CN105021827B - The application in preparation detection inflammation and fibrosis product of the material of detection Serum angiogenin sample albumen 2 content - Google Patents
The application in preparation detection inflammation and fibrosis product of the material of detection Serum angiogenin sample albumen 2 content Download PDFInfo
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Abstract
The material that the invention discloses detection Serum angiogenin sample albumen 2 content is preparing the application detected in inflammation and fibrosis product.The present invention tests discovery, in serum, angptl2 content has dependency with degree of inflammation and the fibrosis of chronic HBV infection patient's liver, angptl2 content can judge inflammation degree and fibrosis as the single index of Non-Invasive, detection people's inflammation degree and/or the product of fibrosis can be prepared by the material of detection Serum angiogenin sample albumen 2 content or together with the agents in combination of the common clinical index of other hepatopaths of detection, whether diagnosis or auxiliary diagnosis of liver disease patient need carry out the product of liver puncture detection or examination or assist whether examination needs to carry out the product of liver puncture hepatopath.
Description
Technical field
The present invention relates to the material detecting Serum angiogenin sample albumen 2 content in biomedical sector in preparation detection
Application in inflammation and fibrosis product.
Background technology
Asia-Pacific and hepatopathy association of the U.S. are recommended about chronic HBV (HBV) the infected Treatment decsion guide:
(HBeAg is cloudy for ALT >=2ULN, HBV DNA >=20000IU/mL (HBeAg positive) or HBV DNA >=2000IU/mL
Property person) Patients with Chronic HBV Infection need to give antiviral therapy.And for being unsatisfactory for the gray area patient of above-mentioned dividing value, then need
The auxiliary of transcutaneous aspiration biopsy of liver lesions pathological examination determines therapeutic scheme.Liver puncture pathology show in hyperphlogosis or obvious fiber
Change person need to carry out antiviral therapy immediately.But transcutaneous aspiration biopsy of liver lesions is aggressive inspection, there is interpretation and error of sampling,
And have hemorrhage, gallbladder leakage equivalent risk, it is not suitable for being applied to all patients.And existing non-invasive method is only applicable to
The judgement of hepatic fibrosis degree, and study population is concerned only with Patients with Chronic Hepatitis B, is not suitable for all
The judgement of chronic HBV infection patient treatment decision-making.Therefore, clinic needs exploitation non-invasive method adjuvant clinical treatment badly
The formulation of decision-making.
Angiopoietin-like protein 2 (Angiopoetin-like protein 2, angptl2) is angiogenin
One of white family member of sample, can by increase metalloproteases expression and activity thus regulate the deposition of extracellular matrix
And degraded.The functional receptor integrin wide expression of PP1158 in macrophage, vascular endothelial cell,
The thin surface of fat.
Summary of the invention
The technical problem to be solved is how to detect chronic HBV (HBV) infected patient liver
Degree of inflammation and fibrosis, and determine the Treatment decsion of patient.
For solve above-mentioned technical problem, present invention firstly provides following 1)-5) in arbitrary purposes:
1) material of detection Serum angiogenin sample albumen 2 (angptl2) content is at preparation detection people's inflammation
And/or the application in fiberization product；
2) detection Serum angiogenin sample albumen 2 content, hepatitis B e antigen, HBV DNA content and alanine
The application in preparation detection people's inflammation degree and/or fibrosis product of the material of transaminase (ALT) content；
3) using Serum angiogenin sample albumen 2 as detection people's inflammation degree of mark and/or fibrosis journey
Material used in the degree method application in preparation detection people's inflammation degree and/or fibrosis product；
4) arbitrary application in following Y1-Y3:
Whether Y1, the material of detection Serum angiogenin sample albumen 2 content need to carry out in preparation examination or auxiliary examination
Application in liver puncture hepatopath's product；
Y2, detection Serum angiogenin sample albumen 2 content, hepatitis B e antigen, hepatitis B virus DNA contain
Whether the material of amount and alanine aminotransferase content needs to carry out liver puncture hepatopath's product in preparation examination or auxiliary examination
In application；
Y3, using Serum angiogenin sample albumen 2 as detection people's inflammation degree of mark and fibrosis
Whether material used in method needs to carry out the application in liver puncture hepatopath's product in preparation examination or auxiliary examination；
5) arbitrary application in following Z1-Z3:
Z1, the material of detection Serum angiogenin sample albumen 2 content in preparation diagnosis or auxiliary diagnosis of liver disease patient are
No need carry out the application in liver puncture detection product；
Z2, detection Serum angiogenin sample albumen 2 content, hepatitis B e antigen, hepatitis B virus DNA contain
Whether the material of amount and alanine aminotransferase content needs to carry out liver puncture detection in preparation diagnosis or auxiliary diagnosis of liver disease patient
Application in product；
Z3, using Serum angiogenin sample albumen 2 as detection people's inflammation degree of mark and/or fibrosis journey
Whether material used in degree method needs to carry out in liver puncture detection product in preparation diagnosis or auxiliary diagnosis of liver disease patient
Application.
For solving above-mentioned technical problem, present invention also offers the product of following M1 or M2:
M1, detection people's inflammation degree and/or fibrosis product, for described detection Serum angiogenin sample egg
The material of white 2 content；
M2, detection people's inflammation degree and/or fibrosis product, for described detection Serum angiogenin sample egg
White 2 content, hepatitis B e antigen, HBV DNA content and the material of ALT content.
In the present invention, it is raw that the material of described detection Serum angiogenin sample albumen 2 content can include detecting serum blood vessel
Become reagent and/or the instrument of element sample albumen 2 content, as detected Serum angiogenin sample albumen by enzyme linked immunoassay
Reagent needed for 2 content and instrument.Specifically, the material of detection Serum angiogenin sample albumen 2 content can wrap
Include Serum angiogenin sample albumen 2, Serum angiogenin sample albumen 2 antibody and carry out enzyme-linked immunosorbent assay
(ELISA) other reagent required for and instrument, certainly, above-mentioned detection Serum angiogenin sample albumen 2 content
Material can be only made up of Serum angiogenin sample albumen 2 and Serum angiogenin sample albumen 2 antibody, it is possible to only by
Serum angiogenin sample albumen 2 forms, it is possible to be only made up of Serum angiogenin sample albumen 2 antibody.Described blood
Clear angiopoietin-like albumen 2, described Serum angiogenin sample albumen 2 antibody and carry out enzyme-linked immunosorbent assay
(ELISA) other reagent required for all can independent packaging.
In the present invention, described detection Serum angiogenin sample albumen 2 content, hepatitis B e antigen, HBV DNA
The material of content and ALT content can be by the material of detection Serum angiogenin sample albumen 2 content, detection hepatitis B
The material composition of the material of e antigen, the material of detection HBV DNA content and detection ALT content.Detection serum blood vessel
Generate the material of element sample albumen 2 content, the material of detection hepatitis B e antigen, the material of detection HBV DNA content
Reagent and/or test kit and/or instrument is may each comprise with the material of detection ALT content.
In the present invention, described Serum angiogenin sample albumen 2 antibody can be Serum angiogenin sample albumen 2 Dan Ke
Grand antibody and/or Serum angiogenin sample albumen 2 polyclonal antibody.
In the present invention, described Serum angiogenin sample albumen 2 can be the Serum angiogenin sample egg of label labelling
White 2.
In the present invention, described Serum angiogenin sample albumen 2 concretely human serum Angiopoietin-like protein 2.
In the present invention, described Serum angiogenin sample albumen 2 can be aminoacid sequence be the egg of sequence 1 in sequence table
White matter.
In the present invention, described Serum angiogenin sample albumen 2 antibody can be with biotin labeled serum angiogenesis
Element sample albumen 2 antibody.
In the present invention, described Serum angiogenin sample albumen 2 antibody can recognize that aminoacid sequence is SEQ in sequence table
The protein of ID No.1.
In the present invention, the material of described detection Serum angiogenin sample albumen 2 content can be described serum angiogenesis
Element sample albumen 2 and/or described Serum angiogenin sample albumen 2 antibody.
In the present invention, the material of described detection Serum angiogenin sample albumen 2 content can be to pass through enzyme linked immunoassay
Detect the reagent needed for described Serum angiogenin sample albumen 2 content and instrument.
In the present invention, the hepatopath that described people concretely chronic HBV (HBV) infects.Described hepatopathy
Patient can be chronic HBV (HBV) the infected.
Serum blood in the present invention, in described Serum angiogenin sample albumen 2 content concretely human serum or blood plasma
Pipe generates element sample albumen 2 concentration；HBV DNA concentration in described HBV DNA content concretely human serum or blood plasma；
Concentration of ALT in described ALT content concretely human serum or blood plasma.
In the present invention, described detection people's inflammation degree and/or fibrosis product can be to be used for detecting people's liver inflammation
Disease degree and/or the various reagent of fibrosis or test kit.Described diagnosis or auxiliary diagnosis of liver disease patient whether need into
Row liver puncture detection product can be for diagnosing or assist whether diagnosis of liver disease patient needs to carry out the various examinations of liver puncture detection
Agent or test kit.Whether described examination or auxiliary examination need to carry out liver puncture hepatopath's product can be for examination or auxiliary
Help whether examination needs to carry out various reagent or the test kit of liver puncture hepatopath.
In actual applications, can be by the material of detection Serum angiogenin sample albumen 2 content and other indexs of detection
Agents in combination is prepared detection people's inflammation degree and/or the product of fibrosis together, is diagnosed or assist diagnosis liver
Patient whether needs to carry out the product of liver puncture detection or examination or whether auxiliary examination needs to carry out liver puncture hepatopath's
Product.Other indexs can be the common clinical index of hepatopath, as HBV DNA content in human serum or blood plasma, third
Propylhomoserin transaminase (ALT) content, hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), blood are little
Plate (PLT) counting, glutamic oxaloacetic transaminase, GOT (AST) content, glutamyl transpeptidase (GGT) content, albumin (Abumin)
Content, total bilirubin (Tbil) content, prothrombin time (PT), it is possible to for fibrosis model, as APRI,
FIB-4 and AAR.
The material detecting other indexs can be the reagent and/or instrument utilizing conventional method to use when detecting.Described product can
For reagent or test kit, it can be also the system being made up of with instrument reagent or test kit.
In the present invention, determine that the method for hepatopath's therapeutic scheme is as follows according to Serum angiogenin sample albumen 2 content:
Detection chronic HBV infection patients serum's Angiopoietin-like protein 2 content, if chronic HBV infection patients serum's blood
Pipe generates element sample albumen 2 content >=7.36ng/ml, and this patient need to carry out antiviral therapy immediately, if hepatopath
Serum angiogenin sample albumen 2 content≤3.95ng/ml, this patient is not required to treatment, if Patients with hepatic diseases purifies the blood
Pipe generates element sample albumen 2 content more than 3.95ng/ml less than 7.36ng/ml, and this patient need to carry out liver and wear and determine and control
Treatment scheme.
Determine that chronic HBV infection patient treatment protocol also can first detect hepatopath's HBV DNA content, alanine turns ammonia
Enzyme (ALT) content and HBeAg state, if patient is unsatisfactory for Asia-Pacific and hepatopathy association of the U.S. about chronic type b
Treatment standard immediately in hepatitis virus (HBV) the infected Treatment decsion guide and follow up a case by regular visits to standard, according to serum blood vessel
Generate element sample albumen 2 content and determine that the method for hepatopath's therapeutic scheme determines hepatopath's therapeutic scheme.Asia-Pacific and U.S.
Hepatopathy association of state about the treatment standard immediately in chronic viral hepatitis B guide be HBeAg be positive, HBV
DNA >=20000IU/mL, ALT >=2ULN or HbeAg are negative, HBV DNA >=2000IU/mL, ALT >=2ULN；
Asia-Pacific and hepatopathy association of the U.S. mark about following up a case by regular visits in chronic HBV (HBV) the infected Treatment decsion guide
Accurate is positive, HBV DNA >=2 × 10 for HBeAg7< ULN or HBeAg is negative, HBV for IU/mL, ALT
DNA<2000IU/mL、ALT<ULN。
Described liver is worn and does pathological examination for liver puncture is taken liver organization.
Described inflammation degree and described hepatic fibrosis degree all carry out classification according to Ishak standard.Described liver
Degree of inflammation can be slight and/or middle severe；Described subinflammatory liver activity index (hepatic activity
Index, HAI) it is 0-4 (i.e. 0≤HAI≤4), the Serum angiogenin sample of the subinflammatory hepatopath of liver
Albumen 2 content≤3.95ng/ml, the liver activity index of described middle hyperphlogosis is more than or equal to 5 (i.e. HAI >=5),
The Serum angiogenin sample albumen 2 content >=7.36ng/ml of the hepatopath of hyperphlogosis in liver.Described liver is fine
Dimensionization degree can be obvious fibrosis and/or non-obvious fibrosis；Described obvious fibrosis is that Fibrosis is more than or equal to
3 (i.e. F >=3), the Serum angiogenin sample albumen 2 content >=7.36ng/ml of the hepatopath of liver obvious fibrosis,
Described non-obvious fibrosis be Fibrosis be 0-2 (i.e. 0≤F≤2), the hepatopath of the non-obvious fibrosis of liver
Serum angiogenin sample albumen 2 content≤3.95ng/ml.
It is demonstrated experimentally that angptl2 content is related with inflammation degree and fibrosis in serum: in serum
Angptl2 content increases with inflammation degree and fibrosis and increases (P=0.000), and in serum
Angptl2 content and the good relationship of inflammation classification, p=0.000, spearman rho=0.352；In serum
Angptl2 content and the good relationship of hepatic fibrosis classification, P=0.000, spearman rho=0.389.ALT
Normally time (ALT ＜ ULN), in liver in hyperphlogosis (HAI >=5) and obvious fibrosis (F >=3) patients serum
The content of angptl2 the most relatively mild inflammation (0≤HAI≤4) and non-obvious fibrosis (0≤F≤2) patient are high
(P=0.025, P=0.024).During ULN≤ALT≤2ULN and ALT >=2ULN, in patients serum, angptl2's contains
Amount raises with inflammation and the fibrosis order of severity the most respectively.
It is demonstrated experimentally that be better than fiber with angptl2 content in serum as single index diagnosis liver obvious fibrosis
Change model APRI, FIB-4 and AAR: for chronic HBV infection patient, only with angptl2 in serum
Content is 0.707 as area (AUC) under the receiver operating curves of single index diagnosis liver obvious fibrosis, and
It is respectively 0.672,0.661 with the AUC of fibrosis model APRI, FIB-4 and AAR diagnosis liver obvious fibrosis
With 0.553.Hyperphlogosis (HAI >=5) or hepatic fibrosis (F >=3) in angptl2 energy independent prediction liver,
P=0.015, OR=0.788 (95%CI:0.650,0.955).
It is demonstrated experimentally that infect about chronic HBV (HBV) for being unsatisfactory for Asia-Pacific and hepatopathy association of the U.S.
The standard for the treatment of immediately in person's Treatment decsion guide and the chronic HBV infection patient following up a case by regular visits to standard, single
In the diagnosis of index angptl2, the AUC of hyperphlogosis or obvious fibrosis is 0.691, and " cross validation leaving-one method " is tested
Hyperphlogosis or the robustness of obvious fibrosis in card angptl2 diagnosis, it was demonstrated that single index can correctly judge 64.0%
Patient.When with angptl2 content being hyperphlogosis and obvious fibrosis during 7.36ng/ml diagnoses for dividing value, special
The opposite sex (true negative rate, i.e. actual the most ill and be diagnosed as the probability of non-patient) and positive prediction rate (test diagnosis
For positive, it is really the probability of patient) it is respectively 91.76%, 72%；It is that 3.95ng/ml is with angptl2 content
In dividing value eliminating when hyperphlogosis and obvious fibrosis diagnosis, (true negative rate, i.e. reality are the most ill and are examined for specificity
Break the probability for non-patient) and negative predictive rate (test diagnosis is negative patient, is really negative probability) is respectively
78.41%, 70.8%.
The present invention, by checking that the content of serum angptl2 formulates the Treatment decsion of Patients with Chronic HBV Infection, can avoid
The patient of 49.7% carries out clinical liver puncture.
It is demonstrated experimentally that angptl2 content can judge inflammation degree and fibrosis journey as the single index of Non-Invasive
Degree, can judge the degree of inflammation of chronic HBV (HBV) infected patient liver with angptl2 content
And fibrosis, it is also possible to judge chronic by the common clinical index of angptl2 content Yu other hepatopaths
The degree of inflammation of Hepatitis virus infected patient liver and fibrosis；Can be by detection Serum angiogenin sample egg
The material preparation of white 2 content detects people's inflammation degree and/or the product of fibrosis, diagnoses or assist diagnosis liver
Patient whether needs to carry out the product of liver puncture detection or examination or whether auxiliary examination needs to carry out liver puncture hepatopath's
Product, it is also possible to the material of Serum angiogenin sample albumen 2 content and the common of other hepatopaths of detection will be detected
The agents in combination of clinical indices is prepared detection people's inflammation degree and/or the product of fibrosis together, is examined
Disconnected or auxiliary diagnosis of liver disease patient whether needs to carry out the product of liver puncture detection or examination or whether auxiliary examination needs to carry out liver
Puncture the product of hepatopath, and further determine that the Treatment decsion of patient.
Accompanying drawing explanation
Fig. 1 is angptl2 content and inflammation degree and the relation of fibrosis in serum.Wherein, A is
Angptl2 content and the relation of inflammation degree；B is the relation of angptl2 content and hepatic fibrosis degree.
Fig. 2 is that the diagnosis of single index angptl2 needs liver to wear to determine the middle hyperphlogosis of Treatment decsion group patient or substantially fine
The ROC curve of dimensionization.Wherein, 1 represents dividing value 3.95ng/ml, and 2 represent dividing value 7.36ng/ml.
Fig. 3 is 173 examples for not meeting Asia-Pacific and hepatopathy association of the U.S. about chronic viral hepatitis B guide immediately
Treatment standard and follow up a case by regular visits to the Treatment decsion flow chart of gray area patient of standard.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further described in detail, the embodiment be given only for
Illustrate the present invention rather than in order to limit the scope of the present invention.
Experimental technique in following embodiment, if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, the most commercially obtain.
Explanation of nouns involved in following embodiment:
Receiver Operating Characteristics (receiver operating characteristic, ROC) reflects sensitivity
And the balance between specificity, under ROC curve, area is important experimental accuracy index, and under ROC curve, area is more
Greatly, the diagnostic value of test is the biggest.
Sensitivity (True Positive Rate): reality is ill and is correctly judged as ill percentage rate by test standard, spirit
Sensitivity is the bigger the better, and ideal sensitivity is 100%.
Specificity (true negative rate): reality is anosis and is correctly judged as anosis percentage rate by test standard, special
Different degree is the bigger the better, and preferable specificity is 100%.
Statistical analysis in following embodiment all uses SPSS17.0 software to carry out.Measurement data mean ± standard deviation
Represent, use Kruskal-Wallis and Mann-Whitney U-tests to be analyzed；Group data uses
Chi-squared test is analyzed.Dependency between variable and pathological grading uses Spearman ' s rank
Test is analyzed.Binary logistic returns and is used for determining independent influencing factor.Variable is examined inflammation is Fibrotic
Disconnected performance ROC is analyzed and is evaluated, and is expressed as area under curve (area under the curve, AUC), quick
Perception, specificity, positive prediction rate (test diagnosis is positive, is really the probability of patient), negative predictive rate (examination
Test and be diagnosed as negative patient, be really the probability of non-patient), accuracy rate.Leave-one-out cross-validation method is to variable
Diagnosis robustness verify.
Embodiment 1, angptl2 may be used to determine the Treatment decsion of chronic HBV infection patient
1. object of study: (1) case is originated: 309 example Chronic HBV (hepatitis B virus, B-mode liver
Scorching virus) infected patient.(2) inclusive criteria: age 18-65 year；HBsAg positive history half a year and above (blood
In clear, the detection by quantitative of HBsAg uses with Roche Holding Ag of U.S. test kit (RocheHBsAg II
assay)).(3) exclusion standard: merge chronic HCV, AIDSinfected patient, merges heritability
The basic patients such as hepatopathy, medicine liver, non-alcoholic fatty liver disease；Primary hepatocarcinoma, liver cirrhosis patient and anemia of pregnant woman.
All object of study all sign Informed Consent Form before entering group.
2, angptl2 may be used to determine the Treatment decsion of chronic HBV infection patient
Liver puncture histopathological examination: by 309 example chronic HBV infection patients under guidance of Doppler color according to mark
Accurate hepatic pathology punctures standard to be carried out.Hepatic tissue punctures more than length 2.0cm of specimen, comprises at least 11 completely
Portal area.Liver puncture specimen through fixing, dehydration, transparent, waxdip, embed, cut into slices after, carry out the dyeing of conventional H E,
Specific stain (including reticular fiber, Masson trichrome stain) and immunohistochemical staining (HBsAg, HBcAg and CK7).
Pathologic specimen is unified carries out centralization blind interpretation.Inflammation degree and liver fibrosis are all marked according to Ishak
Standard carries out classification.Inflammation degree is slight and middle severe；Subinflammatory liver activity index (hepatic
Activity index, HAI) it is 0-4 (i.e. 0≤HAI≤4), the liver activity index of middle hyperphlogosis is more than or equal to
5 (i.e. HAI >=5).Hepatic fibrosis degree is obvious fibrosis and non-obvious fibrosis；Obvious fibrosis is Fibrosis
More than or equal to 3 (i.e. F >=3), non-obvious fibrosis be Fibrosis be 0-2 (i.e. 0≤F≤2).
The needle biopsy of liver (liver biopsy) having 11 example patients in 309 example chronic HBV infection patients is defective
(liver is worn tissue and is less than 2.0CM, or less than 11 portal areas), remaining 298 example patient's liver biopsy is qualified.
Hematology and biochemical analysis are all as the criterion with patient's result in liver puncture 4 weeks.
The detection by quantitative of serum HBV DNA uses Roche Holding Ag of U.S. COBAS AmpliPrep/COBAS TaqMan
It is analyzed (detection range: 2.0 × 101–1.7×108IU/ml).Hepatitis B e antigen and B-mode in serum
Hepatitis e TPPA uses U.S. RocheAssays carries out qualitative analysis.In serum, alanine turns
In ammonia enzyme (ALT) and serum, the automatic clinical chemistry analyzer that the most all uses of glutamic oxaloacetic transaminase, GOT (AST) detects.
According to Asia-Pacific and hepatopathy association of the U.S. about chronic viral hepatitis B guideline development clinical treatment decision-making mark
Accurate (being shown in Table 1), by corresponding with standard for the treatment of immediately, the standard regulating liver-QI of following up a case by regular visits to wears the patient of standard and is divided into and treating immediately
Group, follow up a case by regular visits to group and need liver to wear to determine Treatment decsion group.
In the patient that this 298 example biopsy specimen is qualified, 101 examples meet standard for the treatment of immediately (HBeAg (+), HBVDNA
>=20000, ALT >=2ULN or HBeAg (-), HBV DNA >=2000, ALT >=2ULN), belong to treatment group immediately,
The patient of this group should carry out antiviral therapy immediately；24 examples meet the standard of following up a case by regular visits to (HBeAg (+), HBVDNA >=2 ×
107, ALT < ULN or HBeAg (-), HBV DNA < 2000, ALT < ULN), belong to and follow up a case by regular visits to group, the patient of this group is not
Need treatment；Remaining 173 example is stood about chronic viral hepatitis B guide for not meeting Asia-Pacific and hepatopathy association of the U.S.
I.e. treatment standard and follow up a case by regular visits to the gray area patient of standard, belonging to needs liver to wear to determine Treatment decsion group, according to Asia-Pacific and the U.S.
Hepatopathy association need to use liver puncture to formulate Treatment decsion about chronic viral hepatitis B guide.Need liver to wear to determine
In Treatment decsion group patients serum the content of HBV DNA, HBsAg, ALT and AST relatively follow up a case by regular visits to organize height treat more immediately
Organize low.Needing liver to wear 0≤F≤2 in the 173 example patients determining Treatment decsion group and account for 115 examples (66.5%), F >=3 account for
58 examples (33.5%), 0≤HAI≤4 account for 115 examples (66.5%), and HAI >=5 account for 58 examples (33.5%).
Table 1, according to Asia-Pacific and hepatopathy association of the U.S. about the Treatment decsion standard of chronic viral hepatitis B guideline development
Measure Serum angiogenin sample albumen 2 (serum angiogenesis in the blood samples of patients that 298 example biopsy specimens are qualified
Element sample albumen 2 aminoacid sequence as shown in sequence 1 in sequence table) content: use ELISA kit Human
ANGPTL2 Assay kit(Immuno-Biological Laboratories Co.,Ltd,Japan)(Human
Containing identifying the antibody of Serum angiogenin sample albumen 2 and as the serum of standard substance in ANGPTL2 Assay kit
Angiopoietin-like protein 2) it is analyzed.In order to avoid blood multigelation, blood preparation is the most i.e. divided
Install, and be stored in-80 DEG C of refrigerators.All detections completed in 2 weeks.In order to ensure the credibility of detected value, between multiple hole
The coefficient of variation is more than 10% and standard song R side being both needed to less than 0.99 remeasures.Measurement scope 0.05ng/ml is extremely
3.5ng/ml, sample standard deviation does 10 times of dilutions.
The Clinical symptoms of each group patient is shown in Table 2.
Table 2, the Clinical symptoms of patient
Analyzing angptl2 content and inflammation and Fibrotic relation in serum, result is as shown in Figure 1.In serum
Angptl2 content increases with inflammation and Fibrosis levels and increases (P=0.000), and angptl2 in serum
Content and the good relationship of inflammation classification, p=0.000, spearman rho=0.350, at 155 example 0≤HAI
In the patient of≤4, angptl2 content 4.55 ± 2.01ng/ml, in the patient of 143 example HAI >=5, angptl2
Content is 5.68 ± 2.37ng/ml；Angptl2 content and the good relationship of hepatic fibrosis classification in serum,
P=0.000, spearman rho=0.352, in the patient of 200 example 0≤F≤2, angptl2 content is 4.52
± 1.75ng/ml, in the patient of 98 example F >=3, angptl2 content is 6.27 ± 2.69ng/ml.Only use serum
Below the middle angptl2 content receiver operating curves as single index diagnosis liver obvious fibrosis (i.e. F >=3)
Long-pending (AUC) is 0.707, and diagnoses liver obvious fibrosis with fibrosis model APRI, FIB-4 and AAR previously
AUC be respectively 0.672,0.661 and 0.553 (table 3), show with angptl2 content in serum as single
Index diagnosis liver obvious fibrosis is better than fibrosis model APRI, FIB-4 and AAR.
Table 3, Angptl2 and the comparison of other Model Diagnosis liver obvious fibrosis
ALT chromatographic analysis shows: during ALT normal (ALT ＜ ULN), hyperphlogosis (HAI >=5) and substantially in liver
The content the most relatively mild inflammation (0≤HAI≤4) of angptl2 and non-obvious fibre in fibrosis (F >=3) patients serum
Dimensionization (0≤F≤2) patient is high (P=0.025, P=0.024).During ULN≤ALT≤2ULN and ALT >=2ULN,
In patients serum, the content of angptl2 raises (being shown in Table 4) with inflammation and the fibrosis order of severity the most respectively.
Table 4, when ALT difference is layered, angptl2 and the Fibrotic relation of inflammation
Determine in 173 example patients of Treatment decsion group needing liver to wear, hyperphlogosis (HAI in single factor analysis display liver
>=5) angptl2 content, AST content, GGT content and PT are respectively and in obvious fibrosis (F >=3) patients serum
In mild inflammation (0≤HAI≤4) and non-obvious fibrosis (0≤F≤2) patients serum angptl2,
AST, GGT and PT, and its HBsAg, Albumin content significant lower (table 5), show angptl2 in serum
Content, AST content, GGT content, PT, HBsAg, Albumin content have with inflammation and fibrosis
Dependency.To angptl2 content in serum, AST content, GGT content, PT, HBsAg, Albumin content with
And clinic generally believes influential factor (age more than 40 years old, sex, Body Mass Index more than 24)) carry out many because of
Element is analyzed and is found, hyperphlogosis (HAI >=5) or the obvious fiber of liver in high level angptl2 energy independent prediction liver
Change (F >=3), P=0.015, OR=0.788 (95%CI:0.650,0.955).
Table 5, need liver to wear to determine in Treatment decsion group, angptl2 and the Fibrotic single factor test of inflammation and multiplicity
Determine 173 example patients of Treatment decsion group for needing liver to wear, in the diagnosis of single index angptl2 hyperphlogosis or
The AUC of obvious fibrosis is 0.691 (Fig. 2).Leave-one-out (staying one) cross-validation method carries further
Showing, single index can correctly judge the patient of 64.0%.When diagnosing with concentration 7.36ng/ml of this index for dividing value
When middle hyperphlogosis and obvious fibrosis, specificity (true negative rate) and positive prediction rate (test diagnosis is positive,
It is really the probability of patient) it is respectively 91.76%, 72%；Hyperphlogosis and substantially in getting rid of with 3.95ng/ml for dividing value
During fibrosis diagnosis, (test diagnosis is negative patient, is really non-patient for specificity (true negative rate) and negative predictive rate
Probability) be respectively 78.41%, 70.8%.Can be using angptl2 content >=7.36ng/ml in serum as middle severe
Inflammation or obvious fibrosis dividing value, using angptl2 content≤3.95ng/ml in serum as get rid of in hyperphlogosis or
Obvious fibrosis dividing value, needs liver to wear the trouble having 86 example patients (49.7%) in the 173 example patients determining Treatment decsion group
Person need not do liver puncture and i.e. can determine that therapeutic scheme (Fig. 3), wherein angptl2 content >=7.36ng/ml in serum
21 example patients should carry out antiviral therapy immediately；The 65 example patients of angptl2 content≤3.95ng/ml in serum
It is not required to treatment；In serum, Serum angiogenin sample albumen 2 content is less than the 87 of 7.36ng/ml more than 3.95ng/ml
Patient need to carry out further liver puncture to determine therapeutic scheme.The present invention is by checking that the content of serum angptl2 comes
Formulate the Treatment decsion of Patients with Chronic HBV Infection, the patient of 49.7% can be avoided to carry out clinical liver puncture.
Claims (11)
1. the material of detection Serum angiogenin sample albumen 2 content is at preparation detection chronic hepatitis B virus infecton
Application in inflammation degree and/or fibrosis product.
Application the most according to claim 1, it is characterised in that: described detection Serum angiogenin sample albumen 2
The material of content is Serum angiogenin sample albumen 2 and/or Serum angiogenin sample albumen 2 antibody.
Application the most according to claim 1 and 2, it is characterised in that: described detection Serum angiogenin sample egg
The material of white 2 content be by enzyme linked immunoassay detection Serum angiogenin sample albumen 2 content needed for reagent and
Instrument.
Application the most according to claim 1 and 2, it is characterised in that: described Serum angiogenin sample albumen 2
Content is Serum angiogenin sample albumen 2 concentration in human serum or blood plasma.
5. detection Serum angiogenin sample albumen 2 content, hepatitis B e antigen, hepatitis B virus DNA contain
Amount and alanine aminotransferase content material preparation detection chronic hepatitis B virus infecton inflammation degree and/
Or the application in fibrosis product.
Application the most according to claim 5, it is characterised in that: described Serum angiogenin sample albumen 2 content
For Serum angiogenin sample albumen 2 concentration in human serum or blood plasma；Described hepatitis B virus DNA content is behaved
Hepatitis B virus DNA concentration in serum or blood plasma；Described alanine aminotransferase content is in human serum or blood plasma
Alanine aminotransferase concentration.
7. scorching as the detection chronic hepatitis B virus infecton liver of mark using Serum angiogenin sample albumen 2
Material used in disease degree and/or fibrosis method is at preparation detection chronic hepatitis B virus infecton liver
Application in degree of inflammation and/or fibrosis product.
Arbitrary application in the most following Y1-Y3:
Whether Y1, the material of detection Serum angiogenin sample albumen 2 content need to carry out in preparation examination or auxiliary examination
Application in liver puncture chronic hepatitis B virus infecton product；
Y2, detection Serum angiogenin sample albumen 2 content, hepatitis B e antigen, hepatitis B virus DNA contain
Whether the material of amount and alanine aminotransferase content needs to carry out liver puncture chronic hepatitis B in preparation examination or auxiliary examination
Application in virus the infected's product；
Y3, using Serum angiogenin sample albumen 2 as the detection chronic hepatitis B virus infecton liver of mark
It is slow whether material used in degree of inflammation and fibrosis method needs to carry out liver puncture in preparation examination or auxiliary examination
Application in property Hepatitis B Virus Infection product.
Application the most according to claim 8, it is characterised in that: described Serum angiogenin sample albumen 2 content
For Serum angiogenin sample albumen 2 concentration in human serum or blood plasma；Described hepatitis B virus DNA content is behaved
Hepatitis B virus DNA concentration in serum or blood plasma；Described alanine aminotransferase content is in human serum or blood plasma
Alanine aminotransferase concentration.
Arbitrary application in the most following Z1-Z3:
Z1, the material of detection Serum angiogenin sample albumen 2 content in preparation diagnosis or assist the B-mode liver of diagnosing chronic
Whether scorching virus the infected needs to carry out the application in liver puncture detection product；
Z2, detection Serum angiogenin sample albumen 2 content, hepatitis B e antigen, hepatitis B virus DNA contain
Whether the material of amount and alanine aminotransferase content needs in preparation diagnosis or auxiliary diagnosing chronic Hepatitis B Virus Infection
Carry out the application in liver puncture detection product；
Z3, using Serum angiogenin sample albumen 2 as the detection chronic hepatitis B virus infecton liver of mark
Material used in degree of inflammation and/or fibrosis method is at preparation diagnosis or auxiliary diagnosing chronic hepatitis B
Whether poison the infected needs to carry out the application in liver puncture detection product.
11. application according to claim 10, it is characterised in that: described Serum angiogenin sample albumen 2
Content is Serum angiogenin sample albumen 2 concentration in human serum or blood plasma；Described hepatitis B virus DNA content
For the hepatitis B virus DNA concentration in human serum or blood plasma；Described alanine aminotransferase content is human serum or blood plasma
In alanine aminotransferase concentration.
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| CN110596399B (en) * | 2019-08-29 | 2022-07-22 | 首都医科大学附属北京安贞医院 | Application of substance for detecting content of angiopoietin-like protein8 |
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