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(BQ) Part 2 book Clinical chemistry (organ function tests, laboratory investigation) presents the following contents: Laboratory investigations, miscellaneous, inborn metabolic diseases (inborn errors of metabolism).
Chapter 16 Hyperthyroidism* INTRODUCTION The term hyperthyroidism denotes the biochemical, physiological and clinical findings associated with hyperactivity of thyroid gland The condition is characterized by generalized enhancement of metabolic rate and oxygen consumption with or without weight loss Common manifestations of the disease comprise nervousness, emotional lability, insomnia, frequent bowel movements, heat intolerance, excessive sweating and increased weight loss Dyspnoea and palpitations along with oligomenorrhoea and amenorrhoea in premenopausal women also tend to occur THYROTOXICOSIS TYPES AND CAUSES The term thyrotoxicosis signifies the clinical condition when tissues are exposed and respond to excess thyroid hormones The aetiology of the condition might be primary hyperfunction of thyroid gland or any other abnormality leading to increased plasma thyroid hormone levels Therefore, thyrotoxicosis is not a specific disease but a clinical condition which can originate from a variety of problems (Table 16.1) and may or may not be associated with hyperthyroidism The sustained overproduction of thyroid hormones by the gland itself Table 16.1: Types and causes of thyrotoxicosis • With hyperthyroidism I Hyperthyrotropism (increased TSH) • Pituitary tumour • Pituitary resistance to thyroid hormones II Abnormal stimulation • Graves’ disease • Trophoblastic tumour III Functionally autonomous tissue • Adenoma • Multinodular goitre •Without hyperthyroidism • Thyrotoxic factitia • Functioning carcinoma • Struma ovarii • Transient thyrotoxicosis with thyroiditis may be due to excessive secretion of TSH which, in turn, might originate from a pituitary tumour or associated with resistance of pituitary to the raised levels of thyroid hormones Sometimes, the source of thyroid hormones can be extrathyroidal also, e.g., functioning metastatic carcinoma of thyroid and thyrotoxicosis factitia (Hamburger's toxicosis) that results from accidental ingestion of meat containing animal thyroid tissue Autoimmunity also plays a significant role in the causation of thyrotoxic state In the most common form of hyperthyroidism, i.e., Graves’ disease, the culprit is specific antibodies *Contributed by Professor R Chawla, MSc, DMRIT, PhD, Professor of Biochemistry , Faculty of Medicine, AddisAbaba University, Ethiopia, ex-Professor of Biochemistry, Christian Medical College, Ludhiana (Punjab) 172 Part 2: Laboratory Investigations against the TSH receptors, which provide homeostatically unregulated stimulation of the gland, known as long acting thyroid stimulator (LATS) Thyrotoxic state also appears, albeit transiently, in Hashimoto’s thyroiditis because of the leakage of preformed thyroid hormones from the gland due to inflammatory injury I “In Vivo” Thyroid Function Tests Note The distinction between hyperthyroidism and thyrotoxicosis is, thus, very much essential and must be considered not only for diagnosis but also in selecting the treatment protocol Although, the diseases that cause thyrotoxicosis make their own contribution to the overall clinical picture, the manifestations of the thyrotoxic state are largely the same Multinodular toxic goitre (MNG) is frequently associated with hyperthyroid state and autonomy of the nodules is an underlying phenomenon Most often than not, it is a consequence of a long standing simple goitre and therefore, multinodular goitre is a disease of the elderly Sometimes hyperthyroidism is also observed in case of trophoblastic tumours, e.g., choriocarcinoma and hydatidiform mole The Jodbasedow phenomenon is another unusual type of thyrotoxicosis and is induced by exposure to large doses of iodine particularly in areas of endemic iodine deficiency Similar situation can develop in patients with non-toxic nodular goitre on receiving large doses of iodine Radioiodine Thyroid Uptake (RTU) Although the in vitro estimation of the thyroid hormones and related tests have virtually eclipsed the in vivo tests of thyroid function, they still find their application in specific conditions as discussed below (Refer to Chapter on thyroid function tests) Interpretation • Since percentage uptake of the administered radioiodine is proportional to activity of the follicular cells, the increased uptake or early peaking normally are seen in all disorders producing hyperthyroidism Two hours as well as 24 hours uptake are increased • Rarely, in Graves’ disease the 2-hours uptake is elevated and 24-hours-uptake is normal due to very high turnover Such high turnover is always associated with obvious clinical hyperthyroidism In such a situation, another 8-hours observation is recommended and an 8-hour-uptake rather than 24hour-uptake is diagnostic of hyperthyroidism with a very high turnover (Fig 16.1) LABORATORY INVESTIGATIONS The diagnosis of hyperthyroidism is far less enigmatic than hypothyroidism and most often than not the clinician is able to make a diagnosis on the basis of clinical presentation and the laboratory investigations play a supportive role only The evaluation of thyroid status under these circumstances also serves as baseline for monitoring of the therapy and progression of the disease The various thyroid function tests available for evaluation and diagnosis of hyperthyroidism are described under the heads of in vivo and in vitro investigations Fig 16.1: Typical radioiodine uptake curves under various conditions (A) hyperthyroidism; (B) Euthyroid; (C) Thyrotoxicosis without hyperthyroidism Chapter 16: Hyperthyroidism 173 • Thyrotoxicosis not associated with hyperthyroidism, is characterized by subnormal values of RTU Subacute thyroiditis and chronic thyroiditis with spontaneously resolving thyrotoxicosis are the most common examples in this category • In thyrotoxicosis factitia and thyrotoxicosis due to ectopic thyroid tissue, the thyroid gland is suppressed Therefore, RTU is low and most of the administered radioiodine is excreted in urine • In places with endemic goitre, due to chronic iodine deficiency, elevated iodine uptake is common and could interfere with the diagnosis Earlier, the plasma radioiodine levels were investigated in these situations to distinguish hyperthyroidism from iodine deficiency In the former case, plasma levels of radioiodine were significantly higher than the later But these days, plasma radioiodine is seldom measured due to the availability of estimations of thyroid hormones in circulation Note • Several foods and drugs are known to interfere with the thyroid uptake studies and are known to depress the uptake values Ingestion of food rich in iodine such as seafood and medications including amoebicides and antitussives keep the iodine uptake depressed for even up to 30 days • Iodine contrast materials may decrease uptake, from a few weeks (in cases of excretory urography) to several months and even years in cases of contrast myelography and bronchography • Exogenous T3 and T4 hormones decrease TSH secretion and hence depress iodine uptake • The drugs like propylthiouracil block thyroid hormone synthesis, but not trapping step, therefore, actually increasing the uptake • Prolonged ingestion of goitrogenic foods as turnips and cabbage liberate thiocyanates, which competitively suppress the iodine uptake T3 Suppression Test Principle • Werner (1955) recognized the application of this test in confirming hyperthyroidism The premise for the test is that increased levels of circulating T3 inhibit the secretion of TSH As the TSH levels fall, thyroid uptake diminishes Method T3 (25 μg) is administered orally for seven days and radioiodine uptake is measured before and after the therapy Interpretations • Normally, the uptake falls by more than 60% of the baseline value due to decreased levels of TSH • The principal application of the test lies in differentiating borderline hypethyroidism from euthyroid state In the former, the thyroid uptake does not decrease because of autonomous nature of the disease Thyroid Scintigraphy Thyroid imaging can be achieved with a number of techniques including ultrasound and computed tomography, but the most popular and useful modality is scintigraphy with 131I or 99mTc-pertechnitate Indications The major indications of thyroid scanning are: • Palpable nodule(s) in the neck • Assessment of substernal mass • Postoperative search for functioning metastasis • Suspicion of occult malignancy but it has also been used for the evaluation of goitre • Progress of thyroiditis Evaluation of the effects of thyroid stimulating and suppressive therapy 174 Part 2: Laboratory Investigations Method The first radioiodine (131I) thyroid scans were obtained with the help of collimated GeigerMuller tubes which were followed by rectilinear scanners Currently, thyroid scans are obtained with gamma camera or SPECT units after oral or i.v administration of radioiodine (131I) or technetium (99mTc) pertechnitate Another technique available for the purpose is fluorescent scanning, which measures the K X-ray given off when iodine atoms are excited by an incident photon beam The instruments based on fluorescence have been developed and are available commercially but are not very popular Interpretations • Thyroid scintigraphy provides the information regarding morphology of the gland, e.g., size and position of the gland, congenital absence of one lobe, sublingual thyroid or substernal extension, etc • Also provides the regional information like functioning or non-functioning nodule(s) The functioning nodules concentrate the radioiodine to much higher extent than normal thyroid tissue and therefore appear brighter on the scan called “hot spots” whereas non-functioning nodules appear as “cold nodules” because they are unable to concentrate radioactive iodine or pertechnitate • Hyperfunctioning nodules may be multiple or single and are very prominent on the scan because they suppress the surrounding normal thyroid tissue In Graves’ disease, characterized by diffuse hypertrophy, the gland is usually large and more uniform in size (Fig 16.2) and on scan appears very bright with well defined margins but nodularity associated with Graves’ disease has also been reported On the other hand in multinodular goitre, a number of “hot spots” are observed interspersed with minimal normal tissue which is poorly visualized due to suppression by the raised thyroid hormone levels Figs 16.2A to E: Thyroid scintigraphy using 99mTc pertechnitate (A) Graves’ disease, (B) Multinodular goiter, (C) Solitary functioning nodule, (D) Thyroid carcinoma involving left lobe, (E) Colloid cyst • The cold spots on a thyroid scan have for long been associated with malignancy The incidence of malignancy in cold-nodules (20%) is far higher than that in hot-nodules (2%) A number of cold areas interspersed with patches of normal tissue might indicate multiple non-functioning nodules The clinical findings like number, feel and fixation of the nodules are very important in interpreting a cold nodule on a thyroid scan Nodules that involve an entire gland are most likely to be caused by subacute thyroiditis Similarly, large soft nodules with smooth borders are most often benign cysts Further, the nodules associated with hyperthyroidism are most often benign Note The thyroid gland is, sometimes, not visualized in an iodine scan due to: • increased iodine pool; • acute thyroiditis; • chronic thyroiditis; • suppressive or antithyroid medication; • surgical or radioiodine ablation; and • congenital absence of one or both lobes II “In Vitro” Tests for Thyroid Function In vivo tests have predominated for a long time, but with the advancement of laboratory techniques, the in vivo tests are becoming more or less Chapter 16: Hyperthyroidism 175 redundant in the diagnosis of hyperthyroidism, particularly where it is not accompanied by nodular goitre in which case radioiodine thyroid scan may be very helpful As in case of hypothyroidism, a wide range of in vitro tests are now available in the hands of clinician Further, the clinical picture in case of hyperthyroidism is much more clear than that in hypothyroidism and many a times the laboratory investigations just serve as baseline for evaluation of therapy rather than necessary diagnostic aids The earliest methods developed for the estimation of serum levels of thyroid hormones were protein bound iodine (PBI) and butanol extractable iodide (BEI), both of which were painfully laborious and involved extraction of iodine associated with the serum proteins These assays served the clinicians for a number of decades before being replaced by two ingenuous assays, i.e., T3 uptake and competitive protein binding assays; the later then paved the way for the radio and enzyme immunoassays T3 Red Cells Uptake Test Principle The T3 red cell uptake test was developed by Hamolsky et al (1959) and was the first attempt to measure the circulating thyroid hormones and their interaction with the plasma proteins The test was based on competition between serum thyroid hormone binding proteins and washed red cells to bind labelled T3 The test involves incubation of test serum with radiolabelled T3 along with washed RBC The greater the plasma T4 concentration is, fewer the unoccupied binding sites on the transport proteins, hence, larger proportion of the added labelled T3 will be free to be adsorbed on the RBCs The principle is described in Fig 17.2 (Chapter 17 on hypothyroidism) The RBCs in the test were later replaced with a different resins by different manufacturers and a number of commercial kits known as T3-resin uptake kits became available These days the resins have themselves been replaced by the use of specific anti-T3 antibodies, many times coated on the surface of the polypropylene tubes Interpretations The T3 uptake test finds its application in the indirect estimation of free T4 known as free thyroxine index ((FTI) and is particularly useful in conditions where alterations in the total T3 and T4 levels are suspected to be due to changes in the levels of binding proteins especially TBG Various conditions influencing TBG concentrations are described in Table 17.2 (Chapter 17 on hypothyroidism) The test continues to serve the thyroid clinicians even after four decades of its inception Competitive Protein Binding (CPB) Assays Murphy et al (1966) introduced a technique called as saturation analysis This replaced the earlier cumbersome and less reliable estimates of circulating hormones, e.g., protein bound iodine (PBI) or butanol extractable iodide (BEI) and T4 by column In this test serum T4 was extracted by alcohol, which was then incubated with TBG saturated with labelled T4 The labelled T4 displaced from TBG was then scavenged with the help of a resin The test results could differentiate hyperthyroidism but were not as good for hypothyroidism in which case considerable overlap was observed between hypothyroid and euthyroid ranges The major drawback of the assay again was the interference by the serum proteins albeit in the opposite dir-ection to that in T3 uptake Radioimmunoassays of Thyroid Hormones Principle The radioimmunoassay (RIA) technique was introduced in 1959 by Berson and Yalow when they developed an assay system for insulin Their technique was adapted for the estimation of thyroid hormones by Gharib et al (1970) and Chopra et al (1971) The RIA tests are based on the competition between the hormone in serum with exogenously added labelled hormone for 176 Part 2: Laboratory Investigations the limited number of binding sites on the antibodies against that hormone The assays for circulating thyroid hormones involve the release of hormones from the binding proteins which is generally achieved with the help of 8-anilino-1-naphthalene-sulphonic acid (ANS) Advantages Advantages of RIAs involve their extreme sensitivity and simplicity of the procedure which are now available in different formats including IRMA Procedure • Immunometric assays (IRMA): employ multiple sets of highly specific monoclonal antibodies; one of which is labelled with radioiodine and hence, differ from conventional RIAs in their use of labelled antibodies rather than labelled antigens • Enzyme-linked immunosorbent assay (ELISA) techniques: These were developed primarily to avoid the radioisotopes and the associated restrictions/hazards There are various types of ELISA tests available in different formats including the most recent microwells, for the estimation of thyroid hormones These assays are almost as sensitive as RIA and have become more popular due to no requirement of technical personnel and less expensive infrastructure • Chemiluminescence immunoassays (CIA) and fluorescence immunoassays (FIA), both of which are again based on the principle of RIA or IRMA but use luminescent or fluorescent chemicals as labels are the next addition to the list of immunoassays (a) Serum Total T3 and T4 Assays Interpretations • Serum T3 and T4 levels are the most common laboratory investigations of hyperthyroidism because both of them are elevated in most of the hyperthyroidism cases The serum thyroxine RIA can detect hyperthyroidism with a sensitivity as high as 90%, Table 16.2: Various conditions associated with hyperthyroxinemia Clinical condition • Increased T3/T4 Binding: A Increased TBG B Increased TBPA C FDH * D Anti-T4 antibodies E Anti-T3 antibodies • Pituitary and peripheral resistance • Non-thyroidal illness (NTI) • Acute psychiatric illness • Hyperemesis gravidarum • Drugs: A Radiographic contrast agents B Propranolol C Amiodarone D Heparin E Levothyroxine therapy T4 T3 H H H H N H L H H H N or H N or H N H H L N or H N H H H H H L L L N N • FDH: Familial dysalbuminic hyperthyroxinaemia, TBG: Thyroxine binding globulin, TBPA: Thyroxine binding prealbumin, H: High, N: Normal, L: Low whereas tri-iodothyronine has been found to be raised in about 70% of the cases Sometimes, normal T4 values have been found along with raised T3 levels in so-called T3thyrotoxicosis • Increased serum T4 levels can occur from a variety of other causes also (Table 16.2) The most common among these is the increased serum binding proteins The patients with acute hepatitis may have increased serum T4 levels secondary to increases in TBG In hospitalized patients isolated hyperthyroxinaemia in euthyroid patients is almost as common as true hyperthyroidism • Non-thyroidal illnesses (NTI) mostly present with low levels of T3 and T4, but rarely increased T4 concentration has also been observed • In familial dysalbuminaemic hyperthyroxinaemia, inherited as autosomal trait, the plasma concentration of an albumin variant, with an unusally high affinity for T4, is increased As a result, the serum T4 is markedly elevated although clinically, the patient is essentially euthyroid In such a Chapter 16: Hyperthyroidism 177 situation even T3 uptake does not reflect the increase in the intensity of T4 binding (because affinity rather than capacity of T4 binding is raised) and hence free T4 index (FT4I) is raised, often leading to mistaken diagnosis of thyrotoxicosis Estimation of free T4 by radioimmunoassay are mostly normal and hence, can help in the diagnosis; but rarely, high free T4 levels may also be observed in familial dysalbuminaemic hyperthyroxinaemia • Spuriously increased levels of thyroid hormones (T3 or T4) are also found in patients who have developed antibodies against T3 or T4 The condition can be demonstrated by incubating the patient’s serum with radiolabelled T4 and measuring the radioactivity in the immune complexes precipitated with polyethylene glycol (PEG) The increased activity over a parallel run control, would indicate the presence of antibodies to T4 • Serum T3 estimation has been found to be a poor indicator for diagnosing hyperthyroidism, particularly in hospital settings where presence of NTI lowers an otherwise elevated T3 level to bring it within normal limit; whereas the T4 level is affected in very severe disease only • T3 hyperthyroidism occurs in about 4% of the hyperthyroidism patients, but in areas of iodine deficiency, the incidence might be much higher In endemic iodine deficiency patients, the T3 concentration is usually higher than T4 levels and the TSH levels are raised, although the patients are clinically euthyroid (b) Serum Free Thyroxine Assay With the increases in thyroxine binding proteins the corresponding increase in serum T3 and/or T4 occur that are not reflected in clinical state In these situations, the free T4 (or even free T3) is more closely correlated with the patient’s clinical status The assays for the estimation of free hormones in the presence of bound ones have been elusive or cumbersome and hence indirect assays like free T4 Index (FT4I) have found much popularity under these conditions (explained above) The RIA as well as EIA are now available which can measure the free thyroid hormones with reasonable reliability Free T4 assays are in general more reliable than free T3 assays and correlate better with the clinical findings Interpretations • Typically, in hyperthyroidism, whether primary or secondary in origin, the free T3 and T4 levels are found to be increased These elevations correlate very well with the clinical condition and are not affected by the changes in the binding proteins Although it has been claimed that the free T4 levels are within normal limits in non-thyroidal illness (NTI), there are reports that contradict this claim In general, it is agreed that free T4 values represent thyroidal status very well even in hospitalized patients FT4I has also been found to be helpful in NTI patients but is low in critically ill patients Note Certain drugs are known to interfere with free T4 estimations, e.g., serum total T4 as well free T4 levels in patients on phenytoin are about 15 to 30% lower than in normal subjects Similar findings are also observed with carbamazepine treatment Heparin also interferes with free T4 estimations, hence, use of heparinized blood should be avoided for free T4 assays • In familial dysalbuminaemic hyperthyroxinaemia total T3 and T4 as well as FT4I might be elevated although the patient is essentially euthyroid Free T4 assays mostly yield normal values in these patients In view of the above, it appears that the free hormone assays are much more useful in the diagnosis of thyroid diseases, in all clinical conditions, than the total T3/T4 estimations and with the technical improvements in the assay procedures, are becoming more and more popular with the clinicians In the coming years, the free hormone estimations may totally replace the total hormone assays 178 Part 2: Laboratory Investigations Fig 16.3: Development of the TSH assays C Serum Thyrotropin Assay Interpretations Principle and Methodologies: Thyrotropin (TSH) estimation has shown tremendous developmental strides over the last two decades The earliest TSH assays suffered lack of both sensitivity as well as specificity Therefore, falsely elevated TSH levels, due to cross reaction with HCG or FSH and LH, were observed in conditions like pregnancy or postmenopausal states Further, the sensitivity of these assays was higher than the lower limit of normal range and, hence, could not be used for the diagnosis of hyperthyroidism These problems have been solved by the use of highly specific monoclonal antibodies and by immunoradiometric assay (IRMA) The latest TSH assays, popularly called “sensitive TSH assays” or “third generation TSH assays” have sensitivity extending much below the lower limit of normal range (Fig 16.3) and are claimed to have absolute specificity to TSH only These assays have opened the use of TSH estimations to the till now forbidden hyperthyroid state also • Various reports are available emphasizing the application of TSH estimations in hyperthyroidism A new strategy is now developing under which major emphasis is on using TSH as the single primary screening test for all the thyroid disorders including hyperthyroidism The sensitivity of third generation TSH assays for detecting hyperthyroidism has been reported to be as high as 90 to 98% by various workers • The very low or absent TSH in a third generation assay is almost diagnostic of an excess of thyroid hormone levels Further, the low TSH levels in these assays are almost certain signs that the patient will have a suppressed response to TRH, thus obviating the need, in most patients, of performing a TRH stimulation test Note • The test still has to be used with a great degree of caution because falsely suppres- Chapter 16: Hyperthyroidism 179 • • • • sed TSH levels might be observed in a number of clinical conditions The ability of TSH measurement to appropriately assess the thyroid status is, by definition, dependent on the functional and structural integrity of hypothalamic-pituitary axis Rarely, tumours or other lesions of pituitary or hypothalamus may affect TSH feed-back response leading to inappropriate release of TSH Most commonly, disparities between TSH and free T4 levels are related to systemic illnesses, major psychiatric disturbances, acute dopamine or glucocorticoid therapy and pharmacological use of some hormones which may transiently inhibit pituitary TSH secretion Therefore, in such conditions TSH measurement alone might not be enough to provide us with a clear decision In hospitalized euthyroid patients (NTI) again the low TSH levels might be observed, although the level of depression is much above than that found in hyperthyroidism TSH estimations can also serve as an excellent tool for monitoring the response to antithyroid therapy for hyperthyroidism But during the first few months of therapy, the TSH measurements are of little significance because the hypothalamic-pituitary system takes a long time to stabilize against the new thyroid hormone status The persistence of low TSH for prolonged periods reflect a prolonged recovery from profound TSH suppression or a persistent state of subclinical hyperthyroidism Interpretation • In euthyroid cases, the TSH levels increase within 30 minutes but in hyperthyroidism the response to TRH stimulation is either not observed or is very diminished It must be noted that poor TRH response is also observed in case of treated Graves’ disease because circulating TSH is already increased (Table 16.3) Table 16.3: TRH stimulation test—thyroid and pituitary disorders Pre-TRH TSH • Normal