Continuing Education Activity

Subclinical hypothyroidism characteristically presents with normal thyroxine (T4) levels and elevated thyroid stimulating hormone (TSH) levels. The incidence of subclinical hypothyroidism is estimated at 3% to 15%, depending on the population studied. Minor fluctuations in T4 levels result in considerably larger fluctuations in TSH levels. Although TSH levels exhibit wide variability across the population, intra-individual variation remains minimal, which is secondary to a unique individual setpoint within the hypothalamic-pituitary axis for each person. This condition correlates with an increased risk of fatal and non-fatal coronary artery disease events, congestive heart failure, and fatal stroke. This activity reviews the evaluation and management of subclinical hypothyroidism, emphasizing the collaborative role of the interprofessional healthcare team in enhancing patient care. This activity also helps clinicians gain insights into distinguishing characteristics within relevant literature to maximize patient outcomes.

Objectives:

• Identify the clinical features and laboratory parameters indicative of subclinical hypothyroidism in patients, including elevated levels of thyroid-stimulating hormone and normal free thyroxine (T4).
• Screen at-risk populations, such as individuals with a family history of thyroid disorders, for subclinical hypothyroidism using appropriate laboratory tests.
• Select the most suitable thyroid hormone replacement regimen and dosing strategy for patients with subclinical hypothyroidism, considering factors such as age, comorbidities, and medication adherence.
• Collaborate with endocrinologists, primary care physicians, and other healthcare professionals to ensure shared decision-making and optimize the care for patients with subclinical hypothyroidism.

Introduction

Subclinical hypothyroidism characteristically presents with normal thyroxine (T4) levels and elevated thyroid stimulating hormone (TSH) levels.[1] Minor fluctuations in T4 levels result in considerably larger changes in TSH levels.[2] Although TSH levels exhibit wide variability across the population, intra-individual variation remains minimal, which is secondary to a unique individual setpoint within the hypothalamic-pituitary axis for each person.[3] 

Most individuals have a log-linear relationship between TSH and T4. Still, some individuals can have a nonlinear relationship explaining the normal free T4 with TSH ≥10 mIU/L, while others may have a low T4 level.[4] Various studies have reported the incidence of subclinical hypothyroidism to be estimated at 3% to 10% and increasing to 18% to 20% in older patients, depending on the population studied.[5][6] The prevalence of subclinical hypothyroidism tends to be higher in women and older adults.[7] Observational studies have shown that subclinical hypothyroidism (with TSH ≥10 mIU/L) correlates with an increased risk of fatal and non-fatal coronary artery disease (CAD) events, congestive heart failure, and fatal stroke.[8][9][10]

The prevalence of this disorder is bound to increase due to the increased availability of high-sensitivity thyroid function testing. Levothyroxine is the second most commonly prescribed medication in the United States.[11] The increased recognition and treatment or trials with levothyroxine replacement therapy in patients with subclinical hypothyroidism could partly explain why. A study from the United Kingdom showed an increased trend toward treating hypothyroidism between 2005 and 2014, from 2.3% to 3.5% of the total population.[12] 

Etiology

Subclinical hypothyroidism and hypothyroidism share the same etiologies. Worldwide, iodine deficiency is the most common cause of hypothyroidism. However, autoimmune thyroiditis (Hashimoto thyroiditis) is the most common cause of hypothyroidism in the United States. Other causes include post-surgical or post-ablative hypothyroidism, central hypothyroidism, and medication-induced hypothyroidism (lithium, amiodarone, checkpoint inhibitors, and tyrosine kinase inhibitors).[13][14] Higher levels of TSH also occur in individuals with obesity, with TSH levels declining with weight loss.[13][15][16]

Epidemiology

The prevalence of subclinical hypothyroidism varies from 3% to 15% based on the study population.[13][17] Statistical research demonstrates a higher incidence of subclinical hypothyroidism in women and older individuals. Individuals with type 2 diabetes mellitus are also more likely to develop subclinical hypothyroidism.[18] Vanderpump et al, in the Whickham survey, found 8% of women and 3% of men have subclinical hypothyroidism.[6] The risk of subclinical hypothyroidism progression to overt hypothyroidism is 2% to 6% per year.[13] This rate is 3% to 8% in individuals with TSH >10 mIU/L and thyroid peroxidase (TPO) antibody (TPOAb) positivity.[19] The risk of progression to overt hypothyroidism is higher in women, individuals with higher levels of TSH, and individuals with TPOAb positivity.[19][20]

Subclinical hypothyroidism resolved spontaneously in 46% of older participants after 4 years in a prospective study involving 459 individuals aged 65 and older. In another study involving 107 women and men aged 55 or older, spontaneous normalization of TSH occurred in 52% of the participants with TSH <10 mIU/L after a mean follow-up of 32 months.[21] Individuals with TSH <7 mIU/L and TPOAb negativity were more likely to have this resolution.[20]

History and Physical

Subclinical hypothyroidism is asymptomatic most of the time. However, it can present with symptoms of hypothyroidism.[13] Assessing hypothyroid symptoms influences whether thyroid replacement therapy is indicated. The clinical features of hypothyroidism are as follows:[22][14]

• Integumentary: Dry skin, hair loss, loss of an outer third of eyebrows, and facial puffiness.
• Respiratory: Sleep apnea and hoarseness of voice.
• Gastrointestinal: Constipation, dysphagia, loss of appetite, and cholelithiasis.
• Cardiovascular: Diastolic hypertension, bradycardia, pericardial effusions, decreased cardiac output, and dyslipidemia, which occur only in severe and sustained hypotension cases.
• Neurological: Decreased attention span, pseudodementia, and entrapment neuropathies, with carpal tunnel syndrome being the most frequently encountered.
• Musculoskeletal: Muscular weakness, cramps, stiffness, and fatigue.
• Reproductive: Irregular periods, menorrhagia, and decreased libido.
• Metabolic: Weight gain, cold intolerance, and hyponatremia.

Evaluation

The hallmark laboratory finding of subclinical hypothyroidism is an elevated TSH with a normal T4. However, non-thyroidal illness and some medications can cause an elevation of TSH, and they need to be ruled out before a diagnosis of subclinical hypothyroidism is established. In patients with TSH <10 mIU/L and normal free T4, thyroid blood work should be repeated in 3 to 6 months before initiation of therapy as almost half of these patients have a resolution of the thyroid abnormalities.[17] 

TPO antibodies should be checked in patients. If positive for TPO antibodies, this may indicate an autoimmune etiology of hypothyroidism.[22] They correlate with a 2-fold increased risk of progression of subclinical hypothyroidism to overt hypothyroidism.[19][23] The TPO antibody titers decrease with time and do not need repetition. An ultrasound shows a heterogenous and/or atrophic thyroid gland in patients with autoimmune thyroid disease, but this test is not recommended for establishing the diagnosis.[13][24] Since subclinical hypothyroidism has potential associations with cardiovascular disease, congestive heart failure, and cognitive decline, patients should be evaluated for the risk of atherosclerotic cardiovascular disease and other comorbidities.[13]

Treatment / Management

The central question in treating subclinical hypothyroidism is whether to and when to initiate levothyroxine therapy. This decision is challenging, especially for older patients. The factors that need to be considered when deciding on levothyroxine therapy are age, extent of the elevation of TSH, associated cardiovascular risk factors, clinical symptoms of hypothyroidism, and presence of TPOAbs. As a significant proportion of patients with subclinical hypothyroidism have normalization of TSH levels, the first strategy is 'wait and watch.' [25] Repeating TSH levels in 2 to 3 months is essential to confirm sustained elevation of TSH before hormone replacement is initiated.

Both the American Thyroid Association (ATA) and the American Association of Clinical Endocrinology (AACE) recommend starting levothyroxine therapy under the following scenarios:[22]

• TSH is >10 mIU/L
• Presence of hypothyroid symptoms
• Positive TPO antibody
• Women of reproductive age

The age and cardiovascular status of patients should be considered. Treatment is recommended with levothyroxine in patients aged 70 or younger with TSH >10 mIU/L without a history of cardiovascular disease.[26] Patients with subclinical hypothyroidism do not need a full dose of levothyroxine replacement. Depending on the level of TSH elevation and symptoms, they can be started on 25 to 75 mcg levothyroxine. In individuals with a history of cardiovascular disease (without symptoms of active disease) and aged 70 or younger, the lowest dose of levothyroxine 25 mcg should be started to assess tolerability.

In individuals aged 70 or older, the decision is made on a case-by-case basis to initiate levothyroxine therapy based on symptoms and history of cardiovascular disease. Patients with TPO antibody positivity can also be started on levothyroxine replacement since these patients have a two-fold risk of progression to overt hypothyroidism. These recommendations do not apply to pregnant women or women trying to conceive. They should be started on levothyroxine replacement for mild thyroid dysfunction, especially when TPOAb is positive, due to a higher risk of worse pregnancy and fetal outcomes.[27][28][29] The threshold for replacement based on TSH values is also different in this population; further discussion on this topic is beyond the scope of this article.

In the Thyroid Hormone Replacement for Untreated older adults with subclinical hypothyroidism—a randomized placebo-controlled Trial (TRUST), a double-blinded, randomized, placebo-controlled trial, 737 adults who were aged 65 or older above with subclinical hypothyroidism (TSH between 4.60 and 19.99 mIU/L and free T4 within the reference range) were included. A total of 368 participants received low-dose levothyroxine of 50 mcg daily, except in patients with body weight less than 50 kg or a history of coronary artery disease. After 1 year, no difference was noted in the treatment and placebo groups for the hypothyroid symptoms scale and tiredness score. No differences were noted in terms of adverse effects.[30]

A Cochrane review in 2017 involving 350 patients from 12 small clinical trials over 6 to 14 months did not show improvement in symptoms, mood, or quality of life metrics with levothyroxine replacement. Improvement was noted in the lipid profile and some echocardiographic parameters, including myocardial relaxation. A difference in adverse events was reported in 4 clinical trials.[31] The Birmingham Elderly Thyroid Study, another randomized controlled trial by Parle et al in 94 community-dwelling individuals aged 65 or older, showed no improvement in cognitive function with low-dose levothyroxine replacement.[32] Grossman et al conducted a case-control study in 1558 individuals with subclinical hypothyroidism and TSH <10 mIU/L, showing an increased mortality risk with levothyroxine replacement. Factors associated with higher mortality were advanced age, senile dementia, history of cerebrovascular disease, congestive heart failure, and chronic renal failure. There was no higher risk of atrial fibrillation or femoral fractures.[33]

Though multiple studies have shown an increased risk of cardiovascular disease and mortality in elderly patients with subclinical hypothyroidism, no long-term clinical trials have evaluated the effect of levothyroxine replacement on these factors.[34] Treatment decisions should not be based solely on these factors.

Differential Diagnosis

Several non-thyroid factors can transiently elevate TSH levels, potentially leading to misdiagnosis as subclinical hypothyroidism. It is crucial to differentiate between these causes of non-thyroidal TSH elevation and true subclinical hypothyroidism. These factors include:

• Aging associated with a rise in TSH concentration [35][36]
• Nonthyroidal illness [37][38]
• Laboratory assay interference [39][40]
• Adrenal insufficiency
• Chronic renal failure
• Certain medications such as amiodarone, lithium, tyrosine kinase inhibitors, checkpoint inhibitors, metoclopramide, amphetamine, ritonavir, and St Johns wort [41][42]

Prognosis

Almost half of the patients with mild thyroid dysfunction have normalized thyroid function in 1 to 2 years. Almost 25% of these patients progress to overt hypothyroidism.[21][43] An increase in cardiovascular risk factors, cardiovascular events and mortality, congestive heart failure, and decline in renal function is associated with a diagnosis of subclinical hypothyroidism.[44][45][46]

Complications

Cardiovascular Risk

Hypothyroidism is associated with increased vascular resistance and decreased cardiac output.[47] Lack of triiodothyronine (T3) impairs the vasodilatory action of nitric oxide on the vasculature, resulting in increased vascular resistance.[48] Thyroid hormones have positive chronotropic action by directly stimulating the sinoatrial node and positive inotropic effect by modulating myocyte-specific regulatory proteins, increasing cardiac contractility. Lack of thyroid hormone results in bradycardia and decreased cardiac output.[49][50] 

Rodondi et al studied 55,000 patients in a prospective cohort study and found that a TSH between 10.0 and 19.9 mIU/L correlated with an increased risk of coronary artery disease events (hazard ratio of 1.86; CI 1.28-2.80) and cardiovascular mortality (Hazard ratio of 1.58; CI 1.10-2.27).[51] However, Gusekloo et al showed that in older individuals (aged 85 or older), higher TSH levels were associated with a reduced mortality rate.[52] Rodondi et al studied 2730 individuals between the ages of 70 and 79 over a 4-year follow-up period and found a higher risk of congestive heart failure with TSH levels of 7.0 mIU/L or higher.[53] Adrees et al showed that the increased levels of systolic blood pressure (SBP) and diastolic BP (DBP), total cholesterol, triglyceride, LDL-cholesterol, lipoprotein(a), homocysteine, and carotid intima-media thickness were associated with subclinical hypothyroidism in 54 women, which normalized after 18 months of levothyroxine treatment and became similar to euthyroid women.[54]

Functional Capacity

Subclinical hypothyroidism has been associated with decreased muscular strength and exercise capacity. Mainenti et al randomized 23 women with subclinical hypothyroidism to receive levothyroxine or placebo. After 6 months of TSH normalization, an increase in exercise performance was noted in the treatment group.[55]

Cognitive Impairment

Hypothyroidism is associated with cognitive decline. Triiodothyronine plays a vital role in neuronal growth, migration, and myelination. However, studies have yielded conflicting results on the association of subclinical hypothyroidism and cognitive impairment. Pasqualetti et al, in their meta-analysis of 13 studies, found an increased risk of cognitive decline in patients aged 75 or younger with subclinical hypothyroidism.[56] In contrast, Akintola et al, in their meta-analysis of 15 studies, found no increased risk of cognitive impairment with subclinical hypothyroidism.[57]

Mood Disturbances

A meta-analysis by Zhao et al found an association between subclinical hypothyroidism and depression in participants aged 60 or younger and no association in individuals aged 60 or older. No change in depression scores was apparent with levothyroxine replacement.[58] Another meta-analysis by Loh et al involving 12,315 individuals also found a 1.7 times higher risk of depression scores associated with a diagnosis of subclinical hypothyroidism.[59]

Renal Function

Chonchol et al found the prevalence of subclinical hypothyroidism in patients with chronic kidney disease (CKD), not on dialysis, to be 18%. The presence of subclinical hypothyroidism in this population was associated with a progressive decline in the estimated glomerular filtration rate over 2 years.[60] Adrees et al showed that the decreased levels of estimated glomerular filtration rate and increased serum cystatin-C levels were associated with SH in 54 women, and treatment with hypothyroidism led to these levels becoming comparable to levels in euthyroid women.[54]

Deterrence and Patient Education

Patients should be counseled regarding the symptoms of hypothyroidism. They must be advised regarding treatment outcomes when TSH is below and above 10 mIU/L. Patients above 70 mIU/L with mild TSH elevation should be informed regarding the aging-related mild elevation in TSH concentrations, along with the lack of improvement shown in studies. Given the higher risk of cardiovascular risk factors, cardiovascular events, and morality, lifestyle changes should be advised. 

Pearls and Other Issues

Below are pertinent pearls for managing subclinical hypothyroidism:

• Subclinical hypothyroidism characteristically has an elevated TSH and normal T4. While most patients are asymptomatic, some may have symptoms of hypothyroidism.

• Subclinical hypothyroidism requires differentiation from other causes of a transient elevation of TSH (age, medications, renal failure, non-thyroidal illness, and assay interference).

• Subclinical hypothyroidism has potential correlations with an increased risk of cardiovascular disease, cognitive decline, and decreased functional capacity.

• Treatment with levothyroxine should commence if the level of TSH is >10 mIU/L, with positive TPOAb, hypothyroid symptoms, or cardiovascular risk factors.

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team is the best approach to subclinical hypothyroidism management. The central question in treating subclinical hypothyroidism is when to initiate levothyroxine therapy. Factors that need to be considered when deciding on levothyroxine therapy are age, the extent of the elevation of TSH, associated cardiovascular risk factors, clinical symptoms of hypothyroidism, and the presence of TPOAbs.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

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Disclosure: Shiva Kumar Gosi declares no relevant financial relationships with ineligible companies.

Disclosure: Jasleen Kaur declares no relevant financial relationships with ineligible companies.

Disclosure: Vishnu Garla declares no relevant financial relationships with ineligible companies.