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The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 5
Printed in U.S.A.
Changes in Plasma Low-Density Lipoprotein (LDL)- and
High-Density Lipoprotein Cholesterol in Hypo- and
Hyperthyroid Patients Are Related to Changes in Free
Thyroxine, Not to Polymorphisms in LDL Receptor or
Cholesterol Ester Transfer Protein Genes
M. J. M. DIEKMAN, N. ANGHELESCU, E. ENDERT, O. BAKKER,
W. M. WIERSINGA
AND
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam,
1105 AZ Amsterdam, The Netherlands
ABSTRACT
Thyroid function disorders lead to changes in lipoprotein metabolism. Both plasma low-density lipoprotein cholesterol (LDL-C) and
high-density lipoprotein cholesterol (HDL-C) increase in hypothyroidism and decrease in hyperthyroidism. Changes in LDL-C relate
to altered clearance of LDL particles caused by changes in expression
of LDL receptors on liver cell surfaces. Changes in cholesterol ester
transfer activity partly explain changes in HDL-C. It has been suggested that the magnitude of these changes is related to polymorphisms of involved genes. The aim of the present study is to investigate whether the polymorphic AvaII restriction site in exon 13 of the
LDL receptor gene and the polymorphic TaqIB site in intron 1 of the
cholesterol ester transfer protein are associated with the magnitude
of the changes in plasma LDL-C and HDL-C, respectively, in the
transition from the hypo- or hyperthyroid to the euthyroid state.
From a consecutive group of 66 untreated hypothyroid and 60
hyperthyroid patients, 47 Caucasians in each group were analyzed.
Fasting LDL-C and HDL-C were measured at baseline and 3 months
after restoration of the euthyroid state. Genotype was determined by
means of PCR techniques. The homozygous presence of a restriction
site was designated as ⫹/⫹, heterozygous as ⫹/⫺, and absence as ⫺/⫺.
Trend analysis was done with ANOVA.
I
T IS WELL KNOWN that thyroid dysfunction leads to
changes in lipoprotein metabolism. Plasma low-density
lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels increase in hypothyroidism
and decrease in hyperthyroidism (1–3). Furthermore, clearance of chylomicron remnants is decreased in hypothyroidism (4). Changes in LDL-C are mainly attributable to altered
clearance of LDL-C from plasma by changes in the number
of LDL receptors on liver cell surfaces (5, 6). Because the
promoter of the LDL receptor gene contains a thyroid hormone responsive element (TRE), T3 could modulate gene
expression of the LDL receptor (7). HDL-C metabolism is
complex, and changes in plasma levels are due, in part, to
remodeling of HDL-C particles by hepatic lipase and choReceived August 5, 1999. Revision received February 1, 2000.
Accepted February 7, 2000.
Address correspondence and requests for reprints to: M. J. M.
Diekman, Academic Medical Center, Department of Endocrinology
and Metabolism F5-174, Meibergdreef 9, 1105 AZ Amsterdam Zuidoost,
The Netherlands. E-mail: [email protected].
Among hypo- or hyperthyroid patients, subgroups with different
genotypes did not differ in thyroid function pre- or post treatment. The
mean decrease in LDL-C (mmol/L ⫾ SD) in hypothyroid patients with
different AvaII genotypes did not differ: ⫺1.07 ⫾ 1.44 (⫺/⫺, N ⫽ 15),
⫺1.25 ⫾ 1.53 (⫹/⫺, N ⫽ 19), and ⫺1.18 ⫾ 1.01 (⫹/⫹, N ⫽ 13) mmol/L
[not significant (NS)]; neither did the mean increase in hyperthyroid
patients: 1.07 ⫾ 0.90 (⫺/⫺, N ⫽ 18), 0.92 ⫾ 1.00 (⫹/⫺, N ⫽ 21), and
1.20 ⫾ 0.45 (⫹/⫹ N, ⫽ 6) (NS). The mean decrease in HDL-C (mmol/
L ⫾ SD) in hypothyroid patients with different TaqIB genotypes did
not differ: ⫺0.22 ⫾ 0.26 (⫺/⫺, N ⫽ 13), ⫺0.15 ⫾ 0.23 (⫹/⫺, N ⫽ 21),
and ⫺0.12 ⫾ 0.22 (⫹/⫹, N ⫽ 9) (NS); neither did the mean increase
in hyperthyroid patients: 0.29 ⫾ 0.39 (⫺/⫺, N ⫽ 7), 0.26 ⫾ 0.23 (⫹/⫺,
N ⫽ 22), and 0.19 ⫾ 0.31 (⫹/⫹, N ⫽ 18) (NS). Changes in LDL-C and
HDL-C correlated with the logarithm of the change in free T4 (fT4),
expressed as the fT4 posttreatment/fT4 pretreatment ratio (r ⫽ ⫺0.81,
P ⬍ 0.001; and r ⫽ ⫺0.62, P ⬍ 0.001, respectively). In conclusion, in
the transition from hypo- or hyperthyroidism to euthyroidism, no
association is found between AvaII genotype and changes in plasma
LDL-C nor between TaqIB genotype and changes in HDL-C. Changes
in LDL-C and HDL-C correlate with changes in fT4. (J Clin Endocrinol Metab 85: 1857–1862, 2000)
lesterol ester transfer protein (CETP) (8). Activity of both
enzymes decreases in hypothyroidism and increases in hyperthyroidism, correlating with plasma HDL-C (9 –12).
The magnitude of changes in plasma LDL-C and HDL-C
levels, after restoration of the euthyroid state, varies from
patient to patient (1). The extent of these changes depends
both on the severity and duration of the thyroid dysfunction
and on the degree of pretreatment hypercholesterolemia (13–
15). Diet, body weight, and smoking habits can also modify
absolute LDL-C levels (16, 17). In addition to these endocrine
and environmental factors, genetic constitution can explain
some of the interindividual variation. An association between a polymorphic AvaII site in exon 13 of the LDL-R gene
and the extent of cholesterol lowering upon restoration of the
euthyroid state in hypothyroid patients has been reported
(18). Absence of this site was associated with the most
marked hypocholesterolemic response. A polymorphic site
explaining variations in plasma HDL-C during thyroid dysfunction is not known. A candidate could be the TaqIB site
in intron 1 of the CETP gene, because presence of this site is
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DIEKMAN ET AL.
TABLE 1. Changes in thyroid function tests, plasma lipids and lipoproteins, and body mass index in 47 hypothyroid and in 47
hyperthyroid patients, upon restoration of euthyroidism
Hypothyroid (n ⫽ 47)
TSH
fT4
T3
Total cholesterol
LDL-C
HDL-C
Total chol/HDL-C
Apoprotein A
Apoprotein B
Triglycerides
BMI
Hyperthyroid (n ⫽ 47)
Untreated
Euthyroid
Untreated
Euthyroid
66.0 (4.5–162)
6.0 ⫾ 3.7
1.2 ⫾ 0.5
6.79 ⫾ 2.22
4.59 ⫾ 2.02
1.60 ⫾ 0.44
4.4 ⫾ 1.7
1.59 ⫾ 0.26
1.35 ⫾ 0.51
1.25 ⫾ 0.94
25.5 ⫾ 4.3
2.4 (0.18 – 8.5)a
16.3 ⫾ 3.7a
1.8 ⫾ 0.4a
5.43 ⫾ 1.20a
3.47 ⫾ 1.11a
1.43 ⫾ 0.36a
4.0 ⫾ 1.3a
1.53 ⫾ 0.24c
1.07 ⫾ 0.30a
1.14 ⫾ 0.66
25.1 ⫾ 4.2b
⬍0.01 (⬍0.01– 0.04)
42.8 ⫾ 16.7
5.2 ⫾ 2.3
4.49 ⫾ 1.08
2.69 ⫾ 3.70
1.25 ⫾ 0.33
3.7 ⫾ 1.0
1.39 ⫾ 0.31
0.82 ⫾ 0.27
1.11 ⫾ 0.41
22.5 ⫾ 3.9
1.0 (0.01– 8.3)a
14.5 ⫾ 3.1a
2.1 ⫾ 0.7a
5.81 ⫾ 1.21a
3.70 ⫾ 1.10a
1.48 ⫾ 0.42a
4.2 ⫾ 1.6b
1.57 ⫾ 0.33a
1.13 ⫾ 0.30a
1.32 ⫾ 0.61d
24.3 ⫾ 3.6a
Values as mean ⫾ SD, except TSH given as median (range); a P ⬍ 0.005; b P ⬍ 0.01; c P ⫽ 0.05; d P ⫽ 0.02 vs. the untreated stage. TSH (mU/L),
fT4 (pmol/L), T3 (nmol/L), total cholesterol (mmol/L), LDL-C (mmol/L), HDL-C (mmol/L), apoprotein A (g/L), apoprotein B (g/L), triglycerides
(mmol/L), BMI (kg/m2).
FIG. 1. RFLP analysis. Left panel, The PCR product of exon 13 of the
LDL receptor gene (480 bp) contains always one AvaII site resulting
in fragments of 150 and 330 bp. When an extra (polymorphic) AvaII
site is present, the 330-bp fragment yields fragments of 195 and 135
bp. m, Marker lane; arrow, 250 bp. Right panel: The PCR product of
intron 1 of CETP gene (1420 bp) has one TaqIB polymorphic site
yielding bands of 750 and 670 bp when a ⫹ allele is present. The bands
are not fully separated on this example gel (arrow); however, this does
not interfere with the ability to determine the specific genotype.
associated with increased CETP concentrations and reduced
HDL-C concentrations in healthy males (19).
The aim of the present study is to reexamine the association between the AvaII site and changes in LDL-C in hypothyroidism on restoration of the euthyroid state and to
evaluate whether this association is also observed in hyperthyroid patients. At the same time, we studied the relationship between the TaqIB site and the changes in plasma
HDL-C level in these patients.
Subjects and Methods
Patients
Consecutive patients with primary hypothyroidism (n ⫽ 66) or with
primary hyperthyroidism (n ⫽ 60), referred to our out-patient clinic,
were studied. To have a genetically more homogeneous group, we
included only Caucasians in the final analysis.
In the hypothyroid group, 7 patients were non-Caucasians, 6 patients
were lost to follow-up, 6 patients had no AvaII genotyping, and 10 had
no TaqIB genotyping; consequently, 47 patients [median age, 45 yr
(range, 23–75); 13 males] were available for analysis of AvaII; and 43
patients [median age, 45 yr (range, 23–75); 11 males], for analysis of TaqIB
polymorphism. The cause of hypothyroidism was chronic autoimmune
thyroiditis (n ⫽ 31), 131I treatment (n ⫽ 12), thyroidectomy (n ⫽ 2),
prolonged overdose of thiamazol (n ⫽ 1), and subacute thyroiditis (n ⫽
1). Subclinical hypothyroidism was present in 7; and overt hypothyroidism, in 40 patients.
In the hyperthyroid group, 12 patients were non-Caucasians, 1 patient was lost to follow-up, and 2 patients had no AvaII genotyping,
leaving 45 patients [median age, 47 yr (range, 20 –77); 7 male]) for AvaII
and 47 [median age, 47 (range, 20 –77); 9 males] for TaqIB polymorphism
analysis. Causes of hyperthyroidism were Graves’ disease (n ⫽ 32), toxic
multinodular goiter (n ⫽ 14), and toxic adenoma (n ⫽ 1). Subclinical
hyperthyroidism was present in 6; and overt hyperthyroidism, in 41
patients.
None of the patients was on a special diet or used any medication
known to interfere with lipoprotein metabolism; women using oral
anticonceptives (4 in the hypothyroid group and 7 in the hyperthyroid
group) continued to do so until the end of the study. Smoking habits
were noted, as well as length and body weight.
All patients were studied twice: once in the untreated state, and again
at least 3 months after achieving the euthyroid state. Treatment was with
levothyroxine sodium in the case of hypothyroidism or with antithyroid
drugs or 131I in the case of thyrotoxicosis. Blood samples were collected,
after an overnight fast, by venipuncture into evacuated tubes containing
either EDTA (1 g/L) as an anticoagulant for measurement of lipid
profiles, or sodium heparinate as an anticoagulant for thyroid hormone
measurements.
The study was approved by the institutional Medical Ethical Committee, and patients gave their written informed consent.
Methods
Plasma lipids and thyroid function. T4 and total T3 were measured by
in-house RIA methods (20). FT4 was measured by a two-step fluoroimmuno assay (DELFIA, Wallac, Inc., Turku, Finland); TSH was measured by immunofluorometric assay (DELFIA, Wallac, Inc.). Hypothyroidism was defined as an increased plasma TSH. Hyperthyroidism was
defined as a decreased plasma TSH (reference range, 0.4 – 4.0 mU/L) in
combination with an increased plasma free T4 (fT4; reference range,
10 –23 pmol/L) or total T3 (reference range, 1.3–2.7 nmol/L). The euthyroid state for previous hypothyroid patients was defined as a normal
TSH in combination with a normal plasma fT4 and total T3; for previous
thyrotoxic patients, as a normal plasma fT4 and total T3 in the absence
of an increased TSH. Total cholesterol in plasma was measured with an
enzymatic method (CHOD-PAP, catalog no. 1442350; Roche Diagnostics
B.V., Almere, The Netherlands) on a Cobas Bio centrifugal analyzer
(Roche Diagnostics B.V.); HDL-C (after precipitation of very low-density
lipoprotein cholesterol and LDL-C with heparin-Mn2⫹), by the enzymatic CHOD-PAP method. LDL-C was calculated with the Friedewald
formula; triglycerides were measured by an enzymatic method (GPOPAP, catalog no 701912, Boehringer); apolipoprotein A-1 and B were
assayed with an immunonephelometric method on a Behring nephelometric analyzer (Behring Diagnostics, Rijswijk, The Netherlands) according to the protocol and with reagents of the manufacturer.
CHOLESTEROL CHANGES IN THYROID PATIENTS
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TABLE 2. Demographic characteristics of hypothyroid and hyperthyroid patients, according to AvaII genotype of the LDL receptor and to
Taq1B genotype of CETP
Hypothyroid
Genotype
AvaII LDLr
N (males)
Age (yr)
N smokers
Taq1B CETP
N (males)
Age (yr)
N smokers
Hyperthyroid
⫺/⫺
⫹/⫺
⫹/⫹
⫺/⫺
⫹/⫺
⫹/⫹
15 (5)
47 (23– 69)
6 (40%)
19 (4)
42 (28 – 69)
7 (37%)
13 (4)
50 (28 –75)
5 (38%)
18 (5)
47 (25–71)
8 (44%)
21 (2)
48 (24 –76)
10 (48%)
6 (0)
43 (20 –77)
2 (33%)
13 (4)
42 (28 – 65)
8 (65%)
21 (5)
47 (23–75)
8 (38%)
9 (2)
40 (31–58)
3 (33%)
7 (1)
46 (20 – 63)
3 (43%)
22 (6)
38 (23–76)
9 (41%)
18 (2)
49 (25–77)
8 (44%)
FIG. 2. Bar diagrams for changes (⌬) in fT4, LDL-C, apolipoprotein (apo) B, and BMI according to previous hypo- or hyperthyroid state and
AvaII genotype of the LDL receptor. Changes in TSH are given as Box and Whisker plots.
Genetic analysis of polymorphisms. Genomic DNA was extracted from
peripheral leucoctyes according to standard procedures (21). PCR was
performed with primer sets and under conditions as reported (22, 23).
The PCR products were digested with restriction endonuclease AvaII
(Anabaena variabilis) or TaqIB (Thermophilus aquatus) (Boehringer).
The digests were electroforesed on 1% agarose gels, stained with
ethidium bromide, and visualized with ultraviolet detection (Eagle Eye
II, Stratagene, La Jolla, CA). Absence of the restriction site was noted as
(⫺) and presence as (⫹).
Statistical analysis. Data were analyzed using the statistical package SPSS,
Inc. version 6.0 (Chicago, IL). TSH values are given as median and range
because of the skewed distribution of the data and were analyzed by the
Kruskall Wallis test. Paired data on lipoproteins in the transition from
the hypo- or hyperthyroid state to the euthyroid state were compared
by Student’s t test. Data on thyroid function tests and lipoproteins
between groups with different genotypes were compared by means of
ANOVA. All patients, whether hypo- or hyperthyroid, were analyzed
together, along a continuum of ⌬ free T4 (fT4) (expressed as the fT4
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JCE & M • 2000
Vol 85 • No 5
FIG. 3. Bar diagrams for changes (⌬) in fT4, HDL-C, apo A, triglycerides, and BMI, according to previous hypo- or hyperthyroid state and TaqIB
genotype of CETP. Changes in TSH are given as Box and Whisker plots.
posttreatment/fT4 pretreatment ratio). Multivariate linear regression
analysis of ⌬ LDL-C on log (⌬ fT4) was performed with different intercepts and slopes for each AvaII genotype. Multivariate ANOVA (F-test)
was used to test whether the three separate lines coincided. The same
type of analysis was used to study the relationship between ⌬ HDL-C,
log (⌬ fT4), and TaqIB genotype. A two-tailed probability value less than
0.05 was considered to be a significant difference for the F-test (major
endpoint). A two-tailed probability value less than 0.01 was considered
to be a significant difference for all other comparisons.
Results
Changes in thyroid function tests, lipids, lipoproteins, and
body mass index (BMI) for the hypo- and hyperthyroid patient groups are given in Table 1. According to the direction
of thyroid dysfunction, the typical changes in plasma LDL-C
and HDL-C levels were observed. Wide variations were seen
in the individual lipid responses, upon restoration of the
euthyroid state: changes in LDL-C ranged from almost 0 to
⫺5 mmol/L and from ⫺0.8 to 2.8 mmol/L in hypothyroid
and hyperthyroid patients, respectively. Changes in HDL-C
varied from ⫹0.3 to [mimes]0.75 mmol/L and from
[mimes]0.25 to ⫹ 1 mmol/L in hypothyroid and hyperthyroid patients, respectively.
The frequency of the presence of an AvaII site was 43% in
a Caucasian American population (22, 24), and the frequency
of the presence of a TaqIB site was 59% in a healthy male
population (23). The observed frequencies of different alleles
for the AvaII and TaqIB restriction sites in our total patient
group (hypo- and hyperthyroid patients) were 42% and 54%,
respectively. Typical examples of the AvaII and TaqIB polymorphisms, as assessed by inspection of the gels, are given
in Fig. 1.
When hypothyroid and hyperthyroid patient groups were
subdivided according to their AvaII or TaqIB genotypes, no
differences in sex, age, or smoking habits were found among the
different subgroups (Table 2). Changes in thyroid function tests
and BMI were not different either (Figs. 2 and 3). The magnitude
of the changes in LDL-C and apolipoprotein B did not differ
among the AvaII genotypes. Neither were there differences
between the degree of changes in HDL-C, apolipoprotein A, or
triglycerides among the TaqIB genotypes.
When all patients, whether hypo- or hyperthyroid, were
analyzed together, along a continuum of ⌬ f T4 (expressed as
the f T4 posttreatment/f T4 pretreatment ratio), neither was
AvaII genotype associated with the size of the difference in
LDL-C (P ⫽ 0.24) level nor was TaqIB genotype associated
with the size in difference in HDL-C levels (P ⫽ 0.54) (see
Figs. 4 and 5); log (⌬ f T4) correlated both with ⌬ LDL-C (⌬
CHOLESTEROL CHANGES IN THYROID PATIENTS
1861
LDL-C ⫽ 0.05–2.20 log (⌬ f T4), r ⫽ ⫺0.81, P ⬍ 0.001) and with
⌬ HDL-C (⌬ HDL-C ⫽ 0.05– 0.36 log (⌬ f T4), r ⫽ ⫺0.62, P ⬍
0.001)
Discussion
The variable extent of the changes in LDL-C and HDL-C,
upon restoration of the euthyroid state in hypothyroid
patients, as observed in clinical practice, existed also in our
patients. Changes in LDL-C were, however, not associated
with the AvaII polymorphism. This is in contrast with the
results of Wisemann et al (18). Compared with their study,
our hypothyroid patients had a similar age and sex distribution, and the degree of hypothyroidism and changes
in lipoproteins were equal. The frequency of the presence
of an AvaII site in the hypothyroid patients was similar. To
exclude an influence of different genetic background attributable to different ethnicity, we included only Caucasians in the final analysis. The ethnic origin of the Wisemann study group is not mentioned; a different racial
background of their patients might explain the discrepancy with our study results. We extended our observations
to hyperthyroid patients but could not find a relationship
there either. This supports our conclusion that there is a
lack of association between AvaII polymorphism and the
magnitude of changes in LDL-C at different plasma thyroid hormone concentrations.
The hypothesis put forward by Wisemann et al., that the
polymorphic AvaII restriction site indicates a TRE in its surroundings, is original but highly speculative. The putative
presence of such a hormone response element far downstream from the promoter site of the gene would be exceptional. Gene regulation outside the promoter site is a rather
infrequent finding in genes. Moreover, recent studies have
demonstrated a TRE in the promoter of the LDL receptor
FIG. 4. Relationship between the change (⌬) in plasma f T4 (expressed
as the f T4 posttreatment/f T4 pretreatment ratio on a logarithmic
scale) and the change in plasma LDL-C in 47 hypothyroid (open
symbols) and 47 hyperthyroid (solid symbols) patients, upon reaching
euthyroidism, according to their AvaII genotypes of the LDL receptor
gene. Regression line for the total group: ⌬ LDL-C ⫽ 0.05–2.20 log (⌬
f T4); r ⫽ ⫺0.81, P ⬍ 0.001. The f T4 posttreatment/f T4 pretreatment
ratio is less than 1 in the hyperthyroid and greater than 1 in the
hypothyroid group.
FIG. 5. Relationship between the change (⌬) in plasma f T4 (expressed
as the f T4 posttreatment/f T4 pretreatment ratio on a logarithmic
scale) and the change in plasma HDL-C in 43 hypothyroid (open
symbols) and 47 hyperthyroid (solid symbols) patients, upon reaching
euthyroidism, according to their TaqIB genotypes of the CETP gene.
Regression line for the total group: ⌬ HDL-C ⫽ 0.05– 0.36 log (⌬ f T4);
r ⫽ ⫺0.62, P ⬍ 0.001. The f T4 posttreatment/f T4 pretreatment ratio
is less than 1 in the hyperthyroid and greater than 1 in the hypothyroid group.
gene (7). What then might explain the clear differences in
response of LDL-C to treatment between different patients?
Changes in diet or exercise are unlikely explanations, because this would imply a change in life style, which probably
does not occur after diagnosing and treating a benign thyroid
disease. Are there other candidate genes that might influence
the relationship between f T4 and LDL-C? Variation in the
gene coding for liver deiodinase type 1 might lead to different intracellular liver concentrations of T3 with equal
plasma f T4 levels. Genetic variation at the TRE in the promote site of the LDL receptor is another possibility.
Changes in HDL-C were also independent of TaqIB polymorphism. This particular polymorphic site was examined
because it seems to be biologically relevant. In male patients
with coronary heart disease, a relationship between the presence of this polymorphic site and the decrease in vascular
luminal diameter has been found, indicating faster progression of atherosclerosis, compared with individuals in whom
this site is absent. This relationship disappeared after treatment with HMGCoA reductase inhibitors (25). Such a biological significance is not known for the above mentioned
AvaII site.
In conclusion, polymorphisms for AvaII and TaqIB in the
genes for LDL receptor and cholesterol ester transfer protein
do not seem to influence the changes in plasma LDLs and
HDLs occurring after treatment of hypo- and hyperthyroidism. The main determinant of changes in LDL-C and HDL-C,
upon restoration of the euthyroid state, are the changes in
plasma f T4.
Acknowledgments
We thank Dr. A. Soutar for helpful comments.
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DIEKMAN ET AL.
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