DIRECT VERSUS CALCULATED (LDL)

LDL TESTING: DIRECT MEASUREMENTIS SUPERIOR TO CALCULATED!
Why is a Low Density Lipoprotein (LDL) test necessary?
  • Every fifth Indian dies due to a heart attack and 80% Indians have a poor lipid profile (Times of India, ICMR study – 2014)
  • Elevated LDL levels are a strong independent risk factor for heart disease (Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):830-5.)
  • Increased LDL levels are also an independent risk factor for Type 2 diabetes (Adv Lab Med Int. 2012; 2(1): 9 -18). With over 50 million Type 2 diabetics, India is now the diabetes capital of the world (Times of India, 2016)
  • High LDL levels significantly contribute towards increased obesity, hypertension and the metabolic syndrome. (Position Paper of The Obesity Society and the American Society of Hypertension – 2012)
  • As Indians, we have a genotype-phenotype that’s more vulnerable to high LDL levels, CVD and metabolic syndrome (Dr. V. Mohan, Indian J Med Res 125, March 2007, pp 217-230
THE IMPORTANCE OF ACCURATE LDL MEASUREMENTS

As LDL levels majorly contribute towards CVD, Hypertension, Type 2 diabetes, Obesity and the Metabolic Syndrome – Ensuring that we get the accurate and precise measurements of LDL is of paramount importance. An error in the value of LDL could misguide treatment planning and outcomes

HOW IS LDL MEASURED IN A LABORATORY?

Indirect or calculated LDL is derived by the Friedwald formula

Total Cholesterol = HDL + LDL + VLDL

VLDL = Triglyceride / 5

LDL = Total cholesterol – (HDL + Triglyceride / 5)

Friedewald formula

The Direct LDL measurement uses a homogenous assay based on a beta quantification kit that directly measures the LDL component from a serum sample; without needing to rely on TC, TG or HDL levels.

WHY IS THE CALCULATED LDL AN INFERIOR METHOD OF MEASUREMENT?

The drawbacks of using the Friedwald Formula for determining levels of LDL cholesterol are:

  • Calculated LDL is not a directly measured value. It’s an indirect estimation derived via a formula
  • It requires multiple assays and multiple steps each adding a potential source of error
  • It is inaccurate in assessing LDL levels among individuals with elevated triglyceride levels (>400 mg/dL). In addition, it has been reported that the formula becomes increasingly inaccurate at borderline triglyceride levels (200-400 mg/dL). Any lapses in TC, TG and HDL measurements can confound the calculated LDL values.(Indian J EndocrinolMetab. 2014 Jul-Aug; 18(4): 502–504
WHAT MAKES DIRECT LDL MEASUREMENT, A SUPERIOR AND PREFERRED METHOD?
  • It is a direct measurement of LDL by a homogenous assay. This excludes the possibility of any error occurring due to indirect and derived estimations
  • Direct LDL is measured on an automated platform with 2- level controls at a defined interval. The process is standardized
  • It provides an accurate estimation of LDL results regardless of the TG levels
  • As the direct measurement does not rely on other parameters like TC, TG and HDL – it is not influenced or confounded by any errors in the reporting of these other lipid values. It ensures accurate risk stratification of CVD and guides correct treatment planning

Ref: Indian J EndocrinolMetab. 2014 Jul-Aug; 18(4): 502–504.

Pharmacotherapy. 2004 Feb;24(2):167-72.

Pak J Med Sci. 2016 Jul-Aug; 32(4): 955–960

INTERNATIONAL GUIDELINES RECOMMEND DIRECT LDL

Recommend using only direct LDL methods, especially when the LDL is below 70 mg/dL and TG is higher than the range of 15 to 200 mg/dL

ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD) PRIMARY PREVENTION GUIDELINE

LDL values can come from either a fasting lipoprotein panel or a direct LDL test. The lipoprotein panel indirectly calculates LDL cholesterol by using the Friedewald equation (LDL = TC-HDL-TG/). In general, either test can be used, but be aware that the Friedewald equation tends to underestimate LDL when LDL is low (-70) or triglycerides are high (> 150-200). In these cases, the true LDL value can be 10-20 points higher. So, in such cases, consider using a direct LDL test or ensuring that the patient is well below target.

The NCEP ATP III report recognizes the benefit of a truly accurate direct LDL-C that could be used in the non-fasting state.

Third Report of the National Cholestrol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II).

INDIAN STUDY SPANNING APPROX. 15,000 PATIENTS SUPPORTS THE USE OF DIRECT LDL IN TG > 200 AND LDL 130 mg/dL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC413 8905/ Original Article

LDL-cholesterol: Friedwald calculated versus direct measurement-study from a large Indian laboratory database

Subramanian Kannan, Shriraam Mahadevan , Bharath 2 3 4 Ramji , Muthukumaran Jayapaul , V. Kumaravel Consultant, Endocrinology Diabetes and Bariatric Medicine, 1 Narayan Health City, Banglore, Karnataka, Endocrine and 2 Speciality Clinic, Chennai, Assistant Professor Endocrinology, Chettinad Medical College, Chennai, 3Consultant Endocrinologist, Arka Cenre for Hormonal 4 Health, Chennai, Department of Clinical Endocrinolgy, Alpha Hospital and Research Centre, Anuppanady, Madurai, Tamil Nadu, India Background: Validity of Friedwald Formula (FF) in patients with serum triglycerides (TGs)

Results: LDL by FF correlateed with directly measured LDL with correlation coefficient of 0.89 with the best correlation seen in TG levels 100-150. Higher level of TG (>200) underestimates the LDL calculated by FF particularly at LDL values 130 mg/dl. Conclusion: We suggest repeating the LDL by direct assay techniques particularly in patients with TG 200 and when LDL 130. This helps in correctly stratifying the coronary artery disease’ (CADs’) risk and goals of treatment

IN-HOUSE STUDY AT SUBURBAN DIAGNOSTICS

We performed an in-house retrospective analysis of around 1 lakh samples that were tested at our labs for lipid profile. We performed the LDL test for these samples by both the direct and the calculated methods. The objective was to understand the correlation of results between the two methods. Summary of Results:

Triglycerides CategoryNumber of BookingsMean of LDL Cholesterol DirectMean of LDL Cholesterol Calculated
Less than 20088962114105
200-30012683134114
300-4002750133107
400 or more162811877

Across all ranges of TG, the LDL value was under-reported by the calculated or indirect estimation. At the level of TG >200, the calculated LDL method seemed inefficient in reporting the actual LDL and gave consistently lower values. These findings seem consistent with the findings of other larger studies that have shown an underestimation of 20 mg/dL with calculated LDL as compared to direct LDL (Lindsey et al. Pharmacotherapy. 2004;24(2))

KEY TAKE HOME MESSAGES

As per recommendations of international guidelines, for TG levels more than 200 and for LDL levels less than 70 mg/dL, the calculated or indirect method of LDL estimation is not accurate as it provides an underestimated value.

Guidelines recommend opting for the direct LDL measurement in such cases. Direct LDL is an automated assay with controls and provides an accurate estimation of LDL values regardless of TG levels

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