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Iodine excess and hyperthyroidism150 mg iodine are daily required for thyroid hormone synthesis. The thyroid gland has intrinsic mechanismsthat maintain normal thyroid function even in the presence of iodine excess. Large quantities of iodide are pres-ent in drugs, antiseptics, contrast media and food preservatives. Iodine induced hyperthyroidism is frequentlyobserved in patients affected by euthyroid iodine deficient goiter when suddenly exposed to excess iodine. Pos-sibly the presence of autonomous thyroid function permits the synthesis and release of excess quantities of thyroid hormones. The presence of thyroid autoimmunity in patients residing in iodine-insufficient areas whodevelop iodine-induced hyperthyroidism has not been unanimously observed. In iodine-sufficient areas, io-dine-induced hyperthyroidism has been reported in euthyroid patients with previous thyroid diseases. Euthy-roid patients previously treated with antithyroid drugs for Graves’ disease are prone to develop iodine-inducedhyperthyroidism. As well, excess iodine in hyperthyroid Graves’ disease patients may reduce the effectivenessof the antithyroid drugs. Occasionally iodine-induced hyperthyroidism has been observed in euthyroid patientswith a previous episode of post-partum thyroiditis, amiodarone destructive or type II thyrotoxicosis and re-combinant interferon-a induced destructive thyrotoxicosis. Amiodarone administration may induce thyrotox-icosis. Two mechanisms are responsible for this condition. One is related to excess iodine released from thedrug, approximately 9 mg of iodine following a daily dose of 300 mg amiodarone. This condition is an iodine-induced thyrotoxicosis or type I amiodarone-induced thyrotoxicosis. The other mechanism is due to the amio-darone molecule that induces a destruction of the thyroid follicles with a release of preformed hormones. Thiscondition is called amiodarone-induced destructive thyrotoxicosis or type II thyrotoxicosis. Patients develop-ing type I thyrotoxicosis in general have preexisting nodular goiter whereas those developing type II thyro-toxicosis have a normal thyroid gland. The latter group of patients, after recovering from the destructive pro-cess, may develop permanent hypothyroidism as the consequence of fibrosis of the gland.
iodide trap, thereby decreasing the intrathyroid iodide con-centration (2), due to a decrease in the sodium iodide sym- IODINE IS AN ESSENTIAL REQUIREMENT for thyroid hormone porter (NIS) mRNA and protein expression (3). Excess io-
synthesis and in the adult the recommended daily iodine dine ingestion (up to 150 mg/d) also decreases the release intake is 150 mg. In the United States, the median urinary io- of thyroxine (T4) and triiodothyronine (T3) from the thyroid dine excretion is 14.5 mg/dL. Approximately 5.3% of the resulting in small decreases in serum T4 and T3 concentra- population exceeded urinary iodine (UI) of 50 mg/dL and tions with compensatory increases in basal and TRH stimu- 1.3% exceeded 100 mg/dL (1). The thyroid gland has intrin- lated thyrotropin (TSH) concentrations, all values remaining sic regulatory mechanisms that maintain normal thyroid well within the normal range (4–9). These iodine-treated sub- function even in the presence of iodine excess. When large jects remained euthyroid although they continued to ingest amounts of iodine are given to subjects with normal thyroid the excess iodide and serum thyroid hormone and TSH val- function a transient decrease in the synthesis of the thyroid ues returned to basal levels when the iodide was discontin- hormones occurs for approx 48 hours. This acute inhibitory ued. These subtle changes in thyroid function were accom- effect of iodine on thyroid hormone synthesis is called the panied by increased thyroid volume assessed by echography acute Wolff-Chaikoff effect and is due to increased intrathy- (8,9) and a decrease in thyroid blood flow determined by roid iodine concentrations. The escape from or adaption to color Doppler flow imaging (10). The smallest quantity of io- the acute Wolff-Chaikoff effect is a decrease in the thyroid dine, exceeding that consumed with the diet in the United Istituto di Endocrinologia, Università di Milano, Scuola di Specializzazione in Endocrinologia, Università di Parma, Cattedra di En- docrinologia, Università di Ferrara, Italy.
ROTI AND DEGLI UBERTI
TABLE 1. COMMONLY USED IODINE-CONTAINING DRUGS Oral or Local
Isopropamide iodide (e.g., Darbid.Combid) Niacinamide hydroiodide 1 KI (e.g., Iodo-Niacin) Parenteral preparations
Iodochlorhydroxyquin cream (e.g., Vioform) Radiology contrast agents
aNot FDA approved.
bIodine was removed from Organidin and Tuss Organidin in 1995(Adapted from Braverman LE 1986 Iodide-induced thyroid disease. In: Ingbar SH, Braverman LE (eds) Werner’s The Thyroid, 5th ed. Philadelphia, JB Lippincott, p 734.) States, that does not affect thyroid function is 500 mg/d (11).
cal quantities of iodine is almost always due to the admin- The administration of 1 mg of iodine per week for 6 weeks istration of inorganic and organic medicinal compounds.
followed by the administration of 2 mg of iodine weekly foranother 6 weeks did not affect thyroid function (12). Other Sources of Excess Iodine
studies have suggested that the administration of 500 mg io-dine daily induced a small but significant increment of ba- Various drugs and food preservatives contain a large sal and TRH stimulated serum TSH concentrations (13,14).
quantity of iodide that is either absorbed directly or released Ingestion of 1,500 mg of iodine per day for 15 days by eu- after metabolism of the drug. Many vitamin preparations are thyroid subjects invariably resulted in a significant decrease supplemented with about 150 mg of iodine, a quantity that in serum free thyroxine (FT4) concentrations and FT4 Index is considered to be the physiological daily requirement.
with a significant compensatory rise in basal and TRH stim- Iodophors contain large quantities of iodine and are used as ulated serum TSH concentrations (11,13,14). Pharmacologi- udder antiseptics in the dairy industry, resulting in contam- IODINE EXCESS AND HYPERTHYROIDISM
Iodine supplementation for endemic iodine-deficiency goiterIodine excess administration to patients with euthyroid Graves’ disease, especially those in Iodine excess administration to euthyroid subjects with previous episode of: postpartum thyroiditisamiodarone induced destructive thyrotoxicosis (type II)IFN-a–induced thyroid dysfunction Nontoxic nodular goiterAutonomous noduleNontoxic diffuse goiterIodine administration to patients with no recognized underlying thyroid disease, especially in area of mild to moderate iodine deficiency (Adapted from Braverman LE 1986 Iodide-induced thyroid disease. In: Ingbar SH, Braverman LE (eds) Werner’s The Thyroid, 5th ed. Philadelphia, JB Lippincott, p 734.) ination of the milk with iodine. Iodine is also concentrated Iodide-Induced Hyperthyroidism in Endemic by the mammary gland and secreted into the milk and, there- fore, may influence thyroid function in the newborn who isfed cow’s milk. Many iodine-rich products, such as kelp, are Iodine prophylaxis has almost eliminated endemic goiter available in nature food stores. In some areas of Japan, bread in many countries. The incidence of iodide-induced hyper- is made exclusively from seaweed, exposing the population thyroidism in areas previously considered iodine deficient varied from no incidence in Austria to 7% in Sweden after Iodides are present in high concentration in various pro- iodination programs. The incidence of iodine-induced hy- prietary and prescribed expectorants, including iodinated perthyroidism in an endemic goiter area has been estimated glycerol, Organidin, although iodine has been removed from to be up to 1.7% (24). The natural course of the disease was this latter medication in the United States. Another potential mild, and it resolved spontaneously.
source of excess iodine is the use of contrast media in radi- Most patients who developed hyperthyroidism have multi- ologic studies. Preparations used for computed tomography, nodular thyroid disease. Most are euthyroid before iodine arteriography, or pyelography are cleared from the plasma administration, but they may have nonsuppressible ra- relatively quickly, but the iodine released during these pro- dioactive iodine uptakes and low or undetectable serum TSH cedures affects thyroid function. However, a dye commonly values and the serum TSH may fail to respond to thy- used for arteriography, meglumine ioxaglate (Hexabrix), did rotropin-releasing hormone (TRH). Single oral doses of 200, not affect serum T4, T3, or FT4 index up to 56 days after 400, and 800 mg of iodine administered to adult goitrous catheterization but serum TSH was not measured (15). Oc- subjects residing in the Sudan induced four cases of hyper- casionally drinking water may also be a source of excess io- thyroidism. However, in the three groups of subjects, serum dine intake as in some Chinese counties where the drinking TSH concentrations below 0.1 mU/L were present in 5.9% water had an iodine concentration of 300 to 462 mg/L re- to 16.7% of the cases 12 months after iodine administration sulting in the population residing in those areas to have uri- (25). Similar data have been reported 2 years after iodized nary iodine excretion as high as 900 mg/L (16,17). A partial salt distribution in Zaire. Among 190 adult subjects with list of medications and other preparations containing large nodular goiter, 14 subjects (7.4%) developed severe thyro- quantities of iodine is given in Table 1.
toxicosis (26). Thyroid-stimulating antibodies were absent inall. Surprisingly these alterations lasted longer than 1 year Iodide-Induced Hyperthyroidism
(27). Also in Zimbabwe, after the iodination of salt at a levelof 30 to 90 ppm, a threefold increase of iodide-induced hy- Iodide-induced hyperthyroidism is not a single etiologic perthyroidism was observed (28). Furthermore, in that entity. Since the initial description by Coindet in 1821 (18) population, fatal outcomes occurred mainly from cardiac and the subsequent definition by Breuer and Kocher in 1904, complications. Delange et al. (29) have suggested that iodine- iodine-induced hyperthyroidism has been reported in pa- induced hyperthyroidism occurs only when iodine deficient tients with a variety of underlying thyroid diseases. As populations are exposed to a recent (,2 years) excessive in- shown in Table 2, iodide-induced hyperthyroidism may oc- crement of alimentary iodine intake.
cur in patients with iodine-deficiency goiter, in euthyroid It appears, therefore, that masked thyroid autonomy be- Graves’ disease patients after antithyroid drug therapy, in comes evident when iodine repletion permits the au- euthyroid subjects with previous spontaneous and iatrogenic tonomous tissue to synthesize and release excess quantities episodes of thyroid dysfunction, in patients with multi- of thyroid hormone. This is consistent with studies from Bel- nodular goiters who reside in areas of iodine repletion or de- gium and Greece (30,31) where the administration of small ficiency, and in people with no evidence of underlying thy- quantities of iodide (0.5 mg/d) to patients with autonomous roid disease (19–22). The pathogenesis and the epidemiology nodules induced frank hyperthyroidism. In Austria in 1990, of iodide-induced hyperthyroidism have been thoroughly salt iodination was doubled to 20 mg potassium iodide per kilogram salt because before that time the urinary iodine ROTI AND DEGLI UBERTI
excretion ranged from 42 to 72 mg of iodine per gram of cre- port from Boston, Massachusetts, (38), where four of eight atinine (32). This change was accompanied by an increase of patients with goiter developed severe iodine-induced hy- the incidence of overt Plummer’s disease from 30.5 to 41.7 perthyroidism after administration of 180 mg of iodide daily cases per 100,000 in 1992. The importance of thyroid auton- for several weeks. Iodine-induced hyperthyroidism has also omy for the development of iodide-induced hyperthy- been reported in other patients residing in the United States roidism is strengthened by a report of iodide-induced hy- (21,39). It is likely that the susceptible patients had nonsup- perthyroidism in a woman with a multinodular goiter treated with suppressive doses of T4 and simultaneously ex- Iodine-induced hyperthyroidism was identified in 13 of 60 posed to high quantities of iodide (33). Attempts have been hospitalized thyrotoxic elderly subjects in Australia (40,41) made to associate iodide-induced hyperthyroidism to thy- and in Germany (42), after nonionic contrast radiography.
roid autoimmunity, but the results are conflicting. Long-act- These subjects did not have positive TPOAb and a thyroid ing thyroid stimulator (LATS) or LATS protector was found scan revealed the presence of a multinodular goiter. In a in some patients but not in others (24). In another study, no prospective study conducted in elderly subjects, it was ob- change in the incidence of thyroid autoantibodies was found served that frank hyperthyroidism was uncommon after the after oral administration of iodized oil (34). The oral admin- administration of nonionic agents, whereas subclinical hy- istration of 0.2 and 0.5 mg of iodine to patients with small, perthyroidism was observed (43). To reduce the incidence of diffuse goiter and low urinary iodine excretion induced the iodide-induced hyperthyroidism, it has been suggested that occurrence of subclinical transient hyperthyroidism in the methimazole or perchlorate be given the day before and for 5% of patients (35,36). These patients had at baseline posi- 2 weeks after x-ray contrast administration to patients with tive antithyroglobulin (TgAb) and antimicrosomal antibod- thyroid autonomy (44). Other authors have reported that ies (mAb) and titers increased during iodine administration in euthyroid, not at-risk subjects, iodine-induced hyperthy- and decreased after withdrawal. A marked increment of roidism after coronary angiography was rare and therefore overt Graves’ disease from 10.4 to 20.9 cases per 100,000 in prophylactic therapy was not recommended (45). Lawrence 1993 was observed in Austria after the increment of salt io- et al. (46) suggested that the administration of thionamide dination (32). In contrast to these observation suggesting that and perchlorate to elderly patients with a suppressed serum iodine-induced hyperthyroidism may be triggered by the de- TSH and/or palpable goiter might be efficacious. Iodide-in- velopment of thyroid autoimmunity, it has been observed duced thyrotoxicosis has also been described in three trav- that in goitrous schoolchildren, salt iodine supplementation elers (travelers’ thyrotoxicosis) after the ingestion of iodi- was accompanied by a marked increment of the prevalence nated preparations for water purification (47,48). In all three of Tg Ab and less commonly thyroperoxidase antibodies cases, TPOAb were present at the time of the diagnosis of (TPOAb) but not by the occurrence of iodide-induced hy- thyrotoxicosis. Iodide-induced thyrotoxicosis occurred in 1 of 40 patients with simple, noniodine-deficient goiter andnegative antithyroid antibodies who received 1 mL of Iodine-Induced Hyperthyroidism in
iodized oil intramuscularly (49). In these patients, an incre- Iodine-Sufficient Areas
ment of antithyroid antibodies titer was observed. The largedifference in the rate of occurrence of iodide-induced hy- In nonendemic euthyroid goiter areas, the incidence of io- perthyroidism between iodine-deficient and iodine-replete dine-induced hyperthyroidism is low. Goiter prevalence in areas is difficult to explain. It is possible that people with in- the United States is approximately 3.1%, and it is surprising creased iodine intake are resistant to iodine-induced hyper- that only a few cases have been reported since the initial re- thyroidism because the sensitivity of the autoregulatory TABLE 3. FEATURES OF AMIODARONE-INDUCED THYROTOXICOSIS Modified from Bartalena et al. (62)RAIU, radioactive iodine uptake; IL-6, interleukin-6.
IODINE EXCESS AND HYPERTHYROIDISM
mechanism has changed, rendering the thyroid better able perthyroidism is far less common. These differences are at- to handle the excessive quantities of iodide.
tributed to increased ambient iodine intake in the United Unusual episodes of iodine-induced hyperthyroidism States preceding the administration of the drug (60,62).
have been observed in a few patients suffering from severe Amiodarone-induced thyrotoxicosis results from two dif- burns treated with povidone iodine (50) and in a patient who ferent mechanisms. The iodine released during the metabo- had metastatic thyroid carcinoma (51).
lism of the drug is responsible for the thyrotoxicosis in mostcases. Predisposing factors include micronodular and macro- Latent Graves’ Disease
nodular goiter, which are common in older patients whomost often require amiodarone. Thyroid autoimmunity has Antithyroid drug therapy for Graves’ disease reduces thy- also been incriminated as a predisposing factor and antithy- roidal iodine content. Overt hyperthyroidism can develop roid antibodies have been found following amiodarone ad- only if sufficient iodine is available. It has been reported that ministration in some patients (63) but not in others (64).
a small increase in dietary iodine increases the frequency of Amiodarone may also induce destructive thyroiditis result- recurrence of hyperthyroidism after antithyroid drug ther- ing in thyrotoxicosis as suggested by clinical, histologic, and apy. The difference in Graves’ remission rates between the in vitro studies (64–66). The ultrastructural changes of rat thy- United States and Europe is attributed, at least in part, to the roid gland induced by amiodarone are different from those higher iodine intake in the United States (52). Furthermore, induced by excess iodine and are mediated by a disruption the response to thionamide drugs is rapid in Graves’ disease of subcellular organelle function with a marked dilation of patient who reside in iodine-deficient areas and the dose re- the endoplasmic reticulum (67,68). The clinical and labora- quired to control the disease is smaller (53). It is evident, tory characteristics of amiodarone-induced thyrotoxicosis therefore, that large quantities of iodides administered to pa- tients with latent Graves’ disease may result in frank hy- The evaluation of thyroid function is difficult in patients receiving amiodarone therapy. Serum T4 may be elevated, Consonant with this view are the observations in Graves’ serum T3 decreased, due to the blocking effect of the drug disease patients treated with antithyroid drugs. In one study on type 59 deiodinase, and TSH normal or slightly elevated (54) simultaneous administration of methimazole and ipo- or decreased in a euthyroid subject receiving the drug. Hy- date reduced the effectiveness of the antithyroid drug. In an- perthyroidism is the best confirmed by suppressed serum other study, iodide administration to patients rendered eu- TSH and elevated serum T3 and free T3 concentrations as thyroid after antithyroid drug therapy was accompanied by well as by an increase in sex hormone-binding globulin (69).
frank hyperthyroidism in some and with an absent TSH re- The distinction between iodine-induced hyperthyroidism sponse to TRH in others (55). Excess iodide administered to (type I) and destructive thyrotoxicosis (type II) may be hyperthyroid patients with Graves’ disease significantly in- achieved by measurement of serum interleukin-6, which is creased thyrotropin receptor antibody, suggesting that this invariably elevated in the destructive form (70) and by fine- phenomenon was responsible for iodine-induced thyroid needle biopsy, which shows cytologic findings consistent dysfunction in predisposed subjects (56).
with thyroiditis (66). The thyroid radioiodine uptake is al-ways low in the destructive form and is often low in iodine- Patients with Previous Thyroid Diseases
induced thyrotoxicosis but may be normal or rarely elevated Iodide-induced subclinical hyperthyroidism has been ob- in rodent-deficient regions. In the latter, 131I therapy is an al- served in 1 of 11 euthyroid women with a previous episode of postpartum thyroiditis receiving 10 drops of saturated so- Distinction of the two forms is important for determining lution of KI (SSKI) for 90 days (57).
the most efficacious form of therapy. Amiodarone should al- Iodide-induced subclinical, transient hyperthyroidism oc- most always be discontinued. Large doses of antithyroid curred also in 20% of euthyroid patients who previously had drugs are recommended for iodine-induced hyperthy- amiodarone-induced destructive or type II thyrotoxicosis roidism. If this treatment fails, potassium perchlorate (250 (58). These patients had absent TPOAb and thyrotropin re- mg three times daily) should be added (71,72). The latter ceptor antibodies (TSRAb). Also, euthyroid patients with a drug blocks the thyroid iodide trap, thereby decreasing the previous episode of recombinant interferon-a–induced de- structive thyrotoxicosis developed iodide-induced hyper- In patients with destructive thyrotoxicosis, administration thyroidism in 25% of cases after the administration of phar- of large doses of corticosteroids is rapidly effective (66,73).
macological quantities of iodine (59). These patients did not Normal serum T3 concentrations were achieved after an av- erage of eight days. Relapses are frequent as the prednisonedose was tapered (74). Surgery has been successfully usedfor the treatment of amiodarone-induced thyrotoxicosis (75).
Amiodarone-Induced Thyroid Disease
After recovering from amiodarone-induced destructive Amiodarone, a benzofuranic derivative containing 75 mg thyrotoxicosis, patients may develop permanent hypothy- of iodine per 200-mg tablet, is widely used for the long-term roidism (66,76) as a result of fibrosis of the gland (77). The treatment of cardiac arrhythmias. Approximately 9 mg of io- iodine-perchlorate discharge test was positive in 60% of eu- dine is released daily during the metabolism of the drug (300- thyroid patients who had recovered from amiodarone-in- mg dose, which is prolonged with a half-life of approxi- duced destructive thyrotoxicosis (78). The long-term admin- mately 100 days. Amiodarone-induced hyperthyroidism istration of 300 mg of iodide daily to these patients induced occurs in about 10% of patients residing in iodine-deficient a marked increase in basal and TRH-stimulated serum TSH areas (60,61). In the United States, amiodarone-induced hy- concentrations, which returned to normal after iodide with- ROTI AND DEGLI UBERTI
drawal. Finally, adult patients with b-thalassemia have been 7. Philippou G, Koutras DA, Piperingos G, Souvatzoglou A, shown to be particularly prone to develop both hyperthy- Moulopoulos SD 1992 The effect of iodide on serum thyroid roidism and hypothyroidism during amiodarone therapy for hormone levels in normal persons, hyperthyroid patients, heart failure or cardiac arrhythmias (79).
and in hypothyroid patients on thyroxine replacement. Clin In view of the high incidence of thyroid dysfunction, amio- Endocrinol (Oxf) 36:573–578.
darone should be administered with caution to patients with 8. Le Mar HJ, Georgitis WJ, McDermott MT 1995 Thyroid preexisting goiter or a history of thyroid disease. Before be- adaptation to chronic tetraglycine hydroperiodide water pu- ginning amiodarone treatment, a careful examination is re- rification tablet use. J Clin Endocrinol Metab 80:220–223.
quired; TSH and TPOAb values are mandatory. During 9. Namba H, Yamashita S, Kimura H, Yokoyama N, Otsuru A, Izumi M, Nagataki S 1993 Evidence of thyroid volume in- amiodarone treatment measurement of serum TSH concen- crease in normal subjects receiving excess iodide. J Clin En- trations is required approximately every 6 months in order docrinol Metab 76:605–608.
to detect the development of mild thyroid disorders.
10. Arntzenius AB, Smit LJ, Schipper J, van der Heide D, Mein- ders AE 1991 Inverse relation between iodine intake and thy- Acknowledgments
roid blood flow: Color doppler flow imaging in euthyroid This work was supported in part by Grants 93.00405.CT04, humans. J Clin Endocrinol Metab 73:1051–1055.
94.02481, CT04, 9500940, CT04 from Consiglio Nazionale 11. Paul T, Meyers B, Witorsch RJ, Pino S, Chipkin S, Ingbar SH, delle Ricerche (Rome, Italy) Grant “Patologia della Tiroide: Braverman LE 1988 The effect of small increases in dietaryiodine on thyroid function in euthyroid subjects. Metabo- Indagine dei Fattori Etiopatogenetici” of Ministero Pubblica lism 37:121–124.
12. Jonckheer MH, Michotte Y, Van Steirteghem AC, Deconinck Portions of this Paper are identical to recent works by the F 1983 The adaptation of the human thyroid gland to a phys- E Roti and LE Braverman 1996 Iodine Deficiency and Thy- iological regimen of iodide intake: Evidence for a transitory roid Function. Nauman J, Glinoer D, Braverman LE, inhibition of thyroid hormone secretion modulated by the Hostalek U, (eds) In Thyroid and Iodine, Proceedings of the intrathyroidal iodine stores. J Endocrinol Invest 6:267–272.
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A. Ersin ACAR 2011 Spring Semester Course Content: A) Modification of functional groups 1. Reduction 1. Heterogeneous catalysis 2. Homogeneous catalysis 3. Hydrogenation of C=C by diimide 4. Asymetric hydrogenation of acids (esters)-acylaminoacrylics 1.2. Hydrogenolysis of C-O, C-S, C-X, N-O, O-O bonds 1. H2/Pd (Pt, Ni) 2. Hydrogenolysis of C-Het at α position of C=O 1. Re