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Some basic problems in clinical application of blood lipid analysis
时间:2016-06-23   浏览:848次

Determination of serum lipid, lipoprotein and apolipoprotein has been widely used in the epidemiology and clinical study of atherosclerosis (AS). Aim to determine the level of blood lipids to assess the risk of AS disease, and not to the diagnosis of AS disease (such as coronary artery disease). However, it is necessary for the diagnosis of hyperlipidemia and abnormal lipoprotein.
1 the concept of risk factors
Some of the body's physiological characteristics of certain diseases have a certain degree of association, the general said these characteristics as a risk factor for disease, now the term is used not only in the physiological indicators,, and can also be used to lifestyle, such as smoking, behavior patterns and characteristics.
Many of the foreign literature generally pay attention to the relationship between dyslipidemia (including high Tc, LDL-C, high Tg, low HDL-C) and atherosclerosis, but blood lipid levels only for estimating the risk of atherosclerotic diseases, coronary heart disease, for example, it is a multifactorial disease, dyslipidemia is a major risk factor for coronary heart disease (CHD). For example: high TC to the occurrence of coronary heart disease is more, but not all of the high Tc occurred events of coronary heart disease, the majority of our patients with coronary heart disease (CHD) Tc meet ****** levels were, TC significantly increased only 20% to 30% of cases. In addition, other diseases have also caused the rise of TC. Clinical requirements a diagnostic marker with high sensitivity and high specificity, for coronary heart disease, TC neither specific is not sensitive, so TC although some disorders of lipid metabolism (such as the index for the diagnosis of familial hypercholesterolemia), but the index for the diagnosis of coronary artery disease does not, but coronary heart disease risk factors.
In fact in coronary heart disease diagnostic criteria are not included in this TC a, other lipid parameters such as LDL-C, apoB, HDL-C, apoAI, LP (a) etc. mostly reflects the state of the lipid metabolism, also used as an estimate of the degree of coronary heart disease risk, but not in the diagnosis of coronary heart disease (CHD) index. Clinically used to treat the biochemical tests as diagnostic criteria, many clinical research papers in the evaluation of a new blood lipid indicators, the average statistical differences between the coronary heart disease (CHD) and the control group, lightly said the index can be used as a diagnosis of coronary heart disease, this is wrong. There are two kinds of people in the crowd, a people do not attach importance to hyperlipidemia, negligence, and another person is too much care about the blood lipid changes, fear suffering from coronary heart disease, mistakenly lipids as coronary heart disease (CHD) performance, this error understanding may come from medical and health workers, and popular science reading misleading. It is necessary to correct the deviation of this understanding, to avoid the risk factors as a diagnostic indicator, in order to achieve a reasonable application of blood lipid analysis, appropriate evaluation of its application value.

2 reference value concept
Has long been generally applied "normal value" word, but few people question, in fact, the concept of "normal" is very vague and biochemical index of the measured values are mostly not clear "normal" and "abnormal" boundaries. In the 20 years, the academic circles generally adopt the "reference value" and "reference range" instead of "normal value" and "normal range" ". The reference value is the physiological and biochemical parameters obtained by the specific method under specified conditions. In serum TC, for example, there is no clear that the so-called "normal range", it varies with the living conditions of the population. People around the world average level disparity, such as some African National TC average low to 3.1mmol/L (24), Europe has up to 6.98mmol/L 270mg/dl, middle-aged Beijing roughly in 465 to 4.91mmol/L (180 ~ 190mg/dl) and Pengxian County, Sichuan Province, middle-aged farmers only 3.36mmol/L (130 mg / dl).
Beijing authorities are also the staff, TC level is also due to work and living environment. Therefore, the survey data should be referred to as the "reference value" and specify the conditions (such as regional, time, gender, age, living standards, health status, sample collection and processing methods, determination methods, statistical methods, TC... And so on. "Reference value" is generally not add "attribute", it was written "normal reference value", "physiological reference value" and so on are wrong. For division of the TC level, now usually according to whether easy suffering from atherosclerotic cardiovascular disease were classified as "appropriate level", "margin" and "dangerous levels", avoid using "normal value" of the word, nor does it suggest that with a satisfactory level, "the optimum level", think they are difficult to confirm. In short "reference value" is under the specific conditions of the results of the investigation data, but level division is man-made, is based on a large number of epidemiological data and clinical experience by experts to discuss the development of, so "reference value" for different regions and different populations vary, but the division standard should be the unification of the whole country.
3 the division of the appropriate level of blood lipid and the risk level
Because the blood fat reference value of each region is different, if the reference value is formulated by statistical method, then there are many high blood lipid standards, which are not consistent. But since the 1980s advocates to significantly increased risk of coronary heart disease as high serum TC, other indexes of blood lipid (TG, HDL-C and LDL-C) also according to this principle as the level of classification, also according to dangerous levels of intervention and establishing treatment goals. According to the prospective data (MRFIT, 36 million people, 6.5 years), if design TC5.2mmol/L (200 mg / dl) death from coronary heart disease relative risk (R. R.) to "1", is 3.9, 6.5 and 7.8 mmol / L (150, 250, 300mg/dl) r. R respectively for "0.7", "2", "4", so TC6.5mmol/L (DL), is significantly increased the risk of coronary artery disease.
TC as low as 3.9mmol/L (150mg/dl) when coronary heart disease is rare, in the end TC low to what level of coronary heart disease will not happen? Now the majority of people think that there is no threshold, but it is usually believed that security level is TC3.9mmol/L 180mg/dl, TC level of our country is low, coronary heart disease is much less than the European and American countries, have people think TC4.7mmol/L (180mg/dl) or more coronary heart disease rate increased.
In 1984 the United States National Institutes of Health (NIH) unified understanding conference, is generally believed that 25% of Americans TC in a dangerously high levels, so the development of human plasma TC 75 percentile level, as adults over the age of 40 moderate risk level. Now the United States cholesterol education program NCEP-ATP III report (2001) the TC < 5.2mmol/L (< 200 mg / dl = appropriate level, 5.2 ~ 6.2mmol/L (200 ~ 239mg/dl) marginal increased. Is more than or equal to 6.2 mmol / L (more than or equal to 240mg/dl) for high serum TC and develop HDL-C < 1.0 mmol / L (< 40 mg / dl = to coronary heart disease risk levels, greater than or equal to / L (more than or equal to 60mg/dl) as a negative risk factor, LDL-C is divided into five levels, the TG were divided into four levels. Many countries in Europe and the United States have developed a similar classification standards and intervention guidelines, but some are based on the experience of the development, there is no evidence of a large number of research data. Chinese Medical Association of cardiovascular disease to discuss the development of China's "hyperlipidemia prevention and treatment recommendations", the specific provisions of the European and American standards for comparison, see Table 1, the treatment target see table 2. Such programs should be revised through practice.

Selection of 4 AS cardiovascular lipid risk factors
Specify the NCEP-ATP III project is what we call the "old three", TC, HDL-C and TG were measured, then calculate the LDL-C, the prevention and treatment of dyslipidemia in the construction of the provisions of the is the four, in clinical application of the four is enough.
The author in patients with coronary heart disease in clinical research, TC, TG, LDL-C, apoB and LP (a) etc. index, higher than the control group of P90 distribution for the positive, HDL-C and its subclasses, and ApoA I to lower than control group of P10 distribution is positive, the positive rate of coronary heart disease (CHD), TC, LDL-C, HDL-C, TC are close to 30%, and the positive rate of HDL-C and apoAI for 50 ~ 60%, LP (a) is 20%. The serum lipoprotein mainly has HDL, LDL, VLDL and a unique Lp (a), the clinical can choose to represent the experimental project of these kinds of lipoprotein. Lp (a) determination of the biggest problem is difficult to achieve the method of standardization. But it has no obvious correlation with other blood lipid indexes, and it is an independent variable that can be used. The main component of VLDL is TG, but the content of apoC II, C III, E and B is less. VLDL increase in the number of these apo changes as TG increased significantly. Therefore, coronary heart disease does not need to use apoC II, C III and E determination. All kinds of tests on behalf of HDL and LDL, apoAI, apoB determination in coronary heart disease risk discrimination in May and HDL-C, LDL-C were comparable, but there are also some reports that ApoA I is better than that of HDL-C and HDL-C than ApoA I.
In fact, HDL-C reflects the metabolic state of HDL carrying lipid, while apoA I can reflect the synthesis and decomposition of HDL particles. Some people think that the serum apoA I can be used directly to determine the use of HDL-C technology is simple, so that as long as the test apoA I can omit HDL-C, in fact, this is wrong. Especially in the case of apoA I test technology is not clearance, or the preferred HDL-C is appropriate. Now, some people advocate apoB as preferred indicators because in atherosclerosis (as) of strong small and dense low-density lipoprotein (LDL cholesterol pattern B), with a higher proportion of apoB and big and light LDL (type A) LDL compared, apoB and more ch less, so it can be LDL-C, while not high, but serum apoB increased the so-called "high apoB lipid protein syndrome. It reflects increased LDL cholesterol pattern B. So apoB and LDL-C simultaneously determine the benefit of clinical judgment. In short, according to the quality of the technical personnel and the selection of the new three [apoA I, apoB and Lp (a)] in coronary heart disease clinical.
As for special inspection items, only for clinical research or special cases. For example, LPL and LCAT activity assay, LDL receptor activity or receptor gene mutation were examined, some apoLP deficiency (e.g. apoC II deficiency), apoLP gene mutation, apoE polymorphism and gene mutation, etc.. In recent years, the small and dense LDL and oxidation of LDL and coronary heart disease are related, the new coronary heart disease risk factors such as homocysteine determination, etc.. Although some indexes have clinical significance, it is still limited to the study of lipoprotein. Our application of molecular biology technology in the study of lipoprotein metabolism also has 10 years the, but in addition to the obvious pathogenic gene of hereditary disease (such as familial hypercholesterolemia of the LDL receptor gene defects), most of them not suitable for clinical application. AS cardiovascular disease is a multi factor disease, of course, is also a multi gene involved in the disease, which is a complex problem. The relationship between Alzheimer's disease and APOE genotype of relatively simple, for example, most believe that apo E genotype 4 people prone to Alzheimer's disease, but epsilon 4 can not be as the index for the diagnosis of senile dementia, according to our hospital neurology investigation of senile dementia (74 cases) of epsilon 4 allele frequency only 0.21, while the control group (78 cases of healthy old man) was 0.11, only statistically different for diagnosis obviously invalid.

Clinical application of different in scientific research, should choose the relatively mature test, otherwise in vain to increase workload and cost effectiveness. In the absence of serious research, the clinical significance is not clear or operation method is not reliable, it is not desirable to expand the application, the domestic often have to pursue the advanced behavior of the new test, should be corrected.
5 standardization of lipid measurement
Determination of blood lipids in laboratory test results of cholesterol and other items with horizontal and vertical comparability, the requirements to achieve the required accuracy. The core of the standardization work is the accuracy of traceability. Therefore, we should establish a reliable reference system as the basis for the accuracy, then the accuracy of transfer to the routine determination in the routine determination system can be traced back to the reference system to provide the accuracy of foundation up. At present, our country has built the TC reference system, has already approved the TC reference serum (national first level standard). Reference systems for other projects are still under study.
The clinical chemistry reference serum (level two) should be universal, but the calibration solution produced by the reagent manufacturer can only be applied to a particular analytical system, rather than a generic one. The labeled value of the calibration liquid is often modified according to the matrix deviation, and the corresponding reagent can be used to make the determination of the patient's specimen to get more accurate results. So the value of the calibration liquid is not the actual value. It is quite wrong to use a calibration solution of a commodity reagent in other commodity analysis systems for calibration purposes. Of course, the market for the sale of the use of the serum as a calibration liquid, but also very wrong.
The epidemiological study of cardiovascular disease needs to be done to compare the blood lipid levels between the international and local levels. In the same group of blood lipids longitudinal study, the multi center cooperation research and the clinical curative effect observation also requests to be standardized to four blood fat determination. Clinical need to develop the appropriate level of blood lipids or the level of the division of the four criteria, the treatment of pointers and therapeutic targets, but also must be based on the standardization of blood lipids. But blood lipids were measured not standardized requires a unified method for the determination, but required between the experimental values obtained are consistent with a number of specimens of blood lipid determination, requirements for the determination of value falls in the allowable "fine density" (CV) and no accuracy (bias) in. See table 3.
According to the current part of the city's blood lipid analysis of the quality of the survey, from the requirements of Table 3 still far away, 65 hospitals after 4 years, 3 times the results of the assessment TC about 59%, TG and HDL-C standard only 13% and 34%.
Blood lipid determination should begin with the analysis of ready to start, including subjects of preparation, specimen collection and storage, selection of eligible time and qualified calibrator, selection and use of, for there is no recommended method of project, the best use of international common method, including the formulation of the reagent and operating procedures. To strengthen the study, improve the quality of the products, the quality of the identification of the agent.

Table 1 classified [mmol/L (mg/dl) for cardiovascular and blood lipid risk level
III
Suggestions for prevention and treatment of dyslipidemia in China (1997)
European Society of Cardiology, etc. (1998) *
United States NCEP-ATP (2001)
TC
Appropriate level
Less than 5.2 (200)
-
< 5.2 (200)
Critical range
5.2 ~ 5.7 (219 ~ 201)
-
5.2 ~ 6.2 (239 ~ 201)
rise
More than 5.7 (220)
> 5 (190)
More than 6.2 (240)
LDC-C
Appropriate level
Less than 3.1 (120)
-
< 2.6 (100) * *
Close to the appropriate level
-
-
2.6 ~ 3.3 (129 ~ 100) * *
Critical range
3.1 ~ 3.6 (139 ~ 121)
-
3.4 ~ 4.1 (159 ~ 131)
rise
More than 3.6 (140)
> 3 (115)
4.1 ~ 4.9 (189 ~ 160)
High
-
-
More than 4.9 (190)
HDC-C
Appropriate level
More than 1 (40)
-
-
low
Less than 0.9 (35)
< 1 (40)
< 1 (40)
high
-
-
More than 1.6 (60)
TG
Appropriate level
< 1.7 (150)
-
< 1.7 (150)
Critical range
-
-
1.7 ~ 2.2 (199 ~ 150)
rise
More than 1.7 (150)
> 2 (180)
2.3 ~ 5.6 (499 ~ 200)
High
-
-
More than 5.6 (500)
Note: * the number of mg/dl in brackets is the original note, for the simple number
**NCEP-ATP- document writing "the most appropriate level" and "close to the most appropriate (higher than the most appropriate)", please refer to "the new revision of the blood lipid levels in the program" a text [Chinese Journal, 2001, 24 (5): 261]
Table 2 mg/dl ([mmol/L) in the treatment of patients with hyperlipidemia in our country.
Dietary treatment criteria
Standard for drug therapy
Therapeutic target value
AS disease (-)
TC > 5.69 (220)
> 6.21 (240)
< 5.69 (220)
AS risk factors (-)
LDL-C > 3.62 (140)
> 4.14 (160)
< 3.62 (140)
AS disease (-)
TC > 5.17 (200)
> 5.69 (220)
< 5.17 (200)
AS risk factor (+)
LDL-C > 3.10 (120)
> 3.62 (140)
< 3.10 (120)
AS disease (|+)
TC > 4.65 (180)
> 5.17 (200)
< 4.65 (180)
LDL-C > 2.59 (100)
> 3.10 (120)
< 2.59 (100)
Table 3 technical goals of the National Cholesterol Education Program in the United States (1995)
Blood lipid index
Inaccuracy (relative deviation)
Non fine density (CV)
Total error *
TC
Less than 3%
Less than or equal to 3%
Less than or equal to 8.9%
TG
Less than 5%
Less than or equal to 5%
Less than or equal to 15%
HDL-C transition target
Less than 10%
Less than or equal to 6%
Less than or equal to 22%
1998
Less than 5%
Less than or equal to 6%
Less than or equal to 13%
LDL-C
Less than 4%
Less than or equal to 4%
Less than or equal to 12%

* total error = relative deviation + 1.96CV


Laboratory report on the evaluation of a biochemical test of clinical significance are often affected by the influence of square law. For example, the current in determination of apoAI, apoB, some domestic reagent quality is unqualified, calibration solution is not reliable, operation just a simple and abandon principle, that distorts the judgment of clinical significance, this kind of undesirable tendency should pay attention to, the unknown clinical workers using unreliable data write a summary, adverse consequences can be imagined. (turn from: China Laboratory Medicine Network; the author: Beijing Hospital, Li Jianzhai)

 

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