0021-972X/79/4905-0726$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright© 1979 by The Endocrine Society
Vol. 49, No. 5 Printed in U.S.A.
Plasma High Density Lipoprotein Cholesterol in Thyroid Disease* DALMACIO AGDEPPA, CHAMEL MACARON, TILAK MALLIK, AND N. D. SCHNUDA Departments of Medicine and Pathology, Edgewater Hospital, and the Chicago Medical School, Chicago, Illinois 60660
ABSTRACT. The plasma levels of high density lipoprotein cholesterol (HDL-C) were reduced in 16 hyperthyroid female patients compared to 37 euthyroid women (33.5 ± 8 vs. 51.5 ± 13 mg/dl (mean ± SD); P < 0.001), When 5 patients were restudied after restoration of the euthyroid state, plasma HDL-C increased from 29 ± 5 to 43 ± 11.5 mg/dl (P < 0.05). In addition, in 22 hypothyroid women, HDL-C levels were also diminished com-
pared to the euthyroid group (43.4 ± 15.5 vs. 51.5 ± 13 mg/dl; P < 0.05). Nine patients were restudied after L-T 4 replacement therapy; their levels of HDL-C increased but not to a statistically significant degree. The daily administration of 0.3 mg L-T 4 to eight normal male volunteers for 1 month did not significantly affect HDL-C levels. (J Clin Endocrinol Metab 49: 726, 1979)
T
HE VALUE of high density lipoprotein cholesterol (HDL-C) measurement has been recently rediscovered, although the initial work appeared in the 1950s (1). Indeed, several epidemiological surveys indicated that HDL-C levels are a better predictor of coronary artery disease than total cholesterol and constitute an independent antirisk factor, whereby a high level appears to protect against ischemic heart disease (2-5). Moreover, increased longevity was found in subjects with raised HDL-C levels (6). In addition, HDL-C levels show a negative correlation with triglyceride (TG) levels. Thus, serum HDL-C concentrations are low in the hypertriglyceridemias, whether primary or associated with uremia, uncontrolled diabetes mellitus, weight gain, or a diet very rich in carbohydrates (7, 8). As exceptions, alcohol and estrogens seem to induce an increase in both TG and HDL-C levels (9). The metabolism of HDL-C is presently being clarified. The chylomicrons and HDL are rich in apoproteins A-I and A-II, and chylomicron serves as a precursor for HDL (10). Furthermore, HDL is also synthesized in the intestine and liver (11). HDL may interfere with cellular uptake of cholesterol (12-14) and appears to be involved in removing cholesterol from peripheral tissue and transporting it back to the liver, where it is catabolized and excreted (15). However, the degrada-
tion of HDL remains largely unknown. Many studies have been published regarding the impact of hyperthyroidism and hypothyroidism on lipid metabolism (16-22). One report has appeared concerning HDL-C levels in hypothyroidism (23). Our purpose in this paper is to present data on the alteration of plasma HDL-C in thyroid disorders and to assess the effects of the normalization of T4 levels on the levels of HDL-C. Materials and Methods We studied 37 euthyroid healthy female subjects, 22 female hypothyroid patients (of whom 9 were restudied after L-T 4 replacement therapy), and 16 hyperthyroid female patients. To keep homogeneity in our study, we excluded all male patients because the majority of the patients were female and because of the sex difference in HDL-C levels. The age of the control group, 42.4 ± 15 yr (mean ± SD), was younger than that of the hypothyroid group (63.8 ± 12 yr) but was not significantly different from that of the hyperthyroid group (50.5 ± 16.7). In most instances, the hypothyroid patients were overtly hypothyroid and on no drugs when studied, and none were obese. All had primary hypothyroidism with markedly elevated TSH levels, except for one case with hypothalamic hypothyroidism. The hyperthyroid group was investigated before institution of drug therapy, except in two cases where propranolol and propylthiouracil were started a few days before sampling. These drugs were omitted on the morning that blood was drawn. The hyperthyroid group included 12 cases of Graves' disease and 4 cases of multinodular toxic goiter. In addition, we investigated a fourth group of subjects which consisted of 8 adult male healthy volunteers studied when euthyroid, after taking 0.3 mg L-T 4 daily for a month.
Received September 19, 1978. Address requests for reprints to: N. D. Schnuda, M.D., Department of Pathology, Edgewater Hospital-Mazel Medical Center, 5700 North Ashland Avenue, Chicago, Illinois 60660. * This work was supported by General Research Support Grant BR5366 from the General Research Support Branch, Division of Research Facilities and Resources, NIH. 726
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 17 November 2015. at 14:21 For personal use only. No other uses without permission. . All rights reserved.
PLASMA HDL-C IN THYROID DISEASE
727 Hypothyroid (N=9$)
Assays Venous blood was drawn from all subjects after an overnight fast. A tube with no anticoagulant was secured for T4, T 3 resin uptake, and TSH levels, and another tube containing disodium EDTA was used for the lipid profile. The tubes with disodium EDTA were centrifuged, and the plasma was stored at —20 C until assay [freezing has been previously shown not to affect HDL analysis (5)]. T4, T3 resin uptake, and TSH were analyzed by RIA. In our laboratory, the normal values for T4 were 5-12 /ig/dl, for T3 resin uptake were 25-35%, and for TSH were less than 8 /xIU/ml. TGs and total cholesterol (TC) were analyzed by enzymatic procedures. For the HDL-C, the plasma were treated with sodium phosphotungstate-Mg+2, followed by centrifugation and subsequent measurement of HDL-C in the supernatant using the same method as for TC (22). The levels of low density lipoprotein cholesterol (LDL-C) were determined indirectly using the formula of Friedewald, Levy, and Fredrickson (24): LDL-C = TC - [HDL-C + (TG/5)]. This formula is valid for blood specimens whose TG levels are less than 400 mg/dl in the absence of type III and chylomicronemia. All patients in this series met these criteria. For statistical analysis we used Student's t test for nonpaired (Fig. 1) and paired data (Figs. 2 and 3 and Table 1). Pearson's correlation coefficient (r) was used to show the degree of linear association among the different variables. The results are expressed as the mean ± SD. Results In agreement with other studies, we found substantially higher HDL-C levels in women (51.5 ± 13 mg/dl) than in men (32 ± 8.4) and a very slight difference among the different age groups after age 40 yr (4). Although our control euthyroid group is younger than the hypothyroid group, this difference in age should not affect the results.
360 320 280 240 200 160 120 80 40
P=0.02
Before Rx
After Rx
***
10
TC LDL-C HDL-C TG T4 FIG. 2. Plasma lipid levels and serum T4 in nine hypothyroid subjects before and after thyroid replacement therapy (mean + SD). *, P < 0.05; '*, P
Vol. 49, No. 5 Printed in U.S.A.
Plasma High Density Lipoprotein Cholesterol in Thyroid Disease* DALMACIO AGDEPPA, CHAMEL MACARON, TILAK MALLIK, AND N. D. SCHNUDA Departments of Medicine and Pathology, Edgewater Hospital, and the Chicago Medical School, Chicago, Illinois 60660
ABSTRACT. The plasma levels of high density lipoprotein cholesterol (HDL-C) were reduced in 16 hyperthyroid female patients compared to 37 euthyroid women (33.5 ± 8 vs. 51.5 ± 13 mg/dl (mean ± SD); P < 0.001), When 5 patients were restudied after restoration of the euthyroid state, plasma HDL-C increased from 29 ± 5 to 43 ± 11.5 mg/dl (P < 0.05). In addition, in 22 hypothyroid women, HDL-C levels were also diminished com-
pared to the euthyroid group (43.4 ± 15.5 vs. 51.5 ± 13 mg/dl; P < 0.05). Nine patients were restudied after L-T 4 replacement therapy; their levels of HDL-C increased but not to a statistically significant degree. The daily administration of 0.3 mg L-T 4 to eight normal male volunteers for 1 month did not significantly affect HDL-C levels. (J Clin Endocrinol Metab 49: 726, 1979)
T
HE VALUE of high density lipoprotein cholesterol (HDL-C) measurement has been recently rediscovered, although the initial work appeared in the 1950s (1). Indeed, several epidemiological surveys indicated that HDL-C levels are a better predictor of coronary artery disease than total cholesterol and constitute an independent antirisk factor, whereby a high level appears to protect against ischemic heart disease (2-5). Moreover, increased longevity was found in subjects with raised HDL-C levels (6). In addition, HDL-C levels show a negative correlation with triglyceride (TG) levels. Thus, serum HDL-C concentrations are low in the hypertriglyceridemias, whether primary or associated with uremia, uncontrolled diabetes mellitus, weight gain, or a diet very rich in carbohydrates (7, 8). As exceptions, alcohol and estrogens seem to induce an increase in both TG and HDL-C levels (9). The metabolism of HDL-C is presently being clarified. The chylomicrons and HDL are rich in apoproteins A-I and A-II, and chylomicron serves as a precursor for HDL (10). Furthermore, HDL is also synthesized in the intestine and liver (11). HDL may interfere with cellular uptake of cholesterol (12-14) and appears to be involved in removing cholesterol from peripheral tissue and transporting it back to the liver, where it is catabolized and excreted (15). However, the degrada-
tion of HDL remains largely unknown. Many studies have been published regarding the impact of hyperthyroidism and hypothyroidism on lipid metabolism (16-22). One report has appeared concerning HDL-C levels in hypothyroidism (23). Our purpose in this paper is to present data on the alteration of plasma HDL-C in thyroid disorders and to assess the effects of the normalization of T4 levels on the levels of HDL-C. Materials and Methods We studied 37 euthyroid healthy female subjects, 22 female hypothyroid patients (of whom 9 were restudied after L-T 4 replacement therapy), and 16 hyperthyroid female patients. To keep homogeneity in our study, we excluded all male patients because the majority of the patients were female and because of the sex difference in HDL-C levels. The age of the control group, 42.4 ± 15 yr (mean ± SD), was younger than that of the hypothyroid group (63.8 ± 12 yr) but was not significantly different from that of the hyperthyroid group (50.5 ± 16.7). In most instances, the hypothyroid patients were overtly hypothyroid and on no drugs when studied, and none were obese. All had primary hypothyroidism with markedly elevated TSH levels, except for one case with hypothalamic hypothyroidism. The hyperthyroid group was investigated before institution of drug therapy, except in two cases where propranolol and propylthiouracil were started a few days before sampling. These drugs were omitted on the morning that blood was drawn. The hyperthyroid group included 12 cases of Graves' disease and 4 cases of multinodular toxic goiter. In addition, we investigated a fourth group of subjects which consisted of 8 adult male healthy volunteers studied when euthyroid, after taking 0.3 mg L-T 4 daily for a month.
Received September 19, 1978. Address requests for reprints to: N. D. Schnuda, M.D., Department of Pathology, Edgewater Hospital-Mazel Medical Center, 5700 North Ashland Avenue, Chicago, Illinois 60660. * This work was supported by General Research Support Grant BR5366 from the General Research Support Branch, Division of Research Facilities and Resources, NIH. 726
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 17 November 2015. at 14:21 For personal use only. No other uses without permission. . All rights reserved.
PLASMA HDL-C IN THYROID DISEASE
727 Hypothyroid (N=9$)
Assays Venous blood was drawn from all subjects after an overnight fast. A tube with no anticoagulant was secured for T4, T 3 resin uptake, and TSH levels, and another tube containing disodium EDTA was used for the lipid profile. The tubes with disodium EDTA were centrifuged, and the plasma was stored at —20 C until assay [freezing has been previously shown not to affect HDL analysis (5)]. T4, T3 resin uptake, and TSH were analyzed by RIA. In our laboratory, the normal values for T4 were 5-12 /ig/dl, for T3 resin uptake were 25-35%, and for TSH were less than 8 /xIU/ml. TGs and total cholesterol (TC) were analyzed by enzymatic procedures. For the HDL-C, the plasma were treated with sodium phosphotungstate-Mg+2, followed by centrifugation and subsequent measurement of HDL-C in the supernatant using the same method as for TC (22). The levels of low density lipoprotein cholesterol (LDL-C) were determined indirectly using the formula of Friedewald, Levy, and Fredrickson (24): LDL-C = TC - [HDL-C + (TG/5)]. This formula is valid for blood specimens whose TG levels are less than 400 mg/dl in the absence of type III and chylomicronemia. All patients in this series met these criteria. For statistical analysis we used Student's t test for nonpaired (Fig. 1) and paired data (Figs. 2 and 3 and Table 1). Pearson's correlation coefficient (r) was used to show the degree of linear association among the different variables. The results are expressed as the mean ± SD. Results In agreement with other studies, we found substantially higher HDL-C levels in women (51.5 ± 13 mg/dl) than in men (32 ± 8.4) and a very slight difference among the different age groups after age 40 yr (4). Although our control euthyroid group is younger than the hypothyroid group, this difference in age should not affect the results.
360 320 280 240 200 160 120 80 40
P=0.02
Before Rx
After Rx
***
10
TC LDL-C HDL-C TG T4 FIG. 2. Plasma lipid levels and serum T4 in nine hypothyroid subjects before and after thyroid replacement therapy (mean + SD). *, P < 0.05; '*, P
