Impact of Graves’ hyperthyroidism treatment on lipid profiles and cholesterol dynamics: a prospective observational study

Abstract

Background:

The impact of Graves’ hyperthyroidism treatment on lipid metabolism remains unclear. This prospective observational study aimed to clarify the changes in lipid profiles and associated metabolic pathways, including cholesterol synthesis, absorption, and low-density lipoprotein (LDL) receptor regulation, following treatment.

Methods:

Seventeen patients newly diagnosed with Graves’ hyperthyroidism were enrolled and followed for 6 months after achieving euthyroid status. Serum lipids (total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides), apolipoproteins, non-cholesterol sterols (markers of cholesterol synthesis and absorption), proprotein convertase subtilisin/kexin type 9 (PCSK9), and lipoprotein lipase (LPL) levels were measured at baseline, at euthyroid status (Eu-0M), and 6 months after euthyroid status (Eu-6M).

Results:

After treatment, serum total cholesterol, LDL-C, and HDL-C levels increased rapidly compared to baseline, while triglyceride levels showed a delayed but significant increase at Eu-6M. Levels of apolipoprotein (apo) AI, AII, B, and CIII increased significantly after treatment, whereas apo B-48 increased only at Eu-6M, and apo CII and apo E remained unchanged. Markers of cholesterol synthesis (lathosterol) and absorption (sitosterol, campesterol, and cholestanol) increased significantly after treatment, indicating enhanced cholesterol metabolism. Circulating PCSK9 levels increased significantly and remained elevated, while LPL levels did not change significantly.

Conclusion:

Treatment of Graves’ hyperthyroidism rapidly increases cholesterol levels through enhanced cholesterol synthesis and absorption, possibly mediated by increased circulating PCSK9.

Keywords

Graves’ hyperthyroidism lipid non-cholesterol sterols proprotein convertase subtilisin/kexin type 9

Introduction

Thyroid hormones strongly influence blood lipid profiles, particularly blood cholesterol levels.¹ Blood cholesterol levels are regulated by absorption from the small intestine, endogenous synthesis in the liver, and excretion from the liver as bile acids into the intestine.^2–4 In rodents, thyroid hormones have been reported to decrease intestinal cholesterol absorption,⁵ increase low-density lipoprotein (LDL) receptor (LDL-R) expression on hepatocyte surfaces,^6–9 and decrease hepatic apolipoprotein (apo) B production,^10,11 which is necessary to release cholesterol from the liver into the bloodstream as very low-density lipoprotein (VLDL).¹² These cellular responses contribute to the lowering of blood cholesterol levels. On the other hand, thyroid hormones have also been reported to promote cholesterol synthesis by inducing hydroxymethylglutaryl CoA (HMG-CoA) reductase,^6,9 possibly leading to increased blood cholesterol levels. However, in humans, it is well known that serum LDL-cholesterol (LDL-C) levels are low in patients with hyperthyroidism.¹ Given the substantial differences in cholesterol metabolism between humans and rodents,¹³ there remains an unmet need to further elucidate the influence of thyroid hormones on cholesterol dynamics in humans.

To assess cholesterol dynamics in humans, it is useful to measure serum non-cholesterol sterols, which reflect the endogenous synthesis and intestinal absorption of cholesterol.^14–16 Four serum non-cholesterol sterols are commonly used as markers: lathosterol, sitosterol, campesterol, and cholestanol. Lathosterol is a precursor of cholesterol that is synthesized in the body and is an indicator of total body cholesterol synthesis.^16,17 The plant sterols, sitosterol and campesterol, which cannot be synthesized in the body and are absorbed via Niemann-Pick C1-like 1 (NPC1L1) in enterocytes, serve as markers of cholesterol absorption.^14,16,18 Cholestanol, a metabolite of cholesterol, is also used as an absorption marker.^16,19 Variations in serum non-cholesterol sterols have been studied in patients with dyslipidemia associated with metabolic abnormalities such as type 2 diabetes^16,20,21; however, reports on these variations in endocrine disorders such as hyperthyroidism remain limited. In addition to non-cholesterol sterols, proprotein convertase subtilisin/kexin type 9 (PCSK9), which plays a crucial role in LDL-R degradation,²² is valuable for understanding cholesterol dynamics. To date, only one study by Bonde et al.²³ has reported increased cholesterol absorption markers (sitosterol and campesterol) and PCSK9 without changes in lathosterol after treatment of hyperthyroidism. However, that study included not only patients with Graves’ disease but also those with autonomously functioning thyroid nodules and thyroiditis.

Although previous studies have shown that blood lipid levels increase after hyperthyroidism treatment, the underlying mechanisms remain insufficiently understood in humans.⁶ Therefore, the present study aimed to comprehensively investigate the effect of Graves’ hyperthyroidism treatment on lipid metabolism. Serum lipids, apolipoproteins, non-cholesterol sterols, PCSK9, and lipoprotein lipase (LPL) were measured to characterize lipid profiles and cholesterol dynamics in Graves’ hyperthyroidism and post-treatment euthyroidism.

Materials and methods

Subjects

This study was designed as a single-arm, prospective observational study to investigate the effects of Graves’ hyperthyroidism treatment on lipid profiles and cholesterol metabolism. We enrolled 17 outpatients who were newly diagnosed with Graves’ hyperthyroidism between April 2015 and September 2018. All the patients were diagnosed with Graves’ hyperthyroidism based on elevated thyroid-stimulating hormone (TSH) receptor antibodies (TRAb ⩾ 2.0 IU/L) in the blood and/or elevated ^99mTc-pertechnetate uptake (>1.0%) on thyroid scintigraphy. All participants were prescribed antithyroid medications (thiamazole, propylthiouracil, or potassium iodide) as part of their routine clinical management. No lipid-lowering agents were initiated or continued during the study period. One patient had a history of dyslipidemia, but lipid-lowering treatment had been discontinued more than 2 years prior to study entry. Thus, no participants were receiving lipid-modifying therapy during the observation.

Clinical measurements

Height and weight were measured and used to calculate body mass index (BMI). Blood samples were taken from the patients in the fasting state before treatment (0M, baseline), at the first achievement of euthyroid state after treatment (Eu-0M), and 6 months after achievement of euthyroid state (Eu-6M). TSH, free T3 (fT3), free T4 (fT4), total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triacylglycerol (TG), apo AI, AII, B, B-48, CII, CIII, E, non-cholesterol sterols (sitosterol, campesterol, cholestanol, and lathosterol), PCSK9, and LPL were measured in the blood sera at 0M, Eu-0M, and Eu-6M. In the present study, “euthyroid” was defined as the state that fT3 and fT4 levels are within the normal range, even when TSH was lower than the normal range, because TSH suppression often persists during treatment of Graves’ hyperthyroidism. Eu-0M was defined as the first time point when thyroid hormone levels (fT3 and fT4) returned to the reference range, allowing assessment of immediate metabolic responses to treatment. Eu-6M was selected to evaluate delayed or sustained changes in lipid metabolism and cholesterol dynamics after achieving stable euthyroid status.

Laboratory analysis

TSH, fT3, and fT4 were measured by electro-chemiluminescent immunoassay. TRAb were measured by chemiluminescence (ECLusis TRAb; Roche Diagnostics Ltd., Basel, Switzerland). TC, HDL-C, and TG were measured by enzymatic methods (Sekisui Medical, Tokyo, Japan). LDL-C levels were calculated using the Friedewald formula.^24,25 Apo AI, AII, B, CII, CIII, and E were measured using a turbidimetric immunoassay using Daiichi kits (Sekisui Medical). Apo B-48 was measured by using the apo B-48 CLEIA kit (Fujirebio Inc., Tokyo, Japan). Non-cholesterol sterols were assayed by gas chromatography using GC-2010 (Shimadzu Co., Kyoto, Japan). Pre-heparin LPL mass was determined by using the LPL ELISA Daiichi kit (Sekisui Medical). PCSK9 levels were measured by enzyme-linked immunosorbent assay using the CircuLex Human PCSK ELISA kit (CycLex, Tokyo, Japan).

Statistical analysis

For each variable, the Shapiro-Wilk test was performed to assess normality. Variables with a p-value ⩾ 0.05 were considered normally distributed and are presented as mean ± standard deviation (SD), while those with a p-value <0.05 were considered non-normally distributed and are presented as median [interquartile range (IQR)]. For normally distributed variables, after the repeated measures ANOVA confirmed the presence of variance among the three time points (0M, Eu-0M, and Eu-6M), a paired T-test was used to determine statistical differences at each time point. For non-normally distributed variables, after the Friedman test confirmed the presence of variance among the three time points (0M, Eu-0M, and Eu-6M), the Wilcoxon signed rank test was used to determine statistical differences at each time point. A p-value <0.05 was considered statistically significant. Statistical analyses were performed using JMP Pro 14 software (SAS Institute Inc., Cary, NC, USA) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan).²⁶

Results

Clinical characteristics of the 17 enrolled patients are summarized in Table 1. All patients were positive for TRAb, and increased thyroid uptake of ^99mTc-pertechnetate was confirmed in 16 patients. The euthyroid state was first achieved approximately 4 months after initiating treatment. After achieving euthyroid state, thyroid function parameters (TSH, fT4, and fT3) significantly improved and remained stable throughout the observational period, accompanied by significant increases in body weight and BMI.

Table 1.

Characteristics of the participants.

Variables	0M	Eu-0M	Eu-6M
n (Female/Male)	17 [13/4]	—	—
Age (years)	45.9 ± 11.7	—	—
Duration (days)	0	129 [78–188]	322 [304–381]
Body weight (kg)	51.5 [47.0–63.8]	53.9 [48.8–64.7]**	53.3 [51.3–65.8]***
BMI (kg/m²)	21.3 ± 3.4	22.3 ± 3.8**	23.0 ± 4.0***
TSH (µIU/mL)	0.005 [0.005–0.005]	0.015 [0.005–0.942]***	0.845 [0.059–1.55]***
fT3 (pg/mL)	15.7 ± 6.5	3.1 ± 0.8***	3.1 ± 0.6***
fT4 (ng/dL)	4.34 [2.99–7.04]	1.02 [0.92–1.12]***	1.09 [0.97–1.28]***
TRAb (IU/L)	8.5 [4.4–12.3]	5.4 [3.0–7.2]**	2.2 [1.9–5.1]***
^99mTc uptake (%, n = 16)	7.1 ± 4.0	—	—

Continuous variables are expressed as mean ± SD if normally distributed, or as median [interquartile range] if not.

**p < 0.01, and ***p < 0.001 versus 0M (baseline) by the Wilcoxon signed rank test for non-normally distributed variables or by the paired T-test for normally distributed variables.

0M, before treatment (baseline); ^99mTc uptake, ^99mTc-pertechnetate thyroid uptake; BMI, body mass index; Eu-0M, first achievement of euthyroid state after treatment; Eu-6M, 6 months after the achievement of euthyroid state; fT3, free triiodothyronine; fT4, free thyroxine; SD, standard deviation; TRAb, TSH receptor antibody (third generation assay); TSH, thyroid-stimulating hormone.

Changes in serum lipid parameters at baseline and after treatment of Graves’ hyperthyroidism are shown in Table 2. Serum TC, HDL-C, and LDL-C levels increased significantly and rapidly after treatment (Eu-0M), and remained stable through Eu-6M without further significant changes. Conversely, serum TG levels initially remained unchanged but showed a delayed significant increase at Eu-6M. Overall, non-HDL-C levels increased significantly at Eu-0M and Eu-6M. Levels of apo AI, AII, B, and CIII also increased significantly after treatment, with apo B-48 showing a significant increase only at Eu-6M. In contrast, apo CII and apo E did not change significantly. Markers reflecting cholesterol synthesis (lathosterol) and absorption (sitosterol, campesterol, and cholestanol) increased significantly following treatment, indicating enhanced cholesterol metabolism. Circulating PCSK9 levels increased significantly and remained elevated, possibly contributing to reduced LDL-R expression and subsequent cholesterol elevation. LPL did not show any significant changes after treatment.

Table 2.

Changes in serum lipid parameters.

Variables	0M	Eu-0M	Eu-6M
TC (mg/dL)	135 [133–160]	222 [190–234]***	228 [174–263]***
HDL-C (mg/dL)	49.7 ± 12.6	67.9 ± 20.0***	64.2 ± 20.0***
LDL-C (mg/dL)	77.8 ± 20.9	138.9 ± 43.9***	134.5 ± 37.4***
TG (mg/dL)	74 [59–87]	88 [61–122]	89 [62–167]*
Non-HDL-C (mg/dL)	94.8 ± 19.9	157.1 ± 47.5***	157.1 ± 43.7***
Apolipoproteins
AI (mg/dL)	134 [130–146]	178 [142–186]***	167 [139–186]***
AII (mg/dL)	25.1 [23.5–26.1]	28.4 [27.5–33.7]***	30.8 [28.2–35.7]***
B (mg/dL)	60 [55–68]	93 [82–101]***	96 [79–126]***
B-48 (μg/mL)	2.6 [1.6–3.5]	3.3 [2.1–4.5]	3.8 [2.1–6.0]*
CII (mg/dL)	2.8 [2.3–3.5]	3.3 [2.5–4.2]	3.8 [2.2–5.5]
CIII (mg/dL)	5.9 [5.1–7.2]	8 [7–9.8]**	9.4 [7.2–10.8]***
E (mg/dL)	3.9 [3.2–4.5]	4.0 [3.4–4.4]	4.5 [3.7–4.9]
Non-cholesterol sterols
Sitosterol (μg/mL)	1.2 [1.1–1.6]	2.5 [2.2–3.0]***	2.2 [2.1–3.0]***
Campesterol (μg/mL)	2.2 [1.8–2.6]	4.1 [3.5–4.6]***	3.7 [3.3–5.4]***
Cholestanol (μg/mL)	1.6 [1.5–1.8]	2.8 [2.6–3.3]***	2.7 [2.0–3.5]***
Lathosterol (μg/mL)	1.5 [1.3–2.2]	2.1 [1.7–2.9]**	2.1 [1.5–3.5]**
PCSK9 (ng/mL)	153 [141–203]	210 [165–275]**	231 [192–251]**
LPL (ng/mL)	48 [34–59]	59 [47–79]	63 [52–75]

Continuous variables are expressed as mean ± SD if normally distributed, or as median [interquartile range] if not.

p < 0.05, **p < 0.01, and ***p < 0.001 versus 0M (baseline) by the Wilcoxon signed rank test for non-normally distributed variables or by the paired T-test for normally distributed variables.

0M, before treatment (baseline); Eu-0M, first achievement of euthyroid state after treatment; Eu-6M, 6 months after the achievement of euthyroid state; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LPL, lipoprotein lipase; PCSK9, proprotein convertase subtilisin/kexin type 9; SD, standard deviation; TC, total cholesterol; TG, triacylglycerol.

Discussion

In the present study, we investigated the effect of Graves’ hyperthyroidism treatment on the lipid profile, particularly focusing on cholesterol dynamics. We showed here that TC, LDL-C, and HDL-C levels increased rapidly, followed by TG levels, after treatment of Graves’ hyperthyroidism. These changes in blood cholesterol and TG levels were accompanied by increases in apo AI, AII, B, CIII, and B-48 levels. We also observed significant elevations in serum levels of lathosterol, sitosterol, campesterol, cholestanol, and PCSK9 following treatment of Graves’ hyperthyroidism, suggesting that thyroid hormone normalization enhances both cholesterol absorption and synthesis, resulting in dual modulation of cholesterol metabolism through intestinal and hepatic pathways.

Previous rodent studies have shown that thyroid hormones lower blood LDL-C levels by decreasing intestinal cholesterol absorption⁵ and hepatic apo B production,^10,11 and by increasing LDL-R expression on hepatocyte surfaces.^6,9 Therefore, it is reasonable to speculate that treatment of hyperthyroidism increases LDL-C levels by correcting these perturbations caused by excessive thyroid hormone levels. This study confirmed that treatment resulted in increased serum levels of sitosterol, campesterol, cholestanol, and apo B, suggesting a restoration of decreased cholesterol absorption and apo B production. In addition, elevated PCSK9 levels likely corrected the enhanced LDL-R expression seen in hyperthyroidism. Previous rodent studies also suggested that thyroid hormones stimulate hepatic cholesterol synthesis by inducing HMG-CoA reductase^6,9; therefore, treatment of hyperthyroidism would theoretically suppress cholesterol synthesis. Surprisingly, our findings revealed increased serum lathosterol levels after treatment, indicating increased cholesterol synthesis. Cholesterol synthesis is regulated by HMG-CoA reductase and is subject to negative feedback from intracellular cholesterol levels.³ Increased circulating PCSK9 levels following treatment of hyperthyroidism likely reduced LDL-R expression, thus decreasing intracellular cholesterol levels, which may have subsequently induced HMG-CoA reductase activity, supporting the observed increase in cholesterol synthesis.

Thyroid hormones have been suggested to regulate blood HDL-C levels via several pathways; (1) activation of hepatic triglyceride lipase (HTGL)^27,28 to hydrolyze TG and phospholipid-rich HDL (HDL-2) to a smaller HDL (HDL-3), (2) activation of cholesteryl ester transfer protein to transfer cholesteryl esters from serum HDL to VLDL and LDL,^1,6,27 and (3) increasing expression of scavenger receptor class B type 1 to enhance the uptake of cholesteryl esters from HDL.^29,30 These pathways all typically lead to reduced blood HDL-C levels. It is well known that patients with hyperthyroidism have low HDL-C levels, and several studies have reported HDL-C elevation after treatment, consistent with our findings in Graves’ hyperthyroidism. The major apolipoproteins of HDL are apo AI (70%) and AII (15–20%).³¹ While several studies have shown low apo AI levels in patients with hyperthyroidism that increase significantly after treatment,^23,32,33 results regarding apo AII levels are inconsistent.^23,32,33 Our findings support those of Bonde et al.,²³ showing significant apo AII increases after treatment. Further studies are necessary to clarify the underlying mechanisms regulating apo AII metabolism in hyperthyroidism.

In our study, serum TG levels increased gradually after treatment, in contrast to the rapid cholesterol increase. Previous studies did not report such changes,^23,30 possibly due to shorter observational periods. The delayed TG increase corresponded to changes in apo B-48 levels. Thyroid hormones enhance transcription of LDL-R-related protein 1, promoting uptake of chylomicron (CM) remnants.³⁰ Therefore, increased TG and apo B-48 levels after treatment may result from reduced CM remnant uptake. Although body weight and BMI increased significantly at Eu-0M and Eu-6M, TG changes were not correlated with these factors, as determined by Spearman’s correlation analysis (data not shown). This suggests that increased TG levels after treatment of Graves’ hyperthyroidism cannot be simply explained by weight gain alone.

Based on our results, normalization of thyroid hormone levels in Graves’ disease appears to modulate both cholesterol absorption and synthesis, leading to significant increases in LDL-C, apo B, and B-48 levels, all of which are closely linked to increased atherogenicity. Although anti-atherogenic HDL-C and apo AI levels also increased, non-HDL-C levels increased significantly after the treatment. Therefore, these findings highlight the importance of monitoring blood lipids and apolipoproteins associated with atherosclerosis during and after treatment of hyperthyroidism. If these conditions persist over an extended period, initiating appropriate therapeutic interventions for dyslipidemia should be considered to reduce cardiovascular risk.

The present study had several limitations. First, as a single-arm, observational study without a control group, we could not exclude the possibility that factors other than thyroid hormone influenced lipid profiles. Participants were outpatients whose diets were uncontrolled, potentially influencing lipid changes. Second, lipid profiles were assessed only in the fasting state. Given TG elevation after treatment, assessing postprandial lipid profiles may be necessary. Third, the sample size was small, comparable to previous studies,^23,27 highlighting the need for larger future studies. Fourth, a sex disproportion occurred naturally due to the higher prevalence of Graves’ hyperthyroidism in women³⁴; thus, our study could not assess potential sex differences in lipid profile changes.

Conclusion

After treatment of Graves’ hyperthyroidism, LDL-C and HDL-C levels increased rapidly, followed by delayed TG increases. By evaluating apolipoproteins, non-cholesterol sterols, and circulating PCSK9, we gained comprehensive insights into cholesterol dynamics. Increased LDL-C after treatment appears driven by enhanced cholesterol synthesis and absorption and increased apo B production. Elevated PCSK9 levels may decrease LDL-R expression, inhibiting LDL clearance and thus promoting cholesterol synthesis through reduced intracellular cholesterol. These findings could help improve management and reduce cardiovascular risk associated with thyroid-related dyslipidemia.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Tomoko Nagamine

Mototsugu Nagao

Shunsuke Kobayashi

Mikiko Okazaki-Hada

References

Duntas

. Thyroid disease and lipids. Thyroid 2002; 12: 287–293.

Matthan

Lichtenstein

. Approaches to measuring cholesterol absorption in humans. Atherosclerosis 2004; 174: 197–205.

Kruit

Groen

van Berkel

, et al. Emerging roles of the intestine in control of cholesterol metabolism. World J Gastroenterol 2006; 12: 6429–6439.

Russell

. Fifty years of advances in bile acid synthesis and metabolism. J Lipid Res 2009; 50 Suppl: S120–S125.

Gälman

Bonde

Matasconi

, et al. Dramatically increased intestinal absorption of cholesterol following hypophysectomy is normalized by thyroid hormone. Gastroenterology 2008; 134: 1127–1136.

Sinha

Singh

Yen

. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol 2018; 14: 259–269.

Shin

Osborne

. Thyroid hormone regulation and cholesterol metabolism are connected through Sterol Regulatory Element-Binding Protein-2 (SREBP-2). J Biol Chem 2003; 278: 34114–34118.

Lopez

Abisambra Socarrás

Bedi

, et al. Activation of the hepatic LDL receptor promoter by thyroid hormone. Biochim Biophys Acta 2007; 1771: 1216–1225.

Mullur

Liu

Brent

. Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94: 355–382.

10.

Davidson

Powell

Wallis

, et al. Thyroid hormone modulates the introduction of a stop codon in rat liver apolipoprotein B messenger RNA. J Biol Chem 1988; 263: 13482–13485.

11.

Mukhopadhyay

Plateroti

Anant

, et al. Thyroid hormone regulates hepatic triglyceride mobilization and apolipoprotein B messenger ribonucleic acid editing in a murine model of congenital hypothyroidism. Endocrinology 2003; 144: 711–719.

12.

Glavinovic

Thanassoulis

de Graaf

, et al. Physiological bases for the superiority of apolipoprotein B over low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol as a marker of cardiovascular risk. J Am Heart Assoc 2022; 11: e025858.

13.

Straniero

Laskar

Savva

, et al. Of mice and men: murine bile acids explain species differences in the regulation of bile acid and cholesterol metabolism. J Lipid Res 2020; 61: 480–491.

14.

Miettinen

Tilvis

Kesäniemi

. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am J Epidemiol 1990; 131: 20–31.

15.

Miettinen

Gylling

Nissinen

. The role of serum non-cholesterol sterols as surrogate markers of absolute cholesterol synthesis and absorption. Nutr Metab Cardiovasc Dis 2011; 21: 765–769.

16.

Mashnafi

Plat

Mensink

, et al. Non-cholesterol sterol concentrations as biomarkers for cholesterol absorption and synthesis in different metabolic disorders: a systematic review. Nutrients 2019; 11: 124.

17.

Kempen

Glatz

Gevers Leuven

, et al. Serum lathosterol concentration is an indicator of whole-body cholesterol synthesis in humans. J Lipid Res 1988; 29: 1149–1155.

18.

Altmann

Davis

Jr Zhu

, et al. Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 2004; 303: 1201–1204.

19.

Miettinen

Tilvis

Kesäniemi

. Serum cholestanol and plant sterol levels in relation to cholesterol metabolism in middle-aged men. Metabolism 1989; 38: 136–140.

20.

Gylling

Hallikainen

Pihlajamäki

, et al. Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study. J Lipid Res 2010; 51: 2422–2427.

21.

Lau

Journoud

Jones

. Plant sterols are efficacious in lowering plasma LDL and non-HDL cholesterol in hypercholesterolemic type 2 diabetic and nondiabetic persons. Am J Clin Nutr 2005; 81: 1351–1358.

22.

Zhang

Lagace

Garuti

, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 2007; 282: 18602–18612.

23.

Bonde

Breuer

Lütjohann

, et al. Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans. J Lipid Res 2014; 55: 2408–2415.

24.

Friedewald

Levy

Fredrickson

. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502.

25.

Romaszko

Gromadziński

Buciński

. Friedewald formula may be used to calculate non-HDL-C from LDL-C and TG. Front Med (Lausanne) 2023; 10: 1247126.

26.

Kanda

. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 2013; 48: 452–458.

27.

Tan

Shiu

Kung

. Effect of thyroid dysfunction on high-density lipoprotein subfraction metabolism: roles of hepatic lipase and cholesteryl ester transfer protein. J Clin Endocrinol Metab 1998; 83: 2921–2924.

28.

Ito

Takamatsu

Matsuo

, et al. Serum concentrations of remnant-like particles in hypothyroid patients before and after thyroxine replacement. Clin Endocrinol (Oxf) 2003; 58: 621–626.

29.

Sinha

Singh

Yen

. Thyroid hormone regulation of hepatic lipid and carbohydrate metabolism. Trends Endocrinol Metab 2014; 25: 538–545.

30.

Moon

Kim

, et al. Decreased expression of hepatic low-density lipoprotein receptor-related protein 1 in hypothyroidism: a novel mechanism of atherogenic dyslipidemia in hypothyroidism. Thyroid 2013; 23: 1057–1065.

31.

Davidson

Thompson

. The structure of apolipoprotein A-I in high density lipoproteins. J Biol Chem 2007; 282: 22249–22253.

32.

Muls

Blaton

Rosseneu

, et al. Serum lipids and apolipoproteins A-I, A-II, and B in hyperthyroidism before and after treatment. J Clin Endocrinol Metab 1982; 55: 459–464.

33.

Muls

Rosseneu

Bury

, et al. Hyperthyroidism influences the distribution and apolipoprotein A composition of the high density lipoproteins in man. J Clin Endocrinol Metab 1985; 61: 882–889.

34.

Chaker

Cooper

Walsh

, et al. Hyperthyroidism. Lancet 2024; 403: 768–780.