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 to be 3-15% depending on the population studied. Intraindividual variation in TSH levels is minimal, this is secondary to a unique individual setpoint in the hypothalamic-pituitary axis. This condition correlates with an increased risk of fatal and non-fatal coronary artery disease (CAD) events, congestive heart failure and fatal stroke. This activity reviews the evaluation and treatment of subclinical hypothyroidism and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Review the presentation of subclinical hypothyroidism
• Describe the evaluation of a patient with subclinical hypothyroidism
• Summarize the treatment options for subclinical hypothyroidism
• Outline the value of collaboration and communication among the interprofessional team to improve outcomes for those with subclinical hypothyroidism.

Introduction

Subclinical hypothyroidism characteristically presents with elevated thyroid-stimulating hormone (TSH) and normal thyroxine (T4) levels.[1]Various studies have reported the incidence of subclinical hypothyroidism to be 3-15% depending on the population studied.[2][3] The prevalence of this disorder is bound to increase due to the increased availability of thyroid function testing. Although TSH levels vary widely in the population, intraindividual variation is minimal; this is secondary to a unique individual setpoint in the hypothalamic-pituitary axis.[4] Subclinical hypothyroidism correlates with an increased risk of fatal and non-fatal coronary artery disease (CAD) events, congestive heart failure and fatal stroke.[5][6]

Etiology

Subclinical hypothyroidism and hypothyroidism share the same etiologies. Worldwide iodine deficiency is the most common cause of hypothyroidism. However, in the United States, autoimmune thyroiditis is the most common cause of hypothyroidism. Other causes include post-surgical or post-ablative hypothyroidism, central hypothyroidism, and medication-induced hypothyroidism.[7]

Epidemiology

The prevalence of subclinical hypothyroidism varies from 3 to 15% based on the study population. Statistical research demonstrates a higher incidence of subclinical hypothyroidism in women and elderly individuals. Vanderpump et al. in the Whickham survey found 8% of women and 3% of men to have subclinical hypothyroidism.[3]The risk of subclinical hypothyroidism progression to overt hypothyroidism is 2 to 6% per year. The risk is higher in women having TSH of greater than 10 mIU/ml and positive thyroid peroxidase (TPO) antibody.[8][9]

Pathophysiology

In the USA, the most common cause of hypothyroidism is Hashimoto thyroiditis, characterized by lymphocytic infiltration, fibrosis, and atrophy of the thyroid gland. CD8 cells in the lymphocytic infiltrate are responsible for the destruction of the thyroid gland.[10]

History and Physical

Subclinical hypothyroidism is asymptomatic most of the time. However, it can present with symptoms of hypothyroidism.[7] It is essential to assess hypothyroid symptoms as it influences whether thyroid replacement therapy requires initiation. The clinical features of hypothyroidism are as follows:

1. Integumentary: Dry skin, hair loss, loss of outer 1/3rd of eyebrows, facial puffiness.
2. Gastrointestinal: Constipation, dysphagia, loss of appetite, weight gain, cholelithiasis
3. Cardiovascular: Diastolic hypertension, bradycardia, pericardial effusions
4. Neurological: Decreased attention span, pseudodementia, mononeuropathies (most commonly carpal tunnel syndrome)
5. Musculoskeletal: Muscular weakness, cramps, stiffness, fatigue
6. Reproductive: Irregular periods, decreased libido [11]

Evaluation

The hallmark of subclinical hypothyroidism is an elevated TSH with a normal T4. However there are several non-thyroidal factors which can cause elevation of TSH, and they need to be ruled out before a diagnosis of subclinical hypothyroidism is made. Recommendations are that TSH and T4 need to be repeated at least once after 2-3 months. TPO antibodies which indicate an autoimmune etiology of hypothyroidism should be measured. They correlate with a two-fold increased risk of progression of subclinical hypothyroidism to overt hypothyroidism. The TPO antibody titers decrease with time and do not need repeating. An ultrasound would show a hypoechoic and heterogenous thyroid gland in patients with autoimmune thyroid disease. 

Since subclinical hypothyroidism has potential associations with cardiovascular disease, congestive heart failure, and cognitive decline patients should be evaluated for their risk of atherosclerotic cardiovascular disease and other risk factors.[7]

Treatment / Management

The central question in the treatment of subclinical hypothyroidism is when to initiate levothyroxine therapy. Factors which need to be taken into account to decide on levothyroxine therapy are age, extent of the elevation of TSH, associated cardiovascular risk factors, clinical symptoms of hypothyroidism and presence of thyroid peroxidase antibodies.

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

• TSH is >10 mIU/l or;
• Presence of hypothyroid symptoms or;
• Presence of cardiovascular risk factors or;
• Positive TPO antibody.

The goal of levothyroxine therapy is to normalize TSH. The starting of levothyroxine is 1.6 mcg/kg in the absence of cardiovascular disease. In patients with cardiovascular disease, the starting dose of levothyroxine is 25 mcg and is up-titrated as needed.[11]

Differential Diagnosis

There are several non-thyroid factors which can transiently elevate TSH and lead to misdiagnosis as subclinical hypothyroidism. It is essential to distinguish between these non-thyroid causes of elevation in TSH from true subclinical hypothyroidism.

1. Age
2. Nonthyroidal illness
3. Laboratory assay interference
4. Adrenal insufficiency
5. Chronic renal failure
6. Medications: Amiodarone, metoclopramide, amphetamine, ritonavir, and St. Johns Wort[12]

Complications

1. Cardiovascular risk: Hypothyroidism is associated with increased vascular resistance and decreased cardiac output. Lack of triiodothyronine (T3) impairs the vasodilatory action of nitric oxide on the vasculature resulting in increased vascular resistance. 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.[13][14] Rodondi et al. studied 55,000 patients and found that a TSH of >10 mIU/l correlated with an increased risk of coronary artery disease events (hazard ratio of 1.86) and cardiovascular mortality (Hazard ratio of 1.58).[15] However, Gusekloo et al. showed that in elderly individuals (>85 years) higher TSH levels were associated with a reduced mortality rate.[16] Adrees et al. showed that the increased levels of cholesterol, blood pressure, homocysteine associated with subclinical hypothyroidism normalized after 18 months of levothyroxine treatment.[17]

2. 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 the exercise performance was noted in the treatment group.[18]

3. Cognitive impairment: Hypothyroidism has been known to be associated with cognitive decline. Triiodothyronine plays an important 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 younger than 75 years with subclinical hypothyroidism.[19] In contrast, Akintola et al. in their meta-analysis of 15 studies found no increased risk of cognitive impairment with subclinical hypothyroidism.[20]

Pearls and Other Issues

• 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 a decrease in functional capacity.
• Treatment with levothyroxine should commence if the level of TSH is >10 mIU/l, with positive thyroid peroxidase antibody, the presence of hypothyroid symptoms, or cardiovascular risk factors.

Enhancing Healthcare Team Outcomes

An interprofessional team is the best approach to subclinical hypothyroidism management. The central question in the treatment of subclinical hypothyroidism is when to initiate levothyroxine therapy. Factors which need to be taken into account to decide on levothyroxine therapy are age, the extent of the elevation of TSH, associated cardiovascular risk factors, clinical symptoms of hypothyroidism and presence of thyroid peroxidase antibodies.