WO2012105590A1 - Marqueur de détermination pour une stéatose hépatique non alcoolique et méthode de diagnostic d'une stéatose hépatique non alcoolique à l'aide du marqueur en tant que mesure - Google Patents

Marqueur de détermination pour une stéatose hépatique non alcoolique et méthode de diagnostic d'une stéatose hépatique non alcoolique à l'aide du marqueur en tant que mesure Download PDF

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WO2012105590A1
WO2012105590A1 PCT/JP2012/052216 JP2012052216W WO2012105590A1 WO 2012105590 A1 WO2012105590 A1 WO 2012105590A1 JP 2012052216 W JP2012052216 W JP 2012052216W WO 2012105590 A1 WO2012105590 A1 WO 2012105590A1
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ykl
measuring
test sample
steatohepatitis
nash
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PCT/JP2012/052216
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English (en)
Japanese (ja)
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荻野　淳
安永　邦夫
喬 松田
謙吾 冨田
俊昭 寺谷
紀文 日比
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アステラス製薬株式会社
学校法人慶應義塾
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/576—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis
    • G01N33/5767—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis non-A, non-B hepatitis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/974—Thrombin

Definitions

  • the present invention relates to a differentiation marker (diagnostic marker) for nonalcoholic steatohepatitis and a diagnostic method (detection method) for nonalcoholic steatohepatitis using the marker as an index.
  • Fatty liver disease is a general term for diseases in which neutral fat is deposited in hepatocytes to cause liver disease.
  • Fatty liver disease used to be alcohol-induced liver damage but it has been found that diabetes and obesity also cause similar liver damage.
  • a liver disorder characterized mainly by large droplets of liver fat is called nonalcoholic fatty liver disease (NAFLD).
  • NAFLD is further classified into simple fatty liver (simple steatosis) and nonalcoholic steatohepatitis (NASH), but the prognosis of the disease is greatly different.
  • the pathology of simple fatty liver rarely progresses, but NASH is thought to progress to cirrhosis in 5-20% in 5-10 years.
  • diagnosis of whether a patient has simple fatty liver or NASH has been made by liver biopsy tissue diagnosis, but this is extremely invasive and burdensome to the patient, and also causes liver bleeding. Because there are dangers such as accompanying, there are also facility requirements at the time of enforcement.
  • a blood biochemical method is generally used as a simple test method, but NASH has only a slight increase in a blood biochemical liver function test such as a test for transaminase or ⁇ GTP. Differentiation of NASH is difficult.
  • image diagnostic methods such as abdominal ultrasound, CT, and MRI are useful for the diagnosis of simple fatty liver, but it is difficult to distinguish NASH.
  • NASH is a progressive disease, early detection is desired, but there is currently no means to replace liver biopsy in differential diagnosis.
  • YKL-40 is a protein having a molecular weight of about 40 kDa discovered in 1988 and is also called glycoprotein-39 (gp-39), chitinase 3-like-protein-1 (CHI3L1), etc. (for example, Non-patent Document 1) reference). It has been reported that the amount of YKL-40 in blood is increased in patients with inflammatory diseases and cancers, suggesting that it can be a biomarker for asthma, rheumatoid arthritis, fibrosis and the like.
  • Patent Document 1 discloses that YKL-40 is an inflammatory or degenerative joint disease (eg, rheumatoid arthritis), a disease related to the loss of connective tissue of organs and / or other tissues (eg, cirrhosis), metastatic It is described that it is useful for diagnosing cancer and the like.
  • Patent Document 2 discloses that fibrosis stages F2, F3, and F4 of a patient infected with hepatitis C virus (HCV) can be distinguished from F0 and F1, YKL-40, HA rather than YKL-40 alone. , And a combination of three markers of ⁇ 2-MG is described as being useful.
  • HCV hepatitis C virus
  • Non-Patent Document 2 there was a correlation between the liver fibrosis score and the serum YKL-40 level in HCV-infected patients in the late stage of renal injury (Fig. 1a), but the correlation was higher than other indices It is described that it was not high (FIG. 2). Furthermore, Non-Patent Document 3 describes that the concentration of YKL-40 in the serum of patients with alcoholic liver disease increased in proportion to the severity of the patient. Non-patent document 4 shows that the amount of serum YKL-40 in alcoholic liver disease patients was significantly higher than that in healthy individuals (page 181, left column, lines 16 to 14), and simplicity. Patients without fatty liver and fibrosis had higher serum YKL-40 levels compared with healthy individuals, but lower levels than those with cirrhosis or alcoholic hepatitis with fibrosis (left column on page 182). 19-19 lines from the bottom).
  • Non-Patent Document 5 there was no difference in the amount of YKL-40 in serum between patients with simple fatty liver (NAS score 1-3) and NASH patients (NAS score 4-8). (Page 566, Fig. 1c and left column, lines 4 to 6), and fibrosis markers (YKL-40, etc.) alone cannot distinguish simple fatty liver from NASH (right column, page 567, 3 to 5). Line).
  • Diagnosis of nonalcoholic fatty liver disease is based on the presence or absence of alcohol consumption by excluding viral hepatitis and autoimmune liver disease by blood tests from patients with fatty liver and mild liver damage.
  • the screening is to exclude alcoholic fatty liver and liver damage.
  • hepatic biopsy histology with invasion is required (edited by the Japan Society of Liver Studies, “NASH / NAFLD Clinical Practice Guide”, Bunko Do, 2006, pp. 30-31). Because liver biopsy is a very invasive test, careful judgment is required to perform it.
  • liver biopsy cannot be performed more than once in a short period of time due to the heavy burden on the patient.
  • an object of the present invention is to distinguish between simple fatty liver and NASH in NAFLD patients, which is an alternative to a diagnostic method that places a heavy burden on the patient, such as liver biopsy. Furthermore, simple fatty liver and early NASH It is to provide a differentiation marker that can be used for differentiation.
  • a method for detecting nonalcoholic steatohepatitis which comprises measuring the concentration of YKL-40 in a test sample;
  • a method for discriminating between simple fatty liver and nonalcoholic steatohepatitis which comprises measuring the concentration of YKL-40 in a test sample;
  • a method for confirming the therapeutic effect on nonalcoholic steatohepatitis comprising measuring the concentration of YKL-40 in a test sample;
  • Detection of nonalcoholic steatohepatitis comprising the steps of collecting a test sample from a patient suspected of suffering from nonalcoholic steatohepatitis, and measuring the concentration of YKL-40 in the test sample Method;
  • the present invention also provides: A step of collecting a test sample (for example, blood, serum, plasma) from a patient suspected of suffering from simple fatty liver or nonalcoholic steatohepatitis, and a step of measuring the concentration of YKL-40 in the test sample
  • a method for diagnosing nonalcoholic steatohepatitis comprising: A method for in vitro or ex vivo diagnosis of nonalcoholic steatohepatitis, comprising measuring the concentration of YKL-40 in a test sample; In vitro or ex vivo discrimination method between simple fatty liver and non-alcoholic steatohepatitis, characterized by measuring the concentration of YKL-40 in a test sample; An in vitro or ex vivo confirmation method for therapeutic effects on nonalcoholic steatohepatitis, comprising measuring the concentration of YKL-40 in a test sample; A diagnostic kit for non-alcoholic steatohepatitis, comprising an anti-YKL-40 antibody or a probe or primer for measuring YK
  • the results of microarrays using liver biopsy samples are summarized for each NASH stage using a box plot according to John Tukey's method.
  • the significant difference test is based on Welch's t-test.
  • the results of measuring the amount of YKL-40 in serum are summarized for each NASH stage using a box diagram according to John Tukey's method.
  • Significant difference test is based on Welch's t test.
  • the correlation between the microarray results using liver biopsy samples and the amount of serum YKL-40 is shown.
  • the result of the ROC analysis regarding the discrimination of simple fatty liver and NASH using the amount of YKL-40 in serum is shown.
  • 3 shows the results of ROC analysis regarding the differentiation between simple fatty liver and stage I NASH using serum YKL-40 amount.
  • the present invention relates to a differential marker for nonalcoholic steatohepatitis (NASH), more specifically, a differential marker for distinguishing between simple fatty liver and NASH in nonalcoholic fatty liver disease (NAFLD), YKL-40 is used as a differentiation marker for distinguishing between fatty fatty liver and early NASH.
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • YKL-40 is used as a differentiation marker for distinguishing between fatty fatty liver and early NASH.
  • NAFLD is a liver disorder characterized mainly by large droplets of liver fat, similar to alcoholic liver disorder, although there is no clear drinking history, and simple fatty liver and NASH are categorized. Simple fatty liver is a case in which hepatocytes with lipid droplets are observed in 30% or more, and fat deposition disease is suspected in image diagnosis. However, it is often followed up because only fat deposits are allowed. NASH is a case of steatohepatitis with necrosis, inflammation, and fibrosis in liver tissue, and is considered a severe form of NAFLD. NASH is progressive and often follows the outcome of cirrhosis and liver cancer. Therefore, it is important to distinguish NASH from NAFLD.
  • the most important index is fibrosis.
  • the disease progression rarely progresses rapidly in cases with mild fibrosis, but there are cases in which advanced fibrosis cases progress to liver failure and liver cancer.
  • the degree of fibrosis is mild, there is a high possibility that the progress of fibrosis can be delayed and measures to improve can be selected, but if advanced fibrosis leads to liver failure or liver cancer, eventually liver transplantation is applied. It becomes. Therefore, clarifying the degree of fibrosis (stage) is important for consideration of treatment prognosis, and in particular, detection and intervention during treatment with mild fibrosis is important for improving prognosis. . Brunt et al.
  • Stage 1 Central leaflet (Zone 3)
  • Stage 2 Central leaflet + portal vein area
  • Stage 3 Bridge formation
  • Stage 4 Liver cirrhosis (American Journal of Gastroenterology, 1999, 94, p2467-2474).
  • test sample necessary for carrying out the present invention is collected from a patient suspected of suffering from NASH, for example.
  • test sample for example, blood (for example, whole blood, serum, plasma), saliva, urine, and liver tissue can be used, and serum and plasma are particularly preferable.
  • YKL-40 is a protein with a molecular weight of about 40 kDa, also called glycoprotein-39 (gp-39), chitinase-like protein-1 (CHI3L1), etc.
  • YKL-40 is said to have no chitinolytic activity despite its high homology with chitinolytic enzymes. Moreover, it is said that it is released from activated neutrophils and macrophages and is involved in the remodeling of extracellular matrix, but the detailed function has not been fully elucidated. It is known that expression is increased in diseases mainly consisting of chronic inflammation such as rheumatoid arthritis, asthma and Crohn's disease. In recent years, it has been clarified that expression is increased in various cancers. There is a report on the relationship with liver disease in alcoholic hepatitis and viral hepatitis.
  • the method for measuring the concentration or amount of YKL-40 in the test sample is not particularly limited.
  • an immunological method using an anti-YKL-40 antibody eg, enzyme immunoassay, latex agglutination immunization
  • Measurement method chemiluminescence immunoassay method, fluorescent antibody method, radioimmunoassay method, immunoprecipitation method, immunohistochemical staining, Western blot, etc.
  • molecular biological method for measuring the amount of mRNA for measuring the amount of mRNA.
  • the anti-YKL-40 antibody may be a polyclonal antibody or a monoclonal antibody, and the antibody itself or an antibody fragment maintaining the reaction specificity [for example, Fab, Fab ′, F (ab ′) 2 , or Fv] Can be used.
  • NASH in which fibrosis has been induced correlates with the stage of fibrosis and YKL- 40 dose is increased. Therefore, a patient in whom an increase in the concentration or amount of YKL-40 in the test sample can be determined as NASH. This determination is performed by collecting specimens from the subject patient and healthy subjects and comparing them, or by comparing the normal values of healthy subjects determined in advance with the measured values of patient specimens. However, as shown in Example 3 described later, it is preferable that the determination threshold is determined in advance.
  • simple fatty liver and NASH can be distinguished, but simple fatty liver and early NASH (that is, stage 1) can also be distinguished.
  • stage 1 simple fatty liver and early NASH (that is, stage 1) can also be distinguished.
  • YKL-40 a correlation with YKL-40 was also reported in viral liver disease or alcoholic liver disease, but in all cases, a significant increase in YKL-40 was observed in severe cases.
  • patients with early stage viral liver disease or alcoholic liver disease could not be distinguished from healthy individuals.
  • the therapeutic effect on NASH can be confirmed by measuring the amount of YKL-40 after appropriately treating NASH patients.
  • treatments for NASH patients include diet therapy, exercise therapy, drug therapy, antioxidant therapy, and surgical therapy (intragastric balloon therapy, laparoscopic gastric banding, liver transplantation, etc.), etc. If the amount of YKL-40 in the test sample collected from a patient who has undergone these treatments is reduced as compared to that before treatment, it can be determined that there was a therapeutic effect. On the other hand, if the level is the same as or higher than that before treatment, it can be determined that there is no therapeutic effect, and for example, it is possible to cope with selecting a new treatment method.
  • Example 1 Comprehensive gene expression variation analysis of liver biopsy samples of NAFLD and NASH (1) Liver biopsy and NASH diagnosis As part of a medical practice independent of the study, liver biopsy was performed to confirm the diagnosis of NAFLD patients. The following tests were further conducted on patients whose blood samples were obtained and informed consent was obtained in writing. NASH liver histopathological diagnosis was performed using a scoring system by Brunt et al. As a result, it was found that among 122 subjects, 23 cases of simple fatty liver and 99 cases of NASH were found. Of those determined to be NASH, it was revealed that there were 61 stage I, 28 stage II and 10 stage III by fibrosis score.
  • Example 2 Measurement of YKL-40 in NAFLD and NASH Serum Samples (1) Blood Collection and Serum Preparation The blood collected in Example 1 (1) above was coagulated at room temperature and centrifuged. Serum was prepared. Of these, 76 were able to be analyzed by ELISA, and the breakdown was for 20 simple fatty livers and 56 for NASH. Among those determined as NASH, there were 35 stages I, 16 stages II, and 5 stages III according to the fibrosis score.
  • Example 3 ROC Analysis Using YKL-40 Amount in Serum Samples of NAFLD and NASH
  • AUC was calculated to be 0.74.
  • the cutoff value indicating the maximum efficiency was calculated to be 21.8 ng / mL.
  • the sensitivity was calculated to be 67% and the specificity was 80% (FIG. 4).
  • the AUC was calculated to be 0.69, and the cutoff value indicating the maximum efficiency was calculated to be 21.8 ng / mL.
  • the sensitivity was calculated to be 63% and the specificity was 80% (FIG. 5).
  • the present invention can be used in NAFLD patients to distinguish between simple fatty liver and NASH, and further to distinguish between simple fatty liver and early NASH.
  • this invention was demonstrated along the specific aspect, the deformation

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Abstract

L'invention concerne un marqueur de détermination qui peut être utilisé pour la distinction entre une stéatose simple et NASH, en particulier entre une stéatose simple et le stade initial de NASH, chez un patient atteint de NAFLD. Le marqueur de détermination comprend YKL-40.
PCT/JP2012/052216 2011-02-01 2012-02-01 Marqueur de détermination pour une stéatose hépatique non alcoolique et méthode de diagnostic d'une stéatose hépatique non alcoolique à l'aide du marqueur en tant que mesure WO2012105590A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015535177A (ja) * 2012-10-17 2015-12-10 アンテローム 肝臓に関する炎症性障害の遺伝子シグネチャー
US20160139149A1 (en) * 2014-11-19 2016-05-19 Brown University Chi3l1 for the detection and treatment of nonalcoholic steatohepatitis
WO2017126514A1 (fr) * 2016-01-19 2017-07-27 国立大学法人北海道大学 Procédé servant à détecter la stéatohépatite non alcoolique
CN107407682A (zh) * 2015-04-10 2017-11-28 社会福祉法人恩赐财团济生会 判别肝疾病的病态的方法
CN109072302A (zh) * 2016-03-30 2018-12-21 基恩菲特公司 非酒精性脂肪性肝炎的非侵入性诊断
WO2019094777A1 (fr) * 2017-11-13 2019-05-16 Gilead Sciences, Inc. Compositions et méthodes d'identification et de traitement de maladies hépatiques et de surveillance des résultats du traitement
CN111183360A (zh) * 2017-07-19 2020-05-19 生物辐射欧洲有限公司 同时评估非酒精性脂肪性肝炎和肝纤维化状态的生物标志物组合
WO2021157631A1 (fr) * 2020-02-04 2021-08-12 デンカ株式会社 Méthode d'assistance à la détection de stéatohépatite non alcoolique
WO2022029066A1 (fr) * 2020-08-03 2022-02-10 Genfit Procédé d'évaluation du risque de nash
EP3640644B1 (fr) * 2017-06-13 2022-08-17 Beijing Ditan Hospital, Capital Medical University Marqueur cible gp73 pour détecter la stéatohépatite et procédé d'application de détection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OH, SANGIK: "NON-INVASIVE MARKERS OF FIBROTIC NONALCOHOLIC STEATOHEPATITIS", DIGESTIVE DISEASE WEEK ABSTRACTS AND ITINERARY PLANNER, vol. 2003, no. M1376, 2003, pages A-743 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015535177A (ja) * 2012-10-17 2015-12-10 アンテローム 肝臓に関する炎症性障害の遺伝子シグネチャー
US10626471B2 (en) 2012-10-17 2020-04-21 Enterome Gene signatures of inflammatory disorders that relate to the liver
US20160139149A1 (en) * 2014-11-19 2016-05-19 Brown University Chi3l1 for the detection and treatment of nonalcoholic steatohepatitis
CN107407682A (zh) * 2015-04-10 2017-11-28 社会福祉法人恩赐财团济生会 判别肝疾病的病态的方法
EP3282256A4 (fr) * 2015-04-10 2019-03-06 Social Welfare Organization Saiseikai Imperial Gift Foundation, Inc. Procédé permettant de discriminer un symptôme de maladie hépatique
WO2017126514A1 (fr) * 2016-01-19 2017-07-27 国立大学法人北海道大学 Procédé servant à détecter la stéatohépatite non alcoolique
CN109072302A (zh) * 2016-03-30 2018-12-21 基恩菲特公司 非酒精性脂肪性肝炎的非侵入性诊断
EP3436600B1 (fr) * 2016-03-30 2024-01-17 Genfit Diagnostic non invasif de la stéatose hépatique non alcoolique
CN109072302B (zh) * 2016-03-30 2024-01-16 基恩菲特公司 非酒精性脂肪性肝炎的非侵入性诊断
EP3640644B1 (fr) * 2017-06-13 2022-08-17 Beijing Ditan Hospital, Capital Medical University Marqueur cible gp73 pour détecter la stéatohépatite et procédé d'application de détection
CN111183360A (zh) * 2017-07-19 2020-05-19 生物辐射欧洲有限公司 同时评估非酒精性脂肪性肝炎和肝纤维化状态的生物标志物组合
WO2019094777A1 (fr) * 2017-11-13 2019-05-16 Gilead Sciences, Inc. Compositions et méthodes d'identification et de traitement de maladies hépatiques et de surveillance des résultats du traitement
WO2021157631A1 (fr) * 2020-02-04 2021-08-12 デンカ株式会社 Méthode d'assistance à la détection de stéatohépatite non alcoolique
WO2022029066A1 (fr) * 2020-08-03 2022-02-10 Genfit Procédé d'évaluation du risque de nash

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