Diagnostic Tests

Definitive diagnosis of hypothyroidism requires laboratory evaluation of TSH and free thyroxine (fT4). Once the diagnosis is suspected, complete blood count, complete metabolic panel, TSH, fT4, vitamin D, and lipid panels should be ordered.14 Serum TSH is by far the most sensitive and specific test in the diagnosis of hypothyroidism, and symptom severity is associated with higher levels of TSH.15 Table 2 lists the normal ranges for thyroid laboratory values14; however, what is considered within the upper limit of normal is still widely debated.16 According to the 2012 American Association of Clinical Endocrinologists and American Thyroid Association cosponsored guidelines, “if the upper and lower limits of normal for a third-generation TSH assay are not available, an upper limit of 4.12 mIU/L and a lower limit of 0.45 mIU/L should be considered in iodine-sufficient areas.”4

Additional findings include hyponatremia, hypoglycemia, anemia, increased low-density lipoprotein cholesterol, increased liver enzymes, and increased creatine kinase, all reflecting hypofunctioning of many body systems.3 Measurement of free T3 (fT3) and thyroid peroxidase antibody titers is typically not necessary but affirm the etiology of hypothyroidism and determine whether autoimmunity plays a role.3,17


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Normal TSH values vary widely depending on age, and the ranges of normal values are typically higher in older adults. This is important, as a select number of patients manifest recurrent symptoms despite normal-appearing thyroid values. Assessment of fT3 may be useful in these cases. Although TSH and fT4 may be within normal limits, fT3 may be lower and could account for recurrent symptoms (see box).18 Experts agree that a TSH on the higher range of normal predicts symptomatic hypothyroid deficiency. Typical symptoms with TSH in the lower range of normal probably indicates decreased peripheral conversion from T4 to T3.19

In the case presented, a complete blood count, complete metabolic panel, and lipid and thyroid panels were ordered. All were within normal limits except TSH and fT4, which were 6.71 mIU/L and 0.6 ng/dL, respectively. These results were diagnostic for mild hypothyroidism. At this time the patient’s primary care provider initiated therapy.

Management of Conversion Disorder and Subclinical Hypothyroidism

Conversion Disorder

Some patients with hypothyroidism may be symptomatic and have a normal TSH and fT4, but their fT3 may be slightly low. This indicates a potential problem with the conversion of T4 to T3 in the peripheral tissues.1 This is known as conversion disorder, euthyroid sick syndrome, or nonthyroidal illness syndrome.1 Typical therapy for hypothyroidism is levothyroxine, but not all patients normalize T3 with this therapy because of conversion issues. Multiple studies have been performed to determine the usefulness of combination therapy with levothyroxine and liothyronine for this patient population. Results of some of these studies determined that patients preferred combination therapy.2,3 A meta-analysis of other studies found no significant difference between the 2 therapy groups.4

It has been suggested that there may be a certain patient population that benefits from combination therapy, but because of the short half-life and rapid absorption of liothyronine, multiple doses per day need to be taken to create a stable level of T3.1 Newer studies need to be performed with a longer-acting form of liothyronine to determine the true significance of combination therapy vs monotherapy.

Subclinical Hypothyroidism

Subclinical hypothyroidism (SCH) is described as an elevated TSH and normal fT4 and fT3.2 This is much more common with autoimmune thyroid disease, and about 2% to 5% of patients with SCH progress to overt hypothyroidism every year.5 Undiagnosed and untreated SCH can lead to increased risk for cardiovascular disease, dyslipidemia, liver disease, neuropsychiatric symptoms, and potentially infertility.5 For this reason, early diagnosis is important.

In general, SCH is detected clinically through laboratory testing, and much less by patient symptoms. If present, symptoms are generally nonspecific, similar to those of hypothyroidism. The most frequently reported symptoms include memory impairment, slowness of thinking, muscle cramps, muscle weakness, tiredness, dry skin, feeling colder, hoarseness of voice, puffy eyes, and constipation.5 Diagnosis can be made with typical thyroid testing, but often thyroid peroxidase antibody testing can help determine an autoimmune etiology, as well as serve as an indicator for likelihood of progression to hypothyroidism.6 If tested early on in the disease process, antibodies may not be at a detectable level. In this case, a thyroid ultrasound may be helpful.3

There are 2 classes of SCH: the first with TSH between 4.0 and 10.0 mIU/L, and the second with TSH >10.0 mIU/L.2 There has been debate over whether to treat patients with mildly elevated TSH (4.0-10.0 mIU/L). If SCH is indicated on initial testing, it is wise to repeat testing 2 to 3 months before diagnosing and potentially treating.6 This is in part because of the variations of TSH levels, which can change throughout the day and peak in the evening.6 Ranges also increase with increasing age and are unpredictable in individuals with irregular sleep patterns.6 Individuals who exercise vigorously or have severe depression may also have altered TSH ranges.6

Once SCH is diagnosed, patients are sorted by age, TSH levels, and presence of symptoms to determine whether to treat or not to treat.6 Current guidelines recommend that patients <70 years old with TSH <10 mIU/L but with symptoms, may start a 3-month trial of levothyroxine and be assessed thereafter.6

References
1. Abdalla SM, Bianco AC. Defending plasma T3 is a biological priority. Clin Endocrinol (Oxf). 2014;81(5):633-641.
2. Appelhof BC, Fliers E, Wekking EM, et al. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double‐blind, randomized, controlled clinical trial. J Clin Endocrinol Metab. 2005;90(5):2666-2674.
3. Nygaard B, Jensen EW, Kvetny J, Jarløv A, Faber J. Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Eur J Endocrinol. 2009;161(6):895-902.
4. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2006;91(7):2592-2599.
5. Khan MA, Ahsan T, Rehman UL, Jabeen R, Farouq S. Subclinical hypothyroidism: frequency, clinical presentations, and treatment indications. Pak J Med Sci. 2017;33(4):818-822.
6. Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA Guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215-228.

Treatment

Treatment for hypothyroidism is aimed at slowly stabilizing TSH and fT4 by administering synthetic thyroxine, or levothyroxine.20 The starting dosage of levothyroxine is 1.6 μg/kg/d, or about 25 μg/d.18 Doses can be adjusted according to to patient symptoms and the dose at which TSH normalizes.3

In severe hypothyroidism, initiation of T4 therapy may exacerbate adrenal hypofunction.19 To avoid adrenal insufficiency, patients should also receive supplemental prednisone for the first week of T4 therapy.19 Once initial treatment has begun, monitoring of serum TSH and serum fT4 should be performed every 4 to 6 weeks until TSH is reduced to normal limits and the patient is in a euthyroid state.3 Some patients still have symptoms despite normal thyroid laboratory values; these patients may benefit from slight increases in their levothyroxine dose.3

The patient was started on 50 μg/d of levothyroxine initially. Since that time, the levothyroxine has been titrated up to a dosage of 75 μg/d and the patient has been maintained in a euthyroid state.

Patient Education

It is important to instruct patients on how to properly ingest the medication and what, if any, adverse effects to anticipate. Levothyroxine has a half-life of 14 days and should be taken at the same time every day on an empty stomach with a full glass of plain water.19 Because of the longer half-life, patients who may not be adherent to treatment still receive some benefit from taking levothyroxine. In addition, it is important to inform the patient to take medication 1 hour before breakfast and to avoid medications that interfere with levothyroxine’s metabolism, such as cholestyramine, colestipol, colesevelam, aluminum hydroxide, calcium carbonate, sucralfate, iron sulfate, raloxifene, omeprazole, and lansoprazole.19 Other medications that impair acid secretion, such as sevelamer, lanthanum carbonate, and chromium, may also interfere with levothyroxine therapy.19 If the provider has difficulty titrating the correct dose of levothyroxine to normalize TSH, or if the patient has significant coronary artery disease, the patient should be referred for consultation with an endocrinologist.3

Related Articles

Valerie West, PA-C, is a physician assistant at the Center for Primary Care in Groverton, Georgia, and Michael W. Feltz, MD, is an assistant professor at Augusta University in Augusta, Georgia.

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