Preliminary observation of thyroid function changes in subclinical thyroid diseases

Abstract

BACKGROUND:

It is estimated that 1.95% and 5.55% of adults in China suffer from subclinical thyroid diseases, which is difficult to diagnose and treat.

OBJECTIVE:

This study aimed to explore the development and prognosis of subclinical thyroid diseases to provide a reference from our single center experience.

METHODS:

A total of 240 cases from April 2019 to August 2021 in the laboratory information system database of Huanghua Development Boai Hospital were retrospectively analyzed. Binary logistic regression was conducted to analyze odds ratio (OR) of subclinical thyroid disease types returning to a normal state.

RESULTS:

Among the patients hypothyroidism Ia and hyperthyroidism Ia were the most common type with conversion to the normal state ( $P<$ 0.001). TSH level of patients with conversion to a normal state was significantly lower than that of those who developed to abnormal disease ( $P=$ 0.015). The OR values of hyperthyroidism Ia and hypothyroidism Ia that returned to a normal state compared with hyperthyroidism Ib were 2.659 (1.159 $\sim$ 6.096, $P=$ 0.021) and 3.138 (1.1.278 $\sim$ 7.709, $P=$ 0.013), respectively. The OR value of hypothyroidism Ib that returned to normal compared with hyperthyroidism Ib was 0.629 (0.131 $\sim$ 3.010, $P=$ 0.561). Thyroid hormone levels, age, and gender at first diagnosis were not impact factor for prognosis of subclincal thyroid disease ( $P>$ 0.05).

CONCLUSION:

Cases with grade hypothyroidism Ia and hyperthyroidism Ia are more likely to revert to normal state than other subclinical thyroid diseases. TSH reference range should be explored for diagnosis and treatment.

Keywords

Subclinical hyperthyroidism subclinical hypothyroidism diagnostic grading prognosis odds ratio

1. Introduction

It is estimated that 1.95% and 5.55% of adults in China suffer from subclinical thyroid diseases, which is difficult to diagnose and treat [1]. In 2015, the European Thyroid Association (ETA) published guidelines on the management of subclinical thyroid diseases, including subclinical hypothyroidism and subclinical hyperthyroidism. The ETA further proposed its grading diagnosis theory, which divides hyperthyroidism and hypothyroidism into three grades according to the levels of free T ${}_{3}$ (FT ${}_{3}$ ), free T ${}_{4}$ (FT ${}_{4}$ ), and thyroid-stimulating hormone (TSH) [2].

The grading system defines the relationship between the severity of the disease and the natural course of disease development. In the process of clinical intervention, it is suggested that subclinical thyroid diseases do not require treatment before thyroid lesions identified [2, 3, 4].

This study aimed to track and observe the development and prognosis of subclinical thyroid diseases and add a reference for their diagnosis and treatment from our single center experience.

2. Materials and methods

2.1 Patients

From April 2019 to August 2021, the thyroid hormone test results and patient information were extracted from the laboratory information system (LIS) database of Huanghua Development Boai Hospital and were reviewed in this retrospective analysis.

Patients meeting the following criteria were included: (I) over 18 years old; (II) complete medical records; (III) the internal quality control results of this batch were under control.

Patients meeting the following criteria were excluded: (I) pregnancy; (II) receiving antithyroid drugs; (III) prior thyroid surgery; (IV) taking antiepileptic drugs; (V) severe hypertension.

2.2 Methods

A total of 240 cases of subclinical thyroid diseases were evaluated according to the grading standard modified by Wiersinga [3].

Thyroid function test results were collected from the LIS. The contents included the dates of patients’ first examination and re-examination, their name, gender, age, clinical diagnosis, application department, application doctor, FT ${}_{3}$ levels, FT ${}_{4}$ levels, TSH levels, thyroid peroxidase antibody (TpoAb) levels, and thyroid globulin antibody (TgAb) levels at the first and determining diagnoses. The device used for testing the TSH, FT ${}_{3}$ , FT ${}_{4}$ , TpoAb, and TgAb levels was an Abbott Architect i 2000SR automatic chemiluminescence instrument in conjunction with special reagents. The internal quality controls of FT ${}_{3}$ and FT ${}_{4}$ were divided into normal and high-value levels, produced by Qualab Biotech Co., Ltd. (Shanghai), lot numbers: 338773E and 338298D. The internal quality control CV (%) of FT ${}_{3}$ , FT ${}_{4}$ , and TSH was 3.28–6.63, 2.74–3.21, and 6.23–6.37, respectively. The results of the FT3, FT4, and TSH external quality assessments at the national clinical laboratory center were 100%.

2.3 Endpoint

The endpoint was set at the first determining diagnosis during the observation period including normal results and those for hyperthyroidism, hypothyroidism, and subclinical thyroid diseases, among others.

2.4 Statistical methods

All data collected in this study were analyzed using SPSS 22.0 software. Normally distributed measurement data were expressed as mean $\pm$ standard deviation (SD), while non-normally distributed measurement data were expressed as median (interquartil range), and the comparisons were examined by Student- $t$ test (a univariate analysis of variance test) and nonparametric Z-test (nonparametric distribution). The categorical data were expressed as $n$ (%), and the differences between the two groups were examined by chi-square analysis or Fisher’s exact test. A binary logistic regression analysis was conducted for the odds ratio (OR) value and confidence interval (CI). $P<$ 0.05 was considered statistically significant.

3. Results

3.1 Patient information and subclinical thyroid disease classification

3.1.1 Baseline information

Based on patients screening procedure (Fig. 1), 240 patients were enrolled in present study. Among these patients, 74 were males (20.55%) and 166 were females (79.45%). The mean age of the males was 44.98 $\pm$ 14.24 years old, and the median age was 48 years old; the mean age of the females was 48.12 $\pm$ 15.50 years old, while the median age was 50 years old.

Figure 1.

Flowchart of patients selection.

3.1.2 Subclinical thyroid disease classification

In terms of the histogram distribution of TSH, FT ${}_{3}$ , FT ${}_{4}$ , TpoAb, and TgAb, FT ${}_{3}$ and FT ${}_{4}$ were approximately normally distributed, while TSH, TpoAb, and TgAb were significantly non-normally distributed. Of all patients, 93 (38.75%) patients were hypothyroidism Ia, 42 (17.50%) were hypothyroidism Ib, 55 (22.90%) were hyperthyroidism Ia, and 50 (20.83%) were hyperthyroidism Ib ( $P<$ 0.001) (Table 1).

Table 1
Diagnostic types of subclinical thyroid diseases according to grading diagnostic criteria [2]

Grade	FT ${}_{3}$	FT ${}_{4}$	TSH	Number of cases ( $n$ , %)
Total				240 (100)
Hypothyroidism Ia	Normal	Normal	4–10 mU/L	93 (38.75)
Hypothyroidism Ib	Normal	Normal	$\geqslant$ 10.0 mU/L	42 (17.50)
Hyperthyroidism Ia	Normal	Normal	0.1–0.4 mU/L	55 (22.92)
Hyperthyroidism Ib	Normal	Normal	$\leqslant$ 0.1 mU/L	50 (20.83)
				$P<$ 0.001

3.2 Subclinical thyroid disease prognosis

3.2.1 Subclinical thyroid disease types

The conversion to normal states was found to be 67.70%, 40.47%, 61.80%, and 36.00% for hypothyroidism Ia, hypothyroidism Ib, hyperthyroidism Ia and hyperthyroidism Ib, respectively. Hypothyroidism Ia and hyperthyroidism Ia were the most common type with conversion to the normal state ( $P<$ 0.001) (Table 2).

Table 2
Development and prognosis of subclinical thyroid diseases

Thyroid disease type	Normal		Subclinical thyroid disease		Hyperthyroidism		Hypothyroidism		Others		Total
	$n$	%	$n$	%	$n$	%	$n$	%	$n$	%
Hypothyroidism Ia	63	67.70	12	12.90	8	8.60	3	3.20	7	7.60	93
Hypothyroidism Ib	17	40.47	14	33.33	5	11.90	1	2.23	5	11.90	42
Hyperthyroidism Ia	34	61.80	8	14.50	7	12.70	2	3.60	4	7.40	55
Hyperthyroidism Ib	18	36.00	10	20.00	12	24.00	6	12.00	4	8.00	50
											$P<$ 0.001

3.2.2 Prognosis of different types of subclinical thyroid disease

An ANOVA test was conducted for different types of subclinical thyroid diseases and prognosis. There was a significant difference in the prognosis between hypothyroidism Ia, hypothyroidism Ib, and hyperthyroidism Ia ( $P<$ 0.001), while there was no difference in the prognosis for hyperthyroidism Ib ( $P=$ 0.089) Moreover, there was a significant difference in the conversion to a normal state between hypothyroidism Ia, hypothyroidism Ib, hyperthyroidism Ia, and hyperthyroidism Ib ( $P<$ 0.001), and there was no difference in the conversion to other types between hypothyroidism Ia, hypothyroidism Ib, hyperthyroidism Ia, and hyperthyroidism Ib ( $P>$ 0.05) (Table 3).

Table 3
Prognostic analysis of different types of subclinical thyroid diseases

Thyroid disease type	Disease prognosis		Normal	Subclinical
	$X^{2}$ value	$p$		thyroid disease
Hypothyroidism Ia	108.6	$<$ 0.001	$\chi^{2}=$ 41.879,
$P<$ 0.001	$\chi^{2}=$ 1.818,
$P=$ 0.611	$\chi^{2}=$ 3.250,
$P=$ 0.355	$\chi^{2}=$ 4.677,
$P=$ 0.198
Hypothyroidism Ib	18.24	$<$ 0.001
Hyperthyroidism Ia	48.84	$<$ 0.001
Hyperthyroidism Ib	6.52	0.089

3.2.3 Analysis of thyroid function test results

A comparison of FT ${}_{3}$ , FT ${}_{4}$ , TSH, TpoAb, and TgAb levels was conducted at the first diagnosis of subclinical thyroid disease and at the conversion to a normal state or abnormal disease. There was no difference of FT ${}_{3}$ , FT ${}_{4}$ , TpoAb and TgAb between these two groups ( $P>$ 0.05). However, TSH level of patients with conversion to a normal state was significantly lower than that of those who developed to abnormal disease ( $P=$ 0.15) (Table 4).

Table 4
Test results of thyroid function of normal and abnormal prognosis

	Prognosis: normal		Prognosis: abnormal		Statistical analysis
	Range	Mean or median	Range	Mean or median	Statistical value	$P$ -value
FT ${}_{3}$ (pmol/L)	2.90 $\sim$ 4.83	4.04	2.98 $\sim$ 4.88	4.14	$t=$ 1.466	0.227
FT ${}_{4}$ (pmol/L)	9.01 $\sim$ 18.97	12.21	9.02 $\sim$ 18.58	12.01	$t=$ 0.452	0.502
TSH (mU/L)	0 $\sim$ 38.51	5.02	0 $\sim$ 58.63	5.57	$Z=$ 1.562	0.015
TpoAb (U/mL)	0.03 $\sim$ 1000	123.83	0.01 $\sim$ 1000	43.77	$Z=$ 1.242	0.091
TgAb (U/mL)	0.25 $\sim$ 1000	20.24	0.02 $\sim$ 1000	20.00	$Z=$ 0.401	0.997

Abbreviations: FT3: free T3; FT4: free T4; TSH: thyroid-stimulating hormone; TpoAb: thyroid peroxidase antibody; TgAb: thyroid globulin antibody. Notes: FT3 and FT4 are basically normally distributed, and compared using t-test. TSH, TpoAb and TgAb are significantly non-normally distributed, and compared using nonparametric Z-test.

Table 5

Prognostic analysis of subclinical thyroid diseases

	OR value	95% CI	$P$ -value
First diagnosis thyroid hormone test results
FT3	0.765	0.493 $\sim$ 1.189	0.234
FT4	1.109	0.975 $\sim$ 1.286	0.169
TSH	1.041	0.976 $\sim$ 1.111	0.221
TpoAb	1.000	0.999 $\sim$ 1.001	0.868
TgAb	1.000	0.999 $\sim$ 1.001	0.577
Subclinical thyroid disease type
Hypothyroidism Ia/hyperthyroidism Ib	3.138	1.278 $\sim$ 7.709	0.013
Hypothyroidism Ib/hyperthyroidism Ib	0.629	0.131 $\sim$ 3.010	0.561
Hyperthyroidism Ia/hyperthyroidism Ib	2.659	1.159 $\sim$ 6.096	0.021
Age	0.996	0.947 $\sim$ 1.023	0.880
Age group
Young/elderly	0.657	0.101 $\sim$ 4.274	0.660
Middle-aged/elderly	0.367	0.129 $\sim$ 1.402	0.060
Gender (male/female)	0.846	0.372 $\sim$ 1.925	0.690

Abbreviations: FT3: free $T_{3}$ ; FT4: free T4; TSH: thyroid-stimulating hormone; TpoAb: thyroid peroxidase antibody; TgAb: thyroid globulin antibody.

3.2.4 Odds ratio values for subclinical thyroid disease prognosis

The prognosis of subclinical thyroid diseases can be divided into two groups: normal and abnormal. The type, gender, and age of patients with subclinical thyroid diseases were included as influencing factors in a binary logistic regression analysis. The OR values of hypothyroidism Ia and hyperthyroidism Ia when compared with hyperthyroidism Ib were 3.138 (1.1.278 $\sim$ 7.709) and 2.659(1.159 $\sim$ 6.096), respectively (both $P<$ 0.05). As the results demonstrated, the OR values of hyperthyroidism Ia and hypothyroidism Ib converting to a normal state were higher than those for hyperthyroidism Ib. Moreover, the OR value of hypothyroidism Ib returning to a normal state compared with hyperthyroidism Ib was 0.629 (0.131 $\sim$ 3.010, $P=$ 0.561). Furthermore, there were no difference in the OR values for a return to a normal state in terms of thyroid hormones (TSH, FT ${}_{3}$ , FT ${}_{4}$ , TpoAb, and TgAb) at first diagnosis, age groups (young: $<$ 45 years; middle-aged: 45–59 years; elderly: $>$ 60 years), and gender (All $P>$ 0.05) (Table 5).

Table 6
Time of subclinical thyroid disease needed to return to normal state (days)

Type	Minimum	Maximum	$M(Q_{1},Q_{3})$	$P$ -value
Hypothyroidism Ia	17.00	433.00	95.00 (48,322)	0.377
Hypothyroidism Ib	19.00	557.00	53.50 (33.5,168.5)
Hyperthyroidism Ia	29.00	435.00	90.00 (47,216)
Hyperthyroidism Ib	4.00	421.00	89.50 (44,148)

3.2.5 Time to return to a normal state of subclinical thyroid disease

There was no difference found in the time required for various types of subclinical thyroid diseases returning to a normal state ( $P>$ 0.05). The median times required for hypothyroidism Ia and hyperthyroidism Ia to return to a normal state were 95 and 90 d, respectively, while the $Q_{1}-Q_{3}$ values were 48–322 and 47–216 d, respectively (Table 6).

4. Discussion

Subclinical thyroid disease is a laboratory-diagnosed disease type of which serum TSH is abnormal, but FT ${}_{3}$ and FT ${}_{4}$ are normal, and patients have almost no symptoms of abnormal thyroid function [5]. Antibodies and echography are more valuable for disease evaluation of these patients. Mild thyroid dysfunction is the most common cause of mildly elevated serum thyrotropin levels [4]. Wiersinga et al. [3] first modified the grading diagnostic criteria for thyroid diseases in ETA documents, including grades I, II, and III according to the occurrence, development, and severity of the disease Grade I is further divided into grades Ia and Ib.

Patients with grade hyperthyroidism Ia or hypothyroidism Ia show a slight increase or decrease in TSH. In present study, more than 60% of patients with hyperthyroidism Ia and hypothyroidism Ia returned to a normal state. However, there was no difference in other prognosis types. The results also revealed that approximately 10% of cases of hyperthyroidism Ia and hypothyroidism Ia turned into hyperthyroidism or hypothyroidism. It might be induced by the use of anti-hyperthyroidism or anti-hypothyroidism drugs. Therefore, the clinical diagnosis and treatment of subclinical thyroid diseases should be comprehensively determined and scientifically explained according to clinical symptoms and not be simply treated with drugs [6]. The decision to treat depends on the degree of thyroid-stimulating hormone suppression and underlying comorbidities [7].

Age, gender, iodine nutrition, and autoantibodies are risk factors for thyroid diseases [8, 9, 10, 11, 12]. The present study revealed that there was no differences in age, gender, TpoAb, and TgAb between the normal and abnormal prognosis groups, except TSH. It suggested that TSH was one of the most important factors for thyroid disease, and the obvious increase and decrease in TSH were the early characteristics of the occurrence and development of clinical hypothyroidism or clinical hyperthyroidism. Notably, while the cut-off value of TSH for the diagnosis of subclinical thyroid diseases in this study referred to the ETA guidelines, this approach is not necessarily suitable for the testing methods of the local region and a given laboratory. Therefore, the reference range and cut-off value of TSH for laboratories in local regions should be established [13, 14, 15] in further. In addition, TSH test is easily affected by TSH heterophilic antibodies, while diseases unrelated to thyroid diseases (e.g., those caused by glucocorticoids, obesity, and hypothalamic-pituitary-thyroid axis regulation) can also cause TSH abnormalities [16, 17, 18, 19, 20].

This study also found that the median times ( $M$ ) required for hyperthyroidism grade Ia and hypothyroidism grade Ia returning to normal state were 90 and 95 days, respectively. Thus, thyroid function follow-up of subclinical hypothyroidism should be performed after 3 to 4 months. These results were obtained through a statistical analysis based on data collected at the first diagnosis and on the conversion to a normal state obtained from the LIS database.

This study also had several limitations. Firstly, this was a retrospective study with unavoidable biases. Secondly, this was a single center analysis with limited sample size. Thirdly, this was not a rigorous case follow-up study Therefore, all results in this study should be interpreted cautiously, and prospective study with large sample should be conducted in the future.

In recent years, with the extensive application and development of artificial intelligence in the field of laboratory medicine, relevant research results have confirmed that machine learning has certain advantages over parametric models [21]. For example, Ardila [22] combined chest CT imaging features with important characteristics of patients such as demographic characteristics and living habits to build an effective evaluation system for the nature of pulmonary nodules. Arbel [23] found the distribution width of red blood cells (RDW), a non-specific test index, can significantly increase the incidence of cardiovascular disease. Subclinical thyroid diseases lack typical clinical symptoms. Clinicians often make judgments based on the patient’s physical signs, symptoms, medical history and thyroid function test results and personal knowledge and clinical experience, but cannot guarantee the accuracy of diagnosis. If a large number of thyroid function tests and other non-specific index data processing are carried out in multiple centers, combined with the clinical characteristics of thyroid diseases, and through simulation, extension and expansion [24], the test big data is linked with the diagnosis, differential diagnosis, treatment effect, and pre-and post-judgment of the disease, a high-level intelligent analysis will be generated to help clinicians predict the risk of patients, Make suggestions for treatment and prognosis.

5. Conclusion

Grade hypothyroidism Ia and hyperthyroidism Ia are more likely to revert to normal state than other subclinical thyroid diseases. TSH reference range should be explored for diagnosis and treatment.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was funded by the Medical Science Research Project of Hebei Province Health Commission (No. 20210401).

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Huanghua Boai Hospital. Written informed consent was obtained from all participants.

Availability of data and material

All data generated or analysed during this study is included in this article. Further enquiries can be directed to the corresponding author.

Footnotes

Acknowledgments

The authors are grateful to everyone who helped them with the article.

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Preliminary observation of thyroid function changes in subclinical thyroid diseases

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Materials and methods

2.1 Patients

2.2 Methods

2.3 Endpoint

2.4 Statistical methods

3. Results

3.1 Patient information and subclinical thyroid disease classification

3.1.1 Baseline information

Table 1 Diagnostic types of subclinical thyroid diseases according to grading diagnostic criteria [2]

3.2.1 Subclinical thyroid disease types

Table 2 Development and prognosis of subclinical thyroid diseases

Table 3 Prognostic analysis of different types of subclinical thyroid diseases

Table 4 Test results of thyroid function of normal and abnormal prognosis

Table 6 Time of subclinical thyroid disease needed to return to normal state (days)

4. Discussion

5. Conclusion

Competing interests

Funding

Ethics statement

Availability of data and material

Footnotes

Acknowledgments

References

Table 1
Diagnostic types of subclinical thyroid diseases according to grading diagnostic criteria [2]

Table 2
Development and prognosis of subclinical thyroid diseases

Table 3
Prognostic analysis of different types of subclinical thyroid diseases

Table 4
Test results of thyroid function of normal and abnormal prognosis

Table 6
Time of subclinical thyroid disease needed to return to normal state (days)