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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 906-909

Study of interleukin-6 and its role in hepatic encephalopathy in patients with liver cirrhosis


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University Hospital, Shebin El-Kom, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University Hospital, Shebin El-Kom, Egypt
3 Internal Medicine Department, Almogamaa Altibi Hospital, Tanta, Egypt

Date of Submission19-Oct-2017
Date of Acceptance03-Dec-2017
Date of Web Publication17-Oct-2019

Correspondence Address:
Abdalaziz M M Salama
Internal Medicine Department, Almogamaa Altibi Hospital, Tanta 31511, Gharbia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_704_17

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  Abstract 

Objective
The aim of this work was to study the role of interleukin-6 (IL-6) in hepatic encephalopathy (HE) in patients with liver cirrhosis.
Background
IL-6 is an interleukin that acts as both proinflammatory response and anti-immune response.
Patients and methods
This study included 80 patients divided into three groups: group I represents the control group (20 healthy individuals), group II included patients with liver cirrhosis 'without HE' (30 patients), and group III included patients with liver cirrhosis and HE of different grades (30 patients). Full history taking, clinical examination, and investigations for all cases were done.
Results
There was significant difference in serum IL-6 level among the three groups: normal, liver cirrhosis, and HE groups (44.63 ± 43.08, 85.57 ± 54.24, and 156.5 ± 93.90, respectively; P ≤ 0.0001). There was a significance difference when comparing the mean values of serum IL- 6 in HE group according to Child classification (P < 0.0001).
Conclusion
IL-6 serum level is increased significantly in patients with 'liver cirrhosis and HE' and may be used as a confirmatory diagnostic marker of overt HE.

Keywords: cytokines, hepatic encephalopathy, interleukin.6, liver cirrhosis, microglia


How to cite this article:
Abd El-Atty EA, El Shayeb ESI, El-Rahman Sonbol AA, Salama AM. Study of interleukin-6 and its role in hepatic encephalopathy in patients with liver cirrhosis. Menoufia Med J 2019;32:906-9

How to cite this URL:
Abd El-Atty EA, El Shayeb ESI, El-Rahman Sonbol AA, Salama AM. Study of interleukin-6 and its role in hepatic encephalopathy in patients with liver cirrhosis. Menoufia Med J [serial online] 2019 [cited 2019 Dec 7];32:906-9. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/906/268833




  Introduction Top


Cirrhosis represents the final common histological pathway for a wide variety of chronic liver diseases. The term cirrhosis was first introduced by Laennec in 1826. It is derived from the Greek term scirrhus and is used to describe the orange surface of the liver seen in autopsy [1]. Cirrhosis is a progressive disease in most cases and results in death in the absence of transplants [2]. Hepatic encephalopathy (HE) is a well-recognized and commonly diagnosed syndrome associated with advanced chronic liver disease, and its clinical manifestations range from sleep disturbance to confusion or coma [3]. In rare cases, HE presents with overt seizure activity [4]. When neurological deficits are subtle while the neurological clinical examination is normal, a condition is considered a minimal HE [5]. They are exposed to a risk of developing clinical episodes of HE over time [6]. The presence of HE in cirrhosis is a prognostic marker of severity and a valid indication for liver transplantation, although it is not considered in the model for end-stage liver disease score on which organ distribution is based in most liver transplant centers [7].

Interleukin-6 (IL)-6 is an interleukin that acts as both proinflammatory response and anti-inflammatory cytokine. It is secreted from macrophages and T cells to stimulate immune response [8]. IL-6 is also a myokine which is secreted from the muscle cells and elevated in response to muscle contraction [9]. Activation of cytokine system, as observed in several chronic inflammatory conditions including liver cirrhosis, may result in increased energy expenditure and reduced nutrition intake [10]. Studies indicate that mediators of inflammation [tumor necrosis factor-α (TNF-α), interleukin-Iβ, and IL-6)] may exacerbate the effects of ammonia on the brain leading to more exacerbation of encephalopathy [11]. In addition, there was statistically significant difference between patients without HE and healthy people in term of serum TNF-α, IL-6, IL-8, and IL-12 receptor level [12]. The new findings of microglial activation in HE suggest that this disorder be added to the growing list of conditions with significant central neuroinflammatory component [13]. Moreover, the expression of genes coding for TNF-α, IL-Iβ, and IL-6 was found to be significantly increased and to follow a comparable time course with respect to the increased brain concentrations of cytokines; this confirmed their synthesis in the brain in situ [14].


  Patients and Methods Top


The current study was carried out after obtaining a written consent from all patients and controls and an approval by the Faculty of Medicine, Menoufia University Research Ethics Committee. Study started from April 2016 to February 2017. Exclusion criteria included patients who had other end organ failure, hepatocellular carcinoma, and other active acute inflammatory process. Study was conducted on 80 (60 patients and 20 controls) individuals. Patients (60 patients) were selected from wards of Internal Medicine Department of Menoufia University Hospitals and Health Insurance sector in Gharbia Governorate, Egypt (Elmogamaa Eltibi Hospital). The participants were divided into three groups: group I included 20 healthy individuals of matching age and sex as control group, group II included 30 patients with cirrhotic liver without overt HE, and group III included 30 patients with cirrhotic liver and overt HE of different grades. All studied individuals were subjected to complete history taking, clinical examination, abdominal ultrasound, and laboratory tests including complete blood count, alanine aminotransferase, aspartate aminotransferase, prothrombin time, prothrombin activity, blood urea, serum creatinine, and serum IL-6 level.

Procedure

A tourniquet was placed 1–2 inches above the site of puncture, and then 3 ml of blood is withdrawn in plain vacuum tube. All the blood samples had been taken from the upper limb. The tube was left for 10 min until coagulation takes place, and then centrifuged by Eppendorf centrifuge at a speed of 4000 rpm for 10 min. Then, the serum was separated. All reagents, samples, and standards were prepared, then 50 μl of standard starting from 500 pg/ml, test sample and sample diluent as a blank all were added into the appropriate wells of the strips, then 50 μl of green colored biotin antibody promptly were added to each well. Incubation was done for 1 h 30 min at room temperature. Then, the solution washed with wash buffer, and then 100 μl was ready for use. HRP-Streptavidin solution was added, and the mixture was incubated for 30 min at room temperature. Then it was washed with a wash buffer and 50 μl of TMB One-Step Substrate Reagent (Thermo Fisher Scientific 168 Third Avenue, Waltham, MA, USA). was added to each well. Thereafter, it was incubated for 20 min at room temperature, waiting for results.

Statistical analysis

The collected data were analyzed by statistical package of the social sciences program (SPSS) (released 2011, IBM SPSS for Windows, version 20.0: IBM Corporation, Armonk, New York, USA). Qualitative data were expressed as number and percentage and analyzed by using χ2. Quantitative data were expressed as mean ± SD and analyzed by using analysis of variance test.


  Results Top


A total of 80 (60 patients and 20 controls) individuals were included in our study, including 35 (43.75%) males and 45 (56.25%) females. Patients with HE were divided into four grades according to West Haven scoring system: five patients were grade I, 12 patients were grade II, six patients were grade III, and seven patients were grade IV.

Regarding age, the mean age in group I was 52 ± 4.19 years; in group II, it was 54.45 ± 7.41 years; and in group III, it was 54.25 ± 5.86 years. Regarding sex, group I included eight male and 12 female, group II included 13 male and 17 female, and group III included 14 male and 16 female. There was no significance difference among normal, liver cirrhosis, and HE groups concerning age and sex (P = 0.360 and 0.895, respectively) [Table 1]. There was significance difference when comparing the mean values of the three groups concerning BMI (23.31 ± 2.29, 27.53 ± 3.32, and 29.39 ± 3.49, respectively; P < 0.0001) [Table 1].
Table 1: Comparison among the three groups regarding their characteristics

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When comparing the mean values of normal, liver cirrhosis, and HE groups concerning serum IL-6, there was a significance difference (44.63 ± 43.08, 85.57 ± 54.24, and 156.5 ± 93.90, respectively; P < 0.0001) [Table 2] and [Figure 1].
Table 2: Comparison between serum interleukin-6 mean values in the three groups

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Figure 1: Comparison between serum interleukin-6 (IL-6) mean values in the three group.

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There was a significance difference when comparing the mean values of serum IL-6 in HE group according to Child classification 'A, B, and C' (12.75 ± 17.73, 56.15 ± 23.44, and 137.4 ± 29.47, respectively; P < 0.0001) [Table 3] and [Figure 2].
Table 3: Comparison between serum interleukin- 6 means values in hepatic encephalopathy group according to Child classification

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Figure 2: Comparison between serum interleukin-6 (IL-6) means values in hepatic encephalopathy group according to Child classification.

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  Discussion Top


Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. The progression of liver injury to cirrhosis may occur over weeks to years [15]. This process distorts the normal liver architecture, interferes with blood flow through the liver, and disrupts the functions of the liver [16].

HE is a potentially serious disturbance in central nervous system function that can result from hepatic insufficiency [17].

IL-6 is a pleiotropic cytokine with a wide range of biological activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Its activities are shared by IL-6-related cytokines such as leukemia inhibitory factor, cilliary neurotrophic factor, and oncostatin [18]. Because IL-6 is the dominant factor that initiates the transcriptional program of TH17 cells, we speculated that intrinsic properties of IL-6 might be a major determinant of the priming of pathogenic T cells. To signal into target cells, IL-6 first binds to its receptor subunit IL-6Rα. That complex then associates with gp130 (the signaling subunit of the IL-6 receptor), which results in a heterohexameric signaling complex (IL-6, IL-6Rα and gp130 in a stoichiometry of 2: 2: 2) that triggers productive signaling through IL-6 into the target cell [19]. There is evidence suggesting that toxins generated by the failing liver may play a role in the pathogenesis of neuroinflammation. A wide range of molecules including IL-6 with the potential to threaten the functional integrity of the brain have the capacity to trigger the transformation of microglia from the resting state to the activated state [20].

Regarding sex, there was no significant statistical difference between liver cirrhosis, HE, and control group. This was in agreement with Lokesh et al. [21], who stated that there was no significant statistical difference in the distribution of sex between patient with HE and minimal HE as compared with patients without minimal HE and healthy controls.

There was no significant statistical difference between the three groups; similar results were obtained by Lokesh et al. [21], who stated that there were no significant statistical difference in the distribution of age between patient with HE and minimal HE as compared with patients without minimal HE and healthy controls.

In the present study, there was a significant difference in the distribution of IL-6 among liver cirrhosis, HE, and control group. IL-6 level was significantly higher in patients having different grades of HE compared with patients without HE and healthy controls. Our results were in agreement with those of Vedat et al. [22], who reported that there were statistically significant difference between serum IL-6 levels of patients with liver cirrhosis and healthy participants and between patients with and without HE. Lokesh et al. [21] also reported that IL-6 levels were significantly higher in patient with HE.

Moreover, Odeh et al. [12] stated that there was a statistically significant difference between IL-6 levels in patients having cirrhosis with and without HE. In addition, there is a statistically significant difference in the receptor level of these cytokines between healthy participants and those who have HE.

In our study, there was also significant difference regarding IL-6 according to Child–Pugh classification specially in HE group (group III), which indicates the significant relationship between IL-6 and Child–Pugh classification. Genesca et al. [23] reported that IL-6 has significant correlation with Child score in addition to plasma renin activity, serum and urinary sodium, and mean arterial blood pressure. However, the finding was in contrast to Vedat et al. [22], who reported no statistical relationship between serum IL-6 and Child–Pugh classification and attributed their findings to socioeconomic and environmental factors.


  Conclusion Top


We conclude that IL-6 serum level is increased significantly in patients with 'liver cirrhosis and HE' compared with patients who have only liver cirrhosis.

IL-6 serum level is significantly related to the degree of liver cirrhosis according to Child–Pugh classification in patients with HE.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Qi X, Ye C, Hou Y, Guo X. A large spontaneous intrahepatic portosystemic shunt in a cirrhotic patient. Intractable Rare Dis Res 2016; 5:58–60.  Back to cited text no. 1
    
2.
Olson JC. Acute-on-chronic and decompensated chronic liver failure. Crit Care Clin 2016; 32:301–309.  Back to cited text no. 2
    
3.
Kappus MR, Bajaj JS. Covert hepatic encephalopathy: not as minimal as you might think. Clin Gastroenterol Hepatol 2012; 10:1208–1219.  Back to cited text no. 3
    
4.
Jhun P, Kim H. Nonconvulsive status epilepticus in hepatic encephalopathy. West J Emerg Med 2011; 12:372–374.  Back to cited text no. 4
    
5.
Ortiz M, Jacas C, Cordoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol 2005; 42:S45–S53.  Back to cited text no. 5
    
6.
Amuero J, Montoliú C, Simón-Talero M, Aguilera V, Millán R, Márquez C, et al. Minimal hepatic encephalopathy identifies patients at risk of faster cirrhosis progression. J Gastroenterol Hepatol 2017; [Epub ahead of print].  Back to cited text no. 6
    
7.
Bernardi M, Gitto S, Biselli M. The MELD score in patients awaiting liver transplant: strengths and weaknesses. J Hepatol 2011; 54:1297–1306.  Back to cited text no. 7
    
8.
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011; 1813:878–888.  Back to cited text no. 8
    
9.
Febbraio MA, Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 2005; 33:114–119.  Back to cited text no. 9
    
10.
Gerstner C, Schuetz T, von Baehr V, Roske A, Volk H, Lochs H. Correlation between energy expenditure, nutrient intake, malnutrition and activation of the inflammatory system in patients with hepatic cirrhosis. J Hepatol 2001; 34:195–196.  Back to cited text no. 10
    
11.
Mostafa EF, Ibrahim AM, Elalawi SM. Effect of serum ammonia, TNF-alfa and IL-6 levels on the degree and outcome of hepatic encephalopathy in Egyptian cirrhotic patients. Int J 2015; 3:375–381.  Back to cited text no. 11
    
12.
Odeh M, Sabo E, Srugo I, Oliven A. Relationship between tumour necrosis factor alpha and ammonia in patients with hepatic encephalopathy due to chronic liver failure. Ann Med 2005; 37:603–612.  Back to cited text no. 12
    
13.
Bémeur C, Qu H, Desjardins P, Butterworth RF. IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure. Neurochem Int 2010; 56:213.  Back to cited text no. 13
    
14.
Tanaka S, Ide M, Shibutani T, Ohtaki H, Numazawa S, Shioda S, et al. Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats. J Neurosci Res 2006; 83:557–566.  Back to cited text no. 14
    
15.
Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008; 371:838–851.  Back to cited text no. 15
    
16.
Lefkowitch JH. Scheuer's liver biopsy interpretation E-Book. Columbia University, New York, USA; Elsevier Health Sciences 2015.  Back to cited text no. 16
    
17.
Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol (N Y) 2011; 7:222–233.  Back to cited text no. 17
    
18.
Kishimoto T. Interleukin-6: from basic science to medicine – 40 years in immunology. Annu Rev Immunol 2005; 23:1.  Back to cited text no. 18
    
19.
Heink S, Yogev N, Garbers C, Herwerth M, Aly L, Gasperi C, et al. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol 2017; 18:74–85.  Back to cited text no. 19
    
20.
Van Rossum D, Hanisch UK. Microglia. Metab Brain Dis 2004; 19:393–411.  Back to cited text no. 20
    
21.
Lokesh J, Chander SB, Praveen S, Siddharth S, Amit A, Kumar SS. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis 2012; 44:1027–1031.  Back to cited text no. 21
    
22.
Vedat G, Yehya A, Abdu Rahman K. Relationship between pathogenesis of liver cirrhosis, hepatic encephalopathy and serum cytokine levels: what is the role of tumor necrosis factor α?. Hepatogastroenterology 2011; 58:107–108.  Back to cited text no. 22
    
23.
Genesca J. Interleukin 6, nitric oxide and clinical alteration and heamodynamics in patients with liver cirrhosis. Am J Gastroentrol 2000; 95:323–324.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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