|Year : 2019 | Volume
| Issue : 1 | Page : 68-74
Inflammatory biomarkers as prognostic indicators for liver cirrhosis
Naglaa Abou-Elfattah Tawfik1, Naglaa A El-Gendy2, Hanaa Abou Elyazid Abou Elhassan3, Eman Elshohat Ebrihem4, Rayyh Abdelazeem M Saleh5
1 Department of Internal Medicine, Al-Azhar University, Cairo, Egypt
2 Department of Tropical Medicine, Al-Azhar University, Cairo, Egypt
3 Department of Community Medicine, Community Medicine, Al-Azhar University, Cairo, Egypt
4 Department of Biochemistry, Al-Azhar University, Cairo, Egypt
5 Clinical Pathology, Faculty of Medicine (for Girls), Al-Azhar University, Cairo, Egypt
|Date of Submission||27-Jan-2019|
|Date of Acceptance||07-May-2019|
|Date of Web Publication||12-Sep-2019|
Naglaa A El-Gendy
Faculty of Medicine (for Girls), Al-Azhar University, Nasr City, Al-Abbaseya, Cairo 11754
Source of Support: None, Conflict of Interest: None
Background Severity of liver cirrhosis is commonly assessed by Child–Pugh and model of end-stage liver disease (MELD) scores, which reflect liver dysfunction mainly and do not assess associated systemic events, which influence the failure of other organs.
Aim To study the role of serum level of copeptin (CPP) and high-sensitivity C-reactive protein (hsCRP) as indicators of prognosis in liver cirrhosis and compare these results with usual prognostic scores, raising the importance of proper management of systemic infections in cirrhotic patients to prevent cirrhosis progression.
Patients and methods A cross-sectional study was carried out on 80 cirrhotic patients, who were classified into four equal groups: Child A, B, C, and Child C with systemic infections. Serum CPP and hsCRP were measured by enzyme-linked immunosorbent assay technique.
Results There was a statistically significant increase in CPP serum levels among cirrhotic patients [9.70 (7.70–14.30)] in comparison with its serum level in healthy participants [5.95 (5.40–6.75)]. There were gradually increases of CPP serum levels through Child–Pugh A, B, and C groups [6.40 (5.42–8.05), 10.15 (7.75–14.20), and 13.05 (8.77–17.27), respectively] in comparison with the control group. There were positive correlations of CPP with MELD score, Child–Pugh, and hsCRP (r=0.60, 0.71, and 0.60, respectively, P<0.000). There was a significantly increase in serum level of hsCRP among cirrhotic patients [9.90 (7.12–16.67)] than control group [2.50 (1.67–5.91)]. Its median values and interquartile range concentrations were the lowest among healthy group and increased gradually through Child–Pugh A, B, and C and Child–Pugh C with infection groups [2.50 (1.67–5.91), 7.15 (6.32–9.45), 8.35 (7.12–12.17), 9.20 (6.95–13.15), and 20.35 (14.85–32.22), respectively] (P=0.000). There were significant positive correlations of hsCRP with CPP, MELD score, and Child–Pugh (r=0.51, 0.54, and 0.75, respectively).
Conclusion CPP and hsCRP serum levels can be used as prognostic indicators of liver cirrhosis and account for systemic infections involved in deterioration of liver cirrhosis.
Keywords: Child–Pugh score, copeptin, high-sensitivity C-reactive protein, model of end-stage liver disease score
|How to cite this article:|
Tawfik NA, El-Gendy NA, Elhassan HA, Ebrihem EE, Saleh RM. Inflammatory biomarkers as prognostic indicators for liver cirrhosis. Al-Azhar Assiut Med J 2019;17:68-74
|How to cite this URL:|
Tawfik NA, El-Gendy NA, Elhassan HA, Ebrihem EE, Saleh RM. Inflammatory biomarkers as prognostic indicators for liver cirrhosis. Al-Azhar Assiut Med J [serial online] 2019 [cited 2020 Apr 6];17:68-74. Available from: http://www.azmj.eg.net/text.asp?2019/17/1/68/266732
| Introduction|| |
Chronic hepatitis C virus (HCV) infection leads to liver cirrhosis and hepatocellular carcinoma. It is estimated that ∼160 million individuals worldwide are chronically infected with HCV ,. Egypt is the most affected nation by HCV, with estimated prevalence being 11.9% of the general population .
Child–Pugh score has been widely used to assess the severity of liver dysfunction and was primarily proposed to predict mortality risk in patients undergoing operative management of variceal bleeding, that is, portosystemic shunt surgery .
The primary version of Child–Pugh score included ascites, hepatic encephalopathy, nutritional status, total bilirubin, and albumin. It was modified by adding prothrombin time (PT) or international normalized ratio (INR) and removing nutritional status .
In addition, model of end-stage liver disease (MELD) score was initially proposed to predict mortality risk in patients undergoing transjugular intrahepatic portosystemic shunts. The present version of MELD score involved three objective variables: total bilirubin, creatinine, and INR .
Model Child–Pugh and MELD scores are commonly used in clinical practice to assess severity of liver cirrhosis and to rank the priority of liver transplantation candidates ,.
However, both of them reflect the degree of liver failure but do not reflect systemic infection influence on severity of cirrhosis and functions of other systemic organs .
C-reactive protein (CRP) is a protein mainly synthesized in the liver as part of systemic inflammation. Its synthesis is stimulated by interleukin-6 and is maintained in spite of severity of liver failure . CRP is involved in opsonization and activation of the complement system in response to interleukin-6 secretion . Increased levels of CRP are associated with poor prognosis among patients with cirrhosis .
Copeptin (CPP) is a pre-pro-arginine vasopressin C terminal fragment . It is synthesized mainly in the hypothalamus and stored in the posterior pituitary . Osmotic or nonosmotic stimuli, for example, hemodynamic or stress related, affect CPP release .
CPP serum concentrations reflect the production of vasopressin and is present in more stable form than it. Moreover, its concentration increases much more than cortisol in the event of stress .
Plasma CPP concentration showed significant positive correlations with MELD score, arginine vasopressin (AVP), markers of endogenous vasoconstrictor systems, and renal function parameters. This finding supports that CPP reflects hemodynamic dysfunction and may therefore be an interesting biomarker in cirrhosis .
Many studies correlate CPP levels with different degrees of liver cirrhosis, prediction of cirrhosis complications, and mortality ,,.
The aim of this study was to study the role of serum level of CPP and high-sensitivity C-reactive protein (hsCRP) as biomarkers of disease progression and prognosis of liver cirrhosis and compare these results with usual prognostic scores (Child–Pugh and MELD), raising the importance of proper management of systemic infections in cirrhotic patients to prevent disease progression and improvement of their survival.
| Patients and methods|| |
A cross-sectional study was carried out on 160 participants from March 2017 to December 2017; 80 of them were patients with chronic HCV chronic liver diseases (cases) and 80 were healthy participants (controls).
Cases were selected from the attendants of the Internal and Tropical Medicine Departments of Al-Zahraa University Hospital, Cairo, Egypt. They were divided into three groups according to modified Child–Pugh scoring system for cirrhosis  and a fourth group with Child score more than 10 with systemic infections (peritonitis, urinary tract infection, or chest infection). Each group contained 20 patients.
Inclusion criteria for cases
Middle-age adults diagnosed as having postchronic HCV cirrhosis by HCV antibodies by enzyme-linked immunosorbent assay (ELISA) and quantitative PCR and assessed by clinical examination, liver function tests, and abdominal ultrasound evaluation for signs of liver cirrhosis were included.
Exclusion criteria for cases
Patients with any chronic liver diseases other than HCV infection were excluded.
Healthy participants were age and sex matched with cases. They were selected from relatives of the patients.
Inclusion criteria for controls
Healthy participants were free from any chronic liver diseases proved by clinically, laboratory, and ultrasonography evaluation. After explaining the purpose of the study, an informed consent was taken from each patient and healthy control in adherence with the guidelines of the ethical committee of Al-Zahraa Hospital, Al-Azhar University, Cairo, Egypt.
The studied sample was subjected to the following:
- Full history taking and thorough clinical examination.
- Abdominal ultrasonography examination.
- Laboratory investigations.
Routine laboratory investigations
- Blood sample collection: after overnight fasting, 9 ml of venous blood samples was collected by venipuncture under aseptic conditions from each patient. They were divided as follows:
- A volume of 2 ml was placed in a vacutainer tube containing EDTA for complete blood picture using an automated cell counter model SysmexKx N 21 (Sysmex Corporation, Kobe, Hyogo, Japan).
- A volume of 1.8 ml was placed in a vacutainer tube containing 0.3 ml of 3.8% sodium citrate for the measurement of PT using Sysmex A500 (Sysmex Corporation, Kobe, Hyogo, Japan).
- The remaining was placed in a tube with no anticoagulant and centrifuged within 30 min of collection at 4000 rpm for 10 min, and the serum from blood sample was separated and was divided into three parts: the first part was used for liver and kidney function tests using a Cobas C-311 auto analyzer (Roche Diagnostics, Indianapolis, Indiana, USA), the second part used for investigating hepatitis viral markers of hepatitis C and B
The remaining serum was aliquoted and stored at −20°C for subsequent detection of serum hsCRP and CPP.
- hsCRP assay was measured by ELISA technique using kits supplied by Genway Biotech Inc. (GenWay Biotech Inc., San Diego, California, USA) (Cat # 40-052-115042). The range of the kit for adults was 0.068–8.2 mg/ml .
- Serum CPP assay was measured by ELISA technique using kits supplied by CUSABIO (Biotech Ltd, Wuhan, Hubei China) (Cat # CSB-E12130h). Detection range was 78–5000 pg/ml .
Statistical analysis of collected data was done by using SPSS program (statistical package of social science; SPSS Inc., Chicago, Illinois, USA), version 16 for Microsoft Windows. Data were expressed as mean±SD for quantitative parametric measures. Moreover, median percentiles were used for quantitative nonparametric measures and both number and percentage for categorized data. Comparison between two independent mean groups for parametric data was done by using Student’s t test, whereas χ2 test was used to study the difference between categorized data. Mann–Whitney U test was used to compare two groups regarding nonparametric data. When comparing more than two groups regarding such data, Kruskal–Wallis test was used instead. Spearman’s rho correlation coefficients was calculated for association between nonparametric data. The level of significance was taken at P value less than 0.05, and the results are represented in tables.
| Results|| |
Mean age of cirrhotic patients was 53.10±4.94 years and that of healthy participants was 52.61±4.72 years. More than three-quarters of each group were males (78.8% among cirrhotic patients and 70.0% in controls) ([Table 1]).
Liver affection among cirrhotic patients was clear, as the liver function tests [total bilirubin, serum albumin, PT, alanine transamines (ALT), and aspartate transamines (AST)] among cirrhotic patients [1.80 (1.00–3.07), 2.73±0.77, 17.61±3.59, 34.00 (25.00–47.75) and 48.50 (37.00–64.75), respectively] were significantly worse than healthy ones [0.70 (0.70–0.87), 4.00±0.00, 11.92±0.40, 26.00 (21.00–28.75) and 23.50 (20.00-25.00), respectively]. In addition, kidney function (urea and creatinine) test results were significantly higher among cirrhotic patients [37.50 (27.00–53.00) and 0.80 (0.60–1.17), respectively] than their counterparts [26.50 (20.25–32.50) and 0.70 (0.52–0.80), respectively] ([Table 2]).
Statistically significant lower values regarding blood picture parameters [red blood corpuscle (RBCs), white blood cells (WBCs), hemoglobin (HBG), and platelet) were recorded among cases [3.77±0.62, 4.60 (3.82–6.00), 11.98±0.76, and 184.50 (173.75–199.50), respectively] than healthy participants [4.40±0.51, 5.50 (4.52–7.00), 11.11±1.58, and 95.00 (62.50–153.00), respectively]. Moreover, hsCRP, CPP, and INR were significantly higher among cirrhotic patients [9.90 (7.12–16.67, 9.70 (7.70–14.30), and 1.40 (1.20–1.70), respectively] than their counterparts [2.50 (1.67–5.91), 8.90 (6.60–10.72), and 0.90 (0.90–0.90), respectively] ([Table 3]).
|Table 3 Comparison of blood picture, high-sensitivity C-reactive protein, copeptin, and international normalized ratio results between patients group and control group|
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hsCRP median values and interquartile range (IQR) concentrations were the lowest among healthy group and increased gradually through Child–Pugh A, B, and C and Child–Pugh C with infection groups [2.50 (1.67–5.91), 7.15 (6.32–9.45), 8.35 (7.12–12.17), 9.20 (6.95–13.15), and 20.35 (14.85–32.22), respectively], P value=0.000. In addition, the median value and IQR of CPP concentrations in healthy participants were 5.95 (5.40–6.75) and increased gradually through Child–Pugh A, B, and C groups [6.40 (5.42–8.05), 10.15 (7.75–14.20), and 13.05 (8.77–17.27), respectively], and decreased among Child–Pugh C with infection group [11.50 (9.47–16.02)]; P value=0.000. The same pattern occurred with MELD score, as its median value and IQR were the lowest among healthy participants [1.00 (−2.00 to 3.00)] and increased gradually through Child–Pugh A, B, and C groups [2.00 (−1.75 to 6.75), 10.00 (7.25–13.00), and 14.50 (14.00–17.00), respectively] and then decreased among Child–Pugh C with infection group [13.00 (10.00–17.00)]; P value=0.000 ([Table 4]).
|Table 4 Plasma biomarkers and model of end-stage liver disease score among the studied groups|
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hsCRP had insignificant correlation with age (r=0.11); however, it negatively correlated with serum albumin (r=−0.49) and positively correlated with total bilirubin, PT, ALT, AST, urea, and creatinine (r=0.53, 0.48, 0.20, 0.43, 0.46, and 0.23, respectively). hsCRP negatively correlated with all parameters of blood picture, that is, RBCs, HBG, WBCs, and platelets (r=−0.42, −0.32, −0.12, and −0.51, respectively). Positive correlations of hsCRP with INR, CPP, MELD score, and Child–Pugh were recorded (r=0.52, 0.51, 0.54, and 0.75, respectively). All correlations were significant (P<0.05) except that with age and WBCs (P>0.05) ([Table 5]). CPP had insignificant correlation with age (r=0.08) but negatively correlated with serum albumin (r=−0.65) and positively correlated with total bilirubin, PT, ALT, AST, urea, and creatinine (r=0.63, 0.60, 0.11, 0.46, 0.21, and 0.20, respectively). CPP negatively correlated with all parameters of blood picture, that is, RBCs, HBG, WBCs, and platelets (r=−0.60, −0.06, −0.35, and −0.50, respectively). Positive correlations of CPP with INR, hsCRP, MELD score, and Child–Pugh were recorded (r=0.56, 0.60, 0.60, and 0.71, respectively). All correlations were significant (P<0.05), except those with age, ALT, and WBCs (P>0.05) ([Table 6]).
|Table 5 Correlation of high-sensitivity C-reactive protein with different studied parameters among cirrhotic patients|
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|Table 6 Correlation of copeptin with different studied parameters among cirrhotic patients|
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| Discussion|| |
Child–Pugh and MELD prognostic scores are commonly used by hepatologists but do not denote bacterial infections, which is a common cause of clinical deterioration and death .
The aim of this study was to study the role of CPP and hsCRP as prognostic markers with valuable assessment of cirrhosis more than the usual prognostic scores (Child–Pugh and MELD).
A total of 80 cirrhotic patients were divided into four equal groups according to modified Child–Pugh classification into A, B, C, and Child C with systemic infections. There were statistically significant increases in CPP serum levels among cirrhotic patients [9.70 (7.70–14.30)] in comparison with its serum level in control group [5.95 (5.40–6.75)].
Moreover, there was a gradual increase of CPP serum levels through Child–Pugh A, B, and C groups [6.40 (5.42–8.05), 10.15 (7.75–14.20), and 13.05 (8.77–17.27), respectively] in comparison with control group, and decreased among Child–Pugh C with infection group [11.50 (9.47–16.02)] (P=0.000) in comparison with Child–Pugh C without infection group.
There were positive correlations of CPP with MELD score, Child–Pugh, hsCRP, and serum creatinine (r=0.60, 0.71, and 0.60, respectively; P<0.000).
These results are in agreement with Solà et al.  as they reported that plasma CPP levels significantly increased in decompensated cirrhotic patients in comparison with compensated patients. Moreover, they found significant positive correlation of plasma CPP levels with MELD score and kidney function parameters.
Moreover, Moreno et al.  found that CPP concentrations were higher in infected cirrhotic patients (18.81 pmol/l) versus patients without infection (6.64 pmol/l) (P=0.0007).
In addition, they found that CPP concentrations were positively correlated with Child–Pugh, MELD scores (r=0.43, P<0.0001), and CRP levels (r=0.49, P<0.0001).
Moreover, Kerbert et al.  found serum CPP levels were higher in cirrhotic patients [11 (5.2–24) pmol/l] and positively correlated with MELD score.
The discrepancy in the results of serum levels of CPP in group Child–Pugh C with infection in comparison with Moreno et al.  may be owing different Child–Pugh score, as our patients were Child C, whereas their patients were Child B.
Regarding the results of hsCRP in the current study, there were significantly increases in serum level among cirrhotic patients [9.90 (7.12–16.67] than control group [2.50 (1.67–5.91)]. Its median values and IQR concentrations were the lowest among healthy group and increased gradually through Child–Pugh A, B, C, and Child–Pugh C with infection groups [2.50 (1.67–5.91), 7.15 (6.32–9.45), 8.35 (7.12–12.17), 9.20 (6.95–13.15), and 20.35 (14.85–32.22), respectively]; P value=0.000.
There were significant positive correlations of hsCRP with CPP, MELD score, and Child–Pugh (r=0.51, 0.54, and 0.75, respectively).
These results are in agreement with Kwon et al.  who studied CRP in hospitalized cirrhotic patients with infections and found increased levels of CRP with deteriorated liver functions and infections and concluded that CRP is an independent predictor of infection compared with MELD score.
In addition, Di Martino et al.  found that CRP serum levels correlated with MELD score in cirrhotic patients and did not correlate with severe cirrhosis.
Cervoni and colleagues analyzed the subgroup from the CANONIC study [a large series of patients with cirrhosis (1343 cases) consecutively admitted to 21 European Hospitals with acute decompensation to define the prevalence, diagnostic criteria, natural course, mechanism, and prognosis of acute-on-chronic liver failure] in which serial measures of CRP were available; their prognostic model was still relevant .
Results of hsCRP are against Silvestre et al.  who found significant decreases of CRP serum levels in patients with sepsis and fulminant hepatic failure.
This discrepancy may be owing to difference in the studied patients as the current study involved chronic cirrhotic patients with different Child classes A, B, and C, and one group only with systemic infections, and the study by Silvestre et al.  involved patients with fulminant hepatic failure with sepsis.
| Conclusion|| |
CPP and hsCRP serum levels can be used as prognostic indicators of liver cirrhosis and account for systemic infections, which are involved in deterioration of liver cirrhosis.
Proper management of systemic infections in cirrhotic patients to prevent complications and deterioration of liver cirrhosis is required.
It is recommended to start using the combinations of CRP and CPP as a prognostic model for liver cirrhosis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitisC: an update. Hepatology 2009; 49:1335–1374.
European Association for Study of Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60:392–420.
Kouyoumjian SP, Chemaittelly H, Abu-Raddad L. Characterizing hepatitis c virus epidemiology in Egypt: systematic reviews, meta-analyses, and meta-regressions; 2018. Available at: WWW.nature.com/scientific reports
Accessed date :20 March 2018
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Roger W. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646–649.
Kamath PS, Kim WR. Advanced liver disease study G. The model for end-stage liver disease (MELD). Hepatology (Baltimore, MD) 2007; 45:797–805.
Levesque E, Hoti E, Azoulay D, Ichai P, Habouchi H, Castaing D et al.
Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit. J Hepatol 2012; 56:95–102.
Bota DP, Van Nuffelen M, Zakariah AN, Vincent JL et al.
Serum levels of C-reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver. J Lab Clin Med 2005; 146:347–351.
Marnell L, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005; 117:104–111.
Cervoni JP, Thevenot T, Weil D, Muel E, Barbot O, Sheppard F et al.
C-reactive protein predicts short-term mortality in patients with cirrhosis. J Hepatol 2012; 56:1299–1304.
Land H, Schütz G, Schmale H, Richter D. Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor. Nature 1982; 295:299–303.
Acher R, Chauvet J, Rouille Y. Dynamic processing of neuropeptides: sequential conformation shaping of neurophypophysical preprohomones during intraneural secretory transport. J Mol Neurosci 2002; 18:223–228.
Morgenthaler NG, Struck J, Jochberger S, Dunser S. Copeptin: clinical use of a new biomarker. Trends Endocrinol Metab 2008; 19:43–49.
Timper K, Fenske W, Kuhn F, Frech N, Arici B, Rutishauser J et al.
Diagnostic accuracy of copeptin in the differential diagnosis of the polyuria-polydipsia syndrome: a prospective multicenter study. J Clin Endocrinol Metab 2015; 100:2268–2274.
Kerbert AJ, Weil D, Verspaget HW, Moreno JP, van Hoek B, Cervoni JP et al.
Copeptin is an independent prognostic factor for transplant-free survival in cirrhosis. Liver Int 2016; 36:36530–36537.
Kerbert AJ, Verbeke L, Chiang FW, Laleman W, van der Reijden JJ, van Duijin W et al.
Copeptin as an indicator of hemodynamic derangement and prognosis in liver cirrhosis. PLoS One 2015; 10:0138264.
Sole E, Kerbert JC, Verspaget HW, Moreira R, Pose E, Ruiz P et al.
Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis. J Hepatol 2016; 65:914–920.
Hartman AIH, Creutze JB. Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroenterol 1989; 24:269–276.
Hedlund P. Clinical and experimental studies on C-reactive protein (acute phase protein). Acta Med Scand 1961; 128(Suppl 361):1–71.
Vincent DM, Delphine W, Cervoni JP, Thevenot T. New prognostic markers in liver cirrhosis. World J Hepatol 2015; 7:1244–1250.
Moreno JP, Grandclement E, Monnet E, Clerc B, Agin A, Cervoni JP et al.
Plasma copeptin, a possible prognostic marker in cirrhosis. Liver Int 2013; 33:843–851.
Kwon JH, Jang JW, Kim YW, Lee SW, Nam SW, Jaegal D et al.
The usefulness of C-reactive protein and neutrophil-to-lymphocyte ratio for predicting the outcome in hospitalized patients with liver cirrhosis. BMC Gastroenterol 2015; 15:146.
Di Martino V, Coutris C, Cervoni JP, Dritsas S, Weil D, Richou C et al.
Prognostic value of C-reactive protein levels in patients with cirrhosis. Liver Transplant 2015; 21:753–760.
Cervoni JP, Amoros A, Moreau R, Arroyo V, Jalan R, Saliba F. Prognostic value of C-reactive protein in patients with cirrhosis: external validation from the CANONIC cohort. Hepatology 2014; 60:495.
Silvestre JP, Coelho LM, Póvoa PM. Impact of fulminant hepatic failure in C-reactive protein? J Crit Care 2010; 25:e7–e12.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]