Endocrine Effects of Tobacco Smoking

Konstantinos Tziomalos; Faidon Charsoulis

Disclosures

Clin Endocrinol. 2004;61(6) 

In This Article

Thyroid Gland

Smoking has a significant impact on thyroid function. Thiocyanate, a major component of smoke, derived from hydrogen cyanide, leads to increased excretion of iodine, inhibits iodine uptake by the thyroid, competes with iodide in the organification process (Ermans et al., 1980), and inhibits thyroid hormone synthesis (Fukayama et al., 1992). It is possible that thiocyanate has both anti- and pro-thyroid actions: a pro-thyroid action in normal subjects and an antithyroid action in patients with subclinical and overt hypothyroidism. Nevertheless, it seems more likely that this dual mode of action of tobacco smoke is a result of the effects of multiple components of smoke, such as nicotine, hydroxypyridine metabolites and benzpyrenes, which may also interfere with thyroid function (Ermans et al., 1980; Melander et al., 1981; Sugawara et al., 1982; Sepkovic et al., 1984; Ericsson & Lindgarde, 1991; Utiger, 1998). Variations in iodine intake might also modulate the response to smoking, the predominant action of smoking being antithyroid when iodine intake is low and immunogenic when it is adequate. Whether smoking has any effect on the peripheral actions of thyroid hormone is not known. Smoking might also alter thyroid function indirectly, either through a chronic sympathetic stimulation resulting in increased secretion of thyroid hormones or by causing immunological disturbances (Utiger, 1995).

Both decreased and increased thyroid function (Melander et al., 1981; Christensen et al., 1984; Sepkovic et al., 1984; Ericsson & Lindgarde, 1991; Bertelsen & Hegedus, 1994; Bartalena et al., 1995) have been described in smokers in some studies, but in others smoking has had no effect on thyroid function (Petersen et al., 1991). Most, if not all, of the subjects in these studies were women but the conclusions are probably applicable to men (Utiger, 1998). The noxious effect of smoking on the thyroid gland seems to become apparent when thyroid function is slightly compromised, while in euthyroid patients the pool of circulating thyroid hormones is adequate to compensate for the smoking-induced defect of thyroid hormone action (Muller et al., 1995). Thus, in normal adults smoking has either no effect on thyroid function or a weak pro-thyroid effect, causing small, thyrotrophin-independent increases in thyroid function, most often small increases in serum triiodothyronine concentrations (Utiger, 1998). Among patients with subclinical hypothyroidism, smoking results in a higher mean serum thyrotrophin concentration and a higher ratio of serum triiodothyronine to serum free thyroxine. Thus, smoking may contribute to the high incidence of subclinical hypothyroidism – 10% in some studies (Sawin et al., 1985; Staub et al., 1992). It may also aggravate the peripheral biochemical effects of subclinical hypothyroidism even if it does not aggravate its clinical manifestations (Muller et al., 1995). The finding that all metabolic effects are normalized in smokers treated with thyroxine is an argument for treating all smokers with subclinical hypothyroidism, mostly because of the cardioprotective effect of normalizing serum lipid concentrations; smoking further increases the cardiovascular risk in these patients, and subclinical hypothyroidism per se has also been identified as a strong indicator of risk for myocardial infarction (Muller et al., 1995; Utiger, 1995; Hak et al., 2000). Finally, among patients with overt hypothyroidism, smoking has no effect on serum concentrations of thyrotrophin and thyroid hormones; however, it may aggravate both the clinical manifestations and biochemical effects of overt hypothyroidism (Muller et al., 1995).

There is also substantial evidence that smoking is a risk factor for Graves' hyperthyroidism, and especially Graves' ophthalmopathy (Bartalena et al., 1989; Ericsson & Lindgarde, 1991; Prummel & Wiersinga, 1993; Tallstedt et al., 1993). The odds ratio for smoking among patients with Graves' hyperthyroidism is 1·9, and rises up to 7·7 among those with Graves' hyperthyroidism and ophthalmopathy; the ophthalmopathy is more severe in those who smoke (Prummel & Wiersinga, 1993). Smoking may alter the structure of the thyrotrophin receptor slightly, so that in a susceptible person it becomes more immunogenic and the resulting antireceptor antibodies are more reactive with retro-orbital tissue; furthermore, it might impair restoration of tolerance to thyroid auto-antigens (Utiger, 1998). Alternatively, smoking could augment immunologic responsiveness to whatever factor initiates Graves' hyperthyroidism, sensitize retro-orbital tissue to whatever factor causes ophthalmopathy, or both (Utiger, 1995). The detrimental effect of cigarette smoking in these patients may also be mediated by reduced inhibition of interleukin-1 (IL-1) receptor antagonist on IL-1 stimulation (Hofbauer et al., 1997), even though other studies found no association (Salvi et al., 2000).

Smoking is not a risk factor for chronic autoimmune thyroiditis (Bartalena et al., 1989; Prummel & Wiersinga, 1993), although it was associated with postpartum thyroiditis, a precursor of chronic autoimmune thyroiditis, in one study (Fung et al., 1988).

The association of smoking with thyroid nodularity has not been settled (Christensen et al., 1984; Hegedüs et al., 1985; Berghout et al., 1987; Bertelsen & Hegedus, 1994; Bartalena et al., 1995; Knudsen et al., 2002b). Tobacco smoking has been associated with an increased prevalence of thyroid multinodularity, but not with increased prevalence of solitary thyroid nodules (Knudsen et al., 2002b). Nevertheless, in several other case–control studies, smoking was not a risk factor for either nontoxic or toxic multinodular goitre, indicating that its overall contribution to these disorders must be small (Bartalena et al., 1989; Prummel & Wiersinga, 1993). A stronger association seems to exist in areas with more pronounced iodine deficiency (Knudsen et al., 2002b).

Several epidemiological studies have reported a small inverse association of thyroid cancer with cigarette consumption (Kreiger & Parkes, 2000; Rossing et al., 2000). Results from a pooled analysis of 14 case–control studies conducted in the United States, Europe and Asia suggest that cigarette smoking is associated with a moderately reduced risk of thyroid cancer. The relationship was more pronounced in current smokers than former smokers. There were also significant trends of reduced risk with greater duration and frequency of smoking (Mack et al., 2003). This association was evident in both men and women, in the two major histological groups (papillary and follicular cancers), and in all geographical regions (Mack et al., 2003). These data also demonstrated a trend of decreasing risk with both smoking intensity and duration (Mack et al., 2003). A convincing biological explanation is lacking but three possible biological pathways have been identified. The first one relates to a smoking-related reduction in TSH secretion, as it has long been hypothesized that elevated levels of TSH may increase the risk of thyroid cancer (Henderson et al., 1982; Williams, 1990; Mack et al., 2003). The lower body weight among smokers compared to nonsmokers is a second proposed explanation, as increased body weight was associated with a slightly increased thyroid cancer risk in the above-mentioned pooled analysis (Mack et al., 2003). A third possible biological pathway lies in the potential anti-oestrogenic effect of cigarette smoke; a role for oestrogen in the aetiology of thyroid cancer is hypothesized because of the higher incidence of this cancer in females relative to males (Baron et al., 1990; Galanti et al., 1996; Mack et al., 2003).

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