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Year : 2019  |  Volume : 32  |  Issue : 1  |  Page : 267-274

A study on the relationship between tissue factor expression and liver damage in diabetic patients with hepatitis C virus-related cirrhosis

Clinical Pathology Department, Menoufia University, Shebeen El-Kom, Egypt

Date of Submission12-Jul-2017
Date of Acceptance08-Sep-2017
Date of Web Publication17-Apr-2019

Correspondence Address:
Mona F. M. Salama
Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Menoufia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mmj.mmj_496_17

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The aim of this study was to identify a possible role for tissue factor (TF) in the pathogenesis of hepatic damage in patients with hepatitis C virus (HCV)-related cirrhosis with type 2 diabetes mellitus (T2DM).
HCV infection and T2DM are both prevalent diseases worldwide. The exact mechanism by which type 2 diabetes worsens liver function is needed to be clarified. TF is a key link that connects hemostatic, immune, and inflammatory processes.
Materials and methods
The study included 80 participants divided into three groups: 30 patients with HCV-related cirrhosis and T2DM, 30 cirrhotic patients, and 20 healthy controls. Flow cytometry analysis was used for measuring TF (CD142) and the costimulatory molecule (CD86) on lipopolysaccharide-activated monocytes (CD14 positive cells) in peripheral blood in different studied groups.
Our results have shown higher TF and CD86 expression in cirrhotic patients with T2DM compared with those with cirrhosis and healthy controls (34.06 ± 5.99, 24.65 ± 6.76 and 11.90 ± 3.04 for TF and 72.09 ± 12.57, 49.38 ± 15.07 and 9.35 ± 3.07 for CD86, respectively; P < 0.001). In addition, higher TF expression was associated with deteriorated liver function and higher Child–Pugh grade (P = 0.01).
On the basis of our data, we suggest a possible role for TF in the pathogenesis of liver damage through exaggerating the inflammatory process. This can, at least partially, explain the worsened liver function in HCV-related cirrhosis in patients with T2DM.

Keywords: flow cytometry, hepatitis C virus, monocytes, tissue factor (CD142), type 2 diabetes mellitus

How to cite this article:
El-Edel RH, Abou-El-Ela DH, Osman NF, Salama MF. A study on the relationship between tissue factor expression and liver damage in diabetic patients with hepatitis C virus-related cirrhosis. Menoufia Med J 2019;32:267-74

How to cite this URL:
El-Edel RH, Abou-El-Ela DH, Osman NF, Salama MF. A study on the relationship between tissue factor expression and liver damage in diabetic patients with hepatitis C virus-related cirrhosis. Menoufia Med J [serial online] 2019 [cited 2019 Aug 25];32:267-74. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/267/256121

  Introduction Top

Chronic hepatitis C virus (HCV) and type 2 diabetes mellitus (T2DM) are two major public health problems that cause huge burden worldwide [1]. The WHO reported that 170 million individuals are infected with HCV globally [2]. The infection result in chronic liver disease, hepatocellular carcinoma, and even death from end-stage liver disease [3]. HCV protein induces both innate and adaptive immune responses. Monocytes, a vital component of the innate immune mechanism, once activated, they become a major link between the inflammatory and the hemostatic process [4]. T2DM is a common metabolic disorder affecting more than 150 million people. The disease is characterized by, in addition to defective insulin secretion, insulin resistance (IR) and increased hepatic glucose production which cause hyperglycemia [5].

Tissue factor (TF) is a membrane protein which initiates the hemostasis and acts as a key link between coagulation, inflammatory processes, and immune responses. Activated monocytes show high TF expression and, thus, their accumulation in the liver results in intensification of the inflammatory process and liver damage [6],[7].

Previous studies have shown that T2DM and IR are considerably higher in patients with chronic hepatitis C and diabetes was reported as a risk factor for liver cirrhosis, hepatocellular carcinoma, and poor outcome and reduced response to antiviral therapy in HCV patients [8].

  Aim Top

To estimate the possible role of TF in inducing hepatic damage in HCV-related cirrhosis associated with T2DM.

  Materials and Methods Top

The study included 80 participants divided into three groups. Group I: 30 patients with HCV-related cirrhosis and T2DM, group II: 30 cirrhotic patients, and group III: 20 healthy control patients. Patients were recruited from the Department of Internal Medicine, Menoufia University Hospitals in the period between September 2016 and February 2017. Informed consent was obtained from all involved patients. The protocol was approved by the Ethics Committee of Faculty of Medicine, Menoufia University and was conducted in accordance with the International Ethical Guidelines. Patients with chronic inflammatory disorder, sepsis, renal dysfunction, cancer, hematological malignancy, autoimmune disorders and patients receiving anti-inflammatory, antiplatelets medications and/or chemotherapy were excluded from the study.

Diagnosis of HCV infection and quantification of HCV RNA in the serum was carried out by COBAS TaqMan assay (Roche Diagnostic, Basel, Switzerland). Liver cirrhosis was diagnosed by ultrasound. Diagnosis of T2DM was in accordance with American Diabetes Association criteria [9].

For routine hematology and blood chemistry analysis, blood samples were obtained in sterile venipuncture. Complete blood count was done using automated Sysmex XN-10 Hematology Analyzer (Sysmex, Kobe, Japan). Liver functions, renal function tests, lipid profile, fasting and 2 h blood glucose were measured by AU480 Analyzer (Beckman Coulter, Fullerton, California, USA). Glycated hemoglobin (HBA1c) was quantified by ion exchange chromatography with a DS5 set (DS5, Drew Company, UK).

Flow cytometric analysis

Blood samples obtained on EDTA-containing tubes were used for flow cytometry analysis of CD142, CD86, and CD14 expression on the monocyte membrane. A minimum of 10 000 leukocytes were analyzed in each test tube. Fluorescence-labeled anti-human monoclonal antibodies (eBiosciences, San Diego, California, USA) were used for surface staining and were as follows: FITC labeled anti-CD14, PE labeled anti-CD142, and anti-CD86. One hundred microliter of whole blood was mixed and incubated with 10 μl of each of anti-CD14 and anti-CD142 or with 10 μl of anti-CD86. Appropriately matched FITC-labeled anti-mouse IgG were used as negative control. Tubes were mixed gently and the mixture was incubated for 30 min in the dark at 18–25°C. Erythrocytes were removed by adding 2 ml of optic lyse C lysing solution (ImmunoPrep-Reagenziensystem ABC; Coulter Immunology, California, USA), centrifugation at 300g for 5 min, and by removing the supernatant. Cells were washed twice with PBS and then suspended in 200 μl PBS.

In-vitro stimulation of monocytes by lipopolysaccharides

Whole blood (1 ml) placed in a test tube containing natrium citrate was incubated with 10 μl of lipopolysaccharide (LPS), prepared by dissolving 5 mg in 1 ml high balanced salt solution (LPS Escherichia coli EH100; Sigma Aldrich, Vienna, Austria) and was mixed for 4–6 h at 37°c. Then, 10 μl of properly diluted anti-CD14 and anti-CD142 monoclonal antibodies was added to 100 μl of whole blood stimulated by LPS and incubated in the dark. Lysing, washing, and suspending with PBS were carried out as described previously. Finally, the stained monocytes were analyzed using a flow cytometer with FACS caliber FCM (Beckman Coulter). Forward and side scatter gates were established to exclude cell debris and clumps before the analysis. Monocytes were identified by gating CD14+ events. Positive and negative cells were set according to the negative isotype matched control, and all additional analyses were performed on this population [7].

Statistical analysis

Sample size calculation

The required sample size was estimated using the Power Analysis and Sample Size software (PASS, NCSS statistical software; LLC, Kaysville, Utah, USA) and according to previous studies [7].

A sample size of 80 patients was calculated to achieve a power of 80% and confidence level of 95% for the detection of a statistically significant difference. Results were collected, tabulated, and statistically analyzed by an IBM-compatible personal computer with SPSS statistical package version 20 (Released 2011, IBM SPSS for Windows, version 20.0; IBM Corp., Armonk, New York, USA). Two types of statistical analyses were used, the descriptive statistics, for example, was expressed in number, percentage, mean, and SD and the analytic statistics using one-way analysis of variance F, Student's t-test, and χ2-test. Spearman's correlation coefficient was used to measure the relationship between two variables.

P value of less than 0.05 was considered statistically significant.

  Results Top

The study included 80 participants divided into three groups. Group I: 30 cirrhotic patients with diabetes, group II: 30 patients with cirrhosis, and group III included 20 healthy control patients. Of the two patients' groups, 41 (68.3%) were men and 19 (31.6%) were women. Regarding the Child–Pugh grade, seven (11.6%) patients were grade A, 41 (68.3%) patients were in grade B, while 12 (20%) were of grade C at presentation.

The studied groups were age and sex matched. The demographic, clinical, and biochemical characteristics of the involved patients are summarized in [Table 1].
Table 1: Characteristics of the studied groups

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The result of this study showed that liver function tests as reflected by elevated serum aminotransferases, hyperbilirubinemia (both total and direct), hypoalbuminemia and thrombocytopenia were more significantly affected in cirrhotic patients with diabetes compared with those with cirrhosis while the levels were within normal in the control group (P < 0.001). In addition, the abnormalities in lipid profile [serum cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c)] were more encountered in cirrhotic patients with diabetes compared with cirrhotic nondiabetics and were compared with healthy controls (P < 0.001) [Table 1].

Tissue factor (CD142) expression in the studied groups

Naive monocytes expressed TF (CD142) at low levels (8.44 ± 3.51); however, those levels increased significantly on stimulation with LPS (29.35 ± 7.91; P < 0.001). Monocytic CD142 + was significantly higher in cirrhotic patients with diabetes (34.06 ± 5.99) compared with the other two groups (24.65 ± 6.76 and 11.90 ± 3.04 for cirrhosis and controls, respectively, P < 0.001). In addition, patients with cirrhosis alone had significantly higher monocyte TF compared with healthy control (P < 0.001) [Table 2] and [Figure 1].
Table 2: Tissue factor (CD142), CD86, and CD14 expression on activated monocytes

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Figure 1: Expression of CD142, CD14, and CD86 on stimulated monocytes.

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These results were demonstrated before and after stimulation with LPS (data not shown).

Study of costimulatory molecule CD86 expression: the expression of CD86 was significantly higher in diabetic cirrhotic patients compared with cirrhotic nondiabetic patients and compared with healthy controls [Table 2] and [Figure 1]. There was a positive correlation between TF expression and CD86 (r = 0.70, P < 0.001) [Table 3].
Table 3: Correlation between CD142 expression and other data

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Correlation between TF expression and patients' characteristics: In this study, there was a positive correlation between CD142 expression and serum levels of aspartate aminotransferase, alanine aminotransferase, and bilirubin (both total and direct), (r = 0.58, 0.59, 0.62 and 0.58, respectively, P < 0.001). On the other hand, there was a negative correlation between CD142 levels on peripheral monocyte and the albumin level and platelet count (r=−0.74 and − 0.66, P < 0.001 and 0.002, respectively). The level of TF expression increased in line with the Child–Pugh class, the highest being in patients with class C (P = 0.01) [Table 3] and [Figure 2].
Figure 2: Tissue factor activity in different Child–Pugh grades.

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TF expression exhibited a positive correlation with lipid profile (total cholesterol, triglycerides, and LDL-c).

Interestingly, we demonstrated a positive correlation between HBA1c levels, fasting blood sugar, and 2 h blood glucose and the level of TF expression (r = 0.71, 0.70, and 0.75, respectively; P < 0.001) [Table 3] and [Figure 3].
Figure 3: Flow cytometric analysis of CD142, CD86, and CD14 expression on peripheral blood monocytes: (a) FSC and SSC gating of peripheral blood monocytes (green), (b): CD14 FITC gated monocytes (R1), (c) study of CD142 expression on CD14 positive monocytes, (d) study of CD86 expression on monocytes population gated by forward and side scatter.

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  Discussion Top

TF is a membrane protein which induces proinflammatory cytokines and hence displays an important role in the inflammatory process in addition to its classical role in the initiation of coagulation [10]. There has been epidemiological evidence for the contribution of T2DM to liver disease in those patients; however, the precise mechanism is not clear [11].

The aim of this study was to identify a possible role for TF (CD142) in the pathogenesis of hepatic damage in patients with HCV-related cirrhosis with T2DM.

The current study included three groups: 30 HCV-related cirrhotic patients with diabetes, 30 HCV-related cirrhotic patients, and 20 healthy control patients. The groups were age and sex matched. There was male predominance in the two patients' groups which agrees with other studies and is thought to be related to a higher risk of HCV infection in men [12].

In this study, lipid profile abnormalities (serum cholesterol, triglycerides, LDL-c, and HDL-c) were more encountered in cirrhotic patients with diabetes compared with cirrhotic nondiabetics and healthy control.

In addition, cirrhotic patients with diabetes had more advanced liver damage compared with those with cirrhosis alone and compared with healthy controls as shown by deranged liver enzymes, prothrombin time, and bilirubin together with a decrease in albumin and platelet count.

These results agree with those obtained by Elhawary et al. [13], who demonstrated significantly deranged liver profile in diabetic patients with cirrhosis compared with the cirrhosis group.

In HCV diabetic patients, virus infection is associated with accelerated steatosis that is mediated by increased production of lipogenic substrates, upregulation of lipogenesis, and disruptions of fatty acid metabolism [14]. In addition, IR, a classical feature of T2DM, activates the lipid biosynthetic pathway in the liver resulting in dyslipidemia and increased steatosis, which can accelerate liver fibrosis. Decreased insulin sensitivity also increases the release of free fatty acids from the adipose tissue leading to increased hepatic lipid deposition [15].

Our results showed lower CD142 expression on naïve monocytes and that the level of expression was significantly enhanced upon their exposure and stimulation with LPS. Gerritis et al. [16] haveexplained those findings by the fact that under physiological conditions, monocytes express little TF but its stimulation, for example, by contact with LPS, activate Toll-like receptor-4 leading to increased TF expression in the cytosolic compartment which subsequently translocates to the plasma membrane where it becomes a source for TF-rich microparticle.

The results from the current study have revealed that cirrhotic patients with diabetes had higher monocytic CD142 (TF) expression compared with cirrhotic nondiabetic patients and compared with healthy control (P < 0.001). These results were demonstrated on monocytes before and after stimulation with LPS.

Moreover, TF expression was higher in uncontrolled diabetics compared with patients with good diabetes control as evidenced by the positive correlation between HBA1c level and TF expression.

The above results agree with those published by Abu et al. [17] who looked at the CD142 expression in patients with cirrhosis, diabetes, and healthy controls. They reported significant increase in CD142 expression on peripheral blood stimulated monocyte in diabetics compared with those with cirrhosis and compared with healthy controls. Further subgroup analysis has shown that CD142 expression was higher in cirrhotic patients with diabetes compared with the cirrhotic group.

Al-Ghorouy et al. [18] and Gerritis et al. [19] have reported, in agreement with our results, significantly higher monocyte TF expression in diabetics when compared with normal control and this was more obvious after monocytic stimulation with LPS.

The above results imply a possible relation between diabetes and increased TF expression. Al-Ghorouy et al. [18] suggested that glycated albumin, which is higher in diabetics, induces TF expression on monocytes due to an increase in TF mRNA, which was found to increase by 2–3-fold, likely through the activation of protein tyrosine kinase that increases the gene transcription.

Increased TF expression in diabetics can also be, at least partially, due to IR present in those patients as insulin was reported to induce phosphorylation of its receptors which, subsequently, bind the G-protein (Giα), guanine nucleotide binding membrane protein, forming an induce phosphorylation of its receptors-Giα. This complex increases cAMP, an inhibitor of TF synthesis. Thus, the loss of insulin sensitivity is associated with loss of suppression of TF synthesis [20].

Increased TF expression associated with T2DM, particularly in poorly controlled patients, is a likely contributing factor for increased risk of thrombosis present in those patients and highlights the significance of optimal glycemic control [18].

In addition to IR seen in diabetic hepatitis C patients, slow circulation in the liver leads to long exposure of monocytes to inflammatory mediators in the liver microcirculation resulting in monocyte activation and increase of TF expression leading to enhancement of hepatic fibrogenesis in these patients. Fibrosis, in turn, leads to further sluggish circulation initiating a vicious circle [7].

In this study, the levels of TF expression increased progressively with the Child–Pugh class being higher in stage C. This agrees with the results obtained by Panasiuk et al. [21] and El-Bassiouni et al. [7], who declared a significant increase in CD142 expression on peripheral blood monocyte in cirrhotic patients with Child C compared with those with Child A and B.

Our data has shown higher expression of costimulatory molecule CD86 on the surface of monocytes in diabetic cirrhotic patients compared with the group with cirrhosis and compared with healthy control. Interestingly, there was a positive correlation between CD86 and TF (CD142) expression. It seems that CD86 plays an important role in transmitting stimulatory signals both to immunological and inflammatory cells. In addition, it activates and recruits T cytotoxic lymphocytes to the site of inflammation [17],[21].

Our data also showed a progressive increase in CD14 expression on stimulated peripheral blood monocyte in cirrhotic patients with diabetes compared with cirrhotic nondiabetic patients and compared with healthy controls.

Nupponen et al. [22] reported upregulation of monocytic CD14 in HCV patients and was found to be associated with high inflammatory activity as CD14 plays an important role in inducing monocytes to release the proinflammatory cytokines tumor necrosis factor-α, interleukin (IL) 1, and IL6 that can modulate monocyte activity.

Interestingly, our data has shown a positive correlation between TF expressions and lipid profile (total cholesterol, LDL-c, and triglycerides), liver enzymes (aspartate aminotransferase, alanine aminotransferase), total and direct bilirubin and prothrombin time. On the other hand, negative correlations between the TF levels and platelets, HDL-c and albumin were obtained.

These finding agrees with the results reported by Abu et al. [17] and can be solely due to the common pathogenesis, that is, HCV infection and/or diabetes.

The association, explained earlier, between the severity of hepatic dysfunction and levels of TF expression suggests a possible role for TF in the pathogenesis of liver impairment in those patients and thus patients with cirrhosis and diabetes, who have higher TF expression, are likely to have more hepatic damage.

Liver damage present in patients with HCV infection and diabetes is thought to be due to vascular injury which results in the activation of coagulation factors, thrombin formation, and fibrogenesis [17]. In addition, vascular injury induces inflammatory cytokines which activate monocytes with increased expression of CD14 that results in the release of proinflammatory cytokines (tumor necrosis factor-α, IL1, and IL6) that intensify the inflammatory process and increase hepatocyte susceptibility to apoptosis [23]. Moreover, glycated albumin, IR, and slow circulation in the liver increase the expression of TF that plays a vital role in connecting coagulation, immunological and inflammatory processes leading to enhancement of hepatic fibrogenesis.

  Conclusion Top

On the basis of our results, coexistence of diabetes and HCV-related cirrhosis was associated with more advanced hepatic impairment as evidenced by deteriorated liver function. We suggest TF, which has been shown in our study among others to be expressed at higher levels in diabetics, as a contributing factor in the progress of liver pathology in those patients. It is likely that TF enhances the inflammatory process within the liver parenchyma as it was shown to induce release of proinflammatory cytokines. This raises the possibility of a potential role for anti-inflammatory properties as a potential therapeutic option that can ameliorate liver damage in those patients. However, careful selections need to be made to avoid hepatotoxic medications or using drugs that might interfere with diabetes control.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]


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