Articles on Medical Diseases and Conditions

Tag: TSH

  • Neonatal Hypothyroid Screening

    Congenital hypothyroidism occurs in approximately 1 in 6,000 infants (literature range, 1-3/10,000), which makes it about 3 times as common as phenylketonuria (PKU). Approximately 85% of cases are due to thyroid agenesis and 10% are defects of enzymes in thyroid hormone synthesis, so that about 95% of all cases are primary hypothyroidism and 3%-5% are secondary to pituitary or hypothalamic malfunction. Screening tests that have received the most attention include T4, TSH, and reverse T3.

    There is minimal T4 and T3 placental transfer from mother to fetus in utero. At birth, cord blood T4 values range from the upper half of normal to mildly elevated, compared with nonpregnant adult reference values (e.g., cord blood average levels of 11-12 µg/100 ml [142-154 nmol/L] compared with nonpregnant adult average values of about 9 µg/100 ml [116 nmol/L]). The T3-RIA level is about one third to one half of adult levels, the reverse T3level is about 5 times the adult levels, and the TSH has a mean value about twice that of adults but ranges from near zero to nearly 3 times adult upper limits. There is a strong correlation between birth weight and neonatal T4 and TSH values. At birth, premature infants have T4 values averaging one third lower than those of normal birth weight infants (although individual measurements are variable), with the subsequent changes in T4levels between premature and full-term infants remaining roughly parallel for several days. The TSH value at birth is also about one third lower in premature than in full-term infants but becomes fairly close to full-term infant levels at 24 hours of age.

    After birth, the TSH value surge about 5-7 times birth values to a peak at 30 minutes, then falls swiftly to levels about double birth values at 24 hours. The fall continues much more slowly to values about equal to those at birth by 48 hours and values about one half of birth levels at 4-5 days. After birth, the T4 level increases about 30%-40%, with a plateau at 24-48 hours, and returns to birth levels by about 5 days. The TBG value does not change appreciably.

    There is some disagreement in the literature regarding the best specimen to use for neonatal screening (heel puncture blood spot on filter paper vs. cord blood) and the best test to use (T4 vs. TSH assay). Most screening programs use filter paper methods because cord blood is more difficult to obtain and transport. Most programs use T4 assay as the primary screening test because T4 assay in general is less expensive than TSH assay, because TSH is more likely to become falsely negative when the specimen is subjected to adverse conditions during storage and transport, and because TSH assay values will not be elevated in the 10% of cases that are due to pituitary or hypothalamic dysfunction. Disadvantages of T4 assay include occasional mildly hypothyroid infants with T4 levels in the lower portion of the reference range but with clearly elevated TSH values. In one series this pattern occurred in 2 of 15 hypothyroid infants (13%). Some institutions therefore retest all infants whose T4 values fall in the lower 10% of the reference range. Another problem concerns approximately 20% of neonatal T4 results in the hypothyroid range that prove to be false positive (not hypothyroid), most of which are due to prematurity or decreased TBG.

    In conclusion, the box lists conditions that can produce various T4 (TI or FT4) and TSH patterns.

    Interpretation of T4 and TSH Patterns*

    T4 Low, TSH Low
    Lab error (T4 or TSH)
    Some patients with severe non thyroid illness (esp. acute trauma, dopamine, or glucocorticoid drugs)†
    Pituitary insufficiency
    Cushing’s syndrome (and some patients on high-dose glucocorticoid therapy)
    T3 toxicosis plus dilantin therapy or severe TBG deficiency
    T4 Low, TSH Normal
    Lab error (T4 or TSH)
    Severe nonthyroid illness*
    Severe TBG or albumin deficiency
    Dilantin, valproic acid (Depakene) or high-dose salicylate therapy)
    Moderate iodine deficiency
    Furosemide combined with decreased albumin or TBG
    Few patients with secondary hypothyroidism (mild TSH decrease in patient with previous TSH in upper-normal range)
    Pregnancy in third trimester (many, not all, FT4 kits)
    Some female distance runners in training
    Some patients with mild hypothyroidism plus prolonged fasting or severe non thyroid illness
    Heparin effect (some FT4 kits)
    T4 Low, TSH Elevated
    Lab error (T4 or TSH)
    Primary hypothyroidism
    Some patients with severe non thyroid illness in recovery phase†
    Large doses of inorganic iodide (e.g., SSKI)
    Some patients on lithium or amiodarone therapy
    Some patients on Synthroid therapy with slightly insufficient dose or patient noncompliance
    Some patients on dilantin or high-dose salicylate therapy or with severe TBG deficiency plus some non-hypothyroid cause for elevated TSH
    “T4 low-TSH normal” conditions plus presence of antibodies interfering with TSH assay§
    Severe iodine deficiency
    Some patients (30%) with Addison’s
    Disease interleukin-2 therapy (15%-26% of cases)
    Alpha-interferon therapy (1.2% of cases)
    T4 Normal, TSH Low
    Lab error (T4 or TSH)
    T3 toxicosis
    Mild hyperthyroidism plus decreased TBG, Dilantin therapy, and/or severe non thyroid illness
    Early hyperthyroidism (TSH mildly decreased, T4 upper normal [Free T3 may be elevated])
    Pituitary insufficiency plus increased TBG
    Some patients with Synthroid therapy in slightly excess dose
    Few patients with severe non thyroid illness†
    Some patients 4-6 weeks (2 weeks-2 yrs) after RAI, surgery, or antithyroid drug therapy for hyperthyroidism
    Some patients with multinodular goiter containing areas of autonomy
    “T4 low-TSH low” plus heparin therapy
    T4 Normal, TSH Normal
    Normal thyroid function
    Lab error (T4 or TSH)
    Few patients with early hypothyroidism (only the TRH test abnormal)
    “T4 low-TSH normal” plus heparin therapy†
    T4 Normal, TSH Elevated
    Lab error (T4 or TSH)
    Mild hypothyroidism
    Hypothyroidism plus increased TBG
    Hypothyroidism with slightly inadequate dose of replacement therapy
    Addison’s disease (majority of cases)
    TSH specimen drawn in the evening (peak of diurnal variation)
    Few patients with iodine deficiency (T4 is usually decreased)
    Few patients with severe non thyroid illness in recovery phase†
    Some patients with mild Hashimoto’s disease
    Insufficient time after start of therapy for hypothyroidism; usually need 3-6 weeks (range, 1-8 weeks, sometimes longer when pre-therapy TSH is over 100)
    “T4 normal-TSH normal” status plus antibodies interfering with TSH assay§
    Some patient on lithium therapy (T4 usually but not always decreased)
    Few patients with acute psychiatric illness
    Hypothyroidism with familial dysalbuminemic hyperthyroxinemia
    “T4 low-TSH elevated” plus heparin therapy†
    T4 Elevated, TSH Low
    Lab error (T4 or TSH)
    Primary hyperthyroidism
    Excess therapy of hypothyroidism
    Some patients with active thyroiditis (subacute, painless, early active Hashimoto’s disease)
    Jod-Basedow hyperthyroidism
    TSH drawn 2-4 hours after Synthroid dose (few patients)
    Postpartum transient toxicosis
    Factitious hyperthyroidism
    Struma ovarii
    Hyperemesis gravidarum
    Alpha-interferon therapy (1.2% of cases)
    Interleukin-2 therapy (3%-6% of cases)
    T4 Elevated, TSH Normal
    Lab error (T4 or TSH)
    TBG increased
    Some patients with Synthroid therapy in adequate dose
    Occasional patient with severe nonthyroid illness†
    Some acute psychiatric patients (esp. paranoid schizophrenics)
    T4 sample drawn 2-4 hours after T4 dose
    Peripheral resistance to T4 syndrome (some patients)
    Some patients with pituitary TSH-secreting tumor (when pretumor TSH was low normal)
    Some patients on amiodarone therapy
    Occasional patients on propranolol therapy
    Certain x-ray contrast media‡
    Acute porphyria
    Heroin abuse or acute hepatitis B (causing increased TBG)
    Heparin effect (some FT4 kits)
    Familial dysalbuminemic hyperthyroxinemia (analog FT4 methods)
    Amphetamine or PCP abuse (some patients)
    Desipramine drugs (some patients)
    T4 Elevated, TSH Elevated
    Lab error (T4 or TSH)
    Pituitary TSH-secreting tumor
    Some patients with certain x-ray contrast media‡
    Peripheral resistance to T4 syndrome (some patients)
    Some patients on amiodarone therapy or amphetamines
    “TSH elevated-T4 normal” status plus some independent reason for T4 to become elevated
    Few patients with acute psychiatric illness
    ________________________________________________________________
    *High-sensitivity TSH method is assumed; FT4 or TI can be substituted for T4, but in general are not altered as frequently as T4 in nonthyroid conditions.
    †Depends on individual TSH and/or FT4 kit.
    ‡Telepaque (iopanoic acid) and Oragrafin (ipodate).
    §Some (not all) sandwich-method double-antibody kits, using mouse-derived monoclonal antibody.

  • Thyroid Function Tests: Thyroid stimulation and suppression tests

    Thyrotropin stimulation test. In some patients with myxedema, the question arises as to whether the etiology is primary thyroid disease or a malfunction secondary to pituitary deficiency. Normally, administration of TSH more than doubles a baseline RAIU or T4 value. Failure of the thyroid to respond to TSH stimulation strongly suggests primary thyroid failure, whereas normal gland response implies either a pituitary or hypothalamic problem or else some artifactual abnormality in the original screening tests. The same procedure can be used to confirm the diagnosis of primary hypothyroidism, since the thyroid should not be able to respond to TSH. The test may be helpful in patients who have been on long-term thyroid hormone treatment and who must be reevaluated as to whether the original diagnosis of hypothyroidism was correct. The TSH stimulation test can be done while thyroid hormone is still being administered, whereas it would take several weeks after cessation of long-term therapy for the pituitary-thyroid relationship to reach pretherapy equilibrium. An occasional use for TSH stimulation is to see whether parts of the thyroid that are not functioning on a thyroid scan are capable of function (versus being not capable of function or being suppressed by hypersecretion from other thyroid areas).

    Drawbacks. The TSH stimulation test is performed using bovine TSH. Some persons form antibodies against this material that may interfere with future TSH assay or produce allergic reaction if TSH is used again. Therefore, the test is infrequently used today. To avoid this potential problem, some investigators use a T3 withdrawal test rather than TSH stimulation. A potential problem using RAIU in TSH stimulation tests is some correlation of patient iodine status to degree of RAIU response to TSH. In general, as iodine deprivation increases, RAIU response also increases; iodine overload decreases the RAIU response.

    Triiodothyronine withdrawal test. The patient is placed on T3 therapy for 1 month (instead of other therapy). The T3 is then discontinued for 10 days, after which a serum TSH assay is performed. With medication containing T4 it is necessary to wait at least 4 weeks after withdrawal before routine thyroid function tests (T4, T3, TSH), are performed to allow the thyroid-pituitary-hypothalamic feedback system to regain normal equilibrium. After T3 withdrawal, it takes only 10 days to achieve the same effect. If the patient has primary hypothyroidism, the serum TSH level will be elevated after 10 days without T3. In euthyroid persons or those with secondary and tertiary hypothyroidism, the TSH level will be normal or decreased. The major drawbacks to this procedure are the long time intervals necessary and the fact that not enough experience with this test has been reported to ascertain how many exceptions or false results may be expected. This test also is rarely used today.

    Thyroid suppression test. This is frequently called “T3 suppression,” although T4 could be used instead of T3, and the pituitary rather than the thyroid is the actual organ directly suppressed by T3 administration (the thyroid is affected secondarily). A standard dose of T3 is given daily for 1 week. In normal persons, exogenous T3 (added to the patient’s own T4) suppresses pituitary secretion of TSH, leading to a decrease in patient thyroid hormone manufacture. Values of RAIU or T4 after T3 administration drop to less than 50% of baseline. In hyperthyroidism, the thyroid is autonomous and continues to manufacture hormone (with little change in RAIU or T4 level), although the pituitary is no longer stimulating the thyroid. The suppression test is thought to be very reliable in confirming borderline hyperthyroidism, although there are reports that 25% or more of patients with nontoxic nodular goiter may fail to show suppression. The same basic technique may be used in conjunction with the thyroid scan to demonstrate that a nodule seen on original scan is autonomous. This may be helpful, since reports indicate that 50%-80% of toxic nodular goiter patients have normal RAIU values and many have normal T4 test results. The procedure must be used with caution in elderly persons or patients with cardiac disease. The T3 suppression test has been largely replaced by the TRH test.

  • Thyroid Function Tests: Serum thyrotropin assay (TSH)

    Thyrotropin previously was known as thyroid stimulating hormone (TSH), and the abbreviation TSH is still used. Direct assay of TSH is now possible with commercially available kits that are as easy to use as those for T4 assay. Thyrotropin has a diurnal variation of 2 to 3 times baseline (literature range, 33%-600%), with highest levels occurring at about 10-11 P.M. (range, 6 P.M.-2 A.M.) and lowest levels at about 10A.M. (range, 8 A.M.-4 P.M.).

    Results in thyroid disease. Serum TSH levels are elevated in about 95% of patients with myxedema due to primary thyroid disease, which comprises 95%-96% of hypothyroid patients. Serum TSH levels are low in most cases of secondary (pituitary or hypothalamic) myxedema (about 4% of hypothyroid patients). Some patients with secondary hypothyroidism have normal TSH values when one would expect low TSH levels. The pituitary of these patients is able to secrete a small amount of TSH, not enough to maintain normal T4 levels but enough to leave TSH values within reference range. The T3-RIA values in these patients may be decreased; but in some instances may be low normal, either because of preferential secretion of T3 rather than T4 by subnormal TSH stimulation or because of problems with kit sensitivity in low ranges. In primary hyperthyroidism, serum TSH is decreased; the percentage of patients with decreased values depends on the sensitivity of the particular kit used. Before 1985, most commercially available kits were poorly sensitive in the lower part of their range, and could not easily differentiate low values from zero or from lowormal values. Theoretically, in typical cases of hyperthyroidism the excess thyroid hormone produced causes the pituitary to completely stop production of TSH, reducing serum TSH to zero. The closer a TSH assay can approach zero in detecting TSH, the better it can differentiate between hyperthyroidism and certain other causes for decreased serum TSH (which usually produces a serum TSH value somewhere between lower reference limit and zero). Some nonhyperthyroid etiologies include partial pituitary insufficiency, early or mild hyperthyroidism in some patients, severe non thyroid illness in some patients (depending on the particular TSH assay kit), monitoring thyroid suppressive therapy, and dopamine or high-dose glucocorticoid therapy in some patients.

    Therefore, about 1985, many manufacturers had begun modifying their TSH kits so as to increase sensitivity at the lower end of the TSH assay range in order to differentiate lesser decreases of TSH (less likely due to hyperthyroidism) from marked decreases (more likely due to hyperthyroidism). Manufacturers called the new TSH kits “high-sensitivity,” “ultra sensitive,” or “first, second, and third generation.” Unfortunately, these terms were used in different ways, the two most common being the theoretical lower limit the assay might achieve under the best experimental conditions and the “functional” lower limit the assay usually did achieve with a between-assay coefficient of variation less than 20%. Based on the most common usage in the literature, the theoretical lower limit of detection for first-generation assays could detect TSH as low as 0.3-0.1 mU/L (µU/ml); but their functional lower limit usually was no better than 0.3, frequently was no better than 0.5, and sometimes was 0.6-1.0. Second-generation assays theoretically can detect between 0.1-0.01 mU/L. Most have a functional lower limit between 0.07-0.04 mU/L. Generally, a functional ability to detect less than 0.1 mU/L qualifies the assay for second-generation or high-sensitivity (ultra sensitive) status. In the 1990s, a few third generation kits have been reported; these have a theoretical lower limit of detection between 0.01-0.005 mU/L and functional detection at least below 0.01 mU/L.

    Drawbacks. Evaluations in the literature and my own experience have shown that not all TSH kits (either “standard” or ultra sensitive) perform equally well. Moreover, laboratory error may produce false normal or abnormal results. In addition, there are conditions other than hypothyroidism or hyperthyroidism that can increase TSH values or decrease TSH values (see box 1 and box 2).

    Conditions That Increase Serum Thyroid-Stimulating Hormone Values

    Lab error
    Primary hypothyroidism
    Synthroid therapy with insufficient dose; some patients
    Lithium or amiodarone; some patients
    Hashimoto’s thyroiditis in later stage; some patients
    Large doses of inorganic iodide (e.g., SSKI)
    Severe non thyroid illness in recovery phase; some patients
    Iodine deficiency (moderate or severe)
    Addison’s disease
    TSH specimen drawn in evening (peak of diurnal variation)
    Pituitary TSH-secreting tumor
    Therapy of hypothyroidism (3-6 weeks after beginning therapy [range, 1-8 weeks]; sometimes longer when pretherapy TSH is over 100 µU/ml); some patients
    Acute psychiatric illness; few patients
    Peripheral resistance to T4 syndrome; some patients
    Antibodies (e.g., HAMA) interfering with monoclonal sandwich method of TSH assay
    Telepaque (Iopanic acid) and Oragrafin (Ipodate) x-ray contrast media; some patients
    Amphetamines; some patients
    High altitudes; some patients

    Conditions That Decrease Serum Thyroid-Stimulating Hormone Values*

    Lab error
    T4/T3 toxicosis (diffuse or nodular etiology)
    Excessive therapy for hypothyroidism
    Active thyroiditis (subacute, painless, or early active Hashimoto’s disease); some patients
    Multinodular goiter containing areas of autonomy; some patients
    Severe non thyroid illness (esp. acute trauma, dopamine or glucocorticoid); some patients
    T3 toxicosis
    Pituitary insufficiency
    Cushing’s syndrome (and some patients on high-dose glucocorticoid)
    Jod-Basedow (iodine-induced) hyperthyroidism
    TSH drawn 2-4 hours after Synthroid dose; few patients
    Postpartem transient toxicosis
    Factitious hyerthyroidism
    Struma ovarii
    Radioimmunoassay, surgery, or antithyroid drug therapy for hyperthyroidism; some patients, 4-6 weeks (range, 2 weeks-2 years) after the treatment
    Interleukin-2 drugs (3%-6% of cases) or alpha-interferon therapy (1% of cases)
    Hyperemesis gravidarum
    Amiodarone therapy; some patients
    __________________________________________________
    *High sensitivity TSH method is assumed.

    Some cases of elevated free T4 levels accompanied by TSH values that were inappropriately elevated (above the lower third of the TSH reference range) rather than depressed have been reported. These cases have been due to TSH-producing pituitary tumors, defective pituitary response to thyroid hormone levels, or peripheral tissue resistance to the effects of thyroid hormone (laboratory error in T4 or TSH assay also must be excluded). Some (a minority) of the current TSH kits (predominantly the solid-phase double-antibody technique) may cross-react with hCG if hCG is present in very large amounts. These TSH kits will indicate varying degrees of (false) TSH increase during pregnancy and in the rare syndrome of hyperthyroidism due to massive hCG production by a hydatidiform mole or choriocarcinoma. Likewise, some of the double-antibody kits using the “sandwich” technique with one or both of the antibodies being the monoclonal type may become falsely elevated due to interference by a heterophil-type antibody in the patient serum that reacts with mouse-derived antibodies. This occurs because monoclonal antibodies are usually produced by a fused (hybrid) cell containing a mouse spleen cell that produces the antibody combined with a myeloma tumor cell that reproduces the hybrid for long periods of time. These human antimouse antibodies (HAMAs) usually occur without known cause and in one study were found in 9% of blood donors. Some manufacturers have attempted to counteract or neutralize the effect of these antibodies, with a variable degree of success. Another antibody problem of a different type concerns artifactual interference in TSH assay procedure by anti-TSH antibodies in patients who had previous TSH injections and who developed antibodies against the injected material.

    In severe non thyroid illness, it was soon noticed that a considerable number of the “ultra sensitive” TSH kits produced some abnormal results in clinically euthyroid patients. Previous “standard” TSH kits, although less sensitive in the lower range, generally produced normal TSH values in severe non thyroid illness. The percentage of abnormal results in the ultra sensitive kits varies between different kits. Most abnormality is reported in severe non thyroid illness, and is manifested by decreased TSH in about 15% of cases (range, 0%-72%) and elevated TSH in about 7% of cases (range, 0%-17%). When decreased in true hyperthyroidism, TSH usually is zero; whereas in non thyroid illness it is usually not that low (first generation TSH assays cannot make this distinction). Of those elevated, most (but not all) were less than twice the upper limit of the reference range. The decreased values return toward normal as the patient recovers; in some reports, most of the elevated values occurred in the recovery phase. This has been interpreted as pituitary inhibition during the acute phase of the illness and release of inhibition in the recovery phase

    There is some controversy whether or not elevated TSH levels in some of these conditions (except adrenal insufficiency and heterophil or anti-TSH antibodies) represent a mild hypothyroid state with the pituitary forced to secrete more TSH to maintain clinical euthyroidism. The serum TSH level in primary hypothyroidism is usually elevated to values more than twice normal and frequently to more than 3 times normal, whereas TSH levels in the other conditions frequently are less than twice normal and in most cases are less than 3 times normal.