D-Thyroxine Reduces Lipoprotein(a) Serum Concentration in ...

D-Thyroxine Reduces Lipoprotein(a) Serum Concentration in

Dialysis Patients

CHRISTIANE BOMMER,* EGON WERLE,* INGEBORG WALTER�SACK,*

CHRISTINE KELLER,* FRANK GEHLEN,* CHRISTOPH WANNER,�MATTHIAS NAUCK,� WINFRIED MARZ� HEINRICH WIELAND� and

JURGEN BOMMER*

*Medizjnjsche Universit#{228}tsklinik, Heidelberg, Germany; �Medizinische Universit#{228}tsklinik, Wiirzburg, Germany;

and Medizinische Universit#{228}tsklinik, Freiburg, Germany.

Abstract. Uremia raises lipoprotein(a) (Lp(a)) serum concen-

tration and the risk of arteriosclerosis in dialysis patients. The

treatment of high Lp(a) levels is not satisfactory today. The

decrease of Lp(a) in hypothyroid patients on L-I4 therapy

raised the question of whether dextro-thyroxine (D-thyroxine)

reduces not only serum cholesterol, but also Lp(a) serum

concentration. In a single-blind placebo-controlled study, the

influence of 1)-thyroxine therapy on Lp(a) serum concentration

was evaluated in 30 hemodialysis patients with elevated Lp(a)

serum levels. Lp(a) was quantified in parallel by two methods,

i.e., rocket immunoelectrophoresis and nephebometry, and

apo(a) isoforms were determined by a sensitive immunobbot-

ting technique. Regardless of the apo(a) isoforms, 6 mg/d

D-thyroxine reduced elevated Lp(a) levels significantly by

27 ± 13% in 20 dialysis patients (P < 0.001) compared with

10 control subjects (-9.9 ± 8.4%). In parallel, D-thyroxine

therapy significantly lowered total cholesterol (P < 0.001),

LDL cholesterol (P < 0.001), and LDL cholesterollHDL cho-

lesterob ratio (P < 0.01); raised 14 and 13 serum levels; and

suppressed thyroid-stimulating hormone secretion without

causing clinical symptoms of hyperthyroidism in any of the

patients. D-Ihyroxine reduces elevated serum Lp(a) concentra-

tion in dialysis patients. The effect in nondialysis patients can

be expected but remains to be proven. (I Am Soc Nephrol 9:

90-96, 1998)

Arteriosclerosis is accelerated in patients with end-stage renal

disease (ESRD) ( 1 ). Various risk factors may be involved in

the pathogenesis of arteriosclerosis in ESRD patients, such as

hypertension, impaired glucose tolerance, decreased HDL, and

increased serum levels of triglycerides and also of lipopro-

tein(a) (Lp(a)). During the past 10 yr, Lp(a) has been recog-

nized as an independent risk factor for coronary, cerebral, and

peripheral arteriosclerosis in the healthy population and also in

dialysis patients. In a prospective study, Cressman and cob-

leagues noted a significantly higher plasma level of Lp(a) in

dialysis patients with complications due to arteriosclerosis

compared with patients without such complications (2).

Today, treatment of elevated Lp(a) plasma concentrations is

not satisfactory. A low-cholesterol diet (3), chobestyramine (4),

and (�)hydroxy-(f3)methyl glutaryl-CoA reductase inhibitors

(5-7) did not reduce Lp(a) plasma levels. Niacin therapy was

followed by a significant decrease of Lp(a) bevels, but was

poorly tolerated due to its side effects (8). Gemfibrozib (2 X

600 mg) reduced Lp(a) bevels by 27% in hyperchobesterolemic

patients (9). N-Acetylcysteine also mildly reduced plasma 1ev-

els of Lp(a) (10). Furthermore, sex hormones may influence

Received February 17, 1997. Accepted July 16. 1997.

Correspondence to Dr. lUrgen Bommer. 1 Medizin. Universithtsklinik Heidel-

berg, Bergheimer Strasse 56, D-69 1 15 Heidelberg. Germany.

1046-6673/090i-0090$03.00/0Journal of the American Society of Nephrobogy

Copyright 0 1998 by the American Society of Nephrology

Lp(a) plasma concentrations. The use of estrogen as contracep-

tive (1 1), as postmenopausal hormone therapy (12), or for treat-

ment of men with prostatic cancer was followed by a decrease of

serum Lp(a) levels (13). Recently, bifibrol, a new lipid-lowering

agent, has also been shown to lower Lp(a) concentrations by

approximately 30% (14).

Recent clinical observations indicated that treatment with

the thyroid hormones levo-triiodothyronine (L-13) or levo-

thyroxine (L-14) reduces cholesterol concentrations and also

Lp(a) levels in hypothyroid patients (15-18). This raised the

question of whether dextro-thyroxine (D-thyroxine), which

does not have significant general metabolic effects as L-thy-

roxine, but does lower serum cholesterol levels, is able to

reduce Lp(a) serum concentrations. Therefore, we studied the

effect of D-thyroxine on serum lipids and Lp(a) in dialysis

patients with elevated Lp(a) serum concentrations.

Materials and MethodsPatients

A total of 39 (13 women, 26 men) chronic hemodialysis patientswith a basal Lp(a) concentration of more than 250 mgIL were enrolled

in the study. The mean age was 58.8 ± I I .0 yr (mean ± SD), and theduration of dialysis therapy was 71 .2 ± 79.7 mo. All of the patients

were routinely dialyzed for 5 h 3 times a week using Gambro AK1O

(Gambro, Lund, Sweden) or Fresenius MTS 2008 C or 4008 C

machines (Fresenius, Bad Homburg, Germany), and GFSI5 M, GFS

l5H (Gambro, Hechingen, Germany), F6, F60, F50 diaiyzers (Frese-

nius) or Renak l5U dialyzers (Kawasumi, Shmagawa KU, Tokyo,

D-Thyroxine Lowers Serum Lipoprotein(a) 91

Japan), with a diabysate flow of 500 mi/mm and a blood flow of 240

to 300 mb/mm with a double-needle technique. The dialysis devices

and procedure were kept constant throughout the study period, and

urea reduction rates were consistently >60% and varied only by ± 3%

in the single patient. The underlying renal diseases were giomerulo-

nephritis (n = 15), analgesic nephropathy (n = 4), diabetic nephro-

pathy (n = 6). obstructive nephropathy (“ = 2). amyboidosis (,z 1),

tuberculosis (a = I ), polycystic kidney disease (n = 3), nephroscle-

rosis (ii = 3), and unknown (n 4). Euthyroidism was documented

by the serum concentrations of thyroid-stimulating hormone (TSH),

total thyroxine. and triiodothyronine in all patients during the placebo

period preceding the D-thyroxine treatment. Median values (andranges) were within the normal range: TSH, 1.24 (0.02 to 3.0) mUlL;

total thyroxine, 77. 1 (45 to 132) nmollL; and total triiodothyronine.

1.75 (1 .32 to 2.67) nmollL. Medication of patients included subcuta-

neous or intravenous recombinant human erythropoietin, intravenous

iron gluconate, and orally vitamins, calcium salts, or aluminum-containing phosphate binders, sedatives, digitalis, nitrates, and an-

tidiabetics, but no antilipid therapy other than D-thyroxine. The treat-

ment was kept constant except for minor modifications, which have

no known effect on lipid metabolism. Twelve of the 30 evaluated

patients were continuously treated with antihypertensive drugs. In

only one patient was metoprolol treatment ( I X 50 mg) stopped after

5 wk of the D-thyroxine treatment.

Study Drug Therapy

In this randomized single-blind study, the patients were subdividedinto two groups: control subjects (ii 13) and the D-T4 group (‘1

26). The D-T4 group was further subdivided into D-T4 group 1 (ii =

15), with a placebo period of4 wk, and D-T4 group 2 (n = 11), with

a placebo period of 8 wk, before n-thyroxine treatment was started.

D-Thyroxine (Dynothel#{174}, Fa. Henning, Berlin, Germany) treatmentwas started with 2 mg/d, increased every 4 wk by 2 mg to a maximum

of 6 mg/d. The daily dosage of the medication was organized in

separate pilibox compartments to ensure correct and timely adminis-

tration of the medication. The D-thyroxine therapy was followed by a

b2-wk washout period without further medication. Nine patients were

excluded from the final evaluation: three control subjects for relapse

of vasculitis, decompensating diabetes, or transfer to another dialysis

center; three patients in the D-T4 group 1 for septicemia, tuberculosis,

or noncompliance; and three patients in the D-T4 group 2 due toocclusive bowel disease or obvious noncompliance, and one patient

who refused to continue the study because of itching during the

placebo phase.

During the 32 wk of the study, laboratory tests were performed

before and at 4-wk intervals during the phases of placebo and D-

thyroxine treatment. During the final washout period, measurements

were done after 6 and I 2 wk. The study was conducted in accordancewith the guidelines proposed in the Declaration of Helsinki. The study

protocol was approved by the Ethics Committee ofthe Medical Centerof the University of Heidelberg, and written informed consent was

obtained from the patients.

Assessment of Efficacy

Blood was taken just before a hemodialysis session. Serum and

plasma (heparinized) were refrigerated at 4#{176}Cor frozen at -21#{176}C.All

measurements were done within the next week except for the deter-

mination ofT3, T4, and TSH, which were measured simultaneously at

the end ofthe study after storage at - 2 1#{176}C.The quantification method

of thyroxine and triiodothyronine did not differentiate between the

dextro and levo isoforms.

Lp(a) was measured by two different methods, rocket electrophore-sis and nephebometry. in two different laboratories in Heidelberg and

Freiburg. During the electroimmunodiffusion test (Immuno AG, Vi-enna Austria), Lp(a) formed a rocket-like precipitation in the anti-apo(a) antibody-loaded agarose gel. The length of that rocket-like

precipitation corresponds to the concentration of the Lp(a). Nephelo-

metrically. Lp(a) was determined with polyclonal antibodies (Inkstar,

Stillwater. MN) on a Behring Nephelometer (Behring. Marburg. Ger-

many) as described in detail by Nauck et a/. (19). apo(a) isoform

determination was performed on whole serum, using a sensitive

immunoblotting technique described previously (20) and modified as

follows. Briefly. 12 pA of serum was mixed with 100 pA of samplebuffer containing 5% sodium dodecyl sulfate. 2% mercaptoethanol.and 2% bromphenol blue. After 10 mm of boiling in a waterbath, the

reduced samples were applied to a 4% polyacrylamide electrophoresis

gel and run for approximately 2 h at 30 mA. After electrotransfer of

the proteins to Immobilon polyvinyldifluoride transfer membranes(Millipore, Bedford, MA). membranes were blocked with 3% bovine

serum albumin, incubated with a polyclonal anti-apo(a) antibody

(Immuno AG), and detected with the anti-sheep IgG (Fc) alkaline

phosphatase method. A standard of a defined isoform pool (B, S I , S3,

S4, >54) was used on each gel.

The functional thrombin-coagulable fibrinogen was quantified with

the Clauss method (Bioniatic Sarstedt, NOmbrecht, Germany). Totalcholesterol and triglycerides were measured enzymatically (Boehr-

inger. Mannheim, Germany). VLDL cholesterol (VLDL-C), LDL

cholesterol (LDL-C), and HDL cholesterol (HDL-C) were analyzed

with a combined ultracentrifugation and precipitation technique (2 1).

The “pure” LDL cholesterol, corrected for the content of Lp(a) in theLDL, was calculated as: ‘�pure” LDL LDL-C - 0.3 X Lp(a) (22).

Aspartate aminotransferase, alanine aminotransferase, urea, creati-

nine, and uric acid were measured by the Chem- I chemistry analyzer

(Bayer Technicon. Munich, Germany). C-reactive protein was mea-sured by rate nephelometry with the Array 360 analyzer (Beckman,

Munich, Germany).

Statistical Analysis

Mean values and SEM (±SD) or median values and ranges are

given unless otherwise stated. In the control group and the total group

of D-thyroxine-treated patients, the changes of serum concentration of

lipids and other parameters during the study period were analyzed by

the Wilcoxon matched-pairs signed rank test, if the Friedman two-wayANOVA was significant.

In Caucasian populations, serum Lp(a) concentrations show noGaussian distribution but do show a skewed distribution. In the

Kolmogorov-Smirnov test of normal distribution, normal Gaussian

distribution was also not given in all other laboratory data. possibly

due to the limited number of control subjects and D-thyroxine-treatedpatients. Therefore, the individual serum concentrations of Lp(a) and

other variables assessed during the u-thyroxine treatment period and

washout period were compared with the mean of the two concentra-

tions found during the preceding placebo period. By this method, the

percent changes were calculated for each single laboratory result and

analyzed by the Kruskal-Wallis ANOVA by ranks. Furthermore, at

different points in time, the percent changes of lipids and other

laboratory results in D-thyroxine-treated patients were compared with

those in control patients by the Wilcoxon rank sum test.

ResultsAs measured by electroimmunodiffusion test, mean Lp(a)

decreased significantly from 47.4 ± 22.9 to 34.2 ± 16.6 mg/dl

92 Journal of the American Society of Nephrology

Table 1. Lipids and body weight in D-thyroxine-treated patients and control subjects”

Category Preceding Placebo I 2 wk D-T4 16 wk D-T4 Washout

Lp(a) rocket (mg/dl)

controls 52.2 ± 8.9 (49.3) 47.5 ± 8.0 (40.0) 48.3 ± 9.7 (45.5) 48.2 ± 8.4 (43.5)

D-14 47.4 ± 5.1 (42.5) 34.2 ± 4.0 (335)b 34.2 ± 3.7 (33#{149}5)b 41.4 ± 4.4 (43.5)

Lp(a) nephebometry (mg/db)

controls 52.5 ± 10 (45.8) 49.3 ± 10.5 (35) 57.3 ± 13.3 (49.0) 53.7 ± 6.3 (51.5)

D-14 46.9 ± 4.7 (38.8) 38.7 ± 5.2 (31.0)c 41.2 ± 5.1 (33.0)c 50.7 ± 5.0 (46)

Total cholesterol (mg/dl)

controls 180.7 ± 10.5 (177) 186.1 ± 10.3 (178) 183.6 ± 12 (189) 178.3 ± 10.2 (175)

D-14 192.6 ± 8.5 (195) 163.1 ± 8.3 (162)b 161.1 ± 8.5 (157)b 190 ± 7.4 (185.5)

VLDL-C (mg/dl)

controls 40.2 ± 5.7 (41.5) 49.2 ± 5.3 (53.8) 44.0 ± 6.3 (43.5) 38.3 ± 4.7 (41.5)

D-14 27.8 ± 3.4 (27.0) 23.9 ± 3.6 (24.0) 23.2 ± 3.6 (19#{149}5)d 26.2 ± 3.4 (23.0)

LDL-C (mg/db)

controls 116±9.1 (115.5) 111 ±9.6 (104) 113±8.2 (119) 118.7±9.5 (114.5)

D-I4 128.8 ± 7.4 (130) 103 ± 5.1 (102)C 101 ± 5.1 (985)b 127.8 ± 6.6 (123.5)

“Pure” LDL-C (mg/dl)

controls 100.3 ± 10.2 (101) 96.4 ± 10.1 (93.0) 98.9 ± 9.6 (86) 103.1 ± 10.4 (102)

D-14 114.5 ± 7.9 (117) 93 ± 5.6 (93)L� 90.3 ± 5.5 (86)L� 113 ± 7.4 (100)

HDL-C (mg/dl)

controls 25.4 ± 1.3 (25.0) 26.4 ± 1.3 (26.5) 26.0 ± 1.0 (25.5) 25.7 ± 1.1 (26.0)

D-4 36.2 ± 3.2 (33.3) 36.3 ± 3.7 (32.5) 37.7 ± 3.5 (35.0) 35.6 ± 2.0 (35.0)

LDL-C/HDL-C ratio

controls 4.69 ± 0.4 (4.64) 4.26 ± 0.4 (3.86) 4.44 ± 0.4 (4.57) 4.61 ± 0.4 (4.37)

D-14 3.98 ± 0.4 (4.02) 3.23 ± 0.3 (3.1 1)b 2.93 ± 0.2 (2.91)” 3.80 ± 0.3 (3.86)

Body weight (kg)

controls 64.2 ± 3.7 (64.2) 64.4 ± 3.7 (66.0) 64.6 ± 3.7 (66.0) 64.1 ± 4.2 (64.5)

D-14 69.4 ± 2.5 (68.6) 69.3 ± 2.5 (68.5) 69.6 ± 2.6 (68.8) 69.5 ± 2.7 (68.8)

a Data given as mean ± SEM (median), significantly different compared with preceding placebo period. Wilcoxon matched-pairs signed

rank test.hp <0.001.

ep < 0.01.d p < 0.05.

under 6 mg/d D-thyroxine therapy (Table 1 , Figure 1). This

decrease by 27 ± I 3% is significant compared with the control

patients (P < 0.01). A relevant change of the Lp(a) bevels was

not found in the control group (52.2 ± 28.3 mg/dl at the

beginning, and 48.3 ± 30.6 mg/dl (-9.9% ± 8.4%) after 16

wk of the treatment period. During the next washout period,

Lp(a) serum concentrations reincreased and were similar to

those found in control patients.

When Lp(a) was measured by nephelometry, D-thyroxifle

therapy reduced mean Lp(a) levels from 46.9 ± 21.2 to 38.7 ±

23.3 mg/dl after week 12 and to 41.2 ± 22.6 mg/L after week 16

of therapy (lable 1 ). This is a significant decrease of 20.3 ± I 7.1

and 13 ± 17%, respectively (P < 0.05), compared with the

control patients in whom Lp(a) bevels did not change significantly

(52.5 ± 3 1 .6 mg/db before and 49.3 ± 33.3 mg/dl after week 12,

and 57.3 ± 41 .9 mg/L after week 16 of the treatment period).

After the final washout period, Lp(a) levels were not different in

previously D-thyroxine-treated and control patients.

In parallel, total cholesterol levels decreased from 192.0 ±

37.9 to 161.1 ± 38 mg/dl (16.3 ± 10.5%, P < 0.01) (Figure 2)

during maximal D-thyroxine therapy and remained stable in the

control subjects (180.7 ± 33.3 mg/db versus 183.6 ± 38.02

mg/dl) (Table 1 ). LDL cholesterol remained stable in the

control subjects and decreased from 1 28.8 ± 33. 1 mg/dl to

101 ± 22.8 mg/dl (20.7 ± 10.4%, P < 0.01) (Figure 3) during

D-thyrOxifle therapy. The “pure” LDL was constant in the

control group but decreased in the D-thyroxine-treated patients,

from 1 14.5 ± 35.5 to 90.3 ± 24.7 (P < 0.01) (lable 1). HDL

cholesterol bevels did not change markedly in the control

patients (25.4 ± 4.3 mg/dI versus 26.0 ± 3. 1 mg/dl) or D-

thyroxine-treated patients (36.2 ± 14.1 mg/db versus 37.7 ±

15.2 mg/dI). Furthermore, the LDL cholesterol/HDL chobes-

terol ratio did not change in the control patients (4.7 ± 1.4

versus 4.5 ± I .2) but decreased significantly in the D-thyrox-

me-treated patients, from 4.0 ± 1 .6 to 2.9 ± 1 .0 (23 ± 14.5%,

P < 0.01). The VLDL cholesterol also decreased under D-

thyroxine therapy, from 27.8 ± 15.4 to 23.2 ± 16.3 mg/dl

(19.8 ± 42.2%, P < 0.05). The decrease of serum triglyceride

levels (from 166 ± 76 to 138.5 ± 69.3 mg/dl) agreed with the

fall of VLDL cholesterol levels, but was not significant.

weeks

weeks

u-Thyroxine Lowers Serum Lipoprotein(a) 93

15%

10%

5%

C �o,(� _�,o

� -15%

-25%

-30%

-35%

Lp(a) Rocket Electrophoresis

Figure 1. Changes of lipoprotein(a) (Lp(a)) serum concentration expressed as percentage of the mean Lp(a) level during the preceding placebo

period in the individual patients (mean ± SEM). Control subjects (S), D-T4 group I (U), D-T4 group 2 (A), and all D-T4-treated patients (X).Significant difference of the percent changes between control subjects and all D-T4 patients at the different points of time. *P < 0.05; **� < 0.01

(Wilcoxon rank sum test).

10%

5%

-10%e0 .iroIQ__ R310

-20%

-25%

Cholesterol

Figure 2. Changes of total serum cholesterol concentration expressed as percentage of the mean total cholesterol level during the preceding

placebo period in the individual patients (mean ± SEM). For symbols and significance, see Figure 1.

D-Ihyroxrne therapy increased serum concentrations of 14

from 90.5 ± 25.5 to 147.5 ± 40.8 ng/ml (P < 0.001 ) and of 13

from 1.8 ± 0.4 to 4.1 ± 1.2 ng/mb (P < 0.001) and decreased

ISH serum concentrations from 1 . 1 ± 0.8 mUlL to <0.01

mUlL (P < 0.001). All other variables, including C-reactive

protein, albumin, total protein, and fibrinogen concentration,

remained unaffected in control and D-thyroxine-treated patients

throughout the study period.

Body weight (Table 1) or predialytic pulse rate and BP did

not change markedly. Other clinical symptoms of hyperthy-

roidism were not found in any of the patients in response to the

D-thyroxine therapy. During the preceding placebo period, one

patient reported mild paroxysmal tachycardia, with heart rates

up to 100 beats/mm for 6 d, which stopped spontaneously.

DiscussionIn agreement with previous reports, D-thyroxine therapy

reduced serum levels of total cholesterol, LDL cholesterol,

and, to a lesser extent, VLDL cholesterol (23,24). The decrease

of LDL cholesterol was also evident if the LDL cholesterol was

5%

0%i

-5%

-1

-1

*

pre 4

** **

weeks22 28


wC)C

0

Cw

wa-

LDL-C holesterol

8 12 16

Figure 3. Changes of serum LDL cholesterol concentration expressed as percentage of the mean LDL cholesterol level during the preceding

placebo period in the individual patients (mean ± SEM). For symbols and significance. see Figure 1.

corrected for the Lp(a) content in the LDL fraction (“pure”

LDL cholesterol). In the present study, D-thyroxine therapy

with a maximum dose of 6 mg/d reduced elevated Lp(a) bevels

in uremic patients, and Lp(a) reincreased during the washout

period after 1)-thyroxine treatment. Progressing renal failure is

commonly accompanied by an increase of the Lp(a) serum

concentration. Some reports indicated that, in contrast to other

factors such as growth hormone (25), hypothyroidism (17,18),

or low estrogen levels ( 12,26), uremia induces a specific in-

crease of high molecular Lp(a) isoforms (27) that is reversed

after kidney transplantation (28). In our study, D-thyroxine

reduced Lp(a) in dialysis patients regardless of the molecular

weight of apo(a) isoforms. loday, it is possible to differentiate

34 Lp(a) phenotypes (29). The apo(a) phenotyping method

used in the current study distinguishes six apo(a) isoforms and

thus breaks down the larger number of apo(a) alleles into the

groups originally described by Utermann et al. (30,3 1 ). How-

ever, this is not a relevant limitation of our study, which

included only 30 patients. Given the tremendous heterogenicity

of the apo(a) locus, a phenotyping method with higher resolu-

tion would have revealed different phenotypes in almost all of

the individuals studied. Obviously, analysis of such data would

have required post hoc stratification, and the information

gained by a more sophisticated phenotyping method would not

have been used. When our patients were subdivided into two

groups of Lp(a) phenotypes, i.e., �S2 (B, 51, 52, high molec-

ubar Lp(a)), and >52 (53, 54, >54, low molecular Lp(a))

(27,28), the mean percent reduction of Lp(a) bevels under

D-thyrOxine therapy was identical in both groups. Repeated

determination of apo(a) phenotypes did not indicate a relevant

change in size of Lp(a) in the individual patients during D-

thyroxine therapy. In good agreement with these findings,

antithyroid therapy was followed by a comparable increase of

Lp(a) in hyperthyroid patients with high or low molecular

weight apo(a) phenotypes as well (32).

The question of the optimal and most reliable method of

quantifying serum concentrations of Lp(a) is under continuing

discussion. In the present study, the reduction of Lp(a) was

documented by two different, highly validated methods of

Lp(a) quantification, performed in two separate laboratories.

Thus, it is unlikely that the method of Lp(a) measurement was

influenced by changes of Lp(a) structure or size during the

study period.

The daily dosage of medication was organized in separate

piblbox compartments, so that each patient could always be

certain of taking the tablets. Furthermore, the increase of 14

and 13 serum levels, as well as the complete suppression of

ISH secretion in all D-thyroxine-treated patients, indicated

good compliance. Significant adverse effects such as symp-

toms of hyperthyroidism were not observed during D-thyroxine

therapy, using a very pure D-thyroxine preparation with an

L-I4 content of <0. 1 %.

The mechanism of Lp(a) reduction under D-thyroxine re-

mains unknown. L-Ihyroxine or L-trnodothyronine seems to

induce a higher expression and activity of LDL receptors

followed by enhanced LDL cholesterol catabolism (33). In

cultured fibrobbasts, 13 increases the number of LDL receptors

and the degradation rate of LDL cholesterol (34). A determi-

nant role of LDL receptors in the catabolism of Lp(a) has been

postulated, but is not proven. The Lp(a) kinetics after LDL

apheresis (35) and the fractional catabolic rate of Lp(a) in

subjects with familial hypercholesterolemia suggest that in vivo

Lp(a) is not markedly cleared by an LDL receptor-mediated

mechanism.

Ihe rather constant Lp(a) serum concentration under HMG-

CoA reductase inhibitor therapy followed by upregubation of

n-Thyroxine Lowers Serum Lipoprotein(a) 95

LDL receptors and decrease of LDL serum concentration also

points to some differences in the metabolism of LDL and

Lp(a). In our patients, D-thyroxine therapy reduced both Lp(a)

and LDL cholesterol by an average of approximately 20%. The

individual decreases of Lp(a) and LDL cholesterol did not

correlate significantly but varied markedly from patient to

patient.

In patients exhibiting the same apo(a) isoform, different

production rates of apo(a) may be more important for the

serum levels of Lp(a) than different rates of Lp(a) catabolism

(36). In patients with nephrotic syndrome, Lp(a) serum con-

centration is increased, but normalized when proteinuria dis-

appeared (37). In patients with liver diseases, plasma levels of

apo(a) significantly correlated with the microsomal function

and synthetic capacity of the liver, as indicated by the levels of

serum albumin and coagulation factor activities. In rats, tn-

iodothyronine may suppress apo B messenger RNA (38). De-

Bruin et al. postulated that thyroid hormones directly suppress

synthesis and secretion of the apo(a) moiety of Lp(a) in hu-

mans and animals ( 1 8). Additional studies are needed to clarify

the mechanism of decreasing plasma levels of Lp(a) under

L-14 and D-thyroxine therapy.

Serum levels of L-triiodothyronine and L-thyrOxine tend to

be lower in dialysis patients compared with healthy control

subjects, and in some patients low 13 syndrome is found

(39-41). In the present study, however, hypothyroidism can be

excluded by normal ISH serum levels. Furthermore, a signif-

icant effect of L-thyroxine is unlikely. The D-thyroxine prepa-

ration used contains <0. 1 % L-isoforms. Therefore, the maxi-

mal dose of 6 mg of n-thyroxine included <6 pg of L-14 and

a very small amount of L-I3. Any significant metabolic effect

cannot be attributed to the small amounts of L-I4 and L-13.

Similar doses of that D-thyrOxifle preparation were used in

patients with hyperthyroidism due to pituitary resistance to

thyroid hormones. In such patients, D-thyroxine suppresses

ISH secretion, and the symptoms of hyperthyroidism disap-

pear (42). Hamon et al. treated hypothyroid children after total

thyroidectomy plus radioiodine ablation for thyroid cancer I 0 d

with 24 mg of D-thyroXifle per day. The cholesterol bevels

decreased markedly, and the authors recommended that “the

ban on D-thyroxine could be reevaluated since purer prepara-

tions are available” (43).

In conclusion, the study presented here showed that D-

thyroxine can significantly reduce serum concentration of

Lp(a). Additional studies are required to prove the long-term

effect of o-thyroxine therapy in dialysis patients and the effect

in nondialysis patients, and to evaluate the benefits of lowering

the Lp(a) serum concentration, such as reduced risk of artenio-

sclerosis in patients with elevated Lp(a). Ihe clarification of

the mechanism by which D-thyroxine reduces Lp(a) levels may

help to determine combinations of drugs with different mech-

anisms that lower Lp(a) levels more effectively.

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