WO2006082522A1 - Diagnosis method of hepatic steatosis using biochemical markers - Google Patents
Diagnosis method of hepatic steatosis using biochemical markers Download PDFInfo
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- WO2006082522A1 WO2006082522A1 PCT/IB2006/000333 IB2006000333W WO2006082522A1 WO 2006082522 A1 WO2006082522 A1 WO 2006082522A1 IB 2006000333 W IB2006000333 W IB 2006000333W WO 2006082522 A1 WO2006082522 A1 WO 2006082522A1
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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
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- 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
- C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
- C12Q1/701—Specific hybridization probes
- C12Q1/706—Specific hybridization probes for hepatitis
- C12Q1/707—Specific hybridization probes for hepatitis non-A, non-B Hepatitis, excluding hepatitis D
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- G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
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- G—PHYSICS
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- G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
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- G—PHYSICS
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- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- G16B40/10—Signal processing, e.g. from mass spectrometry [MS] or from PCR
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
Definitions
- the present invention is drawn to a new diagnosis method for detecting the extent of hepatic steatosis in a patient, in particular in a patient who suffers from a disease involving hepatic steatosis or who already had a positive diagnosis test of liver fibrosis and/or presence of liver necroinfiammatory lesions, by using the serum concentration of easily detectable biological markers.
- the invention is also drawn to diagnosis kits for the implementation of the method.
- Fatty liver also named hepatic steatosis, is defined as an excessive accumulation of fat in hepatocytes (Bravo AA, et al. N. Engl. J. Med. 2001:344;495-500; Angulo P. N. Engl. J.
- Fatty liver disease involves the accumulation of triglycerides in hepatocytes, necrosis of hepatocytes, inflammation (Day CP. Best Pract.
- hepatic steatosis Worldwide the prevalence of hepatic steatosis is very high, associated with several factors such as alcohol, diabetes, overweight, hyperlipidemia, insulin resistance, hepatitis C genotype 3, abetalipoproteinemia and some drugs (Bellentani S, et al. Ann. Intern. Med. 2000; 132: 112-7; Levitsky J, Mailliard ME. Semin. Liver Dis. 2004;24:233-47).
- Non-alcoholic fatty liver disease is an adaptive response of the liver to insulin resistance that can trigger non-alcoholic steatohepatitis (NASH), which can itself induce a fibrogenic response that can result in cirrhosis (Day CP. Best Pract. Res. Clin. Gastroenterol. 2002; 16:663-78).
- NASH non-alcoholic steatohepatitis
- hepatic steatosis In patients with alcoholic liver disease (Sorensen TI, et al. Lancet. 1984;2:241-4), chronic hepatitis C (Fabris P, et al. J. Hepatol. 2004;41 :644-51), and perhaps in hepatitis B (Phillips MJ, et al. Am. J. Pathol. 1992;140: 1295-308), the presence of hepatic steatosis is also associated with fibrosis progression, with or without associated necroinflammatory lesions (alcoholic or viral hepatitis).
- liver biopsy is still an invasive and costly procedure, with a potential sampling error, it could be advantageous to have a fast and easy to perform test that would give a good predictive value of the level of hepatic steatosis in the patient.
- FT non-invasive FibroTest
- the present invention provides a method of diagnosis that assesses prospectively the predictive value of a combination of simple serum biochemical markers for the diagnosis of hepatic steatosis, in particular in the liver of a patient who suffers from a disease involving hepatic steatosis or who already had a positive diagnosis test of liver fibrosis and/or presence of liver necroinflammatory lesions.
- the reach of high positive predictive values (prediction of significant hepatic steatosis) or negative predictive values the number of biopsy indications could be reduced. This could be useful for patients and society in order to reduce the cost and the risk of liver biopsies.
- FIG. 1 Flow chart of patients analyzed and included in the training and validation groups.
- FIG. 2 Relationship between SteatoTest, GGT (IU/L) and ALT (IU/L) and the grade of liver steatosis.
- Notched box plots showing the relationship in the training group (FIG.2A); in validation group 1, HCV patients before treatment (FIG.2B); in validation group 2, cured HCV patients (FIG.2C); in validation group 3, alcoholic liver disease (FIG.2D); and in controls, healthy volunteers fasting and non-fasting and non-fasting blood donors (FIG.2E).
- the horizontal line inside each box represents the median and the width of each box the median ⁇ 1.57 interquartile rangeA ⁇ i to assess the 95% level of significance between group medians. Failure of the shaded boxes to overlap signifies statistical significance (P ⁇ 0.05).
- the horizontal lines above and below each box encompass the interquartile range (from 25"' to 75th percentile), and the vertical lines from the ends of the box encompass the adjacent values (upper: 75th percentile plus 1.5 times interquartile range, lower 25th percentile minus 1.5 times interquartile range).
- group 3 almost all patients had steatosis and group SO and Sl were combined.
- FIG. 3 Relationship between SteatoTest, GGT (IU/L) and ALT (IU/L) and the grade of liver steatosis in the integrated database combining controls, training group and validation groups.
- the present invention is therefore drawn to a method for diagnosis of hepatic steatosis in a patient or from a serum or a plasma sample from a patient, comprising the steps of:
- Hepatic steatosis may be associated with several factors such as alcohol, diabetes, overweight, hyperlipidemia, insulin resistance, hepatitis C genotype 3, abetalipoproteinemia and some drugs.
- the present invention is directed to the diagnosis of both alcoholic and non-alcoholic steatosis.
- the best index (“Steatosis score") in term of discrimination was the logistic regression function combining the independent factors.
- the logistic function is obtained by combining the relative weight of each parameter, as individually determined in the logistic regression, with a negative sign when the markers harbor a negative correlation with the stage of hepatic steatosis. Logarithms are used for markers whose values have a very large range.
- ROC Receiver Operating Characteristic
- the diagnosis of the presence or absence hepatic steatosis in the patient can be further refined by the data concerning the expected prevalence of hepatic steatosis in the population.
- the logistic function may further comprise other clinical or biochemical markers.
- the logistic function also comprises the age and gender of the patient.
- the logistic function may also comprise other biochemical markers, such as total bilirubin, haptoglobin, AST (aspartate aminotransferase), glucose, and (cholesterol or HDL-cholesterol).
- the logistic function will comprise at least 1 or 2, more preferably 3 to 5 of these other biochemical markers.
- the logistic function may also comprise total bilirubin, haptoglobin, glucose, and cholesterol.
- biochemical markers that are dosed in step a) of the method according to the present invention are "simple" biochemical markers, which means that they are easily dosed with methods already known in the art (chromatography, electrophoresis, ELISA assay . . . ).
- the different coefficients used for the values obtained for the different markers in the logistic function can be calculated through statistical analysis, as described in the examples.
- a suitable logistic function that can be used for the implementation of the method of the invention is as follows:
- al comprised in the interval of [6.68805 -x% ; 6.68805 +x%], a2 comprised in the interval of [1.55337E-02-x% ; 1.55337E-02+x%], a3 comprised in the interval of [1.161531 -x% ; 1.161531+x%], a4 comprised in the interval of [0.11889-x% ; 0.11889+x%], a5 comprised in the interval of [1.74791-x% ; 1.74791+x%], a6 comprised in the interval of [0.96453-x% ; 0.96453+x%], a7 comprised in the interval of [0.11958-x% ; 0.11958+x%], a8 comprised in the interval of [0.68125-x% ; 0.68125+x%], a9 comprised in the interval of [ 1.17922-x% ; 1.17922+x%] , alO comprised in the interval of [1.46963-x%
- An "interval of [a-x% ; a+x%]" means an interval of [(100-x)/100.a ; (100+x)/100.a].
- x is at most 90, 80 or 70, more preferably at most 60, 50, or 40, even more preferably at most 30, 20, 10 or 5. All a, coefficients are truncated to a number of 5 decimals. For instance, for x equal to 90, al3 is comprised in the interval of [0.03505; 0.66598].
- the numerical definitions for the coefficients in the different functions can vary depending on the number and characteristics of the patients studied. Therefore, the value given for the coefficients of the different markers have to be interpreted as capable to being slightly different, without reducing the scope of the invention.
- a specific usable function, when x is equal to zero, is:
- the invention thus concerns a method as previously described, wherein the end value of the logistic function is further used for the diagnosis of hepatic steatosis grade.
- the different grades of hepatic steatosis are defined according to histological features of liver biopsies. A more precise definition of hepatic steatosis grades is provided in Example 1.
- the method according to the invention may further comprise a step of prediction of the evolution of the disease, based on the hepatic steatosis grade deducted from the end value of the logistic function, hi particular, a Steatosis score at the 0.30 cut off has a very high sensitivity ranging from 85% to 100% according to different groups (Table 4) and a Steatosis score at the 0.70 cutoff has a very high specificity ranging from 83% to 100%. Furthermore as already demonstrated for Fibrotest (Poynard 2004 Clin Chem 2004) many of the discordances between Steato-score and biopsy were due to error of the biopsy (small sample size). It is expected that the method of the invention will reduce the need of liver biopsy by more than 80%.
- a clinician can have an estimate of major histological features leading to cirrhosis or explaining liver tests abnormalities: Steatosis score for steatosis, Fibrosis score (FibroTest, Biopredictive, Paris, France) for fibrosis, Activity score (ActiTest, Biopredictive, Paris, France) for the necrotico-inflammatory features of chronic hepatitis C and B. Biopsy should be indicated only in second line in case of non interpretable components as described for the Fibrosis score (FibroTest), i.e acute inflammation, Gilbert syndrome or hemolysis (Poynard Clin Chem 2004).
- the hepatic steatosis grade deducted from the end value of the logistic function can also be very valuable for the physician to choose a suitable treatment for the patient, according to the stage of the disease.
- said hepatic steatosis grade may be used by the physician to decide whether to perform a liver biopsy on the patient or not.
- the data obtained with the method of the invention can be used to determine the need to perform a liver biopsy on the patient. It is expected that the method of the invention will reduce the need of liver biopsy by around 80%.
- the method of the invention is intended to be used for patients suffering of any disease involving hepatic steatosis, that could develop to cirrhosis.
- a "disease involving hepatic steatosis" is meant any disease that may lead to the development of hepatic steatosis.
- the method of the invention is advantageously performed for detecting hepatic steatosis in patients suffering from a disease included in the group consisting of hepatitis B and C, alcoholism, hemochromatosis, metabolic disease, diabetes, obesity, autoimmune hepatitis, primary biliary cirrhosis, .alpha.1 -antitrypsin deficit, Wilson disease.
- the method of the invention is particularly intended to be used for a patient who was already subjected to a diagnosis test of liver fibrosis and/or presence of liver necroinflammatory lesions.
- the method of the invention is intended to be used for a patient who was already subjected to a FibroTest/Acti-Test diagnostic test, as described in patent US 6,631,330, which is herein incorporated by reference.
- the invention is also drawn to a kit of diagnosis of hepatic steatosis in a patient, comprising instructions allowing to determine the presence or absence of hepatic steatosis in said patient, after dosage of biochemical markers.
- the instructions may comprise the logistic function that has to be used after determination of the dosage of the biochemical markers. It can appear as a printed support as well as a computer usable support, such as a software.
- the instructions may also comprise the ROC curve depending of the threshold that is looked for, to allow the analysis of the end data obtained from the logistic function. They may also comprise different tables that allow to obtain the predictive values, depending of the expected prevalence of hepatic steatosis in the patient population.
- the diagnosis kit according to the present invention may also contain elements allowing the dosage of the biological markers of interest.
- the method of the invention can easily be automated, the dosage of the markers being performed automatically, the data being sent to a computer or a calculator that will calculate the value of the logistic function and analyze it with the aid of the ROC curve, and eventually the prevalence of hepatic steatosis in the patient population.
- the data obtained by the physician is therefore more easily interpretable, and will allow for an improvement in the process for deciding the need of a biopsy or the adequate treatment to prescribe.
- Consecutive patients with available serum, a consistent liver biopsy and a duration of time between serum and biopsy shorter than 3 months were included (FIG.l).
- Non-inclusion criteria included non-available serum, and non-available biopsies and patients because biopsy and serum were collected more than 3 month apart.
- the analysis was performed on a first group (training group) and validated on 3 different groups (validation groups). Training group patients were retrospectively included for this specific analysis, but have been analyzed in previous prospective validation studies of Fibrotest between September 2000 and August 2004 (Poynard T, et al. Comp. Hepatol. 2004;3:8; Myers RP, et al. J Hepatol. 2003;39:222-30; Ratziu V, et al.
- Validation group 1 patients were retrospectively analyzed from a study of hepatic steatosis in patients with chronic hepatitis C (Poynard T, et al. Hepatology. 2003;38:75-85). For this purpose, previously non-treated patients of a prospective multicentre randomized trial of PEG-IFN and Ribavirin were included. The biomarkers and the biopsy results at baseline were used.
- Validation group 2 patients (former Hepatitis C with undetectable HCV patients) were the patients of the same randomized trial as in validation group 1 (Poynard T, et al.
- Validation group 3 patients were retrospectively included for this specific analysis, but were prospectively included between 1998 and 2000 in a cohort of alcoholic patients for which one primary endpoint was the identification of biochemical markers. The details of this cohort have been recently published in a validation study of FibroTest (Naria S, et al. Clin. Gastroenterol. Hepatol. 2005 in press). All were inpatients hospitalized in the Hepato-Gastroenterology Department of H ⁇ pital Antoine Beclere for complications of alcoholic liver disease. Patients' characteristics of the different groups are listed in Table 1. Characteristics Training Validation Validation ⁇ alidation gioup group 1 group 2 group 3
- I ⁇ glyce ⁇ des > 17 mmol/L 67 (22%) 36 (21%) 54 (27%) 20 (32%)
- GGT U/L (7-32 female, 11-49 male) 112(183) 84 (96) 21 (18) 323 (443)
- Haptoglobin g/L (035-200)* 095 (057) 078 (045) 086 (043) 139(063)
- SteatoTest 049 (025) 053 (022) 036 (022) 058 (025) Data are mean (SD) or proportion.
- AST aspartate aminotransferase.
- ALT alanine aminotransferase.
- GGT glutamyl transpeptidase.
- ApoAl apolipoprotein al .
- a control group was also analyzed. It was constituted of fasting and non- fasting apparently healthy volunteers previously included in a validation of FibroTest (Munteanu M,et al. Comp. Hepatol. 2004;3,3) and additional non-fasting blood donors.
- the 10 following biochemical markers were assessed for the different groups : ApoAl, ALT (alanine aminotransferase), AST (aspartate aminotransferase), alpha.2-macroglobulin, GGT (gammaglutamyl transpeptidase), total bilirubin, haptoglobin, cholesterol, glucose, and triglycerides.
- biochemical markers include the 6 components of the FibroTest- ActiTest adjusted by age and gender (patented artificial intelligence algorithm USPTO 6,631,330) plus the AST, cholesterol, glucose, and triglycerides markers and the BMI.
- FibroTest Biopredictive, Paris, France; FibroSURE LabCorp, Burlington, NC, USA was determined as previously published (Poynard T, et al. Comp Hepatol. 2004;3:8; Myers RP, et al. J Hepatol. 2003;39:222-30; Callewaert N, et al. Nature Med 2004;10;l-6; Naria S, et al. Clin Gastroenterol Hepatol in press; Imbert-Bismut F, et al. Clin Chem Lab Med 2004;42:323-33; Sloanu M, et al.Comp Hepatol 2004;3:3).
- Alpha2- macroglobulin, apolipoprotein Al, and haptoglobin were measured using an automatic nephelemeter BNII (Dade Behring; Marburg, Germany).
- ALT, GGT, serum glucose, triglycerides, cholesterol, total bilirubin and haptoglobin were measured by autoanalyzer (Olympus AU 640 Automate) using manufacturer's reagents (Olympus, Rungis France); alpha2-macroglobulin and apolipoprotein Al were measured using an automatic nephelometer (BNII, Dade Behring; Marburg, Germany).
- the primary outcome was the identification of patients with hepatic steatosis grade 2, 3 or 4 (moderate, marked or severe).
- the first stage consisted of identifying factors which differed significantly between these groups by unidimensional analysis using the chi-square, Student t test or Mann-Whitney test.
- the second stage consisted of logistic regression analysis to assess the independent discriminative value of markers for the diagnosis of fibrosis.
- the third step was to construct an index combining these identified independent factors.
- the best index (“Steatosis score”) in term of discrimination was the logistic regression function combining the independent factors.
- the Steatosis score is further referred to as "SteatoTest score”.
- the SteatoTest score ranges from zero to 1.00, with higher scores indicating a greater probability of significant lesions.
- the diagnostic values of the markers were assessed using sensitivities, specificities, positive (PPV) and negative predictive values (NPV), and the areas under the Receiver Operating characteristic (ROC) curves (Hintze JL. NCSS 2003 User Guide. Number Cruncher Statistical Systems 2003 software NCSS, Kaysville, Utah).
- the respective overall diagnostic values were compared by the area under the ROC curves.
- the ROC curve is drawn by plotting the sensitivity versus (1 -specificity), after classification of the patients, according to the value obtained for the logistic function, for different thresholds (from 0 to 1). It is usually acknowledged that a ROC curve the area under which has a value superior to 0.7 is a good predictive curve for diagnosis.
- the ROC curve has to be acknowledged as a curve allowing to predict the quality of a diagnosis method.
- StepTest score is defined as the logistic regression function combining the independent factors that returns the best index in term of discrimination between the presence or absence of hepatic steatosis.
- Apolipoprotein Al 1.46(0.34) 1.42(0.33) 0.30 1.27(0.26) 1.20(0.24) 0.18 1.16(0.28) 1.07(0.25) 0.2 1.67(0.43) 1.48(0.49) 0.49 g/L Haptoglobin, g/L 0.93 (0.60) 0.96 (0.52) 0.19 0.77 (0.45) 0.78 (0.44) 0.84 0.85(0.41) 0.94 (0.56) 0.85 1.55(0.92) 1.38(0.62) 0.85
- Triglycerides mmol/L 1.24(0.95) ' 1.88(1.78) ⁇ 0.0001 1.26(0.72) 1.72(1.0) 0.0008 1.49(0.98) 2.05(1.22) 0.003 1.05(0.51) 1.96(3.15) 0.28
- ALT alanine aminotransferase
- AST aspartate aminotransferase
- GGT ⁇ - glutamyl-transpeptidase
- SteatoTest combines in a multivariate regression analysis adjusted for gender, age and body mass index: alanine and aspartate aminotransferases, alpha-macroglobulin, apolipoprotein A-I, haptoglobin, total bilirubin, and ⁇ -glutamyl-transpeptidase
- Table 2 Characteristics of patients according to the presence of steatosis
- Step 2 The best logistic function (SteatoTest score) combining 9 markers and age, gender and BMI was determined on the training group to be as follows:
- the value of the SteatoTest score combining 9 markers (alpha2-macroglobulin, ALT, apo Al, haptoglobin, GGT, and total bilirubin), adjusted by age, gender and BMI, had a high correlation with the presence or absence of hepatic steatosis, on the training sample as well as on validation samples (Table 2).
- Table 3 Values [Area under the ROC curves (AUROCs)] of Steatosis score, GGT and ALT for the diagnosis of steatosis, in training and validation groups
- Table 4 Diagnostic value of Steatosis score for predicting hepatic steatosis greater than 5%
- the diagnostic value (area under the ROC curve) of the SteatoTest score was highly reproducible between the training group and validation groups 1, 2 and 3 (Table 3).
- the sensitivity was also quite reproducible between the training group and validation groups 1, 2 and 3 (Table 4).
- the sensitivities and specificities of the SteatoTest score observed in the different populations studied will probably increase in a more general population because of the excellent specificity observed in volunteers and blood donors ( Figure 2E), and because of the fact that the present studies have included a limited number of patients with several metabolic risk factors such as morbid obesity.
- the results obtained with the SteatoTest score were compared to those obtained with the use of isolated markers such as GGT and ALT, which are usually considered to be useful markers to indicate the presence or absence of hepatic steatosis.
- isolated markers such as GGT and ALT, which are usually considered to be useful markers to indicate the presence or absence of hepatic steatosis.
- the same standard cut-off value is used for GGT and ALT: 50 IU/L. Under said cut-off value, the diagnostic of hepatic steatosis is considered to be negative, over, it is considered to be positive.
- the SteatoTest score allows a much better discrimination between the presence or absence of hepatic steatosis in all groups analyzed, in particular for the training group and validation group 2 (Table 2).
- Diagnostic values (areas under ROC curves) of the SteatoTest score, GGT 50 IU/L and ALT 50 IU/L for the diagnosis of the main end point (that is, grade 2-4 hepatic steatosis), are displayed in Table 3.
- the SteatoTest score has higher areas under ROC curves than GGT 50 IU/L in all groups analyzed, and that ALT 50 IU/L in the training group and validation group 1 (Table 3).
- Sensitivity, specificity and positive and negative predictive values of the SteatoTest score with a cut-off of 0.30, 0.50, or 0.70, and of GGT 50 IU/L and ALT 50 IU/L are displayed in Table 4.
- a SteatoTest score with a 0.50 cut-off achieved a good sensitivity (0.69, 0.89, 0.68 and 0.62) and a good specificity (0.74, 0.58, 0.79, 1.00), according to training and validation groups respectively. Moreover, such a SteatoTest score with a 0.50 cut-off displays higher positive and negative values than GGT 50 IU/L and ALT 50 IU/L in all groups analyzed, excepted for the negative predictive value of ALT 50 IU/L in validation group 1.
- the discrimination between hepatic steatosis different grades was also analyzed on an integrated base constituted of all the included subjects of the training group, the three validation groups and the control group (884 subjects).
- the present invention presents a combination of at least 5, preferably 9, biochemical markers, adjusted by age, gender and BMI, to be used for the detection of the presence or absence of hepatic steatosis.
- the markers used in the present invention had never been combined in such a way, particularly with the age, gender, and BMI of the patients to give such a good predictive value, as illustrated by the area under the ROC curve.
- the diagnosis method of the invention can be analyzed automatically, after an automatic measurement of the values of the markers, and can advantageously be applied for patients with a hepatic steatosis involving disease to reduce the indication of liver biopsy.
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Application Number | Priority Date | Filing Date | Title |
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JP2007553738A JP2008529030A (en) | 2005-02-03 | 2006-02-03 | Method for diagnosing liver steatosis using biochemical markers |
MX2007009427A MX2007009427A (en) | 2005-02-03 | 2006-02-03 | Diagnosis method of hepatic steatosis using biochemical markers. |
US11/815,332 US20090111132A1 (en) | 2005-02-03 | 2006-02-03 | Diagnosis method of hepatic steatosis using biochemical markers |
BRPI0606840-5A BRPI0606840A2 (en) | 2005-02-03 | 2006-02-03 | method for the in vitro diagnosis of hepatic steatosis or a patient's serum or serum sample, and kit for the diagnosis of hepatic steatosis in a patient |
EP06710408A EP1856536B1 (en) | 2005-02-03 | 2006-02-03 | Diagnosis method of hepatic steatosis using biochemical markers |
DE602006003414T DE602006003414D1 (en) | 2005-02-03 | 2006-02-03 | DIAGNOSTIC PROCESS FOR LIVESTOCK ATTRACTION USING BIOCHEMICAL MARKERS |
CA002596682A CA2596682A1 (en) | 2005-02-03 | 2006-02-03 | Diagnosis method of hepatic steatosis using biochemical markers |
IL185021A IL185021A0 (en) | 2005-02-03 | 2007-08-02 | Diagnosis method of hepatic steatosis using biochemical markers |
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Also Published As
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BRPI0606840A2 (en) | 2010-03-09 |
MX2007009427A (en) | 2008-03-06 |
DE602006003414D1 (en) | 2008-12-11 |
US7860656B2 (en) | 2010-12-28 |
RU2007132921A (en) | 2009-03-10 |
MA29282B1 (en) | 2008-02-01 |
US20060173629A1 (en) | 2006-08-03 |
JP2008529030A (en) | 2008-07-31 |
RU2403576C2 (en) | 2010-11-10 |
ATE412905T1 (en) | 2008-11-15 |
CN101175998A (en) | 2008-05-07 |
EP1856536B1 (en) | 2008-10-29 |
EP1856536A1 (en) | 2007-11-21 |
US20090111132A1 (en) | 2009-04-30 |
CA2596682A1 (en) | 2006-08-10 |
IL185021A0 (en) | 2007-12-03 |
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