[6][7] This is thought to be due to an increased prevalence of NASH, as well as its risk factors of diabetes and obesity, in higher income countries.

[citation needed] Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may have none of the typical risk factors, such as cirrhosis and hepatitis.

[14][22][24][25] On this note, some diabetics who engage in tight insulin control (by keeping it from being elevated) show risk levels low enough to be indistinguishable from the general population.

These mutations in the promoter of TERT lead to a constitutively active telomerase which maintains telomere length and contributes to cell immortality.

In chronic hepatitis B, however, the integration of the viral genome into infected cells can directly induce a noncirrhotic liver to develop HCC.

[20][6] HCC remains associated with a high mortality rate, in part because initial diagnosis commonly occurs at an advanced stage of disease.

[6] In the United States, the American Association for the Study of Liver Diseases(AASLD) recommends ultrasound screenings every six months for people with cirrhosis, with or without measurement of blood levels of the tumor marker alpha-fetoprotein (AFP).

[39] On ultrasound, HCC often appears as a small hypoechoic lesion with poorly defined margins and coarse, irregular internal echoes.

A systematic review found that the sensitivity was 60% and specificity was 97% as compared with pathologic examination of an explanted or resected liver as the reference standard.

[40] Hepatic nodules that are less than 1 centimeter in size on surveillance ultrasound require serial imaging to ensure stability and to monitor for potential transformation to HCC.

For example, while some data support decreased mortality related to screening people with hepatitis B infection, the AASLD notes, “There are no randomized trials [for screening] in Western populations with cirrhosis secondary to chronic hepatitis C or fatty liver disease, and thus there is some controversy surrounding whether surveillance truly leads to a reduction in mortality in this population of patients with cirrhosis.”[38] In a person where a higher suspicion of HCC exists, such as a person with symptoms or abnormal blood tests (i.e. alpha-fetoprotein and des-gamma carboxyprothrombin levels),[41] evaluation requires imaging of the liver by CT or MRI scans.

Optimally, these scans are performed with intravenous contrast in multiple phases of hepatic perfusion to improve detection and accurate classification of any liver lesions.

The advantage of MRI is that it has improved sensitivity and specificity when compared to ultrasound and CT in cirrhotic patients with whom it can be difficult to differentiate HCC from regenerative nodules.

[49] Important features that guide treatment include: The most common sites of metastasis are the lung, abdominal lymph nodes, and bone.

[55] HCC surveillance in those with chronic liver disease with cirrhosis is indicated and generally consists of a twice-yearly ultrasound with or without Alpha-fetoprotein lab testing.

[58] Surgery is only considered if the entire tumor can be safely removed while preserving sufficient functional liver to maintain normal physiology.

Thus, preoperative imaging assessment is critical to determine both the extent of HCC and to estimate the amount of residual liver remaining after surgery.

The immunosuppressive medication required after surgery to prevent rejection of the donor liver also impairs the body's natural ability to combat dysfunctional cells.

If the tumor has spread undetected outside the liver before the transplant, the medication effectively increases the rate of disease progression and decreases survival.

Numerous other molecular targeted drugs are being tested as alternative first- and second-line treatments for advanced HCC, such as lenvatinib and regorafenib.

For instance, in the recent phase III trial IMBrave 150, the combination of atezolizumab and bevacizumab was found to improve both overall and progression-free survival compared to sorafenib alone.

[85] [failed verification] This is partially due to late presentation with tumors, but also the lack of medical expertise and facilities in the regions with high HCC prevalence.

The epidemiology of HCC exhibits two main patterns, one in North America and Western Europe and another in non-Western countries, such as those in sub-Saharan Africa, Central and Southeast Asia, and the Amazon basin.

Males are affected more than females usually, and it is most common between the ages of 30 and 50,[5]: 821–881  Hepatocellular carcinoma causes 662,000 deaths worldwide per year[88] about half of them in China.

In some parts of the world, such as sub-Saharan Africa and Southeast Asia, HCC is the most common cancer, generally affecting men more than women, and with an age of onset between the late teens and 30s.

Foods infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxins pose another risk factor for HCC.

In the United States, the US surveillance, epidemiology, and end results database program, shows that HCC accounts for 65% of all cases of liver cancers.

[90] As screening programs are in place for high-risk persons with chronic liver disease, HCC is often discovered much earlier in Western countries than in developing regions such as sub-Saharan Africa.

[94] Current research includes the search for the genes that are disregulated in HCC, antiheparanase antibodies,[95] protein markers,[96] non-coding RNAs[97] (such as TUC338)[98] and other predictive biomarkers.

[103] A prospective study found that increased hepatocellular cancer risk is associated with higher levels of major circulating bile acids that were measured in people several years prior to tumor diagnosis.