3-1999

Subclinical Hypothyroidism

Demetrios A. Koutras, Athens, Greece
 

Introduction and definition

"Subclinical" literally means without clinical symptoms or signs. In fact, the report of symptoms depends to a large extent on the sensitivity (and anxiety?) of the patient, and the finding of signs on the experience and the zeal of the doctor. So, since "subclinical" hypothyroidism is rather a vague term, it should be better called "minimal thyroid failure" and defined by laboratory rather than unprecise clinical criteria.

One definition is "increased TSH with normal free serum thyroxine (fT4) and triiodothyronine (fT3) levels"1,2. Others call subclinical hypothyroidism the situation with normal serum fT4 and fT3 values and moderately high serum TSH, say up to 10 mU/l, considering very high TSH values as denoting overt hypothyroidism, even if serum fT4 and fT3 are normal.

This last definition, i.e. normal fT4 and fT3 with a TSH between 4.01–10.00 mU/l, is the one preferred by the author.

Prevalence

Subclinical hypothyroidism is quite common. In the Whickham survey in northeast England, Tunbridge and his co-workers found in adults a prevalence of hypothyroidism of 7.5% in women and 2.8% in men (3). The prevalence increased with age. In the Framingham study 10.3% of the population (5.0% of men, 13.6% of women) had a high serum TSH only (4). Wang and Crapo surveyed the literature in 19975. They quote prevalence rates of subclinical hypothyroidism ranging from 1.3 to 10.3% in persons of both sexes, 0.7 to 5.7 in males and 3.0 to 13.6% in females.

Persons with a high TSH had more frequently positive antithyroid autoantibodies (AAB), than those with a normal TSH. An increased prevalence is found in patients with other autoimmune diseases, especially type I diabetes6. In the USA 2% of pregnant women had subclinical hypothyroidism and of these 58% had also positive thyroid autoantibodies (7). In summary, about 5% of adult elderly persons have subclinical hypothyroidism. The prevalence increases with age, is higher in females than in males, and in persons with positive AAB.

Aetiology

The common causes of minimal thyroid failure are the same as for overt hypothyroidism, i.e. usually autoimmunity (1,8). Serum antithyroid autoantibodies, either against thyroglobulin (TgAb, Thyroglobulin Antibodies) and/or against peroxidase (TPOAb, Thyroid Per-Oxidase Antibodies) are usually, but not always, positive. TPOAb antibodies are more commonly positive than TgAb.

Other cases are associated with previous hyperthyroidism treated by either surgery, radioiodine, or drugs. Surgery and radioiodine may leave a functional thyroid mass just a little below normal, hence the minimal thyroid failure. However, many patients are perfectly euthyroid immediately after treatment, and they develop later subclinical hypothyroidism, that finally may become overt. In such cases, the co-existence of a slowly evolving destructive autoimmune process may tip the balance towards hypothyroidism. The same process may explain hypothyroidism after antithyroid drugs or without any treatment. In some ex-thyrotoxic cases, the initial thyrotropin – receptor stimulating autoantibodies may be replaced by thyrotropin – receptor blocking autoantibodies, and so provoke hypothyroidism.

In areas with a moderate or severe iodine deficiency, a large part of the population may be hypothyroid, more frequently to a small or moderate degree, but also as overt cases in severe iodine deficiency.(9–11)

Presumably, all known causes of thyroid failure, such as inborn errors of thyroid hormone synthesis, goitrogens, radiation etc could, if present to the right extent, lead to subclinical hypothyroidism. In some cases, however, no evidence of the aetiologic factor responsible can be found by the presently available methods.

Subclinical thyroid deficiency in the context of pituitary insufficiency is not discussed here.
 

Diagnosis

The diagnosis of subclinical hypothyroidism is quite straightforward: a normal serum fT4 and a moderately high TSH level establish the diagnosis. Serum fT3 is usually normal, and so fT3 estimations do not add much to the diagnosis. Of course, a drug- induced increase in TSH should be ruled out. A slightly abnormal serum TSH value should be confirmed by a second estimation later, since it may be transient or due to drug administration.

These tests should be requested in all middle-aged and elderly persons, and especially those with symptoms and findings possibly associated with mild hypothyroidism, such as tiredness, hypercholesterolemia etc.

However, since "subclinical" by definition excludes the presence of obvious clinical symptoms and signs, and since this condition is quite prevalent, the question arises whether all persons, at least from an age and up, should be screened for a mild thyroid failure. Weetman (12) does not recommend screening of all the healthy adult population, whereas Danese and his co-workers13 claim that screening is cost-effective and should be considered in persons 35 years or older. This is even more important in more elderly females.

The author’s practice is to ask for serum fT4, TSH and autoantibodies (AAB) in all females 35 years old and all males 50 years old, as discussed in more detail later.

Tissue effects

No physician in his/her right mind is happy to treat laboratory values only. Hence, before considering treatment, we want to know whether minimal thyroid failure is accompanied by tissue effects, i.e. mild clinical and/or metabolic abnormalities. All the evidence suggests that this is indeed the case.

Although by definition subclinical hypothyroidism is asymptomatic, a careful evaluation may reveal some clinical abnormalities (2) as well as abnormal laboratory findings in addition to the increased TSH.

Even before the advent of TSH measurements, cases of presumed subclinical hypothyroidism were shown to present metabolic abnormalities. In 1965 our group from Glasgow reported that persons with positive AAB but no clinical evidence of thyroid disease had on average an iodine metabolism pattern similar to that of Hashimoto’s thyroiditis, but milder (14). Later Bastenie and his co-workers from Brussels propagated the idea that persons with positive AAB have on average an increased serum cholesterol and a tendency to develop coronary artery disease (15).

Now abnormalities of lipid metabolism are well established (13,15–21). Total serum cholesterol may not be always increased, but low-density cholesterol is19, whereas high-density is decreased, and apoprotein A may be increased (19,20). In a review of the literature, Tanis et al. (21) found a slightly elevated total serum cholesterol.

These lipid abnormalities are not the only ones found in subclinical hypothyroidism. Our group has shown that flow–mediated, endothelium-dependent vasodilatation is impaired in subclinical hypothyroidism (22). This is shown in Fig. 1. Such a defect is considered an early event in the development of atherosclerosis. Some cardiac parameters also may be abnormal, depending on the degree of hypothyroidism. Subclinical hypothyroidism may cause alterations in systolic time intervals and myocardial contractility, and may increase the risk of atherosclerotic cardiovascular disease when it is superimposed on another underlying cardiac or metabolic disorder (1,23).

Moreover, in patients with subtle changes of thyroid function, as in subclinical hypothyroidism, we could detect an increased prevalence (29.8%) of sideropenia and of manifest sideropenic anemia (15.7%), suggesting that sideropenia is a common finding in patients with subclinical hypothyroidism. Therefore, the control of iron metabolism must be considered in patients in early stages of dysfunction of thyroid gland (Duntas et al.24).

Furthermore, in subclinical hypothyroidism muscle dysfunction is present25, and the stapedial reflex (acoustic or middle-ear muscular reflex) is abnormal (26). Both these abnormalities revert to normal with thyroxine treatment.

Finally, a relation between subclinical hypothyroidism and depression has been suggested (27–30). Monzani et al. (29) observed anxiety, depression, hysteria and other somatic complaints, which improved with thyroxine treatment. Recently Pop et al. (30) found depression to be significantly related to increased TPOAb levels, but not to subclinical or overt hyper- or hypothyroidism. Nevertheless, the high Odds Ratios (2.9 to 7.9) found by Pop et al. (30) in all these thyroid disorders, even if not statistically significant, are very suggestive. It seems likely that if the authors had studied more cases they would reach statistical significance.

  Figure 1  
 
 

To treat or not to treat, that is the question

In order to decide whether thyroxine treatment should or should not be recommended, one requires several (and not just one!) placebo-controlled double-blind randomized trials showing an improvement in the quality and extent of life. Such conclusive evidence is not presently available, although less definitive studies suggests that this may actually be so (24,29,31–33).

Anyway, in many occasions the physicians must reach a decision and give his advice in spite of the insufficient evidence available. Subclinical hypothyroidism is one of these cases. Many authors, including Fenzi et al. (2), Surks and Ocampo (8), Weetman (12), Danese et al (13), recommend thyroxine treatment, but others are more conservative . In his recent review Samuels (34) is ambivalent, recommending treatment in selected cases.

The author is in full agreement with the advice to treat. The lipid profile is usually ameliorated. Tanis et al. (21) found that with treatment total serum cholesterol fell on average by only 0.4 mmol/l in hypercholesterolaemic patients with subclinical hypothyroidism. Even if moderate, this decrease is certainly welcome, and furthermore other lipid abnormalities such as the high density/low density ratio are also ameliorated. In addition, as stated before, there is a subjective feeling of improved well-being (28,29). More definite guidelines about treatment can be found at the end of this review.

Treatment should be done cautiously, especially in elderly cardiac patients (34). The author advises a starting dose of 12.5 µg of thyroxine/day.

The final dose required to keep TSH normal is usually lower than that for overt hypothyroidism (34). This is in agreement with the general rule that, the higher the pre-treatment TSH value, the greater the final dose of thyroxine required.

Sub-subclinical hypothyroidism?

Normal serum TSH values are usually considered those between 0.40 and 4.00 mU/l, with small differences among the various laboratories, depending on the methods used. Normal ranges are commonly defined as the values between the 3rd and 97th percentile (or x ± 2SD) of a group of apparently normal persons. This presupposes that abnormally high (and also low) values are found in about 3% of the "normal" controls. But is this always true? The experience with serum cholesterol has shown that abnormally high (or undesirable) values are found in more than 3% of the population, and now a cholesterol value of 250 mg/dl (or 6.5 mmol/l) is not considered normal any more, even if it is found in a large percentage of the inhabitants of the industralised countries.

The same may be true for the serum TSH values, and there is now evidence, to which our group has contributed, that TSH values between 2.01 and 4.00 mU/l may not be normal, especially if associated with positive autoantibodies. The evidence is as follows:
 

So, it seems appropriate to consider persons with a TSH between 2.01 and 4.00 as being not always entirely normal, but some being at a very early stage of hypothyroidism.
 

Author’s conclusion

Subclinical hypothyroidism is a controversial subject, and there is no consensus on how it should be dealt with. However, increasingly more specialists consider that it should be treated. The evidence provided under "tissue effects" supports this view. Furthermore, as discussed in the preceding section, the author considers that persons with a TSH between 2.01–4.00 mU/l may not be entirely normal, and that at least part of them have an early degree of thyroid failure.

So, what should the practicing physician do? Since there is no universally accepted practice (12,34), the author presents here his personal conclusions, taking of course into consideration all the various reports discussed in this review. These recommendations may be summarized as follows:
 

These conclusions are also shown in Table 1.

Of course, several other factors should be taken into account: The serum fT4 value may tip the balance for or against treatment in patients with marginal TSH alterations, the physician should be more conservative in debilitated persons with cardiac arrhythmias etc, but more willing to prescribe thyroxine in patients with serum lipid abnormalities, e.t.c. Such an individualized attitude is also recommended by Samuels (34).

In other words, the physician must, in some way, practice "holistic" medicine, i.e. decide what to do not on the basis of a single laboratory abnormality, but after considering the patient as a whole, applying his knowledge and experience to the best of the individual patient who has asked for his advice. The Hippocratic dogma "benefit, or (at least) don’t harm" is always true.
 

References

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2. Fenzi G, Salvatore D, de Riu S, Marrano L, Vitale M. Subclinical hypothyroidism. In The Thyroid and Age, eds Pinchera A, Mann K, and Hostalek U, Merck European Thyroid Symposium 1998, April 30–May 2, Schattauer, Stuttgart-New York, 1998, p. 305-314.

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8. Surks MI, Ocampo E. Subclinical thyroid disease. Amer J Med 1996; 100: 217-223.

9. Delange F, Hershman JM, Ermans AM. Relationship between the serum thyrotropin level, the prevalence of goiter and the pattern of iodine metabolism in Idjwi island. J Clin Endocrinol Metab 1971; 33: 261-268.

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20. Staub JJ, Althaus BU, Engler H, Ryff AS, Trabucco P, Marquardt K, Burcckhardt D, Girard J, Weintraub BD. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 1992; 92: 631-642.

21. Tanis BC, Westerdorp BGI, Smelt AHM. Effect of thyroid substitution on hypercholesterolemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol 1996; 44: 643-649.

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24. Duntas LH, Papanastasiou L, Mantzou E, Koutras DA. Incidence of sideropenia and effects of iron repletion treatment in women with subclinical hypothyroidism. Exp Clin Endocrinol Diabetes 1999; in press.

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29. Monzani F, Del Guerra P, Caraccio N, Prunetti CA, Puzzi E, Luisi M. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Invest 1993; 71: 367-371.

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31. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med 1984; 101: 18-24.

32. Nystrom E, Caidahl K, Fager G, Wikkelsö C, Lundberg PA, Lindstedt G. A Double-blind cross-over 12 month study of L-thyroxine treatment of women with ‘subclinical’ hypothyroidism. Clin Endocrinol (Oxf) 1988; 29: 63-76.

33. Diekman T, Lansberg PJ, Kastelein JJP, Wiersinga WM. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med 1995; 155: 1490-1495.

34. Samuels MH. Subclinical thyroid disease in the elderly. Thyroid, 1998; 9: 803-813.

35. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Evans JG, Hasan DM, Rogders H, Tunbridge F, Young ET. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995; 43: 55-68.

36. Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos J, Adamopoulos P, Koutras DA. High serum cholesterol levels in persons with "high-normal" TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol 1998; 138: 141-145.

Demetrios A. Koutras, M.D., Athens

Emeritus Professor of Medicine
Director of the Athens University Endocrine Unit,
"Evgenidion" Hospital,
Athens, Greece
 
Address:
35, Vas. Sofias Ave., 106 75 Athens, Greece