Hypothyroidism and Somatization: Results from E-Mode Patient Self-Assessment of Thyroid Therapy,a Cross-Sectional,International Online Patient Survey

Abstract

Background:

Between 10% and 15% of hypothyroid patients experience persistent symptoms despite achieving biochemical euthyroidism. Unexplained persistent symptoms can be a sign of somatization. This is associated with distress and high health care resource use and can be classified as somatic symptom disorder (SSD). Prevalence rates for SSD differ depending on classification criteria and how they are ascertained, varying between 4% and 25%. As this has not been studied in hypothyroid patients before, the aim of this study was to document somatization in people with hypothyroidism and to explore associations with other patient characteristics and outcomes.

Methods:

Online, multinational cross-sectional survey of individuals with self-reported, treated hypothyroidism, which included the validated Patient Health Questionnaire-15 (PHQ-15) for assessment of somatization. Chi-squared tests with the Bonferroni correction were used to explore outcomes for respondents with a PHQ-15 score ≥10 (probable somatic symptom disorder [pSSD]) versus a PHQ-15 score <10 (absence of SSD).

Results:

A total of 3915 responses were received, 3512 of which contained the valid PHQ-15 data (89.7%). The median score was 11.0 (range 0–30 [confidence interval 10.9–11.3]). The prevalence of pSSD was 58.6%. Associations were found between pSSD and young age (p < 0.001), women (p < 0.001), not working (p < 0.001), having below average household income (p < 0.001), being treated with levothyroxine (LT4) (rather than combination of LT4 and L-triiodothyronine [LT3], LT3 alone, or desiccated thyroid extract) (p < 0.001), expression of the view that the thyroid medication taken did not control the symptoms of hypothyroidism well (p < 0.001), and with number of comorbidities (p < 0.001). pSSD was associated with respondent attribution of most PHQ-15 symptoms to the hypothyroidism or its treatment (p < 0.001), dissatisfaction with care and treatment of hypothyroidism (p < 0.001), a negative impact of hypothyroidism on daily living (p < 0.001), and with anxiety and low mood/depression (p < 0.001).

Conclusions:

This study demonstrates a high prevalence of pSSD among people with hypothyroidism and associations between pSSD and negative patient outcomes, including a tendency to attribute persistent symptoms to hypothyroidism or its treatment. SSD may be an important determinant of dissatisfaction with treatment and care among some hypothyroid patients.

Introduction

Hypothyroidism is common affecting 1–7% of the population.^1
–3 Persistent symptoms occur in 10–15% of hypothyroid patients compared with controls.^4
–6 Hypotheses for the cause of these symptoms include: (a) inability of levothyroxine (LT4) to emulate normal physiology and restore L-triiodothyronine (LT3) at tissue level; (b) confounding effects of comorbidities; (c) autoimmune inflammation; (d) LT4 prescribed or taken by patients suboptimally; (e) people with unexplained symptoms being more likely to be investigated and diagnosed with minor and incidental perturbations of thyroid dysfunction; (f) the impact of the diagnostic label of chronic disease; and (g) somatic symptom disorder (SSD).^7
–9 Direct evidence to support the above propositions is unavailable, although it is likely that all are contributory.

In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), SSD refers to persistent bodily symptoms associated with significant functional impairment, psychological distress, and high health care resource use.¹⁰ SSD is thought to result from an exaggerated awareness of bodily sensations, interpreted as being indicative of underlying disease.^11,12 The etiology of SSD is unclear, although associations with past traumatic experiences, personality traits, and psychosocial stresses have been described.^13,14 Genetic factors predisposing to bodily distress and to chronic pain may contribute.^15,16

SSD is a relatively recent classification, introduced in 2013 in the DSM-V.¹⁰ Reviews describing prevalence rates of earlier classifications related to somatization (such as somatization disorder analyzing 32 studies from 24 countries), reported a pooled estimate of the point prevalence of 16.5%.¹⁷ However, somatization disorder is a severe form of SSD and is limited to distress related to medically unexplained symptoms. In contrast, SSD relates to distress associated with physical symptoms in known medical conditions and medically unexplained symptoms and thus prone to have been underestimated.

A systematic review reported prevalence rates for somatoform disorders in the general population to range from 11% to 21% in younger, 10% to 20% in the middle-aged, and 1.5% to 13% in older age groups.¹⁸ A 2022 review of 59 studies found a mean prevalence of SSD of 12.9% based on self-report.¹⁹ A population-based study in more than 3000 people in Taiwan reported a prevalence of SSD of 5%,²⁰ and a German study of 1780 general practitioners reported a prevalence of SSD of 7.7% among their patients.²¹ Based on the above findings, we can surmise that the prevalence of SSD in the general population is between 5% and 25%.

Studying SSD in hypothyroidism may help to understand the nature of persistent symptoms. Furthermore, identifying SSD may avoid unnecessary and expensive investigations, reduce the risk of inappropriate and harmful therapies,^22

–28 and direct patients and physicians to interventions shown to be helpful in SSD.²⁹

In this study, probable somatic symptom disorder (pSSD, defined as a score ≥10 using the Patient Health Questionnaire-15 [PHQ-15]) in patients with hypothyroidism was explored. The research questions were as follows: what is the prevalence of pSSD among patients with hypothyroidism, and what is the relationship between (a) pSSD and respondent characteristics and (b) pSSD and patient-reported outcomes?

Methods

Study design

Multinational, large-scale, cross-sectional, online questionnaire survey of people with a diagnosis of hypothyroidism. Some of the findings have been published.³⁰

Patient Health Questionnaire-15

The PHQ-15 is a questionnaire that is self-administered. It has been used in research and clinically as a screening test for somatization.³¹ It includes 15 symptoms, which comprise the most frequent somatic complaints encountered in primary care. High scores correlate closely with somatoform disorder, disability, functional impairment, and use of health care resources.³¹ This instrument has been validated and used extensively,³² is equivalent or better in performance to other tools, and is recommended by the American Psychiatric Association.¹⁰ The PHQ-15³¹ has a sensitivity of 78–83% and a specificity of 42–71% for somatization^33,34 and is well suited for use in large-scale studies internationally.³⁵ The PHQ-15 lists 15 somatic symptoms, 13 of which are related to physical symptoms, while 2 (feeling tired or having little energy, and trouble sleeping) are associated with depression.^31,32

Each symptom is scored as 0, 1, or 2 (“not bothered at all,” “bothered a little,” “bothered a lot,” respectively). The sum score is used as a measure for symptom load. A score of ≥10 is associated with somatization equivalent to clinical disorder.³¹ In this study, values of the PHQ-15 were considered valid when the provided answers were undoubtedly ≥10 or <10. Therefore, respondents with a PHQ-15 score of ≥10 were included even if they did not respond to all questions of the PHQ-15 and categorized as having pSSD. Respondents whose scores could not exceed 9 even if the missing data scored maximally were included and categorized as not having SSD. Respondents who had left out parts of the PHQ-15 and could have attained a score indicating SSD were excluded as we could not undoubtedly attribute their responses. pSSD (score ≥10) was used as a research classification rather than a medical diagnosis of SSD.

Questionnaire

The questionnaire was cognitively tested in 30 English-speaking patients with hypothyroidism across 5 rounds in accordance with published methodology.³⁶ Minor changes were made to establish consistent comprehension. Translations of the English version of the questionnaire were made into French, German, Italian, and Spanish. Each translation was performed by two certified native translators. Idioms were replaced with appropriate alternatives. A pilot was conducted in English with 387 respondents (344 completed and 43 partially completed) for data validation, which demonstrated good face validity and response. The final version took 30–45 minutes to complete and was hosted online in Qualtrics between April 11, 2020, and January 3, 2021 (Supplementary Data).

Dissemination

Advertisements and information sheets to explain the purpose of the survey were prepared in the aforementioned five languages and promoted through Thyroid Federation International, a global network of patient thyroid disorder organizations, affiliates, and partners via social media and web pages (Supplementary Fig. S1).

Inclusion criteria

Participants had to be ≥18 years and to be using medication for hypothyroidism.

Institutional review board waiver statement

The non-interventional nature of the survey and the fact that data were anonymized rendered the study exempt from institutional board approval. The study was conducted in accordance with Declaration of Helsinki as revised in 2013. All participants gave informed consent.

Statistical analyses

The data set was calculated to detect a delta of 0.1 in proportions for z-tests, using GPower3.1.9 for a power of 95% and alpha set at 0.05, which calculated the number of participants to be around 1000 (1066). Chi-squared tests with the Bonferroni correction were used, via Python 3.10. A binary PHQ-15 score <10 or ≥10 (corresponding to the absence or presence of pSSD) was used as an independent variable and was compared against 10 dependent variables comprising demographic and other baseline characteristics (gender, age, marital status, employment, ethnicity, years in education, household income, comorbidities, cause of hypothyroidism, treatment for hypothyroidism). In addition, the PHQ-15 binary score was compared against five respondent outcomes:

Attribution of the PHQ-15 symptoms: for each of the symptoms in the PHQ-15, participants were asked whether they attributed the symptom to “the hypothyroidism or side-effects of the hypothyroidism medication,” or to “other causes.”

Control of symptoms of hypothyroidism by medication: participants were asked to respond to the statement “my hypothyroidism medication controls my symptoms well,” with the following response options: “strongly disagree,” “tend to disagree,” “neither agree nor disagree,” “tend to agree,” “strongly agree,” and “uncertain.”

Satisfaction with overall treatment and care for hypothyroidism: participants were asked “how satisfied are you with the overall care and treatment you have received for your hypothyroidism?” with the following response options: “very satisfied,” “slightly satisfied,” “neither satisfied nor dissatisfied,” “slightly dissatisfied,” “very dissatisfied,” and “don't know.”

Impact of hypothyroidism on daily living: participants were asked to respond to the statement “my hypothyroidism has affected everyday activities that people my age usually do (e.g., exercise, household chores, etc.),” with the following response options: “strongly disagree,” “tend to disagree,” “neither agree nor disagree,” “tend to agree,” “strongly agree,” and “uncertain.”

Anxiety, low mood/depression: participants were asked “during the past 4 weeks, how much have you been bothered by anxiety?” and “during the past 4 weeks, how much have you been bothered by low mood/depression?” with the following response options: “bothered a little or bothered a lot,” “not bothered at all.”

Results

Respondent baseline characteristics

A total of 3912 responses were received, 3512 of which contained the valid PHQ-15 data (89.7%) (Table 1). Women comprised 94.4% (3317/3512) of respondents. Most respondents (87.2%; 3063/3512) were older than 30 years. Responses from the United Kingdom dominated (35.6%; 1249/3512). The majority of respondents were white (86.5%; 3039/3512), employed (71.9%; 2524/3512), had received more than 8 years of education (84.45%; 2966/3512), had comorbidities (72.9%; 2560/3512), and were treated with LT4 (75.8%; 2662/3512).

Table 1.

Baseline Respondent Characteristics

Characteristic	n	%
No. of respondents	3512	100
Gender
Man	164	4.7
Woman	3317	94.4
Prefer to self-identify	13	0.4
Prefer not to say	16	0.5
Missing data	2	0.1
Age, years
18–30	236	6.7
31–40	605	17.2
41–50	950	27.1
51–60	850	24.2
Over 60	658	18.7
Missing data	213	6.1
Top 10 countries by respondent number
United Kingdom	1249	35.6
France	591	16.8
Sweden	194	5.5
Finland	146	4.2
Australia	136	3.9
Italy	121	3.4
Germany	114	3.2
Norway	102	2.9
United States of America	100	2.8
Canada	104	3.0
Other countries	503	14.43
Missing data	152	4.43
Marital status
Married/partnership	2319	66.0
Single/divorced	879	25.0
Prefer not to say	58	1.7
Other	39	1.1
Missing data	217	6.2
Employment status
Working (full time, part-time, student, carer)	2524	71.9
Not working	589	16.8
Prefer not to say	55	1.6
Other	127	3.6
Missing data	217	6.2
Ethnic background
White	3039	86.5
Other	204	5.8
Prefer not to say	52	1.5
Missing data	217	6.2
Years of education
8 Years or less	260	7.4
More than 8 years	2966	84.45
Prefer not to say	71	2.0
Missing data	215	6.1
Household income
Above average	1044	29.7
Average	1480	42.1
Below average	612	17.4
Prefer not to say	120	3.4
Missing data	256	7.3
Comorbidities
Median (range)	2 (0–12)	72.9
Missing data	372	10.6
Time since diagnosis of hypothyroidism
<2 Years	357	10.2
2–10 Years	12940	36.7
>10 Years	1787	50.9
Don't know/cannot remember	69	2.0
Missing data	9	0.3
Current treatment for hypothyroidism
LT4	2662	75.8
LT3	69	2.0
DTE	262	7.5
LT4 + LT3	343	9.8
Missing data	176	5.0
Cause of hypothyroidism
Hashimoto/autoimmune disease	1282	36.5
Treatment for Graves' disease or hyperthyroidism	285	8.1
Treatment for thyroid cancer	453	12.9
Treatment for benign goiter	176	5.0
Pregnancy related	135	3.8
Congenital hypothyroidism	46	1.3
Medications	24	0.7
Pituitary disease	24	0.7
Wilson's temperature syndrome	1	0.0
Not known	777	22.1
Variety of other answers provided as free text^a	306	8.7
Missing data	4	0.1

Causes in free text included: “radiation,” “radiotherapy,” “stress,” “viral,” “injury to the thyroid,” “puberty,” “menopause,” “eating disorder,” “none,” “levothyroxine brand switch,” “insulin resistance,” “endocrine disruption,” “fluoridation,” “flu vaccine,” “gallbladder surgery,” “Hereditary,” “genetic,”“hormonal contraceptive,” “allergy,” “aging,” “leaky gut,” ‘hysterectomy,” “mono,” “quitting smoking,” “sluggish thyroid,” “antibiotics,” “Yodo,” “hypothyroidism.”

DTE, desiccated thyroid extract; LT3, L-triiodothyronine; LT4, levothyroxine.

Prevalence of pSSD

The median PHQ-15 score was 11.0 (range 0–30 [confidence interval 10.9–11.3]). Women respondents (n = 3317) had higher PHQ-15 score than men (n = 164) (mean 11.3, standard deviation [SD] 5.7 vs. mean 7.6, SD 5.6, respectively, p < 0.001). Tiredness was the most common symptom experienced by 90.3% (3161/3501) of respondents (Supplementary Table S1).

Associations between pSSD and demographic and other baseline characteristics

Significant associations with pSSD were found with age, gender, employment status, household income, treatment for hypothyroidism, and number of comorbidities (Table 2). By binary categorization into PHQ-15 scores <10 and ≥10, the following groups were identified as having higher pSSD prevalence: aged 18–30 years, women, not working, having below average household income, being treated with LT4 (compared with combination of LT4 and LT3, LT3 alone, or desiccated thyroid extract) (Table 2; Supplementary Table S2), and having one or more comorbidities (Fig. 1). No associations were found between pSSD and marital status, years of education, cause of hypothyroidism, and ethnicity.

FIG. 1.

Association between pSSD (PHQ-15 score ≥10) and respondent characteristics: (a) age, (b) gender, (c) employment, (d) household income, (e) treatment for hypothyroidism, (f) number of comorbidities. The vertical axis shows the proportion (%) of respondents with PHQ-15 score <10 (white bars) and PHQ-15 score ≥10 (black bars), for each grouped category, so that the sum of percentages for each pair of bars (white and black) equals 100. All comparisons between groups were statistically significant at p < 0.001. For each pair of bars, the number of observations (n) is provided. DTE, desiccated thyroid extract; LT3, L-triiodothyronine; LT4, levothyroxine; PHQ-15, Patient Health Questionnaire-15; pSSD, probable somatic symptom disorder.

Table 2.

Chi-Squared Analysis for Independent Variables Against Patient Health Questionnaire-15 Scores <10 and ≥10

Variable	Chi	p	Adjusted significance using the Bonferroni correction
Gender	44.6	1.13E⁻⁰⁹	Significant
Age	59.5	5.75E⁻¹¹	Significant
Marital status	3.2	0.36	Not significant
Employment	62.1	2.05E⁻¹³	Significant
Ethnic background	10.3	0.006	Not significant
Years of education	5.5	0.064	Not significant
Household income	62.8	1.49E⁻¹³	Significant
Cause of hypothyroidism	8.1	0.14	Not significant
Treatment for hypothyroidism	39.1	1.63E⁻⁸	Significant
Number of comorbidities	347.1	1.62E⁻⁶⁸	Significant
Control of hypothyroidism symptoms by medication	482.4	4.32E⁻¹⁰³	Significant
Dissatisfaction with overall care and treatment for hypothyroidism	254.9	4.87E⁻⁵³	Significant
Hypothyroidism has affected everyday activities negatively	501.9	3.29E⁻¹⁰⁴	Significant
Bothered by anxiety	544.2	2.32E⁻¹²¹	Significant
Bothered by low mood or depression	564.4	9.07E⁻¹²⁵	Significant

The adjusted threshold by the Bonferroni method was for the p level of 0.001667.

Associations between pSSD and respondent attributions of causes of symptoms

There was a significant association between pSSD and attribution of symptoms to hypothyroidism or its treatment for 13 of the 15 symptoms, the non-significant symptoms being “fainting spells” and “pain or problems during intercourse” (Fig. 2 and Table 3). Respondents with pSSD were equally likely to blame hypothyroidism or its treatment for typical hypothyroid symptoms (such as constipation, tiredness, or atypical symptoms, such as, stomach pain, backache, or dizziness.)^37,38

FIG. 2.

Attribution of the PHQ-15 symptoms by respondents to hypothyroidism or its treatment. Respondents were asked to indicate if they attributed the symptom to the hypothyroidism or its treatment, or to other causes. Data are shown for those respondents who attributed their symptoms to hypothyroidism or its treatment, by severity of somatization as expressed by PHQ-15 score <10 (white bars) and PHQ-15 score ≥10 (black bars). For each pair of bars, the number of observations (n) is also provided. Comparison between white and black bars was statistically significant at p < 0.001 for all symptoms except “fainting spells” and “pain or problems during intercourse.” The figures in brackets shown in the horizontal axis indicate the number of respondents who had each symptom. The number of valid responses (Table 2) for each symptom is shown in Supplementary Figure S1.

Table 3.

Attribution of Respondents' Symptoms to Hypothyroidism or Its Treatment

Symptom	Attribution of symptom	No SSD (n)	pSSD (n)	Chi	p	Adjusted significance using the Bonferroni correction
Stomach pain	Hypothyroidism or its treatment	46	458	32.2	1.41E⁻⁰⁸	Significant
Stomach pain	Other	260	1004			Significant
Back pain	Hypothyroidism or its treatment	65	441	49.1	2.42E⁻¹²	Significant
Back pain	Other	475	1203			Significant
Pain in arms, legs, or joints (knees, hips, etc.)	Hypothyroidism or its treatment	297	1064	77.2	1.53E⁻¹⁸	Significant
Pain in arms, legs, or joints (knees, hips, etc.)	Other	466	773			Significant
Menstrual cramps or other problems with your periods (women only)	Hypothyroidism or its treatment	51	274	19.2	1.2E⁻⁰⁵	Significant
	Other	249	635			Significant
Headaches	Hypothyroidism or its treatment	100	547	52.5	4.36E⁻¹³	Significant
Headaches	Other	481	1109			Significant
Chest pain	Hypothyroidism or its treatment	27	341	10.0	0.002	Significant
Chest pain	Other	93	564			Significant
Dizziness	Hypothyroidism or its treatment	108	662	12.4	0.0004	Significant
Dizziness	Other	177	673			Significant
Fainting spells	Hypothyroidism or its treatment	13	175	2.2	0.138	Not significant
Fainting spells	Other	13	179			Not significant
Feeling the heart pound or race	Hypothyroidism or its treatment	196	835	10.4	0.0012	Significant
Feeling the heart pound or race	Other	203	596			Significant
Shortness of breath	Hypothyroidism or its treatment	126	712	19.5	1.00E⁻⁰⁵	Significant
Shortness of breath	Other	224	732			Significant
Pain or problems during intercourse	Hypothyroidism or its treatment	49	265	1.1	0.28	Not significant
Pain or problems during intercourse	Other	102	442			Not significant
Constipation, loose bowels, or diarrhea	Hypothyroidism or its treatment	243	909	30.9	2.74e⁻⁰⁸	Significant
Constipation, loose bowels, or diarrhea	Other	368	807			Significant
Nausea, gas, or indigestion	Hypothyroidism or its treatment	109	743	73.7	9.20e⁻¹⁸	Significant
Nausea, gas, or indigestion	Other	377	940			Significant
Feeling tired or having low energy	Hypothyroidism or its treatment	685	1528	79.4	5.05e⁻¹⁹	Significant
Feeling tired or having low energy	Other	447	491			Significant
Trouble sleeping	Hypothyroidism or its treatment	266	1010	102.3	4.84e⁻²⁴	Significant
Trouble sleeping	Other	523	815			Significant

Respondents who had one or more of the symptoms listed in the PHQ-15 questionnaire (scored as “bothered a little” or “bothered a lot”) were further asked to indicate whether they attributed the symptom to “hypothyroidism or its treatment” or to other causes. Respondents were categorized as not having SSD if their PHQ-15 score was <10 and as having pSSD if their PHQ-15 score was ≥10. Comparisons in attribution of symptoms were made between respondents with pSSD with those without SSD by chi-squared tests with the Bonferroni correction. The chi and p-values for the comparisons are shown below. The adjusted threshold by the Bonferroni method was for the p level of 0.001724.

PHQ-15, Patient Health Questionnaire-15; pSSD, probable somatic symptom disorder; SSD, somatic symptom disorder.

Association between pSSD and control of symptoms of hypothyroidism

pSSD was associated with the expression of the view by respondents that the thyroid medication taken did not control the symptoms of hypothyroidism well (Fig. 3a and Table 2).

FIG. 3.

Association between pSSD (PHQ-15 score ≥10) and (a) respondent opinion on whether the hypothyroid medication taken controls symptoms of hypothyroidism well, (b) respondent satisfaction with care and treatment for hypothyroidism, (c) impact of hypothyroidism on daily living. The vertical axis shows the proportion (%) of respondents with PHQ-15 score <10 (white bars) and PHQ-15 score ≥10 (black bars). There was an association between somatic symptom and: respondent opinion that the hypothyroid medication did not control the symptoms of hypothyroidism well (p < 0.001); dissatisfaction with care and treatment of hypothyroidism (p < 0.001); a negative impact of hypothyroidism on daily living (p < 0.001). For each pair of bars, the number of observations (n) is also provided.

Association between pSSD and satisfaction with care and treatment of hypothyroidism

There was a significant association between pSSD and dissatisfaction with care and treatment of hypothyroidism (Fig. 3b and Table 2).

Association between pSSD and impact of hypothyroidism on daily living

There was an association between a negative impact on daily living and pSSD (Fig. 3c and Table 2).

Anxiety, low mood/depression

Both anxiety and low mood/depression were prevalent in respondents with pSSD (82.6%, 1689/2046, and 84.9%, 1739/2049, respectively), and the association was statistically significant (Table 2).

Discussion

SSD is common, associated with persistent symptoms, individual and societal burden, high levels of health care utilization and economic cost.³⁹ Yet there is little information in the literature about SSD in hypothyroidism,^40,41 while impaired quality of life and dissatisfaction with care and treatment are well documented.^42

–45 We used the validated PHQ-15 questionnaire³¹ to assess somatization and to test the hypothesis that SSD is a contributor to persistent symptoms and dissatisfaction. We have used pSSD as a research classification based on self-reported responses to a questionnaire, to gain insights on the nature of persistent symptoms in hypothyroidism. It should be noted that this is not equivalent to a medical diagnosis of SSD (which requires individual assessment by an expert). Respondents' characteristics were similar to hypothyroid patient populations reported in the literature.^1,2,46
–48 The PHQ-15 has been used previously to screen for SSD,^31,49,50 study associations between somatic symptoms and demographic factors⁵¹ and behaviors⁵² and quantify somatic distress associated with specific diseases such as diabetes,⁵³ thus providing potentially useful insights.

The proportion of respondents with pSSD was higher (58.6%) than normative data (7.2%) (Supplementary Table S3).⁵⁴ SSD is common among patients with chronic diseases;^55
–57 thus, it is not surprising that this was also the case in hypothyroidism. The significance of this finding rests with how clinicians approach the common scenario of hypothyroid patients with persistent unexplained symptoms. Research in Europe conducted in 2019–2021^58–77 shows that thyroid specialists usually offer pharmacological solutions to such patients in the form of combination therapy of LT4 with LT3, despite evidence from randomized controlled studies indicating no benefit from combination treatment compared with LT4 alone.^9,45 In the light of these findings, a pharmacological approach is inappropriate for some of these patients, as their underlying psychosocial needs will not be addressed.

The high prevalence of pSSD among participants demonstrated in this study does not support binary “mind” versus “body” dualism, which sometimes leads to dismissive attitudes by health care professionals toward patients with unexplained symptoms. On the contrary, the findings suggest that a biopsychosocial approach⁷⁸ to the conundrum of persistent symptoms despite euthyroid biochemistry may be appropriate. The experience of health care professionals who manage patients with unexplained persistent symptoms suggests that they may respond to empathetic listening, affirmation that their symptoms are real, explanations that physical and psychological symptoms are intimately integrated, avoidance of over-investigation and use of cognitive behavioral and other established psychological therapies, ideally in a multidisciplinary setting.^79,80

In our study, pSSD was associated with young age, women, low household income, employment status, and multiple comorbidities. Some of these variables are likely to be interdependent; however, the above findings are in keeping with other studies of SSD in general populations.^81

–84 The association between pSSD and treatment with LT4 as opposed to LT3-containing treatments may indicate that hypothyroid patients treated with LT3-containing medication become less symptomatic than those treated with LT4, particularly if overtreated (e.g., observations of beneficial effects of high doses of LT3 on mood in patients with resistant depression²²). However, the association between pSSD and LT4 treatment cannot be assumed to be causal, nor is it possible to infer from these data that LT3-containing treatments should be used to provide relief from the symptoms of SSD.

pSSD was associated with attribution of persistent symptoms to hypothyroidism or its treatment, including symptoms not recognized to be associated with hypothyroidism or thyroid hormone replacement. Among the symptoms included in the PHQ-15, tiredness and pain were the most frequently reported symptoms. This aligns with findings that somatization symptoms tend to cluster into four groups: fatigue, pain, cardiorespiratory, and bowel symptoms.⁸⁵ The high prevalence of pain symptoms, especially back pain and headaches in this sample is consistent with the Global Burden of Disease study.⁸⁶ Patients with SSD who experience back pain and headaches that cluster with fatigue may attribute symptoms that occur frequently in the general population to hypothyroidism. The above findings are consistent with insights from other studies relating to the symptomatology of hypothyroidism and how symptoms may be perceived by patients, particularly in view of the fact that most of the symptoms of hypothyroidism are nonspecific and often experienced by the euthyroid population.³⁷

A study of patients with subclinical hypothyroidism who were not aware of their serum thyrotropin (TSH) levels showed no difference in symptoms compared with euthyroid controls.⁸⁷ In another study, patient awareness that they had a thyroid diagnosis was associated with an increased prevalence of symptoms, and conversely, in patients not aware that they had a thyroid diagnosis, a higher serum TSH was associated with fewer symptoms.⁶ Self-knowledge of a diagnosis of hypothyroidism therefore seems to be an important factor in how symptoms are perceived and experienced. Another important factor is that recent studies indicate that the majority of patients diagnosed and started on thyroid hormone replacement have mild or subclinical hypothyroidism,^88,89 or even transient elevation in serum TSH.⁹⁰ Furthermore, several studies and meta-analyses show similar rates of symptoms in subclinical hypothyroid patients as in euthyroid controls.^45,91

An association was found between pSSD and respondent opinion that the thyroid medication taken did not control their symptoms of hypothyroidism well, which could be indicative of a patient belief that all or most persistent symptoms experienced are due to hypothyroidism. This is likely to be false given that persistent symptoms such as those included in the PHQ-15 questionnaire occur in the background general population and particularly in patients with comorbidities other than hypothyroidism. In this respect, it is of interest that evidence from another survey of hypothyroid women indicates that patient beliefs about the nature of their illness may play a role in the development of symptoms, such as depression, anxiety, and anger.⁹²

The association between dissatisfaction with care and treatment of hypothyroidism and pSSD parallels those described for medically unexplained symptoms in general⁹³ and may reflect the frustrating nature of persistent symptoms and inadequacy of available services. Similarly, the association between pSSD and a negative impact of hypothyroidism on daily living was significant and may be subject to patients' attributions of symptoms to hypothyroidism. As SSD is usually established by the age of 30 years,³⁹ in most cases, it precedes the onset of hypothyroidism by 1–2 decades¹ and therefore may be a causal contributor to the phenomenon of persistent symptoms in some patients who are given the diagnosis of hypothyroidism.

The prevalence of self-reported anxiety and low mood/depression among respondents with pSSD was high (72.3% and 71.8%, respectively). It should be noted that these were not medical diagnoses of anxiety or depression, but a research classification self-report. The fact that the survey was carried out during the COVID pandemic may have increased anxiety and low mood/depression and could explain the above high levels. However, an association between hypothyroidism and psychiatric morbidity (including use of anxiolytic and antidepressant medication) has been noted before and seems to hold true both before and after the diagnosis of hypothyroidism.²⁸ An association between SSD and anxiety and depression is well established in the general population.⁹⁴ Our findings suggest that hypothyroid patients presenting with symptoms of SSD have a high likelihood of an underlying anxiety or mood disorder, which is important for clinicians managing patients with hypothyroidism to be aware of.

The cause of persistent symptoms in patients with hypothyroidism is still unknown, a causal relationship with SSD is not established and underlying biological explanations are also plausible. However, our findings are of importance in the management of patients with hypothyroidism and indicate that somatization plays a significant role in the presentation of some of these patients.

The study has limitations. Some nations were overrepresented, the data were self-reported, respondents were invited via patient organizations and social media, there was some sample heterogeneity, the assessments of quality of life, anxiety, and low mood/depression did not utilize validated instruments, informative data on cause of hypothyroidism were unavailable in 28.5% of responses, directly comparative data on prevalence of pSSD in a control population were unavailable, and we had no access to thyroid biochemistry. The high percentage of pSSD needs to be taken in the context of the fact that only a minority (10–15%) of hypothyroid patients report impaired quality of life,⁴⁶ and dissatisfied patients are more likely to respond to surveys.^30,43,44 In mitigation of the above, the large sample size, cognitive testing, piloting, and inclusion of a patient representative in the research team were the strengths.

In conclusion, this study demonstrates a high prevalence of pSSD among people with hypothyroidism who responded to the survey, a tendency to attribute persistent symptoms to hypothyroidism or its treatment and associations between pSSD and negative patient outcomes. SSD may be an important determinant of dissatisfaction with treatment and care among some hypothyroid patients. Our findings require independent confirmation with studies that focus on SSD and address the limitations outlined above. Close collaboration between the disciplines of thyroidology, psychology, and sociology is likely to be key in progressing our understanding in this area.

Footnotes

Acknowledgments

The authors wish to thank the patient organizations and their members for disseminating the survey and for responding to the questionnaire.

Authors' Contributions

P.P.: Conceptualization (lead), methodology (equal), supervision (equal), writing—review and editing (lead). L.H.: Conceptualization (equal), funding acquisition (lead), methodology (equal), review and editing (equal). E.V.N. and E.P.: Conceptualization (equal), methodology (equal), review and editing (equal). C.M.V.D.F.-C.: Methodology (equal), review and editing (equal). A.P.W.: Review and editing (equal). H.A.H.: Data curation (equal), investigation (equal), methodology (equal), project administration (lead), supervision (equal), review and editing (equal). J.A.-M.: Data curation (equal), review and editing (equal), project administration (equal). A.J.T.: Investigation (lead), methodology (lead), project administration (equal), supervision (lead), review and editing (equal). M.B.: Investigation (equal), methodology (equal), project administration (equal), supervision (equal), review and editing (equal). P.L.: Resources (lead), methodology (equal), review and editing (equal), investigation (equal). A.J.P.: Methodology—review and editing (equal), formal analysis (lead), review and editing (equal).

Author Disclosure Statement

P.P., E.V.N., E.P., and A.P.W. report honoraria from IBSA Institut Biochimique SA. L.H. reports honoraria from IBSA Institut Biochimique SA, Lundbeck, Horizon, Merck, and Berlin Chemie. C.M.V.D.F.-C. reports honoraria from Lloyds Register Foundation and Janssen UK. H.A.H., J.A.-M., A.J.T., M.B., P.L., and A.J.P. report no competing financial interests.

Funding Information

This study was funded by IBSA Institut Biochimique SA, (grant no.: 4500131227) who had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

Supplementary Material

Supplementary Figure S1

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Data

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