HCC is resistant to radiotherapy and chemotherapy, and long-term survival of patients occurred only with small asymptomatic HCC [5]. Early detection of HCC is helpful as it improves the prognosis [6]. And, it allows using several modalities as resection, radiofrequency ablation, and transplantation. These modalities improve the outcome in these patients [7].
It is important to recognize HCV-infected patients who are at a higher risk of developing HCC [8]. The difference in the incidences of HCC among different populations may be explained by genetic background [9]. Besides, multiple susceptible genetic loci of HCC were also recognized and validated [10]. Thus, the study of genetics can be added to the tools of risk prediction, allowing better stratification and personalized assessment of optimal long-term management, thereby increasing the efficacy of surveillance programs [2].
The mechanism of development of HCC among chronic hepatitis C patients, including host- and viral-related factors, is still unknown. The differences in the prevalence and the strong gender distribution in HCC are due to differences in the exposure to the causative agents as well as genetic factors, particularly gene polymorphisms of inflammatory cytokines and growth factor ligands and receptors [11].
Vitamin D is not only involved in bone metabolism as a hormone but it also has immunomodulatory, anti-inflammatory, and antifibrotic properties. It also plays an important role in the regulation of cell proliferation, differentiation, and carcinogenesis via VDR [12]. VDR is a member of the nuclear receptor superfamily of ligand-inducible transcription factors, which are involved in many physiological processes, including, cell growth and differentiation, embryonic development, and metabolic homeostasis [13]. VDR performs heterodimerization with auxiliary proteins for effective DNA interaction as the retinoid-X receptors (RXRs). Vitamin D response elements have been recognized in many genes responsible for cellular growth, differentiation, apoptosis, invasion, and metastasis of tumor cells as cell cycle regulators. Therefore, it can be assumed that VDR-mediated signaling pathways and VDR gene polymorphisms are related to carcinogenesis. Furthermore, VDR gene variants can modulate vitamin D effect without affecting serum vitamin D levels [14].
VDR polymorphisms have been studied in chronic liver diseases [15]. Yao et al. (2013) and Hoan et al. (2019) found that VDR polymorphism was a risk predictor and a prognostic molecular marker of HCC in patients with chronic hepatitis B [3, 16].
Polymorphisms are defined as variations in DNA sequence which occur in at least 1% of a certain population and have real biological effects. They have been studied with the aim of explaining association with the risk for common diseases [17]. According to Shastry (2002) and Li et al. (2001), humans have a huge number of polymorphisms that lead to different cellular effects due to different mechanisms such as transcription level modification, posttranscriptional, or posttranslational activity or changes in the tertiary structure of the gene product [17, 18]. Bai et al. (2012) stated that several SNPs have been described in the VDR gene, and some polymorphisms are associated with tumor occurrence in the breast, prostate, skin, colon-rectum, bladder, and kidney [19]. The most common allelic variants studied included a start codon polymorphism Fok1 (T/C) in exon II, Bsm1 (A/G), and APa1 (C/A) polymorphisms in the intron between exon VII and IX and a Taq1 (T/C) variant in exon IX [20]. The Apa-I is a silent SNP. No replacement of the amino acid occurs in the protein. However, it affects mRNA stability [21].
In this study, there was no statistically significant difference between the three studied groups regarding sex distribution. There was a significant difference between HCC and control regarding age but not significantly higher than chronic hepatitis patients. These results were similar to those found by Barooah et al. (2019) [22]. In contrary to our results, Yang and Roberts (2010) reported that the risk of HCC is 2–7 times higher in men than in women, although this ratio varies across the world. Their explanation for this might be due to higher rates of environmental exposure to liver carcinogens (such as smoking or alcohol) and hepatitis virus infections. Also, estrogen might suppress interleukin IL-6 mediated inflammation in women, reducing both liver injury and compensatory proliferation. Moreover, testosterone effects could increase androgen receptor signaling in men, promoting liver cell proliferation [23]. Hammad et al. (2013) reported that HCC is significantly higher in men than women (77.7 and 22.3%, respectively) [24].
In our study, there were significant differences between the three groups regarding direct bilirubin, total bilirubin, serum ALT, serum AST, serum albumin, serum ALP, serum AFP, serum creatinine, serum urea, platelets, INR, and PT. But, there were no significant differences between the three studied groups regarding hemoglobin and BMI. No significant difference was found between HCC and chronic hepatitis groups regarding studied parameters except AFP. Moreover, a significant difference between control and chronic hepatitis groups regarding all parameters except AFP, serum creatinine, and urea.
Similar results were found by Barooah et al. (2019) and Raafat Rowida et al. (2020). They reported that serum levels of ALT, AST, and bilirubin were higher among patients of HCC than those of chronic liver disease [22, 25]. Also, Bruix and Sherman (2011) showed that the serum level of ALT and AST were elevated in HCC especially the advanced cases, and the difference becomes greater as the disease progresses [26]. On the other hand, AFP levels may be normal in up to 40% of patients with HCC, particularly during the early stages (low sensitivity). Elevated AFP levels may be seen in patients with cirrhosis or exacerbations of chronic hepatitis (low specificity) [27].
Our study revealed that patients with HCC had a higher frequency of Apa-I CC genotype compared to those with chronic hepatitis C or control. These results are similar to those found by Barooah et al. (2019), Raafat Rowida et al. (2020), and Hung et al. (2014) [22, 25, 28]. Hung et al. (2014) revealed that patients carrying the corresponding APa-1 CC genotype had a higher prevalence of HCC than those with CA or AA type. They revealed that age, male gender, lower platelet count (< 15 × 104/μL), and Apa-1 CC genotype were independent predictors for developing HCC [28]. Barooah et al. (2019) found that the frequency of the Apa-I CC genotype and ApaI C allele of the VDR gene was significantly higher in HCC and cirrhotic patients than controls. After adjusting for other covariates (age, gender, platelet count, AST, ALT, serum albumin, and viral load), logistic regression analysis showed that the Apa-I CC genotype was independent predictor of HCC development [22]. Baur et al. showed that Apa1 CC genotype was associated with a rapid fibrosis progression in cirrhotic HCV patients [29].
Our study showed a significant relation between Apa-1 VDR genotypes and AFP levels. This result was similar to that found by Raafat Rowida et al. (2020). Similar to our findings, they found that AFP was highest in those with the CC variant and platelet count was low in both CC and CA groups. However, in our study, platelet count did not reach a significant level as detected by them. They also found that Child-Pugh class C was more frequent in the CC group [25].
