SCH is an intermediate condition where those with normal thyroid function transition to hypothyroidism or those with hypothyroidism gradually recover to normal thyroid function. There are major controversies regarding the diagnosis and management of SCH [25, 26]. Although many studies have demonstrated that SCH has adverse effects on various physical functions, the diagnostic criteria for SCH are inconsistent, leaving the medical community perplexed [27]. Relaxing the diagnostic criteria will increase the number of SCH cases, but will also result in the misdiagnosis of genuine hypothyroidism cases as SCH. Our previous study compared five commonly used criteria for diagnosing SCH and found that elevated TSH but normal TT3, TT4, FT3, and FT4 concentrations might be the best criteria for SCH [4]. Since TT3, TT4, FT3, and FT4 were not detected simultaneously, many of the previously diagnosed cases of SCH might have reached the standard for hypothyroidism rather than SCH.
It is universally recognized that dyslipidemia can lead to the progression of atherosclerosis. Therefore, early detection of abnormal blood lipid levels and quick interventions are critical for the treatment of this disease and prevention of large-scale cardiovascular disease (CVD). Many studies have found that those with SCH are characterized by dyslipidemia, hyperglycemia, and cardiovascular dysfunction due to the lack of thyroid hormone. Some studies found an association between SCH and high TSH concentrations with all-cause mortality [28,29,30]. Nevertheless, it is debatable whether patients with SCH, whose thyroid hormones are within the normal range and have only elevated TSH, will experience the same outcomes [31]. For SCH, there are relatively few yet controversial studies on lipid abundance. In some studies, the total cholesterol level of SCH patients is higher than that in individuals with normal thyroid function, and the incidence of hypercholesterolemia is higher than that in normal individuals as well, findings that are positively correlated with the level of TSH [25, 32, 33]. Some studies have found that L-T4 replacement therapy can reduce serum total cholesterol and LDL-C levels in those with SCH [34,35,36]. However, recent guidelines strongly recommend against any hormone therapy for SCH [30]. Despite the lack of clinical symptoms in patients with SCH, it is recommended to opt for early prevention and treatment of ischemic heart disease.
There is an urgent need to identify individuals who are indeed in a state of SCH to accurately determine the physiological consequences of this disorder. In this study, only 685 individuals from 91,453 participants who finished the two physical checkups finally met the SCH standard. Although there were likely more than 685 patients with SCH among those people, these 685 subjects met the diagnostic criteria of SCH in each aspect. The same is true of the control group. Thus, we assume that the subjects of this study, both groups, underwent rigorous screening, which may reflect the true impact of SCH in the population.
When compared with the 10,827 participants in the control group, age, sex distribution, smoking status, thyroid nodules, fatty liver, hypertension, BMI, hemoglobin, TC, LDL-C, HDL-C, FBG, Hcy and UA in the SCH group were significantly different (P < 0.05). Stepwise logistic regression analysis demonstrated that sex, age, TC and body fat percentage were influential factors with statistical significance (P < 0.05), which is consistent with previous studies [13,14,15]. However, when the SCH group was divided into two subgroups (mild and severe), age, sex distribution, smoking status, thyroid nodule, fatty liver, hypertension, BMI, hemoglobin, TC, LDL-C, HDL-C, and UA were all significantly different between the three groups (P < 0.05).
The prevalence of SCH increases with age, and females are more prone to SCH, consistent with clinical characteristics [37]. Age and sex distribution may be significant confounding factors, which was why we matched age and sex distribution and established the strict control group. In further analysis, TC, TG, LDL-C and UA showed statistically significant differences between the SCH group and the strict control group (P < 0.05). However, multivariate logistic regression analysis indicated that no parameters including the above four factors were independent risk factors for SCH, inconsistent with previous studies [14,15,16]. Thus, it is suggested that the differences in TC, TG, LDL-C and UA between the two groups may be caused by other confounding factors.
Many factors can affect blood lipids. Theoretically, if there is a real correlation between two variables, the severity of the two variables is also related. However, we found that there was no statistically significant difference between the mild SCH subgroup and the severe SCH subgroup (P > 0.05), and only TG showed statistically significant difference among the strict control group, the mild SCH subgroup and the severe SCH subgroup, which suggested that SCH severity had no influence on the levels of TC, LDL-C or HDL-C, inconsistent with findings of other studies where the level of total cholesterol in SCH was positively correlated with the level of TSH [14, 15]. A meta-analysis reported that clinical parameters were more likely to be associated with thyroid hormone than with thyrotropin levels [38]. This may explain why there were no significant differences in various biochemical parameters between mild and severe cases of SCH in our study.
On the other hand, the clinical practice guidelines recommend observation rather than routine management of subclinical hypothyroidism because the benefits do not outweigh the risks. At the same time, our work indirectly suggests that in diagnosed SCH patients, and even in severe SCH patients, clinical follow-up and reexamination might be more important than an intervention before fully proving the definite relationship between blood lipids and SCH, especially among Chinese patients.
Strengths and limitations
Our study had many strengths. First, to our knowledge, this was the initial study to evaluate the effects of SCH upon plasma lipid profile in the general Chinese population with rigorous diagnostic criteria. Second, the biological characterization was comprehensive, including age, sex, BMI, FBG, Hcy, UA, etc. Most importantly, the participants have a strict follow up and were re-examined more than 3 months apart (N = 91,453) (Fig. 1). Thirdly, the median interval between the two tests in the SCH group was 425 days, compared with 346 days for the control group. These indicators reflected the long-term status of subjects maintaining the SCH standard, confirming utility of the lipid profile data. Finally, we set up a specific strict control group according to the age and sex composition of SCH group. To some extent, this is the way to eliminate the above confounding factors to the greatest extent.
As one of the limitations of our study, our analysis involved predominantly those of Chinese heritage. Although we have included all available data, our results may not be applicable to other populations. Second, because physical examinations were opportunistic and optional, the loss of follow-up was more severe in this retrospective study. Relatively few subjects met the criteria for SCH, let alone severe SCH. The small sample size may affect the results of the statistical analysis. A long-term prospective cohort study is needed to confirm the effects of the transition from mild to severe SCH on blood lipids. For this reason, proactive countermeasures should be taken to include more subjects to confirm the variation in blood lipid levels in inpatients with SCH. Third, this study was limited to diagnosis without addressing the effect of interventions on SCH.
