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The Starting Dose of Levothyroxine in Primary
Hypothyroidism Treatment
A Prospective, Randomized, Double-blind Trial
Annemieke Roos, MD; Suzanne P. Linn-Rasker, MD; Ron T. van Domburg, PhD;Jan P. Tijssen, PhD; Arie Berghout, MD, PhD, FRCP Background: The treatment of hypothyroidism with le-
parable in the full-dose (n = 25) vs the low-dose group vothyroxine is effective and simple; however, recom- (n=25): thyrotropin, 61 vs 48 mIU/L; free thyroxine, 0.56 mendations for the starting dose vary considerably. To vs 0.64 ng/dL (7.2 vs 8.2 pmol/L); and age, 47 vs 47 years.
our knowledge, the levothyroxine starting dose has never No cardiac complaints or events were documented dur- ing treatment or at bicycle ergometry at baseline, 12 weeks,or 24 weeks. Euthyroidism was reached in the full-dose Methods: We conducted a prospective, randomized,
vs the low-dose group in 13 vs 1 (4 weeks), 19 vs 3 (8 double-blind trial that compared a full starting levothy- weeks), 19 vs 9 (12 weeks), 20 vs 14 (16 weeks), 20 vs roxine dose of 1.6 µg/kg with a low starting dose of 25 18 (20 weeks), and 21 vs 20 (24 weeks) patients (P=.005).
µg (increased every 4 weeks) in patients with newly di- However, signs and symptoms of hypothyroidism and agnosed cardiac asymptomatic hypothyroidism. Safety was quality of life improved at a comparable rate.
studied by documenting cardiac symptoms and events,and efficacy was studied by monitoring thyrotropin and Conclusion: A full starting dose of levothyroxine in car-
free thyroxine levels and by assessing improvement of diac asymptomatic patients with primary hypothyroid- signs and symptoms and quality of life.
ism is safe and may be more convenient and cost- Results: Seventy-five consecutive patients were en-
effective than a low starting dose regimen.
rolled, of whom 50 underwent randomization. At base-line, the severity of hypothyroidism and age were com- Arch Intern Med. 2005;165:1714-1720 PRIMARYHYPOTHYROIDISMISA mostcommonlyprescribeddrugs,seems
effective and simple, recommendations for the starting dose of levothyroxine vary con- siderably: from 50 µg to a full replace- ment dose of 1.6 or 1.7 µg/kg in healthy symptoms of fatigue, weight gain, cold in- from 25 to 50 µg/d in older patients and tolerance, and constipation. Fatigue, one of ease.8-13 The safety and efficacy of differ- ent initial doses of levothyroxine have, to toms,2 and diastolic dysfunction3 can all lead our knowledge, never been studied pro-spectively. Moreover, in daily practice, For editorial comment
see page 1683
of “start low and go slow” irrespective of Author Affiliations:
age or patient. This dogma is based on the Department of InternalMedicine, Medical Centre to an impaired quality of life in patients with association of hypothyroidism with ische- mic heart disease.14,15 Interestingly, and in contradiction to this dogma, high doses of teinemia, and arterial hypertension occur creased risk of premature atherosclerotic Centre, Amsterdam(Dr Tijssen), the Netherlands.
Financial Disclosure: None.
dothyronine (T3) in the treatment of such (REPRINTED) ARCH INTERN MED/ VOL 165, AUG 8/22, 2005 2005 American Medical Association. All rights reserved.
severely ill patients, fatal outcome has been reported.9 to have a constant volume of medication for each patient at ev- Several case series and retrospective studies, dating back ery moment. The liquid formulation of levothyroxine was stable; 4 to 6 decades, have shown considerable variability in the quality after 1 year was unchanged. Two-milliliter syringes the cardiac responses of patients with hypothyroidism were supplied to the patients, and the dose in 1 mL ranged from to thyroid hormone therapy, ranging from precipitating 25 to 200 µg of levothyroxine. Each patient took a volume of 1mL/d. Levothyroxine medication was taken at bedtime, and no acute coronary syndromes in patients without previous other medication was taken at the same time. The study proto- cardiac symptoms14,17 to controlling or even abolishing col was approved by the local ethical committee.
preexisting angina.17,18 These studies can be criticized forbeing retrospective, cross-sectional, or uncontrolled; for having small numbers of patients; or for using desic-cated thyroid preparations that contain differing and there- Serum thyrotropin levels (reference range, 0.4-4.2 mIU/L), T3 fore unpredictable amounts of both levothyroxine and levels (reference range, 84.42-162.34 ng/dL [1.3-2.5 nmol/ T3. Levothyroxine is converted into T3 by type 1 deio- L]), and FT4 levels (reference range, 0.78-1.79 ng/dL [10-23 dinase in the liver.19 The evidence for local deiodination pmol/L]) were determined by a chemiluminescent enzyme im- munoassay (ACS 180; Bayer Diagnostics, Tarrytown, NY). Total dinase20,21 and the increased expression of type 2 deio- cholesterol (reference range, 96.7-251.3 mg/dL [2.5-6.5 mmol/ dinase in the mouse heart during hypothyroidism22 could L]), cholesterol subfractions (high-density lipoprotein choles- indicate mechanisms of adaptation in case of low or high terol; reference range, 38.7-69.6 mg/dL [1.0-1.8 mmol/L]; low- density lipoprotein cholesterol; reference range, 58.0-174.0 mg/dL [1.5-4.5 mmol/L]; and triglycerides; reference range, 0.0- Most reviews report a period of 4 to 6 months before 177.2 mg/dL [0.0-2.0 mmol/L]), creatine phosphokinase (ref- normalization of plasma thyrotropin and free thyroxine erence range, 11-200 U/L), and creatinine (reference range, 0.45- (FT4) levels is attained.8-12 A more rapid normalization 0.90 mg/dL [40-80 µmol/L] in women and 0.51-1.02 mg/dL could be of great benefit to patients with hypothyroid- [45-90 µmol/L] in men) were measured with a Hitachi 911 ana- ism regarding the reduction of cardiac risk factors, im- lyzer (Tokyo, Japan). Homocysteine (reference range, Ͻ2.03 provement of quality of life, and being less cumbersome mg/L [Ͻ15 µmol/L]) was measured by high-performance liq- for regular visits to the clinics. However, the efficacy and safety of different initial doses of levothyroxine have sur-prisingly never been studied prospectively in patients with CLINICAL SCORE AND QUESTIONNAIRES
primary hypothyroidism. This prompted us to comparea full initiating treatment dose of levothyroxine (1.6 µg/ A clinical score of hypothyroidism25 was completed on each visit kg)23 with the classic approach of “start low and go slow” (every 4 weeks during the first 24 weeks of treatment and every in a prospective, randomized, double-blind study. The 12 weeks thereafter) by a blinded physician (A.B.). The 12 symp- aim of the study was to prove that restoration of plasma toms and signs included dry skin, hoarseness, paresthesia, di-minished sweating, constipation, impaired hearing, weight gain, thyrotropin and FT4 levels within the normal reference delayed ankle reflex, cold skin, slow movements, periorbital puffi- range can be performed with a straightforward high- ness, and coarse skin. The symptoms and signs were quantified dose regimen without any increased risk of major ad- as 1 point, meaning present,or 0 points, meaning absent. Two questionnaires were obtained at 0, 12, 24, and 48 weeks. Thisinterval of 12 weeks was chosen to minimize recall bias. The first questionnaire assessed 10 symptoms of hypothyroidism: lack ofenergy, dry skin, constipation, aches and pains, cold intoler-ance, poor memory, depression, weight gain, tiredness after wak- STUDY PARTICIPANTS
ing up, and feeling down.26 Patients scored these symptoms as1, indicating not present; 2, hardly present; 3, present; or 4, se- All patients with hypothyroidism who presented to our hospi- verely present. The second questionnaire was a general quality- tal between September 1999 and August 2002 were screened for of-life questionnaire (the RAND 36-Item Health Survey ques- inclusion. Of these patients, only those with first diagnosed, un- tionnaire27) that concerned 8 scales: physical functioning, social treated primary autoimmune hypothyroidism (serum thyrotro- functioning, role limitations (physical problems), role limita- pin level Ͼ4.2 mIU/L and FT4 levelϽ0.78 ng/dL [Ͻ10 pmol/L]) tions (emotional problems), mental health, vitality, pain, and gen- were included. Patients with a history of cardiac disease or those eral health perception. Scores per scale ranged from 0 to 100, taking cardiac medication, such as ␤-blockers, were excluded.
the highest score indicating the best state of health.
Informed consent was obtained from each patient.
CARDIAC ASSESSMENTS
TREATMENT
At every visit, body weight and continuous pulse rate and blood Patients were randomly assigned to either a high starting levo- pressure in the resting state were measured by a research nurse, thyroxine dose of 1.6 µg/kg or a low dose of 25 µg. Randomiza- and an electrocardiogram (ECG) was acquired. All 12-lead ECGs tion was stratified according to serum thyrotropin level below were analyzed by 1 cardiologist and scored according to pre- or above 50 mIU/L. During treatment, the levothyroxine dos- age of each patient was initially adjusted with increments of 25 At baseline, dobutamine stress echocardiography was per- µg every 4 weeks and from 24 weeks onward every 12 weeks formed as previously described29,30 and analyzed by 2 experi- according to serum thyrotropin and FT4 levels, with serum thy- enced independent and blinded cardiologists. Myocardial is- rotropin and FT4 levels within the normal reference range (eu- chemia was defined as the development of new or worsening thyroidism) as a target of treatment. The medication was pre- of preexisting wall motion abnormalities in at least 2 seg- pared in liquid form24 in 8 different strengths (25-200 µg/mL) (REPRINTED) ARCH INTERN MED/ VOL 165, AUG 8/22, 2005 2005 American Medical Association. All rights reserved.
Table 1. Baseline Characteristics of the Included and Excluded Patients
Included
Included
P Value
P Value
Characteristic
Full-Dose Group
Low-Dose Group
(Full vs Low)
Excluded
(Included vs Excluded)
Systolic blood pressure, mean ± SD, mm Hg Diastolic blood pressure, mean ± SD, mm Hg Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); FT4, free thyroxine; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NA, not available; T3, total triiodothyronine.
SI conversion factors: To convert FT4 to picomoles per liter, multiply by 12.87; T3 to nanomoles per liter, multiply by 0.0154; cholesterol components to millimoles per liter, multiply by 0.0259; triglycerides to millimoles per liter, multiply by 0.0113; creatinine to micromoles per liter, multiply by 88.4; homocysteineto micromoles per liter, multiply by 7.397.
A bicycle ergometer (Lode, Groningen, the Netherlands) was toris: n = 5), medication for long-standing hypertension used for the bicycle ergometry, which was performed as pre- (n = 5), unwillingness to participate in the study (n = 6), viously described.30 During exercise, continuous ECG moni- hypothyroidism due to postpartum thyroiditis (n = 2), toring was performed. Ischemia was defined as an ST depres- pregnancy (n = 1), myxedema (pre)coma (n = 1), or un- sion of 0.1 mV or more, according to the criteria described by willingness to follow the study protocol (n = 1).
Roelandt et al.31 Bicycle ergometry was also used to assess ex- Baseline characteristics of the included and excluded ercise tolerance. Therefore, at the start of ergometry, a targetperformance was assessed for each patient, depending on height, patients are given in Table 1. None of the patients had
age, and sex, according to general accepted criteria. Exercise minimal hypothyroidism with a thyrotropin level less than tolerance was determined by dividing the maximum achieved 10 mIU/L. The echocardiogram at rest showed normal workload per patient by his or her target performance. An ex- wall motions in all patients. None of the patients had si- ercise performance of less than 80% was considered insuffi- lent ischemia. During both dobutamine stress testing and cient. Bicycle ergometry was performed at baseline and re- exercise testing, none of the patients complained of an- gina pectoris. Dobutamine stress echocardiography didnot demonstrate wall motion abnormalities signifying STATISTICAL ANALYSIS
All analyses were performed according to the intention-to-treat approach, although no crossovers occurred after random- LEVOTHYROXINE DOSAGE
ization. Data are expressed as mean ± SD. Statistical compari-sons (differences between full and low starting dose groups) The levothyroxine dose in the full-dose group was in- were performed by means of a 2-group unpaired Wilcoxon rank creased slightly from a mean of 128 µg (1.6 µg/kg) at base- sum test. An unpaired Kruskal-Wallis analysis of variance with line to a mean of 139 µg (1.7 µg/kg) at 48 weeks; in the repeated measures was performed to detect differences over time.
low-dose group, the dose was increased until 16 weeks PϽ.05 was considered statistically significant.
of treatment, after which it remained unchanged, with a
mean of 110 µg (1.5 µg/kg) (Figure 1; full-dose vs low-
STUDY POPULATION
OUTCOMES
Seventy-five consecutive patients with primary hypothy- Laboratory Parameters
roidism were screened for inclusion, of whom 50 under-went randomization, 25 patients to the high-dose group At 4 weeks, median serum thyrotropin level had nor- (thyrotropin Ͻ50 mIU/L: n=11; thyrotropin Ͼ50 mIU/L: malized in the full-dose group (high-dose vs low-dose n = 14) and 25 patients to the low-dose group (thyrotro- group: 4.2 vs 26.7 mIU/L; P = .005), whereas in the low- pin Ͻ50 mIU/L: n=14; thyrotropin Ͼ50 mIU/L: n=11).
dose group, the median thyrotropin level normalized only Twenty-five patients were excluded because of a history at 16 weeks. A similar significant difference between the of cardiac disease (myocardial infarction: n=4; angina pec- full-dose and low-dose groups with regard to the nor- (REPRINTED) ARCH INTERN MED/ VOL 165, AUG 8/22, 2005 2005 American Medical Association. All rights reserved.
No. of Patients With Normal Thyrotropin and FT4 13 (128) 19 (126) 19 (124) 20 (126) 20 (130) 21 (130) Figure 2. Mean total cholesterol and low-density lipoprotein cholesterol
(LDL-C) levels for the full-dose and low-dose groups during treatment. P = .8
and P = .6 for total cholesterol and LDL-C, respectively, for the full-dose
Figure 1. Thyroid parameters (median thyrotropin, mean free thyroxine
group vs low-dose group. To convert total cholesterol and LDL-C to [FT4], and mean total triiodothyronine [T3]) during treatment. Error bars millimoles per liter, multiply by 0.0259.
indicate SD. PϽ.01 for the full-dose group vs low-dose group. To convertFT4 to picomoles per liter, multiply by 12.87; T3 to millimoles per liter,multiply by 0.0154.
mIU/L and in those with a serum thyrotropin level lessthan 50 mIU/L, but no difference in outcome was found.
malization of the mean FT4 and T3 plasma levels was ob- Body weight, heart rate, and blood pressure did not change Initially, total and low-density lipoprotein choles- terol levels decreased over time with no appreciable dif- ference between the 2 groups; thereafter, no change oc-
curred (Figure 2). Serum high-density lipoprotein
No palpitations, angina pectoris, or other cardiac events cholesterol and triglyceride levels did not change over were documented in any of the patients during treat- time. Serum homocysteine levels decreased in the full- ment. No interim dose adjustments because of adverse dose group from 1.45 to 1.16 mg/L (10.7-8.6 µmol/L) and effects were necessary, and in none of the patients did in the low-dose group from 1.46-1.37 mg/L (10.8-10.1 we have to interrupt the study protocol. None of the pa- µmol/L) (P = .2). Median serum creatine kinase levels tients had anginal complaints during bicycle ergometry at 12 and 24 weeks, and continuous ECG monitoring didnot demonstrate ischemia or serious arrhythmias.
Clinical Score, Questionnaires,
At baseline, sinus bradycardia was observed in 43% and Anthropometric Parameters
of patients in the full-dose group and 7% in the low-dose group. At 8 weeks, sinus bradycardia was observed The clinical score and the symptoms of hypothyroidism in 17% and 25% of patients in the full-dose and low- decreased until 24 weeks of treatment at a comparable dose groups, respectively. Prolongation of the QT inter- rate in both groups (Figure 3). The quality of life im-
val corrected for heart rate (QTc Ͼ0.43 milliseconds) was proved on all 8 scales for both groups (Table 2), with
observed in 10% of patients in both groups at baseline.
no significant difference between the full-dose and the At 8 weeks, prolonged QTc interval was observed in 4% low-dose groups. At baseline, the 2 groups differed for of patients in the full-dose group and 13% of patients in the role limits due to physical functioning. We per- the low-dose group. Exercise performance improved in formed a subgroup analysis concerning the responses in the full-dose group from 92% to 102% (PϽ.001) and re- patients with a serum thyrotropin level greater than 50 mained unaltered in the low-dose group.
(REPRINTED) ARCH INTERN MED/ VOL 165, AUG 8/22, 2005 2005 American Medical Association. All rights reserved.
older; hence, the mean age of included patients was rela-tively young. However, the included patients repre- Since we did not observe any cardiac adverse events, we sented a wide age spectrum (range, 22-86 years; median believe that it is safe to treat patients with hypothyroid- age, 46 years). None of the included patients had asymp- ism with a full replacement dose of levothyroxine (1.6 tomatic cardiac ischemia demonstrated by dobutamine µg/kg) if they have no history of ischemic heart disease.
stress echocardiography or bicycle ergometry.30 The preva- Such a treatment strategy is more practical and conve- lence of asymptomatic or silent coronary artery disease nient for the patients and will make outpatient control in patients with untreated primary hypothyroidism is un- known, but our findings suggest that it might be very low.
We excluded patients with a cardiac history from this Although bicycle ergometry may have limited sensitiv- study. Therefore, the findings of our study are possibly ity and specificity for detection of coronary artery dis- not applicable to patients with coronary artery disease.
ease (55%-70% and 85%-95%, respectively32), with low- The patients who were excluded from our study were est sensitivity in young women, we also performeddobutamine stress echocardiography in our patients,which is the most specific noninvasive test for assessingcoronary artery disease, with a sensitivity and specific- Our results show that when levothyroxine was given in a full replacement dose of 1.6 µg/kg, it took approxi- mately 4 weeks for serum thyrotropin and FT4 levels tonormalize. This is more rapid than stated in most re- ports.8-12 On the other hand, Spencer et al33 showed thatwhen levothyroxine was given in a single high dose of 2 mg intravenously, thyrotropin levels declined toward nor- mal within 5 days. Several explanations exist for the ob- served buildup of a steady state in our patients. First, only approximately 75% of oral levothyroxine is absorbed.34 Sec- ond, in patients with hypothyroidism, serum T3 is de-rived from T4 by deiodination; therefore, serum T4 levels have to be higher than in patients without thyroid dis-ease.23 Third, the half-life of serum levothyroxine in pa- tients with hypothyroidism is approximately 10 days; therefore, it takes approximately 5 to 6 weeks to reachsteady-state T4 levels.12 At the end of the study, serum thyrotropin levels had not normalized in all patients. In- adequate treatment has been found to occur in a sub- stantial percentage of patients treated for hypothyroid- ism.35 The explanation in our patients could be suboptimal compliance and varying intestinal absorption of levothy-roxine. The small but significant difference in final le- vothyroxine dose between the 2 groups is unexplained.
A difference between the 2 randomized groups in com- pliance or intestinal absorption of levothyroxine seemsimprobable.
Figure 3. Mean symptoms and clinical scores for full-dose and low-dose
In the reviews on treatment of hypothyroidism, most groups during treatment. P = .4 and P = .8 for the symptoms score andclinical score, respectively, for the full-dose vs low-dose group.
authors state that the period of normalization of the clini- Table 2. Quality-of-Life Scores During Treatment in 8 Categories From the RAND 36-Item Health Survey Questionnaires*
Full-Dose Group by Week
Low-Dose Group by Week
P Value
(Full vs Low Dose)
(REPRINTED) ARCH INTERN MED/ VOL 165, AUG 8/22, 2005 2005 American Medical Association. All rights reserved.
cal scores, symptoms, and quality of life is approxi- mately3 to 6 months.9,36 However, the effects of treat-ment of hypothyroidism on quality of life have been 1. Esposito S, Prange AJ, Golden RN. The thyroid axis and mood disorders: over- systematically studied only in patients with subclinical hy- view and future prospects. Psychopharmacol Bull. 1997;33:205-217.
pothyroidism.37 These studies showed conflicting results 2. Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromus- and included patients with a variety of causes of hypothy- cular findings in thyroid dysfunction: a prospective clinical and electrodiagnos- roidism, and methods were not always clearly described.
tic study. J Neurol Neurosurg Psychiatry. 2000;68:750-755.
3. Tielens ET, Pillay M, Storm C, Berghout A. Changes in cardiac function at rest For these reasons, these studies could not be compared before and after treatment in primary hypothyroidism. Am J Cardiol. 2000; with the results of our study. The absence of a more rapid normalization of the clinical scores, symptoms, and qual- 4. Diekman T, Demacker PNM, Kastelein JJP, Stalenhoef AFH, Wiersinga WM.
ity of life in the high starting dose group is not well un- Increased oxidizability of low-density lipoproteins in hypothyroidism. J Clin En- docrinol Metab. 1998;83:1752-1755.
5. Fommei E, Iervasi G. The role of thyroid hormone in blood pressure homeosta- spond to tissue T4 levels, as has been shown in rat models,38 sis: evidence from short-term hypothyroidism in humans. J Clin Endocrinol Metab.
and that most tissues need a longer time for recovery from long-lasting hypothyroidism. Alternatively, the fact that 6. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998; we did not observe a difference in the rate of improve- 7. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endo- ment in the 2 groups could be explained by adaptations crinol Metab. 2003;88:2438-2444.
of the metabolism of thyroid hormones in states of hypo- 8. Lindsay RS, Toft AD. Hypothyroidism. Lancet. 1997;349:413-417.
thyroidism. The local production of T3 from T4 by type 2 9. Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid iodothyronine deiodinase, particularly in the brain, is in- disease. Ann Intern Med. 1993;119:492-502.
creased during hypothyroidism, whereas the degrada- 10. Toft AD. Thyroxine therapy. N Engl J Med. 1994;331:174-180.
11. Singer PA, Cooper DS, Levy EG, et al. Treatment guidelines for patients with hy- tion of T3 by type 3 iodothyronine deiodinase is reduced, perthyroidism and hypothyroidism. JAMA. 1995;273:808-812.
thus prolonging the residence time of T3.39 However, we 12. Nieuwenhuijzen Kruseman AC, Geelhoed-Duijvesteijn PH. Substitutie therapie bij might also have missed a more rapid normalization be- hypothyreoidie. Ned Tijdschr Geneeskd. 1987;131:1803-1807.
cause the questionnaires were not repeated until 12 weeks 13. Roberts CGP, Ladenson PW. Hypothyroidism Lancet. 2004;363:793-803.
14. Smyth CJ. Angina pectoris and myocardial infarction as complications of myx- edema: with especial reference to the danger of treatment with thyroid preparations.
Our study supports the recommendation of a full re- placement starting dose of levothyroxine of 1.6 µg/kg in 15. Becker C. Hypothyroidism and atherosclerotic heart disease: pathogenesis, medi- healthy adult patients younger than 65 years.9 More- cal management, and the role of coronary artery bypass surgery. Endocr Rev.
over, our study also provides evidence that it is safe to treat patients older than 65 years with hypothyroidism 16. Ridgway EC, McCammon JA, Benotti J, Maloof F. Acute metabolic responses in myxedema to large doses of intravenous L-thyroxine. Ann Intern Med. 1972; with a full replacement dose of levothyroxine if they have no history of ischemic heart disease. We believe that by 17. Keating FR, Parkin TW, Selby JB, Dickinson LS. Treatment of heart disease as- adopting such a policy, the need for frequent biochemi- sociated with myxedema. Prog Cardiovasc Dis. 1961;3:364-381.
cal and clinical monitoring implicit in the “start low and 18. Levine HD. Compromise therapy in the patients with angina pectoris and hypo- go slow” alternative is obviated. It will further enhance thyroidism: a clinical assessment. Am J Med. 1980;69:411-417.
19. Leonard JL, Visser TJ. Biochemistry of deiodination. In: Hennemann G, Dek- compliance and make outpatient control more cost- ker M, eds. Thyroid Hormone Metabolism. New York, NY: Marcel Dekker; effective and convenient for the patients. Our study re- sults apply only to patients without suspected silent is- 20. Salvatore D, Bartha T, Harney JW, Larsen PR. Molecular, biological and bio- chemia. Therefore, it is not known what the starting dose chemical characterization of the human type 2 selenodeiodinase. Endocrinology.
1996;137:3308-3315.
should be in patients with hypothyroidism who have car- 21. Croteau W, Davey JC, Galton VA, St Germain DL. Cloning of the mammalian type diac disease, but it seems prudent to start at a lower dose.
II iodothyronine deiodinase: a selenoprotein differentially expressed and regu-lated in human and rat brain and other tissues. J Clin Invest. 1996;98:405-417.
Accepted for Publication: March 7, 2005.
22. Wagner MS, Morimoto R, Dora JM, Benneman A, Pavan R, Maia AL. Hypothy- Correspondence: Arie Berghout, MD, PhD, FRCP, De-
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partment of Internal Medicine, Medical Centre Rijnmond- 23. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH.
Zuid, Groene Hilledijk 315, 3075 EA, Rotterdam, the Replacement dose, metabolism, and bioavailability of levothyroxine in the treat- ment of hypothyroidism. N Engl J Med. 1987;316:764-770.
Previous Presentation: This study was presented at the
24. Trantow T, Herzog R, Gegenheimer L, Lücker PW. A new method for the deter- 85th Annual Meeting of the Endocrine Society; June, 21, mination of the bioavailability of thyroid hormone preparations. Methods FindExp Clin Pharmacol. 1994;16:133-140.
2003; Philadelphia, Pa; and at the Annual Meeting of the 25. Zulewski H, Müller B, Exer P, Miserez AR, Staub J-J. Estimation of tissue hypo- European Thyroid Association; October 22, 2003; Ed- thyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997;82:771-776.
Acknowledgment: We are grateful to Ineke Jongste,
26. Lazarus JH, Hall R, Othman S, et al. The clinical spectrum of postpartum thyroid RN, for excellent nursing service at our clinics, Stieneke disease. QJM. 1996;89:429-435.
27. Van der Zee KI, Sanderman R. Het Meten van de Algemene Gezondheidstoe- K. Zoet-Nugteren, MD, for analyzing the dobutamine stand met de RAND-36, een Handleiding. Groningen, the Netherlands: Noordelijk stress echocardiograms, Jacobus Ligthart, MD, for sur- Centrum voor Gezondheidsvraagstukken, Rijks Universiteit Groningen; 1993.
veillance of the randomization procedure, Dennis J.
28. Fisch C. Electrocardiography and vectorcardiography. In: Braunwald E, ed. Heart Theunissen, pharmacist, for the preparation of the levo- Disease: A Textbook for Cardiovascular Medicine. 4th ed. Philadelphia, Pa: WB thyroxine study medication, and Theo J. Visser, PhD, 29. Geleijnse ML, Fioretti PM, Roelandt JRTC. Methodology, feasibility, safety and and Petros Perros, MD, for their critical review of the diagnostic accuracy of dobutamine stress echocardiography. J Am Coll Cardiol.
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30. Roos A, Zoet-Nugteren SK, Berghout A. Evaluation of cardiac ischaemia in car- 35. Canaris GJ, Manowitz NR, Mayor G, Rigdway EC. The Colorado disease preva- diac asymptomatic newly diagnosed untreated patients with primary lence study. Arch Intern Med. 2000;160:526-534.
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Errors in Data. In the Original Investigation by Russell
et al titled “Effects of Prehypertension on Admissions and
Deaths: A Simulation,” published in the October 25, 2004,
issue of the ARCHIVES (2004;164:2119-2124), an inad-
vertent error occurred in how the exercise and alcohol
consumption variables were handled in the simulation
model used to calculate the impact of prehypertension
and residual hypertension. This resulted in data errors
in Table 2 and Table 3 on page 2122 and subsequent er-
rors wherever these data were cited in the abstract and
the text. In addition, the column headings in Table 3
should have read “Change,” as these were absolute
changes, not percentage changes. Even though the main
finding of the study was essentially unchanged, correct-
ing the data errors completely would have required pub-
lication of an extensive correction, including republica-
tion of correct data points in the abstract and throughout
the text, along with republication of the corrected tables.
To present the findings as clearly as possible, the entire
corrected article now appears on the ARCHIVES Web site
in the October 25 issue (available at http://archinte
.ama-assn.org/cgi/content/full/164/19/2119), replacing the
incorrect version.
(REPRINTED) ARCH INTERN MED/ VOL 165, AUG 8/22, 2005 2005 American Medical Association. All rights reserved.
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rate of unexplained anemia. Blood. 2004;104:2263-2268.
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15. Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons.
5. Penninx BWJH, Pahor M, Cesari M, et al. Anemia is associated with disability and decreased physical performance and muscle strength in the elderly. J Am 16. Storring PL, Gaines Das RE. The International Standard for Recombinant DNA– Geriatr Soc. 2004;52:719-724.
Derived Erythropoietin: collaborative study of four recombinant DNA-derived eryth- 6. Chaves PHM, Ashar B, Guralnik JM, Fried LP. Looking at the relationship be- ropoietins and two highly purified human urinary erythropoietins J Endocrinol.
tween hemoglobin concentration and prevalent mobility difficulty in older wom- en: should the criteria currently used to define anemia in older people be 17. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM.
reevaluated? J Am Geriatr Soc. 2002;50:1257-1264.
Serum erythropoietin concentration in chronic renal failure: relationship to de- 7. Cesari M, Penninx BW, Laurentani F, et al. Hemoglobin levels and skeletal muscle: gree of anemia and excretory renal function Blood. 1979;54:877-884.
results from the InCHIANTI Study. J Gerontol A Biol Sci Med Sci. 2004;59: 18. McGonigle RJ, Boineau FG, Beckman B, et al. Erythropoietin and inhibitors of in vitro erythropoiesis in the development of anemia in children with renal disease.
8. Nissenson AR, Goodnough LT, Dubois RW. Anemia: not just an innocent bystander? J Lab Clin Med. 1985;105:449-458.
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19. Hsu C-Y, McCulloch CE, Curhan GC. Epidemiology of anemia associated with 9. McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and chronic renal insufficiency among adults in the United States: results from the renal insufficiency are independent risk factors for death among patients with Third National Health and Nutrition Examination Survey. J Am Soc Nephrol. 2002; congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol. 2002;13:1928-1936.
20. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney func- 10. Artz AS, Fergusson D, Drinka PJ, et al. Prevalence of anemia in skilled-nursing tion with anemia: the Third National Health and Nutrition Examination Survey home residents. Arch Gerontol Geriatr. 2004;39:201-206.
(1988-1994). Arch Intern Med. 2002;162:1401-1408.
11. Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW. The effect of age on cre- 21. Cumming RG, Mitchell P, Craig JC, Knight JF. Renal impairment and anemia in atinine clearance in men: a cross-sectional and longitudinal study. J Gerontol.
a population-based study of older people. Intern Med J. 2004;34:20-23.
22. Baracskay D, Jarjoura D, Cugino A, Blend D, Rutecki GW, Whittier FC. Geriatric 12. Kario K, Matsuo T, Nakao K. Serum erythropoietin levels in the elderly. Gerontology.
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Errors in Figure and Text. In the Original Investiga-
tion by Roos et al titled “The Starting Dose of Levothy-
roxine in Primary Hypothyroidism Treatment,” pub-
lished in the August 8/22 issue of the ARCHIVES (2005;
165:1714-1720), there were errors in Figure 1 and in the
text. In Figure 1, the lower row on the bottom should have
read “Low Dose” instead of “Full Dose.” In the second para-
graph of the “Safety” subsection, the first sentence should
have read “At baseline, sinus bradycardia was observed in
40% of patients in the full-dose group and 28% in the low-
dose group.”
(REPRINTED) ARCH INTERN MED/ VOL 165, OCT 24, 2005 2005 American Medical Association. All rights reserved.

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