A 68-year-old woman presents to your clinic to establish care after 20 years without a clinician. Her only complaint is mild fatigue that has been occurring for a year or more. A thorough history reveals no significant past medical conditions and a family history that is remarkable for coronary heart disease (father) and stomach cancer (brother). A comprehensive physical examination is unremarkable. Basic screening laboratory tests are ordered, including a thyroid-stimulating hormone (TSH) level, which returns elevated at 9.2 mU/L. The patient returns to the clinic for a free thyroxine (T4) value, which is found to be within normal limits. She is diagnosed with subclinical hypothyroidism. Should she be started on levothyroxine therapy?
This question is one that many clinicians have asked since thyroxine became the standard of treatment for hypothyroidism in 1950.1 Unlike overt hypothyroidism, which is treated with levothyroxine for symptomatic relief and cardiovascular disease (CVD) risk reduction, the treatment recommendations for subclinical hypothyroidism remain controversial; studies are conflicting on whether patients with subclinical hypothyroidism receive similar benefits with levothyroxine therapy. This article discusses subclinical hypothyroidism, treatment recommendations, and whether levothyroxine therapy is beneficial for patients, especially concerning CVD risk reduction.
CAUSES AND EPIDEMIOLOGY
The most common form of hypothyroidism is primary hypothyroidism, caused by a defect in the thyroid gland's synthesis and release of thyroid hormone.2 Iodine deficiency is the most common cause of primary hypothyroidism worldwide. The most common cause of primary hypothyroidism in iodine-sufficient areas is autoimmune (Hashimoto) thyroiditis, which is associated with antithyroid peroxidase (anti-TPO) antibodies. Other possible causes include external radiation exposure, thyroidectomy, and infiltrative processes such as lymphoma, sarcoidosis, and hemochromatosis.
Primary hypothyroidism can further be divided into overt hypothyroidism and subclinical hypothyroidism.3 Subclinical hypothyroidism is much more common than overt hypothyroidism, affecting at least 4.3% of the US population, compared with 0.3% who are affected by overt hypothyroidism.2 The incidence of subclinical hypothyroidism is greater in women, increases with age, and is more common in white patients than black patients.4 Although hypothyroidism is more commonly associated with iodine deficiency, geographic areas or countries that are iodine-sufficient have been shown to have higher incidences of subclinical hypothyroidism than those that are insufficient (about 6% incidence versus about 3%).4 Excess iodine present in these areas is believed to inhibit iodine organification, and, thus, thyroid hormone synthesis. This is known as the Wolff-Chaikoff effect.5
Subclinical hypothyroidism is primarily a laboratory diagnosis, and most patients have no symptoms or very mild ones. Therefore, many patients will be detected based on risk factors and screenings. With the exception of neonates, however, the guidelines for screening the general population without risk factors vary between experts. The American Thyroid Association (ATA) recommends screening for hypothyroidism starting at age 35 years, with repeat screening every 5 years; the US Preventive Services Task Force does not recommend screening at any age for hypothyroidism in asymptomatic adults.6,7 Several medical conditions are known to be associated with hypothyroidism, including atrial fibrillation, type 1 diabetes, hyperlipidemia, breast cancer, and Down syndrome.8 Screening in these populations could lead to earlier detection and treatment of subclinical hypothyroidism, but there are no firm recommendations about screening frequency.
The most accepted initial screening test for overt or subclinical hypothyroidism is a serum TSH, as shown in Figure 1. The normal range for TSH levels varies slightly, but typically 0.4 to 4 mU/L is considered normal.9 In both overt and subclinical hypothyroidism, the patient's TSH level is elevated. If TSH is elevated, the next step is to order a free thyroxine (FT4) level. A FT4 below the average normal range of 0.6 to 1.6 ng/dL is diagnostic of overt hypothyroidism; one within the normal range is consistent with subclinical hypothyroidism.10 A notable exception to this is central hypothyroidism, which occurs with damage to the pituitary-hypothalamic axis.11 In these patients, TSH will be low to normal, with a low FT4.11 Additional thyroid-specific laboratory tests may include anti-TPO antibodies, which can distinguish the cause of the hypothyroidism as Hashimoto thyroiditis.2 For patients with subclinical hypothyroidism, anti-TPO antibodies are not routinely obtained unless the decision to treat is in question. The presence of anti-TPO antibodies supports treatment, as they suggest an increased risk of progression from subclinical to overt disease.12
If the patient's symptoms are refractory to treatment, a serum triiodothyronine (FT3) value can be obtained to determine if a conversion problem exists for patients with overt hypothyroidism.13 An FT3 does not provide much value in the diagnosis of subclinical hypothyroidism because these patients mostly present as asymptomatic.4
Other associated laboratory tests include a complete blood cell (CBC) count and comprehensive metabolic panel (CMP), which may reveal other conditions that would explain a patient's symptoms, including anemia, hyponatremia, or hypoglycemia.9 A lipid panel and creatine kinase also are warranted because of the effects of thyroid hormones on lipid metabolism and muscles. Hypothyroidism rarely requires imaging, but ultrasonography will be useful if thyroid nodules are present or suspected.5
CLINICAL PRESENTATION AND ASSESSMENT
The clinical manifestations of subclinical hypothyroidism often correlate to the patient's TSH level.14 Most patients with a TSH level less than 10 mU/L are asymptomatic. Patients with a TSH greater than 10 mU/L may present with the symptoms of overt hypothyroidism, which include fatigue, cold intolerance, constipation, and weight gain.15 Other possible manifestations include coarse hair, hoarseness, dry skin, brittle nails, periorbital edema, and depression.
Physical examination findings in a person with hypothyroidism also vary greatly depending on the severity of the disease and the cause of the hypothyroidism.15 Most patients with subclinical hypothyroidism present without abnormal physical examination findings.14 If an abnormal finding is present, it typically is a less-severe physical manifestation of overt hypothyroidism. Some potential physical examination findings include brittle hair, macroglossia, hypohidrosis, peripheral or periorbital edema, facial puffiness, neck goiter, bradycardia, muscle weakness, and delayed ankle reflexes.16
The symptoms of hypothyroidism are vague, affect many body systems, and manifest variably depending on disease severity. Therefore, the differential diagnosis is extensive and depends on the patient's presenting symptoms. For example, fatigue could also indicate anemia, obstructive sleep apnea, depression, cancer, heart failure, infection, fibromyalgia, or many other conditions. Additional symptoms of constipation, weight gain, dry skin, and cold intolerance each have their own associated differential diagnoses. If a patient presents with one or more of these vague symptoms, obtain a TSH to exclude or include hypothyroidism in the differential diagnosis.
Although diagnosis of subclinical hypothyroidism is almost exclusively through laboratory findings, an isolated elevation in TSH with a normal T4 level does not necessarily provide a diagnosis of subclinical hypothyroidism. Non-thyroid-related influences could temporarily raise the TSH level, including obesity, moderate-to-severe chronic kidney disease, and adrenal insufficiency. Body mass index (BMI) correlates positively with TSH in patients who are obese, and can normalize with weight loss. Other conditions linked to causing elevations in TSH include recovering from a non-thyroid-related illness and taking medications such as amiodarone, amphetamine, and metoclopramide.17 About 35% of patients with an isolated elevation in TSH normalize within 2 years.17 As a result, before beginning treatment for subclinical hypothyroidism, obtain a repeat TSH level in 3 months for patients with an isolated elevation in TSH; a persistent elevation is consistent with the diagnosis of subclinical hypothyroidism.18
The associations between overt hypothyroidism and cardiovascular complications have been thoroughly established throughout the years.15 Hypothyroidism reduces cardiac output and cardiac contractility, increases diastolic BP, and disrupts lipid metabolism, specifically by elevating total cholesterol and low-density lipoprotein (LDL) cholesterol.19
Hueston and Pearson concluded in their 2004 study of 8,228 total participants (215 with subclinical hypothyroidism) that subclinical hypothyroidism was not associated with cholesterol or triglyceride abnormalities after adjusting for influencing variables.20 More recently, Hyland and colleagues found no increased risk of coronary heart disease, heart failure, or cardiovascular death in patients age 65 years and older with subclinical hypothyroidism.19
The number of studies supporting an association between subclinical hypothyroidism and cardiovascular complications surpasses the number of studies that do not, however. Two large retrospective studies (N = 13,915 and N = 17,046, respectively) performed by Meng and colleagues and Zhao and colleagues in 2015 found a positive association between serum TSH, total cholesterol, and LDL cholesterol.21,22 Zhao's analysis estimated a 0.0147 mmol/L increase in total cholesterol for every 1 mIU/L increase in TSH in patients ages 40 to 49 years, and a 0.0551 mmol/L increase in those ages 60 to 69 years.22 Additionally, a study conducted in 2016 by Grossman and colleagues with 17,440 patients age 65 years and older determined an increase in mortality in patients with a TSH greater than 6.38 mIU/L.23 Lastly, a meta-analysis performed by Moon and colleagues in 2017 consisting of 555,530 patients from 35 studies concluded that subclinical hypothyroidism was associated with CVD and mortality, especially in patients with high CVD risks.24 However, the association was not observed in patients age 65 years or older, contradicting the results of Grossman and colleagues and supporting the results of Hyland and colleagues.24 Given the evidence in these large, recent studies, the relationship between subclinical hypothyroidism and CVD is relatively well established. Whether treatment will reduce this risk remains a question.
Recommended treatment for all patients with overt hypothyroidism is levothyroxine, a synthetic thyroid hormone.18 The starting dose for younger patients without CVD is 1.6 mcg/kg/day. Lower starting doses of 12.5 to 25 mcg/day with gradual dose increases are recommended for older adults and patients with CVD.25 In all patients, the levothyroxine dose should be adjusted based on the TSH level. TSH levels should be monitored every 6 to 8 weeks after a levothyroxine dose change to confirm a therapeutic TSH value. The target TSH range for patients age 70 years and younger is 0.5 to 2.5 mU/L, and 1 to 5 mU/L for patients age 65 to 70 years.5 Once a therapeutic TSH is achieved, monitor the patient's TSH level every 6 to 12 months.25
Treatment for patients with subclinical hypothyroidism is much less well defined. Levothyroxine is not FDA-approved for the treatment of subclinical hypothyroidism, although it is the standard of care for those who are to be treated. Per the 2012 ATA/American Association of Clinical Endocrinologists' clinical guidelines for hypothyroidism in adults (and reaffirmed by the ATA in its 2014 guidelines), it is always recommended to treat anyone with a TSH greater than 10 mU/L.6,26 For patients with elevated TSH that is less than 10 mU/L, other factors need to be considered, as shown in Table 1. Unfortunately, the research that has been conducted since the publication of these guidelines has not further clarified the issue. Studies about symptoms, quality of life, and cardiovascular risk still show conflicting results.
A 2016 cohort study conducted by Winther and colleagues with 78 patients concluded that 6 months of levothyroxine therapy improved the health-related quality of life in patients with autoimmune overt and subclinical hypothyroidism.27 Conversely, the much larger placebo-controlled TRUST trial by Stott and colleagues, consisting of 737 adults with subclinical hypothyroidism, concluded that levothyroxine did not provide any symptomatic benefits in patients with subclinical hypothyroidism.28 Although this trial was one of the largest studies to evaluate symptomatic improvement with levothyroxine treatment in patients with subclinical hypothyroidism, it was limited because the initial severity of symptoms was mild, and most patients were asymptomatic. Consequently, no improvement would have necessarily been expected with treatment.
An additional follow-up study to the TRUST trial conducted by Blum and colleagues evaluated 185 participants from the original trial to determine if treatment with levothyroxine in patients with subclinical hypothyroidism resulted in any improvement on two markers for stroke risk, carotid intima-media thickness and carotid plaque burden.29 The study concluded that the normalization of TSH with levothyroxine treatment did not affect carotid intima-media thickness and carotid plaque burden, but these parameters were not measured before the start of the trial and could have initially measured minimal to none. The Blum study directly conflicts with a meta-analysis performed by Zhao and colleagues in 2017 of nine publications (247 patients with subclinical hypothyroidism), the results of which showed a decrease in carotid intima-media thickness with levothyroxine treatment compared with measurements before treatment.30 Further supporting treatment of subclinical hypothyroidism in relation to cardiovascular risk factors, a 2017 meta-analysis by Abreu and colleagues evaluated the effects of levothyroxine treatment on lipid profiles in patients with subclinical hypothyroidism.31 The analysis of five studies and 253 patients found a significant decrease in total cholesterol and LDL cholesterol in the patients treated with levothyroxine compared with the placebo groups. However, Andersen and colleagues concluded in 2016 after retrospective evaluation of 61,611 patients with established heart disease that treatment of subclinical hypothyroidism with levothyroxine did not reduce mortality, hospital admissions, or major adverse cardiac reactions.32 This study did not evaluate additional individual risk factors contributing to cardiac outcomes and did not have specific information about treatment, including treatment length and treatment adherence.
COMPLICATIONS OF TREATMENT
Studies have shown that about 40% of patients with overt hypothyroidism may be overtreated.18 Another 40% fail to reach therapeutic TSH levels even with treatment.19 This variability can be attributed, in part, to medication administration issues. For optimal and consistent absorption, levothyroxine must be taken on an empty stomach, either 30 to 60 minutes before or 3 to 4 hours after the intake of any food or beverage.25 Many significant drug interactions can alter levothyroxine absorption, affecting its effectiveness and adverse reactions. Levothyroxine also has a very long half-life and takes 6 weeks or more to reach steady state. During this time, patients may have continuing symptoms; conversely, the recommended weight-based dosing may overestimate the appropriate dose initially if not based on lean body weight, putting patients at greater risk for adverse reactions. Levothyroxine may worsen the conditions shown in Table 1.19,25 The TRUST trial showed no difference in adverse reactions (including atrial fibrillation, heart failure, fracture, or osteoporosis) between older patients treated with levothyroxine for subclinical hypothyroidism and those treated with placebo.28
The progression rate to overt hypothyroidism is 2.6% yearly in patients who do not have TPO antibodies and 4.3% yearly in those with TPO antibodies.33 Treatment of subclinical hypothyroidism may halt or slow the progression to overt hypothyroidism, but there is no evidence to support this effect.33 Patients must continue to have TSH monitored at least yearly and be educated to report symptoms or adverse reactions.
Hypothyroidism typically can be diagnosed and managed by a primary care clinician; however, an endocrinologist referral may be warranted in certain cases. For example, refer patients if the diagnosis or cause is uncertain, if the patient has a past medical history of thyroid disease or has a goiter, or if the patient is pregnant or wishes to become pregnant.17
Although subclinical hypothyroidism affects a significant portion of the population, guidelines for treating it remain unclear due to a lack of consistency in related studies. Current recommendations are to treat all patients with a TSH greater than 10 mU/L, as well as those with a TSH less than 10 mU/L who are under age 70 years, are pregnant, are infertile, are experiencing symptoms of hypothyroidism, have a goiter, have anti-TPO antibodies, or have elevated CVD risk.21 Other patients also may benefit from treatment, and the decision to initiate levothyroxine therapy is left to the clinician. At this time, more studies appear to support an association between subclinical hypothyroidism and cardiovascular risk factors, thus supporting treatment in order to reduce these risks. Clinicians must compare risks of levothyroxine treatment with the potential advantages, including this reduction in CVD risk and possible symptomatic improvement.
For the case patient, as a relatively healthy 65-year-old woman with a first-degree relative with CVD, the advantages of treatment likely outweigh the risks, although her symptoms are minimal. However, more information on her health status and history are warranted, specifically her bone-mineral density or FRAX score. Ultimately, more conclusive studies addressing the symptomatic or cardiovascular benefits from levothyroxine therapy, and studies comparing the long-term effects of subclinical hypothyroidism in both observed and treated patients could help establish definitive treatment guidelines.
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