You Take the High Road and I Take the Low Road, and You’ll Get to Normal Before Me
Abstract & Commentary
By Allan J. Wilke, MD, Residency Program Director, Associate Professor of Family Medicine, University of Alabama at Birmingham School of Medicine - Huntsville Regional Medical Campus, Huntsville. Dr. Wilke reports no financial relationship to this field of study.
Synopsis: For healthy patients without heart disease, starting levothyroxine at full dose is safe and shortens the time to a euthyroid state.
Source: Roos A, et al. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med. 2005;165:1714-1720.
Although it is standard teaching to recommend the "start low, go slow" approach when correcting hypothyroidism with levothyroxine (T4),1 this has not been studied prospectively. Roos and colleagues set out to remedy that. Screening all hypothyroid patients in their Rotterdam hospital from September 1999 to August 2002, they selected those whose disease had never before been diagnosed or treated and was due to an autoimmune disease (most likely Hashimoto disease). Serum thyrotropin (thyroid stimulating hormone or TSH) levels had to be > 4.2 mIU/L and free T4 (FT4) levels < 0.78 ng/dL. They explicitly excluded patients with known heart disease or who were taking heart medication. Other exclusion criteria were hypothyroidism secondary to postpartum thyroiditis, pregnancy, myxedema coma, and unwillingness to follow the study protocol.
A total of 75 patients were screened; 25 were excluded. Patients were stratified by TSH levels (50 mIU/L was the cutoff point) and randomized to either the low-dose group (T4 25 mg daily) or the full-dose group (T4 1.6 mg/kg daily). Each group had 25 subjects. T4 dosage was adjusted based on TSH and FT4 levels at every visit (initially every 4 weeks and, after 24 weeks, every 12 weeks) until the TSH and FT4 levels were in the normal range. Subjects and investigators were blinded to dosage by supplying all the medication in 1 mL aliquots of varying concentrations. At each visit, a physician calculated a clinical score based on signs and symptoms of hypothyroidism,2 and vital signs and an electrocardiogram were obtained. Subjects completed 2 questionnaires, one dealing with hypothyroid symptoms and the other a quality-of life (QOL) scale at the start of the study and at 12, 24, and 48 weeks. Initially, all subjects underwent a dobutamine echocardiogram and bicycle ergometry to assess for cardiac ischemia and exercise tolerance. The bicycle ergometry was repeated at 12 and 24 weeks.
The subjects were an average of 47 years old (range, 22-86) and predominantly female (78%). The 2 groups were similar at baseline with regard to body mass index (BMI), heart rate (HR), blood pressure (BP), and serum biochemical levels (thyroid hormones, lipid profile, creatine kinase, creatinine, and homocysteine). Bradycardia was observed in 43% of the full-dose group and 7% of the low-dose group. The dobutamine and exercise stress tests were all normal. The 2 groups only differed in role limits due to physical functioning (a QOL sub-score) with subjects in the full-dose group functioning better than the subjects in the low-dose group; Roos et al could not account for this difference. Subjects in the excluded group differed only in average age (62 years) when compared to the 2 study groups.
At the end of the study, the full-dose group was taking an average of 139 µg of T4 daily compared to 110 µg in the low-dose group; this was not statistically different. The full-dose group had average TSH, FT4, and T3 in the euthyroid rage at 4 weeks and the low-dose group at 16 weeks; this was statistically significant. Total cholesterol, LDL cholesterol, and homocysteine levels decreased in both groups with no significant difference. There was no difference in the clinical score, QOL scale, or the subjects’ own scores of hypothyroid symptoms at any point during the study with both groups showing improvement over baseline. There was no change in BMI, HR, or BP. Sub-group analysis based on TSH levels (above or below 50 mIU/L) failed to show a difference. There were no cardiac symptoms in any patient. Exercise tolerance improved in the full-dose group.
Commentary
In their introduction, Roos et al review the reason why we have been reluctant to start hypothyroid patients on full-dose replacement: the association of ischemic heart disease with hypothyroidism. They also argue why this association may be spurious and list the potential benefits of full-dose replacement (quicker resolution of symptoms and correction of biochemical markers). Their study did demonstrate the latter, but is a difference of 12 weeks (4 vs 16 weeks) clinically significant if the subjects did not notice a difference? An editorialist3 does not think so, and I (and Roos et al) partially agree. By design, this study excluded the very patients that we worry about, those with heart disease. The results can only be applied to otherwise healthy individuals with no known heart disease. "No known heart disease" does not exclude patients with silent ischemia. Roos et al were able to exclude those folks with dobutamine and exercise stress tests, an expensive proposition at best. The results do not apply to individuals who have thyroid cancer or are hypothyroid secondary to surgery or radioiodine therapy; they should receive full-dose replacement.
So, if all we can offer our hypothyroid patients is a quicker return to normal of some biochemical levels, have we really done them any favors? Probably not. We could consider an intermediate dose of 50 or 75 µg daily in those patients with "no known heart disease", knowing that the resolution of symptoms is unlikely to occur much sooner than starting at 25 mg and titrating the dose every 4 weeks. "First, do no harm" continues to be good advice.
References
1. Toft AD. Thyroxine therapy. N Engl J Med. 1994;331: 174-180; Erratum in: N Engl J Med. 1994;331:1035.
2. Zulewski H, et al. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997;82:771-776.
3. Wartofsky L. Levothyroxine therapy for hypothyroidism: should we abandon conservative dosage titration? Arch Intern Med. 2005;165:1683-1684.
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