Department of Endocrinology, University G. DAnnunzio, 66100 Chieti, Italy
Address all correspondence and requests for reprints to: Fabrizio Monaco, M.D., Department of Endocrinology, University G. DAnnunzio, 66100 Chieti, Italy. E-mail: hmonac{at}tin.it.
The last comprehensive classification of thyroid diseases has been reported by the American Thyroid Association in 1969. It was based largely on thyroid function; classification by etiology was considered premature, by pathology nonuseful to the clinician (1), and the clinical evolution and follow-up have not yet been evaluated. Goiter, without specifying the dimension of the enlargement, was a focal point of the classification, divided into nontoxic and toxic forms (2). With the adoption of American Thyroid Association classification, the American Thyroid Association voted that the classification ".... be reviewed periodically and revised as further knowledge might require" (1).
During the last 30 yr books on thyroid (3, 4) and endocrine diseases have not revised the classification or nomenclature of thyroid diseases (5, 6, 7). No revision has been made despite our greater understanding of the molecular mechanisms underlying hormonogenesis. We now distinguish thyroid dysfunction at the target tissue level and can identify receptor and postreceptor pathophysiology as syndromes of resistance to thyroid hormones (8, 9). We now recognize genetic defects of thyroid hormonogenesis (3, 4), postpartum thyroiditis (10), the evolution of diffuse to nodular goiter (11, 12, 13, 14), and the complex effects of iodine on the function of endemic goiter (15). However, recent technology has allowed many countries to screen for congenital hypothyroidism, so that the clinical consequences of this syndrome should disappear as a clinical entity throughout the world in the next 1020 yr (15, 16). We now better recognize the clinical evolution of thyroid diseases that frequently change their functional behavior with time from that observed at the onset of disease, i.e. from hyper- to hypofunction (17, 18, 19, 20). The clinical evolution of thyroid function is of fundamental clinical importance, because it implies continuous follow-up with consequent updating of therapy. Today the presence of goiter cannot be considered a basis for classification, but only a parameter. We often see diseases before goiter onset, and environmental factors can affect thyroid function without a modification of thyroid morphology. In fact, many thyroid diseases occur without the presence of goiter, i.e. thyrotoxicosis factitia, postpartum thyroiditis, and even Graves disease.
In the 1980s, the importance of environmental contributions and the reversibility of some thyroid diseases were recognized (21). In the 1990s the importance of the transient and bipolar clinical evolution of several thyroid diseases was stressed, and the need to update the nomenclature of thyroid diseases was acknowledged (22). Some recent books on internal medicine have begun to report some of the newly identified thyroid diseases as special topics, taking into account molecular mechanisms of thyroid diseases and the evolution of autoimmune thyroid diseases (23, 24). The new classification of thyroid diseases presented herein is a proposal to stimulate discussion of previous classification to codify these diseases in a clinically useful manner. New terms are often forged to eliminate the criticism of those already existing; in turn, they become similarly criticized. The writer is perfectly aware that his proposal is based on his own experience, and he hopes that it will be subject to the positive criticism needed to generate an updated classification.
Thyroid function
The functional behavior of the thyroid is fundamental in most thyroid diseases and represents the basis for diagnosis and therapy. Euthyroidism, hyperthyroidism, and hypothyroidism, clinical states reflecting normal, excessive, or defective levels of thyroid hormones, were the basis of classification (1, 2). Today it is necessary to distinguish whether hormone levels reflect a primary biosynthetic problem of the thyroid gland, destruction of thyroid cells with release of thyroid hormones, iatrogenic causes, or changes resulting from target tissue abnormalities. Thus, the suggestion is to define as hyper-, eu-, or hypothyroidism a disease with increased, normal, or low levels of thyroid hormones at the cellular level.
Euthyroidism means normal production of thyroid hormones by the thyroid and normal levels in the circulation and at the cellular level. For example, diffuse goiter that with time becomes nodular (11, 12) should be called euthyroid if it is accompanied by normal circulating hormones. It seems improper to define this type of goiter as nontoxic, because hypothyroidism is not considered. In fact, relative hypofunction due to a partial insufficiency of hormonogenesis occurs relatively often as the diffuse goiter becomes nodular with time. Subgroupings of sporadic or endemic should be reserved for epidemiological, not functional, purposes (1).
Hyperthyroidism means clinical symptomatology due to excessive circulating and intracellular thyroid hormones. It is now necessary to distinguish whether the excess is due to thyroid hyperfunction and overproduction of thyroid hormones or to excess levels without thyroid hyperfunction and increased biosynthesis, i.e. excess intake, excess release without synthesis, or syndromes of pituitary resistance to thyroid hormones. In the latter cases it is more appropriate to use the term thyrotoxicosis, which indicates the presence of an excessive amount of thyroid hormones not overproduced by the gland. If the hormones are produced by the thyroid, we have hyperthyroidism with thyroid gland hyperfunction; if the excess level of thyroid hormones is not derived from the thyroid or is derived from the thyroid by excess secretion rather than production, we have thyrotoxicosis without thyroid gland hyperfunction.
Hypothyroidism is almost always due to the lack of thyroid hormone production and inadequate replacement therapy. Yet today we must distinguish generalized and peripheral resistance to thyroid hormones in which there is normal thyroid function, but the receptor/postreceptor recognition system in target organs is defective.
Clinical evolution
The function of the thyroid in many thyroid diseases frequently changes from that observed at the onset of disease. Diffuse goiter, which becomes nodular with time (11, 12, 13, 14), may maintain normal hormonal production for many years, but may be associated with hypothyroidism or hyperthyroidism depending on iodine supply (25, 26). Hyperthyroidism and hypothyroidism are frequently due to autoimmune thyroid diseases (27, 28). Autoimmune hyper- or hypothyroidism may depend on the presence of stimulating or blocking autoantibodies whose presence can vary with time (28). The natural history of Graves disease is now characterized by remissions and exacerbations; 1015% of patients will progress to hypothyroidism (29, 30, 31, 32). It is now clear that Hashimotos can remit or can progress to hyperthyroidism because of the presence of TSH receptor autoantibodies or destructive changes causing excess hormone secretion (27, 28). It can also progress to hypothyroidism because of the appearance of blocking antibodies or because the gland is destroyed. Graves disease may spontaneously culminate in Hashimotos thyroiditis and hypothyroidism; conversely, Hashimotos thyroiditis, may change to Graves disease associated with hyperthyroidism. Even if Graves disease and Hashimotos thyroiditis have separate genetic backgrounds, it is clear they are closely related diseases. Postpartum thyroiditis occurs in approximately 512% of all postpartum women, and many patients will suffer recurrences after subsequent pregnancies. Postpartum thyroiditis can have a hyperthyroid phase, similar to that observed in silent thyroiditis, followed by a transient hypothyroid phase (33, 34).
From all of the above, it is evident that the physician must know both the natural history of the disease and the modification of the disease induced by therapy. Graves and postpartum thyroiditis are treated with antithyroid drugs at the onset of disease, but when patients become hypothyroid, thyroid hormone supplementation is needed. Polar means that the function and clinical characteristics of disease can change, as evident in postpartum thyroiditis (33, 34), subacute thyroiditis (35, 36), Hashimotos disease (37), or even Graves disease (18, 19, 20, 38); I suggest polar, and not bipolar, because the function can change from hyper- to hypo- to euthyroidism and vice versa. The term bipolar is, in fact, used in multiple medical diseases; for example, in manic-depressive illnesses (39) or affective disorders manifest by sequential periods of anorexia and bulimia. Stimulating and blocking receptor antibodies causing opposite clinical manifestations are argued to exist in pituitary hypophisitis, causing hyper- or hypofunction (40, 41, 42, 43, 44, 45), and in adrenal cortical disease, causing Cushings or Addisons disease (46, 47, 48, 49, 50, 51, 52, 53).
This classification takes into account the fact that most thyroid diseases are life-long problems, but that transient thyroid diseases also exist. A transient disease lasts only a few months (<1 yr), spontaneously reverting to normal. It is a useful distinction in understanding functional evolution and responses to treatment. Transient goiter may be present in puberty, pregnancy, and menopause. Environmental, iatrogenic, and physiological factors can transiently change clinical function in thyroid disorders (3, 4, 5, 6, 7, 23, 24) or derangements of the autoimmune system (27, 28, 29, 30).
As a result, I think that it is important for the physician to consider not only the functional presentation, but also the evolution of many thyroid diseases as a function of time, because polar manifestations require continuous, permanent follow-up and updated therapies. Thus, I suggest including in an updated classification two new terms (Tables 1 and 2
): polar and transient.
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The time has arrived for a revision of the classification of thyroid diseases considering the recognition of new disease entities, greater understanding of the molecular and immune mechanisms responsible for defects, and disease evolution. The suggestion for a new classification otherwise remains based primarily on thyroid function, but must also take into consideration the clinical evolution of the disease (Tables 1 and 2
). It is obvious that any classification can be criticized, but I believe it necessary to review this subject after a 35-yr period in accord with the invitation of the American Thyroid Association that the classification "... had to be reviewed periodically and revised as further knowledge might require."
Addendum
The following terms are not reported in the tables because they are not actual diseases, but stages of thyroid mild/severe disease. 1) Incidentaloma is an asymptomatic, small, nonpalpable thyroid mass (<1 cm) incidentally discovered by high resolution imaging techniques that can be a benign or cancerous lesion and thus may or may not require therapeutic intervention. 2) Subclinical hyperthyroidism is defined as an asymptomatic state in which circulating concentrations of free T3 and T4 are normal, but serum sensitive TSH is suppressed. It is not a disease entity, but a mild stage of thyroid hyperfunction. 3) Subclinical hypothyroidism is defined as an asymptomatic state in which circulating concentrations of free T3 and T4 are normal, but serum TSH is slightly elevated. It is not a disease entity, but a mild stage of thyroid hypofunction. 4) Thyrotoxic storm or crisis is the extreme accentuation of severe, neglected hyperthyroidism. 5) Hypothyroid or myxedematous coma is the end stage of severe, untreated, long-standing hypothyroidism.
Received August 30, 2002.
Accepted January 14, 2003.
References
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