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  1. 1. How to Treat Pull-out section EARN CPD POINTS Complete How to Treat quizzes online ( or in every issue – see page 28. inside Troubles with thyroxine? Practical points in managing thyroid problems Detecting and managing subclinical thyroid dysfunction Thyroid issues in reproductive medicine Importance of the laboratory-clinical interface in the investigation of thyroid disorders The author PROFESSOR JIM STOCKIGT, a Melbourne endocrinologist with a special interest in thyroid disorders, is in practice at Epworth Hospital and is professor of medicine at Monash University and senior Thyroid disorders endocrinologist at the Alfred Hospital. He recently presented an invited review on thyroxine bioavailability at the American Thyroid Association meeting in Vancouver. Background GOITRE and abnormalities of thy- that sustained mild thyroid dysfunc- older patients with persistent mild When symptoms do not resolve roid function are common and tion causes tissue abnormalities. thyrotoxicosis due to nodular thy- completely in hypothyroid patients include a wide range of clinical pre- The case for early treatment of roid disease. treated with thyroxine, the ques- sentations and challenges. Nowa- mild thyroid dysfunction is, so far, We generally assume that thyrox- tion of whether this group would days, the fully developed textbook based on the likelihood of preventing ine replacement is trouble free, but benefit from supplementation with features of thyrotoxicosis and long-term harm, rather than proof there has been recent uncertainty and triiodothyronine has been con- hypothyroidism have become of benefit. It seems illogical to insist some confusion about its shelf-life, tentious. Again, the answer appears uncommon because laboratory test- on strict evidence-based proof of bioavailability and optimal storage. to be no. ing is usually initiated at an early benefit for a theoretically sound, Symptoms of thyroid dysfunction The last decade has seen the emer- stage, when only a few clinical fea- safe, inexpensive therapy when the are so diverse that there is wide over- gence of a wide range of important tures are present. required long-term studies may never lap with people reporting symptoms, issues that relate thyroid function to The relationship between mild, or be done. who have no demonstrable thyroid reproductive medicine. Some of these ‘subclinical’ laboratory abnormali- Examples of such treatment abnormality, even with the most sen- points have not yet received suffi- ties and presenting symptoms may include thyroxine replacement for sitive available tests. Such individuals cient attention and remain impor- sometimes be difficult to establish, persistent subclinical hypothy- do not appear to benefit from alter- tant challenges in continuing educa- but there is now reasonable evidence roidism, and radioiodine therapy for ation of their thyroid status. tion. 4 February 2005 | Australian Doctor | 21
  2. 2. How to treat – thyroid disorders Troubles with thyroxine? It now appears Practical points in managing that thyroxine EFFECTIVE thyroid replace- Figure 1: Letter from a concerned patient after being can safely be Amiodarone-induced thyrotoxicosis ment was first achieved more instructed by the pharmacist to take dispensed thyroxine stored at cool THE diagnosis of amiodarone-induced thyrotoxicosis is dif- than 110 years ago using thy- home in an iced pack and keep it refrigerated. room temperatures ficult because clinical features are often atypical, especially in roid extract, which remained patients with established heart disease. Weight loss, proximal the standard preparation for several weeks. myopathy and deterioration of cardiovascular function are until the 1960s, when syn- often prominent features. thetic L -thyroxine sodium Many patients on amiodarone are also taking an antico- became available. agulant. In contrast to the general rule that drug require- One of the strong argu- ments increase in thyrotoxicosis and decrease in hypothy- ments for preferring the syn- roidism, the opposite occurs with anticoagulants. In thetic preparation has been its thyrotoxicosis the degradation of coagulation factors is supposed purity and stan- increased. Thus, an unexpected decrease in warfarin require- dardisation, but it is now clear ment can be the initial clue to the development of amio- that there are ongoing prob- darone-induced thyrotoxicosis. lems. In 1982, after reports of increased potency when stan- Temporary hypothyroidism after dardisation by iodine content radioiodine treatment of thyrotoxicosis became obsolete, the routine Hypothyroidism commonly follows radioiodine treatment dose was revised downwards of thyrotoxicosis, more often in Graves’ disease than in nodu- by about 25%. lar thyroid disorders. When the TSH level becomes elevated Between 1982 and 1997 without marked clinical features of hypothyroidism in the there were problems with first year after radioiodine treatment, the deficiency may be tablet content, shelf-life, sta- either temporary or permanent. bility and absorption, related If partial replacement is given with thyroxine (Eutroxsig, possibly to particle size, Oroxine) 0.05mg daily, serum TSH level can still be fol- excipients such as lactose or Figure 2: A recent, more practical, approach to the storage of lowed as an index of endogenous thyroid function. A pro- corn starch, and variable dis- thyroxine. gressive rise in TSH level is an indication for permanent full solution. This resulted in the replacement, while a return of serum TSH level to normal or recall for sub-potency of subnormal values suggests the thyroid remains active. some thyroxine preparations in the US. Distinguishing between replacement These issues generally and suppressive dosage of thyroxine received little publicity and Replacement use of thyroxine generally aims to achieve a clinicians were sometimes TSH target level of 0.5-2mU/L. However, in some situations, caught unawares by technical particularly in patients with differentiated thyroid cancer, problems in the formulation and in the treatment of some euthyroid goitres, treatment of thyroxine. aims to achieve subnormal levels of TSH in the range 0.05- Thyroxine has a narrow 0.2mU/L, to minimise TSH stimulation of thyroid tissue. therapeutic index, with well- During suppressive therapy, the free T4 estimate is usually recognised adverse conse- slightly above normal, but the free triiodothyronine (T3) quences of subclinical or should not be elevated. In some patients with differentiated iatrogenic hyper- or hypo- thyroid cancer, the aim of treatment is to suppress TSH to thyroidism. Highly sensitive undetectable levels, while avoiding the adverse effects of TSH assays allow even overt thyrotoxicosis. minor dose discrepancies to Monitoring both serum T3 and T4 levels is usually recom- be detected in a way that mended. The need for continuing suppressive treatment should was impossible until about be periodically reviewed to minimise the possibility of adverse 10 years ago. effects on bones and the potential for cardiac arrhythmia. There has been sufficient doubt about the equivalence Recognising acute thyrotoxicosis and interchangeability of vari- in the elderly: seek the iodine source ous preparations for the US Spontaneous progression towards thyrotoxicosis in nodular Food and Drug Administra- disease is usually slow. However, patients with autonomous tion to require new drug nodular thyroid disease can become thyrotoxic if they are applications to be filed exposed to iodine excess, sometimes in the form of radiolog- between 1997 and 2000. ical contrast agents. When thyrotoxicosis appears to develop However, no gold standard acutely, it is important to seek a history of iodine excess. of bioavailability or bioe- packs, or whose employment TSH level remains the cor- Iodine-induced thyrotoxicosis may initially be resistant to quivalence could be specified. classification would be down- nerstone of optimal therapy. antithyroid drugs, and emergency thyroidectomy is occa- The emphasis has so far been graded if they depend on a Assessment of serum TSH sionally required if the condition is severe and unresponsive. on studies of absorption as refrigerated medication, for level every 6-12 months, or However, the condition can eventually be self-limiting. an index of bioavailability, example, in the military. The three months after a change It is important to recognise this entity, which differs from but this technique is impre- inconvenience for travelling of dose, brand or batch, is other forms of thyrotoxicosis in its presentation, response to cise and has major problems. and holidays is obvious. generally recommended. therapy and outcome. Uncertainty, confusion A recent softening of the It is clear that therapeutic and dispute have followed manufacturer’s directive, preparations should be stan- Factitious thyrotoxicosis on a background of compe- published in a newsletter dardised as much as possi- Occasionally patients ingest thyroid hormone in excess, usu- tition for market share, arbi- from the Australian Thyroid ble, but recent doubts about ally with the objective of weight loss. When they present trage of products and com- Foundation (figure 2), places uniform potency, stability with features of thyrotoxicosis, standard treatment is inef- panies, and the emergence of the issue in perspective. It and absorption of thyroxine fective, although beta blockers alleviate some of the features less expensive and less prof- now appears that thyroxine emphasise the need for peri- of thyroid hormone excess. itable generic preparations. can safely be stored at cool odic measurement of serum Clues to factitious thyrotoxicosis include: Concern about the shelf-life room temperatures for sev- TSH level. For standard ■ Thyrotoxicosis without palpable goitre. of thyroxine appears to be eral weeks. replacement, a TSH value in ■ Marked thyroxine excess with a relatively low serum T3 behind the recent Australian Worldwide, at least 100 the range 0.5-2.0mU/L will level. directive that the preparation million people take thyrox- confirm efficacy, correct ■ Absent isotope uptake on nuclear scanning. should be stored refrigerated, ine. Consumers, health care dosage and patient compli- ■ Undetectable serum thyroglobulin in the presence of thyroid but the database for this deci- providers and insurers have ance. hormone excess. sion has not been made an incentive to choose the Thyroxine absorption can Management may require sensitive counselling about the public. Some pharmacists least expensive medication, be impaired by a wide vari- adverse effects of long-term thyroid hormone excess. There have taken a very hard line by which may involve change ety of other medications, in may be associated diuretic or purgative abuse, as well as suddenly insisting that the of brand, on the presump- particular, calcium, iron, occult vomiting. preparation should be trans- tion of equivalence. Batch- cholestyramine, aluminium ported home in a refrigerated to-batch consistency from products, and soy or bran Lack of response to thyroid pack (figure 1). the same source is often preparations. Absorption is hormone replacement therapy While the issue may seem taken for granted, but may best on an empty stomach, When a patient fails to respond to usual replacement doses of trivial, it is crucial for those not be reliable. with at least four hours sep- thyroxine, as judged from persistent symptoms and continu- who need their medications to In clinical practice, peri- aration from other medica- ing elevation of serum TSH level, it is first important to be organised in Webster odic assessment of serum tions, if possible. check compliance. 22 | Australian Doctor | 4 February 2005
  3. 3. thyroid problems Oral medications such as Figure 3: Contrast between typical appearances of severe primary hypothyroidism (left) and treatment can often safely be hypothyroidism, such as iron supplements, calcium hypopituitarism (right). Note that serum immunoreactive TSH level is often normal in the latter started with full replacement lethargy, low mood, weight carbonate, aluminium disorder. dosage, for example, in gain or cold intolerance are hydroxide and soy prepara- healthy euthyroid patients common, often without any tions can impair the absorp- after near-total thyroidectomy, abnormality of thyroid func- tion of thyroxine if taken at or when suppressive therapy tion. It has been contentious the same time. It is sound is resumed after temporary whether such patients will advice to take thyroxine on withdrawal of treatment for get symptomatic benefit an empty stomach, separated thyroid cancer follow-up. (In from thyroxine treatment. by at least four hours from my view, the advice given in Information is still limited, other medications. the product information, in but studies that correct for Even when these interfer- MIMS and in the Australian placebo effects have shown ences are ruled out, some Medicines Handbook is no clear response. patients appear to have an unnecessarily conservative in The use of thyroid hor- abnormally high thyroxine this respect). mone supplements on the requirement for reasons that basis of symptoms alone is remain unclear. In primary Thyroid dysfunction in not justified. An early tran- hypothyroidism, serum TSH polycystic ovary syndrome sient response may represent level generally gives a reli- Several recent reports docu- a placebo effect that can lead able index of replacement, ment a two-threefold increase to dose escalation to levels provided that about four in the prevalence of immune that represent clear over- weeks have elapsed to allow thyroid dysfunction, in partic- treatment. A symptomatic a particular dose to achieve ular hypothyroidism, in response that occurs within steady-state conditions. women with polycystic ovary a few hours or days after syndrome. starting treatment is likely to Primary hypothyroidism: be non-specific. has the diagnosis been Is thyroxine alone The question of whether proven? sufficient for optimal individuals with serum TSH During replacement there is treatment of levels in the upper normal no simple test that identifies Table 1: Disorders medications. cancer, thus avoiding the hypothyroidism? range (3-5mU/L) might ben- patients with true primary associated with an In the event of fever or sore debilitating symptoms of The thyroid gland normally efit requires further study. hypothyroidism. If the initial increased prevalence throat, the medication should transient hypothyroidism. secretes both T4 (thyroxine) While such values are statis- documentation is not avail- of thyroid dysfunction be withdrawn and not Thyrogen is expensive and and the more active T3 (tri- tically ‘normal’, they are well able, it is generally appropri- restarted until the neutrophil has restricted availability iodothyronine). Most T3 is above the normal TSH set- ate to continue replacement, ■ Previous thyroid disease count has been checked. under PBS guidelines (previ- formed by conversion from point for most people. provided thyroxine is not or surgery Minor neutropenia of about ous thyroxine withdrawal thyroxine in organs such as In this situation, a thera- being used to excess. ■ Goitre 1.0 x 10 9 is generally not associated with major emo- liver and kidney, a process peutic trial may be justified, A marginally elevated ■ Associated autoimmune regarded as an indication for tional disturbance, as docu- that also occurs when thyrox- especially if positive peroxi- serum TSH level or positive disease(s) withdrawal of antithyroid mented by a consultant psy- ine is ingested. dase antibody confirms an peroxidase antibody test drug. chiatrist). The question of whether T3 underlying immune process ■ Type 1 diabetes indicate that primary is required in addition to thy- with the likelihood of later hypothyroidism is likely. ■ Previous post-partum Adjustment of thyroxine Monitoring antithyroid drug roxine for optimal replace- progression to overt hypothy- When a distinction must be thyroid dysfunction dosage therapy: a case study ment has been contentious, roidism. made, serum TSH level three ■ Down syndrome Thyroxine has a narrow ther- A young woman presents but there are no conclusive weeks after treatment has ■ Turner’s syndrome apeutic index and there are with moderately severe thy- studies that show clear benefit. Detection of secondary stopped will be definitive. ■ Chronic renal failure strong reasons to avoid iatro- rotoxicosis due to Graves’ dis- Three recent double-blind hypothyroidism due to It is useful to provide genic subclinical hyper- or ease and is started on car- crossover studies showed no hypopituitarism patients with newly diag- ■ Irradiation of head and hypothyroidism. Precise dose bimazole 10mg bd. What benefit from using T3 in addi- The diagnosis of thyroid fail- nosed hypothyroidism with neck adjustment is generally based follow-up program is appro- tion to thyroxine, in terms of ure secondary to deficiency the initial diagnostic docu- ■ Radical laryngeal or on serum TSH level, aiming priate? symptom relief, cognitive of pituitary TSH secretion mentation, to avoid any pharyngeal surgery generally for a target value in Response to antithyroid function, quality of life or sat- relies mainly on clinical future doubt. ■ Recent Cushing’s the range 0.5-2.0mU/L. drugs vary widely between isfaction with treatment. acumen (figure 3). The syndrome In contrast to North Amer- patients and it is important to Despite assertions on the major clues relate to other Who to test for thyroid ica and Europe, where thy- avoid over-treatment. In con- Internet, there are no bona features such as: ■ Thalassaemia major dysfunction roxine is sold in a range of trast to most other medica- fide descriptions of a sustained ■ Amenorrhoea. Abnormal thyroid function, ■ Primary pulmonary about 12 tablet sizes from tions, it is customary to begin defect in the conversion of T4 ■ Past history of obstetric either overt, or subclinical hypertension 25µg to 300µg, only 50µg, treatment with a substantial to T3 in adults, and there is complications. (when only serum TSH level ■ Polycystic ovary 100µg and 200µg tablets are dose of antithyroid drug that no legitimate basis for advo- ■ Visual impairment. is abnormal), occurs in up to syndrome available in Australia. Precise, is likely to control the disor- cating additional T3 treatment ■ Headache. 10% of women over 55. It is ■ Pituitary surgery or simple dose adjustment is still der, and to individualise drug in the belief that patients have ■ Hypotension. now suggested that thyroid irradiation possible without cutting dose, (usually substantial dose this defect. ■ Fine wrinkling of the skin function be checked at pre- tablets, because thyroxine has reduction) during follow-up In standard replacement ■ Abnormal pallor ■ Severe head injury sentation for medical care in a half-life of about a week. testing. therapy it may not be suffi- ■ Any other features of pitu- this group (ie, case finding, ■ Premature infants of very Using alternate-day doses A further test of thyroid cient to merely restore TSH itary dysfunction, includ- rather than true population low birthweight is one approach, but it is function after 3-4 weeks and thyroxine levels into the ing hyponatraemia or screening). ■ Therapeutic agents: simpler to adjust the dose, should include serum T3 broad reference range. Serum hypoglycaemia. The benefits of this strat- — Amiodarone based on days of the week. level, which may remain TSH is logarithmically dis- Failure to identify central egy in younger women or in For example, 200µg on selectively elevated despite tributed and most people hypothyroidism is the major — Lithium males have not been estab- Monday, Wednesday and normalisation of T4. Serum appear to have a set-point in weakness of the current ‘TSH- lished, unless these patients — Thalidomide Friday, with 100µg on the TSH level can remain sup- the range 0.5-2.0mU/L. first’ strategy of first-line thy- have another disorder asso- — Interferon alpha ribavirin other four days, achieves a pressed for several months, Unless there is a con- roid function testing. Serum ciated with an increased — Interleukin 2 mean daily dose of 140µg, regardless of response. traindication, thyroxine dose immunoreactive TSH level is prevalence of thyroid dys- close to the mean optimal It is appropriate to decrease should be adjusted to often normal in hypopitu- — Therapeutic use of function (table 1). When dose for most adults. the drug dose by half when achieve TSH values in this itarism (there is diminished antibodies serum TSH level is in the If the dose is changed, at thyroid hormone levels have range. Periodic monitoring bioactivity of the secreted gly- lower normal range — Growth hormone least six weeks should elapse dropped by about half, even if every 6-12 months is appro- coprotein) and the diagnosis (<3mU/L), testing need not treatment before reassessment. Patients they are still elevated. Car- priate to document individ- can be missed on the basis of be repeated for five years. should be counselled against bimazole or propylthiouracil ual response and also to a normal serum TSH level. making arbitrary short-term must not be abruptly with- accommodate variations in Subnormal serum thyrox- Side effects of antithyroid dose changes based on acute drawn when thyroid hormone the potency or absorption of ine without the expected drugs symptoms. levels become normal. thyroxine preparations. increase in serum TSH level All patients treated with should suggest the possibility either carbimazole (Neo- Use of Thyrogen in thyroid Initiation of thyroxine Do patients with of hypopituitarism. How- Mercazole) or propyl- cancer follow-up therapy symptoms that suggest ever, this profile is non-spe- thiouracil should be informed Recombinant human TSH While it is appropriate to hypothyroidism but with cific and is a frequent tran- verbally and in writing about (Thyrogen) is now available begin thyroxine replacement normal tests of thyroid sient finding during any agranulocytosis as an occa- and can be used as an alter- at low dose (25-50µg daily) in function benefit from severe illness, especially if sional but potentially life- native to thyroxine with- the elderly, especially if there is replacement? there is associated high-dose threatening side effect of these drawal in cases of thyroid possible cardiac ischaemia, Symptoms that suggest glucocorticoid therapy. 4 February 2005 | Australian Doctor | 23
  4. 4. How to treat – thyroid disorders Detecting and managing subclinical thyroid dysfunction THERE is still controversy about the Figure 4: The prevalence of hypothyroidism after radioiodine treatment of Subclinical thyrotoxicosis matrix by osteoclasts). Notably, two importance of subclinical thyroid thyrotoxicosis is lower in multinodular goitre (left), than in Graves’ disease Cardiac function. The Framingham years of suppressive T4 therapy for dysfunction, a common finding, (right). Typical nuclear scans are shown. study showed that subclinical thyro- euthyroid goitre was associated with defined as the persistence of an toxicosis, defined only by suppres- a 3-4% decline in the lumbar spine abnormal serum TSH level before sion of TSH level, carried a threefold bone density.1 the serum free T4 and T3 estimates increased risk of AF within 10 years. become clearly abnormal. Doses of thyroxine sufficient to Subclinical hypothyroidism An abnormality of serum TSH suppress TSH level, equivalent to Symptomatic benefit. Small double- without a thyroid hormone abnor- those used for differentiated thyroid blind trials suggest that about 25% mality was regarded mainly as a cancer, increase the prevalence of of women with elevated TSH but prognostic indicator until recently. atrial premature beats and increase normal free T4 levels show improve- However, evidence now suggests that left ventricular mass index. ment in non-specific symptoms. In subclinical thyroid dysfunction, Iodine-induced thyrotoxicosis. Sub- contrast, double blind studies sug- defined only by a persistent TSH clinical thyrotoxicosis due to gest that similar symptoms do not abnormality, is associated with autonomous nodular thyroid disease improve in women who have com- abnormal tissue function. carries the risk of progression to pletely normal test results. It seems likely that the abnormal severe overt thyrotoxicosis after Atherosclerosis. Mild thyroid failure serum TSH reflects a deviation away iodine exposure. appeared to be an independent risk from that person’s finely tuned set- Several studies have shown a ferences such as ethnic predisposi- A Melbourne study demonstrated factor for both MI (odds ratio 1.3- point for the TSH-thyroid hormone prevalence of 1-2% overt thyrotoxi- tion or variations in iodine intake. that recent iodine exposure, often 4.0) and radiologically-visible aortic relationship. cosis and overt hypothyroidism in European findings indicate that from the radiological contrast agents atherosclerosis in a study of Dutch While there is a sound factual basis women that increases with age; hypothyroidism is more common used in CT scans, could be identified women over 55.2 for the view that subclinical thyroid prevalence in males is generally 10 with abundant iodine intake, while in up to 25% of elderly patients pre- It was suggested that attributable dysfunction may be harmful, high- times lower. Estimates of subclinical goitre and subclinical thyrotoxico- senting with thyrotoxicosis. risk from subclinical hypothy- quality evidence of benefit from inter- dysfunction are 4-5 times higher, sis are more common with low Osteoporosis. Longstanding overt roidism was comparable to that of vention will take years to accumu- with about 10% of women over 55 iodine intake. thyrotoxicosis is an important risk other major risk factors, such as late and it may be reasonable to showing an increase in serum TSH factor for osteoporosis, but the evi- hypercholesterolaemia, hyperten- intervene without being bound by level that progresses with age. Adverse effects of subclinical dence is less clear for subclinical thy- sion, smoking and diabetes. the restrictions of the evidence-based After 20 years’ follow-up, the thyroid dysfunction rotoxicosis. Vascular compliance. Flow-mediated doctrine, provided that the interven- likelihood of overt hypothyroidism The potential adverse effects of Some studies of postmenopausal endothelium-dependent vasodilata- tion is safe and affordable. is about eight times greater if either subclinical thyroid dysfunction are women either treated with T4 suffi- tion may be impaired even in patients A twofold alteration in serum T4 assay for thyroid peroxidase anti- listed in table 2 (facing page). In cient to suppress TSH level, or having with borderline hypothyroidism or level, up or down from the set-point body was positive or if serum TSH some instances the adverse out- subclinical thyrotoxicosis due to high-normal serum TSH level. for a person, is associated with 10- level was increased in the initial come, such as the increased preva- multinodular goitre, show decreased Cardiac function. There is evidence 100-fold changes in serum TSH level tests. lence of AF over 10 years when ini- mean bone density and increase in from echocardiographic studies in the opposite direction, so TSH However, findings from one tial serum TSH level is suppressed, urinary excretion of pyridinoline that mild thyroid failure can abnormalities will generally precede region do not necessarily apply in has been documented by careful cross-links (from the breakdown of increase systemic vascular resis- diagnostic T4 or T3 changes. other populations, because of dif- retrospective clinical studies. type 1 collagen, released from bone tance and impair cardiac systolic Thyroid issues in reproductive medicine POTENTIAL abnormalities before conception because Figure 5: Percentage miscarriage in unselected pregnancies in ■ Avoid radioiodine treatment If thyroid over-activity is of thyroid function are impor- maternal thyroid status has its women with positive (blue bars) and negative (gold bars) in women of childbearing mild, it can be treated with tant in many situations related major influence on fetal brain thyroid peroxidase antibodies. Composite results from five age until pregnancy has been carefully monitored antithy- 4 to reproductive medicine, development in the first studies reviewed in Abramson and Stagnaro-Green, 2001. excluded. roid drug, or left untreated including: trimester. 30 ■ Avoid over-treatment of thy- until after pregnancy. If the P<.01 ■ Impaired fertility. rotoxicosis, especially in the disorder is severe with a high ■ Recurrent miscarriage. Pregnancy after radioiodine P<.05 third trimester, because requirement for antithyroid 25 ■ Alterations in maternal thy- therapy antithyroid drugs cross the drug or obstructive features, Per cent Miscarriage P<.05 roxine requirement. Previous radioiodine therapy 20 placenta and may cause fetal thyroidectomy during the ■ Effect of maternal hypothy- for thyrotoxicosis or differen- hypothyroidism and poten- second trimester may be P<.05 P<.05 roidism on fetal brain devel- tiated thyroid carcinoma does 15 tially obstructive goitre. required. opment. not preclude subsequent preg- ■ Assess the newborn for pos- ■ Management of thyrotoxi- nancy. Careful follow-up sible neonatal thyrotoxico- Hyperemesis and molar 10 cosis during pregnancy. studies have shown no sis. pregnancy ■ Postpartum thyroid dys- adverse fetal outcome. In general, the minimum Transient maternal thyrotoxi- 5 function. Pregnancy must be possible dose of antithyroid cosis in the first trimester ■ Breastfeeding while taking absolutely ruled out at the drug should be used, with occurs with trophoblastic antithyroid drugs. time of radioiodine treatment 0 reduction of dose as term tumours or with severe hyper- Stagnaro- Glinoer Lejeune Singh Lijima ■ Screening for detection of and an interval of at least six Green (1991) (1993) (1995) (1997) approaches. If in doubt, slight emesis gravidarum, resulting neonatal hypothyroidism. months between treatment (1990) under-treatment with subnor- from interaction of chorionic and conception is strongly mal levels of TSH is prefer- gonadotrophin with the TSH Maternal issues before advised. opment is critically dependent able to over-treatment. receptor. conception on maternal thyroxine. Hence, Propylthiouracil is some- Impaired fertility and Assisted reproduction the suggestion that women times preferred to carbima- The fetus and the neonate recurrent miscarriage The frequency of abnormal taking thyroxine replacement zole, because of concern about Prediction of neonatal Several studies have shown thyroid function in women should increase their dosage fetal skin and scalp malfor- thyrotoxicosis impaired fertility, an increased receiving assisted reproduction by about 25% as soon as mations, but the evidence is Measuring TSH-receptor anti- rate of recurrent miscarriage is sufficiently high to make pregnancy is confirmed. not strong. If a woman bodies during pregnancy gives and adverse pregnancy out- measuring serum TSH level an Replacement therapy becomes pregnant while well some indication of the likeli- comes in women with essential part of routine pre- should be carefully monitored controlled with carbimazole, hood of transient neonatal immune thyroid disorders liminary investigations. by serum TSH levels because a change to propyl-thiouracil thyrotoxicosis due to transpla- (figure 5). gross maternal thyroid hor- is not mandatory. cental passage of stimulating Maternal issues during mone excess does have an Fetal thyroid size should be antibodies. Role of pre-conception pregnancy adverse effect on fetal out- monitored to rule out an The infant of a mother with assessment of thyroid function Increased thyroxine come. adverse effect due to transpla- autoimmune thyroid disease, Routine pre-pregnancy assess- requirement in hypothyroidism cental passage of antithyroid whether past or present, ment of thyroid function is Women receiving thyroxine Managing thyrotoxicosis drugs. Monitoring of fetal should be monitored for receiving increasing attention replacement for hypothy- Graves’ disease. Thyrotoxico- growth and heart rate is useful tachycardia, exophthalmos, and may become established roidism generally require a sis due to Graves’ disease gen- to rule out the rare entity of goitre, diarrhoea or poor practice in the light of recent dose increase of 25-30% erally becomes milder during intrauterine thyrotoxicosis. weight gain. studies that show an adverse during pregnancy. pregnancy, with a tendency to Nodular thyroid disease. This effect of even mild thyroid Recent serial TSH studies flare-up in the post-partum type of thyrotoxicosis does Potential iodine deficiency deficiency on fetal brain devel- suggest an increase in replace- period. Three important rules not generally show the preg- Until recently it had been opment. ment is already necessary in apply to the management of nancy-related fluctuations assumed that there was To be maximally effective, the first trimester during the Graves’ disease during preg- characteristic of immune thy- almost no iodine deficiency in screening would be preferable period when fetal brain devel- nancy: roid dysfunction. Australia, but this is now in 26 | Australian Doctor | 4 February 2005
  5. 5. Importance of the and diastolic function. Table 2: Adverse effects of Therapeutic approach laboratory-clinical interface Reduced cardiorespiratory work capac- A persistent abnormality should always ity during maximal exercise was reversed subclinical thyroid dysfunction that may benefit from treatment be confirmed before considering treat- in the investigation of by T4 treatment sufficient to normalise ment of subclinical thyroid dysfunction. serum TSH levels. Lipids. Correction of overt hypothy- Subclinical thyrotoxicosis The argument for active treatment is probably stronger for subclinical hypothy- thyroid disorders ■ Progression to overt thyrotoxicosis roidism decreases levels of total and LDL ■ Overt thyrotoxicosis after exposure to roidism, or mild thyroid failure, than it is THE ordering, inter- Figure 6: Example of an unhelpful cholesterol, apolipoprotein A1, apo B and iodine for subclinical thyrotoxicosis. pretation and applica- clinical comment accompanying a apo E, but there is no consensus on ■ Threefold increased risk of AF after 10 Conservative thyroxine therapy tion of thyroid func- specimen for laboratory analysis. whether T4 treatment of mild thyroid years aimed at normalising TSH is simple, tion tests poses some failure is beneficial. ■ Osteoporosis accentuated inexpensive and generally safe, continuing challenges A recent review suggested that T4 treat- although full replacement may not be at the interface ment of mild thyroid failure decreases Subclinical hypothyroidism (mild warranted in old age, because of asso- between clinical and mean total and LDL cholesterol levels, thyroid failure) ciated ischaemic heart disease. laboratory medicine. ■ Non-specific symptoms may improve without an effect on HDL cholesterol or Mild thyroid failure should be actively Because of the diverse triglyceride levels.3 However, in severe with treatment treated before, during and between preg- clinical presentations ■ Progression to overt hypothyroidism dyslipidaemia, T4 treatment to normalise nancies because of the adverse effects of of thyroid dysfunc- TSH level produced significant reductions (~5% a year) even mild thyroid deficiency on fetal brain tion, testing is often initiated by specialists and GPs who may ■ Adverse effect on fetal brain in total and LDL cholesterol only if pre- development in the first trimester. be unfamiliar with the interpretation of current assays, or with treatment TSH values were >10 mU/L. development The benefits of treating subclinical thy- effects that interfere with these techniques. ■ Possible independent risk factor for rotoxicosis must be balanced against the Laboratory reports can be helpful, but the quality of a written Assessment for potential thyroid atherosclerosis short- and long-term side effects of treat- comment depends on the available clinical information and on ■ Possible adverse effects on vascular failure associated with thyroid ment. In mild Graves’ disease, most spe- the training and experience of the reporter. Some clinicians do peroxidase antibody (TPO Ab) compliance cialists would opt for follow-up rather not provide any useful clinical information to the laboratory and ■ Possible beneficial effect on plasma When isolated TSH excess in mild thyroid than immediate intervention, because of this trend continues among some recent graduates (figure 6). failure is associated with a positive thy- lipids the chance of spontaneous remission and Without relevant clinical information, laboratory special- ■ Possible benefit in depressive illness roid peroxidase antibody test, there is the potential for antithyroid drug side ists may not be able to make a useful response when results about a twofold increase in the risk of effects, in particular agranulocytosis. appear to be anomalous or ambiguous. With only a few words, progression to overt hypothyroidism, and In autonomous nodular thyroid disease such as, “on antithyroid drug”, “on thyroxine”, “on amio- a positive result has been used as justifi- the likelihood of hypothyroidism after darone”, “sepsis”, “pregnant”, or “pituitary disorder”, a clin- cation for active treatment. radioiodine treatment is lower and the ician can provide background information that will place an This antibody has a higher positive chance of remission is less than in Graves’ unusual result in context. Without such information, an assay predictive value than measurement of disease (figure 4). Thus, early radioiodine artefact may need to be ruled out, but this is often difficult and serum TSH level in identifying an treatment is often appropriate for mild time consuming. increased risk of postpartum dysfunc- or subclinical thyrotoxicosis due to nodu- Thyroid test results that are prone to misinterpretation with- tion, or medication-induced hypothy- lar goitre, especially in the elderly, in out the relevant clinical information are listed in table 3. While roidism due to lithium, amiodarone or whom the consequences of untreated thy- the overall proportion of such results may be low, there is beta interferon. rotoxicosis are more serious. substantial potential for misinterpretation, for waste of time and money by unnecessary further investigation, and, ulti- mately, for missed diagnosis and mismanagement. Discordant or apparently anomalous results When results appear to be anomalous or unexpected, the clin- doubt on the basis of recent tion of treatment is the key doses are not sufficient to whether deficiency is perma- ical context, including the medication history, should first be studies of urinary iodine factor that determines later influence the infant’s thyroid nent. A high proportion of reviewed. The following steps can be helpful: excretion during pregnancy. intellectual development — function. women who have had post- ■ Measurement of serum TSH level by a method sufficiently Until further data are avail- hence the need to regard Postpartum thyroid dysfunc- partum hypothyroidism con- sensitive to identify the degree of TSH suppression. (Note that able, the use of iodised salt neonatal hypothyroidism as tion. Autoimmune thyroid dis- tinue to show some evidence while serum TSH level is often subnormal during a non- should be widely recom- an emergency. ease is often first diagnosed of thyroid deficiency, with thyroidal illness, it is rarely suppressed to the very low levels mended, especially in women Imaging studies are usually during the 6-12 months after possible adverse effect on a [<0.03mU/L] typical of thyrotoxicosis). of childbearing potential. done to distinguish thyroid pregnancy. It may manifest as subsequent pregnancy. ■ Follow-up sampling to establish whether the abnormality is agenesis from ectopia. In some thyrotoxicosis, hypothy- Hence, it is generally transient or persistent. (Many transient abnormalities do not Neonatal screening for instances neonatal hypothy- roidism, or a fluctuating pat- appropriate to continue require further detailed investigation). congenital hypothyroidism roidism may be transient, tern in which a period of thy- replacement and defer tem- ■ Estimation of serum free thyroxine (T4) level by an alterna- After a critical period in the sometimes due to transplacen- rotoxicosis is followed by porary withdrawal of thy- tive method, to identify discrepancies between methods. first trimester when maternal tal passage of antibodies that hypothyroidism, with eventual roxine until after childbear- ■ Measurement of serum total T4 level to establish whether the thyroid function influences block the action of TSH, a return to normality and a high ing has been completed. serum free T4 estimate is disproportionately high or low fetal brain development, the mechanism that is the reverse likelihood of recurrence after a because of a pre-analytical or method-dependent artefact. fetal thyroid gland normally of neonatal thyrotoxicosis. subsequent pregnancy. Diagnostics ■ Evaluation of the sample for possible heterophilic antibody becomes the major source of Treatment may be with- Presentations can be Interpretation of thyroid interference. thyroid hormone for the fetus drawn briefly for several diverse, with symptoms such function tests during pregnancy ■ Investigation of the patient and family members for evidence after 12-16 weeks’ gestation. weeks at 4-6 years of age, fol- as depression, agitation, unex- Standard reference intervals of unusual binding abnormalities or hormone resistance. By that time, critical brain lowed by measurement of pected weight changes, weak- may not be directly applica- development has occurred, so serum TSH level to establish ness, heat intolerance or pal- ble to the interpretation of Table 3: Situations in which laboratory tests of that even complete absence of whether a permanent defi- pitations. The possibility of thyroid function tests during thyroid function can be inconclusive or misleading the fetal gland is compatible ciency exists. thyroid dysfunction should be pregnancy. without the clinical context with near-normal intellectual considered in any woman Estimates of free T4 are gen- CLINICAL CONTEXT ASSAY RESULTS development, provided that Prematurity with post-partum ill-health. erally correct for the oestro- Free T4 free T3 TSH replacement begins within a Extremely premature infants Post-partum thyrotoxicosis gen-induced increase in total Pregnancy ↓* ↓, N N week or two of birth. Hence, often have very low levels of can be initially treated with T4 concentration that results Antithyroid drug treatment, initial months ↑, N, ↓ ↑, N, ↓ U the importance of neonatal T3 and T4, probably due to beta blockers. Standard from the increased concentra- Recent T4 therapy for hypothyroidism N N ↑ screening. immaturity of the pituitary- antithyroid drugs are gener- tion of thyroxine-binding Hypothyroidism, appropriate T4 dose ↑ N N Prompt detection of con- thyroid axis, as well as a form ally withheld until persistent globulin, but there are impor- Hypothyroidism, intermittent compliance ↑, N ↑ genital hypothyroidism of the ‘sick euthyroid syn- over-function is confirmed by tant differences between vari- Appropriate T4 suppressive therapy ↑ N U, ↓ should now be universal drome’ seen in critically ill re-testing in 3-4 weeks. ous methods of free-hormone Recombinant TSH, suppressive T4 ↑ N ↑↑ from routine heel-prick mea- adults. Most authorities favour For post-partum thyrotoxi- estimation during pregnancy. Hypopituitarism ↓ ↓, N surement of TSH level on thyroid hormone replacement. cosis it is generally not appro- The true concentration of Phenytoin ↓* ↓, N the 3rd-5th day after deliv- priate to recommend ablative free T4 decreases by up to Critical illness ↓* ↓ ↓ ery. If TSH level is high, an Postpartum treatment, either by surgery or 25% in late pregnancy, but Heparin effect in critical illness ↓, N, ↑* ↓ ↓ abnormality should be con- Antithyroid drugs and lacta- radioiodine, until persistence this change is obscured by Recovery phase of critical illness ↓, N ↑ firmed by concurrent mea- tion. The previous belief that has been confirmed during at some methods in which the Drugs that inhibit binding of T4 and T3 ↓* ↓* ↓, N surement of thyroxine level. breastfeeding should be least a year of appropriately free T4 estimate depends on to thyroid-binding globulin If primary hypothyroidism avoided in women treated adjusted antithyroid drug the concentration of albumin. Amiodarone effect in euthyroid subject ↑ ↓ N is demonstrated, replacement with antithyroid drugs is not treatment. Serum TSH levels are gen- Acute T4 overdose ↑↑ ↑, N N with an initial dose of thy- supported by more recent In contrast, post-partum erally reliable, with somewhat roxine, 8-10µg/kg/day must conclusive research. While hypothyroidism should be lower values towards the end T4 = thyroxine; T3 = triiodothyronine; TSH = thyroid-stimulating begin immediately to min- antithyroid drugs are treated with thyroid hormone of the first trimester as a result hormone imise permanent intellectual detectable in breast milk, the replacement along standard of the TSH-like effect of chori- U = undetectable; ↓ = low; N = normal; ↑ = high; ↑↑ = very high impairment. Speed of initia- concentrations with standard lines, even if it is not certain onic gonadotrophin. *Effect depends on assay method 4 February 2005 | Australian Doctor | 27