Specialized Thyroid Tests
A number of specialized tests are available for the evaluation of specific aspects of thyroid hormone biosynthesis, secretion, turnover, distribution, and absorption. Their primary application is of investigative nature. They are only briefly mentioned here for the sake of completeness.
The test involves the intravenous administration of tracer MIT or DIT labeled with radioiodide. Urine, collected over a period of four hours, is analyzed by chromatography or resin column separation. Normally, only 4-8% of the radioactivity is excreted as such; the remainder appears in the urine in the form of iodide.480 Excretion of larger amounts of the parent compound indicates inability to deiodinate iodotyrosine. The test is useful in the diagnosis of a dehalogenase defect (see Chapter 16).
After administration of RAI, the isotopically labeled compounds synthesized in the thyroid gland and those secreted into the circulation can be analyzed by immunologic, chromatographic, electrophoretic, and density gradient centrifugation techniques.481 Such tests serve to evaluate the synthesis and release of thyroid hormone, as well as to delineate the formation of abnormal iodoproteins.
The iodine kinetic procedure is used to evaluate overall iodide metabolism and to elucidate the pathophysiology of thyroid diseases. The analysis involves follow-up of the fate of administered radioiodide tracer by measurement of thyroidal accumulation, secretion into blood, and excretion in the urine and feces.482 Double tracer techniques and programs for computer-assisted analysis of data are available.
Failure to achieve normal serum thyroid hormone concentration after administration of replacement doses of thyroid hormone is usually due to poor compliance, occasionally to the use of inactive preparations, and rarely, if ever, to malabsorption. The last can be evaluated by the simultaneous oral and intravenous administration of the hormone labeled with two different iodine isotope tracers. The ratio of the two isotopes in blood is proportional to the net absorbed fraction of the orally administered hormone.483,484 Under normal circumstances, approximately 80% of T4 and 95% of T3 administered orally are absorbed. Hypothyroidism and a variety of other unrelated conditions have little effect on the intestinal absorption of thyroid hormones. Absorption may be diminished in patients with steatorrhea, in some cases of hepatic failure, during treatment with cholestyramine, and with diets rich in soybeans. The absorption of thyroid hormone can also be evaluated by the administration of a single oral dose of 100 µg T3 or 1 mg T4, followed by their measurement in blood sampled at various intervals.485,486
Turnover kinetic studies require the intravenous administration of isotope-labeled tracer T4 or T3.487-491 The half-time (t1/2) of disappearance of the hormone is calculated from the rate of decrease in serum trichloroacetic acid precipitable, ethanol extractable, or antibody precipitable isotope counts. Compartmental analysis can be used for the calculation of the turnover parameters.488,489 The calculated daily degradation (D) or production rate (PR) is the product of the fractional turnover rate (K), the extrathyroidal distribution space (DS), and the average concentration of the hormone in serum. Noncompartmental analysis may be used for the calculation of kinetic parameters.488 The metabolic clearance rate (MCR) is defined as the dose of the injected labeled tracer divided by the area under its curve of disappearance. The PR is then calculated from the product of the MCR and the average concentration of the respective nonradioactive iodothyronine measured in serum over the period of the study. Simultaneous studies of the T4 and T3 turnover kinetics can be carried out by injection of both hormones, labeled with different iodine isotopes.488,490,491
Average normal values in adults for T4 and T3, respectively, are: t1/2 = 7.0 and 0.8 days; K = 10% and 90% per day; DS = 11 and 30 liters of serum equivalent; MCR = 1.1 and 25 liters/day; and PR = 90 and 25 µg/day.
The hormonal PR is accelerated in thyrotoxicosis and diminished in hypothyroidism. In euthyroid patients with TBG abnormalities, the PR remains normal, since changes in the serum hormone concentration are accompanied by compensatory changes in the fractional turnover rate and the extrathyroidal hormonal pool.492 A variety of nonthyroidal illnesses may alter hormone kinetics491,493 (see Chapter 5).
The kinetics of production of various metabolites of T4 and T3 in peripheral tissues and their further metabolism can be studied. Most methods use radiolabeled iodothyronine tracers injected intravenously.489-491 Their disappearance is followed in serum samples obtained at various intervals of time after injection of the tracers by means of chromatographic and immunologic techniques of separation. Kinetic parameters can be calculated by noncompartmental analysis or by two or multiple compartment analysis. Estimates have been made by the differential measurement in urine of the isotopes derived from the precursor and its metabolite. They are in agreement with measurements carried out in serum.494 Conversion rates (CR) of iodothyronines, principally generated in peripheral tissues, can be calculated from the ratio of their PR, and that of their respective precursors. Some iodothyronines, such as T3, are secreted by the thyroid gland as well as generated in peripheral tissues. Studies to calculate the CR require administration of thyroid hormone to block thyroidal secretion.493
On the average 35% and 45% of T4 are converted to T3 and rT3, respectively, in peripheral tissues. The conversion of T4 to T3 is greatly diminished in a variety of illnesses (see Chapter 5) of nonthyroidal origin and in response to many drugs (Table 5-3). Degradation and monodeiodination of iodothyronines can be estimated without the administration of isotopes. They are, however, less accurate. The conversion of T4 to T3 can be estimated semiquantitatively by the measurement of serum TT3 concentration after treatment with replacement doses of T4.493
The metabolism and PRs of a variety of compounds related to thyroid physiology can be studied using their radiolabeled congeners and application of the general principles of turnover kinetics. Studies of TSH have demonstrated changes related not only to thyroid dysfunction but also associated with age, kidney, and liver disease.495,496 Studies of the turnover kinetics of TBG have shown that the slight increases and decreases of serum TBG concentration associated with hypothyroidism and thyrotoxicosis, respectively, are due to changes in the degradation rate of TBG rather than synthesis.492
Transfer of hormone from blood to tissues can be estimated in vivo by two techniques. A direct method follows the accumulation of the administered labeled hormone tracer by surface counting over the organ of interest.497 An indirect method follows the early disappearance from plasma of the simultaneously administered hormone and albumin, labeled with different radioisotope tracers.498 The difference between the rates of disappearance of the hormone and albumin represents the fraction of hormone that has left the vascular (albumin) space and presumably has entered the tissues.