Prednisolone treatment in thyrotoxicosis 489 Postgrad Med J: first published as 10.1136/pgmj.72.850.489 on 1 August 1996. Downloaded from Treatment of thyrotoxicosis resistant to carbimazole with corticosteroids

EB Jude, J Dale, S Kumar, PM Dodson

Summary 37 pmol/l (normal 1-24 pmolIl), free triiodo- We report two patients whose thyrotox- thyronine of 12.7 pmolIl (4.2-7.1 pmolIl) and icosis failed to respond to conventional thyroid stimulating hormone of 0.2 mU/l treatment with carbimazole. The patients (0.3-3.8 mU/l). Thyroid antimicrosomal and remained persistently hyperthyroid, both antithyroglobulin antibody titres were 1:400 clinically and biochemically, despite sev- and negative, respectively. She was treated with eral months of carbimazole therapy at the carbimazole 30 mg daily but two months later maximum recommended doses. Predni- she was still clinically thyrotoxic and her free solone 20 mg per day was then given in thyroxine was 41.6 pmol/l. The carbimazole addition to the antithyroid drug and a was increased to 60 mg daily. She was also dramatic reponse observed in both cases. prescribed propranolol but it had to be They were then successfully treated with discontinued owing to respiratory wheeze. radioiodine. Four months later, on the maximum recom- Prednisolone has not been previously mended dose of carbimazole, she felt no better used to treat patients with hyperthyroid- and her free thyroxine was 46 pmol/l. Non- ism who have not responded to thiona- compliance with the prescribed medication mide drugs. Our experience suggests that was suspected, but on repeated questioning corticosteroids may be potentially useful she asserted that she was taking her treatment for controlling thyrotoxicosis in combina- regularly. She was then started on predniso- tion with carbimazole before definite lone 20 mg daily in addition to the carbima- treatment can be instituted. zole. There was marked improvement in her symptoms within four weeks and she was Keywords: thyrotoxicosis, prednisolone, carbimazole clinically euthyroid, which was confirmed with resistance a free thyroxine of 28.8 pmol/l. At this stage she was given radioactive iodine 400 MBq. Two months later her free thyroxine was Thionamides have been used in the treatment 17.7 pmol/l (figure). The carbimazole was then

of hyperthyroidism for over 50 years. Most stopped and prednisolone was gradually with- http://pmj.bmj.com/ patients respond within four to six weeks of drawn; 15 months hence she is euthyroid and initiating treatment and the dose is reduced to clinically well. a maintenance level for a further six to 12 months. Rarely, patients are found not to Case 2 respond to antithyroid drugs (carbimazole or A 46-year-old woman presented with symp- propylthiouracil) and this poses a difficult toms of tremors, weight loss, tiredness, in- management Such are usual- problem. patients creased sweating, irritability and inability to on September 28, 2021 by guest. Protected copyright. ly thought to have failed to comply with their concentrate at work. On examination she had a medication. Corticosteroids are often used in the man- agement of thyroid crisis.' However, they have prednisolone not been recognised as useful therapy in the 140- management of patients not responding to antithyroid drugs alone. We report two pa- 120 - tients who remained persistently thyrotoxic E0100 / \ RAI despite treatment with carbimazole at the E recommended dose for four months. r- 80 Department of Q 80-cX S pednisoone Medicine, 0) Birmingham Heart- Case 1 lands Hospital, A 30-year-old woman had had symptoms of Birmingham thyrotoxicosis with palpitations, mood B9 5SS, UK changes, heat intolerance, weight loss and 0 EB Jude J Dale diarrhoea for six months. On examination she ' S Kumar was lean (body mass index 19), and had sinus 0 3 6 9 12 15 18 21 24 PM Dodson tachycardia with a heart rate of 120 beats/min. time (months) She had a diffuse goitre with a bruit and fine Correspondence to tremor of her hands, but no eye signs apart Figure Serum free thyroxine concentrations for Case Dr PM Dodson 1 (0) and Case 2 (0) during treatment with from lid lag. Thyroid function tests confirmed carbimazole and the effect of adding prednisolone. Accepted 13 November 1995 hyperthyroidism with free thyroxine of RAI=radioactive iodine 490 Jude, Dale, Kumar, Dodson

diffuse goitre with an audible bruit, but no eye signs of Graves' disease. Her pulse rate was Summarynlearning points 100 beats/min, regular. She had fine tremors of * resistance to antithyroid drugs in the treatment Postgrad Med J: first published as 10.1136/pgmj.72.850.489 on 1 August 1996. Downloaded from her fingers and mild proximal muscle weak- of thyrotoxicosis is not unknown ness. Thyroid function tests confirmed thyro- * prednisolone has been shown to ameliorate the toxicosis (serum free thyroxine 73.8 pmol/l, symptoms of hyperthyroidism and hence can free triiodothyronine > 43.2 pmol/l and thyroid be used as an adjunct in the treatment of stimulating hormone < 0.1 mU/l). Her antimi- thyrotoxicosis when patients do not respond to crosomal and antithyroglobulin antibody titres antithyroid drugs alone * prednisolone can also be useful in the rapid were 1: 25 600 and negative, respectively. She control of symptoms in the elderly and when was started on carbimazole 45 mg daily which, definitive treatment for thyrotoxicosis has been three months later was increased to 60 mg daily planned, such as radioiodine because of persistent hyperthyroidism. Two months later her serum free thyroxine was > 125 pmol/l and her symptoms had worsened. She denied noncompliance to treatment. She was then commenced on prednisolone 20 mg measures to reduce their serum free thyroxine daily in addition to the carbimazole. In the next concentration. In our two patients we used two weeks her symptoms had improved and she prednisolone to good effect. The addition of was able to go back to work. Four and eight prednisolone as an adjunct to carbimazole weeks later her free thyroxine was 71.2 and produced significant clinical improvement 63.6 pmol/l, respectively. In view of the con- and made it safe for the patients to have siderable improvement in symptoms and since radioiodine treatment. the free thyroxine level was down to 50% of her Prednisolone is not used as a mode of levels prior to prednisolone, she received radio- achieving euthyroid status in patients with active iodine 400 MBq. Four and six months hyperthyroidism, though it is often used in later her free thyroxine was 44.9 pmol/l and thyroid crisis. Studies have shown a rapid 5 pmol/l (figure). The carbimazole was there- decline in serum thyroid hormone concentra- fore discontinued and prednisolone was gradu- tion following the acute administration of ally withdrawn. She is now being treated with glucocorticoids.4-7 The effect of corticoster- thyroxine owing to hypothyroidism and is well. oids on the thyroid gland in hyperthyroidism is obscure. Graves' disease is an autoimmune Discussion disorder,' both cell- and antibody-mediated.8 The latter is a syndrome complex due to the Carbimazole is widely used in the management action on the thyroid of IgG immunoglobulins of hyperthyroidism. It acts by inhibiting the that may be antibodies against components or oxidation and organic binding of thyroid regions of the thyroid plasma membrane, iodide" 2 as well as having an immunosuppres- possibly regions that include the receptor for sive effect upon the thyroid itself. It is some thyroid stimulating hormone itself. Thus, the months before the patient is rendered euthyr- reason why patients respond to corticosteroids oid, therefore compliance with treatment is could be two-fold. The more immediate effect http://pmj.bmj.com/ essential. Failure to take the medication is could be the inhibition of conversion of generally thought to be the reason for lack of thyroxine to triiodothyronine in the peripheral response to treatment, but the true prevalence tissue,5 blocking the release of thyroxine from of carbimazole resistance is unknown. There the thyroid. It may also lead to suppression of are few reports in the literature of patients not the immune response and hence decreased responding to the maximum recommended stimulation of the thyroid gland by the altered

dose of 60 mg carbimazole daily.' It is not clear immune response and cell-mediated immu- on September 28, 2021 by guest. Protected copyright. why such patients do not respond. Both our nity. Clearly, further studies are needed to patients denied noncompliance. Our first examine the effect of such immunosuppressive patient also had diarrhoea but there was no therapy in Graves' disease. clinical evidence to suggest malabsorption. Our experience suggests that there are some Although it is possible to measure drug levels, patients who may benefit from the use of this is rarely done in clinical practice and was corticosteroids as an adjunct to antithyroid not performed in our patients. However, the drugs in the treatmnent of Graves' disease. Such observation that both patients demonstrated patients would include those in whom the significant improvement once given predniso- response to carbimazole has been poor and lone suggests that compliance was unlikely to also those patients in whom rapid remission of have been the problem. the disease is required, such as in the elderly Before definitive treatment of thyrotoxicosis and in patients with thyrotoxic heart disease. with subtotal thyroidectomy or ablation with These cases demonstrate the potential value of radioiodine, it is necessary to control hy- prednisolone in rapid control ofthyrotoxicosis, perthyroidism so as to reduce the risk of where a decision has been made to proceed precipitating thyroid crisis.'l Hence patients with definitive treatment such as surgery or not responding to carbimazole need fulrther radioiodine.

1 Wilson JD, Foster DW. Textbook of endocrinology, 8th edn. 3 Hall R, Lazarus JH. Changing iodine intake and the effect WB Saunders Co, 1992. on thyroid disease. BMJ' 1987; 294: 721-2. 2 Goodman AG, Rall TW, Nies AS, Taylor P. The 4 Williams DE, Chopra IJ, Orgiazzi J, Solomon DH. Acute pharmacological basis of therapeutics, 8th edn. Oxford: effects of corticosteroids on thyroid activity in Graves' Pergamon Press, 1991. disease. J Clin Endocrinol Metab 1975; 41: 354- 61. Prednisolone treatment in thyrotoxicosis 491

5 Chopra IJ, Williams DE, Orgiazzi J, Solomon DH. Opposite 7 Ozawa Y, Daida H, Shimizu T, Shishiba Y. Rapid effects of dexamethazone on serum concentrations of improvement of thyroid function by using glucocorticoid indicated for the preoperative preparation of subtotal 3,3',5'-triiodothyronine (reverse T3) and 3,3',5'-triiodothyr- Postgrad Med J: first published as 10.1136/pgmj.72.850.489 on 1 August 1996. Downloaded from onine (T3).J Clin Endocninol Metab 1975; 41: 911 -20. thyroidectomy in Graves' disease. Endocrinol Japon 1983; 6 Croxon MS, Hall TD, Nicoloff JT. Combination drug 30: 93-100. therapy for treatment ofhyperthyroid Graves' disease. JT Clin 8 Volpe R. Immunoregulation in autoimmune thyroid Endocrinol Metab 1977; 45: 623- 30. disease. N Engl I Med 1987; 316: 44- 6.

Congestive cardiac failure following laxative withdrawal

JA Riley, AR Brown, BE Walker

Summary with the recommended adult dose of two We report the case of a 60-year-old tablets, she soon increased this to five tablets woman who presented with weakness and per day. This produced a liquid, easily passed hypokalaemia due to excessive use of stool within a few hours. laxatives. When the laxatives were with- Whilst on holiday in Spain in 1993 she felt drawn, she developed severe congestive weak and exhausted and was told she had a low cardiac failure requiring treatment with a blood pressure. By the time ofher return home diuretic and angiotensin-converting en- the symptoms had become more severe and zyme inhibitor. There was no underlying eventually resulted in her admission to hospital. cardiac abnormality, and these drugs were On admission, her blood pressure was 105/ eventually stopped with no recurrence of 60 mmHg. Clinically her heart was normal and the cardiac failure. The possible mechan- there was no evidence of cardiac failure. Urea isms of heart failure following laxative and electrolytes were within the normal range withdrawal is discussed. except for serum potassium which was found to be low at 2.6 mmol/l. Her prescribed Keywords: laxative abuse, hyperaldosteronism, car- medication consisted of medroxyprogesterone, diac failure sucralfate, ranitidine and co-dydramol. In the absence of any other obvious cause for

her hypokalaemia, laxative abuse was sus- http://pmj.bmj.com/ Laxatives account for a significant proportion pected. She admitted to taking the Fam-Lax of over-the-counter (OTC) pharmacy sales - she had simply been following instructions (C37m in 1994 out of a total of £1268m not to strain at stool. OTC pharmacy and grocery sales). The wide The laxatives were withdrawn and oral variety and easy availability can lead to potassium supplements started (Sando-K excessive use, inappropriate dosage, and even 2 bid). Serum potassium rose rapidly to

abuse of these medicines. Loss of fluid and normal levels over the next four days (figure). on September 28, 2021 by guest. Protected copyright. electrolytes in diarrhoea may result in second- ary hyperaldosteronism and hypokalaemia. Oedema may be a feature of the recovery phase after laxative withdrawal. 6 Aldosterone (100-450 pmol/1) We describe a patient whose excessive 2070 2450 270 180 laxative intake led to life-threatening cardiac failure after the laxatives were withdrawn. E Case report E A 60-year-old woman underwent a bilateral St James's University salpingo-oophorectomy for endometrial carci- Hospital, Leeds noma in December 1987. She made a good o 3 LS9 7TF, UK QL _ Department of recovery and routine follow-up showed no E Pharmacy evidence of recurrence. Following the opera- JA Riley tion, she was told to avoid straining at stool 2 Medicine for the C and was prescribed Fybogel sachets and senna K+ K+ K+ K+ Elderly tablets. She felt this laxative regimen did not AR Brown 1 Medical Directorate have the desired effect and some months later, 0 2 4 6 8 10 12 14 16 18 20 BE Walker on the advice of a friend, she started to take Fam-Lax (phenolphthalein and rhubarb) days Accepted 13 November 1995 which she bought over-the-counter. Starting Figure Serum potassium and aldosterone levels