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
CLOZARIL: Starting a Patient 1. Call the CLOZARIL National Registry (CNR) to obtain a rechallenge number and to confirm that you and your pharmacy are registered. 2 . Obtain a baseline WBC with ANC from patient. If within normal limits, WBC ≥ 3500/ mm3, ANC ≥ 2000/ mm3, prescribe CLOZARIL tablets. 3. Submit WBC and ANC information to the registered pharmacy. 4. Please be pre