FRONTLINE CANCER: Fighting liver cancer, Part 1

Among the myriad of malignancies that plague us, liver cancer doesn’t generally register. It’s not among the top 10 cancers in the United States. It doesn’t get the same media attention as prostate, breast or lung cancers that, along with colon and pancreas, constitute the nation’s deadliest cancers.

But liver cancer — or more precisely, hepatocellular carcinoma (HCC) — is the second most common cause of cancer death in the world, killing roughly 750,000 people each year. Only lung cancer kills more.

HCC is less common in the U.S., but its incidence and mortality rates are rising. “If things continue the way they are, liver cancer may eventually become the dominant form of cancer death in this country,” said Claude Sirlin, MD, a professor of radiology at UC San Diego School of Medicine and co-leader of the Moores Cancer Center Imaging Program.

The news is even bleaker for San Diegans because HCC prevalence here is measurably higher than the national average.

Cancer is always a tough foe, but beating HCC is a particularly tough fight. To understand why requires a brief biology lesson. HCC usually arises in patients with pre-existing cirrhosis, a condition in which the liver is scarred by years or even decades of inflammation and injury. A cirrhotic liver can become a sort of cancer factory — the chronic inflammation and fibrosis that leads to cirrhosis also predisposes liver cells to develop genetic mutations and other changes that can lead to cancer. Patients with both cirrhosis and HCC face a terrifying reality: cancer treatments can worsen the cirrhosis; cirrhosis treatments can worsen the cancer.

Currently, the primary cause of HCC is hepatitis B and C virus infections that occurred decades ago. In the 1970s and 1980s, millions of Americans unknowingly contracted hepatitis C through contaminated blood transfusions. Since 1990, there have been reliable blood tests to help prevent transfusion-acquired disease. This cause of HCC will eventually subside, assisted by emerging treatments for hepatitis B and C. The hepatitis B vaccination has already made a dramatic impact on HCC prevention worldwide. No vaccine is currently available for hepatitis C, but several are under development. (Unlike hepatitis B and C, a hepatitis A infection does not cause chronic liver disease and is rarely fatal.)

But other more problematic factors have emerged: obesity and diabetes.

It is now known that obesity and diabetes can lead to HCC, even in the absence of viral hepatitis and other factors that can injure the liver, such as excessive alcohol consumption.

Obesity is associated with excessive fat within liver cells (sometimes called non-alcoholic fatty liver disease or NAFLD). If the fatty liver becomes inflamed, it results in nonalcoholic steatohepatitis (NASH) which can progress to cirrhosis and, finally, liver cancer. NASH is the second leading causal factor for liver transplants in the U.S. An estimated 150 million Americans are obese. One hundred million of them have NAFLD. Up to 20 million may have NASH. Of those patients with NASH, 5 million people are projected to develop cirrhosis over a 30-year period and of them, 2 to 3 percent will develop HCC each year.

Diabetes afflicts almost 30 million Americans, or roughly 9 percent of the population. Another 27 million Americans may have undiagnosed diabetes. When you have diabetes, you are less sensitive to insulin, the hormone that regulates blood glucose levels. The body’s typical response to that problem is to produce more insulin, but insulin, it turns out, is a kind of fertilizer for progressive fibrogenesis in the liver hat may in turn lead to HCC.

There’s also a genetic component to HCC. A family history significantly increases the risk in first-degree relatives, who necessarily require greater screening. And some demographic groups, such as Mexican-Americans, Pacific-Islanders and Asian-Americans, are disproportionately affected by the disease.

“It’s a major concern,” says Rohit Loomba, MD, associate professor of medicine and founding director of the NAFLD Translational Research Unit at UC San Diego Medical Center-Hillcrest. “Liver cancer targets the minorities in the United States, particularly the men.” California has among the highest incidence of HCC in the U.S., and NASH is significantly more prevalent in Hispanics than non-Hispanic Whites in San Diego County.

•Coming in the May 28 issue: Basic and clinical research offer new tools — and hope.