INTRODUCTION
In 2020, primary liver malignancy was the third most common cause of cancer related death among men and women worldwide and 75%–85% of those deaths were attributed to HCC. Over the past few decades, the incidence rates of HCC have steadily increased in many countries, whereas the overall 5—year survival rate is less than 20%. It has been estimated that the incidence of HCC will surpass one million people annually by the year 2025. At diagnosis, HCC is frequently associated with a poor prognosis due to detection of advanced stage tumors. This is partly due to the lack of timely diagnostic biomarkers, obvious symptomology in earlier stages, and a low frequency of radical resectable HCC at the time of diagnosis. Clinical studies have reported a significant difference in the progression of HCC based on ethnicity. Regardless of etiology, approximately 90% of HCC cases occur in the setting of chronic liver inflammation. Prior to the development of HCC, a sustained inflammatory response leads to the concurrent remodeling and regeneration of hepatocytes, which causes fibrotic deposition that eventually progresses to cirrhosis. Globally, chronic liver damage caused by infection with hepatitis B (HBV) or C virus (HCV) accounts for the majority of HCC cases. The likelihood of HCC increases with chronic alcohol ingestion, consumption of aflatoxin, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hemochromatosis, and alpha-1-antitrypsin deficiency. Comorbid conditions, such as diabetes mellitus, obesity, and metabolic syndrome, also facilitate the progression of HCC. Notably, the prevalence of diabetes and obesity was significantly higher in patients with HCC, compared to patients diagnosed with viral and alcohol cirrhosis.
Differences in ethnicity and geography have been shown to significantly affect all-cause mortality and increase the risk of HCC. The majority of HCC cases and the lowest survival rates after treatment primarily occur in Asia and Sub-Saharan Africa, predominately due to HBV infection, whereas HCV infections are the most common cause in the United States. Figure illustrates the global prevalence of HCC. HCC disproportionately affects disadvantaged minorities, leading to disparities in the initial detection, stage at diagnosis, and overall mortality rate. A National Health and Nutrition Examination Survey reported that in the United States, individuals of African-American descent living in southern states are more likely than other ethnicities to be diagnosed with chronic HCC. Asians have the highest overall incidence of HCC, followed by African-Americans, Hispanics, and non-Hispanic Caucasians. HBV may be further classified into its 10 known genomes (A–J) and emerging research indicates that certain HBV genotypes play a role in determining clinical outcomes. Native Alaskans have higher rates of HCC when infected with HBV genotypes A, C and F, compared to patients with genotype B or D. Disparities in the incidence of HCC are also significantly correlated with an individual's age, sex, socioeconomic status, and place of residence. Individuals of African descent have a significantly higher mortality rate from HCC compared to other ethnic groups. Mathur et al. reported that the mortality rate in these individuals are 12%, 10%–12% and 16% greater than Caucasians, Hispanics, and Asians, respectively. There are significant differences in disease burden, treatment, and outcomes of HCC, based on ethnicity and gender. Consequently, early detection, high-quality prevention, and evidence-based treatment will be necessary to significantly decrease these HCC disparities.
[IMAGE OMITTED. SEE PDF]
This review aims to discuss the epidemiology of ethnic and geographical disparities in patients who have been diagnosed with HCC, the gene–environment parameters, along with the types of treatments that have been shown to affect survival rates among these patients.
EPIDEMIOLOGY OF
The majority of hepatocellular carcinoma (HCC) cases are due to chronic HBV and HCV infection. Host variations in age, genetics, gender, as well as environmental factors, affect the ethnic-specific HCC rates in different geographical regions. These are likely due to differences in the severity and infectious capacity of HBV and HCV. (Figure ).
[IMAGE OMITTED. SEE PDF]
Hepatitis
HBV is a DNA virus transmitted by exposure to infectious blood or bodily fluids which includes vertical transmission. Globally, HBV is the leading causative factor of HCC. Yearly, there are approximately 60 000 new cases of HBV in the United States, with approximately 75% of the 350–400 million worldwide population with chronic HBV being of Asian descent. A productive HBV infection leads to HCC development through direct and indirect mechanisms. HBV infection can induce inflammation which causes continuous necrosis of infected hepatocytes or uncontrollably stimulate the proliferation of adult hepatocytes. HBV primarily affects the functionality of healthy hepatocytes by promoting replication which leads to liver damage, fibrosis, and cirrhosis in conjunction with the host immune response. A whole genome sequencing study in HBV-associated HCC patients was conducted to identify any genetically altered pathways that could be correlated with HCC progression. There was a significant correlation between the expression of SYT12, GATM and FN1 in patients with early onset HBV-related HCC, whereas there was a significant correlation in the expression of STAT1, ALB, MLL4 and TERT in patients with late onset HCC. Additionally, HBV induces HCC formation through the activation or deactivation of various tumorigenic pathways. In the normal liver, β-catenin is a membrane localized protein which can be activated via HBV on hepatocytes. There is potential that activation of this pathway may be involved in the somatic genetic and nongenomic events in HCC. Activation of β-catenin signaling is considered an early event in HCC pathogenesis. Prominent signaling can lead to the overexpression of β-catenin which results in the proliferation of cancer stem cells in HCC. Mutations within the gene coding for ß-catenin (CTNNB1) was observed in 20%–35% of primary HCC patients. HBV can damage DNA and create mutations within cancer promoting genes such as TP53. Oncogenic activation of certain genes can ultimately lead to tumor progression. One study's results indicated that among 81 patients, the most frequently mutated oncogene was beta-catenin (15.9%) and the most frequently mutated tumor suppressor gene was TP53 (35.2%). The two major oncogenic mutations linked to the progression of HCC were the Wingless-related integration site (Wnt)/beta-catenin and JAK/STAT pathways, which were altered in 62.5% and 45.5% of patients, respectively. The risk of HCC development is significantly increased in patients with higher rates of HBV replication. The incidence of HCC and mortality rates significantly increase when a country's prevalence of HBV is greater than 2%. The annual risk of HCC is 0.5% for patients that are asymptomatic but express the protein hepatitis B serum antigen (HBsAg) and 0.8% for patients with chronic HBV. Chronic HBV carriers have a 10%–25% risk of developing HCC with 80%–90% of HBV-related HCC cases occurring in patients with cirrhosis. Notably, HBV-induced cirrhosis produces a 100-fold greater risk of developing HCC, compared to HBV infected patients without cirrhosis.
Hepatitis
HCV infection is another risk factor that increases the likelihood of HCC. The estimated global prevalence of HCV is approximately 2.5%, with the highest prevalence in Central Asia and Central Africa. Globally, it has been estimated that approximately 170 million people are infected with HCV, and this varies among geographical regions. From 1990 to 2005, there was a decrease in the incidence of HCV infected patients in certain higher-income areas, such as Western Europe, Southern Africa, and Australia; however, there was a significant increase in the incidence of HCC in lower-income areas, such as Central Africa and Central Asia. Egypt has one of the highest rates of HCC in the world, which was primarily due to the parenteral treatment of schistosomiasis from 1950 to 1980. The reuse of needles that were inadequately sterilized during this time increased the transmission of blood-borne pathogens, including HCV. Long-standing HCV may progress to liver fibrosis and cirrhosis, which increases the risk of HCC. Approximately 15% – 40% of patients spontaneously clear HCV, with 50% – 80% developing a chronic infection, 20% – 30% developing cirrhosis or liver failure, and 2% – 5% developing HCV-induced HCC. HCV is a major etiological factor for HCC, and studies indicated that at least 70% of patients with HCC have serum anti-HCV antibodies. Patients that are infected with HBV and HCV have a significantly higher risk of developing HCC compared to than those infected with HBV or HCV alone. The proteins that have oncogenic potential in HCC are the core, nonstructural 3 (NS3), nonstructural 5A (NS5A) and nonstructural 5B (NS5B). Clinical studies have shown that the levels of these proteins are positively correlated with an increased risk of HCC. It has been hypothesized that HCV increases the risk of HCC by producing mutations that create chronic inflammation, by increasing the levels of certain pro-inflammatory cytokines, cell-cycle dysregulation, and inhibition of the transcription of tumor-suppressor genes. HCV infection causes hepatocarcinogenesis by inducing the progressive accumulation of genetic mutations, which promotes malignant transformation, and by increasing hepatocyte turnover through chronic liver damage, which creates inflammatory and oxidative stress. HCV infection induces inflammation within the liver, causing the accumulation of lymphocytes, an increase in the levels of reactive oxygen species (ROS), and certain cytokines. The chronic inflammation produced by HCV can produce fibrinogenesis and hepatic stellate cell activation, angiogenesis, DNA damage and mutations due to dysfunctional apoptosis, thereby increasing the risk of HCC.
Aflatoxin
Aflatoxins are naturally occurring carcinogens produced by Aspergillus flavus and parasiticus that can contaminate food supplies of human and animals such as maize, wheat, and peanuts. The consumption of aflatoxins can cause hepatotoxicity and immunotoxicity and the most potent of these compounds is aflatoxin B1 (AFB1). Aflatoxin is recognized as a “Group A” because it can produce a significantly increase in the occurence of HCC. Aflatoxin consumption primarily occurs in countries that have warm and humid environments and thus exposure to AFB1 is most common in Southeast Asia, South America, and Sub-Saharan Africa. A meta-analysis estimated that AFB1 alone increases the risk of HCC by 6-fold and exposure to AFB1 and HBV synergistically increases the risk of HCC by 54-fold. In China, the replacement of maize with rice as a dietary staple decreased the incidence of HCC. One study suggested that mutations of p53 contribute to the development of HCC approximately half of the time. AFB1 produces the mutation of G to T at codon 249 of the p53 gene, which leads to serine being replaced by arginine. This mutation ultimately decreases the anti-tumor efficacy of the p53 gene, which increases the development of HCC.
Genetic susceptibility
Ethnic and geographical disparities in the incidence of HCC are correlated with genetic factors that produce differences in the severity of HCC. These genes can be separated into four different categories, depending on their function within the cell. The genes implicated in the pathogenesis of HCC include the regulation or modulation of: (1) DNA damage response (p53); (2) growth inhibition and apoptosis mannose 6-phosphate (M6P), Mother against decapentalpegic homolog 2 (SMAD2); (3) cell cycle control (Retinoblastoma transcriptional corepressor 1 (RB)1, cyclinD) and (4) cell–cell interactions (Adenomatous polyposis coli (APC; also known as deleted in polyposis 2.5) and E-cadherin). Alterations in these genes are typically due to single nucleotide and copy number polymorphisms, which increase the susceptibility of developing and progressing to HCC. Aberrant activation of telomerase by mutations secondary to chromosome translocations or gene amplification, are the most common genetic alterations that cause HCC. Hereditary diseases, such as hemochromatosis (HFE), tyrosinemia (FAH), alpha-1-antitrypsin deficiency, porphyrias (HMBS, UROD), glycogen storage diseases, and Wilson's disease increase the probability of developing HCC. Furthermore, mutations in the p36.22 region of chromosome 1, which contains genes that code for certain tumor suppression proteins, can increase the risk of HCC (Table ). Patients with HCC have numerous gene mutations. TP53 and CTNNB1 are the most commonly mutated genes (by 29.1% and 28.6% of total cases, respectively). Aflatoxin and vinyl chloride cause epoxidation, which is responsible for the TP53 mutation. By introducing vinyl chloride, A: T is inverted to T: A. Subsequent responsible mutation present in HCC were AX1N1 (7.5%), ARID2 (8.2%), ALB (10.2%), APOB (9.8%), and ARID1A (8.8%). The ARID2 and ARID1A leads to remodeling of regulatory mechanisms which also occur in other cancers such as ovarian, lung and pancreatic cancer. The mutation predisposes to chronic liver disease primarily due to iron overload, copper overload, and metabolic disturbances. A mutation in HNF1A may develop into benign tumors with the potential to convert to malignancies.
TABLE 1 Genetic mutation associated with HCC.
| Gene mutation | Remarks | Reference |
| TP53 (tumor protein 53) or p53 | Mutation increases the number of chromosomal rearrangements. | |
| IRF2 (interferon regulatory factor 2) | The inactivation, deletion, splicing, or missense mutations within this gene increase the risk of HCC. IRF2 mutations produces hyperploidy and increases chromosomal instability. There is an increase in chromosomal proliferation, but over expression results in apoptotic cell death. |
|
| ARID2 (AT-rich interactive domain) | ARID2 is a component of the PBAF complex. Mutations within this gene have been correlated an increase in the risk of HCC. | |
| PNPLA3 (patting-like phospholipase domain containing protein 3) | Mutations that decrease the activity of this enzyme causes macrovesicular steatosis and VLDL retention which increases the risk of developing HCC. | |
| NFE2L2 (Nuclear factor erythroid 2-related factor 2) | NFE2L2 codes for the protein NRF2, a transcriptional factor required to maintain the redox balance within the cell. This gene is mutated in 6.4% of HCC cases. | |
| KEAP1 (Kelch-like ECH associated protein 1) | Certain mutations in NFE2L2 inhibit KEAP1—mediated degradation of ubiquitin-proteasome, which impairs the oxidative stress response increasing the risk of HCC. | |
| PIK3CA (phosphatidylinositol-4,5-biophosphate 3-kinase catalytic subunit alpha) and TP53 | Mutations in both genes occur primarily in patients infected with HBV, which produces an increase in the viral load of HBV and severity of HCC. | |
| CDH8 (chromodomain helicase DNA binding protein 8) and PROKR2 (prokineticin receptor 2) | The CDH8 and PROKR2 genes mutated in 2.4% and 1.6% of HCC patients, respectively. | |
| RPS6KA3 (Ribosomal protein S6 kinase A3) | RPS6KA3 gene encodes for ribosome S6 protein kinase2 (RSK2). RSK2 protein activates the RAS/MAPK pathway. Mutations in this gene inactivate RSK2 function which directly increases the risk of HCC without cirrhosis. |
Nongenetic factors that increase the risk of
Alcohol abuse
The chronic consumption of alcohol is a well-established, nongenetic factor that is positively correlated with the development of HCC. Globally, alcohol-induced liver damage is the most prevalent cause of chronic liver damage. The metabolism of ethanol creates pathologic oxidative, metabolic, and inflammatory stress that causes hepatocyte injury and dysfunction. Over time, chronic alcohol consumption may progress to steatosis, steatohepatitis, cirrhosis, and potentially HCC. In recent years, the annual consumption of alcohol per capita has increased in the United States and it has been estimated that approximately 7% of adults meet the criteria for alcohol dependence or alcohol use disorder. Furthermore, the consumption of alcohol has significantly increased in men and younger individuals in Asia. Chronic liver disease, precipitated by long-term alcohol consumption, is responsible for 30% of HCC cases worldwide, and this number is expected to increase in the future. Geographically, the rates of alcohol consumption vary by region, and as a result, countries with notable consumption have a higher incidence of alcohol-associated HCC. Recent clinical data indicate that excessive alcohol consumption in European countries accounts for 40%–50% of all liver malignancies. The Global Burden of Disease study of 2019 estimated that alcohol-associated HCC accounted for 35%, 33%, and 27% of overall HCC mortality in Europe, North and South America, and Southeast Asia, respectively. Eastern Mediterranean and Western Pacific countries reported the lowest rates of alcohol-associated HCC deaths at 10% and 11%, respectively. The consumption of 80 g/day for more than a decade increases the probability of HCC by 5-fold. A study in the U.S. reported that heavy drinkers (>7 drinks per day) had an 87% increased risk of developing HCC, compared to nondrinkers. Similarly, a meta-analysis reported a 16% increase in the likelihood of the development of HCC in individuals that consumed more than three drinks a day. In addition, there was a synergistic increase in the risk of developing HCC in people that consumed alcohol and were concurrently infected with HBV or HCV, compared to either factor alone.
Nonalcoholic fatty liver disease (
Clinical studies have shown that patients diagnosed with diabetes, obesity, or metabolic syndrome, who drink little or no alcohol, are significantly more likely to be develop nonalcoholic fatty liver disease (NAFLD), which can increase the risk of HCC. The pathophysiology of NAFLD results from the accumulation of fat within the liver in the absence of a secondary cause which may ultimately progress into cirrhosis. The estimated worldwide prevalence of NAFLD is approximately 25% and the incidence continues to increase. NAFLD's prevalence parallels the obesity epidemic that is primarily observed in western countries and it is the most rapid growing indication for liver transplantation. The rapid rise in NAFLD is projected to become the primary etiological factor for producing HCC in certain countries. One study from the United Kingdom reported a < 10% to 34.8% increase in NAFLD-associated HCC from 2000 to 2010. Similarly, another study in France indicated that the prevalence of NAFLD-associated HCC increased from 2.6% (1995–1999) to 19.5% (2010–2014). The prevalence of NAFLD-associated HCC will increase by 146% from 2015 to 2030, based on a Markov model that uses historical and projected rates of diabetes and obesity in the United States. The BRIDGE international study (n = 18 031 from 2005 to 2011) reported that the geographical regions with the highest prevalence of NAFLD-associated HCC were North America (12%), Europe (10%), South Korea (6%), and Taiwan (5%). Furthermore, this large international study revealed that lower rates of NAFLD-associated HCC occurred in China (1%) and Japan (2%). Based on the predictions from Este et al., China and Japan are projected to have an increase in NAFLD-associated HCC by 86% and 47%, respectively.
Nonalcoholic steatohepatitis (
As NAFLD progressively worsens, it can potentially transform into its inflammatory subtype known as NASH. The transition from NAFLD to NASH is hypothesized to result from: (1) the accumulation of lipids within the liver, which increases insulin resistance and (2) chronic insulin resistance induces molecular and cellular changes within the hepatocytes, while also producing hepatic inflammation. Insulin resistance produced by NAFLD causes a compensatory hyperinsulinemic response which facilitates the development of primary liver malignancy. It has been estimated that approximately 20% of all cases of NASH slowly progress to advanced cirrhosis. Risk factors associated with the development of NASH are similar to those for NAFLD, such as metabolic syndrome, obesity, and insulin resistance. Similar to NAFLD, the incidence of NASH-associated HCC parallels the obesity epidemic and is increasing worldwide. As countries adapt a more sedentary lifestyle with poorer diets, the risk of developing NASH increases. One study in the United States reported that the prevalence of NASH increased from 1.51% in 2010 to 2.79% in 2020. The increase incidence of NASH among individuals is also expected to occur in China, India, Indonesia, Pakistan, Bangladesh and the Philippines, where the prevalence of type 2 diabetes has been increasing over the past decade. Annually, approximately 0.7% to 2.6% of patients diagnosed with NASH will develop HCC in the United States and Europe. In a large survey of cirrhotic Japanese patients, 31.5% of patients diagnosed with NASH-cirrhosis had HCC. HCC cases with no secondary cause are known as cryptogenic HCC. It is likely that NASH-associated HCC is significantly underestimated, and consequently, its true prevalence remains to be determined. The identification of these cases will contribute to the increase in rise of NASH-associated HCC.
Obesity
Obesity has been identified as an independent risk factor for the occurrence of primary liver malignancy. Clinical data indicates that obese patients, compared to nonobese patients, have higher plasma levels of leptin, which is a proinflammatory, proangiogenic, and profibrogenic cytokine. Leptin activates the JAK pathway, which increases the probability of increase cell growth, thereby leading to cancer progression. Excess body fat has been shown to decrease the ultrasound detection of HCC and this is 3- to 8-fold more likely to occur in obese patients, compared to patients of healthy weight. Finally, obese patients are significantly more likely to die from liver cancer, compared to individuals of normal weight. As previously indicated in the NAFLD and NASH sections of this article, obesity has become an increasing problem worldwide. Obesity leads to the development of several other comorbid conditions, such as metabolic syndrome, type 2 diabetes, NAFLD and NASH, all of which have been implicated in the progression of HCC. One study from South Korea followed 700 000 men over 10 years and the results indicated that men with BMIs greater than 30, had an increased risk of developing HCC. Similarly, a North American prospective study reported that men with BMIs greater than or equal to 35, had a 4.5-fold increased relative risk of dying from liver cancer, compared to those with normal body-weight.
Sex disparities
It is well established that there are significant sex disparities in the incidence of HCC. Males are 2–8 time more likely to develop HCC compared to females, regardless of the geographic region and ethnicity. The prevalence of risk factors for the development of HCC in the general population has fluctuated over time, whereas the sex disparity has remained constant, suggesting that sex hormones play a role in the pathogenesis of HCC. Studies have shown that estrogen may decrease the risk of HCC by decreasing the levels of pro-inflammatory mediators, such as IL-6, androgens and vascular endothelial growth factor, which may decrease the progression to HCC. Men chronically infected with HBV that have hypertension and diabetes, are at a higher risk of developing HCC when their serum testosterone levels are higher, compared to individuals who are healthy. However, it has been reported that increased plasma levels of androstenedione, an androgenic compound, are correlated with a lower risk of HCC.
GEOGRAPHICAL AND ETHNIC DISPARITY IN
Globally, according to estimates by the World Health Organization (WHO), there were 905 677 new cases of HCC and 830 180 deaths in 2020. HCC is one of the top five most common causes of cancer-related death in Northern and Western Africa, Eastern and South-Eastern Asia, Central America, Western Asia, and certain countries in Europe (i.e., Bosnia, France, Romania and Italy). A study by Rumgay et al. predicted an increase in newly diagnosed cases of HCC per year by 55%, between 2020 and 2040, with 1.3 million deaths in 2040, which is 56.4% higher than the mortality rate reported in 2020. There is a significant variation in the disease burden of HCC between different ethnicities and geographical regions that parallels the geographical distribution of HBV and HCV. More than 80% of HCC cases occur in low-income countries, notably in East Asia and sub-Saharan Africa, where the transmission of viral hepatitis is high due to a low socio-economic status (SES). More than half of the HCC cases in the United States of America (USA), Egypt and Pakistan, can be attributed to chronic HCV, which is the cause of 20% of all HCC cases worldwide. Furthermore, chronic HBV infection is the most prevalent cause of HCC in Central Asia, sub-Saharan African and South-East Asian countries.
The highest incidence (54.3%) and mortality (54.1%) from HCC occurs in Eastern Asia, with Mongolia reporting 85.6 new cases per 100 000 people. HCC is the most frequently diagnosed cancer in Vietnam, Cambodia, Thailand, Egypt, Mongolia and Laos. A recent decrease in newly diagnosed cases of HCC was reported in South Korea, China and the Philippines, due to mass immunization for HBV. However, an increase in the prevalence of risk factors, such as NAFLD obesity, diabetes, high alcohol consumption and smoking, has contributed to an increase in the incidence of HCC cases in the USA and other industrialized nations. Furthermore, patients born between 1945 and 1965 have a higher incidence of HCC, due to a higher prevalence of HCV infection. It has been hypothesized that HCC will be the third leading cause of cancer-related deaths in the United States, with an estimated 122% increase in incidence by 2030.
There is a significant variation among countries in the age of onset of HCC. A diagnosis of HCC at an early age (30–60 years) is more common in Asiatic and the majority of African countries. In contrast, in North America, Japan, USA European nations, the median age at onset is >60 years. A study of 1552 patients with HCC from even countries in Africa reported a median age of HCC onset of 45 years. Individuals born in West Africa had the earliest age of HCC onset (>40 years). Greater than 60% of HCC cases in China, Europe, North America and Korea, are diagnosed at intermediate or advanced stages, resulting in poor outcomes. Clinical data from Japan and Taiwan indicate the optimal clinical outcomes due to regular and intensive surveillance programs for HCC. Furthermore, patients in these countries had a significantly higher median survival, compared to individuals living in sub-Saharan Africa, where the median survival of patients diagnosed with HCC was 2.5 months. However, the survival of patients diagnosed with HCC remains poor, even in high-income countries. A recent study of seven high-income countries by Rutherford et al. reported that Australia had the highest 3-year survival rate from HCC (28%), and Denmark had the lowest (17%), between 2012 and 2014. Another study evaluating the 5-year survival from 2010 to 2014 reported that in European countries, the survival rate was less than 10%, compared to 30% for Japan.
Several studies have shown that there are significant ethnic disparities in the incidence of HCC. Mahimpundu et al. reported a higher incidence of HCC among African Americans (10.2 per 100 000), compared to Caucasian Americans (6.3 per 100 000). The etiological factors of HCC were also found to be disproportionate, as the causative factors for HCC in African Americans were tobacco and alcohol use, compared to HCV infection and diabetes for Caucasian Americans. Individuals of Hispanic ethnicity in the United States had the highest prevalence of NAFLD, with a high risk of progression to NASH. Immigration has been postulated to play a major role in the higher rates of HCC within ethnic minorities in the United States, Western Europe, Australia, and Canada.
In the USA, over the past few years, there has been an increase in the incidence of HCC in Hispanic men (4.7% per year since 2000), compared to non-Hispanic Caucasian and African-American populations. In contrast, there has been a decrease in the incidence of HCC in middle-aged African-Americans (17.2% decrease per year since 2012), compared to other ethnic groups. Ethnic minorities that have a low SES and are at a higher risk of developing HCC, are not screened on a regular basis, and this increases the probability of being diagnosed at an advanced stage, resulting in a worse prognosis. Ha et al. reported that in the USA, African-American HCC patients had higher odds [Odds ratio (OR): 1.20], whereas Asians Americans had lower odds (OR: 0.87), of having advanced stage tumors at the time of diagnosis, compared to Caucasian Americans.
The 5-year survival rate in African Americans (21%) is significantly lower, compared to Caucasian Americans (25%), even after combining all of the stages of HCC. Data from a 2016 study in the USA indicated a descending decrease in mortality from HCC for Hispanic Americans, non-Hispanic Asians/Pacific Islanders, Native Americans/Native Alaskans, African Americans and Caucasian Americans. In ethnic groups with a low SES, non-Hispanic Asians/Pacific Islanders were significantly more likely to be diagnosed with HCC at a local stage, whereas Native Americans/Native Alaskans had the lowest likelihood. A significant variation in therapeutic outcomes has been reported in the USA between patients of different ethnicities. Ethnic minorities and patients with a low SES received the lowest rates of curative treatments. This occurred even in patients undergoing potentially curative treatments, such as liver transplantation and surgical resection. Furthermore, African–American patients had higher mortality rates, compared to Caucasian Americans, regardless of the SES. Data from the Surveillance Epidemiology & End Results (SEER) database indicated that African American patients had higher mortality rates (HR: 1.11), whereas Hispanic Americans had similar mortality rates (HR: 0.97) and Asian Americans had a 16% lower mortality rate, compared to Caucasian Americans. African Americans had lower odds of receiving liver transplantation, compared to patients of other ethnicities. Moreover, African–Americans had a lower 2- and 5-year graft survival and higher in-hospital mortality after liver transplantation, compared to Caucasian Americans. However, USA cancer register data suggested that the highest mortality rates occur in New York, California and Florida among Korean, Vietnamese and Chinese patients.
The ethnic disparity in the outcomes of HCC, as a result of inadequate healthcare access in vulnerable populations, suggest that implementation of large-scale interventions will be required to mitigate the mortality due to HCC.
Difference in epigenetics
Epigenetics involves alterations in gene expression by the external environment that occurs in the absence of changes in the DNA sequences. Alterations in epigenetic factors have been reported to be significantly correlated with the progression and outcomes in patients diagnosed with HCC. DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs, are the primary epigenetic factors affecting the carcinogenic processes that cause HCC. Furthermore, DNA hypermethylation and hypomethylation have been shown to play a role in the development of HCC. The activation of certain proto-oncogenes and the presence of a higher number of somatic mutations, were shown to be correlated with hypomethylation. In contrast, DNA repair, angiogenesis, alterations in the metabolism of carcinogens and cell cycle regulation are significantly affected by abnormal hypermethylation. Hypermethylation leads to modifications in the WNT/ß-catenin signaling pathway, which causes the accumulation of ß-catenin, which increases the probability of oncogenesis. For example, mutations in micro-RNA (miR)-1273f upregulates cell proliferation, migration and invasion which facilitates the prevalence of extracellular vesicles HCC. Some studies have reported a significant correlation between miRNAs and DNA methylation. miRNAs are noncoding RNA molecules composed of an average of 22 nucleotides. The combination of miRNAs and DNA methylation inactivate various tumor suppressor genes. A recent study by Varghese et al. reported ethnic disparities in the miRNA sequences and DNA methylation patterns of in liver tissue samples from individuals with HCC. The expression of miRNAs, such as miR-150, miR-155 and miR-146a, were upregulated in HCV-infected African–American patients, compared to European Americans. Has-miR-139-5p, a tumor suppressor gene, was observed to be significantly downregulated in African–Americans, Asian Americans, and European Americans, compared to those without HCC. In the future, a deeper analysis of epigenetic factors, with respect to ethnic disparities, could be useful in providing an improved understanding the progression novel biomarkers, treatment options, and outcomes in HCC patients.
Overall, there is a significant variation in the underlying etiology, cancer stage at diagnosis, prognosis and mortality between different ethnic groups. Understanding these variations and implementing preventative and control strategies should improve patient outcomes and decrease these disparities.
VARIATIONS IN
It has been estimated that HCC causes 90% of all primary liver cancer diagnoses. Although HCC occurs throughout the world, it has an uneven distribution. Sub-Saharan Africa and East Asia account for the highest number of age-related HCC cases. In China, liver cancer accounts for approximately 50% of all cancer-related deaths.
Insufficient treatment resources and a lack of timely diagnosis can be linked to the HBV epidemic in Sub-Saharan Africa. In these regions, less than 1% of HBV patients are diagnosed, although appropriate diagnostic methods are available. In Sub-Saharan Africa, only 15% of patients that receive an early diagnosis of HBV go to hospitals and pharmacies for the required treatment. Tenofovir is one of the most commonly used drugs to treat HBV. Tenofovir, at a dosage of 80–300 mg/day (depending on certain patient factors), is one of the primary treatments for HBV. A study in Australia reported that tenofovir decreased the plasma levels of HBV by 71%, 80%, and 89%, after 12, 24, and 36 months of treatment, respectively. However, despite the efficacy of tenofovir against HBV, according to WHO, Sub-Saharan Africa has the second highest HBV burden in the world at 81 million people. This is compared to the Western Pacific region, which has the highest HBV burden at 116 million. Tenofovir is not utilized on a sufficient scale in these regions, which can be attributed to the high cost of tenofovir in the private sector, as well as the need for continual, lifelong treatments. The high rate of HBV transmission from mothers to children that occurs in nations, such as Africa, can be prevented using tenofovir, telbivudine, or lamivudine, during the last third trimester. A study in 1509 patients from Taiwan (6–26 years old) indicated that HBV vaccination in infants significantly decreased their risk of developing HCC. However, in 2017, only 19% of African nations administered HBV vaccines at birth. Thus, African nations with the highest levels of HBV infection should utilize the protective effects from vaccinations to prevent HBV, ultimately decreasing the incidence of HCC.
The comorbidity of HCC and HIV has been shown to greatly increase mortality, compared to having either disease alone. A meta-analysis by Stabinski et al. indicated that HIV-HBV co-infection in sub-Saharan African individuals ranged from 0% to 24.8%, with a median co-infection rate of 7.8%. Furthermore, an increase in liver-related mortality was reported by Thio et al. in HIV-HBV co-infected individuals with lower nadir CD4+ T cell counts of 100 cells/μL, compared to 250 cells/μL. The traditional therapeutic management of HCC may not be maximally efficacious because the response of CD4+ T cells in HBV infection is significantly decreased due to an HIV-induced decrease in CD4+ T cell number. Furthermore, certain drugs used to treat HIV can produce hepatotoxicity, thereby increasing the risk of severe liver damage. A novel drug combination that may be useful for the treatment of HCV and HIV coinfection is elbasvir (an inhibitor of NS5A), and grazoprevir (an inhibitor of HCV NS3/4A protease), which together inhibit HCV replication. A clinical study of 218 patients indicated that treatment with a foxed dose tablet containing 100 mg a day of grazoprevir and 50 mg a day of elbasvir for 12 weeks produced a sustained virology response (SVR) of 96% without producing severe adverse effects. Similarly, the treatment of cirrhotic patients coinfected with HCV and HIV with pibrentasvir (an inhibitor of HCV NS5A) and glecaprevir (an inhibitor of HCV NS3/4A protease), produced an SVR of 98%. In a study of 335 patients, the combination of 90 mg of ledipasvir (an NS5A inhibitor) and 400 mg of sofosbuvir (an inhibitor of HCV NS5B), administered once a day for 12 weeks in patients with HCV genotype 1 or 4 produced an SVR of 96%.
Globally, NAFLD occurs in approximately 25% of the population, with a range of 13% in Africa to 42% in Southeast Asia. A multicenter study of 1336 patients from 6 different countries (between 2005 and 2015) reported that 9% of the cases of HCC were secondary to NAFLD. It is predicted that by 2030, 50% of the population in the USA will be diagnosed as being obese. The prevalence of NAFLD is 1%–2% in the United States, whereas its prevalence is 7.6%–34.2% in the pediatric population worldwide. It has been reported that up to 20% of patients diagnosed with NAFLD-HCC undergo liver resection. NAFLD is common in South America and the Middle East, but it is rare in Africa. Diabetes, NASH, age, steatosis, and obesity are positively correlated with a diagnosis of NAFLD-HCC, which increases the probability of liver failure after liver resection surgery. A recent study of 68 950 liver transplant patients in Europe reported a 1.2%–8.4% increase in the proportion of NASH patients receiving liver transplants from 2002 to 2016. When comparing geographical regions in the United States, the liver transplant ratio was 11.0% and 5%, in Caucasian Americans and African–Americans, respectively, in the southern states, compared to 7.2% and 3.8%, respectively, in non-southern states. Mathur et al. reported the average survival rate in early-stage HCC patients that were treated using invasive therapy for 5 years was 17.9%, based on all ethnic groups, with the rates for patients of African, Caucasian, Hispanic and of other ethnicities at 12.2%, 18.2%, 15.2% and 17.1%, respectively. Overall, 32.8% of patients received invasive therapy. African–American patients had a 12% higher mortality rate compared to Caucasian American patients, whereas Hispanic Americans had a similar mortality rate, and Asian Americans had a 16% lower mortality rate. This data indicates that the same treatment regimen produced different morality rates, depending on the ethnicity of the patient.
Globally, despite the significant variations in the risk factors for HCC, the treatment regimens for HCC are virtually identical. Liver transplantation (LT) is an intervention that is used to treat certain patients with HCC. Approximately 15%–50% of patients with HCC undergo LT. The use of LT in early-stage HCC patients, where the size of the tumor is 3 cm or less and there is an absence of invasion or metastasis, produces a 75% survival rate 4 years after transplantation, with a recurrence rate of 10%–15%. Clinical data indicates that LT is used less commonly in patients of African ethnicity, compared to Caucasians. One of the major issues regarding the use of LT is the scarcity of organ donors. Another approach that can be used in HCC patients is local ablation. Local ablative treatments are a less intrusive form of surgery that can be used in patients diagnosed with early stage disease. Furthermore, it can be used in management of various disease involving methods such as percutaneous ethanol injection, radiofrequency, and laser ablation. This approach has been shown to be associated with a lower risk of adverse effects and mortality, compared to surgical resection or transplantation. Patients diagnosed with unresectable, intermediate-stage HCC can be treated using trans-arterial chemoembolization (TACE). This treatment modality involves the administration of embolic-inducing compounds within the blood vessels that ultimately reduce or abolish the tumor blood vessels. Furthermore, TACE prevents the loss of chemotherapeutic drugs from the tumors, thus concentrating the drug within the cancerous cells. A randomized control study reported that the median survival of patients is increased from 16% to 20% when TACE was used to treat various types of cancers, compared a to an oil-in-water emulsion. Another treatment, known as a drug-eluting bead (DEB), has been reported to increase the efficacy of TACE therapy when used concurrently. DEB decreases the diffusion of drug to the peripheral circulation and increases the local drug concentration, which increases the anti-tumor efficacy of TACE. The mortality rate from HCC is decreased by approximately 7% in patients who were treated using TACE, compare to non-TACE treated patients.
Another approach for the treatment of HCC is the use of certain monoclonal antibodies (mABs). The U.S. FDA has approved the use of sorafenib, atezolizumab–bevacizumab, and lenvatinib as first-line treatments for patients diagnosed with advanced stage HCC. Lenvatinib, an inhibitor of VEGF, FGF, and PDGF receptors, was reported to be efficacious in certain HCC patients. A Phase III, multicenter clinical trial was conducted in the Asian-pacific, European, and North American regions, that compared the efficacy of lenvatinib to sorafenib at various oral doses in patients with untreated HCC. The dose of levantinib ranged from 8 to 12 mg/day which was given to 478 patients and 400 mg of sorafenib was given twice a day to 476 patients for a total of 28 days. The study concluded that lenvatinib was noninferior to sorafenib in the overall survival of untreated HCC patients. The most common adverse effects produced by lenvatinib were hypertension, diarrhea, decreased appetite, and weight loss, compared to erythrodysaesthesia in patients treated with sorafenib. In another phase III clinical trial, the efficacy of a 2:1 dose ratio of atezolizumab and bevacizumab was evaluated in 336 patients. The overall survival was 67.2% for patients treated with atezolizumab-bevacizumab, compared to 54.6% for patients treated with sorafenib. The results indicated that the combination of atezolizumab and bevacizumab produce a significantly greater overall survival compared to sorafenib (NCT03434379). Nivolumab is a fully human immunoglobulin G4anti-PD-1 monoclonal antibody that has been approved for the treatment of certain cancers In September 2017, nivolumab was approved by the US FDA as a second line treatment for liver cancer in patients that did not respond to sorafenib. A phase III clinical study with 743 patients evaluated the efficacy and safety of 240 mg of intravenously nivolumab every 2 weeks, compared to 400 mg of sorafenib, twice daily, until disease progression or unacceptable toxicity was detected. Overall, the results indicated that nivolumab had favorable clinical outcomes and a good safety profile for the treatment of HCC. Although it did not significantly improve survival when compared to sorafenib, it provided a potential treatment for patients that cannot be treated with tyrosine kinase inhibitors. The efficacy of mAbs for the treatment of HCC is dependent upon age, progression of the disease, comorbidities, geographical location, and genetic variation. Figure summarizes the BCBL classification of liver malignancy and its associated treatment algorithm, including several novel approaches for the treatment of HCC.
[IMAGE OMITTED. SEE PDF]
LIMITATIONS THAT PRODUCE DISPARITIES IN CLINICAL OUTCOMES FOR
Ethnic and gender differences impact the prevalence, mortality and treatment outcomes of HCC. However, the scientific and medical community must look beyond only reporting disparities and identify and target the specific determinants that impact the incidence and progression of HCC. The multidimensional nature of HCC requires clinical and social interventions to address the complexity of diagnosis and treatment modalities. Ethnic and geographical disparities for HCC are well-established and the lack of routine surveillance, which results in delayed diagnosis, is one of the key factors that produces the disparities in HCC. The poor prognosis for socio-economically vulnerable populations is the result of various contextual and individual variables. Contextual-level measures, also known as Social Determinants of Health (SDoH), include neighborhoods, access to healthcare insurance, education and poverty, significantly affect the clinical outcomes of HCC. Patients with nonprivate insurance have been shown to have significantly worse outcomes, even when thoroughly evaluated, regardless of their HCC stage at presentation. A recent study indicated that lack of healthcare insurance was a major factor in decreasing the overall survival (OS) in many patients. Indeed, a median OS of 34 months, compared to a median OS of 9-months, has been reported for privately insured and noninsured patients, respectively. Nevertheless, having healthcare insurance does not necessarily result in improved outcomes. Out-of-pocket expenses, such as clinic visits, may affect anyone with limited financial capacity. Individual level barriers, such as culture, language and logistic barriers, including transportation and caretaker expense, are factors that significantly affect clinical outcomes. However, variations in access to healthcare do not fully explain the disparities seen in HCC. For example, epigenetic modulators such as obesity, viral hepatitis, diabetes, NAFLD, and chronic stress due to poverty and discrimination, impact the molecular basis of cancer and its prognosis. Healthcare providers and systems must make dedicated effort to provide equal care to all patients to improve therapeutic outcomes and decrease the disparities that occurs in HCC patients. The multifactorial etiology behind the disparities that alter the incidence and progression of HCC among different ethnic and geographical groups requires significant and specific considerations when determining the optimal treatment regimen.
CONCLUSION AND FUTURE GUIDANCE
Ethnic and geographical differences play a significant role in both the incidence and mortality rate of HCC. The poor prognosis for these patients is often a result of a late diagnosis due to inadequate screening measures. It is widely accepted that there are several factors that influence the heterogeneity of HCC. For example, HCV, HBV, age, sex, alcohol consumption, obesity, and genetics contribute to the various outcomes of HCC. Furthermore, a variety of factors can contribute to the sporadic development of HCC. In some populations, these factors are present to different extents and magnitudes. Understanding the various etiologies behind the development and progression of HCC between different populations may help with a timelier diagnosis and improve overall outcomes. While this issue is being thoroughly investigated, additional research will be required. Unfortunately, there are no reliable early biomarkers for HCC and preventative and other screening measures have not been fully implemented in certain countries. Several treatment options are unavailable to patients due to financial constraints and their overall scarcity. Improvements in early detection, effective and affordable treatment plans, and preventative measures can decrease the disparities that are present in ethnic and geographic populations of HCC patients.
Ethnic differences can have a significant impact on HCC assessment and treatment. Some ethnic groups have higher rates of HCC due to factors such as viral hepatitis infections, alcohol consumption, and nonalcoholic fatty liver disease. In addition, access to health care and resources may differ, which can impact the type of treatment and follow-up care. When assessing HCC patients, ethnic differences must be taken into consideration to ensure effective treatment. This can include factors such as cultural beliefs, patient attitudes toward health care, patient preferences, and disparities in access to care. The use of standardized outcome measures and assessment tools should be culturally sensitive and validated. The impact of ethnicity and other demographic factors on treatment response and outcomes can also be better understood by collecting data.
To address the ethnic differences in HCC assessment and treatment across regions several factors can be considered. The development of international clinical practice guidelines that take into account patient populations, health systems, and resources can lead to global consensus. Through the use of evidence-based clinical practice guidelines and standardized outcome measures, HCC patients can be assessed and treated more consistently. International clinical trials and registry data can also be used to determine the most effective treatments and assessment methods. By standardizing the assessment method and approach, it will be possible to compare results and outcomes between countries, improving patient care and advancing understanding of HCC. By assuring that all patients receive appropriate treatment and follow-up care, improving the availability and quality of health care services in underserved communities can help address disparities in access to care. Health care providers can improve patient outcomes by providing education and training about the latest developments in the assessment and treatment of HCC, including culturally sensitive approaches. The collection and sharing of patient demographics, treatment response, and outcomes can improve our understanding of the impact of geographical location on HCC treatment. International sharing of this data could facilitate the development of effective and equitable treatments. Finally, the promotion of collaborations between health care providers, researchers, and patient advocacy groups can ultimately advance the understanding of liver cancer worldwide.
AUTHOR CONTRIBUTIONS
Vivek Chavda: Conceptualization (equal); data curation (equal); investigation (equal); validation (equal); visualization (equal); writing – original draft (equal). Kelsee K. Zajac: Formal analysis (equal); methodology (equal); resources (equal); writing – original draft (equal). Jenna Lynn Gunn: Visualization (supporting); writing – original draft (supporting). Pankti Balar: Formal analysis (supporting); visualization (supporting); writing – original draft (supporting). Avinash Khadela: Validation (supporting); writing – original draft (supporting). Dixa Vaghela: Software (supporting); visualization (supporting); writing – original draft (supporting). Shruti Soni: Formal analysis (supporting); investigation (supporting); methodology (supporting); validation (supporting). Charles R. Ashby: Formal analysis (equal); investigation (equal); project administration (equal); supervision (equal); validation (equal); visualization (equal); writing – review and editing (equal). Amit K. Tiwari: Conceptualization (equal); formal analysis (equal); funding acquisition (equal); supervision (equal); writing – original draft (equal); writing – review and editing (equal).
ACKNOWLEDGMENTS
We would like to thank the L. M. College of Pharmacy, India and University of Toledo, OH for their support of resources. Figures were created using Biorender.com.
CONFLICT OF INTEREST STATEMENT
The authors have stated explicitly that there are no conflicts of interest in connection with this article.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
ETHICS STATEMENT
The work submitted to Cancer Reports has been done in accordance with these guidelines and that is has been performed in an ethical and responsible way, with no research misconduct, which includes, but is not limited to data fabrication and falsification, plagiarism, image manipulation, unethical research, biased reporting, authorship abuse, redundant or duplicate publication, and undeclared conflicts of interest.
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209‐249. doi:
Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16‐27. doi:
Reveron‐Thornton RF, Teng MLP, Lee EY, et al. Global and regional long‐term survival following resection for HCC in the recent decade: a meta‐analysis of 110 studies. Hepatol Commun. 2022;6(7):1813‐1826. doi:
Ozakyol A. Global epidemiology of hepatocellular carcinoma (HCC epidemiology). J Gastrointest Cancer. 2017;48(3):238‐240. doi:
Kobayashi T, Aikata H, Kobayashi T, Ohdan H, Arihiro K, Chayama K. Patients with early recurrence of hepatocellular carcinoma have poor prognosis. Hepatobiliary Pancreat Dis Int. 2017;16(3):279‐288. doi:
Ren Z, Ma X, Duan Z, Chen X. Diagnosis, therapy, and prognosis for hepatocellular carcinoma. Anal Cell Pathol (Amst). 2020;2020: [eLocator: 8157406]. doi:
Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi:
Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and Management of Hepatocellular Carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723‐750. doi:
Tanaka M, Miyajima A. Liver regeneration and fibrosis after inflammation. Inflamm Regener. 2016;36(1):19. doi:
Fung J, Lai C‐L, Yuen M‐F. Hepatitis B and C virus‐related carcinogenesis. Clin Microbiol Infect. 2009;15(11):964‐970. doi:
Mu X‐M, Wang W, Jiang Y‐Y, Feng J. Patterns of comorbidity in hepatocellular carcinoma: a network perspective. Int J Environ Res Public Health. 2020;17(9):3108. doi:
Blonski W, Kotlyar DS, Forde KA. Non‐viral causes of hepatocellular carcinoma. World J Gastroenterol. 2010;16(29):3603‐3615. doi:
Dongiovanni P, Romeo S, Valenti L. Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. World J Gastroenterol. 2014;20:12945‐12955. doi:
Russo FP, Zanetto A, Pinto E, et al. Hepatocellular carcinoma in chronic viral hepatitis: where do we stand? IJMS. 2022;23(1):500. doi:
Liu Y, Liu L. Changes in the epidemiology of hepatocellular carcinoma in Asia. Cancer. 2022;14(18):4473. doi:
Franco RA, Fan Y, Jarosek S, Bae S, Galbraith J. Racial and geographic disparities in hepatocellular carcinoma outcomes. Am J Prev Med. 2018;55(5 Suppl 1):S40‐S48. doi:
Tarocchi M. Molecular mechanism of hepatitis B virus‐induced hepatocarcinogenesis. WJG. 2014;20(33):11630‐11640. doi:
Kim AK, Singal AG. Health disparities in diagnosis and treatment of hepatocellular carcinoma. Clin Liver Dis (Hoboken). 2014;4(6):143‐145. doi:
Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and nutrition examination survey 2003 to 2010. Ann Intern Med. 2014;160(5):293‐300. doi:
El‐Serag HB, Lau M, Eschbach K, Davila J, Goodwin J. Epidemiology of hepatocellular carcinoma in Hispanics in the United States. Arch Intern Med. 2007;167(18):1983. doi:
Norder H, Couroucé A‐M, Magnius LO. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes. Virology. 1994;198(2):489‐503. doi:
Stuyver L, de Gendt S, van Geyt C, et al. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol. 2000;81(Pt 1):67‐74. doi:
Arauz‐Ruiz P, Norder H, Robertson BH, Magnius LO. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol. 2002;83(Pt 8):2059‐2073. doi:
Ching LK, Gounder PP, Bulkow L, et al. Incidence of hepatocellular carcinoma according to hepatitis B virus genotype in Alaska native people. Liver Int. 2016;36(10):1507‐1515. doi:
Flores YN, Datta GD, Yang L, et al. Disparities in hepatocellular carcinoma incidence, stage, and survival: a large population‐based study. Cancer Epidemiol Biomarkers Prev. 2021;30(6):1193‐1199. doi:
Muhimpundu S, Conway RBN, Warren Andersen S, et al. Racial differences in hepatocellular carcinoma incidence and risk factors among a low socioeconomic population. Cancers (Basel). 2021;13(15):3710. doi:
Mathur AK, Osborne NH, Lynch RJ, Ghaferi AA, Dimick JB, Sonnenday CJ. Racial/ethnic disparities in access to care and survival for patients with early‐stage hepatocellular carcinoma. Arch Surg. 2010;145(12):1158‐1163. doi:
Thylur RP, Roy SK, Shrivastava A, LaVeist TA, Shankar S, Srivastava RK. Assessment of risk factors, and racial and ethnic differences in hepatocellular carcinoma. JGH Open. 2020;4(3):351‐359. doi:
Giannini EG, Cucchetti A, Erroi V, Garuti F, Odaldi F, Trevisani F. Surveillance for early diagnosis of hepatocellular carcinoma: how best to do it? World J Gastroenterol. 2013;19(47):8808‐8821. doi:
Mittal S, El‐Serag HB. Epidemiology of HCC: consider the population. J Clin Gastroenterol. 2013;47:S2‐S6. doi:
El‐Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264‐1273.e1. doi:
Xie Y. Hepatitis B virus‐associated hepatocellular carcinoma. Adv Exp Med Biol. 2017;1018:11‐21. doi:
Kowdley KV, Wang CC, Welch S, Roberts H, Brosgart CL. Prevalence of chronic hepatitis B among foreign‐born persons living in the United States by country of origin. Hepatology. 2012;56(2):422‐433. doi:
McMahon BJ. Hepatitis B‐related sequelae. Prospective study in 1400 hepatitis B surface antigen‐positive Alaska native carriers. Arch Intern Med. 1990;150(5):1051‐1054. doi:
Nebbia G, Peppa D, Maini MK. Hepatitis B infection: current concepts and future challenges. QJM. 2012;105(2):109‐113. doi:
Kan Z, Zheng H, Liu X, et al. Whole‐genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23(9):1422‐1433. doi:
Monga SP. β‐Catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015;148(7):1294‐1310. doi:
Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. β‐Catenin signaling in hepatocellular carcinoma. J Clin Investig. 2022;132(4): [eLocator: e154515]. doi:
He S, Tang S. WNT/β‐catenin signaling in the development of liver cancers. Biomed Pharmacother. 2020;132: [eLocator: 110851]. doi:
Hussain SP, Schwank J, Staib F, Wang XW, Harris CC. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007;26(15):2166‐2176. doi:
Burns GS, Thompson AJ. Viral hepatitis B: clinical and epidemiological characteristics. Cold Spring Harb Perspect Med. 2014;4(12): [eLocator: a024935]. doi:
McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19(2):223‐238. doi:
Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor‐Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. 2008;14(27):4300‐4308. doi:
Petruzziello A, Marigliano S, Loquercio G, Cozzolino A, Cacciapuoti C. Global epidemiology of hepatitis C virus infection: an up‐date of the distribution and circulation of hepatitis C virus genotypes. World J Gastroenterol. 2016;22(34):7824‐7840. doi:
Li H‐C, Lo S‐Y. Hepatitis C virus: virology, diagnosis and treatment. World J Hepatol. 2015;7(10):1377‐1389. doi:
Frank C, Mohamed MK, Strickland GT, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet. 2000;355(9207):887‐891. doi:
Mahale P, Torres HA, Kramer JR, et al. Hepatitis C virus infection and the risk of cancer among elderly US adults: a registry‐based case‐control study. Cancer. 2017;123(7):1202‐1211. doi:
Alter HJ, Seeff LB. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long‐term outcome. Semin Liver Dis. 2000;20(1):17‐36. doi:
Colombo M, Kuo G, Choo QL, et al. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet. 1989;2(8670):1006‐1008. doi:
Donato F, Boffetta P, Puoti M. A meta‐analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer. 1998;75(3):347‐354. doi:
Shi J, Zhu L, Liu S, Xie W. A meta‐analysis of case–control studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma in China. Br J Cancer. 2005;92(3):607‐612. doi:
Banerjee A, Ray RB, Ray R. Oncogenic potential of hepatitis C virus proteins. Viruses. 2010;2(9):2108‐2133. doi:
Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35‐S50. doi:
Selimovic D, El‐Khattouti A, Ghozlan H, Haikel Y, Abdelkader O, Hassan M. Hepatitis C virus‐related hepatocellular carcinoma: an insight into molecular mechanisms and therapeutic strategies. World J Hepatol. 2012;4(12):342‐355. doi:
Vescovo T, Refolo G, Vitagliano G, Fimia GM, Piacentini M. Molecular mechanisms of hepatitis C virus–induced hepatocellular carcinoma. Clin Microbiol Infect. 2016;22(10):853‐861. doi:
Zampino R, Marrone A, Restivo L, et al. Chronic HCV infection and inflammation: clinical impact on hepatic and extra‐hepatic manifestations. WJH. 2013;5(10):528‐540. doi:
Rusyn I, Lemon SM. Mechanisms of HCV‐induced liver cancer: what did we learn from in vitro and animal studies? Cancer Lett. 2014;345(2):210‐215. doi:
Gourama H, Bullerman LB. Aspergillus flavus and aspergillus parasiticus: Aflatoxigenic fungi of concern in foods and feeds: a review. J Food Prot. 1995;58(12):1395‐1404. doi:
Kumar P, Mahato DK, Kamle M, Mohanta TK, Kang SG. Aflatoxins: a global concern for food safety, human health and their management. Front Microbiol. 2017;7:1‐10. doi:
International Agency for Research on Cancer. Overall… Google Scholar. https://scholar.google.com/scholar_lookup?journal=IARC+Monogr+Eval+Carcinog+Risks+Hum+Suppl&title=Overall+evaluations+of+carcinogenicity:+an+updating+of+IARC+Monographs+volumes+1+to+42&volume=7&publication_year=1987&pages=1‐440&pmid=3482203&. Accessed Nov. 21, 2022
Hamid AS, Tesfamariam IG, Zhang Y, Zhang ZG. Aflatoxin B1‐induced hepatocellular carcinoma in developing countries: geographical distribution, mechanism of action and prevention. Oncol Lett. 2013;5(4):1087‐1092. doi:
Liu Y, Chang C‐CH, Marsh GM, Wu F. Population attributable risk of aflatoxin‐related liver cancer: systematic review and meta‐analysis. Eur J Cancer. 2012;48(14):2125‐2136. doi:
Sun Z, Chen T, Thorgeirsson SS, et al. Dramatic reduction of liver cancer incidence in young adults: 28 year follow‐up of etiological interventions in an endemic area of China. Carcinogenesis. 2013;34(8):1800‐1805. doi:
Nogueira JA, Ono‐Nita SK, Nita ME, et al. 249 TP53 mutation has high prevalence and is correlated with larger and poorly differentiated HCC in Brazilian patients. BMC Cancer. 2009;9(1):204. doi:
Obuseh FA, Jolly PE, Kulczycki A, et al. Aflatoxin levels, plasma vitamins a and E concentrations, and their association with HIV and hepatitis B virus infections in Ghanaians: a cross‐sectional study. J Int AIDS Soc. 2011;14(1):53. doi:
Macias RIR, Monte MJ, Serrano MA, et al. Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics. Aging (Albany NY). 2021;13(19):23416‐23434. doi:
Clifford RJ, Zhang J, Meerzaman DM, et al. Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma. Hepatology. 2010;52(6):2034‐2043. doi:
Guichard C, Amaddeo G, Imbeaud S, et al. Integrated analysis of somatic mutations and focal copy‐number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694‐698. doi:
Dragani TA. Risk of HCC: genetic heterogeneity and complex genetics. J Hepatol. 2010;52(2):252‐257. doi:
Shibata T. Genomic landscape of hepatocarcinogenesis. J Hum Genet. 2021;66(9):845‐851. doi:
Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1): [eLocator: a001008]. doi:
St. Pierre R, Kadoch C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev. 2017;42:56‐67. doi:
Müller M, Bird TG, Nault J‐C. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol. 2020;72(5):990‐1002. doi:
Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hot spot in the p53 gene in human hepatocellular carcinomas. Nature. 1991;350(6317):427‐428. doi:
Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 2008;26:535‐584. doi:
Jiang H, Cao HJ, Ma N, et al. Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1‐snail axis. Proc Natl Acad Sci U S A. 2020;117(9):4770‐4780. doi:
Pirazzi C, Valenti L, Motta BM, et al. PNPLA3 has retinyl‐palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014;23(15):4077‐4085. doi:
DeNicola GM, Karreth FA, Humpton TJ, et al. Oncogene‐induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475(7354):106‐109. doi:
Tao J, Krutsenko Y, Moghe A, et al. Nuclear factor erythroid 2–related factor 2 and β‐catenin coactivation in hepatocellular cancer: biological and therapeutic implications. Hepatology. 2021;74(2):741‐759. doi:
Taguchi K, Yamamoto M. The KEAP1–NRF2 system in cancer. Front Oncol. 2017;7:85. doi:
Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1‐Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568‐13573. doi:
Boyault S, Rickman DS, de Reyniès A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45(1):42‐52. doi:
Kim H, Park C‐K, Lee SJ, Rha SY, Park KH, Lim HY. PIK3CA mutations in hepatocellular carcinoma in Korea. Yonsei Med J. 2013;54(4):883‐887. doi:
Mills AA. The chromodomain helicase DNA‐binding chromatin remodelers: family traits that protect from and promote cancer. Cold Spring Harb Perspect Med. 2017;7(4): [eLocator: a026450]. doi:
Schneider A, Mehmood T, Pannetier S, Hanauer A. Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of coffin‐Lowry syndrome: altered ERK/MAPK in the mrsk2_KO hippocampus. J Neurochem. 2011;119(3):447‐459. doi:
Testino G, Leone S, Borro P. Alcohol and hepatocellular carcinoma: a review and a point of view. WJG. 2014;20(43):15943‐15954. doi:
Ganne‐Carrié N, Nahon P. Hepatocellular carcinoma in the setting of alcohol‐related liver disease. J Hepatol. 2019;70(2):284‐293. doi:
Dunn W, Shah VH. Pathogenesis of alcoholic liver disease. Clin Liver Dis. 2016;20(3):445‐456. doi:
Subramaniyan V, Chakravarthi S, Jegasothy R, et al. Alcohol‐associated liver disease: a review on its pathophysiology, diagnosis and drug therapy. Toxicol Rep. 2021;8:376‐385. doi:
Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004;127(5):S87‐S96. doi:
Huu Bich T, Thi Quynh Nga P, Ngoc Quang L, et al. Patterns of alcohol consumption in diverse rural populations in the Asian region. Glob Health Action. 2009;2(1):2017. doi:
Huang DQ, Mathurin P, Cortez‐Pinto H, Loomba R. Global epidemiology of alcohol‐associated cirrhosis and HCC: trends, projections and risk factors. Nat Rev Gastroenterol Hepatol. 2023;20(1):37‐49. doi:
GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990‐2019: a systematic analysis for the global burden of disease study 2019. Lancet. 2020;396(10258):1204‐1222. doi:
Burra P, Zanetto A, Germani G. Liver transplantation for alcoholic liver disease and hepatocellular carcinoma. Cancer. 2018;10(2):46. doi:
Petrick JL, Campbell PT, Koshiol J, et al. Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling project. Br J Cancer. 2018;118(7):1005‐1012. doi:
Turati F, Galeone C, Rota M, et al. Alcohol and liver cancer: a systematic review and meta‐analysis of prospective studies. Ann Oncol. 2014;25(8):1526‐1535. doi:
Yuan J‐M, Govindarajan S, Arakawa K, Yu MC. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. Cancer. 2004;101(5):1009‐1017. doi:
Calzadilla Bertot L, Adams LA. The natural course of non‐alcoholic fatty liver disease. Int J Mol Sci. 2016;17(5):774. doi:
Allen AM, Therneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: a 20 year‐community study. Hepatology. 2018;67(5):1726‐1736. doi:
White DL, Kanwal F, El‐Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10(12):1342‐1359.e2. doi:
Adams LA, Lymp JF, St. Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population‐based cohort study. Gastroenterology. 2005;129(1):113‐121. doi:
Stickel F, Hellerbrand C. Non‐alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut. 2010;59(10):1303‐1307. doi:
Shaker M. Liver transplantation for nonalcoholic fatty liver disease: new challenges and new opportunities. WJG. 2014;20(18):5320‐5330. doi:
Dyson J, Jaques B, Chattopadyhay D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60(1):110‐117. doi:
Pais R, Fartoux L, Goumard C, et al. Temporal trends, clinical patterns and outcomes of NAFLD‐related HCC in patients undergoing liver resection over a 20‐year period. Aliment Pharmacol Ther. 2017;46(9):856‐863. doi:
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123‐133. doi:
Park J‐W, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 2015;35(9):2155‐2166. doi:
Day CP, Saksena S. Non‐alcoholic steatohepatitis: definitions and pathogenesis. J Gastroenterol Hepatol. 2002;17(Suppl 3):S377‐S384. doi:
Almeda‐Valdés P, Cuevas‐Ramos D, Alberto Aguilar‐Salinas C. Metabolic syndrome and non‐alcoholic fatty liver disease. Ann Hepatol. 2009;8:S18‐S24. doi:
Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois‐Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015;35(10):2203‐2217. doi:
Takuma Y, Nouso K. Nonalcoholic steatohepatitis‐associated hepatocellular carcinoma: our case series and literature review. World J Gastroenterol. 2010;16(12):1436‐1441. doi:
Ascha MS, Hanouneh IA, Lopez R, Tamimi TA‐R, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51(6):1972‐1978. doi:
Degasperi E, Colombo M. Distinctive features of hepatocellular carcinoma in non‐alcoholic fatty liver disease. Lancet Gastroenterol Hepatol. 2016;1(2):156‐164. doi:
Hamid O, Eltelbany A, Mohammed A, Alsabbagh Alchirazi K, Trakroo S, Asaad I. The epidemiology of non‐alcoholic steatohepatitis (NASH) in the United States between 2010‐2020: a population‐based study. Ann Hepatol. 2022;27(5): [eLocator: 100727]. doi:
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047‐1053. doi:
Sanyal AJ, Banas C, Sargeant C, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43(4):682‐689. doi:
Michitaka K et al. Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol. 2010;45(1):86‐94. doi:
Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int. 2016;36(3):317‐324. doi:
Hashimoto E, Tokushige K. Hepatocellular carcinoma in non‐alcoholic steatohepatitis: growing evidence of an epidemic? Hepatol Res. 2012;42(1):1‐14. doi:
Sohn W, Lee HW, Lee S, et al. Obesity and the risk of primary liver cancer: a systematic review and meta‐analysis. Clin Mol Hepatol. 2021;27(1):157‐174. doi:
Aleffi S, Petrai I, Bertolani C, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005;42(6):1339‐1348. doi:
Saxena NK, Sharma D, Ding X, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin‐mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67(6):2497‐2507. doi:
Simmons O, Fetzer DT, Yokoo T, et al. Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis. Aliment Pharmacol Ther. 2017;45(1):169‐177. doi:
Gupta A, das A, Majumder K, et al. Obesity is independently associated with increased risk of hepatocellular cancer‐related mortality: a systematic review and meta‐analysis. Am J Clin Oncol. 2018;41(9):874‐881. doi:
Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4(8):579‐591. doi:
Zhang C, Liu S, Yang M. Hepatocellular carcinoma and obesity, type 2 diabetes mellitus, cardiovascular disease: causing factors, molecular links, and treatment options. Front Endocrinol. 2021;12: [eLocator: 808526]. doi:
Oh SW, Yoon YS, Shin S‐A. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. JCO. 2005;23(21):4742‐4754. doi:
Mittal S, El‐Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Supplement 1):S2‐S6. doi:
Kotsiliti E. Understanding HCC sex disparities. Nat Rev Gastroenterol Hepatol. 2022;19(3):147. doi:
Sukocheva OA. Estrogen, estrogen receptors, and hepatocellular carcinoma: are we there yet? World J Gastroenterol. 2018;24(1):1‐4. doi:
Yip TC, Wong GL, Chan HL, et al. Elevated testosterone increases risk of hepatocellular carcinoma in men with chronic hepatitis B and diabetes mellitus. J Gastroenterol Hepatol. 2020;35(12):2210‐2219. doi:
Petrick JL, Florio AA, Zhang X, et al. Associations between prediagnostic concentrations of circulating sex steroid hormones and liver cancer among postmenopausal women. Hepatology. 2020;72(2):535‐547. doi:
Cancer Today. http://gco.iarc.fr/today/home. Accessed Nov. 23, 2022
Rumgay H, Arnold M, Ferlay J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77(6):1598‐1606. doi:
Dasgupta P, Henshaw C, Youlden DR, Clark PJ, Aitken JF, Baade PD. Global trends in incidence rates of primary adult liver cancers: a systematic review and meta‐analysis. Front Oncol. 2020;10:1‐17. doi:
McGlynn KA, Petrick JL, El‐Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73(Suppl 1):4‐13. doi:
Sayiner M, Golabi P, Younossi ZM. Disease burden of hepatocellular carcinoma: a global perspective. Dig Dis Sci. 2019;64(4):910‐917. doi:
Maucort‐Boulch D, de Martel C, Franceschi S, Plummer M. Fraction and incidence of liver cancer attributable to hepatitis B and C viruses worldwide. Int J Cancer. 2018;142(12):2471‐2477. doi:
Zhang C, Cheng Y, Zhang S, Fan J, Gao Q. Changing epidemiology of hepatocellular carcinoma in Asia. Liver Int. 2022;42(9):2029‐2041. doi:
Chang M‐H, You SL, Chen CJ, et al. Long‐term effects of hepatitis B immunization of infants in preventing liver cancer. Gastroenterology. 2016;151(3):472‐480.e1. doi:
Ioannou GN, Green P, Kerr KF, Berry K. Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD‐related cirrhosis for risk stratification. J Hepatol. 2019;71(3):523‐533. doi:
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589‐604. doi:
Islami F, Miller KD, Siegel RL, Fedewa SA, Ward EM, Jemal A. Disparities in liver cancer occurrence in the United States by race/ethnicity and state. CA Cancer J Clin. 2017;67(4):273‐289. doi:
Asafo‐Agyei KO, Samant H. Hepatocellular Carcinoma. StatPearls. StatPearls Publishing; 2022 http://www.ncbi.nlm.nih.gov/books/NBK559177/. Accessed Sep. 18, 2022
Lin L, Yan L, Liu Y, Qu C, Ni J, Li H. The burden and trends of primary liver cancer caused by specific etiologies from 1990 to 2017 at the global, regional, national, age, and sex level results from the global burden of disease study 2017. Liver Cancer. 2020;9(5):563‐582. doi:
Ngatali Christian FS, Boumba ALM, Ebatetou A, et al. Hepatocellular carcinoma induced by viruses: epidemiological, clinical and therapeutic aspects In pointe noire (Congo Brazzaville). Cancer Sci Res. 2020;3(1):1‐5. doi:
Yang JD, Gyedu A, Afihene MY, et al. Hepatocellular carcinoma occurs at an earlier age in Africans, particularly in association with chronic hepatitis B. Am J Gastroenterol. 2015;110(11):1629‐1631. doi:
Kudo M. Management of hepatocellular carcinoma in Japan as a world‐leading model. Liver Cancer. 2018;7(2):134‐147. doi:
Yang JD, Mohamed EA, Aziz AO, et al. Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa liver cancer consortium. Lancet Gastroenterol Hepatol. 2017;2(2):103‐111. doi:
Kim YA, Kang D, Moon H, et al. Survival in untreated hepatocellular carcinoma: a national cohort study. PLoS One. 2021;16(2): [eLocator: e0246143]. doi:
Rutherford MJ, Arnold M, Bardot A, et al. Comparison of liver cancer incidence and survival by subtypes across seven high‐income countries. Int J Cancer. 2021;149(12):2020‐2031. doi:
Rich NE, Noureddin M, Kanwal F, Singal AG. Racial and ethnic disparities in non‐alcoholic fatty liver disease in the USA. Lancet Gastroenterol Hepatol. 2021;6(6):422‐424. doi:
Pinheiro PS, Callahan KE, Jones PD, et al. Liver cancer: a leading cause of cancer death in the United States and the role of the 1945–1965 birth cohort by ethnicity. JHEP Rep. 2019;1(3):162‐169. doi:
Ajayi F, Jan J, Singal AG, Rich NE. Racial and sex disparities in hepatocellular carcinoma in the USA. Curr Hepatol Rep. 2020;19(4):462‐469. doi:
Rich NE, Yopp AC, Singal AG, Murphy CC. Hepatocellular carcinoma incidence is decreasing among younger adults in the United States. Clin Gastroenterol Hepatol. 2020;18(1):242‐248.e5. doi:
USCS Data Visualizations. https://gis.cdc.gov/grasp/USCS/DataViz.html. Accessed Nov. 23, 2022
Sobotka LA, Hinton A, Conteh LF. African Americans are less likely to receive curative treatment for hepatocellular carcinoma. World J Hepatol. 2018;10(11):849‐855. doi:
Wagle NS, Park S, Washburn D, et al. Racial, ethnic, and socioeconomic disparities in curative treatment receipt and survival in hepatocellular carcinoma. Hepatol Commun. 2022;6(5):1186‐1197. doi:
null Wu C, Morris JR. Genes, genetics, and epigenetics: a correspondence. Science. 2001;293(5532):1103‐1105. doi:
Toh TB, Lim JJ, Chow EK. Epigenetics of hepatocellular carcinoma. Clin Transl Med. 2019;8(1):13. doi:
Wahid B, Ali A, Rafique S, Idrees M. New insights into the epigenetics of hepatocellular carcinoma. Biomed Res Int. 2017;2017:1‐16. doi:
Hama N, Totoki Y, Miura F, et al. Epigenetic landscape influences the liver cancer genome architecture. Nat Commun. 2018;9(1):1643. doi:
Calvisi DF, Ladu S, Gorden A, et al. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest. 2007;117(9):2713‐2722. doi:
Koni M, Pinnarò V, Brizzi MF. The Wnt Signalling pathway: a tailored target in cancer. IJMS. 2020;21(20):7697. doi:
Wolinska E, Skrzypczak M. Epigenetic changes affecting the development of hepatocellular carcinoma. Cancer. 2021;13(16):4237. doi:
O'Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol. 2018;9:402. doi:
Varghese RS, Zhou Y, Chen Y, Barefoot ME, Tadesse M, Ressom HW. Epigenetic changes associated with mechanisms of disparities in hepatocellular carcinoma. Paper presented at: 2020 42nd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), Montreal, QC, Canada, 2020, pp. 5320–5325; 2020. doi:
Kedar Mukthinuthalapati VVP, Sewram V, Ndlovu N, et al. Hepatocellular carcinoma in sub‐Saharan Africa. JCO Glob Oncol. 2021;7:756‐766. doi:
Zheng R, Qu C, Zhang S. Liver cancer incidence and mortality in China: temporal trends and projections to 2030. Chin J Cancer Res. 2018;30:571‐579. doi:
El‐Kassas M, Elbadry M. Hepatocellular carcinoma in Africa: challenges and opportunities. Front Med (Lausanne). 2022;9: [eLocator: 899420]. doi:
Béguelin C, Fall F, Seydi M, Wandeler G. The current situation and challenges of screening for and treating hepatitis B in sub‐Saharan Africa. Expert Rev Gastroenterol Hepatol. 2018;12(6):537‐546. doi:
Tenofovir Dosage Guide + Max Dose, Adjustments. Drugs.com. https://www.drugs.com/dosage/tenofovir.html. Accessed 22, 2022
Lovett GC, Nguyen T, Iser DM, et al. Efficacy and safety of tenofovir in chronic hepatitis B: Australian real world experience. World J Hepatol. 2017;9(1):48‐56. doi:
Hepatitis B. https://www.who.int/news-room/fact-sheets/detail/hepatitis-b. Accessed Nov. 20, 2022
Spearman CW, Afihene M, Ally R, et al. Hepatitis B in sub‐Saharan Africa: strategies to achieve the 2030 elimination targets. Lancet Gastroenterol Hepatol. 2017;2(12):900‐909. doi:
Xu W‐M, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double‐blind, placebo‐controlled study. J Viral Hepat. 2009;16(2):94‐103. doi:
Pan CQ, Duan Z, Dai E, et al. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324‐2334. doi:
Han G‐R, Cao MK, Zhao W, et al. A prospective and open‐label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol. 2011;55(6):1215‐1221. doi:
Breakwell L, Tevi‐Benissan C, Childs L, Mihigo R, Tohme R. The status of hepatitis B control in the African region. Pan Afr Med J. 2017;27(Suppl 3):17. doi:
Okeke E, Mark Davwar P, Mullen B, et al. The impact of HIV on hepatocellular cancer survival in Nigeria. Trop Med Int Health. 2021;26(3):335‐342. doi:
Thio CL, Seaberg EC, Skolasky R Jr, et al. HIV‐1, hepatitis B virus, and risk of liver‐related mortality in the multicenter cohort study (MACS). The Lancet. 2002;360(9349):1921‐1926. doi:
Fenwick C, Joo V, Jacquier P, et al. T‐cell exhaustion in HIV infection. Immunol Rev. 2019;292(1):149‐163. doi:
Clinton JW, Kiparizoska S, Aggarwal S, Woo S, Davis W, Lewis JH. Drug‐induced liver injury: highlights and controversies in the recent literature. Drug Safety. 2021;44:1125‐1149. doi:
PubChem, Elbasvir. https://pubchem.ncbi.nlm.nih.gov/compound/71661251. Accessed Dec. 30, 2022
PubChem, Grazoprevir. https://pubchem.ncbi.nlm.nih.gov/compound/44603531. Accessed Dec. 30, 2022
Rockstroh J, Nelson M, Katlama C, et al. Efficacy and safety of grazoprevir (MK‐5172) and elbasvir (MK‐8742) in patients with hepatitis C virus and HIV co‐infection (C‐EDGE CO‐INFECTION): a non‐randomised, open‐label trial. Lancet HIV. 2015;2(8):e319‐e327. doi:
PubChem, Pibrentasvir. https://pubchem.ncbi.nlm.nih.gov/compound/58031952. Accessed Dec. 30, 2022
PubChem, Glecaprevir. https://pubchem.ncbi.nlm.nih.gov/compound/66828839. Accessed Dec. 30, 2022
Rockstroh J, Lacombe K, Viani RM, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients coinfected with hepatitis C virus and human immunodeficiency virus type 1: the EXPEDITION‐2 study. Clin Infect Dis. 2018;67(7):1010‐1017. doi:
PubChem, Ledipasvir. https://pubchem.ncbi.nlm.nih.gov/compound/67505836. Accessed Dec. 30, 2022
PubChem, Sovaldi. https://pubchem.ncbi.nlm.nih.gov/compound/45375808. Accessed Dec. 30, 2022
Naggie S, Cooper C, Saag M, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV‐1. N Engl J Med. 2015;373(8):705‐713.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease‐meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73‐84. doi:
Debes JD, Chan AJ, Balderramo D, et al. Hepatocellular carcinoma in South America: evaluation of risk factors, demographics and therapy. Liver Int. 2018;38(1):136‐143. doi:
Ward ZJ, Bleich SN, Cradock AL, et al. Projected U.S. state‐level prevalence of adult obesity and severe obesity. N Engl J Med. 2019;381(25):2440‐2450. doi:
Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017;377(21):2063‐2072. doi:
Anderson EL, Howe LD, Jones HE, Higgins JPT, Lawlor DA, Fraser A. The prevalence of non‐alcoholic fatty liver disease in children and adolescents: a systematic review and meta‐analysis. PLoS One. 2015;10(10): [eLocator: e0140908]. doi:
Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study—PubMed. https://pubmed.ncbi.nlm.nih.gov/26599351/. Accessed Nov. 20, 2022
Ahmed MH, Noor SK, Bushara SO, et al. Non‐alcoholic fatty liver disease in Africa and Middle East: an attempt to predict the present and future implications on the healthcare system. Gastroenterol Res. 2017;10(5):271‐279. doi:
Ge X, Zheng L, Wang M, Du Y, Jiang J. Prevalence trends in non‐alcoholic fatty liver disease at the global, regional and national levels, 1990–2017: a population‐based observational study. BMJ Open. 2020;10(8): [eLocator: e036663]. doi:
Haldar D, Kern B, Hodson J, et al. Outcomes of liver transplantation for non‐alcoholic steatohepatitis: a European liver transplant registry study. J Hepatol. 2019;71(2):313‐322. doi:
de Villa V, Lo CM. Liver transplantation for hepatocellular carcinoma in Asia. Oncologist. 2007;12(11):1321‐1331. doi:
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693‐699. doi:
Saidi RF, Hejazii Kenari SK. Challenges of organ shortage for transplantation: solutions and opportunities. Int J Organ Transplant Med. 2014;5(3):87‐96.
Facciorusso A, Serviddio G, Muscatiello N. Local ablative treatments for hepatocellular carcinoma: an updated review. World J Gastrointest Pharmacol Ther. 2016;7(4):477‐489. doi:
Chavda VP, Solanki HK, Davidson M, Apostolopoulos V, Bojarska J. Peptide‐drug conjugates: a new Hope for cancer management. Molecules. 2022;27(21):7232. doi:
Negro R, Greco G. Percutaneous ethanol injection in combination with laser ablation for a 100 ml partially cystic thyroid nodule. Case Rep Endocrinol. 2018;2018:1‐3. doi:
Huang G‐T, Lee PH, Tsang YM, et al. Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study. Ann Surg. 2005;242(1):36‐42. doi:
European Association for the Study of the Liver and European Organisation for Research and Treatment of Cancer. EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908‐943. doi:
Ramsey DE, Kernagis LY, Soulen MC, Geschwind J‐FH. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol. 2002;13(9):S211‐S221. doi:
Lee S. Transarterial chemoembolization (TACE) for liver cancer. Can Cancer Soc. https://cancer.ca/en/cancer-information/cancer-types/liver/treatment/transarterial-chemoembolization. Accessed Dec. 22, 2022
Zhang L, Sun JH, Ji JS, et al. Imaging changes and clinical complications after drug‐eluting bead versus conventional transarterial chemoembolization for unresectable hepatocellular carcinoma: multicenter study. Am J Roentgenol. 2021;217(4):933‐943. doi:
Chavda VP. Chapter 1—Nanotherapeutics and nanobiotechnology. In: Mohapatra SS, Ranjan S, Dasgupta N, Mishra RK, Thomas S, eds. Applications of Targeted Nano Drugs and Delivery Systems. Elsevier; 2019:1‐13. doi:
Kong J‐Y, Li S‐M, Fan H‐Y, Zhang L, Zhao H‐J, Li S‐M. Transarterial chemoembolization extends long‐term survival in patients with unresectable hepatocellular carcinoma. Medicine (Baltimore). 2018;97(33): [eLocator: e11872]. doi:
Tella SH, Kommalapati A, Mahipal A, Jin Z. First‐line targeted therapy for hepatocellular carcinoma: role of atezolizumab/bevacizumab combination. Biomedicine. 2022;10(6):1304. doi:
Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;2014: [eLocator: 638747]. doi:
Yamashita T, Kudo M, Ikeda K, et al. REFLECT—a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020;55(1):113‐122. doi:
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first‐line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non‐inferiority trial. Lancet. 2018;391(10126):1163‐1173. doi:
Raedler LA. Opdivo (Nivolumab): second PD‐1 inhibitor receives FDA approval for Unresectable or metastatic melanoma. Am Health Drug Benefits. 2015;8:180‐183.
Motzer RJ, Tannir NM, McDermott D, et al. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal‐cell carcinoma. N Engl J Med. 2018;378(14):1277‐1290. doi:
Ansell SM, Lesokhin AM, Borrello I, et al. PD‐1 blockade with Nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311‐319. doi:
Wolchok JD, Chiarion‐Sileni V, Gonzalez R, et al. Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345‐1356. doi:
Larkin J, Chiarion‐Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23‐34. doi:
Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non‐small cell lung cancer‐recent advances and future perspectives: targeted therapies for treatment of NSCLC. Int J Cancer. 2016;138(11):2549‐2561. doi:
Vokes EE, Ready N, Felip E, et al. Nivolumab versus docetaxel in previously treated advanced non‐small‐cell lung cancer (CheckMate 017 and CheckMate 057): 3‐year update and outcomes in patients with liver metastases. Ann Oncol. 2018;29(4):959‐965. doi:
C. for D. E. and Research. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. 2019; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-hcc-previously-treated-sorafenib. Accessed Dec. 29, 2022
Guo A, Pomenti S, Wattacheril J. Health disparities in screening, diagnosis, and treatment of hepatocellular carcinoma. Clin Liver Dis. 2021;17(5):353‐358. doi:
Choi DT, Davila JA, Sansgiry S, et al. Factors associated with delay of diagnosis of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2021;19(8):1679‐1687. doi:
Braveman P, Gottlieb L. The social determinants of health: It's time to consider the causes of the causes. Public Health Rep. 2014;129(1_suppl 2):19‐31. doi:
Cucchetti A, Gramenzi A, Johnson P, et al. Material deprivation affects the management and clinical outcome of hepatocellular carcinoma in a high‐resource environment. Eur J Cancer. 2021;158:133‐143. doi:
Kronenfeld JP, Ryon EL, Goldberg D, et al. Survival inequity in vulnerable populations with early‐stage hepatocellular carcinoma: a United States safety‐net collaborative analysis. HPB. 2021;23(6):868‐876. doi:
McWilliams JM. Health consequences of Uninsurance among adults in the United States: recent evidence and implications. Milbank Q. 2009;87(2):443‐494. doi:
Rao A, Rich NE, Marrero JA, Yopp AC, Singal AG. Diagnostic and therapeutic delays in patients with hepatocellular carcinoma. J Natl Compr Cancer Netw. 2021;19(9):1063‐1071. doi:
Rich NE, John BV, Parikh ND, et al. Hepatocellular carcinoma demonstrates heterogeneous growth patterns in a multicenter cohort of patients with cirrhosis. Hepatology. 2020;72(5):1654‐1665. doi:
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
© 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Abstract
Background
Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. The incidence of HCC is affected by genetic and non‐genetic factors. Genetically, mutations in the genes, tumor protein P53 (TP53), catenin beta 1 (CTNNB1), AT‐rich interaction domain 1A (ARIC1A), cyclin dependent kinase inhibitor 2A (CDKN2A), mannose 6‐phosphate (M6P), smooth muscle action against decapentaplegic (SMAD2), retinoblastoma gene (RB1), cyclin D, antigen presenting cells (APC), AXIN1, and E‐cadherin, have been shown to contribute to the occurrence of HCC. Non‐genetic factors, including alcohol consumption, exposure to aflatoxin, age, gender, presence of hepatitis B (HBV), hepatitis C (HCV), and non‐alcoholic fatty liver disease (NAFLD), increase the risk of HCC.
Recent Findings
The severity of the disease and its occurrence vary based on geographical location. Furthermore, men and minorities have been shown to be disproportionately affected by HCC, compared with women and non‐minorities. Ethnicity has been reported to significantly affect tumorigenesis and clinical outcomes in patients diagnosed with HCC. Generally, differences in gene expression and/or the presence of comorbid medical diseases affect or influence the progression of HCC. Non‐Caucasian HCC patients are significantly more likely to have poorer survival outcomes, compared to their Caucasian counterparts. Finally, there are a number of factors that contribute to the success rate of treatments for HCC.
Conclusion
Assessment and treatment of HCC must be consistent using evidence‐based guidelines and standardized outcomes, as well as international clinical practice guidelines for global consensus. Standardizing the assessment approach and method will enable comparison and improvement of liver cancer research through collaboration between researchers, healthcare providers, and advocacy groups. In this review, we will focus on discussing epidemiological factors that result in deviations and changes in treatment approaches for HCC.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details
1 Department of Pharmaceutics and Pharmaceutical Technology, L M College of Pharmacy, Ahmedabad, India
2 Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Ohio, USA
3 Pharmacy Section, L M College of Pharmacy, Ahmedabad, India
4 Department of Pharmacology, L M College of Pharmacy, Ahmedabad, India
5 PharmD Section, L M College of Pharmacy, Ahmedabad, India
6 Department of Pharmaceutical Sciences, College of Pharmacy, St. John's University, New York, New York, USA
7 Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, USA