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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 1853-1860
Copyright © 2001 by The Endocrine Society

Special Articles

Oral Cholecystographic Agents and the Thyroid

Milena Braga and David S. Cooper

Division of Endocrinology and Metabolism (M.B., D.S.C.), Sinai Hospital, Baltimore, Maryland 21215; Serviço de Endocrinologia e Metabologia do Paraná (M.B.), Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil 80.060-240; Johns Hopkins University School of Medicine (D.S.C.), Baltimore, Maryland 21215

Address all correspondence and requests for reprints to: David S. Cooper, M.D., Division of Endocrinology, Sinai Hospital of Baltimore, Baltimore, Maryland 21215. E-mail: dcooper{at}lifebridgehealth.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Summary and Conclusions
 References
 
Oral cholecystographic agents (OCAs) are known to affect thyroid hormone metabolism by acting as potent inhibitors of type I and type II deiodinases, blocking the conversion of T4 to T3 and rT3 to T2. In addition, iodine released from the drug blocks thyroid gland secretion of thyroid hormone. These properties make OCAs a potentially useful drug therapy in patients with hyperthyroidism and other thyrotoxic disorders. Short-term treatment with OCAs rapidly reduces serum T3 levels, with a lesser effect on T4 levels. OCAs are not useful for long-term treatment, which is usually followed by exacerbation of hyperthyroidism with continued use. The lack of significant side effects makes these drugs an excellent short-term option in situations where a rapid clinical improvement is critical.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Summary and Conclusions
 References
 
ORAL CHOLECYSTOGRAPHIC AGENTS (OCAs) have been widely used in the past for radiological visualization of the gallbladder. Reports of hyperthyroidism in patients with multinodular goiter after oral cholecystography aroused curiosity about possible effects of these compounds on thyroid function. In 1976, Burgi et al. (1) reported that oral cholecystography with iopanoic acid had effects on peripheral metabolism of thyroid hormones. When compared with other iodinated radiographic agents, OCAs were found to affect the thyroid gland through actions other than those caused solely by iodine release, suggesting that the chemical structures of these compounds might have unique effects on thyroid hormone turnover. Subsequent in vitro animal and human pharmacologic studies have shown marked OCA-induced alterations in cellular T4 transport and metabolism. Potentially beneficial clinical results have been observed when these agents have been used to treat hyperthyroid patients in a variety of contexts.

Recently, ipodate has been withdrawn from the market in the United States. Considering that OCAs represent a useful alternative for treating thyrotoxicosis in special situations, this could become a serious problem. In this study, we review the clinical pharmacology and mechanism of action of these compounds. We also discuss their potential therapeutic applications in the treatment of thyrotoxicosis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Summary and Conclusions
 References
 
A review of the literature through a Medline search was performed, including studies in English published between 1966 and 1999, with keyword combinations of oral cholecystographic agents and thyroid, iopanoic acid and thyroid, and ipodate and thyroid. References cited in retrieved studies with data concerning effects of OCAs on thyroid function were also included and were supplemented by pharmacology texts and product information supplied by manufacturers.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Summary and Conclusions
 References
 
Historical perspective

Iopanoic acid was first introduced in 1951 as an improved OCA, with fewer side effects compared with formerly used imaging agents. Before the widespread use of ultrasound, cholecystography was considered to be the most sensitive method for the diagnosis of gallbladder disease, and iopanoic acid was the most frequently used agent (2). Later, many other approaches to gallbladder imaging were developed (3).

Structure

Iopanoic acid is a triiodobenzene ring compound with a high degree of lipid solubility (Fig. 1Go). The phenolic ring provides binding sites for iodine atoms, the binding of which is facilitated by the presence of the amino group. An ethyl group attached to the second carbon makes the drug more hydrophilic (2). The other OCAs differ from iopanoic acid at both the 4 position on the benzene ring and substitutions on the ethyl side chain. Iodine confers the radiopaque property on these compounds and its content varies among different agents. The iodine content of iopanoic acid, the one remaining OCA currently available in the United States, is shown in Table 1Go, along with the other analogs.



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  		Figure 1. Reproduced with permission from S. H. Ingbar and L. E. Braverman: The Thyroid, 5th ed. (66 ).

 

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  		Table 1. Oral cholecystographic agents and their iodine content

 
In vitro and animal studies

Effects on hepatic and kidney cells. OCAs primarily act as inhibitors of type I and type II 5'deiodinases. Studies performed in rat liver homogenates with iopanoic acid have shown an inhibition of T4 to T3 conversion, as well as reverse T3 (rT3) degradation (4, 5). Sodium diatrizoate, another iodinated contrast agent, had a small inhibitory effect on rT3 degradation, but no statistically significant inhibition of T4 to T3 conversion (4, 5). Although the inhibition of deiodinase activity in kidney and liver in vitro is competitive (5), noncompetitive inhibition is observed in rats in vivo (6). The inhibition of 5' deiodination by iopanoic acid was studied in the kidney, liver, and thyroid gland of thyroidectomized rats by St. Germain (6). He showed that the inhibition of type I deiodinase maximum velocity values was proportional to the amount of iopanoic acid administered; 0.04 mg iopanoic acid per 100 g body weight produced a decrease in 5'deiodinase maximum velocity of 52%, whereas 4 mg/100 g body weight produced a decrease of 66%, although Km remained unchanged. The inhibitory process started immediately after iopanoic acid administration. Maximum inhibition was seen 5 h after the dose, and it persisted for more than 60 h (6).

DeGroot and Rue (7) demonstrated competitive inhibition of 50% on T3 binding to liver nuclear receptors by 1.2 x 10-4 M ipodate and other agents in vitro, although this effect could not be demonstrated in vivo. Similar results were obtained by Burman et al. (8) who demonstrated inhibition of T3 binding by ipodate to liver nuclear receptors at 10-3 and 10-4 M, with a 65% and 15% inhibition, respectively, in vitro and in vivo. The authors postulated that a similar chemical structure among iodothyronines and ipodate would allow interaction with the receptor. Interestingly, in neither of these studies, could another OCA (tyropanoate) be shown to have significant competitive properties with T3 for the nuclear receptor site (7, 8).

Effects on the pituitary. Inhibition of pituitary conversion of T4 to T3 has also been observed with iopanoic acid in vivo in rats (9). A dose of 5 mg/100 g body weight given before administration of 125I-labeled T4 to thyroidectomized rats prevented thyrotroph suppression by T4. Furthermore, there was a significant reduction of 125I-labeled T3 generation from intrapituitary conversion of 125I-labeled T4. It has been shown that this inactivation of pituitary 5' type II deiodinase is irreversible and relates directly to binding of iopanoic acid to the active site of the enzyme (10). Because type I deiodinase also is found in the pituitary (11), an effect of OCAs on this system is also possible.

Type II deiodinase seems to be more sensitive to the inhibitory effect of iopanoic acid compared with type I deiodinase. In hypothyroid rats (where type II deiodinase activity is increased), iopanoic acid (0.04 mg/100 g body weight) inactivated approximately 80% of type II deiodinase in pituitary and cerebral cortex (10), whereas in hyperthyroid rats (where type I deiodinase is increased) a 100-fold larger amount was required to induce the same degree of reduction of type I deiodinase activity in the liver and kidney (6).

Effects on the thyroid. Both ipodate and iopanoic acid inhibit deiodination of T4 to T3 in dog thyroid glands (12). Looking for the specific sites of action on the gland, Laurberg (13) demonstrated interesting results after perfusing both lobes separately with different compounds. Compared with perfusion with iodide, a rapid and reversible inhibition of secretion of T3, rT3, T4, 3,3' T2 and 3',5' T2 was observed with 10-3 M ipodate. This inhibitory effect was proportional to the ipodate concentration, although even with the smallest concentration (10-4 M) a significant inhibition was still present. Moreover, TSH activation of cAMP was inhibited by ipodate. This was demonstrated in dogs in vivo after infusion of TSH and ipodate and measurement of cAMP in the thyroid effluent, and in vitro after incubating thyroid slices with ipodate. The number of colloid droplets, visualized by staining of tissue slices from perfused thyroid lobes, showed a significant reduction when ipodate was added to perfused cAMP, compared with cAMP alone; inhibition of thyroglobulin proteolysis and liberation of T4 and T3 was also demonstrated.

Type III deiodinase. A weak inhibition of type III deiodinase has also been observed with OCAs as reflected by small reduction of T4 to rT3 conversion in rat brain and skin (14, 15).

Studies in humans

Pharmacodynamics. Iopanoic acid is the most commonly used OCA and has been the most studied (16). Similarities in the chemical structure of iopanoic acid and ipodate suggest that they may share pharmacodynamic properties. After ingestion, iopanoic acid is promptly absorbed by passive diffusion through the small intestinal mucosa (2). The presence of bile salts in the duodenum is essential for its diffusion through the intestine wall, and a high fat content in the diet is important for more effective absorption. Immediately after absorption, iopanoic acid enters the blood stream, binds to albumin, and is transported to the liver. Once inside the hepatocytes, iopanoic acid conjugates with glucuronic acid and is secreted in the billiary canaliculi. Bile is its main mode of excretion (65%), whereas the kidneys account for the remaining 35% (2).

OCAs and thyroid hormone metabolism. Due to their ability to strongly inhibit the phenolic (outer ring) deiodination process, OCAs potently reduce the conversion of T4 to T3 (1, 17, 18). In hyperthyroid patients, an average 70% reduction of serum T3 levels was observed after 48 h of ipodate. It also inhibited the conversion of rT3 to T2, resulting in increased serum rT3 levels (410% at 24 h) (17).

In some subjects, elevated serum T4 levels (total and free) in response to OCAs administration have also been observed, and they seem to follow a rise in serum TSH concentrations. In fact, the rise in serum T4 levels after iopanoic acid is prevented if TSH is suppressed by exogenous T3 (19). This suggests that in normal subjects, the rise in T4 level after OCAs is probably due both to TSH stimulation of the thyroid gland, as well as decreased T4 metabolism.

Although all the OCAs induce similar changes in thyroid hormone metabolism, the agents differ in the time required for these effects to be manifested. Evaluating the time course of the response of T3, rT3, T4, and TSH to a 3-day administration of 3 g iopanoic acid or ipodate sodium, Suzuki et al. (20) reported a greater increase in serum rT3 with ipodate (136 ± 27 ng/dL on the second day) when compared with 45 ± 7 ng/dL on the first day after iopanoic acid. Serum T4 levels showed a rise after both agents (from 10.0 ± 1.6 µg/dL to 13.9 ± 2.7 µg/dL 2 days after iopanoic acid and from 10.1 ± 2.1 µg/dL to 12.4 ± 3.2 µg/dL 3 days after ipodate), and T3 levels decreased (from 161 ± 6 ng/dL to a nadir of 119 ± 2 ng/dL, 12 h after iopanoic acid, and from 136 ± 22 ng/dL to 101 ± 18 ng/dL on day 3 after ipodate). The decrement was statistically significant from baseline after both agents and no difference between them was observed.

In 1978, Wu et al. (17) reported changes in serum thyroid hormone levels after administration of ipodate to euthyroid controls and patients with thyroid disease. In normal patients, after a single 3-g dose of sodium ipodate, serum T3 had a maximum decrease of 32% on day 4, whereas rT3 and T4 increased on the second and third day, respectively (52% and 17%). The same occurred in hypothyroid patients on T4 replacement, in whom T3 decreased by 44% on the fourth day, rT3 rose by 64% on the third day, and T4 continuously increased by 37.6% until the seventh and final day of the study.

Effects on the pituitary gland. Although not all human studies have shown a change in basal TSH levels after OCA administration, thyrotroph sensitivity is increased, as demonstrated by an exaggerated TSH response to TRH. Normal subjects showed a significantly greater peak TSH response to TRH stimulation after the administration of 3 g iopanoic acid for 3 days (30 ± 6.9 mU/L vs. 14.0 ± 2.9 mU/L; P < 0.005) (20). Similar results were achieved in another study before and after 5 days following a single 3-g dose of iopanoic acid. However, this rise in TSH could be blocked by exogenous T3 administration (19). Based on temporal observations, it appears that serum T3 levels decline before the rise in TSH levels, suggesting reduced T3 feedback at the level of the pituitary and probably also due to inhibition of intrapituitary conversion of T4 to T3 (9).

Ipodate has been shown to induce a blunted response of TSH to TRH in euthyroid obese male subjects during a 7-day fast and a 6-day period of a weight maintenance diet when compared with control subjects (21). The control group showed a mean peak serum TSH response of 7.2 ± 2.1 mU/L after TRH administration during the fasting period, which was significantly reduced compared with the levels observed during the fed period (11.9 ± 2.6 mU/L). When ipodate (3 g) was given on days 1 and 5 of the fasting period, the mean serum TSH peak was higher during the fasting period when compared with the fed period (13.9 ± 2.5 mU/L vs. 12.4 ± 2.4 mU/L; P < 0.05). The explanation for the differences in pituitary responsiveness is unknown.

Effects on T4 binding to hepatocytes. In addition to effects on peripheral T4 metabolism, OCAs also displace T4 from binding sites in hepatocytes. Felicetta et al. (22) evaluated the effects of tyropanoate and ipodate on T4 binding to hepatocytes in vivo. Five subjects were given 125I-labeled T4 and evaluated for hepatic and serum radioactivity before and after the administration of a single dose of 6 g tyropanoate or 12 g ipodate. An increase in serum radioactivity and free T4 levels along with a fall in hepatic radioactivity was observed with both OCAs, although less significant after ipodate.

Effects of OCA on protein binding of thyroid hormones. OCAs cause displacement of T3 and T4 from their protein binding sites. This was first described in 1964 when a rise in the 131I-labeled triiodothyronine red cell uptake test was noted (23). This in vitro test is based on the uptake of labeled T3 by erythrocytes, which serve as a binding surface. The rise in 131I uptake was presumed to reflect a higher amount of circulating free hormone due to inhibition of T3 binding to serum proteins. Braverman et al. (24) reported small T3 uptake increases after a single dose of ipodate (3 g) in most, but not all patients using other adsorbents such as resins and charcoal. Another study showed that the displacement of thyroid hormone from binding to albumin is minimal after 3–4 g ipodate, although a more significant displacement may be observed after higher doses of ipodate (12 g). In vitro, at a 10-3 M concentration, ipodate induced a 62% displacement, whereas iopanoic acid was responsible for a 55% displacement and tyropanoate for 45% (25).

Effects on other routes of iodothyronine metabolism. Although deiodination is the predominant route for thyroid hormone metabolism (80%), reactions such as sulfation, deamination, and decarboxylation are also important. Sulfation of iodothyronines is described as a process that facilitates deiodination, although the clinical significance of the sulfate derivatives of iodothyronines is yet unknown (26). Chopra et al. (27) showed that ipodate administration increased serum T3 sulfate (3 g, single dose), T4 sulfate (28) (3 g, single dose), and rT3 sulfate (29) (1 g/day) in hyperthyroid patients, although the mechanism is not clear.

Clinical uses

Hyperthyroidism due to Graves’ disease. In contrast to what has been observed in normal subjects, hyperthyroid patients given a single 3-g dose of ipodate showed a more marked reduction in T3 levels 8 h after ipodate, with a nadir at 48 h (decreasing to 70% of baseline level), which remained below baseline levels for 1 week. rT3 showed a striking increase (410%) 24 h after ipodate. Surprisingly, serum T4 levels decreased by 24% 3 days after ipodate, opposite to what occurred in euthyroid and hypothyroid patients, probably through direct inhibition of hormone release by the thyroid gland (17).

When given as short-term treatment (18–21 days) in patients with Graves’ disease, serum T3 and T4 showed a rapid reduction after ipodate or iopanoic acid (30, 31, 32). Because T3 levels remained decreased for up to 5 days after a single dose of ipodate (17), one would expect maintenance of decreased levels with repeated administration. In fact, when a dose of 3 g was given every third day for 12 days, serum T3 was maintained at low levels, with a slow rise toward baseline levels 3 days after withdrawal of the agent (30). Subsequent studies showed that a smaller daily dose of 1 g was as effective as 3 g given every third day (32). In parallel with changes in the hormone profile, clinical signs and symptoms of hyperthyroidism also improved, evidenced by a rise in body weight and a decrease in resting pulse rate and pulse pressure (31). Other studies showed that the administration of ipodate or iopanoic acid at a daily dose of 500 mg was as effective as a dose of 1 g/day in restoring T3 and T4 levels to normal (33, 34). However, lower doses of 500 mg every other day showed a high rate of relapse (35). These early data suggested the possibility that ipodate may have an important role in the management of hyperthyroidism.

Ipodate has been compared with other antithyroid drugs in several studies. After 21 days of therapy, patients treated with ipodate (1 g/day) showed a significantly more rapid decrease in serum T3 and T4 levels compared with propylthiouracil (PTU; 600 mg/day) (31). It was also shown to be effective as an adjunctive therapy when given with other antithyroid drugs, by promoting a more rapid decrease in T3 levels and pulse rate. This was observed when sodium ipodate was added to methimazole and was compared with either methimazole alone or methimazole plus saturated solution of potassium iodide (36) (Figs. 2Go and 3Go). Similar results were observed when patients treated with PTU plus propranolol were given sodium ipodate (1 g daily) for 6–13 days vs. patients who were only given PTU plus propranolol (37).



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  		Figure 2. Effects of methimazole (MMI) (•), MMI plus ipodate ({blacksquare}), and MMI plus SSKI ({blacktriangleup}) on serum T4 and T3 (36 ).

 


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  		Figure 3. Effects of methimazole (MMI) (•), MMI plus ipodate ({blacksquare}), and MMI plus saurated solution of potassium iodide ({blacktriangleup}) on heart rate (36 ).

 
With OCA metabolism, large amounts of inorganic iodine are released into the circulation, reflected by increased serum total and inorganic iodine content (1082 ± 114 and 110 ± 43 µg/dL, respectively) in four patients treated with ipodate 500 mg/day (33) and by increased urinary iodine excretion (38). However, the suppressive effects of iodine on thyroid hormone synthesis (the Wolff-Chaikoff effect) and release may be attenuated by a subsequent escape phenomenon. This phenomenon is well known in patients with Graves’ disease that are treated with iodine (39). Among 40 patients treated with iopanoic acid (500 mg/day) for up to 1 yr, 22 patients were classified as having a poor response to the treatment. Eighteen of them had an initial improvement that was followed by an exacerbation of hyperthyroidism during the first 6 months of treatment. Fifteen percent (6 of 40) were classified as having an excellent response and 30% (12 of 40) were classified as having a partial improvement in their hyperthyroidism when followed for up to 7–12 months (34) (Fig. 4Go). In reviewing the data from this study, it appears that patients with higher baseline serum T3 values and larger goiters were less likely to respond favorably to iopanoic acid, although formal statistical testing was not performed by the authors. Martino et al. (38) described different responses to long-term treatment with 500 mg/day sodium ipodate as follows: among 12 patients, 5 (42%) showed sustained remission for 22 months during therapy, whereas in 7 patients (58%) recurrence of hyperthyroidism was observed as early as 14 days of treatment. Furthermore, some patients may also develop resistance to antithyroid drug therapy after long-term treatment with OCAs (15–30 days), possibly related to high intrathyroidal iodine levels (38, 40).



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  		Figure 4. Mean serum T3, T4, and free T4 concentrations at monthly intervals in groups A (6 patients, excellent control of hyperthyroidism to iopanoic acid treatment), group B (12 patients, partial response, one of the thyroid hormones did not reach normal range during therapy), and group C (22 patients, no response to iopanoic acid) (34 ).

 
Low levels of inorganic iodine (10–12 µg/dL) were found in the serum from 2 patients 7–21 days after discontinuation of ipodate therapy (33). A partial or complete recovery of 24-h radioiodine uptake is seen if the measurement is performed 1–4 weeks after treatment cessation, which would allow radioactive iodine treatment (32, 33). However, long-term efficacy data in patients treated with radioactive iodine after OCAs are not available.

Antithyroid antibody titers have been measured before and after OCA treatment in patients with Graves’ disease in a few studies. In general, no immunomodulatory properties have been observed with these compounds (34, 40). Martino et al. (38) measured TSH receptor antibodies when studying patients during long-term treatment with ipodate. Of 12 patients, 5 became euthyroid during treatment, and in one of them thyrotropin receptor antibody became negative, whereas the other 7 patients relapsed after 14 days of therapy, and no changes in thyrotropin receptor antibody levels were observed in this group.

Cardiovascular parameters were monitored with a Swan-Ganz catheter in 5 hyperthyroid patients with heart failure (functional class II to III) treated with 45 mg/day methimazole and a single 3-g dose of ipodate (41). A significant decrease in systolic pressure and pulse pressure was observed 24 h after ipodate. Heart rate decreased from a mean of 132 ± 8 beats/min to 110 beats/min, cardiac index fell 36.7% 12 h after ipodate, and a near normalization of stroke volume and total systemic resistance was noted. Although left ventricular work improved progressively, right ventricular work remained normal, and no significant changes were observed for left ventricular ejection fraction, pulmonary resistance, and right atrial, pulmonary artery, and pulmonary wedge pressures. T3 levels decreased in parallel with all improvements by 67% after 24 h.

Other uses of OCAs in hyperthyroidism (Table 2Go)

Preoperative preparation. Conventional preparation with iodine compounds and antithyroid drugs usually takes 4–6 weeks to achieve a euthyroid state. Baeza et al. (42) reported a rapid method of preparing patients using iopanoic acid (500 mg every 6 h), along with betamethasone (0.5 mg every 6 h) and propranolol (40 mg every 8 h). After 5 days, the 14 patients involved in the study had a 70% reduction in pulse rate with normalization of serum T3 levels. There were no surgical complications, and on gross examination the appearance of the thyroid resembled glands that had been treated with iodine. Other studies showed that for preoperative preparation, sodium ipodate (500 mg, twice daily) in combination with PTU and beta-blockers in 14 patients (43) or 500 mg daily in 7 patients (44) significantly reduced T3 and free T4 levels within 3–4 days. Using these regimens, all reported patients did well perioperatively, apart from one patient who had persistent tachycardia and required beta-blockers (43).


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  		Table 2. Potential uses of OCAs in hyperthyroidism

 
Allergy to antithyroid drugs. When conventional agents are contraindicated due to allergy or side effects, OCAs may be used as a short-term treatment to rapidly control hyperthyroidism or to prepare for definitive treatment with surgery. A 3-yr-old patient with Graves’ disease was treated with ipodate (500 mg every other day) to prepare for subtotal thyroidectomy after urticaria developed on PTU treatment; however, recurrence of clinical signs and a rise in T3 and T4 levels was observed after 12 days of treatment (45). Radioactive iodine therapy may also be possible, as thyroidal radioiodine recovery of uptake can be seen as early as 2 weeks after withdrawal (32).

Levothyroxine overdose. The potent inhibition of 5'deiodinase, resulting in decreased conversion of T4 to T3, makes OCAs a potentially effective therapy for the treatment of accidental levothyroxine overdose (thyroid hormone poisoning) (46, 47). Iopanoic acid was used to treat a 2-yr-old child with accidental ingestion of a unknown dose of levothyroxine, who had severe agitation, fever, and tachycardia. Iopanoic acid therapy (125 mg daily) achieved rapid amelioration of clinical and hormonal parameters. When the daily dose was omitted by mistake, a clinical exacerbation was observed, suggesting that clinically significant control of the thyrotoxicosis was being achieved with the drug (48). Suspected thyrotoxicosis factitia may also be controlled with OCA. Long-term (1 yr) administration of iopanoic acid (1 g/day or 2 g three times a week) was effective in reducing T3 levels to 50% percent of pretreatment levels in a patient presumed to be taking levothyroxine 0.5 mg/day (49).

Thyrotoxicosis following subacute thyroiditis. Thyroidal inflammation in subacute thyroiditis causes leakage of preformed hormone into the blood stream. The only effective treatments available are beta-blockers to treat cardiovascular symptoms, and nonsteroidal anti-inflammatory drugs or steroids to decrease inflammation. Sodium ipodate has been demonstrated to be useful in treating clinical symptoms of thyrotoxicosis in five patients with subacute thyroiditis at a dose of 0.5 g daily or every other day (50). The OCAs may also be useful in treating thyrotoxicosis due to other forms of thyroiditis, including silent thyroiditis, and amiodarone-induced thyroiditis although further studies are necessary.

Neonatal hyperthyroidism. Neonatal hyperthyroidism resulting from transplacental crossing of thyroid stimulating immunoglobulins from mothers with Graves’ disease has traditionally been managed with antithyroid drugs and beta-adrenergic blocking drugs. Karpman et al. (51) administered ipodate 0.5 g every 3 days for 21 days and 1 g every 3 days for 39 days as an alternative therapy to treat a newborn with severe hyperthyroidism, and observed a rapid decrease of T3 and T4 levels along with a clinical improvement (weight gain, infant’s ability to feed). No side effects were noted, and the child on his last examination at 15 months had normal development. Similar results were also obtained in another hyperthyroid newborn with PTU, propranolol, and ipodate (250 mg) on the first day, followed by 125 mg daily (0.6 g/m2·day). An improvement in congestive heart failure and reduction in goiter size was rapidly observed (52). Iopanoic acid (500 mg every third day) for 60 days proved to be as effective as ipodate (53).

Adverse reactions

Most studies of short- or long-term treatment with OCAs have not shown any adverse effects. Periodic blood tests (complete blood count, electrolytes, hepatic and renal function) performed during and after treatment have been normal (33).

Minor adverse effects. Some minor adverse reactions have been described in patients when given OCAs for the purpose of cholecystography. This probably is related to administration of a higher dose, which is necessary for an adequate visualization of the gallbladder. Although most patients (62.5%) reported no adverse effects, gastrointestinal complaints were most commonly seen in 400 patients after a single dose of 3 g iopanoic acid (54). These adverse effects included diarrhea (25.3%), mild nausea (5.8%), and vomiting (0.5%). Other minor side effects, such as dysuria, were reported in 13.7% of the subjects.

Major adverse effects. Acute renal failure has been described in rare patients receiving OCAs for imaging in the presence of preexisting renal and/or liver disease. For cholecystography, the average dose of OCAs is 3 g, and it was a common practice to repeat the dose if visualization of gallbladder was inadequate. Renal failure has occurred in healthy patients, as well as those with hepatic/renal disease, who received single doses higher than 6 g. The mechanisms by which OCAs lead to renal damage are not clear. However, direct tubular toxicity, a decrease in glomerular filtration rate, and obstructive renal failure caused by crystal deposition in renal tubules [OCAs have uricosuric properties (55)] have all been implicated (56, 57, 58, 59, 60). One case each of thrombocytopenia and athrombocytosis after iopanoic acid have also been reported with doses ranging from 500 mg to 3 g, with complete recovery after prednisone therapy (61, 62). Dehydration may be a relative contraindication for OCA therapy because of an increased risk of renal dysfunction.

Pregnancy

No clinical trials assessing the safety of OCAs in pregnancy have been conducted. However, three pregnant women have been treated for a short time during the second trimester in preparation for thyroidectomy without any side effects. These women delivered babies with normal weight and without any chemical or laboratory abnormalities suggesting thyroid dysfunction (42).

To our knowledge, there have been no long-term animal studies with OCAs examining the potential effects on carcinogenicity or mutagenicity.

Breast-feeding

Iopanoic acid is distributed in breast milk in an insignificant amount (63). Although breast-fed infants have not shown any adverse reaction to this compound, it is not advised for nursing mothers. The excretion of sodium ipodate in breast milk is unknown (64).


   Summary and Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Summary and Conclusions
References
 
OCAs may be useful as initial therapy in thyrotoxicosis from any cause, including levothyroxine poisoning, when a rapid decrease in T3 levels is desired. Some studies have suggested an early escape from the effect of OCAs during long-term treatment, but other studies did not find this to be the case for up to 22 months of OCA therapy. Also, the combination of OCAs and antithyroid drugs may cause resistance later on, according to some reports, presumably because of the enhanced iodine concentration within the gland. Use of OCAs should be reserved for those patients with severe hyperthyroidism or thyroid storm, or who have significant comorbidity (e.g. myocardial infarction, sepsis, stroke). OCAs may be useful as preparation for surgery, and in other rare circumstances. Further research in hyperthyroid patients is still needed. At this time, iopanoic acid is the only OCA still marketed in the United States, raising concern about the continued availability of this useful class of drugs (65).

Received October 24, 2000.

Revised January 24, 2001.

Accepted February 5, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Summary and Conclusions
 References
 

  1. Burgi H, Winpfheimer C, Buerger A, Zaunbauer W, Rosler H, Lemarchand-Beraud T. 1976 Changes of circulating thyroxine, triiodothyronine, and reverse triiodothyronine after radiocontrast agents. J Clin Endocrinol Metab. 43:1203–1210.[Abstract]
  2. Berk RN, Loeb PM, Goldberger LE, Sokoloff J. 1974 Oral cholecystography with iopanoic acid. N Engl J Med. 24:204–210.
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