Friedewald Formula Research Articles

Rationale for Use of Non–High-Density Lipoprotein Cholesterol Rather Than Low-Density Lipoprotein Cholesterol as a Tool for Lipoprotein Cholesterol Screening and Assessment of Risk and Therapy

The plasma level of low-density lipoprotein (LDL) cholesterol is the “gold standard” for estimating the lipoprotein-related risk for complications of atherosclerotic vascular disease. LDL cholesterol concentrations are commonly estimated by the Friedewald formula that requires only the measurement (after overnight fasting) of plasma cholesterol and triglycerides along with high-density lipoprotein (HDL) cholesterol. This value, however, is not in fact a true estimate of LDL cholesterol but rather of LDL cholesterol along with variable, usually smaller, amounts of intermediate-density lipoprotein (IDL) cholesterol and lipoprotein(a). Estimation of LDL cholesterol levels by the Friedewald formula becomes progressively less accurate as plasma triglyceride concentrations increase, and the formula is generally considered inapplicable when triglyceride levels exceed 400 mg/dL. We believe that a very simple measurement—non–HDL cholesterol (serum cholesterol minus HDL cholesterol)—has considerable potential as a screening tool for identifying dyslipoproteinemias, for risk assessment, and for assessing the results of hypolipidemic therapy. Unlike the estimation of LDL cholesterol levels by the Friedewald formula, the estimation of non–HDL cholesterol concentrations requires no assumptions about the relation of very-low-density (VLDL) cholesterol levels to plasma triglyceride concentrations. This method includes all of the cholesterol present in lipoprotein particles now considered to be potentially atherogenic [VLDL, IDL, LDL, and lipoprotein(a)]. This article provides examples of the utility of non–HDL cholesterol concentrations in clinical medicine.

Use of the Friedewald Formula to Estimate LDL-Cholesterol in Patients with Chronic Renal Failure on Dialysis

Increased plasma cholesterol, particularly that portion associated with LDL, is an established risk factor for coronary heart disease (1)(2). As a consequence, it is widely recommended (3) that LDL-cholesterol be determined in individuals with increased total cholesterol. Because isolation of the LDL fraction requires ultracentrifugation, a technique not generally available in service laboratories, the concentration of LDL-cholesterol is usually calculated by the formula of Friedewald et al. (4). The Friedewald formula provides an adequate estimate of LDL-cholesterol for most fasting specimens but is known to be less reliable as triglyceride concentration increases (5). Moreover, in patients with chronic renal failure, in whom an accumulation of remnant particles and increased concentrations of IDL-cholesterol have been found (6)(7), the estimate is possibly further compromised (8). Here we report results on specimens obtained from patients on dialysis with chronic renal failure that show no greater disparity between measured and estimated LDL-cholesterol concentrations than those seen in other patient groups in which the Friedewald formula is frequently used. Additionally we have reexamined the effect of IDL and VLDL composition on the reliability of estimations made with the formula. Two sets of blood specimens taken 6 months apart were obtained from 106 patients receiving hemodialysis or continual ambulatory peritoneal dialysis (9). Within this 6-month period, some patients received an inhibitor of hydroxymethylglutaryl-CoA reductase, some an inhibitor of angiotensin-converting enzyme, some both treatments, and some placebo only. Blood collected after an overnight fast and separated within 4 h provided serum specimens for analysis. Total …

A More Valid Measurement of Low-Density Lipoprotein Cholesterol in Diabetic Patients

PURPOSE: This study was conducted to determine if the direct low-density lipoprotein (LDL) cholesterol assay would provide a more valid measure of LDL cholesterol in diabetic patients compared with the Friedewald equation.PATIENTS AND METHODS: Fasting plasma from 148 diabetic patients, 40 with insulin-dependent diabetes (IDDM) and 108 with non-insulin-dependent diabetes (NIDDM) with triglyceride levels <400 mg/dL, were analyzed for LDL cholesterol using the Friedewald equation, the direct LDL assay, and beta-quantification. Forty-six diabetic patients with triglyceride levels ≥400 mg/dL were also studied to determine the validity of the direct LDL cholesterol assay with hypertriglyceridemia.RESULTS: The Friedewald equation and the direct LDL cholesterol assay correlated well with beta-quantification (r = 0.969 and r = 0.971, respectively) for LDL cholesterol determination in diabetic patients. Although the Friedewald equation in comparison with beta-quantification underestimated (8%) LDL cholesterol values in diabetic patients, the direct LDL cholesterol assay had a mean bias of <1%. Also, the underestimation by the Friedewald equation exceeded 10% for the triglyceride subgroup of 200 to 400 mg/dL. Furthermore, the accuracy of the direct LDL cholesterol assay was superior to the Friedewald equation since LDL cholesterol levels determined by the two methods coincided within ±10% of beta-quantification in 85% and 68% of diabetic patients, respectively (P = 0.0005). Similar results for both the Friedewald equation and the direct LDL cholesterol assay in comparison with beta-quantification were seen when diabetic patients were subgrouped into IDDM and NIDDM. Also, the direct LDL cholesterol assay appeared to provide a reliable estimate in patients with triglycerides ≥400 mg/dL.CONCLUSION: The results of our studies indicate that the direct LDL cholesterol assay is a more reliable and accurate method than the Friedewald formula for LDL cholesterol determination in diabetic patients and is more rapid and cost effective than the reference method.

High correlation but lack of agreement between direct high-performance gel chromatography analysis and conventional indirect methods for determining lipoprotein cholesterol

Low-density lipoprotein-cholesterol (LDL-C) is currently estimated clinically by using the Friedewald formula, when plasma triglycerides are < 4000 mg/L, or as the difference between infranatant and high-density lipoprotein-cholesterol (HDL-C) values after ultracentrifugation of plasma at native density, when plasma triglycerides are > or = 4000 mg/L (beta quantification). HDL-C is measured by selective precipitation of apolipoprotein B-containing lipoproteins from whole plasma or from the density > 1.006 kg/L infranatant. We compared these conventional methods for LDL-C and HDL-C with "high-performance" gel chromatography (HPGC), a method that directly and simultaneously measures both LDL-C and HDL-C in a single, microliter volume of plasma. Not surprisingly, we found that the results by all these methods were highly correlated. However, LDL-C values were significantly higher and HDL-C values significantly lower by the direct HPGC method than by the conventional methods (paired t-test). In addition, both Bland-Altman plots and concordance correlation analyses indicated lack of agreement between the methods' results in the majority of patients' subgroups.

Muscular response to mechanical overload in hypercholesterolemic patients treated with simvastatin: isokinetic evaluation through computerized dynamometry

This study was designed to evaluate changes in the functioning of striated muscle during treatment with simvastatin. Muscular activity was assessed by computerized dynamometry, which was used to determine maximum torque, total work performed, maximum power, torque acceleration energy, endurance ratio, and recovery ratio. Total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDL-C) were determined using Friedewald's formula. Fifteen outpatients (10 women and 5 men; mean age, 55.7 ± 7.8 years) with primary hypercholesterolemia (LDL-C >4.14 mmol/L) who had not received lipid-lowering therapy in the previous 30 days and who were participating in atherosclerotic-disease primary-prevention programs were selected. All patients received simvastatin 10 mg/d for 30 days, followed by 20 mg/d for 30 more days. Dynamometric measurements were obtained on three occasions: (1) at baseline; (2) after 30 days of treatment with simvastatin 10 mg/d; and (3) after 30 more days of treatment with simvastatin 20 mg/d. On the same days, blood samples were collected for determination of serum lipid levels (total cholesterol, triglycerides, and high-density lipoprotein cholesterol) and serum enzyme activities (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase), and electroneuromyographic tests were performed to analyze sensitive and motoneuron conduction response.

When to treat dyslipidaemia of patients with chronic renal failure on haemodialysis? A need to define specific guidelines

There are no specific recommendations for management of dyslipidaemia in patients with chronic renal failure (CRF) on haemodialysis, in which atherosclerosis is a common cause of morbidity and mortality. The aim of the present study was to analyse different approaches based on low-density lipoprotein (LDL) cholesterol (measured and calculated with a formula), non-high-density lipoprotein (HDL) cholesterol, and HDL cholesterol levels in the clinical management of dyslipidaemia in haemodialysis patients. Calculated LDL cholesterol by the Friedewald formula was compared with measured LDL cholesterol after separation by ultracentrifugation n 101 male patients with CRF on haemodialysis and in 101 healthy control subjects. Calculated LDL cholesterol coincided with measured LDL cholesterol, with less than 10% error, in 54 patients (53.4%) and in 75 controls (74.2%). Calculated LDL cholesterol was overestimated, with an error of 10% or more with respect to measured LDL cholesterol, in 37.6% of patients and in 23.7% of controls, and underestimated in 8.9% and 1.9% respectively. Despite a good correlation between calculated and measured LDL cholesterol, the intraclass correlation coefficients demonstrate a poor concordance between calculated and measured LDL cholesterol, both in patients and controls. Only 17 patients were at non-HDL cholesterol level risk defined as higher than 4.28 mmol/l. HDL cholesterol levels lower than 0.9 mmol/l were found in 70% of patients and in 23% of controls. LDL or non-HDL cholesterol levels may not be appropriate for management of lipoprotein abnormalities in CRF patients. Further studies must clarify whether HDL cholesterol may be the best lipoprotein parameter for evaluating cardiovascular risk in these patients.

When to treat dyslipidaemia of patients with chronic renal failure on haemodialysis? A need to define specific guidelines

There are no specific recommendations for management of dyslipidaemia in patients with chronic renal failure (CRF) on haemodialysis, in which atherosclerosis is a common cause of morbidity and mortality. The aim of the present study was to analyse different approaches based on low-density lipoprotein (LDL) cholesterol (measured and calculated with a formula), non-high-density lipoprotein (HDL) cholesterol, and HDL cholesterol levels in the clinical management of dyslipidaemia in haemodialysis patients. Calculated LDL cholesterol by the Friedewald formula was compared with measured LDL cholesterol after separation by ultracentrifugation in 101 male patients with CRF on haemodialysis and in 101 healthy control subjects. Calculated LDL cholesterol coincided with measured LDL cholesterol, with less than 10% error, in 54 patients (53.4%) and in 75 controls (74.2%). Calculated LDL cholesterol was overestimated, with an error of 10% or more with respect to measured LDL cholesterol, in 37.6% of patients and in 23.7% of controls, and underestimated in 8.9% and 1. 9% respectively. Despite a good correlation between calculated and measured LDL cholesterol, the intraclass correlation coefficients demonstrate a poor concordance between calculated and measured LDL cholesterol, both in patients and controls. Only 17 patients were at non-HDL cholesterol level risk defined as higher than 4.28 mmol/l. HDL cholesterol levels lower than 0.9 mmol/l were found in 70% of patients and in 23% of controls. LDL or non-HDL cholesterol levels may not be appropriate for management of lipoprotein abnormalities in CRF patients. Further studies must clarify whether HDL cholesterol may be the best lipoprotein parameter for evaluating cardiovascular risk in these patients.

Performance of a direct LDL-cholesterol method compared to beta quantification

Abstract

Poor applicability of the Friedewald formula in the assessment of serum LDL cholesterol for clinical purposes

Objective: To determine the accuracy of the estimation of serum low-density lipoprotein (LDL) cholesterol concentration by the Friedewald formula. Methods: Modifications of the calculation formula are presented on the basis of ultracentrifugal separation of serum high-density lipoprotein and LDL cholesterol in the specimens collected (n = 1215) in a nationwide health survey. Results: The formulas obtained from different subject groups differed relatively little from each other. The accuracy of the original Friedewald formula was poor; in about 36% of the subjects the error was more than 5% compared with ultracentrifugally obtained results. By applying the currently recommended coronary heart disease (CHD) risk categorizations, high proportions (5%–28%) of the subjects were classified into wrong CHD risk categories when LDL cholesterol was calculated with any of the formulas. At high serum triglyceride levels, misclassifications were especially common. Conclusions: We conclude that even the most accurate LDL cholesterol calculation methods should be used with caution while classifying subjects into categories of CHD risk. In hypertriglyceridemic subjects, the calculation formulas probably should not be used at all.

Friedewald formula

Journal Article Friedewald formula Get access L G Rijks L G Rijks Search for other works by this author on: Oxford Academic Google Scholar Clinical Chemistry, Volume 41, Issue 5, 1 May 1995, Page 761, https://doi.org/10.1093/clinchem/41.5.761 Published: 01 May 1995

Risk of breast cancer in relation to blood lipids: a prospective study of 31,209 Norwegian women

In this prospective study, the relationship between blood lipids and breast cancer risk was examined. Between 1977 and 1983, 31,209 Norwegian women, 20 to 54 years of age, attended a health screening carried out by the Norwegian National Health Screening Services. The screening consisted of a questionnaire, anthropometric measurements, and nonfasting blood drawn for analysis of total serum cholesterol (TC), triglyceride (TG), and high density lipoprotein (HDL) cholesterol. Low density lipoprotein (LDL) cholesterol was calculated by the Friedewald's formula. During the seven to 13 years of follow-up, 302 breast cancer cases were identified by linkage to the Norwegian Cancer Registry. After adjustment for some of the known risk factors of breast cancer, the relative risk of women in the highest quartile of TC compared with women in the lowest quartile was 0.87 (95 percent confidence interval [CI] = 0.61-1.23). The corresponding relative risks and CIs were 0.82 (CI = 0.58-1.16) for TG, 1.02 (CI = 0.73-1.42) for HDL, and 0.93 (CI = 0.67-1.29) for LDL. No association between breast cancer risk and blood lipids was found in the total population, nor when the data were divided into those diagnosed before or after the age of 50 as a dividing line between pre- and postmenopausal diagnosis.

Effect of serum lipoprotein(a) on estimation of low-density lipoprotein cholesterol by the Friedewald formula

The calculation of serum low-density lipoprotein cholesterol (LDL-C) by the Friedewald formula does not account for the cholesterol associated with lipoprotein(a) [Lp(a)]. To quantify the contribution of Lp(a) cholesterol to total serum cholesterol, we measured concentrations of serum Lp(a) by an ELISA and concentrations of other serum lipids and lipoproteins by standard assays in 23 normolipemic women, ages 50-60 years. In measuring serum high-density lipoprotein we found that polyethylene glycol 6000 precipitated > 99.8% of all Lp(a). When serum Lp(a) concentrations were < or = 300 mg/L, 301-600 mg/L, and > 600 mg/L, the uncorrected serum LDL-C was overestimated, respectively, by a mean of 4.1% (n = 7), 8.5% (n = 8), and 21.4% (n = 8). Serum Lp(a) concentrations were positively correlated with percentage overestimation (P < 0.001), but were not correlated with either corrected or uncorrected serum LDL-C. We conclude that the Friedewald formula should be modified to take into account the contribution of Lp(a) cholesterol to total serum cholesterol.

Limitations of the Friedewald formula for estimating low-density lipoprotein cholesterol in alcoholics with liver disease

The accuracy of the Friedewald formula in estimating low-density lipoprotein (LDL) cholesterol was investigated in 47 alcoholic patients with liver disease (21 minimal-change, 26 cirrhotic) by comparing the results with those obtained by sequential preparative ultracentrifugation. In 14% of subjects with minimal-change disease, the error in the estimated LDL cholesterol was 50% +/- 9% (mean +/- SD; range 40-59%) and was related to the degree of attendant hypertriglyceridemia (r = 0.98; P < 0.001). A similar degree of error was observed in patients with cirrhosis, despite the absence of hypertriglyceridemia; an abnormal VLDL cholesterol: triglyceride ratio was the contributory factor in the discrepancy. We conclude that, as is the case in other clinical pathologies in which abnormalities of lipoprotein composition have been described (e.g., diabetes), the Friedewald formula to estimate LDL cholesterol may be inappropriate in chronic alcoholics, particularly those in whom a degree of hepatic dysfunction may be suspected.

Increase of high-density lipoprotein cholesterol at ovulation in healthy women

Plasma cholesterol is believed to vary more in women than in men, with the menstrual cycle, yet our review of the literature found no consistent pattern. We examined variations in plasma lipoproteins in relation to ovarian hormones in 12 healthy, menstruating women. Twenty fasting blood samples were obtained on alternate days over one menstrual cycle; ovulation was timed by hormone measurements. Plasma was analysed enzymatically for total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triacylglycerol (TAG). Low-density lipoprotein cholesterol (LDL-C) was estimated by the Friedewald formula. The greatest effect was seen in HDL-C. Concentrations increased by 12% ( P < 0.001) between the times of menstruation and ovulation and remained elevated until the following premenstrual phase. The height of peak oestradiol concentrations at ovulation was significantly associated with HDL-C in that phase ( r = + 0.75, P < 0.01), and with mean HDL-C concentrations over the whole cycle ( r = +0.65, P < 0.05). TC and LDL-C also increased at ovulation, by 9% ( P < 0.005) and 11% ( P < 0.025) respectively, although the effect was more transient. This study demonstrates that consistent changes in plasma lipoproteins do occur during the menstrual cycle.

Preliminary screening of the relationship of serum lipids to survival of chronic dialysis patients.

To assess the predictive value of serum lipid measurements in dialysis patients once the initial decrease on early dialysis had occurred, we obtained random serum cholesterol and triglyceride levels in stable, chronic dialysis patients who were then followed up to 9 years. Derived LDL (DLDL) was estimated by the Friedewald formula, calculated for all HDL levels between 30 and 45 mg/dL, and evaluated statistically against a panel of vascular disease markers, including clinical assessment for coronary, peripheral, and cerebrovascular disease; ECG, both standard and ambulatory; two-dimensional echocardiogram; and medications. Survival was calculated from entry (not dialysis onset) for 58 hemodialysis and 33 peritoneal dialysis patients. The 91 patients (49 males, 74 diabetics) were divided by cholesterol level (> or = 175 mg/dL = 53, < 175 = 38), triglyceride (> or = 175 mg/dL = 55, < 175 = 36), and DLDL (> or = 75 = 58, < 75 = 24). High total cholesterol was present in a larger proportion of females than low cholesterol, but groups were not different with respect to all vascular determinants, including survival (mean = 33.4 months vs. 43.2, p = NS). High vs. low triglyceride groups were not different with respect to vascular indicators, except for both incidence of abnormal standard ECG (69% vs. 42%, p < 0.05) and survivals (mean = 42.0 vs. 30.7, p < 0.05; 1 year = 80% vs. 56%, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Change in LDL particle size is associated with change in plasma triglyceride concentration.

Low density lipoprotein (LDL) particle size is inversely associated with plasma triglyceride concentration in cross-sectional analyses. In the present study, changes in the LDL particle size of 227 participants of the Framingham Offspring Study were analyzed longitudinally by nondenaturing gradient gel electrophoresis at two examinations that were separated by 3-4 years. All subjects had triglyceride concentrations < 400 mg/dl at both exams. Using laser scanning densitometry to assess mean LDL particle size, 56% of samples displayed a change in size: 41% had a one-band size change, 13% had a two-band change, and 2% had a three-band change. These changes in size corresponded to a 15% change in pattern type, based on pattern A and B terminology. There was a significant inverse association between change in LDL size and change in triglyceride (p < 0.0001) and glucose (p < 0.004) concentrations, body weight (p < 0.02), and age (p < 0.03). There was also a significant positive association with change in high density lipoprotein (HDL) cholesterol concentration (p < 0.0001). Change in LDL cholesterol concentration, as calculated by use of the Friedewald formula, however, showed no significant association with change in LDL size (p < 0.9). There was also no significant association with change in smoking or blood pressure, but there was a nonsignificant inverse trend associated with alcohol intake (p < 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Contents of apolipoprotein A-I, A-II and B of the human serum fractions for high-density and low-density lipoproteins prepared by common precipitation methods.

Two common precipitation methods for the determination of HDL-cholesterol in human serum were used, dextran sulphate/MgCl2 and phosphowolframate/MgCl2. They yield supernatants which contained almost all of the apoA-I and apoA-II lipoproteins but no lipoprotein apoB. The correlations between chol-HDL and apoA-I were about the same with these methods (r = 0.79 and 0.80). The correlation between the precipitation methods and ultracentrifugal analysis for chol-HDL was highly significant (r = > 0.95). Correspondingly, two common precipitation methods for the determination of LDL-cholesterol in human serum, buffered heparin, and polyvinyl sulphate procedures, produced sediments, which contained the major proportion of the apoB and only small amounts of apoA-I and apoA-II. However, yields of only 69.0-80.2% were obtained for apoB from the sediments and of 85.8-89.4% from supernatants calculated as the difference from chylomicron free serum. This difference might be due to alterations of the molecular structure of apoB by the precipitation reagents. Comparison of the results with the precipitation methods to those using the Friedewald formula showed excellent agreements (r = > 0.91). Very comparable results were also obtained in the case of marked hypertriglyceridaemia provided that the serum samples were briefly centrifuged before analysis of chol, chol-HDL, and triglyceride values for the formula of chol-LDL. The precipitation methods for chol-LDL showed very good agreement with the values obtained by ultracentrifugal analysis (r = > 0.93). There were no remarkable differences in the correlation of apoB and chol-LDL values measured by different methods (r = 0.85). According to the present results it was found that highly significant correlations existed between chol/chol-HDL or chol-LDL/chol-HDL and apoB/apoA-I ratios (p < 0.001). It is quite evident that apoB and apoA-I values could be used to replace chol-LDL and chol-HDL values when the risk for the cardiovascular diseases is to be assessed.

Influence of intermediate-density lipoproteins on the accuracy of the Friedewald formula

Values of low-density lipoprotein (LDL) cholesterol (C) according to the Friedewald formula (Clin Chem 1972;18:499-502) were compared with those obtained by lipoprotein fractionation in 98 healthy subjects (control group), 135 specimens from patients with peripheral vascular and cerebrovascular disease (atherosclerotic group), and 45 with chronic renal failure on hemodialysis (CRF group). All had concentrations of total cholesterol between 3.23 and 7.76 mmol/L (1.25-3.00 g/L) and triglycerides less than 3.39 mmol/L (less than 3.00 g/L). The percentage error of calculated LDL-C was 4% in controls with a cholesterol/triglycerides (C/TG) ratio for very-low-density lipoprotein (VLDL) of 0.20, but greater than 60% in those with a (C/TG)VLDL ratio of 0.40. The percentage of error in sera of patients with atherosclerosis and chronic renal failure was higher than in controls with a similar mean (C/TG)VLDL ratio. The percentage of error of calculated LDL-C increases progressively with the increase in the C/TG intermediate-density lipoprotein (IDL) ratio, both in controls and in the atherosclerotic and CRF groups. Similar findings are observed when the mean percentage of error of measured LDL-C is evaluated. The percentage of error from calculated LDL-C in the atherosclerotic and CRF groups is significantly lower than that obtained by comparison of LDL-C separated by ultracentrifugation when the "broad cut" LDL (IDL plus LDL, both by ultracentrifugation) was used. The high percentage of errors found in the groups of patients studied underlines the need for caution when assessing the reliability of the Friedewald formula, particularly in cases in which disturbances in IDL composition are suspected.

Use of cholesterol/triglyceride ratio and the Friedewald formula

Journal Article Use of cholesterol/triglyceride ratio and the Friedewald formula Get access William G Gillespy William G Gillespy 108 Park Lane New Castle , PA 16105 Search for other works by this author on: Oxford Academic Google Scholar Clinical Chemistry, Volume 37, Issue 6, 1 June 1991, Pages 1132–1133, https://doi.org/10.1093/clinchem/37.6.1132a Published: 01 June 1991

Portable Cholesterol Analyzers

To the Editor.— Kaufman et al 1 reported that they calculated low-density lipoprotein cholesterol concentration by subtracting the high-density lipoprotein cholesterol concentration and one fifth of the triglyceride concentration from the total cholesterol concentration. 2 As I have stated elsewhere, 3 this equation was developed with conventional units and must be adapted before application with Systeme International (SI) units: the triglyceride concentration must be divided by 2.18 instead of 5. Also, the Friedewald formula is valid only if the triglyceride level is below 4.52 mmol/L. 4,5 Kaufman et al 1 excluded specimens only if they were lipemic, but those with triglyceride concentrations between 4.52 and 6.77 mmol/L are not necessarily grossly lipemic, so the absence of lipemia does not mean that the equation can be validly applied in this range.