Chronic liver disease is often a precursor to hepatocellular carcinoma

In an earlier blog, the implications of evolving risk factors for hepatocellular carcinoma (HCC) and their impact on its surveillance were reviewed. Here we consider the fundamentals of chronic liver disease (CLD) as they relate to HCC.

Chronic liver disease

Chronic liver disease is a common clinical condition. It is characterized by a continuous and progressive process of inflammation, tissue destruction, and aberrant tissue regeneration, which lead to hallmark features of CLD—fibrosis and cirrhosis.

About 4.5 million adults living in the United States (nearly 2%) have a diagnosis of CLD. Estimates suggest that CLD kills 40,000 people annually. The most common chronic diseases of the liver include viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease (NAFLD).

Chronic liver disease begins with inflammation (hepatitis), which can progress to fibrosis. Fibrosis is perpetuated by ongoing liver injury in a complex feedback loop that leads to progressive disease and advanced fibrosis. The rate of progression depends on the etiology of CLD and on environmental and demographic factors such as age. The final stage of CLD is cirrhosis, in which permanent tissue scarring may lead to a serious decline in liver function.

Key causes of chronic liver disease

Chronic viral hepatitis infections are common causes of CLD throughout the world. These infections are due to several viruses, including hepatitis B, C, and sometimes D. In the United States hepatitis C virus (HCV) is the primary cause of infection; hepatitis B virus (HBV) infection is more common in other parts of the world. Infections with HCV or HBV, or coinfections, are risk factors for HCC.

Alcoholic liver disease is commonly associated with CLD. It can be considered as a spectrum of related conditions that are driven by chronic alcohol abuse that characteristically leads to an accumulation of fat in the liver. Alcoholic liver disease is a risk factor for HCC.

Alcoholic liver disease includes the following conditions:

• Alcoholic fatty liver with or without hepatitis
• Alcoholic hepatitis, which may be reversed through abstinence from alcohol
• Cirrhosis

Nonalcoholic fatty liver disease is, in contrast with alcoholic liver disease, not a result of excessive alcohol consumption. Obesity and other metabolic disorders such as type 2 diabetes are risk factors for NAFLD and account for an alarming increase in the number of cases of NAFLD in the United States. Nonalcoholic fatty liver disease includes simple steatosis, which is an accumulation of fat in the liver with little to no evidence of inflammation, and a form called nonalcoholic steatohepatitis, or NASH, in which the liver becomes inflamed.

The natural course of NAFLD may lead to cirrhosis, which increases the risk for HCC. In some patients who have NAFLD and NASH, HCC can develop in the absence of cirrhosis.

Cirrhosis as a harbinger of hepatocellular carcinoma

Cirrhosis permanently disrupts the architecture and function of the liver. Changes in architecture are grossly apparent as evidenced by the widespread presence of nodules. Declining function affects the production of clotting factors, detoxification of metabolites, and excretion of bile.

Approximately 40% of patients in the United States who have CLD have cirrhosis. The number of cases of cirrhosis can only be estimated because cirrhosis is often undiagnosed, especially among patients who have NAFLD. Estimates also suggest that cirrhosis is most frequently observed in patients 45 to 54 years of age.

Cirrhosis occurs late in CLD and is often a precursor to hepatocellular carcinoma (HCC). The incidence of HCC is increasing in the United States; consequently, patients who have cirrhosis should undergo surveillance for HCC, which when discovered early may be managed with potentially curative treatment.

What causes cirrhosis?

The most common conditions that lead to cirrhosis are also the most common forms of CLD:

• Chronic viral hepatitis as a result of HCV or HBV infection
• Alcoholic liver disease
• NAFLD

Autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, several inherited liver diseases, and chronic heart failure can lead to cirrhosis. Long-term use of some medications can also contribute.

Cirrhosis and liver cancer

Cirrhosis leads to a number of serious complications; the most common serious complication is portal hypertension. Cirrhosis may also progress to end-stage liver disease and primary liver cancer.

Hepatocellular carcinoma

The most common form of liver cancer is HCC, which is the fastest growing cause of cancer-related deaths in the United States.

• Early detection of HCC allows for potentially curative treatment options; therefore, the health of patients who have cirrhosis should be monitored closely

Cirrhosis is often a harbinger of HCC. A diagnosis of cirrhosis in at-risk patients should trigger routine biannual surveillance to help detect HCC in its early stage.