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. 2024 Aug 28;15(1):102406. doi: 10.1016/j.jceh.2024.102406

Evolving Global Etiology of Hepatocellular Carcinoma (HCC): Insights and Trends for 2024

Abraham Koshy 1
PMCID: PMC11426038  PMID: 39346785

Abstract

The epidemiology of HCC is changing all over the world and the incidence of HCC is expected to continue increasing over the next 30 years. The changes are in the predisposing factors. Hepatitis B and hepatitis C as predisposing etiologies are decreasing while NAFLD/MAFLD is increasing. The increase in MAFLD is so great that despite the decrease in hepatitis B and C, the overall incidence of HCC is increasing. HCC in persons below the age of 20 years has distinct characteristics different from that of HCC in adults. The changing etiology of hepatocellular carcinoma has implications for the early detection, prevention, the stage of HCC at time of detection and in the treatment of HCC. The extent of these changes and their significance are discussed.

Keywords: cancer, liver, alcohol, diabetes mellitus, obesity

According to the global cancer registry, HCC was the 6th commonest cancer in incidence and the 3rd largest contributor to cancer mortality, in 2022 (Figure 1).1 It also estimates that the incidence will continue to increase over the next 30 years, in both men and women (Figure 2). Global cancer observatory also estimates that India has a relatively low age-standardized HCC rate of 2.7/100,000 population (Figure 3). However, the mortality due to HCC in India was estimated by the Indian Council of Medical Research (ICMR) to be 6.8/100,000 population.2 There have been three INASL recommendations on hepatocellular carcinoma but these have not specifically reviewed the evolving etiology or epidemiology of HCC.3, 4, 5

Figure 1.

Figure 1

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Global cancer site ranking.1

Figure 2.

Figure 2

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Estimated numbers from 2022 to 2050, Males and Females, age [0-85+] Liver and intrahepatic bile ducts,.1

Figure 3.

Figure 3

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Age-standardized rate (Asia) per 100,000, Incidence, Both sexes, in 2022 Liver and intrahepatic bile ducts.1 ASR, Age-Standardized Rate.

HCC is more common in men than in women. The combined data of two large studies from India show that 86% were male.6,7 The reason is not clear. Hypothesis includes: a) Hormonal differences: Estrogen is believed to have a protective role in the development of HCC. b) Gender-specific lifestyle and social environments: These include alcohol consumption, smoking, higher prevalence of HBV and HCV infection. c) Lower adiponectin levels found in men may account for the increased incidence of HCC in men (Figure 4,8,9). The effect of testosterone may be mediated by several substances that act like oncogenes. They include SRY, CCRK, Foxa, miR-216a and miR-22 which are all up-regulated in males (Figure 4,10). Sex-determining region Y (SRY) codes for testis determining factor (TDF) which is increased in HCC cell lines. Transgenic mice overexpressing TDF are more prone to HCC. SRY acts through the PI3K, AKT, mTOR pathway.10 Cell cycle-related kinase (CCRK) acts as an HCC promoter through the beta-catenin, T cell factor pathway. CCRK transcription is increased by androgen.10 Forkhead box a (Foxa) is essential for androgen signaling to promote HCC. Up-regulation of miR-216a and miR-22 also promote HCC in males.10 The inhibition of HCC in females may be mediated through estrogen or the X chromosome (Figure 4). They act like tumor suppressors. The inhibition of HCC through estrogen may be through miR-18a, PTPRO, IL-6, GPER, TAM and NLRP3.10 The inhibition of HCC through the X chromosome may be through LncRNA FTX and XIST. miR-18a inhibits estrogen receptor transcription, reduces the protective effect of estrogen and is increased in HCC in women.10 The receptor type tyrosine-protein phosphate (PTPRO) is up-regulated by estrogen and acts as a tumor suppressor by STAT3 inactivation.10 Interleukin 6 (IL-6) is produced by Kuppfer cells. IL-6 acts as an oncogene. Estrogen reduces IL-6 production in Kuppfer cells. HCC is associated with elevated IL-6 levels in women and that IL-6 contributes to gender differences.10 G-protein coupled estrogen receptor (GPER) is a membrane estrogen receptor. GPER acts as a tumor suppressor through the mTORc2 pathway.10 Tumor-associated macrophages (TAMs) play a role in tumor development and progression. Estrogen suppresses the alternative pathway (M2) of TAM activation, thereby suppressing HCC.10 Nucleotide-binding domain leucine-rich-containing family pyrin domain-containing family 3 (NLRP3) acts as a tumor suppressor. NLRP3 is increased by estrogen through the NLRP3 inflammasome.10 The X chromosome acts as a tumor suppressor. LncRNA FTX reduces the inactivation of the X chromosome. In hepatocytes, women express more LncRNA FTX than men. Reduced LncRNA FTX correlates with HCC. X chromosome inactivation escape molecule (XIST) acts as a tumor suppressor. Women express more XIST than men through TET2/YY1 binding to the promoter region of XIST (Figure 4,11).

Figure 4.

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Postulated hormonal mechanism to explain why HCC is more common in men than in women.8 Adapted from Greten TF. J Exp Med. 2019;216:1014-1015.

Most HCCs are found in patients with cirrhosis irrespective of sex. The combined data of two large studies in India show that show 78% had cirrhosis.6,7 The reason is not clear. The accumulation of somatic mutations with the duration of disease is a possibility. Significant number of patients with HBV and NASH may develop HCC before development of cirrhosis.12,13 HBV is directly oncogenic. The reason for NASH predisposing to HCC without cirrhosis is not clear, although several potential pathways are under investigation.14,15 However, the studies showing HCC without cirrhosis are based on surrogate markers and not on histology, except in a few individual cases.

HCC increases with age in both men and women. The combined data of two large studies in India and a meta-analysis show peak incidence in the 60 to 69 age group (Figure 5,6,7,16). There may be multiple reasons. a) Prevalence of cirrhosis increases with age. b) There is a longer exposure to the predisposing factors such as HBV, NASH and alcohol with age. c) Accumulation of somatic mutations with age and the duration of cirrhosis.17

Figure 5.

Figure 5

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Age at detection of HCC in India,.6,7

CHANGE IN HCC PREDISPOSING FACTORS OVER TIME

Effect of HBV Vaccination and Treatment

The Shanghai Vaccination Program was accompanied by decrease of age-standardized rates (ASRs) of HCC from 33.38 in males and 11.65 in females per 100,000 in 1973 to 17.34 in males and 5.60 in females in 2014, respectively (Figure 6,18,19) and treatment of HBV with anti-viral drugs reduce HCC rate (Figure 7,20). These measures have reduced the HBV induced HCC over the last 5 decades. A meta-analysis of 60 publications from India between 1990 and 2023 showed a decreasing prevalence of HBV and increasing prevalence of NASH as an etiologic factor in HCC.16 However, in some parts of the world, HBV is still the major predisposing factor.

Figure 6.

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Incidence of HCC from 1973 to 2014 in Shanghai City.18

Figure 7.

Figure 7

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Treatment of HBV with antivirals reduces incidence of HCC.20,22 HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ETV, entecavir; LAM, lamivudine; TDF, tenofovir disoproxil fumarate.

Effect of HCV Treatment

Treatment of HCV with anti-viral drugs reduce HCC rate (Figure 8,21,22). Treatment of HCV has reduced HCV induced HCC over the last 2 decades.

Figure 8.

Figure 8

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Treatment of HCV with antivirals reduces incidence of HCC.20,22 HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SVR, sustained viral response.

Effect of Increasing Obesity, Diabetes, and NASH

Globally, obesity is increasing at about 2% per year (Figure 9,23). Globally, diabetes has been increasing over the last 3 decades (Figure 10,24). The global prevalence of NAFLD has increased from 26% in 2005 to 38% in 2016 (Figure 11,25,26). Increasing obesity, diabetes and NASH has made NASH the fastest growing cause of hepatocellular carcinoma waiting for liver transplant in the USA (Figure 12,27). Globally, the increasing NASH has overtaken the decreasing contribution of HBV and HCV, so that the total number of HCC is increasing.1 A multicenter study and a meta-analysis from India also showed a decreasing prevalence of HBV and increasing prevalence of NASH as an etiologic factor in HCC.16,28

Figure 9.

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Global trend in obesity.23

Figure 10.

Figure 10

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Age-standardized global rate of diabetes.24

Figure 11.

Figure 11

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Global prevalence of NAFLD increasing over time, %.25,61

Figure 12.

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NASH HCC.27 ALD, alcohol-associated liver disease; CHB, chronic hepatitis B; CHC, chronic hepatitis C; NASH, non-alcoholic steatohepatitis.

IMPLICATION OF CHANGE IN PREDISPOSING FACTORS IN DETECTION OF EARLY HCC

The combined data of two large studies in India show that in India, HCC is usually detected at a late stage when curative therapy is not possible.6,7 APASL guidelines recommend surveillance for all patients with cirrhosis irrespective of etiology, to detect early HCC. Surveillance by ultrasound with or without AFP is recommended. In addition, AASLD recommends surveillance for HBsAg positive Asian men over the age of 40, HBsAg positive Asian women over the age of 50 and HBsAg positive persons with a first-degree family member with HCC, even if they do not have cirrhosis.29 There is no uniform international recommendation regarding surveillance for patients with NASH without cirrhosis. However, there is increasing evidence that a significant proportion of patients with NASH develop HCC before they are detected to have cirrhosis.30 AGA recommends that HCC surveillance be considered for patients with NASH if they have evidence of advanced fibrosis. A Fib-4 score of >2.67 appears a reasonable cut-off.31,32

There is no consensus on the methodology to enhance early detection of HCC. Several methods may be considered. These include optimal identification of at risk individuals and using optimal screening tests.33 Optimal identification of at risk individuals may include one-time assessment for fibrosis stage in all overweight individuals, diabetics, those with HBsAg positive and those using excessive alcohol assessed by 3-question Audit C questionnaire.33 PAGE-B score is a simple risk calculator for patients with chronic hepatitis B. It uses age, sex and platelet count to calculate the risk score.33 A Fib-4 > 2.67 may be used for patients with NAFLD/MAFLD. Optimal screening requires improved risk calculators. Optimal screening requires better implementation of currently recommended 6-monthly US and AFP. Multiple barriers have been identified at both the patient and provider level.33 They include awareness of the benefits of screening, the cost of screening and logistics. Automated screening reminders may help. Automatic scheduling of abbreviated MRI for those with unsatisfactory US visualization may also help.34 However, there are no clear solutions.

There are several emerging screening modalities. These include biomarkers, abbreviated MRI and radiomics.35 Biomarkers include DCP (PIVKA), GALAD, aMAP, circulating long noncoding RNA and micro RNAs, circulating tumor cells (ctDNA), cell-free DNA (cfDNA) including DNA methylation,36 DNA fragmentation37 and extracellular vesicle-based biomarkers.35 Multi-cancer early detection (MCED) tests use ctDNA sequence and methylation.33 Abbreviated MRI, uses reduced number of sequences with equal sensitivity and specificity as standard CEMRI, reducing time and cost.34 Radiomics uses mathematic modeling of the digital data from CT or MRI with artificial intelligence to analyze lesions in seconds and assist the radiologist in interpretation.33 These emerging technologies require further validation before being incorporated into the standard of care. The 2022 Chinese guidelines for HCC surveillance recommends aMAP (age-Male-ALBI-Platelets) scoring for all men aged more than 40 years with HBV or HCV, alcohol abuse, NASH or family history of HCC; and surveillance for those with aMAP score >60.38 The 2021 Japanese guidelines on HCC recommends combining AFP, AFP-L3 fraction, and PIVKA-II/DCP for HCC surveillance with cut-off values of 10 ng/mL, 10%, and 40 mAU/mL respectively.39

IMPLICATION OF CHANGE IN PREDISPOSING FACTORS IN PREVENTION OF HCC

The advances in the management of HBV and HCV had a significant impact on the prevention of HCC. However, increasing NASH related HCC demands new strategies to prevent HCC. Exercise and maintenance of normal weight have the greatest impact on NASH prevention. FDA has recently approved GLP-1 analogs semaglutide, and tirzepatide for weight reduction but not for NASH.40,41 Tirzepatide reduces weight by about 20%. Retatrutide targets GLP-1, GIP and glucagon receptors.42 Retatrutide normalized liver fat in 90% of patients in phase 2 study but is still in phase 3 trial.42,43 Resmetirom is an oral, once-daily, liver-targeted thyroid hormone receptor (THR-β) selective agonist44 and has become the first drug to be approved for NASH.45 Survodutide and CagriSema are two other new drugs in phase 3 trial.46,47 The 20% weight reduction, reduction of liver fat to normal levels and reduction in inflammation and fibrosis in 25% of patients with the new drugs is very promising. In future, some of these drugs may be used in combination. However, it will take 10–20 years for the new drugs to show an effect on HCC prevention.

STAGE OF HCC AT TIME OF DETECTION AND ITS IMPLICATION IN TREATMENT OF HCC

A large study in India, showed that HCC is usually detected at a late stage when curative therapy is not possible.6 HCC surveillance improves early detection, curative treatment and survival in patients with cirrhosis.48 However, in the USA, less than 20% of patients with cirrhosis undergo regular surveillance for HCC.49 Several barriers have been identified.50 Large scale adoption of surveillance is necessary to improve early detection of HCC and in turn, have an epidemiologic effect on survival of patients detected with HCC.

PEDIATRIC HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma can occur in children, although only 1% of HCC occur in those less than 20 years.51,52 Primary liver cancers account for 1–2% of all pediatric solid cancers.53 In children, primary liver cancers have a bimodal age distribution (Figure 13,54). Hepatoblastoma occur in children below the age of 8, is associated with high serum alpha-fetoprotein, have embryonic cell features on histology and are usually beta catenin stain positive on immunohistochemistry.55 They will not be discussed further. Hepatocellular carcinoma in children usually occurs between the ages of 8 and 18.54 Major risk factors for pediatric HCC are peri-natal HBV transmission and metabolic disorders such as Tyrosinemia (Table 1,56). Universal HBV vaccination at birth since 1984 has resulted in reduction of pediatric HCC in Taiwan (Figure 14,57). Universal HBV vaccination at birth was introduced in USA in 1991 and the age adjusted rate of HCC in children have remained the same since 2002.52 Therefore, the impact of universal HBV vaccination at birth, on the incidence of HCC in children is expected predominantly in the in the first 10 years after introduction of universal vaccination. In India, universal HBV vaccination of infants was introduced in a phased manner between 2002 and 2012.58 In India, HBV induced HCC in children was reported in 2006.59 Since 2006, the risk factors reported for HCC in children in India, have been mainly Tyrosinemia, and cholestatic liver disorders (Table 1). Hepatocellular carcinoma in children has many etiologic and epidemiologic features that are different from hepatocellular carcinoma in adults (Table 2). There is no recommendation to screen children below the age of 8 for hepatoblastoma. It has been suggested that persons between the ages of 8 and 20 years, who are HBsAg positive or have tyrosinemia be screened every 6 months with US and AFP just like adults, but the recommendation has not been incorporated into guidelines.60

Figure 13.

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NCCR database. All ICCC Sites Combined Incidence Rates by Age at Diagnosis, 2016–2020.54 ICCC, International Classification of Childhood Cancer; NCCR, National Childhood Cancer Registry.

Table 1.

Underlying Liver Disorders Which are Risk Factors for HCC in Persons Below 20 years of Age, Detected at Liver Transplantation, n = 226.56

Risk factor % (n = 226) India (n = 22, Supplementary Table 1) Turkey (n = 6,62)
Tyrosinemia 34% 6 1
Biliary atresia 11% 2
PFIC 8% 3 4
HBV 7% 5
Alagille 4% 3
Others 35% 3 1
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HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PFIC, progressive familial intrahepatic cholestasis.

Figure 14.

Figure 14

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Reduction in HCC in age group 6–19 after universal HBV vaccination in Taiwan.57 Pre-HBV vaccination (PreVac), 1973 to 1984, Post-HBV vaccination (PostVac), 1984 to 2004.

Table 2.

Differences Between HCC in Adults Versus HCC in Persons Below the Age of 20.

Pediatric and adolescent Adult
Incidence52 1% of adult 100% (Reference)
Risk factors60 HBV, Metabolic liver disease HBV, NASH, alcohol
M:F ratio52 1:1 4:1
Incidence52 Constant Increasing
Fibrolamellar type60,63 20% 5%
Staging for treatment4,64,65 PRETEXT BCLC
Chemotherapy4,60,65 PLADO atezolizumab + bevacizumab
5-year survival51,52,54 50% 20%
Contraindication to LTx4,65 Metastasis, vascular invasion Beyond Milan
Benefit of surveillance60,66,67 Uncertain Universally accepted
Benefit of down-staging prior to LTx56,68,69 Uncertain Universally accepted
Presence of cirrhosis51,52,60 50% 80%
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BCLC, Barcelona clinic liver cancer; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; NASH, nonalcoholic steatohepatitis; PLADO, PLADO chemotherapy consisting of cisplatin and doxorubicin; PRETEXT, pre-treatment extent of disease staging system.

Credit authorship contribution statement

The author confirms sole responsibility for the following: study conception and design, data collection, analysis and interpretation of results, and manuscript preparation.

Funding

This study was internally funded.

Consent

Research guidelines of the Ethical Committee, Lakeshore Hospital, Kochi, India, for the protection of Human subjects were followed.

Ethics statement

The study was performed conforming to the Helsinki Declaration of 1975, as revised in 2000 and 2008 concerning human and animal rights, and that the authors followed the policy concerning informed consent as shown on Springer.com.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jceh.2024.102406.

Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.docx (22.2KB, docx)

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