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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 525-531

Study of serum tumor necrosis factor-α in patients with liver cirrhosis


1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission25-Mar-2014
Date of Acceptance03-Jun-2014
Date of Web Publication31-Aug-2015

Correspondence Address:
Ahmed Salah Abdel-Aziz
Department of Tropical Medicine, Shebin El-Kom, Menoufia 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163913

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  Abstract 

Objective
This study is designed to evaluate the serum level of tumor necrosis factor-α (TNF-a) in patients with liver cirrhosis and determine the possible relation between TNF-α and various complications of liver cirrhosis.
Background
TNF is a pleiotropic cytokine, mainly produced by monocytes and macrophages and implicated in several physiological and pathological conditions. Several studies have shown that serum levels of TNF-α are significantly elevated in patients with liver diseases.
Patients and methods
This study was conducted on 70 cirrhotic patients (group I) who were divided into three subgroups according to the Child-Pugh scoring system: group Ia comprised 15 patients with Child A; group Ib comprised 15 patients with Child B; and group Ic comprised 40 patients with Child C. The study also included 10 healthy controls (group II). The serum level of TNF-α was evaluated in all patients.
Results
A highly significant increase in the mean value of serum TNF-a was found in the liver cirrhosis group with significant positive correlation between serum level of TNF-α and Child-Pugh score. There was a highly significant increase in the mean value of serum TNF-α in encephalopathic patients in comparison with nonencephalopathic patients in the cirrhotic subgroups, with significant positive correlation between clinical grades of hepatic encephalopathy (HE) and TNF-α. Serum TNF-α was the only independent predictor for the development of HE.
Conclusion
Serum levels of TNF-α correlate positively with the severity of hepatic dysfunction and with the severity of HE in patients with liver cirrhosis. TNF-α may be a possible mediator in the pathogenesis of HE in cirrhotic patients.

Keywords: cytokines, encephalopathic factor, hepatic encephalopathy, liver cirrhosis, tumor necrosis factor-α


How to cite this article:
Sabry HS, El-Hendy AA, Mohammed HI, Essa AS, Abdel-Aziz AS. Study of serum tumor necrosis factor-α in patients with liver cirrhosis. Menoufia Med J 2015;28:525-31

How to cite this URL:
Sabry HS, El-Hendy AA, Mohammed HI, Essa AS, Abdel-Aziz AS. Study of serum tumor necrosis factor-α in patients with liver cirrhosis. Menoufia Med J [serial online] 2015 [cited 2020 Apr 6];28:525-31. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/525/163913


  Introduction 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. Indeed, patients with hepatitis C may have chronic hepatitis for as long as 40 years before progressing to cirrhosis [1] .

Many forms of liver injury are marked by fibrosis, which is defined as an excess deposition of the components of the extracellular matrix (i.e. collagens, glycoproteins, and proteoglycans) within the liver. This response to liver injury is potentially reversible. In contrast, in most patients, cirrhosis is not a reversible process. In addition to fibrosis, the complications of cirrhosis include, but are not limited to, portal hypertension, ascites, hepatorenal syndrome, and hepatic encephalopathy (HE) [2] .

Tumor necrosis factor (TNF) is a pleiotropic cytokine, mainly produced by monocytes and macrophages and implicated in several physiological and pathological conditions [3] . TNF occurs in two forms: TNF-α (cachectin), which is synthesized by T cells, mast cells, monocytes, macrophages, Kupffer cells, astrocytes, and TNF-β, which is synthesized by lymphocytes and natural killer cells, hence the earlier term lymphotoxin [4] .

The cytokine TNF-α is a well-known member of the TNF superfamily consisting of at least 18 ligands and 29 different receptors involved in numerous cellular processes. TNF signals through two distinct receptors, TNFR1 and TNFR2, thereby controlling the expression of cytokines, immune receptors, proteases, growth factors, and cell cycle genes, which in turn regulate inflammation, survival, apoptosis, cell migration, proliferation, and differentiation [5] .

Several studies have shown that serum levels of TNF-α are significantly elevated in patients with acute and chronic liver diseases, where these elevations are independent of the etiology of the underlying disease. Serum levels of TNF-α are significantly higher in patients with cirrhosis than in those without cirrhosis, reaching the highest levels in decompensated cirrhosis [6] .

TNF-α serum levels are clearly elevated in patients with fulminant hepatitis. In addition, it was found that serum TNF-α levels were significantly higher in patients with fulminant hepatitis who died compared with patients who survived. Significantly elevated serum levels of TNF-α were also found in patients with chronic liver disease of different etiologies, such as hepatitis B and C, alcoholic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, and hemochromatosis [7] .

Indeed, TNF-α is strongly involved in the pathogenesis of liver injury in most liver diseases [8] .


  Patients and methods Top


A total of 70 cirrhotic patients were selected from 97 patients attending the Outpatient Clinic and/or Inpatient Department of the Hepatology and Gastroenterology Unit at Shebin El-Kom Teaching Hospital during the period April-October 2013. The study population comprised 23 women and 47 men and their ages ranged from 27 to 62 years with a mean of 48.7 ± 7.1 years. Ten healthy individuals of matched age and sex were also selected as a control group. Patients were diagnosed with liver cirrhosis on the basis of clinical examination, ultrasonographic findings, and laboratory investigations.

Patients and controls were divided into two groups: group I included the 70 patients with liver cirrhosis and group II included the 10 healthy controls. Group I was divided into three subgroups according to the Child-Pugh scoring system: group Ia comprised 15 patients with liver cirrhosis of Child-Pugh class A; group Ib comprised 15 patients with liver cirrhosis of Child-Pugh class B, and group Ic comprised 40 patients with liver cirrhosis of Child-Pugh class C.

Exclusion criteria

  1. Pregnant women.
  2. Patients on interferon-based therapy.
  3. Patients on anti-TNF-α therapy.
  4. Patients with end-stage renal disease and/or renal failure (but not patients with hepatorenal syndrome).
  5. Patients with neuropsychiatric disorders other than HE.
  6. Patients with rheumatologic diseases.
  7. Patients with active tuberculosis disease.
All patients and controls were subjected to full history taking, full clinical examination, abdominal ultrasonography, and laboratory investigations including evaluation of complete blood count, erythrocyte sedimentation rate, and random blood sugar, liver function tests, α-fetoprotein, creatinine and blood urea nitrogen, serum electrolytes, hepatitis C virus (HCV) antibody and HBsAg, and serum level of TNF-α. Ascitic fluid analysis was performed for all patients admitted into the hospital with ascites.

Serum level of TNF-α was measured using Accucyte human TNF-α, which is a competitive enzyme immune assay (EIA) [AssayPro: AssayMax Human TNF-α enzyme-linked immunosorbent assay (ELISA) kit (AssayPro Company, St. Charles, MO, USA)].

Sample collection and measurement of tumor necrosis factor-α

  1. A sample of venous blood was taken from each participant and centrifuged at 5000 rpm for 10 min. The serum was stored immediately at −20°C.
  2. Serum TNF-α was determined by means of ELISA, using the IDELISATM Human TNF-α ELISA kit (Neogene Company, USA).
Principle

The method is a solid-phase sandwich ELISA. It utilizes a monoclonal antibody (capture antibody) specific for human TNF-α coated on a 96-well plate. Standards and samples are added to the wells, and any human TNF-α present binds to the immobilized antibody. The wells are washed, and biotinylated polyclonal antihuman TNF-α antibody (detection antibody) is added. After a second wash, avidin-horseradish peroxidase is added, producing an antibody-antigen antibody sandwich. The wells are again washed, and a substrate solution is added, which produces a blue color in direct proportion to the amount of human TNF-α present in the initial sample. The stop buffer is then added to terminate the reaction. This results in a color change from blue to yellow. The wells are then read at 450 nm [9] .

Calculation of the results

A standard curve was constructed by plotting the adjusted average absorbance for each reference standard against its concentration in pg/ml on a logarithmic scale. The adjusted average absorbance was obtained by subtracting the average of the negative control absorbance from the average of each observed absorbance. The corresponding concentration of human TNF-α in pg/ml in samples was determined by plotting the adjusted absorbance value for each sample on the standard curve.


  Results Top


  1. Highly significant increase in the mean value of serum TNF-α in group I (liver cirrhosis) in comparison with group II (control group), as shown in
  2. [Table 1].
  3. Highly significant positive correlation between serum level of TNF-α and Child-Pugh score in cirrhotic subgroups as shown in [Figure 1].
  4. Highly significant increase in the mean value of serum TNF-α in encephalopathic patients in comparison with nonencephalopathic patients in cirrhotic subgroups, as shown in [Table 2].
  5. Statistically significant positive correlation between clinical grades of HE (according to West Haven criteria) and TNF-α in cirrhotic subgroups, as shown in [Figure 2].
  6. Significant increase in the number of patients who developed HE due to infectious complications [spontaneous bacterial peritonitis (SBP) and other infections], as shown in [Table 3].
  7. There was no statistically significant difference in the mean value of serum TNF-α in patients with HE due to infectious and noninfectious precipitating factors, as shown in [Table 4].
  8. Serum TNF-α is the only independent predictor for the development of HE, whereas SBP and other infections are dependent risk factors as shown in [Table 5].
  9. A cutoff point of TNF-α 38.1 pg/ml or more may predict the occurrence of HE in cirrhotic patients with a sensitivity of 88% and a specificity of 75%, as shown in the receiver operating characteristic curve in [Figure 3].
Figure 1: Pearson's correlation shows highly signifi cant positive correlation between serum level of tumor necrosis fa ctor-¦Á (TNF-¦Á) and Child– Pugh score in cirrhotic subgroups

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Figure 2: Spearman's correlation shows statistically significant positive correlation between clinical grades of hepatic encephalopathy (according to West Haven criteria) and tumor necrosis factor-¦Á (TNF-¦Á) in cirrhotic subgroups

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Figure 3: Receiver operating characteristic (ROC) curve revealed that a cutoff point of tumor necrosis factor-¦Á 38.1 pg/ml or more may predict the occurrence of hepatic encephalopathy in cirrhotic patients with a sensitivity of 88% and specifi city of 75%.

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Table 1 Mean values of serum tumor necrosis factor-¦Á in the studied groups

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Table 2 Mean values of serum tumor necrosis factor-¦Á in cirrhotic patients with and without hepatic encephalopathy

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Table 3 Comparison between the number of patients with and those without hepatic encephalopathy regarding the most common precipitating factors

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Table 4 Mean value of serum tumor necrosis factor-¦Á in patients with hepatic encephalopathy due to infectious and noninfectious precipitating factors

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Table 5 Multivariate logistic regression analysis of the possible predictors for hepatic encephalopathy

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  Discussion Top


In the present study, HCV infection was the most common cause of liver diseases in cirrhotic subgroups. This comes in agreement with the results of Strickland [10] , who reported that 70-90% of patients in Egypt with chronic hepatitis, cirrhosis, or hepatocellular carcinoma had HCV infections. The relationship between the serum level of TNF-α and etiology of liver disease could not be assessed because HCV infection was the most common cause of liver diseases in cirrhotic subgroups. However, Alvarado et al. [11] showed elevation in the level of TNF-α in patients with chronic HCV in their study. This could be because TNF-α triggers a partially overlapping set of antiviral defense mechanisms and serum level of TNF-α reflects the progression of inflammation. Increased TNF-α in patients with chronic hepatitis C may contribute to the role of innate immunity in stimulating the adaptive immune responses, thus suggesting the role of TNF-α in antibody production [12] .

Statistical analysis revealed highly significant increase in the mean value of serum TNF-α in patients with liver cirrhosis compared with healthy controls in this study. This result is in agreement with that of Tilg et al. [7] , who studied serum level of different cytokines (including TNF-α) in patients with chronic liver diseases. They found that serum level of TNF-α increases significantly in chronic liver diseases and reaches its maximum in decompensated cirrhosis. They suggested that this elevation in the cytokine levels represent a consequence of liver dysfunction rather than inflammatory disease [7] . Zhang et al. [13] studied the serum level of TNF-α and interleukin (IL)-6 in patients with chronic liver diseases and reported that serum level of TNF-α was significantly elevated in patients compared with controls. They suggested that high serum level of TNF-α is an important mediator in the pathogenesis of liver necrosis and alterations in microcirculation [13] . Similar results were reported by Yuan et al. [14] and Lee et al. [15] .

The current study also showed highly significant positive correlation between the serum level of TNF-α and Child-Pugh score from A to C in cirrhotic subgroups. This result is in agreement with that of Tilg et al. [7] , who reported a statistically significant positive relationship between the elevated level of TNF-α and severity of liver disease. Zhang et al. [13] studied the serum and ascitic fluid levels of several cytokines including TNF-α in patients with chronic hepatitis and liver cirrhosis. They found that serum level of TNF-α was significantly higher in patients with liver cirrhosis than in those with chronic hepatitis and in patients with ascites (decompensated) than in patients with compensated cirrhosis. They concluded that TNF-α and other cytokines may participate in the pathogenesis of chronic hepatitis and liver cirrhosis [16] . Similarly, Lee et al. [15] reported that plasma levels of TNF-α and IL-6 increase significantly in cirrhotic patients and this elevation was significantly correlated to the severity of liver dysfunction. Also, Huang et al. [17] evaluated the serum level of cytokines (including TNF-α) in HCV-related liver diseases. They reported that serum level of TNF-α was significantly higher in patients with liver cirrhosis and/or hepatocellular carcinoma than in patients with acute and chronic hepatitis C. This elevation was correlated with indices of hepatic dysfunction (prothrombin time and indocyanine green retention ratio) than with parameters of hepatic inflammation (ALT and AST) [17] . Moreover, Wang et al. [18] reported that elevated level of TNF-α was significantly related to disease severity and nutrition status in patients with liver cirrhosis and hepatocellular carcinoma. In contrast, Kiki et al. [19] found that TNF-α levels were negatively correlated with Child-Pugh score in patients with liver cirrhosis. However, patients in that study were composed mostly of those with Child B and C stage cirrhosis. There were only three patients with Child A stage cirrhosis, and hence no statistical comparison could be made because of the small amount of samples. Only the mean TNF-α level of the patients with Child A stage cirrhosis was higher than both Child B and C ones and chronic hepatitis cases. Also, all cases were hepatitis B virus related and the authors did not investigate other etiological agents. They attribute the increase in TNF-α level in active hepatitis and early-stage cirrhosis to sustained inflammation, tissue necrosis, and fibrogenesis; in contrast, it is not increased in advanced-stage cirrhosis characterized by minimal inflammation and marked fibrosis.

The present study revealed that patients with liver cirrhosis and HE have significantly higher serum levels of TNF-α compared with those without HE. Also, there was a statistically significant positive correlation between clinical grades of HE (according to West Haven criteria) and TNF-α in cirrhotic patients. These results agreed with those of Odeh et al. [6] , who studied the serum level of TNF-α in 74 patients with chronic liver disease. They found that serum level of TNF-α was significantly higher in patients with HE and reported a highly significant difference between different clinical grades of HE. They concluded that serum level of TNF-α was the only significant independent predictor of the severity of HE, which may indirectly support the possibility that TNF-α might be an encephalopathic factor in patients with chronic liver failure. They also reported that the presence of high serum levels of TNF-α in patients with HE and the positive correlation between serum levels of this cytokine and severity of liver disease may indicate that these high serum levels of TNF-α might be related, at least in part, to the severity of liver disease and/or its complications, such as portal hypertension, splenic enlargement and congestion, bowel congestion, and others [6] . Similar results were reported by Chu et al. [20] , who found a significant correlation between plasma levels of TNF-α and severity of HE in rats with fulminant hepatic failure. Moreover, it has been shown that low TNF-α production was protective against the development of severe encephalopathy in patients with acetaminophen-induced acute liver failure [21] . Other studies such as those by Iwai et al. [22] , Nagaki et al. [8] , and Streetz et al. [23] studied the role of TNF-α in the pathogenesis and prognosis of acute hepatic failure. These studies reported high levels of TNF-α in patients with HE due to acute hepatic failure. These levels were correlated with the prognosis being higher in patients who died than in those who survived. Moreover, Odeh et al. [24] studied the serum level of TNF-α in 121 patients with chronic liver disease, including 81 patients with overt HE, and they found that there was a positive correlation between the serum level of TNF-α and venous blood ammonia levels. They also found that both TNF-α and ammonia levels were significantly correlated with the severity of HE [24] .

The current study showed significant increase in the number of patients who developed HE due to infectious complications (SBP and other infections). SBP was present in 39.4% and other infections was present in 30.3% of patients with HE. This comes in concordance with the findings of Ram et al. [25] , who studied 122 patients with HE and found that SBP was present in 48.4% of patients. Another study carried out by Devrajani et al. [26] on 87 patients admitted to a tertiary care hospital concluded that different factors play a key role in precipitating HE, and infection was the most common dominant factor, which was present in 67% of those patients. This could be because the severity of liver dysfunction found in cirrhosis leads to altered host defenses, which may result in high prevalence of bacterial infections, and the presence of HE in the course of cirrhosis is surely a marker of severe liver dysfunction [27] .

The present study showed that there was no statistically significant difference in the mean serum TNF-α level in patients with HE due to infectious and noninfectious precipitating factors, indicating that the high serum levels of TNF-α associated with HE are not specific for the presence of infections in these patients. These findings coincide with Odeh et al. [6] , who studied serum level of TNF-α in patients with HE due to infectious precipitating factors (SBP and other infections) and noninfectious precipitating factors (including upper gastrointestinal bleeding) and found that there was no statistically significant difference between the two groups.

In this study we compared SBP and other infections with TNF-α in a multivariate logistic regression analysis and found that serum TNF-α was the only independent predictor for the development of HE, whereas SBP and other infections were dependent risk factors. Also we found that a cutoff point of TNF-α 38.1 pg/ml or more, with a sensitivity of 88%, specificity of 75%, positive predictive value of 71%, and negative predictive value of 86%, may predict the development of HE in patients with liver cirrhosis. These findings are in agreement with those of Odeh et al. [6] , who studied the relation between serum level of TNF-α in patients with HE and infectious precipitating factors for HE and found that TNF-α was the only significant independent predictor of HE and its severity.

The above results may suggest that TNF-α has a possible role in the pathogenesis of HE. This can be supported by several experimental findings and metabolic derangements that were found to be mediated by TNF-α and may be involved in the pathogenesis of HE. First, TNF-α has been implicated in several hemodynamic alterations in liver cirrhosis [28] . Second, inhibition of TNF-α production in rats with portal hypertension is accompanied by amelioration of the hyperdynamic state and even a decrease in portal pressure [20] . Third, TNF-α and IL-6 induce significant changes in the morphology and permeability of central nervous system-derived endothelial cells and significantly increase the rate of ammonia diffusion. These changes were dose dependent and reversible. By these actions, TNF-α can increase ammonia concentration and consequently ammonia toxicity to the central nervous system [29] . Fourth, recombinant TNF-α administration in rats induces a decline in plasma level of branched chain amino acids [30] . Fifth, elevation of TNF-α in rats during sepsis (determined by experimental injection of endotoxin) was associated with increased muscle catabolism and proteolysis with marked decrease in branched chain amino acids and relative increase in aromatic amino acids [31] . Finally, local administration of TNF-α and IL-1 in the rat cortex and corpus striatum significantly increased the densities of peripheral-type benzodiazepine receptors [32] . Similarly TNF-α significantly increased the peripheral-type benzodiazepine binding sites in cultured polygonal astrocytes [33] .

Taken together, the results of this study demonstrated a strong positive relationship between serum levels of TNF-α and severity of hepatic dysfunction and severity of HE, and these results may indirectly support the possibility that TNF-α might be an encephalopathic factor in patients with chronic liver failure.


  Conclusion Top


  1. Serum levels of TNF-α correlate positively with the severity of hepatic dysfunction and the severity of HE in patients with liver cirrhosis.
  2. TNF-α may be a possible mediator that may be implicated in the pathogenesis of HE in cirrhotic patients, and, at a cutoff point 38.1 pg/ml or more, TNF-α can predict the occurrence of HE in patients with advanced cirrhosis, especially in the presence of infectious complications (SBP and other infections), with a sensitivity of 88%, specificity of 75%, positive predictive value of 71%, and negative predictive value of 86%.

  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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

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



 

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