Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
HCC most commonly occurs in those with chronic liver disease especially those with cirrhosis or fibrosis, which occur in the setting of chronic liver injury and inflammation. HCC is rare in those without chronic liver disease. Chronic liver diseases which greatly increase the risk of HCC include hepatitis infection such as (hepatitis B, C or D), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, or exposure to toxins such as aflatoxin, or pyrrolizidine alkaloids. Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency, markedly increase the risk of developing HCC. The five-year survival in those with HCC is 18%.
As with any cancer, the treatment and prognosis of HCC varies depending on tumor histology, size, how far the cancer has spread, and overall health of the person.
The vast majority of HCC cases and the lowest survival rates after treatment occur in Asia and sub-Saharan Africa, in countries where hepatitis B infection is endemic and many are infected from birth. The incidence of HCC in the United States and other higher income countries is increasing due to an increase in hepatitis C virus infections. The incidence of HCC due to NASH has also risen sharply in the past 20 years, with NASH being the fastest growing cause of HCC. 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. It is more than three times as common in males as in females, for unknown reasons.
Signs and symptoms Most cases of HCC occur in people who already have signs and symptoms of chronic liver disease. They may present with worsening symptoms or without symptoms at the time of cancer detection. HCC may present with non-specific symptoms such as abdominal pain, nausea, vomiting, or feeling tired. Some symptoms that are more closely associated with liver disease include jaundice, abdominal swelling due to fluid in the abdominal cavity, easy bruising from blood clotting abnormalities, loss of appetite, unintentional weight loss, abdominal pain, nausea, vomiting, or feeling tired.
Risk factors Since HCC mostly occurs in people with cirrhosis of the liver, risk factors generally include factors which cause chronic liver disease that may lead to cirrhosis. Certain risk factors are more highly associated with HCC than others. For example, while heavy alcohol consumption is estimated to cause 60–70% of cirrhosis, the vast majority of HCC occurs in cirrhosis attributed to viral hepatitis (although there may be overlap). Recognized risk factors include: Chronic viral hepatitis (estimated cause of 80% cases globally) Chronic hepatitis B (about 50% cases) Chronic hepatitis C (about 25% cases) Toxins: Alcohol use disorder: the most common cause of cirrhosis Aflatoxin Iron overload state (hemochromatosis) Pyrrolizidine alkaloids Metabolic: Nonalcoholic steatohepatitis: up to 20% progress to cirrhosis Nonalcoholic fatty liver disease Type 2 diabetes (probably aided by obesity) Congenital disorders: Alpha 1-antitrypsin deficiency Wilson's disease (controversial; while some theorise the risk increases, case studies are rare and suggest the opposite where Wilson's disease actually may confer protection) Hemophilia, although statistically associated with higher risk of HCC, this is due to coincident chronic viral hepatitis infection related to repeated blood transfusions over lifetime.
The significance of these risk factors varies globally. In regions where hepatitis B infection is endemic, such as southeast China, hepatitis B is the predominant cause. In populations largely protected by hepatitis B vaccination, such as the United States, HCC is most often linked to causes of cirrhosis such as chronic hepatitis C, obesity, and excessive alcohol use.
Certain benign liver tumors, such as hepatocellular adenoma, may sometimes be associated with coexisting malignant HCC. Evidence is limited for the true incidence of malignancy associated with benign adenomas; however, the size of hepatic adenoma is considered to correspond to risk of malignancy and so larger tumors may be surgically removed. Certain subtypes of adenoma, particularly those with β-catenin activation mutation, are particularly associated with increased risk of HCC.
Chronic liver disease is rare in children and adolescents; however, congenital liver disorders are associated with an increased the chance of developing HCC. Specifically, children with biliary atresia, infantile cholestasis, glycogen-storage diseases, and other cirrhotic diseases of the liver are predisposed to developing HCC in childhood.
Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may have none of the typical risk factors, such as cirrhosis and hepatitis.
Diabetes mellitus
The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5 to 7.1 times the nondiabetic risk) depending on the duration of diabetes and treatment protocol. A suspected contributor to this increased risk is circulating insulin concentration such that diabetics with poor insulin control or on treatments that elevate their insulin output (both states that contribute to a higher circulating insulin concentration) show far greater risk of hepatocellular carcinoma than diabetics on treatments that reduce circulating insulin concentration. 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. This phenomenon is thus not isolated to diabetes mellitus type 2, since poor insulin regulation is also found in other conditions such as metabolic syndrome (specifically, when evidence of nonalcoholic fatty liver disease or NAFLD is present) and again evidence of greater risk exists here, too. While there are claims that anabolic steroid abusers are at greater risk (theorized to be due to insulin and IGF exacerbation), the only evidence that has been confirmed is that anabolic steroid users are more likely to have the benign hepatocellular adenomas transform into the more dangerous hepatocellular carcinoma.
Pathogenesis
Hepatocellular carcinoma, like any other cancer, develops when epigenetic alterations and mutations affecting the cellular machinery cause the cell to replicate at a higher rate and/or result in the cell avoiding apoptosis. In particular, chronic infections of hepatitis B and/or C can aid the development of hepatocellular carcinoma by repeatedly causing the body's own immune system to attack the liver cells, some of which are infected by the virus, others merely bystanders. Activated immune-system inflammatory cells release free radicals, such as reactive oxygen species and nitric oxide reactive species, which in turn can cause DNA damage and lead to carcinogenic gene mutations. Reactive oxygen species also cause epigenetic alterations at the sites of DNA repair.
Many genes responsible for cell proliferation, apoptosis or cell senescence and differentiation are commonly mutated in HCC and are implicated in tumor formation. Mutations in the telomerase reverse transcriptase (TERT) promoter are seen in 47–60% of HCC cases. The HBV genome commonly inserts into hepatocytes' TERT promoter site contributing to oncogenesis. These mutations in the promoter of TERT lead to a constitutively active telomerase which maintains telomere length and contributes to cell immortality. Mutations in the tumor suppressor gene TP53 are seen in about 30% of cases of HCC. And mutations in Wnt signalling (which is responsible for embryogenesis and cell homeostasis) are also seen in HCC, specifically CTNNB1 mutations seen in 30% of cases and AXIN1 mutations seen in 10% of cases. Mutations of genes involved in chromatin remodeling such as ARID1A and ARID2 are also seen in 10% and 5% of HCC cases respectively.
While this constant cycle of damage followed by repair can lead to mistakes during repair, which in turn lead to carcinogenesis, this hypothesis is more applicable, at present, to hepatitis C. Chronic hepatitis C causes HCC through the stage of cirrhosis. In chronic hepatitis B, however, the integration of the viral genome into infected cells can directly induce a noncirrhotic liver to develop HCC. Alternatively, repeated consumption of large amounts of ethanol can have a similar effect. The toxin aflatoxin from certain Aspergillus species of fungi is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflatoxin and hepatitis B in settings such as China and West Africa has led to relatively high rates of hepatocellular carcinoma in these regions. Other viral hepatitides such as hepatitis A have no potential to become a chronic infection, thus are not related to HCC.
Bile salts from the hepatocyte cytoplasm are transferred by the bile salt export pump into the bile canaliculi. A deficiency in bile salt export resulting from a mutation in the gene ABCB11 (ATP-binding cassette, subfamily B member 11) that encodes the bile salt export pump can result in intrahepatic toxic accumulation of bile salts. Individuals with such mutations have an increased incidence of hepatocellular carcinoma or cholangiocarcinoma (bile duct cancer).
Diagnosis
Methods of diagnosis in HCC have evolved with the improvement in medical imaging. The evaluation of both asymptomatic patients and those with symptoms of liver disease involves blood testing and imaging evaluation. Historically, a biopsy of a tumor was required to prove an HCC diagnosis. However, imaging (especially MRI) findings may be conclusive enough without histopathologic confirmation.
Screening HCC remains associated with a high mortality rate, in part because initial diagnosis commonly occurs at an advanced stage of disease. As with other cancers, outcomes are significantly improved if treatment is initiated earlier in the disease process. Since the vast majority of HCC cases occur in people with certain chronic liver diseases, especially those with cirrhosis, liver cancer screening is recommended in this population. 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). Elevated levels of AFP are associated with active HCC disease, though their reliability can be inconsistent. At levels >20, sensitivity is 41–65% and specificity is 80–94%. However, at levels >200, sensitivity is 31% and specificity is 99%.
On ultrasound, HCC often appears as a small hypoechoic lesion with poorly defined margins and coarse, irregular internal echoes. When the tumor grows, it can sometimes appear heterogeneous with fibrosis, fatty change, and calcifications. This heterogeneity can look similar to cirrhosis and the surrounding liver parenchyma. 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. The sensitivity increases to 79% with AFP correlation. 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.