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Classification of Thyroid Diseases: Suggestions for a Revision
0013-7227/03/$15.00/0                                                          The Journal of Clinical Endocrinology & Met...
Monaco • Clinical Perspective                                                           J Clin Endocrinol Metab, April 200...
1430   J Clin Endocrinol Metab, April 2003, 88(4):1428 –1432                                                    Monaco • C...
Monaco • Clinical Perspective                                                             J Clin Endocrinol Metab, April 2...
1432   J Clin Endocrinol Metab, April 2003, 88(4):1428 –1432                                                              ...
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Classification of Thyroid Diseases: Suggestions for a Revision


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Classification of Thyroid Diseases: Suggestions for a Revision

  1. 1. Classification of Thyroid Diseases: Suggestions for a Revision Fabrizio Monaco J. Clin. Endocrinol. Metab. 2003 88: 1428-1432, doi: 10.1210/jc.2002-021260 To subscribe to Journal of Clinical Endocrinology & Metabolism or any of the other journals published by The Endocrine Society please go to: Copyright © The Endocrine Society. All rights reserved. Print ISSN: 0021-972X. Online
  2. 2. 0013-7227/03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(4):1428 –1432 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2002-021260 CLINICAL PERSPECTIVE Classification of Thyroid Diseases: Suggestions for a Revision FABRIZIO MONACO Department of Endocrinology, University G. D’Annunzio, 66100 Chieti, Italy The last comprehensive classification of thyroid diseases stressed, and the need to update the nomenclature of thyroid has been reported by the American Thyroid Association in diseases was acknowledged (22). Some recent books on in- 1969. It was based largely on thyroid function; classification ternal medicine have begun to report some of the newly by etiology was considered premature, by pathology non- identified thyroid diseases as special topics, taking into ac- useful to the clinician (1), and the clinical evolution and count molecular mechanisms of thyroid diseases and the follow-up have not yet been evaluated. Goiter, without spec- evolution of autoimmune thyroid diseases (23, 24). The new ifying the dimension of the enlargement, was a focal point of classification of thyroid diseases presented herein is a pro- the classification, divided into nontoxic and toxic forms (2). posal to stimulate discussion of previous classification to With the adoption of American Thyroid Association classi- codify these diseases in a clinically useful manner. New fication, the American Thyroid Association voted that the terms are often forged to eliminate the criticism of those classification “. . . . be reviewed periodically and revised as already existing; in turn, they become similarly criticized. further knowledge might require” (1). The writer is perfectly aware that his proposal is based on During the last 30 yr books on thyroid (3, 4) and endocrine his own experience, and he hopes that it will be subject to diseases have not revised the classification or nomenclature the positive criticism needed to generate an updated of thyroid diseases (5–7). No revision has been made despite classification. our greater understanding of the molecular mechanisms un- derlying hormonogenesis. We now distinguish thyroid dys- Thyroid function function at the target tissue level and can identify receptor and postreceptor pathophysiology as syndromes of resis- The functional behavior of the thyroid is fundamental in tance to thyroid hormones (8, 9). We now recognize genetic most thyroid diseases and represents the basis for diagnosis defects of thyroid hormonogenesis (3, 4), postpartum thy- and therapy. Euthyroidism, hyperthyroidism, and hypothy- roiditis (10), the evolution of diffuse to nodular goiter (11– roidism, clinical states reflecting normal, excessive, or de- 14), and the complex effects of iodine on the function of fective levels of thyroid hormones, were the basis of classi- endemic goiter (15). However, recent technology has allowed fication (1, 2). Today it is necessary to distinguish whether many countries to screen for congenital hypothyroidism, so hormone levels reflect a primary biosynthetic problem of the that the clinical consequences of this syndrome should dis- thyroid gland, destruction of thyroid cells with release of appear as a clinical entity throughout the world in the next thyroid hormones, iatrogenic causes, or changes resulting 10 –20 yr (15, 16). We now better recognize the clinical evo- from target tissue abnormalities. Thus, the suggestion is to lution of thyroid diseases that frequently change their func- define as hyper-, eu-, or hypothyroidism a disease with in- tional behavior with time from that observed at the onset of creased, normal, or low levels of thyroid hormones at the disease, i.e. from hyper- to hypofunction (17–20). The clinical cellular level. evolution of thyroid function is of fundamental clinical im- Euthyroidism means normal production of thyroid hor- portance, because it implies continuous follow-up with con- mones by the thyroid and normal levels in the circulation sequent updating of therapy. Today the presence of goiter and at the cellular level. For example, diffuse goiter that cannot be considered a basis for classification, but only a with time becomes nodular (11, 12) should be called eu- parameter. We often see diseases before goiter onset, and thyroid if it is accompanied by normal circulating hor- environmental factors can affect thyroid function without a mones. It seems improper to define this type of goiter as modification of thyroid morphology. In fact, many thyroid nontoxic, because hypothyroidism is not considered. In diseases occur without the presence of goiter, i.e. thyrotox- fact, relative hypofunction due to a partial insufficiency of icosis factitia, postpartum thyroiditis, and even Graves’ hormonogenesis occurs relatively often as the diffuse goi- disease. ter becomes nodular with time. Subgroupings of sporadic In the 1980s, the importance of environmental contribu- or endemic should be reserved for epidemiological, not tions and the reversibility of some thyroid diseases were functional, purposes (1). recognized (21). In the 1990s the importance of the transient Hyperthyroidism means clinical symptomatology due to and bipolar clinical evolution of several thyroid diseases was excessive circulating and intracellular thyroid hormones. It 1428
  3. 3. Monaco • Clinical Perspective J Clin Endocrinol Metab, April 2003, 88(4):1428 –1432 1429 TABLE 1. Abridged classification of thyroid diseases is now necessary to distinguish whether the excess is due to thyroid hyperfunction and overproduction of thyroid hor- I. Diseases characterized by (tissue) euthyroidism mones or to excess levels without thyroid hyperfunction and A. Euthyroid goitera 1. Diffuse (chronic) increased biosynthesis, i.e. excess intake, excess release with- 2. Nodular (chronic) out synthesis, or syndromes of pituitary resistance to thyroid 3. Diffuse (transient) hormones. In the latter cases it is more appropriate to use the B. Tumors term thyrotoxicosis, which indicates the presence of an ex- 1. Benign (single nodule) 2. Malignant cessive amount of thyroid hormones not overproduced by a. Differentiated (papillary and follicular) the gland. If the hormones are produced by the thyroid, we b. Undifferentiated (anaplastic) have hyperthyroidism with thyroid gland hyperfunction; if c. Medullary the excess level of thyroid hormones is not derived from the C. Thyroiditis thyroid or is derived from the thyroid by excess secretion 1. Acute thyroiditis 2. Subacute thyroiditis (De Quervain’s) (in the euthyroid rather than production, we have thyrotoxicosis without thy- phase: polar disease)b roid gland hyperfunction. 3. Chronic autoimmune thyroiditis or Hashimoto’s disease (in Hypothyroidism is almost always due to the lack of thy- the euthyroid phase: polar disease)c roid hormone production and inadequate replacement ther- 4. Postpartum and silent thyroiditis (in the euthyroid phase: polar disease)c apy. Yet today we must distinguish generalized and periph- 5. Riedel’s thyroiditis eral resistance to thyroid hormones in which there is normal II. Diseases characterized by (tissue) hyperthyroidism thyroid function, but the receptor/postreceptor recognition A. With thyroid gland hyperfunction system in target organs is defective. 1. Hyperthyroid goiter with thyroid-associated ophthalmopathy or Basedow-Graves’ diseased 2. Multinodular hyperthyroid goiter or Plummer’s disease Clinical evolution 3. Autonomous nodule (hyperthyroid) The function of the thyroid in many thyroid diseases 4. Rare forms: excessive exogenous iodine, hyperthyroidism due to Hashimoto’s disease (Hashitoxicosis), postpartum frequently changes from that observed at the onset of thyroiditis (in the hyperthyroid phase), pituitary resistance disease. Diffuse goiter, which becomes nodular with time to thyroid hormones, TSH-secreting pituitary adenoma, (11–14), may maintain normal hormonal production for chorionic gonadotropin-secreting tumor, adenoma or many years, but may be associated with hypothyroidism carcinoma (follicular) of the thyroid or hyperthyroidism depending on iodine supply (25, 26). B. Thyrotoxicosis (without thyroid gland hyperfunction) 1. Excessive, exogenous thyroid hormones (thyrotoxicosis Hyperthyroidism and hypothyroidism are frequently due factitia and iatrogenic) to autoimmune thyroid diseases (27, 28). Autoimmune 2. Postinflammatory or from destruction of the thyroid hyper- or hypothyroidism may depend on the presence of 3. Amiodarone-induced stimulating or blocking autoantibodies whose presence C. Transient hyperthyroidism III. Diseases characterized by (tissue) hypothyroidism can vary with time (28). The natural history of Graves’ A. With thyroid gland hypofunction disease is now characterized by remissions and exacerba- 1. Primary hypothyroidism tions; 10 –15% of patients will progress to hypothyroidism a. Adult (iatrogenic (surgery, 131I therapy, external (29 –32). It is now clear that Hashimoto’s can remit or can radiotherapy), chronic autoimmune thyroiditis (in the progress to hyperthyroidism because of the presence of hypothyroid phase), Graves’ disease (end-stage), diffuse and nodular goiter, iodine deficiencyf TSH receptor autoantibodies or destructive changes caus- b. Neonatal congenital (ectopia, agenesis, ing excess hormone secretion (27, 28). It can also progress dyshormonogenesis) to hypothyroidism because of the appearance of blocking 2. Secondary: hypothalamic-pituitary hypothyroidism (or antibodies or because the gland is destroyed. Graves’ dis- central) 3. Dyshormonogenetic congenital goiter ease may spontaneously culminate in Hashimoto’s thy- B. Without hypothyroidism 1. Generalized and peripheral resistance to thyroid hormones (receptor and postreceptor defects) C. Transient hypothyroidism d It is improper to define Basedow-Graves’ disease as diffuse goiter IV. Thyroid-associated ophthalmopathyg because there are either forms without goiter or the goiter with time V. Abnormal thyroid parameters without thyroid diseases may change from diffuse into nodular. It has to be noted that no (nonthyroidal illness, deficit of TBG, etc.) exhaustive studies on the frequency of the change of function as well a Goiter is an increase of the thyroid volume ( 40 ml, twice the as of the goiter prevalence are available up to now. e normal volume of the adult thyroid), determined by ultrasound. It is It has to be noted that, probably, now the most frequent forms of insufficient now to define goiter as indefinite enlargement of the hypothyroidism are iatrogenic and those due to chronic autoimmune thyroid (i.e. based only on clinical parameters) when by imaging thyroiditis can not be accompanied by goiter in the atrophic variant. techniques it is possible to detect lesions as small as 2 mm. Thus, the term goiter is specified only when present. It has to be b Subacute thyroiditis can manifest three clinical phases: initially emphasized that no exhaustive studies on the most frequent forms of hyperthyroid, due to thyroid destruction, a middle phase, euthyroid, hypothyroidism are available today. f and a final end-stage hypothyroid. Thus, the disease is classified in In severe iodine deficiency areas, in which it is observed endemic the three functional states: hyper-eu-hypothyroidism. goiter, hypothyroidism can develops over the years due to progressive c Autoimmune thyroiditis manifests generally two clinical phase: impairment of thyroid hormone biosynthesis or concurrent autoim- a hyperthyroid phase in general due either to iodine intake (Hashi- mune thyroid disease. g moto) or to derepression of the immune system (postpartum and silent I suggest to use this definition instead of eye changes of Graves’ thyroiditis) and an end-stage hypothyroid phase. The euthyroid disease because eye changes can occur in many autoimmune thyroid phase, lasting sometimes for decades, is asymptomatic. diseases.
  4. 4. 1430 J Clin Endocrinol Metab, April 2003, 88(4):1428 –1432 Monaco • Clinical Perspective TABLE 2. Detailed classification of thyroid diseases TABLE 2. Continued I. Diseases characterized by (tissue) euthyroidism 1. Chronic autoimmune thyroiditis (with or without goiter)e A. Euthyroid goiter (chronic)a 2. Iatrogenic (surgery, 131I-therapy)e 1. Diffuse 3. Diffuse and nodular goiter a. Sporadic 4. Severe iodine deficiencyf b. Endemic (iodine deficiency) b. Neonatal congenital (ectopia, agenesis, 2. Nodular dyshormonogenesis (iodine metabolism, thyroglobulin a. Uninodular biosynthesis, enzymatic defects) 1. Sporadic 2. Pituitary (or secondary) hypothyroidism (tumor, 2. Endemic (iodine deficiency) inflammation, infiltration, trauma, TSH deficiency, isolated b. Multinodular or panhypopituitarism) 1. Sporadic 3. Hypothalamic (or tertiary) hypothyroidism (tumor, 2. Endemic (iodine deficiency) inflammation, infiltration, trauma) 3. Euthyroid diffuse goiter (transient) B. Without hypothyroidism a. Menarche, pregnancy, menopause (in iodine-deficient 1. Generalized and peripheral resistance to thyroid hormones environments) (receptor and postreceptor defects) b. Iatrogenic (antithyroid substances), iodide (deficiency/ C. Transient hypothyroidism excess), environmental/diet (goitrogens, drugs, etc.) 1. Adult forms [iodine deficiency/excess, drug induced, B. Tumors environmental/diet, postpartum and subacute thyroiditis 1. Benign (single nodule) (hypothyroid phase)] a. Adenoma 2. Neonatal forms (iodine deficiency/excess, maternal b. Unusual tumors (teratoma, lymphoma, etc.) goitrogen ingestion/antithyroid substances, maternal 2. Malignant antibodies) a. Differentiated IV. Thyroid associated ophthalmopathyg 1. Papillary 1. Only signs 2. Follicular 2. Soft tissue involvement with signs and symptoms b. Undifferentiated (anaplastic) 3. Proptosis (exophthalmos) 1. Small cell 4. Extraocular muscle involvement 2. Giant cell 5. Corneal involvement c. Medullary 6. Sight loss d. Other malignant (lymphoma, sarcoma, metastatic tumors) V. Abnormal thyroid parameters without thyroid diseases C. Thyroiditis (nonthyroidal illness, deficit of TBG, etc.) 1. Acute thyroiditis See Table 1 for footnotes. 2. Subacute thyroiditis (De Quervain’s) (in the euthyroid phase: polar disease)b 3. Chronic autoimmune thyroiditis or Hashimoto’s disease (in the euthyroid phase: polar disease)c roiditis and hypothyroidism; conversely, Hashimoto’s 4. Postpartum and silent thyroiditis (in the euthyroid phase: thyroiditis, may change to Graves’ disease associated with polar disease)c hyperthyroidism. Even if Graves’ disease and Hashimo- 5. Riedel’s thyroiditis to’s thyroiditis have separate genetic backgrounds, it is II. Diseases characterized by (tissue) hyperthyroidism A. With thyroid gland hyperfunction clear they are closely related diseases. Postpartum thy- 1. Diffuse hyperthyroid goiter with thyroid associated roiditis occurs in approximately 5–12% of all postpartum ophthalmopathy or Basedow-Graves’ diseased women, and many patients will suffer recurrences after 2. Multinodular hyperthyroid goiter or Plummer’s disease subsequent pregnancies. Postpartum thyroiditis can have 3. Autonomous nodule (hyperthyroid) 4. Rare forms: excessive exogenous iodine, chronic a hyperthyroid phase, similar to that observed in silent autoimmune (i.e. Hashitoxicosis) and postpartum thyroiditis, followed by a transient hypothyroid phase thyroiditis (in the hyperthyroid phase, polar diseases), (33, 34). pituitary resistance to thyroid hormones, TSH-secreting From all of the above, it is evident that the physician must pituitary adenoma, chorionic gonadotrophin-secreting know both the natural history of the disease and the mod- tumors (choriocarcinoma, hydatiform mole, embryonal carcinoma of the testis), follicular adenoma or carcinoma of ification of the disease induced by therapy. Graves’ and the thyroid postpartum thyroiditis are treated with antithyroid drugs at B. Thyrotoxicosis (without thyroid gland hyperfunction) the onset of disease, but when patients become hypothyroid, 1. Excessive, exogenous thyroid hormones (thyrotoxicosis thyroid hormone supplementation is needed. Polar means factitia, iatrogenic thyrotoxicosis) (see also transient hyperthyroidism) that the function and clinical characteristics of disease can 2. Postinflammatory (subacute thyroiditis) or from destruction change, as evident in postpartum thyroiditis (33, 34), sub- of the thyroid (see also transient hyperthyroidism) acute thyroiditis (35, 36), Hashimoto’s disease (37), or even 3. Amiodarone induced Graves’ disease (18 –20, 38); I suggest polar, and not bipolar, C. Transient hyperthyroidism because the function can change from hyper- to hypo- to 1. Adult forms (excessive exogenous iodine intake, excess of thyroid hormone intake, post-131I therapy, hyperthyroid euthyroidism and vice versa. The term bipolar is, in fact, used phase of polar diseases postpartum, silent and subacute in multiple medical diseases; for example, in manic-depres- thyroiditis) sive illnesses (39) or affective disorders manifest by se- 2. Neonatal forms (maternal antibodies) quential periods of anorexia and bulimia. Stimulating and III. Diseases characterized by (tissue) hypothyroidism A. With hypothyroidism blocking receptor antibodies causing opposite clinical man- 1. Primary hypothyroidism: ifestations are argued to exist in pituitary hypophisitis, caus- a. Adult ing hyper- or hypofunction (40 – 45), and in adrenal cortical disease, causing Cushing’s or Addison’s disease (46 –53).
  5. 5. Monaco • Clinical Perspective J Clin Endocrinol Metab, April 2003, 88(4):1428 –1432 1431 This classification takes into account the fact that most References thyroid diseases are life-long problems, but that transient 1. Werner SC 1969 Classification of thyroid diseases. Report of the committee on thyroid diseases also exist. A transient disease lasts only a nomenclature. American Thyroid Association. J Clin Endocrinol Metab 29: few months ( 1 yr), spontaneously reverting to normal. It is 860 – 862 2. Werner SC, Ingbar SH 1978 Diseases of the thyroid. In: Werner SC, Ingbar SH, a useful distinction in understanding functional evolution eds. The thyroid: a fundamental and clinical text, 4th Ed. New York: Harper and responses to treatment. Transient goiter may be present and Row; 389 –393 in puberty, pregnancy, and menopause. Environmental, iat- 3. Braverman LE, Utiger RD, eds. 2000 The thyroid: a fundamental and clinical text, 8th Ed. Philadelphia: Lippincot Williams & Wilkins; 515–719 rogenic, and physiological factors can transiently change 4. Falk SA 1997 Thyroid disease, 2nd Ed. Philadelphia: Lippincott-Raven clinical function in thyroid disorders (3–7, 23, 24) or derange- 5. Wartofsky L 2001 The thyroid gland. In: Becker KL, ed. Principles and practice ments of the autoimmune system (27–30). of endocrinology and metabolism, 3rd Ed. Philadelphia: Lippincott Williams & Wilkins; 308 – 471 As a result, I think that it is important for the physician to 6. Utiger RD 2001 The thyroid: physiology, thyrotoxicosis, hypothyroidism, and consider not only the functional presentation, but also the the painful thyroid. In: Felig P, Frohman LH, eds. Endocrinology and Metab- evolution of many thyroid diseases as a function of time, olism, 4th Ed. Princeton: McGraw-Hill; 261–347 7. Larsen PR, Davies TF, Hay ID 1998 The thyroid gland. In: Wilson JD, Foster because polar manifestations require continuous, permanent DW, Kronenberg HM, Larsen PR, eds. Williams textbook of endocrinology, 9th follow-up and updated therapies. Thus, I suggest including Ed. Philadelphia: Saunders; 389 –515 in an updated classification two new terms (Tables 1 and 2): 8. Beck-Peccoz P, Chatterejee VKK 1994 The variable clinical phenotype in polar and transient. thyroid hormone resistance syndrome. Thyroid 506:225–232 9. Refetoff S, Usala SJ 1993 The syndromes of resistance to thyroid hormones. Finally, I think that the term Graves’ ophthalmopathy Endocr Rev 14:348 –399 should not be used any more. In fact, it is suggested as more 10. Amino N, Mori H, Iwatani Y, Tanizawa O, Kawashima M, Tsuge I, Ibaragi appropriate to define the ocular complication that is more K, Kumahara Y, Miyai K 1982 High prevalence of transient postpartum thyrotoxicosis and hypothyroidism. N Engl J Med, 306:849 – 852 often observed in Grave’s disease as thyroid-associated oph- 11. Studer H, Peter HJ, Gerber H 1989 Natural heterogeneity of thyroid cells: the thalmopathy because the ocular complication is present not basis for understanding thyroid function and nodular goiter growth. Endocr only in Graves’ disease, but also in many thyroid autoim- Rev 10:125–135 12. Elte JWF, Bussemaker JK, HaaK A 1990 The natural history of euthyroid mune diseases (such as chronic autoimmune thyroiditis, au- multinodular goiter. Postgrad Med J 66:186 –190 toimmune hypothyroidism, and sometimes autoimmune 13. Studer H, Gerber H 1991 Intrathyroidal iodine: heterogeneity of iodocom- thyroid disease that is still euthyroid). pounds and kinetic compartmentalization. Trends Endocrinol Metab 2:29 –35 14. Peter HJ, Studer H, Forster R, Gerber H 1982 The pathogenesis of hot and cold The time has arrived for a revision of the classification of follicles in multinodular goiter. 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