Introduction
Hepatocellular carcinoma (HCC; ICD-10 C22.0) is the predominant histological subtype of primary liver cancer, accounting for approximately 75–85% of all primary liver malignancies. It must be distinguished from intrahepatic cholangiocarcinoma (ICC; C22.1) and combined hepatocellular-cholangiocarcinoma, as these entities differ in etiology, treatment, and prognosis. Most global statistics for "liver cancer" (C22) aggregate HCC and ICC, and this distinction has important implications for comparability across datasets. The following narrative review synthesizes data from the International Agency for Research on Cancer (IARC) GLOBOCAN 2022 estimates, the Global Burden of Disease (GBD) studies (2021 and 2023), and supporting epidemiological analyses to characterize the global and regional burden of HCC in adults.
Global and Regional Burden: Incidence and Mortality
In 2022, GLOBOCAN estimated 865,269 new liver cancer (C22) cases globally, representing 4.3% of all cancers, and 757,948 deaths, accounting for 7.8% of all cancer deaths — ranking liver cancer 6th in incidence and 3rd in cancer mortality worldwide 2. HCC-specific estimates for 2022 identified 684,659 new HCC cases with an age-standardized incidence rate (ASR — a summary measure adjusted to a standard population to enable fair geographic and temporal comparisons) of 6.8 per 100,000, and 597,434 HCC-related deaths with an ASR mortality of 5.9 per 100,000 1. A parallel analysis of the broader liver cancer category yielded a global age-standardized incidence rate (ASIR) of 8.6 per 100,000 and age-standardized mortality rate (ASMR) of 7.4 per 100,000, with a mortality-to-incidence ratio (MIR) of 0.86 — reflecting the high case fatality characteristic of this malignancy 5.
Using GBD 2021 data, total prevalent HCC cases in 2021 reached 739,299 (95% uncertainty interval [UI]: 673,114–821,948), with an age-standardized prevalence rate of 8.68 per 100,000 4.
Table 1: Global HCC Burden Summary (2021–2022)
| Metric | Estimate | Source |
|---|---|---|
| New HCC cases (2022) | 684,659 | 1 |
| HCC ASR incidence (2022) | 6.8 per 100,000 | 1 |
| HCC deaths (2022) | 597,434 | 1 |
| HCC ASR mortality (2022) | 5.9 per 100,000 | 1 |
| Liver cancer ASIR (2022) | 8.6 per 100,000 | 5 |
| Liver cancer ASMR (2022) | 7.4 per 100,000 | 5 |
| Prevalent liver cancer cases (2021) | 739,299 | 4 |
| Age-standardized prevalence rate (2021), liver cancer | 8.68 per 100,000 | 4 |
Sex stratification is pronounced. Males bear approximately 2.6–2.7 times the burden of females. In 2022, males accounted for 69.35% of liver cancer cases (600,676 cases; ASR 12.7 per 100,000) and 68.78% of deaths (521,826 deaths; ASR 10.9 per 100,000), compared with female ASRs of 4.8 per 100,000 for incidence and 4.1 per 100,000 for mortality 25. GBD 2021 data confirmed that males constituted 70.41% of prevalent cases (520,500 cases; age-standardized prevalence rate 127.6 per 100,000) versus 29.59% for females (218,700 cases; rate 49.5 per 100,000) 4.
Regional heterogeneity is extreme. Eastern Asia (WHO Western Pacific Region, WPR) dominates globally, contributing 49.96% of all liver cancer cases (432,684 cases; ASIR 14.7 per 100,000). China alone accounted for 42.45% of global cases (367,657 cases; ASIR 15.0 per 100,000) 5. Mongolia exhibited the highest national ASIR at 96.1 per 100,000 — far exceeding any other country 5. Northern Africa (Eastern Mediterranean Region, EMR) recorded an ASIR of 14.2 per 100,000 and the highest ASMR globally at 13.7 per 100,000 5. Asia overall accounted for 69.98% of all HCC deaths (530,928 deaths; ASMR 8.7 per 100,000) 5. The Latin America and Caribbean subregion (part of the WHO Americas Region, AMR) recorded the lowest age-standardized mortality rate at 2.45 per 100,000 and the fewest deaths (15,055) among major world regions 4. The MIR varied inversely with the Human Development Index — countries with very high HDI had MIR of 0.76, while low-HDI countries had MIR of 0.96 — reflecting differential access to surveillance and treatment 5.
Temporal Trends (1990–2022) and Contextual Drivers
GBD 2021 data document a near-doubling of prevalent HCC cases from 345,912 (95% UI: 299,826–376,632) in 1990 to 739,299 in 2021, with the age-standardized prevalence rate rising from 7.75 to 8.68 per 100,000 4. Crucially, while absolute burden has grown due to population aging and growth, age-standardized mortality rates have declined by approximately 3.75% from 1990 to 2021 overall, with East Asia, South Asia, and Oceania achieving a more substantial 19.65% decrease in ASR mortality — likely reflecting the impact of HBV vaccination programs and improved antiviral therapies 49.
In contrast, HCC rates have increased in Western countries (United States, Australia, several European nations), driven by rising obesity, metabolic syndrome, and alcohol-related liver disease 9. In the United States, age-adjusted HCC incidence in Hispanics has surpassed that in Asians, signaling shifting demographic and metabolic risk factor patterns 9.
The introduction of interferon-free direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection represents the most transformative pharmacological intervention of the past decade for HCC prevention. DAA treatment has been projected to prevent 526,084 cirrhosis cases and 256,315 HCV-associated deaths by 2040 if treatment rates quadruple 6. Registry analyses confirmed a 32% reduction in HCV-related decompensated cirrhosis liver transplant wait-listing in the DAA era compared to the interferon era 7, and European Liver Transplant Registry data showed HCV-related liver transplants declined from 21.1% to 10.6% of all transplants between 2014 and 2017 8.
Etiology: Regional Attribution and Key Pathways
An estimated 78.4% (536,571/684,659) of global HCC cases in 2022 were attributable to nine evaluated modifiable risk factors across three categories: infectious, behavioral/toxic, and metabolic 1.
Table 2: Etiologic Attribution of HCC by Risk Factor Category and Region (2022)
| Category | Global Attribution | Regional Highlights |
|---|---|---|
| Infections (HBV, HCV, C. sinensis) | 65.9% of attributable cases | HBV: 72.5% in Eastern Asia (WPR); HCV: 43.9% in Northern Africa (EMR) |
| Behavioral/toxic (alcohol, smoking, aflatoxin B1) | 22.4% | Alcohol: 24.9% in Western Europe (EUR); Smoking: 24.5% in Northern America (AMR) |
| Metabolic (obesity, T2DM, MASLD/NAFLD) | 19.7% | Rising contribution globally, especially in high-income regions |
Nonalcoholic fatty liver disease (NAFLD) — affecting an estimated 25.2% of the global population — represents the most rapidly expanding etiologic driver of HCC, with its burden closely tied to obesity and type 2 diabetes mellitus epidemics expected to worsen globally 1115. While HBV and HCV remain the leading global drivers, the transition toward metabolic liver disease is increasingly reflected in shifting transplant indications, with NASH-related liver transplant wait-listing increasing by 81% in the DAA era 78. Cirrhosis — regardless of underlying etiology — remains the dominant shared pathophysiological pathway to HCC in approximately 80–90% of cases. Overlapping etiologies (e.g., HBV/HCV co-infection, HCV plus alcohol, NAFLD plus diabetes) are common and compound individual risk.
Disease Burden: Mortality, DALYs, and Quality-of-Life Impact
HCC imposes an enormous burden of premature mortality and disability. Disability-Adjusted Life Years (DALYs) represent the sum of Years of Life Lost (YLLs) due to premature death and Years Lived with Disability (YLDs) due to disease morbidity. In 2021, HCC generated 12.88 million DALYs (95% UI: 11.67–14.47 million) globally, with an age-standardized DALY rate of 149.28 per 100,000 4. YLLs dominated the DALY burden at 12,761,100 (95% UI: 11,560,500–14,332,200; age-standardized rate 147.81 per 100,000), reflecting HCC's high lethality and predilection for working-age and older adults 4. YLDs — capturing disability among those living with HCC — were 126,500 (95% UI: 89,500–167,800; rate 1.47 per 100,000) and have nearly doubled since 1990 4.
Mortality by age group revealed that the highest absolute number of HCC deaths occurs in the 65–69 age group for both sexes; however, the highest age-specific mortality rates occur in the 90–94 group for men and the 95+ group for women 4. Quality-of-life impacts in adults with HCC are substantial, encompassing pain, fatigue, ascites, hepatic encephalopathy, and treatment-related adverse effects. Patient-reported outcomes (PROs), including physical functioning and global health status, have been identified as independently prognostic in 93% of cancer clinical trials reviewed 18, supporting their incorporation into HCC clinical research and practice.
Data Sources, Key Definitions, and Limitations
Primary data sources include GLOBOCAN 2022 (IARC), the GBD 2021 and GBD 2023 studies (IHME), and supporting registry-based analyses 124512. Interactive visualization is available through the Global Cancer Observatory (GCO; gco.iarc.who.int) and GBD Compare/Cancer Compare tools 31314. GLOBOCAN liver cancer data (C22) include both HCC and ICC, and some HCC-specific estimates are derived through histological subtype modeling; exact proportions vary by registry quality and diagnostic practice.
Key limitations include: (1) variable registry coverage, particularly in Sub-Saharan Africa (AFR) and parts of South-East Asia (SEAR), where underreporting may substantially underestimate true burden; (2) coding heterogeneity between HCC (C22.0) and unspecified liver cancer (C22.9) across national registries; (3) lead-time bias introduced by expanding surveillance programs in high-resource settings, which can artificially inflate incidence without representing true disease increase; (4) limited granularity of WHO-region-specific annual percent change data in the retrieved literature, with trend analyses primarily reported by GBD analytical subregion rather than by the six WHO regions; and (5) projection uncertainty for 2023–2026, as GBD 2023 data extend estimates to 2023 and are accessible via interactive tools but specific numeric DALY/YLL/YLD extracts for the 2023–2026 period were not available in the retrieved materials 12.
In summary, HCC remains a major global health challenge characterized by rising absolute incidence despite declining age-standardized mortality in Asia, a profound shift from viral to metabolic etiologies in high-income settings, and a disproportionate burden among males and in the Western Pacific and Eastern Mediterranean regions. Continued investment in HBV vaccination, DAA scale-up, metabolic risk reduction, and early surveillance is essential to reverse current trends.