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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 3  |  Page : 685-692

Study of interleukin-22 in patients with liver cirrhosis in Menoufia University Hospitals, Egypt


1 Department of Microbiology and Immunology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission12-Feb-2015
Date of Acceptance07-Apr-2015
Date of Web Publication22-Oct-2015

Correspondence Address:
Amal M Abd El-Hameed Dawoud
Toukh Dalaka Village, Tala City, Menoufia Governorate, 32613
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.167892

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  Abstract 

Objectives
The aims of the study were to determine serum levels of interleukin-22 (IL-22) in patients with liver cirrhosis in Menoufia University Hospitals and to detect its relation with the degree of liver cirrhosis and determine the serum level of IL-22 in relation to morbidity of patients with advanced liver cirrhosis.
Background
IL-22 was recently identified as a crucial parameter of pathology in experimental liver damage. Assuming that IL-22 has hepatoprotective properties in liver diseases, IL-22 may be a relevant factor for progression of liver cirrhosis.
Patients and methods
The study was conducted on 40 liver cirrhotic patients and 20 age-matched and sex-matched healthy individuals. All patients were subjected to history taking, complete medical examination, and thorough laboratory and radiological investigations. Serum IL-22 levels were measured by means of the ELISA technique.
Results
Hepatitis C virus was the major cause of liver cirrhosis in our studied group (72.5%). The majority of patients presented with liver cirrhosis-related complications at the time of inclusion into the study. Liver cirrhotic patients had significant elevation in serum levels of IL-22 when compared with healthy people (P < 0.001). IL-22 serum levels were elevated in liver cirrhosis regardless of its etiology. IL-22 serum levels were significantly more elevated in patients with ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, hepatic encephalopathy, and esophageal varices as compared with patients without these complications (P = 0.05, 0.03, 0.04, 0.004, and 0.05, respectively). IL-22 serum levels showed a statistically significant positive correlation with Model for End-stage Liver Disease score (P < 0.001) and Child-Pugh score (P = 0.006).
Conclusion
Serum IL-22 is significantly elevated in liver cirrhotic patients and it may be relevant for the prognosis of advanced liver cirrhosis.

Keywords: Interleukin-22, liver cirrhosis, Model for End-stage Liver Disease


How to cite this article:
El-Hendawy GR, Labib AZ, Nouh MA, Abd El-Hameed Dawoud AM. Study of interleukin-22 in patients with liver cirrhosis in Menoufia University Hospitals, Egypt. Menoufia Med J 2015;28:685-92

How to cite this URL:
El-Hendawy GR, Labib AZ, Nouh MA, Abd El-Hameed Dawoud AM. Study of interleukin-22 in patients with liver cirrhosis in Menoufia University Hospitals, Egypt. Menoufia Med J [serial online] 2015 [cited 2020 Feb 24];28:685-92. Available from: http://www.mmj.eg.net/text.asp?2015/28/3/685/167892


  Introduction Top


Liver cirrhosis is a major yet largely preventable cause of global health burden and is mostly attributed to hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol consumption [1]. Egypt has the highest prevalence of HCV in the world, estimated nationally at 14.7% [2].

Identification of processes that lead to deterioration of liver cirrhosis and development of complications is regarded as key to successful implementation of novel treatment regimens aiming at hard-to-treat patients suffering from hepatitis of diverse etiologies [3].

Interleukin-22 (IL-22) is an important cytokine that plays a pleiotropic protective, but sometimes also pathological, role in several tissues/organs, including the liver [4]. IL-22 is a member of the IL-10 family of cytokines and represents an important effector molecule of activated T helper 22 (Th22), Th1, and Th17 cells, as well as cytotoxic T-cell subsets [5].

The direct effects of IL-22 are restricted to nonhematopoietic cells; its receptors are expressed on the surface of only epithelial cells and some fibroblasts in various organs, including parenchymal tissue of the gut, lung, skin, and liver [6].

Through activation of signal transducer and activator of transcription 3 (STAT3) signaling cascades, the cytokine induces proliferative and antiapoptotic pathways, as well as antimicrobial molecules, that help to prevent tissue damage and aid in its repair [7].

The function of IL-22 is difficult to generalize [8]. Recent studies have shown that IL-22 may be involved in the pathogenesis of autoimmune diseases including psoriasis, Crohn's disease, rheumatoid arthritis, and Sjögren's syndrome. IL-22 is also involved in the survival of cells in the liver, lungs, and gut [9].

IL-22, a survival factor for hepatocytes, is highly elevated and correlates with the grade of inflammation in patients with viral hepatitis. IL-22 promotes proliferation of liver progenitor cells, which are activated and induced to compensate for liver function owing to the bipotential capacity of these cells to differentiate into hepatocytes and biliary epithelial cells in cases of severe or chronic liver injury [10]. In hepatocytes, IL-22 stimulates upregulation of expression of a variety of antiapoptotic, mitogenic [11], and antioxidative [12] and mitochondrial DNA repaired genes [13].

IL-22 induces the senescence of hepatic stellate cells, thereby ameliorating liver fibrogenesis [14].

Various preclinical studies have been conducted in recent years that emphasize the broad therapeutic potential of recombinant IL-22 in liver, pancreatic, intestinal, and lung pathophysiology associated with epithelial injury [15].

The aim of our study was to determine serum levels of IL-22 in patients with liver cirrhosis in Menoufia University Hospitals and to detect its relation with the degree of liver cirrhosis and determine the serum level of IL-22 in relation to morbidity of patients with advanced liver cirrhosis.


  Materials and methods Top


Study population and selection of patients

The study was conducted from November 2013 to October 2014 at Menoufia University Hospitals (Egypt). The study protocol was approved by the local ethics committee of Menoufia University. All participants gave written informed consent before inclusion into the study.

The study comprised two groups: group I included 40 cirrhotic patients (29 male and 11 female) admitted to the Tropical Medicine Department and National Liver Institute in Menoufia University Hospitals and group II included 20 age-matched and sex-matched healthy individuals.

Inclusion criteria were age at least 18 years and the presence of liver cirrhosis. Liver cirrhosis was either proven histopathologically or by explicit morphological criteria of liver cirrhosis with ultrasound, computerized tomography, or MRI.

Exclusion criteria were patients with organ transplantation, patients with early to terminal stages of hepatocellular carcinoma, and patients with other conditions known to be associated with elevated serum levels of IL-22, such as rheumatoid arthritis and psoriasis.

All patients were subjected to full history taking, complete medical examination, and thorough laboratory and radiological investigations.

Evalua tion of liver cirrhosis-related complications

All patients were subjected to complete medical examination and thorough investigations to evaluate the following forms of liver-related complications during hospital admission: ascites, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, esophageal varices, and hepatic encephalopathy.

Collection of blood samples

About 5-7 ml of venous blood was aseptically drawn from all patients. Three milliliters was transferred slowly into a plain tube. The serum was allowed to separate in a serum separator tube (about 4 h) at room temperature, followed by centrifugation at ~1000g for 15 min. The serum samples were aliquoted and stored at -80°C until further use for IL-22 quantification, and repeated freeze-thaw cycles were avoided. In addition, the rest of the blood samples were subsequently used for clinical chemistry.

Ascitic fluid samples

About 50 ml of ascitic fluid was obtained under aseptic conditions from patients suspected to have SBP. The site of an ascitic tap is away from the midline, at the point of maximal dullness, and ideally in the left iliac fossa, two finger breadths medial and two ventral to the anterior superior iliac spine (Runyon's spot) [16].

Clinical chemistry

Hematology and biochemistry analyses were performed at the local laboratory of Menoufia University Hospitals.

Laboratory investigations included the following:

  1. Liver function tests [total bilirubin, direct bilirubin, total protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, g-glutamyl transpeptidase, and international normalized ratio (INR) for prothrombin time and concentration].
  2. Viral hepatitis markers (HBsAg and HCV antibodies).
  3. Kidney function tests (serum urea and creatinine).
  4. Complete blood picture.
  5. C-reactive protein (CRP).
  6. Abdominal paracentesis was done for the studied patients with ascites and suspected to have SBP and ascitic fluid examined for polymorphonuclear leukocytes.


All parameters of liver function tests (except for prothrombin time), parameters of kidney function tests, and CRP were evaluated using an Integra 400 autoanalyzer (Roche Diagnostics Corporation, Indianapolis, Indiana, USA).

Prothrombin time and concentration were assessed using Thromborel-S (human thromboplastin containing calcium) from Behring Diagnostic Inc., USA.

HBsAg was evaluated using the electrochemiluminescence immunoassay intended for use on Roche COBAS e 411 analyzer with Elecsys HBsAg II Quant reagent kits (Roche Diagnostics, Indianapolis, IN). HCV antibodies were detected using third-generation enzyme-linked immunosorbent assay (ELISA). Complete blood picture was evaluated on an autoanalyzer Siemens Healthcare Diagnostics, Advia 2120 Hematology System, USA.

Quantification of interleukin-22 serum levels

Serum IL-22 levels were quantified using Boster's human IL-22 ELISA kits according to the manufacturer's instructions (Boster Biological Technology Co. Ltd, Fremont, California, USA). Boster's human IL-22 ELISA kit was based on standard sandwich ELISA technology. A monoclonal antibody from mouse specific for IL-22 was precoated onto 96-well plates. Standards (Escherichia coli, A34-I179) and test samples were added to the wells. A biotinylated detection polyclonal antibody from goat specific for IL-22 was added subsequently and was followed by washing with TBS buffer. Avidin-biotin-peroxidase complex was added and unbound conjugates were washed away with TBS buffer. Horseradish peroxidase (HRP) substrate tetramethylbenzidine (TMB) was used to visualize HRP enzymatic reaction. TMB was catalyzed by HRP to produce a blue color product that changed into yellow after adding acidic stop solution. The density of yellow is proportional to the human IL-22 amount of sample captured in the plate.

Statistical analysis

The data collected were tabulated and analyzed by statistical package for the social sciences (SPSS, version 20; SPSS Inc., Chicago, Illinois, USA) software, on an IBM compatible computer.

The results were expressed as range, mean ± SD. The χ2 -test, the Mann-Whitney test, the t-test, and the Kruskal-Wallis test were used for analysis. P values less than 0.05 were considered significant.

Pearson's correlation was used for normally distributed quantitative variables, whereas Spearman's correlation was used for quantitative variables that were not normally distributed or when one of the variables was qualitative.


  Results Top


Patient characteristics

This study included 40 cirrhotic patients (29 male and 11 female). The patient characteristics are presented in [Table 1]. The mean age of the studied patients was 56.15 ± 9.33 years. The majority of patients were male. The major cause of liver cirrhosis was chronic viral hepatitis C and B. The majority of patients presented with decompensated liver cirrhosis at the time of inclusion into the study. The most frequent liver cirrhosis-related complication was ascites.
Table 1: Patient characteristics

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There was a highly statistically significant difference between the two studied groups as regards IL-22 serum levels (P < 0.001). Serum levels of IL-22 in the studied group of patients ranged from 537.84 to 969.46 pg/ml (mean 807.47 ± 77.75 pg/ml), whereas in the control group IL-22 serum level ranged from 2.70 to 18.72, with a mean value of 4.88 ± 6.19, as shown in [Table 2].
Table 2: Comparison between studied groups of cases and controls as regards serum levels of interleukin-22 (pg/ml)

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To exclude a potential bias we investigated whether age, sex, residence, occupation, socioeconomic status, and smoking influence the IL-22 serum concentration. In our study, IL-22 level was not affected by any of them in patients with liver cirrhosis, as all had P value more than 0.05, as shown in [Table 3].
Table 3: Relationship between serum levels of interleukin-22 (pg/ml) in the studied group of cases and their demographic characteristics

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In the present study, no significant differences became apparent between levels of IL-22 in the sera from patients with liver cirrhosis due to chronic HBV or chronic HCV. For autoimmune and primary liver cirrhosis, the number of patients was too small to draw a valid conclusion as shown in [Table 4].
Table 4: Relationship between serum levels of interleukin-22 (pg/ml) among the studied group of cases and etiology of their liver disease

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IL-22 serum levels were significantly more elevated in patients with ascites, hepatorenal syndrome, SBP, hepatic encephalopathy, and esophageal varices as compared with patients without these complications (P = 0.05, 0.03, 0.04, 0.004, and 0.05, respectively) as shown in [Table 5].
Table 5: Relationship between serum levels of interleukin-22 (pg/ml) in the studied group of cases and liver cirrhosis-related complications

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Potential correlations of the cytokine with serum albumin (surrogate marker of liver synthetic capacity), CRP (surrogate marker of ongoing inflammation), ALT, and AST (surrogate markers of liver damage) were analyzed. Serum creatinine and blood urea are markers of renal functions. A strong positive correlation was found between serum IL-22 and CRP levels (P < 0.001). Furthermore, significant negative correlations between serum levels of IL-22 and albumin (P = 0.001), as well as ALT (P = 0.05), were observed. The Model for End-stage Liver Disease (MELD) score includes the laboratory parameters for creatinine, bilirubin, and INR for prothrombin time. In the present study, there was a significant positive correlation between MELD score and IL-22 serum levels (P < 0.001). Interestingly, creatinine and INR but not bilirubin correlated with IL-22 serum levels, as shown in [Table 6].

IL-22 serum levels have positive correlation with Child-Pugh score (P = 0.006). Serum levels of IL-22 increased from class A to class B but with no statistically significant difference (P = 0.80). IL-22 serum levels significantly increased from class B to class C (P = 0.01), as shown in [Table 7] [Figure 1],[Figure 2],[Figure 3],[Figure 4] and [Figure 5].
Figure 1: Mean value of interleukin-22 serum levels in cases and controls.

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Figure 2: Relationship between serum levels of interleukin-22 and complications of liver disease in the studied cases.

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Figure 3: Correlation between serum levels of interleukin-22 (pg/ml) and alanine aminotransferase serum levels in the studied group of cases.

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Figure 4: Relationship between interleukin-22 (pg/ml) and Model for End-stage Liver Disease score in the studied group of cases.

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Figure 5: Interleukin-22 serum levels among different classes of Child– Pugh score.

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Table 6: Relationship between serum levels of interleukin-22 (pg/ml) in the studied group of cases and other assessed laboratory parameters

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Table 7 Relationship between serum levels of interleukin-22 (pg/ml) among the studied group of cases and Child– Pugh classification

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  Discussion Top


This study was performed at Menoufia University Hospitals to study serum levels of IL-22 in patients with liver cirrhosis, and to detect its relation with the degree of liver cirrhosis and determine the serum level of IL-22 in relation to morbidity of patients with advanced liver cirrhosis.

Our data show that, compared with healthy individuals, IL-22 serum levels were significantly elevated in patients with liver cirrhosis. This is in agreement with the study conducted by Jiang et al. [17], who documented that serum IL-22 was significantly upregulated in patients with chronic hepatitis compared with controls. Kronenberger et al. [3] in Germany also documented that IL-22 serum levels were significantly elevated in patients with liver cirrhosis.

To exclude a potential bias we investigated whether age or sex may influence the IL-22 serum concentration. In the present study, systemic IL-22 level was not affected by either in liver cirrhotic patients (both P>0.05). These results matched those of Cotta et al. [18] in Italy and Leipe et al. [19] in Germany. In the current study, residence, occupation, socioeconomic status, and smoking did not affect IL-22 serum levels in patients with liver cirrhosis (all P>0.05). Leipe et al. [19] also reported that smoking did not alter the baseline IL-22 serum level.

In the present study, we observed no significant difference in the IL-22 levels in sera from patients with prevalent etiologies of liver disease - that is, HCV and HBV. This matches the results obtained by Dambacher et al. [20], who showed that there was no significant difference between hepatic IL-22 mRNA levels in patients with viral and nonviral hepatitis, suggesting that primarily hepatic inflammation with infiltration of IL-22-producing T cells and not the viral infection itself contributes to the increased IL-22 levels.

We compared liver cirrhosis-related complications between patients with IL-22 serum levels. IL-22 serum levels were significantly more elevated in patients with ascites, hepatorenal syndrome, SBP, and hepatic encephalopathy as compared with patients without these complications (P = 0.05, 0.03, 0.04, and 0.004, respectively). These observations altogether indicate that high IL-22 serum levels may reflect the severity of liver disease; Kronenberger et al. [3] also documented the same results.

In this study, IL-22 was found to be positively correlated with CRP. As known so far, IL-22 seems to play a role in inflammatory processes - for example, through upregulation of acute-phase reactants in the liver cells including CRP as reported by Brand et al. [21] and Bleicher et al. [22].

In the present study, there was significant negative correlation between the serum level of IL-22 and serum albumin. This matches the results of the study by Oral et al. [23] conducted in Turkey, who reported that IL-22 induces acute-phase responses such as anemia, weight loss, elevated platelet numbers, increased levels of serum amyloid A and fibrinogen, and decreased levels of serum albumin. Our observations indicate that high IL-22 serum levels may reflect the severity of liver disease in which liver synthetic capacity is reduced, providing another explanation for decreased serum albumin with increased IL-22 serum levels.

Furthermore, significant negative correlation between serum levels of IL-22 and ALT was observed. This is in agreement with the study conducted by Kronenberger et al. [3]. Further, Cobleigh and Robek [4] reported that adoptive transfer of IL-22-expressing Th17 cells into IL-22 (-/-) (negative) mice resulted in a reduction in serum ALT and AST levels after concanavalin A injection, indicating that IL-22 provides protection against liver damage in this model.

In the present study, there were significant positive correlations between serum levels of IL-22 and INR, as well as serum creatinine. This is in agreement with the results of Kronenberger et al. [3]. IL-22 serum levels may reflect the severity of liver disease in which liver synthetic capacity is reduced, providing an explanation for increased INR with increased IL-22 serum levels. Also, renal affection may occur in advanced liver disease (hepatorenal syndrome), explaining the positive correlation between IL-22 serum levels and creatinine.

In the present study, IL-22 serum level correlated positively with the MELD score (P < 0.001), in agreement with the results of Bingold et al. [24] in Germany and those of Kronenberger et al. [3]. This indicates that high IL-22 serum levels may reflect the severity of liver disease and that IL-22 is associated with deterioration of liver function and subsequent mortality of cirrhotic patients. Park et al. [25] also reported a positive correlation between serum IL-22 and liver injury in a mouse model of T-cell hepatitis. In agreement with these findings, Zhao et al. [26] in China found that liver-infiltrating IL-22 (+) cells were largely increased in HBV-infected patients with liver cirrhosis, compared with those without liver cirrhosis or healthy subjects, and were positively associated with liver fibrosis staging scores.

El-Basuoni et al. [27] revealed that the frequency of circulating Th17 cells (Th17 cells can produce a cocktail of cytokines such as IL-17A, IL-17F, IL-21, and IL-22) was increased in patients with chronic hepatitis B viral infection compared with healthy controls, and was significantly higher in patients with chronic hepatitis B-associated cirrhosis. Xiang et al. [28] found that IL-22 in chronic hepatitis B patients shows negative correlation with liver necroinflammation and fibrosis stage.

In the present study, serum IL-22 levels were significantly associated with Child-Pugh classification of liver cirrhosis (P = 0.006). Serum levels of IL-22 increased from class A to class B but with no statistically significant difference (P = 0.8). IL-22 serum levels significantly increased from class B to class C (P = 0.01). This is in agreement with the study conducted by Zhao et al. [26], who documented that IL-22 production by CD4 and CD8 T cells was higher in liver cirrhosis patients with Child-Pugh C score, compared with those with Child-Pugh A or B scores.


  Conclusion Top


From this study we can conclude that liver cirrhotic patients have significant elevation in serum level of IL-22 and it is more elevated in patients with decompensated liver cirrhosis. IL-22 serum levels showed a statistically significant association with Child-Pugh and MELD score. Thus, IL-22 levels correlate positively with the degree of liver cirrhosis.

Further research is recommended to clearly evaluate the correlation between IL-22 and liver cirrhosis severity. A better understanding of the intrahepatic microenvironments that influence the pathological versus protective effects of IL-22 will be significant for the development of new immunotherapeutic approaches that target IL-22 or IL-22-producing cells.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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