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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2532-2536
Copyright © 1999 by The Endocrine Society

Original Studies

Thyroxine Replacement Therapy Enhances Clearance of Chylomicron Remnants in Patients with Hypothyroidism

Moshe Weintraub, Itamar Grosskopf, Yana Trostanesky, Gideon Charach, Ardon Rubinstein and Naftali Stern

Department of Internal Medicine C, Metabolic Unit and Institute of Endocrinology, Tel Aviv-Elias Sourasky Medical Center, and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 64239, Israel

Address all correspondence and requests for reprints to: Itamar Grosskopf, M.D., Department of Internal Medicine C, Tel Aviv-Elias Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. E-mail: igrossko{at}tasmc.health.gov.il


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To further confirm the benefit of replacement therapy in terms of risk for coronary artery disease, we evaluated the effect of T4 on postprandial lipoproteins in patients with hypothyroidism. Nine normolipidemic patients (aged 62.75 ± 7.6 yr) with TSH of 32.2 ± 13.2 mU/L and free T4 of 0.66 ± 0.17 ng/mL were treated with T4 (50–100 µg/day) for at least 4 months. The behavior of postprandial lipoproteins was assessed before and during treatment by determining retinyl palmitate levels in the total plasma, chylomicrons (Sf >1000) and chylomicron remnants (Sf < 1000) fractions for 8 h after a mixed meal plus vitamin A. During T4 treatment, serum levels of TSH and FT4 were 4.4 ± 4.9 mU/L and 1.2 ± 0.34 ng/mL (P = 0.001 and P = 0.002), respectively. Fasting low density lipoprotein cholesterol decreased from 166 ± 35 to 135 ± 23 mg/dL (P = 0.035). Retinyl palmitate (RP) levels in the chylomicron remnant fraction was reduced significantly during therapy from 6948 ± 2790 to 5174 ± 2401 µg/L·h (area under the curve ± SD; P = 0.014). Total plasma RP and chylomicron RP remained unchanged. We conclude that T4 enhances the clearance of chylomicron remnants in normolipidemic patients with hypothyroidism.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPOTHYROIDISM was shown in numerous studies to be a cause of an atherogenic fasting lipid profile by increasing low density lipoprotein cholesterol (LDL-C) and decreasing high density lipoprotein cholesterol (HDL-C) levels (1, 2, 3, 4). Fasting triglycerides were found by some investigators (5, 6), but not by others (7), to be generally normal in nonobese patients with hypothyroidism. However, reports of the effect of hypothyroidism on the expression of type III hyperlipidemia (8, 9) suggest that an alteration in thyroid status may also modulate the metabolism of postprandial lipoproteins (PPLP), chylomicrons, and chylomicron remnants (CR), lipoproteins that accumulate in this hyperlipoproteinemia and cause advanced atherosclerosis (10, 11, 12).

Most of our lives are spent in the postprandial state, during which time the vessel wall is exposed to postprandial lipoproteins for extended periods of time. These lipoproteins are metabolized on the endothelial surface of arteries, and their cholesterol becomes incorporated into the artery wall, where it may stimulate the formation of atherosclerotic lesions (13, 14, 15, 16, 17). Thus, the accumulation of PPLP in plasma may foster the development of coronary artery disease even when fasting lipid and lipoprotein levels are normal (18, 19, 20, 21, 22). The objective of the present study was to examine the metabolism of PPLP in hypothyroid humans and the effect of hormone replacement therapy on it.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Nine subjects (eight females and one male) with hypothyroidism were enrolled in the study. Inclusion criteria included blood levels of TSH above 10 mIU/mL and free T4 (FT4) levels below 1.0 ng/dL, a body mass index less than 40 kg/m2, a normal liver and normal renal function, serum glucose levels less than 110 and 140 mg/dL during fasting and 120 min after a 75-g glucose load, respectively, and signing written informed consent. The study was approved by the Tel Aviv Medical Center ethical committee.

Study design

The study consisted of a baseline phase and a treatment phase. Patients were asked not to alter their diets, routine physical activities, or smoking habits throughout the study period.

In the baseline phase, three blood samples were drawn for fasting lipid and lipoprotein determinations, and participants underwent a vitamin A-fat loading test. Hormone replacement therapy was then started with 50–100 µg T4/day. TSH and FT4 blood levels were determined at 3-week intervals to adjust the T4 dosage. Three months later, blood was again drawn for fasting lipid and lipoprotein assessment, and the vitamin A fat-loading test was repeated.

Vitamin A-fat loading test

The vitamin A-fat loading test was performed as previously described (23). Briefly, after an overnight 12-h fast, the subjects were given a fatty meal plus 60,000 U aqueous vitamin A/m2 body surface. The fatty meal contained 50 g fat/m2 body surface and consisted of 65% of calories as fat, 20% as carbohydrate, and 15% as protein. It contained 600 mg cholesterol/1000 cal. The polyunsaturated/saturated ratio was 0.3. The meal was given as a milkshake, scrambled eggs, bread, and cheese and was eaten within 10 min. Vitamin A was added to the milkshake. After the meal, the subjects fasted for 8 h, but drinking water was allowed ad libitum. To measure the levels of retinyl palmitate (RP), blood samples were drawn before the meal and every hour thereafter for 8 h. All participants tolerated the meal well, and none had diarrhea or other symptoms of malabsorption.

Analysis of samples

Venous blood was drawn from the forearm and transferred to a tube containing sodium ethylenediamine tetraacetate. Samples were immediately centrifuged at 1500g for 15 min, and 1 mL plasma was stored wrapped in foil at -20 C for retinyl ester assay. An aliquot of 2.5 mL plasma was transferred to a 0.5 x 2-in. cellulose nitrate tube and overlayered with 2.5 mL sodium chloride solution (density, 1.006 g/mL). The tubes were subjected to preparative ultracentrifugation for 1.6 x 106 g/min in a Beckman Coulter, Inc. SW-55 rotor (Fullerton, CA) to float chylomicron particles with an Sf above 1000. The chylomicron-containing supernatant was removed and brought to a total volume of 2 mL with saline. The infranatant was brought to a volume of 5 mL with saline. Aliquots of supernatant and infranatant (0.5 mL) were wrapped in foil and assayed for retinyl ester. This procedure separates a predominantly chylomicron population from a predominantly chylomicron remnant population (23, 24).

Retinyl ester assay

The assays were carried out in subdued light with high performance liquid chromatography grade solvents. Retinyl acetate was added to the samples as an internal standard. The samples were then mixed with ethanol (4 mL), hexane (5 mL), and water (4 mL), with vortexing carried out between each addition. Two phases were formed, and 4 mL of the upper (hexane) phase were removed and evaporated under nitrogen (25). The residue was dissolved in a small volume of benzene, and an aliquot was injected into a 5-µm high performance liquid chromatography ODS-18 radial compression column; 100% methanol was used as the mobile phase at a flow rate of 2 mL/min. The effluent was monitored at 340 nm, and the RP peak was identified by comparison to the retention time of purified standard (Sigma Chemical Co., St. Louis, MO). In agreement with a previous report (26), it was found that 75–80% of the total plasma retinyl esters were accounted for by RP. In addition, the distribution of retinyl esters remained constant throughout the study. The amounts of RP in plasma and lipoprotein fractions were quantitated by the area ratio method (27), using retinyl acetate as a reference (28). The efficiency of extraction of retinyl esters was more than 95%, and the variance of triplicate assays was less than 5.4% of the mean.

Lipid and lipoprotein determinations

Cholesterol and triglycerides were measured enzymatically using the reagents cholesterol 236991 and triglyceride 126012 (Boehringer Mannheim, Indianapolis, IN). HDL-C was determined after precipitation of whole plasma with dextran sulfate-magnesium. The LDL-C concentration was calculated using Friedewald’s method (29).

Apolipoprotein E isoform determination

DNA was extracted from white blood cell. PCR was performed according to the method described by Wenham et al. (30).

Statistical analysis

Values are expressed as the mean ± SD. The differences between fasting lipid and lipoprotein levels and PPLP behavior (by calculating the area under the curve for triglycerides in whole plasma and the RP curves in whole plasma, chylomicron fraction, and CR fraction) before and during hormone replacement therapy were analyzed for significance using the paired t test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Salient characteristics of the study participants are shown in Table 1Go. FT4 increased to the normal range, and the TSH blood level was normalized during treatment with T4. During treatment, mean fasting LDL-C levels decreased by 12% (P = 0.035). Fasting total cholesterol, HDL-C, and triglycerides blood levels remained unchanged during treatment.


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  		Table 1. Salient characteristics of the nine study participants before and during T4 replacement therapy

 
The triglycerides increment (above fasting level) in whole plasma and RP levels in whole plasma, chylomicron fraction (Sf > 1000), and nonchylomicron fraction (Sf < 1000) before and during T4 treatment up to 8 h after vitamin A-fat loading are shown in Table 2Go and Fig. 1Go. The mean total plasma triglycerides increment significantly decreased by 20% (P = 0.02). The mean nonchylomicron fraction for RP was significantly reduced by 11.6% (P = 0.049). The mean total plasma and chylomicron fraction for RP did not change significantly during treatment (Fig. 1Go). By carefully observing the curves of postprandial triglycerides and RP before and during treatment, a clear difference was seen in the metabolic response to treatment during the first 3 h after fat loading compared to that during the last 5 h after fat loading. Figure 1Go illustrates that during the initial 3 h, an increase was found in the whole plasma RP, the chylomicron fraction (Sf > 1000) RP, and the nonchylomicron fraction (Sf < 1000) RP levels during T4 treatment. This, however, was not statistically significant. Three to 8 h after the fatty meal, the mean whole plasma triglycerides and nonchylomicron fraction RP levels, but not the chylomicron fraction RP levels, were significantly lowered by 31% (P = 0.01) and 26% (P = 0.014), respectively, when treatment was given compared with RP levels without treatment (Table 3Go).


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  		Table 2. Area below whole plasma triglycerides increment curve and area below whole plasma, chylomicron fraction (Sf > 1000), and nonchylomicron fraction (Sf < 1000) retinyl palmitate (RP) curve 0–8 h after vitamin A-fat loading in nine patients with hypothyroidism, before and during T4 treatment

 


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  		Figure 1. Effect of T4 treatment on whole plasma triglycerides increments (A) and chylomicron (Sf > 1000; B) and nonchylomicron (Sf < 1000; C) RP concentrations 0–8 h after vitamin A-fat loading in nine patients with hypothyroidism. Squares, Before treatment; triangles, during treatment.

 

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  		Table 3. Area below whole plasma triglycerides increment curve and area below whole plasma, chylomicron fraction (Sf > 1000), and nonchylomicron fraction (Sf < 1000) retinyl palmitate (RP) curve 3–8 h after vitamin A-fat loading in nine patients with hypothyroidism, before and during T4 treatment

 
The individual responses, measured as the area under the nonchylomicron fraction RP curve 3–8 h after the fatty meal, are shown in Fig. 2Go. Seven of nine participants responded to T4 treatment with a decrease in RP levels.



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  		Figure 2. Individual responses of postprandial nonchylomicron (Sf < 1000)-RP concentration, measured as the area under the curve 3–8 h after a fatty meal in nine patients with hypothyroidism, with and without T4 treatment.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We showed in this study a significant decrease in the CR fraction (Sf < 1000) after acute fat loading during treatment with T4 compared with CR concentrations before treatment. These results suggest that in the hypothyroid state in addition to the well known increase in the fasting LDL-C level, another lipid disorder exists, i.e. accumulation of CR. Thus, T4 treatment reduces the atherogenicity that may result from these particles.

Abrams et al. (5) found no abnormality in chylomicron lipolysis in patients with hypothyroidism. They were, however, unable to report on the metabolic behavior of the CR. Other investigators (31, 32, 33, 34) showed significantly decreased clearance of CR in hypothyroid rats. The clearance of chylomicrons, however, was undisturbed. Treatment of hypothyroid rats with T3 reversed the inhibition of hepatic remnant uptake (32). This could be explained in part by findings in previous works. LPL, which is essential for the degradation of chylomicrons (35), was shown to be unaffected by thyroid hormone replacement (5, 36). By contrast, hepatic triglyceride lipase, which facilitates the degradation and uptake of CR (35), was demonstrated to markedly increase during T4 administration (36). Hepatocyte B-E receptors that are responsible for the uptake of LDL and CR were depressed by hypothyroidism, with a rapid increase in expression in response to the administration of thyroid hormone (37, 38, 39).

Our results are in agreement with the findings of animal studies and indirect human studies. The postfat load reduction in CR-RP, but not in chylomicron, levels during replacement therapy compared to their levels before treatment is suggestive of disturbed CR metabolism in the hypothyroid state in humans.

Although a significant reduction was found in the area under the curve for CR during thyroid hormonal replacement, it was obvious from RP curves that PPLP behave differently in the first 3 h after a fatty meal compared to their behavior during the following 5 h. A constant increase, although not statistically significant, of the postprandial RP level was found in the first 3 h during hormonal replacement in the chylomicron fraction as well as in the CR fraction. However, in the last 5 h of the postprandial curves, the RP level in the chylomicron fraction remained unchanged, whereas its level in the CR fraction decreased significantly. How can we explain the increase in the first 3 h? Is this a result of changes in gastrointestinal fat absorption caused by a correction of thyroid dysfunction? Many studies on fat absorption have shown it to be very efficient and unaffected by age, drugs, and regular hormonal changes (40). On the other hand, Shafer et al. (41) demonstrated that thyroid hormonal replacement markedly reduced gastrointestinal transit time. This means that it improved the abnormal gut motility found in hypothyroid patients. This may explain the slower appearance of the chylomicrons and CR in the first 3 h after the fatty meal before replacement therapy was introduced to the study participants.

It needs to be stressed, in view of the small size of study group, that the results should be interpreted with caution. Also, the two participants who did not respond to T4 in terms of a decrease in CR-RP need to be addressed. Patient 6 had a slight increase in CR-RP (7.6% vs. a mean decrease of 25.5%). This patient did not reveal any clinical or laboratory clue for her deviant response. Patient 3 had a marked increase in CR-RP (21%). Her past history was positive for coronary artery disease and arterial hypertension. We showed previously that both of this conditions are associated with disturbed metabolism of PPLP (21, 42). In addition, her insulin response to a standard oral glucose load was exceedingly higher during T4 treatment than during the pretreatment phase, whereas in all other participants it remained unchanged. This shows that she might have an additional metabolic disorder that could explain her aberrant PPLP response.

In conclusion, we demonstrated improved clearance of CR in hypothyroid patients when hormonal replacement therapy was given. Our findings support the results of animal studies, suggesting an impaired liver uptake of these PPLP in the hypothyroid state. This abnormality cannot be detected by following fasting lipid levels. This may further explain the increased risk for coronary artery disease in patients with hypothyroidism and should probably encourage early initiation of treatment for these patients, i.e. even in subclinical cases (43).

Received November 9, 1998.

Revised February 5, 1999.

Accepted March 17, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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