Unusual Thyroid Lesions - ITS by Muthukrishnan Jayaraman | Papers by Muthukrishnan

Thyroid Research and Practice Thyroid Research and Practice Journal of the Indian Thyroid Society Editorial Office: Department of Endocrinology, Amrita Institute of Medical Sciences, Elammakara PO, Cochin - 682026, Kerala. Tel : 0484-4001030. Fax : 0484 - 2802020. E-mail : adwa@aims.amrita.edu CONTENTS. Vol : 5; No : 3, Sept - December 2008 EDITORIAL Glucocorticoids for thyroid-associated orbitopathy : suppressing the irrepressible? ............ 67 AG Unnikrishnan, S Bhat, R Bharath RV Jayakumar, H Kumar REVIEW ARTICLE Hyperthyroidism-related muscular disease ................................................................................. 70 AG Unnikrishnan ORIGINAL ARTICLES Unusual thyroid lesions : a clinicopathological exercise ..........................................................78 A Verma, J Muthukrishnan, KVS Harikumar, KD Modi, S Jha, B Kalyani Cytotoxic effects of low dose 131 I therapy - assessment .............................................................83 of chromosomal aberration and micronucleus as biomarkers S Sudha, PS Sundaram, S Padma, K Sasikala CASE REPORTS Thyroid vignette ................................................................................................................................. 90 MP Baruah, S Hazarika, U Bhuyan, S Baruah, K Saikia OTHERS Thyroid Images .................................................................................................................................. 92 Compiled by R Bharath, AG Unnikrishnan, S Sundaram, PS Sundaram Thyroid Watch .................................................................................................................................... 94 Compiled by M G Pillai 65 Thyroid Research and Practice Thyroid Research and Practice Journal of the Indian Thyroid Society Editorial Office: Department of Endocrinology, Amrita Institute of Medical Sciences, Elammakara PO, Cochin - 682026, Kerala. Tel : 0484-4001030. Fax : 0484 - 2802020. E-mail : adwa@aims.amrita.edu Editor-in-Chief R V Jayakumar Executive Editor A G Unnikrishnan Associate Editors Harish Kumar Vasantha Nair S Vaidyanathan P S Sundaram Advisory Board S Vittal (Chennai) J K Agrawal (Varanasi) K V Krishnadas (Trivandrum) V Bhatia (Lucknow) Nikhil Tandon (New Delhi) N Kochupillai (New Delhi) A M Samuel (Mumbai) Padma S Menon (Mumbai) Shashank Joshi (Mumbai) Aravindan Nair (Vellore) R K Sahay (Hyderabad) K M Prasannakumar (Bangalore) S K Singh (Varanasi) G R Sridhar (Vishakapatnam) B Krishna (Mumbai) M S Seshadri (Vellore) Gopalakrishnan Nair (Cochin) Subhankar Choudhury (Kolkata) D K Hazra (Agra) A C Ammini (New Delhi) M V Muraleedharan (Trichur) B K Das (Lucknow) C S Pandav (Delhi) Dheeraj Kapoor (New Delhi) Bharat Trivedi (Ahmadabad) Prakash Abraham (U K) 66 The Indian Thyroid Society (ITS) is a registered society (Reg. No : ER 450/2003, dated 28.5.2003) founded in 2003. The society aims to provide a forum for all surgeons, endocrinologists, nuclear physicians and physicians with a special interest in thyroidology. The journal will publish original articles, reviews, case reports and other articles of interest to doctors interested in thyroidology. Queries regarding the submission of the manuscript, subscription to the journal or membership to the society may be addressed to: The Editor, Thyroid Research and Practice, Indian Thyroid Society, Registered Office: Dept of Endocrinology, Amrita Institute of Medical Sciences,Cochin-682026, Kerala. The subscription charge for life membership to the society and lifetime subscription to the journal together is Rs 1500/- which is to be submitted by a DD or Cheque drawn in favor of the Indian Thyroid Society, payable at Cochin and sent to the ITS Office. The Indian Thyroid Society acknowledges that this journal is supported by a grant from Abbott India Limited. The Society also thanks Dr. R. Bharath and Dr. A. Premkumar for editorial assistance work. Thyroid Research and Practice Editorial Glucocorticoids for thyroid-associated orbitopathy : suppressing the irrepressible? AG Unnikrishnan*, S Bhat**, R Bharath* RV Jayakumar*, H Kumar* Thyroid-associated orbitopathy (TAO), also called Graves’ Ophthalmopathy is the commonest orbital inflammatory disorder in adults. The disease is thought to be due to antigenic mimicry between peptides in the eye and the thyroid gland.1 Extraocular muscles, fibroblasts and adipose tissues are all postulated sources of antigens. Recent studies indicate that orbital fibroblasts act as sentinel cells which initiate lymphocyte recruitment. A host of genetic factors, as well as environmental factors like smoking can predispose to the progression of TAO.2 The most important pathological feature of TAO is the swelling of extraocular muscles. The increase is due to connective tissue enlargement, lymphocyte infiltration, fibroblast excess and interstitial edema due to deposition of glycosaminoglycans. Retro-orbital connective tissue is also involved. The disease results in extraocular muscle swelling, diplopia, muscle weakness, proptosis, conjunctival congestion and periorbital soft tissue swelling. In severe cases, corneal involvement and optic nerve compression can result in blindness.3-5 TAO is classically associated with hyperthyroidism. However, patients may be euthyroid or even hypothyroid at presentation. While control of thyroid function is obviously important, the progression of eye disease is often de-linked from the thyroid hormone function. While immunosuppression, radiation and surgery have all been traditional options, their exact position in the management of thyroid associated orbitopathy (TAO) continue to be debated.3-5 Of particular concern is the use of steroid regimens, as any form of steroid therapy places the patient at significant risk of steroid-induced adverse effects. These disadvantages need to be weighed against the inhibitory effects of *Dept of Endocrinology, Amrita Institute of Medical Sciences, Elamakkara P.O., Cochin - 682026 ** Consultant Ophthalmologist, Giridhar Eye Institute, Kadavanthra, Cochin Corresponding author: AG UNNIKRISHNAN E-mail: unnikrishnanag@aims.amrita.edu steroids on the inflammation-abetting cells like lymphocytes and fibroblasts. Indeed it has been reported that steroid treatment can result in a good outcome in upto 85% of subjects with TAO.6 Soft tissue signs, recent-onset eye muscle dysfunction and dysthyroid optic neuropathy can all improve. Who are the patients responding best to steroid therapy? While this is controversial, there is general consensus that subjects in the acute inflammatory phase respond best. There are two distinct phases of TAO: i.e. the acute progressive phase and the chronic stable phase. Treatments to alter the natural history of orbitopathy (like steroids/ radiation) are best resorted to in the acute phase, where the disease is active. On the 67 Thyroid Research and Practice other hand, treatments to restore function and improve appearance (like surgery) are best attempted in the chronic phase. New methods to assess disease activity have helped in fixing the window period for disease-modifying therapies like glucocortocoids and radiation. Of particular importance is the use of a color atlas to grade the severity of orbitopathy.7 This uses photographs showing components of the external eye displaying varying degrees of clinical manifestations of orbitopathy. Objective interpretation of these clinical clues can help in classifying subjects as being in the active phase of the disease. A more traditional option is the use of the NOSPECS classification or the Clinical Activity Score, but it must be stressed that no single technique is hundred percent reliable. 5, 8 7 iatrogenic Cushing syndrome. In some patients, repeated, short courses of glucocortocoids may suffice, while in other subjects, a combination with another immunosuppressant would be desirable. The choice of appropriate agent for combination immunosuppression is often an individual one, and the traditional candidate agents are: methotrexate, azathioprine, cyclophosphamide and cyclosporine.12 From an ocular perspective, steroids can hasten glaucoma as well as cataract formation. 12 And from a systemic perspective hyperglycemia and osteoporosis are important considerations. In subjects who are already thyrotoxic and thus at risk of osteoporosis, the institution of steroid therapy increases the risk of osteoporosis. This risk is further increased in a postmenopausal age group, as these women are at particular risk of developing osteoporosis. While evidence-based guidelines are lacking, the use of calcium/ vitamin D supplements and performing a bone density measurement to screen for osteoporosis may be considered in selected cases at high risk of osteoporosis. In view of the side effects of steroid therapy, it is best to avoid glucocortocoids in very mild/ stable forms of orbitopathy. In severe cases or moderate cases associated with impending/ existing complications, glucocorticoid therapy should be considered. A special situation where glucocorticoid therapy is considered even in moderate, uncomplicated cases of TAO is in preparation of radioiodine therapy for Graves’ disease. It is well known that radioiodine therapy can worsen retinopathy, and glucocorticoid therapy has been used in the peri-I-131 therapy period to prevent this worsening. In very severe cases of orbitopathy, the role of multi-modality therapy is fast emerging as an option. In a recent study, patients (n=15) with severe, active TAO and optic nerve compression were randomized to two groups: pulsed intravenous methyl prednisolone or primary surgical decompression.13 Five out of the six (80%) subjects in the surgery arm required steroid therapy, and 4 out of the 9 (i.e. 45%) patients in the steroid therapy arm required surgery. These results clearly suggest that intravenous methyl prednisolone followed by surgery if necessary could be a reasonable choice of therapy. What about local steroids to avoid the side effects of systemic steroid therapy? With regard to retrobulbar steroids, the response rate is expected to be slower than systemic therapy. While subjects with increased disease activity are candidates for steroid therapy, systemic steroid therapy is almost always offered to subjects with optic nerve compression or severe / acute proptosis. While there are other issues in the management of TAO like radiation protocols, effect of smoking on TAO, use of diverse surgical techniques like decompression, strabismus repair, blepharoplasty etc, they are well beyond the scope of this article, which focuses on glucocorticoid therapy in this setting. In general, radiation therapy is considered as a second-line therapy after glucocorticoid regimens. 9 Several steroid regimens have been in use, which is a testimony to the fact that TAO is an irrepressible disease, i.e. no therapy can claim absolute success. A conventional regimen is to use prednisolone 60 to 80 mg/ day, either singly or in divided doses. This dose is given for about 15 days, and tapered over the next 4 weeks. An increasingly preferred option is to use intravenous pulsed methyl prednisolone delivery, as this has been shown to be more effective. 10, 11 However, acute liver injury and life-threatening liver damage has been reported at high cumulative doses of intravenous methyl prednisolone. It has been suggested that a cumulative dose of less than 8g is safe. An important problem with steroid therapy is that it has little post-treatment effect. In other words, the antiinflammatory effects of glucocortocoids last only as long as they are given. Inflammatory symptoms can even rebound if steroid therapy is abruptly discontinued. 12 However, continuing glucocorticoid therapy for 2-3 years continuously till TAO remits is fraught with the risk of developing a florid, 68 Thyroid Research and Practice In addition, retrobulbar injections run the risk of side effects of injecting into a small, tight, inflamed compartment like the orbit. 12 Topical steroids can reduce ocular surface inflammation, but cannot promise to cure the deep-seated orbital inflammation. Clearly, while topical therapies have their individual place, at a broad glance, systemic steroid therapy seems to be superior. Recent consensus statements have emerged to clarify the roles of glucocorticoid therapy, orbital radiation and surgery in the management of orbitopathy.14 However, none of these therapies can offer a complete cure. These treatments can only promise to temporarily suppress/ slow the natural history of this irrepressible disease. New therapies like cytokine antagonist and octreotide therapy have been tried with modest effects,15, 16 but research must continue to test new therapies that promise to change the natural history of this disease. 7. Dickinson A, Perros P. Controversies in the clinical evaluation of active thyroid-associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment. Clin Endocrinol (Oxf) 2001;55:283-303. 8. Mourits MP, Koornneef L, Wiersinga WM, et al. Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol 1989;73:639-44. 9. McNab AA, Cockerham KP, Kennerdell JS,et al. Does radiotherapy have a role in the management of thyroid orbitopathy? Br J Ophthalmol 2002; 86:102-7. 10. Kahaly GJ, Pitz S, Hommel G, et al. Randomized single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 2005;90:5234-40. 11. Kauppinen-Makelin R, Karma A, Leinonen E, et al. High dose intravenous methylprednisolone pulse therapy versus oral prednisone for thyroid-associated ophthalmopathy. Acta Ophthalmol Scand 2002;80:316-21. References 1. Kazim M, Goldberg RA, Smith TJ. Insights into the pathogenesis of thyroid-associated orbitopathy: Evolving rationale for therapy. Arch Ophthalmol 2002;120:380-6. 2. Manji N, Carr-Smith JD, Boelaert K, et al. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J Clin Endocrinol Metab 2006; 91:4873-80. 3. Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves’ Disease and ophthalmopathy. Endocr Rev 2003; 24:802-35. 4. Cawood T, Moriarty P, O’Shea D. Recent developments in thyroid eye disease. BMJ 2004;329:385-90. 5. Bartalena L, Pinchera A, Marcocci C. Management of Graves’ Ophthalmopathy: Reality and perspectives. Endocr Rev 2000;21:168-99. 6. Marcocci C, Bartalena L, Tanda ML, et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ Ophthalmopathy: Results of a prospective, single-blind, randomized Study. J Clin Endocrinol Metab 2001; 86:3562-7. 12. Lee H, Rodgers I, Woog J. Evaluation and management of Graves’ orbitopathy. Otolaryngol Clin North Am 2006;39:923-42. 13. Wakelkamp I, Baldeschi L, Saeed P, et al. Surgical or medical decompression as a first-line treatment of optic neuropathy in Graves’ ophthalmopathy? A randomized controlled trial. Clin Endocrinol (Oxf) 2005; 63:323-8. 14. Bartalena L, Baldeschi L, Dickinson A, et al. Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008;158:273-85. 15. Wemeau JL, Caron P, Beckers A, et al. Octreotide (Long-Acting Release Formulation) treatment in patients with Graves’ Orbitopathy: Clinical results of a four-month, randomized, placebo-controlled, double-blind Study. J Clin Endocrinol Metab 2005; 90:841-8. 16. Salvi M, Vannucchi G, Campi I, et al. Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 2007;156:33-40. 69 Thyroid Research and Practice Review Article Hyperthyroidism-related muscular disease AG Unnikrishnan Abstract Muscular disorders can occur in hyperthyroidism. These include thyrotoxic myopathies and thyrotoxic periodic paralysis. Thyrotoxic myopathies are the commonest manifestation, and usually affect the proximal muscles. Occasionally, these myopathies may be more localized in nature, and several examples of discrete involvement, for instance bulbar paralyses and diaphragmatic weakness have been reported in medical literature. Thyrotoxic periodic paralysis is an acute severe form of muscle weakness and declining potassium levels that is associated with thyrotoxicosis. In addition, Graves’ Ophthalmopathy, which involves the extra-ocular muscles, is associated with, but not causally linked to thyroid hormone excess. Finally, the prevalence of myasthenia gravis is higher in subjects with thyrotoxicosis. This article will focus on the spectrum of muscular involvement seen in subjects with thyrotoxicosis. Key words: Thyrotoxic myopathy, periodic paralysis, hypokalemia, Myasthenia Gravis. Introduction Thyroid hormones play an important role in the metabolism of skeletal muscles. It has been suggested that complex effects of thyroid hormones on skeletal muscle gene expression mediate this effect.1 Hyperthyroidism is associated with a high metabolic rate, muscle protein breakdown, and weight loss. Muscular disorders are, thus, quite common in hyperthyroidism. The spectrum of muscular diseases in hyperthyroidism Department of Endocrinology and Diabetes Amrita Institute of Medical Sciences Elamakkara, Cochin 682026, India Corresponding Author AG UNNIKRISHNAN E-mail: unnikrishnanag@aims.amrita.edu essentially encompasses four disorders (Table 1) Table 1. Spectrum of muscular disorders in hyperthyroidism Thyrotoxic myopathy Thyrotoxic Periodic Paralysis Due to associated diseases Thyroid-associated Orbitopathy Myasthenia Gravis Directly related to hyperthyroidism 70 Thyroid Research and Practice Thyrotoxic Myopathy Thyrotoxic myopathy is a common manifestation, seen in about 60-80% of subjects with thyrotoxicosis.2,3 Fatigue, weakness and cramps are common complaints.4 Characteristically, the disease involves the pectoral and the pelvic girdle muscles. The iliopsoas and the quadriceps are commonly involved, and usually the weakness is not extremely severe.5 In these muscle groups, weakness and wasting is often noticed, and this is usually symmetric. Fasiculations are rare. Wasting of the temporalis and interossei may be seen in many patients, and in severe cases, there is generalized skeletal muscle wasting. Serum creatinine kinase levels are normal, and do not correlate with the severity.5 Electromyography is usually normal. There is evidence that severe degrees of involvement are becoming less common in developing countries, probably owing to earlier diagnosis. More and more cases of focal muscular involvements are being reported, involving the bulbar and respiratory muscles, especially the diaphragm.6, 7 Treatment Thyrotoxic myopathy rapidly responds to restoration of a euthyroid state with anti-thyroid drug therapy. In a prospective follow up study of subjects with hyperthyroidism, all muscular symptoms disappeared within an average period of 3 months, and complete restoration of power occurred in all subjects at the end of one year.5 Thyrotoxic subjects with bulbar and respiratory muscle weakness also respond promptly to the restoration of a euthyroid state.6,7 Therapy with beta blockers can partially improve generalized weakness in thyrotoxic subjects, leading authors to hypothesize that both thyrotoxic and adrenergic effects mediate muscle weakness in these subjects.8 Thyrotoxic Periodic Paralysis Thyrotoxic periodic paralysis (TPP) is a reversible disorder characterized by acute muscle weakness, hypokalemia (often with potassium levels <3.0 mEq/L), and hyperthyroidism.9 It is commoner in Asian men, and affects them in the third to fifth decades.10 Thyrotoxic periodic paralysis (TPP) is an endocrine emergency, and the classic presentation is that of acute severe muscle weakness involving all four extremities. 10 a high degree of clinical suspicion is essential to make the diagnosis, because arrhythmias or respiratory failure can occur.11,12 Fatal TPP has also been reported. 13 Etiopathogenesis The exact etiopathogenesis of the illness remains a mystery, but the attack is often brought on after strenuous exertion and a carbohydrate-rich meal.14 Subjects with TPP have paralysis only when they are thyrotoxic. Graves’ disease is the most common association, and an association with HLADRw8 has been reported.15 However, the specific etiology does not seem to be important, as TPP has been reported in association with almost any form of thyrotoxicosis, including nodular goitre, thyroiditis, amiodarone-induced hyperthyroidism and thyroxine overdosage.9 Excess Na+, K+ATPase in hyperthyroidism has been the cornerstone of the pathogenesis, as this pump stimulates the exit of sodium ions out of the cell and couples it with the entry of potassium ions into the cell.16 It has been reported that Na+,K+-ATPase activity is significantly higher in these subjects with thyrotoxicosis and paralysis when compared with thyrotoxic subjects without paralysis. 16 Thyrotoxicosis is well known to be a hyperadrenergic state, and β-2 adrenergic receptor stimulation results in excess activation of the Na+, K+-ATPase pump.17 The exact cause of the hyperadrenegic state has been a subject of debate, but some reasons have been proposed: catecholamine secretion, catecholamine sensitivity and the molecular similarities that exist between thyroid hormones and catecholamines.9 The relation of TPP to strenuous exertion is probably related to the worsening of the adrenergic state. Moreover, it has also been postulated that thyroid hormones directly increase Na+, K+-ATPase activity.16 Several HLA antigen subtypes have been described, notably HLA-DRw8 in Japanese, and several subtypes in the Chinese population too.15,18 Ethnic differences could be due to genetic mutations in the control of Na+, K+-ATPase activity within the same HLA antigen subtype. Male predominance may reflect the stimulatory action of androgen on Na+, K+-ATPase activity.19 Meal related paralysis might be because of mealinduced insulin secretion, as insulin can push potassium ions into the cell, and cause hypokalemia.20 Insulin also has a direct action on potassium conductance in skeletal muscle 71 Sometimes, overt features of hyperthyroidism are lacking, and Thyroid Research and Practice membranes.21 Another theory is that TPP is a channelopathy. Because TPP is very similar to familial periodic paralysis (FPP), it has been postulated that TPP too, like FPP, is an ion channelopathy involving the skeletal muscle, though this has been a matter of controversy. 22-28 nephrogenic diabetes insipidus (and therefore polyuria), which might falsely lower the urinary K+, but this will not falsely affect the urine potassium: creatinine ratio. Urinary calcium is often high due to the resorptive effects of thyrotoxicosis on the bone (thyrotoxicosis removes calcium from bone and the excess calcium is lost in the urine).9 Urine phosphorous is low as phosphorous enters the cells, and is not lost in the urine. ECG is also a useful test, because in addition to the U-waves seen in hypokalemia, sinus tachycardia or sinus arrest, high QRS voltage, Wenckebach atrioventricular block, and even ventricular fibrillation has been reported in TPP. 40,41 Electromyography shows low amplitude electrical compound muscle action potential (CMAP), which disappears during remission, suggesting that the defect lies in the muscle.42,43 The exercise test can be a useful test to diagnose periodic paralysis.44 However, it cannot differentiate between TPP and FPP, as exercise can precipitate weakness in both forms. However, after epinephrine infusion, subjects with FPP show reductions in CMAP, whereas no change occurs in TPP.9, 45 Treatment Immediate therapy consists of giving oral or intravenous potassium therapy to correct hypokalemia. Rather than aggressive, high dose infusions, low dose K+ supplementation could well be the preferred treatment in the future, as reports have suggested that K+ infused at 10mEq/hr more than controls was associated with a two-fold shorter period of recovery, but with a high incidence of rebound hyperkalemia (which was correlated with the potassium chloride dose).46,47 However, this is controversial and for the moment, judicious replacement of potassium, with a careful monitoring for rebound hyperkalemia seems to be the right therapeutic option. Propranolol, when given either orally or intravenously, has been shown to have a beneficial effect on paralytic symptoms.48 Propranolol, being a nonselective beta-blocker, seems to exercise benefits on both heart rate (β-1 effect) and K+ level (β-2 effect). Only well designed randomized studies will clarify whether a combination of low dose potassium supplementation with non-selective beta blockade will become the therapy of choice in future.9,49 It must be noted that acetazolamide, a drug used for familial periodic paralysis, must not be used for TPP, as it can worsen the attacks.50 Recent studies have shown three novel single nucleotide polymorphisms in Ca (v) 1.1 (the calcium channel gene), which are situated at or near the thyroid hormone–responsive element. Clinical Features Clinical features of TPP begin insidiously, with a prodrome of cramps, aches and muscle stiffness. Proximal weakness supervenes, and this is followed by flaccid quadriplegia. The following systems are spared: sensation, mental function and functions involving the bulbar and ocular muscles. The classic description is that of an Asian male in his third decade, presenting with weakness after exertion or a carbohydraterich meal. Notably, TPP does not occur during exercise, but in the resting period after exercise. Deep tendon reflexes are sluggish. Thyrotoxic features may be subtle, and nearly onehalf of the patients have no symptoms during the attack. Between attacks, the subjects are normal, and do not show persistent weakness characteristic of thyrotoxic myopathy. 30-36 29 Laboratory findings The serum potassium falls, but sometimes the value is still within the normal range. Hypophosphatemia, probably due to the entry of phosphorous into the cell, has also been reported, and might play an additional role in muscle weakness.37-39 Acid base status is usually normal, as the entry of potassium into the cell is accompanied by the exit of sodium/ hydrogen ions outside the cell, and the bicarbonate that buffers the excess hydrogen ions often results in a small decline in the serum bicarbonate level. However, anxiety can provoke minor respiratory alkalosis and respiratory failure can trigger a mild acidosis in this setting. Urine potassium is a useful test, and would be low (<20meq/L) because hypokalemia is related to intracellular K entry and not because of renal losses. However, the urine potassium: creatinine ratio (a value less than 2 mEq/mmol is seen in TPP) is a better test.9 This is because hypokalemia can result in secondary + 72 Thyroid Research and Practice The definitive therapy of TPP is the correction of hyperthyroidism, which can be achieved by anti-thyroid drugs, surgery or radioiodine therapy, depending on the etiology of thyrotoxicosis, and individualized to the thyrotoxic subject suffering from TPP. Definitive control of thyrotoxicosis completely abolishes the attacks of TPP. While waiting for the normalization of thyroid function, the patient may be asked to avoid precipitants. Prophylactic K is ineffective as the potassium levels are usually normal between attacks. About 2 weeks of antithyroid drug therapy might be necessary before the risk of developing TPP has ameliorated. 51 Thyroid-associated orbitopathy Thyroid-associated orbitopathy (TAO) is an autoimmune disease affecting the orbit associated with Graves’s hyperthyroidism. The disease results in extraocular muscle swelling, diplopia, muscle weakness, proptosis, conjunctival congestion and periorbital soft tissue swelling. In severe cases, corneal involvement and optic nerve compression can result in blindness. Some evidence of orbitopathy, clinical or radiological, is present in about 70% subjects with Graves’ disease.53 Ophthalmopathy can occur concurrently with, or precede or even follow the onset of thyrotoxicosis in these subjects. The disease is thought to be due to antigenic mimicry between peptides in the eye and the thyroid gland. Extraocular muscles, fibroblasts and adipose tissues are all postulated sources of antigens.54,55 Recent studies indicate that orbital fibroblasts act as sentinel cells which initiate lymphocyte recruitment. 55 A host of genetic factors, as well as environmental factors like smoking can predispose to the onset or progression of TAO.56 The most important pathological feature of TAO is the swelling of extraocular muscles. The increase is due to connective tissue enlargement, lymphocyte infiltration, fibroblast excess and interstitial edema due to deposition of glycosaminoglycans.55,56 The disease results in a restrictive tightness of the muscle, as muscle inflammation results in adherence to surrounding structures. This could result in diplopia. In 10-20% of cases, there is some paralysis of muscle function too. The most common muscles restricted are the inferior and medial recti. Thus, patients find difficulties in the upward or lateral gaze. The orbit is a small cone, and a relative 52 9 + increase in orbital contents will cause proptosis, and the eye protrudes out through the anteriorly placed base of this cone. If compression at the narrow, posterior end of the orbit occurs, the optic nerve can be dangerously compressed. The disease appears to evolve in two phases: as the early active lymphocyte proliferation phase gives way to a late chronic phase stage of fibrosis. Several criteria have evolved to assess the activity of the disease (which predicts the response to steroids/ radiotherapy) as well as to assess the severity of TAO, which is useful in monitoring outcomes of therapy. 57, 58 Investigations may show hyperthyroidism or the patient may be euthyroid, or even rarely hypothyroid. Anti-thyroid antibodies, especially TSH-receptor antibodies (a hallmark of Graves Disease) are a useful test if thyroid functions are normal. CT/MR imaging shows the classic spindle-like spreading of the recti muscles (>4 mm) without involvement of the tendons (Figure 1). The rectus muscles are the most Figure 1. Characteristic enlargement of extraocular muscles (A, B) with relative sparing of tendons in one of our patients with thyroid-associated orbitopathy commonly involved (inferior>medial > superior). Sometimes, the inferior rectus enlargement is focal, mimicking a tumor (figure 2). Advantages of MR over CT is that the former can delineate compressive optic nerve changes better, and may also distinguish the active lymphocytic inflammatory phase 73 Thyroid Research and Practice these include cytokine antagonists like infliximab.64 Octreotide has also bee tried with partial success.65 In view of a recent report suggesting that pioglitazone (a PPAR agonist) caused deterioration of thyroid orbitopathy, it has been proposed that PPAR antagonism may be a possible target for future intervention.66 Myasthenia Gravis in Hyperthyroidism Myasthenia Gravis (MG) is an autoimmune disease of the neuromuscular junction and occurs due to antibodies directed against the acetylcholine receptor. About 5-10% of subjects with myasthenia have autoimmune thyroid diseases though Figure 2. Shows the typical enlargement of an extra-ocular muscle (A) in our patient with thyroid-associated orbitopathy. This can sometimes be mistaken for an orbital tumor this is controversial.67, 68 The association is probably due to a common predisposition to organ-specific immunity, and not the direct result of either MG or hyperthyroidism. Particularly important is Graves Disease, which is characterized by TSHreceptor antibodies that stimulate the thyroid gland and produce hyperthyroidism. However, the prevalence of of orbitopathy from the chronic fibrotic stage. The Octreoscan (a radionuclide scan using indium-labeled octerotide) is fast emerging as a useful test as it is sensitive to orbital inflammation, because it is a good index of disease activity. In a large multicenter study, disease activity was associated with the need for aggressive immunosuppressive therapy. In this study, subjects had classic features of the disease: proptosis (63%), eye motility dysfunction (49%), keratopathy (16%) and optic nerve involvement (21%). Treatment Three modalities are available for therapy of TAO: medical, surgical and radiotherapy. In the early active phase of the disease, the treatment options include medical therapy, radiation and surgery. A recent study has shown that intravenous methylprednisolone given weekly is superior to oral prednisolone therapy. 61 Radiation therapy is also useful, and could be reserved for drug-unresponsive cases. Surgery is indicated in optic nerve compression. In the chronic burntout disease with residual deficits, surgery may be used to correct diplopia or improve cosmetic appearance. 52 Radioiodine therapy given for thyrotoxicosis can worsen moderate and severe orbitopathy, but does not appear to adversely affect minimally active orbitopathy. 63 62 60 59 autoimmune thyroid diseases in MG is low, i.e. only about 0.2%.67 It has been reported that MG in hyperthyroidism is milder, and that ocular myasthenia, rather than generalized myasthenia is more commonly associated with hyperthyroidism.67 The reasons for the association could either are be a common genetic susceptibility, or an immunological cross reactivity between thyroid and eyemuscle antigens, or both. Usually, thyrotoxic symptoms precede or occur concurrently with MG. Rarely, thyroidassociated orbitopathy and MG can co-exist, and in this regard, the presence of either ptosis or paresis in a patient with thyroid-associated orbitopathy should alert the suspicion of coexistent MG.69 Diplopia is a common feature of both thyroidassociated orbitopathy and myasthenia gravis. Subjects with myasthenia do not have proptosis or periorbital edema, but may have exotropia or weakness of the orbicularis oculi muscles. Treatment Therapeutic considerations for MG in thyrotoxicosis are essentially no different from conventional therapy for MG. Combined medical treatment for both thyrotoxicosis and myasthenia can be undertaken simultaneously.70 Concurrent thyroidectomy and thymectomy at the same sitting also has been reported.71 Newer therapies for orbitopathy have been proposed for the future: 74 Thyroid Research and Practice References 1. Clement K, Viguerie N, Diehn M, et al. In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res 2002;12:281-91. 2. Ramsay ID. Electromyography in thyrotoxicosis. Q J Med 1965;34:255-67. 15. Tamai H, Tanaka K, Komaki G, et al. HLA and thyrotoxic periodic paralysis in Japanese patients. J Clin Endocrinol Metab 1987;64:1075-8. 16. Chan A, Shinde R, Chow C, et al. In vivo and in vitro sodium pump activity in subjects with thyrotoxic periodic paralysis. 1991; 303 17. Brown M, Brown D, Murphy M. Hypokalemia from β 2- 3. Puvanendran K, Cheah JS, Naganathan N, et al. Thyrotoxic myopathy. A clinical and quantitative analytic electromyographic study. J Neurol Sci 1979;42:441-51. receptor stimulation by circulating epinephrine. N Engl J Med 1983;309:1414-9. 18. Hawkins B, Ma J, Lam K, et al. Association of HLA antigens 4. Weetman AP. Graves’ Disease. N Engl J Med 2000;343:123648. 5. Duyff RF, Van den Bosch J, Laman DM, et al. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000;68:750-5. 6. Chiu W, Yang C, Huang I, et al. Dysphagia as a manifestation of thyrotoxicosis: report of three cases and literature review. Dysphagia 2004;19:120-4. 7. Goswami R, Guleria R, Gupta A, et al. Prevalence of diaphragmatic muscle weakness and dyspnea in Graves’ disease and their reversibility with carbimazole therapy. Eur J Endocrinol 2002; 147:299-303. 8. Olson B, Klein I, Benner R, et al. Hyperthyroid myopathy and the response to treatment. Thyroid 1991;1:137-41. 9. Lin S. Thyrotoxic periodic paralysis. Mayo Clin Proc 2005;80:99-105. 10. Goh SH. Thyrotoxic periodic paralysis: reports of seven patients presenting with weakness in an Asian emergency department. Emerg Med J 2002;19:78-9. 11. Liu Y, Tsai W, Chau T, Lin S. Acute hypercapnic respiratory failure due to thyrotoxic periodic paralysis. Am J Med Sci 2004;327:264-7. with thyrotoxic Graves’ disease and periodic paralysis in Hong Kong Chinese. Clin Endocrinol (Oxf) 1985;23:245-52. 19. Guerra M, Rodriguez del Cas A, Battaner E, et al. Androgens stimulate preoptic area Na+,K+-ATPase activity in male rats. Neurosci Lett 1987;78:97-100. 20. Chan A, Shinde R, Chow C, et al. Hyperinsulinaemia and Na+, K(+)-ATPase activity in thyrotoxic periodic paralysis. Clin Endocrinol (Oxf) 1994;41:213-6. 21. Ruff RL. Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K current. Neurology 1999;53: 1556-60 22. Ng W, Lui K, Thai A, et al. Absence of ion channels CACN1AS and SCN4A mutations in thyrotoxic hypokalemic periodic paralysis. Thyroid 2004;14:187-90. 23. Dias da Silva M, Cerutti J, Tengan C, et al. Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel alpha1 subunit gene (Cav1.1) are not associated with thyrotoxic hypokalaemic periodic paralysis. Clin Endocrinol (Oxf) 2002; 56:367-75. 24. Kim T, Song J, Kim W, Shong Y. Arg16Gly polymorphism in β 2-adrenergic receptor gene is not associated with thyrotoxic periodic paralysis in Korean male patients with Graves’ disease. Clin Endocrinol (Oxf) 2005;62:585-9. 25. Cannon S. Ion-channel defects and aberrant excitability in 12. Fisher J. Thyrotoxic periodic paralysis with ventricular fibrillation. Archives of Internal Medicine 1982;142:1362-4. 13. Randall B. Fatal hypokalemic thyrotoxic periodic paralysis presenting as sudden, unexplained death of a Cambodian refugee. Am J Forensic Med Pathol 1992;13:204-6. 14. Kelley DE, Gharib H, Kennedy FP, et al. Thyrotoxic periodic paralysis. Report of 10 cases and review of electromyographic findings. Arch Intern Med 1989;149:2597-600. myotonia and periodic paralysis. Trends Neurosci 1996; 19:3-10. 26. Dias Da Silva MR, Cerutti JM, Arnaldi LAT, et al. A Mutation in the KCNE3 Potassium Channel Gene Is Associated with Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis. J Clin Endocrinol Metab 2002;87:4881-4. 27. Tang N, Chow C, Ko G, et al. No mutation in the KCNE3 potassium channel gene in Chinese thyrotoxic hypokalemic 75 Thyroid Research and Practice periodic paralysis patients. Clin Endocrinol (Oxf) 2004;61: 109-12. 28. Lane A, Markarian K, Braziunene I. Thyrotoxic periodic paralysis associated with a mutation in the sodium channel gene SCN4A. J Pediatr Endocrinol Metab 2004;17:1679-82. 29. Kung AWC, Lau KS, Fong GCY, et al. Association of Novel Single Nucleotide Polymorphisms in the Calcium Channel {alpha}1 Subunit Gene (Cav1.1) and Thyrotoxic Periodic Paralysis. J Clin Endocrinol Metab 2004;89:1340-5. 30. Pimentel L, Hansen KN. Thyroid disease in the emergency department: A clinical and laboratory review. Journal of Emergency Medicine 2005;28:201-9. 31. Lin Y, Wu C, Pei D, et al. Diagnosing thyrotoxic periodic paralysis in the ED. Am J Emerg Med 2003;21:339-42. 32. Sinharay R. Hypokalaemic thyrotoxic periodic paralysis in an Asian man in the United Kingdom. Emerg Med J 2004;21: 120 1. 33. Gordon D, Agrawal L, Swade T, et al. Thyrotoxic hypokalemic periodic paralysis: six cases in non-Asian patients. Endocr Pract 1998;4:142-5. 34. Paul B, Hirudayaraj P, Baig MW. Thyrotoxic periodic paralysis: an unusual presentation of weakness. Emerg Med J 2003; 20:7e. 35. Ober K. Thyrotoxic periodic paralysis in the United States. Report of 7 cases and review of the literature. Medicine (Baltimore) 1992;71:109-20. 36. Magsino C, Ryan A. Thyrotoxic periodic paralysis. South Med J 2000;93:996-1003. 37. Norris K, Levine B, Ganesan K. Thyrotoxic periodic paralysis associated with hypokalemia and hypophosphatemia. Am J Kidney Dis 1996;28:270-3. 53. Kahaly G. Imaging in thyroid-associated orbitopathy. Eur J 38. Nora N, Berns A. Hypokalaemic, hypophosphatemic thyrotoxic periodic paralysis. Am J Kidney Dis 1989;13:247-9. 54. Bahn RS, Heufelder AE. Pathogenesis of Graves’ 39. Guthrie GP, Jr, Curtis JJ, Beilman KM. Hypophosphatemia in thyrotoxic periodic paralysis. Archives of Internal Medicine 1978; 138:1284-1285. 40. Chia B, Lee K, Cheah J. Sino-atrial Wenckebach conduction in thyrotoxic periodic paralysis: a case report. Int J Cardiol 1995; 47:285-9. 41. Ee B, Cheah J. Electrocardiographic changes in thyrotoxic periodic paralysis. J Electrocardiol 1979;12:263-79. 42. Puvanendran K, Cheah J, Wong P. Electromyographic (EMG) study in thyrotoxic periodic paralysis. Aust N Z J Med 1977;7:507-10. 76 43. Engel A, Lambert E, Rosevar J, et al. Clinical periodic paralysis. Am J Med 1965;38:626-40. and electromyographic studies in a patient with primary hypokalemic 44. Tengan CH, Antunes AC, Gabbai AA, et al. The exercise test as a monitor of disease status in hypokalaemic periodic paralysis. J Neurol Neurosurg Psychiatry 2004;75:497-9. 45. Kelley DE, Gharib H, Kennedy FP, et al. Thyrotoxic periodic paralysis. Report of 10 cases and review of electromyographic findings. Archives of Internal Medicine 1989;149:2597-600. 46. Manoukian MA, Foote JA, Crapo LM. Clinical and metabolic features of Thyrotoxic periodic paralysis in 24 Episodes. Arch Intern Med 1999;159:601-6. 47. Lu K, Hsu Y, Chiu J, et al. Effects of potassium supplementation on the recovery of thyrotoxic periodic paralysis. Am J Emerg Med 2004;22:544-7. 48. Lin S, Lin Y. Propranolol rapidly reverses paralysis, hypokalemia, and hypophosphatemia in thyrotoxic periodic paralysis. Am J Kidney Dis 2001;37:620-3. 49. Tassone H, Moulin A, Henderson S. The pitfalls of potassium replacement in thyrotoxic periodic paralysis: a case report and review of the literature. J Emerg Med 2004; 26:157-61. 50. Shulkin D, Olson B, Levey G. Thyrotoxic periodic paralysis in a Latin-American taking acetazolamide. Am J Med Sci 1989;297:337-8. 51. Rone J, Brietzke S. Euthyroid thyrotoxic periodic paralysis. Mil Med 1991;156:434-6. 52. Bartalena L, Pinchera A, Marcocci C. Management of Graves’ Ophthalmopathy: Reality and Perspectives. Endocr Rev 2000;21:168-99. Endocrinol 2001;145:107-18. Ophthalmopathy. N Engl J Med 1993; 329:1468-75. 55. Prabhakar BS, Bahn RS, Smith TJ. Current Perspective on the Pathogenesis of Graves’ Disease and Ophthalmopathy. Endocr Rev 2003;24:802-35. 56. Wiersinga WM, Prummel MF. Pathogenesis of Graves’ Ophthalmopathy-Current Understanding. J Clin Endocrinol Metab 2001;86:501-3. 57. Mourits MP, Prummel MF, Wiersinga WM, et al. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clinical Endocrinology 1997;47:9-14. Thyroid Research and Practice 58. Rose GE. Clinical activity score as a guide in the management of patients with Graves’ orbitopathy. Clinical Endocrinology 1997;47:15-8. 59. Prummel M, Bakker A, Wiersinga W, et al. Multi-center study on the characteristics and treatment strategies of patients with Graves’ orbitopathy: the first European Group on Graves’ Orbitopathy experience. Eur J Endocrinol 2003;148:491-5. 60. Cawood T, Moriarty P, O’Shea D. Recent developments in thyroid eye disease. BMJ 2004; 329:385-90. 61. Kahaly GJ, Pitz S, Hommel G, et al. Randomized single blind trial of intravenous versus oral steroid monotherapy in Graves’ Orbitopathy. J Clin Endocrinol Metab 2005;90:5234-40. 62. Bartalena L, Marcocci C, Pinchera A. Orbital Radiotherapy for Graves’ Ophthalmopathy. J Clin Endocrinol Metab 2004;89: 13-4. 63. Perros P, Kendall-Taylor P, Neoh C, et al. A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimally active Graves’ Ophthalmopathy. J Clin Endocrinol Metab 2005;90:5321-3. 64. Tao JP, Siddens J. Infliximab treatment of refractory thyroid associated orbitopathy. Invest Ophthalmol Vis Sci 2005; 46:4263-7. 65. Wemeau JL, Caron P, Beckers A, et al. Octreotide (Long-Acting Release Formulation) Treatment in patients with Graves’ Orbitopathy: Clinical results of a four-month, randomized, placebo-controlled, double-blind study. J Clin Endocrinol Metab 2005;90:841-8. 66. Starkey K, Heufelder A, Baker G, et al. Peroxisome Proliferator-Activated Receptor-{gamma} in thyroid eye disease: Contraindication for Thiazolidinedione use? J Clin Endocrinol Metab 2003;88:55-9. 67. Marino M, Ricciardi R, Pinchera A, et al. Mild clinical expression of Myasthenia Gravis associated with autoimmune thyroid diseases. J Clin Endocrinol Metab 1997;82:438-43. 68. Weissel M. Mild clinical expression of Myasthenia Gravis associated with autoimmune thyroid disease. J Clin Endocrinol Metab 1997; 82:3905-10. 69. Yaman A, Yaman H. Ocular myasthenia gravis coincident with thyroid ophthalmopathy. Neurol India 2003;51: 100-1. 70. Teoh R, Chow C, Kay R, et al. Response to control of hyperthyroidism in patients with myasthenia gravis and thyrotoxicosis. Br J Clin Pract 1990;44:742-4. 71. Naganathan N, Nambiar R, Tan N, et al. A case of myasthenia gravis with thyrotoxicosis treated by combined subtotal thyroidectomy and total thymectomy. Br J Surg 1977; 64:817-8. 77 Thyroid Research and Practice Original Article Unusual thyroid lesions : a clinicopathological exercise A Verma*, J Muthukrishnan*, KVS Harikumar*, KD Modi*, S Jha **, B Kalyani *** Abstract Thyroid disorders are a common platform where endocrinology, surgery and pathology departments need frequent interaction. We report four challenging thyroid cases that were diagnosed post operatively after histopathological examination are quite uncommon and challenging for a clinician involved in thyroid practice. Our first case is a patient for whom functioning papillary thyroid carcinoma was diagnosed, had multinodular goiter and features of hyperthyroidism with histopathological changes of papillary thyroid carcinoma and rest of the gland was normal. Another case of large goiter with obstructive symptoms with anasarca and proteinuria underwent emergency surgery and was diagnosed as amyloidosis of thyroid on basis of gross appearance and histopathological changes. Solitary fibrous tumor and lymphangioma of thyroid gland were two other rare cases that were diagnosed after diligent histopathological work-up. Pathologists experienced in thyroid diseases can be of great help in managing unusual thyroid lesions. These are rare conditions and they posed a management challenge till final diagnosis was achieved. Pathologists with awareness about such entities, in close interaction with the treating physician and surgeon, can contribute a lot in diagnosing such unusual conditions. Key Words : Thyroid, Amyloidosis, Solitary fibrous tumor, Lymphangioma. *Department of Endocrinology and Metabolism, **Surgical Endocrinology ***Department of Pathology, Medwin Hospitals, Chirag Ali Lane, Nampally, Hyderabad – 500001 Corresponding Author: KD MODI Email: drkdmodi@yahoo.co.in Introduction Thyroid disorders requiring pathological evaluation and surgical management form a small but significant subset of medical endocrinology practice. At our centre, out of total outpatient load of 600-700 per month, thyroid cases contribute 20-25%. Every month on an average 25-30 fine needle cytology for thyroid are performed and 10-15 cases are operated. 78 Thyroid Research and Practice Over the past decade, we encountered certain unusual thyroid lesions which were a challenging surgical and pathological exercise. Functioning papillary carcinoma of thyroid masquerading as Graves’ disease, suspected case of amyloidosis of thyroid, solitary fibrous nodule, thyroid lymphangioma were some of the interesting cases which warrant documentation. We believe that these cases will be of interest to practicing clinicians and pathologists dealing with thyroid disorders. Case 1 A case of Functioning Papillary carcinoma of thyroid masquerading like Graves’ disease: A 35 years old lady presented with history suggestive of thyrotoxicosis for 5 years. On examination, she had grade III goiter with bilateral exopthalmous and tachycardia. Her thyroid profile was suggestive of uncontrolled hyperthyroidism. Xray chest showed miliary mottling, suggestive of metastasis. Thyroid microsomal antibody was negative. Total thyroidectomy was performed after controlling her hyperthyroid state with increased dosage of anti-thyroid drugs, beta-blockers and colloidal Iodine. A 65 years old female presented with a progressively enlarging goiter of 11 years duration with dysphagia and hoarseness of voice of one-month. She had pedal edema for the past 6 months. Clinically, she was euthyroid and Pemberton’s sign was positive (suggestive of superior vena caval compression). She had impaired renal parameters (Blood urea: 55 mg/dL, S. Creatinine: 2.0 mg/dL and Proteinuria : urine albumin 2+). Ultrasonography revealed bilateral normal sized kidneys with increased echogenicity. Fine needle aspiration cytology of thyroid revealed cheesy aspirate, but was inconclusive. Figure 1.1. Graves’ disease with multifocal papillary carcinoma. In view of a large goiter with obstructive symptoms, she was subjected to subtotal thyroidectomy. Per-operatively thyroid On gross examination, thyroid gland was firm and rubbery. Cut surface was lobular with a grayish white area. (Figure 1.1) On histopathology, the section showed part of a papillary tumor with delicate fibrovascular cores covered by cuboidal gland was seen infiltrating the retroesophageal space. Resected gland on gross appearance was large, irregular with soft to firm consistency and cut section showed yellow white color with a glassy appearance. Figure 1.2. Papillary carcinoma of thyroid, delicate fibrovascular cores covered by cuboidal cells displaying crowded ground glass nucleus seen. (H & E stain, 400X) cells displaying crowded ground glass nucleus. Rest of the thyroid gland did not show lymphocytic infiltration, fire flare cells (marginal vacuoles) or other features of hyperthyroidism (scanty colloid, tall columnar cells etc.) (Figure 1.2) Case 2 Suspected case of Amyloidosis of thyroid gland: 79 Thyroid Research and Practice Histopathological examination of sections stained in hematoxyllin and eosin (H&E) revealed thyroid follicles and stroma showing deposition of homogenous eosinophilic material. (Figure3) Based on gross proteinuria, thyromegaly with obstructive symptoms, cheesy material with glassy appearance on gross examination with homogenous eosinophilic material on histopathology, amyloidosis of thyroid gland along with renal amyloidosis was suspected. Renal biopsy was planned but could not be done. Figure 3.1 Fibrous tumor of thyroid Histopathological examination of sections stained with H & E revealed spindle-shaped bland fibroblastic cells set in a background of collagenous matrix, infiltrating between thyroid follicles. (Figure 3.2) Figure 2. Suspected case of Amyloidosis of thyroid- Thyroid follicles and stroma showing homogenous eosinophilic material. (H&E stain, 400 X) Case 3 Solitary Fibrous Tumor of thyroid: A 55 years old elderly male presented with progressively enlarging goiter of 4 years duration. He had obstructive symptoms in form of breathing difficulty and dysphagia for 2 weeks. Clinically, he was euthyroid with a left sided thyroid nodule of 6 X 7 cms size that was firm in consistency. There were no palpable lymph nodes and both the carotids were not adherent to thyroid nodule. He was subjected to left hemithyroidectomy to relieve the obstructive symptoms. A 35 years old male presented with progressively increasing, On gross examination, thyroid gland was well circumscribed with regular surface, firm in consistency and cut section showed white tan. (Figure 3.1) large midline neck swelling of 2 months duration. Clinically, he had a firm, grade III goiter with retrosternal extension. There was no lymphadenopathy or signs of superior vena caval compression. 80 Figure 3.2 Fibrous tumor of thyroid, spindle-shaped bland fibroblastic cells set in a background of collagenous matrix seen, infiltrating between thyroid follicles. (H & E stain, 400X) Case 4 Lymphangioma of thyroid: Thyroid Research and Practice On surgical exploration, a large cystic lesion extending to retrotracheal and retrosternal space was seen. Hemithyroidectomy was performed. Patient was followed up for 2 ½ years after surgery without any specific complaint. Grossly, the resected thyroid gland was irregular, with nodular surface and soft to firm consistency, cut section showed cyst with normal surrounding thyroid gland. (Figure 4.1) Discussion In this study we have presented four unusual thyroid lesions. Three of these cases presented with mediastinal compression. Final diagnosis in all these cases could be established only after histopathological evaluation. Due to rarity of occurrence these cases would be of academic interest and a learning exercise for practising clinician and pathologist. Our first case with symptoms of hyperthyroidism had papillary thyroid carcinoma. The association of Graves’ disease and thyroid carcinoma is very well known.1 Presence of nodule in case of Graves’ disease should alarm us for associated papillary thyroid carcinoma. However, a functioning papillary thyroid carcinoma presenting with thyrotoxicosis is rare 2 where rest of the gland is normal, as seen in our case. Possibly, this was a case of papillary carcinoma with autonomy within the tumor; however preoperative FNAC and radio-isotope scan showing functional state of rest of the thyroid gland would have thrown more light on confirmation of the diagnosis. Figure 4.1 Lymphangioma of thyroid. Amyloidosis of thyroid gland is a rare occurrence. It may be secondary to either primary or secondary systemic Histopathological examination of sections stained with H&E revealed a cyst wall lined by flat endothelial cells with elongated nuclei and supported by fibrocollagenous stroma. Thyroid tissue was seen attached to the cyst wall. (Figure 4.2) These typical changes were consistent with lymphangioma. amyloidosis or localized organ involvement. It can be confused with a neoplastic goitre both clinically and cytologically. Diagnosis should be suspected in a case of systemic amyloidosis with rapidly growing diffuse goitre and renal dysfunction.3 As our patient had proteinuria and anasarca, renal involvement as a part of systemic amyloidosis was likely. However renal biopsy could have confirmed the possibility which otherwise looked very likely. Solitary fibrous tumors (SFT) represent a rare subset of soft tissue tumors. Until now, only nine cases have been reported.4 Previously considered being of serosal origin and solely limited to the pleural cavity, the tumor has been described in other locations like head and neck region. Extrathoracic SFT in the soft tissues of the trunk and the extremities are very rare. Complete surgical resection is commonly accepted as treatment Figure 4.2 Lymphangioma of thyroid, cyst wall lined by flat endothelial cells with elongated nuclei and supported by fibrocollagenous stroma seen. (H & E stain, 400X) of choice. Due to delayed presentation with recurrence or metastasis, long follow-up periods should be maintained. 81 Thyroid Research and Practice Lymphangioma of thyroid is a benign lesion that results from abnormal development of the lymphatic system. Intrathoracic lymphangiomas have occasionally been known to arise within the mediastinum, but thyroid lymphangiomas are extremely rare. It may present as solitary hypofunctioning thyroid nodule. Preoperative diagnosis of lymphangioma based on FNAC or imaging is difficult and is often confirmed on histopathology only. In our case too the diagnosis was confirmed by two different pathologists. Limitations of the study 5 solitary fibrous tumor of thyroid and lymphangioma of thyroid were some of the most unusual cases in our experience. A high index of suspicion for these rare disorders by pathologist and a diligent work up prior to management can reduce the morbidity associated with such surprise entities. Needless to say, a close teamwork among departments of medical and surgical endocrinology and department of pathology contributed to a great extent in dealing with these cases. Acknowledgement : Ms Mrunalini Reddy and Ms G. Tirumala Being retrospectively selected, complete work up for all cases was not available. Pre operative radio isotope thyroid scan could have explained more about functioning status of thyroid gland in case of function papillary thyroid carcinoma. Renal biopsy and Congo red staining of the thyroid specimen in case of amyloidosis of thyroid could have strengthened our suspicion. Follow up for fibrous tumor of thyroid and amyloidosis of thyroid was not available. Conclusion Thyroid nodules form the main bulk of referrals from an endocrinologist to a pathologist and thyroid surgeon. While dealing with the routine cases, sometimes we face rare and unusual entities, which pose diagnostic and therapeutic challenge. We have presented a collection of such cases from our archive and the lessons learnt from them. Functioning metastatic papillary thyroid carcinoma presenting as hyperthyroidism, suspected case of amyloidosis of thyroid, for secretarial assistance References 1. Terzioglu T, Tezelman S, Onaran Y, et al. Concurrent hyperthyroidism and thyroid carcinoma. Br J Surg 1993; 80(10):1301-2. 2. Rachelle N. Bitton, Issac Sachmechi, et al. Papillarycarcinoma of the thyroid with manifestations resembling Graves’ disease. Endocr Pract 2001;7(2):106-9. 3. A Hrivo, I Peter, B Bankuti, et al. Amyloid goiter. Orv Hetil 1999;140(12):653-7. 4. Rodriguez Ingrid, Ayala Enrique, Caballero Carmelo et al. Solitary fibrous tumor of the thyroid gland: report of seven cases. American Journal of Surgical Pathology 2001;25(11):1424-8. 5. Gardner DF, Frable WJ. Primary lymphangioma of the thyroid gland. Archives of Patholology & Laboratory Medicine 1989;113(9):1084-5. 82 Thyroid Research and Practice Original Article Cytotoxic effects of low dose 13II therapy - assessment of chromosomal aberration and micronucleus as biomarkers S. Sudha*, P S Sundaram **, S Padma **, K. Sasikala*** Abstract There are articles describing the various cellular effects after a high dose I 131 therapy, which serves as the first line of management in postoperative cases of differentiated thyroid carcinoma. We aimed to study the cytotoxic effects of a low dose 131 I therapy used as treatment modality for hyperthyroid patients. Peripheral 131 blood lymphocytes from a group of 20 patients, who received I sodium iodide solution orally, were studied for the presence of Chromosomal Aberrations (CA) and Micro Nucleus (MN) using micronucleus assay. The study was conducted using blood samples of such patients drawn prior to the treatment, on 7th day and 30th day after the treatment. The results indicate a positive relationship between dose, CA and MN frequency. A statistically significant increase in CA and MN frequency in 7th day post therapy and a decrease in mean levels of CA and MN at 30th day post therapy were observed when compared to pretherapy. This study showed that the cytogenetic damage induced by a low dose beta emitter like reversible. Keywords: Low dose * Department of Biotechnology, Karpagam Arts and Science College,Coimbatore,Tamil Nadu ** Department of Nuclear Medicine, Amrita Institute of Medical sciences,Cochin,Kerala *** Unit of Human Genetics, Department of Zoology, Bharathiar University,Coimbatore,Tamil Nadu Corresponding Author: S SUDHA E-mail: sudhasellappa@yahoo.co.in 131 131 I is minimal and I therapy, hyperthyroidism, chromosomal aberrations, micronucleus assay. Introduction The use of 131 I has continued to remain a mainstay of therapy for hyperthyroidism. 131 Despite the advantages of beta radionuclide therapy with I, side-effects can also occur in these patients because normal tissues are exposed to radiation. In hyperthyroid patients treated with 131I , the end point is permanent hypothyroidism. The complications are transient & minimal. In presence of a large avidly trapping thyroid gland, possibility 83 Thyroid Research and Practice of radiation thyroiditis exists post 131I treatment. The growing awareness of subtle short- and long-term consequences of this therapy outweighs the potential therapeutic benefit of this one time therapy. and then remains constant. Thus 131I administration produces a targeted therapy producing no “crossfire” or destruction to surrounding normal tissue. Iodine uptake is heterogeneous in both normal and tumoral Physical Properties of 131I 131 thyroid tissues. This is mainly related to a heterogeneous expression of Sodium Iodide Symporter or NIS. 2 This heterogeneous expression and the short path of beta rays explain the heterogeneous dose distribution in multinodular goitres that may be responsible for pitfalls in 131I therapy. 131 I is produced in nuclear reactors by neutron irradiation of tellurium dioxide and during the fissioning of uranium.1 The physical half-life of 131I is 8.02 days. It is popularly known as a magic bullet as it has both beta and gamma radiation components which can be harmoniously used for therapeutic and diagnostic benefit. Beta particles are emitted from 131 I treatment takes advantage of the fact that thyroid cells I are the only cells in the body, which has the ability to absorb iodine after oral administration. The amount of radioiodine used in the treatment of hyperthyroidism and thyroid cancer is different. Higher dosages of 131I are used in the treatment of residual thyroid and functioning metastases of differentiated thyroid cancer. The side effects as a result of this treatment are dose dependent. It can produce sialadenitis, altered taste, radiation sickness, solid organ malignancies to name a few. However dosages of 131I used for hyperthyroidism produces only transient changes in tissues & blood cells. 3 The cellular effects of low levels of ionizing radiation can be studied using cytogenetic assays.4 Blood cells best suited for studying the effects of radiation are the peripheral blood lymphocytes, which are most sensitive to ionizing radiation.5 Low energy and high energy ionizing radiation can disrupt molecules and produce many types of DNA damage, ranging from isolated base damage or single-strand breaks to simple double-strand breaks and more complex DNA alterations involving clustered damage sites with multiple breaks and/or base changes, lethal mutations and carcinogenesis. The chromosomal changes can be observed and counted once the DNA is lysed and chromosomes are separated to identify the severity of human radiation exposure that has occurred. The cellular changes that can be expected are chromosome aberrations, sister chromatid exchanges and micronuclei. The quantity of DNA damage and the range of complexity depend on the type of radiation and whether the radiation is produced at sites on or near the DNA. 131 atoms with various energies, with the maximal beta energy being 606 keV and the mean energy being 191 keV. After the emission of a beta particle, the 131I atom emits gamma rays. The major gamma radiations emitted are at 364 and 637 keV. These beta and gamma radiations account for 90% of the radiation from 131 I . Radioiodine is available as Sodium iodide of high specific activity in the form of a clear, colourless tasteless solution or as capsules, for oral ingestion. It is rapidly and completely absorbed in the upper intestine. Intravenous route of administration is recommended for patients who are unable to ingest the solution or capsules. Biodistribution and cellular effects of 131I Once the patient ingests 131I, there is active gastric absorption, which is further enhanced by the fasting status of the patient. Through the blood stream the tracer proceeds to the avidly tapping thyroid gland and gets concentrated there. The dosage of 131 I has been thus adjusted so as to deliver 10 to 25,000 rads of beta particle irradiation to thyroid follicular cells. As ionizing radiation loses its energy, it disrupts chemical bonds throughout the cell, inflicting devastating damage on the DNA molecule and triggering cellular dysfunction and ultimately death of thyroid follicular cells.1 Most of the radiation dose is delivered by beta particles emitted from radioiodine, which is concentrated & organified by the thyroid follicular cells. These beta particles penetrate only upto a depth of 2 mm into tissue. The mean absorbed dose delivered by beta particles for a given radioactive concentration increases with the radius of tissue up to 10 mm 84 I treated hyperthyroid patients provide a good opportunity to study cytogenetic damage induced by known doses of 131I Thyroid Research and Practice and therefore to carry out risk estimations in people exposed to such a radionuclide. At present, a great majority of such studies have been performed in peripheral blood lymphocytes from exposed patients, as lymphocytes are the most radiosensitive cells in our body. Besides the epidemiological studies that provide estimates of cancer risk, there are several chemical and biological endpoints that allow monitoring of populations exposed to genotoxic carcinogens and to understand the mechanisms of carcinogenesis.6 Aim and objectives The purpose of our study was to assess the possible chromosomal damage induced by 131 I therapeutic exposure, by analysing the frequency of both binucleated cells with micronuclei and total number of MicroNuclei (MN) & Chromosomal Aberrations (CA) in cultured peripheral blood lymphocytes of treated patients. CA and MN are the best-established biomarkers of chromosomal damage and are used in invitro testing of chemicals/radiation for genotoxicity and also as an invivo biomarker when exposed to genotoxin.8 Because of the sensitivity of these methods, MN and CA were used to assess the extent of DNA damage in hyperthyroid patients in pre and post 131 Materials and methods Samples The study was performed with a total of 20 hyperthyroid patients (M: F = 9: 11), age ranging between 23-61 years, mean of 49 years. All patients were clinicaly and biochemically evaluated. Basic blood investigations along with serum free T4, T3 and TSH estimations were performed on their initial visit to the endocrinologist. Technetium thyroid scintigraphy was performed in all patients to further categorize them into Graves’ disease, toxic multinodular goiter and autonomous toxic nodule. Patients with scintigraphic diagnosis of subacute thyroiditis were excluded from the study. The therapeutic treatment consisted of 131I given orally as an adjuvant radiation dose to destroy thyroid follicular cells. All patients recruited for this study were explained the details of the treatment, and that radiation safety measures are to be followed for 10 days after the treatment. Patients were adviced to stop iodised salt, seafoods and iodide containing medications for atleast 3 weeks prior to this treatment. Antithyroid medications like carbimazole were stopped a week prior to the date of therapy. Based on the trapping function of thyroid gland established by Technetium scan, patients were divided for empirical 131I dosage as 5-10 mCi, 10-15 mCi and above 15 mCi of I 131. In our study, 12 patients had Graves’ disease and received a dose of 5-10 mCi, 5 patients had Toxic multinodular goiter and received 10 – 15 mCi and 3 patients had autonomous thyroid nodule and were administered 15mCi of 131I therapy. 5 ml of heparinised blood was collected from these patients prior to administering low dose 131 I therapy setting. An ex vivo/ in vitro analysis of lymphocytes in the presence of cytochalasin-B (added 44 hours after the start of cultivation), an inhibitor of actins, allows us to distinguish easily between mononucleated cells which did not divide and binucleated cells which completed nuclear division during in vitro culture. Indeed, in these conditions the frequencies of mononucleated cells provide an indication of the background level of chromosome/genome mutations accumulated in vivo and the frequencies of binucleated cells with MN a measure of the damage accumulated before cultivation plus mutations expressed during the first in vitro mitosis. The combination of the micronucleus assay with Fluorescence In Situ Hybridisation (FISH) with a probe labeling the centromeric region of the chromosomes (FISH assay) allows discrimination between micronuclei containing a whole chromosome (centromere positive micronucleus) and an acentric chromosome fragment (centromere negative micronucleus). 9 I. Subsequently blood samples were collected from these patients 7 days and 30 days after the therapy to look for DNA changes. Chromosomal Analysis Chemicals used RPMI1640 (Gibco) fetal calf serum (Gibco) phytohaemagglutinin – M (Gibco) dimethyl sulphoxide 5ul / mL (E.Merk, India) colchicines 0.20mg/mL (Micro lab) cytochalatin – B (Sigma) 85 Thyroid Research and Practice Procedure Peripheral blood cultures were prepared according to Moorhead et al11 and Hungerford et al.12 0.5ml of the blood sample was inoculated under aseptic conditions into a culture vial containing 5.0ml of culture medium, 1.0ml of AB serum and 0.2ml of phytohaemagglutinin. The cultures were incubated at 370C for a period of 72 hours. The dividing cells were arrested at the metaphase stage by adding 0.05ml of colchicines solution (0.01%) 30 minutes before harvesting the culture. The contents of the vials were centrifuged at 1000 rpm for 10 minutes at the end of colchicine treatment. The supernatant was discarded and 6ml of hypotonic solution was added to the test tube after disturbing the cell button. The contents of the test tubes were incubated for 7 minutes and a freshly prepared fixative (Methanol: Glacial acetic acid 3:1v/v) was added and centrifuged at 1000rpm for 10 minutes. Later the supernatant was discarded and two or three changes of fixative were given to obtain colourless cell pellet. The slides bearing chromosome spreads were treated with 0.25% trypsin for 3 to 10 seconds and were stained in 4% buffered Giemsa solution for 3 minutes. At least 100 metaphases were examined for the occurrence of different types of abnormality i.e. gaps, fragments, breaks etc. Criteria to classify the different types of aberrations were in accordance with the recommendation of EHC 46 for environmental monitory of human population. Micronucleus analysis Results The lymphocytes were cultured according to the method of Fenech and Morley.13 Pokeweed mitogen (Gibco BRL) was used to stimulate the lymphocytes to proliferate in culture. A Figure 4. Photograph showing the chromosomal aberrations in a female patient with Graves’ disease (30th day post 131I therapy) 2-Translocation Figure 3. Photograph showing the chromosomal aberrations in a female patient with Graves’ disease (30th day post 131I therapy) 1-Break, 4-Fragment solution of cytochalasin B (Aldrich Chemical Co.) was added 44 hrs after the commencement of the culture. The cultures were terminated 72 hrs after initiation. Scoring of MN was limited to bi-nucleated lymphocytes with preserved cytoplasm according to the criteria proposed by Countryman and Heddle. 14 The results were expressed as the average percentage of micro nucleated cells per binucleated cells. Statistical analysis The data were subjected to Students ‘t’ test to determine significant difference between the groups.15 Values are expressed in mean ± S.D. There are more female patients with hyperthyroidism than males in our study. Blood grouping analysis revealed Group ‘B’ to be predominant among female hyperthyroid subjects. In male subjects with hyperthyroidism Group ‘O’ was predominant. Disease duration in female hyperthyroids revealed 1-2 yrs to be predominant time period, followed by 6 month – 1yr, < 6 months and > 2 yrs. 6 months – 1 yr disease duration was predominant in male hyperthyroid subjects Figure 1. Photograph showing the bi-nucleated cells without micronuclei in Graves’ disease Figure 2. Photograph showing the bi-nucleated cells with micronuclei in Graves’ disease (7th day post 131I therapy) followed by 1-2 yrs, <6 months and > 2 yrs. Distribution of symptoms in male and female hyperthyroid subjects showed the predominant symptoms to be weight loss followed by increased appetite, tremors, increased sweating, palpitations and mental disturbances. 86 Thyroid Research and Practice In cytogenetic study, there is a significant increase in chromosomal aberrations in the 7th day post 131I therapy blood samples when compared to the pretreatment samples. This CA is a transient phenomenon as there is a significant decrease of the same when observed in the 30 day post 131 In MN analysis, a clear dose dependent increase in micronuclei was present in binucleated cells when compared to pretreatment samples (Table 2). MN was significantly increased at 7th day post therapy samples. A similar dose dependent increase was observed in 7th and 30th day post therapy samples. I therapy samples (Table 1). A dose dependent increase in the number of chromosomal aberrations was observed in 7th day and 30th day post therapy samples. Table 1. The Frequency of Chromosomal Aberrations (CA) in 131I-treated hyperthyroid patients before and after therapy. Treatment Dose (mCi) Number of subjects(N=20) Abnormal metaphases without gaps Number Mean + SE Chromosome aberrations Gaps Fragments and breaks Number % Number % 1 0 1 2 3 3 2 2 2 0.35 0 0.46 0.25 0.98 1.00 1.03 0.56 0.54 2 2 1 5 6 6 4 4 4 1.26 1.93 1.08 2.09 1.98 2.00 1.68 1.67 1.46 Sample I 5-10 10-15 >15 Sample II 5-10 10-15 >15 Sample III 5-10 10-15 >15 * Values significant at 5% level 12 5 3 12 5 3 12 5 3 2 1 2 5 7 6 4 6 6 0.60 ±0.47 0.53 ±0.62 0.66 ± 0.14 1.24 ± 0.42* 2.03 ± 0.94* 2.64 ±0.03* 1.00 ± 0.56* 1.67 ± 0.34* 2.85 ±0.67* Sample I: Pre therapy, Sample II: 7th day post therapy, Sample 30th day post therapy Table 2. The Frequency of Micronuclei observed in 131I treated hyperthyroid patients, before and after therapy. Treatment Dose (mCi) Sample I 5-10 10-15 >15 Sample II 5-10 10-15 >15 Sample III 5-10 10-15 >15 *Values significant at 5% level Sample I: Pretherapy, Sample II: 7th day post therapy, Sample III : 30th day post therapy 87 Number of subjects (N=20) 12 5 3 Number of Binucleated cells counted 500 500 500 Mean number of micronuclei (Mean +SE) 0.86 ± 0.52 1.2 ± 0.91 0.9 ± 0.41 12 5 3 12 5 3 500 500 500 500 500 500 2.3 ±0.08* 2.9 ± 0.02* 2.4 ± 0.31* 2.2 ±0.67* 2.0±0.47* 3.1 ±0.82* Thyroid Research and Practice Discussion The results revealed that low dose 131 Radiation induced ionization may act directly on the cellular component molecules or indirectly on water molecules I therapy induces causing formation of water derived radicals. Radicals react with nearby molecules in a very short time resulting in breakage of chemical bonds or oxidation of the affected molecules. The DNA is a major target for radiation damages because DNA distraction can kill or mutate human cells. Double strand DNA breaks may play a major role in these biological effects.20,21 The relatively low frequency of chromosomal aberrations and MN induced by 131I in-vivo with cumulative 131I supports the contention that cytogenetic damage of this therapy with 5 to 15 mCi of 131 chromosomal abnormalities in the form of increased CA and MN as early as 7 days after treatment. Similar observations on chromosomal numerical abnormalities and structural aberrations in 131 I hyperthyroid subjects were reported by Guitizeer et al.16 Ramirez et al reported a 1.8 fold increase in the frequency of 17p breaks after Iodine-131 therapy in hyperthyroid patients17. There is a minimal cytogenetic damage in the peripheral blood lymphocytes of 131 I treated hyperthyroid patient in comparison with controls in their study. Similar results were observed by Guitizeer et al. Structural aberrations were observed in cultured PBL of hyperthyroid patients.19 Micronuclei are small nuclei like particles seen apart from the nucleus in an irradiated cell. They enclose acentric fragments or whole chromosomes that have not been included in the main nuclei at cell division and in the cytoplasm.7 Therefore, the presence of micronuclei can indirectly denote chromosome breakage or impairment of the mitotic spindle . It has been shown that ionizing radiation induces micronuclei in human lymphocytes. In spite of the variability of dose-response relations, there is a quantitative relationship between radiation dose and frequency of micronuclei, which can be used for biological dosimetry. The sensitivity of cytokinesis blocked micronuclei assay is well established. 19 131 18 I in graves’ hyperthyroid patients is minimal. Although the chromosomal aberrations and micronucleus frequency after one month post therapy count has reduced, data show that radiation-induced cellular lesions persist for months following relatively brief radiation exposure to beta emitters. Conclusion To conclude, we found that low dose 131 I treated I therapy induces transient chromosomal abnormalities in the form of increased CA and MN as early as 7 days after treatment, which reverts back to normal at 30 days following therapy. However, analysis of a larger number of individuals is necessary to further confirm these results. This is the first analysis to determine the genotoxic risk associated with hyperthyroidism in South India. 131 I treatment of In our study it was observed that the increase in micronuclei after therapy were not statistically significant which is explained by the fact that the amount of radiation induced to cells may be minimal. Watanebe et al in their study reported an increase in MN after gradually decreased . A different type of apparent adaptive response has been well documented for the induction of chromatid-type breaks and micronucleus in human lymphocytes stimulated to divide. In most studies, a priming or adaptive dose of about 10 mGy significantly reduced the frequency of chromosomal aberrations and mutations induced a few hours later by 1–3 Gy. 88 2 131 References 1. Richard J R, Martin J S. The evolving Role of Nuclear medicine 2005;46(1):28-37. 2. Sgouros G, Kolbert K, Sheikh A. Patient-specific dosimetry for 131 131 I for the I therapy and they found that treatment of Differentiated thyroid carcinoma. The journal of number of MN peaked at 3 days after 131I administration and I thyroid cancer therapy using 124 I PET and 3-dimensional- internal dosimetry (3D-ID) software. J Nucl Med 2004;45: 1366-72. 3. Blackwell N, Stevenson AC and Wiernik G. Chromosomal findings in patients treated with small doses of iodine-131. Mutat Res 1974;25: 397-402. Thyroid Research and Practice 4. Fenech M.The in vitro micronuleus technique. Mutat Res 2000;455:81- 95. 5. Sara G, Elisabeth C, Pere G, et al. Cytogenetic damage after 131iodine treatment for hyperthyroidism and thyroid cancer. Eur J Nucl Med 1999;26:1589-96. 6. Coggle J E. Biological effects of Radiation. Radiation and Cancer 1983:147-76. 7. Eric J Hall, Amato J Giaccia. DNA strand breaks & chromosomal aberrations Radiobiology for the Radiologist 2006:16-28. 8. Coggle J E. Genetic Effects of ionizing radiation. Biological effects of Radiation 1983:111-25. 9. Heddle JA, Cimino MC, Hayashi M, et al. Micronuclei as an Index of cytogenetic damage: past, present, and future. Environ Mol Mutagen 1991;18:277-91. 10. Müller W U, Nusse M, Miller BM, et al. Micronuclei: a biological indicator of radiation damage. Mutat Res 1996;366:163-9. 11. Moorhead PS, Novell PC, Mellman WJ, et al. Chromosome preparation of leukocyte culture from peripheral blood. Ex Cel Res 1960;20:613-5. 12. Hungerford DA. Pachytene chromosome maps of human chromosomes 19 and 20. Cytogenet Cell Genetics 1960;27: 97- 200. 13. Fenech M, Morley AA. Measurement of micronuclei in human lymphocytes. Mutat Res 1983;148:29-36. 21. Shadley JD, Wiencke JK. Induction of the adaptive response by X-rays is dependent on radiation intensity. Int J Radiat Biol 1989;56:107-18. 20. Monsieurs MA, Thierens HM, Van DW, et al. Estimation of risk based on biological dosimetry for patients treated with radioiodine. Nucl Med Commun 1999;10:911-7. 15. Fisher RA, Yates F. Statistical table for biological agricultural and medical research. Oliver and Boyd Edinburgh 1963:138. 16. Gutiérrez S, Carbonell E, Galofre P, et al. Micronuclei induction by 131I exposure. Study in hyperthyroidism patients. Mutat Res 1997;373:39-45. 17. Ramírez S, Puerto P, Galofre EM, et al .Multicolour FISH detection if radioactive iodine induced 17ce-p53 chromosomal breakages in buccal cells from therapeutically exposed patients. Carcinogenesis 2000;21(8):1581-86. 18. Gutierrez S, Carbonell E, Galofre P, et al. Cytogenetic damage after 131-iodine treatment for hyperthyroidism and thyroid cancer. A study using the micronucleus test. Euro.J.Nuc Med 1999;26:1589-96. 19. Ramirez MJ, Surralles J, Galofre P, et al. FISH analysis of 1cen1q12 breakage, chromosome1 numerical abnormalities and centromeric content of micronuclei in buccal cells from thyroid cancer and hyperthyroidism patients treated with radioactive iodine. Mutagenesis 1999;14:121-7. 14. Countryman PI, Heddle JA. The production of micronuclei from chromosome aberrations in irradiated cultures of human lymphocytes. 1976:321-32. 89 Thyroid Research and Practice Case Report Thyroid vignette MP Baruah*, S Hazarika** , U Bhuyan***, S Baruah***, K Saikia *** Abstarct Non thyroidal illness syndrome is used to describe alterations in thyroid function in various clinical situations and is cytokine mediated. We report a case of an 65 year old male with cough and low grade fever for 6 months. He had right side Hydro pneumothorax, exudative pleural effusion, high ESR, leucocytosis, transaminitis, prerenal azotemia and stress ulcers in stomach. His thyroid function showed low TSH and low normal freeT4. A technetium pertechnectate (99mTc) scintiscan of the thyroid was performed which showed absent uptake. Though not a standard indication for thyroid scintigraphy, NTIS is encountered quite frequently in clinical practice, and hence it is pertinent to discuss this well documented case. Key words: Thyroid, Non thyroidal illness syndrome, Thyroid scintigraphy Introduction Non thyroidal illness syndrome (NTIS; synonym: euthyroid sick syndrome, low T3 syndrome) is not a true syndrome, but is used to describe alterations in thyroid function in various clinical situations.1,2 Low serum T3 is the most common biochemical alteration encountered, while the decrease in T4 is less common and heralds graver outcome. TSH level is either low or inappropriately normal in relation to concurrent thyroid hormone level. * Department of Endocrinology, Excel Center, Guwahati **Department of Radiodiagnosis, International Hospital, Guwahati ***Department of Nuclear Medicine, Nucleomed,Guwahati Corresponding Author: MANASH PRATIM BARUAH E-mail: manashbaruahinini@yahoo.co.in Case report A 65year old male, without any previous history of chronic illnesses like diabetes mellitus, hypertension, renal dysfunction and thyroid dysfunction presented with cough associated with low-grade fever for 6 months and chest pain for 1 month. Associated evidence of a catabolic condition of moderate severity was also present. Further evaluation revealed clinical and radiological evidence of hydro-pneumothorax with collapse consolidation of lower lobe on the right lung. Pleural fluid was found to be exudative with presence of relative lymphocytosis on analysis. However repeated sputum microscopy did not reveal the presence of acid-fast bacilli. Ongoing inflammation 90 Thyroid Research and Practice was evidenced by leukocytosis and high ESR. Concurrent multi-system involvement was evidenced by stress hyperglycemia, pre renal azotemia, mild hyper bilirubinemia and elevated liver enzymes (all of which with the exception of liver enzymes had come down during the course of treatment). Upper gastro-intestinal endoscopy revealed gastric erosion signifying concurrent stress. Patient was treated with antitubercular drugs (isoniazide, rifampicin, ethambutol and pyrizinamide) along with a short course of 3 generation cephalosporin based on clinical and radiological evidence. He did not receive glucocorticoids during his illness. Thyroid function was ordered only towards the end of 2nd week in the hospital keeping in view of catabolic condition. While TSH level (0.26mIU/L) was found to be quite low (reference range 0.5-5mIU/L), FreeT3 (4.2pmol/L) was at the lowest decile of reference range(4.0-8.3). FreeT4 was within normal range. For further correlation a Technetium pertechnectate (99mTc) scintiscan of the thyroid was performed in which absent uptake was documented (Figure 2.). Discussion Non thyroidal illness syndrome (NTIS; synonym: euthyroid sick syndrome, low T3 syndrome) is not a true syndrome, but is used to describe alterations in thyroid function in various clinical situations.1,2 Low serum T3 is the most common biochemical alteration encountered, while the decrease in T4 is less common and heralds graver outcome. TSH level is either low or inappropriately normal in relation to concurrent thyroid hormone level.3 Proinflammatory cytokines [tumor rd necrosis factor (TNF), interleukins (e.g. IL-1 and IL-6), and interferon], when administered to man or experimental animals, have caused changes in thyroid function tests that resemble NTIS. These chemical factors are likely to be responsible for low TRH secretion from hypothalamus resulting in low TSH.4 Nucleotides used in thyroid uptake scan gets an entry into thyrocytes through the sodium iodide symporter, an action largely influenced by TSH (or TSH receptor antibody as in Graves disease). Low or absent thyroid uptake of nucleotide in our patient with NTIS is obviously due to low TSH level. Currently available standard reviews have not yet included NTIS as a cause of low uptake scan.5 Though not a standard indication for thyroid scintigraphy, NTIS is encountered quite frequently in clinical practice, and hence it is pertinent to discuss this well documented case. References: 1. Adler SM, Wartofsky L. The Nonthyroidal illness syndrome. Endocrinology and Metabolism Clinics of North America 2007; 36(3):657-72. 2. DeGroot L, Jameson J. Nonthyroidal illness syndrome. Endocrinology 2006;2101-12. 3. Wartofsky L, Burman KD.Alterations in thyroid function in patients with systemic illness:the “euthyroid sick syndrome”. Endocrine reviews 1982;3:164-212. 4. Chopra IJ. Euthyroid Sick Syndrome: Is It a Misnomer?. J Clin Endocrinol Metab 1997;82(2):329-34. 5. Mcdougall R. In vivo radionucleotide tests and imaging.The Thyroid : A fundamental & clinical text. Lipincott Williams & Wilkins, Philadelphia, USA 2005;309-28. 91 Thyroid Research and Practice Thyroid Images Compiled by R Bharath*, AG Unnikrishnan*, S Sundaram**, PS Sundaram** *Department of Endocrinology and Diabetes **Department of Nuclear Medicine Amrita Institute of Medical Sciences Elamakkara, Cochin Figure 1. Techentium Pertechnetate scan showing physiological tracer distribution in oropharynx, salivary glands bilaterally Figure 2.99m Tc MIBI scan planar image showing homogenous tracer distribution in both lobes of thyroid A 49 years old lady presented to the emergency department with history of frequent episodes of central chest pain which also radiates to posterior thoracic wall for the past 10 days. The pain is not associated with sweating, vomiting or diaphoresis. She has normal menstrual cycles. She also had episodes of palpitation during rest and while doing moderate exertion. She had lost 7 Kg. weight in last 4 months. She had undergone thyroidectomy 23 years back, when she developed a goitre with difficulty in swallowing. She could neither give 92 details about the type of surgery done nor brought any previous medical records. She was not on any medications after the surgery. On examination, her Body Mass Index was 19.6Kg/m2. Her pulse rate was 110/minute and was regular. Her blood pressure was 120/68mmHg. She had fine tremors in both hands. There was no goitre or cervical lymph nodes. She had no signs of thyrotoxic ophthalmopathy. An Electrocardiogram done in emergency department was normal except sinus tachycardia. Her X-ray chest revealed superior Thyroid Research and Practice Figure 3. SPECT images of thyroid showing the retrosternal goitre in continuation with right lower pole of thyroid. mediastinal widening with a mass lesion and normal cardiac silhouette. Her Free Thyroxine (FT4) level was 3.22ng/dL (Normal- 0.93-1.71ng/dL) and Thyroid Stimulating Hormone (TSH) was <0.005mIU/mL (Normal-0.27-4.2mIU/mL). She was started on Neomercazole and β adrenergic antagonist after which she felt improvement in palpitation. A contrast enhanced CT chest was done which showed a 10 x 8 x 8cm, enhancing mass lesion in superior mediastinum, Compressing SVC and non visualised innominate vein with multiple venous collaterals in mediastinum and chest wall. Patient was referred to the department of nuclear medicine for a Technetium thyroid scintigraphy to assess her thyroid trapping function. After IV injection of 4 mCi of Techentium Pertechnetate ( 99mTc04), high resolution static images of thyroid were acquired using a dual head variable angle Gamma Camera. Technetium Thyroid Scintigraphy showed physiological tracer distribution in oropharynx, salivary glands bilaterally. There was no clear delineation of both lobes of thyroid with poor technetium uptake. In this clinical situation of suspicious retrosternal goiter ideally I 131 thyroid scntigraphy should be done. But as patient had a recent iodine contrast CT and also that patient was not prepared for I 131 thyroid scan in the form of avoiding iodised salt and sea foods. A Techetium Sesta MIBI (Methoxy IsoButyl Isonitrile) scan was performed. Ten minutes after IV injection of 99mTc MIBI, the scan showed homogenous tracer distribution in both lobes of thyroid. There was significant MIBI tracer distribution in anterior mediastinum. SPECT images clearly delineated the retrosternal goiter in continuation with right lower pole of thyroid. The patient underwent total thyroidectomy and sternotomy. The mediastinal mass was removed in total and the patient required thyroxine replacement during the followup visit after surgery. Histopathological examination of the tumor showed a multinodular goitre with no features of malignancy. 93 Thyroid Research and Practice Thyroid Watch Compiled by M G Pillai Consultant Endocrinologist PVS memorial Hospital, Cochin 1. Thyroid autoimmunity and radiation exposure: Sera of adolescents from paired contaminated and noncontaminated villages of Belarus, Ukraine and Russia were studied along with controls from Sardinia and Denmark 13-15 years after the Chernobyl accident. A significantly increased prevalence in anti TPO antibodies was seen in exposed population; but the prevalence was less compared to an earlier study done 6-8 years after the exposure. JCEM 93:2729-36. 2. Alzheimer’s disease and subclinical thyroid dysfunction: In a 12.7 year follow up of the Framingham study population, increased incidence of Alzheimer’s disease was seen in women with TSH in the lowest and highest tertiles compared to those in the middle range. Arch Intern Med. 2008 Jul 28;168(14):1514-20. 3. Total thyroidectomy and Graves’ opthalmopathy: In a cohort of 35 patients with recurrent Graves’ disease with ophthalmopathy, total thyroidectomy was followed by significant reduction in NOSPECS score. Negative TRAb levels were seen within 6 months. Asian J Surg. 2008 Jul;31(3):115-8. 4. Cardiovascular fitness in treated congenital hypothyroidism(CH): When compared with controls, young adults with CH diagnosed by neonatal screening and replacement initiated from the first month of life were found to have left ventricular diastolic dysfunction, impaired exercise capacity, and increased intima-media thickness. The number of episodes of plasma TSH levels less than 0.5 mU/liter and greater than 4.0 mU/liter from the age of 1 yr onward, and mean TSH plasma levels during puberty were independent predictors of cardiopulmonary performance indexes. JCEM 93: 2486-91. 5. Iodine prophylaxis and gestational thyroid insufficiency: In a study from a mildly iodine deficient area, use of iodized salt for at least 2 years prior to conception was found to confer a relative risk reduction of 82.5 % for maternal thyroid insufficiency during gestation when compared to starting after conception. JCEM. 93:2616-21. 6. TRIAC in euthyroid goitre: In comparison to levothyroxine, TRIAC was found to be significantly more effective in reducing thyroid volume in euthyroid goitres. TRIAC was associated with fewer adverse events. Changes in bone mineral density, serum deoxypyridinoline, 94 serum osteocalcin and the lipid profile did not differ between the two treatment arms though the Apo B level fell more strongly on TRIAC than on T4.Bull Acad Natl Med. 2007 Nov;191(8):1705-15. 7. Minimally invasive video assisted thyroidectomy (MIVAT) in children: MIVAT technique was found to be as safe and effective as conventional thyroidectomy using Kocher’s incision to treat both benign and malignant diseases of the thyroid gland in this series of 35 pediatric patients. All children except one was discharged on the first postoperative day itself. Procedures ranged from lobectomy to total thyroidectomy with prophylactic central node dissection. Transient hypoparathyroidism was observed in the patient who underwent central neck lymphadenectomy. J Pediatr Surg. 2008 Jul;43(7):1259-61. 8. Thyroidectomy in Hashimoto’s: In this retrospective analysis of 474 patients with Hashomoto’s thyroiditis who underwent thyroidectomy for various indications like suspicion of cancer, goitre and local symptoms, cancer was found in 53 % of patients though it was suspected pre operatively only in 28%. There were no permanent surgical complications; transient hypocalcemia was common; a few patients had transient recurrent laryngeal nerve palsy and hematoma. Thyroid. 2008 Jul;18(7): 729-34. 9. Twinkling sign in USG suggestive of cancer: Presence and specific patterns of distribution of B flow imaging twinkling signs was found to predict both benign and malignant thyroid nodules with good specificity. Other characterstics suggestive of malignancy like microcalcifications, hypoechogenicity, absence of a halo, and a predominantly solid composition were found in different percentages in both histologically verified malignant and benign nodules. J Ultrasound Med. 2008 Aug;27(8):1187-94. 10. Phosphodiesterase 8 B (PDE8B) gene variants associated with thyroid function: Single nucleotide polymorphisms located in intron 1 of PDE8B which encodes a high affinity cAMP-specific phosphodiesterase was found to be strongly associated with TSH levels with each additional copy of the minor A allele associated with an increase of 0.13 muIU/ml in TSH. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction. Am J Hum Genet. 2008 Jun; 82(6):1270-80. Thyroid Research and Practice Thyroid Research and Practice Guidelines for manuscript submission Thyroid Research and Practice will publish original articles, case reports, pictorial images and reviews relevant to thyroidology. Letters to the editor will also be published. The manuscripts will be considered for peer review only if neither the article nor any part of it has been published or submitted elsewhere prior to submission to the journal. This restriction does not apply to abstracts published with scientific meetings. Submit three copies with original figures and a copy on disk. Use standard-sized paper and double -space throughout. Address all submissions to : The Editor, Thyroid Research and Practice, Indian Thyroid Society, Regd Office: Amrita Institute of Medical Sciences, Elamakkara P.O., Cochin - 682 026, Kerala, India. The Covering Letter A covering letter should be submitted. This must be signed by all authors and should indicate the corresponding author (with the address, phone number, fax number and e-mail address). The letter should state that the final manuscript has been approved by all authors, that the study has not been published (or submitted elsewhere) so far and also that the authors accept total responsibility for the study. If there is any financial grant that requires acknowledgment, it is to be documented on this page. Other guidelines: The abstract should be less than 250 words and need not be structured 3 to 10 keywords may be provided Legends for figures should be triple-spaced on a separate sheet. Original articles must follow the sequence : Introduction, Methods, Results and Discussion. The Thyroidology Images section must have a title and a short description of less than 80 words. Case reports must have an abstract, introduction, description of the case and a short discussion. 4. 3. 2. 1. Mondal A, Patra DK. Efficacy of fine needle aspiration cytology in the diagnosis of tuberculosis of the thyroid gland: a study of 18 cases. J Laryngol Otol 1995; 109: 36-8 Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) Diabetes Care 1997; 20:614-20. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in dia betic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation . 1998;98:2513-9. Boyages SC. Primary pediatric hypothyroidism and endemic cretinism. In: Bardin CW, ed. Current therpy in endocrinology and metabolism. 5th Ed. S t. Louis: Mosby, 1994: 94-8. Units of Measurement Authors should express all measurements in conventional units and it will be appreciated if Systéme International (SI) units are provided in parentheses. Figures and tables are to use only conventional units. For any further clarifications, the authors may correspond with the editor, or visit the website: www.icmje.org, where the uniform requirements for manuscripts submitted to biomedical journals are described more exhaustively. 95 References References must be numbered in the order that they are cited. The submitters should list all the authors when they are six or less; if there are seven or more authors, then list the first three, then “et al” The following are some examples: Thyroid Research and Practice Application Form for journal subscription and membership of the Indian Thyroid Society 1. 2. 3. Name (in block letters) ……………………………………………………………………………………………… Specialty (circle) : Physician / Nuclear Physician/ Surgeon/ Endocrinologist Address…………………………………………………………………………………………….…………………….. ……………………………………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………………………………… E-mail/ Fax ………………………………………………………………Telephone numbers…………………………….... (Please pay Rs 1500/- for a one-time life membership to the Indian Thyroid Society, which includes a life subscription to the journal also. The payment may be made by demand draft or by cheque drawn in favor of “Indian Thyroid Society” Department of Endocrinology, AIMS, Cochin and payable at Cochin. The application form and the cheque/DD may be sent by post to: The Secretary, Indian Thyroid Society, Registered Office: Dept of Endocrinology, Amrita Institute of Medical Sciences, Cochin-682 026, Kerala. Please add Rs 20/- for outstation cheques) I agree to abide by the rules and regulation of the Indian Thyroid Society. Signature : ................................................................... Date : .................. Name : ................................................................... 96