The Cholesterol Guidelines and the Clinical Laboratory

An Expanding Repertoire of Tests

Sridevi Devaraj, PhD, DABCC, FRSC; Ishwarlal Jialal, MD, PhD, FRCPATH, DABCC, DABCL


Am J Clin Pathol. 2019;152(2):120-121. 

Recently, the updated 2018 guidelines for the management of hypercholesterolemia to prevent atherosclerotic cardiovascular diseases (ASCVD) were published.[1] It appears that the recommendations were based on the level (quality) of scientific evidence and the class (strength) of recommendation. Furthermore, in addition to primary and secondary prevention, severe hypercholesterolemia, women, and diabetes, they provide guidelines for different ethnicities, chronic inflammatory diseases, and human immunodeficiency virus, and hence are very comprehensive. There are several important differences from the 2013 guidelines that are relevant to clinical pathologists.[2] In a previous editorial in the American Journal of Clinical Pathology,[3] the role of the clinical laboratory was reviewed because there was much confusion about lipid testing following initiation of statin therapy with the 2013 guidelines, which was clarified in that editorial. In this communication, we highlight the issues that are germane to the clinical laboratory with respect to the new 2018 guidelines. Low-density lipoprotein-cholesterol (LDL-C) is still the cornerstone of therapy but the committee acknowledged the issues with reporting low levels of LDL-C (<70 mg/dL) in the face of hypertriglyceridemia (triglycerides >200 mg/dL). This will be discussed further because it is so pivotal to the management of ASCVD.

In patients 40 to 75 years of age without diabetes and with 10-year risk of 7.5% to 19.9% using the pooled cohort equation (intermediate risk), the laboratory plays a key role because risk-enhancing factors in this group include persistently elevated LDL-C levels equal to or greater than 160 mg/dL, metabolic syndrome (three out of five features, including: HDL <40 or <50 mg/dL in men and women, respectively, triglycerides >175 mg/dL, and glucose ≥100 mg/dL), chronic kidney disease (CKD) with measurement of creatinine and estimated glomerular filtration rate (eGFR <60 mL/min/m2), and persistent elevations of triglycerides equal to or greater than 175 mg/dL. In this group, optional risk factors include apolipoprotein B equal to or greater than 130 mg/dL (which equates to a LDL-C of ≥160 mg/dL) if triglycerides are greater than 200 mg/dL; high-sensitivity C-reactive protein equal to or greater than 2.0 mg/L; ankle-brachial index (ABI) less than 0.9; and lipoprotein(a) equal to or greater than 50 mg/dL if there is a family history of premature ASCVD or ASCVD not explained by major risk factors in the index patient.

The new guidelines now include CKD, defined as a eGFR less than 60 mL/min/m2, as a high-risk condition and metabolic syndrome as a risk-enhancing factor for clinician-patient risk discussion. What is very interesting, especially with the increasing prevalence of metabolic syndrome in the United States, is that they recommend using a higher cutoff, greater than 175 mg/dL, for triglycerides rather than the traditional 150 mg/dL. Their argument for this higher cutoff point is that it incorporates both fasting and nonfasting triglyceride levels. However, they do not state what level should be used if the patient is fasting.

The 2018 guidelines also recommend measurement of the lipid profile in the nonfasting state in adults age 20 years and older to estimate risk and document baseline LDL-C. In those patients in whom nonfasting lipid profile documents a high triglyceride (≥400 mg/dL), they recommend confirmation using a fasting lipid profile. Previously, an abundance of studies supporting the importance and validity of a nonfasting lipid profile, especially in pediatric populations, have been reported.[4] They also recommend monitoring non-HDL-C in the lipid profile.

In a previous article we highlighted the major pitfalls of using the Friedewald equation when triglycerides are greater than 200 mg/dL and the calculated LDL-C less than 70 mg/dL.[5] We recommend the direct LDL-C or the non-HDL-C because both do not require a nonfasting sample or modified LDL estimate using the Martin equation in these scenarios. We are glad that the guideline committee has acknowledged this expertise and contribution of laboratorians.

In younger diabetic patients, between 20 and 39 years old, both type 1 and type 2, the guidelines now include in addition to increased duration of diabetes retinopathy, neuropathy, or decreased ABI less than 0.9, albuminuria equal to or greater than 30 μg albumin/mg creatinine and eGFR less than 60 mL/min/1.73 m2, as diabetes-specific risk-enhancing factors that can inform initiation of statin therapy or intensification of statin therapy in older diabetic patients.

Furthermore, inclusion of children and adolescents to estimate risk is an important advancement in the recent guidelines. Children and adolescents older than 10 years of age with persistent elevation of LDL greater than 190 mg/dL are a target for initiation of statin therapy. In those with familial hypercholesterolemia or early CVD, the guidelines recommend fasting and/or nonfasting lipoprotein profile as early as 2 years of age. Again, for primary prevention, a nonfasting lipid profile is recommended at 9 to 11 years of age and followed at 17 to 20 years of age.

To assess adherence to statin and other therapies, lipid measurements need to be performed at 4 to 12 weeks after initiation of therapy or following dose adjustment and then repeated every 3 to 12 months as needed. Standardization and harmonization efforts are underway for both apolipoprotein B and lipoprotein(a) measurements and clinical laboratorians have played a major role in standardization thus far with availability of World Health Organization reference materials. Apolipoprotein B is available on most automated immunoassay platforms.

In conclusion, the laboratory continues to play a major role in the assessment and management of ASCVD. The laboratory has a major role to exclude secondary causes, such as hypothyroidism, cholestasis (bilirubin and alkaline phosphatase), and nephrotic syndrome (serum albumin and albuminuria), and to document CKD with eGFR. Furthermore, prior to statin therapy, baseline creatine kinase and alanine aminotransferase testing is recommended, and creatine kinase testing if myalgias arise on therapy. However, the pivotal measurement continues to be LDL-C, and much more work is needed to provide a precise and more accurate value in this era of proprotein convertase subtilisin/kexin type 9 therapy in which patients are achieving LDL-C levels less than 30 mg/dL with reduction in ASCVD events. It is encouraging that the guidelines committee continues to acknowledge the important role of the clinical laboratory in the diagnosis and management of ASCVD and has advocated expanding its role in risk assessment.