Dr. Ron’s Research Review – January 30, 2019

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This week’s research review focuses on lithium and iodine for thyrotoxicosis

A study compared the relative therapeutic efficacy of iodine (I) and lithium (Li) in thyrotoxicosis, investigate possible additive effects of these agents, and examine their effect upon thyroidal release. 17 thyrotoxic patients were assigned to groups given either I (n = 9) or Li (n = 8) alone during an initial treatment period, with the alternate drug added as combination treatment during a second treatment period. Half of the patients received methimazole (MMI). Three additional thyrotoxic patients received I during both treatment periods to evaluate the possibility of cumulative I effect upon thyroidal release during the second treatment period. During the first treatment period either I or Li induced comparable, significant (P < 0.05) decreases in thyroidal release. In response to Li, there was a 55% decrease in the slope of PB125I: PB131I with MMI and a 52% decrease without MMI. In response to I, there was a 70% decrease in the slope of PB125I : PB131I with MMI and a 57% decrease without MMI. Further significant (P < 0.05) decreases in the slopes of these ratios during the second, combined treatment period (I + Li) occurred only in those patients who had initially received I. No further decreases in the second treatment period were seen in patients receiving I during both treatment periods. Thus, I and Li together display additive inhibition of thyroidal release only if I is administered initially, but the combination, if Li is used first, does not appear to be more effective than Li alone. (Boehm et al., 1980)

A study investigated the clinical characteristics of childhood thyrotoxicosis and effectiveness of inorganic iodide in the early phase of treatment.  Sixty-seven pediatric patients (53 girls/14 boys, 11.1±3.4 years of age), with newly diagnosed thyrotoxicosis due to Graves disease were recruited. Forty-nine patients were treated with antithyroid drugs alone, while 18 patients were treated with combination of antithyroid drugs and potassium iodide. Mean triiodothyronine and free thyroxine levels were significantly lower (P<0.05) in the group receiving combined therapy of antithyroid drugs and potassium iodide after 2 weeks of treatment compared to the patients receiving antithyroid drugs alone. Eight weeks after the initiation of treatment, thyroid function tests in the two groups did not show significant differences. The use of potassium iodide in combination with antithyroid drug is effective for more rapid normalization of thyroid hormones in the early phase treatment of childhood thyrotoxicosis. (Jeong et al., 2014)

A 67-year-old woman was admitted with signs and symptoms of Graves thyrotoxicosis. Biochemistry results were as follows: TSH was undetectable; FT4 was >6.99 ng/dL (0.7-1.8); FT3 was 18 pg/mL (3-5); TSI was 658% (0-139). Thyroid uptake and scan showed diffusely increased tracer uptake in the thyroid gland. The patient was started on methimazole 40 mg BID, but her LFTs elevated precipitously with features of fulminant hepatitis. Methimazole was determined to be the cause and was stopped. After weighing pros and cons, lithium was initiated to treat her persistent thyrotoxicosis. Lithium 300 mg was given daily with a goal to maintain between 0.4 and 0.6. High dose Hydrocortisone and propranolol were also administered concomitantly. Free thyroid hormone levels decreased and the patient reached a biochemical and clinical euthyroid state in about 8 days. Though definitive RAI was planned, the patient has been maintained on lithium for more than a month to control her hyperthyroidism. Trial removal of lithium results in reemergence of thyrotoxicosis within 24 hours. Patient was maintained on low dose lithium treatment with lithium level just below therapeutic range which was sufficient to maintain euthyroid state for more than a month. There were no signs of lithium toxicity within this time period. Conclusion. Lithium has a unique physiologic profile and can be used to treat thyrotoxicosis when thionamides cannot be used while awaiting elective radioablation. Lithium levels need to be monitored; however, levels even at subtherapeutic range may be sufficient to treat thyrotoxicosis. (Prakash et al., 2015)

A study compared methimazole (MMI) treatment with MMI + potassium iodide (KI) treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission. A total of 134 untreated patients with Graves' disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4- to 5-year observation. Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb-ELISA. Goitre size was estimated by ultrasonography. RESULTS:  After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P < 0.05) of patients in Group 2. Furthermore, normal FT4 after 2 weeks of treatment was observed in 27% of patients in Group 3 and 54% (P < 0.05) of patients in Group 4. Similarly, FT3 normalized more rapidly in Groups 2 and 4 than in Groups 1 and 3. None of the patients showed an increase in thyroid hormones or aggravation of disease during combined treatment with MMI and KI. The remission rates in Groups 1, 2, 3 and 4 were 34%, 44%, 33% and 51%, respectively, and were higher in the groups receiving combined therapy but differences among four groups did not reach significance. Combined treatment with MMI and KI improved the short-term control of Graves' hyperthyroidism and was not associated with worsening hyperthyroidism or induction of thionamide resistance. (Takata et al., 2010)

Thirty-eight normal volunteers and 10 patients with untreated thyrotoxicosis were each given 0.5 ml of Lugol's solution daily for 10 days. On days 0, 5, 10, 15 and 20, serum levels of T4, free T4, T3 and TSH (by sensitive immunoradiometric assay) were measured. In normal subjects, the serum concentrations of free T4 declined significantly at day 10 while TSH levels were significantly increased at days 5, 10 and 15. Serum levels of T4 and T3 did not change significantly. All the observed changes took place within the limits of normal ranges for the hormones mentioned. In contrast, in the thyrotoxic subjects, both T4 and T3 were significantly decreased at days 5 and 10, while serum TSH remained below detection limit (0.14 mU/l) throughout the study. Short exposure to excessive iodide in normal subjects affects T4 and T3 release and this effect could be partially overcome by compensatory increase in TSH. In thyrotoxicosis, lack of compensatory increase in TSH results in rapid decreases in T4 and T3 levels. The integrity of the hypothalamo-pituitary-thyroidal axis may be effectively assessed by measuring TSH response to iodide suppression, using a highly sensitive immunoradiometric assay. (Tan et al., 1989)

Dr. Ron

 


Articles

 

Lithium and iodine combination therapy for thyrotoxicosis.
            (Boehm et al., 1980)  Download
In order to compare the relative therapeutic efficacy of iodine (I) and lithium (Li) in thyrotoxicosis, investigate possible additive effects of these agents, and examine their effect upon thyroidal release, 17 thyrotoxic patients were assigned to groups given either I (n = 9) or Li (n = 8) alone during an initial treatment period, with the alternate drug added as combination treatment during a second treatment period. Half of the patients received methimazole (MMI). Three additional thyrotoxic patients received I during both treatment periods to evaluate the possibility of cumulative I effect upon thyroidal release during the second treatment period. A double isotope technique was utilized as an index of thyroidal release, employing 125I as an intrathyroidal label and [131I]T4 as a marker of T4 disposal. During the first treatment period either I or Li induced comparable, significant (P < 0.05) decreases in thyroidal release, as measured by slopes of ratios of serum PB125I:PB131I and by percentage inhibition of fractional T4 release rate. In response to Li, there was a 55% decrease in the slope of PB125I: PB131I with MMI and a 52% decrease without MMI. In response to I, there was a 70% decrease in the slope of PB125I : PB131I with MMI and a 57% decrease without MMI. Further significant (P < 0.05) decreases in the slopes of these ratios during the second, combined treatment period (I + Li) occurred only in those patients who had initially received I. No further decreases in the second treatment period were seen in patients receiving I during both treatment periods. Thus, I and Li together display additive inhibition of thyroidal release only if I is administered initially, but the combination, if Li is used first, does not appear to be more effective than Li alone.

Effects of short-term potassium iodide treatment for thyrotoxicosis due to Graves disease in children and adolescents.
            (Jeong et al., 2014)  Download
PURPOSE:  Graves disease is the most common cause of hyperthyroidism in children. Inorganic iodide has been used in combination with antithyroid drugs for more effective normalization of thyroid hormones in some cases of severe thyrotoxicosis. This study aimed to investigate clinical characteristics of childhood thyrotoxicosis and effectiveness of inorganic iodide in the early phase of treatment. METHODS:  Sixty-seven pediatric patients (53 girls/14 boys, 11.1±3.4 years of age), with newly diagnosed thyrotoxicosis due to Graves disease were recruited. Forty-nine patients were treated with antithyroid drugs alone, while 18 patients were treated with combination of antithyroid drugs and potassium iodide. Initial thyroid function tests and levels of thyroid antibodies were recorded for all patients. Thyroid function tests were repeated 2 and 8 weeks after the initiation of treatment. Measurement thyroid antibodies were done 8 weeks after the initiation of treatment. RESULTS:  Mean triiodothyronine and free thyroxine levels were significantly lower (P<0.05) in the group receiving combined therapy of antithyroid drugs and potassium iodide after 2 weeks of treatment compared to the patients receiving antithyroid drugs alone. Eight weeks after the initiation of treatment, thyroid function tests in the two groups did not show significant differences. CONCLUSION:  The use of potassium iodide in combination with antithyroid drug is effective for more rapid normalization of thyroid hormones in the early phase treatment of childhood thyrotoxicosis, but larger studies with adequate power are needed in future.

Lithium as an Alternative Option in Graves Thyrotoxicosis.
            (Prakash et al., 2015)  Download
A 67-year-old woman was admitted with signs and symptoms of Graves thyrotoxicosis. Biochemistry results were as follows: TSH was undetectable; FT4 was >6.99 ng/dL (0.7-1.8); FT3 was 18 pg/mL (3-5); TSI was 658% (0-139). Thyroid uptake and scan showed diffusely increased tracer uptake in the thyroid gland. The patient was started on methimazole 40 mg BID, but her LFTs elevated precipitously with features of fulminant hepatitis. Methimazole was determined to be the cause and was stopped. After weighing pros and cons, lithium was initiated to treat her persistent thyrotoxicosis. Lithium 300 mg was given daily with a goal to maintain between 0.4 and 0.6. High dose Hydrocortisone and propranolol were also administered concomitantly. Free thyroid hormone levels decreased and the patient reached a biochemical and clinical euthyroid state in about 8 days. Though definitive RAI was planned, the patient has been maintained on lithium for more than a month to control her hyperthyroidism. Trial removal of lithium results in reemergence of thyrotoxicosis within 24 hours. Patient was maintained on low dose lithium treatment with lithium level just below therapeutic range which was sufficient to maintain euthyroid state for more than a month. There were no signs of lithium toxicity within this time period. Conclusion. Lithium has a unique physiologic profile and can be used to treat thyrotoxicosis when thionamides cannot be used while awaiting elective radioablation. Lithium levels need to be monitored; however, levels even at subtherapeutic range may be sufficient to treat thyrotoxicosis.

Benefit of short-term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves' disease.
            (Takata et al., 2010)  Download
OBJECTIVE:  Combined treatment with anti-thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves' disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission. DESIGN AND PATIENTS:  A total of 134 untreated patients with Graves' disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4- to 5-year observation. MEASUREMENTS:  Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb-ELISA. Goitre size was estimated by ultrasonography. RESULTS:  After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P < 0.05) of patients in Group 2. Furthermore, normal FT4 after 2 weeks of treatment was observed in 27% of patients in Group 3 and 54% (P < 0.05) of patients in Group 4. Similarly, FT3 normalized more rapidly in Groups 2 and 4 than in Groups 1 and 3. None of the patients showed an increase in thyroid hormones or aggravation of disease during combined treatment with MMI and KI. The remission rates in Groups 1, 2, 3 and 4 were 34%, 44%, 33% and 51%, respectively, and were higher in the groups receiving combined therapy but differences among four groups did not reach significance. CONCLUSIONS:  Combined treatment with MMI and KI improved the short-term control of Graves' hyperthyroidism and was not associated with worsening hyperthyroidism or induction of thionamide resistance.

Effects of Lugol's solution on thyroid function in normals and patients with untreated thyrotoxicosis.
            (Tan et al., 1989)  Download
Thirty-eight normal volunteers and 10 patients with untreated thyrotoxicosis were each given 0.5 ml of Lugol's solution daily for 10 days. On days 0, 5, 10, 15 and 20, serum levels of T4, free T4, T3 and TSH (by sensitive immunoradiometric assay) were measured. In normal subjects, the serum concentrations of free T4 declined significantly at day 10 while TSH levels were significantly increased at days 5, 10 and 15. Serum levels of T4 and T3 did not change significantly. All the observed changes took place within the limits of normal ranges for the hormones mentioned. In contrast, in the thyrotoxic subjects, both T4 and T3 were significantly decreased at days 5 and 10, while serum TSH remained below detection limit (0.14 mU/l) throughout the study. Short exposure to excessive iodide in normal subjects affects T4 and T3 release and this effect could be partially overcome by compensatory increase in TSH. In thyrotoxicosis, lack of compensatory increase in TSH results in rapid decreases in T4 and T3 levels. The integrity of the hypothalamo-pituitary-thyroidal axis may be effectively assessed by measuring TSH response to iodide suppression, using a highly sensitive immunoradiometric assay.

 

References

Boehm, TM, et al. (1980), ‘Lithium and iodine combination therapy for thyrotoxicosis.’, Acta Endocrinol (Copenh), 94 (2), 174-83. PubMed: 7415757
Jeong, KU, HS Lee, and JS Hwang (2014), ‘Effects of short-term potassium iodide treatment for thyrotoxicosis due to Graves disease in children and adolescents.’, Ann Pediatr Endocrinol Metab, 19 (4), 197-201. PubMed: 25654065
Prakash, I, ES Nylen, and S Sen (2015), ‘Lithium as an Alternative Option in Graves Thyrotoxicosis.’, Case Rep Endocrinol, 2015 869343. PubMed: 26425375
Takata, K, et al. (2010), ‘Benefit of short-term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves’ disease.’, Clin Endocrinol (Oxf), 72 (6), 845-50. PubMed: 19912243
Tan, TT, et al. (1989), ‘Effects of Lugol’s solution on thyroid function in normals and patients with untreated thyrotoxicosis.’, Clin Endocrinol (Oxf), 30 (6), 645-49. PubMed: 2591064