This rare syndrome occurs in older children and in adults. It is manifested by virilism in females and by excessive masculinization in males. It may be due to idiopathic adrenal cortex hyperplasia, adrenal cortex adenoma, or cortex carcinoma. Tumor is more common than hyperplasia in these patients. Virilism in a female child or adult leads to hirsutism, clitoral enlargement, deepening of the voice, masculine contour, and breast atrophy. The syndrome may be simulated in females by idiopathic hirsutism, arrhenoblastoma of the ovary, and possibly by the Stein-Leventhal syndrome. Urinary 17-KS values are elevated with normal or decreased 17-OHCS values when the adrenal is involved. Ovarian arrhenoblastoma gives normal or only slightly elevated urine 17-KS values, since androgen is produced in smaller quantities but is more potent, thus giving clinical symptoms without greatly increased quantities. In prepubertal boys, the symptoms of virilism are those of precocious puberty; in men, excessive masculinization is difficult to recognize. A similar picture may be associated with certain testicular tumors.
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Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH), also known as the “adrenogenital syndrome,” is an uncommon condition caused by a congenital defect in one of several enzymes that take part in the chain of reactions whereby cortisol is manufactured from its precursors. There are at least six fairly well-defined variants of CAH that result from the various enzyme defects. The most common of these are types I and II, which are due to C21-hydroxylase enzyme deficiency. All CAH variants are inherited as autosomal recessive traits. The clinical and laboratory findings depend on which metabolic pathway—and which precursor in the metabolic pathway— is affected. All variants affect the glucocorticoid (cortisol) pathway in some manner. In CAH due to 21-hydroxylase defect (types I and II) and in CAH type III, although formation of cortisone and cortisol is blocked, the precursors of these glucocorticoids are still being manufactured. Most of the early precursors of cortisone are estrogenic compounds, which also are intermediates in the production of androgens by the adrenal cortex. Normally, the quantitative production of adrenal androgen is small; however, if the steroid precursors pile up (due to block in normal formation of cortisone), some of this excess may be used to form more androgens.
Three things result from these metabolic pathway abnormalities. First, due to abnormally high production of androgen, secondary sexual characteristics are affected. If the condition is manifest in utero, pseudohermaphroditism (masculinization of external genitalia) or ambiguous genitalia occur in girls and macrogenitosomia praecox (accentuation of male genitalia) occurs in boys. If the condition does not become clinically manifest until after birth, virilism (masculinization) develops in girls and precocious puberty in boys. In CAH variants IV, V, and VI there is some degree of interruption of the adrenal androgen pathway, so that the external appearance of the female genitalia is not significantly affected and subsequent virilization is minimal or absent. External genitalia in genotypic boys appear to be female or ambiguous.
Second, the adrenal glands themselves increase in size due to hyperplasia of the steroid-producing adrenal cortex. This results because normal pituitary production of ACTH is controlled by the amount of cortisone and hydrocortisone produced by the adrenal. In all variants of congenital adrenal hyperplasia, cortisone production is partially or completely blocked, the pituitary produces more and more ACTH in attempts to increase cortisone production, and the adrenal cortex tissue becomes hyperplastic under continually increased ACTH stimulation.
Third, when the mineralocorticoid pathway leading to aldosterone is blocked, there are salt-losing crises similar to those of Addison’s disease. This occurs in CAH types II, IV, and VI. On the other hand, hypertension may develop if there is accumulation of a salt-retaining precursor (CAH type III) in the mineralocorticoid pathway or a mineralocorticoid production increase due to block in the other adrenal pathways (CAH type V).
Since 21-hydroxylase deficiency is responsible for more than 90% of the CAH variants and the others are rare, only laboratory data referable to this enzyme defect (CAH types I and II) will be discussed.
The CAH 21-hydroxylase deficiency is brought to the attention of the physician by either abnormalities in newborn external genitalia (CAH types I and II, the most common cause of female pseudohermaphroditism) or salt-losing crises (type II, constituting one third to two thirds of 21-hydroxylase deficiency cases). In later childhood, virilization is the most likely clinical problem. In patients with ambiguous genitalia, a buccal smear and chromosome karyotype establish the correct (genotypic) sex of the infant. In salt-losing crises, the infant is severely dehydrated and may develop shock. The serum sodium level is low and the serum potassium level is high-normal or elevated. For a number of years, the diagnosis was made through elevated urine 17-KS levels (metabolites of androgens) and increased urinary pregnanetriol levels (metabolite of 17-OH-progesterone). However, 17-KS values may normally be 4-5 times as high in the first 2 weeks of life as they are after 4 weeks, and pregnanetriol values may be normal in some neonates with CAH in the first 24-48 hours of life. At present, plasma 17-OH-progesterone is considered the best screening test for neonatal 21-hydroxylase deficiency. After the first 24 hours of life, plasma 17-OH-progesterone is markedly elevated in most patients with CAH type I or II. Also, plasma specimens are easier to obtain in neonates or infants than 24-hour urine collections. However, plasma 17-OH-progesterone may be elevated to some extent by pulmonary and other severe illnesses. Also, because there is diurnal variation, the blood specimen should be drawn in the morning.
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Adrenal Cortex Hormones
This chapter will begin with adrenal cortex hormones and conclude with adrenal medulla hormones. The adrenal medulla produces epinephrine and norepinephrine. The relationships of the principal adrenal cortex hormones, their actions, and their metabolites are shown in Fig. 30-1. The adrenal cortex is divided into three areas. A narrow outer (subcapsular) region is known as the “zona glomerulosa”. It is thought to produce aldosterone. The cortex middle zone, called the “zona fasciculata”, mainly secretes 17-hydroxycortisone, also known as “hydrocortisone” or “cortisol”. This is the principal agent of the cortisone group. A thin inner zone, called the “zona reticularis”, manufactures compounds with androgenic or estrogenic effects. Pathways of synthesis for adrenal cortex hormones are outlined in Fig. 30-2. Production of cortisol is controlled by pituitary secretion of adrenal cortex-stimulating hormone, or adrenocorticotropic hormone (corticotropin; ACTH). The pituitary, in turn, is regulated by a feedback mechanism involving blood levels of cortisol. If the plasma cortisol level is too high, pituitary action is inhibited and ACTH production is decreased. If more cortisol is needed, the pituitary increases ACTH production.
Fig. 30-1 Derivation of principal urinary steroids.
Fig. 30-2 Adrenal cortex steroid synthesis. Important classic alternate pathways are depicted in parentheses, and certain alternate pathways are omitted. Dotted lines indicate pathway that normally continues in another organ, although adrenal capability exists.
Excess or deficiency of any one of adrenal cortex hormones leads to several well-recognized diseases which are diagnosed by assay of the hormone or its metabolites. In diseases of cortisol production, three assay techniques form the backbone of laboratory diagnosis: 17-hydroxycorti-costeroids (17-OHCS), 17-ketosteroids (17-KS), and direct measurement of cortisol. Before the use of these steroid tests in various syndromes is discussed, it is helpful to consider what actually is being measured.
17-Hydroxycorticosteroids
These are C21 compounds that possess a dihydroxyacetone group on carbon number 17 of the steroid nucleus (Fig. 30-3). In the blood, the principal 17-OHCS is hydrocortisone. In urine, the predominating 17-OHCS are tetrahydro metabolites (breakdown products) of hydrocortisone and cortisone. Therefore, measurement of 17-OHCS levels can be used to estimate the level of cortisone and hydrocortisone production. Estrogen therapy (including oral contraceptives) will elevate plasma 17-OHCS values, although degradation of these compounds is delayed and urine 17-OHCS levels are decreased.
Fig. 30-3 Adrenal cortex steroid nomenclature. A, basic 17-OHCS nucleus with standard numerical nomenclature of the carbon atoms. B, configuration of hydrocortisone at the C-17 carbon atom. C, configuration of the 17-KS at the C-17 carbon atom.
17-Ketosteroids
These are C19 compounds with a ketone group on carbon number 17 of the steroid nucleus (see Fig. 30-3). They are measured in urine only. In males, about 25% of 17-KS are composed of metabolites of testosterone. The remainder of 17-KS in males and nearly all 17-KS in females is derived from androgens other than testosterone, although lesser amounts come from early steroid precursors and a small percentage from hydrocortisone breakdown products. Testosterone itself is not a 17-KS. The principal urinary 17-KS is a compound known as dehydroisoandrosterone (dehydroepiandrosterone; DHEA). This compound is formed in the adrenal gland and has a weak androgenic effect. It is not a metabolite of cortisone or hydrocortisone, and therefore 17-KS cannot be expected to mirror or predict levels of hydrocortisone production.
In adrenogenital or virilization syndromes, high levels of 17-KS usually mean congenital adrenal hyperplasia in infants and adrenal tumor in older children and adults. In both conditions, steroid synthesis is abnormally shifted away from cortisone formation toward androgen production. High 17-KS levels are occasionally found in testicular tumors if the tumor produces androgens greatly in excess of normal testicular output. In Cushing’s syndrome, 17-KS production is variable, but adrenal hyperplasia is often associated with mild to moderate elevation, whereas adrenal carcinoma frequently produces moderate or marked elevation in urinary values. In adrenal tumor, most of the increase is due to DHEA.
Low levels of 17-KS are not very important because of normal fluctuation and the degree of inaccuracy in assay. Low levels are usually due to a decrease in DHEA. This may be caused by many factors, but the most important is stress of any type (e.g., trauma, burns, or chronic disease). Therefore, normal 17-KS levels are indirectly a sign of health.
Plasma cortisol
Plasma cortisol, like thyroxine, exists in two forms, bound and unbound. About 75% is bound to an alpha-1 globulin called “transcortin,” about 15% is bound to albumin, and about 10% is unbound (“free”). The bound cortisol is not physiologically active. Increased estrogens (pregnancy or estrogenic oral contraceptives) or hyperthyroidism elevates transcortin (raising total serum cortisol values without affecting free cortisol), whereas increased androgens or hypothyroidism decreases transcortin. In addition, pregnancy increases free cortisol. A marked decrease in serum albumin level can also lower total serum cortisol levels. There is a diurnal variation in cortisol secretion, with values in the evening being about one half those in the morning. Lowest values are found about 11 P.M.
Cortisol test methods. All current widely used assays for serum cortisol measure total cortisol (bound plus free). There are three basic assay techniques: Porter-Silber colorimetric, Mattingly fluorescent, and immunoassay. The Porter-Silber was the most widely used of the older chemical methods. It measures cortisol, cortisone, and compound S (see Fig. 30-2), plus their metabolites. Ketosis and various drugs may interfere. The Mattingly fluorescent procedure is based on fluorescence of certain compounds in acid media at ultraviolet wavelengths. It is more sensitive than the Porter-Silber technique, faster, requires less blood, and measures cortisol and compound B but not compound S. Certain drugs that fluoresce may interfere. Immunoassay has two subgroups, competitive protein binding (CPB) and radioimmunoassay (RIA) or enzyme immunoassay (EIA). The CPB technique is the older of the two. It is based on competition of patient cortisol-like compounds with isotope-labeled cortisol for space on cortisol-binding protein. CPB measures cortisol, cortisone, compound S, and compound B. Advantages are small specimen requirement and less interference by drugs. RIA or EIA is based on competition of patient cortisol with labeled cortisol for anticortisol antibody. The method is nearly specific for cortisol, with less than 20% cross-reaction with compound S. In certain clinical situations, such as congenital adrenal hyperplasia or the metyrapone test, it is important to know what “cortisol” procedure is being performed to interpret the results correctly.
All techniques measure total blood cortisol, so that all will give falsely increased values if increases in cortisol-binding protein levels occur due to estrogens in pregnancy or from birth control pills. Stress, obesity, and severe hepatic or renal disease may falsely increase plasma levels. Androgens and phenytoin (Dilantin) may decrease cortisol-binding protein levels. In situations where cortisol-binding protein levels are increased, urine 17-OHCS or, better, urine free cortisol assay may be helpful, since urine reflects blood levels of active rather than total hormone.
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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
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*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. -
Thyroiditis
The usual classification of thyroiditis includes acute thyroiditis, subacute thyroiditis, chronic thyroiditis, and Riedel’s struma.
Acute thyroiditis is generally defined as acute bacterial infection of the thyroid. Signs, symptoms, and laboratory data are those of acute localized infection.
Riedel’s struma consists of thyroid parenchymal replacement by dense connective tissue. In some cases at least this presumably represents scar tissue from previous thyroiditis. Thyroid function tests are either normal (if sufficient normal thyroid remains) or indicate primary hypothyroidism.
Subacute thyroiditis (granulomatous thyroiditis or de Quervain’s disease) features destruction of thyroid acini with a granulomatous reaction consisting of multinucleated giant cells of the foreign body reaction type and large histiocytes. The etiology is unknown but possibly is viral or autoimmune. The classic syndrome of subacute thyroiditis includes thyroid enlargement (usually less than twice normal size) with pain and tenderness, symptoms of thyrotoxicosis, substantially increased ESR, increased T4, T3-RIA, and THBR (T3U) values, and decreased RAIU values. Thyroid scans demonstrate patchy isotope concentration throughout the thyroid gland (occasionally, only in focal areas) or else very little uptake. Classic cases have been reported to progress through four sequential stages: hyperthyroidism, followed by transient euthyroidism, then hypothyroidism, and then full recovery. Recovery in most cases takes place in 3-5 months. The classic syndrome is estimated to occur in approximately 50%-60% of patients with subacute thyroiditis. Milder or nonclassic cases lack the symptoms and laboratory findings of thyrotoxicosis. However, the ESR is usually elevated, and the RAIU value is usually decreased.
Painless thyroiditis (also called “silent thyroiditis”) describes a group of patients with a syndrome combining some elements of subacute thyroiditis with some aspects of chronic thyroiditis (Hashimoto’s disease). These patients have nonpainful thyroid swelling with or without clinical symptoms of thyrotoxicosis. Laboratory data include increased T4, T3-RIA, and THBR values, decreased RAIU value, patchy thyroid scan, and normal or minimally elevated ESR. Painless thyroiditis thus differs from subacute thyroiditis by lack of pain in the thyroid area and by normal ESR. Although some consider this syndrome to be a painless variant of subacute thyroiditis, biopsies of most cases have disclosed histologic findings of chronic lymphocytic thyroiditis rather than subacute thyroiditis. The reported incidence of this condition has varied from 5%-30% of all cases of hyperthyroidism. However, one report suggests that the incidence varies with geographic location, with the highest rates being in the Great Lakes region of the United States and in Japan.
Postpartum transient toxicosis is a syndrome that is said to occur in as many as 5%-6% (literature range, 5%-11%) of previously euthyroid postpartum women. There is transient symptomatic or asymptomatic thyrotoxicosis with elevated T4 and low RAIU values, similar to the findings in thyrotoxic silent thyroiditis. This episode in some cases is followed by transient hypothyroidism. Thyroid autoantibody titers are elevated, suggesting lymphocytic thyroiditis.
Chronic thyroiditis is characterized histologically by dense lymphocytic infiltration of the thyroid with destruction of varying amounts of thyroid parenchyma. Chronic thyroiditis is frequently divided into two subdivisions: lymphocytic thyroiditis, most frequent in children and young adults, and Hashimoto’s disease, found most often in adults aged 30-50 years. In both cases females are affected much more often than males. In approximately one half of chronic thyroiditis patients, serum T4 levels are normal and the patients are clinically euthyroid. In 20%-40% the T4level is decreased, and there may be variable degrees of hypothyroidism. In some patients with decreased T4 levels the T3-RIA may be normal and presumably is responsible for maintaining clinical euthyroidism. The RAIU value is normal in 30%-50% of cases. In 10%-30% the RAIU value is increased, especially in the early stages of the disease. In fact, an elevated RAIU value with a normal T4 value definitely raises the possibility of active (early) chronic thyroiditis. The ESR is usually normal. Thyroid scan discloses generalized patchy isotope distribution in approximately 50% of cases and focal patchy or reduced uptake in 5%-10% more. In approximately one third of cases various precursors of T4 or abnormal thyroglobulin derivatives are released from damaged thyroid acini. In about 5% of patients with chronic thyroiditis, release of thyroid hormone derivatives produces hyperthyroidism with increased serum T4 levels. The RAIU value may be elevated or decreased. If the RAIU value is decreased, these patients might be considered part of the “thyrotoxic silent thyroiditis” group. On the other hand, some patients with chronic thyroiditis eventually develop sufficient damage to the thyroid to produce permanent hypothyroidism.
Lymphocytic thyroiditis and Hashimoto’s disease are very similar, and some do not differentiate between them. However, in lymphocytic thyroiditis the goiter tends to enlarge more slowly, abnormal iodoproteins tend to appear more often, and the RAIU value tends to be elevated more frequently. Hashimoto’s disease tends to have more histologic evidence of a peculiar eosinophilic change of thyroid acinar epithelial cells called “Askenazi cell transformation.” Exact diagnosis of chronic thyroiditis is important for several reasons: to differentiate the condition from thyroid carcinoma, because a diffusely enlarged thyroid raises the question of possible thyrotoxicosis, and because treatment with thyroid hormone gives excellent results, especially in childhood lymphocytic thyroiditis.
Thyroid autoantibodies. Both subgroups of chronic thyroiditis are now considered to be either due to or associated with an autoimmune disorder directed against thyroid tissue. Autoantibodies against one or another element of thyroid tissue have been detected in most cases. In addition, there is an increased incidence of serologically detectable thyroid autoantibodies in rheumatoid-collagen disease patients, conditions themselves associated with disturbances in the body autoimmune mechanisms. There are two major subgroups of thyroid autoantibodies, those active against thyroglobulin and those directed against the microsome component of thyroid cells. There are several different techniques available to detect these antibodies, including, in order of increasing sensitivity: latex agglutination (antithyroglobulin antibodies only), immunofluorescence, hemagglutination (also known as the tanned [tannic acid-treated] red blood cell [or TRC] test), and radioassay. At present radioimmunoassay and immunofluorescence are not widely available, and most reference laboratories use some modification of the hemagglutination test.
In general, antimicrosomal antibodies are found more often in chronic thyroiditis than antithyroglobulin antibodies. Antithyroglobulin antibodies are found less often in diseases other than chronic thyroiditis, but this increase in specificity is only moderate, and neither test has adequate selectivity for chronic thyroiditis (Table 29-1). High titers are much more likely to be associated with chronic thyroiditis than with nontoxic nodular goiter or thyroid carcinoma. High titers of antimicrosomal antibodies (or both antimicrosomal and antithyroglobulin antibodies) are not specific for chronic thyroiditis, because patients with Graves’ disease or primary hypothyroidism may have either high or low titers. Normal or only slightly elevated titers, however, constitute some evidence against the diagnosis of chronic thyroiditis.
Table 29-1 Thyroid autoantibody test results in thyroid diseases (hemagglutination method)*
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Monitoring of Replacement Therapy
Desiccated thyroid and presumably other T4 and T3 combinations result in T3-RIA values that may become elevated for several hours after administration and then decrease into the reference range. T4 values remain within the reference range if replacement is adequate. In the few instances when clinical evidence and T4 results disagree, TSH assay is helpful. Elevated TSH values suggest insufficient therapy. Unfortunately, low TSH values using standard TSH kits is not a reliable indicator of over treatment since most of these kits produce considerable overlap between normal persons and those with decreased values in the low reference range area. Ultra sensitive TSH kits should solve this problem if the kit is reliable.
L-Thyroxine (Synthroid, Levothroid) results in T3-RIA values that, in athyrotic persons, are approximately two thirds of those expected at a comparable T4 level when thyroid function is normal. This is due to peripheral tissue conversion of T4 to T3. The T3-RIA values are more labile than T4 values and are more affected by residual thyroid function. The standard test to monitor L-thyroxine therapy is the T4 assay. There is disagreement whether T4 values must be in the upper half of the T4 reference range or whether they can be mildly elevated. In general, when the TSH value returns to its reference range, the T4 level stabilizes somewhere between 2 µg above and below the upper limit of the T4 range. T4 elevation more than 2 µg above reference range probably suggests too much dosage. A minority believe that T4 values should not be above the reference range at all. On the other hand, T4 values in the lower half of the reference range are usually associated with elevated TSH levels and probably represent insufficient replacement dose. Some investigators favor T3-RIA to monitor therapy rather than T4 or TSH. The THBR value is most often within reference range with adequate replacement dose but has not been advocated for monitoring therapeutic effect.
One report indicates that dosage requirement decreases after age 65 years.
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Comments Regarding Use of Thyroid Tests
As previously noted, some thyroidologists and laboratorians advocate screening for thyroid disease with a single test, often citing need for cost containment. The ultra sensitive TSH appears to be advantageous for this purpose. The T4 test result is more frequently normal in mild disease and more frequently abnormal in the absence of thyroid disease than is the ultra sensitive TSH. The FT4 test has many of the same problems as the T4 test, although the FT4 is less frequently affected by non thyroid conditions. The major problem with the one-test approach is that the clinician becomes very dependent on the laboratory to select a reliable method or commercial kit. I can verify that not all commercially available kits are equally reliable and that it takes search for published evaluations of the exact manufacturer’s kit under consideration in addition to extensive evaluation of the kit in the potential user’s own laboratory to establish proof of reliability. In addition, each laboratory should establish its own reference range using a statistically satisfactory number (at least 20) of blood donors or other clinically normal persons.
Finally, one has to consider the possibility of laboratory error, even though it may not be frequent on a statistical basis. For these and other reasons, some order two tests rather than one for screening purposes, such as the FT4 plus the ultra sensitive TSH. If both test results are normal, this is very reassuring. If one or both are abnormal, either or both can be repeated to verify abnormality. The diagnosis sometimes can be made with this evidence plus clinical findings, or additional tests may be needed.
Since the T4 (or its variants) and the ultra sensitive TSH are being used extensively to screen for and diagnose thyroid disease, it might be useful to catalog the patterns encountered using these two tests and some of the conditions that produce these patterns (see the box).
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Summary of Laboratory Tests in Hypothyroidism
From the preceding discussion, several conclusions seem warranted:
1. Serum T4 is the most widely used screening test for hypothyroidism, but some physicians use FT4 or serum TSH assay instead. Values in the upper half of the T4 and FT4 reference range are strong evidence against hypothyroidism unless the TBG level is increased (congenital, pregnancy, or estrogen induced).
2. The THBR test is useful to detect TBG-induced alterations in T4.
3. The new FT4 methods circumvent the majority of TBG-induced problems and significantly reduce the number of pseudo hypothyroid cases due to severe non thyroidal illness. However, even the FT4 may give falsely decreased results in seriously ill patients.
4. The TSH assay is the most useful single test to confirm primary hypothyroidism. In occasional patients a TRH test may be necessary.
5. Certain conditions may produce decreased T4 levels, increased TSH levels, or both in occasional patients without primary hypothyroidism. -
False Laboratory Euthyroidism in Hypothyroid Patients
Normal T4 values in a hypothyroid patient may occur in the following conditions:
1. In early or very mild hypothyroidism. Serum TSH values are usually elevated. Some investigators have reported patients in whom the T4 and TSH values were both within reference range, but the TRH test result exhibited an exaggerated response suggestive of hypothyroidism.
2. When the T4 level in a hypothyroid person is artifactually increased into the normal population reference range. This may be due to elevated TBG levels or because the reference range overlaps with values for some patients with mild hypothyroidism. The TSH level should be elevated in most cases, unless the reason for the patient’s hypothyroidism is pituitary insufficiency. -
Pseudohypothyroidism
Pseudo hypothyroidism may be defined as a deceased T4 level in a euthyroid person. This may occur with (1) decreased TBG or TBG binding (congenital or drug induced), (2) certain medications (e.g., phenytoin, lithium, dopamine, corticosteroid), (3) some patients with severe non thyroidal illness, (4) some clinically euthyroid patients with Hashimoto’s thyroiditis, (5) after recent therapy of hyperthyroidism or thyroid cancer with radioactive iodine (some patients eventually develop true hypothyroidism), (5) Cushing’s syndrome, (7) in some patients with SSKI therapy, and (8) severe iodine deficiency.
Most of these conditions have been discussed previously (see the box). The TSH levels are normal when the TBG level is decreased and in most of the drug-induced causes of nonhypothyroid T4 decrease. Cushing’s syndrome is associated with decreased T4, T3-RIA, TSH, and TBG levels in most patients. The TRH test results usually show a blunted TSH response. The TSH level becomes elevated in some (usually a minority) of patients with the remainder of the conditions listed above (also see the box); TSH values are usually (but not always) less than 3 times the upper limit of the reference range and most frequently are less than twice that limit. Decreased T4 levels with elevated TSH levels in thyroiditis and following radioiodine therapy might be considered true hypothyroidism, even if it is only temporary, especially since some of these patients go on to develop clinical as well as laboratory hypothyroidism. Lithium carbonate therapy might be included in pseudo hypothyroidism since the abnormalities it produces are reversible. On the other hand, in some cases of long-term therapy the laboratory abnormalities persist after medication is stopped. About 8%-10% of patients have decreased T4 levels, and about 15% (range, 2.3%-30%) of patients develop some degree of elevated serum TSH levels. This may develop in less than a month or may take several months. In about 5% of patients the clinical as well as laboratory indices are compatible with true myxedema.