sign in sign up
<<
Home , Levothyroxine, Thyroid function tests

CME

establishing the diagnosis and differential Abnormal routinely able to detect levels as low as diagnosis of Cushing’s syndrome. J Clin 0.02 mU/l. Dynamic testing of TSH Endocrinol Metab 2003;88:5299–306. responses (eg to thyrotropin-releasing 7 Newell-Price J, Trainer P, Perry L et al. A stimulating single sleeping midnight has 100% hormone) are now redundant. sensitivity for the diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 1995;43: levels: when and 545–50. Abnormal thyroid stimulating 8 Papanicolaou DA, Yanovski JA, Cutler GB hormone Jr, Chrousos GP, Nieman LK. A single who to treat midnight cortisol measurement When is the thyroid stimulating distinguishes Cushing’s syndrome from hormone abnormal? pseudo-Cushing states. J Clin Endocrinol Anthony P Weetman MD DSc FRCP FMedSci, Metab 1998;83:1163–7. Professor of Medicine and Dean, The Physicians frequently talk about ‘normal 9 Findling JW, Raff H. Screening and Medical School, Sheffield range’ when discussing laboratory diagnosis of Cushing’s syndrome. values, but biochemists use ‘reference Endocrinol Metab Clin North Am 2005;34: Clin Med 2008;8:208–11 range’. The latter term comprises 95% of 385–402, ix–x. 10 Raff H, Raff JL, Findling JW. Late-night measurements made on healthy volun- salivary cortisol as a screening test for teers. ‘’ is not only Cushing’s syndrome. J Clin Endocrinol Thyroid stimulating hormone (thyro- semantically correct but also emphasises Metab 1998;83:2681–6. tropin, TSH) measurement is the most that in any test some healthy individuals 11 Newell-Price J, Morris DG, Drake WM widely used test to determine whether a will have values outside the range. TSH et al. Optimal response criteria for the human CRH test in the differential patient has thyroid dysfunction. There is levels within a healthy population are not diagnosis of ACTH-dependent Cushing’s a negative feedback loop between the normally distributed but have a long tail syndrome. J Clin Endocrinol Metab 2002; thyroid and pituitary so TSH levels of values towards the upper limit. 87:1640–5. represent a tissue response to ambient Some individuals in the upper half of 12 Lindsay JR, Nieman LK. Differential thyroid hormone levels. When pituitary the reference range may develop hypothy- diagnosis and imaging in Cushing’s 1 syndrome. Endocrinol Metab Clin North function is normal, the inverse relation- roidism decades later, leading to recent Am 2005;34:403–21, x. ship between serum TSH and free suggestions that the TSH reference range 13 Ilias I, Torpy DJ, Pacak K et al. Cushing’s thyroxine (FT4) levels is log/linear: a is too wide as it includes individuals who syndrome due to ectopic corticotropin small increase in FT4 will produce a large may already have mild thyroid auto- secretion: twenty years’ experience at the decrease in TSH and vice versa. Thus, an immune damage.2 However, the reference National Institutes of Health. J Clin Endocrinol Metab 2005;90:4955–62. abnormal TSH level is a sensitive, but not range of TSH is unchanged when individ- 14 Isidori AM, Kaltsas GA, Pozza C et al. The specific, marker of thyroid dysfunction. uals in populations with a normal ectopic adrenocorticotropin syndrome: intake are rigorously screened to exclude clinical features, diagnosis, management, 3 Measurement of thyroid any evidence of thyroid autoimmunity. and long-term follow-up. J Clin Endocrinol Therefore, current reference ranges for Metab 2006;91:371–7. stimulating hormone 15 Assié G, Bahurel H, Coste J et al. TSH remain around 0.4–4.5 mU/l, with Corticotroph tumor progression after Improvements in methodology have some variation between laboratories adrenalectomy in Cushing’s disease: increased the sensitivity of TSH mea- depending on the exact assay method a reappraisal of Nelson’s Syndrome. J Clin surement, with third-generation assays used.4 Endocrinol Metab 2007;92:172–9.

Table 1. Causes of raised thyroid stimulating hormone (TSH).

Cause of raised TSH Free thyroid hormone level

Primary : Overt ↓ Subclinical N Poor to levothyroxine replacement ↑, N or ↓ Assay interference (heterophilic antibodies) N Non-thyroidal illness (recovery phase) N or ↓ Some cases of TSH- resistance N or ↓ Secondary : Some cases of TSH-secreting adenoma* ↑ Some cases of thyroid hormone resistance** ↑

* TSH is immunoreactive but bioinactive. ** Patients are euthyroid; elevated free thyroid hormone levels compensate for relative resistance.

208 Clinical Medicine Vol 8 No 2 April 2008 CME Endocrinology

TSH values do not change significantly determine the appropriate treatment. improvement in neuropsychological through daylight hours and there is no However, patients are frequently encoun- function and symptoms when levothy- need to take sex or age into account in tered in whom the TSH is abnormal but roxine is given.8 Moreover, some individ- adults.5 However, in , TSH FT3 and FT4 levels are both normal. Sub- uals with elevated TSH levels inevitably levels normally fall during the first clinical hyperthyroidism (low TSH) or lie outside a reference range which trimester due to the thyroid-stimulating subclinical hypothyroidism (high TSH) includes only 95% of the healthy popula- action of chorionic gonadotropin. Also, may both progress to overt or clinical thy- tion, and clearly will not have any some drugs, illnesses and other factors roid disease, in which case the need for response to treatment. can alter serum TSH levels (Tables 1 treatment is clear, but controversy exists On the other hand, about 2% of and 2) and must be excluded before con- regarding the need for treatment in the patients with subclinical hypothyroidism cluding that an abnormal TSH represents subclinical phase. and TSH below 10 mU/l progress to overt thyroid dysfunction. hypothyroidism annually, rising to 4% if Subclinical hypothyroidism TPOAbs are also present. This joint man- Investigations agement statement was challenged subse- In all cases in which treatment is con- quently by several experts who wrote a Many laboratories simultaneously mea- templated, the persistence of an elevated commentary indicating that there are clin- sure TSH and FT4; if only a TSH value is TSH should be documented on two sam- ical grounds for treatment because many provided, the FT4 level must be mea- ples 2–3 months apart; this will help rule endocrinologists have direct experience of sured if there is a newly detected out non-thyroidal illness as a cause. individual patients who derive sympto- abnormal TSH level.5,6 If the TSH is low Subclinical hypothyroidism affects 4–8% matic benefit from treatment.9 Part of the and the FT4 normal, free tri-iodothyro- of the population, increasing with age. hesitation in starting levothyroxine is that nine (FT3) should also be measured as around 20% of patients may end up FT3 rises before FT4 in hyperthyroidism. Treatment overtreated, resulting in subclinical (or, Measurement of anti- body levels (TPOAb) is helpful in deter- A joint statement on management in mining whether the patient has thyroid 2004 from the American Association of Key Points autoimmunity and in predicting future Clinical Endocrinologists, American Serum thyroid stimulating hormone thyroid dysfunction. Thyroid Association and the Endocrine (TSH) is a sensitive measure of Society7 concluded that treatment with thyroid function, but abnormal TSH does not inevitably imply thyroid Subclinical levothyroxine is indicated if the TSH is greater than 10 mU/l. At this level, symp- dysfunction When the TSH is elevated and free T4 low, toms are more likely and the risk is high Diagnosis of subclinical thyroid the patient has primary hypothyroidism of future progression to overt hypo- dysfunction requires the and requires levothyroxine treatment. thyroidism. For TSH values between the exclusion of other causes of an Conversely, if the TSH is low (typically upper limit of the reference range and abnormal TSH and a sustained TSH abnormality over at least undetectable) and the FT4 (or FT3 in 10 mU/l, the panel could not find even 2–3 months T3-toxicosis) elevated, the patient has fair evidence of any adverse effect of sub- thyrotoxicosis and further investigations clinical hypothyroidism. Most studies Levothyroxine treatment is indicated are necessary to identify the cause and have also failed to show a consistent in subclinical hypothyroidism if the TSH is above 10 mU/l; the benefits of treatment are debatable below this level

Table 2. Causes of low thyroid stimulating hormone (TSH). The commonest cause of raised TSH in patients taking levothyroxine is Cause of low TSH Free thyroid hormone level poor adherence to treatment

Primary hyperthyroidism: Adverse effects from subclinical ↑ Overt hyperthyroidism are inversely Subclinical N proportional to the TSH level; Pregnancy, first trimester N* treatment should be considered if Non-thyroidal illness (acute phase) N or ↓ the TSH is below 0.1 mU/l, especially if there are other risk Overtreatment with levothyroxine N or ↑ factors , N Secondary hypothyroidism (pituitary disease, ↓ KEY WORDS: levothyroxine, subclinical congenital TSH deficiency) hyperthyroidism, subclinical hypothyroidism, thyroid disease, * Some patients may develop transient gestational hyperthyroidism leading to . thyroid stimulating hormone level, thyroxine

Clinical Medicine Vol 8 No 2 April 2008 209 CME Endocrinology

rarely, clinical) thyrotoxicosis – an iatro- Table 3. Causes of raised thyroid 0.1 mU/l and the lower limit of the refer- genic state that may have greater potential stimulating hormone (TSH) in a patient ence range, there was felt to be fair risk to the patient than subclinical taking levothyroxine. evidence supporting a risk of adverse car- hypothyroidism (see below). It is also • Insufficient levothyroxine diac effects, but not important to remember that a TSH value • Malabsorption syndromes, especially (AF), and no evidence for an adverse of 10 mU/l as a single cut-off for treatment effect on bone mineral density (BMD). makes little scientific sense. Reference • Drugs However, with TSH values below ranges vary between laboratories and • Impaired absorption of levothyroxine 0.1 mU/l, an increased risk of AF seems within-assay variation may have a blurring (ferrous sulphate, , established and there is also fair evidence effect on the exact point at which a group hydroxide, , supporting a risk of reduced BMD, espe- is biochemically defined.4 calcium supplements) cially in postmenopausal women, but At present, therefore, the field remains • Altered levothyroxine insufficient evidence linking this to an (, , controversial. There are increasing and , hormone replacement increased risk of fracture. The caveats reassuring data that any cardiovascular therapy, ) with regard to precise cut-off levels for 4 risks from subclinical hypothyroidism • Failure to break down tablets (try TSH need to be borne in mind, and with TSH values below 10 mU/l are very crushing tablets) many studies have not distinguished 10,11 low or absent. My practice is to give • Testing too early after levothyroxine between suppressed (<0.1 mU/l) and low patients in this category a three-month dose increase (allow 6–8 weeks for TSH levels when looking at adverse effects trial of levothyroxine at doses sufficient TSH to fall) on health of subclinical hyperthyroidism. to bring the TSH into the reference • Poor adherence to treatment (most common cause) range. Treatment is continued if symp- Treatment toms improve; if there is no improve- ment, treatment can be stopped. Annual So far there have been no long-term trials testing of TSH levels is necessary to with overt hypothyroidism taking to assess the benefit of treatment. If the ensure identification of any progression. levothyroxine usually require a 25–50% cause is exogenous, current recommenda- A common scenario which mimics sub- dose increase in the first trimester. tions are to reduce the dose of levo- clinical hypothyroidism is the patient with thyroxine and bring TSH levels to within the reference range. The exception is established hypothyroidism who is taking Subclinical hyperthyroidism levothyroxine and has elevated TSH but when TSH suppression is deliberate in the normal (or even high) FT4 levels. The As with subclinical hypothyroidism, it is treatment of or, less com- most common cause is poor adherence to essential to document a persistently low monly now, . Indeed, there is an treatment (Table 3) but reasons such as TSH over several months before consid- increasing move to maintain TSH values the development of angina should be ering treatment. The prevalence of sub- in the lower part of the reference range in 13 sought. Tactful management can usually clinical hyperthyroidism depends on the low-risk thyroid cancer patients. If the improve the situation, particularly if the TSH cut-off level used to define the pop- cause is endogenous then is no clear indi- patient is reassured that it is safe and ulation: for TSH values below 0.1 mU/l, cation to treat individuals with TSH levels sensible to take any missed tablets: the prevalence is about 0.5%, rising to above 0.1 mU/l, although some clinicians levothyroxine can even be given once a about 3% for TSH levels below 0.4 mU/l. might consider radioiodine (or an week. It is more common in areas of past or antithyroid drug) in postmenopausal present iodine deficiency as this increases women with suggestive symptoms, disease or low BMD.14 For those with Pregnancy the formation of thyroid nodules which can develop autonomous function. TSH levels below 0.1 mU/l, treatment A different set of considerations apply for Annually, around 5% of patients with with radioiodine or an antithyroid drug women who are or want to become preg- subclinical hyperthyroidism due to should be considered, especially in the nant. The fetus is totally dependent on nodular thyroid disease progress to overt elderly and those with heart disease or low maternal T4 transferred across the pla- hyperthyroidism. The commonest cause BMD. centa in the first trimester of pregnancy of subclinical hyperthyroidism is exoge- and the fetal thyroid does not become nous due to overtreatment with levo- References fully functional until mid-pregnancy. thyroxine (it should properly be called 1 Vanderpump MP, Tunbridge WM, French Good data show an adverse effect of low subclinical thyrotoxicosis as the thyroid JM et al. The incidence of thyroid disorders maternal T4 levels on fetal brain devel- is clearly not overactive in this state). in the community: a twenty-year follow-up opment, even in those with only subclin- Adverse effects of subclinical hyper- of the Whickham Survey. Clin Endocrinol ical hypothyroidism.12 All such women thyroidism have been reviewed by the (Oxf) 1995;43:55–68. 2 Wartofsky L, Dickey RA. The evidence for a should therefore receive levothyroxine same expert panel that drew up recom- narrower thyrotropin reference range is and are very likely to require increased mendations for subclinical hypo- compelling. J Clin Endocrinol Metab 2005; doses as pregnancy progresses – women thyroidism.7 For TSH values between 90:5483–8.

210 Clinical Medicine Vol 8 No 2 April 2008 CME Endocrinology

3 Brabant G, Beck-Peccoz P, Jarzab B et al. Is treatment (eg for asthma there a need to redefine the upper normal or rheumatoid arthritis) may affect up to limit of TSH? Eur J Endocrinol 2006;154: 1% of the UK population and 3% of the 633–7. 4 Beckett G, MacKenzie F. Thyroid Wiebke Arlt MD DSc FRCP, Professor of elderly. More women than men are guidelines – are thyroid-stimulating Medicine, MRC Senior Clinical Fellow, affected. Age at manifestation varies but hormone assays fit for purpose? Ann Clin Division of Medical Sciences, University of is usually around 20–40 years for Biochem 2007; 94(Pt 3):203–8. Birmingham, Birmingham autoimmune adrenalitis and 30–60 years 5 Baloch Z, Carayon P, Conte-Devolx B et al; in secondary adrenal failure.1 Most Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory Clin Med 2008;8:211–15 patients suffering from CAH manifest medicine practice guidelines. Laboratory neonatally; AI due to other causes is a support for the diagnosis and monitoring rare event in childhood. of thyroid disease. Thyroid 2003;13:3–126. 6 Association for Clinical Biochemistry, Adrenal insufficiency (AI) is caused by: British Thyroid Association, British Clinical presentation primary adrenal failure due to loss Thyroid Foundation. UK guidelines for the • use of thyroid function tests. or destruction of the adrenal glands Adrenal insufficiency represents a con- http://acb.org.uk/docs/tftguidelinefinal.pdf or a block in steroid production (as tinual diagnostic challenge as most signs (accessed 10 August 2007) in congenital adrenal hyperplasia and symptoms are rather non-specific 7 Surks MI, Ortiz E, Daniels GH et al. (CAH)) or and may be misleading, resulting in Subclinical thyroid disease: scientific review and guidelines for diagnosis and • secondary failure (ie impairment of delayed diagnosis. Every second patient management. JAMA 2004;291:228–38. the corticotropic axis in the is diagnosed only after presentation with 8 Jorde R, Waterloo K, Storhaug H et al. hypothalamic-pituitary region). an and most will see more Neuropsychological function and than three doctors prior to diagnosis. symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine Epidemiology and causes Acute AI (ie life-threatening adrenal treatment. J Clin Endocrinol Metab 2006; (Tables 1 and 2) 91:145–53. crisis) typically presents with severe 9 Gharib H, Tuttle RM, Baskin J et al. Five per 10,000 population are affected hypotension or hypovolaemic shock, Subclinical thyroid dysfunction: a joint by AI, three because of hypothalamic- accompanied by vomiting, nausea, statement on management from the pituitary disease and one each from abdominal tension, and in some cases American Association of Clinical 1 Endocrinologists, the American Thyroid primary AI and CAH. Suppression of even severe neurological dysfunction Association, and the Endocrine Society. the corticotropic axis due to exogenous including coma. In children, it often J Clin Endocrinol Metab 2005;90:581–5. 10 Rodondi N, Newman AB, Vittinghoff E et al. Subclinical hypothyroidism and the Key Points risk of , other cardiovascular events, and death. Arch Intern Med 2005; Adrenal insufficiency (AI) is either of primary origin, mostly due to autoimmune- 165:2460–6. mediated destruction of the , or of secondary origin, in most cases 11 Walsh JP, Bremner AP, Bulsara MK et al. caused by tumours located in the hypothalamic-pituitary region affecting the Subclinical thyroid dysfunction as a risk regulatory control of adrenal cortisol release factor for cardiovascular disease. Arch Intern Med 2005;165:2467–72. Common clinical symptoms of AI (fatigue, nausea, and myalgia) are 12 Haddow JE, Palomaki GE, Allan WC et al. rather non-specific and may lead to considerable delay in diagnosis. Acute AI is Maternal thyroid deficiency during life-threatening and may present with , severe hypotension or hypovolaemic pregnancy and subsequent neuro- shock, abdominal tension and, in some cases, even coma psychological development of the child. N Engl J Med 1999;341:549–55. Diagnostic tests should never delay treatment in cases of suspected acute AI. The 13 British Thyroid Association, Royal College short synacthen test is the most suitable tool for establishing the diagnosis of of Physicians of London. Guidelines for AI; baseline cortisol is of limited value management of thyroid cancer (Perros P, ed) 2nd edn. Report of the Thyroid Cancer Therapeutic management of AI always requires cortisol replacement. Monitoring is Guidelines Update Group. London: RCP, based on clinical judgment. Mineralocorticoid replacement can be monitored by 2007. supine and erect blood pressure, urea and , and plasma 14 Cooper DS. Approach to the patient with activity. (DHEA) replacement therapy can be a subclinical hyperthyroidism. J Clin beneficial option, in particular in women with signs of deficiency due Endocrinol Metab 2007;92:3–9. to lack of adrenal DHEA production

Recent data indicate significantly impaired well-being, increased rates of disablement, inability to work and mortality. Optimisation of therapeutic strategies in AI are therefore an important target of future research

KEY WORDS: Addison’s disease, adrenal insufficiency, , cortisol, dehydroepiandrosterone

Clinical Medicine Vol 8 No 2 April 2008 211