High iodine (substrate) turnover Graves’ disease: the intriguing ‘rapid responder’ variant of thyrotoxicosis

Ann Clin Biochem 2008;45:612-615
doi:10.1258/acb.2008.008098
© 2008 Association for Clinical Biochemistry

 

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Case Reports


Rinkoo Dalan1,
Melvin Khee-Shing Leow1,2 and
David Chee-Eng Ng3


1 Department of Endocrinology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433;
2 Singapore Institute for Clinical Sciences (A*STAR), Brenner Centre for Molecular Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077;
3 Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore 169608


Corresponding author: Rinkoo Dalan. Email: rinkoo_dalan{at}ttsh.com.sg




Abstract

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Factors determining the responsiveness to antithyroid drugs(ATDs) in Graves’ disease are not fully known. Notwithstandingthe typical pattern and tempo of thyroid hormone responses tothionamides, the existence of an unusual subset of Graves’ diseasewith extraordinarily rapid thyroid hormone responses to ATDswill prove challenging even to the expert clinician. Termed‘rapid responder Graves’ disease’ or ‘highturnover Graves’ disease’, the serum thyroxine (FT4) andtriiodothyronine (FT3) of patients with this variant of thyrotoxicosiscan decline precipitously during the initiation of ATDs andyet escalate acutely upon discontinuation of pharmacologicalintervention. We describe a case that presented with low serumFT4 and FT3 in association with suppressed serum thyrotropin(TSH) concentrations soon after starting carbimazole even ata low dose. The erratic clinical course comprising largely ofserum FT4 nadirs and peaks is elaborated to facilitate appreciationof the difficulty in the stabilization of the thyroid with ATDs.The possible pathogenetic mechanisms for the chaotic fluctuationsin thyroid hormones to minor changes in thionamide dose adjustmentsare discussed as well.





Background

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Some patients with Graves’ disease respond well to antithyroiddrug (ATD) treatment but others do not. Although ATDs are requiredfor prolonged periods to improve thyroid function in many patients,there are some who respond to ATDs very rapidly; their thyroidhormone concentrations plunges to hypothyroid ranges at an earlystage of the treatment. There are no known predictors of a rapidresponse to ATDs. We describe a case of rapidly responsive Graves’disease to ATDs and discuss the possible pathogenetic mechanismsof this ‘rapid responder’ phenomenon.





Case report

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A 72-year-old Chinese gentleman first presented after an episodeof acute gastroenteritis. He lost 5 kg over six months despitenormal appetite, and also experienced occasional palpitations.He denied heat intolerance, chronic diarrhea, neck pain or swelling.

His family history was negative for thyroid problems. He residedin Singapore, an iodine-replete area, for much of his life.His dietary habits were remarkable for his high consumptionof seafood.

Clinically, his heart rate was regular at 110 per minute andhis blood pressure was 110/70 mmHg. His palms were moist, associatedwith fine finger tremors. However, signs of thyroid eye diseaseand a goiter were notably absent. Except for hyper-reflexia,the physical examination was otherwise unremarkable.

A thyroid function test done during this episode of acute illness revealed low free thyroxine (FT4) at 3 pmol/L (RI: 8–21) and a suppressed TSH of <0.01 mIU/L (RI: 0.34–5.60) attributed to non-thyroidal illness for which he was monitored conservatively. A month later, he developed overt thyrotoxic symptoms during which his FT4 spontaneously rose to 59 pmol/L while TSH remained suppressed at <0.01 mIU/L. Serum TSH receptor antibody was raised to >40 IU/L. A pertechnetate (Tc-99m) thyroid scan revealed increased tracer uptake suggestive of a diffuse hyperfunctioning thyroid gland typical of Graves’ disease. Thyroiditis and factitious hyperthyroidism were thus excluded, as tracer uptake is reduced in both of these conditions. He was diagnosed with Graves’ disease and started on carbimazole (CMZ) 5 mg b.i.d. Two weeks later, his FT4 concentrations declined precipitously to 8 pmol/L while his TSH remained suppressed at <0.01 mIU/L. Within another three weeks, his FT4 concentrations reached a nadir of 4 pmol/L. At this time, his dose was decreased to CMZ 5 mg o.d. However, about one month later, his FT4 concentrations persisted at 4 pmol/L. The dose of CMZ was further down-titrated to 2.5 mg o.d. However, he continued to have hypothyroxinaemia. T3 toxicosis1 and T3-predominant thyrotoxicosis,2 the latter defined by elevated serum-free triiodothyronine (FT3) concentrations in the face of hypothyroxinaemia and suppressed TSH concentrations after initiation of ATD treatment, were excluded as FT3 done concurrently was also low at 3.9 pmol/L (RI: 4.3–8.3). Overexpression of TSH receptor-blocking antibodies was excluded based on TSH receptor stimulation-blocking antibodies (TSBAb) at 233.0% (RI: <71% indicates blocking). A trial of ATD withdrawal was done at this point. After two weeks, his FT4 concentrations increased swiftly to 31 pmol/L and his TSH remained suppressed at 0.2 mIU/L (Table 1). He clearly had Graves’ diseasethat demonstrated ‘supersensitivity’ to ATD treatment.



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Table 1 Serial thyroid function test variations during carbimazole therapy in our patient

 

A radioiodine (I-131) uptake study was performed on 22 May 2007. CMZ was withdrawn for one week before the uptake study was undertaken. After the administration of 11 µCi of I-131, uptake measurementwas done. The uptake at four hours was calculated at 63%, whichwas much higher than the uptake measured at 24 hours (42%),suggesting very high iodine turnover in this patient.





Discussion

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Factors determining hyper-responsiveness to ATDs in Graves’ disease are unknown. It has been observed that thyrotoxicosis is relatively more resistant to treatment in areas of iodine excess,3 while thyrotoxicosis responds very rapidly in areas of iodine deficiency.4 Contrary to an expected resistance to ATDs, given our patient’s iodine-sufficient locale and his iodine-rich diet, his conspicuous absence of refractoriness coupled with extraordinary sensitivity to ATDs unveils a most unusual outcome worthy of further enquiry. In addition, patients with relatively larger intrathyroidal pools are more resistant to ATDs5 when compared to patients with small intrathyroid pools who are more sensitive to ATDs.6 This is a likely contributory factor, givenhis ‘high iodine turnover’ I-131 uptake characteristicswhich would diminish the size of his iodine pool.

The pharmacology of thionamides (i.e. propylthiouracil [PTU], methimazole [MMI] and CMZ) and biochemistry of thyroid hormone synthesis are briefly revisited next. The uptake of these drugs is stimulated by TSH and inhibited by iodide, and they are typically concentrated several fold in the thyroid gland.7 Low doses of MMI and PTU inhibit thyroid peroxidase (TPO)-catalyzed iodination of thyroglobulin transiently and reversibly, whereas the effect of a higher dose is irreversible.8 The inhibition is also dependent on the ratio of the thionamide drug and iodide concentration. While it is irreversible at lower iodide concentrations, it is only transient at high iodide concentrations.8 Under conditions of reversible inhibition, thionamides compete with tyrosyl residues for iodide and are rapidly oxidized.9 Iodination resumes once metabolism of the drug is complete. Conversely, thionamides are only partially oxidized at high drug/iodide ratios. In this situation TPO is inactivated, presumably by covalent bonding of oxidized drug to the prosthetic haem group of the enzyme, and iodination is irreversibly blocked.10 To account for theobservations in rapid responder Graves’ disease, one of thepotential mechanisms is an overly active TPO, whereby enzymekinetics itself directly induces a state of high iodine turnoverwhich leads to a low iodide:thionamide ratio, thus favouringacute irreversible inhibition of TPO and sharp decline in thyroidhormone concentrations. Upon thionamide discontinuation andwashout, new TPO enzyme synthesis re-establishes rapid iodinationand organification with swift escalations in serum thyroid hormones.

In one study, Graves’ disease patients with rapid turnover of intrathyroidal iodine with small intrathyroidal pool were more likely to respond rapidly to ATDs. Such rapid responders demonstrated higher I-123 uptake at three hours when compared with 24 hours.6

A much less explored alternative plausible hypothesis is the limitation in the other critical substrate (tyrosine) for thyroid hormone production. Importantly, only a few specific rather than all tyrosyl residues within the entire thyroglobulin dimer are amenable to iodination in a sequential pattern determined by the structure of the native protein.11 Thus, in situations with highly accelerated TPO activity, a state of relative tyrosyl residue insufficiency can conceivably occur even in the presence of an adequate intrathyroidal iodine pool. In accordance with Michaelis-Menten principles of enzyme-substrate kinetics, thyroid hormone synthesis rapidly declines as the available tyrosyl substrate becomes limiting. Also, an overactive TPO may catalyze iodination of tyrosyl residues in albumin or thyroglobulin fragments.12 As no thyroactive hormones are formed, the metabolically inactive protein secreted into the circulation drains thyroidal iodide reserves further.12 Figure 1 represents a schematic ofthe possible pathogenetic mechanisms.



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Figure 1 Diagram depicting pathogenetic mechanisms of the rapid responder Graves’ disease. (a) In a typical Graves’ disease patient, increased concentrations of TSI increases thyroglobulin synthesis and increases iodine turnover with increased substrates for iodination and thyroid hormone formation. (b) In a typical Graves’ disease patient treated with antithyroid drugs (ATDs), where the iodide to ATD ratio is high, there is a reversible inhibition of thyroid peroxidase (TPO) enzyme with a decrease in thyroid hormone formation with periods of escape, wherein the concentrations of thionamides drop. (c) In Graves’ disease with high iodine turnover, wherein the iodide:ATD ratio is low, ATD irreversibly inhibits the TPO enzyme. This coupled with possibly a lesser degree of thyroid hyperplasia and relatively lower thyroglobulin synthesis may rapidly deplete the substrates available for thyroid hormone formation. On withdrawal of the drug, rapid iodination resumes when new TPO enzyme formation occurs. Size of the boxes indicates size of pool with smaller pools indicated by smaller boxes. ATD, antithyroid drug; c-AMP, cyclic adenosine monophosphate; DIT, di-iodotyrosine; H2O2, hydrogen peroxide; I–, iodide; I+, oxidized iodide; MIT, mono-iodotyrosine; mRNA, messenger ribonucleic acid; PDS, pendrin; T3, triiodothyronine; T4, thyroxine; TPO, thyroid peroxidase; TPO–, inhibited TPO after combination with ATD; TRAb, thyroid receptor anitbody

 

Notably, during the period of acute illness when the patient was not on any ATD, his FT4 concentration was very low, thus suggesting that although he had Graves’ disease, decreased TSH-stimulated mRNA synthesis or increased deiodinase-3 activity as seen in non-thyroidal illness13 will tend to result in a rapid decline in circulating thyroid hormones. In summary, this patient’s perplexing variant of thyrotoxicosis is aptly diagnosed as high iodine turnover or rapid responder Graves’ disease.6 Becausethis variant of Graves’ disease is rarely described and probablyconfusing to clinicians, our case report thus serves to highlightthe existence of this entity and contribute to the limited knowledgebase for physicians and endocrinologists.





Conclusion

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Postulated mechanisms for a rapid responder Graves’ disease include:

  1. A high iodine turnover with consequent low intrathyroidal iodine pool results in an increase in ATD:iodine ratio with irreversible blockade of an overactive, yet ATD-supersensitive TPO enzyme; upon withdrawal of the drug and resumption of TPO mRNA synthesis, an acute rebound of thyroid hormones occurs.
  2. Thyroglobulin synthesis, although accentuated by TSH receptor antibodies, is outstripped by an overactive TPO with resultant diminution of its reservoir and available specific tyrosine substrate iodination-organification sites when compared to patients with typical Graves’ disease. Decreased substrates for thyroid hormone biosynthesis, possibly coupled with limited goitrous thyroid hyperplasia, would additionally predispose to rapid development of hypothyroidism upon exposure to ATD.

 

This case underscores the importance of serial monitoring andastute interpretation of the thyroid function tests after startingATD. It is crucial to recognize these unusual subset of Graves’disease with high iodine turnover to avoid over-treatment. Givenits rarity, it is highly beneficial for the novice intriguedby such atypical responses to consult an experienced clinicalbiochemist, endocrinologist or thyroidologist. These patients,if medically treated, are best maintained on low doses of ATDand monitored frequently.

 

 

(Accepted July 18, 2008)



REFERENCES

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 REFERENCES


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  7. Lang JC, Lees JF, Alexander WF, et al. Effect of variations in acute and chronic iodine intake on the accumulation and metabolism of methimazole by the rat thyroid gland. Differences from propylthiouracil. Biochem Pharmacol 1983;32:241–7[Medline]
  8. Engler H, Taurog A, Luthy C, et al. Reversible and irreversible inhibition of thyroid peroxidase-catalyzed iodination by thioethylene drugs. Endocrinology 1983;112:86–95[Medline]
  9. Taurog A, Dorris ML, Guziec FS. Metabolism of 35S-and 14C labelled 1-methyl-2 mercaptoimidazole in vitro and in vivo. Endocrinology 1989;124:30–9[Medline]
  10. Doerge DR. Mechanism-based inhibition of lactoperoxidase by thiocarbamide goitrogens: identification of turnover and inactivation pathways. Biochemistry 1988;27:3697–700[Medline]
  11. Gavaret JM, Deme D, Nunez J, Salvatore G. Sequential reactivity of tyrosyl residues of thyroglobulin upon iodination catalyzed by thyroid peroxidase. J Biol Chem 1977;252:3281–5[Free Full Text]
  12. Greenspan FS. The thyroid gland. In: Greenspan FS, Gardner DG, eds. Basic and Clinical Endocrinology. 7th edn. USA: Mc Graw Hill Companies, 2004:215–94
  13. Peeters RP, Wouters PR, Van Toor H, et al. Serum rT3 and T3/rT3 are prognostic markers in critically ill patients and are associated with post-mortem tissue deiodinase activities. J Clin Endocrinol Metab 2005;90:4559–65[Abstract/Free Full Text]


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