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March 04, Paper 2, Question 3

Outline the clinical biochemistry of hypothyroidism. Discuss the role of the laboratory in the diagnosis and management of this condition.

Figure 1. Negative feedback system of thyroid hormone regulation.

Hypothyroidism occurs when insufficient amounts of the thyroid hormones thyroxine (T4) and tri-iodothyronine (T3) are delivered to the tissues. Thyroid hormones are responsible for the control of many metabolic processes and a deficiency leads to clinical picture of cold, fatigue, weight gain, constipation, and dry skin, hair and nails.

The commonest causes of hypothyroidism are those affecting the thyroid gland itself and thus production of thyroid hormones. This results in a reduction of negative feedback at the anterior pituitary (figure 1), and to a lesser extent at the hypothalamus, and thus to an increased release of TSH. This is termed primary hypothyroidism. Common causes of primary hypothyroidism are Hashimoto’s thyroiditis (auto-immune), and post-surgical thyroidectomy or radio-iodine treatment for Grave’s disease. Developmental abnormalities, tumours and other infiltrative conditions which destroy thyroid tissue are less common causes. Congenital defects of hormonogenesis and drugs such as amioderone and lithium can also produce this biochemical picture. Inadequate iodine intake results in decreased uptake by the thyroid, organification and thus T4 and T3 production. Pituitary and hypothalamic conditions are rare causes of hypothyroidism due to inadequate secretion of TSH or TRH. This is termed secondary hypothyroidism. TSH levels may be low or inappropriately normal in the face of low thyroid hormone levels. A clinical picture of hypothyroidism can also be seen in thyroid hormone resistance. In this rare condition there is a defect in thyroid hormone receptors so levels of TSH, T4 and T3 are all raised.

Hypothyroidism is more common in women, and prevalence increases with age. Patients often present with non-specific symptoms such as fatigue, and the diagnosis relies heavily on biochemistry results. The approach to screening for hypothyroidism varies between laboratories. The simplest and cheapest strategy is to test TSH only as a front-line test and cascade to fT4 if TSH is raised above the reference range. This approach relies on the fact that the majority of hypothyroid patients will have a raised TSH level, however this strategy could miss patients with pituitary or hypothalamic disease who could have a TSH in the reference range despite low levels of fT4. For this reason the UK Guidelines for the Use of Thyroid Function Tests recommend that both TSH and fT4are measured when screening for hypothyroidism, and this approach is followed by many labs.

The UK Guidelines state that a TSH level of > 10 mIU/L along with a fT4 level below the reference range is diagnostic of overt primary hypothyroidism in an ambulatory patient. (Thyroid function can be temporarily affected in acutely ill patients without an underlying thyroid problem. An important role of the laboratory is to ensure results from acutely ill patients are not misinterpreted, and to discourage thyroid function testing in such patients unless severe hypo- or hyperthyroidism is suspected). The quoted upper limit of 10mIU/L is somewhat arbitrary and does not take into account the difference in bias in the different assays in use.

A TSH level between the upper limit of the reference range and 10mIU/L, along with a fT4 level within the reference range indicates subclinical hypothyroidism. This should be confirmed after 3-6 months to exclude a transient rise in TSH. The laboratory may also offer or advise on the use of tests for thyroid peroxidise antibodies (or less commonly thyroglobulin antigen antibodies), as patients with subclinical disease who are antibody positive are more likely to go on to develop overt hypothyroidism. Another important role of the laboratory is to provide interpretation of thyroid function tests, and to advise clinicians on how often testing should be repeated in patients with subclinical disease (annually if antibody positive, and every 3 years if antibody negative. Closer monitoring is recommended if the patient is pregnant, has a goitre or if the TSH level is rising).

If TSH is within the reference range, and the patient is not on medication known to affect thyroid function, then primary hypothyroidism is excluded, however secondary hypothyroidism should be considered if the clinical picture is suggestive.

It is important for the laboratory to consider the times when thyroid function tests are available and the turnaround times. In some laboratories immunoassay is run on a separate analytical platform from general biochemistry and it may be difficult to provide results outside of core hours. In the majority of cases there is little urgency however in the rare thyroid emergencies (myxoedema coma and hyperthyroid crisis) a rapid result is required as biochemistry is often used to make the diagnosis.

As well as screening in symptomatic patients there are a number of other circumstances where patients may be tested for hypothyroidism. Laboratories may provide guidance to their users as to which groups of patients should be tested and how frequently. Laboratory staff authorising results may suggest or add-on thyroid function tests in patients with dyslipidaemia as this may be due to hypothyroidism. Women with a history of post-partum thryoiditis should have TSH measured annually, type I diabetes annually, type II diabetes at diagnosis, Down’s and Turner’s syndrome annually, patients on amioderone every 6 months, patients on lithium every 6-12 months and following radio-iodine or thyroidectomy every 3 months for the first year and then annually.

Thyroid hormones are essential for normal foetal and neonatal development. Congenital hypothyroidism is a common preventable cause of mental retardation,

and there is a national screening programme for this based in the measurement of TSH in a blood spot (Guthrie Card). Screening for congenital hypothyroidism is restricted to specialist centres. There are no symptoms at birth as the neonate has been receiving thyroid hormones from its mother across the placenta. The sample for TSH should be taken 2-8 days after birth. If the TSH is raised (> 20mIU/L) measurement of TSH and fT4 should be undertaken immediately to confirm the result. Biochemical screening is essential for this condition as by the time symptoms are evident the level of thyroid hormones will have dropped and permanent damage may have been done.

Optimisation of thyroxine replacement is guided in the main by thyroid function tests, although it is important the patient’s symptoms are also taken into account. The recommend approach is to increase thyroxine gradually, titrating dose against TSH concentration, with the aim to keep TSH within the reference range. Over-replacement of thyroxine can lead to adverse effects in terms of cardiovascular outcome.

It is recommended that both TSH and fT4 are measured whilst optimising thyroxine dose as misleading results may be produced by patients who are poorly compliant. (A similar strategy is used for patients on tri-iodothyronine, but measuring fT3 instead of fT4).

When a stable thyroxine dose has been achieved, measurement of TSH alone is sufficient. TSH should be checked annually as requirements may change with ageing. There is an increased requirement for thyroxine in pregnant women, and absorption may also be decreased. Inadequate thyroxine leads to an increased risk of foetal death and IQ deficits. It is recommended that TSH and fT4 are measured in each trimester. The aim in the first trimester is to keep fT4 near the upper end of the range, and TSH in the lower half of the range.

The laboratory should provide assistance to users in the case of unusual thyroid function test results. The laboratory should have a strategy for the investigation of assay interferences such as heterophilic antibodies (i.e. linear dilutions, antibody blocking tubes, repeat analysis by another method). The laboratory should also be able to provide advice about the investigation of more unusual cases of hypothyroidism such as hypopituitarism and end-organ resistance.

The laboratory must ensure that it provides methods which are accurate and reliable. They must be well controlled internally and perform to an acceptable standard in external quality assurance schemes. The laboratory should also ensure that suitable and ideally locally derived reference ranges are in use. Almost all laboratories in the UK now use free T3and T4 assays which are unaffected by change in concentration of thyroid binding proteins and are thus thought to be more reliable than total hormone measurements.

In summary, the main roles of the laboratory in the diagnosis and management of hypothyroidism are to provide appropriate and reliable assays, to advise users of which tests to use when and how often they should be repeated, and to provide interpretation of results and advice on further investigations. The laboratory may often be called upon for advice in more unusual and challenging cases. Specialist laboratories also provide the crucial congenital hypothyroidism screening programme.

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Peripheral tissues

T3

+

_

+

TSH

TRH

T4

Thyroid

Anterior pituitory

Hypothalamus

_

TRH = thyrotropin releasing hormone

TSH = thyroid stimulating hormone (thyrotropin)

T4 = thyroxine

fT4 = free thyroxine

T3 = tri-iodothyronine

fT3 = free tri-iodothyronine

Reference ranges and units

TSH 0.4 – 1.0 mIU/L

fT4 9 – 25 pmol/L

fT3 2.8 – 7.5 pmol/L

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