Cholesterol Levels

Specimen Collection

Cholesterol levels are measured from serum. A nonfasting lipid test can be performed at any time without fasting, while a fasting lipid test requires a 12-hour fast, with water being the only exception. Total and HDL cholesterol (HDL-C) are measured directly from serum. 

The Friedewald equation, developed in the 1960s, has been widely used to estimate LDL-C for both research and clinical purposes.[1] The equation is expressed as: LDL-C = (Total cholesterol) − (HDL-C) − (Triglycerides/5), in mg/dL. The equation assumes a fixed factor of 5 for the ratio of fasting triglyceride levels (up to 4.5 mmol/L) to VLDL-C (TG: VLDL-C).[1] Optimizing LDL-C levels has been the primary focus for current guidelines from organizations such as the European Society of Cardiology, the European Atherosclerosis Society,[2] and the American Heart Association and American College of Cardiology.[3]

The Friedewald equation has several limitations:[4]

• The estimated LDL-C level is inaccurate in patients with hypertriglyceridemia (up to 4.5mmol/L or 400 mg/dL), where ultracentrifugal single-spin analysis or immunoprecipitation techniques are warranted.
• The equation underestimates LDL-C levels in patients with lower LDL-C (<25 mg/dL or 0.6 mmol/L).
• The equation underestimates IDL and some VLDL remnants, which are considered atherogenic.

In a comprehensive cross-sectional analysis, Martin et al proposed a novel calculation that is more accurate than the Friedewald equation, regardless of whether the blood samples are obtained from fasting or nonfasting individuals.[5]Fasting Versus Nonfasting Lipid ProfilesWhile fasting LDL-C remains the standard for initiating lipid-lowering therapy, an ongoing debate exists among healthcare specialists regarding the use of fasting versus nonfasting lipid profiles. The rationale behind this discussion stems from the fact that triglyceride levels can be affected by recent food intake and the limitations inherent in the Friedewald equation.[6][7]

Nonfasting lipid profiles offer several advantages, including greater clinical accessibility and simplicity for both patients and healthcare providers. In contrast, fasting lipid profiles require patients to make an additional visit, which can be inconvenient for both patients and clinicians. Moreover, the accuracy of fasting lipid profiles relies on patient compliance.Many current guidelines propose that nonfasting LDL-C holds similar significance to fasting LDL-C.[8][9] However, a fasting lipid panel is strongly recommended for patients with type 2 diabetes, obesity, those taking medications that may affect lipid levels (such as thiazides and beta-blockers),[10] and individuals with excessive intake of alcohol.[11] Apolipoproteins 

As per the joint American College of Cardiology Foundation/American Heart Association 2010 guidelines, the measurement of apolipoproteins, lipid particle size, and density is not recommended for cardiovascular risk assessment (Level III).

Indications

Indications for screening or obtaining a lipid profile vary between adults and children, as mentioned below. 

• The National Health and Nutrition Examination Survey (NHANES) from 1999 to 2006 reported a 20% prevalence of dyslipidemia among adolescents, with higher lipid levels observed in those with elevated BMI.[12] Among adolescents with dyslipidemia, only 0.8% may require pharmacological treatment.[13] The 2011 guidelines from the United States National Heart, Lung, and Blood Institute (NHLBI) recommend screening all children for dyslipidemia to identify those with familial hypercholesterolemia, as these patients are at increased risk for morbidity and early mortality.[14] For children with cardiovascular risk factors such as hypertension, obesity, diabetes, or a family history of cardiovascular disease, a fasting lipid test is recommended. In contrast, a non-fasting lipid test is preferred for those without known cardiovascular risks.

• In adults, the most common indications for lipid profile testing include:[15][16]
  • Screening due to a family history of lipid disorders, such as familial hypercholesterolemia.
  • Assessing the 10-year risk of CVDs using tools such as the 2008 Framingham General Cardiovascular Risk Score or the JBS3 Risk Score.
  • Pancreatitis.
  • Managing ASCVDs. 
  • Evaluating the need for lipid-lowering therapy.

Potential Diagnosis

DyslipidemiasPrimary disorders of lipid metabolism, such as familial hypercholesterolemia, chylomicronemia, familial combined hyperlipidemia, and familial dysbetalipoproteinemia, are classified according to the Fredrickson phenotype.[17] Secondary dyslipidemia can result from conditions such as diabetes mellitus, hypothyroidism, obstructive liver diseases, chronic renal failure, and the use of certain medications. Drugs that can increase LDL-C levels include retinoids, cyclosporine A, and phenothiazines, while drugs that can decrease HDL-C levels include progestins, androgens, beta-blockers, and anabolic steroids.Based on the types of lipid abnormalities, dyslipidemias can be categorized into high total cholesterol, high LDL-C, high non–HDL-C, high triglycerides, and low HDL-C. According to the Adult Treatment Panel III (ATP III) guidelines, the standard lipid levels are as follows:[18]

• Fasting triglyceride levels
  • Normal: Less than 150 mg/dL 
  • Hypertriglyceridemia: 150 to 499 mg/dL
  • Very high or severe hypertriglyceridemia: Greater than 500 mg/dL

• LDL-C levels
  • Optimal: Less than 100 mg/ dL
  • Near optimal/above optimal: 100 to 129 mg/dL
  • Borderline high: 130 to 159 mg/dL
  • High: 160 to 189 mg/dL
  • Very high: Greater than 190 mg/dL 

• HDL-C levels 
  • Low: Less than 40 mg/dL
  • High: Greater than or equal to 60 mg/dL

Metabolic Syndrome 

There are 5 definitions of the metabolic syndrome, as mentioned below.

• The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), 2005
• International Diabetes Federation(IDF), 2006
• European Group for the Study of Insulin Resistance (EGIR), 1999
• World Health Organization (WHO), 1999
• American Association of Clinical Endocrinologists (AACE), 2003

Among these, the NCEP Adult Treatment Panel III  definition is the most widely used. Metabolic syndrome is diagnosed when 3 or more of these parameters are abnormal—triglycerides, HDL-C, glucose, blood pressure (for hypertension), and obesity.

• HDL-C: Less than 1.0 mmol/L (40 mg/dL) in men and less than 1.3 mmol/L (50 mg/dL) in women, or individuals receiving pharmaceutical treatment for low HDL-C, such as niacin or fibrates.
• Triglycerides: Greater than or equal to 1.7 mmol/L (150 mg/dL) or drug treatment with niacin or fibrates for elevated triglycerides.
• Glucose: Greater than or equal to 5.6 mmol/L (100 mg/dL), or individuals on drug treatment for elevated blood glucose.
• Obesity: Waist circumference greater than or equal to 102 cm in men and 88 cm in women.
• Blood pressure: Greater than or equal to 130/85 mm Hg, or individuals on drug treatment for hypertension.

Atherosclerotic Cardiovascular Disease

• Coronary heart disease presents as myocardial infarction, angina pectoris, heart failure, or coronary death.
• Cerebrovascular disease presents as stroke or transient ischemic attack.
• Peripheral artery disease presents as intermittent claudication.
• Aortic atherosclerosis and thoracic or abdominal aortic aneurysm.

The above-mentioned conditions are often collectively referred to as "CVD."

Atherosclerosis is the primary culprit in most cases of coronary heart disease.[19] Lipids and lipoproteins are well-established risk factors for developing ASCVD. Large clinical trials have demonstrated that lipid-lowering therapy can significantly reduce the risk of ASCVD events.[20][21]

Several factors are considered in a 10-year cardiovascular risk assessment, including:

• Age (between 20 and 79)
• Sex
• Race
• Systolic blood pressure  
• Diastolic blood pressure  
• Total cholesterol
  • LDL-C
  • HDL-C
• History of diabetes
• Current hypertension, statin, and aspirin treatment

The 10-year risk for ASCVD is categorized as follows:

• Low-risk: Less than 5%
• Borderline risk: 5% to 7.4%
• Intermediate risk: 7.5% to 19.9%
• High risk: Greater than or equal to 20%

Risk-enhancing factors such as a family history of premature ASCVD, metabolic syndrome, chronic kidney disease, premature menopause, chronic inflammatory disorders, high-risk ethnic groups (eg, South Asian), persistent elevations of LDL-C greater than or equal to 160 mg/dL or triglycerides greater than or equal to 175 mg/dL, high-sensitivity C-reactive protein greater than or equal to 2.0 mg/L, and ankle-brachial index less than 0.9. 

Normal and Critical Findings

For dyslipidemia, obtaining a detailed family history is crucial. Identifying family members with abnormal cholesterol deposits in the skin or eyes, premature coronary heart disease, or elevated cholesterol during childhood helps establish a diagnosis. A physical examination of the patient should include attention to abnormal cholesterol deposits in the skin or eyes, such as tendon xanthomata, which are commonly found in the Achilles tendons and the dorsum of their hands, and xanthelasma, which are soft, yellow plaques often present on the eyelids. A fasting lipid profile typically reveals most abnormalities. However, evaluation for secondary causes of hyperlipidemia is also warranted. The clinician may offer genetic testing for LDLR, APOB, and PCSK9 gene mutations, although the benefits of such testing are not yet well-established.

Patient Safety and Education

First and foremost, educating individuals about a heart-healthy lifestyle is essential. LDL-C is a significant contributor to the development of ASCVD, with a target level of 50 to 70 mg/dL recommended to prevent plaque formation in the blood vessels. According to current guidelines, patients should undergo a 10-year risk assessment, and those with a risk greater than 10% should be strongly considered for statin therapy. While low levels of HDL-C are associated with an increased risk of CVD, recent studies have shown that HDL-C–raising therapies do not provide clinical benefit. Therefore, routine use of such treatments is not recommended.

Clinical Significance

Primary prevention recommendations for adults aged 40 to 75 with an LDL-C level of 70 to 189 mg/dL focus on managing high LDL-C and low HDL-C levels, which are risk factors for coronary heart disease.[22][23] Large clinical trials have demonstrated that lowering LDL-C levels significantly reduces cardiovascular events and mortality rates. However, current consensus guidelines do not recommend targeting HDL-C for primary prevention of coronary artery disease.[24] Nevertheless, recent studies have suggested that serum cholesterol efflux capacity may have prognostic value in patients with CAD.[25]

According to the 2018 Guideline on the Management of Blood Cholesterol,[26] clinicians should aim to lower LDL-C levels by more than 50% using maximally tolerated statin therapy in individuals with ASCVD. For very high-risk ASCVD patients who are already on statin therapy but have an LDL-C level of more than 70 mg/dL, clinicians should consider adding nonstatin therapy, such as ezetimibe. Furthermore, for individuals on maximally tolerated statin therapy along with ezetimibe, a PCSK9 inhibitor should be considered.

Ezetimibe is preferred over initiating a PCSK9 inhibitor due to its cost and greater convenience. High-intensity statin therapy should be initiated regardless of the 10-year ASCVD risk in individuals with severe hypercholesterolemia (LDL-C level ≥190 mg/dL). Moderate-intensity statin therapy should be initiated in diabetic patients aged 40 to 75 with an LDL-C level greater than or equal to 70 mg/dL, regardless of their 10-year ASCVD risk. For nondiabetic patients with an LDL-C level greater than or equal to 70 mg/dL and a 10-year ASCVD risk of more than 7.5%, moderate-intensity statin therapy should be considered. 

Statin Intensity 

Moderate-intensity statin therapy is expected to reduce LDL-C levels by 30% to 50% with the following regimens:

• Lovastatin 40 mg daily
• Pravastatin 40 mg daily
• Simvastatin 40 mg daily
• Atorvastatin 10 to 20 mg daily
• Rosuvastatin 5 to 10 mg daily
• Pitavastatin 4 mg

High-intensity statin therapy is expected to achieve an LDL-C reduction of 50% or more with the following regimens: 

• Atorvastatin 40 to 80 mg
• Rosuvastatin 20 to 40 mg

In most cases, it is not recommended to intensify statin therapy for patients already on moderate-intensity statins. The efficacy of statin therapy should be evaluated six to eight weeks after initiation. Statin therapy management should be adjusted if statin-induced muscle adverse events, elevated aminotransferase levels, or renal dysfunction, such as proteinuria, develop. However, routine monitoring of serum creatine kinase levels is not currently recommended for patients on statins. For medical practitioners, it is advisable to consider obtaining a baseline CK level before initiating statin therapy. Educating patients on lifestyle modifications, medication compliance, and the importance of promptly recognizing and reporting any new onset of muscle discomfort or weakness is crucial.