Eur J Clin Pharmacol (1991) 40:439-451 003169709100109T
5>be[mseCel]e9 @ Springer-Verlag 1991
Special article The effects of drugs on tests of thyroid function P. H. Davies and J. A. Franklyn Department of Medicine,University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK Received: August 22, 1990/Accepted:October 10,1990
Summary. Many drugs affect tests of thyroid function through alterations in the synthesis, transport and metabolism of thyroid hormones, as well as via influences on thyrotrophin (TSH) synthesis and secretion. Despite effects on circulating thyroid hormone and TSH levels, few drugs result in important changes in clinical thyroid state, but difficulty in interpretation of thyroid function tests often results. Commonly prescribed drugs including anticonvulsants, non-steroidal anti-inflammatory drugs, betaadrenoceptor antagonists, steroid hormones and heparin may result in abnormal thyroid function tests in the absence of clinical features of thyroid dysfunction. In contrast, lithium and iodine containing drugs, including radiographic contrast agents and amiodarone, may result rarely in overt thyroid disease. Key words: Thyroid hormones, TSH, drug interaction; circulating concentration, thyroid function Many commonly prescribed drugs have marked effects on the synthesis, transport, and metabolism of thyroid hormones. The major mechanisms whereby drugs affect tests of thyroid function are: - alteration in thyroid hormone binding protein concentrations; - inhibition of thyroid hormone binding to binding proteins; - alteration in the peripheral metabolism of thyroid hormones. - In addition, some drugs exert direct effects on the secretion of thyrotrophin (TSH) by the anterior pituitary and hence affect the synthesis and secretion of thyroid hormones by the thyroid gland. Despite these effects, few drugs cause important changes in clinical thyroid state, although they may cause marked changes in biochemical tests of thyroid function, leading to difficulty in interpretation. Before considering specific effects of drugs on these tests, it is important to review briefly the physiology of thyroid hormone synthesis, transport, metabolism, and action.
Thyroid hormone synthesis, transport, metabolism, and action The synthesis by the thyroid follicular cells of the two major thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), is dependent upon the availability of iodine. Dietary iodine is reduced to iodide before absorption in the small intestine, and is taken up into the follicular cell by processes of active transport and passive diffusion. Once inside the cell, iodide is oxidized through the action of thyroid peroxidases (organification) and combines with the tyrosyl residues of thyroglobulin molecules to give rise to mono-iodotyrosines and di-iodotyrosines. Thyroglobulin is a large glycoprotein and is the major synthetic product of the thyroid follicular cell and the precursor and storage form of the thyroid hormones. The iodotyrosines, which form part of the parent thyroglobulin molecule, are coupled to form T4 and T3. Iodinated thyroglobulin is then removed into the follicular lumen, where it is stored as colloid. When the thyroid cell is stimulated by TSH, thyroglobulin is resorbed by pinocytosis and T4 and T3 are released into the circulation after proteolysis. T4 and T3 are poorly soluble in water and are transported in serum bound to three transport proteins, thyroxine binding globulin (TBG), thyroxine binding prealbumin (TBPA), and albumin (Table 1). Since TBG represents the major thyroid hormone binding protein, circulating concentrations of total T4 and T3 vary directly with changes in TBG concentration. Only 0.03% of total T4 and 0.3% of total T3 circulates in the "free" or nonprotein bound form, but it is this small unbound fraction which enters the cell and is responsible for the biological actions of thyroid hormones. There is increasing evidence
Table 1. The distribution of thyroid hormones in plasma (% bound to thyroxine binding globulin (TBG), thyroxine binding pre-albumin (TBPA),and albumin) TBG TBPA A l b u m i n Unbound T4 70 20 10-15 0.03 T3 80 10 10-15 0.3
R H. Davies and J. A. Franklyn: Drug interactions of thyroid functions
440 I
I
Ho© . I
I
(T4)
I
I
Ho©G}R I
.oOo©R
I
(T3)
I
I
I
(3,5-T2)
(rT3)
I
I
I
(3,3-T2)
(3.5-T 2)
I
I
(3-T 1)
(3-T1)
(To)
R=CH2,CH(NH2),COOH
Fig. ]. Pathway of deiodination of thyroxine that thyroid hormones are taken up into cells, and perhaps into cell nuclei, not only by a process of passive diffusion but also via energy-dependent active uptake systems. Although T4 is the circulating thyroid hormone found in greatest concentrations in both its bound and unbound forms, it is likely that T4 itself has little or no biological activity, since most of the tissue effects of T4 can be explained by conversion to T3 outside the thyroid gland. Peripheral conversion of T4 to T3 by the enzyme 5'-monodeiodinase accounts for approximately 80% of T3 production, the re-
TRE
mainder being in the thyroid gland. In most tissues, such as the liver and kidney, intracellular T3 is derived predominantly from circulating T3, but in the pituitary and central nervous system at least 50% is derived from local deiodination of T4. While the circulating concentration of T3 is therefore the major determinant of T3 action, the tissue availability of T3 may be modulated, at least in some organs such as the pituitary, by the activity of 5'-monodeiodinase. As well as deiodinating T4 to T3, deiodinases are involved in the serial removal of iodine atoms from thyroid hormones, a process which represents one of the major degradative pathways (Fig. 1). T4 is deiodinated to the active hormone T3, but in addition the removal of an iodine in the 5"-position results in the production of reverse T3 (rT3), a biologically inactive isomer of %. Reverse T3 is further deiodinated by 5'-monodeiodinase to a di-iodothyronine. Both the conversion of T4 tO T3 and the deiodination of reverse T3 by 5'-monodeiodinase may be inhibited in a number of common clinical situations, for example in patients with liver and renal failure or after surgery or myocardial infarction. Some drugs also inhibit 5'-monodeiodinase, and in these circumstances a fall in circulating T3 concentration characteristically occurs in association with a reciprocal rise in reverse T3. Other major metabolic pathways involved in the degradation of thyroid hormones include oxidative decarboxylation and conjugation with glucuronic acid or sulphate in the liver, the metbolites being excreted in the bile. Deconjugation by gut flora allows enterohepatic circulation of these iodinated compounds. None of the products of degradation of T4 (other than T3) has been shown to have any significant biological activity. Once inside the cell, illustrated diagrammatically in Fig. 2, T3 associates with cytosolic binding proteins and is transported to the nucleus. Although it has been postulated that there are extranuclear sites of thyroid hormone action, such as mitochondria, there is overwhelming evidence that
P
O pel
•Z3---q--I---ED-d'
Nuclear T 3 receplor
O
mRNA
@
I
I
TRANSLATION
®
¢5 T
Fig.2. A diagrammatic representation of the cellular actions of T3. Circulating T3 outside the cell is bound to proteins such as thyroxine binding globulin (T) or in the non-protein bound or free form and it is the free fraction which enters the cell by diffusion or by active uptake via surface membrane receptors (M). Once inside the cell, T3is transported to the nucleus (right) where it binds with high affinity to specific nuclear receptor proteins. Nuclear receptors in turn bind with high affinity to specific DNA sequences or T3 response elements (TREs) in order to stimulate or inhibit the transcription of specific genes to messenger (m)RNA
R H. Davies and J. A. Franklyn:Drug interactionsof thyroid functions
_; I TRH ®
anterior
pituitary
®
~
TSH
T3,T4 thyroid
Fig.3. Hypothalamic-pituitary-thyroidfeedbackaxis
the majority, and perhaps all, of the biological effects of T~ are mediated by high affinity binding to specific receptors within the nucleus. These receptors in turn bind with high affinity to specific sequences of DNA in order to stimulate or inhibit gene transcription in a tissue and gene-specific manner, and it is through these effects that the major metabolic actions of thyroid hormones are mediated. The major stimulus to the synthesis and secretion of T4 and T3 by the thyroid gland is the action of TSH upon the follicular cell. T4 and T3 in turn exert negative feedback upon the synthesis and secretion of TSH by the pituitary and it is this feedback system which plays a critical role in the maintenance of thyroid homoeostasis (Fig. 3). Superimposed on this system is the tonic stimulatory effect of the hypothalamic peptide thyrotrophin releasing hormone (TRH), which is transported directly by the hypophyseal portal circulatory system to the anterior pituitary. From this basic understanding of thyroid physiology has evolved a number of biochemical tests which provide measures of thyroid function and which are used as aids to the diagnosis of hypothyroidism and hyperthyroidism. The development of these tests is described below.
The development of tests of thyroid function Until the 1940's the laboratory provided little help to the clinician in his attempts to assess thyroid status. A method for the measurement of serum protein bound iodine was first described by Sandall and Kolthoff (1937) and was widely used thereafter as a test of thyroid function. The
441
concentration of protein bound iodine is directly related to the serum concentration of T4 and T3, but it soon became clear that treatment with any iodine-containing drug or iodine contamination in the laboratory led to spuriously high results. Methods for the direct measurement of circulating thyroid hormone concentrations soon superceded measurements of protein bound iodine, after description of the technique of hormone immunoassay by Yalow and Berson (1959). Specific and sensitive radioimmunoassay methods for T4 and T3 were subsequently described (Chopra et al. 1971; Chopra 1972) and led to the routine use of measurements of total T4 and total T3 as tests of thyroid function. Since some 99.97% of circulating T4 is protein bound, measurement of total T4 is highly dependent upon concentrations of binding protein and does not provide a direct measure of the concentration of unbound hormone, which represents the biologically active component. Indirect measures of unbound T4 and unbound T3 ("free" T4 and T3), which take into account thyroid hormone binding sites, were therefore developed. The T3 uptake test provides a measure of unoccupied protein binding sites, and together with a measurement of total T4 it can be used to derive a free T4 index (FTI). Methods for the direct measurement of the major T4 binding protein TBG were also described (Bradwell et al. 1976) and these led to the use of the T4/TBG ratio as a routine test of thyroid function in some centres, since this ratio also provides an indirect measure of free T4 concentration in serum. However, it became clear that both the FTI and T4/TBG ratio may misclassify some subjects, especially at extremes of TBG concentrations, and these tests have therefore been superseded by methods for the direct estimation of unbound thyroid hormone concentrations. The assays of unbound hormone concentrations first described involved the separation of bound and unbound hormone using a semi-permeable membrane (equilibrium dialysis). While this method is often regarded as the gold standard for the measurement of unbound thyroid hormones, it is technically difficult and therefore not applicable in routine use. So-called analogue methods for the measurement of free T4 and free T3 were subsequently developed and have been widely adopted as routine tests of thyroid function in the United Kingdom and elsewhere. These methods use radiolabelled analogues of T4 and T3 which bind with high affinity to anti-T4 or anti-T3 antibodies but which do not bind significantly to thyroid hormone binding proteins. The radiolabelled analogue is mixed with serum and antibody is added; analogue and unbound thyroid hormone then compete for antibody binding, and the quantity of analogue bound is inversely proportional to the concentration of unbound T4 or T3 in the test serum. Since the thyroid hormones T4 and T3 are major regulators of TSH secretion from the pituitary, as illustrated in Fig. 3, the serum TSH concentration has been used widely as a marker of thyroid function since the development of TSH radioimmunoassays in the early 1970's. The assays first introduced were poorly specific, because of cross-reactivity with gonadotrophins in serum, since TSH shares a common o~ subunit with luteinizing hormone, follicle
R H. Davies and J. A. Franklyn: Drug interactions of thyroid functions
442 stimulating hormone, and chorionic gonadotrophin. Furthermore, routine radioimmunoassays were unable to differentiate normal from reduced concentrations of TSH, so that while measurements of TSH were relevant to the diagnosis of primary thyroid failure with increased secretion of TSH, they were of no help in differentiating normal subjects from those with hyperthyroidism, and hence suppressed TSH secretion. This limitation has been overcome by the recent development of immunoradiometric assays for TSH with improved sensitivity, which are able to distinguish low and normal TSH values [Sheppard and Black 1987]; such assays have now been adopted by many centres as a first-line test of thyroid function. The introduction of sensitive TSH assays has also led to the realization that measurement of TSH provides as much information about pituitary TSH secretion as does the T R H test; there is a close correlation between serum TSH values measured in a sensitive assay and the increase in circulating TSH observed 30 or 60 min after the intravenous injection of TRH. This observation means that T R H administration is now used infrequently in the investigation of thyroid function. Having reviewed briefly the development of tests of thyroid function, we shall discuss the major effects of drugs on the results of these tests as well as the occurrence of overt thyroid dysfunction associated with drug therapy. The effects of drugs on tests of thyroid function outlined in this review are summarized in Table 2.
increasing popularity of multivitamin supplements, although iodine deficiency remains an enormous problem worldwide [Anonymous 1990]. There is little consensus regarding optimum iodine intake, although the minimum iodine requirement for health is approximately 150 gg per day [Wenlock et al. 1982]. Iodine exerts complex effects on thyroid function, effects which vary depending upon whether iodine is given acutely in a large dose or whether there is long-term increased exposure; its effects also vary depending upon whether it has been given in the context of previous iodine deficiency or in the presence of overt or subclinical thyroid disease. Iodine administration has the potential to disrupt thyroid function at almost every step of hormone production and release, hence inducing thyroid hormone deficiency. Thyroidal uptake and organification of iodine may be inhibited by iodine in excess, leading to reduced hormone synthesis; this acute influence of iodine is known as the Wolff-Chaikoff effect. Two mechanisms have been proposed to explain this phenomenon [Phillips et al. 1988]. Iodination of tyrosine requires reactive enzyme-bound iodine, and excessive iodide ions may compete for this active moiety, thereby inhibiting organification. Alternatively, iodine in excess may result in overproduction of the activated iodine form, which may then damage thyroid peroxidase or structural proteins, inhibiting thyroid hormone synthesis. Furthermore, excess iodine may directly inhibit the effects of TSH on the thyroid cell mediated via adenyl cyclase, impairing thyroid hormone release. Proteolytic mechanisms essential to hormone release are further potential sites of iodine inhibition [Wartofsksy et al. 1970]. In addition to these direct effects of iodine on the thyroid gland, it has been recognised that iodine may modulate thyroid hormone metabolism by inhibiting the action of 5'-monodeiodinase and hence the conversion of T4 to T3 [Grubeck-Lobenstein et al. 1980]. Immune mechanisms have also been implicated in mediating the effects of iodine on the thyroid gland. The cor-
The effects of iodine and iodine-containing drug It has long been recognised that iodine administration may give rise to both underactivity and overactivity of the thyroid gland and may affect tests of thyroid function in the absence of overt thyroid disease. Dietary iodine intake has increased in recent years in developed countries with the widespread use of iodized salt and bread and the
Table 2. Summary of the effects of drugs on tests of thyroid function. The symbols $, ~--~,and 1"indicate that measurements may be respectively reduced, unchanged, or increased Drug
Free T4
Free T3
rT3
TSH
TRH test
Iodine
,1,
$
e-~
1"
1"
Radiographic contrast media
1"
$
1"
1"
?
Amiodarone Phenytoin Carbamazepine Phenobarbitone Aspirin Fenclofenac Phenylbutazone Propranolol Lithium Corticosteroids Oestrogens Heparin
$ $ $ $ 1" $ $ ? ~-~ $~-÷ ~ 1"
$ -J, $~-~ $~--~ 1" $ 1" $ ~-~ -],---> ~ $
1" e-~ ~ ~-~ e-~ ~-~ e-~ I" e-~ $
5>be[mseCel]e9 @ Springer-Verlag 1991
Special article The effects of drugs on tests of thyroid function P. H. Davies and J. A. Franklyn Department of Medicine,University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK Received: August 22, 1990/Accepted:October 10,1990
Summary. Many drugs affect tests of thyroid function through alterations in the synthesis, transport and metabolism of thyroid hormones, as well as via influences on thyrotrophin (TSH) synthesis and secretion. Despite effects on circulating thyroid hormone and TSH levels, few drugs result in important changes in clinical thyroid state, but difficulty in interpretation of thyroid function tests often results. Commonly prescribed drugs including anticonvulsants, non-steroidal anti-inflammatory drugs, betaadrenoceptor antagonists, steroid hormones and heparin may result in abnormal thyroid function tests in the absence of clinical features of thyroid dysfunction. In contrast, lithium and iodine containing drugs, including radiographic contrast agents and amiodarone, may result rarely in overt thyroid disease. Key words: Thyroid hormones, TSH, drug interaction; circulating concentration, thyroid function Many commonly prescribed drugs have marked effects on the synthesis, transport, and metabolism of thyroid hormones. The major mechanisms whereby drugs affect tests of thyroid function are: - alteration in thyroid hormone binding protein concentrations; - inhibition of thyroid hormone binding to binding proteins; - alteration in the peripheral metabolism of thyroid hormones. - In addition, some drugs exert direct effects on the secretion of thyrotrophin (TSH) by the anterior pituitary and hence affect the synthesis and secretion of thyroid hormones by the thyroid gland. Despite these effects, few drugs cause important changes in clinical thyroid state, although they may cause marked changes in biochemical tests of thyroid function, leading to difficulty in interpretation. Before considering specific effects of drugs on these tests, it is important to review briefly the physiology of thyroid hormone synthesis, transport, metabolism, and action.
Thyroid hormone synthesis, transport, metabolism, and action The synthesis by the thyroid follicular cells of the two major thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), is dependent upon the availability of iodine. Dietary iodine is reduced to iodide before absorption in the small intestine, and is taken up into the follicular cell by processes of active transport and passive diffusion. Once inside the cell, iodide is oxidized through the action of thyroid peroxidases (organification) and combines with the tyrosyl residues of thyroglobulin molecules to give rise to mono-iodotyrosines and di-iodotyrosines. Thyroglobulin is a large glycoprotein and is the major synthetic product of the thyroid follicular cell and the precursor and storage form of the thyroid hormones. The iodotyrosines, which form part of the parent thyroglobulin molecule, are coupled to form T4 and T3. Iodinated thyroglobulin is then removed into the follicular lumen, where it is stored as colloid. When the thyroid cell is stimulated by TSH, thyroglobulin is resorbed by pinocytosis and T4 and T3 are released into the circulation after proteolysis. T4 and T3 are poorly soluble in water and are transported in serum bound to three transport proteins, thyroxine binding globulin (TBG), thyroxine binding prealbumin (TBPA), and albumin (Table 1). Since TBG represents the major thyroid hormone binding protein, circulating concentrations of total T4 and T3 vary directly with changes in TBG concentration. Only 0.03% of total T4 and 0.3% of total T3 circulates in the "free" or nonprotein bound form, but it is this small unbound fraction which enters the cell and is responsible for the biological actions of thyroid hormones. There is increasing evidence
Table 1. The distribution of thyroid hormones in plasma (% bound to thyroxine binding globulin (TBG), thyroxine binding pre-albumin (TBPA),and albumin) TBG TBPA A l b u m i n Unbound T4 70 20 10-15 0.03 T3 80 10 10-15 0.3
R H. Davies and J. A. Franklyn: Drug interactions of thyroid functions
440 I
I
Ho© . I
I
(T4)
I
I
Ho©G}R I
.oOo©R
I
(T3)
I
I
I
(3,5-T2)
(rT3)
I
I
I
(3,3-T2)
(3.5-T 2)
I
I
(3-T 1)
(3-T1)
(To)
R=CH2,CH(NH2),COOH
Fig. ]. Pathway of deiodination of thyroxine that thyroid hormones are taken up into cells, and perhaps into cell nuclei, not only by a process of passive diffusion but also via energy-dependent active uptake systems. Although T4 is the circulating thyroid hormone found in greatest concentrations in both its bound and unbound forms, it is likely that T4 itself has little or no biological activity, since most of the tissue effects of T4 can be explained by conversion to T3 outside the thyroid gland. Peripheral conversion of T4 to T3 by the enzyme 5'-monodeiodinase accounts for approximately 80% of T3 production, the re-
TRE
mainder being in the thyroid gland. In most tissues, such as the liver and kidney, intracellular T3 is derived predominantly from circulating T3, but in the pituitary and central nervous system at least 50% is derived from local deiodination of T4. While the circulating concentration of T3 is therefore the major determinant of T3 action, the tissue availability of T3 may be modulated, at least in some organs such as the pituitary, by the activity of 5'-monodeiodinase. As well as deiodinating T4 to T3, deiodinases are involved in the serial removal of iodine atoms from thyroid hormones, a process which represents one of the major degradative pathways (Fig. 1). T4 is deiodinated to the active hormone T3, but in addition the removal of an iodine in the 5"-position results in the production of reverse T3 (rT3), a biologically inactive isomer of %. Reverse T3 is further deiodinated by 5'-monodeiodinase to a di-iodothyronine. Both the conversion of T4 tO T3 and the deiodination of reverse T3 by 5'-monodeiodinase may be inhibited in a number of common clinical situations, for example in patients with liver and renal failure or after surgery or myocardial infarction. Some drugs also inhibit 5'-monodeiodinase, and in these circumstances a fall in circulating T3 concentration characteristically occurs in association with a reciprocal rise in reverse T3. Other major metabolic pathways involved in the degradation of thyroid hormones include oxidative decarboxylation and conjugation with glucuronic acid or sulphate in the liver, the metbolites being excreted in the bile. Deconjugation by gut flora allows enterohepatic circulation of these iodinated compounds. None of the products of degradation of T4 (other than T3) has been shown to have any significant biological activity. Once inside the cell, illustrated diagrammatically in Fig. 2, T3 associates with cytosolic binding proteins and is transported to the nucleus. Although it has been postulated that there are extranuclear sites of thyroid hormone action, such as mitochondria, there is overwhelming evidence that
P
O pel
•Z3---q--I---ED-d'
Nuclear T 3 receplor
O
mRNA
@
I
I
TRANSLATION
®
¢5 T
Fig.2. A diagrammatic representation of the cellular actions of T3. Circulating T3 outside the cell is bound to proteins such as thyroxine binding globulin (T) or in the non-protein bound or free form and it is the free fraction which enters the cell by diffusion or by active uptake via surface membrane receptors (M). Once inside the cell, T3is transported to the nucleus (right) where it binds with high affinity to specific nuclear receptor proteins. Nuclear receptors in turn bind with high affinity to specific DNA sequences or T3 response elements (TREs) in order to stimulate or inhibit the transcription of specific genes to messenger (m)RNA
R H. Davies and J. A. Franklyn:Drug interactionsof thyroid functions
_; I TRH ®
anterior
pituitary
®
~
TSH
T3,T4 thyroid
Fig.3. Hypothalamic-pituitary-thyroidfeedbackaxis
the majority, and perhaps all, of the biological effects of T~ are mediated by high affinity binding to specific receptors within the nucleus. These receptors in turn bind with high affinity to specific sequences of DNA in order to stimulate or inhibit gene transcription in a tissue and gene-specific manner, and it is through these effects that the major metabolic actions of thyroid hormones are mediated. The major stimulus to the synthesis and secretion of T4 and T3 by the thyroid gland is the action of TSH upon the follicular cell. T4 and T3 in turn exert negative feedback upon the synthesis and secretion of TSH by the pituitary and it is this feedback system which plays a critical role in the maintenance of thyroid homoeostasis (Fig. 3). Superimposed on this system is the tonic stimulatory effect of the hypothalamic peptide thyrotrophin releasing hormone (TRH), which is transported directly by the hypophyseal portal circulatory system to the anterior pituitary. From this basic understanding of thyroid physiology has evolved a number of biochemical tests which provide measures of thyroid function and which are used as aids to the diagnosis of hypothyroidism and hyperthyroidism. The development of these tests is described below.
The development of tests of thyroid function Until the 1940's the laboratory provided little help to the clinician in his attempts to assess thyroid status. A method for the measurement of serum protein bound iodine was first described by Sandall and Kolthoff (1937) and was widely used thereafter as a test of thyroid function. The
441
concentration of protein bound iodine is directly related to the serum concentration of T4 and T3, but it soon became clear that treatment with any iodine-containing drug or iodine contamination in the laboratory led to spuriously high results. Methods for the direct measurement of circulating thyroid hormone concentrations soon superceded measurements of protein bound iodine, after description of the technique of hormone immunoassay by Yalow and Berson (1959). Specific and sensitive radioimmunoassay methods for T4 and T3 were subsequently described (Chopra et al. 1971; Chopra 1972) and led to the routine use of measurements of total T4 and total T3 as tests of thyroid function. Since some 99.97% of circulating T4 is protein bound, measurement of total T4 is highly dependent upon concentrations of binding protein and does not provide a direct measure of the concentration of unbound hormone, which represents the biologically active component. Indirect measures of unbound T4 and unbound T3 ("free" T4 and T3), which take into account thyroid hormone binding sites, were therefore developed. The T3 uptake test provides a measure of unoccupied protein binding sites, and together with a measurement of total T4 it can be used to derive a free T4 index (FTI). Methods for the direct measurement of the major T4 binding protein TBG were also described (Bradwell et al. 1976) and these led to the use of the T4/TBG ratio as a routine test of thyroid function in some centres, since this ratio also provides an indirect measure of free T4 concentration in serum. However, it became clear that both the FTI and T4/TBG ratio may misclassify some subjects, especially at extremes of TBG concentrations, and these tests have therefore been superseded by methods for the direct estimation of unbound thyroid hormone concentrations. The assays of unbound hormone concentrations first described involved the separation of bound and unbound hormone using a semi-permeable membrane (equilibrium dialysis). While this method is often regarded as the gold standard for the measurement of unbound thyroid hormones, it is technically difficult and therefore not applicable in routine use. So-called analogue methods for the measurement of free T4 and free T3 were subsequently developed and have been widely adopted as routine tests of thyroid function in the United Kingdom and elsewhere. These methods use radiolabelled analogues of T4 and T3 which bind with high affinity to anti-T4 or anti-T3 antibodies but which do not bind significantly to thyroid hormone binding proteins. The radiolabelled analogue is mixed with serum and antibody is added; analogue and unbound thyroid hormone then compete for antibody binding, and the quantity of analogue bound is inversely proportional to the concentration of unbound T4 or T3 in the test serum. Since the thyroid hormones T4 and T3 are major regulators of TSH secretion from the pituitary, as illustrated in Fig. 3, the serum TSH concentration has been used widely as a marker of thyroid function since the development of TSH radioimmunoassays in the early 1970's. The assays first introduced were poorly specific, because of cross-reactivity with gonadotrophins in serum, since TSH shares a common o~ subunit with luteinizing hormone, follicle
R H. Davies and J. A. Franklyn: Drug interactions of thyroid functions
442 stimulating hormone, and chorionic gonadotrophin. Furthermore, routine radioimmunoassays were unable to differentiate normal from reduced concentrations of TSH, so that while measurements of TSH were relevant to the diagnosis of primary thyroid failure with increased secretion of TSH, they were of no help in differentiating normal subjects from those with hyperthyroidism, and hence suppressed TSH secretion. This limitation has been overcome by the recent development of immunoradiometric assays for TSH with improved sensitivity, which are able to distinguish low and normal TSH values [Sheppard and Black 1987]; such assays have now been adopted by many centres as a first-line test of thyroid function. The introduction of sensitive TSH assays has also led to the realization that measurement of TSH provides as much information about pituitary TSH secretion as does the T R H test; there is a close correlation between serum TSH values measured in a sensitive assay and the increase in circulating TSH observed 30 or 60 min after the intravenous injection of TRH. This observation means that T R H administration is now used infrequently in the investigation of thyroid function. Having reviewed briefly the development of tests of thyroid function, we shall discuss the major effects of drugs on the results of these tests as well as the occurrence of overt thyroid dysfunction associated with drug therapy. The effects of drugs on tests of thyroid function outlined in this review are summarized in Table 2.
increasing popularity of multivitamin supplements, although iodine deficiency remains an enormous problem worldwide [Anonymous 1990]. There is little consensus regarding optimum iodine intake, although the minimum iodine requirement for health is approximately 150 gg per day [Wenlock et al. 1982]. Iodine exerts complex effects on thyroid function, effects which vary depending upon whether iodine is given acutely in a large dose or whether there is long-term increased exposure; its effects also vary depending upon whether it has been given in the context of previous iodine deficiency or in the presence of overt or subclinical thyroid disease. Iodine administration has the potential to disrupt thyroid function at almost every step of hormone production and release, hence inducing thyroid hormone deficiency. Thyroidal uptake and organification of iodine may be inhibited by iodine in excess, leading to reduced hormone synthesis; this acute influence of iodine is known as the Wolff-Chaikoff effect. Two mechanisms have been proposed to explain this phenomenon [Phillips et al. 1988]. Iodination of tyrosine requires reactive enzyme-bound iodine, and excessive iodide ions may compete for this active moiety, thereby inhibiting organification. Alternatively, iodine in excess may result in overproduction of the activated iodine form, which may then damage thyroid peroxidase or structural proteins, inhibiting thyroid hormone synthesis. Furthermore, excess iodine may directly inhibit the effects of TSH on the thyroid cell mediated via adenyl cyclase, impairing thyroid hormone release. Proteolytic mechanisms essential to hormone release are further potential sites of iodine inhibition [Wartofsksy et al. 1970]. In addition to these direct effects of iodine on the thyroid gland, it has been recognised that iodine may modulate thyroid hormone metabolism by inhibiting the action of 5'-monodeiodinase and hence the conversion of T4 to T3 [Grubeck-Lobenstein et al. 1980]. Immune mechanisms have also been implicated in mediating the effects of iodine on the thyroid gland. The cor-
The effects of iodine and iodine-containing drug It has long been recognised that iodine administration may give rise to both underactivity and overactivity of the thyroid gland and may affect tests of thyroid function in the absence of overt thyroid disease. Dietary iodine intake has increased in recent years in developed countries with the widespread use of iodized salt and bread and the
Table 2. Summary of the effects of drugs on tests of thyroid function. The symbols $, ~--~,and 1"indicate that measurements may be respectively reduced, unchanged, or increased Drug
Free T4
Free T3
rT3
TSH
TRH test
Iodine
,1,
$
e-~
1"
1"
Radiographic contrast media
1"
$
1"
1"
?
Amiodarone Phenytoin Carbamazepine Phenobarbitone Aspirin Fenclofenac Phenylbutazone Propranolol Lithium Corticosteroids Oestrogens Heparin
$ $ $ $ 1" $ $ ? ~-~ $~-÷ ~ 1"
$ -J, $~-~ $~--~ 1" $ 1" $ ~-~ -],---> ~ $
1" e-~ ~ ~-~ e-~ ~-~ e-~ I" e-~ $
