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Original Studies |
Division of Pharmacology (E.A.L., P.M.U.), Division of Endocrinology, Department of Internal Medicine (B.G.N.), Division of Endocrine Surgery, Department of Surgery (J.E.V.), Section for Medical Informatics and Statistics (O.N.), Department of Biochemical Endocrinology (A.A.), University Hospital of Bergen, N-5021 Bergen, Norway
Address all correspondence and requests for reprints to: Dr. Ernst A. Lien, Department of Biochemical Endocrinology, University Hospital of Bergen, N-5021 Bergen, Norway. E-mail: ernst.lien{at}ikb.uib.no
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Abstract |
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We conducted a longitudinal study on 17 patients who had undergone total thyroidectomy for thyroid cancer. During 6 weeks of discontinued T4 substitution before radioscintigraphy (phase I), they attained a hypothyroid state, which was reversed by resupplementation (phase II). Plasma tHcy, serum creatinine, serum and red blood cell folate, serum cobalamin, and serum cholesterol were determined at 2-week intervals throughout phases I and II.
There was a progressive and parallel increase in tHcy (mean, 27%), serum creatinine (37%), and serum cholesterol (100%) during phase I, and these values returned to the original level within 4–6 weeks after reinitiating T4 therapy. Serum and red blood cell folate levels showed only minor, but statistically significant, changes. In a bivariate model, serum creatinine and serum cholesterol were strongly associated with the changes observed in tHcy during short term hypothyroidism.
In conclusion, we found a transient increase in both plasma tHcy and serum cholesterol during short term iatrogenic hypothyroidism, and the tHcy response is probably mainly explained by concurrent changes in renal function. The increase in both plasma tHcy and serum cholesterol may confer increased cardiovascular risk in hypothyroid patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hypothyroidism is associated with high cholesterol and lipoprotein levels, which are normalized after thyroid hormone replacement (6, 7, 8). The atherogenic lipid profile in particular, but also other abnormalities (9, 10, 11), have been suggested to be responsible for the increased cardiovascular morbidity in hypothyroid patients (6, 7, 8).
Total homocysteine (tHcy) in plasma has recently been proposed as an independent risk factor for occlusive cardiovascular disease (12, 13). The plasma level is affected by several life-style and physiological factors and is elevated under conditions of impaired folate and cobalamin status and in renal failure (12).
We recently reported that plasma tHcy is influenced by thyroid status. Hypothyroid patients had higher plasma tHcy levels than healthy controls and hyperthyroid patients, but a tendency toward low tHcy in hyperthyroidism did not reach statistical significance (14). The heterogeneity of the study population with respect to age, vitamin status, and severity of disease (14) probably reduced the power of this cross-sectional investigation.
In the present work we further investigated the effect of thyroid status on alterations in plasma tHcy levels. We carried out a longitudinal investigation of patients who had undergone total thyroidectomy for thyroid cancer, and who attained an acute iatrogenic hypothyroid state during a transient stop of T4 supplementation before diagnostic 131I scintigraphy.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The patients included had undergone total thyroidectomy due to
thyroid cancer. Seventeen consecutive patients who discontinued thyroid
hormone supplementation before diagnostic 131I
scintigraphy were included. Their mean age was 49 yr (range, 28–78
yr), and 35% were males (Table 1
).
T4 supplementation was stopped for 5–6 weeks and
was resumed 2 days after 131I scintigraphy, with
a dose escalation over 2–3 weeks. All patients gave their informed
consent to participate in the study. Fasting blood samples were drawn
immediately before discontinuing supplementation (designated time point
-6 weeks) and thereafter at 2-week intervals (-4 and -2
weeks) until scintigraphy was carried out (time zero). This
period, from -6 to 0 weeks, is referred to as phase I. After
resumption of T4 supplementation, fasting blood
samples were drawn at 2-week intervals (2, 4, 6, and 8 to 10 weeks) for
up to 10 weeks. The period from 0 to 10 weeks is referred to as phase
II. We did not obtain complete blood sampling from all patients. Nine
patients were included from the time the supplementation was
discontinued, whereas 16 of the patients participated from the time of
restart of T4 replacement therapy (Table 1).
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The blood samples for tHcy determination [10 mL in ethylenediamine tetraacetate Vacutainer tubes (Becton Dickinson Vacutainer Systems Europe, Meylan, France)] were centrifuged within 30 min at 3000 x g for 5 min before analysis. Plasma tHcy levels were determined by a method based on high pressure liquid chromatography and fluorescence detection (15). The between-day precision (coefficient of variation) of the method is less than 3%.
Serum cobalamin was determined with a microparticle enzyme intrinsic factor assay run on an IMx system from Abbott Laboratories (Abbott Park, IL). Serum and red blood cell (RBC) folate were assayed using the Quantaphase folate radioassay produced by Bio-Rad Laboratories, Inc. (Hercules, CA). Cholesterol and creatinine were determined using the Technicon Chem 1 system (Technicon Instruments Corp., Tarrytown, NY).
TSH and T3 in serum were measured using the AutoDELFIA hTSH Ultra kit and AUTODELFIA T3 kit from Wallac, Inc. (Turku, Finland). The precision of the TSH assay, expressed as between-assay coefficient of variation, was 4.9% for samples between 0.5–8.3 mIU/L; that for the T3 assay was below 4.5% for values between 1.0–4.0 nmol/L.
Statistical analyses
To investigate the various determinants of plasma tHcy as well as the change in the tHcy level during the study period, analyses of covariance using an unbalanced repeated measure design allowing for missing values, were used (5V module in BMDP) (16). Analyses were performed separately for phase I and phase II, with time zero being the last time point of phase I and the first time point of phase II.
The change in tHcy over time was represented by a linear time trend, coded as 0, 1, 2, and 3 in phase I and 0, 1, 2, 3, 4, and 5 in phase II; thus, the estimated coefficients represent the change in tHcy relative to that at the previous visit. A quadratic or curve-linear term was also tested in some models. Because it did not improve the models, it is not included in the data presented.
In the various models, several structural forms of the within-subject covariance matrix were tested. Because the results showed minor variation with different covariance structures, and compound symmetry tended to be the most appropriate according to Akaike’s information criterion (17), the latter structure was applied in all of the models presented. The default Newton-Raphson algorithm was used to compute maximum likelihood, because other algorithms gave similar results.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After discontinuation of T4 supplementation
for 6 weeks, all 17 subjects attained a hypothyroid state, as evidenced
by a TSH level higher than 50 mIU/L and low T3
levels (Fig. 1).
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Plasma tHcy increased gradually from a median concentration of
10.9 to 13.1 µmol/L (mean, 27%) during 6 weeks of discontinued
T4 supplementation, i.e. phase I.
After T4 administration was resumed, tHcy slowly
declined and reached the original level within 4–6 weeks (Fig. 2). The changes both during phases I and
II were highly significant (P < 0.001; Table 2).
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There was a moderate decrease in serum and RBC folate after
T4 supplementation was discontinued (phase I),
which reached statistical significance for RBC folate
(P < 0.02). After restart of T4
supplementation (phase II), both RBC and serum folate increased
(P < 0.01). The serum cobalamin showed a different
response characterized by stable levels during phase I and a
significant (P < 0.001) decrease during phase II (Fig. 2
and Table 2).
Both serum creatinine and total cholesterol increased during phase I
(P < 0.001) and decreased during phase II
(P < 0.001). Notably, the patterns of these changes
closely followed those in plasma tHcy (Fig. 2 and Table 2).
Covariations
The changes in tHcy over time during phases I and II were assessed
before and after adjustment for potential covariates, which include
creatinine, vitamins, and serum cholesterol. Adjustment for creatinine
abolished the change in tHcy in phase I (P = 0.92),
whereas it was only attenuated in phase II (P = 0.001).
After adjustment for RBC or serum folates or cobalamin in bivariate
models, the tHcy changes were still highly significant in phases I and
II (P 
0.005). In contrast, adjustment for
cholesterol had strong effects in both phases (P = 0.13
and 0.14, respectively). These data are in accordance with a strong
association between the values for tHcy and creatinine in phases I and
II (P = 0.001) and between tHcy and cholesterol,
particularly in phase II (P = 0.001). Only weak
associations between tHcy and the vitamins (P 
0.06)
were observed.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The main finding is a gradual increase in plasma tHcy during
development of the hypothyroid state and a return of the tHcy level
when T4 supplementation was resumed. Notably, the
increase (phase I) and decrease (phase II) take place over weeks. A
similar time course was observed for serum creatinine and total
cholesterol. The kinetics of these changes might reflect the turnover
rate of T4, which has a half-life of about 7 days
in humans (18). This is supported by comparing tHcy and thyroid hormone
kinetics during phases I and II (Figs. 1 and 2).
The results of the present study are in accordance with the recent observation that plasma tHcy is high in hypothyroid patients and tends to be low in hyperthyroid patients (14). The apparent close relation between the plasma tHcy and thyroid hormone levels during phases I and II indicates a hormone effect on homocysteine metabolism, distribution, or clearance. A similar argument can be made for the creatinine and cholesterol responses.
Reversible elevation of serum creatinine has previously been reported during discontinuation and resumption of T4 supplementation (19). We observed a close relation between plasma tHcy and serum creatinine in iatrogenic hypothyroidism. Both the tHcy and creatinine responses can be explained by the hypodynamic circulation in hypothyroidism (20). Thyroid hormones are cardiotonic agents, which increase cardiac output while lowering systemic vascular resistance (21, 22), resulting in increased renal blood flow (20). This, in turn, may increase the glomerular filtration rate, which is related to serum creatinine (23), but also closely associated with plasma tHcy (24, 25). The mechanism behind renal homocysteine clearance is debated (26), but may be explained by an important role of renal metabolism in the overall homocysteine homeostasis (27).
An alternative explanation for the concurrent elevation of plasma tHcy and serum creatinine during iatrogenic hypothyroidism is the formation of homocysteine in conjunction with creatine-creatinine synthesis, which is related to muscle mass (28). However, creatinine formation was not increased in hypothyroid patients in one study (29). Furthermore, significant changes in muscle mass during the short study period are unlikely. Taken together, these data give no support to the idea (14) that increased tHcy during hypothyroidism is due to enhanced homocysteine production.
We observed a moderate transient decline in both serum and RBC folate during discontinuation of T4 supplementation. This is in agreement with the finding published previously by us (14) and others (30), demonstrating elevated serum folate in hyperthyroidism and low levels in hypothyroidism. The folate response could be related to direct effect of thyroid hormones on folate-metabolizing enzymes, including methylenetetrahydrofolate reductase (31). Folate status has been established as a major determinant of tHcy level (32). However, in the present study the changes in vitamin levels are minor and show only weak, nonsignificant, correlations with tHcy. This suggests that impaired folate status is not responsible for the transient hyperhomocysteinemia during discontinuation of T4 supplementation.
The mechanism and implication of the significant drop in serum cobalamin during the phase II of the observation period are uncertain. It may reflect cobalamin depletion caused by, but lagging behind, the iatrogenic hypothyroidism due to the long half-life of tissue cobalamin (33). Others have shown that cobalamin levels are reduced (30) or unchanged during hypothyroidism (30, 34).
In line with previous studies (35, 36, 37), serum cholesterol levels increased during the development of hypothyroidism and decreased to control values after 6 weeks of replacement therapy. Notably, cholesterol showed covariation with both tHcy and creatinine. This responsiveness suggests that thyroid hormones influence cholesterol metabolism or disposition (38). There is one report on homocysteine effects on cholesterol production and secretion (39). This may contribute to the covariation between cholesterol and homocysteine observed in the present study, but also to the moderate associations observed in some epidemiological studies (40, 41, 42).
In conclusion, plasma tHcy increased during well defined, short term hypothyroidism, and there was a concurrent, transient increase in both serum creatinine and serum cholesterol. Increased serum creatinine levels probably reflect a reduced glomerular filtration rate, which, in turn, is linked to impaired renal homocysteine clearance and hyperhomocysteinemia. The medical implication of the concurrent increases in serum cholesterol and tHcy levels is a possible strong interactive effect between these two cardiovascular risk factors (43), which may explain in part the accelerated atherosclerosis in hypothyroid patients.
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Footnotes |
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Received June 16, 1999.
Revised September 15, 1999.
Accepted November 19, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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hydroxylase by thyroid hormone. Arch Biochem Biophys. 323:404–408.[CrossRef][Medline]
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