Graves’ disease is the most common cause of hyperthyroidism in children and adolescents, affecting ∼0.1 per 100,000 children and 3 per 100,000 adolescents per year.1
Typical symptoms of hyperthyroidism are tachycardia, weight loss despite increased appetite, tremor, restlessness, heat intolerance, and weakness, among others.2
It is not uncommon for children and adolescents who present with these symptoms to first be diagnosed with primary attention deficit/hyperactivity disorder (ADHD) or anxiety before considering a diagnosis of hyperthyroidism.3,4
In anecdotal experience, many patients with hyperthyroidism also express anxiety-related symptoms. If these symptoms were due only to elevated thyroid hormone, these symptoms would be expected to resolve with treatment. Many times the treatment of anxiety-related conditions continues well beyond the control of clinical hyperthyroidism.
Attributing these symptoms to the thyroid disease itself can lead to delays in seeking mental health care.5 The American Thyroid Association has published clinical practice guidelines for the management of hyperthyroidism; However, these guidelines do not address the mental health aspect of the disease. 6
The paucity of mental health recommendations may be influenced by the limited number of studies evaluating the association of mental health diagnoses in this patient population.
Data available from the psychiatric literature demonstrate higher rates of thyroid disease in patients with known underlying psychiatric illness.7 It has been estimated that ∼40% to 80% of children with hyperthyroidism meet criteria for ADHD.8
The literature is replete with case reports and case series of comorbid mental health disorders and hyperthyroidism: presenting as transient psychosis, 9 psychotic symptoms 2 months after diagnosis and treatment of Graves’ disease, 10 and one patient with a history of anxiety admitted for attempted suicide and was eventually found to have Graves’ Disease.11
Several of these reports also demonstrated improvement in, but not complete resolution of psychiatric symptoms after treatment of the underlying thyroid condition. Many of these individuals continued to require monitoring for persistent, although less severe, psychiatric symptoms.3,4
There have also been attempts to assess the prevalence of neuropsychiatric symptoms in people first diagnosed with Graves’ Disease through case-control studies, with those having higher levels of depression and anxiety compared to controls.12
Although there is evidence to suggest that these symptoms decrease with appropriate treatment of the underlying condition, 13 others demonstrate persistence of hyperactive behavior up to 6 months after the start of treatment.14
Although this information provides evidence to support a link between mental health disorders (MSDs) and thyroid disorders, these studies mostly consist of case reports in the pediatric population and a few larger case series in adults.3 ,9–13
Larger scale pediatric studies assessing the presence of mental health diagnoses in patients with hyperthyroidism would be valuable to help inform primary care providers and specialists in their evaluation of patients presenting with hyperthyroidism to provide mental health services. appropriate and to inform the creation of guidelines.
In the current study, the authors used data obtained through the Military Health Data Repository (MDR). It was hypothesized that the prevalence of mental health disorders would be higher in those diagnosed with hyperthyroidism compared to controls without a diagnosis of hyperthyroidism.
The goal was to use these data to inform whether additional screening should be performed, with the ultimate goal of achieving an effective screening tool to improve care for children and adolescents with hyperthyroidism.
| Methods |
The US Department of Defense MDR was the sole data source for this study. The MDR represents nearly 10 million active beneficiaries, comprised of military personnel, retirees and their families, who receive care within military hospitals and clinics as well as through Tricare, the insurance arm of the Department of Defense, within a vast network of civilian medical facilities throughout the United States.
Each beneficiary is a recipient of universal healthcare benefits with reliable access to care and minimal out-of-pocket costs, which help reduce bias associated with barriers to care. Every eligible child enrolled in the Military Health System (SSM) has access to care under this system.
Although children may receive care under alternative health insurance if they are dually enrolled, only a nominal number of children are expected to receive any care outside of SSM. The MDR contains the most comprehensive data collection on health care provided to MHS beneficiaries, allowing users to capture, validate, and distribute comprehensive SSM data.
The research data were derived from an institutional review board protocol with a waiver of consent approved by Naval Medical Center Portsmouth in Virginia. All data were de-identified prior to analysis, and the research was conducted in accordance with federal and state laws, including the Health Insurance Portability and Accountability Act of 1996 and port security guidelines.
> Study population
The MDR was consulted over a 9-year period spanning fiscal years (FY) 2008 through 2016. For inclusion, beneficiaries had to be eligible to care for at least 1 month during this time frame and be between 10 and 18 years.
The 1-month enrollment was chosen to allow for more complete data capture in a transient population and to eliminate individuals who may have been treated at a military treatment facility but were not covered by Tricare.
Within any year under study, there were ∼2.5 million eligible children in the SSM. Patients were identified by using all International Classification of Diseases , Ninth Revision (FY 2008-2015) and International Classification of Diseases , Tenth Revision (FY 2016) codes for hyperthyroidism, ADHD, anxiety, depression, mood disorder. adaptation, bipolar disorder and suicidal ideation, self-harm and/or suicide attempt (IS/AL/INTS).
To meet inclusion criteria for the above diagnoses, subjects were required to have 2 separately documented outpatient visits coded with the diagnosis or 1 inpatient diagnosis. Each patient received a unique identification, called an Electronic Data Person Number.
Additionally, if a patient had >1 mental health diagnosis (e.g., adjustment disorder and ADHD), the patient was included in both categories. The TSMs evaluated were not mutually exclusive; There could be patients counted across multiple diseases.
> Statistical analysis
The prevalence of hyperthyroidism and each of the included SMTs was evaluated independently. The prevalence ratio of each of the SSMs studied was evaluated by comparing the prevalence of the condition in those with hyperthyroidism to the reference standard of children in the SSM without a diagnosis of hyperthyroidism.
The use of the prevalence ratio allowed us to compare the prevalence of each SST in those exposed versus those not exposed to hyperthyroidism. The prevalence of hyperthyroidism was stratified by age and year of initial diagnosis.
The timing of each SST was categorized as before (<90 days from hyperthyroidism diagnosis), concomitant (±90 days from first recorded hyperthyroidism diagnosis), or after (>90 days from hyperthyroidism diagnosis).
> Power calculation
Comparing 2 proportions, and assuming that 13% 15 of unexposed children (without hyperthyroidism) have a mental health diagnosis and that 40% 8 of exposed children (with hyperthyroidism) have a mental health diagnosis (α = 0.05 ; β = 0.2) with the same number of subjects in each exposure group, the target sample size would be 41 subjects in each group.
Increasing the ratio between the unexposed and exposed groups produces a smaller number of subjects needed in the exposed group, with 16 people being the minimum number needed in the exposed group.
Sex was assessed by effect modification by comparing prevalence ratio confidence intervals (CIs) for male and female beneficiaries. If present, stratified prevalence rates were presented.
If absent, sex was assessed for confounding by comparing the crude CI prevalence rate with the adjusted Mantel-Haenszel prevalence rate. If no effect modifier or confounder was present, the crude proportion was presented.
Data analysis was performed using SAS version 9.4 for Windows (SAS Institute, Inc, Cary, NC). α = 0.05 was used to evaluate statistical significance.
| Results |
> Prevalence of hyperthyroidism
A total of 2480 individuals (n = 1894; 76% female) between the ages of 10 and 18 years with a diagnosis of hyperthyroidism were identified during fiscal years 2008-2016. The patients identified were most commonly female and between the ages of 16 and 18 years.
The prevalence of hyperthyroidism in the time period studied was 0.95 in 1000, which is consistent with the reported prevalence in the population.
The annual prevalence of hyperthyroidism was stable over time. Notably, the overall period prevalence is higher (∼0.95 per 1000). This can be explained by a relatively constant denominator with a variable numerator, which is a reflection of the transient military population.
> Prevalence of specified SST
Bipolar disorder and IS/AL/INTS were the least commonly diagnosed in the time period studied (1.3% and 1.2%, respectively) and adjustment disorder and ADHD were the most commonly diagnosed (7, 4% and 7.6%, respectively). Again, these prevalences are consistent with reported population norms.
> Prevalence relationships
The prevalence of each of the TSMs consulted was higher in those with a diagnosis of hyperthyroidism than in those without it. Prevalence ratios ranged from 1.7 (ADHD) to 4.9 (bipolar disorder).
Sex was found to be an effect modifier for those with anxiety, bipolar disorder, and depression, with males diagnosed with hyperthyroidism being more likely to also be diagnosed with these SMTs than females diagnosed with hyperthyroidism.
Therefore, stratified prevalence rates were presented for these conditions. Sex was neither an effect modifier nor a confounder in adjustment disorder, ADHD, or IS/AL/INTS. The greatest elevation in prevalence was in male beneficiaries with hyperthyroidism and bipolar disorder (prevalence ratio [PR] 6.7; 95% CI 5.1–8.9).
There was no difference in prevalence between male and female sex for patients with adjustment disorder, ADHD and IS/AL/INTS. There was a significant difference by sex for the remaining TSMs (anxiety, bipolar disorder and depression).
> Time of diagnosis
For each of the TSMs examined, with the exception of IS/AL/INTS, the mental health diagnosis was most commonly made before the diagnosis of hyperthyroidism (P < 0.05), the highest proportion of patients was diagnosed with ADHD before receive a diagnosis of hyperthyroidism (68.3%). There was no difference in time to IS/AL/INTS compared to hyperthyroidism diagnosis.
| Discussion |
The authors found a clear association between the diagnosis of hyperthyroidism and each of the following: IS/AL/INTS, depression, bipolar disorder, anxiety, ADHD, and adjustment disorder.
Hyperthyroidism was more commonly diagnosed in women (76.4% female; 23.6% male), which is in line with the literature demonstrating a female predominance in hyperthyroidism.16
Each of the SMDs described was also more common in women, with the exception of ADHD. Furthermore, the relative proportion of the study population with each of the described TSMs was similar to the standards reported in the population.
The currently available literature, consisting primarily of case reports, highlights the identification of previously recognized TSMs in the setting of newly found thyroid disease.
Compared to previous studies, this study adds the strength of a large patient data set and the ability to decipher the timing of mental health diagnosis in relation to hyperthyroidism diagnosis.
Among patients ever diagnosed with hyperthyroidism and 1 of the listed TSMs, the authors’ study found that the diagnosis of hyperthyroidism most commonly occurred after mental health diagnosis, with the exception of IS/AL/INTS.
Specifically, this study found that IS/AL/INTS was almost 5 times more common in those diagnosed with hyperthyroidism than in those who were never diagnosed with hyperthyroidism, supporting the findings of existing case studies.11,17
These case studies described patients who exhibited suicidal behavior before their diagnosis of hyperthyroidism, corresponding to the 40% of patients in the authors’ study who did not have a diagnosis of hyperthyroidism until after exhibiting suicidal behavior. This is perhaps the most worrying of the authors’ findings.
It is challenging to know when symptoms of undiagnosed hyperthyroidism amplified an already present SST leading to suicides or if the diagnosis of hyperthyroidism was distressing to the individual to the point where suicidality was considered.
This old hypothesis could be elaborated in the future by evaluating the prevalence rates of IS/AL/INTS in individuals with other chronic autoimmune diseases. It is also possible that in some of these individuals, there was an overlap of more than 1 SST due to hyperthyroidism.
From the researchers’ perspective, preventing IS/AL/INTS through early detection and diagnosis of concomitant SST and/or hyperthyroidism would be the most necessary outcome to achieve.
The authors’ study also highlighted that ADHD was 2 times more common in those people diagnosed with hyperthyroidism than in those who were never diagnosed with hyperthyroidism, with the majority of patients diagnosed with hyperthyroidism after receiving an ADHD diagnosis. This is important because, as 1 study highlights, lack of recognition of hyperthyroidism can affect the effectiveness of treatment for disorders such as ADHD.4
An additional consideration is that several of the medications used to treat TSMs can affect the thyroid axis. For example, stimulants, such as methylphenidate , can cause a slight decrease in total and free thyroxine. However, these laboratory abnormalities would be more likely to lead to a misdiagnosis of hypothyroidism (rather than hyperthyroidism).18
Lithium was associated with the development of goiter, hypothyroidism through inhibition of thyroid hormone release, or hyperthyroidism due to thyroiditis or Graves’ disease . 19
Tricyclic antidepressants and the antipsychotic phenothiazine have demonstrated an association with hypothyroidism in both animal and in vitro studies, a link that is speculated in humans through effects on noradrenergic and/or serotonergic systems or through induction of autoimmune hypothyroidism. , respectively.20
Quetiapine was associated with hyperthyroidism in the pediatric population, as described in Danish case reports.21
It is possible, although not evaluated, that thyroid examination was more commonly performed in those treated with lithium. Bipolar disorder is the mental health disorder for which lithium is most commonly used as a treatment.
Therefore, it is possible that the increased prevalence rate of bipolar disorder in those with a diagnosis of hyperthyroidism is in part explained by the increased investigation of the thyroid axis in this population.
There are additional limitations of this study that should be considered when interpreting the results. First, data is extracted from billing codes within medical records. Therefore, they relied on the initial medical provider to properly document the correct diagnosis at the correct time.
For example, as noted above, an incorrect diagnosis of hyperthyroidism could be documented if a provider included clinically insignificant elevations in thyroxine or triiodothyronine levels or reductions in thyroid hormone stimulation beyond laboratory standards.
However, the investigators sought to mitigate this by only classifying patients with hyperthyroidism if diagnoses were made during at least 2 separate outpatient visits or once as an inpatient. Additionally, the diagnosis of hyperthyroidism could have been delayed if it was not initially considered and examined by the medical provider.
This would have an impact on the recorded diagnosis time. Because of the nature of the International Classification of Diseases, Ninth Revision and the International Classification of Diseases , Tenth Revision coding , researchers were unable to distinguish Graves’ Disease from other causes of hyperthyroidism.
The investigators in this study were unable to manually review each of the patient records to determine details related to diagnosis or time.
Therefore, both the veracity of the diagnosis itself as well as the time is subject to documentation. The study sample was also limited to patients who had full access to medical care under military health insurance policies.
Therefore, patients with limitations in access to care were not included in this study; however, this should be a small number given that patients in this health system have universal health care coverage.
The data set included a small number of individuals whose sex was identified as "missing," meaning that their sex could not be identified as male or female when assessing whether sex affected a particular diagnosis. Additionally, a pharmacy review was not performed to look at the medications taken by each patient.
Therefore, an additional limitation is that the effects of medication on the thyroid could not be determined from the authors’ data set. Another potential limitation to consider is the possibility of verification bias. For example, patients may have been diagnosed with TSM due to the medical care they were already receiving when diagnosed with hyperthyroidism.
Psychiatry literature emphasizes the importance of ruling out other medical conditions before making a mental health diagnosis. However, the authors’ research suggests that potentially both hyperthyroidism and mental health diagnoses can be associated with each other’s health diagnoses and not necessarily be mutually exclusive.
The authors doubt that hyperthyroidism is the cause of mental health disorders, although this certainly could at least partially explain the authors’ results.
There is likely a multifactorial relationship explaining this association, including but not limited to the overlap in symptoms of hyperthyroidism and many of the listed SMTs leading to a misdiagnosis or late diagnosis, a new medical diagnosis as a trigger for mental health symptoms, or a biological process (autoimmune or otherwise) that could lead to TSM.
Unfortunately, due to the retrospective nature and data limited to billing codes, they were unable to describe the objectives in granular enough detail to answer these questions. However, future efforts should be directed to explain the association between these conditions.
| Conclusions |
The authors’ study highlights the increased prevalence of TSMs in patients with a diagnosis of hyperthyroidism as well as the often delayed timing of hyperthyroidism diagnosis, raising the importance of appropriate patient screening.
Clinicians should seek out resources to use during their future encounters with patients with these mental health disorders so that they can better recognize and treat a potential overlapping diagnosis of hyperthyroidism.
Thyroid disorder should be considered in a patient who presents to his or her primary care provider with a positive screen for anxiety or depression or symptoms suggestive of another mental health diagnosis.
Most importantly, given the recognition of increased risk of suicide in patients with hyperthyroidism, future research should be directed at determining the most effective screening tool to recognize potential mental health diagnosis in patients with hyperthyroidism.
