine/Iodide Load (50 mg)
in 6 Normal Female Subjects and in 1 Patient with Iodide Transport Defect
= Mean of 6 normal female subjects
= Patient with iodide transport defect
Prior to intervention
- % iodide load excreted = 90%
- Baseline serum iodide = 0.016 mg/L
iodide le
c
m inorgani
u
Time Post ingestion of Iodoral 50 mg load
The patient excreted 90% of the iodine load, but her basal serum inorganic iodide level was very low - 0.016 m/L. This pattern suggests a defect in the iodine retention mechanism. This resulted in a bromide detoxification reaction. The observation that in some cases a repeat loading test patient became very fatigued. In addition, she devel- three months after orthoiodosupplementation resulted oped facial and body acne, most likely due to mild in a decreased percentage load excreted instead of the bromism. However, one positive response to the chlo- expected increase. This explains why in some cases ride load was that urinary frequency decreased signifi- patients feel better on orthoiodosupplementation al- cantly during that week. This was the first time that though the repeat loading test three months following frequency of urination became normal since the onset orthoiodosupplementation reveals a greater retention of iodine and a drop in percentage load excreted. The milder forms of iodine retention defect will probably be Discussion
overlooked until a more refined procedure is worked To our knowledge, this is the first case report of a pa- out to assess accurately the efficiency of the iodine tient with evidence of a very defective retention mecha- transport mechanism. To be discussed later, the sali- nism for iodine who was studied with serial serum io- vary/serum iodide ratio may be the test that will detect dide levels prior to and following intervention. A com- various levels of iodine transport defect, the greater the bination of orthoiodosupplementation in amounts of ratio, the more efficient the transport system. iodine the patients could tolerate and administration of the antioxydant vitamin C via the oral route improved We have previously observed that some patients who the performance of the iodine retention mechanism. experienced side effects while on orthoiodosupplemen- Repair of a defective iodine cellular transport mecha- tation excreted large amounts of bromide in the urine. nism following orthoiodosupplementation combined Orthoiodosupplementation induced and increased mo- with a complete nutritional program may explain our THE ORIGINAL INTERNIST Fall 2005 bilization of bromine from storage sites with increased plementation. This patient was not taking a bromide- urinary excretion of bromide.4,6,12 The halide, bromide, containing medication. Her elevated serum and urine was measured in the serum and urine samples of the sec- bromide levels are most likely from a dietary source. ond loading test. Bromide levels were markedly ele- vated in the 24-hour urine collections, at 192 mg/24 Some patients require up to two years of orthoiodosup- hours, compared to 3-12 mg/24 hours reported in normal plementation to bring post loading urine bromide levels subjects.8,9 Serum bromide levels were markedly elevated below 10 mg/24 hours, if chloride load is not included in with a baseline of 141 mg/L, with post-iodine load values the bromine detoxification program. Rapid mobilization as high as 202 mg/L (Figure 3). The renal clearance of of bromine from storage sites with orthoiodosupplemen- bromide in adult subjects not ingesting large amount of tation, combined with increased renal clearance of bro- chloride is around 1 L/24 hr. Therefore, the 24-hour mide with a chloride load, often causes side effects. In- urine bromide levels at steady state conditions should be creasing fluid intake and adding a complete nutritional equal to the amount of bromide in one liter of serum. program to orthoiodosupplementation minimizes these The levels of bromide in serum and urine were some 20 side effects. In this patient, rapid mobilization of bro- times higher than expected in normal subjects. Since mine from storage sites with iodine and increased excre- chloride increases renal clearance of bromide,10,11 she tion of bromide from chloride loading resulted in side was placed on sodium chloride (Celtic Sea Salt) at 10 effects of severe fatigue and facial and body acne, but gm/day for one week. After one day on chloride, urine urinary frequency improved significantly for the first bromide levels increased to 530 mg/24 hours and after time in five years. The patient was asked to score the the seventh day to 760 mg/24 hours. With a daily aver- effect of treatment modalities on her overall well-being, age excretion of (530+760)/2 = 645 mg, she excreted with a score of 1 being the worst and 10 being best. She 645 x 7 = 4,515 mg of bromide during that week. Her gave a score of 3 while on Syntroid compared to a score serum bromide level after seven days on the chloride of 5 following one year on orthoiodosupplementation at load decreased markedly to 43.2 mg/L, from a pre- a daily average of 6.25 mg iodine; three months on vita- chloride load of 141 mg/L. Since orthoiodosupplemen- min C at 3 gm/day; and seven days on the chloride load. tation increases markedly urine excretion of bro- mide,4,6,12 it is likely that the patient's total body bromine We are currently preparing a protocol for the evaluation of content was much higher prior to starting the iodine sup- Serum Profile of Inorganic Iodide Levels Following the Iodine/Iodide Load (50 mg)
in 6 Normal Subjects and in 1 Patient with Iodide Transport Defect
Following 3 Months of Intervention with Sustained-Release Vitamin C at 3 mg/day
= M e a n o f 6 n or m a l fe m a le su b je c ts
= P a tie n t w ith io d id e tr a n sp o r t d e fe c t
P o st 3 m o n th s V ita m in C 3 g /d a y
- % io d id e lo a d ex cre te d = 4 9.2 %
- B a selin e se ru m io d id e = 0.4 2 m g /L
iodid
c
ni
a
T im e P o st in g e stio n o f Io d o r a l 5 0 m g lo a d
She excreted 49.2% of the iodine load and the baseline serum level was 0.42 mg/L, evidence of improved function of the io-dine cellular transport mechanism. patients not responding to orthoiodosupplementation and 2) Abraham GE. "The safe and effective implementation of or- with evidence of a defective whole body iodine retention thoiodosupplementation in medical practice." The Original In-ternist, 2004; 11(1):17-36. mechanism. The results of the loading test showing 90% 3) Abraham GE. "The concept of orthoiodosupplementation and its or greater excretion of the iodine load combined with clinical implications." The Original Internist, 11(2):29-38, 2004. baseline serum iodide levels below 10-6M (<0.13 4) Brownstein D. Iodine: Why You Need It, Why You Can't Live mg/L). The evaluation of such patients ideally should Without It. Medical Alternative Press, West Bloomfield, MI, include antibody titer to the sodium iodide symporter. 5) Flechas JD. Personal communication, July 22, 2005. Several organs in the human body beside the thyroid 6) Abraham GE. "The historical background of the iodine project." gland are capable of concentrating 20-40 fold peripheral The Original Internist, 2005; 12(2):57-66. iodide levels against a gradient.13 The salivary glands 7) Abraham GE. "Serum inorganic iodide levels following inges- have this capability, possessing a sodium iodide sym- tion of a tablet form of Lugol solution: Evidence for an entero-hepatic circulation of iodine." The Original Internist, 2004; porter system similar to the thyroidal iodide symporter.13 The least invasive way to assess response to interven- 8) Miller ME and Cappon CJ. "Anion-exchange chromatographic tions in these patients would be to measure iodide levels determination of bromide in serum." Clin Chem, 1984; in saliva and serum and to calculate the ratio of saliva iodide/serum iodide. A ratio near unity would indicate a 9) Sangster B, Blom JL, Sekhuis VM, et al. "The influence of so- dium bromide in man: A study in human volunteers with special severe defect/damage of the symporter function. An emphasis on the endocrine and the central nervous system." Fd increase in the ratio following intervention would reflect an improvement in the symporter function. We are plan- 10) Rauws AG. "Pharmacokinetics of bromide ion - An overview." ning to measure this ratio in normal subjects in order to 11) Sticht G and Käferstein H. "Bromine." In: Handbook on Toxic- ity of Inorganic Compounds. Seiler HG and Sigel H, editors. REFERENCES
12) Abraham GE. "Iodine supplementation markedly increases uri- nary excretion of fluoride and bromide. Townsend Letter, 2003; 1) A b r a h a m G E , F l e c h a s J D , a n d H a k a l a J C. "Orthoiodosupplementation: Iodine sufficiency of the whole 13) Brown-Grant K. "Extrathyroidal iodide concentrating mecha- human body." The Original Internist, 2002; 9(4):30-41. nisms." Physiol Rev, 1961; 41:189-213. u Serum Profile of Bromide Levels Post Iodine Loading
2 4 h r u rin e b ro m id e lev el = 1 92 m g
ic bromid
T im e p o st in g estio n o f Io d o ra l 5 0 m g lo a d
The heavy horizontal line represents the upper limit of serum bromide levels reported in normal subjects. THE ORIGINAL INTERNIST Fall 2005

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