Etiology, Mechanism and Treatment of Liver Cancer

*Aqsa Nazir, Muhammad Aqib and Muhammad Usman*

### **Abstract**

Liver cancer or hepatocellular carcinoma (HCC) is a malignant tumor in liver tissue and worldwide it is fourth leading death cause among all cancers. The most common causes of liver cancer are hepatitis B or C virus infections, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), smoking and obesity. The development and metastasis of liver cancer is a multistage and branched process of morphological and genetic traits. Various corresponding signaling pathways such as Yes-Associated Protein-Hippo Pathway (YAP-HIPPO), Wnt/β-catenin and inflammation by interleukin-6 (IL-6), tumor necrosis factor (TNF), nuclear factor-Κb (NF-κB), biological pathways including epithelial–mesenchymal transition (EMT), tumor microenvironment, tumor-stromal interactions and cancer stem cells and gut microbial dysbiosis are allied to both origination, progression and metastasis of liver cancer. Numerous therapeutic approaches are classified into different categories such as pharmacological therapy including sorafenib, lenvatinib and ramuciruma, surgery of HCC patients includes surgical resection, adjuvant therapy after surgical resection and liver transplantation. Locoregional ablative therapy includes cryotherapy, ethanol injection and radiofrequency ablation, cytotoxic chemotherapy, natural compounds such as piperine, as curcumin and oleocanthal, oncolytic virus therapy, immunotherapies and nanotechnology.

**Keywords:** hepatocellular carcinoma (HCC), inflammation, disease progression, Dysbiosis, hepatitis B and C

### **1. Introduction**

Liver cancer is a malignant tumor which is commonly occurs in cirrhosis and chronic liver disease patients. Liver cancer comprises of different types, the most common type is hepatocellular carcinoma (HCC) or primary liver cancer and other rarely occurring types includes hepatoblastoma and intrahepatic cholangiocarcinoma depend upon their origin such as liver stem cells, hepatocytes, cholangiocytes, and hepatoblasts [1]. Worldwide, the fourth leading cause of all cancers related deaths is primary liver cancer or HCC and its prevalence is 75% of all types of liver cancers. Out of all types of cancer related patients, every fifth male and seventh in female is diagnosed with liver cancer. Moreover, World Health Organization (WHO) declared that if it is not properly treated then ultimately in 2030 more than one million individuals will die from this ailment [2].

The liver cancer is most prevalent in Middle and Western Africa and East and Southeast Asia countries, whereas lowest ratio was found in Northern and Eastern Europe and South-Central and Western Asia. The variation in prevalence of liver cancer in different regions is due to diverse exposure to hepatitis viruses and other environmental pathogens. As in developing countries, 60% infection is caused by hepatitis B virus (HBV) and 33% infection is caused by hepatitis C virus (HCV) of total liver cancer. Currently, in United States and Central Europe, liver cancer prevalence and mortality is also increased to an alarming situation as more than 750,000 new cases annually, because of high HCV by regular drug use and nonalcoholic fatty liver disease by obesity epidemic, or might be due to alcohol-related cirrhosis. In spite of the advancement, liver cancer is still one of the most challenging cancer to treat. The clinical output remains low and about one-third patients eligible to curative approaches of HCC such as local destructive therapies, surgery and liver transplantation. The surgical removal is possible in 5–15% of patients in early stages, without cirrhosis and due to reduced hepatic restoration capacity in later stages. Therefore, the survival rate can be increased by early diagnosis and application of curative approaches. In early HCC treatment the five-year survival rate is 47–53%, which is still not satisfactory. However, the chances of recurrence of HCC remain high even after curative treatment [3].

#### **2. Risk factors**

The most common etiological risk factors of liver cancer are hepatitis B or C virus infections, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and chronic alcohol consumption, although smoking, obesity, iron overload and diabetes are also associated with liver cancer [4]. Worldwide about 80% of HCC is allied to chronic infections of hepatitis B and C viruses, as hepatitis B virus is responsible more than the hepatitis C virus. About 10–25% HCC or cirrhosis deaths cause by hepatitis B viruses and it mainly affect in early age of life. The vaccine for hepatitis B marketed in 1982, have been targeted to newborns. In 2017, about 187 WHO member countries vaccinated the newborns and globally 84% population received three doses of hepatitis B vaccine. However, hepatitis C virus rarely affect children, and only 15–45% patients recovered from this and remaining people lead to chronic infection of liver. It is asymptomatic, and for many years, chronic infections not clinically evident [5].

Alcohol and smoking are major contributor to liver cancer. The USA studies showed that light-to-moderate alcohol consumption which is less than three drinks per day significantly reduced HCC risk [6]. The alcohol consumption is more in high societies as compared to low income regions, while smoking ratio is high in middle and low income regions as compared to high income countries. A report in 2014 found that cigarette smoking at that time was linked with a 70% high risk of liver cancer, while 40% in previous years [7]. Obesity cause low grade inflammation, leads to metabolic dysfunction, development of NAFLD to NASH, cirrhosis, fibrosis and in turn liver cancer. Research claimed that overweight and obesity cause 18% and 83% high risks of liver cancer and the HCC risk twice with the diabetes disease [5].

Some other risk factors of liver cancer are congenital abnormalities, toxic aflatoxin or arsenic contaminated food and autoimmune liver diseases. The congenital abnormalities include hemochromatosis, Wilson's disease, alpha-1-antitrypsin deficiency and hereditary tyrosinemia. However, the aflatoxins are released by the fungi such as

*Etiology, Mechanism and Treatment of Liver Cancer DOI: http://dx.doi.org/10.5772/intechopen.106020*

*Aspergillus parasiticus* and *Aspergillus flavus* in contaminated food. The autoimmune hepatitis is also a cause of liver cirrhosis and HCC but the chances of occurrence is far less than the hepatitis B and C viruses [8–10]. All these risk factors are cumulative and influence each other such as if a person is suffering with hepatitits B or C and consume alcohol then he will be at severe risk of the pathogenesis of HCC by the interplay of environmental, viral, diet and host factors. These factors develop chronic liver disease which may lead to liver cirrhosis by numerous mutagens for example oxidative stress, chemical exposure and deviation in the DNA repair leads to genome alteration which ultimately results in cancerous genome in which chronic inflammation, reactive oxygen and nitrogen species, and mutation are the main aspects of hepatocytes necrosis.
