Human beta-defensin-1 is a highly predictive marker of 60 days mortality in patients with acute-on-chronic liver failure

Μέγεθος: px

Εμφάνιση ξεκινά από τη σελίδα:

Download "Human beta-defensin-1 is a highly predictive marker of 60 days mortality in patients with acute-on-chronic liver failure"

Ὡρος Δοξαράς
6 χρόνια πριν
Προβολές:

1 Human beta-defensin-1 is a highly predictive marker of 60 days mortality in patients with acute-on-chronic liver failure Ilianna Mani,Alexandra Alexopoulou, Larisa Vasilieva, Emilia Hadziyannis, Danai Agiasotelli, Theodoros Alexopoulos, Dimitrios Zampetas, Spyros P Dourakis 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece

2 Conflict of interest No conflict of interest to declare

3 Introduction Acute on chronic liver failure Syndrome that occurs in cirrhotic patients and consists of A. Episode of acute decompensation B. Organ failure C. High rates of short term mortality (20-80 %) Moreau R et al. Gastroenterology 2013;144:

4 THE CLIF-ORGAN FAILURE SCORE SYSTEM for diagnosing patients with ACLF CLIF-SOFA score Organ/System Liver Bilirubin (mg/dl) Kidney Creatinine (mg/dl) Brain West Haven scale for hepatic encephalopathy Coagulation INR Circulatory system Mean arterial pressure -MAP (mm/hg) Respiratory system PaO2/FIO2 (mmhg) or SaO2/FIO2 Sub-score <6 6 and < <2 2 and < or renal replacement Grade 0 Grade 1-2 Grade 3-4 < &< < 70 Vasopressors >300 or > and >200 or >214 and or 214 Gastroenterology 2013;144:

5 Introduction Defensins are natural antimicrobial peptides, produced by epithelial cells and involved in the defense mechanisms of the mucous membranes, protecting against bacterial translocation Specifically, human beta-defensin-1 (hbd-1) is expressed in the epithelia of multiple tissues (pancreas, kidneys, respiratory tract, urogenital system, mammary glands) including the digestive tract. In a recent study, hbd-1 levels are high in cirrhotic patients, independently of the etiology of cirrhosis. Kaltsa et al, Annals of gastroenterology 29:63-70, 2016 Schneider et al, Journal of Molecular Medicine 83: , 2005

6 Aim Estimation of As an indicator of severity of liver disease hbd-1 Correlation with laboratory characteristics Prediction of mortality in 30, 60 and 90 days in patients with decompesated cirrhosis with and without acute event.

7 Methods Observational study of 125 consecutive patients (89 ) with decompensated cirrhosis Median (interquartile range - IQR) ΜΕLD 17.0 ( ) Median Child-Pugh 8.0 ( ) Exclusion criteria: - Hepatocellular carcinoma - Extrahepatic cholestasis

8 Methods Serum hbd-1 Group 1 (ACLF) N = 39 Overall (n = 125) Group 2 (AD) N = 46 Group 3 (DC without acute event) N = 40 Control group (Healthy controls) N = 15 hbd-1in ascites (N = 57) Age, years (Median, IQR) Overall (n = 125) Controls (n=15) 60 (51-68) 63 (50-64) Gender, 89 (71.2) 11 (73.3) P ΑCLF = Acute-on-Chronic Liver Failure, AD = Acute Decompensation without ACLF, DC= Decompensated Cirrhosis without acute event

9 All patients were: Methods - examined at emergency department unit. Their clinical, epidemiological and laboratory data were collected. - hospitalized - underwent intensive investigation for possible infection. Cultures were received of blood, ascites and urine - received the appropriate treatment for hepatic encephalopathy, hepatorenal syndrome, variceal bleeding and / or infection, accordingly. - Followed up for three months. hbd-1 was evaluated in serum and ascites by enzymelinked-immunosorbent-assay (ELISA) Statistical analyses were performed with IBM SPSS, version 22.

10 Etiology of cirrhosis

11 Incidence of documented infection in ACLF Documented infection NO YES Documented infection Ν= 11

12 Clinical characteristics epidemiological data Comparisons of clinical characteristics between the 3 groups of study : ACLF, AD, DC (P1 ACLF vs AD non ACLF, P2 ACLF vs without acute event) Characteristics Total (125) ACLF (N=39) AD (N=46) DC (Ν=40) P1 P2 Age (years), Median (IQR) 60 (51-67) 53 (48-62) 57 (51-66) 65.5 ( ) Gender (males %) Diabetes mellitus (n, %) Coronary disease (n, %) 89 (71.2) 25(64.1) 33(71.7) 31 (77.5) (23.4) 11 (28.9) 7(15.2) 11(27.5) (9.6) 1 (2.6) 6(13) 5(12.5)

13 Comparisons of laboratory characteristics between the 3 groups of study : ACLF, AD, DC (P1 ACLF vs AD non ACLF, P2 ACLF vs without acute event) Median (IQR) Laboratory characteristic Total (N =125) ACLF (N=39) AD (N=46) DC (N=40) P1 P2 Hemoglobin (g/dl) 10 ( ) 9.6( ) 10.2( ) 10.3(9-12.4) White blood cells 10 6 /L 6650 ( ) 8070( ) 7790( ) 4935( ) <0.001 Polymorphonuclear leukocytes x10 6 /L 4637( ) 5618( ) 5576( ) 3190( ) <0.001 Platelets 10 6 /L 115( ) 102(70-144) 130( ) 102.5( ) CRP mg/dl 21.9 (8-46.1) 23.9 ( ) 29.6( ) 11( ) Total bilirubin (mg/dl) 4.2 ( ) 14.5( ) 4.2( ) 2.3( ) <0.001 <0.001 AST (IU/L) 68( ) 93 (40-152) 91 (55-136) 44.5( ) ALT (IU/L) 34 (20-53) 36(18-67) 38.5( ) 23( ) INR 1.6 (1.3-2) 2( ) 1.5( ) 1.4( ) <0.001 <0.001 Albumin (g/dl) 2.6 ( ) 2.6(2.2-3) 2.5(2.3-3) 2.8( ) Creatinine (mg/l) 1 ( ) 1.5( ) 0.8( ) 1 ( ) < Na + (meq/l) 132( ) 131( ) 132( ) 133( ) Child-Pugh score 11(9-12) 12(11-13) 10(9-11) 9 (8-11) <0.001 <0.001 CLIF-of score 10 (9-11) MELD score 17 ( ) 27 (22-32) 16.5(12-20) 13 (11-18) <0.001 <0.001

hbd-1 (ng/ml) Comparison of levels of hbd-1 between the 3 groups of study : ACLF, AD, DC P < 0.001 P < 0.001 P < 0.001 38.30 (22.55 66.28) 20.74 (13.93 30.

14 hbd-1 (ng/ml) Comparison of levels of hbd-1 between the 3 groups of study : ACLF, AD, DC P < P < P < ( ) ( ) ( ) ACLF AD DC ΑCLF = Acute-on-Chronic Liver Failure, AD = Acute Decompensation without ACLF, DC= Decompensated Cirrhosis without acute event

15 hbd-1 (ng/ml) Comparison of levels of hbd-1 between patients with decompensated cirrhosis without acute event and healthy controls P = ( ) ( ) DC without acute event Healthy controls

16 Ascitic fluid hbd-1 (ng/ml) Serum hbd-1 (ng/ml) Comparison of levels of hbd-1 between serum and ascitic fluid P < ( ) ( ) 57 patients with ascites

17 hbd-1 (ng/ml) There was no correlation between levels of serum hbd- 1 and C reactive protein (CRP) in overall patients r = CRP (mg/dl)

18 hbd-1 (ng/ml) There was a trend of serum hbd-1 to correlate with C- reactive protein (CRP) in ACLF r = CRP (mg/l)

Sensitivity hbd-1 predicted mortality in 60 days more accurately than CRP in ACLF patients 1.0 36.625 ng/ml * 24.00 mg/dl * hbd-1 CRP hbd-1 c-statistic = 0.834 Sensitivity = 84.

19 Sensitivity hbd-1 predicted mortality in 60 days more accurately than CRP in ACLF patients ng/ml * mg/dl * hbd-1 CRP hbd-1 c-statistic = Sensitivity = 84.2% Specificity = 73.7% Negative predictive value (NPV) = 82.4% Positive predictive value (PPV) =76.2% CRP c-statistic = Sensitivity= 61.1 % Specificity = 63.2 % 1 - Specificity

00 mg/dl * hbd-1 c-statistic = 0.907 Sensitivity = 80% Specificity = 93.3% PPV=88.

20 Sensitivity The accuracy of hbd-1 to predict mortality in 60 days improved substantially in ACLF group if alcoholic hepatitis was excluded ng/ml * mg/dl * hbd-1 c-statistic = Sensitivity = 80% Specificity = 93.3% PPV=88.9% NPV=87.5% CRP c-statistic = Sensitivity = 60.0 % Specificity = 80.0% hbd-1 CRP 1 - Specificity

Cumulative probability of survival Comparison of 60-day mortality between patients with high ( 36.625 ng/ml) and low (< 36.

21 Cumulative probability of survival Comparison of 60-day mortality between patients with high ( ng/ml) and low (< ng/ml) hbd-1 values in ACLF group hbd-1 < ng/ml P (Log rank) = hbd ng/ml Hazard ratio ( ), for hbd vs. hbd-1 < P = Days

22 Factors predicting 60-days mortality in ACLF patients in multivariate analysis Age (years) (per year) Gender ( vs ) Univariate analysis Multivariate analysis HR (95% CI) P HR (95% CI) P ( ) ( ) ( ) ( ) MELD score ( ) < ( ) Na ( ) ( ) CLIF-C ACLF ( ) ( ) CRP ( ) ( ) Documented ( ) Infection hbd ( ) ( ) 0.045

23 Conclusions Levels of hbd-1 were not higher in patients with decompensated cirrhosis without acute event compared to healthy controls Higher values of hbd-1 were assessed in serum compared to ascites hbd-1 values were higher in ACLF compared to AD and DC groups High serum hbd-1 was detected at presentation in patients with ACLF who died during the 60-day-follow-up period. Serum hbd-1 is an accurate predictor of short-term mortality in patients with ACLF and it may be superior to CLIF C ACLF score.

25 Introduction Prognostic markers of mortality in ACLF CLIF (Chronic Liver Failure) Consortium ACLF (CLIF-C ACLF) score sensitivity 64%, specifity 75%. Arroyo et al, J Hepatol 2015, 62: Markers and scores of liver function (INR, MELD score, Na-MELD) Markers of inflammation (CRP, λευκά, MERTK + tyrosine kinase receptor), Markers of oxidative stress πχ advanced glycation end - product specific receptor - RAGE), Markers of hepatocellular apoptosis (cyto - keratin 18) Hemodynamic parameters (change in the hepatic venous pressure gradient) Wlodzimirow et al, Liver Int 2013, 33:40-52

26 Incidence of documented infection in all patients NO YES Documented infection Ν= 28

27 Λοίμωξη N / % Αυτόματη βακτηριακή περιτονίτιδα / αυτόματη μικροβιαιμία 16 (57.1) Λοίμωξη αναπνευστικού 7 (25%) Λοίμωξη ουροποιητικού 3 (10.7%) Άλλο 2 (7.2%) ΣΥΝΟΛΟ 28

28 hbd-1 + OEΧΗΑ Μέλλον??????????????? Έγκαιρη μεταμόσχευση

29 ΟΡΙΣΜΟΣ ΟΞΕΙΑΣ ΕΠΙ ΧΡΟΝΙΑΣ ΗΠΑΤΙΚΗΣ ΑΝΕΠΑΡΚΕΙΑ (ΟΕΧΗΑ) Σύνδρομο που εμφανίζεται σε κιρρωτικούς ασθενείς και χαρακτηρίζεται από: A. Οξεία ρήξη της αντιρρόπησης B. Ανεπάρκεια οργάνων C. Υψηλή θνητότητα 28 ημερών > 15% Moreau R et al. Gastroenterology 2013;144:

30 In AD-group neither serum hbd-1 nor CRP seemed to be associated with poor survival (cstatistics and 0.596, respectively). In DC-group serum hbd-1 and CRP were equally accurate markers in predicting mortality (cstatistics and 0.808, respectively).

Εισαγωγή Μειωμένη ανοσιακή απάντηση: Διαταραχή ακεραιότητας

Εντερικός αυλός Βακτηριακά προιόντα Βακτήρια LPS Liver Enterocyte

Λεμφοκύτταρα Systemic involvement Μεσεντέριος λεμφαδένας Ηπατική

31 Εισαγωγή Μειωμένη ανοσιακή απάντηση: Διαταραχή ακεραιότητας βλενογόννου Μειωμένη τοπική άμυνα Διαταραχή συστηματικής ανοσίας Εντερικός αυλός Βακτηριακά προιόντα Βακτήρια LPS Liver Enterocyte TNF-α NO Μακροφάγα Ηπατική βλάβη LPS NO TNF-α Πυλαία φλέβα Λεμφοκύτταρα Systemic involvement Μεσεντέριος λεμφαδένας Ηπατική εγκεφαλοπάθεια Alexopoulou A, Agiasotelli D, Vasilieva LE, Dourakis SP. Ann Gastroenterol. 2017;30:

32 Υλικό με θετική καλλιέργεια στους ασθενείς με διαπιστωμένη λοίμωξη ΥΛΙΚΟ ΜΕ ΘΕΤΙΚΗ ΚΑΛΛΙΕΡΓΕΙΑ Αρνητική καλλιέργεια αίματος και ασκιτικού υγρού Θετική καλλιέργεια αίματος ή/και ασκιτικού υγρού

33 hbd-1 (ng/ml) Eπίπεδα hbd-1 μεταξύ ασθενών με μη-αντιρροπούμενη Κίρρωση χωρίς οξεία επιδείνωση (ΜΑΚ) υγιών μαρτύρων P = ( ) ( )

34 hbd-1 (ng/ml) Correlation between levels of serum hbd-1 and procalcitonin in overall patients r = P < PCT (ng/dl)

35 hbd-1 (ng/ml) Correlation between levels of serum hbd-1 and procalcitonin in ACLF r = P = PCT (ng/dl)

Σχετικά έγγραφα

ΟΞΕΙΑ ΕΠΙ ΧΡΟΝΙΑΣ ΗΠΑΤΙΚΗ ΑΝΕΠΑΡΚΕΙΑ: ΔΙΑΓΝΩΣΗ ΠΡΟΓΝΩΣΤΙΚΑ ΣΥΣΤΗΜΑΤΑ-ΘΕΡΑΠΕΙΑ

ΟΞΕΙΑ ΕΠΙ ΧΡΟΝΙΑΣ ΗΠΑΤΙΚΗ ΑΝΕΠΑΡΚΕΙΑ: ΔΙΑΓΝΩΣΗ ΠΡΟΓΝΩΣΤΙΚΑ ΣΥΣΤΗΜΑΤΑ-ΘΕΡΑΠΕΙΑ Αλεξάνδρα Αλεξοπούλου Επίκουρη Καθηγήτρια Β Πανεπιστημιακή Παθολογική Κλινική Ιπποκράτειο ΓΝΑ CANONIC STUDY 1343 ασθενείς