J. Clin. Endocrinol. Metab. 2003 88: 1428-1432, doi: 10.1210/jc.2002-021260  

Fabrizio Monaco  

Classification of Thyroid Diseases: Suggestions for a Revision

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CLINICAL PERSPECTIVE

Classification of Thyroid Diseases: Suggestions fora Revision

FABRIZIO MONACO

Department of Endocrinology, University G. D’Annunzio, 66100 Chieti, Italy

The last comprehensive classification of thyroid diseaseshas been reported by the American Thyroid Association in1969. It was based largely on thyroid function; classificationby etiology was considered premature, by pathology non-useful to the clinician (1), and the clinical evolution andfollow-up have not yet been evaluated. Goiter, without spec-ifying the dimension of the enlargement, was a focal point ofthe classification, divided into nontoxic and toxic forms (2).With the adoption of American Thyroid Association classi-fication, the American Thyroid Association voted that theclassification “. . . . be reviewed periodically and revised asfurther knowledge might require” (1).

During the last 30 yr books on thyroid (3, 4) and endocrinediseases have not revised the classification or nomenclatureof thyroid diseases (5–7). No revision has been made despiteour greater understanding of the molecular mechanisms un-derlying hormonogenesis. We now distinguish thyroid dys-function at the target tissue level and can identify receptorand postreceptor pathophysiology as syndromes of resis-tance to thyroid hormones (8, 9). We now recognize geneticdefects of thyroid hormonogenesis (3, 4), postpartum thy-roiditis (10), the evolution of diffuse to nodular goiter (11–14), and the complex effects of iodine on the function ofendemic goiter (15). However, recent technology has allowedmany countries to screen for congenital hypothyroidism, sothat the clinical consequences of this syndrome should dis-appear as a clinical entity throughout the world in the next10–20 yr (15, 16). We now better recognize the clinical evo-lution of thyroid diseases that frequently change their func-tional behavior with time from that observed at the onset ofdisease, i.e. from hyper- to hypofunction (17–20). The clinicalevolution of thyroid function is of fundamental clinical im-portance, because it implies continuous follow-up with con-sequent updating of therapy. Today the presence of goitercannot be considered a basis for classification, but only aparameter. We often see diseases before goiter onset, andenvironmental factors can affect thyroid function without amodification of thyroid morphology. In fact, many thyroiddiseases occur without the presence of goiter, i.e. thyrotox-icosis factitia, postpartum thyroiditis, and even Graves’disease.

In the 1980s, the importance of environmental contribu-tions and the reversibility of some thyroid diseases wererecognized (21). In the 1990s the importance of the transientand bipolar clinical evolution of several thyroid diseases was

stressed, and the need to update the nomenclature of thyroiddiseases was acknowledged (22). Some recent books on in-ternal medicine have begun to report some of the newlyidentified thyroid diseases as special topics, taking into ac-count molecular mechanisms of thyroid diseases and theevolution of autoimmune thyroid diseases (23, 24). The newclassification of thyroid diseases presented herein is a pro-posal to stimulate discussion of previous classification tocodify these diseases in a clinically useful manner. Newterms are often forged to eliminate the criticism of thosealready existing; in turn, they become similarly criticized.The writer is perfectly aware that his proposal is based onhis own experience, and he hopes that it will be subject tothe positive criticism needed to generate an updatedclassification.

Thyroid function

The functional behavior of the thyroid is fundamental inmost thyroid diseases and represents the basis for diagnosisand therapy. Euthyroidism, hyperthyroidism, and hypothy-roidism, clinical states reflecting normal, excessive, or de-fective levels of thyroid hormones, were the basis of classi-fication (1, 2). Today it is necessary to distinguish whetherhormone levels reflect a primary biosynthetic problem of thethyroid gland, destruction of thyroid cells with release ofthyroid hormones, iatrogenic causes, or changes resultingfrom target tissue abnormalities. Thus, the suggestion is todefine as hyper-, eu-, or hypothyroidism a disease with in-creased, normal, or low levels of thyroid hormones at thecellular level.

Euthyroidism means normal production of thyroid hor-mones by the thyroid and normal levels in the circulationand at the cellular level. For example, diffuse goiter thatwith time becomes nodular (11, 12) should be called eu-thyroid if it is accompanied by normal circulating hor-mones. It seems improper to define this type of goiter asnontoxic, because hypothyroidism is not considered. Infact, relative hypofunction due to a partial insufficiency ofhormonogenesis occurs relatively often as the diffuse goi-ter becomes nodular with time. Subgroupings of sporadicor endemic should be reserved for epidemiological, notfunctional, purposes (1).

Hyperthyroidism means clinical symptomatology due toexcessive circulating and intracellular thyroid hormones. It

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doi: 10.1210/jc.2002-021260

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is now necessary to distinguish whether the excess is due tothyroid hyperfunction and overproduction of thyroid hor-mones or to excess levels without thyroid hyperfunction andincreased biosynthesis, i.e. excess intake, excess release with-out synthesis, or syndromes of pituitary resistance to thyroidhormones. In the latter cases it is more appropriate to use theterm thyrotoxicosis, which indicates the presence of an ex-cessive amount of thyroid hormones not overproduced bythe gland. If the hormones are produced by the thyroid, wehave hyperthyroidism with thyroid gland hyperfunction; ifthe excess level of thyroid hormones is not derived from thethyroid or is derived from the thyroid by excess secretionrather than production, we have thyrotoxicosis without thy-roid gland hyperfunction.

Hypothyroidism is almost always due to the lack of thy-roid hormone production and inadequate replacement ther-apy. Yet today we must distinguish generalized and periph-eral resistance to thyroid hormones in which there is normalthyroid function, but the receptor/postreceptor recognitionsystem in target organs is defective.

Clinical evolution

The function of the thyroid in many thyroid diseasesfrequently changes from that observed at the onset ofdisease. Diffuse goiter, which becomes nodular with time(11–14), may maintain normal hormonal production formany years, but may be associated with hypothyroidismor hyperthyroidism depending on iodine supply (25, 26).Hyperthyroidism and hypothyroidism are frequently dueto autoimmune thyroid diseases (27, 28). Autoimmunehyper- or hypothyroidism may depend on the presence ofstimulating or blocking autoantibodies whose presencecan vary with time (28). The natural history of Graves’disease is now characterized by remissions and exacerba-tions; 10 –15% of patients will progress to hypothyroidism(29 –32). It is now clear that Hashimoto’s can remit or canprogress to hyperthyroidism because of the presence ofTSH receptor autoantibodies or destructive changes caus-ing excess hormone secretion (27, 28). It can also progressto hypothyroidism because of the appearance of blockingantibodies or because the gland is destroyed. Graves’ dis-ease may spontaneously culminate in Hashimoto’s thy-

TABLE 1. Abridged classification of thyroid diseases

I. Diseases characterized by (tissue) euthyroidismA. Euthyroid goitera

1. Diffuse (chronic)2. Nodular (chronic)3. Diffuse (transient)

B. Tumors1. Benign (single nodule)2. Malignant

a. Differentiated (papillary and follicular)b. Undifferentiated (anaplastic)c. Medullary

C. Thyroiditis1. Acute thyroiditis2. Subacute thyroiditis (De Quervain’s) (in the euthyroid

phase: polar disease)b

3. Chronic autoimmune thyroiditis or Hashimoto’s disease (inthe euthyroid phase: polar disease)c

4. Postpartum and silent thyroiditis (in the euthyroid phase:polar disease)c

5. Riedel’s thyroiditisII. Diseases characterized by (tissue) hyperthyroidism

A. With thyroid gland hyperfunction1. Hyperthyroid goiter with thyroid-associated

ophthalmopathy or Basedow-Graves’ diseased

2. Multinodular hyperthyroid goiter or Plummer’s disease3. Autonomous nodule (hyperthyroid)4. Rare forms: excessive exogenous iodine, hyperthyroidism

due to Hashimoto’s disease (Hashitoxicosis), postpartumthyroiditis (in the hyperthyroid phase), pituitary resistanceto thyroid hormones, TSH-secreting pituitary adenoma,chorionic gonadotropin-secreting tumor, adenoma orcarcinoma (follicular) of the thyroid

B. Thyrotoxicosis (without thyroid gland hyperfunction)1. Excessive, exogenous thyroid hormones (thyrotoxicosis

factitia and iatrogenic)2. Postinflammatory or from destruction of the thyroid3. Amiodarone-induced

C. Transient hyperthyroidismIII. Diseases characterized by (tissue) hypothyroidism

A. With thyroid gland hypofunction1. Primary hypothyroidism

a. Adult (iatrogenic (surgery, 131I therapy, externalradiotherapy), chronic autoimmune thyroiditis (in thehypothyroid phase), Graves’ disease (end-stage), diffuseand nodular goiter, iodine deficiencyf

b. Neonatal congenital (ectopia, agenesis,dyshormonogenesis)

2. Secondary: hypothalamic-pituitary hypothyroidism (orcentral)

3. Dyshormonogenetic congenital goiterB. Without hypothyroidism

1. Generalized and peripheral resistance to thyroid hormones(receptor and postreceptor defects)

C. Transient hypothyroidismIV. Thyroid-associated ophthalmopathyg

V. Abnormal thyroid parameters without thyroid diseases(nonthyroidal illness, deficit of TBG, etc.)

a Goiter is an increase of the thyroid volume (�40 ml, twice thenormal volume of the adult thyroid), determined by ultrasound. It isinsufficient now to define goiter as indefinite enlargement of thethyroid (i.e. based only on clinical parameters) when by imagingtechniques it is possible to detect lesions as small as 2 mm.

b Subacute thyroiditis can manifest three clinical phases: initiallyhyperthyroid, due to thyroid destruction, a middle phase, euthyroid,and a final end-stage hypothyroid. Thus, the disease is classified inthe three functional states: hyper-eu-hypothyroidism.

c Autoimmune thyroiditis manifests generally two clinical phase:a hyperthyroid phase in general due either to iodine intake (Hashi-moto) or to derepression of the immune system (postpartum and silentthyroiditis) and an end-stage hypothyroid phase. The euthyroidphase, lasting sometimes for decades, is asymptomatic.

d It is improper to define Basedow-Graves’ disease as diffuse goiterbecause there are either forms without goiter or the goiter with timemay change from diffuse into nodular. It has to be noted that noexhaustive studies on the frequency of the change of function as wellas of the goiter prevalence are available up to now.

e It has to be noted that, probably, now the most frequent forms ofhypothyroidism are iatrogenic and those due to chronic autoimmunethyroiditis can not be accompanied by goiter in the atrophic variant.Thus, the term goiter is specified only when present. It has to beemphasized that no exhaustive studies on the most frequent forms ofhypothyroidism are available today.

f In severe iodine deficiency areas, in which it is observed endemicgoiter, hypothyroidism can develops over the years due to progressiveimpairment of thyroid hormone biosynthesis or concurrent autoim-mune thyroid disease.

g I suggest to use this definition instead of eye changes of Graves’disease because eye changes can occur in many autoimmune thyroiddiseases.

Monaco • Clinical Perspective J Clin Endocrinol Metab, April 2003, 88(4):1428–1432 1429

roiditis and hypothyroidism; conversely, Hashimoto’sthyroiditis, may change to Graves’ disease associated withhyperthyroidism. Even if Graves’ disease and Hashimo-to’s thyroiditis have separate genetic backgrounds, it isclear they are closely related diseases. Postpartum thy-roiditis occurs in approximately 5–12% of all postpartumwomen, and many patients will suffer recurrences aftersubsequent pregnancies. Postpartum thyroiditis can havea hyperthyroid phase, similar to that observed in silentthyroiditis, followed by a transient hypothyroid phase(33, 34).

From all of the above, it is evident that the physician mustknow both the natural history of the disease and the mod-ification of the disease induced by therapy. Graves’ andpostpartum thyroiditis are treated with antithyroid drugs atthe onset of disease, but when patients become hypothyroid,thyroid hormone supplementation is needed. Polar meansthat the function and clinical characteristics of disease canchange, as evident in postpartum thyroiditis (33, 34), sub-acute thyroiditis (35, 36), Hashimoto’s disease (37), or evenGraves’ disease (18–20, 38); I suggest polar, and not bipolar,because the function can change from hyper- to hypo- toeuthyroidism and vice versa. The term bipolar is, in fact, usedin multiple medical diseases; for example, in manic-depres-sive illnesses (39) or affective disorders manifest by se-quential periods of anorexia and bulimia. Stimulating andblocking receptor antibodies causing opposite clinical man-ifestations are argued to exist in pituitary hypophisitis, caus-ing hyper- or hypofunction (40–45), and in adrenal corticaldisease, causing Cushing’s or Addison’s disease (46–53).

TABLE 2. Detailed classification of thyroid diseases

I. Diseases characterized by (tissue) euthyroidismA. Euthyroid goiter (chronic)a

1. Diffusea. Sporadicb. Endemic (iodine deficiency)

2. Nodulara. Uninodular

1. Sporadic2. Endemic (iodine deficiency)

b. Multinodular1. Sporadic2. Endemic (iodine deficiency)

3. Euthyroid diffuse goiter (transient)a. Menarche, pregnancy, menopause (in iodine-deficient

environments)b. Iatrogenic (antithyroid substances), iodide (deficiency/

excess), environmental/diet (goitrogens, drugs, etc.)B. Tumors

1. Benign (single nodule)a. Adenomab. Unusual tumors (teratoma, lymphoma, etc.)

2. Malignanta. Differentiated

1. Papillary2. Follicular

b. Undifferentiated (anaplastic)1. Small cell2. Giant cell

c. Medullaryd. Other malignant (lymphoma, sarcoma, metastatic tumors)

C. Thyroiditis1. Acute thyroiditis2. Subacute thyroiditis (De Quervain’s) (in the euthyroid

phase: polar disease)b

3. Chronic autoimmune thyroiditis or Hashimoto’s disease (inthe euthyroid phase: polar disease)c

4. Postpartum and silent thyroiditis (in the euthyroid phase:polar disease)c

5. Riedel’s thyroiditisII. Diseases characterized by (tissue) hyperthyroidism

A. With thyroid gland hyperfunction1. Diffuse hyperthyroid goiter with thyroid associated

ophthalmopathy or Basedow-Graves’ diseased

2. Multinodular hyperthyroid goiter or Plummer’s disease3. Autonomous nodule (hyperthyroid)4. Rare forms: excessive exogenous iodine, chronic

autoimmune (i.e. Hashitoxicosis) and postpartumthyroiditis (in the hyperthyroid phase, polar diseases),pituitary resistance to thyroid hormones, TSH-secretingpituitary adenoma, chorionic gonadotrophin-secretingtumors (choriocarcinoma, hydatiform mole, embryonalcarcinoma of the testis), follicular adenoma or carcinoma ofthe thyroid

B. Thyrotoxicosis (without thyroid gland hyperfunction)1. Excessive, exogenous thyroid hormones (thyrotoxicosis

factitia, iatrogenic thyrotoxicosis) (see also transienthyperthyroidism)

2. Postinflammatory (subacute thyroiditis) or from destructionof the thyroid (see also transient hyperthyroidism)

3. Amiodarone inducedC. Transient hyperthyroidism

1. Adult forms (excessive exogenous iodine intake, excess ofthyroid hormone intake, post-131I therapy, hyperthyroidphase of polar diseases � postpartum, silent and subacutethyroiditis)

2. Neonatal forms (maternal antibodies)III. Diseases characterized by (tissue) hypothyroidism

A. With hypothyroidism1. Primary hypothyroidism:

a. Adult

TABLE 2. Continued

1. Chronic autoimmune thyroiditis (with or without goiter)e

2. Iatrogenic (surgery, 131I-therapy)e

3. Diffuse and nodular goiter4. Severe iodine deficiencyf

b. Neonatal congenital (ectopia, agenesis,dyshormonogenesis (iodine metabolism, thyroglobulinbiosynthesis, enzymatic defects)

2. Pituitary (or secondary) hypothyroidism (tumor,inflammation, infiltration, trauma, TSH deficiency, isolatedor panhypopituitarism)

3. Hypothalamic (or tertiary) hypothyroidism (tumor,inflammation, infiltration, trauma)

B. Without hypothyroidism1. Generalized and peripheral resistance to thyroid hormones

(receptor and postreceptor defects)C. Transient hypothyroidism

1. Adult forms [iodine deficiency/excess, drug induced,environmental/diet, postpartum and subacute thyroiditis(hypothyroid phase)]

2. Neonatal forms (iodine deficiency/excess, maternalgoitrogen ingestion/antithyroid substances, maternalantibodies)

IV. Thyroid associated ophthalmopathyg

1. Only signs2. Soft tissue involvement with signs and symptoms3. Proptosis (exophthalmos)4. Extraocular muscle involvement5. Corneal involvement6. Sight loss

V. Abnormal thyroid parameters without thyroid diseases(nonthyroidal illness, deficit of TBG, etc.)

See Table 1 for footnotes.

1430 J Clin Endocrinol Metab, April 2003, 88(4):1428–1432 Monaco • Clinical Perspective

This classification takes into account the fact that mostthyroid diseases are life-long problems, but that transientthyroid diseases also exist. A transient disease lasts only afew months (�1 yr), spontaneously reverting to normal. It isa useful distinction in understanding functional evolutionand responses to treatment. Transient goiter may be presentin puberty, pregnancy, and menopause. Environmental, iat-rogenic, and physiological factors can transiently changeclinical function in thyroid disorders (3–7, 23, 24) or derange-ments of the autoimmune system (27–30).

As a result, I think that it is important for the physician toconsider not only the functional presentation, but also theevolution of many thyroid diseases as a function of time,because polar manifestations require continuous, permanentfollow-up and updated therapies. Thus, I suggest includingin an updated classification two new terms (Tables 1 and 2):polar and transient.

Finally, I think that the term Graves’ ophthalmopathyshould not be used any more. In fact, it is suggested as moreappropriate to define the ocular complication that is moreoften observed in Grave’s disease as thyroid-associated oph-thalmopathy because the ocular complication is present notonly in Graves’ disease, but also in many thyroid autoim-mune diseases (such as chronic autoimmune thyroiditis, au-toimmune hypothyroidism, and sometimes autoimmunethyroid disease that is still euthyroid).

The time has arrived for a revision of the classification ofthyroid diseases considering the recognition of new diseaseentities, greater understanding of the molecular and immunemechanisms responsible for defects, and disease evolution.The suggestion for a new classification otherwise remains basedprimarily on thyroid function, but must also take into consid-eration the clinical evolution of the disease (Tables 1 and 2). Itis obvious that any classification can be criticized, but I believeit necessary to review this subject after a 35-yr period in accordwith the invitation of the American Thyroid Association thatthe classification “. . . had to be reviewed periodically and re-vised as further knowledge might require.”

Addendum

The following terms are not reported in the tables because they arenot 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 tech-niques that can be a benign or cancerous lesion and thus may or maynot require therapeutic intervention. 2) Subclinical hyperthyroidismis defined as an asymptomatic state in which circulating concentra-tions of free T3 and T4 are normal, but serum sensitive TSH issuppressed. It is not a disease entity, but a mild stage of thyroidhyperfunction. 3) Subclinical hypothyroidism is defined as an asymp-tomatic state in which circulating concentrations of free T3 and T4 arenormal, but serum TSH is slightly elevated. It is not a disease entity,but a mild stage of thyroid hypofunction. 4) Thyrotoxic storm or crisisis the extreme accentuation of severe, neglected hyperthyroidism. 5)Hypothyroid or myxedematous coma is the end stage of severe,untreated, long-standing hypothyroidism.

Acknowledgments

Received August 30, 2002. Accepted January 14, 2003.Address all correspondence and requests for reprints to: Fabrizio

Monaco, M.D., Department of Endocrinology, University G. D’Annunzio,66100 Chieti, Italy. E-mail: hmonac@tin.it.

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1432 J Clin Endocrinol Metab, April 2003, 88(4):1428–1432 Monaco • Clinical Perspective