Year : 2013 | Volume
: 10 | Issue : 4 | Page : 9--11
David S Cooper
The Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
David S Cooper
The Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Subclinical hypothyroidism (SH), defined as an elevated serum TSH level, but normal serum Free T4 and T3 levels, is a common laboratory finding, but its clinical significance remains uncertain and controversial. This brief review will summarize the definition, epidemiology, current data related to the effects of SH on cardiovascular risk and in pregnancy, and clinical guidelines on therapy.
|How to cite this article:|
Cooper DS. Subclinical hypothyroidism.Thyroid Res Pract 2013;10:9-11
|How to cite this URL:|
Cooper DS. Subclinical hypothyroidism. Thyroid Res Pract [serial online] 2013 [cited 2022 Sep 26 ];10:9-11
Available from: https://www.thetrp.net/text.asp?2013/10/4/9/106807
Subclinical hypothyroidism is a term that is used to describe the situation in which serum thyroid stimulating hormone (TSH) levels are elevated, but serum thyroid hormone levels (free T4, T3) are normal. In most patients, serum TSH levels are <10 mU/l, although occasional patients may have levels between 10-20 mU/l, but can still have levels of free T4 that are within the range of normal.  In most patients, the cause of subclinical hypothyroidism is autoimmune (Hashimoto's) thyroiditis, although many other causes have been identified (e.g., lithium therapy, external radiation, etc.). Indeed, anything that can cause overt hypothyroidism (defined as a low free T4 with a high TSH) can also cause subclinical hypothyroidism. Thus, it is correct to say that subclinical hypothyroidism is actually a form of "mild" hypothyroidism. From a clinical point of view, the main issue is whether this very mild form of hypothyroidism is clinically significant, and whether it even warrants detection by screening, and it diagnosed, whether it requires treatment. It is also true that there are some situations in which elevated serum TSH levels are not due to subclinical hypothyroidism. Obesity is the most important clinical example of this situation, with high serum TSH likely mediated by central effects of leptin to stimulate hypothalamic TRH secretion. 
While subclinical hypothyroidism is extremely common, occurring in 4-20% of adults depending on age, sex, race, dietary iodine intake, and other factors, recent data on the statistical distribution of serum TSH levels in normal healthy individuals has added to the controversy of how to define a "normal" serum TSH level. Re-analysis of data from the United States National Health and Nutrition Epidemiologic Survey (NHANES) has shown that serum TSH levels rise with age in normal healthy people who are free of thyroid disease.  In fact, in people who are in their 70s-90s, the 95 percentile for TSH may go as high as 6-9 mU/l. Thus, an 80 year old woman with a serum TSH of 6.3 mU/l and a normal free T4 level may be a normal healthy individual, rather than a person with subclinical hypothyroidism. Therefore, the frequently cited high prevalence of subclinical hypothyroidism in the general population, especially in the elderly, needs to be re-examined in light of these new data.
Most patients who have subclinical hypothyroidism feel well and have no symptoms to suggest hypothyroidism. On the other hand, there are patients who have typical symptoms of hypothyroidism, but in fact, the number and type of symptoms (e.g., cold intolerance, constipation, difficulty losing weight, etc.) are similar in frequency and severity to euthyroid age matched controls. This is in keeping with the very low specificity of typical "hypothyroid symptoms". In the elderly, several large studies have shown that subclinical hypothyroidism is not associated with physical function, cognitive dysfunction, depression, or anxiety.  Indeed, one study showed that subclinical hypothyroidism in people aged 70-79 years was associated with increased walking speed, a measure of fitness, compared to euthyroid controls.  Another showed that elderly persons over age 85 years with subclinical hypothyroidism had a lower mortality rate than "normal" euthyroid controls. 
Potential cardiovascular risk is the major morbidity associated with subclinical hypothyroidism. Some studies have suggested a decrease in diastolic function with exercise and possible reduced exercise tolerance in patients with subclinical hypothyroidism.  There is also impairment in vascular smooth muscle relaxation and arterial stiffness that has been observed, but the clinical significance of these observations is uncertain.  Some studies have also shown that patients with subclinical hypothyroidism may have dyslipidemia, especially in those patients who also are smokers or who had insulin resistance.  Some prospective studies have shown an increase risk of cardiovascular disease and cardiovascular mortality in subclinically hypothyroid patients, whereas other studies have not demonstrated this finding. A recent meta analysis of the 11 prospective cohort studies did show an increased risk of coronary heart disease, but this increase was only seen in persons with serum TSH levels >10 mU/l.  Another retrospective study has shown that treating subclinical hypothyroidism seems to have beneficial effects to lower cardiovascular morbidity in persons between age 40 and 70 years, but not in persons aged 70 years or more.  Finally, heart failure is more common in elderly people with serum TSH levels >8-10 mU/l. 
The prevalence of subclinical hypothyroidism in women of reproductive age ranges from 0.5-5%. In pregnant women, the prevalence of hypothyroidism, mostly subclinical hypothyroidism is around 2.5%.  Various studies have shown an increase risk of miscarriage, preterm delivery, and gestational hypertension in women with subclinical hypothyroidism, although the frequency of these adverse outcomes is lower than is seen in women who have overt hypothyroidism.  Thyroid hormone is also important for normal fetal brain development, and some have suggested that untreated maternal subclinical hypothyroidism is associated with a decrease in the intellectual potential of the offspring.  However, a recent randomized prospective study was not able to confirm this finding.  and also did not show a higher rate of adverse pregnancy outcomes in untreated women with subclinical hypothyroidism.
Based on the foregoing, replacement therapy for subclinical hypothyroidism remains controversial. While prospective data show improvement in some cardiovascular risk factors (e.g., serum lipids, carotid intimal thickening), there are no prospective trials showing improved cardiovascular outcomes with treatment. Similarly, there are no prospective trials that have shown improvement in pregnancy outcomes in women with subclinical hypothyroidism who have been treated with levothyroxine, although recent clinical practice guidelines recommend treatment in this situation.  In general, most clinicians agree that patients who have serum TSH levels >10 mU/l should be treated, since they have an increased risk of progression to overt hypothyroidism, might be more frequently symptomatic, and might have an increased risk of cardiovascular disease.  On the other hand, patients with serum TSH levels between 5 and 9 mU/l should be treated depending on the clinical situation (treatment more likely to be of benefit in young and middle-aged persons and persons with possible symptoms of hypothyroidism, depression, goiter, or cardiovascular risk factors). Elderly patients with a mildly elevated serum TSH might not be truly hypothyroid, and even if they are, they are less likely to benefit from treatment; indeed, they might even be harmed, since treatment is associated with often associated with inadvertent iatrogenic hyperthyroidism.  Thus, only with prospective randomized controlled trials, looking at clinically relevant outcomes such as cardiovascular morbidity or mortality, will the question of treatment be answered satisfactorily and convincingly.
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