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CLINICAL PERSPECTIVE
Classification of Thyroid Diseases: Suggestions for
a Revision
FABRIZIO MONACO
Department of Endocrinology, University G. DAnnunzio, 66100 Chieti, Italy
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 non-
useful to the clinician (1), and the clinical evolution and
follow-up have not yet been evaluated. Goiter, without spec-
ifying 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 classi-
fication, 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 (57). No revision has been made despite
our greater understanding of the molecular mechanisms un-
derlying hormonogenesis. We now distinguish thyroid dys-
function at the target tissue level and can identify receptor
and postreceptor pathophysiology as syndromes of resis-
tance to thyroid hormones (8, 9). We now recognize genetic
defects 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 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 dis-
appear as a clinical entity throughout the world in the next
10 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 of
disease, i.e. from hyper- to hypofunction (1720). The clinical
evolution 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 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. 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 were
recognized (21). In the 1990s the importance of the transient
and bipolar clinical evolution of several thyroid diseases was
1428
Copyright 2003 by The Endocrine Society
doi: 10.1210/jc.2002-021260
stressed, and the need to update the nomenclature of thyroid
diseases was acknowledged (22). Some recent books on in-
ternal medicine have begun to report some of the newly
identified thyroid diseases as special topics, taking into ac-
count molecular mechanisms of thyroid diseases and the
evolution of autoimmune thyroid diseases (23, 24). The new
classification of thyroid diseases presented herein is a pro-
posal 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 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 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 in-
creased, normal, or low levels of thyroid hormones at the
cellular level.
Euthyroidism means normal production of thyroid hor-
mones 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 eu-
thyroid if it is accompanied by normal circulating hor-
mones. 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 goi-
ter 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
Monaco Clinical Perspective
TABLE 1. Abridged classification of thyroid diseases
I. Diseases characterized by (tissue) euthyroidism
A. Euthyroid goitera
1. Diffuse (chronic)
2. Nodular (chronic)
3. Diffuse (transient)
B. Tumors
1. Benign (single nodule)
2. Malignant
a. Differentiated (papillary and follicular)
b. Undifferentiated (anaplastic)
c. Medullary
C. Thyroiditis
1. Acute thyroiditis
2. Subacute thyroiditis (De Quervains) (in the euthyroid
phase: polar disease)b
3. Chronic autoimmune thyroiditis or Hashimotos disease (in
the euthyroid phase: polar disease)c
4. Postpartum and silent thyroiditis (in the euthyroid phase:
polar disease)c
5. Riedels thyroiditis
II. Diseases characterized by (tissue) hyperthyroidism
A. With thyroid gland hyperfunction
1. Hyperthyroid goiter with thyroid-associated
ophthalmopathy or Basedow-Graves diseased
2. Multinodular hyperthyroid goiter or Plummers disease
3. Autonomous nodule (hyperthyroid)
4. Rare forms: excessive exogenous iodine, hyperthyroidism
due to Hashimotos disease (Hashitoxicosis), postpartum
thyroiditis (in the hyperthyroid phase), pituitary resistance
to thyroid hormones, TSH-secreting pituitary adenoma,
chorionic gonadotropin-secreting tumor, adenoma or
carcinoma (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 thyroid
3. Amiodarone-induced
C. Transient hyperthyroidism
III. Diseases characterized by (tissue) hypothyroidism
A. With thyroid gland hypofunction
1. Primary hypothyroidism
a. Adult (iatrogenic (surgery, 131I therapy, external
radiotherapy), chronic autoimmune thyroiditis (in the
hypothyroid phase), Graves disease (end-stage), diffuse
and nodular goiter, iodine deficiencyf
b. Neonatal congenital (ectopia, agenesis,
dyshormonogenesis)
2. Secondary: hypothalamic-pituitary hypothyroidism (or
central)
3. Dyshormonogenetic congenital goiter
B. Without hypothyroidism
1. Generalized and peripheral resistance to thyroid hormones
(receptor and postreceptor defects)
C. Transient hypothyroidism
IV. 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 the
normal volume of the adult thyroid), determined by ultrasound. It is
insufficient now to define goiter as indefinite enlargement of the
thyroid (i.e. based only on clinical parameters) when by imaging
techniques it is possible to detect lesions as small as 2 mm.
b
Subacute thyroiditis can manifest three clinical phases: initially
hyperthyroid, due to thyroid destruction, a middle phase, euthyroid,
and a final end-stage hypothyroid. Thus, the disease is classified in
the 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 silent
thyroiditis) and an end-stage hypothyroid phase. The euthyroid
phase, lasting sometimes for decades, is asymptomatic.
J Clin Endocrinol Metab, April 2003, 88(4):1428 1432 1429
is now necessary to distinguish whether the excess is due to
thyroid hyperfunction and overproduction of thyroid hor-
mones or to excess levels without thyroid hyperfunction and
increased biosynthesis, i.e. excess intake, excess release with-
out 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 ex-
cessive 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 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 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
(1114), 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 exacerba-
tions; 10 15% of patients will progress to hypothyroidism
(29 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 caus-
ing 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 dis-
ease may spontaneously culminate in Hashimotos thy-
d
It is improper to define Basedow-Graves disease as diffuse goiter
because there are either forms without goiter or the goiter with time
may change from diffuse into nodular. It has to be noted that no
exhaustive studies on the frequency of the change of function as well
as of the goiter prevalence are available up to now.
e
It has to be noted that, probably, now the most frequent forms of
hypothyroidism are iatrogenic and those due to chronic autoimmune
thyroiditis can not be accompanied by goiter in the atrophic variant.
Thus, the term goiter is specified only when present. It has to be
emphasized that no exhaustive studies on the most frequent forms of
hypothyroidism are available today.
f
In severe iodine deficiency areas, in which it is observed endemic
goiter, hypothyroidism can develops over the years due to progressive
impairment 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 thyroid
diseases.
1430 J Clin Endocrinol Metab, April 2003, 88(4):1428 1432
TABLE 2. Detailed classification of thyroid diseases
I. Diseases characterized by (tissue) euthyroidism
A. Euthyroid goiter (chronic)a
1. Diffuse
a. Sporadic
b. Endemic (iodine deficiency)
2. Nodular
a. Uninodular
1. Sporadic
2. Endemic (iodine deficiency)
b. Multinodular
1. Sporadic
2. 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. Adenoma
b. Unusual tumors (teratoma, lymphoma, etc.)
2. Malignant
a. Differentiated
1. Papillary
2. Follicular
b. Undifferentiated (anaplastic)
1. Small cell
2. Giant cell
c. Medullary
d. Other malignant (lymphoma, sarcoma, metastatic tumors)
C. Thyroiditis
1. Acute thyroiditis
2. Subacute thyroiditis (De Quervains) (in the euthyroid
phase: polar disease)b
3. Chronic autoimmune thyroiditis or Hashimotos disease (in
the euthyroid phase: polar disease)c
4. Postpartum and silent thyroiditis (in the euthyroid phase:
polar disease)c
5. Riedels thyroiditis
II. Diseases characterized by (tissue) hyperthyroidism
A. With thyroid gland hyperfunction
1. Diffuse hyperthyroid goiter with thyroid associated
ophthalmopathy or Basedow-Graves diseased
2. Multinodular hyperthyroid goiter or Plummers disease
3. Autonomous nodule (hyperthyroid)
4. Rare forms: excessive exogenous iodine, chronic
autoimmune (i.e. Hashitoxicosis) and postpartum
thyroiditis (in the hyperthyroid phase, polar diseases),
pituitary resistance to thyroid hormones, TSH-secreting
pituitary adenoma, chorionic gonadotrophin-secreting
tumors (choriocarcinoma, hydatiform mole, embryonal
carcinoma of the testis), follicular adenoma or carcinoma of
the thyroid
B. Thyrotoxicosis (without thyroid gland hyperfunction)
1. Excessive, exogenous thyroid hormones (thyrotoxicosis
factitia, iatrogenic thyrotoxicosis) (see also transient
hyperthyroidism)
2. Postinflammatory (subacute thyroiditis) or from destruction
of the thyroid (see also transient hyperthyroidism)
3. Amiodarone induced
C. Transient hyperthyroidism
1. Adult forms (excessive exogenous iodine intake, excess of
thyroid hormone intake, post-131I therapy, hyperthyroid
phase of polar diseases postpartum, silent and subacute
thyroiditis)
2. Neonatal forms (maternal antibodies)
III. Diseases characterized by (tissue) hypothyroidism
A. With hypothyroidism
1. Primary hypothyroidism:
a. Adult
Monaco Clinical Perspective
TABLE 2. Continued
1. Chronic autoimmune thyroiditis (with or without goiter)e
2. Iatrogenic (surgery, 131I-therapy)e
3. Diffuse and nodular goiter
4. Severe iodine deficiencyf
b. Neonatal congenital (ectopia, agenesis,
dyshormonogenesis (iodine metabolism, thyroglobulin
biosynthesis, enzymatic defects)
2. Pituitary (or secondary) hypothyroidism (tumor,
inflammation, infiltration, trauma, TSH deficiency, isolated
or panhypopituitarism)
3. Hypothalamic (or tertiary) hypothyroidism (tumor,
inflammation, infiltration, trauma)
B. Without hypothyroidism
1. 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, maternal
goitrogen ingestion/antithyroid substances, maternal
antibodies)
IV. Thyroid associated ophthalmopathyg
1. Only signs
2. Soft tissue involvement with signs and symptoms
3. Proptosis (exophthalmos)
4. Extraocular muscle involvement
5. Corneal involvement
6. Sight loss
V. Abnormal thyroid parameters without thyroid diseases
(nonthyroidal illness, deficit of TBG, etc.)
See Table 1 for footnotes.
roiditis and hypothyroidism; conversely, Hashimotos
thyroiditis, may change to Graves disease associated with
hyperthyroidism. Even if Graves disease and Hashimo-
tos thyroiditis have separate genetic backgrounds, it is
clear they are closely related diseases. Postpartum thy-
roiditis 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 mod-
ification 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), sub-
acute thyroiditis (35, 36), Hashimotos disease (37), or even
Graves disease (18 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-depres-
sive illnesses (39) or affective disorders manifest by se-
quential periods of anorexia and bulimia. Stimulating and
blocking receptor antibodies causing opposite clinical man-
ifestations are argued to exist in pituitary hypophisitis, caus-
ing hyper- or hypofunction (40 45), and in adrenal cortical
disease, causing Cushings or Addisons disease (46 53).
Monaco Clinical Perspective
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, iat-
rogenic, and physiological factors can transiently change
clinical function in thyroid disorders (37, 23, 24) or derange-
ments of the autoimmune system (2730).
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.
Finally, I think that the term Graves ophthalmopathy
should not be used any more. In fact, it is suggested as more
appropriate to define the ocular complication that is more
often observed in Graves disease as thyroid-associated oph-
thalmopathy because the ocular complication is present not
only in Graves disease, but also in many thyroid autoim-
mune diseases (such as chronic autoimmune thyroiditis, au-
toimmune hypothyroidism, and sometimes autoimmune
thyroid disease that is still euthyroid).
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 consid-
eration 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 re-
vised 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 tech-
niques 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 concentra-
tions 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 asymp-
tomatic 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.
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. DAnnunzio,
66100 Chieti, Italy. E-mail: hmonac@tin.it.
J Clin Endocrinol Metab, April 2003, 88(4):1428 1432 1431
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