Full text of DOI:10.1007/BF03343816

J. Endocrinol. Invest. 24: 72-77, 2001
Side-effects of iodized oil administration in patients
with simple goiter
F. Azizi and N. Daftarian
Endocrine Research Centre, Shaheed Beheshti University of Medical Sciences, Eveen, Tehran, I.R. Iran
ABSTRACT. The objective of this study was to
determine side-effects associated with iodized
oil injection in patients with simple goiter. In an
iodine-deficient population, 3420 patients with
simple goiter, who were not taking supplemen-
tal iodine, were chosen for this study. They re-
ceived a single intramuscular injection of 1 ml
iodized oil, containing 480 mg iodide. Clinical
and laboratory evaluations were performed ev-
ery 3 months for one year and every 6 months
for the next 4 years. The incidence of hypo- and
hyperthyroidism was 0.6% each, with equal
prevalence in both sexes. Most cases of hypo-
and hyperthyroidism were observed during the
first 5 months after the injection. Eight cases of
hyperthyroidism were asymptomatic. A further
8 patients had overt thyrotoxicosis and required
treatment with methimazole for 18 months.
Recurrence of hyperthyroidism was observed in
one patient. Five hypothyroid patients were di-
agnosed only by abnormal thyroid function tests,
and 4 cases needed no treatment. Others re-
ceived T4 treatment for a mean of 14.5 months.
Among 14 T4-treated patients, recurrence of hy-
pothyroidism occurred in 7 patients after treat-
ment was discontinued. Twenty-nine patients
(0.8%) were afflicted with dermatologic compli-
cations. The most common dermatologic side-ef-
fect was urticarial reaction. In 15 subjects, skin
lesions appeared 8 to 14 days after injection. It
is concluded that side-effects of iodized oil in-
jection are rare, and in most cases the complica-
tions are transient and self-limited. The occur-
rence of iodine induced hyperthyroidism follow-
ing iodized oil administration is close to the ratio
observed in spontaneous thyrotoxicosis.
(J. Endocrinol. Invest. 24: 72-77, 2001)
©2001, Editrice Kurtis
INTRODUCTION
following iodized oil administration (5, 6). However,
no systematic, prospective study has been per-
formed to evaluate side-effects of iodized oil ad-
ministration.
Goiter is hyperendemic in many parts of Iran (2). In
addition to goiter, other IDD, such as impaired
physical and intellectual growth, hearing deficit and
hypothyroidism, have been reported (7, 8). Since
iodized oil injection has been one of the basic
strategies of controlling IDD in Iran, this prospec-
tive study was conducted to determine the com-
plications of iodized oil injection in patients with
simple goiter.
Iodine deficiency is one of the major health prob-
lems in the world. It causes a wide range of disor-
ders from simple goiter to overt cretinism with se-
vere psychomotor retardation (1). The main strate-
gy of controlling iodine deficiency disorders (IDD) is
universal salt iodization. However, when iodized salt
is not available and, in remote areas with severe io-
dine deficiency, administration of iodized oil has
been advised (2).
The most important reported complication of
iodized oil injection has been hyperthyroidism,
which is prevalent in older patients and in those
with multinodular goiter (3-5). Hypothyroidism is
seen less frequently than hyperthyroidism and is
usually observed as a disturbance in thyroid func-
tion tests (4). There have been contradictory reports
regarding the appearance of thyroid autoimmunity
MATERIALS AND METHODS
Patients with simple goiter, entered in this prospec-
tive study, had been referred to an endocrinologist,
were not taking supplemental iodine and had nor-
mal thyroid function test. Only those with clinical
and biochemical evidence of hypo- or hyperthy-
roidism were excluded. Three-thousand six-hun-
dred and fifty-eight patients were recruited into the
study during 2 years and 3420 completed the
Key-words: Simple goiter, hypothyroidism, hyperthyroidism, iodized oil.
Correspondence: Prof. F. Azizi, P.O. Box: 19395-4763, Tehran, I.R. Iran.
E-mail: Azizi@ERC-IRAN.com
Accepted June 13, 2000.
72

Side-effects of iodized oil
10
8
study. Patients were residents of Tehran City and
suburbs, known to be an iodine deficient region
with mean urinary iodine in school-children of
35.8 19.1 μg/l (8). All patients were evaluated be-
fore and every 3 months during the first year and
every 6 months during the subsequent 4 years after
intramuscular injection of 1 ml of iodized oil solu-
tion containing 480 mg iodide (Lipiodol, Guerbet,
France). In each visit, the patients underwent clini-
cal examination. Symptoms and signs of thyroid
dysfunction were sought and approximate thyroid
weight was estimated by one of us (F.A.). A 10 ml
blood sample was also obtained.
Serum concentrations of T3, T4, TSH and T3 resin
uptake were measured by commercial kits from
Kodak-Amerlex, England. Antithyroid antibodies in-
cluding antithyroglobulin and antimicrosomal anti-
bodies were measured by hemoaglutination me-
thod by commercial kits from Broughs-Wellcome,
England. Reference ranges for serum parameters
for euthyroid adult subjects are: T4: 4.5-12.5 μg/dl,
T3: 80-200 ng/dl and TSH: 0.1-5.0 mU/l.
6
4
2
0
<3
3-6 6-9 9-12 12-18 18-24 24-3030-60 60-72
Time since injection (month)
Fig. 1 - Time of occurrence of hyperthyroidism following iodized
oil injection. Twelve out of 20 cases were detected within 3 to
9 months after intervention.
Hyperthyroidism
This study was approved by the appropriate human
research review committee and the patients gave
informed consent. The difference in quantitative
variables before and after injection was evaluated
by paired t test. P value of less than 0.05 was con-
sidered significant.
Thyrotoxicosis was observed in 20 patients (0.6%)
with a male/female ratio of 1/9. Mean age in study
population and hyperthyroid patients was not sig-
nificantly different. Diffuse goiter was observed in
14 cases and nodular goiter in 6 patients. Estimated
thyroid weight in 16 hyperthyroid patients did not
change significantly after iodized oil injection
(36.6 5.1 and 36.1 5.5 g before and after injec-
tion, respectively). Most cases occurred during the
first 3-6 months after injection (Fig. 1).
The results of serum T4, T3 and TSH concentrations
in 20 hyperthyroid patients before lipiodol injection
and at the time of diagnosis are depicted in Table
1. In 8 patients, hyperthyroidism was detected on-
ly by relying on thyroid function tests, whereas the
other 12 patients showed some of the following
signs and symptoms: palpitation and tachycardia,
weight loss, irritability and nervousness, easy fati-
gability and proximal muscle weakness. Lid lag and
stare was observed in thyrotoxic patients, but none
had signs of Graves’ ophthalmopathy. Prior to
iodized oil injection, antithyroid antibodies were
RESULTS
Three-thousand four-hundred and twenty patients
with simple goiter including 89.6% femal and
10.4% mal completed the study. Female/male ra-
tio was 9/1. Mean age of patients was 21.5 14.1
years, with a range of 5 to 44 years. During 5 years
of follow-up, 3380 patients remained euthyroid.
At the onset of the study, they did not differ from
the 40 patients who later developed thyroid dys-
function in age, goiter size and nodularity, and
serum concentrations of T4, T3 and TSH. In pa-
tients, who remained euthyroid, mean estimated
thyroid weight decreased from 38.5 to 27.1 g in
5 years.
Table 1 - Serum thyroid hormones and TSH concentrations prior to iodized oil injection and at the time of diagnosis in 20 patients
with hyperthyroidism.
Time
T4 (μg/dl)
Resin uptake
T3 (ng/dl)
TSH (mU/l)
Prior to injection
At the time of diagnosis
Normal range
8.7 1.9
17.2 3.9*
4.5-12.5
29.4 2.4
34.8 4.7*
25-35
133 32
339 185*
80-200
1.86 1.4
0.46 0.3*
0.1-5.0
*p<0.001, compared to values prior to injection.
73

F. Azizi and N. Daftarian
10
8
and one patient presented with the typical clinical
picture of hypothyroidism. The clinical findings
were: mild drowsiness, poly- and hypermenorrhea,
decreased appetite, slight weight gain, and mild
puffiness. Prior to iodized oil injection antithyroid
antibodies were negative in all patients. After in-
jection, in 5 out of 11 patients tested, thyroid anti-
bodies became positive.
6
4
Four patients showed improvement of hypothy-
roidism without receiving any drug therapy. It took
4.0 4.2 months before normalization of thyroid
function tests. Pharmacologic therapy with thyroid
hormone preparations was necessary in 16 patients.
The average duration of treatment was 14.5
months. Recurrence of hypothyroidism was ob-
served in 7 patients necessitating re-administration
of thyroid medications.
2
0
<3
3-6
6-9 9-12 12-18 18-24 24-30 30-36
Time since injection (month)
Fig. 2 - Time of occurrence of hypothyroidism following iodized
oil injection. Fourteen out of 20 cases occurred during first 6
months following injection, only 3 cases were detected after 9
months.
Dermatologic complications
Skin complications were observed in 29 patients
(0.8%) with a mean age of 30.3 9.8 years. The high-
est incidence rate was observed in age groups of
20-29, 30-39 and 40-49 years with 9, 8 and 7 cases,
respectively.
The distribution of the patients concerning the tim-
ing of dermatologic complication is illustrated in
Figure 3. Most of the complications were observed
during the first 8-14 days after injection. Among the
29 patients with dermatologic problems, 4 had dif-
fuse, generalized lesions and 25 only revealed lo-
calized lesion at the site of injection.
During the first 24 hours after the injection, there
was only one case of dermatologic complication,
manifesting as localized swelling, redness, and in-
duration, and being followed by multiple pruritic
nodules after a few days. Pathologic examination
revealed the lesion to be erythema nodosum. This
was successfully treated with topical medications.
During the first 24-48 hours after injection, skin prob-
lems were observed in 5 patients, 2 of which had
generalized eruptions and 3 had localized lesions.
Localized lesions were manifested by swelling, red-
ness, induration, and mild pruritus; whereas gener-
alized eruptions manifested as urticarial lesions and
negative in all patients. After injection, only one pa-
tient had increased antibodies.
Eight patients did not show any clinical signs of hy-
perthyroidism and improved without treatment.
Palpitation was controlled with propranolol in 4 pa-
tients. Eight patients were given methimazole 20
mg per day for 4 weeks and 5-10 mg daily there-
after. The average duration of treatment was 18
months. Recurrence of hyperthyroidism was ob-
served in only one case, that had spontaneous im-
provement without methimazole therapy.
Hypothyroidism
Hypothyroidism was observed in 20 patients (0.6%)
with a female/male ratio 9/1. Diffuse goiter was ob-
served in 14 cases and nodular goiter in 6 patients.
Estimated thyroid size was 34.5 5.3 before and
38.4 7.1 g after injection (NS). Most cases of hy-
pothyroidism were observed during the first 6
months after injection (Fig. 2).
The results of thyroid function tests and serum TSH
in 20 hypothyroid patients are depicted in Table 2.
Fourteen patients had mild symptoms and signs
Table 2 - Serum thyroid hormones and TSH concentrations prior to iodized oil injection and at the time of diagnosis in 20 patients
with hypothyroidism.
Time
T4 (μg/dl)
Resin uptake
T3 (ng/dl)
TSH (mU/l)
Prior to injection
At the time of diagnosis
Normal range
8.5 1.8
2.4 1.9*
4.5-12.5
28.8 3.1
26.6 3.0*
25-35
156 38
84 45*
80-200
1.4 0.7
116 88*
0.1-5.0
*p<0.001, compared to values prior to injection.
74

Side-effects of iodized oil
16
14
12
10
8
er reports can be attributed to the larger population
of the study group, differences in patients’ selection,
or genetic and immunologic backgrounds. In our
study, the incidence rate of hyperthyroidism was
equal in the two sexes, because the female/male ra-
tios of both study population and hyperthyroids were
similar at 9/1. Whereas in a study in Yugoslavia, the
male/female ratio of hyperthyroidism increased from
1/10 to 1/6 as a result of iodine supplementation
(11). On the other hand, hyperthyroidism did not
tend to be more prevalent in higher age groups in
our study; in other words, the mean age of the hy-
perthyroid patients was not greater than that of the
study population. Nevertheless, it should be noted
that there have been few patients in our study who
were older than 40 years.
Present data indicate that it is not possible to pre-
dict the occurrence of hypo- or hyperthyroidism on
the basis of patients’ age, thyroid size, and goiter
type. This is in accordance with the study per-
formed in Malaysia (4). Additionally, change in thy-
roid size following iodized oil injection cannot be
used for diagnosis of hyperthyroidism.
The diagnosis of hyperthyroidism has been made
in 8 patients only by considering biochemical cri-
teria. In the study conducted in Malaysia, 8 cases
with hyperthyroidism had distinct clinical findings
(4). The self-limiting nature of complication in
asymptomatic patients made no treatment neces-
sary. In other studies, no recurrence of hyperthy-
roidism has been reported. Observing one such
case in our study can be attributed to the long-term
follow-up to the patients.
The yearly incidence of hyperthyroidism in women
is 0.08% per year (12), and, over 5 years, 0.40% of
women may develop hyperthyroidism. Therefore,
the 0.6% rate observed in the present study comes
very near the spontaneous background level of hy-
perthyroidism. This is in contrast to the higher inci-
dence of iodide-induced thyrotoxicosis seen in
African countries (13).
6
4
2
0
<1
1-3
4-7
8-14
15-21
Time since injection (day)
Fig. 3 - Time of occurrence of dermatologic side-effects fol-
lowing iodized oil injection. More than half of the cases occurred
within 8 to 14 days following injection.
pruritic, edematous and erythematous patches and
plaques. Six patients were afflicted with skin prob-
lems during days 3-7 after injection. One patient
had generalized, erythematous, maculopapular rash
and 5 patients had localized lesions.
During 8-14 days after injection, 15 localized skin
problems were observed. The lesions manifested
as swelling, redness, induration and mild pruritus.
The improvement of the lesions took 8.6 4.1 days.
Six patients were given corticosteroid treatment
and other 9 patients showed improvement of their
lesions without any treatment. After 14 days, two
cases of localized skin problems were observed. In
one of these cases, in addition to the localized le-
sion, there was a feeling of vaginal pruritus, which
was spontaneously resolved.
DISCUSSION
In this study, side-effects of iodized oil injection in
euthyroid patients with simple goiter were studied.
Two percent of patients developed either hy-
pothyroidism, hyperthyroidism or skin lesions.
Thyrotoxicosis and skin complications were self-lim-
ited, but hypothyroidism was persistent in a few pa-
tients.
The total incidence rate of hyperthyroidism after
iodized oil supplementation was 0.6%. This finding is
somewhat different from other reports. In a study of
420 Malaysian patients, 8 cases of clinical and 4 cas-
es of biochemical hyperthyroidism (1.7%) were de-
tected (4). Among 960 patients in Ecuador, 3 pa-
tients and following 2025 injections in Peru, one case
developed hyperthyroidism (9, 10). The present
prospective study dealt with a larger population of
patients; therefore, the observed difference with oth-
The presence of antithyroid antibodies following
high-dose iodine supplementation has been relat-
ed to increased prevalence of thyroid autoimmuni-
ty by some researchers (14). The incidence rate of
such a condition in our study has been low.
The incidence rate of hypothyroidism in our study
(0.6%) is greater than that of the previous studies.
In a study performed in Sudan, no cases of hy-
pothyroidism were observed following administra-
tion of intramuscular iodized oil to 1161 patients
and oral iodized oil to 2316 patients (15). In anoth-
er study performed in Greece, no cases of hy-
pothyroidism were observed in 58 patients with
simple goiter who were given iodized oil injection
75

F. Azizi and N. Daftarian
3. Martins M.C., Lima N., Knoble M., Medeiros-Neto G.
Natural course of iodine-induced thyrotoxicosis
(Jodbasedow) in endemic goiter area: A 5-year fol-
low-up.
(14). The increased incidence of hypothyroidism in
our study can be attributed to the larger study pop-
ulation, longer follow-up of the patients, or the in-
creased proportion of patients with disturbances in
iodine organification (16). It is known that patients
with subclinical Hashimoto’s thyroiditis will demon-
strate irreversible hypothyroidism when exposed to
high doses of iodine (17). This possibility cannot be
easily ruled out.
The recurrence of hypothyroidism was more preva-
lent than that of hyperthyroidism; the precise cause
of this observation is unknown, but the presence of
an underlying thyroid disorder should be consid-
ered in these cases. The presence of antithyroid an-
tibodies in some of these cases is a confirmation of
underlying thyroid pathology.
J. Endocrinol. Invest. 1989, 12: 239-244.
4. Maberly G.F., Corcoran J.M., Eastman C.J.
The effect of iodized oil on goiter size, thyroid func-
tion, and the development of Jod-Basedow phe-
nomenon.
Clin. Endocrinol. (Oxf.) 1982, 17: 253-259.
5. Stanbury J.B., Ermans A.E., Bourdoux P., Todd C.,
Oken E., Tonglet R., Vidor G., Braverman L.E.,
Medeiros-Neto G.
Iodine-induced hyperthyroidism: Occurrence and
epidemiology.
Thyroid 1998, 83-100.
6. Knoble M., Medeiros Neto G.A.
The incidence rate of dermatologic complications
was 0.8%. The occurrence of dermatologic compli-
cations may take days after the injection of the
drug. According to the type of allergic reaction, a
skin rash is manifested from a few minutes to 24-
48 hours after sensitization of the patient (18). The
skin problems observed in the patients are: hyper-
sensitivity reaction type I, urticarial lesions, erythe-
ma nodosum, and hypersensitivity reaction type III
of diffuse maculopapular eruptions.
It is concluded that the incidence rates of thyroidal
and extrathyroidal side- effects following injection
of iodized oil are low, and it is not possible to pre-
dict the occurrence of these complications in dif-
ferent individuals according to the patients’ age,
thyroid size, and goiter type. The low incidence of
these side- effects should encourage the use of
iodized oil as a convenient and inexpensive method
of iodine supplementation in remote regions and
as a therapeutic method in hypothyroid children
and adolescents with severe iodine deficiency (19).
Follow-up of all patients should be performed in 3-
to 6-month intervals for 2 years following injection,
and, if symptoms of thyroid derangement occur,
biochemical studies should be supplemented.
Iodized oil treatment for endemic goiter does not in-
duce the surge of positive serum concentration of
anti-thyroglobulin or anti-microsomal antibodies.
J. Endocrinol. Invest. 1986, 9: 321-324.
7. Azizi F., Kalani H., Kimiagar M., Ghazi A., Sarshar A.,
Nafarabadi M., Rahbar N., Noohi S., Mohajer M.,
Yassai M.
Physical, neuromotor, and intellectual impairment in
noncretinous schoolchildren with iodine deficiency.
Int. J. Vitam. Nutr. Res. 1995, 65: 199-202.
8. Azizi F., Sarshar A., Nafarabadi M., Ghazi A.,
Kimiagar M., Noohi S., Rahbar N., Bahrami A.,
Kalantari S.
Impairment of neuromotor and cognitive develop-
ment in iodine-deficient schoolchildren with normal
physical growth.
Acta Endocrinol. 1993, 129: 501-504.
9. Fierro-Benitez R., Penafiel W., Degroot L.J., Ramirez I.
Endemic goiter and endemic cretinism in the Andean
region.
N. Engl. J. Med. 1969, 280: 296-302.
10. Pretell E., Moncloa F., Salinas R., Kawano A., Guerra-
Garcia, Gutierrez L., Beteta L., Pretell J., Wan M.
Prophylaxis and treatment of endemic goiter in Peru
with iodized oil.
J. Clin. Endocrinol. Metab. 1969, 280: 1586-1590.
11. Nuovo J.A., Wartofsky L.
Adverse effects of iodide.
REFERENCES
In: Becker K.L. (Ed.), Principles and practice of en-
docrinology and metabolism.
1. Thilly C.H., Delange F., Stanburt J.B.
Epidemiologic surveys in endemic goiter and cre-
tinism.
Lippincott, Philadelphia, 1995, p. 332.
12. Vanderpump M.P.J., Tunbridge W.M.G., French
J.M., Appleton D., Bates D., Clarr F., et al.
In: Stanbury J.B., Hetzel B.S. (Eds.), Endemic goiter
and endemic cretinism: Iodine nutrition in health and
disease.
The incidence of thyroid disorders in the communi-
ty: A twenty-year follow-up of the Wickham Survey.
Clin. Endocrinol. 1995, 43: 55-67.
John Wiley, New York, 1980, p. 157.
2. Azizi F., Kimiagar M., Nafarabadi M., Yassai M.
Current status of iodine deficiency disorders in the
Islamic Republic of Iran.
13. Delange F., De Benoist B., Alnwick D.
Risks of iodine-induced hyperthyroidism after cor-
rection of iodine deficiency by iodized salt.
Thyroid 1999, 9: 545-556.
E.M.R. Health Serv. 1990, 8: 23-27.
76

Side-effects of iodized oil
14. Safran M., Paul T.L., Roti E., Braverman L.E.
Environmental factors affecting autoimmune thyroid
disease.
17. Braverman L.E., Ingbar S.H., Vagenakis A.G.
Enhanced susceptibility to iodide myxedema in pa-
tients with Hashimoto’s disease.
J. Clin. Endocrinol. Metab. 1971, 32: 515-521.
Endocrinol. Metab. Clin. North Am. 1987, 16: 327-342.
18. Habif T.P.
15. Eltom M., Karlsson F.A., Kamal A.M., Bostrom H.,
Dahlberg P.A.
Exanthem and drug eruptions.
In: Habif T.P. (Ed.), Clinical dermatology, a color
guide to diagnosis and therapy.
Mosby, St Louis, 1996, p. 404.
The effectiveness of oral iodized oil in the treatment
and prophylaxis of endemic goiter.
J. Clin. Endocrinol. Metab. 1985, 61: 1112-1117.
19. Azizi F., Kimiagar M., Ghazi A.A., Nafarabadi M.
The effects of iodized oil injection in eu- and hy-
pothyroid iodine deficient girls.
16. Wolff J.
Iodide goiter and pharmacologic effect of excess io-
dide.
J. Endocrinol. Invest. 1997, 20: 18-23.
Am. J. Med. 1969, 47: 101-124.
77