Education and debate

Grand Rounds--St Bartholomew's Hospital: A lump in the chest

We present the case of a patient with an intrathoracic mass. Anthony Weetman, professor of medicine in Sheffield, comments on the case summary.

Case history

A 45 year old woman presented with a three month history of dyspnoea, itchy skin, palpitations, increased sweating, loose stools, orthopnoea, and muscle weakness. On examination she looked unwell, and she had a pulse of 200 beats/min in atrial fibrillation, a jugular vein pulse raised 5-6 cm, normal heart sounds, and a central trachea with bibasal crackles. The thyroid was not palpable. Electrocardiography confirmed atrial fibrillation. Echocardiography showed trivial mitral and tricuspid regurgitation with minimally impaired ventricular function.

A chest x ray film showed a mass adjacent to the left heart border; on lateral view it was located anteriorly with a well defined smooth superior border (fig 1). Computed tomography showed a left sided anterior mediastinal mass (fig 2 (top)). After injection of intravenous contrast medium, the heart and the great vessels were enhanced normally, with minimal enhancement of the mass (fig 2 (centre)). Radiologically, the differential diagnosis (box) included an ectopic thyroid, but the characteristic features of continuity with the thyroid in the neck and intense enhancement with contrast were lacking (fig 2 (bottom)).

View larger version (112K): [in this window] [in a new window]   View larger version (78K): [in this window] [in a new window]   Fig 1--Top: Plain chest radiograph showing left sided paracardiac mass. Bottom: Chest radiograph (lateral view) showing this mass lying anteriorly in retrosternal region with smooth, well defined superior margin

View larger version (51K): [in this window] [in a new window]   View larger version (53K): [in this window] [in a new window]   View larger version (57K): [in this window] [in a new window]   Fig 2--Top: Computed tomogram before intravenous contrast medium at level of mid-ascending aorta showing left sided soft tissue mass of mixed density; a clear plain of fat can be seen between the mass and the mediastinal structures. Centre: Computed tomogram at slightly lower level after intravenous contrast medium, showing that, unlike a typical goitre, the mass does not enhance appreciably. Bottom: Computed tomogram at level of sternoclavicular junction after intravenous contrast medium without any evidence of soft tissue mass, showing that no connection existed between the mass and the normal thyroid in the neck

A malignant germ cell tumour was discounted owing to a normal concentration of ß human chorionic gonadotrophin, but the marker of ovarian carcinoma, carcinoma-associated antigen 125, was raised (235 U/ml, normal <37 U/ml).

Electrocardiography later showed runs of supraventricular and ventricular tachycardia. Treatment with amiodarone 200 mg three times daily, after an intravenous loading dose, was begun together with propranolol 40 mg three times daily.

The thyroid function tests done on admission were available on day 3 and confirmed thyrotoxicosis. The serum thyroxine concentration was slightly raised at 180 nmol/l (normal range 58-174 nmol/l), but the free thyroxine was 68.8 pmol/l (11-24 pmol/l); triiodothyronine concentration was 3.50 nmol/l (1.07-3.11 nmol/l), and the serum thyroid stimulating hormone concentration was suppressed to <0.1 mU/l (0.4-5.0 mU/l). Serum alkaline phosphatase concentration was raised at 324 U/l (25-100 U/l).

INITIAL MANAGEMENT

Clinically, she was now noted to be thyrotoxic. Amiodarone was stopped, and treatment with propylthiouracil 600 mg, prednisolone 20 mg, frusemide 80 mg, and amiloride 10 mg daily was started. Scanning with technetium-99m pertechnetate showed definite, but reduced, uptake in the region of the thyroid in the neck (0.08% of injected dose, normal 0.4-4.0%). The intrathoracic mass also took up pertechnetate to an extent that was consistent with either a vascular tumour or ectopic thyroid tissue. On day 8 despite propylthiouracil, prednisolone, and propranolol, the thyroxine concentration rose to above 300 nmol/l with further increase in the free thyroxine and triiodothyronine (fig 3). The thyroid stimulating hormone receptor, thyroglobulin, and thyroid peroxidase autoantibodies were reported as negative. For the continuing atrial fibrillation she was given warfarin and digoxin. By day 17, the thyroxine concentration had decreased, with increased free thyroxine and triiodothyronine concentrations. Propylthiouracil was now doubled to 1.2 g/day. By day 30 a clinical improvement was seen (thyroxine 262 nmol/l, free thyroxine 66.2 pmol/l, triiodothyronine 4.06 nmol/l). The same day, however, she developed earache with discharge and genital pain due to a 2 cm discharging abscess on the labia majora. A full blood count showed a normal haemoglobin concentration (159 g/l) and normal white cell count (9.3x10⁹/l) but an absence of neutrophils. Agranulocytosis induced by propylthiouracil was diagnosed, and cefotaxime 1 g and gentamicin 80 mg were started, both intravenously and three times a day. Propylthiouracil was stopped.

Bone marrow aspirate showed slightly reduced cellularity with normal erythropoiesis and megakaryocyte formation with reduced granulopoiesis. Promyelocytes were present but there were reduced numbers of later myeloid precursors with absent neutrophils.

Differential diagnosis of a mass in the
anterior mediastinum1
Common
Lymphadenopathy:
 Lymphoma, other reticuloses, metastases,
  granulomas
Thymic masses:
 Thymoma, lymphoma, thymolipoma, carcinoma,
  carcinoid, cysts, hyperplasia
Teratodermoid tumours:
 Benign, malignant
Retrosternal goitre
Uncommon
Vascular:
Tortuous brachiocephalic artery, ascending aorta
 aneurysm
Lymphangioma (cystic hygroma)
Lipoma, liposarcoma
Pleuropericardial cyst
Mesenchymal tumours (50% malignant):
 Fibroma, fibrosarcoma, haemangioma, haemangiopericytoma,
  haemangioendothelioma
Parathyroid adenoma
Plasmacytoma
Osteochondroma
Chondrosarcoma

POST-AGRANULOCYTOSIS MANAGEMENT

In view of the severity of her overall situation, the patient was given intravenously a bolus dose of 300 µg (30 million units) granulocyte colony stimulating factor.^{2 3} The following day the neutrophil count was 100x10⁶/l and completely normal at 7000x10⁶/l after 48 hours.

The other main drugs used for thyrotoxicosis, carbimazole and perchlorate, also carry a risk of agranulocytosis.⁴ Therefore potassium iodide (180 mg daily) was prescribed to block thyroid hormone synthesis. By day 40, the thyroxine concentration was 308 nmol/l and the free thyroxine and triiodothyronine concentrations 83.4 pmol/l and 4.33 nmol/l respectively (fig 3). The serum propranolol concentration on 80 mg eight hourly was relatively low at 10 µg/l (38.6 nmol/l). Increasing propranolol to 120 mg three times a day achieved the more therapeutic concentration of 89 µg/l (343.2 nmol/l.^{5 6}

View larger version (33K): [in this window] [in a new window]   Fig 3--Thyroxine and triiodothyronine concentrations during clinical course

On day 45 her symptoms deteriorated, with agitation, tremor, diarrhoea, shortness of breath, and atrial fibrillation at a rate of 150 beats/min. With the diagnostic criteria of Burch and Wartofsky (precipitant history, cardiovascular dysfunction, gastrointestinal and hepatic dysfunction, central nervous system effects, thermoregulatory dysfunction), this clinical picture was compatible with an impending thyroid storm.⁷ Alternative treatments were considered. Lithium was rejected as it is toxic and operates within a narrow therapeutic range.⁸ On day 43, the oral cholecystographic agent sodium ipodate was started 1 g daily and increased to 2 g after three days.^{9 10} Triiodothyronine fell rapidly from 5.43 nmol/l to a nadir of 3.25 nmol/l on the third day of treatment with sodium ipodate. Thereafter the triiodothyronine started to "escape" (fig 3). Treatment with sodium ipodate was associated with clear clinical improvement of her tremor, diarrhoea, and shortness of breath. Immediate surgery was therefore planned as the triiodothyronine concentration was relatively controlled around 4.0 nmol/l. To prevent a thyroid storm prophylaxis was started with hydrocortisone 100 mg six hourly and chlorpromazine 50 mg eight hourly intramuscularly.

SURGERY AND AFTERMATH

At surgery a bulky mass was removed from the left hemithorax attached to the inferior pole of the thymus. There was no suprasternal extension or continuity with the thyroid in the neck. The excision specimen weighed 191 g (normal 25 g). The variegated appearance macroscopically was due to thyroid nodules with colloid formation. Circumferentially there was involuted thymic tissue but no evidence of malignancy. Immunohistochemistry showed that C cells were absent from this ectopic thyroid tissue. In small areas evidence existed of lymphocytic thyroiditis but not of destruction of thyroid follicle cells. Postoperatively, hydrocortisone was stopped after 24 hours and chlorpromazine after 48 hours, and prednisolone had been reduced to 5 mg daily within 48 hours.

By day 59 she was biochemically and clinically euthyroid: her serum thyroxine concentration was 153 nmol/l and triiodothyronine concentration 1.18 nmol/l with the thyroid stimulating hormone remaining suppressed (fig 3). Serum cortisol concentration at 0900, 48 hours after prednisolone had been stopped, was normal (445 nmol/l). A week after surgery the triiodothyronine and thyroxine concentrations fell below the lower limits of normal (thyroxine to 43 nmol/l; triiodothyronine to 0.74 nmol/l). Perioperatively and postoperatively no features of thyroid storm were seen. She was discharged home with controlled atrial fibrillation, taking digoxin and warfarin.

At review in the outpatient clinic six weeks after surgery, she was clinically euthyroid and in sinus rhythm (serum thyroxine concentration 101 nmol/l, triiodothyronine concentration 1.22 nmol/l, and thyroid stimulating hormone 3.1 mU/l). The alkaline phosphatase was also normal (95 U/l). A repeat scan of the thyroid with ^99mTc showed normal uptake within a normal neck thyroid without intrathoracic uptake. The concentration of carcinoma associated antigen postoperatively was normal (24 U/ml).

Comment

The thyroid gland develops as an endodermal proliferation of the primitive buccopharyngeal cavity in the third week of fetal life. As the heart descends caudally, the adherent thyroid also descends to its definitive position in the neck by the sixth or seventh week of gestation. These facts serve to explain the positions of ectopic thyroid (box).¹¹

In the treatment of thyrotoxicosis, both propylthiouracil and carbimazole inhibit the thyroid synthesis of thyroxine and triiodothyronine and also have immunosuppressant effects. Furthermore, propylthiouracil reduces the conversion of thyroxine to triiodothyronine, as do propranolol, metoprolol, and atenolol but not other ß blockers, such as sotalol.¹⁷ ß Blockers also ameliorate the sympathetic manifestations of thyrotoxicosis. Potassium iodide prevents the synthesis of thyroxine and triiodothyronine and inhibits the release of thyroid stimulating hormone (the Wolff-Chaikoff effect). Prednisolone reduces secretion of thyroxine and conversion of thyroxine to triiodothyronine.

The Committee on Safety of Medicines reviewed agranulocytosis induced by drugs and found that antithyroid drugs were responsible for 7% of cases of agranulocytosis (27% of which were fatal).¹⁸ In the case presented, the neutrophil count recovered rapidly after granulocyte colony stimulating factor was given, but spontaneous recovery was also possible.^{19 20}

A novel feature of this case was the use of sodium ipodate (Oragrafin). Sodium ipodate and thyroxine have closely similar ring structures. The main antithyroid effect of sodium ipodate is through complete inhibition of thyroxine deiodinase in all tissues of the body, unlike potassium iodide, which is only partially active.⁹ Wu et al found that triiodothyronine was reduced by 35% eight hours after a single dose of 3 g sodium ipodate with a nadir 70% below the initial value at 48 hours.¹⁰ Martini et al reported 12 thyrotoxic patients, all of whom had normal triiodothyronine concentration after seven days of treatment with sodium ipodate, although seven relapsed after 14-42 days.²¹ Potassium iodide has a greater effect in reducing the thyroxine concentration but the metabolically more active triiodothyronine was reduced the most by ipodate.²²

CASE ANALYSIS

This patient had an aberrant intrathoracic thyroid, a rare variant of a retrosternal goitre. Lahey did not encounter a retrosternal thyroid unattached to the thyroid in the neck in over a thousand operations.²³ Subsequent reports have shown that aberrant thyroid tissue can exist separately from the neck thyroid with thyrotoxocosis.^{24 25 26 27 28} Initially in the case presented the thyrotoxicosis was mild and was probably made worse by iodine from the contrast medium used in the computed tomography (5 mg iodine) and by amiodarone treatment. The association between thyrotoxicosis and contrast medium is well recognised.^{29 30} This patient's thyroxine:triiodothyronine ratio doubled between presentation and two weeks later. The drugs that she received--amiodarone, prednisolone, propranolol, and propylthiouracil--all inhibit thyroxine deiodinase.

Antithyroid drugs do not work well in the presence of excess iodine because they inhibit the thyroid peroxidase enzyme by direct competition with iodine. High dose propylthiouracil overcomes this problem but might have precipitated agranulocytosis in this case.³¹ Perchlorate is useful in thyrotoxicosis caused by excess iodine as it discharges thyroidal iodine, but agranulocytosis is a risk.^{19 32}

Formation of ectopic thyroid tissue12 13 14 15 16
Developmental ectopia
Predictable (from thyroid embryology):
 Usual--midline between tongue and upper anterior
  neck
 Unusual--mediastinum, oesophagus, trachea,
  pericardium, intracardiac, duodenum, porta
  hepatis, pituitary
Unpredictable:
 Lateral neck area, breast, vagina
Benign neoplastic thyroid tissue as part or whole of
 teratoma
Testes, mediastinum, ovary
Malignant neoplastic thyroid tissue:
Follicular thyroid carcinoma metastasis, malignant
 change in teratoma
Struma ovarii

Lithium has been recommended for thyrotoxicosis induced by iodine, but it has a narrow therapeutic range and the block in thyroid hormone synthesis is transient.^{33 34} Sodium ipodate was initially successful and allowed safe surgery. At this stage the sodium ipodate would only work by inhibiting thyroxine deiodinase. Figure 3 clearly shows this: the triiodothyronine concentration plummeted but the thyroxine concentration continued to climb. The only other treatment that could have been used is plasmapheresis.

Discussion

JD: Did the development of heart failure in this patient suppress the clinical signs of thyrotoxicosis? Recently I managed a 26 year old patient with biochemical thyrotoxicosis who presented in severe heart failure with absence of tremor, lid retraction, and lid lag. With resolution of the heart failure, all the clinical signs of severe thyrotoxicosis became apparent.

MB: In the syndrome of hidden or apathetic hyperthyroidism there can be severe heart failure with atrial fibrillation but no obvious hyperthyroidism. This was described by Lahey et al in 1931.³⁵ There can be great discrepancies between hormone concentrations and clinical toxicity.³⁶

SM: The rarity of thyroxine-only toxicosis in clinical practice has been mentioned. In our experience this state is usually encountered in patients with severe non-thyroidal illness with concomitant thyrotoxicosis. These patients can have a raised thyroxine concentration and suppressed thyroid stimulating hormone but a completely normal or even subnormal triiodothyronine concentration.³⁷

DL: An interesting aspect of the pathology is the absence of thyroid C cells. These derive from the lateral anlagen, which correspond to the ultimobranchial bodies in other species.³⁸ The absence of C cells suggests that the aberrant thyroid tissue came from the median or lingual anlage rather than the lateral anlagen in this patient, with failure of fusion of the aberrant tissue with the lateral anlagen.

ID: If this patient's ectopic thyroid had been in the neck, it would be called a colloid goitre. This patient therefore had thyrotoxicosis due to ectopic colloid thyroid tissue.

AR: What common features make some ß blockers but not others useful in managing thyrotoxicosis?

MB: The major reason that propranolol is the best ß blocker is that it crosses the blood-brain barrier, permitting its centrally mediated antianxiety action. There is also a weak ancillary action--it blocks conversion of thyroxine to triiodothyronine. Not all ß blockers have this effect.¹⁷

KS: I remember being told that digoxin does not work well in thyrotoxicosis induced by atrial fibrillation. Is this true?

MB: Circulating digoxin is cleared faster than normal in thyrotoxicosis but there is resistance to the action of digoxin even if adequate doses are given. Higher doses are needed, and this patient had a maintenance dose of 0.5 mg digoxin daily. For similar reasons, high doses of propranolol are needed. Measuring plasma propranolol concentrations is useful, with an aim of achieving over 50 µg/l (192.8 nmol/l).^{5 6}

We thank Dr Rodney Reznek, consultant radiologist; Keith Britton, professor of nuclear medicine; Dr Michael Murphy, consultant haematologist; and Dr David Lowe, reader in pathology, for their contribution to the case presentation. We acknowledge the contributions of the patient's general practitioner, Dr M Dharmarajah, and the cardiothoracic surgeons, Mr S J Edmondson and Mr R Uppal, in the management of the case presented and thank Patrick Purcell of the department of endocrinology for the illustration. Advice on the use of sodium ipodate was obtained from Dr David Solomon, University of California, Los Angeles.

The BMJ welcomes grand rounds from other hospitals.

1. Armstrong P. Tomographic evaluation of the questionably enlarged pulmonary hilum. In: Armstrong P, ed. Critical problems in diagnostic radiology. Philadelphia: Lippincott, 1983.
2. Tamai H, Mukuta T, Matsubayashi S, Fukata S, Komaki G, Kuma K, et al. Treatment of methimazole-induced agranulocytosis using recombinant human granulocyte colony stimulating factor (rhG-CSF). J Clin Endocrinol Metab 1993;77:1356-60. [Abstract]
3. Patton WN, Holyoake TL, Yates JM, Boughton BJ, Franklin IM. Accelerated recovery from drug-induced agranulocytosis following G-CSF therapy. Br J Haematol 1992;80:564-5. [Medline]
4. Barzilai D, Sheinfeld M. Fatal complications following use of potassium perchlorate in thyrotoxicosis: report of two cases and a review of the literature. Isr J Med Sci 1966;2:453-6. [Medline]
5. Hellman R, Kelly KL, Mason WD. Propranolol for thyroid storm. N Engl J Med 1977;297:671-2. [Medline]
6. Feely J, Forrest A, Gunn A, Hamilton W, Stevenson I, Crooks J. Propranolol dosage in thyrotoxicosis. J Clin Endocrinol Metab 1980;51:658-61. [Abstract]
7. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: thyroid storm. Endocrinol Metab Clin North Am 1993;2:263-77.
8. Schou M. Pharmacology and toxicology of lithium. Annu Rev Pharmacol Toxicol 1976;16:231-43. [Medline]
9. Burghi H, Wimpfheimer C, Burger A, Zaunbauer W, Rosler H, Lemarchand-Beraud T. Changes of circulating thyroxine, triiodothyronine and reverse triiodothyronine after radiographic contrast agents. J Clin Endocrinol Metab 1976;43:1203-10. [Abstract]
10. Wu S-Y, Chopra IJ, Soloman DH, Bennett LR. Changes in circulating iodothyronines in euthyroid and hyperthyroid subjects given ipodate (Oragrafin), an agent for oral cholecystography. J Clin Endocrinol Metab 1978;46:691-7. [Abstract]
11. Toran-Allerand CD. Normal development of the hypothalamic-pituitarythyroid axis: Ontogeny of the neuroendocrine unit. In: Ingbar SH and Braverman LE, eds. Werner's the thyroid. London: Lippincott, 1986:7-23.
12. Strohschneider T, Timm D, Worbes C. Ectopic thyroid gland in the liver. Chirurg 1993;64:751-3. [Medline]
13. Salvatori M, Rufini V, Corsello SM, Saletnich I, Rota CA, Barbarino A, et al. Thyrotoxicosis due to ectopic retrotracheal adenoma treated with radioiodine. J Nucl Biol Med 1993;37:69-72.
14. Doria E, Agostoni P, Fiorentini C. Accessory thyroid gland in the right ventricle. Chest 1989;96:424-5. [Abstract/Free Full Text]
15. Ruchti C, Balli-Antunes M, Gerber HA. Follicular tumor in the sellar region without primary cancer of the thyroid. Am J Clin Path 1987;87:776-80. [Medline]
16. Okstad S, Mair IW, Sundsfjord JA, Eide TJ, Nordrum I. Ectopic thyroid tissue in the head and neck. J Otolaryngol 1986;15:52-5. [Medline]
17. Perrild H, Hansen JM, Skovsted L, Christensen LM. Different effects of propranolol, alprenolol, sotalol, atenolol and metoprolol on serum T3 and rT3 in hyperthyroidism. Clin Endocrinol 1983;18:139-42. [Medline]
18. Drug-induced neutropenia and agranulocytosis. Current Problems in Pharmacovigilance 1993;19:10-1.
19. International Agranulocytosis and Aplastic Anaemia Study. Risk of agranulocytosis and aplastic anaemia in relation to use of antithyroid drugs. BMJ 1988;297:262-5.
20. Fukata S, Murakami Y, Kuma K, Sakane S, Ohsawa N, Sugawara M. G-CSF levels during spontaneous recovery from drug-induced agranulocytosis. Lancet 1993;342:1495.
21. Martini E, Balzano S, Bartalena L, Loviselli A, Sica V, Petrini L, et al. Therapy of Graves' disease with sodium ipodate is associated with a high recurrence rate of hyperthyroidism. J Endocrinol Invest 1991;14:847-51. [Medline]
22. Roti E, Robuschi G, Manfredi A, D'Amato L, Gardine E, Salvi M, et al. Comparative effects of sodium ipodate and iodide on serum thyroid hormone concentrations in patients with Graves' disease. Clin Endocrinol 1985;22:489-96. [Medline]
23. Lahey FH. Intrathoracic goiters. Surg Clin North Am 1945;25:609-18.
24. Falor WH, Kelly TR, Jackson JB. Intrathoracic goiter. Surg Gynecol Obstet 1963;117:604-10.
25. Hall TS, Caslowitz P, Popper C, Smith GW. Substernal goiter versus intrathoracic aberrant thyroid: a critical difference. Ann Thorac Surg 1988;46:684-5. [Abstract]
26. Katlic MR, Wang CA, Grillo HC. Substernal goiter. Ann Thorac Surg 1985;39:391-9. [Abstract]
27. Allen MD, Thompson NW. Rationale for the operative management of substernal goiters. Surgery 1983;94:969-77. [Medline]
28. Katlic MR, Grillo HC, Wang CA. Substernal goiter: analysis of 80 patients from the Massachusetts General Hospital. Am J Surg 1985;149:283-7. [Medline]
29. Martin FI, Tress BW, Colman PG, Deam DR. Iodine-induced hyperthyroidism due to nonionic contrast radiography in the elderly. Am J Med 1994;95:78-82.
30. De Bruin TWA. Iodine-induced hyperthyroidism with computed tomography contrast fluids. Lancet 1994;343:1160-1.
31. Reinwein D, Benker G, Lazarus JH, Alexander WD. European Multicentre Study Group on Antithyroid Drug Treatment. A prospective randomized trial of antithyroid drug dose in Graves' disease therapy. J Clin Endocrinol Metab 1993;76:1516-21. [Abstract]
32. Reichert LJM, de Rooy HAM. Treatment of amiodarone induced hyperthyroidism with potassium perchlorate and methimazole during amiodarone treatment. BMJ 1989;298:1547-8.
33. Fradkin JE, Wolff J. Iodine-induced thyrotoxicosis. Medicine 1983;62:1-20. [Medline]
34. Kennedy RL, Griffiths H, Gray TA. Amiodarone and the thyroid. Clin Chem 1989;35:1882-7. [Abstract/Free Full Text]
35. Lahey FH. Apathetic thyroidism. Ann Surg 1931;93:1026. [Medline]
36. Hidden hyperthyroidism [editorial]. BMJ 1970;iv:386.
37. Surks MI, Chopra IJ, Mariash CN, Nicoloff JT, Solomon DH. American thyroid association guidelines for use of laboratory tests in thyroid disorders. JAMA 1990;263:1529-32. [Abstract]
38. Williams ED, Toyn CE, Harach HR. The ultimobranchial gland and congenital thyroid abnormalities in man. J Pathol 1989;159:135-41. [Medline]