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Clinical approach to goitre
8 Clinical approach to goitre GIANFRANCO FENZI CLAUDIO MARCOCCI FABRIZIO AGHINI-LOMBARDI ALDO PINCHERA
Most thyroid diseases manifest themselves through symptoms resulting from either an excess or a deficiency of thyroid hormones, or through local symptoms related to the presence of a goitre. It is not uncommon, however, to discover a thyroid disorder in a patient who seeks medical advice for other reasons, particularly in iodine-deficient areas, where there is a high prevalence of non-toxic goitre.
CLINICAL EVALUATION The clinical evaluation of goitre is based upon a carefully taken history, an accurate physical examination of the thyroid, as well as of neighbouring neck structures, and finally an evaluation of the patient's metabolic state. It is important to establish how long the goitre has been present: longstanding goitre suggests benign disease, unless there has been a recent rapid enlargement. A detailed list of drugs being taken by the patient should be recorded, with particular reference to those with known goitrogenic action or those containing iodine. Severe tenderness suggests subacute thyroiditis; a sudden pain in a nodule or in an apparently normal gland is most likely to be the result of haemorrhage. Local symptoms of goitre are uncommon, and large goitres are usually well tolerated, unless partly or wholly retrosternal, when difficulty in swallowing and shortness of breath are common. The family history is also important. A familial goitre developing in adult life is likely to be due either to iodine deficiency or to autoimmune thyroiditis, while in childhood it suggests iodine deficiency or dyshormonogenesis. The metabolic state of the patient should be ascertained through careful questioning. It is important to remember that the majority of patients with goitre are euthyroid. Symptoms of hypothyroidism are often mild and so slow in developing that the patient may feel they are merely due to natural ageing. On the other hand, goitrous patients may often present with symptoms suggesting hyperthyroidism, such as anxiety, weight loss, palpitations and sweating. Frequently these symptoms are the result of a concomitant Bailli&re's Clinical Endocrinology and Metabolism--Vol. 2, No. 3, August 1988
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emotional disorder. Finally, it is common for the patient, after becoming aware of his/her goitre to attribute a variety of local and general complaints to the thyroid condition, although careful evaluation will reveal that they are not dependent on the thyroid enlargement. Frequently the patient's and physician's attention are focused on the thyroid enlargement; however, the ultimate goal is to establish a functional and anatomical diagnosis. These two aspects cannot always be considered independently, since the functional state will often narrow the possible specific diagnoses. Although largely dependent on the metabolic state, the anatomical diagnosis is mainly based upon the physical examination of the thyroid gland and on ancillary techniques of imaging. For local examination of the neck the patient should be seated in a well lit place, ideally facing a window. The physician should pay attention to any neck enlargement and/or lumps, and to its (their) mobility on swallowing. The normal thyroid is barely visible even with the neck fully extended. Therefore, a visible thyroid is enough to establish the presence of a goitre. Mobility during swallowing distinguishes thyroidal from other masses arising in the neck. However, when the goitre is so large as to occupy all the space available in the neck, or in cases of Riedel's thyroiditis or invasive carcinoma, movement on swallowing is lost. In palpation of the neck the examiner should outline the thyroid gland and determine the limits of the borders of the lateral lobes. The normal gland can usually be appreciated on palpation and it feels rubbery. The gland is considered enlarged when the lateral lobes are larger than the terminal phalanx of the thumb of the subject. A useful grading system has been suggested by the World Health Organization, particularly for epidemiological studies (Table 1). Irregularity of the surface, increased firmness, tender areas and nodules should be recorded. When a nodule is found, the physician should evaluate its size and establish whether it is solitary or associated with other nodules. Tenderness is typical of acute or subacute thyroiditis or recent haemorrhage. In Hashimoto's thyroiditis the gland is firm and nodular, whereas a stony hard consistency is more suggestive of thyroid carcinoma or Riedel's thyroiditis. The presence of the pyramidal lobe is typical of diseases characterized by diffuse thyroid enlargement and it should be distinguished from the 'Delphian' (pre-tracheal) lymph node. A vascular thrill may be felt and is suggestive of hyperthyroidism. In this case a continuous systolic bruit is commonly heard. In patients with a retrosternal goitre raising the arm produces congestion of the face and Table 1. Grading of thyroid size for epidemiological studies.
Stage 0: Stage la: Stage lb: Stage 2: Stage 3:
No goitre Goitre detectable only by palpation and not visible, even when the neck is fully extended. Goitre palpable and visible only when the neck is fully extended; nodular glands are included, even if not goitrous. Goitre visible with the neck in normal position; palpation is not needed for diagnosis. Very large goitre which can be recognized at a considerable distance,
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673
respiratory distress, as a result of further narrowing of the thoracic inlet, already occupied by the retrosternal goitre, increasing compression of the veins and trachea (Pemberton's sign). The value of thyroid palpation cannot be overstated. When performed properly, it can disclose nodules that do not appear on scintiscan because of their small size, peripheral or posterior location, or tracer uptake equal to that of the surrounding tissue. Often palpation reveals nodules which need further evaluation. Palpation cannot distinguish solid from cystic thyroid nodules, but a very hard and firm nodule and the concomitant presence of cervical lymphadenopathy may increase the suspicion of thyroid malignancy. Other neck structures may be involved in thyroid disease. When a goitre is present, particularly if it extends into the mediastinum, compression of adjacent structures produces several physical signs. Deviation and/or compression of the trachea may cause dyspnoea, cough and inspiratory stridor. Hoarseness may indicate involvement of the recurrent laryngeal nerve, which should be confirmed by laryngoscopy. Hoarseness may also be observed when thyroid inflammation spreads beyond the capsule, or when a rapidly enlarging thyroid nodule stretches the nerve. Once physical examination has established the presence of a goitre, several questions have to be answered: 1. 2. 3. 4. 5. 6.
Is the goitre endemic or sporadic? Is the goitrous patient euthyroid, hyper- or hypothyroid? Is there any evidence of thyroid autoimmunity? Is the goitre diffuse or nodular? If nodular, is there any evidence of malignancy? Is there any evidence of compression and/or displacement of neighbouring structures?
ENDEMIC AND SPORADIC GOITRE
Although measurement of the urinary iodine excretion is the only assay able to confirm and quantitate iodine deficiency in a particular area, individual determinations are of limited value since the excretion of iodine varies considerably from day to day, depending on the variation of iodine intake. Thus, when a patient resides in an area previously not evaluated for iodine deficiency, a large number of urinary samples from that area are required to establish the role of iodine deficiency in goitre development. Familial goitre, especially in children, should raise the question of genetically transmitted hormonogenesis defects that can be demonstrated using appropriate diagnostic procedures. Overt or subclinical hypothyroidism is generally present in these cases. Measurement of thyroid iodine uptake is still a useful procedure when a familial goitre is suspected (Harden et al, 1968). Except in the rare case of iodide transport deficiency the rate of uptake is increased. The perchlorate discharge test should also be performed to ascertain whether an organification defect is present (McGirr,
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1960; Parker and Beierwaltes, 1961). A positive test can also be observed in Hashimoto's thyroiditis, a condition which should be excluded by measurement of thyroid autoantibodies. When the perchlorate test is negative additional tests may be performed to identify the specific defect (see Chapter 12). ASSESSMENT OF THYROID STATUS
In this section our attention will be focused on tests commonly used in the initial assessment of thyroid status, which include determination of total serum thyroxine (T4) (TT4) and tri-iodothyronine (T3) (TT3), free thyroid hormone indices (FT41 and FT3I), and thyroid stimulating hormone (TSH) (by conventional radio-immunoassay). In a recent study we have evaluated the sensitivity and specificity (Galen and Gambino, 1980; Pinchera et al, 1984) of individual tests for the evaluation of the thyroid status in 145 normal subjects and in 1253 consecutive patients referred to our Institution for thyroid evaluation. For the detection of hypothyroidism (Table 2) serum TSH assay showed Table 2. Comparison of thyroid function test: hypothyroidism versus normal subjects.
Sensitivity (%) Specificity (%) Predictive value of positive for study group (%) for 1% prevalence (%) Efficiency (%)
TT4
FT4I
TT3
FT3I
TSH
71 99
71 99
45 97
55 97
94 100
98 41 90
98 41 89
90 23 79
92 16 82
i00 100 96
the highest sensitivity, specificity, predictive value and efficiency, confirming its well established value in the diagnosis of primary thyroid failure. TT4 and FT4I had a high specificity (99%) but low sensitivity (71%): none of the normal subjects had values below the normal range, but a consistent minority of hypothyroid patients, particularly those with mild or subclinical hypothyroidism, showed values in the normal range. TT3 and FT3I had low sensitivity, in keeping with the concept that normal values are often found in patients with mild or moderate hypothyroidism (Pinchera et al, 1984). For the detection of hyperthyroidism (Table 3) FT3I and FT4I had a slightly higher'value than that of TT4 o r TT3, FT3I having a higher sensitivity than FT4I, because of the occurrence of T3 toxicosis in some patients with toxic adenoma or toxic multinodular goitre (Martino et al, 1985). No difference was found in patients with toxic diffuse goitre. On the contrary, FT4I showed a greater specificity when compared with FT3I (99% vs 92%). Thus, when a single test has to be performed, FT4I may be preferable in iodine-sufficient areas, where toxic diffuse goitre accounts for the large majority of cases of hyperthyroidism. On the other hand, FT3I may be
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CLINICAL APPROACHTO GOITRE
Table 3. Comparison of thyroid function tests: hyperthyroidism versus normal subjects. TT4
FT4I
TT3
FT3I
TSH
Toxic diffuse go#re Sensitivity (%) Specificity (%)
86 97
93 99
95 90
99 92
85 80
Toxic mu#inodular goitre Sensitivity (%) Specificity (%)
69 97
78 99
83 90
92 92
82 80
Toxic adenoma Sensitivity (%) Specificity (%)
36 97
41 99
95 90
95 92
79 80
performed in iodine-deficient areas, where toxic adenoma and toxic multinodular goitre are frequently encountered. TSH determination had a low diagnostic value, since common radio-immunoassays of TSH do not clearly differentiate low-normal from hyperthyroid values (Pinchera et al, 1984). This problem has recently been overcome by the development of ultrasensitive immunoradiometric TSH assays (Wehmann et al, 1979; Spencer and Nicoloff, 1980; Evans et al, 1985; Martino et al, 1986; Carayon et al, 1987) which should, using monoclonal antibodies, discriminate between normal subjects (who have detectable TSH) and hyperthyroid patients (who have undetectable TSH) (Figure 1; Martino et al, 1986). Furthermore, the use of the ultrasensitive TSH assay can avoid the need for the timeconsuming and expensive TRH test, previously performed in cases of questionable slight hyperthyroidism, when the conventional TSH assay was used. It is interesting to note that six out of 64 patients with non-toxic goitre had undetectable serum TSH, with no response to thyrotrophin releasing hormone (TRH) administration (Martino et al, 1986). These findings are compatible with pre-clinical hyperthyroidism due to the presence of autonomously functioning areas within the gland, a common development in non-toxic goitre. Measurement of s e r u m FT4 and FT3 concentrations may also be helpful in the assessment of thyroid function (Martino et al, 1982; Spencer, 1985; Pacchiarotti et al, 1986). In hyperthyroid patients mean concentrations of free thyroid hormones were clearly increased and complete discrimination from normal subjects was obtained using FT3 measurements, while borderline FT4 values were observed in some cases. In hypothyroid patients mean concentrations of free thyroid hormones were clearly decreased. In some cases there was an overlap in FT3 values between hypothyroid and normal subjects, whereas FT4 was reduced in all. Thus, as is the case of free thyroid hormone indices, measurement of FT4 is of greater value than that of FT3 in the identification of hypothyroidism, while the reverse is true for hyperthyroidism (Figure 2). From these data it appears that TSH measurement by ultrasensitive methods is sufficient as a single test to recognize both hyperthyroid as well as hypothyroid patients. When such a method is not available, measurement of free thyroid hormones (or FT4I and FT3I) is recommended for the evalu-
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ation of patients with suspected hyperthyroidism, while TSH still remains the more sensitive and specific test to detect hypothyroidism. CLINICAL RELEVANCE OF CIRCULATING THYROID AUTOANTIBODIES
Humoral and cellular immune responses are both involved in autoimmune diseases of the thyroid gland (Weetman and McGregor, 1984; Pinchera et al, 1985; Volp6, 1986). Several antigen-antibody systems have been identified, involving different constituents of the thyroid gland: thyroglobulin (Tg), the microsomal antigen, the second antigen of the colloid, the cell surface antigen(s), the antigen(s) related to the TSH receptor, and the thyroid hormones themselves. Recent studies have clearly shown that the microsomal antigen is located on the surface of thyroid follicular cells and is chemically and immunologically identical to the thyroid peroxidase (TPO) (Czarnocka et al, 1985; Portmann et al, 1985; Mariotti et al, 1987); for this reason, from now on, the term TPO will be used as synonymous with the microsomal antigen. The most widely employed tests for thyroid autoimmunity are measurements of anti-Tg and anti-TPO antibodies by passive haemagglutination or radio-immunoassay. Significant titres of anti-Tg antibodies are found in 50-70% of patients with Hashimoto's thyroiditis or newly diagnosed idiopathic myxoedema, in about one third of those with Graves' disease and in a small percentage of patients with thyroid carcinoma and other thyroid disorders. Anti-TPO antibodies are detectable by passive haemagglutination in almost all patients with Hashimoto's thyroiditis, in most of those with idiopathic myxoedema or Graves' disease, and much less frequently in other thyroid disorders. When the results of anti-Tg and anti-TPO antibody tests in various thyroid disorders are compared, it is evident that anti-TPO antibodies frequently occur in the absence of anti-Tg antibodies, while only rarely is the reverse observed (Weetman and McGregor, 1984). Thus, it would appear that anti-TPO antibody determination provides a more sensitive index of thyroid autoimmunity than the anti-Tg antibody test. We believe that measurement of both types of antibodies is required since they explore two different antigen-antibody systems. If a single test has to be used for screening, preference should be given to the anti-TPO antibody assay. It is worth noting that the presence of thyroid antibodies is of limited value in establishing the precise nature of the goitre, since it only indicates that an autoimmune response has been triggered. Recently we have studied the prevalence of anti-Tg and anti-TPO antibodies by passive haemagglutination in a large number of subjects from an area of moderate iodine deficiency (Fenzi et al, 1986a,b). Adults with non-toxic goitre showed a significant increase in the frequency of positive anti-Tg and/or anti-TPO test (17%), compared with age-matched controls from an iodine-sufficient area. In children residing in this iodine deficient area the presence of goitre was not related to thyroid autoantibodies in their
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parents (Fenzi et al, 1986a). These data suggest that thyroid autoimmune phenomena do not play an important role in goitrogenesis, but may occur in endemic goitre as a consequence of the iodine deficiency disorder. TSH receptor antibodies are detected by their ability to inhibit the binding of 125I-TSH to the TSH receptor (TBII) or to stimulate thyroid adenylate cyclase or iodide uptake (TSAb) (Vitti et al, 1982). They are generally found in up to 90% of patients with active Graves' disease, and, much less frequently in patients with other thyroid disorders. In our series TSAb and TBII have been found only occasionally in patients with Hashimoto's thyroiditis and toxic nodular goitre (Figure 3). The latter patients also showed elevated values of anti-TPO and/or anti-Tg antibodies. These data are best interpreted by assuming that this group of patients with toxic nodular goitre is heterogeneous and comprises patients with nodular Graves' disease as well as nodular toxic goitres without autoimmune stigmata (Vitti et al, 1982; Marcocci et al, 1983; Pinchera et al, 1985). Recently, in patients with goitrous diseases, such as non-toxic goitre and endemic goitre, some authors claimed to find thyroid growth stimulating antibodies (TGSAb) in the absence of other thyroid autoantibodies (Drexhage et al, 1980; Smyth et al, 1982; Schatz et al, 1988; Medeiros-Neto et al, 1986). Our laboratory was unable to obtain similar results; the presence of TGSAb was generally associated with the presence of TSAb in Graves' disease, while negative TGSAb results were obtained in sporadic non-toxic goitre and endemic goitre (Fenzi et al, 1986a). These results are in keeping with recent reports from other laboratories (Zakarija, 1987; Gfirtner et al, 1987). A possible explanation for this discrepancy may be differences in assay sensitivity, in patient selection, and to the possibility 10083.3 78
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Figure 3. Incidence of thyroid antibodies in Graves' disease and endemic goitre. Thyroglobulin and microsomal autoantibodies were measured by passive haemagglutination. TSH bindinginhibiting antibody (TBII) by radioreceptor assay. Thyroid stimulating antibody (TSAb) by adenylate cyclase accumulation in FRTL-5 cells. Thyroid growth-stimulating antibody by 3H-thymidine incorporation in FRTL-5 cells.
CLINICAL APPROACH TO GOITRE
679
that other growth factors, present in the samples tested (particularly when non-purified IgG were used), may be responsible for positive results. Clearly, further studies are required to define the role and the diagnostic value of TGSAb in non-toxic goitre. DIAGNOSIS OF NODULAR GOITRE Several advances have been made in the diagnosis of thyroid disorders; in particular the use of high resolution ultrasonography helps to confirm the presence of a nodule in a goitre felt by palpation (Blum et al, 1972; Tannahill et al, 1978; Austin, 1982; Swaenepoel et al, 1982). Small nodules, less than 0.5 cm, can be reliably detected by ultrasonography and the precise size of a nodule as well as of the gland can be defined. Furthermore, ultrasonography often shows that a nodule, apparently solitary on palpation, is actually associated with other smaller nodules. Moreover, this technique allows the distinction between solid and cystic lesions and confirmation of the thyroidal origin of a neck lump. Finally, sonography can be used to perform a more precise needle aspiration of a thyroid nodule, confirming the presence of the needle within the nodular lesion to be sampled. On the other hand, ultrasonography does not provide any information on the functional activity of a nodule. In this respect a thyroid scan, particularly with radio-iodine, still maintains its validity. Diagnostic problems in nodular goitre The presence of nodule(s) constitutes a diagnostic problem, the main goal being to ascertain whether the nodule is benign or malignant (Beckers, 1979; Molitch et al, 1984; Miller, 1985). An increased concentration of calcitonin in a patient with a thyroid nodule is always indicative of medullary thyroid cancer. At present, no other serum markers are available to discriminate between benign and malignant nodule(s). The cytological examination of material obtained by fine needle aspiration allows recognition of papillary and undifferentiated thyroid malignancies, although follicular forms cannot easily be identified by this technique (Walfish et al, 1977; Gharib et al, 1984). More details in the approach to the diagnosis of thyroid nodule are discussed in Chapter 13 of this book. It is often necessary to establish whether thyroid enlargement, particularly nodular, is producing any significant compression and/or displacement of neighbouring structures, providing an objective basis for complaints of local discomfort. X-ray of the neck and the chest on both orthogonal positions should be performed. At the neck level displacement and/or narrowing of the trachea can be observed and examination with barium may occasionally demonstrate displacement of the cervical oesophagus (Figure 4) in patients with large goitres. Less penetrating pictures may show intrathyroidal calcification and will also indicate the size of the goitre and its retrosternal extension. For the latter purpose computerized tomography (CT) scan and magnetic resonance
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Figure 4. X-ray tomographyof a large imdular goitre with calcificationand retrosternal extension. Note the displacementand narrowingof tracheaand cervicaloesophagus.
imaging (MRI) will usually provide a more precise picture of the mediastinal involvement and of the relationship between the goitre and surrounding vascular structures (Wolf et al, 1977; Blum et al, 1984). CONCLUSIONS In the evaluation of a patient referred to the physician with a thyroid enlargement a careful clinical approadl will usually establish the diagnosis. In addition to assessing the nature of the goitre, the diagnostic procedure should include evaluation of thyroid function and the recognition of markers of thyroid autoimmunity. The basis of diagnosis is an accurate history and careful physical examination. Laboratory data will always be needed tr confirm the diagnosis. The presence of nodule(s) requires exclusion c thyroid malignancy and evaluation of local compression of neighbourir structures.
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REFERENCES
Austin CW (1982) Ultrasound evaluation of thyroid and parathyroid disease. Seminars in Ultrasound 4: 250-262. Beckers C (1979) Thyroid nodules. Clinics in Endocrinology and Metabolism 8: 191-196. Blum M, Goldman AB, Herskovic A e t al (1972) Clinical Application of Thyroid Echography. New England Journal of Medicine 287:1164-1170. Blum M, Reede DL, Seltzer TF et al (1984) Computerized axial tomography in the diagnosis of thyroid and parathyroid disorders. American Journal of Medicine 287: 34-39. Carayon P, Martino E, Bartalena L e t al (1987) Clinical usefulness and limitations of serum thyrotropin measurement by ultrasensitive methods. Hormone Research 26: 105-117. Czarnocka B, Ruf J, Ferrand Met al (1985) Purification of the human thyroid peroxidase and its identification as the microsomal antigen involved in autoimmune thyroid diseases. FEBS Letters 190: 14%152. Drexhage HA, Bottazzo GF & Doniach D (1980) Evidence for thyroid growth stimulating immunoglobulins in some goitrous thyroid diseases. Lancet ii: 287-292. Evans M, Croxson MS, Wilson TM et al (1985) The screening of patients with suspected thyrotoxicosis using a sensitive TSH radioimmunoassay. Clinical Endocrinology 22: 445-451. Fenzi GF, Giani C, Ceccarelli Pet al (1986a) Role of autoimmune and familial factors in goiter prevalence. Studies performed in a moderately endemic area. Journal of Endocrinological Investigation 9: 161-164. Fenzi GF, Bartalena L, Lombardi A et al (1986b) Thyroid autoimmunity and endemic goiter. Endocrinologia Experimentalis 20: 49-56. Galen RS & Gambino SL (1980) Beyond normality: the predictive value and the efficiency of medical diagnoses. New York: John Wiley & Sons. G~irtner R, Tsavella C, Bechtner G e t al (1987) Evidence that thyroid growth promoting activity of immunoglobulin preparations is due to contamination with EGF. Acta Endocrinologia 115: 256-259. Gharib H, Goellner JR, Zinsmeister AR et al (1984) Fine needle aspiration biopsy of the thyroid. The problem of suspicious cytologic findings. Annals of Internal Medicine 101: 25-28. Harden R McG, Alexander WD, Chisholm CJS et at (1968) The salivary iodide trap in men: clinical applications. Proceedings of the Royal Society of Medicine 61: 647-649. McGirr EM (1960) Sporadic goiter due to dyshormonogenesis. In Astwood EB (ed.) Clinical Endocrinology, vol. 1, pp 133-141. New York: Grune & Stratton. Mariotti S, Anelli S, Ruf Jet al (1987) Comparison of serum thyroid microsomal and thyroid peroxidase autoantibodies in thyroid diseases. Journal of Clinical Endocrinology and Metabolism 65: 987-993. Marcocci C, Valente WA, Vinchera A et al (1983)Journal of Endocrinological Investigation 6" 463-471. Martino E, Sardano G, Pacchiarotti A e t al (1982) Free thyroid hormones in hyperthyroidism. In Albertini A & Ekins RP (eds) Free Hormones in blood, pp 265-274. Amsterdam: Elsevier Biomedical Press. Martino E, Pacchiarotti A, Aghini Lombardi F et al (1985) Serum free thyroxine in patients with T3 toxicosis. Acta EndocrinoIogia 110: 354-359. Martino E, Bambini G, Bartalena Let al (1986) Human serum thyrotropin measurement by ultrasensitive immunoradiometric assay as a first line test in the evaluation of thyroid function. Clinical Endocrinology 24: 141-148. Medeiros-Neto G, Halpern A, Cozzi ZS et al (1986) Thyroid growth immunoglobulinsin large multinodular endemic goiters: effect of iodized oil. Journal of Clinical Endocrinology and Metabolism 63: 644-650. Miller MJ (1985) Evaluation of thyroid nodules: Accent on needle biopsy. Medical Clinics of North America 69: 1063-1077. Molitch ME, Beck JR, Dreisman M e t al (1984) The cold thyroid nodule: an analysis of diagnostic and therapeutic options. Endocrine Reviews g: 185-199. Pacchiarotti A, Martino E, Bartalena Let al (1986) Serum free thyroid hormones in subclinical hypothyroidism. Journal of Endocrinological Investigations 9: 315-319.
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Parker RH & Beierwaltes WH (1961) Inheritance of defective organification of iodine in familial goitrous cretinism. Journal of Clinical Endocrinology and Metabolism 21" 21-26. Pinchera A, Martino E, Bartalena L et al (1984) Radioimmunoassay utilization in the assessment of thyroid status. In Albertini A, Ekins RP & Galen RS (eds) Cost-benefit and predictive value of radioimmunoassay, pp 151-156. Amsterdam: Elsevier Science Publishers. Pinchera A, Fenzi GF, Vitti Pet al (1985) Significanceof thyroid autoantibodies in autoimmune thyroid disease. In Walfish PG, Wall JR & Volp6 R (eds) Autoimmunity and the thyroid, pp 139-151. New York: Academic Press. Portmann L, Hamada N, Heinrich Get al (1985) Antithyroid peroxidase antibody in patients with autoimmunethyroid disease: possible identity with antimicrosomal antibody. Journal of Clinical Endocrinology and Metabolism 61: 1001. Schatz H, Beckmann FH & Floren M (1983) Radioassay for thyroid growth stimulating immunoglobulins (TGI) with cultivated porcine thyroid follicles. Hormone and Metabolic Research 15: 626-627. Smyth PPA, Neylan D & O'Donovan DK (1982) The prevalence of thyroid stimulating antibodies in goitrous disease assessed by cytochemical section bioassay. Journal of Clinical Endocrinology and Metabolism 54: 357-361. Spencer CA (1985) The comparative clinical value of free T4 estimation using different methodological approaches. NUC Compact 16: 321-326. Spencer CA & Nicoloff TJ (1980) Strategy for improvement of the sensitivity and the specificity of the human TSH radioimmunoassay. Clinica Chimica Acta 108: 415-424. Swaenepoel L, Demeester-Mirkine N, Sacre R et al (1982) Ultrasound examination of the thyroid. Fortschritte der Roengtenstr 1: 12. TannahillAJ, Hooper MJ, England Met al (1978) Measurement of thyroid size by ultrasound, palpation and scintiscan. Clinical Endocrinology 8: 483--486. Vitti P, Valente WA, Ambesi-Impiombato FS et al (1982) Graves' IgG stimulation of continuously cultured rat thyroid cells: a sensitive and potentially useful clinical assay. Journal of Endocrinological Investigation 5: 17%181. Volp6 R (1986) Autoimmune thyroid disease--a perspective. Molecular Biology and Medicine 3: 25-51. Walfish PG, Hazani E, Strawbridge HT et al (1977) Combined ultrasound and needle aspiration cytology in the assessment and management of hypofunctioning thyroid nodule. Annals of Internal Medicine 87: 270-274. Weetman AP & McGregor AM (1984) Autoimmune thyroid disease: developments in our understanding. Endocrine Reviews 5: 309-355. Wehmann RE, RubensteinHA & Nisula BC (1979) A sensitive convenient r adioimmunoassay procedure which demonstrated that serum TSH is suppressed below the normal range in thyrotoxic patients. Endocrine Research Communications 6: 249-255. Wolf BS, Nakagwa H & Hsu-Chong YEH (1977) Visualization of the thyroid gland with computed tomography. Radiology 123: 68-73. Zakarija M (1987) Heterogeneity of TSH receptors directed antibodies (CRAt) and their significance. In Vinchera A et al (eds) Thyroid Plutoimmunity. New York: Plenum Press.
Most thyroid diseases manifest themselves through symptoms resulting from either an excess or a deficiency of thyroid hormones, or through local symptoms related to the presence of a goitre. It is not uncommon, however, to discover a thyroid disorder in a patient who seeks medical advice for other reasons, particularly in iodine-deficient areas, where there is a high prevalence of non-toxic goitre.
CLINICAL EVALUATION The clinical evaluation of goitre is based upon a carefully taken history, an accurate physical examination of the thyroid, as well as of neighbouring neck structures, and finally an evaluation of the patient's metabolic state. It is important to establish how long the goitre has been present: longstanding goitre suggests benign disease, unless there has been a recent rapid enlargement. A detailed list of drugs being taken by the patient should be recorded, with particular reference to those with known goitrogenic action or those containing iodine. Severe tenderness suggests subacute thyroiditis; a sudden pain in a nodule or in an apparently normal gland is most likely to be the result of haemorrhage. Local symptoms of goitre are uncommon, and large goitres are usually well tolerated, unless partly or wholly retrosternal, when difficulty in swallowing and shortness of breath are common. The family history is also important. A familial goitre developing in adult life is likely to be due either to iodine deficiency or to autoimmune thyroiditis, while in childhood it suggests iodine deficiency or dyshormonogenesis. The metabolic state of the patient should be ascertained through careful questioning. It is important to remember that the majority of patients with goitre are euthyroid. Symptoms of hypothyroidism are often mild and so slow in developing that the patient may feel they are merely due to natural ageing. On the other hand, goitrous patients may often present with symptoms suggesting hyperthyroidism, such as anxiety, weight loss, palpitations and sweating. Frequently these symptoms are the result of a concomitant Bailli&re's Clinical Endocrinology and Metabolism--Vol. 2, No. 3, August 1988
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emotional disorder. Finally, it is common for the patient, after becoming aware of his/her goitre to attribute a variety of local and general complaints to the thyroid condition, although careful evaluation will reveal that they are not dependent on the thyroid enlargement. Frequently the patient's and physician's attention are focused on the thyroid enlargement; however, the ultimate goal is to establish a functional and anatomical diagnosis. These two aspects cannot always be considered independently, since the functional state will often narrow the possible specific diagnoses. Although largely dependent on the metabolic state, the anatomical diagnosis is mainly based upon the physical examination of the thyroid gland and on ancillary techniques of imaging. For local examination of the neck the patient should be seated in a well lit place, ideally facing a window. The physician should pay attention to any neck enlargement and/or lumps, and to its (their) mobility on swallowing. The normal thyroid is barely visible even with the neck fully extended. Therefore, a visible thyroid is enough to establish the presence of a goitre. Mobility during swallowing distinguishes thyroidal from other masses arising in the neck. However, when the goitre is so large as to occupy all the space available in the neck, or in cases of Riedel's thyroiditis or invasive carcinoma, movement on swallowing is lost. In palpation of the neck the examiner should outline the thyroid gland and determine the limits of the borders of the lateral lobes. The normal gland can usually be appreciated on palpation and it feels rubbery. The gland is considered enlarged when the lateral lobes are larger than the terminal phalanx of the thumb of the subject. A useful grading system has been suggested by the World Health Organization, particularly for epidemiological studies (Table 1). Irregularity of the surface, increased firmness, tender areas and nodules should be recorded. When a nodule is found, the physician should evaluate its size and establish whether it is solitary or associated with other nodules. Tenderness is typical of acute or subacute thyroiditis or recent haemorrhage. In Hashimoto's thyroiditis the gland is firm and nodular, whereas a stony hard consistency is more suggestive of thyroid carcinoma or Riedel's thyroiditis. The presence of the pyramidal lobe is typical of diseases characterized by diffuse thyroid enlargement and it should be distinguished from the 'Delphian' (pre-tracheal) lymph node. A vascular thrill may be felt and is suggestive of hyperthyroidism. In this case a continuous systolic bruit is commonly heard. In patients with a retrosternal goitre raising the arm produces congestion of the face and Table 1. Grading of thyroid size for epidemiological studies.
Stage 0: Stage la: Stage lb: Stage 2: Stage 3:
No goitre Goitre detectable only by palpation and not visible, even when the neck is fully extended. Goitre palpable and visible only when the neck is fully extended; nodular glands are included, even if not goitrous. Goitre visible with the neck in normal position; palpation is not needed for diagnosis. Very large goitre which can be recognized at a considerable distance,
CLINICAL APPROACH TO GOITRE
673
respiratory distress, as a result of further narrowing of the thoracic inlet, already occupied by the retrosternal goitre, increasing compression of the veins and trachea (Pemberton's sign). The value of thyroid palpation cannot be overstated. When performed properly, it can disclose nodules that do not appear on scintiscan because of their small size, peripheral or posterior location, or tracer uptake equal to that of the surrounding tissue. Often palpation reveals nodules which need further evaluation. Palpation cannot distinguish solid from cystic thyroid nodules, but a very hard and firm nodule and the concomitant presence of cervical lymphadenopathy may increase the suspicion of thyroid malignancy. Other neck structures may be involved in thyroid disease. When a goitre is present, particularly if it extends into the mediastinum, compression of adjacent structures produces several physical signs. Deviation and/or compression of the trachea may cause dyspnoea, cough and inspiratory stridor. Hoarseness may indicate involvement of the recurrent laryngeal nerve, which should be confirmed by laryngoscopy. Hoarseness may also be observed when thyroid inflammation spreads beyond the capsule, or when a rapidly enlarging thyroid nodule stretches the nerve. Once physical examination has established the presence of a goitre, several questions have to be answered: 1. 2. 3. 4. 5. 6.
Is the goitre endemic or sporadic? Is the goitrous patient euthyroid, hyper- or hypothyroid? Is there any evidence of thyroid autoimmunity? Is the goitre diffuse or nodular? If nodular, is there any evidence of malignancy? Is there any evidence of compression and/or displacement of neighbouring structures?
ENDEMIC AND SPORADIC GOITRE
Although measurement of the urinary iodine excretion is the only assay able to confirm and quantitate iodine deficiency in a particular area, individual determinations are of limited value since the excretion of iodine varies considerably from day to day, depending on the variation of iodine intake. Thus, when a patient resides in an area previously not evaluated for iodine deficiency, a large number of urinary samples from that area are required to establish the role of iodine deficiency in goitre development. Familial goitre, especially in children, should raise the question of genetically transmitted hormonogenesis defects that can be demonstrated using appropriate diagnostic procedures. Overt or subclinical hypothyroidism is generally present in these cases. Measurement of thyroid iodine uptake is still a useful procedure when a familial goitre is suspected (Harden et al, 1968). Except in the rare case of iodide transport deficiency the rate of uptake is increased. The perchlorate discharge test should also be performed to ascertain whether an organification defect is present (McGirr,
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G.F. FENZI ET AL
1960; Parker and Beierwaltes, 1961). A positive test can also be observed in Hashimoto's thyroiditis, a condition which should be excluded by measurement of thyroid autoantibodies. When the perchlorate test is negative additional tests may be performed to identify the specific defect (see Chapter 12). ASSESSMENT OF THYROID STATUS
In this section our attention will be focused on tests commonly used in the initial assessment of thyroid status, which include determination of total serum thyroxine (T4) (TT4) and tri-iodothyronine (T3) (TT3), free thyroid hormone indices (FT41 and FT3I), and thyroid stimulating hormone (TSH) (by conventional radio-immunoassay). In a recent study we have evaluated the sensitivity and specificity (Galen and Gambino, 1980; Pinchera et al, 1984) of individual tests for the evaluation of the thyroid status in 145 normal subjects and in 1253 consecutive patients referred to our Institution for thyroid evaluation. For the detection of hypothyroidism (Table 2) serum TSH assay showed Table 2. Comparison of thyroid function test: hypothyroidism versus normal subjects.
Sensitivity (%) Specificity (%) Predictive value of positive for study group (%) for 1% prevalence (%) Efficiency (%)
TT4
FT4I
TT3
FT3I
TSH
71 99
71 99
45 97
55 97
94 100
98 41 90
98 41 89
90 23 79
92 16 82
i00 100 96
the highest sensitivity, specificity, predictive value and efficiency, confirming its well established value in the diagnosis of primary thyroid failure. TT4 and FT4I had a high specificity (99%) but low sensitivity (71%): none of the normal subjects had values below the normal range, but a consistent minority of hypothyroid patients, particularly those with mild or subclinical hypothyroidism, showed values in the normal range. TT3 and FT3I had low sensitivity, in keeping with the concept that normal values are often found in patients with mild or moderate hypothyroidism (Pinchera et al, 1984). For the detection of hyperthyroidism (Table 3) FT3I and FT4I had a slightly higher'value than that of TT4 o r TT3, FT3I having a higher sensitivity than FT4I, because of the occurrence of T3 toxicosis in some patients with toxic adenoma or toxic multinodular goitre (Martino et al, 1985). No difference was found in patients with toxic diffuse goitre. On the contrary, FT4I showed a greater specificity when compared with FT3I (99% vs 92%). Thus, when a single test has to be performed, FT4I may be preferable in iodine-sufficient areas, where toxic diffuse goitre accounts for the large majority of cases of hyperthyroidism. On the other hand, FT3I may be
675
CLINICAL APPROACHTO GOITRE
Table 3. Comparison of thyroid function tests: hyperthyroidism versus normal subjects. TT4
FT4I
TT3
FT3I
TSH
Toxic diffuse go#re Sensitivity (%) Specificity (%)
86 97
93 99
95 90
99 92
85 80
Toxic mu#inodular goitre Sensitivity (%) Specificity (%)
69 97
78 99
83 90
92 92
82 80
Toxic adenoma Sensitivity (%) Specificity (%)
36 97
41 99
95 90
95 92
79 80
performed in iodine-deficient areas, where toxic adenoma and toxic multinodular goitre are frequently encountered. TSH determination had a low diagnostic value, since common radio-immunoassays of TSH do not clearly differentiate low-normal from hyperthyroid values (Pinchera et al, 1984). This problem has recently been overcome by the development of ultrasensitive immunoradiometric TSH assays (Wehmann et al, 1979; Spencer and Nicoloff, 1980; Evans et al, 1985; Martino et al, 1986; Carayon et al, 1987) which should, using monoclonal antibodies, discriminate between normal subjects (who have detectable TSH) and hyperthyroid patients (who have undetectable TSH) (Figure 1; Martino et al, 1986). Furthermore, the use of the ultrasensitive TSH assay can avoid the need for the timeconsuming and expensive TRH test, previously performed in cases of questionable slight hyperthyroidism, when the conventional TSH assay was used. It is interesting to note that six out of 64 patients with non-toxic goitre had undetectable serum TSH, with no response to thyrotrophin releasing hormone (TRH) administration (Martino et al, 1986). These findings are compatible with pre-clinical hyperthyroidism due to the presence of autonomously functioning areas within the gland, a common development in non-toxic goitre. Measurement of s e r u m FT4 and FT3 concentrations may also be helpful in the assessment of thyroid function (Martino et al, 1982; Spencer, 1985; Pacchiarotti et al, 1986). In hyperthyroid patients mean concentrations of free thyroid hormones were clearly increased and complete discrimination from normal subjects was obtained using FT3 measurements, while borderline FT4 values were observed in some cases. In hypothyroid patients mean concentrations of free thyroid hormones were clearly decreased. In some cases there was an overlap in FT3 values between hypothyroid and normal subjects, whereas FT4 was reduced in all. Thus, as is the case of free thyroid hormone indices, measurement of FT4 is of greater value than that of FT3 in the identification of hypothyroidism, while the reverse is true for hyperthyroidism (Figure 2). From these data it appears that TSH measurement by ultrasensitive methods is sufficient as a single test to recognize both hyperthyroid as well as hypothyroid patients. When such a method is not available, measurement of free thyroid hormones (or FT4I and FT3I) is recommended for the evalu-
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Figure 1. Serum TSH concentrations in normal (133) subjects, untreated overt hyperthyroidism (115), primary (96) and central (22) hypothyroidism. Undetectable values were observed in all hyperthyroid subjects, excluding two patients (open circle) with hyperthyroidism due to TSH secreting pituitary tumour. Note logarithmic scale for TSH.
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CLINICALAPPROACHTOGOITRE
677
ation of patients with suspected hyperthyroidism, while TSH still remains the more sensitive and specific test to detect hypothyroidism. CLINICAL RELEVANCE OF CIRCULATING THYROID AUTOANTIBODIES
Humoral and cellular immune responses are both involved in autoimmune diseases of the thyroid gland (Weetman and McGregor, 1984; Pinchera et al, 1985; Volp6, 1986). Several antigen-antibody systems have been identified, involving different constituents of the thyroid gland: thyroglobulin (Tg), the microsomal antigen, the second antigen of the colloid, the cell surface antigen(s), the antigen(s) related to the TSH receptor, and the thyroid hormones themselves. Recent studies have clearly shown that the microsomal antigen is located on the surface of thyroid follicular cells and is chemically and immunologically identical to the thyroid peroxidase (TPO) (Czarnocka et al, 1985; Portmann et al, 1985; Mariotti et al, 1987); for this reason, from now on, the term TPO will be used as synonymous with the microsomal antigen. The most widely employed tests for thyroid autoimmunity are measurements of anti-Tg and anti-TPO antibodies by passive haemagglutination or radio-immunoassay. Significant titres of anti-Tg antibodies are found in 50-70% of patients with Hashimoto's thyroiditis or newly diagnosed idiopathic myxoedema, in about one third of those with Graves' disease and in a small percentage of patients with thyroid carcinoma and other thyroid disorders. Anti-TPO antibodies are detectable by passive haemagglutination in almost all patients with Hashimoto's thyroiditis, in most of those with idiopathic myxoedema or Graves' disease, and much less frequently in other thyroid disorders. When the results of anti-Tg and anti-TPO antibody tests in various thyroid disorders are compared, it is evident that anti-TPO antibodies frequently occur in the absence of anti-Tg antibodies, while only rarely is the reverse observed (Weetman and McGregor, 1984). Thus, it would appear that anti-TPO antibody determination provides a more sensitive index of thyroid autoimmunity than the anti-Tg antibody test. We believe that measurement of both types of antibodies is required since they explore two different antigen-antibody systems. If a single test has to be used for screening, preference should be given to the anti-TPO antibody assay. It is worth noting that the presence of thyroid antibodies is of limited value in establishing the precise nature of the goitre, since it only indicates that an autoimmune response has been triggered. Recently we have studied the prevalence of anti-Tg and anti-TPO antibodies by passive haemagglutination in a large number of subjects from an area of moderate iodine deficiency (Fenzi et al, 1986a,b). Adults with non-toxic goitre showed a significant increase in the frequency of positive anti-Tg and/or anti-TPO test (17%), compared with age-matched controls from an iodine-sufficient area. In children residing in this iodine deficient area the presence of goitre was not related to thyroid autoantibodies in their
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G.F. FENZI ET AL
parents (Fenzi et al, 1986a). These data suggest that thyroid autoimmune phenomena do not play an important role in goitrogenesis, but may occur in endemic goitre as a consequence of the iodine deficiency disorder. TSH receptor antibodies are detected by their ability to inhibit the binding of 125I-TSH to the TSH receptor (TBII) or to stimulate thyroid adenylate cyclase or iodide uptake (TSAb) (Vitti et al, 1982). They are generally found in up to 90% of patients with active Graves' disease, and, much less frequently in patients with other thyroid disorders. In our series TSAb and TBII have been found only occasionally in patients with Hashimoto's thyroiditis and toxic nodular goitre (Figure 3). The latter patients also showed elevated values of anti-TPO and/or anti-Tg antibodies. These data are best interpreted by assuming that this group of patients with toxic nodular goitre is heterogeneous and comprises patients with nodular Graves' disease as well as nodular toxic goitres without autoimmune stigmata (Vitti et al, 1982; Marcocci et al, 1983; Pinchera et al, 1985). Recently, in patients with goitrous diseases, such as non-toxic goitre and endemic goitre, some authors claimed to find thyroid growth stimulating antibodies (TGSAb) in the absence of other thyroid autoantibodies (Drexhage et al, 1980; Smyth et al, 1982; Schatz et al, 1988; Medeiros-Neto et al, 1986). Our laboratory was unable to obtain similar results; the presence of TGSAb was generally associated with the presence of TSAb in Graves' disease, while negative TGSAb results were obtained in sporadic non-toxic goitre and endemic goitre (Fenzi et al, 1986a). These results are in keeping with recent reports from other laboratories (Zakarija, 1987; Gfirtner et al, 1987). A possible explanation for this discrepancy may be differences in assay sensitivity, in patient selection, and to the possibility 10083.3 78
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0 Graves' disease
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Figure 3. Incidence of thyroid antibodies in Graves' disease and endemic goitre. Thyroglobulin and microsomal autoantibodies were measured by passive haemagglutination. TSH bindinginhibiting antibody (TBII) by radioreceptor assay. Thyroid stimulating antibody (TSAb) by adenylate cyclase accumulation in FRTL-5 cells. Thyroid growth-stimulating antibody by 3H-thymidine incorporation in FRTL-5 cells.
CLINICAL APPROACH TO GOITRE
679
that other growth factors, present in the samples tested (particularly when non-purified IgG were used), may be responsible for positive results. Clearly, further studies are required to define the role and the diagnostic value of TGSAb in non-toxic goitre. DIAGNOSIS OF NODULAR GOITRE Several advances have been made in the diagnosis of thyroid disorders; in particular the use of high resolution ultrasonography helps to confirm the presence of a nodule in a goitre felt by palpation (Blum et al, 1972; Tannahill et al, 1978; Austin, 1982; Swaenepoel et al, 1982). Small nodules, less than 0.5 cm, can be reliably detected by ultrasonography and the precise size of a nodule as well as of the gland can be defined. Furthermore, ultrasonography often shows that a nodule, apparently solitary on palpation, is actually associated with other smaller nodules. Moreover, this technique allows the distinction between solid and cystic lesions and confirmation of the thyroidal origin of a neck lump. Finally, sonography can be used to perform a more precise needle aspiration of a thyroid nodule, confirming the presence of the needle within the nodular lesion to be sampled. On the other hand, ultrasonography does not provide any information on the functional activity of a nodule. In this respect a thyroid scan, particularly with radio-iodine, still maintains its validity. Diagnostic problems in nodular goitre The presence of nodule(s) constitutes a diagnostic problem, the main goal being to ascertain whether the nodule is benign or malignant (Beckers, 1979; Molitch et al, 1984; Miller, 1985). An increased concentration of calcitonin in a patient with a thyroid nodule is always indicative of medullary thyroid cancer. At present, no other serum markers are available to discriminate between benign and malignant nodule(s). The cytological examination of material obtained by fine needle aspiration allows recognition of papillary and undifferentiated thyroid malignancies, although follicular forms cannot easily be identified by this technique (Walfish et al, 1977; Gharib et al, 1984). More details in the approach to the diagnosis of thyroid nodule are discussed in Chapter 13 of this book. It is often necessary to establish whether thyroid enlargement, particularly nodular, is producing any significant compression and/or displacement of neighbouring structures, providing an objective basis for complaints of local discomfort. X-ray of the neck and the chest on both orthogonal positions should be performed. At the neck level displacement and/or narrowing of the trachea can be observed and examination with barium may occasionally demonstrate displacement of the cervical oesophagus (Figure 4) in patients with large goitres. Less penetrating pictures may show intrathyroidal calcification and will also indicate the size of the goitre and its retrosternal extension. For the latter purpose computerized tomography (CT) scan and magnetic resonance
680
G. F, FENZI ET AL
Figure 4. X-ray tomographyof a large imdular goitre with calcificationand retrosternal extension. Note the displacementand narrowingof tracheaand cervicaloesophagus.
imaging (MRI) will usually provide a more precise picture of the mediastinal involvement and of the relationship between the goitre and surrounding vascular structures (Wolf et al, 1977; Blum et al, 1984). CONCLUSIONS In the evaluation of a patient referred to the physician with a thyroid enlargement a careful clinical approadl will usually establish the diagnosis. In addition to assessing the nature of the goitre, the diagnostic procedure should include evaluation of thyroid function and the recognition of markers of thyroid autoimmunity. The basis of diagnosis is an accurate history and careful physical examination. Laboratory data will always be needed tr confirm the diagnosis. The presence of nodule(s) requires exclusion c thyroid malignancy and evaluation of local compression of neighbourir structures.
CLINICAL APPROACH TO GOITRE
681
REFERENCES
Austin CW (1982) Ultrasound evaluation of thyroid and parathyroid disease. Seminars in Ultrasound 4: 250-262. Beckers C (1979) Thyroid nodules. Clinics in Endocrinology and Metabolism 8: 191-196. Blum M, Goldman AB, Herskovic A e t al (1972) Clinical Application of Thyroid Echography. New England Journal of Medicine 287:1164-1170. Blum M, Reede DL, Seltzer TF et al (1984) Computerized axial tomography in the diagnosis of thyroid and parathyroid disorders. American Journal of Medicine 287: 34-39. Carayon P, Martino E, Bartalena L e t al (1987) Clinical usefulness and limitations of serum thyrotropin measurement by ultrasensitive methods. Hormone Research 26: 105-117. Czarnocka B, Ruf J, Ferrand Met al (1985) Purification of the human thyroid peroxidase and its identification as the microsomal antigen involved in autoimmune thyroid diseases. FEBS Letters 190: 14%152. Drexhage HA, Bottazzo GF & Doniach D (1980) Evidence for thyroid growth stimulating immunoglobulins in some goitrous thyroid diseases. Lancet ii: 287-292. Evans M, Croxson MS, Wilson TM et al (1985) The screening of patients with suspected thyrotoxicosis using a sensitive TSH radioimmunoassay. Clinical Endocrinology 22: 445-451. Fenzi GF, Giani C, Ceccarelli Pet al (1986a) Role of autoimmune and familial factors in goiter prevalence. Studies performed in a moderately endemic area. Journal of Endocrinological Investigation 9: 161-164. Fenzi GF, Bartalena L, Lombardi A et al (1986b) Thyroid autoimmunity and endemic goiter. Endocrinologia Experimentalis 20: 49-56. Galen RS & Gambino SL (1980) Beyond normality: the predictive value and the efficiency of medical diagnoses. New York: John Wiley & Sons. G~irtner R, Tsavella C, Bechtner G e t al (1987) Evidence that thyroid growth promoting activity of immunoglobulin preparations is due to contamination with EGF. Acta Endocrinologia 115: 256-259. Gharib H, Goellner JR, Zinsmeister AR et al (1984) Fine needle aspiration biopsy of the thyroid. The problem of suspicious cytologic findings. Annals of Internal Medicine 101: 25-28. Harden R McG, Alexander WD, Chisholm CJS et at (1968) The salivary iodide trap in men: clinical applications. Proceedings of the Royal Society of Medicine 61: 647-649. McGirr EM (1960) Sporadic goiter due to dyshormonogenesis. In Astwood EB (ed.) Clinical Endocrinology, vol. 1, pp 133-141. New York: Grune & Stratton. Mariotti S, Anelli S, Ruf Jet al (1987) Comparison of serum thyroid microsomal and thyroid peroxidase autoantibodies in thyroid diseases. Journal of Clinical Endocrinology and Metabolism 65: 987-993. Marcocci C, Valente WA, Vinchera A et al (1983)Journal of Endocrinological Investigation 6" 463-471. Martino E, Sardano G, Pacchiarotti A e t al (1982) Free thyroid hormones in hyperthyroidism. In Albertini A & Ekins RP (eds) Free Hormones in blood, pp 265-274. Amsterdam: Elsevier Biomedical Press. Martino E, Pacchiarotti A, Aghini Lombardi F et al (1985) Serum free thyroxine in patients with T3 toxicosis. Acta EndocrinoIogia 110: 354-359. Martino E, Bambini G, Bartalena Let al (1986) Human serum thyrotropin measurement by ultrasensitive immunoradiometric assay as a first line test in the evaluation of thyroid function. Clinical Endocrinology 24: 141-148. Medeiros-Neto G, Halpern A, Cozzi ZS et al (1986) Thyroid growth immunoglobulinsin large multinodular endemic goiters: effect of iodized oil. Journal of Clinical Endocrinology and Metabolism 63: 644-650. Miller MJ (1985) Evaluation of thyroid nodules: Accent on needle biopsy. Medical Clinics of North America 69: 1063-1077. Molitch ME, Beck JR, Dreisman M e t al (1984) The cold thyroid nodule: an analysis of diagnostic and therapeutic options. Endocrine Reviews g: 185-199. Pacchiarotti A, Martino E, Bartalena Let al (1986) Serum free thyroid hormones in subclinical hypothyroidism. Journal of Endocrinological Investigations 9: 315-319.
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Parker RH & Beierwaltes WH (1961) Inheritance of defective organification of iodine in familial goitrous cretinism. Journal of Clinical Endocrinology and Metabolism 21" 21-26. Pinchera A, Martino E, Bartalena L et al (1984) Radioimmunoassay utilization in the assessment of thyroid status. In Albertini A, Ekins RP & Galen RS (eds) Cost-benefit and predictive value of radioimmunoassay, pp 151-156. Amsterdam: Elsevier Science Publishers. Pinchera A, Fenzi GF, Vitti Pet al (1985) Significanceof thyroid autoantibodies in autoimmune thyroid disease. In Walfish PG, Wall JR & Volp6 R (eds) Autoimmunity and the thyroid, pp 139-151. New York: Academic Press. Portmann L, Hamada N, Heinrich Get al (1985) Antithyroid peroxidase antibody in patients with autoimmunethyroid disease: possible identity with antimicrosomal antibody. Journal of Clinical Endocrinology and Metabolism 61: 1001. Schatz H, Beckmann FH & Floren M (1983) Radioassay for thyroid growth stimulating immunoglobulins (TGI) with cultivated porcine thyroid follicles. Hormone and Metabolic Research 15: 626-627. Smyth PPA, Neylan D & O'Donovan DK (1982) The prevalence of thyroid stimulating antibodies in goitrous disease assessed by cytochemical section bioassay. Journal of Clinical Endocrinology and Metabolism 54: 357-361. Spencer CA (1985) The comparative clinical value of free T4 estimation using different methodological approaches. NUC Compact 16: 321-326. Spencer CA & Nicoloff TJ (1980) Strategy for improvement of the sensitivity and the specificity of the human TSH radioimmunoassay. Clinica Chimica Acta 108: 415-424. Swaenepoel L, Demeester-Mirkine N, Sacre R et al (1982) Ultrasound examination of the thyroid. Fortschritte der Roengtenstr 1: 12. TannahillAJ, Hooper MJ, England Met al (1978) Measurement of thyroid size by ultrasound, palpation and scintiscan. Clinical Endocrinology 8: 483--486. Vitti P, Valente WA, Ambesi-Impiombato FS et al (1982) Graves' IgG stimulation of continuously cultured rat thyroid cells: a sensitive and potentially useful clinical assay. Journal of Endocrinological Investigation 5: 17%181. Volp6 R (1986) Autoimmune thyroid disease--a perspective. Molecular Biology and Medicine 3: 25-51. Walfish PG, Hazani E, Strawbridge HT et al (1977) Combined ultrasound and needle aspiration cytology in the assessment and management of hypofunctioning thyroid nodule. Annals of Internal Medicine 87: 270-274. Weetman AP & McGregor AM (1984) Autoimmune thyroid disease: developments in our understanding. Endocrine Reviews 5: 309-355. Wehmann RE, RubensteinHA & Nisula BC (1979) A sensitive convenient r adioimmunoassay procedure which demonstrated that serum TSH is suppressed below the normal range in thyrotoxic patients. Endocrine Research Communications 6: 249-255. Wolf BS, Nakagwa H & Hsu-Chong YEH (1977) Visualization of the thyroid gland with computed tomography. Radiology 123: 68-73. Zakarija M (1987) Heterogeneity of TSH receptors directed antibodies (CRAt) and their significance. In Vinchera A et al (eds) Thyroid Plutoimmunity. New York: Plenum Press.