Use of Lithium/ Iodine Combination for Grave’s Disease

Use of Lithium/ Iodine Combination for Grave’s Disease

by Jeffrey Dach MD

In this article, we will present the case for combined use of Lithium carbonate and Iodine for treatment of Graves Autoimmune hyperthyroidism. Header Image Thyroid Gland Microscopic View of Graves Disease Courtesy of WIkimedia Commons.

Lithium for Manic Depression

Lithium Carbonate has been used as a psychiatric drug to treat manic depression for well over a hundred years. Similar to Iodine, Lithium is actively concentrated within the thyroid cells to acheive a concentration three to four times higher than that of plasma. This is accomplished by the Sodium/Iodide Symporter, the active transport mechanism for Iodine, which also concentrates Lithium.(1-2)

Lithium Blocks Thyroid Hormone Synthesis and Release

Lithium blocks thyroid hormone synthesis and release. Lithium also improves the retention of iodine by the thyroid gland. In 2020, Dr. Czarnywojtek writes the properties of Lithium make it ideal as an adjunct for radioactive iodine therapy with I-131:

[Lithium salts] inhibit the formation of colloid in thyrocytes, change the structure of thyroglobulin, weaken the iodination of tyrosines, and disrupt their coupling… Moreover, lithium strengthens the retention of I-131 in the thyroid gland, which effectively prevents transient exacerbation of hyperthyroidism (due to the discontinuation of antithyroid medications and the administration of I-131)…the use of lithium adjuvant therapy enables to obtain the most satisfactory effects in I-131 therapy and potentially facilitates the treatment of thyrotoxicosis (prior to I-131 therapy)…An additional benefit is the use of adjuvant lithium therapy to increase the iodine uptake of the thyroid gland, which allows to obtain satisfactory results in treatment with radioactive iodine and potentially facilitates the treatment of thyrotoxicosis. In addition, because of the numerous side effects of lithium and its narrow therapeutic index, its concentration in the blood must be constantly monitored. Emphasis Mine (2)

As mentioned above, Lithium increases the retention of iodine in the thyroid, a useful feature when used in combination with Iodine, preventing the iodine escape phenomenon, the escape from the inhibitory effects of iodine.

Jonathan Wright MD – Success with Lithium Iodine Combination

Jonathan Wright MD, a legendary pioneer in natural medicine, found success with the combination of Lithium and Iodine for the long-term treatment of Graves’. Dr. Wright writes:

I have my patients use five drops of Lugol’s iodine three times a day for two or three days. (90-100 mg/day) Then I have them add 300 milligrams of lithium carbonate three times a day in addition to the Lugol’s Solution … (3) quoted from Dr Jonathan Wright.

In 1972, Dr. R Temple at the Mayo Clinic published the first clinical investigation of lithium treatment for Graves’ disease. Using high-dose lithium for 10 individuals, they reported that thyroid hormone levels fell by 20-30 percent within five days.  Twenty-six years later, in a review of more than 10 successful trials of lithium therapy for Graves’ disease, the authors wrote:

a small number of studies have documented [lithium’s] use in the treatment of patients with Graves’ disease… it’s efficacy and utility as an alternative anti-thyroid [treatment] are not widely recognized…Lithium normalizes [thyroid hormone] levels in one to two weeks…toxicity precludes its use as a first-line or long-term therapeutic agent…(4)

But if they had just added flaxseed oil and vitamin E to their treatment, they would have basically eliminated the risk of toxicity.  In fact, every individual (except one) whom I’ve (Dr. Wright) treated with iodine-iodide (in the form of Lugol’s Solution) and high dose lithium has had blood tests for thyroid hormone return to normal within two weeks. Their tests then stay normal as long as they use the Lugol’s solution and high dose lithium. (3-4) end quote Dr. Jonathan Wright.

Comparing Iodine and Lithium for Thyrotoxicosis

In 1980, Dr. T. M. Boehm and Wartofsky at Walter Reed Army Hospital compared the relative efficacy of iodine and lithium in 17 patients with thyrotoxicosis. Half the patients also received methimazole (MMI).  Further studies using radiolabeled Iodine-125 provided an index of thyroid hormone release from the thyroid gland. I-131 Radiolabeled T4 was used as a marker of the T4 disposal, or degradation by the liver. The slope of the ratio of I-125/I-131 in the serum indicated the per cent inhibition of T4 release from the thyroid gland.(5)

The Iodine and Lithium treatments induced a similar reduction in T4 thyroidal release.  The combination of Iodine and Lithium showed an additive inhibition on T4 release only if Iodine was started first, and then Lithium added a few days later.  This explains why Dr Wright’s protocol starts the Iodine first.

Treatment with Lithium caused a similar reduction in T4 thyroidal release with or without MMI.  The MMI had no additive effect when combined with Lithium.

When MMI was combined with Iodine, there was a more profound reduction indicating an additive effect of Iodine with MMI. This additive effect of combining Iodine with Methimazole was used in 2022 by Dr. Okamura in treatment of 504 Graves disease patients with Potassium Iodide alone.  The problem of Iodine resistant or “escaped” patients was solved by adding methimazole 5-15 mg per day in combination with the potassium iodine 100 mg per day, with good control of the hyperthyroidism.(5-6)

Methimazole Mechanism of Action

When compared to Iodine or Lithium, Methimazole has a different mechanism of action, irreversibly blocking the TPO enzyme responsible for iodination of thyroglobulin, thus blocking hormone synthesis. In 2005, Dr. Cooper writes:

MMI [Methimazole] inhibits thyroid hormone synthesis by preventing the iodination of tyrosine residues in thyroglobulin by thyroid peroxidase. (7)

Kinetic Studies of Lithium in Graves Disease

In 1972, Dr. R.M. Temple studied the use of Lithium to treat thyrotoxicosis, performing I-131 kinetic studies in seven thyrotoxic women with Lithium levels of 1 mEq/L.  Dr Temple found Lithium treatment “inhibited hormonal and nonhormonal thyroid iodine release,” while methimazole did not inhibit release.  Dr. Temple writes that Lithium and Iodine have a similar mechanism of action, and felt that for prolonged therapy, Lithium must be combined with methimazole.  He writes:

Neither inhibition of release nor hormone disappearance seemed affected by methimazole (Release: 52% decrease without methimazole, 60% with methimazole; hormone disappearance: approximately 60% decrease in both)…For prolonged therapy, therefore, a thiocarbamide drug [methimazole or propylthiouracil] must be used in conjunction with Lithium. The similarity of inhibition of iodine release from the thyroid produced by Lithium and iodides is discussed. (4)

Lithium Alone for Long Term Control of Graves Thyrotoxicosis

In 1974, Dr. J. Lazarus used Lithium as sole therapy for six months in eleven thyrotoxic Graves’ Disease patients. All had long-standing severe disease (mean duration five and a half years) with characteristic relapsing, remitting course. Eight of the eleven were clinically euthyroid after 2 weeks of Lithium treatment and remained so for the 6 months of the study. Dr. J. Lazarus comments that there was “no iodide type escape phenomenon even after 6 months.” This is an obvious advantage over Iodine alone therapy which is limited to short term use because of the escape phenomenon. Dr. J. Lazarus writes:

This study has shown that an adequate dosage of lithium is effective in rapidly producing a euthyroid state in a thyrotoxic patient. Lithium administration maintained the euthyroid state for the duration of therapy but clearly had no significant effect on Graves’ disease [The auto-immune component] itself in this group of patients. However, all these patients had long-standing severe disease (mean duration five and a half years) characterized by several relapses and remissions.  In the present study there was no iodide type escape phenomenon even after 6 months… It [Lithium] seems to be as effective as iodide in blocking hormone release … Its use is therefore indicated in cases of hyperthyroidism in which it is necessary to reduce hormone levels very rapidly, especially if the patient is sensitive to iodides…Also, lithium could be administered for longer than 2 weeks with no danger of an escape phenomenon as seen with iodides…This study has shown that the therapeutic effect depends on the serum level, which is readily and easily measured. In general, side effects are few and rapidly disappear once the patient is stabilized on therapy. Nevertheless, lithium does have toxic effects and should not be administered when renal function is impaired or serum-electrolytes are abnormal. (8)

Comparing Lithium to Methimazole – No Significant Difference

In 1976, Dr. Kristensen compared the use of Lithium to the use of Methimazole in 24 patients with newly diagnosed Graves thyrotoxicosis. 13 were treated with Methimazole alone 40 mg/d and 11 with Lithium Carbonate alone rendering a serum level of 0.5 to 1.3 mEq/L.  Dr. Kristensen found a similar reduction in Free T4 levels for both treatment modalities.  However, the Lithium treated patients had more side effect. He writes:

The lithium treatment brought about a fall in serum-thyroxine iodine (T4I) of 27.0%, and in the free-thyroxine index (F.T.I.) of 38.1% after 10 days. A comparison of the two patient groups with regard to the fall in F.T.I. after 3 and 10 days showed no statistically significant difference; similarly, the calculated confidence limits appeared to exclude any difference of clinical importance. 8 of the 11 patients subjected to lithium treatment had side-effects, so that the general condition, which was already affected by the hyperthyroidism, was worsened. It is concluded that lithium cannot be considered superior to thiocarbamides [Methimazole] for the rapid control of thyrotoxicosis.(9) Emphasis Mine

How to Avoid Lithium Side Effects

Most of the Lithium side effects can be prevented with Vitamin E, Flax Seed Oil and Vitamin B6 (pyridoxine, P-5-P version), and zinc. In 2004, Dr. Jonathan Wright made recommended to alleviate Lithium Toxicity  with use of the following supplements:

An initial dosage of flaxseed oil, one tablespoon (15ccs) three times daily, along with 800 IU of vitamin E (mixed tocopherols). Later dosage is reduced to flaxseed oil to one tablespoon daily along with 400 IU of vitamin E. (10-19)

Lithium Induced Hand Tremor

A common adverse effect of Lithium is hand tremor, which may be alleviated with addition of Vitamin B6. Make sure to use the P-5-P version of B6.  Lithium toxicity may be avoided with the use of Flax Seed Oil Essential Fatty Acids, and Vitamin E as mentioned above. (10-19)

Auto-Immune Thyroid Disease – Greater Sensitivity to Inhibitory Effect of Lithium and Iodine

In 1976, Dr. Kenneth Burman studied six euthyroid Graves’ Disease patients, all euthyroid for 11 months following treatment with radioactive iodine, and one patient euthyroid following medical treatment with methimazole.  The 7 euthyroid Graves Disease patients were given lithium carbonate 300 mg three times daily which maintained the serum lithium level between 0.5 and 1.0 mEq/L.  Dr. Berman comments that in normal healthy controls, lithium does not usually induce hypothyroidism. However, in the 7 euthyroid Graves patients, Lithium did cause hypothyroidism with reduction in Free T3 and Free T4 in all seven.

Dr Berman writes people with auto-immune thyroid disease are more sensitive to the inhibitory effects of either agent, lithium, or iodine, as their mechanism of action appears similar, producing hypothyroidism.  Euthyroid people (normal controls) however, seem to be resistance to this effect. In Dr Berman’s opinion, the beneficial effect of Lithium may be due its ability to increase the intrathyroidal iodine content, and this increased iodine may inhibit both thyroid hormone synthesis and release. If this is true, then this would explain why the Lithium /Iodine combination is so effective to control thyrotoxicosis. Dr Berman writes:

Recently it has become apparent that subjects with a history of thyroid abnormalities such as diffuse toxic goiter [Graves’ Disease] or Hashimoto’s thyroiditis may be extremely sensitive to the antithyroid effects of iodine even though they may be euthyroid prior to the administration of this drug…Lithium decreases hormonal synthesis and thyroidal secretion, but does not appear to affect iodine uptake. [i.e allows iodine uptake] Consequently, intrathyroidal iodine content may actually increase during lithium administration, and excessive quantities of intrathyroidal iodine may inhibit both thyroid hormone synthesis and release. The normal thyroid gland, however, will gradually overcome the inhibitory effects of iodine upon thyroid hormone synthesis and restore normal synthetic ability despite intrathyroidal iodine concentrations that remain elevated. Patients with diffuse toxic goiter [Graves’ Disease] may be unable to re-establish normal autoregulation of thyroidal iodine economy, possibly due to a defect in organic binding. As a result, there may be enhanced sensitivity for the development of hypothyroidism during treatment with either lithium or iodine… these observations support the thesis that the inhibitory effects of lithium and iodine upon thyroid hormone synthesis or secretion may involve a similar mechanism of action since increased thyroidal iodine content may be a consequence of therapy with either agent.(20)

Note the above comment, Lithium increases intrathyroidal iodine content.  This is advantageous for radioablation in the Graves’ Disease patient in which accumulation of radioactive iodine within the thyroid is desired for more effective treatment. This also explains the advantage of combined Lithium and Iodine treatment of Graves’ disease, as the Lithium makes the Iodine accumulate and retain within the thyroid gland with more effective inhibition of organification and thyroid hormone release.  In addition, this combination of Lithium and Iodine prevents the Iodine escape phenomenon with relapse of hyperthyroidism, also named the Jod-Basedow Phenomenon. (20-21)

Lithium for Radiographic Contrast and Amiodorone Thyrotoxicosis

In 1984, Dr. C. Wunsch studied the short-term combination of lithium and methimazole in hyperthyroidism induced by iodine containing radiographic contrast material finding Lithium effective without severe side effects. (22-25)

Lithium for Methimazole Failures

In 1998, Dr. Benbassat treated four patients with Lithium, who failed Methimazole to control hyperthyroidism, finding Lithium to be effective. Dr. Benbassat writes:

We describe four patients treated with lithium for the control of hyperthyroidism. Conventional therapy with propylthiouracil and/or methimazole was tried initially, but the patients were either unresponsive or developed side effects during the drug administration. Within several days of reaching therapeutic levels of lithium, a euthyroid state was achieved in three of the four cases. Our observations support the use of lithium as an alternative antithyroid drug in the treatment of hyperthyroidism in certain defined indications, a clinical use that is not widely known. (26)  Emphasis Mine.

Lithium in Preparation for Radioablation or Thyroidectomy

In 2006, Dr Shek used Lithium in 13 thyrotoxic patients in preparation for radioablation or thyroidectomy for Grave’s Disease. Dr. Shek writes:

A satisfactory response, defined as a fall by 40% or more in free thyroxine levels and clinical improvement, was achieved in eight patients within 1 to 2 weeks of lithium therapy. In four others, response occurred in 3 to 5 weeks. Response was slow and inadequate in one patient due to ‘escape’. The median dosage of lithium was 750 mg daily, with a range of 500 to 1500 mg daily. The median serum lithium level was 0.63 mmol/L. Lithium toxicity was observed in one patient…A relatively low dose of lithium offers a safe and effective alternative means of controlling thyrotoxicosis in patients who cannot tolerate or do not respond to thionamides [methimazole]. (27)

Lithium in Preparation for Radio-Ablation

In 2008, Dr. Fulya Akin used Lithium to prepare 5 patients with Graves’ disease and one patient with toxic nodular goiter for radioablation with I-131.  Lithium was used as second line because of adverse reactions or ineffectiveness of Thionamides (Methimazole). Dr. Fulya Akin writes:

This report shows that lithium carbonate can be safely used preoperatively or prior to radioiodide therapy in circumstances where antithyroid medications are contraindicated and are ineffective in obtaining an euthyroid status.  When administered (800–1,200 mg daily) to patients suffering from Graves’ thyrotoxicosis, the serum T 4 and T 3 levels have been shown to decrease by as much as 35% and most patients become clinically euthyroid within 2 weeks of treatment. (28)(30-35)

Lithium in Preparation for Thyroidectomy

In 2018, Dr. G. Nair preferred not to use SSKI (Iodine) to prepare his thyrotoxic patients for thyroidectomy.  Instead, he used thionamide drugs (thyroid blocking drugs) for 162 patients. However, in six patients who could not tolerate thionamides, instead, Dr Nair used Lithium in preparation for thyroidectomy. Lithium was combined with Dexamethasone and propranolol (Beta Blocker).  Dr Nair writes:

Lithium is concentrated by the follicular cells [thyroglobulin producing thyroid cells lining the follicles] and inhibits thyroidal iodine uptake [uptake into thyroglobulin, i.e. organification] and iodotyrosine coupling, alters thyroglobulin structure, and thereby inhibits thyroid hormone secretion.[8] We had used combination of lithium carbonate and dexamethasone in refractory HT [hyperthyroidism] as preoperative regimen…. Lithium carbonate was used in combination with dexamethasone and propranolol in six patients. Indications for lithium salts were drug reactions (n = 3) and failure to control toxicity with 60 mg of carbimazole for 2 months (n = 3)…The entire cohort underwent total thyroidectomy… We used a combination of lithium carbonate and dexamethasone in selected patients of the series and found effective biochemical and clinical control of toxicity. None of the patients experienced drug-related side effects…The rate of complications did not differ in six patients who received lithium salts from the other subgroups. (8)(29)

Lithium and Iodine Combination Treatment

Because of “Iodine escape” in 9-10 per cent of cases, Iodine alone was deemed inadequate for long term control of the Graves’ disease. Perhaps a combination of iodine with a second drug could be effective? In 2022, Dr Okamura succesfully used methimazole as the second drug added to Iodine in combination.(6)

Another effective combination is Iodine/Lithium. The combination of Iodine with Lithium Carbonate has been found effective for long term treatment of Graves’ Disease. A subset of these patients may go into remission. Lithium carbonate dosage for Grave’s Disease is usually 300 mg three times a day.  Blood levels are checked periodically to avoid toxicity.

Conclusion: Another error in modern endocrinology is ignoring the use of Lithium in combination with Iodine to treat Graves’ hyperthyroidism, and in preparation for radio-ablation or thyroidectomy.

Articles with Related Content

Iodine for Treatment of Graves Disease Part One

Iodine for Treatment of Graves Disease Part Two

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com

References

1) Amdisen, A. “Lithium treatment of mania and depression over one hundred years.” Current trends in lithium and rubidium therapy. Springer, Dordrecht, 1984. 11-26.

2) Czarnywojtek, A., et al. “Effect of lithium carbonate on the function of the thyroid gland: Mechanism of action and clinical implications.” J Physiol Pharmacol 71.2 (2020): 191-199.

3) Wright, Jonathan,”Reversing hyperthyroidism by Jonathan Wright MD”, Nutrition & Healing Newsletter Sept 8, 2011.

4) Temple, R. M. J. J., et al. “The use of lithium in the treatment of thyrotoxicosis.” The Journal of Clinical Investigation 51.10 (1972): 2746-2756.

5) Boehm, Timothy M., et al. “Lithium and iodine combination therapy for thyrotoxicosis.” European Journal of Endocrinology 94.2 (1980): 174-183.

6) Okamura, Ken, et al. “Iodide-sensitive Graves’ hyperthyroidism and the strategy for resistant or escaped patients during potassium iodide treatment.” Endocrine Journal (2022): EJ21-0436.

7) Cooper, David S. “Antithyroid drugs.” New England Journal of Medicine 352.9 (2005): 905-917.

8) Lazarus, J. H., et al. “Treatment of thyrotoxicosis with lithium carbonate.” The Lancet 304.7890 (1974): 1160-1163.

9) Kristensen, O., H. Harrestrup Andersen, and G. Pallisgaard. “Lithium carbonate in the treatment of thyrotoxicosis: a controlled trial.” The Lancet 307.7960 (1976): 603-605.

10) Wright, Jonathan V. “Lithium, part 1: protect and renew your brain.” Townsend Letter for Doctors and Patients 247-248 (2004): 78-82.

11) Wright, Jonathan V. “Lithium, part 2: other effects.” Townsend Letter for Doctors and Patients 249 (2004): 59-62.

12) Miodownik, Chanoch, Eliezer Witztum, and Vladimir Lerner. “Lithium-induced tremor treated with vitamin B6: a preliminary case series.” The International Journal of Psychiatry in Medicine 32.1 (2002): 103-108.

13) Umar, Musa U., Aliyu A. Isa, and Asmaul H. Abba. “High dose pyridoxine for the treatment of tardive dyskinesia: clinical case and review of literature.” Therapeutic Advances in Psychopharmacology 6.2 (2016): 152-156.

14) Reda FA, Escobar JJ, Scanlan JM. Lithium Carbonate in the Treatment of tardive dyskinesia. Am J Psych 1975;132(5):560-562.

15) Ibrahim, Ahmed Th, et al. “The protective effects of vitamin E and zinc supplementation against lithium-induced brain toxicity of male albino rats.” Environment and Pollution 4.1 (2015): 9.

16) Omar, H. E., et al. “The protective effects of zinc and vitamin E supplementation against kidney toxicity by lithium in rats.” European Journal of Biological Research 6.1 (2016): 21-27.

17) Bondok, Adel A., et al. “Lithium Carbonate-Induced Nephrotoxicity in Albino Rats and the Possible Protective Effect of Vitamin E: Histological and Immunohistochemical Study.” The Egyptian Journal of Anatomy 41.1 (2018): 105-118.

18) Gupta, Neena, Meghan Gibson, and Ellen C. Wallace. “Lithium-induced chronic kidney disease in a pediatric patient.” Case Reports in Pediatrics 2019 (2019).

19) GA, Modawe, and N. M. ElBagir. “Lithium Carbonate Therapy Causes Nephrotoxicity and its Alleviation with Ascorbic Acid in Wistar Albino Rats.”

20) Burman, Kenneth D., et al. “Sensitivity to lithium in treated Graves’ disease: effects on serum T4, T3 and reverse T3.” The Journal of Clinical Endocrinology & Metabolism 43.3 (1976): 606-613.

21) Rose, Hannah R., and Hassam Zulfiqar. “Jod Basedow Syndrome.” StatPearls [Internet]. StatPearls Publishing, 2022.

22) Wünsch, C., and H. J. Heberling. “Results of lithium treatment in severe hyperthyroidism.” Deutsche Zeitschrift fur Verdauungs-und Stoffwechselkrankheiten 44.1 (1984): 26-31.

23) Dickstein, G., et al. “Lithium treatment in amiodarone-induced thyrotoxicosis.” The American journal of medicine 102.5 (1997): 454-458.

24) Boeving, Anke, et al. “Use of lithium carbonate for the treatment of amiodarone-induced thyrotoxicosis.” Arquivos Brasileiros de Endocrinologia & Metabologia 49 (2005): 991-995.

25) Claxton, Scott, et al. “Refractory amiodarone‐associated thyrotoxicosis: An indication for thyroidectomy.” Australian and New Zealand Journal of Surgery 70.3 (2000): 174-178.

26) Benbassat, Carlos A., and Mark E. Molitch. “The Use of Lithium in the Treatment of Hyperthyroidism.” The Endocrinologist 8.5 (1998): 383-388.

27) Shek, C. C., et al.”Use of lithium in the treatment of thyrotoxicosis.” Hong Kong Med J 12.4 (2006): 254-9.

28) Akin, Fulya, Guzin Fidan Yaylali, and Mehmet Bastemir. “The use of lithium carbonate in the preparation for definitive therapy in hyperthyroid patients.” Medical Principles and Practice 17.2 (2008): 167-170.

29) Nair, Gopalakrishnan C., et al. “Preoperative preparation of hyperthyroidism for thyroidectomy–Role of supersaturated iodine and lithium carbonate.” Indian Journal of Endocrinology and Metabolism 22.3 (2018): 392.

30) Abd-ElGawad, Mohamed, et al. “Lithium carbonate as add-on therapy to radioiodine in the treatment on hyperthyroidism: a systematic review and meta-analysis.” BMC endocrine disorders 21.1 (2021): 1-11.

31) Thakkar, Aditi, and Constance Lee Chen. “A Case for Lithium Pretreatment Prior to Radioactive Iodine Ablation in Grave’s Disease.” Journal of the Endocrine Society 5.Suppl 1 (2021): A906.

32) Kumar, Sanny B., et al. “Dose optimization of lithium to increase the uptake and retention of I-131 in rat thyroid.” Radiation and Environmental Biophysics 58.2 (2019): 257-262.

33) Dharan, Shalini Sree, et al. “A prospective clinical trial on the efficacy of lithium as adjuvant therapy to radioiodine in the treatment of hyperthyroidism (RAILIT study).” Endocrine Abstracts. Vol. 65. Bioscientifica, 2019.

34) Martin, Niamh M., et al. “Adjuvant lithium improves the efficacy of radioactive iodine treatment in Graves’ and toxic nodular disease.” Clinical endocrinology 77.4 (2012): 621-627.

35) Bogazzi, Fausto, et al. “Impact of lithium on efficacy of radioactive iodine therapy for Graves’ disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal.” The Journal of Clinical Endocrinology & Metabolism 95.1 (2010): 201-208.

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Additional References

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26 year old male in Blast crisis

2022 Sharma COMBINATION Lithium Carbonate 900 mg/d and SSKI 150 mg/d to Control Graves Thyrotoxicosis

62) Sharma, Pranjali P. “Use of Lithium in Hyperthyroidism Secondary to Graves’ Disease: A Case Report.” The American Journal of Case Reports 23 (2022): e935789-1.

We present a case of GD managed by Li therapy with oral iodine solution. A 26-year-old man, admitted with acute blast crisis secondary to chronic myeloid leukemia (CML), reported palpitations, 40-lb weight loss, heat intolerance, and fatigue. An examination revealed sinus tachycardia, elevated body temperature, and thyromegaly. Laboratory evaluation confirmed hyperthyroidism (TSH <0.005 mcIU/l, FT4 5.57 ng/dl, TT3 629 ng/dl) secondary to GD (TRAb >40 IU/l, TSIg 178%).

Thionamides and surgery were contraindicated due to pancytopenia from a blast crisis.

Thyroid functions improved with therapy (TSH 0.007 mcIU/l, FT4 0.82 ng/dl, TT3 122 ng/dl) with stable Li level (0.5–0.8 mmol/l).

Conclusions:  Li inhibits iodine uptake through interference with sodium-iodide symporter and tyrosine iodination, thyroglobulin structure changes, peripheral deiodinase blockage, and preventing TSH and TSIg stimulation. Our case shows that a low therapeutic level of Li, in combination with oral iodine, can suppress thyroid overactivity without adverse effects. We suggest that low-dose Li carbonate is a safe and effective adjunctive antithyroid medication to be considered if primary therapies for hyperthyroidism are unavailable.

Methimazole and propylthiouracil (PTU) are the most common ATDs used in the United States. Relatively mild adverse effects from ATDs include pruritus, rash, urticaria, arthralgias, arthritis, nausea, vomiting, or abnormal taste, occurring in up to 13% patients [2]. Serious adverse effects include agranulocytosis, hepatotoxicity, and vasculitis [1]. Agranulocytosis is more likely to occur with any dose of PTU than with low-dose methimazole and can be life-threatening [1], while it is dose-dependent with methimazole [3]. It usually occurs within the first 2–3 months of therapy; however, the overall incidence is relatively low, at 0.1–0.5%\\

Finally, after 2 weeks of inpatient hospital stay, oral Li carbonate 300 mg 3 times a day, with SSKI

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Sharma (duplicate)  Blast Crisis I      n 26 y/o male
Combination SSKI  150 mg and Lithium Carbonate 900 mg to control Graves

Sharma, Pranjali P. “Use of Lithium in Hyperthyroidism Secondary to Graves’ Disease: A Case Report.” The American Journal of Case Reports 23 (2022): e935789-1.

A 26-year-old man, admitted with acute blast crisis secondary to chronic myeloid leukemia (CML), reported palpitations, 40-lb weight loss, heat intolerance, and fatigue. An examination revealed sinus tachycardia, elevated body temperature, and thyromegaly. Laboratory evaluation confirmed hyperthyroidism (TSH <0.005 mcIU/l, FT4 5.57 ng/dl, TT3 629 ng/dl) secondary to GD (TRAb >40 IU/l, TSIg 178%). Thionamides and surgery were contraindicated due to pancytopenia from a blast crisis. Inability to maintain post-radiation precautions precluded use of RAI.

Finally, after 2 weeks of inpatient hospital stay, oral Li carbonate 300 mg 3 times a day, with SSKI 50 mg/drop 1 drop 3 times a day, was introduced. Li levels were monitored every 2–3 days. Two weeks into treatment, FT4 and TT3 dropped to 4.51 ng/dl and 359 ng/dl, respectively.

At hospital discharge 1 month later, thyroid tests showed improvement (TSH 0.007 mcIU/l, FT4 0.82 ng/dl, TT3 122 ng/dl) (Figure 1) with stable Li level (within 0.5–0.8 mmol/l)

So far, he remains on oral Li carbonate 300 mg 3 times a day and SSKI 50 mg/drop 1 drop 3 times a day, without adverse effects. Most recent laboratory test results continue to show an undetectable TSH, but FT4 and TT3 are within normal range (1.42 ng/dl and 98 ng/dl, respectively). The ultimate plan for this patient is a total thyroidectomy when his cell counts improve.

 

2021 Mori – Graves Resistant to Methimazole – Short term  control w Lithium, Dexa , Iodine 150/d prep for thyroidectomy – 14 year old girl

63) Mori, Yusaku, et al. “Very rare case of Graves’ disease with resistance to methimazole: a case report and literature review.” The Journal of International Medical Research 49.3 (2021).

Although we carefully increased the doses of MMI (to 120 mg/day) administered to the patient we describe, her serum thyroid hormone concentration remained too high to be measured . However, she became euthyroid when combination therapy of 150 mg/day MMI with lithium carbonate, dexamethasone and inorganic iodine was instituted, and total thyroidectomy was then performed. The patient experienced no major complications and was discharged from the hospital post-operatively.

A 14-year-old girl initially presented with symptoms of general fatigue, palpitations, and excessive sweating. Fifteen mg/day of MMI was administered as the initial treatment. The patient became euthyroid after 3 months and her thyroid hormone concentration remained stable thereafter, while she administered 5 to 10 mg/day MMI.

When the patient was 19 years old, her serum thyroid hormone concentration began to increase, and her attending physician increased the MMI dose to 40 mg/day and recommended the patient to undergo radioiodine ablation or thyroidectomy to control her hyperthyroidism.

When the patient was 21 years old, her hyperthyroidism became uncontrollable, even at a dose of 90 mg/day MMI, which is above the standard dose range.3 She also required hospitalisation for 2 weeks because of severe insomnia.

we treated the patient’s disease with 120 mg/day MMI,7 which is a much higher dose than the standard dose range for MMI,3 but her serum thyroid hormone concentration remained too high to be measured (Figure 2). Therefore, we initiated additional therapy with 200 mg/day lithium carbonate, followed by

800 mg/day lithium carbonate,11

4 mg/day dexamethasone12 and

153 mg/day inorganic iodine.12

However, the patient’s thyroid hormone concentration remained high; therefore, the thyroidectomy was postponed. After further intensifying the drug therapy to 150 mg/day MMI,7 800 mg/day lithium carbonate, 6 mg/day dexamethasone and 306 mg/day inorganic iodine, the patient’s serum thyroid hormone concentration normalized. Therefore, total thyroidectomy was performed 7 days after hospitalisation. The patient’s thyroid gland weighed 86 g, which is approximately six-to-seven times heavier than a normal thyroid gland.13

MMI inhibits thyroid hormone synthesis by preventing the iodination of tyrosine residues in thyroglobulin by thyroid peroxidase.3

Combination therapy of MMI with corticosteroid and inorganic iodine is a strategy that is commonly used for the management of thyroid storm; 8 mg/day dexamethasone and up to 200 mg/day inorganic iodine are recommended in the guidelines for the management of thyroid storm published by the Japan Thyroid Association and the Japan Endocrine Society

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2021 Thakkar – Lithium Pretreatment for RAI in Graves

64) Thakkar, Aditi, and Constance Lee Chen. “A Case for Lithium Pretreatment Prior to Radioactive Iodine Ablation in Grave’s Disease.” Journal of the Endocrine Society 5.Suppl 1 (2021): A906.

Radioactive iodine ablation (RAIA) therapy with Iodine-131 (I-131) is an established treatment for grave’s thyrotoxicosis. However, there is 10 to 20% chance of treatment failure. Lithium, a drug used to treat bipolar disorder, has significant effects on thyroid function. The most clinically relevant is the inhibition of thyroid hormone release. It is also known to inhibit colloid formation, and is involved in blocking organic iodine as well as thyroid hormone release from the thyroid gland without an effect on radioiodine uptake. This leads to increased radioiodine retention in the thyroid gland.

In hyperthyroid Graves’ patients, radioactive iodide uptake is enhanced due to presence of TSH receptor antibody, however, radioiodide is also rapidly discharged because of its increased turnover. Lithium can significantly reduce the release of iodine from the thyroid gland and thus increase iodine retention. There is evidence to suggest that adjuvant lithium can increase thyroidal radioiodine uptake in patients with a low baseline RAIU (< 30%). This case demonstrate that lithium can be used safely prior to RAI therapy in cases of RAI ablation failure even with low baseline RAIU.

2021 Fantin  LI Pretreatement before RAI –  lithium was used to control thyrotoxicosis and prevent further increase in TH levels associated with RAI therapy

65) Fantin, Esther H., and Iuri Martin Goemann. “Successful Management of Hyperthyroidism With Lithium and Radioiodine in a Patient With Previous Methimazole-Induced Agranulocytosis.” Journal of the Endocrine Society 5.Supplement_1 (2021): A958-A958.

Discussion: Serum thyroid hormone (TH) concentrations usually increase after RAI therapy for Graves’ disease, a worrisome fact in patients with increased risk for cardiovascular complications. Previous studies report that preRAI treatment with lithium prevents changes in serum TH concentrations and enhances RAI therapy’s effectiveness.

Here, treatment with lithium was used to control thyrotoxicosis and prevent further increase in TH levels associated with RAI therapy. Lithium is particularly suitable for patients with ATD-related side effects before definitive therapy (radioiodine or thyroidectomy). The antithyroid effect of lithium in this setting should be further studied.

2019 – Tay RAI Treatment Failure – Large Goiter Size and High TSH Receptor AB levels

Tay, Wei Lin, et al. “High thyroid stimulating receptor antibody titre and large goitre size at first-time radioactive iodine treatment are associated with treatment failure in Graves’ disease.” Ann Acad Med Singap 48.6 (2019): 181-187.

Conclusion: Larger goitre size and higher TRAb titre predict lower success of RAI therapy in GD patients. Treatment decisions and strategies should be customised for patients who present with these characteristics.

2021 Ahmed RAI with adjunctive Lithium superior to RAI alone

Ahmed, Fahad Wali, et al. “Meta-analysis of randomized controlled trials comparing the efficacy of radioactive iodine monotherapy versus radioactive iodine therapy and adjunctive lithium for the treatment of hyperthyroidism.” Endocrine Research 46.4 (2021): 160-169.

Adjuvant Li with RAI for ≤ 7 days showed significantly higher cure rate compared to RAI alone, whereas > 7 days of adjuvant Li with RAI did not show any difference in cure rate compared to RAI alone. RAI with adjunctive Li was associated with a significantly higher cure rate for patients with Graves’ disease compared to RAI alone. There was no significant difference between RAI with adjunctive Li and RAI alone for toxic nodular thyroid disorder (toxic nodule and toxic multinodular goiter) and thyroid volume >40 grams and ≤40 grams.

Conclusions: RAI with adjunctive Li therapy demonstrated superiority over RAI therapy alone with regards to both curing hyperthyroidism and, reduced time till cure, with a limited side effect profile.

Bogazzi, Fausto, et al. “Impact of lithium on efficacy of radioactive iodine therapy for Graves’ disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal.” The Journal of Clinical Endocrinology & Metabolism 95.1 (2010): 201-208.

Lithium might increase RAI effectiveness by increasing RAI retention in the thyroid.

Two hundred ninety-eight patients were treated with RAI plus lithium (900 mg/d for 12 d) and 353 with RAI alone.

Conclusions: RAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves’ disease.

Lithium/PTU  treatment in amiodarone-induced thyrotoxicosis

Dickstein, G., et al. “Lithium treatment in amiodarone-induced thyrotoxicosis.” The American journal of medicine 102.5 (1997): 454-458.

The third group (9 patients) was given 300 mg PTU and lithium daily. The initial Lithium dose was 300 mg 3 times per day. Serum lithium levels were measured weekly and lithium doses adjusted to bring this to 0.6 to 1.2 mEq/L.’  The study period was 10 weeks. All patients on the combined treatment (Li/PTU) normalized their T4 levels within 4 to 5 weeks,

We suggest that lithium may be used safely and efficiently for treatment of amiodarone (and probably other cases of iodine-induced) thyrotoxicosis.

This treatment should probably be reserved for cases of severe thyrotoxicosis or in patients in whom this complication may endanger their lives. Thyroid functions are expected to return to normal within 1 month of treatment. The indications for its use have not been established, probably because of the high efficiency of the regular antithyroid drugs, and the fear of possible complications of lithium treatment. However, serious complications rarely occur unless lithium serum levels exceed 1.4 mEq/‘L.’

==================================

TAKEUCHI, KEISUKE, et al. “Significance of iodide-perchlorate discharge test for detection of iodine organification defect of the thyroid.” The Journal of Clinical Endocrinology & Metabolism 31.2 (1970): 144-146.

Perchlorate tests were performed after oral administration of radioiodine without carrier iodide (conventional perchlorate test) or with 500 μg of 127I (iodide-perchlorate test). In neither test was there a significant discharge of 131I in control subjects. In subjects treated with l-methyl-2-mercaptoimidazole positive discharge was observed with the iodide-perchlorate test, but not with conventional perchlorate test. Of 8 patients with Hashimoto’s thyroiditis, only 2 showed positive discharge tests by the conventional perchlorate test, whereas the iodide-perchlorate test was positive in all these patients.

TAJIRI, JUNICHI, et al. “Studies of hypothyroidism in patients with high iodine intake.” The Journal of Clinical Endocrinology & Metabolism 63.2 (1986): 412-417.

Twenty-two patients with spontaneously occurring primary hypothyroidism were studied to evaluate the spontaneous reversibility of the hypothyroid state. Twelve (54.5%) became euthyroid after restriction of iodine intake for 3 weeks (reversible type). In the remaining 10 patients, thyroid function did not improve with restriction of iodine alone, and thus, replacement therapy was required, (irreversible type). In the reversible type, 1) radioactive iodine uptake after 1 week of restricted iodine intake was higher than in the irreversible type [50.0 +/- 12.2% (+/- SD) vs. 4.3 +/- 3.2%; P less than 0.01], 2) the perchlorate discharge test was positive in 2 of 10 patients, and 3) the iodine-perchlorate discharge test, carried out in 7 of 8 patients with negative perchlorate discharge test, was positive in 6. Seven patients with the reversible type were given 25 mg iodine daily for 2-4 weeks; all became hypothyroid again. Two patients had a history of habitual ingestion of seaweed (25.4 and 43.1 mg iodine, respectively), but the remaining 10 patients ingested ordinary amounts of iodine (1-5 mg) daily. The patients with reversible hypothyroidism had focal lymphocytic thyroiditis changes in the thyroid biopsy specimen, whereas those with irreversible hypothyroidism had more severe destruction of the thyroid gland. These results indicate the existence of a reversible type of hypothyroidism sensitive to iodine restriction and characterized by relatively minor changes in lymphocytic thyroiditis histologically. Attention should be directed to this type of hypothyroidism, because thyroid function may revert to normal with iodine restriction alone.

BUCHANAN, W. WATSON, et al. “Iodine metabolism in Hashimoto’s thyroiditis.” The Journal of Clinical Endocrinology & Metabolism 21.7 (1961): 806-816.

A comprehensive study of iodine metabolism is reported in 40 cases of Hashimoto’s thyroiditis. The results showed a dissociation between the mean absolute (or stable) iodine uptake by the thyroid (2.0 ;μg. per hour, which was normal) and the serum level of protein-bound iodine (2.5 μg. per 100 ml., which was significantly decreased). These findings indicate that the thyroid gland traps a normal quantity of iodine, but lacks the capacity to utilize it efficiently to form thyroid hormone. This faulty utilization of iodine is apparently a form of acquired dyshormonogenesis. Evidence of its nature is provided by         and by the presence of a butanol-insoluble iodinated protein in the plasma in many cases. The intrathyroidal exchangeable iodine was markedly reduced in almost all cases. This, and not the presence of the butanol insoluble iodinated protein, explains the frequent discrepancy between the high level of PBI131 and the low level of PBI in serum. Standard radioiodine tests (thyroidal uptake and plasma activity) yield misleading results unless the foregoing abnormalities in stable iodine metabolism are taken into account.

Our previous study of the iodide-perchlorate test in patients with Hashimoto’s thyroiditis led to us to assess the significance of the test in patients with Graves’ disease. Perchlorate tests were performed by a conventional method (ClO4 test) and a modified technique in which a dose of 250 or 500 μg 127I was added to the tracer 131I (I-ClO4 test).

SUZUKI, HOJI, and KEIMEI MASHIMO. “Significance of the iodide-perchlorate discharge test in patients with 131I-treated and untreated hyperthyroidism.” The Journal of Clinical Endocrinology & Metabolism 34.2 (1972): 332-338.

In the I-ClO4 test (500 μg 127I), a significant discharge was observed in the thyrotoxic patients, as well as in the patients rendered euthyroid by 131I treatment. With the smaller dose of 127I (250 μg), only 131I-treated patients showed significant iodide-perchlorate discharge. The magnitude of dischargeability (discharge percent) in the 131I-treated patients was greater than in thyrotoxic patients. ClO4 tests were negative in both the thyrotoxic and 131I-treated euthyroid patients. Chronic treatment with iodide induced hypothyroidism in 5 of 7 euthyroid patients who had been treated with 131I. The ClO4 test was negative in all patients except one, whereas the I-ClO4 test was positive in 6 of 7 patients. It would appear that the susceptibility of patients with Graves’ disease to acute and chronic iodide loads may be enhanced after 131I treatment, presumably by impairment of the thyroidal organic binding mechanism. The latter is more frequently detectable by the iodide-perchlorate test.

Andersen, B. Friis. “Iodide perchlorate discharge test in lithium-treated patients.” European Journal of Endocrinology 73.1 (1973): 35-42.

In patients with lithium-induced goitre the conventional perchlorate discharge test is negative. With a small dose of carrier iodide the perchlorate test is more sensitive. This iodide perchlorate discharge test (IPT) was made on twelve patients, all under lithium-treatment for over one year and on fifteen control subjects. In the first group there was a greater discharge in the test (Lithium prevents organification of Iodine) than in the latter group (Control). By increasing the lithium-doses or by stopping them, the discharge by the IPT alters correspondingly. Sensitivity to iodine is increased by lithium-treatment, perhaps because of a greater thyroid/serum ratio for iodide.

Morgans, M. E., and W. R. Trotter. “Defective organic binding of iodine by the thyroid in Hashimoto’s thyroiditis.” The Lancet 269.6968 (1957): 553-555.

Hilditch, T. E., et al. “Defects in intrathyroidal binding of iodine and the perchlorate discharge test.” European Journal of Endocrinology 100.2 (1982): 237-244.

The kinetics of [123I] iodide uptake were studied when organification of iodine by the thyroid gland was normal and when this binding function was diminished by drugs or disease. Each study was terminated by a sodium perchlorate discharge test (300–600 mg iv) at 60 min or, in some cases, 10–30 min. The results confirmed that binding takes place rapidly in the uninhibited gland with the binding rate constant being at least 0.150 min-1. Discharge from the uninhibited gland is less than 3.5% of the gland uptake when perchlorate is given 60 min after the radioiodide. Subjects with an intrinsic binding defect manifested discharges of 11% of greater of the 60 min uptake and the estimated binding rate constants ranged from 0.003–0.057 min-1. Thyrotoxic subjects receiving 5 mg carbimazole twice daily manifested discharges ranging from 5.4–64.2%, and in those receiving 20 mg twice daily the observed discharges were 67.6–94.6% of the 60 min uptake. The study shows that a correctly performed perchlorate discharge test will detect minimal inhibition of iodine binding. An important factor is the duration of the follow-up period after perchlorate is given. In some of the cases studied discharge was not complete until 60 min after the perchlorate.

Gray, H. W., et al. “Intravenous perchlorate test in the diagnosis of Hashimoto’s disease.” The Lancet 303.7853 (1974): 335-338.

In a study of patients with non-toxic goitre, the intravenous perchlorate-discharge test indicated the presence of defective organification of thyroidal iodide in nearly all patients with Hashimoto’s disease but in less than half those with simple goitre. Diagnostic discrimination was improved by setting limits of significant discharge at a minimum of 1% of the administered dose of iodine-131. Using this criterion, 80% of patients with Hashimoto’s disease but only 12% of patients with simple goitre had a positive test. In clinical practice, the test seemed most valuable in the differential diagnosis of non-toxic goitre in those euthyroid patients with low titres of serum-antithyroid-antibodies.

Roti, E., et al. “Effects of chronic iodine administration on thyroid status in euthyroid subjects previously treated with antithyroid drugs for Graves’ hyperthyroidism.” The Journal of Clinical Endocrinology & Metabolism 76.4 (1993): 928-932.

Ten euthyroid women (mean age, 56 yr) who had hyperthyroid Graves’ disease successfully treated with methimazole 36.4 +/- 4.7 months earlier were evaluated before, during, and after the administration of 10 drops SSKI daily for 90 days.

Serum AbTPO increased slightly, but significantly, during SSKI administration in the 7 women with positive values at baseline (P < 0.05). TSH-RAb remained undetectable. After SSKI withdrawal, the 10 women were reevaluated 60 and 120 days later. Two women developed a blunted TSH response to TRH, but normal serum T4 and T3 concentrations, and 2 women developed overt hyperthyroidism, with undetectable basal and TRH-stimulated serum TSH and elevated serum T4 and T3 concentrations, requiring methimazole therapy. All values in the remaining 6 women were similar to those present before SSKI administration.

These results suggest that some euthyroid patients with a history of antithyroid drug therapy (Methimazole) for Graves’ disease may develop thyroid dysfunction during and after excess iodine administration. The development of subclinical hypothyroidism during SSKI administration was not clinically important, but the occurrence of overt hyperthyroidism after SSKI was discontinued did require antithyroid drug therapy. It is advisable, therefore, to avoid iodine-containing substances in euthyroid patients with a history of antithyroid drug therapy for Graves’ disease.

ROTI, E., et al. “Impaired intrathyroidal iodine organification and iodine-induced hypothyroidism in euthyroid women with a previous of postpartum thyroiditis.” The Journal of clinical endocrinology and metabolism 73.5 (1991): 958-963.

Postpartum thyroiditis (PPT) is common and occurs in 1.7 to 16.7% of pregnant women, depending upon the study population. Most of these women develop transient hypothyroidism and thyroid function usually returns to normal. We have studied 11 euthyroid women with a previous history of PPT to determine the incidence of subtle defects in thyroid function measured by iodide-perchlorate (I-ClO4) discharge tests and TRH tests and to determine whether these women would develop iodide-induced hypothyroidism.

Seven (64%) had positive I-ClO4 discharge tests and 5 (46%) had an abnormally high TSH response to TRH. Thyroid antimicrosomal and antithyroid peroxidase were positive in 8 women (73%) with a previous episode of PPT.

The administration of pharmacological amounts of iodide (10 drops of saturated solution of potassium iodide daily) for 90 days to these 11 women resulted in elevated basal and TRH stimulated serum TSH concentrations in 8 (72.7%) compared to TSH values during iodide administration to women who had never been pregnant. Antimicrosomal and antithyroid peroxidase concentrations did not change during iodide administration.

These findings strongly suggest that euthyroid women with a previous episode of PPT have permanent subtle defects in thyroid hormone synthesis and are inordinately prone to develop iodide-induced hypothyroidism, similar to findings previously reported in euthyroid subjects with Hashimoto’s thyroiditis, with a previous episode of painful subacute thyroiditis, or previously treated with radioactive iodine or surgery for Graves’ disease.

Markou, K., et al. “Iodine-induced hypothyroidism.” Thyroid 11.5 (2001): 501-510.

Iodine is an essential element for thyroid hormone synthesis. The thyroid gland has the capacity and holds the machinery to handle the iodine efficiently when the availability of iodine becomes scarce, as well as when iodine is available in excessive quantities. The latter situation is handled by the thyroid by acutely inhibiting the organification of iodine, the so-called acute Wolff-Chaikoff effect, by a mechanism not well understood 52 years after the original description.

It is proposed that iodopeptide(s) are formed that temporarily inhibit thyroid peroxidase (TPO) mRNA and protein synthesis and, therefore, thyroglobulin iodinations.

The Wolff-Chaikoff effect is an effective means of rejecting the large quantities of iodide and therefore preventing the thyroid from synthesizing large quantities of thyroid hormones. The acute Wolff-Chaikoff effect lasts for few a days and then, through the so-called “escape” phenomenon, the organification of intrathyroidal iodide resumes and the normal synthesis of thyroxine (T4) and triiodothyronine (T3) returns.

This is achieved by decreasing the intrathyroidal inorganic iodine concentration by down regulation of the sodium iodine symporter (NIS) and therefore  permits the TPO-H2O2 system to resume normal activity.

However, in a few apparently normal individuals, in newborns and fetuses, in some patients with chronic systemic diseases, euthyroid patients with autoimmune thyroiditis, and Graves’ disease patients previously treated with radioimmunoassay (RAI), surgery or antithyroid drugs, the escape from the inhibitory effect of large doses of iodides is not achieved and clinical or subclinical hypothyroidism ensues.

Iodide-induced hypothyroidism has also been observed in patients with a history of postpartum thyroiditis, in euthyroid patients after a previous episode of subacute thyroiditis, and in patients treated with recombinant interferon-a who developed transient thyroid dysfunction during interferon-a treatment. The hypothyroidism is transient and thyroid function returns to normal in 2 to 3 weeks after iodide withdrawal, but transient T4 replacement therapy may be required in some patients. The patients who develop transient iodine-induced hypothyroidism must be followed long term thereafter because many will develop permanent primary hypothyroidism.

Eigenmann, F., and H. Bürgi. “Lithium acetate, a useful and well tolerated thyrostatic for selected cases of hyperthyroidism.” Schweizerische Medizinische Wochenschrift 108.47 (1978): 1850-1853.

Lithium acetate treatment of 6 patients with hyperthyroid Graves’ disease and 6 patients with toxic nodular goiter is reported. Lithium acetate was administered either as monotherapy (group A) or combined with 45 mg carbimazole or methimazole (group B). A control group of 8 patients received methimazole or carbimazole only (group C). Lithium either alone or combined with thionamide drugs consistently lowered serum thyroxine and triiodothyronine with marked clinical improvement. After 7 days of treatment thyroxine was reduced by 28% (group A), 43% (group B) and 36% (group C). The respective decrease in triiodothyronine was 42%, 50% and 46%. The differences between three groups were not statistically significant. We conclude that lithium is a useful antithyroid agent for selected patients, since it is safe and effective even in severe cases, does not interfere with radioiodine uptake for diagnostic or therapeutic purposes and provides an alternative for patients allergic to thionamides.

Turner, J. G., et al. “An evaluation of lithium as an adjunct to carbimazole treatment in acute thyrotoxicosis.” European Journal of Endocrinology 83.1 (1976): 86-92.

The rate of control of thyrotoxicosis during the first 2 weeks of treatment was documented in 63 patients. Twenty-three patients received carbimazole 40 mg plus lithium carbonate 750 mg daily and a comparable group of 20 patients were given carbimazole 40 mg plus potassium iodide 120 mg daily. In the lithium treated patients the mean percentage fall of serum T4 after 2 weeks treatment was 49% and the fall in serum T3 57%. The results were similar in the iodide treated patients; the mean falls in serum T4 and T3 being 47% and 64%, respectively. Serum lithium values varied between 0.1-1.25 mEq./l; lithium side effects were minor. In a companion study 20 patients were treated with carbimazole alone. The responses in this group were less impressive; the mean falls in serum T4 and T3 at 2 weeks being 18% and 36%, respectively. It is concluded that lithium is a safe adjunct to conventional antithyroid drug therapy in the initial treatment of acute thyrotoxicosis.

Eulry, F., J. Orgiazzi, and R. Mornex. “Do lithium salts have a place in the treatment of severe hyperthyroidism?(author’s transl).” La Nouvelle Presse Medicale 6.33 (1977): 2955-2958.

In a patient with hyperthyroidism resulting in cachexia, severe cardiac complications and functional renal failure, and a second case of hyperthyroidism refractory to carbimazole as a result of iodine overload, the administration of 1 to 3 g of lithium gluconate every 1 to 3 days, in association with carbimazole, led to persistent clinical and biological improvement in 8 to 16 days. In the first case, the course was complicated by neurological intolerance (blood lithium 0.98 mEq/l) which responded to the temporary interruption of treatment and by a transient escape of thyroid function from the effects of lithium which disappeared after a slight adjustment in the dose.

In the second case, the course under treatment was favourable from the outset. Thus in forms of hyperthyroidism in which usual forms of treatment are inadequate and where there is a risk of “acute crises”, lithium may be valuable as adjuvant therapy. If the dose is regularly modified in order to obtain a daily blood lithium level of less than 0.60 mEq/l, and on condition of close clinical, electrocardiographic and ionic surveillance, cardiac and renal failure and neuropsychiatric disturbances do not prevent the use of lithium, which the authors feel to be of irreplaceable value.

Jonderko, G., and C. Marcisz. “Short-term use of lithium carbonate in the treatment of thyrotoxicosis.” Zeitschrift fur die Gesamte Innere Medizin und Ihre Grenzgebiete 34.15 (1979): 408-411.

The examinations were performed on 3 groups of altogether 65 persons with thyreotoxicosis, the cause of which was either Basedow’s disease or struma nodosa. The first group received metizol (thiamazol) in a daily dosage of 60 mg, the second group lithium carbonate (1.0 up to 1.5 g/a day), the third group metizol together with lithium carbonate. The groups were of the same value, concerning the degree of the symptoms of hyperthyroidism. The examinations showed that when lithium carbonate is used alone at the earliest a significant decrease of the serum T4 and T3 concentration as well as of the T3 binding index appears. After a treatment of seven days the therapeutic effects even up. Under the lithium therapy an essential improvement of the clinical findings was achieved. The combined therapy with lithium and metizol did not exhibit any advantages in this respect. The side-effects observed under the lithium therapy are no essential clinical problem.

Hedley, J. M., et al. “Low dose lithium-carbimazole in the treatment of thyrotoxicosis.” Australian and New Zealand journal of medicine 8.6 (1978): 628-630.

Fifteen patients with thyrotoxicosis were treated with low dose sustained release lithium carbonate 400 mg, combined with carbimazole 40 mg daily, and the therapeutic response was followed over a two week period. This response was compared with that obtained in a similar group of patient treated with carbimazole alone. Li-carbimazole treatment brought about a fall in the mean total serum T4 of 57.4% compared with a drop of 32.8% in patients treated with carbimazole alone. The mean serum T3 fell by 69.4% in the Li-carbimazole group compared with 47.3% in the group treated with carbimazole only. No lithium adverse effects were encountered.

Kauschansky, A., and M. Genel. “Preoperative treatment of intractable hyperthyroidism with acute lithium administration.” European journal of pediatric surgery 6.05 (1996): 301-302.

We present a 15-year-old girl with an unusual clinical course of intractable thyrotoxicosis that was resistant to thiocarbamide therapy and propranolol. Although the latter beta adrenergic blocking agent has been used as the sole drug in the preparation of thyrotoxicosis patients for thyroidectomy, it was unsatisfactory for control of our case. In contrast, the patient’s clinical response to lithium carbonate 900-1500 mg/d for 10 days was very good and no side effects were observed. This demonstrates the importance of lithium as the drug of choice in thyrotoxic emergencies and uncontrolled preoperative patients when rapid and safe inhibition of thyroid hormone secretion is required.

Khalifa, Maram, Hassaan B. Aftab, and Vitaly Kantorovich. ““Fueling the Fire”-Irish Sea-Moss Resulting in Jod-Basedow Phenomenon in a Patient With Grave’s Disease.” Journal of the Endocrine Society 5.Supplement_1 (2021): A906-A906.

Conclusion: Irish sea moss is a readily available herbal supplement with  high, variable amounts of iodine. Despite little scientific evidence, it is often marketed to improve goiter amongst other health benefits. The recommended daily iodine intake per the FDA is 150 mcg. Higher amounts are expected to initially cause a short-lived suppression of thyroid function; the Wolff-Chaikoff effect, followed by “escape” and accelerated production of thyroid hormone in abnormal thyroid gland, known as Jod-Basedow phenomenon. In our case, the patient unknowingly worsened her underlying Grave’s disease due to the Jod-Basedow effect. Of note, apparently she had a longer than expected course of Wolff-Chaikoff effect preceding the thyrotoxic state due to sporadic irregular intake of sea moss. Discontinuing sea moss led to clinical and biochemical improvement of hyperthyroidism without requiring thionamide therapy.

Prakash, Ishita, Eric S. Nylen, and Sabyasachi Sen. “Lithium as an Alternative Option in Graves Thyrotoxicosis.” Case Reports in Endocrinology (2015).  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.

Lithium has been shown to increase the retention of radioactive iodine (RAI) in the thyroid of patients with Graves’ thyrotoxicosis [15], in turn, leading to improvement of the efficacy of this therapy. Lithium given before or concomitantly with RAI has been shown to provide more immediate control of hyperthyroidism, by decreasing the release of preformed thyroid hormone, without decreasing the uptake of the RAI [16]. This effect is reminiscent of the Wolff-Chaikoff effect, where increased iodine content inside the follicular cell blocks release of hormone. This effect, much like the effect of iodine, is transient. Older literature notes the similarity of lithium to iodine and recommends its use only for short-term, rapid suppression [17]. However, our case highlights the fact that lithium has several other mechanisms of action that contribute to long-term control of thyrotoxicosis.

Studies have shown that lithium doses of 600 mg−1000 mg daily (300 mg every 8 hours), as well as lithium blood levels of 0.6–1.2 mmol/L, are best to control thyrotoxicosis. To avoid toxicity, it is best if serum lithium levels are maintained < 1.0 mmol/L, around 0.5 mmol/L. [14].

Our case illustrates that a low therapeutic level of lithium even around 0.2 mmol/L is sufficient to suppress thyroid overactivity without causing side effects. Lithium at a low dose appears to be an effective antithyroid medication even for a few months.

Leung, Angela M., and Lewis E. Braverman. “Iodine-induced thyroid dysfunction.” Current opinion in endocrinology, diabetes, and obesity 19.5 (2012): 414.

Following the cloning of the sodium iodide symporter (NIS), which actively transports iodine into the thyroid, in 1996 by Dai et al. [11], the effect of excess iodine on thyroid function in the rat was revisited. In 1999, it was reported that in the normal rat thyroid, there was a marked decrease in NIS expression by 24 h following excess iodine administration [12]. This was accompanied by the disappearance of the inhibition of thyroid hormone synthesis and the resumption of normal thyroid function. Thus, it is likely that escape from the acute Wolff–Chaikoff effect is associated with decreases in NIS synthesis, resulting in a decrease in intrathyroidal iodine concentrations, and the resumption of normal thyroid hormone synthesis.

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