Effect of Lipoprotein(a) on the Diagnosis of Familial Hypercholesterolemia: Does it Make a Difference in the Clinic?

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Abstract

BACKGROUND: Diagnostic tools for familial hypercholesterolemia (FH) rely on estimation of LDL cholesterol concentration. However, routine measurement or calculation of LDL cholesterol concentration using the Friedewald equation contains a cholesterol contribution from lipoprotein(a) [Lp(a)]. We investigated whether Lp(a) influences the phenotypic diagnosis of FH by commonly used clinical criteria. METHODS: A cohort of 907 adult index patients attending a clinic were studied. The Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) diagnostic criteria were estimated before and after adjusting LDL cholesterol concentration for the cholesterol content (30%) of Lp(a). Diagnostic reclassification rates and area under the ROC (AUROC) curves in predicting an FH mutation were also compared. RESULTS: Seventy-four patients defined by DLCN criteria (8.2%) and 207 patients defined by SB criteria (22.8%) were reclassified to "unlikely" FH after adjusting LDL cholesterol for Lp(a) cholesterol. The proportion of FH patients defined by DLCN (probable/definite) and SB (possible/definite) criteria decreased significantly in patients with increased Lp(a) (>0.5 g/L; n = 330) after Lp(a) cholesterol adjustment (P < 0.01). The overall reclassification rate was significantly higher in patients with Lp(a) concentration >1.0 g/L (P < 0.001). The AUROC curve for LDL cholesterol concentration ≥191 mg/dL (≥5.0 mmol/L), DLCN criteria, and SB criteria in predicting an FH mutation increased significantly after adjustment (P < 0.001). There was no significant difference in AUROC curve before and after Lp(a) cholesterol adjustment at an LDL cholesterol concentration ≥251 mg/dL (≥6.5 mmol/L). CONCLUSIONS: Adjusting LDL cholesterol concentration for Lp(a) cholesterol improves the diagnostic accuracy of DLCN and SB criteria, especially with Lp(a) >1.0 g/L and LDL cholesterol <251 mg/dL (<6.5 mmol/L). Lp(a) should be measured in all patients suspected of having FH. © 2019 American Association for Clinical Chemistry.
Original languageEnglish
Pages (from-to)1258-1266
JournalClinical Chemistry
Volume65
Issue number10
DOIs
Publication statusPublished - Oct 2019

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Hyperlipoproteinemia Type II
Lipoprotein(a)
LDL Cholesterol
Cholesterol
Lipids
ROC Curve
Area Under Curve
Mutation

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@article{1d66b859b4034bf0a2da33f10deda922,
title = "Effect of Lipoprotein(a) on the Diagnosis of Familial Hypercholesterolemia: Does it Make a Difference in the Clinic?",
abstract = "BACKGROUND: Diagnostic tools for familial hypercholesterolemia (FH) rely on estimation of LDL cholesterol concentration. However, routine measurement or calculation of LDL cholesterol concentration using the Friedewald equation contains a cholesterol contribution from lipoprotein(a) [Lp(a)]. We investigated whether Lp(a) influences the phenotypic diagnosis of FH by commonly used clinical criteria. METHODS: A cohort of 907 adult index patients attending a clinic were studied. The Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) diagnostic criteria were estimated before and after adjusting LDL cholesterol concentration for the cholesterol content (30{\%}) of Lp(a). Diagnostic reclassification rates and area under the ROC (AUROC) curves in predicting an FH mutation were also compared. RESULTS: Seventy-four patients defined by DLCN criteria (8.2{\%}) and 207 patients defined by SB criteria (22.8{\%}) were reclassified to {"}unlikely{"} FH after adjusting LDL cholesterol for Lp(a) cholesterol. The proportion of FH patients defined by DLCN (probable/definite) and SB (possible/definite) criteria decreased significantly in patients with increased Lp(a) (>0.5 g/L; n = 330) after Lp(a) cholesterol adjustment (P < 0.01). The overall reclassification rate was significantly higher in patients with Lp(a) concentration >1.0 g/L (P < 0.001). The AUROC curve for LDL cholesterol concentration ≥191 mg/dL (≥5.0 mmol/L), DLCN criteria, and SB criteria in predicting an FH mutation increased significantly after adjustment (P < 0.001). There was no significant difference in AUROC curve before and after Lp(a) cholesterol adjustment at an LDL cholesterol concentration ≥251 mg/dL (≥6.5 mmol/L). CONCLUSIONS: Adjusting LDL cholesterol concentration for Lp(a) cholesterol improves the diagnostic accuracy of DLCN and SB criteria, especially with Lp(a) >1.0 g/L and LDL cholesterol <251 mg/dL (<6.5 mmol/L). Lp(a) should be measured in all patients suspected of having FH. {\circledC} 2019 American Association for Clinical Chemistry.",
author = "Chan, {Dick C.} and Jing Pang and Hooper, {Amanda J.} and Bell, {Damon A.} and Burnett, {John R.} and Watts, {Gerald F.}",
year = "2019",
month = "10",
doi = "10.1373/clinchem.2019.306738",
language = "English",
volume = "65",
pages = "1258--1266",
journal = "Clinical Chemistry",
issn = "0009-9147",
publisher = "AMER ASSOC CLINICAL CHEMISTRY",
number = "10",

}

TY - JOUR

T1 - Effect of Lipoprotein(a) on the Diagnosis of Familial Hypercholesterolemia

T2 - Does it Make a Difference in the Clinic?

AU - Chan, Dick C.

AU - Pang, Jing

AU - Hooper, Amanda J.

AU - Bell, Damon A.

AU - Burnett, John R.

AU - Watts, Gerald F.

PY - 2019/10

Y1 - 2019/10

N2 - BACKGROUND: Diagnostic tools for familial hypercholesterolemia (FH) rely on estimation of LDL cholesterol concentration. However, routine measurement or calculation of LDL cholesterol concentration using the Friedewald equation contains a cholesterol contribution from lipoprotein(a) [Lp(a)]. We investigated whether Lp(a) influences the phenotypic diagnosis of FH by commonly used clinical criteria. METHODS: A cohort of 907 adult index patients attending a clinic were studied. The Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) diagnostic criteria were estimated before and after adjusting LDL cholesterol concentration for the cholesterol content (30%) of Lp(a). Diagnostic reclassification rates and area under the ROC (AUROC) curves in predicting an FH mutation were also compared. RESULTS: Seventy-four patients defined by DLCN criteria (8.2%) and 207 patients defined by SB criteria (22.8%) were reclassified to "unlikely" FH after adjusting LDL cholesterol for Lp(a) cholesterol. The proportion of FH patients defined by DLCN (probable/definite) and SB (possible/definite) criteria decreased significantly in patients with increased Lp(a) (>0.5 g/L; n = 330) after Lp(a) cholesterol adjustment (P < 0.01). The overall reclassification rate was significantly higher in patients with Lp(a) concentration >1.0 g/L (P < 0.001). The AUROC curve for LDL cholesterol concentration ≥191 mg/dL (≥5.0 mmol/L), DLCN criteria, and SB criteria in predicting an FH mutation increased significantly after adjustment (P < 0.001). There was no significant difference in AUROC curve before and after Lp(a) cholesterol adjustment at an LDL cholesterol concentration ≥251 mg/dL (≥6.5 mmol/L). CONCLUSIONS: Adjusting LDL cholesterol concentration for Lp(a) cholesterol improves the diagnostic accuracy of DLCN and SB criteria, especially with Lp(a) >1.0 g/L and LDL cholesterol <251 mg/dL (<6.5 mmol/L). Lp(a) should be measured in all patients suspected of having FH. © 2019 American Association for Clinical Chemistry.

AB - BACKGROUND: Diagnostic tools for familial hypercholesterolemia (FH) rely on estimation of LDL cholesterol concentration. However, routine measurement or calculation of LDL cholesterol concentration using the Friedewald equation contains a cholesterol contribution from lipoprotein(a) [Lp(a)]. We investigated whether Lp(a) influences the phenotypic diagnosis of FH by commonly used clinical criteria. METHODS: A cohort of 907 adult index patients attending a clinic were studied. The Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) diagnostic criteria were estimated before and after adjusting LDL cholesterol concentration for the cholesterol content (30%) of Lp(a). Diagnostic reclassification rates and area under the ROC (AUROC) curves in predicting an FH mutation were also compared. RESULTS: Seventy-four patients defined by DLCN criteria (8.2%) and 207 patients defined by SB criteria (22.8%) were reclassified to "unlikely" FH after adjusting LDL cholesterol for Lp(a) cholesterol. The proportion of FH patients defined by DLCN (probable/definite) and SB (possible/definite) criteria decreased significantly in patients with increased Lp(a) (>0.5 g/L; n = 330) after Lp(a) cholesterol adjustment (P < 0.01). The overall reclassification rate was significantly higher in patients with Lp(a) concentration >1.0 g/L (P < 0.001). The AUROC curve for LDL cholesterol concentration ≥191 mg/dL (≥5.0 mmol/L), DLCN criteria, and SB criteria in predicting an FH mutation increased significantly after adjustment (P < 0.001). There was no significant difference in AUROC curve before and after Lp(a) cholesterol adjustment at an LDL cholesterol concentration ≥251 mg/dL (≥6.5 mmol/L). CONCLUSIONS: Adjusting LDL cholesterol concentration for Lp(a) cholesterol improves the diagnostic accuracy of DLCN and SB criteria, especially with Lp(a) >1.0 g/L and LDL cholesterol <251 mg/dL (<6.5 mmol/L). Lp(a) should be measured in all patients suspected of having FH. © 2019 American Association for Clinical Chemistry.

U2 - 10.1373/clinchem.2019.306738

DO - 10.1373/clinchem.2019.306738

M3 - Article

VL - 65

SP - 1258

EP - 1266

JO - Clinical Chemistry

JF - Clinical Chemistry

SN - 0009-9147

IS - 10

ER -