Serum Interleukin-22 as a Marker of Decompensated Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients
Abou Youssef, R., Elshayeb, A., Deghady, A., Hosny, N. (2025). Serum Interleukin-22 as a Marker of Decompensated Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients. EKB Journal Management System, 15(2), 205-214. doi: 10.21608/aeji.2025.348250.1443
Rania AM Abou Youssef; Ayman Elshayeb; Akram Deghady; Noura Hosny. "Serum Interleukin-22 as a Marker of Decompensated Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients". EKB Journal Management System, 15, 2, 2025, 205-214. doi: 10.21608/aeji.2025.348250.1443
Abou Youssef, R., Elshayeb, A., Deghady, A., Hosny, N. (2025). 'Serum Interleukin-22 as a Marker of Decompensated Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients', EKB Journal Management System, 15(2), pp. 205-214. doi: 10.21608/aeji.2025.348250.1443
Abou Youssef, R., Elshayeb, A., Deghady, A., Hosny, N. Serum Interleukin-22 as a Marker of Decompensated Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients. EKB Journal Management System, 2025; 15(2): 205-214. doi: 10.21608/aeji.2025.348250.1443

Serum Interleukin-22 as a Marker of Decompensated Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients

Afro-Egyptian Journal of Infectious and Endemic Diseases
Article 11, Volume 15, Issue 2, June 2025, Page 205-214  XML PDF (402.65 K)
Document Type: Original Article
DOI: 10.21608/aeji.2025.348250.1443
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Authors
Rania AM Abou Youssef email 1; Ayman Elshayeb1; Akram Deghady2; Noura Hosny1
1Tropical Medicine Department, Faculty of Medicine, Alexandria University, Egypt.
2Clinical Pathology Department, Faculty of Medicine, Alexandria University, Egypt.
Abstract
Background and study aim: Chronic liver disease (CLD), when associated with chronic hepatitis C virus (HCV) infection, typically develops into cirrhosis and hepatocellular carcinoma (HCC). Early identification and accurate staging of the transition from compensated to decompensated cirrhosis are imperative for effective intervention and improved patient outcomes. HCC is the fourth leading cause of cancer death in Egypt. Consequently, the identification of novel biomarkers for early HCC diagnosis remains an essential clinical need. Interleukin-22 (IL-22), a cytokine implicated in hepatic fibrogenesis in the context of HCV infection, has emerged as a promising candidate biomarker warranting further investigation.  Our study aimed to identify the serum levels and diagnostic performance of Interleukin-22 in HCV decompensated cirrhotic patients as well as HCC patients.
Patients and Methods: The study was conducted on 80 individuals from Alexandria Main University Hospital, Tropical Medicine Department; they were divided into four groups. The first three groups consisted of 20 patients each. Group I included 20 patients with HCV-induced decompensated liver cirrhosis without HCC, group II included 20 patients with compensated liver cirrhosis without HCC while group III included 20 patients with HCC. Group IV consisted of 20 healthy controls. Serum  IL-22 was measured by ELISA.
Results: Serum IL-22 was significantly higher in HCC patients than in patients with decompensated and compensated cirrhosis. There was also a statistically significant difference between cirrhotic patients and controls (p=0.016).  Serum IL-22 was significantly higher in decompensated cirrhosis patients than in patients with compensated cirrhosis.  The Serum IL-22 cutoff point discriminating HCC cases from decompensated cirrhotic cases was  >81 ng/ml, with a sensitivity of 95%, specificity of 95%, positive predictive value of 95%, and negative predictive value of 95%.
Conclusion:  Serum IL-22 is a sensitive biomarker that could predict the development as well as the aggressiveness of HCC in cirrhotic patients.

Highlights
  • IL-22 is implicated in several liver illnesses, including cirrhosis, fibrosis, and inflammation.
  • Significant high IL22 in patients with decompensated cirrhosis could suggest its use as an important marker of the progression of the cirrhotic process.
  • The high diagnostic accuracy of IL22 could suggest its use as a promising marker of HCC.
Keywords
Interleukin-22 (IL-22); HCC; Chronic Hepatitis C; Cirrhosis
Full Text

INTRODUCTION

Hepatitis C virus infection is one of the most significant health concerns in human civilizations. Today, the virus infects 170 to 200 million individuals worldwide, with an additional 40,000 persons adding to the figure each year, (more than 3% of the global population).[1] Egypt had the highest HCV prevalence worldwide. Egypt developed a feasible paradigm of care for managing that severe illness which has the highest global disease prevalence. This paradigm could treat around 4 million patients.   Although Egypt has made great efforts in managing such diseases, several obstacles can delay the disease's total elimination [2].

Hepatitis C virus (HCV) is the most common reason for chronic liver disease, cirrhosis, hepatocellular carcinoma, and eventually liver transplantation in several countries, and it is also the most common reason for liver transplantation. Several factors affect the prognosis of chronic HCV infection such as age, race, gender, and the immune response of the virus. A chronic HCV infection will develop in about 55% to 85% of people infected with the virus. They also have a higher risk of developing extrahepatic symptoms,  compensated and decompensated cirrhosis, and ultimately HCC [3].

Liver cirrhosis is the last stage of a multistep process, initiated from a primary hepatotoxic effect and resulting in insufficient liver function due to excessive hepatocyte destruction, Despite having the highest functional reserve of any organ, the cirrhotic liver rapidly loses its ability of compensation for the chronic influence of a causal agent due to severe biochemical and physiological alterations [4].

Necrosis occurs after hepatic injury by HCV and is followed by hepatocyte proliferation [5]  This repetitive cycle of destruction and regeneration leads to chronic liver disease development and finally cirrhosis [6]. Cirrhosis is marked by abnormal liver nodule formation which is encircled by collagen deposition and liver scarring. Eventually, hyperplastic nodules emerge, progressing to dysplastic nodules, and ultimately resulting in the formation of HCC [7].

In Egypt, hepatocellular carcinoma (HCC) ranks as the fourth cause of cancer-related deaths [8] and the sixth most common cancer worldwide [9].  The incidence of this disease has increased due to the advancements in screening programs and diagnostic technologies, raising the rate of cirrhotic patient survival, which raises the rate of HCC development, as well as hepatitis C virus (HCV), which is considered the commonest cause of HCC and hepatic cancers in Egypt. It takes 20 to 40 years for HCC to develop as a result of HCV [10].

 Both host-induced immune responses and virus-induced factors influence HCV carcinogenesis. Although there is only evidence of HCV's direct carcinogenic effect on liver cells in experimental animals, studies have revealed that HCV core protein may induce oxidative stress metabolism and cause lipogenesis [11]. 

HCV viral proteins may promote the development of HCC by deactivating tumor suppressor genes, and cell cycle checkpoints, or by stimulating growth and division-promoting signaling pathways [12]. HCV's nonstructural protein genes activate hepatic stellate cells and trigger transforming growth factor-beta, which both lead to fibrosis and hepatocellular carcinoma (HCC) [13]. HCV-induced immune response is modulated through persistent inflammation, tumor necrosis factor, and interferons (IFNs) [14].

IL-22 was initially discovered as a gene that reacted to interleukin-9 (IL-9) in T lymphoma cells of mice  . It was originally known as IL-10-related T-cell-derived inducible factor (IL-TIF) due to its encoding of a glycosylated protein sharing 22% sequence identity with interleukin-10 (IL-10) [15].

 In human genome, the gene of IL-22 is found on chromosome 12q15, near to the interleukin-26 (IL-26) and interferon-c (IFN-c) genes, forming an interleukin gene cluster . The chromosomal structure of IL-22 contains six exons and five introns, showing comparable sizes and organizational patterns when compared to IL-10 [16].

It has been shown that Th17 cells are able to produce IL-22 and IL-17 together [17]. When it was found that IL-22 affects hepatocytes by interacting with the IL-22R1/IL-10R2 receptor complex, its dual function became evident. Investigations were done to determine IL-22R1 receptor expression to determine the functional targets of IL-22 [18].

HCV patients had considerably high levels of IL-22-producing T helper (Th17) cells in their livers [19].  In contrast to cholestatic liver disorders, HCV hepatitis showed higher hepatic IL-22 mRNA expression. However, antiviral proteins 2',5'-oligoadenylates, and MxA synthesis as well as  IFN-α/β expression were not significantly affected by IL-22, indicating that in vitro models of virus C infection and replication show a lack of antiviral activity [20].

IL-22 is implicated in several liver illnesses, including cirrhosis, fibrosis, and inflammation.    After the hepatic injury, HSCs predominantly cause liver fibrosis, expressing elevated levels of IL-22R1 and IL-10R2. Both in vivo and in vitro studies show that IL-22's ability to suppress HSC apoptosis and improve their survival by stimulating anti-apoptotic genes. [21]

Notably, the recognized tumor-infiltrating leukocytes (TILs) of human HCC have markedly elevated IL-22 expression, with higher levels seen in advanced tumor grades [22].  Additionally, IL-22 enhanced the progression of HCC by activating STAT3 signaling, thereby inducing the expression of pro-tumorigenic genes like CyclinD1, Bcl-2, Bcl-XL, and the known vascular endothelial growth factor (VEGF), which facilitate growth and metastasis of the tumor   [23].

Our study aimed to identify the serum levels and diagnostic performance of Interleukin-22 in HCV decompensated cirrhotic patients as well as HCC patients. We also studied the relation between serum IL-22 and Fib-4, APRI, and Child-Pugh scores.

PATIENTS AND METHODS

The study involved eighty participants divided into four groups: 20 patients had decompensated liver cirrhosis caused by HCV (Child-Pugh B or C),20 patients had compensated liver cirrhosis caused by HCV (Child-Pugh A),20 patients with HCV-induced liver cirrhosis and HCC, and 20 healthy volunteers as a control group. Participants with other conditions like sepsis, spontaneous bacterial peritonitis, hepatorenal syndrome, or malignancies were excluded. All participants underwent a clinical examination and medical history, with a focus on identifying signs of chronic liver disease.

Laboratory tests were conducted to assess liver function, kidney function, blood glucose levels, and serum electrolytes. The APRI and FIB-4 scores, which are non-invasive measures to diagnose liver fibrosis, were also calculated. Serum Interleukin-22 level was measured using an ELISA test.

Imaging studies, including abdominal ultrasounds, were performed to assess the liver, spleen, and presence of ascites or focal lesions. If any focal lesions were detected on ultrasound, a triphasic CT scan of the liver was conducted for further evaluation. Informed consent was obtained from all the participants before their involvement in the study.

Statistical analysis

 Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp) Qualitative data were described using numbers and percentages. The Shapiro-Wilk test was used to verify the normality of distribution Quantitative data were described using range (minimum and maximum), mean, standard deviation, median, and interquartile range (IQR). The significance of the obtained results was judged at the 5% level. The used tests were the Chi-square test, Monte Carlo correction, F-test (ANOVA),  Kruskal Wallis test, Receiver operating characteristic curve (ROC), Sensitivity,  Specificity, Positive Predictive value (PPV), and Negative Predictive value (NPV).

RESULTS

Patients with decompensated cirrhosis (Mean = 49.8 ng/L) and HCC (Mean = 97.3 ng/L) had significantly higher serum interleukin-22 levels than patients with compensated cirrhosis (Mean = 28 ng/L) and healthy controls (Mean = 9 ng/L; P<0.001), according to the study. Moreover, IL22 levels were significantly higher in HCC patients than in decompensated patients (P<0.05).

Additionally, IL-22 levels showed a significant positive correlation with tumor size in HCC patients (r = 0.481, P = 0.032), and with serum AFP levels in decompensated cirrhosis (r = 0.459, P = 0.042) and HCC patients (0.581, P = 0.007). Also, IL-22 levels were positively correlated with non-invasive fibrosis markers (APRI and FIB-4 scores) in all patient groups (P<0.05). Additionally, in patients with HCC, IL-22 levels in patients with Child Class C (Mean = 58.4 ng/L) were higher than in patients with Child Class B (Mean = 45.1 ng/L; P = 0.016).

Importantly, a serum IL-22 level of >34 ng/ml was identified as a potential cutoff value for discriminating between compensated and decompensated cirrhosis with high sensitivity (95%) and specificity (80%). Moreover, a cutoff value of >81 ng/L showed good diagnostic performance in differentiating between HCC patients from decompensated cirrhosis (AUC = 0.976, sensitivity = 95%, specificity = 95%). High levels of IL22 were a good predictor of HCC in decompensated cirrhosis according to Univariate logistic regression analysis.

 Table I Comparison between the four studied groups considering Serum Interleukin 22-level

 

 

Group I

(n = 20)

Group II

(n = 20)

Group III

(n = 20)

Group IV

(n = 20)

F

p

Serum Interleukin 22 level (ng/L)

 

 

 

 

 

 

Min. – Max.

33.0 – 94.0

19.0 – 39.0

81.0 – 121.0

6.0 – 90.0

110.980*

<0.001*

Mean ± SD.

49.75 ± 15.21

28.85 ± 6.39

97.30 ± 11.24

18.75 ± 21.90

Median (IQR)

46.50

(40.0 – 49.50)

28.0

(23.50 – 34.0)

96.0

(89.0 – 103.0)

9.0

(7.0 – 18.50)

p0

<0.001*

0.001*

<0.001*

 

 

 

Sig. bet. Groups.

p1<0.001*,p2<0.001*,p3=0.034*

 

 

 

Serum Interleukin 22 level Units (ng/L= nanogram per liter ),

n= number of patients,

IQR=Interquartile rang

SD =Standard deviation.

         DISCUSSION

Chronic liver disease (CLD), especially chronic hepatitis C virus (HCV) infection, frequently progresses to cirrhosis and hepatocellular carcinoma (HCC), constituting a substantial global health concern  [24, 25]. The progression from compensated to decompensated cirrhosis is a pivotal point characterized by the emergence of complications and elevated mortality risk  [26, 27]. Early detection and precise staging of these stages are important for effective intervention and enhanced patient outcomes. ((28) This study investigated the possibility of using the cytokine interleukin-22 (IL-22), which is involved in tissue healing and immunological regulation, as a biomarker to differentiate between various stages of liver disease in HCV-infected patients  [29,30,31].

The study population comprised 80 subjects, who were divided equally among four groups: cirrhosis with HCC, compensated cirrhosis, decompensated cirrhosis, and a healthy control group. The age and sex of the groups were matched.

The FIB-4 index and APRI score are non-invasive markers of hepatic fibrosis. In comparison to the compensated cirrhosis and control groups, the decompensated cirrhosis and HCC groups had considerably higher scores on both measures. According to a study by Patel et al. (2023), which assessed the performance of FIB-4 and APRI scores in monitoring severe fibrosis (≥F2) and significant cirrhosis (F4) in chronic HCV-infected patients. this observation is consistent with the anticipated progress of hepatic fibrosis in chronic HCV infection.  They confirmed the findings in our study by finding that individuals with advanced fibrosis and -cirrhosis had higher APRI and FIB-4 scores than patients with mild or no fibrosis  [32,33,34].

The primary finding of our study is that serum IL-22 levels were significantly higher in all patient groups than in the control group, with the HCC group showing the greatest elevation followed by the DC group. (Figure 1) This observation aligns with previous studies that have reported elevated IL-22 levels in HCC patients, indicating its strong involvement in HCC progression in people who have HCV-related cirrhosis, as the study by Jiang et al. (2016) which found that serum IL-22 levels were significantly higher in patients with HCC compared to cirrhotic patients and healthy controls  [35]. Similarly, a meta-analysis by Zhao et al. (2021) reported that patients with chronic liver disease who had higher IL-22 levels were more likely to develop HCC  [36].

Furthermore, we observed positive correlations between serum IL-22 levels and several key parameters. In the HCC group, IL-22 levels correlated positively with both tumor size and serum AFP levels. This finding aligns with previous research suggesting that IL-22 may enhance tumor growth and invasiveness in HCC, as in the study by Jiang et al. (2016) which revealed a positive relationship between serum IL-22 levels and tumor size in patients with HCC, suggesting that IL-22 may participate in tumor growth [35].  Another study by Kronenberger et al. (2012) demonstrated that patients with decompensated cirrhosis who had higher levels of IL-22 had worse outcomes, suggesting that IL-22 may be a prognostic marker [32]

The positive relationship found between serum IL-22 levels and tumor size in HCC patients further supports that IL-22 has a role in tumor growth. This finding aligns with previous research showing a relationship between IL-22 expression and HCC tumor size [36,37] . Additionally, the positive relationship between IL-22 and AFP,(figure 2) another well-established tumor marker, suggests that these two biomarkers may complement each other in diagnosis and monitoring HCC [38].

Interestingly, our study found the difference in IL-22 levels between Child-Pugh B and C patients in the decompensated cirrhosis (DC) group was not significant. This suggests that IL-22 may reflect the presence and the severity of liver disease, but it might not be able to distinguish between various decompensation stages within the DC group. However, future studies including larger sample sizes in each group are required to confirm this observation. On the other hand, in the HCC patients, we noted that levels of IL-22 were significantly higher in patients classified as Child-Pugh C compared with Child-Pugh B. This finding aligns with Kronenberger et al. (2012), which is a previous study that found that elevation of  IL-22 levels was related to increased mortality and hepatic complications in patients with advanced cirrhosis [32].

Patients with portal vein thrombosis (PVT) in the HCC group had higher IL-22 levels than those without PVT. This finding raises the possibility that IL-22 has a role in the development or progression of PVT, a major prognostic factor in HCC [39]. The effect of IL-22 on PVT development in a mouse with HCC was examined in a study by Maruyama et al. (2022). They discovered that IL-22 overexpression promoted PVT development, whereas IL-22 deficiency restricted its formation.  These results confirm that IL-22 is a viable therapeutic target for PVT prevention or treatment in HCC [40].

Our study investigated the use of serum IL-22 as a diagnostic marker for differentiating between different stages of HCV-related liver disease. ROC curve analysis revealed that IL-22 had an excellent discriminatory power in distinguishing between all study groups. (figure 3) These high AUC values suggest that IL-22 has a significant potential for accurate diagnosis as shown in previous studies [40, 41].

The diagnostic accuracy of IL-22 in differentiating between compensated and decompensated cirrhosis, as well as between HCC and decompensated cirrhosis was high. These findings imply that IL-22 could be an effective tool for monitoring disease progression, even in its early stages, as well as identifying patients at risk of developing HCC. The ability to differentiate between compensated and decompensated cirrhosis could also help in tailoring treatment strategies and predicting prognosis   [42, 43].

Univariate logistic regression analysis further supported the diagnostic potential of IL-22. Serum IL-22 levels have emerged as a strong marker of HCC in patients with decompensated cirrhosis. This data shows that IL-22 could be included in clinical algorithms for HCC surveillance and diagnosis [44].

CONCLUSION

The remarkably increased levels of IL22 in patients with HCC imply that it could be used as a potential for HCC development in patients having liver cirrhosis.

A significant positive correlation was found between IL22 and each tumor number and size could suggest its use as a biomarker of the aggressiveness of HCC.

Significant high IL22 in patients with decompensated cirrhosis could suggest its use as an important marker of the progression of the cirrhotic process.

The high diagnostic accuracy of IL22 could suggest its use as a promising marker of HCC.

The significant positive association between IL22 and Fib-4 and APRI scores suggests its role in the fibrotic process.

LIST OF ABBREVIATIONS

HCV; Hepatitis C virus

CLD; Chronic liver disease

HCC; Hepatocellular carcinoma

IL-22 ; Interleukin-22

IFNs ; Interferons

HSC: Hepatic stellate cells.

VEGF; vascular endothelial growth factor

 APRI Score; Aspartate Aminotransferase To Platelet Ratio Index Score.

AFP; Alpha Feto Protein.

DC; Decompensated Cirrhosis.

PVT; Portal Vein Thrombosis. 

Ethics approval and consent to participate:

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Institutional Review Board (IRB)” of Faculty of medicine Alexandria University and with the Helsinki Declaration of 1964 and later versions.. Consent was obtained from all patients. All patients included in this research gave written informed consent to publish the data contained within this study.

Funding: This study had no funding from any resource.

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests: The authors declare that they have no competing interests.

Authors’ contributions: AE Carried out the study design, selection of cases, and review of the research. AD performed the laboratory investigations. NH, Cases selection and follow-up of cases, sharing in writing the research. RAMA. Performed clinical assessment of the cases, wrote the research, and reviewed the results and statistics. "All authors read and approved the finalmanuscript”.

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