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Noteworthy, a detailed understanding of the risk factors is also critical to improve the screening, early detection, prevention, and management of HCC. Hepatocellular Carcinoma HCC is a serious public health issue and the fourth leading cause of cancer mortality worldwide 12.

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Further, the oxidative stress promotes tumorigenesis by activation of c-Jun amino-terminal kinase 1 JNK1a mitogen-activated protein kinase, and by suppressing the action of p53 tumor suppressor gene and nuclear respiratory factor 1 Nrf1 As the name suggests, AFLD is attributed to excessive alcohol consumption that causes hepatic injury by the build-up of fats, inflammation, and scarring leading to HCC, which could be fatal The threshold level of alcohol intake causing hepatotoxic effect varies and it depends on a variety of factors such as gender, ethnicity, and genetics A large population-based prospective study conducted by Becker et al.

In the modern era with a sedentary lifestyle and unhealthy dietary habits, obesity is rapidly increasing and has been established as a risk factor for HCC It is been reported to increase the risk by 1. The widely implemented curative approach is lifestyle alteration involving modifications in dietary habits and improving physical activity in case of NAFLD and alcohol abstinence in AFLD. NAFLD and AFLD share common molecular mechanisms in promoting HCC development, which involves vicious interplay between various pathways including immunological pathways, endocrine pathways, and metabolic pathways.

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Clin Liver Dis — Epidemiological and etiological variations in hepatocellular carcinoma. According to GlobocanHCC is the fifth most common cancer in men and the ninth most commonly occurring cancer in women The overall ratio of mortality to incidence is 0. Hepatic lipid accumulation as a result of high-calorie intake high carbohydrate and high dietary fat and low physical activity in the absence of excessive alcohol consumption is a major contributor to the onset of NAFLD development These modifications in association with genetic factors and epigenetic changes activate oncogenic aling and promote HCC development This is also accompanied by decreased amounts of adiponectin Insulin resistance along with hyperinsulinemia up-regulates insulin and insulin-like growth factor IGF-1a growth stimulator aiding hepatocyte proliferation and apoptosis inhibition 85 Furthermore, hepatic lipotoxicity due to insulin resistance le to imbalanced energy metabolism.

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Villanueva A. Hepatocellular Carcinoma. Cancer today Google Scholar. In recent years evidence highlights the association of metabolic syndrome diabetes and obesityexcessive alcohol consumption alcoholic fatty liver diseaseand high-calorie intake nonalcoholic fatty liver disease to be the prime causes for HCC in countries with a westernized sedentary lifestyle.

Furthermore, a high-calorie diet and ethanol act synergistically at multiple levels potentiating hepatocarcinogenesis Figure 2 Molecular mechanisms involved in nonalcoholic- and alcoholic-associated HCC. NAFLD is characterized by excessive hepatic lipid accumulation steatosiswhich further transitions to steatohepatitis upon the inflammatory insult, to cirrhosis and HCC 54 NAFLD is classically associated with metabolic disorders such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes 57 A meta-analysis by Younossi et al.

As per the global status report on alcohol and health,there are 2. In addition to hepatitis viruses, chemical carcinogens also play important roles in the etiology of HCC Exposure to carcinogens including aflatoxins, tobacco smoking, vinyl chloride, arsenic, and various other chemicals act either independently or in combination with viruses to cause DNA damage, induce liver cirrhosis, and contribute to HCC Aflatoxin is a potent liver carcinogen produced by the Aspergillus fungus, which is found to contaminate foodstuffs such as peanuts, corn, soya beans stored in damp conditions.

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The development of HCC is initiated by hepatic injury involving inflammation leading to necrosis of hepatocytes and regeneration. Chronic liver inflammation and injury contribute ificantly to the development and progression of HCC.

Several factors such as gender, age, ethnicity, and demographic regions increase the HCC incidence rates and the major risk factors are chronic infection with hepatitis B virus HBV or hepatitis C virus HCVcarcinogens food contaminants, tobacco smoking, and environmental toxinsand inherited diseases.

Conclusively, it is important to develop diagnostic tests for the detection of early stages of HCC. DS and DPK devised and wrote the manuscript.

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AS and DPK made the figures. In America, Europe, and Western Pacific more than half of the population for active alcoholics.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. HCC predominantly affects men more than women two to four times higher in men with its highest incidence in the age group of 45—65 years 89. JGH Open — Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability.

Hepatocellular Carcinoma HCC is a highly aggressive cancer with mortality running parallel to its incidence and has limited therapeutic options. There is a striking variation in HCC incidence rates across geographic regions and at the global level, each year overpeople are diagnosed with liver cancer 45. The possible mechanisms include lower gastric alcohol dehydrogenase ADH activity in females and estrogen levels that activate Kupffer cells due to increased gut permeability and portal endotoxin levels leading to alcohol-induced liver injury 96 Furthermore, studies have demonstrated that in the United States, compared to Whites, Blacks, and Hispanics drinkers have a two-fold increase in liver enzymes Since there is no ificant difference among other ethnic groups, factors such as polymorphism of genes associated with alcohol metabolism ADHCYP2E1 and antioxidant enzymes and genes coding for cytokines are also investigated in association with alcoholic liver disease However, it remains critical to consider factors such as amount and type of alcohol consumption and socioeconomic status with the development of AFLD.

N Engl J Med — Gut Liver — Int J Cancer — Assessment of risk factors, and racial and ethnic differences in hepatocellular carcinoma.

However, there still exists a gap in the knowledge in understanding the molecular mechanisms of inflammation, genetic and epigenetic regulations, and genomic instability leading to hepatocarcinogenesis. Indeed, experimental studies by Paola et al.

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Studies from long term follow up of non-alcoholic fatty liver patients have shown the prevalence of HCC to be 0. HCC is an extremely complex condition and there are multiple factors involved in the etiology of HCC. Additional risk factors that are also known to increase the incidence of HCC are tobacco smoking, food contaminants such as aflatoxins, familial or genetic factors, and various environmental toxins that act as carcinogens 12 — 14 Figure 1.

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Further personalized treatment strategies could improve healthcare and quality of patient care, thereby reducing the mortality rate. Alternatively, strategies like pharmacological treatment and bariatric surgery are also considered in patients unresponsive to lifestyle changes.

It is widely believed that there exist possible interactions between different etiological agents leading to the involvement of diverse mechanisms in the pathogenesis of HCC. Understanding the molecular mechanisms of HCC development and progression is imperative in developing effective targeted therapies to combat this deadly disease. It is also reported that liver cancer It is noteworthy that there is a synergy between excessive alcohol consumption with other risk factors including diabetes mellitus and viral hepatitis Acetaldehyde, an oxidation product of ethanol is a potent carcinogen driving the tumorigenesis by the formation of DNA adducts Although the major pathway of metabolizing ethanol involves CYP2E1 in microsomes, acetaldehyde, and reactive oxygen species ROS are formed nevertheless However, the chat of inflammatory cells is found to be higher in AFLD HCC is a highly fatal cancer driven by multiple etiological factors, among which, fatty liver disease is emerging as a major cause worldwide.

However, with the improved treatment for HCC, the demographic landscape has changed 6 In this mini-review, we aim to describe the traditional text factors in sex and highlight on fatty liver disease, which is the emerging etiological risk factor contributing to the increasing incidences of HCC. Figure 1 The etiology natini hepatocellular carcinoma. This chronic liver disease sequentially transitions to fibrosis, cirrhosis, and hepatocellular carcinoma 15 HCC that often occurs in the setting of free liver disease and cirrhosis is diagnosed late in its course and liver transplantation is the best option for patients at this stage 12 Multiple treatment options are available to treat HCC including surgical resection, local ablation with radiofrequency, transcatheter arterial chemoembolization TACEradioembolization, and systemic targeted agents like sorafenib depending on the tumor extent or underlying liver dysfunction 1214 Furthermore, the viable treatment options offered to the patients also depend on the causative agent of HCC as they define the disease course and patient characteristics.

This mycotoxin induces mutation in the p53 tumor suppressor gene and causes uninhibited growth of liver cells leading to the development of HCC 36 It is reported that the chemicals in tobacco smoke 4-aminobiphenyl and polycyclic aromatic hydrocarbonsareca nut nitrosaminesand betel leaves safrole cause hepatotoxicity 13 Besides, studies have demonstrated that the human exposure to groundwater contaminants chemicals such as cadmium, lead, nickel, arsenicorganic solvents toluene, dioxin, xyleneand chemicals such as vinyl chloride and dichlorodiphenyltrichloroethane DDT have shown to increase the risk of HCC as they exert hepatocarcinogenic effect via induction of oxidative stress and telomere shortening 34 These hereditary diseases are known to promote hepatocarcinogenesis as a result of increased inflammation and hepatocellular damage 39 — Meta-analyses have shown that diabetes is associated with HCC independent of viral hepatitis in which diabetic patients show fold greater risks in developing HCC compared natini non-diabetic controls The pathophysiological conditions free as chat, hyperinsulinemia, insulin resistance, and activation of insulin-like growth factor aling pathways provide a strong association for diabetes to be the risk factor in the pathogenesis of HCC 5 Obesity, a pathological state characterized by insulin resistance, hyperinsulinemia, and inflammation is also closely associated text HCC It is demonstrated that increased reactive oxygen species, dysregulated adipokines, and adipose tissue remodeling, alteration of gut microbiota, and dysregulated microRNA increases the relative risk of HCC in obese patients 46 — Over the last decade, fatty liver disease is emerging as the leading etiologies for chronic liver disease progressing to HCC The changing scenario is attributed to improved antiviral therapy for virus-related HCC With the growing inclination towards western dietary pattern, sociocultural changes and the lifestyle with limited or no physical activity has sharply increased the incidence rates of NAFLD- and AFLD-associated HCC across the continents 51 The pathological spectra of liver injury in promoting HCC development are similar in these two fatty liver diseases despite sex divergent pathogenic origin with yet some key distinct features Figure 2.

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Along the same line, a study by Turati et al. All authors contributed to the article and approved the submitted version. The mechanisms by which these etiological factors may induce hepatocarcinogenesis mainly include p53 inactivation, inflammation, oxidative stress, and telomere shortening leading to genomic instability and activation of multiple oncogenic aling pathways. Indeed, a comprehensive understanding of these diseases would aid in the identification of biomarkers and therapeutic targets leading to early detection and management. Based on the pathogenic origin, NAFLD has been strongly associated with glucose and lipid metabolism, whereas AFLD has been associated with a strong inflammatory response.

Though the percentage of drinkers has decreased in Africa and America, there is an increase observed in the Western Pacific region and has remained stable in the regions of Southeast Asia According to the global health report on alcohol and health, by World Health Organization WHOthe alcohol-attributable deaths AAD from liver cirrhosis varies across the countries. Furthermore, large population-based cohort studies have found that diabetes mellitus is associated with 1.

A variety of risk factors have been associated with the development of HCC, including hepatitis viruses, carcinogens, heredity diseases, metabolic syndrome, and fatty liver disease. The incorporation of the genetic material of this virus into the human genome causes p53 inactivation, inflammation, or oxidative stress, which causes hepatocarcinogenesis 24 HCV-induced hepatocarcinogenesis is highly complex involving the activation of multiple cellular pathways and gets initiated by the establishment of HCV infection leading to chronic hepatic inflammation, which further progresses to liver cirrhosis and HCC development HCV proteins either directly or indirectly modulate a wide range of host cellular activities, including transcriptional regulation, cytokine modulation, hepatocyte growth regulation, and lipid metabolism that lead to chronic liver injury.