Summary

Thyrotoxicosis is one of the most common endocrine problems encountered in ambulatory care. Graves' disease and toxic multinodular goitre accounted for over 90% of the cases (Table 1). A careful history and a physical examination supplemented by a few laboratory tests are all that is necessary to unveil other less common causes of thyrotoxicosis. Six patients with symptoms of thyrotoxicosis are presented for discussion. The majority of thyrotoxic patients can be managed by primary care physician. Management depends on a proper diagnosis and a careful titration of antithyroid drugs to avoid overtreating patients. Patients with atypical presentation such as high fever, severe eye symptoms, refractory to medical therapy or associated with pregnancy, need a specialist consultation.

摘要

甲狀腺功能亢進 (簡稱甲亢)是急診最常見的內分泌疾病。九成以上是由自身免疫因素引起的 Graves' 病、和毒性多結節性甲狀腺腫所引起。大部份典型病 例都可以透過病人症狀及體檢得到診斷。比較少見的病例亦可從基本的檢驗分析得以鑑別。本文作者以六個病例分享治療心得。大部份的甲亢病人可以由基層醫生處理，主要以於及早診斷和逐步加抗甲狀腺藥以免過度治療，只有遇到非典型的病例，包括高熱、嚴重眼部症狀，有抗藥性和懷孕的病人需要轉到專科治療。

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Table 1: Causes of thyrotoxicosis

Primary hyperthyroidism Graves' disease Multinodular toxic goitre Toxic adenoma Metastatic thyroid cancer (not common) Secondary hyperthyroidism Pituitary adenoma secreting TSH hormone (rare) Trophoblastic tumour secreting Human Chorionic gonadotrophin Thyrotoxicosis without hyperthyroidism Thyroiditis (de Quervain thyroiditis, postpartum thyroiditis) Excessive thyroxine administration

Introduction

Thyroid disease is the second most common endocrine problem after diabetes mellitus. Hyperthyroidism and hypothyroidism are two problems commonly seen in day-to-day practice. The average prevalence rate for hyperthyroidism is about 1.0% in a population study performed in England in 1982. The female to male ratio is about 10:1.¹ The incidence of hyperthyroidism is 0.8% in a cohort study over 20 years.² Hyperthyroidism is more common among the younger age group. In this article, I will present six cases with hyperthyroidism, and will discuss briefly their management.

Definition Hyperthyroidism means hyper-function of the thyroid gland while thyrotoxicosis means high metabolic rate as a result of raised blood thyroxine. In most situations, they are used interchangeably. Symptoms of hyperthyroidism are related to the high metabolic rate and enhanced sympathetic activity. Patients may complain of palpitations, heat intolerance, insomnia, tremor of hands, and weight loss despite having a good appetite. However, there might be weight gain if the patient is eating more calories than he/she uses. The patient is easily fatigued, and muscle weakness can be a chief complaint. For a lady with hyperthyroidism, menstrual disturbance can occur with secondary amenorrhoea in severe toxicosis. Uncontrolled hyperthyroidism during pregnancy can put the patient at risk of miscarriage. During the toxic phase, there might be transient osteoporosis, which usually improves after correction of the hyperthyroid state.3 Physical signs that will be helpful in confirming clinical suspicion of hyperthyroidism include: Generalised restlessness with staring eyes Lid-lag and lid retraction Periorbital swelling and exophthalmos in Graves' disease Thyroid gland enlargement * Enlarged goitre with bruit Fine tremor of the outstretched hands Moist palms Tachycardia with pulse over 100/min Atrial fibrillation, especially common among the elderly Other less common signs include thick skin over the shin (pretibial myxoedema), alopecia, and acropachy.
*	The author usually uses a simple tape to measure the girth of the thyroid gland three times to obtain an average size of the gland. One can also grade the enlargement by WHO criteria:
	Grade 0	=	no thyroid enlargement
	Grade 1	=	enlarged thyroid which can be seen upon extension of the patient's neck
	Grade 2	=	enlarged thyroid which can be seen easily without extension of neck
	Grade 3	=	enlarged thyroid which is obvious at a distance

Case 1

A 27 years old female presented in 1998 with weight loss of 20 pounds within 2 months despite having a good appetite. In fact, she felt hungry all the time. She also complained of profuse sweating and heat intolerance. She became anxious and irritable, and was admitted to hospital because of confusion. Physical examination revealed a thin lady with a staring look and retraction of the upper eyelids. Her pulse was 100 beats per minute and regular. Her palms were moist, and fine tremor was demonstrated with her outstretched hands. Neck measurement was 33/34/33 cm with an easily identifiable enlarged goitre without neck extension (WHO Grade 2). Laboratory investigations revealed sTSH <0.03mIU/l (normal range 0.35- 5.5mIU/L), fT₄ 57.1pmol/l (11.5-23.2pmole/L) and fT₃ 18.6 pmol/l (3.5-6.5pmole/L). Antithyroid globulin was 1:1280, and anti-microsomal antibodies 1:6400. She was given a course of carbimazole for 18 months. In September 2000, she had a relapse with toxic symptoms, and biochemical findings showed undetectable TSH <0.03mIU/l and fT₄ 60pmol/l. Ablative radioactive iodine I131 (RAI) therapy was discussed with and accepted by the patient. RAI was given in December 2000. Since then, she remained euthyroid with stable eye condition.

Discussion

In hyperthyroidism, laboratory investigations usually reveal an increase in fT₄ (free thyroxine) or fTI (free thyroxine index) and an undetectable TSH. We use sTSH as a screening test for suspected hyperthyroidism, and the laboratory will proceed to perform fTI if the initial sTSH is abnormal.⁴ Occasionally, serum T₃ may be required in cases of T₃ toxicosis in which fT₄ is normal with a suppressed TSH. Rarely is a radioiodine uptake scan or a TRH stimulation test required to diagnose hyperthyroidism. The most common cause of hyperthyroidism among the young population is Graves' disease, which is an autoimmune disease. Antithyroglobulin and antimicrosomal antibodies are markers of the autoimmune process, but they do not correlate with the aetiology of the disease itself. Thyroid stimulating immunoglobulin (TSI) or Long Acting Thyroid Stimulator (LATS) is present in the sera of many patients, and proposed to be related to the development of the disease. Due to its low sensitivity, it is not used in routine clinical practice. But in special situation such as Graves' disease complicating pregnancy, high titre of TSI will alert the physician to the possibility of neonatal Graves' disease.

The mainstay of treatment is thionamide of which methimazole or carbimazole and propylthiouracil (PTU) are most commonly used in Hong Kong. In practice, both of them are effective in the control of hyperthyroidism. Carbimazole has a longer half-life, and can be given as a single daily dose, which will probably improve compliance. In vitro studies suggest that carbimazole has immuno-modulating effects, and may have theoretical advantage over PTU. Because PTU has a shorter half-life, it is usually given in divided doses. Nonetheless, the other school of thought is that since the action of antithyroid drugs depends on intra-thyroid concentration PTU can be given as a single daily dose just like carbimazole. PTU is more protein bound, and will cross the placenta less readily as compared with carbimazole. It is the preferred treatment for young thyrotoxic females, especially during pregnancy. However, patients on carbimazole who do become pregnant should be reassured that the risk is low, and this should not be an indication for the termination of pregnancy. The mean starting dose for carbimazole is 20-40mg/day, while for PTU, it is 300-800mg/day. Treatment usually begins with a higher dose, and continues for 4-6 weeks to render the patient euthyroid. Then the dose should be reduced, and kept at the lowest possible dose to prevent a relapse. General consensus is that PTU or carbimazole should be continued for 18 months to reduce the chance of a relapse, which can be as high as 60% after withdrawal of the antithyroid drug. Poor drug compliance is the major cause of treatment failure. There is a high prevalence of skin rash with antithyroid drugs, and itchiness is also common. If it is not very severe, one can try an antihistamine or switch to another thionamide. A potentially severe side effect of thionamide is leucopenia, which is more common with carbimazole especially if a high dose is used. The incidence of severe side effects such as leucopenia fortunately is very rare - the annual incidence is 0.8-3.3 cases/year/million.⁵ Some authors recommend a complete blood picture as baseline, but most will agree that periodic screening is not indicated. The patient should be warned to report any sore throat or fever during the course of treatment especially in the first few months. It is suggested that if the patient has a relapse after completion of a full course of antithyroid treatment, then they should be offered radioactive iodine I131 (RAI), or partial thyroidectomy for definitive treatment. However, use of I131 or subtotal thyroidectomy can be considered as the first line treatment in multinodular goitre or patients who are intolerant to oral antithyroid medication.

 

Case 2 Multinodular goitre FY F/76

Madam FY, an elderly lady, presented in 1995 with an enlarged goitre and an undetectable TSH <0.03 and fTI 165 (72-145nmol/l). She was wasted with a staring look, and had a sinus tachycardia of 110/min. Both antithyroglobulin and antimicrosomal antibodies were negative. Ultrasonography demonstrated enlargement of both lobes of the thyroid with several heterogeneous isoechoic masses of various sizes. Retrosternal extension was noted especially over the right side. Calcified foci were noted within the lesions. Throughout the years of follow up, she had not been very co-operative and declined RAI or thyroid surgery. She was reluctant to have blood tests, and always requested long follow-up intervals in order to accommodate her son's working schedule. She was always accompanied by her son during her OPD visits since she was too old to come alone. Throughout the years she was maintained on low doses of propylthiouracil, and her TSH remained suppressed as shown in the following serial blood tests.

Received
date/td>	29 Apr 00	1 Nov 00	3 Mar 01
TSH	< 0.03 L	< 0.03 L	0.03 L	(0.35-5.50) mIU/L
fT4	22.5	20.9	17.2	(11.5-23.2) pmol/L
fT3	6.1	-	-	(3.5-6.5) pmol/L

Discussion

The aetiology of toxic multinodular goitre is believed to be due to autonomous hyperplastic nodule induced by chronic iodine deficiency. Unlike Graves' disease which is characterised by cycles of relapse and remission, multinodular goitre is a progressive disease, and some believe that all multinodular goitres will progress to the toxic state should the patient live long enough. It is more common among the elderly, and the clinical features differ from the young because of reduced sympathetic activity. Atrial fibrillation, delirium, and unexplained heart failure are more common among the elderly with hyperthyroidism. Enlarged goitre with nodular surface is characteristic, but the goitre may not be palpable if it lies behind the sternum. Antithyroid antibodies are usually negative, and eye sign save not common. Ultrasound will confirm asymmetric enlargement of the thyroid gland usually with multiple nodules. Treatment is usually RAI or subtotal thyroidectomy. But many of the elderly are reluctant or not fit for surgery, and usually decline RAI. Sometimes a low dose antithyroid drug, e.g., PTU 50mg can be given for 2-3 years to prevent relapse.

Case 3

Exogenous thyroxine

A 23 years old lady who was a ward steward in a local hospital presented to a regional hospital with weight loss of 10 pounds within two months. Clinical examination revealed a tense young lady with no goitre and no eye signs. She was discharged with the presumptive diagnosis of flu-like illness. While pending thyroid function test results, she was admitted to another hospital because of vomiting. Thyroid function test results were as follows: TSH=0.03mIU/l (0.35-5.5), fT₄=38.6pmol/l (11.5-23.2), T₃=3.6pmol/l (3.5-6.5), and the pregnancy test was negative. She was discharged with carbimazole and maxolon, but was then readmitted a few days later in a comatose state and eventually succumbed. Post-mortem found a small thyroid of 11.4gm (normal 20 - 40gm).

Microscopy revealed no morphologic evidence of hyperthyroidism or thyroiditis. The brain showed no evidence of encephalitis or meningitis. The blood viral titres were normal, and the brain and heart tissue viral cultures were also negative. Blood and urine toxicology were not informative. The histology of thyroid tissue was reviewed, and reported that the "thyroid tissue was normal, no specific pathology, exogenous thyroxine stimulation, rather than an endogenous cause for her hyperthyroidism had to be considered."

Discussion

The metabolic effect of thyroxine had long been used as a body slimming pill. However, due to its side effects particularly related to the cardiovascular system, and skeletal system and its potential for abuse, the FDA had banned thyroid hormone or its analogue Triax to be used as a slimming pill.⁶ This case illustrates the potential legal implication of malpractice and the importance of taking a full drug history including over-the-counter drugs.

Case 4

Acute suppurative thyroiditis

Madam Lee, 65 years of age, was a known diabetic with hypertension for over 10 years. She used to attend the government outpatient clinic. She was taking Daonil 5mg om and noon. She was admitted on the 3rd of December 2000 for fever (40) and non-specific dizziness for 1 day. Systemic enquiry was unremarkable. Sepsis work up was done, and intravenous Augmentin was given. The fever responded well to treatment. Blood culture yielded gram-negative bacilli - Klebsiella pneumoniae. Urinalysis revealed no abnormalities . She was discharged on the 8th of December 2000, but was readmitted on the 12th of December 2000 due to a painful neck swelling for 4 days. The pain increased with swallowing, and the fever went up to 38.7. Physical examination revealed tenderness over the anterior neck especially on the left side. Urgent CT scan of the neck revealed a swollen left thyroid gland - large thyroid nodule with a thick rim enhancement (4cm - 3cm). Fine needle aspirate yielded blood stained aspirate, which grew Klebsiella and Candida. A course of iv Zinacef and oral Fluconazole was given on 15/12/00. TSH was 0.09mIU/L (0.35-5.5), fT₄ 26.3 pmol/L (11.5-23.2), fT₃ 4.8 (3.5-6.5), and ESR 130 on 20/12/00. Repeat ultrasound of the thyroid revealed an abscess of 1.6 ? 2.3cm in size. Upon subsequent follow up, the swelling disappeared, and her thyroid function test was normal.

Discussion

Acute suppurative thyroiditis is not uncommon among immunosuppressed patients. The bacterial pathogens, most commonly staphylococcus aureus and anaerobic streptococcus, invade the thyroid either by haematological or lymphatic spread, or sometimes by direct trauma. The clinical features of fever and chill and systemic symptoms together with a painful thyroid swelling often lead to clinical suspicion. Due to release of thyroid hormone from the destroyed gland, the patient may have mild thyrotoxic symptoms, which usually subside spontaneously in a few days. Thyroid nodule fine needle aspiration and ultrasonography are helpful in making the diagnosis. Treatment is parenteral antibiotics, and antithyroid medication is rarely required.

Case 5

de Quervain's Thyroiditis

In the early 2001, a 51 year old lady with an unremarkable past medical history presented to us with a history of painful neck swelling for three weeks and fever for about two weeks. There was a high swinging fever yet the patient did not appear septic. The goitre was diffusely enlarged and painful to touch. Biochemically, the patient was diagnosed with hyperthyroidism with TSH <0.03mIU/l (0.35-5.5) and fT₄ 70pmol/l (11.5-23.2). Her ESR was 140, and CRP 46. Her blood culture was negative. Needle aspiration of the thyroid gland produced no blood or pus nor any growth.

USG: multinodular goitre, solid, R 3.4cm, L 2.6cm

The patient was started on a relatively low dose of 15mg carbimazole in view of the 'toxic' biochemistry. De Quervain's thyroiditis was suspected and confirmed by the histology report. The fT₄ was down to 7.5pmol/L (11.5-23.2) in 4 weeks with the treatment, and the carbimazole was stopped.

Discussion

Sub-acute thyroid or de Quervain's thyroiditis is due to viral infection with various viral agents incriminated. The patient will complain of a painful neck swelling and also frequently dysphagia. Fever is common. Physical examination will reveal an extremely tender goitre which is usually asymmetrically enlarged, and appears firm in consistency. The painful neck swelling will characteristically increase in size rapidly. It differs from suppurative thyroiditis in being apparently less septic. Despite the high fever, the patient interestingly appears 'normal'. Sometimes the fever can last for weeks, and presents as fever of unknown origin. Laboratory test will reveal a mild elevation of fT₄ or fT₃, with normal or low sTSH. However, antithyroid antibodies may be mildly elevated. ESR is usually high and frequently over 50 mm in 1 hour. Again, fine needle aspiration is very helpful. High serum fT₄ in the presence of low uptake on thyroid isotope scan is the hallmark of de Quervain's thyroiditis. It is very sensitive to antithyroid drug treatment. In most cases only a beta-blocker is required for symptomatic control as the disease is self-limiting. Simple analgesic and low dose prednisone are effective in pain control.⁷

Case 6

Gestational thyrotoxicosis

NB, aged 34, is a mother with two children and 7-weeks pregnant. Her last menstrual period was on the 6th of September 2001. She was admitted because of vomiting 5-6 times for 2 weeks. Her bowel motion was normal. She had no symptom of dysuria or fever. Physical examination revealed adequate hydration with no signs of frank thyrotoxicosis and/or enlarged goitre.

Ultrasonography was normal. Thyroid function tests on 30 July 2001 revealed low TSH , high fT₄, and negative antithyroid antibodies.

Date 9 Nov 99 30 Jul 01 30 Jul 01 TSH 1.26 0.05 L < 0.03 L (0.35-5.50) mIU/L fT4 11.8 25.1 H 24.5 H (11.5-23.2) pmol/L

Discussion

Clinically, the hypermetabolic state of pregnancy may mimic hyperthyroidism, and biochemically the total serum T₄ is increased while the FT₄ and the TSH will be normal. However, genuine hyperthyroidism can be difficult to differentiate from transient gestational hyperthyroidism due to the hyperemesis gravidarum in which the TSH will be low and the fT₄ may increase. The advice is that any young lady who presents with thyrotoxic symptom must be asked about her menstrual history. Any thyroid disease complicating pregnancy should be managed jointly by the obstetrician and the endocrinologist.

Conclusion

The cases illustrated here are intended to point out that one must look for the aetiology of the disease after making the diagnosis of hyperthyroidism. As in the case of thyroiditis or gestational thyrotoxicosis, antithyroid drugs are of no use and may be harmful. In Graves' disease, which is the most common form of hyperthyroidism especially among females of reproductive age, the standard regimen is 16-24 months of antithyroid medication. In general, the hyperthyroid state may be under control within 6-8 weeks, and a decrease in fT₄ is the best indicator that the patient is compliant, and that the toxic state is under control. The next target is the normalisation of TSH, and this may take months. Occasionally, it may remain suppressed for one to two years. Definitive treatment in terms of RAI or surgery should be offered to patients in relapse. Long term remission by antithyroid medications only is not possible for multinodular goitre, which is usually due to autonomous nodules. Therefore, either surgery or radioactive iodine should be considered.

Key messages

1. Graves' disease and multinodular goitre account for 90% of the aetiology of thyrotoxicosis. Other less common causes of toxicosis are adenoma, thyroiditis, gestational, and iatrogenic.
2. sTSH is the first screening test for suspected thyrotoxicosis.
3. Thyrotoxicosis due to thyroiditis is usually mild and transient.
4. Subacute thyroiditis can present with a painful neck swelling and pyrexia of unknown origin.
5. Medical therapy is the first line therapy for Graves' disease. Other well-accepted options include subtotal thyroidectomy or radioactive iodine (RAI), and the pros and cons of these options should be discussed with each individual patient.

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References