Paparella: Volume I: Basic Sciences and Related Principles
Section 8: General Medical Principles
Chapter 37: Endocrinology
Robert H. Maisel, David S. Cross
Since the work of Claude Bernard, it has been axiomatic that the internal environment is maintained in a constant state (Cannon's principle of homeostasis). Throughout the internaland external stresses of normal life, disease, or injury, the body returns to an appropriate stateof equilibrium. It has been taught that the internal chemical processes are under the controlof the anterior pituitary gland, which by secretion of trophic hormones regulates end-organmanufacture of steroids and thyroxine while more directly regulating other key metabolicprocesses by its output of growth hormone and other substances. This concept is outmodedsince it is known that the pituitary has its own master regulator. The hypothalamus is the finalcommon pathway between the brain and the pituitary.
Significant advances have been made recently in identifying and characterizing the pathways of neural control over the pituitary and its trophic hormones. Hormones arechemical substances synthesized in the body that exert regulatory effects on the target tissue.
In general, the effect of hypothalamic hormones over the pituitary is stimulatory. Interruptionof the neural pathways leading to the hypothalamus results in diminished secretion of thecorresponding pituitary hormones, with the exception of prolactin, which increases withremoval of hypothalamic control. The various hormones that have been identified that exerthypothalamic control over the pituitary include peptide chains, which contain from 3 to 44amino acids, and dopamine. A thorough understanding of the interactions of these regulatorypathways is required of the head and neck surgeon.
The Pituitary Gland
The pituitary is a small structure weighing approximately 0.5 gm. It is located within the sphenoid bone at the base of the skull. Functionally the pituitary is divided into twoanatomic sections, an anterior portion known as adenohypophysis and a posterior portionknown as the neurohypophysis.
Current functional concepts of regulation of the anterior pituitary postulate control by a three-level system of brain, hypothalamus, and pituitary, utilizing a complex organizationof feedback loops. A close association between the neural and endocrine systems isdemonstrated in anterior pituitary control. Regulation of the six major hormones secreted bythe anterior pituitary is subject to cortical control through several neurotransmitter compounds,including dopamine, norepinephrine, serotonin, acetylcholine, histamine, and gamma-aminobutyric acid.
Central nervous system transmission of the various neurotransmitter compounds occurs through axodendritic and axoaxonic connections to the hormone containing nerve fibers in thehypothalamus. Utilizing these neurotransmitter substances, the synapses provide controlsignals to at least 10 different types of neurons located in the median eminence of the hypothalamus. This hypophyseotropic area contains discrete populations of uniquehypothalamic neurons that are neurosecretory and produce a group of substances known asthe hypothalamic regulating peptides. These neurosecretory neurons release their regulatingpeptides as neurosecretory granules that may be either facilitatory or inhibitory in type andare carried by the hypothalamic-hypophyseal portal capillaries to the anterior pituitary gland.
These regulating peptides then influence anterior pituitary cells to synthesize and secrete thespecific trophic hormones of the anterior pituitary (Table 1). Further regulation of the anteriorpituitary occurs via feedback loops. In this way, peripheral hormones whose production iscontrolled by pituitary trophic hormones may influence the ultimate release of the pituitarytrophic hormones via facilitative or inhibitory feedback at the level of the CNSmonoaminergic neuron, the hypothalamic neurosecretory neuron, or the anterior pituitarytrophic cell itself.
Table 1. Hypothalamic Regulatory Factors
Luteinizing hormone-releasing hormone (LHRH) Growth hormone release-inhibiting hormone (Somatostatin) Prolactin release-inhibiting factor (PIF) Diseases of the Anterior Pituitary and Hypothalamus
Pituitary disease may be discretely anatomic or purely functional in type. A variety of disorders that may interfere with the sensitive neuroendocrine control of the anteriorpituitary are being newly defined. Typically, discrete anatomic lesions are those mostcommonly sought. Vascular lesions in the form of ischemia to the anterior pituitary may occureither as the result of thrombosis or because of decreased circulation through thehypothalamic-hypophyseal portal circulation as a result of hypotension. Sheehan's syndromeis a form of ischemic necrosis of the anterior pituitary associated with postpartumhypotension. Post-traumatic hypopituitarism is a rarely described condition. However, recentevidence suggests that this condition may be a consequence of closed head trauma and ismuch more frequent that previously believed (Paxson and Brown, 1976; Brown and McMillin,1977). In some cases, post-traumatic disorders of the pituitary gland are believed to besecondary to shearing of the pituitary stalk, especially in the case of panhypopituitarism inthe setting of a basal skull fracture.
Tumors of the anterior pituitary, the hypothalamus, and the surrounding suprasellar area are among the lesions frequently under the care of the head and neck surgeon. Theseconstitute a large variety of adenomas of the anterior pituitary trophic cells as well ascraniopharyngioma and related cystic lesions. In addition, significant petitur destruction of thearea may occur as a consequence of invasion by other CNS disorders, particularly pinealomas.
Infiltrative and inflammatory disorders affecting the anterior pituitary and hypothalamus include the various forms of histiocytosis X as well as sarcoidosis. Syndromesof granulomatous disorders include Hand-Schüller-Christian disease, characterized by polyuria,exophthalmos, and skull defects; Letterer-Siwe disease, a similar but more rapidly progressiveform of disease; and eosinophilic granuloma, in which similar pathologic findings are presentin isolated areas of bone. Symptoms of diabetes insipidus are present in approximately 50 percent of patients with Hand-Schüller-Christian disease as well as growth failure,hypogonadism, and panhypopituitarism. Sarcoidosis, although relatively rare in the centralnervous system, often affects the hypothalamus and pituitary. Symptoms of diabetes insipidus,galactorrhea secondary to hyperprolactinemia, anterior pituitary insufficiency, somnolence, andhyperphagia have been associated with sarcoidosis.
Radiation-induced hypothalamic dysfunction is occasionally seen after radiation therapy for intracranial neoplasms. Children are more likely to develop the disorder thanadults. The delay in onset ranges from 1 to 10 years following therapy of at least 4000 radsto the hypothalamus or pituitary in the course of treatment for intracranial tumors andnasopharyngeal and maxillary sinus carcinomas.
Autoimmune disorders have been described as potential causes of functional pituitary impairment. Characterized by lymphocytic hypophysitis, the condition is seen occasionallyin postpartum women who present with symptoms of an expanding pituitary mass lesion orwith hypopituitarism. The pathologic lesion consists of parenchymal replacement of pituitarytissue with lymphoid follicles and may present in association with other autoimmune-mediateddisorders such as lymphocytic thyroiditis, pernicious anemia, hypoparathyroidism, and adrenalinsufficiency.
Congenital disorders of the anterior pituitary gland include cystic lesions resembling craniopharyngioma and syndromes of congenital hypopituitarism, which may be due tocirculatory insufficiency during the birth process or to hypotension and related problems inthe mother. Additional syndromes of congenital pituitary insufficiency associated with a smallphallus and panhypopituitarism in the newborn with structural anomalies of the face are welldocumented. A syndrome of wide midface with relative hypertelorism, a wide nasal bridge,and absence of the pituitary gland has been described (Brown and Klain, 1978). Congenitalhypopituitarism usually becomes manifested as an intractable form of hypoglycemia in thefirst few hours of life. In cases in which an incomplete form exists, hypoglycemia may beconsiderably more subtle and may not appear until the infant is several weeks or months ofage.
Various functional disorders of the hypothalamus and pituitary gland are of interest to the otolaryngologist. Hypothalamic hypogonadism presenting with anosmia representsKallmann's syndrome of olfactory-genital dysplasia. This may be seen with other associateddeficits such as cranial nerve deafness and color blindness. Midline developmental defects canoccur including cleft lip and palate as well as hypoplasia of the anterior commissure, olfactorybulb, and hypothalamus (Lieblich et al, 1982).
The neurohypophysis or posterior pituitary gland may exhibit two classic functional abnormalities. Neurogenic diabetes insipidus is characterized by partial or complete loss ofthe posterior pituitary hormone (ADH, vasopressin). ADH acts upon the distal convoluted tubule of the kidney and the renal collecting ducts, facilitating reabsorption of water. In theabsence of ADH, up to 15 per cent of the total glomerular filtrate is not reabsorbed, leadingto significant polyuria. Associated with this fluid loss is polydipsia and, eventually,dehydration if fluid replacement is inadequate. The serum is extremely concentrated, withelevated serum osmolality and serum sodium levels. In addition, the high urine volume isextremely dilute, with low urine osmolality and specific gravity. Most commonly, diabetesinsipidus occurs as an idiopathic syndrome and is frequently encountered postoperativelyfollowing neurosurgical procedures. In addition, it is commonly seen following head trauma.
At least 95 per cent of the cases of postsurgical and post-traumatic diabetes insipidus are ofa transient nature. The majority of patients with this condition exhibit significant polyuria andpolydipsia with concomitant serum and urine changes, but this clinical picture tends to resolvewithin 2 weeks.
The syndrome of inappropriate ADH secretion (SIADH) is encountered less frequently than diabetes insipidus. This syndrome is related to an increased release of ADH directly fromthe hypothalamus or the neurohypophysis as well as increased sensitivity of the kidneys tonormal circulating levels of the ADH. SIADH may be seen following neurosurgicalprocedures or head trauma. Pulmonary disease, particularly aspiration syndromes or disorderscharacterized by diminished pulmonary compliance, may cause release of ADH-like peptidesinto the circulation, producing a syndrome identical in its manifestation to SIADH of aneurogenic origin. Clinical signs involve circulatory volume overload with diminished urineoutput. Patients exhibit extremely dilute serum with diminution of serum osmolality andrelative dilutional hyponatremia and hypochloremia. Urine output is significantly diminished,and the urine is highly concentrated, as measured by both increased urinary specific gravityand urine osmolality.
Diagnostic Studies of the Pituitary Gland and the Hypothalamus
Determination of pituitary function may be made by direct measurement of the pituitary trophic hormones. All the pituitary trophic hormones may be measured byradioimmunoassay, as may all the peripheral hormones released under pituitary control. Inaddition, specific radioimmunoassay for ADH is available.
Provocative stimulation studies for the pituitary trophic hormones are frequently carried out in order to duplicate physiologic circumstances and to indicate anterior pituitaryreserve and dynamic drive.
The most frequently used provocative release studies for anterior pituitary function involve the thyrotropin-releasing hormone (TRH) test and a variety of provocative tests forgrowth hormone. TRH may also be used as a releasing substance for prolactin as well as forthyroid-stimulating hormone (TSH). Simultaneous determinations of prolactin provide furtherinformation with regard to integrity of the anterior pituitary gland. Growth hormone isstimulated by a variety of substances. The most frequently used are oral L-dopa and arginineadministered intravenously. Intravenous insulin at doses of 0.05 to 0.1 unit per kg of bodyweight may also be used.
Recently, an anterior pituitary trophic hormone, beta-lipotropin, has been described.
This molecule undergoes conversion within the pituitary gland and the peripheral circulation to a variety of smaller substances. The most important by-products of this larger trophichormone are a group of substances called the endorphins, which occupy endogenousmorphine-like receptors within the central nervous system. These substances may playimportant roles with regard to dreaming, behavior, perception, and altered states ofconsciousness.
radioimmunoassay and may be an additional important parameter of assessment of anteriorpituitary function.
Evaluation of disorders of the posterior pituitary gland involves direct measurement of ADH with accompanying determinations of urine osmolality and specific gravity and serumosmolality. Water deprivation testing with determination of serial ADH levels andaccompanying osmolalities may be helpful in determining the degree of insufficiency of theposterior pituitary gland.
Replacement Therapy in Hypopituitarism
Complete replacement therapy for deficits of anterior pituitary trophic hormones can be adequately and effectively provided. Most patients who need therapy have only partialdeficits requiring minimal dose hormone replacement. However, in the case of completedestruction of the total anterior and posterior pituitary gland, all essential factors can be safelyprovided (Table 2).
Table 2. Hypopituitary Replacement Therapy
Trophic Hormone
30 mg (20 mg PO every AM, 10 mg every PM) 200 mg IM (enanthate) every 10 to 17 days TSH deficiency may be compensated by replacement of thyroid hormone, using levothyroxine sodium in daily doses in the range of 150 microg/m2/day. Deficiencies ofadrenocorticotrophic hormone (ACTH) are treated with a variety of steroid preparations. Oralhydrocortisone preparations in the range of 15 to 20 mg/m2/day may be given two or threetimes daily. Cortisone acetate may also be used at doses 20 to 25 per cent higher than thosefor hydrocortisone. Deficiencies of the gonadotropins are managed with exogenous sexhormone replacement. For males, testosterone preparations, such as testosterone enanthate ortestosterone cyclopropionate, may be administered in doses of 100 to 200 mg intramuscularlyevery 2 to 4 weeks. Adequacy of dosage is determined by maintenance of secondary sex characteristics and libido and adequacy of sexual performance and behavior. For females,gonadotropin deficiencies are replaced by providing estrogen and progesterone. This may bedone using oral conjugated estrogens (Premarin) and medroxyprogesterone acetate (Provera)combinations or commercially available sequential oral contraceptives. In estrogenreplacement, minimal low-dose estrogens should be used to avoid the complications ofhyperestrogenation. Human growth hormone replacement is available but is restricted to thegrowing child in whom some benefit may be anticipated. Growth hormone is now availableas a product of recombinant DNA, thereby avoiding the question of a transmissible agent inthe prepared human product. It may be administered in doses of 0.5 microg, given byintramuscular injection three times per week.
Deficiencies of posterior pituitary function resulting in diabetes insipidus may be treated using ADH hormone preparations. A long-acting preparation (Pitressin tannate in oil)is available. This preparation may be given in doses of 1 to 5 units (usually 0.5 mL ofsuspension) intramuscularly. The duration of action varies, depending on the size of the doseadministered and the size of the patient. Clinical responses vary from 18 to 36 hours afterinjection, with most patients requiring injections four to five times weekly. A shorter-actingpreparation (aqueous Pitressin) is available for patients exhibiting transient syndromes ofdiabetes insipidus. This preparation is administered in doses of 1 to 5 units intramuscularlyevery 6 to 8 hours, depending on clinical response. Recently, a new therapeutic agent, 1-deamino-(8-D-arginine)-vasopressin (DDAVP), has become available. DDAVP is an idealtherapeutic agent for the management of diabetes insipidus. This is a highly purified, potent,and therapeutically consistent preparation that is not injectable. DDAVP is administeredintranasally via a plastic catheter. The duration of antidiuretic effect following the initial doseof DDAVP is 20 to 24 hours. Subsequent doses last 8 to 12 hours. Patients with persistentdiabetes insipidus may be managed on dosages of 5 to 10 microg of DDAVP administeredtwice daily (Uden and Brown, 1978; Brown and Uden, 1979).
The Thyroid Gland
Anatomy and Histology
The thyroid gland is one of the largest of the endocrine structures, with an average weight of approximately 20 gm in adult white Americans (Ingbar, 1985). The capacity forgrowth of the thyroid gland is great and its enlargement into goitrous structures weighingseveral hundred grams is not unusual.
The thyroid gland is made up of two lateral lobes with a connecting thinner structure between them known as the isthmus. In addition, a pyramidal lobe is often identifiable as aprojection upward from the isthmus just lateral to the midline and most frequently on the leftside; it is most discrete when the remainder of the gland is enlarged. The right lobe of thethyroid gland frequently has a richer blood supply than the left. Normally, it is the larger ofthe two lobes and has a tendency to increase in size to a greater degree in those disorders ofthe thyroid gland associated with a generalized increase in size.
Blood flow to the thyroid may be in the range of 4 to 6 ml/min/g of tissue, which is at least twice as great as blood flow to the kidney. In situations of diffuse toxicity and goiterwith associated hyperthyroidism, blood flow as great as l L/min has been documented, since increased vascularity causes a palpable thrill, or more commonly, the auscultatory bruit. Thisassociation of progressively increased vascularity with increased thyroid mass in situationsof hyperactivity is important when considering thyroidectomy in patients with thyrotoxicosis.
The remarkable absolute increase in thyroidal blood flow as well as the increase in the truesize of vascular structures to the gland must be kept in mind at all times.
The thyroid gland is composed of multiple, closely packed, saclike structures referred to as follicles. Each of these follicles is filled with a clear protein colloid material that makesup the major constituent of thyroid tissue. The size of such follicles show great heterogeneitywithin the same gland, usually between 150 and 250 microns. The structure of the follicularepithelium varies depending on the degree of glandular activity and stimulation, tending tobe columnar when most active and flattened when inactive. Twenty to forty such follicles maybe anatomically defined by connective tissue structures to form discrete lobules, each suppliedby a single artery. There may be considerable heterogeneity with regard to the anatomicstructure and function between discrete and even neighboring lobules within the same thyroidgland.
In addition to the follicular cells, the thyroid tissue also contains perifollicular or C- cells. These cells are located within the medullary portion of the thyroid gland and producea specific calcium-lowering polypeptide hormone known as calcitonin. The C-cells are foundwithin the follicular epithelium and also within the interstitium of the gland but are neverfound bordering the follicular lumen. The importance of the calcitonin-producing cells is inregard to the behavior and clinical characteristics of medullary carcinoma of the thyroid,which appears to be derived exclusively from these cells. Recently, the C-cell has been shownto be part of a discrete system of cells arising from common embryologic tissue referred toas the neural crest. This system, known as amine precursor uptake and decarboxylation(APUD), is of great clinical significance (see section on MEN syndrome).
Thyroid Hormone Synthesis: Physiology and Biochemistry
The biosynthesis of the thyroid hormones occurs in three discrete sequential stages: (1) the active transport of iodine into the thyroid follicular cell; (2) the oxidation of theseiodine molecules and their incorporation into tyrosine molecules, known as organification, toform iodothyronines within the thyroglobulin proper; and (3) the coupling of inactiveiodotyrosine into hormonally active iodothyronines, specifically triiodothyronine (T ) and tetraiodothyronine or thyroxine (T ). The hormonally active T3 and T4 molecules are then held in specific peptide linkages to form the substance thyroglobulin, which is the majorcomponent of colloid within the thyroid follicular cell.
The initial step of thyroid hormone synthesis is uptake by active transport of iodide into the thyroid follicular cell. In addition to iodide itself, other anions, specificallyperchlorate and thiocyanate, may also be used and undergo uptake - a factor that is of boththerapeutic and diagnostic importance in terms of functional thyroid testing. The second stepinvolves the oxidation and actual organic binding of the iodide molecule onto tyrosine,forming the endocrinologically inactive monoiodotyrosine and diiodotyrosine. This is anextremely critical step in thyroid hormone biosynthesis. Specific defects in thyroid synthesisthat, in turn, lead to functional hypothyroidism appear to be focused on this step. Forexample, the autoimmune thyroid disorders such as Hashimoto's thyroiditis, or chronic lymphocytic thyroiditis, appear to be associated with specific antibody formation against theenzymes involved in the organification step. This immunologic attack on the enzymemachinery involved in organification underlies the eventual thyroid deficiency that occurs inpatients with such conditions. The functional manipulation of this phase of thyroid hormonesynthesis is critical to the understanding of specific thyroid function studies.
The release and secretion of the active thyroid hormones triiodothyronine and thyroxine from the intrafollicular thyroglobulin involve two additional biochemical steps: (1)the hydrolysis of the thyroglobulin by a thyroid protease enzyme and peptidase, which leadsto the liberation of free iodinated amino acids; and (2) the release of these activeiodothyronines into the circulation.
The ability of the thyroid gland to concentrate iodine is not unique, as this may occur in other tissues of endodermal origin. Most notable are the salivary glands and the gastricglands. Isotopic scanning and radionuclide counting of the thyroid gland must take intoconsideration that the salivary glands also take up and incorporate such isotopes.
Regulation of Thyroid Function: The Hypothalamic-Pituitary-Thyroid Complex
As is the case with most other endocrine tissues, recent evidence suggests a close functional relationship both anatomically and physiologically, between the thyroid and thepituitary glands. In addition, sophisticated regulatory control of the pituitary gland by highercortical centers and the hypothalamus, in turn, influences the activity of the thyroid gland.
Sophisticated autoregulatory control of thyroid function by the gland itself also plays animportant role (Reichlin et al, 1972).
The functional sequence of regulatory control of the thyroid gland involves multiple levels as well as a complex system of long and short feedback loops. Initial input into centersof the higher cerebral cortex results in the transport of neuroinformation to the area of thehypothalamus. Specifically, discrete neurosecretory cells are found within the medianeminence of the hypothalamus. Specific cells produce thyroid-releasing hormone (TRH), atripeptide composed of glutamic acid, histidine, and proline. This hormone is released via thehypothalamic-pituitary portal circulation and transported to the anterior pituitary gland, wherecells are stimulated by TRH both to synthesize and to release TSH. TSH is then released fromthe anterior pituitary into the general circulation, where it is transported to the thyroid gland.
At the level of the thyroid cell, and specifically within the follicular cell complex, TSH exertsfacilitative effects on all the previously mentioned steps in both thyroid hormone biosynthesisand thyroid hormone secretion. Recent evidence shows that the uptake of iodide by thethyroid gland is directly influenced by TSH stimulation, and perhaps more specifically,evidence also shows that the organification and binding of the iodide to form the activethyroid hormones T3 and T4 are TSH dependent. In addition, the hydrolysis of thethyroglobulin releasing T3 and T4 into the circulation is also influenced by TSH. Therefore,at multiple sites, the presence of increased amounts of TSH leads to increased thyroidhormone synthesis and secretion.
As the levels of T3 and T4 in the circulation increase, they eventually reach a level sufficient to maintain their required biologic effects. This results in decreased stimulationfrom the cortical centers to the hypothalamus as well as direct signals to the hypothalamus to decrease the synthesis and secretion of TRH, producing decreased stimulation to theanterior pituitary, with resultant decreased synthesis and release of TSH. This processdecreases T3 and T4 synthesis and secretion. As a result, intact thyroid gland functionrequires multiple levels of functional integrity at the central nervous system, hypothalamus,and pituitary levels as well as at the level of the gland itself.
These neuroendocrine principles involved in the regulation of thyroid gland function are important not only in understanding the mechanisms of various thyroid disorders but alsoin providing the underlying basis for additional function tests.
Thyroid Function Testing
Thyroid-Stimulating Hormone (TSH) Test
Recent developments in the laboratory assessment and interpretation of thyroid status have been chronicled in the literature. Tests that have been considered the standard for routineevaluation, although still used throughout the United States, are currently undergoing majorchanges. These changes are occurring in part owing to technological advances that allow moresensitive, rapid, and accurate evaluation of the thyroid endocrine axis. In addition, themedical-economic climate is such that pressure is brought to bear on obtaining a singleconvenient and inexpensive test for assessing thyroid status.
Formerly, the measurement of total T4, free T4, and T3 with evaluation of TSH response to intravenous TRH administration was required for evaluation of the thyroidhormone status of an individual. In the instance of normal hormonal balance, this test requiredmultiple assays for the characterization of normal function. It has become increasingly evidentthat a sensitive assay of a serum TSH will permit the clinician to know at a glance whetheror not thyroid hormone balance is present. Previous radioimmunoassays (RIAs) wererelatively insensitive to the low levels of TSH seen in subclinical or clinical hyperthyroidism,and tedious serial dilutions were required to assay the high levels seen in primaryhypothyroidism.
With the development of immunoradiometric assays (IRMAs), a markedly sensitive, fast, and convenient assay became available to delineate fairly clearly and accurately thestatus of a patient's thyroid function. Although RIAs were insensitive to the TSH levelspresent in 13 per cent of normal subjects, IRMAs were able to quantify 100 per cent of theTSH levels in normal control subjects. Specifically, RIAs have a working range of 0.5 to 15microU/mL, and IRMAs are sensitive to a working range of 0.05 to 200 microU/mL(Ridgeway, 1988).
Because of expanded sensitivity of TSH quantitation by IRMAs, it is now possible to obtain accurate measurements in the initial TSH assay of serum from hypothyroid individuals.
Hyperthyroid individuals will have low or not quantifiable TSH levels that, if performed byIRMA, will clearly suggest their hyperthyroid status. Unlike the results from previous assays,patients with hyperthyroidism are always distinguishable from euthyroid control subjects and,in IRMA assays, frequently have values below the detection limit. The enhanced ability toseparate euthyroid control subjects from patients with hyperthyroidism suggests that theIRMA of TSH can accurately discriminate in a single test normal subjects from those with either enhanced or depressed TSH secretion.
Conditions that enhance TSH secretion involve the entire spectrum of primary thyroid gland failure, including iodine deficiency, faulty hormone synthesis, and loss of functioningfollicles. In addition to spontaneous or idiopathic causes, gland hypofunction followingthyroid surgery can be expected to lead to an elevated TSH. It should be pointed out that 30per cent of those patients receiving radioiodine therapy for treatment of thyroid disorders willhave hypofunctioning thyroid tissue at 5 years. Suppression of TSH levels can be expectedto result from clinical or subclinical hyperthyroidism, a hyperfunctioning thyroid nodule,multinodular goiter, overzealous thyroid replacement therapy, and medications includingdopamine or glucocorticoid therapy. Isolated hypopituitary hypothyroidism is rare, with onlya few case reports describing the entity in the literature. Secondary hypopituitarism is evenrarer, occurring either in association with other hypothalamic syndromes or through isolatedhypothalamic TRH insufficiency.
With the use of the IRMA for the measurement of TSH, a new approach to thyroid immunoradiometric assay suggests that the TSH and the T4 assay provide the best initialscreening laboratory tests for the evaluation of suspected thyroid imbalance (Surks et al,1990). Current clinical uses of serum TSH measurement include diagnosis of primaryhypothyroidism as well as hyperthyroidism, differentiation of primary versus secondaryhypothyroidism, and evaluation of TSH reserve using the TRH stimulation test. Recently, theTSH assay has been used in assessing the adequacy of thyroid replacement (Hay, 1988). Analgorithm has been offered in the literature to allow the rapid and economical assessment ofthyroid hormone disorders with a minimum of testing (Toft, 1988).
Total Tetraiodothyronine Concentration (TT ) Test
The currently available test for total thyroxine concentration measures iodothyronines; therefore, it is unaffected by contaminant iodide. The test measures both protein-boundthyroxine as well as free thyroxine (recall that it is the free thyroxine that is responsible formetabolic effects at the cellular level). Protein-bound thyroxine accounts for 99.97 per centof the total T4. Wide fluctuations in the amount of protein-bound T4 occur, making ameaningful interpretation difficult without further tests to delineate the bound protein fromthe free T4.
Free Thyroxine (FT ) Test
Free T4 measurement is an absolute measure of unbound hormone using a radioimmunoassay technique. This test can accurately delineate the thyroid status of anindividual in the setting of altered protein binding.
Thyroxine-Binding Globulin (TBG) Test
In the setting of an abnormal total thyroid hormone level in the serum, this test can differentiate apparent hyperthyroidism or hypothyroidism from the setting of increased ordecreased thyroid-binding protein. Factors that increase TBG include pregnancy, use of birthcontrol pills, acute hepatitis, acute intermittent porphyria, and some medications (eg, Trilafon).
Decreased levels of thyroglobulin occur with the administration of androgens, high-doseglucocorticoids, and in settings of major illness and acromegaly.
T Resin Uptake (T RU) Test
The T3RU assay is based on competition between available TBG-binding sites and a synthetic resin for added radioactive T3. It is an indirect measure of free T4 concentration.
The free thyroxine index is a derived quantity that attempts to correct for the variations inthyroid hormone carrier. It is generally defined as a total T4 multiplied by the T3 uptake. Ifavailable binding sites are increased, such as in hypothyroidism and instances of increasedthyroid-binding globulin, more radioactive T3 will fill them and, consequently, less will betaken up by the resin, giving a low T3RU. If available binding sites are decreased, as inhyperthyroidism and in settings of decreased TBG, less radioactive T3 can bind to them, morewill be on the resin, and the T3RU will be high.
Total Triiodothyronine Concentration (TT ) Test
Although is an excellent test of hyperthyroidism with good correlation with clinical status and degree of therapeutic control of hyperthyroidism, the same problems of proteinbinding that apply to total thyroxine also apply to the measurement of triiodothyronine. Ofthe total T3, 99.7 per cent is bound to protein carriers, with the biologically active freehormone comprising only 0.3 per cent of the total amount. The TT3 discriminates poorlybetween normal and hypothyroid individuals. This assay does provide a useful test inidentifying surreptitious T3 ingestion.
Free Triiodothyronine (FT ) Test
This is a sensitive radioimmunoassay that correlates well with the clinical status of an Protein-Bound Iodine (PBI) Test
This test provides a measure of all organic iodides in a serum sample. It includes T4, T3, and other iodothyronines as well as iatrogenic sources. This test is useful in diagnosingHashimoto's thyroiditis as well as other organification defects. The PBI quantitatively exceedsthe total T4 in serum by greater than 2 microg/dL.
Test for Antithyroid Antibodies
This test is useful in diagnosing autoimmune thyroid disorders (Graves' disease, Hashimoto's). Antimicrosomal serum antibodies are most useful in making the determinationwhen they are positive in serum. Rarely, they can be elevated in pediatric patients.
Reverse T (RT ) Test
This test provides a measurement of an inactive structural variant of T3. The element is found only in the fetus and decreases within the first 7 days after birth. RT3 is the bestscreening test for neonatal hypothyroidism.
Thyrotropin-Releasing Hormone (TRH) Test
This test is an excellent tool for the assessment of the status of the pituitary-thyroid axis and involves the administration of TRH, usually as an intravenous bolus injection ofTRH (7 microg/kg) in 1 mL of normal saline over 5 to 10 seconds. Blood is then collectedfor determination of TSH at 0, 15, 30, 45, 60, and 90 minutes. The peak TSH response isexpected between 20 and 45 minutes. The application of the test is two-fold. First, it is usedto determine the ability of the pituitary gland to respond to the hypothalamic peptide TRH.
A normal pituitary gland releases TSH in response to TRH. Second, it is used to distinguishtertiary from secondary hypothyroidism.
T or T Suppression Test
This test is based on the principle that, in normal subjects, thyroid function is almost completely suppressible by exogenous thyroid hormone via its inhibitory effects on pituitaryTSH secretion. In some patients with thyroid disease (eg, Graves' disease, some nodulargoiters), thyroid function is not TSH dependent and hence is not TSH suppressible byexogenous thyroid hormone. The T3 or T4 suppression test is useful in confirming the hotnodule, as the autonomously functioning nodule is not suppressed by the lack of TSHstimulation but appears as a hyperfunctioning spot on the thyroid scan. Following a baseline24-hour uptake 123I scan, 25 microg of T3 is administered for 8 days prior to repeating thethyroid scan. A normal response is defined as a greater than 50 per cent fall in the 24-houruptake after 8 days of triiodothyronine therapy.
Radioactive Iodine Uptake (RAIU) Test
This test measures the percentage of a dose of orally administered 123I or 131I taken up by the thyroid gland over a fixed interval, usually 24 hours. In most cases, hyperthyroidpatients have elevated 24-hour uptakes and hypothyroid patients have depressed uptakescompared with normals. The normal range for uptake is 8 to 30 per cent of the administerediodine after 24 hours. Hypothyroidism and hyperthyroidism appear in all three categories(increased, normal, and decreased); therefore, radioisotopic studies are rarely indicated in theinitial workup of suspected thyroid dysfunction. The major clinical utility is in the evaluationof thyroid nodules (cold versus hot).
Radioisotope Scintiscanning
Radioisotope scintiscanning is useful in assessing the size, location, and functional status of thyroid nodules. Like the thyroid uptake scan, scintiscanning is performed afteradministration of an oral dose of 123I or 131I, and the patient's functional status determined bythe relative uptake of isotope by a nodule. Nodules may appear as hot, cold, or warm,depending on the uptake of radioisotope within a given nodule. The majority of nodules thattake up the radioactive iodides tend to be of a benign nature, whereas those that do not takeup the radionuclides are referred to as cold and have a greater propensity for malignancy.
Technetium 99m (Tc 99m) may be used to limit the radiation dose, particularly in children.
If only morphology of the gland is of interest, Tc-99m scanning provides the necessaryinformation with the minimum radiation exposure. Caution is advised in the interpretation ofnodules on Tc-99m scans, because nodules that would be interpreted as cold on 123I or 131I scans may appear as warm nodules on Tc-99m scans, limiting the clinical usefulness of Tc-99m scanning.
Specific considerations when ordering a thyroid scan are as follows: (1) Scanning should be done under basal conditions. Patients should not be on exogenous thyroidmedications, which block uptake and suppress endogenous TSH, causing poor visualizationof active thyroid tissue. (2) Scanning should be carried out from just above the base of thetongue down into the mediastinum. When attempting to identify aberrant thyroid tissue, it iscritical that the entire pathways of downward migration of the thyroid be explored. (3) It isimportant to remember that other tissues are capable of trapping radioactive isotopes.
The specifics of scanning for the presence or absence of thyroid tissue as well as the position and presence of ectopic thyroid tissue are obvious. Identification of thyroid size andactivity may vary with the experience of the observer, but scans are uniformly helpful in thisregard. Certain thyroid diseases may show changes that are not universal but that arediagnostically helpful when present. Chronic lymphocytic thyroiditis appears in a spottydistribution throughout the gland. This disorder causes areas of variable activity within thegland, producing a characteristic "salt-and-pepper" appearance. Areas of diminished activityalternating with areas of normal or even accentuated activity are suggestive of chroniclymphocytic thyroiditis.
Perchlorate Discharge Test
The perchlorate discharge test is useful in instances in which an organification defect is suspected (Pendred's syndrome) or when considering Hashimoto's thyroiditis. The test isperformed by giving a small dose of radioactive iodine, followed by an uptake scintiscan after1 hour. Afterward, a dose of oral perchlorate (KClO ) is given to inhibit further thyroid trapping and a repeat scintiscan is performed 1 hour later. In normal individuals, 85 to 90 percent of the 131I seen at the first scan should be present at the second scan 1 hour later becauseit will be organified and unaffected by the competitive perchlorate anion. A normal glanddischarge no more than 10 to 15 per cent. This test is used in the diagnosis of congenitalorganification enzyme defects and the acquired immunologic forms of hypothyroidism. Thistest, together with the supportive evidence of a PBI and T discrepancy, elevated antibody titers, and a clinical picture compatible with chronic lymphocyte thyroiditis, has supersededthe need for biopsy in this disorder.
Ultrasound Thyroid Scanning
Ultrasound thyroid scanning is useful in establishing the nature of a palpable thyroid nodule as a cystic versus a solid lesion. Sensitive to lesions of about 0.5 cm in diameter,ultrasound can also provide a guide to the fine needle aspiration of small lesions.
Goiter Differential Diagnosis
The presence of thyroid enlargement (goiter) alone is not diagnostic and is present in hypothyroidism, hyperthyroidism, and in euthyroid individuals. Enlargement of the thyroidmay be present as a result of tumors, vascular anomalies, benign accumulations of increasedamounts of colloid within the follicular cell, abscesses, and other forms of acute or subacute inflammation and infection of the gland (Table 3).
Some characteristics of the thyroid gland, particularly in its enlargement, may give helpful diagnostic clues. Thyroid enlargement in Graves' disease tends to be more uniformand symmetric. If asymmetry is present, the majority of patients usually have selective of theright lobe. The gland is soft, nontender, and mobile. A palpable thrill or bruit may be present.
The gland may be smooth or irregular over its surface, but nodularity is rarely present.
Table 3. Differential Diagnosis of Goiter
Simple colloid (juvenile goiter)Chronic lymphocytic thyroiditisGraves' diseaseEndemic iodine deficiencyExcessive exogenous iodine uptake or ingestion of goitrogensThyroid neoplasiaToxic nodular goiter (Plummer's disease)Subacute thyroiditisAcute thyroiditis (suppurative, with abscess formation)Post-traumatic intrathyroidal or adnexal hemorrhage.
In chronic lymphocytic thyroids, the gland is usually asymmetrically enlarged, again with selective enlargement of the right lobe. Typically, the isthmus is palpable and makes upa significant proportion of the enlarged thyroid mass. A pyramidal lobe extending from thesuperior surface of the thyroid isthmus is palpable. Such glands tend to be somewhat firm andrubbery. The surface may be smooth or may demonstrate a multinodular character. Discretelypalpable anatomically defined nodules are not characteristic. The gland usually is not tender,but early in the course of the disease, there may be minimal pain or discomfort on palpation.
In a large number of cases, anterior cervical lymphadenopathy may also be noted. Acute andsubacute infections of the thyroid gland producing thyroiditis may be associated with anextremely tender thyroid.
Pain on swallowing and extreme tenderness on palpation suggest acute thyroiditis. The association of symptoms of systemic infection, as well as accompanying fever and anantecedent history of infection, provides important clues. Glands exhibiting such symptomsmay also be warm to the touch and have a sensation of throbbing and hyperemia.
Neoplasms of the thyroid may be discretely palpable. Malignant lesions are fixed to the thyroid surface and usually are not mobile. They may be associated with fibrosis andtenderness. Firm, hard lymph nodes to the area of lymphatic drainage from the thyroid maybe present. Discrete mucosal neuromas on the tongue and in the buccal mucosa may be animportant clue to the presence of medullary carcinoma of the thyroid associated with themultiple endocrine neoplasia type III syndrome.
The presence of an enlarged thyroid gland or the appearance of a thyroid nodule is always an indication of underlying thyroid disease and should prompt further investigation.
Diagnostic Workup of the Thyroid Nodule
Having confirmed the presence of a nodule on physical examination, the selection of the appropriate diagnostic tests remains controversial. In the workup of the solitary thyroidnodule, there are a few statistics to guide the selection of appropriate diagnostic tests. Amongthese, 17 per cent of cold thyroid nodules are malignant. In addition, 9 per cent ofhypofunctioning and normally functioning (warm) thyroid nodules are malignant. One shouldalso recall that autonomously functioning hot nodules almost never are carcinomas; however,these constitute only 5 per cent of solitary nodules. At some centers, the palpable thyroidnodule is an immediate indication for the performance of a fine needle aspiration. This,however, is contingent on the availability of a highly trained pathologist with an interest inassessing cytology smears. The immediate aspiration precludes further radionuclide imagingand ultrasound studies for a period of several weeks following the nodule aspiration becausethe presence of a hematoma in the region of a nodule would make further testsuninterpretable. We believe FNA to be an excellent technique for assessing the cellularity ofa nodule after the functioning status of the nodule has been established. An algorithm isoffered for the workup of a solitary thyroid nodule.
Hypothyroidism, or decreased function of the thyroid gland, can occur as a result of either (1) primary disease due to absence of the gland, surgical ablation, or destruction of thegland or (2) congenital absence or maldevelopment of the gland. In addition, secondaryhypothyroidism may occur in decreased TSH stimulation to the thyroid (Table 4). Clinicalhypothyroidism presents a variable spectrum of disorders ranging from mild thyroiddeficiency to complete absence of thyroid function. The onset of hypothyroidism may beextremely insidious, and the typical clinical manifestations may take years to appear and maynot be noticeable to others. This gradual development of the hypothyroid state is due not onlyto the possibly slow progression of the thyroid dysfunction but also to the equally slowappearance of the clinical manifestations after the thyroid failure has occurred. Of course,more rapid development of the hypothyroid state is seen on the acute withdrawal ofreplacement therapy, in secondary hypothyroidism, and in situations following surgicalremoval of the thyroid gland without adequate replacement therapy.
The symptoms of hypothyroidism, particularly the early ones, are highly variable and nonspecific. The clinical manifestations vary considerably with the age of the patient. Thenewborn infant with congenital hypothyroidism may present with the classic picture ofathyrotic cretinism, characterized by edematous facies and enlarged tongue, high-pitched crysecondary to the laryngeal edema, generalized myxedema, and umbilical hernia, and muscularhypotonia. In addition, other signs of decreased systemic metabolism may become manifestas prolonged jaundice and decreased renal function. The manifestations in children may besimilar to those in adult, but the child classically present with growth failure. Children inwhom significant thyroid deficiency exists have progressive decline in growth chartmeasurements and show accompanying delays in skeletal maturation, as reflected by bone agex-ray determinations of epiphyseal maturation. Diminished school performance and mentaland physical lethargy accompany growth failure as the predominant manifestations inchildhood. In the adult, fatigue and lethargy are the most common manifestation, anddifficulties in performing daily tasks with decreased work performance are quite common.
Progressive constipation also occurs with great frequency. Cold sensitivity is often present,and menstrual disturbances are usual in the female. The voice may have a husky quality caused by submucosal laryngeal edema. Periorbital edema may become manifest late in thecourse of the disease. As hypothyroidism progresses, coarsening of the body features mayappear that is caused by changes in the mucopolysaccharide of connective tissues. This ismost obvious in the face. Physical examination may demonstrate cold skin, particularly in thedistal acral parts of the extremities; decreased sweating; thickening of the tongue; anddecreased deep tendon reflexes, particularly a slowing of the return phase of the Achillestendon reflex.
Table 4. Etiology of Hypothyroidism
1. Postablative (postsurgical thyroidectomy)2. Congenital hypothyroidism (nongoitrous) 3. Endemic goiter (iodine deficiency)4. Goiter due to antithyroid substances a. Antithyroid drugsb. Naturally occurring goitrogenic food substances 5. Iodine-induced goiter6. Genetic defects in thyroid hormone biosynthesis a. Iodide transport defectb. Organification defect, i.e., defective organification with c. Iodotyrosine coupling defect, i.e., defective coupling, associated with deafness (Hollander's syndrome) 7. Autoimmune thyroid deficiency (acquired biosynthetic defects), chronic lymphocytic thyroiditis (Hashimoto's thyroiditis)B. Secondary hypothyroidism (decreased TSH) 1. Tumors (adenomas)2. Congenital deficiencies of the anterior pituitary3. Vascular disorders a. Intrapituitary hemorrhageb. Sheehan's syndrome Laboratory Studies Specific to Hypothyroidism
All forms of hypothyroidism are characterized by a decrease in the concentration of circulating hormones. Determination of serum T4 levels by radioimmunoassay provides avaluable indicator of chemical hypothyroidism. However, serum TSH values may provide animportant indicator of the true state of hypothyroidism for two reasons. (1) The serum TSHvalues reflect changes in the thyroid state long before serum T4 level may be noted to besubnormal. Consequently, a rise in TSH levels above the normal range can reflect not onlytrue hypothyroidism but early chemical hypothyroidism. (2) The serum TSH determinationassists in the differentiation of primary thyroid failure, because elevations of the serum TSHconcentration are present in this disorder. However, pituitary failure with clinical manifestations of hypothyroidism, low serum T4 concentrations, and low-to-absentconcentrations of serum TSH reflect anterior pituitary dysfunction. To assist further in thedifferentiation of primary and secondary hypothyroidism, the TRH stimulation test is used.
Low serum T4 levels and accompanying low-to-absent TSH concentrations with failure of theserum TSH level to rise in response to a bolus of the intravenous TRH suggest a deficiencyin the anterior pituitary gland. A positive response of serum TSH to TSH that is associatedwith low T4 and low basal TSH levels may suggest the possibility of underlyinghypothalamic disease producing secondary pituitary insufficiency with tertiary hypothyroidism.
Accordingly, additional studies of the central nervous system for a possible intracranialneoplasm are indicated.
Table 5. Symptoms of Hypothyroidism (Myxedema)
Symptoms Incidence (%)
Symptoms Incidence (%)
In primary hypothyroidism, serum cholesterol concentrations may also be increased, with values in excess of 300 mg/dL. However, in secondary and tertiary forms ofhypothyroidism, hypercholesterolemia may not be present. The serum (PBI) determination isalso helpful in assessing the hypothyroid state in that an elevated PBI level associated witha subnormal T4 concentration may suggest the presence of abnormal iodinated materials inthe serum compatible with an organification defect. This, in turn, suggests a cause for thehypothyroidism. Other changes in the hypothyroid state include increased concentrations ofserum enzymes such as creatinine phosphokinase (CPK), serum glutamic-oxaloacetictransaminase (SGT), and lactic dehydrogenase (LDH). In addition, an abnormally prolongedAchilles reflex time may be observed and may be measured by kinomometry.
Nuclear medicine studies, such as radioactive technetium and iodine scans, iodine 131 uptake, perchlorate washout, also play important diagnostic roles.
Electrocardiogram (EKG) changes include bradycardia and prolongation of conduction times. Changes in the ST segment and T-waves are typical in hypothyroidism. With long-standing hypothyroidism leading to clinical myxedema, dramatic changes in the myocardiummay occur (cardiomyopathy). The performance of EKG is essential prior to providing any sort of stress involving anesthesia or surgery. Of particular importance is the use of the EKG indetermining the rate of replacement of thyroid hormone when treatment is initiated. If EKGchanges or other clinical signs of cardiomyopathy are present, replacement therapy must beinitiated extremely slowly so as to not precipitate congestive heart failure in an alreadydecompensated myocardium.
Chronic Lymphocytic Thyroiditis (Hashimoto's Thyroiditis)
By far the most common cause of goiter and hypothyroidism is autoimmune chronic lymphocytic thyroiditis, or Hashimoto's thyroiditis. Certainly Hashimoto's thyroiditis is themost common cause of sporadically appearing goiter in children and very likely also the mostcommon cause in the adult population.
Cell-mediated immunity plays an important role in initiating the pathogenesis of Hashimoto's thyroiditis. There is an initial T-lymphocyte attack on thyroid tissue due to aninitial viral insult with a common antigen association. The genetic predisposition towardautoimmune thyroiditis may be released, and the T-lymphocytes may attack thyroid tissue.
Secondary humoral antibody changes follow the cellularly mediated pathogenesis. The resultof this combined immunologic attack on thyroid tissue is a slow and progressive destructionof functionally active follicular thyroid tissue with eventual fibrosis and atrophy of the gland.
Hashimoto's thyroiditis is three to five times as common in females as in males. It has a bimodal incidence of occurrence. In the pediatric population, the average age of onset is 13years. The disorder is rarely seen after 18 years of age until its second and higher peakoccurrence between the ages of 30 and 50 years. In all age distributions, the femalepredominance persists. Approximately 70 per cent of patients are clinically euthyroid, withgoiter being the basis of presentation. Twenty per cent of the patients are hypothyroid whenfirst seen, and 10 per cent or less may present initially with transient thyrotoxicosis. Inclinically euthyroid patients, careful laboratory evaluation reveals specific evidence compatiblewith impending hypothyroidism and demonstrable defects in thyroxine synthesis (specificallyorganification) as well as immunologic evidence for this condition.
It is important to emphasize that Hashimoto's thyroiditis may be associated with the development of additional autoimmune conditions. Other endocrinopathies may occur inassociation with Hashimoto's thyroiditis or may follow years later. Commonly observedassociations are thyroiditis and diabetes as well as thyroiditis with either adrenal insufficiencyor hypoparathyroidism. In addition, it may be associated with other systemic autoimmunediseases such as rheumatoid arthritis, pernicious anemia, and autoimmune disorders of thecentral and peripheral nervous systems. Once Hashimoto's thyroiditis is diagnosed, the patientand family are informed of the possibility of the patient's developing other autoimmunediseases. Laboratory studies of the patient with Hashimoto's thyroiditis reflect very clearlyboth the underlying immunologic abnormalities and the organification defect. Although themajority of patients present with normal serum T4 concentrations, most have impendinghypothyroidism on the basis of elevated serum TSH levels. Since goiter is universally present,a Tc-99m thyroid scan is useful in demonstrating the increased thyroid morphology inHashimoto's thyroiditis. Immunologic assessment for antithyroid antibodies (antimicrosomalantithyroid antibody) frequently demonstrates elevated titers. These laboratory studies usuallyprovide sufficient confirmation of Hashimoto's thyroiditis. Other studies, specifically those involving antithyroglobulin antibodies, are less helpful. Biopsy is unnecessary.
Clinical Manifestations. The clinical manifestations of Hashimoto's thyroiditis vary
according to the degree of hypothyroidism present. Typical hypothyroidism becomes manifestinitially in the minority of patients, and, as previously stated, goiter is the outstanding clinicalcharacteristic of this condition. In a few patients, the disease may progress extremely rapidly,leading to an initial phase of mild symptomatic thyrotoxicosis. This condition is universallytransient over several weeks to 2 months. On physical examination, the thyroid gland eithermay be smooth or may have a nodular consistency.
Both lobes of the gland are usually enlarged, with one lobe (usually the right) often being larger than the other. Enlargement of the pyramidal lobe and thyroid isthmus isextremely common. Compression of surrounding structures is extremely rare. In extremelyrare neonatal goiters, severe tracheal compression with respiratory decompensation due to boththe thyroidal mass and the surrounding edema of the cervical structures may indicate the needfor tracheostomy as well as thyroidectomy. Goiters, when present, usually show little changeafter the appearance of the initial manifestations. Less than 20 per cent of untreated patientsshow subsequent further enlargement. Waxing and waning of the size of the gland ischaracteristic, even during treatment. With thyroid replacement, the gland initially mayundergo significant involution, only to enlarge again later. The gland usually becomes fibroticand eventually decreases in size.
Treatment. Replacement therapy should be initiated with appropriate doses of thyroid
hormone. The predominant indicator for hormone replacement is an elevated serum TSHconcentration. Therapy should be guided by serially following the serum TSH values. Levelsof thyroid hormone replacement are required that keep the serum T4 level within theappropriate range and suppress the serum TSH concentration. As the disease progresses, andparticularly in the growing pediatric patient, dosages must increase accordingly. Thyroidhormone replacement continues throughout life. Surgical intervention is indicated only forextrinsic compression of surrounding structures. Cosmetic procedures to reduce the size ofthe thyroid gland are probably not appropriate. Long-term follow-up for this condition isindicated for (1) appropriate adjustment of the thyroid dose in terms of progression of thedisease, (2) observation for the development of associated systemic diseases, and (3)observation for thyroid neoplasia that may indicate the emergence of clinically overt thyroidmalignancy, which is very rare. However, neoplasms, particularly of the papillary type, havebeen described.
Genetic Disorders of Thyroid Hormone Synthesis Associated with Deafness
Defective Organification and Deafness (Pendred's Syndrome). This condition is a
variant of the usual congenital organification defect in which goiter is present along withdeafness. Unlike the deafness commonly seen in severely hypothyroid individuals, which isusually of the conductive type and returns to normal with the administration of replacementtherapy, the deafness in Pendred's syndrome is of the receptive type. This type of deafnesslikely results from the strong association of Pendred's syndrome with Mondini's cochlearmalformation (Johnsen et al, 1987). Vestibular function is usually reported as normal. Goiterand decreased hearing usually becomes manifest in childhood. The thyroid abnormalities areusually minimal, and although goiter is present, patients are usually euthyroid or only mildly hypothyroid. These conditions are familial, and a great deal of heterogeneity in presentationis observed between families (Bax, 1966).
The cause of this syndrome is somewhat controversial. The more frequent euthyroid state seen in affected patients makes the possibility of intrauterine hypothyroidism leading toabnormal development of the acoustic apparatus improbable. The possibility of the presenceof a common toxic substance that influences both thyroid and auditory function has beenproposed but has not been identified. Very likely a multigenetic focus underlies this defect,having effects on both the thyroid gland and the inner ear. Such genetic foci may also beinvolved in regulating the activity of the enzymes required for organification. Such peroxidaseenzymes may also play an important role in the early development of the inner ear.
Pedigrees of families with Pendred's syndrome have established that autosomal recessive defect. However, because of the multigenetic focus and heterogenousmanifestations, great variance is seen within such families (Proctor, 1977). Approximately 7per cent of congenitally deaf individuals have been found to have Pendred's syndrome.
Diagnosis of this condition is suggested in patients presenting with receptive hearing loss, goiter, and variable degrees of hypothyroidism. Confirmation is based on normal or lowserum T4 concentrations and accompanying elevations of serum TSH. Other criteriacompatible with the organification defect, such as an increased serum PBI level comparedwith the level of serum T4 and functional demonstrations of significant washout with Tc-99mstudies, further confirm the diagnosis. Absence of elevated antithyroid antibody titers willdifferentiate this condition from Hashimoto's thyroiditis.
Defective Coupling and Deafness (Hollander's Syndrome). A family has been
described in which goiter and deafness occurred in several family members in their late 20s.
The patients were euthyroid with a normal serum T4 level. Studies of surgically removedthyroid tissue demonstrated a partial defect in the coupling mechanism in thyroxinebiosynthesis (Hollander et al, 1964).
Disorders of Maldescent. Embryologic defects in the descent of the thyroid along its
normal course of migration include lingual thyroid and aberrant thyroid gland, which can befound at any site in the thyroglossal duct tract from the foramen cecum to the mediastinum.
Medical Management of Hypothyroidism
The treatment of hypothyroidism depends on adequate replacement with thyroid hormone. Multiple preparations exist for replacing the thyroid hormones. The most commonlyused is synthetic levothyroxine sodium (Synthroid). Various forms of desiccated whole thyroidremain on the market, but in recent years the lower cost of synthetic thyroid versus biologicpreparations, as well as their greater purity and reliability, has made synthetic thyroidpreparations the method of choice. Levothyroxine sodium is equivalent to thyroxine or T4.
Various regimens of replacement are referred to in the literature, but doses of 100 microg/m2of Synthroid are the most commonly recommended initial therapy. Thyroid hormone isusually administered as a single dose on awakening in the morning. The half-life of levothyroxine sodium is approximately 72 hours, making the administration of a single dailydose adequate for physiologic needs. Average replacement doses in the adolescent and adultare 150 microg/day. Titrating the dose of levothyroxine in an individual to a normal serumthyrotropin level is a very accurate means of ensuring the proper replacement.
Precautions that should be observed in thyroid hormone replacement are most apparent for patients with significant long-standing hypothyroidism and particularly for those with anycardiovascular abnormalities. In patients with severe hypertension, myxedematous heartdisease unrelated to the hypothyroid state, or any situation in which cardiovascular dynamicspotentially may be altered, caution is indicated. As a general rule in such situations,replacement should be begun at dosages of 25 to 35 per cent of the regular dosagerequirement for the first week of treatment. If the patient tolerates such dosages adequately,the dosage may then be increased over 4 weeks to the full dosage, as tolerated.
Thyroid preparations of pure T3 (Cytomel) are also available. Since T3 is the active form of thyroid hormone and T4 requires deiodination (conversion to T3), it would seem thatreplacement with pure T3 preparations would be advantageous. However, the conversion ofT4 (Synthroid) to T3 occurs rapidly and universally. Essentially, there are no reports of theinability to convert Synthroid to active T3. The utility of Cytomel and other pure T3preparations is extremely limited and such forms of thyroid replacement should not be usedroutinely.
In postsurgical care in which thyroid hormone replacement is essential and the oral route cannot be used, parenteral preparations are available. Dosage equivalents are maintainedfor the parenteral preparations as well as the oral preparations. Such agents are administereddaily. Depo preparations exist but are not recommended.
The major indicators of adequate thyroid hormone replacement are the clinical signs showing resolution of hypothyroidism, and in the young child, an adequate, recovered patternof growth. Follow-up laboratory studies include the serum T4 determination, which shouldbe maintained within the normal range, and the serum TSH determination, which may falleither within the normal range or be suppressed below normal. Using the sensitive new TSHassay, it may be possible to titrate the dose of thyroxine to a normal TSH level, therebyeliminating overtreatment (Toft, 1988). In the setting of thyroid replacement and subnormalTSH levels, it is important to carefully monitor the patient for signs of hyperthyroidism.
Surgical Implications of the Hypothyroid State
Hypothyroidism in patients who require surgical procedures usually creates no major problems if the diagnosis is known. Severe hypometabolic problems, hypothermia,hypovolemia, and difficulty in handling medication and anesthesia may be present. Patientswith such conditions have decreased renal function with a decreased glomerular filtration rate.
In addition, hepatic dysfunction and changes in hepatic enzyme levels may be present inpatients with long-standing hypothyroidism. Problems in degradation and excretion of variousanalgesic medications as well as turnover rates of antibiotics and other substances may thenoccur. Such difficulties correlate with the degree and duration of untreated hypothyroidism.
If possible, surgical procedures should be delayed until the patient is euthyroid.
Patients with known hypothyroidism who have been given adequate doses of thyroid replacement and are euthyroid have no special problems during surgery. It is imperative,however, that they continue to receive thyroxine on a regular basis via either the oral or theparenteral route. Evaluation of thyroid function just prior to surgery is essential.
Patients not previously known to he hypothyroid and particularly those with clinical myxedema require special consideration. In addition to the problems just mentioned,myxedema may lead to difficulties with wound healing, and biochemical changes caused bymucopolysaccharides of connective tissue may lead to additional wound complications.
Cardiovascular complications must also be considered. Normochromic, normocytic anemiais common in long-standing hypothyroidism. In hypothyroidism of the autoimmune type, thepossibility of concomitant adrenal insufficiency, diabetes mellitus, or hypoparathyroidism mustbe considered. The unrecognized presence of these conditions can severely complicate theoperative and postoperative course in such patients. In the hypothyroid patient, the metabolicturnover of other hormones may be compromised. Consequently, it may become extremelydifficult to assess the endocrine status in such patients until thyroid regulation is complete.
Thyrotoxicosis (Hyperthyroidism)
Thyrotoxicosis refers to the biochemical and physiologic consequences that result from excessive quantities of active thyroid hormone entering the circulation (Table 6). This processmay occur under a variety of circumstances involving the endogenous release of increasedamounts of thyroid hormones caused by overproduction by the thyroid itself, or it may be dueto exogenous factors (thyrotoxicosis factitia) as a result of excessive ingestion of thyroidhormones.
Table 6. Symptoms and Signs of Thyrotoxicosis
HyperdefecationDiarrheaAnorexiaConstipationWeight gain Clinical Manifestations
A variety of changes are produced in the skin, including increased warmth and moisture. The hair is often very fine and breaks easily. Alopecia may occur, and the nails maybe soft and breakable.
Eye abnormalities are extremely common in thyrotoxicosis. Most commonly, retraction of the upper lid is seen, demonstrated by a rim of white sclera between the lid and the limbusof the eye. Movements of the lids are often jerky and may be spasmodic. These eyeabnormalities occur in all forms of thyrotoxicosis. However, the specific petiturophthalmopathy is uniquely characteristic of thyrotoxicosis due to Graves' disease.
Cardiovascular manifestations in thyrotoxicosis are among the most dramatic and frequent consequences. Owing to the hypermetabolic state and the need to eliminate excessivebody heat, increased circulatory demands occur. Cardiac output is increased, and peripheralvascular resistance is decreased, along with an increase in stroke volume and heart rate.
Tachycardia is always present. Systolic pressure is significantly increased and diastolicpressure is decreased, producing a wide pulse pressure. Palpitation is often experienced, andsystolic murmurs are frequently present. These signs usually resolve when a euthyroid stateis restored. Cardiac arrhythmias are common in thyrotoxicosis and are usuallysupraventricular. Ten per cent of patients with thyrotoxicosis have atrial fibrillation.
Respiratory symptoms due to thyrotoxicosis become manifest most commonly by dyspnea that is usually not associated with heart failure. Vital capacity may be reduced, withweakness of the respiratory muscles. In addition, the hypermetabolic state may produceincreases in oxygen utilization out of proportion to the rate of ventilation.
The gastrointestinal system is variably affected with increased appetite in patients with thyrotoxicosis and, depending on the balance of metabolic rate and dietary intake, weight lossor gain. Bowel motility may be affected, and although true diarrhea is rare, frequent bowelmovements of formed stools commonly occur. Hepatic dysfunction may occur in those withthyrotoxicosis, particularly in long-standing and severe cases. Hepatomegaly is present in themost severe cases and jaundice, though rare, may occur.
Nervous system manifestations are almost invariably present. These commonly are exhibited as increased nervousness, emotional lability, behavior changes, and hyperactivity.
Nervousness is characterized by extreme restlessness, shortness of attention span, and a needtoo be continually involved in various activities in spite of fatigue. Emotional instability isa prominent symptom. In advanced cases the severe behavioral manifestations may mimicsevere manic-depressive psychosis and frank schizophrenia. Other nervous system changesmay include fine, rhythmic tremors of the hands and tongue as well as the eyelids whentightly closed.
Alterations in renal function are rarely present in thyrotoxicosis. Minimal urinary tract symptoms occur, including mild polyuria that is often present initially and is associated withincreased thirst and water intake.
Laboratory Studies Specific to Hyperthyroidism
With the advent of sensitive IRMAs for the measurement of TSH, the diagnosis of clinical or subclinical hyperthyroidism has been greatly simplified. The improved sensitivityof currently available tests allows the differentiation, with 100 per cent specificity, ofthyrotoxic patients from normal subjects. This capacity suggests that serum TSH is the bestinitial test used in making the diagnosis of hyperthyroidism.
Serum T4 levels are elevated in 90 to 95 per cent of patients with thyrotoxicosis.
Circulating T4 levels are increased as a result of increased thyroxine synthesis and releasefrom the overactive thyroid gland. However, the predominant hormonal elevations arereflected in the determination of serum T3 levels by radioimmunoassay. Although the levelsof serum T4 may be significantly elevated in this condition, the serum T3 levels most clearlyreflect the degree of increased thyroidal activity due both to increased thyroid release of T3and to increased peripheral conversion of T4 and T3. Five to ten per cent of patients withthyrotoxicosis have normal serum T4 levels. Such situations are termed isolated T3thyrotoxicosis. On medical treatment, the serum T4 levels return to normal before serum T3levels by as early as 4 to 8 weeks. The persistence of symptoms of thyrotoxicosis in thepresence of normal serum T4 levels is clearly correlated with the persistent elevation of theserum T3 levels.
Antithyroid antibodies are also of assistance in the diagnosis of thyrotoxicosis specifically due to Graves' disease. Because this condition is an immunologically mediatedthyroid disease, increased titers of humoral antithyroid antibodies occur. The sameconsiderations with regard to specific antithyroid antibody tests that were discussed inassociation with Hashimoto's thyroiditis also apply in the immunologic evaluation of Graves'disease. Titers of 1:1600 to 1:6400 are commonly seen in Graves' disease.
Radioisotope scintillation scanning of the thyroid plays a role in evaluating thyrotoxicosis. Such studies provide information on the absolute size of the thyroid gland,which is increased in 97 per cent of patients with true thyrotoxicosis. Relative increasedactivity of the thyroid gland may also be determined by the rate of incorporation ofradioisotopes by the thyroid gland. Delineation of masses due to multinodular goiter and toxicadenoma may be clearly defined with scans using radioactive iodine or Tc-99m. Thyroidscanning is extremely helpful in differentiating true thyroid disease from factitioushyperthyroidism. When thyrotoxicosis is induced by excessive exogenous thyroid hormone,the thyroid gland is uniformly diminished in size owing to the suppression of TSH.
An EKG is routinely performed on all patients with suspected or confirmed hyperthyroidism because recent medical regimens for the treatment of thyrotoxicosis haveused beta-blocking agents such as propranolol. Therefore, an assessment of cardiovascularstatus is indicated prior to the administration of such drugs.
Ophthalmologic assessment is routine in patients with suspected or confirmed thyrotoxicosis. Baseline Hertel's exophthalmometry for detecting proptosis is indicated bothto determine the presence of existing eye changes in suspected Graves' disease and as abaseline for following such patients. Visual acuity is determined, and a careful ophthalmologicassessment of other eye changes is further documented.
Hyperthyroid exophthalmos is a confusing and severe medical problem. The patient should be fully evaluated and recognized to be euthyroid before surgery is undertaken. Theindications for surgery include loss of visual acuity, exposure keratitis, corneal ulcer, pain inthe eye, and occasionally pure cosmesis. A Hertel exophthalmometer is used to measure theeyes preoperatively and also intraoperatively to ensure that balance is achieved between thetwo eyes. The technique is discussed in a separate section on ophthalmology.
Radioactive iodine uptake studies are of minimal value in current evaluations of thyrotoxicosis. The use of this functional test has been superseded by the availability of thenew TSH tests.
The TRH stimulation test may also be helpful in deciding when to terminate suppressive medical therapy or in determining whether or not a thyrotoxic state exists in rarecases in which equivocal serum T3 and T4 values exist.
Graves' Disease
The most common cause of excessive thyroid hormone production is Graves' disease.
Less common causes include toxic adenoma of the thyroid and the hyperthyroid phase ofchronic lymphocyte thyroiditis.
Graves' disease is currently considered a humoral immune disorder resulting from a defect of immune surveillance. This permits a mutated clone of thyroid-directed lymphocytesto survive and interact with an antigen on the thyroid cell membrane. The result is theproduction of a thyroid-stimulating immunoglobulin directed against the TSH receptor (Volpe,1976). This thyroid-stimulating immunoglobulin then attaches to the TSH receptor on thethyroid cell membrane, which results in stimulation of the thyroid cell similar to that thatwould occur with TSH. The end result is an immunologically mediated increase in productionof thyroid hormones.
Since this condition is an autoimmune disorder, future therapy will be directed toward alleviating the underlying immune process. Present treatment for Graves' disease is directedtoward the control of excessive thyroid hormone production. This may be accomplished eitherby suppression of thyroid hormone synthesis by using antithyroid drugs or by destruction ofthyroid tissue by means of radioactive iodine or thyroidectomy. In addition, less specificforms of therapy are also used, and most recently, the sympathetic blocking agent propranololhas been used to provide relief of symptoms in this condition.
Methods of Treatment
Thyroidectomy. Surgery for Graves' disease should be reserved for selected patients
in whom successful remission with drug therapy is not possible and for young children oradolescents for whom radioactive iodine treatment is contraindicated. Thyroidectomy in thepediatric age group has been restricted to those patients in whom noncompliance toantithyroid medication has been adequately demonstrated or to a small number of patients inwhom toxic reactions to antithyroid drugs make their continued use unacceptable. It isessential that patients being considered for surgery be made euthyroid by means of drugtherapy for at least 4 weeks prior to surgery. The utilization of nonspecific agents such aspropranolol is highly recommended during the month previous to surgery and throughout the operative and immediate postoperative period. Dosages of propranolol of 1 to 2 mg/kg/day,broken down to be administered three times a day, have been adequate.
The use of iodine (Lugol's solution) as a means of reducing vascularity of the thyroid gland and preparing patients for surgery has not been universally accepted. Earlier indicationsfor its use predate the availability of propranolol and antithyroid medications. Those patientswith cardiac disease who require digitalization and antiarrhythmic agents should be euthyroidand well controlled prior to entering the operating room.
Although the complications of thyroidectomy are minimal in most centers, these sequelae are well defined and well documented. The major complications includepostoperative hypoparathyroidism that is either transient or permanent, hemorrhage, damageto the recurrent laryngeal nerves, and risks of anesthesia. Only hypoparathyroidism isconsidered a likely complication. Postoperative hypothyroidism is not considered to be acomplication but almost an essential desired result. Therefore, significant thyroid tissue shouldbe removed, with the residual left in place only to the extent that the parathyroid glands willbe identified. If enough thyroid tissue remains, the patient does not develop hypothyroidismand is at risk for later reactivation of clinical Graves' disease. However, patients and theirfamilies are told that hypothyroidism will likely occur sooner or later in the postoperativecourse. In a report on a large series, the incidence of postoperative hypothyroidism followingsubtotal thyroidectomy was 40 per cent in the first 18 months, with an additional 10 per centdeveloping late hypothyroidism in the decade following surgery (Hedley et al, 1983).
Hypothyroidism may be subtle in those patients in whom it begins many years postoperatively. Such situations appear to be due to functional remnants of thyroid eventuallyundergoing immune destruction. The basic antithyroid immunoglobulin attack persists in theremnants and eventually leads to destruction of thyroid tissue in a disease process similar tochronic lymphocytic thyroiditis. Acute hypothyroidism after surgery develops due to totalresection of functional thyroid tissue.
Postoperative hypoparathyroidism occurs in 1 to 2 per cent of patients following subtotal thyroidectomy. Many investigators report that up to 10 per cent of the patients mayhave subtle forms of hypoparathyroidism, which become manifest during calcium deficiencyand periods of severe stress. Transient hypoparathyroidism lasting from 8 to 48 hours mayoccur in up to 50 per cent of patients following subtotal thyroidectomy. This appears to besomewhat more common in the pediatric population. Paralysis of the vocal cords due torecurrent laryngeal nerve injury may occur in up to 5 per cent of patients, although theincidence approaches zero with an experienced surgeon. This condition is usually unilateral.
In most cases, it produces alterations in the characteristics of the voice and may result inchronic hoarseness. Bilateral recurrent laryngeal nerve paralysis leads to airway obstruction,although vocal function is good, and may require a tracheostomy.
Statistics regarding the postoperative persistence of hyperthyroidism vary but probably average about 5 per cent. The recurrence of Graves' disease in the postoperative gland is afunction of the amount of thyroid tissue removed initially. The incidence of this recurrenceis probably between 5 and 10 per cent, although it appears that immunologic destruction ofpersistent thyroid remnants is more likely with consequent hypothyroidism than is recurrenceof active hyperthyroidism.
Radioactive Iodine Therapy. The retention of iodine in significant amounts is the
unique function of the thyroid gland. This factor makes the use of therapeutic radioactiveiodine extremely appealing and suggests that the thyroid is the ideal organ for such therapy(Volpe et al, 1960). Iodine 131, a predominantly beta-emitting isotope, has a half-life of 8days. Less than 10 per cent of the radiation from this source is of the gamma type. Becausebeta emissions travel only small distances within the thyroid gland, the administration of thisisotope has a minimum effect on surrounding structures. This allows for the application ofconsiderable doses of radiation without threatening tissues other than the thyroid itself. Theprinciple of iodine 131 radiation treatment is that only some cells are destroyed and othersare left intact. Consequently, the absolute synthesis of thyroid hormone is reduced. Theadvantages of this treatment are its convenience and the fact that it can generally beadministered to the patient as a single dose without necessitating admission to the hospital.
Surgical complications and the burden of regularly taking medication are eliminated.
However, the specific dose of radiation necessary to selectively destroy thyroid cells is somewhat arbitrary. Clinical effects are first noted 1 month following treatment, andimprovement follows gradually thereafter. Associated with these effects is a progressivediminution in the size of the goiter. Approximately 80 per cent of patients so treated establisheuthyroid or hypothyroid status after a single dose. Second and third doses may be requiredin the remaining patients.
The most important side effect with this radioactive iodine treatment is hypothyroidism. The incidence of this complication varies, but in most centers, it is between20 and 70 per cent. Between 20 and 30 per cent of patients become hypothyroid during thefirst year following therapy, and this incidence increases to 50 to 70 per cent of patients inthe first 10 years following treatment. Since the condition may be progressive over a longperiod of time as greater amounts of thyroid tissue become less active, progressive increasesin exogenous thyroid dosage may be needed.
Although other complications remain primarily theoretical, they have resulted in contraindication of radioactive iodine therapy in a large number of centers and have causedexclusion of its use in pediatric and adolescent patients. These potential complications includeleukemia, genetic mutations, and an increased incidence of carcinoma of the thyroid. Studiesrelated to determining the incidence of these complications have not yet clearly demonstratedthat any of these effects are related to radioactive iodine therapy. However, such risks maybe real, and the use of radioactive iodine therapy has been restricted.
Antithyroid Drug Treatment. At the present time, two specific antithyroidal agents,
propylthiouracil (PTU) and methimazole (Tapazole), are used in the treatment of Graves'disease. Propylthiouracil has been the drug of choice, particularly in the pediatric patient, forcontrolling Graves' disease. This drug appears to act by inhibiting critical enzyme systemsinvolved in thyroxine synthesis, thereby reducing the amount of thyroid hormone releasedfrom the gland. It also acts peripherally in inhibiting the conversion of T4 and T3.
Methimazole appears to exert its effect exclusively by blocking thyroid hormone synthesiswithin the gland.
A recommended initiating dose for propylthiouracil is 6 to 7 mg/kg of body weight/day, and the drug is administered every 8 hours. In both cases, the duration of action of the medications is 8 to 10 hours. Patients are followed at 2-week intervals with serum T4and T3 determinations by radioimmunoassay. Dosages of propylthiouracil are maintained at6 to 7 mg/kg/day until the serum T3 level returns to normal values. At that time, the dosageis reduced to one-half of the initiating dose. Following complete clinical remission ofsymptoms, the dose is slowly and progressively diminished for up to 3 years, at which timedrug therapy is discontinued, and clinical and laboratory responses are followed. Anotherprogram recommends that single doses of propylthiouracil in the range of 0.5 to 1. 5mg/kg/day is often enough to maintain a euthyroid state.
The goiter may enlarge during this type of therapy, and this enlargement may be due to progression of the underlying autoimmune process, which is not ameliorated orsignificantly affected by such drug therapy. Likewise, the exophthalmos may progress orrecede independently of the patient's thyroid status or response to antithyroid medication.
Complications of drug therapy include agranulocytosis, which occurs in approximately 0.5 percent of patients. This complication appears to be an idiosyncratic type of reaction; however,the incidence tends to be reduced with maintenance of lower doses of propylthiouracil andmethimazole. This complication develops rather quickly and cannot be foreseen by performingfrequent routine white blood cell counts. Clinical manifestations that may suggest the presenceof the condition include severe pharyngitis with accompanying fever as well as rashes. Ifpatients develop any of these symptoms, the medication should be discontinued immediatelyand a white blood cell performed. This type of agranulocytosis is usually reversible, and ifdetected in the acute phase, it may be of only minimal clinical significance. Other side effectsreported include joint pains, muscle pains, jaundice, fever, hepatitis, neuritis, loss of tastesensation, toxic psychoses, lymphadenopathy, loss of hair pigmentation, and a lupus-likesyndrome.
Parathyroid Hormone and Calcium Metabolism
The regulation of calcium metabolism in the body is formally under the control of two hormones. Until 1960, the only identified internal regulator of serum calcium was parathyroidhormone. This was first discovered in 1925 by Collip, who extracted the active principle frombovine parathyroid glands. This hormone has since been discovered to be intimately involvedin the regulation of calcium metabolism by its effects on bone, kidney, and gastrointestinalabsorption. The other agent long recognized to play a basic role in mobilizing calcium isvitamin D. Its role, however, appeared permissive and not regulatory. However, it is nowknown that the vitamin and the hormone interact closely with a more recently discoveredhormone produced by the C-cells of the thyroid gland and named thyrocalcitonin (TCT). Theaction of this latter hormone appears to be that of inhibiting bone resorption, in contrast tothat of parathyroid hormone, which stimulates resorption. TCT appears to have a burst effectin preventing hypercalcemia. Thus, TCT, which appears to be the regulator, actssynergistically with phosphate, which is the enhancer.
Usually, there are two to six parathyroid glands, although four is the more common number. In the adult, each of these glands, usually in close approximation to the thyroidgland, is 5 x 3 mm in size and weighs approximately 35 mg. The microscopic anatomy ofthese glands indicates that oxyphil cells appear at about the time of puberty. These cells, aswell as the fat cells that appear in the stroma in late childhood, increase in number until theyoccupy 50 per cent of the volume of the gland. There are two types of chief cells that comprise cords, sheets, and acini in a loose areolar stroma. The light chief cell, an inactivecell, has abundant glycogen. The dark chief cell, an active cell, has a less well-defined cellmembrane and shows some glycogen. The oxyphil cell normally has no significant role inproduction of parathyroid hormone (PTH), whereas the ultrastructure of the active form ofthe chief cell indicates that this is the producer of parathyroid hormone.
PTH contains 84 amino acids and the amino terminal 34 residue has full biologic activity measured in vivo and in vitro. Deletion of two-thirds of the carboxyl terminal end isallowed. This is similar to ACTH.
Proparathyroid hormone, the precursor of PTH, is found in the glandular tissue but only rarely in serum samples. It has a 6- to 20-peptide sequence at the amino terminal.
Clinical detection of PTH by radioimmunoassay shows that the plasma contains hormonal fragments as well as intact 84-amino-acid PTH. The dominant fragment in serumis the carboxyl terminal fragment. This is the inactive fragment, and therefore, much of theassayable amino acid circulating hormone is biologically inactive. Three generally usefulamino acid assays have been described, one for the N-terminal PTH, one for the carboxylterminal PTH, and one specific for the midportion of the molecule.
In 1941, Albright showed that low serum calcium levels produced parathyroid hyperplasia. PTH hyperfunction in vitamin D deficiency has been noted and is due todecreased serum calcium levels, which are, in turn, secondary to decreased calciumabsorption. The negative feedback hypothesis formulated in 1955 by McClean has held trueand indicates that this gland, like the pancreas, is not under the control of the master pituitarygland. Further studies have suggested that calcium affects both parathyroid hormone synthesisand secretion, whereas magnesium ion concentrations affect only secretion. At the cellularlevel, proparathyroid hormone is created at the ribosomes and converted in the endoplasmicreticulum to PTH. A low calcium diet increases the conversion efficiency without increasingthe synthesis of proparathyroid hormone. Ectopic peptide formation by derepression in atumor cell can produce hypercalcemia without evidence of bony metastasis. Frequently, apatient with multiglandular parathyroid hyperplasia or adenomas actively secretes bothproparathyroid hormone and intact PTH.
The two primary actions of PTH are (1) inhibition of phosphate resorption by the renal tubule and (2) resorption of phosphate and calcium from the bone by stimulating the activityof the osteoclasts. The two secondary actions are (1) increased calcium absorption from thegastrointestinal tract and (2) action of the renal tubule that enhances calcium resorption.
Specifically, PTH acts on the proximal tubule to activate cyclic adenosine monophosphate(cAMP) and to inhibit sodium, phosphate, and calcium reabsorption. In the distal tubule, thishormone further inhibits phosphate reabsorption but increases calcium reabsorption. These tworenal sites of action of PTH result in its phosphaturic and anticalciuric effects and an increasein cAMP secretion. This latter finding is another mechanism used in the chemical detectionof hyperparathyroidism.
In all of its functions, vitamin D is actively involved with PTH, particularly after hydroxylation in the liver and further hydroxylation in the kidney to the metabolically activeform 1.25-dihydrocholecalciferol. Calcium absorption from the gut is independent of phosphate serum calcium ion concentration. The mechanism is activated by PTH and leadsto increased activity of vitamin D by increasing the rate of hydroxylation to the active form.
PTH also stimulates hydroxylase activity, which produces increased calcium absorption.
However, this activity is delayed more than 24 hours after PTH enters the bloodstream;therefore, supplemental parenteral calcium ion may be needed in acutely hypoparathyroid orhypocalcemic patients.
There is little lag time before PTH activity on the target cell ceases. The large calcium pool in bone allows the body homeostasis for wide ranges and durations.
The C-terminal residue is normal in hypercalcemia of metastatic bone cancer and other nonparathyroid hormone causes of hypercalcemia.
Primary hyperparathyroidism is a disorder of mineral metabolism characterized by a defect in the normal feedback control of parathyroid hormone secretion by the plasma calciumconcentration. Secondary hyperparathyroidism is a disorder characterized by a primarydisruption of mineral homeostasis leading to a compensatory increase in parathyroid glandfunction and size. Hyperparathyroidism is the most common disorder of the gland and is dueto adenoma 88 per cent of the time, hyperplasia 11 per cent of the time, and carcinoma 1 to2 per cent of the time. Hypercalcemia, on the other hand, is most frequently caused bymalignant disease that is usually unrelented to the parathyroid glands and is most frequentlydue to osteolytic metastases. Other nonparathyroid causes for hypercalcemia includesarcoidosis, milk alkaline syndrome, adrenal insufficiency, and prolonged bed rest.
OccasiÁnally, metabolically active nonparathyroid neoplasms have been the source of thehypercalcemia. In general, excess parathyroid hormone secretion produces increasedphosphaturia and hypocalciuria accompanied by hypercalcemia and hyperchloremic acidosis.
The renal synthesis of vitamin D increases intestinal absorption and acts with the parathyroidhormone to decalcify bone.
Hyperparathyroidism is frequently detected clinically by the presence of renal calculi, vague gastrointestinal symptoms, or skeletal pain. Acute or severe disease causes centralnervous system (CNS) symptoms. The EKG shows a decreased Q-T interval. Typically, theserum calcium concentration is elevated and the serum phosphate level is abnormally low.
The alkaline phosphatase level is elevated only in the presence of bone disease. Subperiostealabsorption of bone is associated with the condition, as well as peptic ulcer disease and epulisof the jaw.
The differential diagnosis is reviewed for each patient because neck and mediastinal exploration is mandatory if other causes for the hypercalcemia are excluded by routinestudies. The biochemical battery for detection of this disorder is discussed later.
Hypovitaminosis D (greater than 50,000 units per day) produces hypercalcemia with hyperphosphatemia, which together with blood samples showing normal levels of PTH,differentiates this condition from primary hyperparathyroidism. Hypercalcemia due to bonymetastasis is identified by an abnormal radiograph or scan in conjunction with an increasedalkaline phosphatase level as well as the usual complaint of bone pain in a patient with metastatic carcinoma. Pseudohyperparathyroidism has been described since 1937 and isusually due to secretion of a polypeptide hormone from the primary tumor. The ectopichormone is frequently indistinguishable from normal parathyroid hormone. However, carefulbiochemical study may distinguish this ectopic hormone-producing tumor from primarybenign hyperplasia of the parathyroid glands.
The routine differential findings are as follows: A serum chloride level below 102 mEq/L is usual in primary hyperparathyroidism but infrequent in pseudohyperparathyroidism.
Similarly, subperiosteal bone destruction and renal calculi are less frequently found inpseudohyperparathyroidism. This bone destruction is most frequently due to lung and renaltumors, whereas hypercalcemia due to bony metastasis is most frequently seen with breastcancer. Measuring levels of C-terminal fragment PTH (or inactive PTH (iPTH)) in proportionto the serum calcium levels aids in differentiation. This ratio is found to be greater inpseudohyperparathyroidism than in primary hyperparathyroidism. Therefore, the C-terminalfragment is the best differential diagnostic agent. Venous blood from the tumor region maybe measured for intact PTH and the values compared with those of neck vein blood. This willfrequently indicate the source of the PTH. The tumor assay for PTH is most definitive in itsdiagnosis.
It is important to differentiate primary and pseudohyperparathyroidism in patients with a thoracic or abdominal cancer because synchronous parathyroid disease may occur. Thehypercalcemia must be treated directly by removal of the overproducing tissue, whether thisis lung cancer or hyperplastic parathyroid tissue. In pseudohyperparathyroidism, theparathyroid tissue is normal and is not hyperplastic. This situation has thwarted the hypothesisthat the lesion is on the parathyroid glands. If chemical and venous catheter studies areinconclusive, neck exploration is indicated to detect adenoma in treated renal or lung cancerpatients whose course is expected to be protracted. Removal of a primary secretingmalignancy of the lung or kidney as well as eradicating all evidence of metastases returns thecalcium metabolism to normal. Recurrence of calcium imbalance suggests regrowth of thetumor or the presence of a growth on the parathyroid gland.
Acute hypercalcemia is almost always due to metastatic disease. Its treatment is urgent, since rapid death may occur. Much of the treatment requires overcoming the effectsof hypercalcemia. This includes hydration as well as salt loading to oppose the dehydrationdue to the gastrointestinal symptoms and the renal effects of hypercalcemia, such as stonesand concentrated urine. Preparations used include the diuretic furosemide as well as steroids,which are most effective in metastatic bone disease and are almost always ineffective inhyperparathyroidism. Increasing phosphate and milk in the diet decreases calcium absorptionfrom the gut. Mithramycin chemotherapy as a single dose of 25 microg/kg has been usedsuccessfully against tumors. This chemotherapeutic antibiotic inhibits DNA-dependent RNAsynthesis, and its effects, which last 1 week, may be due to PTH antagonism. Removing theproducing tissue, if possible, is obviously the best treatment.


Appendix 2 - Commissioning Best Value Programme Cash releasing schemes Comments There are two elements to the Falls Programme; a new community falls pathway and NWAS deflections. The primary care falls pathway to pilot in two practices. This has been delayed as one of the practices originally identified has withdrawn from the process. A replacement practice has been identified but is likely

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