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Departments of Epidemiology (M.D.D., C.L.M., N.R.P.) and Health Policy and Management (N.R.P.) and Center for Clinical Trials (M.D.D., C.L.M.), The Johns Hopkins University School of Hygiene and Public Health; Endocrine Cost-Effectiveness Study Unit (M.D.D., P.W.L., N.R.P.) and Divisions of Endocrinology and Metabolism (P.W.L.) and General Internal Medicine (N.R.P.), The Johns Hopkins University School of Medicine; and Welch Center for Prevention, Epidemiology and Clinical Research (N.R.P.), The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2223
Address correspondence and requests for reprints to: Neil R. Powe, M.D., The Johns Hopkins University, 2024 East Monument Street, Suite 2-600, Baltimore, Maryland 21205-2223. E-mail: npowe{at}jhmi.edu
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Abstract |
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Our data sources included MEDLINE, between January 1966 and May 1999, and review of references from relevant articles.
There were 1,786 published studies identified, 461 abstracts reviewed, 74 articles retrieved, 24 articles evaluated against predetermined entry criteria, and 13 studies systematically reviewed and abstracted.
All studies reported serum total cholesterol concentration changes during T4 treatment, 12 reported triglyceride changes, 10 reported high-density lipoprotein (HDL) cholesterol changes, and 9 reported low-density lipoprotein (LDL) cholesterol changes.
There were 247 patients in 13 studies. The mean decrease in the serum total cholesterol concentration was -0.20 mmol/L (-7.9 mg/dL), with a 95% confidence interval of -0.09 to -0.34. The decline in serum total cholesterol was directly proportional to its baseline concentration. Studies enrolling hypothyroid participants receiving suboptimal T4 doses reported significantly larger decreases in serum total cholesterol after thyroid-stimulating hormone normalization than studies enrolling previously untreated individuals with mild thyroid failure [-0.44 mmol/L (-17 mg/dL) vs. -0.14 mmol/L (-5.6 mg/dL), P = 0.05]. The change in serum LDL cholesterol concentration was -0.26 mmol/L (-10 mg/dL), with a 95% confidence interval of -0.12 to -0.41. Serum HDL and triglyceride concentrations showed no change.
These results, although based on fewer than 250 patients, suggest that T4 therapy in individuals with mild thyroid failure lowers mean serum total and LDL cholesterol concentrations. The reduction in serum total cholesterol may be larger in individuals with higher pretreatment cholesterol levels and in hypothyroid individuals taking suboptimal T4 doses. There do not seem to be significant effects of T4 on serum HDL or triglyceride concentrations.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsCommentReferences |
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Treatment with T4 sodium is often initiated for two reasons. First, therapy may prevent progression to the symptomatic stage of overt hypothyroidism, which otherwise occurs at a rate of about 5% per year in those with mild thyroid failure (6, 7, 8, 9, 10). Second, therapy may also reduce symptoms of thyroid hormone deficiency that have been shown to be present and reversible in about 25% of individuals with mild thyroid failure (11, 12, 13, 14). However, it has been less clear whether a relationship exists between mild thyroid failure and serum total, low-density lipoprotein (LDL), or high-density lipoprotein (HDL) cholesterol levels.
Despite various assessments of the literature, the relationship between mild thyroid failure and serum lipid levels is still ambiguous (15, 16, 17, 18). Part of the difficulty stems from the range of studies and study designs addressing the topic. Some cross-sectional studies suggest that serum cholesterol levels are significantly higher in individuals with mild thyroid failure than in euthyroid individuals (13, 19, 20, 21, 22), In other cross-sectional studies, the differences are not statistically significant (23, 24, 25). Still, other cross-sectional studies of hypercholesterolemic individuals report higher prevalences of mild or overt thyroid failure than in normocholesterolemic control groups (26, 27, 28, 29). Even in prospective studies, some authors consider participants to have mild thyroid failure at TSH levels that may be more indicative of overt hypothyroidism than mild thyroid failure (30, 31, 32)
Mild thyroid failure may be present for many years before overt hypothyroidism (33). Therefore, because there is a well-established relationship between an elevated serum cholesterol concentration and atherosclerotic vascular disease (34), knowing whether the treatment of mild thyroid failure with T4 has the potential to improve lipid profiles is important. Hence, the purpose of this review is to systematically evaluate available prospective studies, to estimate the effect of T4 therapy on serum lipids across the relevant studies, and to explore potential reasons for the variation in conclusions among these studies.
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Materials and Methods |
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We conducted a literature review and analysis of published studies providing measures of the effect of treating mild thyroid failure on serum cholesterol levels. To be included, a study had to meet the following six entry criteria: 1) the study must have been a prospective evaluation of the effect of levothyroxine therapy; 2) the mean pretreatment basal serum TSH concentration must have been above the upper limit of normal for the assay used in the study, but less than 20 mU/L; 3) individual patients with serum TSH levels between the upper limit of normal and 10 mU/L must have been included; 4) relevant lipoprotein data must have been provided for the subset of patients with mild thyroid failure if other patient types were included in the analysis; 5) the study must have included the mean serum TSH concentration both before and after T4 treatment; and 6) the study must have included the mean serum total cholesterol level with a variance estimate both before and after T4 treatment.
In the event that a study included data for subsets of patients stratified by TSH levels, data for the group with the lowest TSH concentrations consistent with the definition of mild thyroid failure (usually TSH 5 to 10 mU/L) were used.
Literature search
To identify the relevant published literature, we conducted a comprehensive, text-word MEDLINE search of both thyroid disease and cholesterol between January 1966 and May 1999. The references from these papers were used to find articles missed in the MEDLINE search. We also contacted many of the authors of papers to request data and information about other unidentified studies.
Evaluation of study design
Two reviewers (M.D.D. and N.R.P.) evaluated the studies using a
13-item checklist of factors related to study internal and external
validity (Table 1
). If an item was not
reported it was not considered to have been done. Discrepancies between
reviewers were resolved by agreement. A simple score was calculated by
assigning one point for each of the 13 items on the checklist.
Sub-scores were calculated for factors related to internal and external
validity.
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Changes in serum lipoprotein concentrations [total, LDL, and HDL cholesterol; triglycerides; apolipoprotein A; apolipoprotein B; and lipoprotein(a)] and their variances were abstracted from each study. If variances were not available, P values were abstracted. In all other cases, baseline and follow-up concentrations and variances were abstracted.
Analyses
The main results were calculated using both fixed and random
effects models (35). Serum lipoprotein changes were weighted according
to the reciprocal of their squared SE. (The main results
were also calculated using the sample size as the weight, and the
results were virtually the same.) In the fixed effects analyses,
homogeneity was assessed both overall and within subgroups using a
2 test. Using weighted ANOVA, the studies were
stratified according to individual items on the study design checklist.
Weighted linear regression was used to evaluate the relationship
between the baseline level of serum cholesterol and the change in serum
cholesterol. Publication bias was assessed using common graphical and
computational techniques. All statistical analyses and figures were
performed using S-PLUS 4.5 (Mathsoft, Inc., Seattle, WA) and
Microsoft Corp. Excel 97 (Microsoft Corp.,
Redmond, WA).
For each study without a control group, change was calculated as the mean difference between the final and pretreatment measurements for study participants. For each study with a control group, change was calculated as the difference between the two group mean differences. Hence, negative numbers reflect a decrease after initiation of therapy.
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Results |
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There were 1,786 studies identified using MEDLINE. Irrelevant articles were eliminated by inspection of the title, if possible (e.g. letters to the editor). Three authors reviewed abstracts (M.D.D., N.R.P., and P.W.L.) of the remaining 461 articles. The remaining 66 studies were retrieved, as were 9 additional citations discovered by reviewing references and communicating with investigators. Of the 75 retrieved studies, 44 nontreatment studies and 6 studies of overt hypothyroidism were eliminated. Of the 25 remaining studies of mild thyroid failure, 12 were excluded after examination against the entry criteria (36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47). The remaining 13 studies were used in the analyses (11, 12, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58).
Evaluation of study characteristics
No study fulfilled all 13 criteria related to internal and
external validity. Tables 2 and 3 show the overall number of criteria
fulfilled in each study, ranging from three to eight, with a median of
six. Sample sizes ranged from 7–33, with a median of 15. Only three
studies were randomized, all with placebo controls. All studies
enrolled at least 75% women, with six enrolling only women. Mean ages
in the studies ranged from 32–71 yr.
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Seven of the studies neither discussed losses to follow-up nor gave sufficient information from which this could be determined. Of the 127 participants in the remaining six studies, 14 were lost to follow-up. Only four of these individuals were reported to have symptoms that were potentially related to T4 treatment. Others were in the placebo arm of a study (n = 3), reported unrelated reasons for discontinuing (n = 4), or were not characterized (n = 3).
Total cholesterol
Figure 1A and Table 4 show the changes in the mean serum
total cholesterol concentration for each study. The serum total
cholesterol level declined after initiation of therapy by -0.20 mmol/L
with a 95% confidence interval (CI) of -0.09 to -0.34 (-7.9 mg/dL;
95% CI, -3.3 to -13) using a fixed effects model. However, the
2 test (P = 0.05) suggested
that the studies might be too dissimilar to combine. Because of this
heterogeneity, a random effects model was also used, which allowed
cholesterol changes to vary not only within each of the studies (as
reflected by the study SE), but also between
different studies. Using this approach, the mean change was not
appreciably different, -0.24 mmol/L (95% CI, -0.06 to -0.42).
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LDL cholesterol
Nine of the 13 studies reported serum LDL cholesterol data (Fig. 1B
and Table 4). In the fixed effects model, the mean LDL cholesterol
reduction was -0.26 mmol/L, with a 95% CI of -0.12 to -0.41 (-10
mg/dL; 95% CI, -4.0 to -16). The results were more heterogeneous
than would be expected by chance (P = 0.02). However,
the reduction was similar using a random effects model, -0.30 mmol/L
(95% CI, -0.01 to -0.54) after therapy.
HDL cholesterol
Ten of the 13 studies reported serum HDL cholesterol
concentrations (Fig. 1C and Table 4). There was an increase in HDL
cholesterol after therapy by 0.08 mmol/L, with a 95% CI of 0.04–0.13
(3.2 mg/dL; 95% CI, 1.6–4.9) in the fixed effects model. Although
statistically significant, the increase was driven primarily by one
study (53). Again, these results were more heterogeneous than would be
expected by chance (P < 0.001). However, the results
were similar, although nonsignificant, using a random effects approach,
0.02 mmol/L (95% CI, -0.09 to 0.12).
Triglycerides and apolipoproteins
Twelve of the 13 studies reported changes in the serum
triglyceride concentration (Fig. 1D). Using a fixed effects model, the
mean change was -0.01 (95% CI, -0.08 to 0.06). The test for
homogeneity was not rejected, indicating that the results were similar
across all of the studies (P = 0.65).
Six studies reported changes in the serum apolipoprotein B concentration. The average fixed effects decrease was -8.5 mg/dL (95% CI, -4.2 to -13), and the results were more heterogeneous than would be expected (P = 0.05). These same six studies reported changes in serum apolipoprotein A concentration: the average fixed effects increase was 1.1 mg/dL (95% CI, -3.6 to 5.8) and homogeneity was not rejected (P = 0.27). Only one study (51) examined the concentration of serum lipoprotein(a) and reported a slight, nonsignificant increase.
Subgroups of studies
The random effects model is one method of addressing the heterogeneity of the results across studies. However, because the fixed and random effects did not yield very different results, we explored the presence of systematic variability across studies (i.e. differences among studies related to the study characteristics) using the fixed effects model. When the studies were divided into subgroups based on study characteristics, some of the fixed effects model heterogeneity was reduced.
Inadequately controlled hypothyroidism
Two types of mild thyroid failure patients were enrolled in the 13 studies: patients with untreated mild thyroid failure (mild patients) and patients with a history of overt hypothyroidism, but whose T4 dose was not sufficient to normalize the serum TSH level (overt patients). Stratifying the studies according to these two types of patients created two statistically distinct groups (P = 0.05). The change in the serum total cholesterol concentration was much higher in the overt patient studies (-0.44 mmol/L; 95% CI, -0.18 to -0.70) than in the mild patient studies (-0.14 mmol/L, 95% CI, -0.01 to -0.28). However, the heterogeneity within the mild patient studies was of borderline significance (P = 0.07), suggesting that additional factors might be associated with the change in serum cholesterol concentration within this group.
Internal validity
Studies that incorporated four or more (of eight) design factors related to internal validity had a nonsignificant reduction in mean serum total cholesterol concentration (-0.04 mmol/L; 95% CI, -0.21 to 0.12), whereas the remaining studies had a larger reduction of -036 mmol/L (95% CI, -0.52 to -0.20). These two groups were significantly different (P = 0.008).
Other subgroups
The three randomized trials were compared with the uncontrolled studies but the two groups were not statistically different. Dividing the studies into groups according to the average age of participants, participant pretreatment TSH level, participant final TSH level, overall study score, gender representation in the study, and use of free T4 testing for diagnosis did not divide the studies into statistically different groups.
Baseline serum total cholesterol concentration
The change in serum total cholesterol concentration and its
initial level (Fig. 2) were correlated
(r = 0.55). Because a change from baseline and the baseline value
itself can be statistically correlated in the absence of a true
association, the correlation between the sum of the pretreatment and
final cholesterol levels and their difference was calculated and found
to be similar (0.43) (59). Using weighted regression, the decrease in
serum total cholesterol concentration was 0.04 mmol/L larger
(i.e. -0.04 mmol/L; 95% CI, -0.08 to 0) for every
10-mg/dL increase in the baseline concentration. When controlling
instead for studies that enrolled overt patients (see definition above)
(50, 51) the slope increased to -0.07 mmol/L (95% CI, -0.11 to
-0.02).
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Dividing the sample into three mutually exclusive groups produced results similar to the regression analyses for the serum total cholesterol level, creating three statistically distinct groups: 1) studies that enrolled individuals with a history of overt hypothyroidism showed a mean serum total cholesterol reduction of -0.44 mmol/L, with a 95% CI of -0.18 to 0.70 (-17 mg/dL; 95% CI -6.9 to 27); 2) studies that did not enroll overt patients but did enroll individuals with a mean baseline serum cholesterol level more than 6.2 mmol/L (240 mg/dL) showed a mean reduction of 0.37 mmol/L, with a 95% CI of -0.15 to -0.59 (-14 mg/dL; 95% CI, -5.7 to -23); and 3) studies that did not enroll overt patients but did enroll individuals with a mean baseline serum cholesterol level 6.2 mmol/L or less (240 mg/dL) showed a mean reduction of -0.02 mmol/L, with a 95% CI of -0.18 to 0.15 (-0.7 mg/dL; 95% CI, -7.1 to 5.7).
Results from excluded studies
The total cholesterol changes in the 11 excluded studies (from the 24 to which exclusion criteria were applied) ranged from -0.26 mmol/L to -2.40 mmol/L, with a median of -0.59 mmol/L (-23 mg/dL).
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Comment |
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Individuals with pretreatment total cholesterol levels over 240 mg/dL seem to achieve larger reductions in the concentration of serum cholesterol, as do hypothyroid individuals taking too small a dose of T4. This delineation is appealing because of its compatibility with current cholesterol screening guidelines that use 6.2 mmol/L as a cutoff. Furthermore, it provides an impetus to regularly monitor patients taking T4.
These total cholesterol reductions are smaller than those suggested by another review on this topic (-0.4 mmol/L) (15). However, only eight studies (62%) are common between the analyses. Although the previous analysis has been the only review available, it does not address several important issues. Our systematic review of the treatment of mild thyroid failure and its effect on serum lipid levels incorporates additional serum lipoprotein changes, accounts for the statistical assumptions necessary for analyzing these particular studies where the necessary variances are unavailable, and, most importantly, assesses the wide differences among the various studies on this topic. This last issue is important because of the inherent difficulty in explaining the disparate results published in the literature.
Factors affecting cholesterol change
The highly variable results across studies of mild thyroid failure have sparked debate about whether serum cholesterol concentrations can be reduced with T4 treatment. By systematically examining the characteristics among studies, it is possible to understand, and perhaps explain, much of the heterogeneity. One explanation is that there exists a relationship between the baseline concentration of serum total cholesterol and its change after the initiation of T4 therapy, especially when the results of studies enrolling patients with suboptimally treated hypothyroidism are included in a separate stratum. This hypothesis is indirectly supported by a randomized, controlled study that enrolled hypercholesterolemic patients with normal serum TSH levels and showed a significant total cholesterol reduction (-0.28 mmol/L) after T4 treatment, especially for individuals with high-normal serum TSH levels (-0.74 mmol/L) (47).
Also, suboptimally treated patients with hypothyroidism may achieve larger reductions in serum total cholesterol concentrations than individuals with mild thyroid failure. This difference may be related both to differences in relative circulating concentrations of T4 and T3 in these thyroid states and to different rates of T4-to-T3 conversion in the liver and pituitary. In mild thyroid failure, thyroidal T3 secretion is increased to compensate for falling T4 levels. In subjects with little or no remaining thyroid gland function (i.e. overt hypothyroidism) this compensation mechanism is not as robust (60). Hence, the response to serum T4 changes may be exaggerated. In addition, conversion of T4-to-T3 is greater in the pituitary than in the liver (61). As a result, at a given elevated TSH level, the effect of thyroid hormones in the liver, and on the LDL receptor in particular, may reflect a more severely hypothyroid state than exists in the pituitary. In combination, these lines of argument suggest that hypothyroid individuals on insufficient T4 therapy would have a greater serum cholesterol reduction for the same T4-induced suppression of TSH from comparably elevated TSH levels.
Limitations
Most of the studies did not include a control group. While adjustments were made for some potential confounders within these studies, the limited sample size makes simultaneous adjustment for more than two at a time problematic from a statistical viewpoint. In particular, these data cannot answer the question of whether there is an elevated level of serum TSH above which treatment is more likely to be associated with reductions in total or LDL cholesterol. Finding such thresholds requires more data than the 13 available observations. The ability to answer this kind of question is limited further because these studies describe the experiences of just 247 patients, mostly in nonrandomized designs. Larger, randomized studies would provide a firmer basis for widespread treatment recommendations and would allow for the exploration of clinically important hypotheses. Nevertheless, these studies represent the current evidence in the peer-reviewed literature on which clinicians must base their treatment decisions.
The reason for the relationship between the decrease in the serum total cholesterol level and the baseline level is uncertain. Possible explanations include statistical correlation between changes and baseline levels, regression to the mean within each study, and differences among studies in the control of other interventions (i.e. diet, exercise, and medications).
However, statistical correlation between changes and baseline levels
has been ruled out by finding a strong correlation between change and
the sum of baseline and follow-up serum cholesterol levels. Regression
to the mean within studies also may not be sufficient to explain the
relationship. Of the studies not enrolling previously hypothyroid
patients, the only one that enrolled individuals based on a single,
elevated cholesterol test (48) stands out from the rest in Fig. 2.
Because regression to the mean is likely to have contributed to the
large treatment effect in this particular study, that it stands out
from the others suggests that any effect of regression to the mean may
be small. Furthermore, three studies included control groups and would
not be expected to show regression to the mean.
Other participant behavioral factors that may have caused a decline in serum lipid concentrations may have been present in some studies. Some of the studies attempted to assess diet, exercise, weight changes, and medications, but this was not universal. When the studies were stratified by the score for internal validity, the results were significantly different between the groups: the studies that attempted to control extraneous factors potentially related to cholesterol changes showed no change in total cholesterol. Studies that were less meticulous showed greater changes. Therefore, differences in the study results may be related to the degree to which each study controlled lifestyle factors (medications, diet, and exercise), incorporated randomization and control groups in the design, and treated individuals carefully with regard to dosing and length of follow-up. However, inspection of the relationship between the internal validity score and cholesterol change does not reveal a graded association, making this explanation less convincing (plot not shown).
The potential for publication bias exists. It is entirely plausible that many small studies might have never been published, which could change the results of this review. However, because the range of sample sizes is so narrow, and because most studies did not report statistically significant results, publication bias may be less likely.
Implications of treatment
The benefits of T4 treatment have been analyzed in the context of a decision and cost-effectiveness analysis of screening for mild thyroid failure (62). In the decision model, screening was shown to be a favorable strategy because treatment yielded improvements in the symptoms associated with mild thyroid failure, prevented progression to overt hypothyroidism, and reduced serum cholesterol levels. And, although serum cholesterol reduction with T4 was modest (4.3%) in the model, it provided an important economic benefit by decreasing the need for more expensive lipid-lowering medications. Therefore, cholesterol reduction is an important aspect of T4 treatment, even though the benefit of reducing serum cholesterol on cardiovascular disease and mortality has not been clearly demonstrated in the population with the highest prevalence of mild thyroid failure (i.e. adults over age 65, especially women) (63).
One still needs to regularly monitor individuals taking T4 to minimize the potential for iatrogenic effects (16, 64). However, a trial of Ts treatment for individuals with both elevated serum TSH and cholesterol concentrations seems to be a reasonable strategy. The potential for modest reductions in serum total and LDL cholesterol levels coupled with the potential for reducing subtle symptoms of mild thyroid failure and preventing progression to hypothyroidism provides a sound basis for considering therapy. Furthermore, careful re-titration of the T4 dose in patients with hypothyroidism may also have beneficial effects on serum lipids and should not be ignored.
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Footnotes |
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Received January 24, 2000.
Revised April 12, 2000.
Accepted May 22, 2000.
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J. A. Franklyn, M. C. Sheppard, and P. Maisonneuve Thyroid Function and Mortality in Patients Treated for Hyperthyroidism JAMA, July 6, 2005; 294(1): 71 - 80. [Abstract] [Full Text] [PDF]
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M. B. Hapon, S. M. Varas, G. A. Jahn, and M. S. Gimenez Effects of hypothyroidism on mammary and liver lipid metabolism in virgin and late-pregnant rats J. Lipid Res., June 1, 2005; 46(6): 1320 - 1330. [Abstract] [Full Text] [PDF]
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N. Caraccio, A. Dardano, and F. Monzani Subclinical Thyroid Disease and Cardiovascular Disease JAMA, March 2, 2005; 293(9): 1059 - 1060. [Full Text] [PDF]
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S. Gullu, H. Sav, and N. Kamel Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism Eur. J. Endocrinol., March 1, 2005; 152(3): 355 - 361. [Abstract] [Full Text] [PDF]
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D. S. Cooper Thyroid Disease in the Oldest Old: The Exception to the Rule JAMA, December 1, 2004; 292(21): 2651 - 2654. [Full Text] [PDF]
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J. J. Diez and P. Iglesias Spontaneous Subclinical Hypothyroidism in Patients Older than 55 Years: An Analysis of Natural Course and Risk Factors for the Development of Overt Thyroid Failure J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4890 - 4897. [Abstract] [Full Text] [PDF]
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 W. J. Hueston and W. S. Pearson Subclinical Hypothyroidism and the Risk of Hypercholesterolemia Ann. Fam. Med, July 1, 2004; 2(4): 351 - 355. [Abstract] [Full Text] [PDF]
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F. Monzani, N. Caraccio, M. Kozakowa, A. Dardano, F. Vittone, A. Virdis, S. Taddei, C. Palombo, and E. Ferrannini Effect of Levothyroxine Replacement on Lipid Profile and Intima-Media Thickness in Subclinical Hypothyroidism: A Double-Blind, Placebo- Controlled Study J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2099 - 2106. [Abstract] [Full Text] [PDF]
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 M. Helfand Screening for Subclinical Thyroid Dysfunction in Nonpregnant Adults: A Summary of the Evidence for the U.S. Preventive Services Task Force Ann Intern Med, January 20, 2004; 140(2): 128 - 141. [Abstract] [Full Text] [PDF]
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M. I. Surks, E. Ortiz, G. H. Daniels, C. T. Sawin, N. F. Col, R. H. Cobin, J. A. Franklyn, J. M. Hershman, K. D. Burman, M. A. Denke, et al. Subclinical Thyroid Disease: Scientific Review and Guidelines for Diagnosis and Management JAMA, January 14, 2004; 291(2): 228 - 238. [Abstract] [Full Text] [PDF]
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 S. Fazio, E. A. Palmieri, G. Lombardi, and B. Biondi Effects of Thyroid Hormone on the Cardiovascular System Recent Prog. Horm. Res., January 1, 2004; 59(1): 31 - 50. [Abstract] [Full Text]
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A. R. Cappola and P. W. Ladenson Hypothyroidism and Atherosclerosis J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2438 - 2444. [Full Text] [PDF]
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 B. A Ineck and T. M. Ng Effects of Subclinical Hypothyroidism and its Treatment on Serum Lipids Ann. Pharmacother., May 1, 2003; 37(5): 725 - 730. [Abstract] [Full Text] [PDF]
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B. Biondi, E. A. Palmieri, G. Lombardi, and S. Fazio Effects of Subclinical Thyroid Dysfunction on the Heart Ann Intern Med, December 3, 2002; 137(11): 904 - 914. [Abstract] [Full Text] [PDF]
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N. Caraccio, E. Ferrannini, and F. Monzani Lipoprotein Profile in Subclinical Hypothyroidism: Response to Levothyroxine Replacement, a Randomized Placebo-Controlled Study J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1533 - 1538. [Abstract] [Full Text] [PDF]
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L. Wartofsky Update in Endocrinology Ann Intern Med, October 16, 2001; 135(8_Part_1): 601 - 609. [Full Text] [PDF]
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M. T. McDermott and E. C. Ridgway Subclinical Hypothyroidism Is Mild Thyroid Failure and Should be Treated J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4585 - 4590. [Full Text] [PDF]
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J. W. Chu and L. M. Crapo The Treatment of Subclinical Hypothyroidism Is Seldom Necessary J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4591 - 4599. [Full Text] [PDF]
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C. Meier, J.-J. Staub, C.-B. Roth, M. Guglielmetti, M. Kunz, A. R. Miserez, J. Drewe, P. Huber, R. Herzog, and B. Muller TSH-Controlled L-Thyroxine Therapy Reduces Cholesterol Levels and Clinical Symptoms in Subclinical Hypothyroidism: A Double Blind, Placebo-Controlled Trial (Basel Thyroid Study) J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4860 - 4866. [Abstract] [Full Text] [PDF]
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 D. S. Cooper Subclinical Hypothyroidism N. Engl. J. Med., July 26, 2001; 345(4): 260 - 265. [Full Text] [PDF]
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