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Iodine Research

Resource Network of The Iodine Movement


Hyperthyroidism research continued on pg 2 ,  pg 3)

The historical background of the iodine project.
Abraham GE
The Original Internist, 12(2):57-66, 2005

For hyperthyroidism, physicians then used Lugol solution in daily amounts ranging from 6 mg to
180 mg, with the most common dose of 90 mg, resulting in success rates as high as 90%.
Radioiodide and goitrogens called antithyroid drugs were not available to U.S. physicians until the
late 1940’s, after World War II.

With the advent of radioiodide and goitrogens as alternatives to Lugol solution in patients with
hyperthyroidism, thyroidologists became very destructive, causing hypothyroidism in 90% of these
unfortunate patients."

In a survey of U.S. thyroidologists, some 70% used radioiodide to treat hyperthyroidism instead of
Lugol solution used previously to treat this condition safely and effectively with a success rate as
high as 90%, compared to a thyroid destruction rate of 90% with radioiodide.

Reappraisal of the risk of iodine-induced hyperthyroidism: an epidemiological population survey.
Azizi F, Hedayati M, Rahmani M, Sheikholeslam R, Allahverdian S, Salarkia N.
J Endocrinol Invest. 2005 Jan;28(1):23-9.
[abstract only]

The occurrence of iodine-induced hyperthyroidism (IIH) has been reported after iodine
supplementation from clinics and hospitals, but not following an epidemiologic survey. We studied
the prevalence of thyroid derangement in a population following iodine supplementation. One yr
after more than 75% of the population had been consuming 40 ppm iodized salt; information
regarding history of endemic goiter and iodized salt production, distribution, consumption and
monitoring were collected in four cities of the Islamic Republic of Iran. A total of 6048 subjects were
randomly selected. All subjects were assessed for size of goiter, and urinary iodine and serum T4,
T3, TSH, anti-thyroglobulin and anti-thyroperoxide were measured. Before iodine supplementation,
all four cities were areas of endemic goiter. The rate of household consumption of iodized salt was
50, 75 and 90% in 1994, 1995 and 1996, respectively. Ninety-one percent of the salt samples
contained 15-55 ppm iodide. Total goiter rate was 57, 62 and 68%; median urinary iodine was 188,
197 and 190 microg/l in the age groups of 6-18, 19-40 and >40 yr, respectively. Prevalence of
clinical and subclinical hyperthyroidism was 0.34 and 0.41 and those of clinical and subclinical
hypothyroidism were 0.51 and 1.07%, respectively. Nine point eight and 18% in the 19-40 yr age
group and 17.6 and 25.6% in >40 yr old subjects had positive anti-thyroperoxidase and anti-
thyroglobulin, respectively. This systemic epidemiologic study in an iodine deficient population
showed that, following a well-executed iodine supplementation program, the occurrence of IIH is

Effect of fluorine on thyroidal iodine metabolism in hyperthyroidism.
Galletti PM, Joyet G
J Clin Endocrinol Metab. 1958 Oct;18(10):1102-10.

Prolonged administration of a daily dose of 5-10 mg of fluoride to patients with hyperthyroidism
may cause clinical improvement together with a significant fall in the level of plasma protein-bound
iodine and a reduction in the basal metabolic rate.  Studies with radioactive fluorine failed to
demonstrate any important accumulation of fluorine within the thyroid in vivo. Thyroidal, blood and
urinary radioiodine studies suggest that fluorine inhibits the thyroid iodide-concentrating
mechanism.  Fluorine does not impair the capacity of the gland to synthesize thyroid hormone
when there is an abundance of iodide in the blood.  However, inhibition of the thyroidal
concentrating capacity when the total iodide pool is low will impose a critical limitation of hormonal
synthesis, and may explain the therapeutic effect.

Comparison of Methimazole and Propylthiouracil in Patients with Hyperthyroidism Caused by
Graves' disease.
Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N.
J Clin Endocrinol Metab. 2007 Mar 27; [Epub ahead of print]

Context: Although methimazole (MMI) and propylthiouracil (PTU) have long been used to treat
hyperthyroidism caused by Graves' disease, there is still no clear conclusion about the choice of
drug or appropriate initial doses.

Objective: To compare the MMI 30mg/day-treatment with the PTU 300mg/day- and MMI 15mg/day-
treatment in terms of efficacy and adverse reactions.

Design, Setting and Participants: Patients newly diagnosed with Graves' disease were randomly
assigned to one of the three treatment regimes in a prospective study at four Japanese hospitals.

Main outcome measurements: Percentages of patients with normal serum free T4 (FT4) or free T3
(FT3) and frequency of adverse effects were measured at 4, 8 and 12 weeks.

Results: MMI 30mg/day normalized FT4 in more patients than PTU 300mg/day and MMI 15mg/day
for the whole group (240 patients) at 12 weeks (96.5% vs. 78.3%, P=0.001, and 86.2%, P=0.023,
respectively). When patients were divided into two groups by initial FT4, in the group of the
patients with severe hyperthyroidism (FT4: 7ng/dl or more, 64 patients) MMI 30mg/day normalized
FT4 more effectively than PTU 300mg/day at 8 and 12 weeks and MMI 15mg/day at 8 week,
respectively (P<0.05). No remarkable difference between the treatments was observed in patients
with initial FT4 less than 7ng/dl. Adverse effects, especially mild hepatotoxicity, were higher with
PTU and significantly lower with MMI 15mg/day compared with MMI 30mg/day.

Conclusion: MMI 15mg/day is suitable for mild and moderate Graves' disease, while MMI 30mg/day
is advisable for severe cases. PTU is not recommended for initial use.

[Treatment with inorganic iodine for Graves' hyperthyroidism]
Noh JY, Chino T, Ito K.
Nippon Rinsho. 2006 Dec;64(12):2269-73. Review. Japanese.
[abstract only]

"Nowadays, patients with Graves' hyperthyroidism are initially treated with methimazole or
propylthiouracil. Several serious adverse reactions like agranulocytosis are caused by these
drugs. Inorganic iodine decreases serum thyroid hormone concentrations in patients with Graves'
hyperthyroidism without adverse reaction, but this effect usually continues only a limited time.
However, a virtually complete remission or longstanding euthyroid state may be obtained with
inorganic iodine therapy alone in patients with mild Graves' disease, who show small thyroid
volume and low TRAb titers. Inorganic iodine therapy may become one of the treatment methods in
the patients with mild Graves' hyperthyroidism."

Increase in incidence of hyperthyroidism predominantly occurs in young people after iodine
fortification of salt in Denmark.
Pedersen IB, Laurberg P, Knudsen N, Jorgensen T, Perrild H, Ovesen L, Rasmussen LB.
J Clin Endocrinol Metab. 2006 Oct;91(10):3830-4. Epub 2006 Jul 18.

CONTEXT: To prevent goiter and nodular hyperthyroidism, iodine fortification (IF) of salt was
introduced in Denmark in 1998. We prospectively registered all new cases of overt
hyperthyroidism in two areas of Denmark before and for the first 6 yr after iodine fortification.

METHODS: We used a computer-based register of all new cases of hyperthyroidism in two
population subcohorts with moderate iodine deficiency (Aalborg, n = 310,124) and mild iodine
deficiency (Copenhagen, n = 225,707), respectively. Data were obtained 1) before IF (1997-
1998); 2) during voluntary IF (1999-2000); 3) during the early (2001-2002) period of mandatory IF;
and 4) during the late (2003-2004) period with mandatory IF.

RESULTS: The overall incidence rate of hyperthyroidism increased [baseline, 102.8/100,000/year;
voluntary IF, 122.8; early mandatory IF, 140.7; late mandatory IF, 138.7 (P for trend <0.001)].
Hyperthyroidism increased in both sexes (P < 0.001) and in all age groups: 0-19, 20-39, 40-59,
and 60+ yr (P for trend <0.001). The increase was relatively highest in young adults aged 20-39
yr: late mandatory IF (percent increase from baseline), age 20-39, 160%, P < 0.001; age 40-59,
29%, P < 0.01; age 60+ yr, 13%, P = not significant.

CONCLUSION: Even a cautious iodization of salt results in an increase in the incidence rate of
hyperthyroidism. Contrary to current concepts, many of the new cases were observed in young
subjects, and are presumably of autoimmune origin. Furthermore, monitoring is expected to show
a decrease in the number of elderly subjects suffering from nodular hyperthyroidism.

The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives.
Laurberg P, Jorgensen T, Perrild H, Ovesen L, Knudsen N, Pedersen IB, Rasmussen LB, Carle A,
Vejbjerg P.
Eur J Endocrinol. 2006 Aug;155(2):219-28.
[abstract only]

OBJECTIVE: Denmark was an area of iodine deficiency, and mandatory iodine fortification of table
salt and salt in bread (13 p.p.m. iodine) was initiated in 2000/2001. The Danish investigation on
iodine intake and thyroid disease (DanThyr) is the monitoring of the iodine fortification program.

DESIGN AND METHODS: DanThyr consists of three main parts: a study of population cohorts
initialized before (n=4649) and after (n=3570) iodization of salt, a prospective identification of
incident cases of overt hyper- and hypothyroidism in a population of around 550,000 people since
1997, and compilation of data from the national registers on the use of thyroid medication, thyroid
surgery, and radioiodine therapy. Studies were carried-out in parallel in subcohorts living in areas
with differences in iodine content of ground water.

RESULTS: The study showed profound effects of even small differences in iodine intake level on
the prevalence of goiter, nodules, and thyroid dysfunction. Mild and moderate iodine deficiency
was associated with a decrease in serum TSH with age. Other environmental factors were also
important for goiter development (increase in risk, smoking and pregnancy; decrease in risk, oral
contraception and alcohol consumption), and the individual risk depended on the genetic
background. Environmental factors had only a minor influence on the prevalence of thyroid
autoantibodies in the population. There were more cases of overt hypothyroidism in mild than in
moderate iodine deficiency caused by a 53% higher incidence of spontaneous (presumably
autoimmune) hypothyroidism. On the other hand, there were 49% more cases of overt
hyperthyroidism in the area with moderate iodine deficiency. The cautious iodine fortification
program, aiming at an average increase in iodine intake of 50 mug/day has been associated with a
50% increase in incidence of hyperthyroidism in the area with the most severe iodine deficiency.
The incidence is expected to decrease in the future, but there may be more cases of Graves'
hyperthyroidism in young people.

CONCLUSION: A number of environmental factors influence the epidemiology of thyroid disorders,
and even relatively small abnormalities and differences in the level of iodine intake of a population
have profound effects on the occurrence of thyroid abnormalities. Monitoring and adjustment of
iodine intake in the population is an important part of preventive medicine.

Large differences in incidences of overt hyper- and hypothyroidism associated with a small
difference in iodine intake: a prospective comparative register-based population survey.
Pedersen IB, Knudsen N, Jorgensen T, Perrild H, Ovesen L, Laurberg P.
J Clin Endocrinol Metab. 2002 Oct;87(10):4462-9.

Around 3-4 billion people in the world are covered by iodine supplementation programs to prevent
developmental brain damage and other iodine deficiency (ID) disorders. Mild ID is associated with
more hyperthyroidism and less hypothyroidism in the population than a high iodine intake.
Knowledge of the iodine intake levels where the shifts in incidences occur is important for planning
of iodine supplementation programs. A computer-based register linked to thyroid diagnostic
laboratories was used to continuously identify all new cases of overt hyper- and hypothyroidism in
two population cohorts with moderate and mild ID, respectively (Aalborg, n = 310,124; urinary
iodine, 45 micro g/liter; and Copenhagen, n = 225,707; urinary iodine, 61 micro g/liter). The
investigation was initiated before iodization of salt in Denmark and was part of the monitoring
program. In 1997-1998, the incidence rate of overt hyperthyroidism was high in the area with the
lowest iodine intake (92.9/100,000 per year) compared with the area with only mild ID (65.4/100,
000 per year). Standardized rate ratio was 1.49, and 95% confidence interval was 1.22-1.81. The
opposite relationship was present for overt hypothyroidism (moderate ID, 26.5/100,000 per year;
mild ID, 40.1/100,000 per year; standardized rate ratio, 0.73; 95% confidence interval, 0.55-0.97).
The different incidence rates were confirmed during each of the two following years. The results of
this prospective investigation of the incidence of overt hyper- and hypothyroidism suggest that
iodine supplementation of a population may increase the incidence of overt hypothyroidism, even if
the population is moderately iodine-deficient. In such a population, the increase in risk of
hypothyroidism should be weighed against the risk of ID disorders such as hyperthyroidism due to
multinodular toxic goiter. The optimal level of iodine intake to prevent thyroid disease may be a
relatively narrow range around the recommended daily iodine intake of 150 microgram.


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