Lipoprotein particles in patients with pediatric Cushing disease and possible cardiovascular risks

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Abstract

Background:

Cardiovascular (CV) complications are the most significant cause of mortality in adults with Cushing disease (CD); little is known about CV risk factors in children with CD. Measurement of lipoprotein particles by nuclear magnetic resonance (NMR) spectroscopy is a novel technology to assess CV risk. The objective of the current study is to analyze the NMR lipid profile in pediatric CD patients before and 1 year after remission.

Methods:

NMR lipid profile was obtained via the Vantera NMR analyzer, using frozen serum samples from 33 CD patients (mean age 13.8 ± 4.0 years) evaluated between 1997 and 2017 at the National Institutes of Health (NIH) Clinical Center (CC).

Results:

GlycA, triglyceride-rich particles (TRLP medium and very small sizes), LDL particles (LDLP total and large size), HDL particles (HDLP total, medium and small sizes), total cholesterol, LDL cholesterol, HDL cholesterol, GlycA inflammatory biomarker, Apolipoprotein B and Apolipoprotein A1 concentrations showed statistically significant changes after remission of CD (p<0.05).

Conclusion:

In our study population, most of the lipid variables improved post-CDremission, with the exception of HDL and apoA1, indicating that NMR lipoprotein profile may be a helpful tool in assessing the cardiovascular risk in pediatric patients with CD.

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Most cited references 20

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Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy.

Elias Jeyarajah, William C Cromwell, James D. Otvos (2006)

Laboratory measurements of plasma lipids (principally cholesterol and triglycerides) and lipoprotein lipids (principally low-density lipoprotein [LDL] and low-density lipoprotein [HDL] cholesterol) are the cornerstone of the clinical assessment and management of atherosclerotic cardiovascular disease (CVD) risk. LDL particles, and to a lesser extent very-low-density lipoprotein [VLDL] particles, cause atherosclerosis, whereas HDL particles prevent or reverse this process through reverse cholesterol transport. The overall risk for CVD depends on the balance between the "bad" LDL (and VLDL) and "good" HDL particles. Direct assessment of lipoprotein particle numbers us now possible through nuclear magnetic resonance spectroscopic analysis.

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Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance.

W. T. Garvey, S. Kwon, D. Zheng … (2003)

The insulin resistance syndrome (IRS) is associated with dyslipidemia and increased cardiovascular disease risk. A novel method for detailed analyses of lipoprotein subclass sizes and particle concentrations that uses nuclear magnetic resonance (NMR) of whole sera has become available. To define the effects of insulin resistance, we measured dyslipidemia using both NMR lipoprotein subclass analysis and conventional lipid panel, and insulin sensitivity as the maximal glucose disposal rate (GDR) during hyperinsulinemic clamps in 56 insulin sensitive (IS; mean +/- SD: GDR 15.8 +/- 2.0 mg. kg(-1). min(-1), fasting blood glucose [FBG] 4.7 +/- 0.3 mmol/l, BMI 26 +/- 5), 46 insulin resistant (IR; GDR 10.2 +/- 1.9, FBG 4.9 +/- 0.5, BMI 29 +/- 5), and 46 untreated subjects with type 2 diabetes (GDR 7.4 +/- 2.8, FBG 10.8 +/- 3.7, BMI 30 +/- 5). In the group as a whole, regression analyses with GDR showed that progressive insulin resistance was associated with an increase in VLDL size (r = -0.40) and an increase in large VLDL particle concentrations (r = -0.42), a decrease in LDL size (r = 0.42) as a result of a marked increase in small LDL particles (r = -0.34) and reduced large LDL (r = 0.34), an overall increase in the number of LDL particles (r = -0.44), and a decrease in HDL size (r = 0.41) as a result of depletion of large HDL particles (r = 0.38) and a modest increase in small HDL (r = -0.21; all P < 0.01). These correlations were also evident when only normoglycemic individuals were included in the analyses (i.e., IS + IR but no diabetes), and persisted in multiple regression analyses adjusting for age, BMI, sex, and race. Discontinuous analyses were also performed. When compared with IS, the IR and diabetes subgroups exhibited a two- to threefold increase in large VLDL particle concentrations (no change in medium or small VLDL), which produced an increase in serum triglycerides; a decrease in LDL size as a result of an increase in small and a reduction in large LDL subclasses, plus an increase in overall LDL particle concentration, which together led to no difference (IS versus IR) or a minimal difference (IS versus diabetes) in LDL cholesterol; and a decrease in large cardioprotective HDL combined with an increase in the small HDL subclass such that there was no net significant difference in HDL cholesterol. We conclude that 1) insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) in type 2 diabetes, the lipoprotein subclass alterations are moderately exacerbated but can be attributed primarily to the underlying insulin resistance; and 3) these insulin resistance-induced changes in the NMR lipoprotein subclass profile predictably increase risk of cardiovascular disease but were not fully apparent in the conventional lipid panel. It will be important to study whether NMR lipoprotein subclass parameters can be used to manage risk more effectively and prevent cardiovascular disease in patients with the IRS.

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Morbidity and mortality in Cushing's disease: an epidemiological approach.

J Etxabe, Miguel A Salazar Vázquez (1994)

Although Cushing's disease is a well documented clinical entity, there is no epidemiological information about it. The present study tries to obtain this information. Forty-nine patients affected by Cushing's disease living in Vizcaya (Spain) between 1975 and 1992 were considered for an epidemiological study. The prevalence of known cases at the end of 1992 was 39.1 per million inhabitants. The average incidence of newly diagnosed cases was 2.4 cases per million people per year. Cushing's disease was more frequent in women (n = 46) than in men (n = 3), with a ratio of 15:1. Diabetes mellitus and hypertension were observed in 38.7 and 55.1% of patients, respectively. Remission of Cushing's disease was achieved in 36 out of 41 patients (87.5%). In general, the mortality was higher than that expected for the control population (standardized mortality ratio, SMR 3.8, 95% confidence interval, CI 2.5-17.9, P < 0.03). Concerning the cause of death, the SMR of vascular disease was 5 (95% CI 3.4-48.6, P < 0.05). Higher age, persistence of hypertension and abnormalities of glucose metabolism after treatment, were independent predictors of mortality (multivariate analyses, P < 0.01). Prevalence of Cushing's disease was 39.1 cases/million inhabitants and average incidence was 2.4 cases/million per year. Mortality was elevated, due to vascular disease, associated with higher age, persistence of hypertension and impaired glucose metabolism.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0100714

Journal ID (pubmed-jr-id): 6400

Journal ID (nlm-ta): Pediatr Res

Journal ID (iso-abbrev): Pediatr. Res.

Title: Pediatric research

ISSN (Print): 0031-3998

ISSN (Electronic): 1530-0447

Publication date Nihms-submitted: 6 June 2019

Publication date (Electronic): 21 May 2019

Publication date (Print): September 2019

Publication date PMC-release: 21 November 2019

Volume: 86

Issue: 3

Pages: 375-381

Affiliations

[1 ] Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland;

[2 ]Biostatistics and Clinical Epidemiology Service, National Institutes of Health, Bethesda, Maryland;

[3 ]National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland

[4 ]Division of Pediatric Endocrinology, Department of Pediatrics, University of California San Francisco, San Francisco, California

Author notes

Correspondence: Angeliki Makri, MD, MSc, Building 10, Rm 2E-5140, 10 Center Drive, Bethesda, Maryland, 20892, Tel +1 301-827-1492, Fax +1 301-451-3959, angeliki.makri@ 123456gmail.com

Author Contributions:

Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; A.Makri, A.Cheung, N.Sinaii, AT.Remaley, M.Sampson, M.Keil, E.Belyavskaya, C.Lyssikatos, M.De La Luz Sierra, CA.Stratakis, M.Lodish.

Drafting the article or revising it critically for important intellectual content; A.Makri, N.Sinaii, CA.Stratakis, M.Lodish.

Final approval of the version to be published: AT.Remaley, CA.Stratakis, M.Lodish

Article

Manuscript ID: NIHMS1529369

DOI: 10.1038/s41390-019-0438-0

PMC ID: 6702083

PubMed ID: 31112990

SO-VID: 114c1db2-e157-4e7e-b98e-dcc0405fe434

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Lipoprotein particles in patients with pediatric Cushing disease and possible cardiovascular risks

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Abstract

Background:

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Most cited references 20

Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy.

Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance.

Morbidity and mortality in Cushing's disease: an epidemiological approach.

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