CLIN. CHEM. 41/2, 226-231 (1995) #{149}Lipids and Llpoprotelns

226 CLINICAL CHEMISTRY, Vol. 41, No. 2, 1995

Changes in Serum Lipoprotein(a) and Lipids During Treatment of HyperthyroidismAnnie W.C. Kung,”4 Richard W.C. Pang,2 Ian Lauder,3 Karen S.L. Lam,’ and Edward D. Janus2

Because of suggestions that thyroid hormones modulateserum Iipoprotein(a) [Lp(a)] concentration, we evaluatedprospectively the serial changes of serum Lp(a), mea-sured as apolipoprotein(a) [apo(a)], and other lipoproteinsin 40 subjects with hyperthyroidism treated with radioac-tive iodine (RAI) therapy. Hyperthyroid patients had lower(P <0.001) concentrations of apo(a), total cholesterol(IC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apo B, buthigher apo A-I concentrations compared with age-matched controls [geometric mean (range)]; apo(a) 81(17-614) vs 187 (17-1 808 lU/L): TC 4.07 ± 0.8 vs 5.22 ±1.00 mmoVL (mean ± SD); LDL-C 2.47 ± 0.89 vs 3.40 ±

0.88 mmoVL; HDL-C 1.05 ± 0.33 vs 1.24 ± 0.34 mmol/L;apo B 0.66 ± 0.23 vs 1.13 ± 0.34 g/L, and apo A-I 2.07± 0.42 vs 1.46 ± 0.28 gIL, respectively. Euthyroidismwas associated with normalization of serum TC, LDL-C,and apo B within 1 month of treatment. However, apo(a)required 4 months to normalize, and HDL-C and apo A-I

were still abnormal 6 months after RAI. Serum apo(a), TC,LDL-C, and ape B were negatively correlated with serumthyroxine (14), free thyroxine index, and triiodothyronine(13) and positively correlated with thyrotropin during thetransitional period from hyperthyroidism to euthyroidism.Parallel changes of these lipoproteins and thyroid hor-mones were also observed after treatment of hyperthy-roidism. In conclusion, thyroid hormones do modulatelipoproteins, particularly Lp(a). The delay in normalizationof apo(a) but not LDL suggests an effect on apo(a)production rather than on LDL removal.

Indexing Ternis thyrotoxicosis/iudioactive iodine/apo!ipoproteins/choJest

Lipoprotein(a) [Lp(a)1 has been demonstrated tohave a thrombogemc and atherogenic influence.5 Itconsists of a carbohydrate-rich apolipoprotein(a)[apo(a)], very similar in structure to plasminogen,covalently linked to a low-density lipoprotein (LDL)-like particle that has apo B100 as its structural protein(1-3). Epidemiologic studies have confirmed that car-diovascular risk is related to increased plasma concen-trations of Lp(a) (4). Lp(a) possesses atherogenic and invitro antifibrinolytic properties and favors the deposi-

Departments of’ Medicine, 2 Clinical Biochemistry, and3 Sta-tistics, The University of Hong Kong, Queen Mary Hospital,Pokfulam Road, Hong Kong.

for correspondence. Fax 852-872-5828.5Nonstandard abbreviations: Lp(a), lipoprotein(a); RAI, radio-

active iodine; TC, total cholesterol; LDL-, HDL-, VLDL-C, low-,high-, and very-low-density lipoprotein cholesterol; ape, apoli-poprotein; T4, thyroxine; FF1, free thyroxine index; T3, triiodothy-romne; TSH, thyrotropin; and TG, triglyceride.

Received June 8, 1994; accepted October 19, 1994.

tion of cholesterol in lesions of the endothelium, thus

posing an increased atherogenic risk (3, 5).Lp(a) is highly heterogeneous in structure, density,

and composition, and its concentrations are understrong genetic influence (6). Recently other factors,including thyroid hormones, sex steroids, and growthhormone, have also been shown to be important in theregulation of circulating Lp(a) concentrations (7-10).However, conflicting data are reported regarding Lp(a)concentrations in patients with thyroid disorders. DeBruin et al. (7) reported that higher Lp(a) concentra-tions are observed in hypothyroid subjects comparedwith euthyroid subjects, whereas others have beenunable to detect significant changes in Lp(a) concen-trations in thyroid disorders (11, 12). The increasedLp(a) concentration may contribute to the increasedrisk of premature coronary artery disease in the hypo-thyroid state.

The present study aimed to evaluate prospectivelyLp(a) and other serum lipoprotein concentrations in 40Chinese subjects with hyperthyroidism and to followthe changes in these lipoproteins over 6 months afterradioactive iodine (RAI) therapy.

Subjects and Methods

Subjects

We prospectively studied 40 subjects (11 men, 29women, including 10 postmenopausal women) withnewly diagnosed hyperthyroidism due to Graves dis-

ease, who were scheduled for RAT. The diagnosis of

Graves disease was based on clinical assessment, con-firmed by a diffuse increased uptake on thyroidal scan

and increased total serum thyroxine (T4) concentration

or free thyroxine index (FTI), with or without thepresence of antithyroid antibodies. All patients hadsuppressed thyrotropin (TSH) concentrations. Theyhad had thyrotoxic symptoms for 4 ± 2 months beforepresentation. Blood samples were taken at diagnosisand at 1,2,4, and 6 months after RAT therapy. Healthylaboratory staff and police recruits of comparable age(n = 119) were used as the reference population forserum lipid and lipoprotein concentrations. Serum ali-quots were stored at -20#{176}Cuntil determination ofserum lipids in batches. All subjects gave informed

consent, and the study was approved by the EthicsCommittee of the University of Hong Kong.

Thyroid Function Tests and Lipid Profiles

Serum total T4 and T-uptake tests were measuredwith a fluorescence polarization immunoassay (AbbottLaboratories, Chicago, IL). Serum FTI was calculatedby dividing the serum T4 value by the T-uptake test.

Controls

119

40:7945 ± 8

62-154

76-1520.8-3.0

0.23-3.7

187 (17-1808) [244, 3661b

1.24 ± 0.75 [1.10, 1.38]

5.22 ± 1.00 (5.03, 5.39]1.24 ± 0.34 [1.18,1.31)

n

M:FAge, yearsT4, nmoVLFriT3, pmoVLTSH, mIU/LApo(a), lU/L

TG, mmoVLTC, mmoVLHDL-C,

mmoi/L

LDL-C,mmoVL

Apo Al, g/L

ApoB,g/L

Hyperthyroid subjects40

11:29

50 ± 10

254 ± 598

302 ± 8085.0 ± 2.08

<0.05

81(17-614) [90, 170]a,b

1.18 ± 0.44 [1.05, 1.33]4.07 ± 0.80 [3.80, 4.34r1.05 ± 0.33(0.96, 1.16]

3.40 ± 0.88 (3.24, 3.57] 2.47 ± 0.89 [2.19, 2.75r

1.46 ± 0.28 (1.41, 1.51)

1.13 ± 0.34(1.06,1.1912.07 ± 0.42 (1.84, 2.3r

0.66 ± 0.23 (0.59, o.73r

CLINICAL CHEMISTRY, Vol. 41, No. 2, 1995 227

Serum total triiodothyronine (T3) was determined byRIA (Amersham, Bucks., UK) and TSH by micropar-tide capture enzyme immunoassay (Abbott).

The Lp(a) concentration was determined by measur-

ing serum apo(a) by an IRMA (Pharmacia, Uppsala,Sweden). The assay is based on the direct sandwich

technique, in which two monoclonal antibodies aredirected against separate antigenic determinants on

the apo(a) molecule. The intraassay variations at low

and high apo(a) concentrations were 2.6% and 1.4%,respectively, and interassay variations were 4.8% and3.8%, respectively. Total cholesterol (TC) and triglyc-eride (TG) were determined enzymatically (BoehringerMannheim, Mannheim, Germany) on a Hitachi 717analyzer. High-density lipoprotein cholesterol (HDL-C)was quantified by the same enzymatic method afterprecipitation of very-low-density lipoprotein (VLDL)and LDL with phosphotungstic acid. LDL-C was calcu-lated according to the Friedewald equation. Apo A-Iand apo B were measured by rate nephelometric im-munoassay with the Beckman Array system (BeckmanInstruments, Brea, CA).

Statistical Methods

Two-sample t-test and confidence interval analyses

were used to compare results for patients and controls.Apo(a) concentrations were log-transformed beforeanalysis because of their skewed distribution. The

longitudinal analysis for each variable was achieved (a)by comparing the mean value at each time point withthe pretreatment mean value by the two-sample t-testand (b) by correlation analysis. Pearson’s correlationanalysis was performed between (i) the interval changefor each variable between time points after treatmentand (ii) the percentage interval change analogous to (i).

P <0.05 was considered significant.

Results

Thyroid Function Tests

All 40 patients had increased serum T4, V1’I, and T3and suppressed TSH, as shown in Table 1. After RAT,the percentage of subjects achieving normalization of

serum T4, FTI, and T3 at 1, 2, 4, and 6 months were57.5%, 77.5%, 92.5%, and 87.5%, respectively. Fivepatients showed a recurrence of hyperthyroidism at 6months after RAT after a period of euthyroidism. Fivesubjects had transient hypothyroidism, whereas twohad permanent hypothyroidism (defined biochemicallyby low T4, FTI, and T3 with increased TSH) lasting for>3 months. Apart from the few subjects who hadhypothyroidism, the TSH concentrations remainedsuppressed (<0.05 mIUfL) in 87.5%, 80%, 67.5%, and55% of the patients at 1, 2, 4, and 6 months, respec-tively.

Lipids

Compared with controls, thyrotoxic patients had

significantly lower amounts of apo(a), TC, LDL-C,HDL-C, and apo B, but higher apo A-I (Table 1). Serum

Table 1. Lipid concentrations (mean ± SD) ofhyperthyroid patients and controls.

#{149}Significant at p <0.001.b Geometric mean (and range); [95% confidence intervalsi.

TG was similar in the patients and the controls. Thereis no sex difference in apo(a) concentrations in bothgroups. The lipoprotein concentrations of the post-menopausal women were not statistically differentfrom those of premenopausal subjects, perhaps becauseof the small number of patients studied.

Because at each time point after treatment some of

the patients were still hyperthyroid, the data of the

subjects who were euthyroid at each time point were

analyzed and compared with the baseline values. WithRAT therapy, there was a progressive and significantincrease in apo(a), TC, LDL-C, and apo B concentra-tions (Table 2). Also, a small but significant increase in

TG was observed. The most significant percentageinterval changes of the lipid concentration from base-line value occurred at 2-4 months after therapy, whenthe serum thyroid hormones returned to the euthyroidrange. Euthyroidism was associated with rapid nor-malization of serum TC, LDL-C, and ape B, which was

achieved within 1 month after treatment. However,apo(a) concentrations took 4 months to normalize com-pletely, whereas HDL-C remained persistently lowerand apo A-I persistently higher even at 6 months afterRAJ (Table 2). Fig. 1 shows the changes in LDL and

apo(a) concentrations of the 28 patients who reachedeuthyroidism at 6 months. A delay in normalization inapo(a) as compared with LDL was evident. Fig. 2 showsthe typical reciprocal changes of apo(a) and LDL withFTI after treatment. Patient 1 had normalization of?I’I within 1 month after RAT. The effect on LDL ofachieving euthyroidism was evident earlier than that

on apo(a), although both showed a parallel increase.Patient 2 had transient hypothyroidism at 2-4 monthsafter RAT; associated with this was a surge in theapo(a) and LDL-C concentrations.

The relation between the serum thyroid hormones

and the lipid concentrations of all 40 patients duringtreatment of hyperthyroidism was also studied. Serum

n

FriApo(a), lU/LTG, mmoVLTC, mmoVLHDL-C, mmoVLLDL-C, mmoVLApe A-I,g/L

ApoB,g/L

0

40302 ± 80

81 (17-614r1.18 ± 0.444.07 ± 0.80

1.05 ± 0.33

2.47 ± 0.77

2.07 ± 0.420.66 ± 0.23

Geometric mean (and range).b Values in brackets are percentage changes compared with pretreatment values.c.dSignificant at c P <0.05 and d p <o.oi vs pretreatment value.

B

300

600 F-

0I I I

0 1 2 3Months

C

L J J

0 1 2 3Months

0I I

0 1 2 3Months

Fig. 1. Serial results of FTI (A), apo(a) (B), and LDL-C (C) of the 28I I I patients who reached euthyroidism at 6 months.4 5 6 Dotted lines in (B)and (C) represent the 95% confidence interval of the mean

of the controls.

228 CLINICAL CHEMISTRY, Vol. 41, No. 2,1995

Table 2. Changes in lipoprotein concentrations with time after treatment of hyperthyroid patients in patients whobecame euthyroid at each time point after RAI therapy.

lime, months

21122 ± 28

90 (17_515)8 [#{247}11.11k’1.47 ± 0.69 [+24.514.86 ± 0.99 [± 19.411.04 ± 0.39 [-1.0]3.15 ± 1.11 [+25.512.18 ± 0.49 [+5.3]0.83 ± 0.19 [+25.7]

2

25113 ± 33

90 (17-435r [+11.1]1.62 ± 0.69 [+37.3]5.30 ± 1.33 [+30.2]1.03 ± 0.41 (-2.01

3.52 ± 1.36 [+41.7]2.20 ± 0.47 (+6.2]0.90 ± 0.29 [+ 36.3]

4

28115 ± 28

148 (17-435r [#{247}82.7]

1.47 ± 0.66 [+ 24.5]5.55 ± 1.28 (+35.1]

0.97 ± 0.36 [-8.7]3.91 ± 1.39 [+58.3]2.14 ± 0.46 [#{247}3.0]

0.98 ± 0.30 [+48.5]

6

28112 ± 30

119(17-765r [+46.9]

1.56± 0.708[+32.2]

5.45 ± 1.63’ [+33.9)0.97 ± 0.24 [-8.7]3.81 ± 166d [+54.2]

2.24 ± 0.49 (+8.2]0.97 ± 028d [+46.9]

600

500

400

200

100 I-

7

6

5

-J

E-j3

-J

2

1

4 5 6

1000

-J

00.

800 F-

400

200

0

4 5 6

apo(a), TC, LDL-C, and apo B were negatively corre-lated with serum T4, FF1, and T3 and positively corre-lated with TSH during the transitional period fromhyperthyroidism to euthyroidism at 1,2, and 4 monthsafter RAT. Correlation coefficients of these measure-

ments at 4 months after RAT are shown in Table 3.Once euthyroidism had been achieved, no correlationwas apparent between the serum lipids and the thyroidhormones. Furthermore, interval differences (differ-ence of the value compared with that at the preceding

1

0 1 2Months

4 6

5

4OO 4-J

o3OO E

0

1200 29

100 1

0 0

800 8

700 7

600 6

500 5

-Ja400

300 3I 0

I -J

.200 2

100 1

0 0

I I I

1 2 4 6

Months

Fig. 2. Serial results for FT1, apo(a), and LDL-C in two patients afterRAI therapy.Top, patient with normalization of Ffl1 month after treatment. The effect ofachieving euthyroidism on LDL was evident earlier than for apo(a) althoughboth showed a parallel increase. Bottom, patient with transIent hypothyroid-ism after RAI. A surge in LDL was followed by a parallel change in apo(a)concentrations.

time point) of apo(a) were correlated with those of TSHbut not T4, FF1, or T3. Otherwise, the interval differ-ences of TG, TC, LDL-C, apo A-I, and apo B werecorrelated negatively with that of the thyroid hormonesand positively with that of TSH at each time pointduring the transitional period from hyperthyroidism toeuthyroidism. The correlation coefficients for theserelations at 2-4 months after RAT are shown in Table4. Similar correlations were observed between thepercentage changes (i.e., compared with the values atthe preceding time point) in these lipid measurementsand in the thyroid hormones (data not shown). These

L0

600 6

CLINICAL CHEMISTRY, Vol. 41, No. 2, 1995 229

Table 3. Correlations (r) between thyroid hormonesand lipoproteins during treatment of hyperthyroidism

at 4 months after RAI therapy.T4 FTI T3 TSH

Apo(a) -0.398 0.358 +0.47c

TG NS NS NS NSTC -0.42’ -0.398 +0.608LDL-C 041b +0.608HDL-C NS NS NS NSApoA-l NS NS NS NSApo B +0.57C

Significant at P <0.05, b P <0.01, and C P <0.005.NS, not significant.

correlations suggested parallel changes of lipid mea-surements and thyroid hormones with time after treat-ment of hyperthyroidism. Because only a few patientsdeveloped permanent hypothyroidism after treatment,we were unable to analyze the effect of hypothyroidism

on the lipid concentrations.

Discussion

The results demonstrate that thyroid hormones mod-ulate Lp(a) and other lipoprotein concentrations. Ourstudy design is unique in that serum lipoproteins andthyroid hormones were monitored serially duringtreatment of hyperthyroidism; thus, correlations couldbe properly assessed between the thyroid hormonesand the lipoproteins. We observed that, first, thyroidhormones were directly correlated with apo(a) duringtreatment of hyperthyroidism and, second, treatmentof hyperthyroidism was associated with parallel in-creases in apo(a), TC, LDL-C, and ape B that were ofsimilar magnitude (56.5%, 33.9%, 54.3%, and 46.9%,respectively). Conflicting results have been reportedwith regard to Lp(a) changes in thyroid disorders.Klausen et al. (11) and Spandrio et al. (12) reported alack of statistically significant influence of thyroidhormones on Lp(a) concentration, whereas de Bruin etal. (7) and Engler and Riesen (13) reported findingssimilar to our present study. The failure of detection ofcorrelation in some of the studies may be related to thesmall number of subjects studied and lack of serialmeasurements. The changes in TC, LDL-C, HDL-C,and apo B with hyperthyroidism were similar to datapublished previously (14). There was a small increasein the TG concentrations after treatment in our study.In contrast, Muls et al. found no significant change andnoted that variable effects had been found in earlierstudies (15).

The effect of thyroid hormones on LDL in humans is

well known. T4 increases LDL receptor-mediated clear-ance of LDL, thus lowering LDL concentrations, aneffect most evident in practice during treatment ofhypothyroidism (16). The way in which the observedreduction of Lp(a) by excess thyroid hormones comesabout is less clear. Plasma concentrations of Lp(a) vary

widely between euthyroid individuals and are to alarge extent genetically determined. In general, lower-

Month 1-2 Month 2-4

Table 4. CorrelatIons (r) of interval change of lipoproteins and thyroid hormones in 40 patientsperiod from hyperthyroidism to euthyroidism after RAI therapy.

during transitional

iFTI hiT3 iTSH if4 LiFTI hiT3 5TSH

A Apo(a) NS NS NS +0.47C NS NS NS +0.33a

A TG 041b NS -0.3 o.32 NS +0.32a

A TC +0.47C -0 42C -O 46C -0 348 +0 338

A LDL-C 0.37 +0.358 -0.298 #{247}0.358AHDL-C NS NS NS NS NS NS NS NSA Apo A-I NS #{247}042b 04b NS +0.40k’

A Apo B O.38 -0.42k’ NS +0.388 -0.398 NS -1-0.398

Significant at a p <0.05, b P <0.01, and c P <0.005.NS, not significant.

230 CLINICAL CHEMISTRY, Vol. 41, No. 2, 1995

molecular-mass isoforms of apo(a) are associated withhigher concentrations (17). Precisely how the differentalleles affect apo(a) production, association with LDLto form Lp(a), and catabolism of Lp(a) is not clear atthis time (18).

Transgenic mouse experiments indicate that human

apo(a) is expressed independently of LDL (19). Meta-bolic studies of the effect of nicotinic acid, which lowersLp(a) markedly, on Lp(a) turnover indicate that thisagent decreases the synthetic rate rather than increas-ing catabolism (20). Thus the effect of T4 could be viaan alteration of apo(a) and consequently Lp(a) produc-tion. Alternatively, because T4 alters LDL receptor

function, it could alter Lp(a) removal via receptors.Although the evidence is still somewhat conflicting, itseems unlikely, from studies in patients with LDLreceptor defects (i.e., familial hypercholesterolemia),that LDL receptors are involved in the catabolism ofLp(a) itself, although this might depend on the partic-ular LDL receptor mutation involved (21, 22). In ourstudy the effects of reduced T4 production after RAItreatment were in the same direction for LDL andLp(a) but the time courses were different. The effect onLDL was evident much earlier, whereas for Lp(a) itwas evident after 4 months. This is consistent with arapid effect on LDL receptor function affecting LDLconcentrations and a much slower effect, primarily onapo(a) production, affecting Lp(a) concentrations. Theknown dramatic effect of hydroxymethylglutaryl-CoAreductase inhibitors on LDL, via receptor upregulation,in the face of no change in apo(a) concentrations in thistreatment, also supports independent mechanisms ofLDL and apo(a) regulation. Further specific studies onapo(a) and Lp(a) kinetics in thyroid disease are neededto give the definitive answer.

We observed in this study that apo A-I concentra-tions were higher in untreated hyperthyroid subjectsthan in normal controls, and the concentrations re-mained high even after treatment. This differs fromthe finding of Muls et a!. (15), who reported that apoA-I concentrations in hyper- or hypothyroid patientswere similar to those in normal controls. Markedincreases in apo A-I concentrations had been observedin rats chronically treated with T4 injection (23). Bothliver and intestinal apo A-I production were increased

by T4, with the action being mediated at both transcrip-tional and posttranscriptional levels. Liver apo A-ImRNA was increased threefold with T4 injection, theincrease caused by an increased stability of nuclearapoA-I RNA precursors in chronic hyperthyroidism(23-25). The persistent increase of apo A-I after treat-ment in our patients may be related to the prolongedperiod of hyperthyroidism before RAT therapy. Sincehyperthyroidism is associated with decreased HDL-Cbut increased apo A-I concentrations, probably changethe structure and density of the HDL-C particle. This,however, needs verification by determination of HDL2

and HDL3 concentrations in these patients. Altered

lipoprotein composition together with decreased cho-

lesteryl ester transfer activity has been observed in

hypothyroidism (26). Change in the cholesterol/cho-lesteryl ester molar ratio in HDL was inversely related

to that of cholesteryl ester transfer activity during

treatment of hypothyroidism, which accounts forhigher HDL-C and free cholesterollcholesteryl esterratio in the hypothyroid state. This finding supportsour observation of decreased HDL-C in hyperthyroidpatients.

In conclusion, thyroid hormones modulate lipopro-

teins, particularly Lp(a). Amounts of apo(a) are low in

hyperthyroidism and revert to normal more slowly

than do LDL concentrations, suggesting an effect on

apo(a) production rather than LDL removal.

We thank Gloria Chan for nursing assistance, Monica Lam forsecretarial support, and J. D. Robinson for assistance in collectionof control samples.

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