Diagnosis of Hypothyroidism
	In contrast to the great variety in clinical presentation and causes of hypothyroidism, there are only two diagnostic strategies. Either hypothyroidism is deliberately screened for by systematic biological testing or, clinical diagnosis being evident, laboratory tests are merely confirmatory. One of the features of the diagnostic process of hypothyroidism is that sensitivity and specificity of the assays of thyroid hormone and of TSH are very high while those of the clinical manifestations are low. This, obviously, favors increasing reliance on near- systematic laboratory thyroid testing, but it does not help refining the diagnostic significance of the signs and symptoms. An other misleading clinical peculiarity in the spontaneous cases of hypothyroidism is the remarkably slow progressivity of the clinical manifestations so that the patients and their family and colleagues remain unaware of the disease for long periods of time. Neonatal screening is the typical example of a systematic dignostic strategy efficient both at the detection and therapeutic levels. The same screening-type approach prevails in situations in which presence or occurrence of hypothyroidism is not unlikely, for instance hypothalamic or pituitary disorders, or a diffuse goiter even more typical of autoimmune thyroiditis if firm, associated with vitiligo or other personal or family history of autoimmune diseases. Iatrogenic hypothyroidism should be looked for systematically, even using recall programms for those patients who had a radical treatment for Graves' hyperthyroidism. Systematic laboratory thyroid testing in selected adult populations - for instance elderly subjects or psychiatric patients - has been studied with various cost-effectiveness results. Serum T4 concentration may be measured by several types of competitive protein binding assays using thyroxine binding protein (TBG) or anti-T4 antibodies. These procedures measure total serum T4 concentration. Because 99.97% of the circulating T4 is bound to TBG, transthyretin and albumin, total T4 concentration is affected by alterations in binding proteins. Therefore various methods have been devised to estimate indirectly or directly the unbound (free) fraction of T4. Free T4 index corrects total T4 with an estimate of the residual TBG capacity. T4/TBG ratio has the same significance. Both methods require two different assays to be performed. Current free T4 radioimmunoassays are both simpler and faster and most are of good sensitivity for the detection of hypothyroidism. Determination of serum T3 concentration, either total or free, is useless for the diagnosis of hypothyroidism because T3 tends to fall later than T4 in patients developing thyroid failure, and may be even elevated in early hypothyroidism. The assay of Serum TSH provides an exquisitely sensitive marker of primary hypothyroidism. Moreover, the combination of elevated TSH and decreased free T4 is diagnostic of primary hypothyroidism. However, this combination may be observed in patients with non-thyroidal illnesses (NTI). The frequency of decreased free T4 in NTI depends partly on the assay method used which is variably affected by the alterations in serum binding protein concentrations or the inhibition of hormone binding to transport proteins in sick patients. Informations on this point are to be provided by the manufacturers of the assay kits. About 5 % of the patients admitted to the hospital for NTI have elevated TSH. In few instances, values may be > 20 ľU/ml. The relationship between serum TSH and free T4 is often altered in NTI or psychiatric disorders. The observation of a slightly elevated TSH and a normal free T4 is typical of NTI. Thyroid test abnormalities due to NTI are reversible with recovery from the causal illness. Therefore, the rule is to retest TSH and free T4 after the acute phase of the disease before considering the diagnosis of thyroid insufficiency. Some treatments, such as dopamine infusion or high dose glucocorticoid therapy may blunt serum TSH so that primary hypothyroidism might present transiently with normal TSH and with low free T4. The combination of a moderately elevated TSH (< 25 ľU/ml) with a normal free T4 defines subclinical hypothyroidism, a common condition which eventually may evolve towards overt hypothyroidism especially in persons with anti-thyroid antibodies. The differential diagnosis of elevated serum TSH includes assay interferences with heterophilic anti-TSH antibodies or the exceptional anti-TSH autoantibodies, an effect of therapy with metoclopramide or domperidone and TSH- secreting pituitary adenoma and the thyroid hormone resistance syndrome. Central hypothyroidism is characterized by the combination of decreased free T4 and decreased TSH. However, TSH may be normal or, rarely, moderately elevated, due to decreased biological activity of the TSH molecule. The TRH test is no longer useful for the diagnosis of primary hypothyroidism. As far as central hypothyroidism is concerned, the TRH test does not distinguish reliably between hypothalamic and pituitary hypothyroidism. The test may contribute to assess the bioactivity of endogenous TSH. The lack of a 30-100% increase in serum T3, 120-180 min after an i.v. injection of 200 mg of TRH is indicative of central hypothyroidism (provided primary hypothyroidism has been excluded), and of the secretion of bio-inactive TSH if concomitant immunoreactive TSH is normal or elevated. Highly specific and sensitive asays are available for anti-TPO and anti-TG antibodies. More than 90 % of patients with autoimmune thyroiditis have anti-thyroid antibodies, especially anti-TPO. Anti-TPO antibodies are detectable in apparently normal people; their prevalence is 0-5 % in subjects less than 60 and increases to 15-20 % in women over 60 years of age; titers are usually in the low or medium range. Elevated titers (> 1000 u/ml) are indicative of a risk of thyroid dysfunction. Anti-TPO antibodies have a strong predictive value for hypothyroidism (odds ratio 1 : 38) in subjects with subclinical hypothyroidism. The presence of anti-TPO-antibodies before or at the beginning of pregnancy is a significant risk factor for postpartum thyroiditis. The assay of anti-TSH receptor antibodies is useful in pregnant women with atrophic primary hypothyroidism. Strong positivity is indicative for a risk of fetal and neo-natal transient hypothyroidism due to blocking anti-TSH receptor antibodies. Antibodies should also be assayed in the hypothyroid neonate whenever the thyroid is normally located. Newborn screening for congenital hypothyroidism is based on T4 and/or TSH measurement on a dried blood spot sample collected 3-5 days after birth. In the T4 measurement-based programs, TSH is assayed in samples with T4 values in the lowest 5-10 %. The TSH cut-off value is 20-40 mU/l. Prompt clinical and biological evaluation of the infants positively screened is mandatory. The diagnosis of congenital hypothyroidism is confirmed by measurements of T4 and TSH serum concentrations. In order to delineate the cause of the disease, complementary thyroid work-up includes thyroid scintiscan, measurement of thyroid uptake of technetium or 123I, thyroid ultrasound and serum thyroglobulin determination; bone age should also be measured. Suspicion of inherited disorders of thyroid function requires a series of specialized biological tests to be programmed in a logical order. In some cases, study of thyroid tissue fragments is appropriate. In vivo measurements include thyroid uptake of iodine, perchlorate discharge test and determination of iodotyrosine dehalogenase activity. Concentration and structure evaluation of circulating and intrathyroidal thyroglobulin is useful. Iodinating and H2O2 production capacities of fresh thyroid tissue can be measured in vitro. The gene or the cDNA coding for the TSH-b subunit, TSH receptor, Gsa, thyroglobulin, thyroperoxidase, the Na+/I- symporter, the thyroid hormone receptor(s) and, possibly, pituitary or thyroid transcription factors, might be tested for abnormalities, as suggested by clinical and biological data. Finally, various tests are available as markers of thyroid hormone action on tissues and functions. Except for TSH, none is sensitive and specific enough to stand as a "thyroid test”. They have to be interpreted against the thyroid hormone and TSH levels as well as the clinical picture of the patient. A non-exhaustive list includes for the a) heart: the resting pulse, cardiac time intervals (PEP/LVET) and the QKd interval (msec); b) bone: bone age, bone mineral density, osteocalcin, pyridinolin and deoxipyridinolin; c) liver: sex hormone binding globulin, blood lipids, ferritin; d) muscles: ankle reflex time, creatine kinase, myoglobin; e) basal metabolic rate.