Results
Hypothyroidism in Older Adults in Context
Thyroid disease, particularly HypoT, is widespread among all age groups, and it is
expected to increase as the population gets older steadily. Clinical diagnosis of
HypoT is challenging, as the TSH reference range needs to be evaluated according to
age. At the same time, when evaluating TSH levels, one must also consider body weight
and other variants such as polypharmacy, comorbidities, and general health conditions.
Since thyroid hormone has a potent regulatory effect on cholesterol metabolism, the
possibility of thyroid dysfunction should be considered in cases of unexplained dyslipidemia.
Once HypoT has been confirmed, treatment requires caution, frequent cardiovascular
monitoring, and individualized (precision) medicine.[7] Treatment of SCH in older adults should be undertaken with care, guided by age,
symptoms, degree of TSH elevation, patient body weight, lean body mass, life expectancy,
and the degree of SCH: a TSH higher than 10 mU/L seems a reasonable threshold, though
it should be regularly reevaluated, while the L-T4 dose needs to be tailored, taking
into account the patient's health condition and the potential presence of dyslipidemia
as well as other metabolic derangements.
L-T4 treatment of overt HypoT can be more challenging in older compared to young patients
because of other comorbidity associations. The population of older adults is growing,
and increasing incidence and prevalence of HypoT with age are observed globally. Older
people have more comorbidities compared to young patients, complicating correct diagnosis
and management of HypoT.[8] Most importantly, cardiovascular complications compromise the usual start dosage
and upward titration of L-T4 due to a higher risk of decompensating cardiac ischemia
and function. It, therefore, takes more effort and care from the clinician, and the
maintenance dose may have to be lower to avoid cardiac manifestations
On the other hand, L-T4 has a beneficial effect on cardiac function by increasing
performance. The clinical challenge should not prevent treatment with L-T4 should
the patient develop cardiac ischemia. The endocrinologist must collaborate with the
cardiologist on prophylactic cardiac measures by invasive cardiac surgery or medical
therapy against cardiac ischemic angina. This usually allows subsequent successful
treatment. Prevalent comorbidities in older adults complicate correct diagnosis since
many concomitant morbidities can result in nonthyroidal illness, resembling mild HypoT
both clinically and biochemically.[8] The diagnosis is further complicated as methods for measuring thyroid function (serum
TSH and fT4) vary immensely according to methodology and background population. It
is thus imperative to ensure a correct diagnosis by etiology (e.g., autoimmunity)
before deciding to treat. Even then, there is controversy regarding whether or not
treatment of such mild forms of HypoT in older adults will improve mortality, morbidity,
and quality of life. This should be studied in large cohorts of patients in long-term
placebo-controlled trials with clinically relevant outcomes. Other cases of HypoT,
for example, medications, iodine overload, or hypothalamus-pituitary-HypoT, each pose
specific challenges to the management of HypoT; these cases are also more frequent
in older adults. Finally, treatment adherence is generally challenging. This is also
the case in older patients, which may necessitate measuring thyroid hormones at individually
tailored intervals, which is important to avoid overtreatment with increased risk
of cardiac morbidity and mortality, osteoporosis, cognitive dysfunction, musculoskeletal
outcomes, and muscle weakness.
A literature appraisal regarding low-value thyroid care in older adults, summarizes
recent findings about screening for thyroid dysfunction and managing HypoT, thyroid
nodules, and low-risk differentiated thyroid cancer.[9] Despite a recent shift to a “less is more” paradigm for clinical thyroid care in
older adults, current studies demonstrate that low-value care practices are still
prevalent. Ineffective and potentially harmful services, such as routine treatment
of SCH, can lead to overtreatment with thyroid hormone, inappropriate use of thyroid
ultrasound, blanket fine-needle aspiration biopsies of thyroid nodules, and more aggressive
approaches to low-risk differentiated thyroid cancers have been shown to contribute
to adverse effects, particularly in comorbid older adults. Low-value thyroid care
is common in older adults. It can trigger a cascade of overdiagnosis and overtreatment,
leading to patient harm and increased health care costs, highlighting the urgent need
for deimplementation efforts.
Subclinical Hypothyroidism in Older Adults
SCH is frequently found in older individuals. International guidelines differ in recommendations
for managing SCH in older individuals.[10] Several data have been published during the past decade on SCH's clinical significance
and treatment in individuals aged 65. Studies showed no significantly increased incidence
of adverse cardiovascular, musculoskeletal, or cognitive outcomes in individuals aged
65 or older when serum TSH concentration was 4.5 to 7.0 mIU/L versus a euthyroid group.
Moreover, in older individuals with SCH, symptoms of HypoT and cardiac and bone parameters
did not improve after L-T4 treatment. These data suggest that treatment with L-T4
should be considered for individuals aged 65 years or older with SCH when TSH concentration
is persistently 7 mIU/L or higher and in the presence of symptoms of HypoT and not
to initiate treatment with TSH concentrations of less than 7 mIU/L.[10] L-T4 doses should be personalized according to age, comorbidities, and life expectancy.
The incidence and determinants of spontaneous normalization of TSH levels in older
adults with SCH were investigated.[11] Pooled data were used from the (1) pretrial population and (2) in-trial placebo
group from two randomized, double-blind, placebo-controlled trials (thyroid hormone
replacement for untreated older adults with subclinical hypothyroidism trial and institute
for evidence-based medicine in old age thyroid 80-plus thyroid trial), comprising
of community-dwelling 65+ adults with SCH from the Netherlands, Switzerland, Ireland,
and the United Kingdom. The pretrial population (N = 2,335) consisted of older adults with biochemical SCH, defined as ≥ 1 elevated
TSH measurement (≥ 4.60 mIU/L) and a fT4 within the laboratory-specific reference
range. Individuals with persistent SCH, defined as ≥ 2 elevated TSH measurements ≥
3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo
group (N = 361) was included. Incidence of spontaneous normalization of TSH levels and associations
between participant characteristics and normalization. In the pretrial phase, TSH
levels normalized in 60.8% of participants in a median follow-up of 1 year. In the
in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up.
Younger age, female sex, lower initial TSH level, higher initial fT4 level, absence
of TPO-Abs, and a follow-up measurement in summer were independent determinants for
normalization. The authors suggested that a third measurement may be recommended before
treatment because TSH levels spontaneously normalized in many older adults with SCH
(also after confirmation by repeat measurement).
Evidence suggests that L-T4 treatment should be initiated, and the effects of therapy
in SCH on symptoms such as weight, quality of life, vitality, cognition, and CVD should
be studied. Calissendorff and Falhammar have recently considered the evidence for
different thyroid hormone medications.[12] In addition, the option to withhold medication when there is an uncertain diagnosis
or lack of clinical improvement is considered. A literature review suggested that
available research supports the idea that levothyroxine should be initiated in patients
with a TSH > 10 mIU/L. Treatment for HypoT is becoming more frequent. Symptoms related
to vitality, weight, and quality of life in SCH often persist with L-T4 treatment,
and other causes should be explored. Patients with cardiovascular risk factors may
benefit from treatment, especially younger patients. Caution is necessary when treating
older adult subjects with L-T4. The authors concluded that lifelong treatment with
L-T4 should normally only be considered in manifest HypoT. However, in SCH with a
TSH > 10 mIU/L, therapy is indicated. A wait-and-see strategy is advocated in milder
subclinical forms to see if normalization occurs. Subgroups with cardiovascular risk
and SCH may benefit from L-T4 therapy.
Treating HypoT is not always easy particularly deciding when to treat SCH, TSH goals
in older adults, and alternatives to levothyroxine monotherapy.[13] Overzealous treatment of symptomatic patients with SCH may contribute to dissatisfaction
among HypoT patients, as potential hypothyroid symptoms in patients with minimal HypoT
rarely respond to treatment. Thyroid hormone prescriptions have increased by 30% in
the United States in the last decade. The diagnosis of SCH should be confirmed by
repeat thyroid function tests, ideally obtained at least 2 months later, as 62% of
elevated TSH levels may revert to normal spontaneously. Generally, treatment is unnecessary
unless the TSH exceeds 7.0 to 10 mIU/L. In a double-blinded RCT, treatment did not
improve symptoms or cognitive function if the TSH is less than 10 mIU/L. While cardiovascular
events may be reduced in patients under age 65 with SCH who are treated with L-T4,
treatment may be harmful in older patients with SCH. TSH goals are age-dependent,
with a 97.5 percentile (upper limit of normal) of 3.6 mIU/L for patients under age
40 and 7.5 mIU/L for patients over age 80. In some HypoT patients who are dissatisfied
with treatment, especially those with a polymorphism in type 2 deiodinase, combined
therapy with L-T4 and L-T3 may be preferred.
A systematic review and meta-analysis evaluated whether L-T4 has a beneficial or harmful
effect on older patients with SCH.[14] A total of 13 articles were included. Meta-analysis results showed that in older
SCH patients, L-T4 could significantly reduce total cholesterol (TC), triglyceride
(TG), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (ApoB). In
addition, L-T4 had no significant effect on bone mineral density (BMD), fatigue, HypoT
symptoms, quality of life, body mass index (BMI), cognitive function, depression,
blood pressure, etc. in older SCH patients. Also, it did not significantly increase
the incidence of adverse events. The authors proposed that L-T4 treatment may reduce
TC, TG, LDL-C, and ApoB among older SCH patients.
Sgarbi and Ward proposed a practical, contemporary approach to decision-making on
SCH.[15] They underscored that the decision-making process needs to consider the risk of
L-T4 overtreatment and the resulting adverse consequences, such as reduction of BMD,
heart failure (HF), and atrial fibrillation (AFib). Hence, current evidence suggests
that individuals with TSH > 10 mU/L who test positive for TPO-Abs or are symptomatic
may benefit from L-T4 treatment. However, a more cautious and conservative approach
is required in older (≥ 65 years of age) and oldest-old (≥ 80 years) patients, particularly
those with frailty, in which the risk of treatment can outweigh the potential benefits.
The latter may benefit from a wait-and-see approach.
Pharmacology and Dosing
L-T4 is the standard therapy for patients with HypoT, a condition that affects up
to 5% of people worldwide. While L-T4 therapy has substantially improved the lives
of millions of HypoT patients since its introduction in 1949, the complexity of maintaining
biochemical and clinical euthyroidism in patients undergoing treatment with L-T4 cannot
be underestimated. Initial dosing of L-T4 can vary greatly and may be based on the
amount of residual thyroid function retained by the patient, the body weight or lean
body mass of the patient, and TSH levels.[16] As L-T4 is usually administered over a patient's lifetime, physiological changes
throughout life will affect the dose of L-T4 required to maintain euthyroidism. Furthermore,
dose adjustments may need to be made in patients with concomitant medical conditions,
in patients taking certain medications, and in older adult patients. Patients undergoing
any weight or hormonal changes may require dose adjustments, and most pregnant women
need increased doses of L-T4. Optimal treatment of HypoT requires a partnership between
patient and physician. The physician is tasked with a vigilant appraisal of the patient's
status based on a thorough clinical and laboratory assessment and appropriate adjustment
of their L-T4 therapy. The patient, in turn, is tasked with medication adherence and
reporting symptomatology and any changes in their medical situation. The goal is consistent
maintenance of euthyroidism without the patient experiencing the adverse events and
negative health consequences of under- or overtreatment.
Whether L-T4 improves hypothyroid symptoms and tiredness among older adults with SCH
and greater symptom burden was considered in a secondary analysis of the randomized,
placebo-controlled trial TRUST (Thyroid Hormone Replacement for Untreated Older Adults
with Subclinical Hypothyroidism Trial), conducted in patients from Switzerland, Ireland,
the Netherlands, and Scotland.[17] Six hundred thirty-eight persons aged 65 years or older with persistent SCH (TSH
level of 4.60N19.9 mIU/L for > 3 months and normal fT4 level) and complete outcome
data were included treated with L-T4 or matching placebo with mock dose titration.
One-year change in hypothyroid symptoms and tiredness scores (range, 0–100; higher
scores indicate more symptoms) on the Thyroid-Related Quality-of-Life Patient-Reported
Outcome Questionnaire among participants with high symptom burden (baseline hypothyroid
symptoms score > 30 or tiredness score > 40) versus lower symptom burden were measured.
One hundred thirty-two participants had hypothyroid symptoms scores greater than 30,
and 133 had tiredness scores greater than 40. The hypothyroid symptoms score improved
among the group with a high symptom burden. Similarly, between those receiving L-thyroxine
(mean within-group change, –12.3) and those receiving placebo (mean within-group change,
–10.4 at 1 year; the adjusted between-group difference was –2.0, p = 0.27). Improvements in tiredness scores were also similar between those receiving
L-T4 (mean within-group change, –8.9) and those receiving placebo (mean within-group
change, –10.9; the adjusted between-group difference was 0.0, p = 0.99). There was no evidence that baseline hypothyroid symptoms score or tiredness
score modified the effects of L-T4 versus placebo (p for interaction = 0.20 and 0.82, respectively). Post hoc analysis, small sample size,
and examination of only patients with 1-year outcome data were done. In older adults
with SCH and high symptom burden at baseline, L-thyroxine did not improve hypothyroid
symptoms or tiredness compared with placebo.
Many hypothyroid patients start L-T4 treatment at a low dose (e.g. 25–50 mcg), especially
older adults, those with residual thyroid function, those with low body weight, and
those with significant (especially cardiac) comorbidities.[18] Almost half of the patients on L-T4 replacement therapy demonstrate either under-
or overtreatment. Many L-T4 preparations have relatively large intervals between tablet
strengths at the lower end of their dose ranges (providing 25, 50, and 75 mcg tablets),
which may represent a barrier to achieving the optimum maintenance treatment for some
patients.[18] The availability of intermediate tablet strengths of L-T4 in the 25 to 75 mcg range
may facilitate precise and effective dose titration of L-T4 and enable convenient
maintenance regimens based on a single L-T4 tablet daily to support adherence to therapy.
On the other hand, Brun et al[19] developed a decision aid tool (DAT) that models L-T4 pharmacometrics and enables
patient-tailored dosage. The aim of this was to speed up dosage adjustments for patients
after total thyroidectomy. The DAT computer program was developed with a group of
46 patients postthyroidectomy, and it was then applied in a prospective randomized
multicenter validation trial in 145 unselected patients admitted for total thyroidectomy
for goiter, differentiated thyroid cancer, or thyrotoxicosis.[19] The L-T4 dosage was adjusted after only 2 weeks, with or without application of
the DAT, which calculated individual fT4 targets based on four repeated measurements
of fT4 and TSH levels. The individual TSH target was < 0.1, 0.1 to 0.5, or 0.5 to
2.0 mIU/L, depending on the diagnosis. Initial postoperative L-T4 dosage was determined
according to a clinical routine without using algorithms. A simplified DAT with a
population-based fT4 target was used for thyrotoxic patients who often went into surgery
after prolonged TSH suppression. Subsequent L-T4 adjustments were carried out every
6 weeks until the target TSH was achieved. When clinicians were guided by the DAT,
40% of patients with goiter and 59% of patients with cancer satisfied the narrow TSH
targets 8 weeks after surgery, compared with only 0 and 19% of the controls, respectively.
The TSH was within the normal range in 80% of DAT/goiter patients 8 weeks after surgery
compared to 19% of controls. The DAT shortened the average dosage adjustment period
by 58 days in the goiter group and 40 days in the cancer group. Applying the simplified
DAT did not improve the dosage adjustment for thyrotoxic patients. In conclusion,
this application of the DAT in combination with early postoperative TSH and fT4 monitoring
offers a fast approach to appropriate L-T4 dosage after total thyroidectomy for patients
with goiter or differentiated thyroid cancer. Estimating individual TSH-fT4 dynamics
was crucial for the model to work, as removing this feature in the applied model for
thyrotoxic patients also removed the benefit of the DAT.
Cardiovascular Disease and Risk Factors
Excess adverse cardiovascular outcomes have been observed in certain patient populations
with HypoT ([Table 1]). Recent literature on the subject is reviewed below.[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27] A worthwhile reading is that of Paschou et al who described the physiologic role
of thyroid hormones on the cardiovascular system to present cardiovascular manifestations
in patients with thyroid disorders, emphasizing molecular mechanisms and biochemical
pathways and summarizing current knowledge of treatment options.[20] Thyroid hormone receptors are located both in the myocardium and vessels, and changes
in their concentrations affect cardiovascular function. Hyperthyroidism or HypoT,
both clinical and subclinical, without the indicated therapeutic management, may contribute
to the progression of CVD. According to recent studies, even mild changes in thyroid
hormone levels increase cardiovascular mortality from 20 to 80%. In more detail, thyroid
disorders have serious effects on the cardiovascular system via a number of mechanisms,
including dyslipidemia, hypertension, systolic and diastolic myocardial dysfunction,
and endothelial dysfunction. On top of clinical thyroid disorders management, current
therapeutics focus on younger patients with SCH. Huang et al explored the relationship
between thyroid dysfunction, TSH levels, and risks of AFib in studies. They conducted
a dose-response meta-analysis on the correlation between the TSH levels and the risk
of AFib.[21] Thirteen studies from 5 databases with 649,293 subjects (mean age, 65.1 years) were
included. The dose-response meta-analysis was conducted by comparing the risk ratios
for incidental AFib associated with different levels of TSH across studies. Subclinical
hyperthyroidism, SCH, and clinical hyperthyroidism were associated with an increased
risk of AFib, whereas clinical HypoT was not associated with a significantly increased
risk of AFib. A nonlinear relationship was observed in two models between the TSH
levels and dangers of AFib. The study indicated that subclinical hyperthyroidism,
SCH, and clinical hyperthyroidism were associated with the risk of AFib. The results
for the TSH levels and risk of AFib were mixed, showing a U-shaped relationship.
Table 1
Summary of recent data and contemporary expert opinion on the impact of hypothyroidism
and thyroid hormone replacement therapy on cardiovascular disease and risk factors
|
Author, year [ref]
|
Study type
|
Setting
|
Conclusions
|
|
Paschou et al, 2022[20]
|
Literature review
|
Focused on physiologic & molecular mechanisms
|
Thyroid disorders have serious effects on the cardiovascular system via plenty of
mechanisms, including dyslipidemia, hypertension, systolic and diastolic myocardial
dysfunction, and endothelial dysfunction. On top of clinical thyroid disorders management,
current therapeutics focus on younger patients with SCH
|
|
Huang et al, 2022[21]
|
Dose-response meta-analysis
|
13 studies on 649,293 patients
|
Subclinical hyperthyroidism, subclinical hypothyroidism, and clinical hyperthyroidism
were associated with the risk of AF. The results for the TSH levels and risk of AF
were mixed, showing a U-shaped relationship
|
|
Delitala et al, 2019[22]
|
Literature review (PubMed up to 2019)
|
Thyroid and cardiovascular risk factors
|
TSH level is the best predictor of cardiovascular disease, particularly above 10 mU/L.
Whether to treat or not patients with SCH will still be based on clinical judgment,
clinical practice guidelines, and expert opinion
|
|
Ettleson, 2023[23]
|
Narrative review (update)
|
Recent literature and opinion
|
The impact of treating SCH on cardiovascular outcomes remains uncertain. Additional
perspectives and trial data are required to evaluate the effects of treatment on cardiovascular
outcomes
|
|
Chrysant, 2020[24]
|
Focused literature review
|
Medline 2012–2019
|
In older subjects, treatment SCH should be individualized and based on symptoms at
the level of TSH and initiated at TSH levels ≥ 10 mIU/L and at low doses to avoid
adverse cardiovascular effects from overtreatment
|
|
Gluvic et al, 2022[25]
|
Literature review and analysis
|
Risk factors and atherosclerotic mechanism
|
This paper summarizes the recent literature on subclinical and clinical HypoT and
atherosclerotic cardiovascular disease and discusses the effects of L-T4 replacement
therapy on restoring biochemical euthyroidism and atherosclerosis processes
|
|
Gencer et al, 2020[26]
|
DB-PC trial nested within TRUST trial
|
185 subjects average age 74 years
|
Systolic and diastolic heart function did not differ after treatment with levothyroxine
compared with placebo in older adults with mild SCH
|
|
Chahine et al, 2019[27]
|
Narrative review
|
Epidemiology, clinical and risk factors
|
HypoT-induced pericardial diseases are underdiagnosed. Initiating treatment early
in the disease process and preventing complications relies on early diagnosis through
systematic screening per guidelines
|
Abbreviations: AF, atrial fibrillation; HypoT, hypothyroid; L-T4, levothyroxine; SCH,
subclinical hypothyroidism; TRUST trial, Multi-Modal Effects of Thyroid Replacement
for Untreated Older Adults with Subclinical Hypothyroidism; TSH, thyroid-stimulating
hormone.
Also, Delitala et al[22] reviewed the literature and found that although some studies have demonstrated that
lipids are elevated in SCH, other studies did not confirm this. Clinical trials have
also shown no clear evidence that L-T4 therapy in subjects with a milder form (TSH < 10 mU/L)
of SCH could improve lipid status and other cardiovascular risk factors. Nevertheless,
TSH level is the best predictor of CVD, particularly above 10 mU/L. They called for
more prospective studies to clarify the cardiovascular risk in patients with mild
SCH and assess the importance of treating older adults to improve or counteract the
correlated risks. However, until clinical recommendations are updated, the decision
to treat or not treat patients with SCH will still be based on clinical judgment,
clinical practice guidelines, and expert opinion. Furthermore, Ettleson[23] concluded that CVD appears to be a major mediator of all-cause mortality in patients
with SCH, in particular those aged at least 60 years of age. In contrast, pooled clinical
trial results did not find that L-T4 reduced the incidence of cardiovascular events
or mortality in this patient population. The impact of treatment of SCH on cardiovascular
outcomes remains uncertain. He called for additional prospective and trial data to
evaluate treatment effects on cardiovascular outcomes in younger populations.[23] Finally, a focused literature review was conducted from 38 papers with pertinent
information.[24] The analysis of results from these papers indicated that the normal levels of TSH
are increasing with the advancement of age from 4 up to 7.5 mIU/L for patients ≥ 75
years of age. Also, several reviewed studies have shown no benefits of treatment.
In contrast, others have shown definite benefits of therapy with L-T4 supplementation
on SCH's clinical and metabolic effects with reductions in CVD, HF, and mortality.
They concluded that treatment is more effective in younger persons and less so in
older persons. Thus, based on the overall evidence, treatment of SCH is indicated
in younger persons with a TSH level > 4.0 mIU/L. In older subjects, treatment should
be individualized and based on the presence of symptoms and the level of TSH and initiated
at TSH levels ≥ 10 mIU/L and at low doses to avoid adverse cardiovascular effects
from overtreatment.[24]
The increased risk of acceleration and extension of atherosclerosis in patients with
HypoT and SCH could be explained by dyslipidemia, diastolic hypertension, increased
arterial stiffness, endothelial dysfunction, and altered blood coagulation.[25] The instability of atherosclerotic plaque in HypoT could cause excessive activity
of the elements of innate immunity, which are characterized by the significant presence
of macrophages in atherosclerotic plaques, increased nuclear factor kappa B expression,
and elevated levels of tumor necrosis factor-α and matrix metalloproteinase-9, with
reduced interstitial collagen; all of them together creates inflammation milieu, resulting
in plaque rupture. Optimal substitution by L-T4 restores biochemical euthyroidism.
In postmenopausal women and older adult patients with HypoT and associated vascular
comorbidity, excessive L-T4 substitution could lead to atrial rhythm disorders and
osteoporosis. Therefore, maintaining TSH levels in the reference range is of interest,
thus eliminating the harmful effects of lower or higher TSH levels on the cardiovascular
system.[25] Furthermore, Gencer et al[26]_conducted a randomized, double-blind, placebo-controlled trial nested within the
TRUST trial. A total of 185 participants (mean age 74.1 years, 47% women) underwent
echocardiography at the end of the trial. After a median treatment, the mean TSH decreased
(n = 96) and remained elevated with placebo (n = 89). The adjusted between-group difference was insignificant for the mean left
ventricular ejection fraction and the E/e ratio. No differences were found for the
secondary diastolic function parameters or interaction according to sex, baseline
TSH, preexisting HF, and treatment duration. Thus, systolic and diastolic heart function
did not differ after treatment with levothyroxine compared with placebo in older adults
with mild SCH.[26]
On a different front, HypoT causes pericardial effusion through increased permeability
of the epicardial vessels and decreased lymphatic drainage of albumin, resulting in
fluid accumulation in the pericardial space. Interestingly, autoimmunity does not
play a major role in the pathophysiology, and most effusions are asymptomatic due
to slow fluid accumulation.[27] The diagnosis is generally made when the pericardial disease is associated with
an elevated TSH level and other secondary causes are excluded. Management consists
of thyroid replacement therapy, along with pericardial drainage in case of tamponade.[27]
Skeletal Health
Both thyroid dysfunction and L-T4 therapy have been associated with bone loss, but
studies on the effect of L-T4 for SCH on bone yielded conflicting results. Three studies
on the subject were published recently.[28]
[29]
[30] The impact of L-T4 therapy for SCH on appendicular bone geometry and volumetric
density was studied in a nested study within the TRUST trial by Büchi et al[28] assessing the effect of L-T4 therapy on bone geometry as measured by peripheral
quantitative computed tomography. In the TRUST trial, community-dwelling adults aged
≥ 65 years with SCH were randomized to L-T4 with dose titration versus placebo with
mock titration.[28] The 98 included participants had a mean age of 73.9 years, 45.9% were women, and
12% had osteoporosis. They were randomized to placebo (n = 48) or L-T4 (n = 50). Annual changes in bone mineral content and volumetric BMD (vBMD) were similar
between placebo and L-T4-treated groups, without significant differences in bone geometry
or vBMD changes, neither at the diaphysis nor the epiphysis. Similarly, Gonzalez Rodriguez
et al[29] assessed the impact of L-T4 treatment on bone in older adults with SCH. Participants
(196 community-dwelling adults over 65) with SCH were randomized to L-T4 with dose
titration versus placebo with computerized mock titration. In conclusion, over 1 year
levothyroxine did not affect bone health in older adults with SCH.[29] Netzer et al[30] reported an ancillary study within two RCTs conducted among adults aged ≥ 65 years
with persistent SCH. Participants received daily levothyroxine with TSH-guided dose
adjustment or placebo and mock titration. The mean age was 77.5 years, and 48.3% were
women.[30] Compared to the placebo, participants in the L-T4 group had similar gait speed at
the final visit (adjusted between-group mean difference, similar handgrip strength
at 1 year, and similar yearly change in muscle mass). These findings suggest that
the ancillary analysis of two RCTs and treatment of SCH did not affect muscle function,
strength, and mass in individuals 65 years and older.[30]
Mental Health and Quality of Life
Several groups addressed the impact of HypoT on mental health and quality of life.[31]
[32]
[33]
[34]
[35]
[36] Recent studies and opinion pieces are briefly discussed below. Du et al[31] investigated the prevalence of abnormal thyroid function and depression in centrally
obese participants and analyzed the relationship between thyroid hormones and depression
with components of central obesity. They randomly selected 858 centrally obese participants
and 500 nonobese controls in this study. For all participants, they measured serum
markers of thyroid functions and metabolism. Centrally obese participants had a higher
prevalence of HypoT and depression than nonobese controls. Serum fT4 levels negatively
correlated with BMI and serum TSH levels and positively correlated with BMI, waist-hip
ratio, and lipids. After excluding participants with HypoT and hyperthyroidism, serum
fT4 levels showed a negative correlation, and serum TSH levels showed a positive correlation
with BMI in the remaining centrally obese participants. Center for Epidemiological
Studies Depression scores positively correlated with BMI. Therefore, a high prevalence
of HypoT and depression among centrally obese participants was observed. FT4 and TSH
are important in weight regulation.[31]
Moon et al[32] addressed the question of whether increasing the L-T4 dose confers additional mood
benefits by a single-blinded before-and-after study of 24 patients with HypoT who
were aged 65 years or older and undergoing L-T4 replacement therapy with stable doses.
Korean version of Geriatric Depression Scale (GDS-K) and Hyperthyroid Symptom Scale
(HSS-K) were assessed at baseline, 3 months after increasing the L-T4 dose by an additional
12.5 mcg/d, and 3 months after returning to the baseline dose. Serum TSH concentrations
decreased at the higher L-T4 dose and recovered after returning to the baseline. Serum
fT4 levels and HSS-K scores were unchanged during the study period. GDS-K scores improved
on the increased dose (p < 0.03), and this improvement was maintained after returning to the baseline dose
(p = 0.01). Higher serum TSH was independently associated with both higher GDS-K and
depression risk among those with depressive mood (GDS-K > 10) at baseline. These data
suggest that depressive mood improves with increased L-T4 dose, without significant
hyperthyroid symptoms or signs, in older adults undergoing thyroid hormone replacement.[32] Also, Wildisen et al[33] assessed the effect of L-T4 on the development of depressive symptoms in older adults
with SCH in the largest trial on this subject. It updated a previous meta-analysis,
including the results of this study. This predefined ancillary study analyzed data
from participants in the TRUST trial described above. This ancillary study included
a subgroup of 472 participants from the Netherlands and Switzerland; after exclusions,
427 participants (211 randomized to levothyroxine and 216 to placebo) were analyzed.
This analysis was conducted from December 1, 2019 to September 1, 2020. Randomization
was done to either levothyroxine or placebo. Depressive symptom scores after 12 months
were measured with the GDS-15, with higher scores indicating more depressive symptoms
(minimal clinically important difference = 2). A total of 427 participants with SCH
(mean age, 74.5 years; 239 women) were included. They found that depressive symptoms
did not differ after levothyroxine therapy compared with placebo after 12 months;
thus, these results do not provide evidence in favor of levothyroxine therapy in older
persons with SCH to reduce the risk of developing depressive symptoms.[33]
Stuber et al[34] reported a nested study within the randomized, placebo-controlled, multicenter TRUST
trial described above. Interventions consisted of daily levothyroxine starting with
50 mcg (25 mcg if weight < 50 kg or known coronary heart diseases) and dose adjustments
to achieve a normal TSH and mock titration in the placebo group. Among 230 participants,
the mean TSH was 6.2 mIU/L at baseline and decreased to 3.1 with L-T4 (n = 119) versus 5.3 with placebo (n = 111, p < 0.001) after 1 year. After adjustment, no between-group difference was detected
at 1 year on perceived physical or mental fatigability. In participants with higher
fatigability at baseline, the adjusted between-group differences at 1 year were not
significantly different. This suggests that L-T4 in older adults with mild SCH provides
no change in physical or mental fatigability.[34] Danicic et al[35] discussed the impact of SCH on health-related quality of life (HRQoL) and the evidence
for L-T4 therapy and exercise therapy to improve HRQoL in SCH. The prevalence of SCH
in Australia is approximately 4 to 5% and is higher in females and older adults. Current
evidence suggests thyroid hormone therapy is not associated with improving HRQoL.
However, there appears to be a subgroup of those with SCH who experience an impairment
in HRQoL and may benefit from treatment. Because the majority of research to date
has been done in older adults, largely asymptomatic individuals, this may only be
representative of some of the SCH population.[35] In addition, alternative treatments, such as exercise therapy, have yet to be explored
in the literature despite exercise therapy's effects on HRQoL in other populations.
Further research is required to define clearly which individuals with SCH are likely
to experience an impaired HRQoL, as well as explore the effects of thyroid hormone
therapy and exercise therapy in these individuals.[35]
A couple of years ago, Eslami-Amirabadi and Sajjadi[36] summarized the literature examining the relationship between thyroid hormonal dysregulation
and cognition or behavior. They present the available imaging and pathological findings
on structural and functional brain changes related to thyroid hormonal dysregulation.
They also propose potential interaction mechanisms between thyroid hormones, autoantibodies,
and cognition/behavior. Effects of gender, ethnicity, and environmental factors are
also briefly discussed. This review highlights the need for long-term prospective
studies to capture the course of brain functional changes associated with the incidence
and progression of thyroid dysregulations and the confounding effects of nonmodifiable
risk factors such as gender and ethnicity. Moreover, double-blind controlled clinical
trials are necessary to devise appropriate treatment plans to prevent cognitive consequences
of over- or undertreatment of thyroid disorders.[36]
Outcomes and Prognosis
Several reports of different types addressed the outcome of hyothyroidism.[37]
[38]
[39]
[40]
[41] Zhong et al[37] evaluated whether elevated endogenous thyrotropin levels contribute to an increased
risk of adverse outcomes, such as all-cause mortality in older adults with SCH.[37] Eight electronic databases were searched for relevant articles from inception until
March 23, 2022. Cohort studies assessing the association between thyrotropin levels
and the risk of mortality among older adults aged ≥ 60 years with SCH were eligible.
The outcomes of interest were either all-cause or cardiovascular-related mortality.
Two independent researchers assessed the eligibility of the studies and collected
data through a previously defined data extraction form. The Newcastle-Ottawa Scale
was used to evaluate the quality of evidence, and multivariate-adjusted hazard ratios
(HRs) were collected as the necessary risk estimate for synthesis. Random-effect models
were applied for meta-analysis. Overall, 13 studies involving 44,514 participants
were included in this meta-analysis. There were no significant differences in the
risk of all-cause mortality and cardiovascular-related mortality between euthyroid
older adults and older adults with SCH. The results remained the same when only older
adults with thyrotropin ≥ 10 mIU/L were assessed. Therefore, high thyrotropin levels
are not associated with increased risk for all-cause mortality as well as cardiovascular-related
mortality in older adults aged ≥ 60 years with SCH, suggesting a superfluousness of
initiating treatment.[37]
A meta-analysis aimed to determine the impact of HypoT on mortality in the older adult
population.[38] Several databases were searched from inception until May 10, 2019. Studies evaluating
the association between HypoT and all-cause and/or cardiovascular mortality in the
older adult population were eligible. Two reviewers independently extracted data and
assessed the quality of the studies. Relative risk was retrieved for synthesis. A
random-effects model for meta-analyses was used. Twenty-seven cohort studies with
1,114,638 participants met the inclusion criteria. Overall, patients with HypoT experienced
a higher risk of all-cause mortality than those with euthyroidism; meanwhile, no significant
difference in cardiovascular mortality was found between patients with HypoT and those
with euthyroidism. Subgroup analyses revealed that overt HypoT rather than SCH was
associated with increased all-cause mortality. The heterogeneity primarily originated
from different study designs (prospective and retrospective) and geographic locations.
Based on the current evidence, HypoT is significantly associated with increased all-cause
mortality instead of cardiovascular mortality among older adults. They observed considerable
heterogeneity, so caution is needed when interpreting the results. Further prospective,
large-scale, high-quality studies are warranted to confirm these findings.[38]
Thyroid hormones have vital roles in development, growth, and energy metabolism. Within
the past two decades, disturbances in thyroid hormone action have been implicated
in aging and the development of age-related diseases. van Heemst[39] reviewed the results from biomedical studies that have identified the importance
of precise temporospatial regulation of thyroid hormone action for local tissue maintenance
and repair. Age-related disturbances in the maintenance of tissue homeostasis are
thought to be important drivers of age-related disease. In most iodine-proficient
human populations without thyroid disease, the mean, median, and 97.5 centiles for
circulating concentrations of the TSH are progressively higher in adults over 80 years
of age compared with middle-aged (50–59 years) and younger (20–29 years) adults. This
trend has been shown to extend into advanced ages (over 100 years). Here, potential
causes and consequences of the altered thyroid status observed in old age and its
association with longevity will be discussed. In about 5 to 20% of adults at least
65 years of age, TSH concentrations are elevated. Still, circulating thyroid hormone
concentrations are within the population reference range, a condition called SCH.
Results from randomized clinical trials that have tested the clinical benefit of thyroid
hormone replacement therapy in older adults with mild SCH will be discussed, as well
as the implications of these findings for screening and treatment of SCH in older
adults.[39]
The associations between (sub-) clinical thyroid dysfunction and disability in daily
living, cognitive function, depressive symptoms, physical function, and mortality
in people aged 80 years and older were evaluated.[40] Four prospective cohorts participating in the Towards Understanding Longitudinal
International Older People Studies (TULIPS) consortium were included. Outcome measures
included disability in daily living (disability in activities of daily living [ADL]
questionnaires), cognitive function (Mini-Mental State Examination [MMSE]), depressive
symptoms (GDS), physical function (grip strength) at baseline and after 5 years of
follow-up, and all-cause 5-year mortality. Of the total 2,116 participants at baseline
(mean age 87 years, range 80–109 years), 105 participants (5.0%) were overtly HypoT,
6.4% had SCH, 85.6% euthyroid, 2.8% subclinically hyperthyroid, and 0.2% overtly hyperthyroid.
Participants with thyroid dysfunction at baseline had nonsignificantly different ADL
scores compared with euthyroid participants at baseline and had similar MMSE scores,
GDS scores, and grip strength. During 5 years of follow-up, there was no difference
in the change of any of these functional measures in participants with thyroid dysfunction.
Compared with the euthyroid participants, no 5-year survival differences were identified
in participants with overt HypoT (HR: 1.0), SCH (HR 0.9), subclinical hyperthyroidism
(HR 1.1), and overt hyperthyroidism (HR 1.5). Results did not differ after excluding
participants using thyroid-influencing medication. Therefore, in community-dwelling
people aged 80 years and older, (sub-) clinical thyroid dysfunction was not associated
with functional outcomes or mortality and may, hence, be of limited clinical significance.
The impact of thyroid hormone therapy on mortality in adults with SCH was summarized
by searching several databases.[41] Studies comparing the effect of thyroid hormone therapy with that of placebo or
no treatment in adults with SCH on all-cause and/or cardiovascular mortality were
included. Five observational studies and 2 RCTs with 21,055 adults were included.
Overall, thyroid hormone therapy was not significantly associated with all-cause or
cardiovascular mortality. Subgroup analyses revealed that thyroid hormone therapy
was significantly associated with lower all-cause and cardiovascular mortality in
younger adults. However, no significant association between thyroid hormone therapy
and mortality was observed in older adults. The use of thyroid hormone therapy does
not provide protective effects on mortality in older adults with SCH.
Patient and Professional Perspectives
The lack of knowledge and understanding of HypoT and a tendency for many people to
attribute the symptoms of HypoT to other causes have led to substantial unawareness
and often late diagnosis of HypoT. Large observational studies and meta-analyses have
shown that about 4 to 7% of community-derived populations in the United States and
Europe have undiagnosed HypoT.[42] About four cases in five of these are SCH, with the remainder being overt HypoT.
The prevalence of undiagnosed HypoT is higher in older subjects, in women, and in
some ethnic groups, consistent with diagnosed disease. The authors suggested that
more research is needed to quantify the clinical burden of undiagnosed HypoT around
the world, with educational efforts aimed at the public and health care professionals
aimed at identifying and managing these individuals. To this end, practice patterns
regarding TSH goals and factors influencing physicians' decision-making when managing
HypoT were evaluated using a case-based survey of a convenience sample of 286 physicians
practicing in relevant disciplines in three developing regions.[43] Three-quarters of physicians stated they would consider patients' age when determining
the TSH goal. The physicians targeted a higher TSH goal in octogenarians, which is
still lower than the age-related reference, indicating awareness regarding inadequate
benefits and an attempt to avoid iatrogenic hyperthyroidism. The authors suggested
that consensus is needed on the role of patients' age in HypoT management, the complexity
of managing HypoT in older adult patients, and the variability in practice patterns
among physicians. They also proposed that addressing these challenges demands ongoing
dialog and collaboration among health care providers to improve patient care and outcomes
in HypoT management across different age groups.
