There can be a sense of fatalism surrounding cancer. While we know that certain behaviors can raise our risks — smoking with lung cancer, eating lots of processed meats with colorectal cancer — cancers also afflict so many people who seemingly do everything right. Behavior can appear inconsequential in the face of what look like overwhelmingly genetic and environmental causes of malignancy.

Maybe that’s why a recent report in the Lancet got so much attention. Besides concluding that global liver cancer rates are poised to jump 75% by 2050, it concluded that more than 60% of liver cancers are preventable.

Some of that has to do with the impact of hepatitis B and hepatitis C in the developing world. In the United States, hepatitis B is a basic childhood vaccination. Hepatitis B therapies and especially hepatitis C cures have sharply dropped the number of hepatitis-related liver cancer cases. But globally, hepatitis B and C still account for 37% of liver cancers, with 29% of global liver cancer cases attributed just to hepatitis C. Alcohol-related liver damage drives 19% of global liver cancer cases, and obesity-related disease another 8%, the report found.

In the United States and in Colorado, those last two factors predominate. They are also preventable, says Dr. James Burton, a University of Colorado School of Medicine transplant hepatologist who specializes in the care of patients with acute and chronic liver disease.

UCHealth Today caught up with Burton, who sees patients at the UCHealth Hepatology Clinic — Anschutz Medical Campus, to talk about the causes and progression of liver disease that can lead to liver cancer, risk factors, screening and treatment.

What causes liver cancer?

First, a clarification. While many cancers can spread to the liver, this is about cancer that originates in the liver. While there are exceptions, such as liver cancers caused by hepatitis B virus infections and hemochromatosis, most primary liver cancers emerge from cirrhosis. The path to cirrhosis starts with chronic inflammation, which can lead to fibrosis — scar tissue. That can then develop into severe fibrosis and, with time, cirrhosis (advanced, irreversible scarring) that in turn can trigger liver cancer.

Burton estimates that about half of UCHealth patients whose liver disease is advanced enough for transplant have landed there because of alcoholic liver disease from long-term drinking. The livers of another quarter of patients were damaged through a pathway that started with obesity-related health issues. It’s called MASLD, for metabolic dysfunction-associated steatotic liver disease.

Previously called nonalcoholic fatty liver disease, or NAFLD, the name change happened because, as Burton put it, “‘nonalcoholic’ described what it wasn’t.”

While MASLD and alcoholic liver disease have different behavioral roots, “under a microscope, the conditions look the same,” Burton says. “If you handed me two biopsies, one from someone with fatty liver disease and the other from someone with alcohol-associated liver disease, I couldn’t tell which was which.”

What’s MASLD all about?

MASLD is caused by a buildup of fat in the liver, which, if associated with inflammation, can lead to scarring and, over time, cirrhosis. Being overweight and obese are risk factors, and a lot of Americans expose themselves to that risk, given that close to three-quarters of U.S. adults qualify as overweight or obese. Estimates of U.S. MASLD prevalence vary, but fully a quarter to a third of adults have it. Burton says he’s seeing younger and younger patients with MASLD.

“You’ve got to lose weight now,” he tells them. “Because, if you don’t start looking after your health now, in your 20s and 30s, by the time you’re in your 50s and 60s, you could end up with cirrhosis.”

Is MASLD in itself dangerous?

No, but it can get dangerous as it progresses. When more than 5% to 10% of the liver’s weight consists of fat, the risk of inflammation goes up. Inflammation is the trigger that can turn MASLD into something called MASH, for metabolic dysfunction-associated steatohepatitis. (The same name changes that brought us MASLD turned what was NASH — nonalcoholic fatty liver disease — into MASH.)

Is MASH dangerous, then?

Yes. MASLD progresses into MASH in about 5% of patients with MASLD, and it can lead to scarring, fibrosis, and cirrhosis. Roughly 10% of MASH patients develop cirrhosis or liver failure, and a Swedish study found that about 8% of those with cirrhosis develop liver cancer within five years, and 12% of them do within 10 years.

Are there medicines for MASLD or MASH?

For MASLD, there are no medicines; for MASH, the answer is yes.

MASLD’s progression can be slowed or even reversed through improving one’s diet with more protein and fewer carbs, exercising, limiting or eliminating alcohol, losing weight, and keeping blood glucose under control if you have diabetes (diabetes being an additional MASLD risk factor). In short, doing things that help you lose weight or keep it off and generally live healthy also helps with MASLD.

There are two U.S. Food and Drug Administration-approved treatments for MASH. The FDA approved resmetirom in March 2024; and recently, on Aug. 15, it approved the weight-loss drug Wegovy (semaglutide) for the disease. Clinical trials showed both to reduce fat buildup and scarring in the liver.

How do I know if I have MASLD (or MASH)?

Because MASLD and MASH can advance without symptoms, and because liver enzyme tests are not a part of standard blood-test panels, it takes deliberate screening.

The first step is a liver enzyme test. If elevated, and the patient also has risk factors such as obesity and diabetes, the next step is imaging with ultrasound. If that shows fat in the liver, MASH is a high probability. Technology such as ultrasound-elastography can then help estimate liver stiffness (and thus fibrosis/cirrhosis). In some cases of MASH, liver biopsy can help deliver a definitive diagnosis and the extent of scarring.

Patients diagnosed with MASH-related fibrosis can combine lifestyle changes with those new medications. Those with cirrhosis should get an ultrasound every six months to look for liver tumors, with CT or MRI follow-up if there’s a mass, Burton says. Liver transplant can then be an option.

“That liver cancer is a big problem is really just an illustration that liver disease is a big problem,” Burton said. “In America, if people are concerned about getting liver cancer, well, you should be concerned about having liver disease.