HCC represents about 90% or more of primary liver tumours that usually develops in a background of advanced liver disease . Approximately, 10–20% of chronically infected patients with HCV will develop liver cirrhosis, and 1–5% of those patients will develop HCC . The continued cytokines induced hepatocyte damage, and hepatocyte regeneration leads to HCC development. The role of cytokines as IL-1, IL-2, IL-6, IL-10, IL-12 and TNF-α in hepatocarcinogenesis has been reported. The management of patients with HCC represents a challenge as it is often complicated by the heterogenic pattern of the disease, the state of underlying liver disorders and the need to coordinate a multidisciplinary healthcare team .
In our study, the mean age of the HCC group was 56.21 ± 4.62 years and 54.27 ± 7.63 years for the cirrhotic group. There was no difference in sex distribution between the two groups (Table 2). In the HCC group, 31 (42.5%) patients had diabetes and19 (26.0%) hypertensive in comparison to 27 (31.8%) and 23 (27.1%) in the cirrhotic group, respectively. This runs parallel to many other studies that concluded that advanced age, male gender and DM are well-known risk factors for HCC . Cirrhosis, due to HCV, was found in almost all our patients. This seems logical and in agreement with Seyda et al. who clarified that most of HCC cases develop in a background of cirrhosis . There was no difference in the sociodemographic and clinicolaboratory parameters between the two groups except for serum albumin, platelets, AST and AFP with P= 0.003, 0.001, 0.001 and < 0.001, respectively. This seems logical as platelet count, AST and serum albumin reflect the severity of the liver disease. It also suggests that the two groups are matched which is extremely important in the inclusion of our patients to avoid the effect of any factor such as age, sex or comorbidities on risk of HCC development, so the increased incidence of HCC is directly related to the effect of gene polymorphism.
In the present study, on genotype testing, as regards TNF-ɑ, 35 (47.9%) of patients were GG, 22 (30.1%) were GA and 16 (21.9%) were AA in the HCC group. In the cirrhotic group, 27 (31.8%) of patients were GG, 25 (29.4%) were GA and 33 (38.8%) were AA. As regards IL-10, 35 (47.9%) of patients were TT, 21 (28.8%) were CT and 23 (31.5%) were CC in the HCC group. In the cirrhotic group, 16 (18.8%) of patients were TT, 29 (34.1%) were CT and 40 (47.1%) were CC. From these data, it appears that the GG genotype of TNF-ɑ and TT genotype of IL-10 showed a higher incidence of HCC in comparison to the cirrhotic group with P = 0.01 and 0.004 (Table 3 and Fig. 1). This goes hand in hand with Aroucha et al. who found that the TT/AT haplotypes of IL-10 and GG haplotype of TNF-ɑ were significantly expressed in patients with HCC . Wei et al. and Cheng et al. agreed [13, 14] also with us but not with Zhou et al. who showed that no association was found between HCC and the TNF-α-238 G/A polymorphism . This contrast may be related to the aetiology of the underlying liver disease, ethnicity or number of included patients.
In 2012, Swiatek found that gene polymorphisms may affect the IL-10 level; he showed that IL-10 -819T was associated with significant low IL-10 expression since it is located in transcript factor binding regions . Aroucha et al. observed an increased frequency of IL-10 -819T genotype in patients with HCC . Moreover, they found a significant association between the TT genotype of IL-10 -819 and multiplicity of lesions and terminal stages of HCC.
As regards TNF-ɑ, the results are conflicting. Talaat et al. and Radwan et al. did not find any significant association between HCC and TNF-ɑ -308 polymorphism in HCV-infected Egyptian patients [17, 18]. On the other hand, Baghel et al. and Karimi et al. demonstrated that patients with TNF-ɑ G allele usually show low TNF-ɑ production in vivo and in vitro [19, 20] despite, Vikram et al. failed to confirm this association . It seems that the balance between IL-10 and TNF-ɑ is crucial for the prevention of development of HCC and that low levels lead to progressive damage to the liver tissue and prevention of wound healing.
Similarly, previous studies found elevated levels of circulating TNF-α in patients with HCC. It is reasonable to speculate that in patients with HCC, the high circulating TNF-α levels found may be attributed to its SNPs. Also, TNF-α may stimulate the release of other inflammatory cytokines and induce the release of other fibrogenic factors, such as interleukin-1, interleukin-6 and tumour growth factor-β which can cause or aggravate liver damage [22, 23].
Previously, immunomodulatory cytokines have been described as pre-malignant mediators in different tumour entities in different studies . In HCC, IL-6 promotes multiple stages of tumour development, including initial hepatocyte proliferation, the transformation of hepatocytes into HCC progenitor cells, and progression to HCC nodules and metastases .
It seems that the balance between TNF-ɑ and IL-10 is mandatory to the development of HCC, since the shift to Th1 pattern-like cytokines in the liver may lead to more inflammation, necrosis of hepatocytes and subsequent regeneration that leads to mutagenesis and activation of protooncogene in the host cells, leading to the development of HCC .
A fine tune of the IL-10 and TNF-ɑ balance may exist, and it looks that this balance is controlled by the level of IL-10, where low levels lead to progressive damage to liver tissue and prevention of wound healing. Also, IL-10 can diminish the response to antiviral treatment .
Our data showed that the TT haplotype of IL-10 was significantly associated with more aggressive tumours in contrast to the other haplotypes with P < 0.001. The portal was found to be thrombosed significantly in the TT haplotype in contrast to the other haplotypes with P < 0.001; they were also associated with the multiplicity of lesions. Similarly, a significant association of portal vein thrombosis, ascites and high AgI with the GG haplotype in contrast to the other haplotypes with P = 0.002, 0.029 and < 0.001, respectively. These data are available in the absence of a statistically significant difference between AgI and sociodemographic and clinicolaboratory characteristics except for AFP and genotype distribution. This suggests that the aggressive pattern of the tumour noticed in these haplotypes is related to the direct effect of gene polymorphism. Aroucha et al. agree with us as they observed a significant correlation of advanced stages and multiple lesions of HCC with the TT (AA) genotype of IL-10 -819 (-592) . However, studies covering this sector are relatively rare.
Our study may be limited by some factors such as the limited number of cases in the study, the lack of data about overall survival of patients and lastly we included only patients with HCV-related cirrhosis which may affect hepatocarcinogenesis.
To summarize, specific genotypes of TNF-ɑ and IL-10 may affect the progression of hepatocarcinogenesis in patients with HCV-related liver cirrhosis.