Microsoft word - subclinical thyroid disease to treat or not to treat
SUBCLINICAL THYROID DISEASE: TO TREAT OR NOT TO TREAT Peter Laurberg
Department of Endocrinology and Medicine, Aalborg Hospital, DK-9000 Aalborg, Denmark , email:
Department of Endocrinology E, Frederiksberg Hospital, DK-2000 Copenhagen, Denmark
Subclinical thyroid disease is defined by an abnormally high (subclinical hypothyroidism) or low
(subclinical hyperthyroidism) serum TSH with peripheral thyroid hormone concentrations within the
Such abnormalities in thyroid function tests are very common in the population and have been
extensively dealt with in textbooks and reviews. At the time of writing a search (limited to title and review)
of Pub Med lists 19 papers on subclinical hypothyroidism during the period 1986-2001 and 8 on
subclinical hyperthyroidism (and many more if all field search is used) (1). The present publication
primarily deals with the controversial issue: Should patients with this abnormality be treated or not.
Yes, if a patient with subclinical thyroid disease prefers to be treated after being adequately investigated
and after being properly informed about the disease and the therapy, therapy should be offered. Whether
or not the patient chooses therapy the importance of regular control should be substantiated.
Below is given a list of points to follow when dealing with a patient with subclinical thyroid disease. In
the following some comments and details on specific points are given.
Checklist when dealing with a patient with subclinical thyroid disease:
1. Verification of the diagnosis by repeated testing after for example 3 months.
2. The subtype of disease (nosological type) should be established.
3. Status on clinical symptoms and signs of the disorder.
4. Status on other risk factors and diseases and evaluation of long-term risks and prognosis.
5. Information of the patient about the disease, and on the possibility of therapy or wait and see control.
Subclinical thyroid disease and severe illness
Transient serum TSH abnormalities are common in hospitalized and especially in severely ill patients,
and in the period after recovery (2,3). This may be induced by the disease or by the medication given.
Subclinical thyroid disease should not be diagnosed and therapy not initiated under such circumstances.
Transient subclinical thyroid disease
In general the causes of subclinical thyroid disease are the same as for overt thyroid disease, and
also the types of therapy are the same. As in overt disease it is important to evaluate the possibility
of a transient state before initiating lifelong medication or before giving destructive therapy.
Subacute or silent thyroiditis should be excluded and the possibility of excessive iodine intake or
medication as the cause for the disorder should be evaluated. During the first year after
radioiodine therapy or thyroid surgery, subclinical thyroid abnormalities are common, and lifelong
or permanent therapy should not be given.
The common causes of subclinical hypothyroidism
Spontaneous subclinical hypothyroidism is common in all populations but more so the higher the
iodine intake (4). The patients can be split in two main subtypes: Those with measurable thyroid
antibodies (TPO-Ab and/or Tg-Ab) in serum and those without.
Antibody positive patients presumably suffer from autoimmune thyroiditis. They have the
highest risk for progressive thyroid failure with in the order of 5-10% of patients progressing from
subclinical to overt hypothyroidism per year (5,6).
The mechanism behind the frequent abnormality of elevated serum TSH without detectable
thyroid antibodies is at present not clarified. These patients may suffer from a different subtype of
autoimmunity with predominant T-cell response. Autopsy studies (7) have demonstrated a
considerably higher frequency of histological thyroiditis than found by investigation of serum
samples in population studies. However other mechanisms may be involved as well. This disorder
is associated with a lower risk of progression to overt thyroid disease (around 2% per year, (5)).
Knowledge on the risk of progression is important for the decision on control interval, especially if
therapy is not given. On the other hand we do not agree that a higher risk of progression supports
early initiation of therapy. The current state should be the dominant basis for the decision on
therapy. If the current state is not sufficiently severe to initiate therapy, this can be initiated when/if
progression is observed. Whether or not therapy is given now, follow-up has to be performed. If
early therapy could prevent progression of thyroid failure and stabilize a state of partial
physiological regulation of thyroid function, this would be an important argument for early therapy.
T4 substitution is often followed by a fall in thyroid antibody levels (8) but controlled studies on the
The common causes of subclinical hyperthyroidism
The importance and dominant cause of subclinical hyperthyroidism depends fundamentally on the
iodine intake level of the population. In a population where the iodine intake is mild to moderately
low (median urinary iodine excretion 25-120 µg/24 h) or has been so within recent decades, the
dominant cause of subclinical hyperthyroidism is autonomous thyroid nodules (4,9). In such areas
subclinical hyperthyroidism is even more frequent than subclinical hypothyroidism, affecting 5-10%
of subjects above 60 years of age (4,9). On the other hand, spontaneous subclinical
hyperthyroidism is not common in high iodine intake areas, where the abnormality is dominated by
patients receiving T4 in high doses (10) as excessive substitution for hypothyroidism or in an
attempt to reduce the size of thyroid nodules, or to prevent recurrence of previous thyroid cancer.
Arguments for and against therapy of subclinical thyroid disease Major arguments in favour of therapy
1. Thyroid function is not fully compensated by the altered serum TSH in subclinical thyroid
disease, and peripheral thyroid hormone action is not normal in the individual subject.
2. Subclinical thyroid disease may be associated with impaired function of various organs, which is
reversible by therapy of the thyroid disorder.
3. Subclinical thyroid disease may increase the long term risk of developing various serious
4. Therapy of subclinical thyroid disease is often uncomplicated and inexpensive with a burden of
control not different from observational control.
5. The likelihood of spontaneous resolution is low with most types of subclinical thyroid disease.
6. In pregnancy impaired thyroid function in the mother may impose a risk to the foetus (11-14).
Major arguments against therapy
1. A considerable proportion of patients will not feel more healthy if treated.
2. Therapy will often involve lifelong intake of medication (subclinical hypothyroidism).
3. Therapy may involve a significant risk of side effects (subclinical hyperthyroidism).
4. The long term-risk from subclinical thyroid disease may depend on other risk factors - and it may
5. More studies are needed to determine precisely the magnitude of clinical abnormalities and
risks associated with the abnormality - and the long-term benefits of therapy.
6. Subclinical thyroid disease is very common. For such common disorders more documentation is
Many of the arguments are similar for subclinical hyper- and hypothyroidism. It is evident that
even if peripheral thyroid hormone values are by definition within laboratory reference ranges the
altered serum TSH signals abnormally low or high thyroid function. When groups of patients are
compared with healthy controls (15),or thyroid hormones in serum are measured before and after
normalisation of serum TSH by therapy (16), the average concentrations of T4 and T3 are
significantly altered. Variation of serum thyroid hormone concentrations in the individual is much
more narrow than the broad laboratory reference ranges (17). Thus, there is ample space for T4
and T3 concentration values being abnormal for the individual within the laboratory reference
ranges. The time of progression of thyroid dysfunction from subclinical to overt (with T4 or T3
leaving the reference range) may vary widely between individuals depending on their normal level
of T4 and T3 being high or low in the reference range (17). Serum TSH is much more (10 times)
sensitive to alterations in thyroid function than serum T4 (18). Thus, TSH will leave the reference
range much earlier than T4 or T3, and give the pattern of subclinical thyroid disease (19).
Clinical consequences of mild thyroid disease
The slightly to moderately abnormal thyroid hormone levels (for the individual) manifest as small
aberrations in peripheral thyroid hormone effects (20-22). Subclinical thyroid disease is by nature
not different from overt thyroid disease but on average a milder abnormality. Consequently the
clinical findings are not different but milder. Careful monitoring of heart function has revealed
functional abnormalities in both subclinical hyper- and hypothyroidism which are reversible upon
therapy (16, 23-25). An uncontrolled study suggests that subclinical hypothyroid patients have a
high frequency of increased intraocular pressure, which is reversible upon therapy (26).
Another important hormone effect is exerted on brain and neuromuscular function. In a
blinded placebo controlled study Jaeschke et al (27) reduced average serum TSH from 12.1 to 4.1
mU/l by T4 administration for more than 6 months in 15 elderly subjects (16 controls). Most of the
series of questionaries and cognitive function tests applied in the study developed in favour of
therapy, but this was only statistically significant (p = 0.01) for a composite psychometric memory
score. The improvement was equivalent to a difference of 8.7 points in an IQ-test. This was
deemed of limited importance by the authors, who advocated a watchful waiting in middle-aged
and older subclinically hypothyroid patients. Such watchful waiting will normally include as much
control and blood tests as therapy. Considering the relatively insufficient dose of T4 administered
in this study, the physiological nature and low price of T4 substitution therapy and the observed
effect on memory, it is hard to agree on their conclusion. In our opinion a decision on watchful
waiting should be taken by the informed patient, not by the doctor or the healthcare system.
Long-term risks associated with subclinical thyroid disease
A major concern in subclinical hypothyroidism is the risk of atherosclerosis. Subclinical
hypothyroidism is associated with an atherogenic lipid profile in serum and T4 substitution is
followed by a less atherogenic profile including a small decrease in serum total cholesterol (0.2 -
0.4 mmol) and a decrease in LDL-cholesterol (28). No large intervention studies on the effect of
substitution therapy on vascular disease and mortality are available. In the Whickham follow-up
study no significant association between cardiovascular disease and subclinical hypothyroidism at
the investigation 20 years earlier was found (29). On the other hand, a recent Dutch study of a
cohort of elderly women, found subclinical hypothyroidism to be associated with the same
proportion of myocardial infarctions as other known risk factors such as hypercholesterolaemia,
hypertension, smoking and diabetes mellitus (30).
In subclinical hyperthyroidism the major concern is the long term risk of atrial fibrillation and
of osteoporosis. Analysis of the Framingham data revealed a 3 fold increase in incidence of atrial
fibrillation in participants with serum TSH < 0.1 mU/l (31). Thyroid hormone increases bone
turnover and many studies have evaluated the association between subclinical hyperthyroidism
and osteoporosis. In a meta-analysis long term TSH suppression by T4 administration was found
to have no effect on bone mass in premenopausal women, whereas postmenopausal women had
an excess bone loss of 0.91% per year (32). Two controlled intervention studies have shown that
therapy of subclinical hyperthyroidism due to multinodular goitre in postmenopausal women
ameliorate bone mineral loss which was around 2% per year in untreated patients (33,34).
The evidence that subclinical hyperthyroidism may have deleterious effects has been obtained in
patients with suppressed serum TSH (<0.1 mU/l). Borderline low TSH (0.1-0.4 mU/l) has not been
Therapy of subclinical hypothyroidism
Thyroxine substitution therapy is straight forward following the guidelines for overt hypothyroidism.
The T4 dose is adjusted to normalize serum TSH. TSH reference ranges may vary depending on
the assay method and reference population. In a Danish population study the 95% reference
range for subjects with no thyroid disease by history, ultrasound and measurement of TPO-Ab was
0.4-3.6 mU/l (35). Often laboratory references are broader and a somewhat arbitrary limit of 4 or 5
mU/l for diagnosing subclinical hypothyroidism is often employed. During therapy small dose
adjustments can stabilize serum TSH around 0.8-2.5 mU/l, followed by yearly lifelong control of
Therapy of subclinical hyperthyroidism
The therapy of choice in patients with multinodular goitre or a solitary hot adenoma is radioiodine.
The risk of complication is higher than for T4 therapy of subclinical hypothyroidism. Around
10-20% of this type of patients develop hypothyroidism over 5 years after radioiodine (36) and
1-2% may develop Graves' Disease due to activation of autoimmunity against the TSH receptor
(37). A beneficial effect of radioiodine is reduction of goitre volume (around 50% after 1-2 years). If
low dose antithyroid medication is given, this has to continue lifelong (38).
Subclinical hypo- and hyperthyroidism are not well-defined disorders, but mild to moderate thyroid
failure or thyroid hyperactivity in continuum with overt thyroid disease.
Many patients with subclinical hypothyroidism have no clear symptoms or signs of the disease,
and will not be able to feel the difference between T4 therapy or not. However 1/4-1/2 of patients
will feel a general improvement in health after normalization of serum TSH (39,40) and improved
memory function can be demonstrated by objective tests (27,41). Risk factors for atherosclerosis
will improve slightly upon therapy and a recent population study in elderly females suggests that
subclinical hypothyroidism may be an independent risk factor for myocardial infarction of similar
magnitude as hypertension, hyperlipidaemia, smoking and diabetes mellitus. Substitution therapy
with T4 is straight forward with few side effects.
Subclinical hyperthyroidism may affect well-being (21) and supranormal supraventricular pacing of
the heart has been demonstrated. This may be the reason for the 3 fold increase in risk of atrial
fibrillation. Postmenopausal women are at increased risk for osteoporosis and bone mineral
density responds favourably to therapy. Patients with suppressed serum TSH due to autonomous
nodules should be offered radioiodine therapy. T4 substitution therapy of hypothyroidism should
be properly controlled to avoid overtreatment. T4 therapy to fully suppress serum TSH should be
limited to patients with a high risk of recurrent thyroid cancer.
Long-term follow-up after therapy is necessary. Some patients are reluctant to receive therapy
and in such cases control of the biochemical and clinical thyroid state as well as other risk factors
It has been argued that labelling, polypharmacia and expenses are prohibiting problems (27).
However, many elderly subjects (in Denmark at least) are now taking series of ill-defined,
undocumented, costly, over the counter 'natural' products to improve their health. If such a person
has an abnormally elevated serum TSH it is certainly more appropriate to substitute with T4 to
2 Spencer C, Eigen A, Shen D, Duda M, Qualls S, Weiss S, Nicoloff J.
Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in
3 Hamblin PS, Dyer SA, Mohr VS, Le Grand BA, Lim CF, Tuxen DV DJ, Stockigt JR.
Relationship between thyrotropin and thyroxine changes during recovery from severe
4 Laurberg P, Bulow Pedersen I, Knudsen N, Ovesen L, Andersen S.
Environmental iodine intake affects the type of nonmalignant thyroid disease.
5 Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J,
Hasan DM, Rodgers H, Tunbridge F, et al.
The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham
6 Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC.
Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the
7 Okayasu I, Hara Y, Nakamura K, Rose NR.
Racial and age-related differences in incidence and severity of focal autoimmune
Rebound increase in serum thyrotropin, anti-'microsomal' antibodies and thyroglobulin after
9 Laurberg P, Nohr SB, Pedersen KM, Hreidarsson AB, Andersen S, Bulow Pedersen
I, Knudsen N, Perrild H, Jorgensen T, Ovesen L.
Thyroid disorders in mild iodine deficiency.
10 Canaris GJ, Manowitz NR, Mayor G, Ridgway EC.
The Colorado thyroid disease prevalence study.
11 Morreale de Escobar G, Obregon MJ, Escobar del Rey F.
Is neuropsychological development related to maternal hypothyroidism or to
J Clin Endocrinol Metab. 2000;85:3975-87.
12 Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O'Heir
CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ.
Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of
13 Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, Faix
Maternal thyroid deficiency and pregnancy complications: implications for
14 Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ,
Vulsma T, Wiersinga WM, Drexhage HA, Vader HL.
Low maternal free thyroxine concentrations during early pregnancy are associated with impaired
15 Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC.
Circulating lipids and minor abnormalities of thyroid function.
16 Faber J, Wiinberg N, Schifter S, Mehlsen J.
Haemodynamic changes following treatment of subclinical and overt hyperthyroidism.
17 S. Andersen, K.M. Pedersen, N.H. Bruun, P. Laurberg
Narrow individual variations in serum T4 and T3 in normal subjects. A clue to the understanding of
Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized
19 Carr D, McLeod DT, Parry G, Thornes HM.
Fine adjustment of thyroxine replacement dosage: comparison of the thyro-trophin releasing
hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and
20 Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ.
Estimation of tissue hypothyroidism by a new clinical score: evaluation of
patients with various grades of hypothyroidism and controls.
21 Biondi B, Palmieri EA, Fazio S, Cosco C, Nocera M, Sacca L, Filetti S,
Endogenous subclinical hyperthyroidism affects quality of life and cardiac
morphology and function in young and middle-aged patients.
J Clin Endocrinol Metab. 2000;85:4701-5.
22 Kumeda Y, Inaba M, Tahara H, Kurioka Y, Ishikawa T, Morii H, Nishizawa Y. Persistent
increase in bone turnover in Graves' patients with subclinical hyperthyroidism.
J Clin Endocrinol Metab. 2000;85:4157-61.
23 Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, Ferrannini E. Effect of
levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind,
J Clin Endocrinol Metab. 2001;86:1110-5.
24 Biondi B, Fazio S, Carella C, Sabatini D, Amato G, Cittadini A, Bellastella A, Lombardi G,
Control of adrenergic overactivity by beta-blockade improves the quality of life in patients receiving
long term suppressive therapy with levothyroxine.
J Clin Endocrinol Metab. 1994;78:1028-33.
25 Ridgway EC, Cooper DS, Walker H, Rodbard D, Maloof F.
Peripheral responses to thyroid hormone before and after L-thyroxine therapy in patients with
J Clin Endocrinol Metab. 1981;53:1238-42.
26 Centanni M, Cesareo R, Verallo O, Brinelli M, Canettieri G, Viceco Andreoli M.
Reversible increase of intraocular pressure in subclinical hypothyroid patients.
27 Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, Harper S, Griffith L,
Does treatment with L-thyroxine influence health status in middle-aged and older adults with
Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism:
29 Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J,
The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year
follow-up study of an English community.
30 Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC.
Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial
infarction in elderly women: the Rotterdam Study.
31 Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, Benjamin EJ,
Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons.
Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment:
33 Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC.
Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism.
34 Faber J, Jensen IW, Petersen L, Nygaard B, Hegedus L, Siersbaek-Nielsen K. Normalization of
serum thyrotrophin by means of radioiodine treatment in subclinical hyperthyroidism: effect on
35 Knudsen N, Bulow I, Jorgensen T, Laurberg P, Ovesen L, Perrild H.
Comparative study of thyroid function and types of thyroid dysfunction in two areas in Denmark
36 Nygård B. Hegedüs L, Gervil M, Hjalgrim H, Søe-Jensen P, Hansen JM.
Radioiodine treatment of multinodular non-toxic goitre.
37 Nygård B, Faber J, Veje A, Hegedüs L, Hansen JM.
Transition of nodular toxic goiter to autoimmune hyperthyreoidism triggered by 131-I therapy.
38 Laurberg P, Buchholtz Hansen PE, Iversen E, Eskjaer Jensen S, Weeke J.
Goitre size and outcome of medical treatment of Graves' disease.
39 Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC.
L-Thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo-controlled trial.
40 Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg PA, Lindstedt G.
A double-blind cross-over 12-month study of L-thyroxine treatment of women with 'subclinical'
41 Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, Baschieri L. Subclinical
hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment.
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