WO2020175719A1 - Composition for predicting prognosis of severe alcoholic hepatitis, and use thereof - Google Patents

Abstract

The present invention relates to a composition for predicting the prognosis of Severe Alcoholic Hepatitis (SAH), and comprises a formulation for detecting Milk fat globule-EGF factor 8 (MFG-E8) as a biomarker for predicting the prognosis of SAH in a serum sample.

Description

Composition for predicting prognosis of severe alcoholic hepatitis and use thereof

The present invention relates to a composition for predicting prognosis of severe alcoholic hepatitis and a method of detecting a biomarker to provide information necessary for predicting the prognosis of severe alcoholic hepatitis.

Alcoholic hepatitis is one of the alcoholic liver diseases that show sudden impairment of liver function due to the destruction of hepatocytes and inflammatory reactions caused by excessive drinking for a long time.Severe alcoholic hepatitis (SAH) has a very poor prognosis. Thus, the short-term mortality rate within one month of the invention reaches 40%.

As an index for predicting the prognosis of such severe alcoholic hepatitis, in the conventional case, the mDF (Modified Discriminant Function) score is 32 points or higher or the case with hepatic encephalopathy is defined as severe alcoholic hepatitis, which means that the mDF score is less than 32 points. In this case, the patient's 28-day survival rate is 90%, whereas when the mDF score is 32 or higher, the patient's 28-day survival rate is 50-65%, showing a poor prognosis.

Such an index for predicting the prognosis of severe alcoholic hepatitis is of great significance because selecting a treatment target by predicting the prognosis of alcoholic hepatitis patients early plays an important role in improving the prognosis of patients.

Furthermore, as an indicator to predict the prognosis of severe alcoholic hepatitis, conventionally, MELD (Model for End Stage Liver Disease) score, Glasgow Alcoholic Hepatitis Score (GAHS) and ABIC (Age, Bilirubin, INR, Creatinine) And scores.

These conventional indicators for predicting the prognosis of severe alcoholic hepatitis are various studies in progress, but each study shows a difference in the cutoff value useful for prognostic evaluation, or there is a problem in that the long-term prognosis predictability is low compared to the short-term prognosis.

On the other hand, MFG-E8 (Milk fat globule-EGF factor 8) is a protein that functions as a key factor that inhibits fibrosis of liver tissue. In addition, it binds to phosphatidylserine exposed on the surface of apoptotic cells to prevent apoptosis. The function of mediating the phagocytosis of dead cells through sonication and binding with intergreen on the surface of phagocytes, the function of reducing the secretion of pre-inflammatory cytokines by blocking the Toll like receptor 4 signaling pathway, and removing accumulated collagen It has also been studied for the function of inhibiting the death of epithelial cells or the function involved in the formation of angiogenesis.

Moreover, among the various functions of the MFG-E8 protein, it is possible to provide functions related to liver regeneration and liver disease improvement by promoting hepatocyte proliferation and blood vessel regeneration, as well as providing functions related to reduction of fibrosis in liver tissue. Prior literature on the technology includes a composition for preventing or treating tissue fibrosis using "Milk fat globule-EGF factor 8 (MFG-E8)" in Korean Patent Application Publication No. 10-2017-0013621 (hereinafter referred to as'prior art') There is this.

The technologies related to the various functional roles that the existing MFG-E8 protein can provide, including these prior art, only reveal that the MFG-E8 protein plays a major role in the mechanism of action for the prevention or treatment of specific symptoms. It is not disclosed that it can be used for the purpose of predicting the prognosis of.

Specifically, technologies related to the various functional roles that the existing MFG-E8 protein can provide, including these prior art, are known as conventional indicators for predicting the prognosis of Severe Alcoholic Hepatitis (SAH) and MFG-E8 protein. It shows a clear difference and does not reveal that it has a use as a biomarker for predicting the prognosis of more accurate severe alcoholic hepatitis.

The present invention was created to solve the above problems, and an object of the present invention is to reveal that the MFG-E8 protein has a use as a biomarker for predicting the prognosis of severe alcoholic hepatitis, and at the same time, the prognosis of conventional severe alcoholic hepatitis It is to provide a composition for predicting the prognosis of severe alcoholic hepatitis, including a preparation for detecting a biomarker having excellent short-term prognosis predictive ability and long-term prognosis predictive ability compared to predictive indicators.

In addition, another object of the present invention is to provide information necessary for predicting the prognosis of severe alcoholic hepatitis by detecting MFG-E8 protein, which has a use as a biomarker for predicting the prognosis of severe alcoholic hepatitis.

In order to achieve the above object, the composition for predicting the prognosis of severe alcoholic hepatitis according to the present invention is MFG-E8 (Milk fat globule-) as a biomarker for predicting the prognosis of severe alcoholic hepatitis (SAH) in a serum sample. It includes an agent for detecting EGF factor 8).

On the other hand, in order to achieve the above object, the method of detecting a biomarker in order to provide information necessary for predicting the prognosis of severe alcoholic hepatitis according to the present invention is the prognosis of severe alcoholic hepatitis (SAH) from a serum sample derived from a test subject. A step of detecting the concentration of MFG-E8 (Milk fat globule-EGF factor 8) which is a biomarker for predicting B step of detecting the concentration of bilirubin from the serum sample derived from the test subject; Step C of calculating an expected MFG-E8 value by substituting the concentration of bilirubin detected in step B into Equation 1 below; D step of calculating a ratio of the concentration value of MFG-E8 detected through the step A to the expected value of MFG-E8 calculated through the step C; And step E of predicting that the test subject will have a poor prognosis of severe alcoholic hepatitis when the ratio of the MFG-E8 concentration value in the serum sample derived from the test subject to the expected MFG-E8 value calculated through step D is less than 0.3; Include.

Here, [Equation 1] corresponds to'the expected value of MFG-E8 (pMFG-E8 Level, Prediected MFG-E8 Level) = 1.527 + 1.841 × concentration of bilirubin'.

In addition, the concentration of bilirubin substituted in Equation 1 may be less than 2mg/dL in order to calculate the expected MFG-E8 value through step C among the concentrations of bilirubin detected through step B.

According to the present invention, there are the following effects.

First, MFG-E8 (Milk fat globule-EGF factor 8) was used as a biomarker to predict the prognosis of severe alcoholic hepatitis (SAH), compared to the conventional indicators for predicting the prognosis of severe alcoholic hepatitis. It is possible to provide accurate and reliable predictive performance for severe alcoholic hepatitis prognosis.

Second, the use of MFG-E8 as a biomarker to predict the prognosis of severe alcoholic hepatitis, compared to the conventional indicators for predicting the prognosis of severe alcoholic hepatitis, has low invasiveness, is easily obtainable, and is highly alcoholic with ease of use. Biomarkers for predicting the prognosis of hepatitis can be used.

Third, by detecting MFG-E8 as a biomarker for predicting the prognosis of alcoholic hepatitis, it can provide accurate and reliable information necessary for predicting the prognosis of severe alcoholic hepatitis.

1 is a graph showing the results of LT-free survival analysis of all test subjects set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis.

2 is a graph showing the results of LT-free survival analysis for each group of test subjects set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis.

3 is a graph showing the distribution and average value analysis results of MFG-E8 protein concentrations for all subjects and groups set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis.

Figure 4 shows the correlation between the concentration of MFG-E8 protein and the concentration of bilirubin of a test subject set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis. This is the graph shown.

Figure 5 is a test subject MFG-E8 protein concentration and GGT (gamma-glutamyltransferase) concentration set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis. It is a graph showing the correlation between the concentrations of.

Figure 6 shows the concentration of the MFG-E8 protein and the Model for End-stage Liver Disease (MELD) score of a test subject set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis. It is a graph showing the correlation between concentrations.

7 is MFG- of the group (n=32, 22.1%) of Serum Bilirubin <2mg/dL among test subjects set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis. This is a graph showing the correlation between the E8 protein concentration and the concentration of bilirubin.

Figure 8 is a distribution and average value analysis results of the expected MFG-E8 protein concentration (pMFG-E8) of all subjects and groups set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis. It is a graph showing.

9 is a correlation between the MFG-E8 protein concentration of a test subject and the expected MFG-E8 protein concentration (pMFG-E8) set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis This is a graph showing the correlation.

Figure 10 is a subgroup analysis of each of four groups classified according to the MFG-E8/pMFG-E8 ratio of a test subject set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis ( This is a graph showing the result of subgroup analysis.

11 is a LT-free for each of four groups classified according to the MFG-E8/pMFG-E8 ratio of a test subject set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis. This is a graph showing the results of the survival rate analysis.

Figure 12 is a set to verify that the MFG-E8 protein of the present invention can function as a biomarker for predicting the prognosis of severe alcoholic hepatitis, two categorized according to the MFG-E8/pMFG-E8 ratio of the severe alcoholic hepatitis patient group in the test subject. This is a graph showing the results of LT-free survival rate analysis for each group.

Preferred embodiments of the present invention will be described in more detail with reference to the accompanying drawings, but technical parts that are already well known will be omitted or compressed for conciseness of description.

1. Description of the composition for predicting the prognosis of severe alcoholic hepatitis

The composition for predicting the prognosis of severe alcoholic hepatitis according to the present invention includes a preparation for detecting a biomarker for predicting the prognosis of severe alcoholic hepatitis (SAH) in a serum sample of a test subject.

Here, the biomarker for predicting the prognosis of Severe Alcoholic Hepatitis (SAH) corresponds to MFG-E8 (Milk fat globule-EGF factor 8) present in a serum sample of a test subject.

In other words, the prognosis of severe alcoholic hepatitis of the test subject is more accurately predicted than in the prior art through the concentration of the MFG-E8 protein present in the serum sample of the test subject, and based on this, the presence or absence of the treatment target of the test subject is determined early. You can definitely decide.

In this regard, the MFG-E8 protein mediates the phagocytosis of dead cells, is involved in the formation of angiogenesis, promotes hepatocyte proliferation and blood vessel regeneration, and provides a function of reducing tissue fibrosis. Although it has been proposed. Until now, there has been no known information on the useful properties of the expression level of MFG-E8 protein in predicting the prognosis of severe alcoholic hepatitis, which is the main mechanism of inflammatory action.

Therefore, in order to provide information necessary for predicting the prognosis of severe alcoholic hepatitis, a method of detecting MFG-E8 protein as a biomarker for predicting the prognosis of severe alcoholic hepatitis, and MFG-E8 protein as a biomarker for predicting the prognosis of severe alcoholic hepatitis The following is a detailed description of the test results that have been verified to have functional characteristics and significance.

2. A method of detecting biomarkers to provide information necessary to predict the prognosis of severe alcoholic hepatitis

In order to provide information necessary for predicting the prognosis of severe alcoholic hepatitis according to the present invention, a process in which a method of detecting a biomarker is performed will be described in detail.

First, the experimenter performing the method detects the concentration of MFG-E8 (Milk fat globule-EGF factor 8) from a plurality of test subjects (patients)-derived serum samples (biological samples), respectively (step A).

Next, the concentration of bilirubin is detected from the serum samples derived from a plurality of test subjects (step B).

Here, it is preferable that only the test subject whose concentration value of bilirubin is less than 2 mg/dL among the detected concentration values of bilirubin performs the MFG-E8 expected value calculation step to be performed later.

Next, each bilirubin concentration value detected from the serum sample derived from the test subject is substituted into [Equation 1] below to calculate expected MFG-E8 (pMFG-E8 Level, Prediected MFG-E8 Level) (step C).

Next, MFG using information on the expected MFG-E8 value calculated based on each bilirubin concentration value detected from a serum sample derived from a test subject and information on the concentration value of MFG-E8 protein detected from a serum sample derived from the test subject. -Calculate the ratio of the FG-E8 protein concentration value to the expected E8 value (step D).

In addition, as described above, the concentration of bilirubin substituted in [Equation 1] for calculating the expected MFG-E8 value is preferably less than 2mg/dL.

Lastly, the experimenter has the prognosis for Severe Alcoholic Hepatitis (SAH) as long as the ratio of the FG-E8 protein concentration value to the expected MFG-E8 value calculated for multiple test subjects is less than 0.3. Is expected to be poor.

3. Description of the use of MFG-E8 (Milk fat globule-EGF factor 8) as a biomarker for predicting the prognosis of severe alcoholic hepatitis and its significance verification test results

See Figs. 1 to 12 for the results of tests performed to verify the use characteristics and significance of MFG-E8, which is a biomarker for predicting the prognosis of severe alcoholic hepatitis (SAH) according to the present invention. This will be described in detail.

Specifically, milk fat globule-EGF factor 8 (MFG-E8) of the present invention as a biomarker for predicting the prognosis of severe alcoholic hepatitis (SAH). Tests such as LT-free survival, Cox-regression analysis, and Pearson's correlation analysis were performed using 138 patients as test subjects, and this test is for the purpose of defining properties by means obvious to those skilled in the art. The following experimental methods were used.

First, 138 patients hospitalized for alcoholic hepatitis were set as the entire test subject, and among them, patients with a Modified Discriminant Function (mDF) score of 32 or higher were set as the severe alcoholic hepatitis patient group (Pts (Patents) with SAH), and the rest It was classified as a control group (Pts(Patents) without SAH).

Accordingly, 52 subjects (35.9%) were classified into the severe alcoholic hepatitis patient group (Pts(Patents) with SAH), and 93 subjects (64.1%) were classified as the control subjects (Pts(Patents) without SAH). .

Next, using each serum sample and patient information derived from each of the test subjects in each group classified as described above and stored in a -80°C Deep Freezer, age, male number and ratio, platelet count, INR (blood Coagulation level) AST (aspartate aminotransferase) concentration, ALT (alanine aminotransferse) concentration, bilirubin concentration, albumin (Albumin) concentration, GGT (gammagglutamyl transferase, Gamma-) The results obtained by obtaining information on glutamyltransferase) concentration, creatinine creatinine concentration, plasma sodium concentration, MELD (Model for End-stage Liver Disease) score, etc. are shown in Table 1 below.

In other words, Table 1 below shows the overall and group-based characteristics of the test subject.

In addition, P indicated in Table 1 below means a P-value value.

	All pts(n=145)	Pts without SAH(n=93)	Pts with SAH(n=52)	P
Age(years)	53.5±10.5	55.0±10.7	50.8±9.4	0.018
Male(n(%))	127(87.6)	82(88.2)	45(86.5)	0.775
Alcohol(g/day)	116.0±71.3	113.2±74.0	121.1±66.7	0.521
Platelet count(×10 9 /L)	112.5±75.1	118.0±77.2	102.7±71.0	0.240
INR	2.2±3.2	1.9±2.5	2.9±4.0	0.062
AST(IU/L)	243.9±643.1	173.9±303.5	369.1±988.3	0.171
ALT(IU/L)	108.1±323.2	104.7±350.3	114.0±271.0	0.869
Bilirubin (mg/dL)	7.2±8.5	4.0±4.8	12.9±10.5	<0.001
Albumin(g/dL)	2.9±0.6	2.9±0.6	2.7±0.5	0.092
GGT(IU/L)	314.0±438.1	384.5±519.2	187.9±174.2	0.001
Creatinine (mg/dL)	1.2±1.0	1.2±1.0	1.2±0.9	0.902
Sodium(mEq/L)	135.8±6.2	136.4±6.0	134.7±6.3	0.108
MELD score	20.6±8.5	17.2±6.0	26.7±9.0	<0.001

(pts: patents, SAH: Severe Alcoholic Hepatitis)

The results of analyzing the LT-free survival (Liver transplantation-free survival) of the severe alcoholic hepatitis patient group and the other control group having such basic characteristics are as shown in FIGS. 1 and 2.

Here, as shown in FIG. 1, 22 test subjects died after 1 year from the time point at which blood was collected from each test subject to obtain a serum sample, and 5 test subjects had livers that do not recover. He had a liver transplant due to insufficiency.

In addition, when comparing the results of the LT-free survival analysis for each group of test subjects as shown in FIG. 2, the LT-free survival level shows a large difference depending on the test subject's severe alcoholic hepatitis, and between the severe alcoholic hepatitis patient group and the rest control group. There was a significant difference (P=0.001).

Next, a Cox-regression analysis was performed on the death or liver transplantation of the test subject, and the results of univariate analysis and multivariate analysis accordingly are as shown in Table 2 below.

	Univariate analysis		Multivariate analysis
	HR (95% Cl)	P	HR (95% Cl)	P
Age	0.971 (0.934-1.010)	0.971	0.971 (0.934-1.010)	0.971
Male	1.888 (0.447-7.973)	0.387
Alcohol	1.000 (0.995-1.005)	0.173
Platelet count	0.995 (0.989-1.002)	0.084	-
INR	1.060 (0.992-1.132)	0.741
AST	1.000 (0.998-1.001)	0.620
ALT	1.090 (1.055-1.125)	<0.001	-
Bilirubin	0.461 (0.206-1.034)	0.060	0.619 (0.264-1.453)	0.271
Albumin	0.461 (0.206-1.034)	0.775
GGT	1.182 (0.898-1.555)	0.233
Creatinine	0.938 (0.883-0.996)	0.038	0.961 (0.901-1.024)	0.218
Sodium	0.995 (0.989-1.002)	0.138
MELD score	1.060 (1.033-1.088)	<0.001	1.049 (1.019-1.080)	0.001

(HR: Hazard ratio, Cl: Confidence interval) Looking at the univariate analysis results through Cox-regression analysis as shown in Table 2, bilirubin concentration, plasma sodium concentration, MELD (Model for End) It can be seen that the information on the -stage Liver Disease) score corresponds to a significant risk factor.

In addition, looking at the results of multivariate analysis through Cox-regression analysis as shown in Table 2, it can be seen that only information on the Model for End-stage Liver Disease (MELD) score corresponds to a significant risk factor.

Next, the concentration value of the MFG-E8 protein was measured from the serum samples of all of the test subjects and each of the groups, and the average value of the total and each group was calculated to obtain a result as shown in FIG. 3.

Here, as shown in FIG. 3, the average concentration of MFG-E8 protein in the serum sample of the whole test subject is 6.8±5.8 ng/mL, and the average concentration of MFG-E8 protein in the serum sample of the severe alcoholic hepatitis patient group is 8.5± 5.2 ng/mL, and the average concentration of MFG-E8 protein in the serum samples of the rest of the control group was 5.8±5.9 ng/mL, indicating that the severe alcoholic hepatitis patient group showed significantly higher results than the control group (P = 0.007)

Next, Pearson's correlation analysis and multivariate linear regression analysis were performed on the concentration of the MFG-E8 protein of the test subject to obtain the results shown in Table 3 below.

Looking at the results in Table 3, the concentration of MFG-E8 protein in the serum sample of the test subject is significant with the concentration of bilirubin, GGT (gamma-glutamyltransferase), and plasma sodium. Showed a relevance.

In addition, as shown in Table 3, the concentration of MFG-E8 protein in the serum sample of the test subject was significantly related to the concentration of bilirubin and GGT (gamma-glutamyltransferase) as a result of multivariate linear regression analysis. Can be seen.

Specifically, as shown in FIG. 4, the correlation between the concentration of MFG-E8 protein and the concentration of bilirubin in a serum sample of a test subject shows a significant relationship.

In addition, as shown in FIG. 5, the correlation between the concentration of MFG-E8 protein in the serum sample of the test subject and the concentration of GGT (gamma-glutamyltransferase) shows a significant relationship.

In contrast, the concentration of the MFG-E8 protein in the serum sample of the test subject showed a correlation with the Model for End-stage Liver Disease (MELD) score as shown in Table 3 and FIG. 6, and the MFG-E8 protein It indicates that the concentration of is not significantly associated with liver transplantation or death. (HR, 1.050; 95% CI, 0.987-1.116; P = 0.122)

	Pearson's correlation coefficient	P	P*
Age	-0.216	0.009	0.302
Platelet count	0.054	0.520
INR	-0.061	0.468
AST	0.023	0.785
ALT	-0.005	0.950
Bilirubin	0.411	<0.001	<0.001
Albumin	0.047	0.573
GGT	0.414	<0.001	<0.001
Creatinine	-0.053	0.525
Sodium	-0.164	0.049	0.810
MELD score	0.211	0.011

(*: Multivariate linear regression analysis) Furthermore, subgroup analysis was performed by classifying three groups according to the concentration of bilirubin in serum for the entire test subject.

Here, the three groups according to the classified bilirubin concentration are the first group with Serum Bilirubin <2mg/dL (n=32, 22.1%), and the second group with Serum Bilirubin ≥2mg/dL and <5mg/dL. (n=54, 37.3%), and the third group was Serum Bilirubin ≥5mg/dL (n=59, 40.7%).

The results of the subgroup analysis on the correlation between the concentration of MFG-E8 protein and the concentration of bilirubin are shown in Table 4 below.

In addition, as shown in Table 4, only in the group with Serum Bilirubin <2mg/dL (n=32, 22.1%), the correlation between the concentration of MFG-E8 protein and the concentration of bilirubin showed a significant relationship. Can be seen.

	Pearson's correlation coefficient	P
Bilirubin <2mg/dL	0.438	<0.001
Bilirubin ≥2mg/dL and <5mg/dL	-0.041	0.766
Bilirubin ≥5mg/dL	0.115	0.388

Based on these results, the concentration of MFG-E8 protein in the serum sample of the test subject increases with the increase of the bilirubin concentration in the serum sample of the test subject. However, in the test subject corresponding to severe alcoholic hepatitis The hypothesis that such a rising pattern does not appear, which is soon related to the prognosis of severe alcoholic hepatitis, can be established. To verify this hypothesis, the group with Serum Bilirubin <2 mg/dL as shown in FIG. 7 (n =32, 22.1%) of MFG-E8 protein concentration and bilirubin concentration-based MFG-E8 expected value based on the concentration of bilirubin (pMFG-E8 Level, Prediected MFG-) [Equation 1] for E8 Level) was derived.

Specifically, [Equation 1] according to this is as follows.

[Equation 1]

MFG-E8 Expected Value (pMFG-E8 Level, Prediected MFG-E8 Level) = 1.527+1.841×Bilirubin Concentration Value (mg/dL)

The average value of the total and group (alcoholic hepatitis patient group (Pts with SAH) and the remaining control group (Pts without SAH)) of the expected MFG-E8 concentration (pMFG-E8) calculated using the above [Equation 1] was calculated, as shown in FIG. I got the same result.

Specifically, the average value of the expected MFG-E8 concentration (pMFG-E8) calculated for the entire test subject is 14.8±15.6 ng/mL, calculated for the alcoholic hepatitis patient group (Pts with SAH) as shown in FIG. The average value of the expected MFG-E8 concentration (pMFG-E8) is 25.2±19.3 ng/mL, and the average value of the expected MFG-E8 concentration (pMFG-E8) calculated for the remaining control group (Pts without SAH) is 8.9±8.8 ng/ In mL, the alcoholic hepatitis patient group (Pts with SAH) showed significant results compared to the control group.

Furthermore, the correlation as shown in Fig. 9 between the expected concentration of MFG-E8 calculated for the entire subject (pMFG-E8) and the concentration of MFG-E8 protein detected for the entire subject (mMFG-E8) ( correlation), and it can be seen that there is a significant correlation.

Accordingly, the detected MFG-E8 compared to the MFG-E8 expected concentration (pMFG-E8) calculated using the detected MFG-E8 protein concentration (mMFG-E8) and the calculated MFG-E8 expected concentration (pMFG-E8). The ratio of the protein concentration (mMFG-E8) was calculated, and univariate analysis and multivariate analysis through Cox regression analysis were performed.

As a result, the mMFG-E8/pMFG-E8 ratio was liver transplantation or death (HR, 0.125; 95% CI, 0.033-0.470; P = 0.002), MELD Score (HR, 1.060; 95% CI, 1.033-1.088; P <0.001) showed a significant association. In addition, the results of multivariate analysis were significantly associated with liver transplantation or death (HR, 0.247; 95% CI, 0.064-0.959; P = 0.043) and MELD Score (HR, 1.043; 95% CI, 1.012-1.076; P = 0.007). Showed.

Furthermore, according to the mMFG-E8/pMFG-E8 ratio, group 1 (<0.3 mMFG-E8/pMFG-E8 ratio (n=32, 22.1%)), group 2 (≥0.3 and <0.6 mMFG- E8/pMFG-E8 ratio (n=44, 30.3%)), group 3 (≥0.6 and <0.9 mMFG-E8/pMFG-E8 ratio (n=28, 19.3%)) and group 4 (>0.9 mMFG-E8) /pMFG-E8 ratio (n=41, 28.3%)) was classified into four groups, and a subgroup analysis was performed.

Accordingly, the results of subgroup analysis for each of the four groups classified according to the MFG-E8/pMFG-E8 ratio are as shown in FIG. 10.

Finally, the LT-free survival rates of each of the four groups classified according to the MFG-E8/pMFG-E8 ratio were analyzed, and the results are as shown in FIG. 11.

As a result, the LT-free survival rate of group 1 with mMFG-E8/pMFG-E8 ratio <0.3 was significantly low (P=0.001), and the LT-free survival rate at 1 year was 53.3% in group 1, group It was 23% in 2, 16% in group 3, and 24% in group 4.

Based on these results, the group 1, <0.3 (n=22, 42.3%) of the group of severe alcoholic hepatitis patients in the test subject group according to the mMFG-E8/pMFG-E8 ratio; Group 2, ≥0.3 (n=30, 57.7%) were classified into two groups, and the LT-free survival rate for each group was analyzed, and the results are as shown in FIG.

Specifically, as shown in Fig. 12, the LT-free survival rate was significantly lower in group 1 than in group 2 (P=0.019), and the 1-year LT-free survival rate was 47.4% in group 1, and in group 2. It was found to be 74.9%.

In conclusion, serum MFG-E8 is secreted according to the degree of cholestasis and aggravates the disease through anti-inflammatory mechanisms. However, when severe alcoholic hepatitis (SAH) is present, in some patients The secretion of MFG-E8 is insufficient and in such cases a poor prognosis is shown.

Therefore, it was confirmed that the concentration of MFG-E8 in the serum is an important biomarker in predicting the prognosis of severe alcoholic hepatitis.

The embodiments disclosed in the present invention are not intended to limit the technical idea of the present invention, but to explain it, and the scope of the technical idea of the present invention is not limited by these embodiments. The scope of protection should be interpreted by the following claims, and all technical ideas within the scope equivalent thereto should be interpreted as being included in the scope of the present invention.

Claims (3)

1. It comprises a preparation for detecting MFG-E8 (Milk fat globule-EGF factor 8) as a biomarker for predicting the prognosis of Severe Alcoholic Hepatitis (SAH) in a serum sample.

   A composition for predicting the prognosis of severe alcoholic hepatitis.
2. To provide information necessary for predicting the prognosis of severe alcoholic hepatitis,

   A step of detecting the concentration of MFG-E8 (Milk fat globule-EGF factor 8), a biomarker for predicting the prognosis of severe alcoholic hepatitis (SAH) from a serum sample derived from the test subject;

   B step of detecting the concentration of bilirubin from the serum sample derived from the test subject;

   Step C of calculating an expected MFG-E8 value by substituting the concentration of bilirubin detected in step B into Equation 1 below;

   D step of calculating a ratio of the concentration value of MFG-E8 detected through the step A to the expected value of MFG-E8 calculated through the step C; And

   E step of predicting that the test subject will have a poor prognosis of severe alcoholic hepatitis when the ratio of the MFG-E8 concentration value in the serum sample derived from the test subject to the expected MFG-E8 value calculated through step D is less than 0.3; including; Characterized by

   Biomarker detection method for predicting the prognosis of severe alcoholic hepatitis.

   [Equation 1]

   MFG-E8 Expected Value (pMFG-E8 Level, Prediected MFG-E8 Level) = 1.527+1.841×Bilirubin Concentration Value
3. The method of claim 2,

   Among the concentrations of bilirubin detected through step B, the concentration of bilirubin substituted in Equation 1 to calculate the expected value of MFG-E8 through step C is less than 2mg/dL.

   Biomarker detection method for predicting the prognosis of severe alcoholic hepatitis.

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