Thyroid hormone has convenient pharmacokinetic properties, a high degree of effectiveness, and a small risk of adverse reactions. The majority of general and specialty practitioners routinely prescribe levothyroxine and only evaluate serum TSH levels. This results in 20% of patients receiving an inadequate dose and 20% given an excessive amount of medication [1
]. Most physicians initiate treatment with a dose at the lower end of the anticipated requirement of 1.6 µg/kg per day. Differences in management include initiation at the full dose versus titration up from a low dose, the addition of T3 in the presence of persistent symptoms, monitoring free T4 and free T3 as well as TSH, and treatment of patients with subclinical hypothyroidism. Even adequately treated hypothyroid patients have constitutional and neuropsychological symptoms and a decreased sense of well-being compared with euthyroid individuals.
It is well known that the magnitude of replacement or suppressive doses of levothyroxine is based on body weight and is affected by gender, weight, cause of hypothyroidism, other medications, comorbidities, diet, and etiology (malignancy vs. autoimmune disease). Estimates based on body weight range from 1.6 µg/kg to 2.56 µg/kg [116
]; however, patients may not fall within this range, especially those with persistent symptoms and other comorbidities. Illnesses including malignancies and those requiring critical care intervention not only can mask the symptoms, and hence the diagnosis, of hypothyroidism but also can affect thyroid hormone metabolism. Recent studies suggest body mass index (BMI) as the optimal tool, as opposed to weight, in determining the appropriate dose in patients after thyroidectomy. In this study, the standard weight-based replacement regimen failed to return the majority of patients to a euthyroid state by overdosing patients with a BMI <25 kg/m2
and underdosing patients with a BMI >30 kg/m2
]. Initiating therapy at the estimated full dose is effective in many patients; however, in patients at extremes of age, with more lean body mass, or with significant comorbidities, it may prove more efficacious to start at a lower dose and titrate up to the targeted dose while evaluating serum TSH and free thryoxine and T3 levels. Using T3 as the primary therapy may be warranted in the small subset of patients in whom levothyroxine has not been proven to alleviate symptoms and who can be compliant with multiple daily doses. Further studies with larger sample sizes and longer follow-up are necessary before its adoption in routine clinical practice. Combining T3 with levothyroxine is more common than single therapy, with some success noted in reported well-being; however, a meta-analysis of randomized controlled trials (RCTs) concluded no difference in effectiveness with combination therapy [120
]. Despite multiple RCTs showing the lack of benefit of combining the two medications, T3 is formulated to mimic normal physiologic profiles, hence the reported better outcomes by some patients.
Supplementing patients diagnosed with subclinical hypothyroidism has not been universally adopted. Despite testing and treatment being relatively inexpensive, safe, and effective, the clinical consequences are not considered important and reversible in a significant proportion of affected patients for experts to justify widespread screening and treatment [122
]. Both overt and subclinical hypothyroidism are associated with chronic diseases that are common in the general population, including cardiovascular disease, peripheral vascular disease, and obesity; however, treating patients with thyroid function abnormalities, even those with subclinical hypothyroidism, can potentially minimize the morbidity and mortality associated with these chronic diseases. T4 supplementation can prevent the progression to overt hypothyroidism, specifically in the elderly and in patients with autoimmune thyroiditis. Reduction of future cardiovascular disease is crucial, considering that even patients with mild disease have higher mean serum totals and LDL cholesterol concentrations, and subtle, reversible changes in myocardial function have been noted on echocardiography [123
]. Even though the higher risk of clinical cardiovascular disease has been noted, the cardiovascular benefit of thyroid hormone treatment has yet to be rigorously tested in an RCT. Last, several small controlled, double-blinded trials have shown improvements in patients’ symptoms and neuropsychological performance indices when compared with placebo; however, they have not been confirmed, and there is a lack of large prospective randomized trials [126
]. Subclinical hypothyroidism is common in the general population. There is a higher number of patients with raised TSH and thyroid antibodies who progress to overt hypothyroidism [129
]; however, patients who present with symptoms and elevated TSH without antibodies may warrant testing. One study demonstrated 3% of these patients progressing to overt hypothyroidism [130
]. No RCTs exist showing that treatment with levothyroxine decreases the incidence of cardiovascular events or mortality. There is expert support for treating patients with serum TSH of ≥10 mIU/L as well as women who are pregnant or intend to become pregnant and for a short-term trial for symptomatic patients with serum TSH <10 mIU/L [112