Reversing The Course Of Nonalcoholic Fatty Liver Disease and Liver Cancer Risk

After giving blood in 1998, Terri Milton received a call from the donor organization alerting her that her liver enzymes were elevated. She saw her doctor, and results from a CT scan and an ultrasound showed that her liver was storing excess fat, which can be a symptom of drinking too much alcohol. But Milton, a Houston resident who was 37 at the time, never imbibed. Her doctor explained that she had nonalcoholic fatty liver disease (NAFLD), a condition that affects about 25% of the U.S. population.

The doctor described the disease as very common and nothing to worry about, and Milton experienced no symptoms at the time. Eight years later, she received a diagnosis of type 2 diabetes. Then, in 2016, she felt pain in her upper right torso and underwent surgery to remove her gallbladder. During the procedure, her surgeon discovered that Milton’s liver had a rough texture. He ordered three biopsies, which revealed advanced cirrhosis, or late-stage scarring of the liver. Eight days after the surgery, she was hospitalized because fluid was accumulating in her abdomen, leading to a 40-pound weight gain. She was experiencing ascites, a symptom of cirrhosis and impaired liver function.

Over the years, Milton’s untreated liver disease had progressed to nonalcoholic steatohepatitis (NASH), an aggressive form of fatty liver disease that leads to liver inflammation and increases

the risk of cirrhosis. In 2018, likely as a result of her progressive liver disease, Milton received the devastating news that she had liver cancer, or hepatocellular carcinoma.

To treat the cancer, her hepatologist suggested transarterial chemoembolization, which blocks the blood supply to the tumor and infuses it with chemotherapy. Now her liver shows no signs of cancer, but she still experiences fatigue and frequent infections as a result of cirrhosis. Eventually, she will need a transplant, which is possible in a small minority of patients whose cancer has not spread beyond the liver or only affects certain portions of the organ.

“I wish my doctor had explained 20 years ago that NAFLD is reversible,” says Milton, 56. “Just losing 10% to 15% of my body weight could have made a significant difference in reversing my fatty liver disease.”

The urgent need to spread this message is gaining momentum nationwide because NAFLD is the fastest- rising cause of liver cancer in Western countries.

More than 42,000 people will receive a liver cancer diagnosis this year in the United States, and data suggests that more than 14% of cases will be associated with NAFLD. Alcohol-related cirrhosis is another major risk factor for liver cancer, but a third is becoming less of a threat: hepatitis B and C infections are causing fewer cases of liver cancer due to advances in antiviral therapies that reduced the progression of these conditions to cirrhosis. The risk factors for NAFLD include obesity, type 2 diabetes and high cholesterol, and researchers are still trying to understand why certain people with this disease progress to NASH, cirrhosis and cancer and others do not.

Findings from a new study also showed a 91% higher risk of developing several forms of cancer in people with NAFLD compared with those without the disease, with the highest risk associated with liver, pancreatic, stomach, colon and uterine cancers.

The researchers were interested in understanding whether the combination of obesity and NAFLD influenced cancer risk, and they found that people with a high body mass index (BMI) and NAFLD faced double the risk of cancer compared with people who were obese only. “This raises questions about the impact of fatty liver,” says study author Dr. Alina Allen, a gastroenterologist at Mayo Clinic in Rochester, Minnesota. “It could be a biomarker for cancer.”

Cancer risk may increase in part because excess fat in the liver, known as steatosis, can stimulate inflammatory cytokines, which are proteins important in cell signaling,

says Dr. Arthur McCullough, a hepatologist at Cleveland Clinic. “This inflammation creates oxidative stress, which can cause alterations in cell growth and tumor suppressor genes,” he explains.

Studies also suggest that the gut microbiome may be linked to NAFLD and NASH. “We know that the nature of the gut bacteria in the intestines can have profound effects on liver function,” says Dr. Scott Friedman, dean for therapeutic discovery and chief of the division of liver diseases at Icahn School of Medicine at Mount Sinai in New York City. “Bacteria can produce different products that activate inflammation in the liver, and we are still trying to understand which bacteria and products produce liver injury.”

EARLY DETECTION EFFORTS

Although the evidence linking NAFLD to cancer is sobering, researchers like Allen make it clear to the people they treat that fat and even scar tissue in the liver can disappear if patients lose weight, limit sugar and exercise more.

“I think the reversibility of many forms of fatty liver disease needs greater attention in primary care settings, and we will make the biggest gains by educating the public,” says Dr. Julia Wattacheril, director of the NAFLD program at New York-Presbyterian/Columbia University Irving Medical Center in New York City. “I’ve found that a significant number of patients lose weight when they are told that they have earlier stages of fatty liver disease that are most likely reversible.”

She gathers details about a patient’s nutrition and exercise habits and discusses any barriers to implementing lifestyle changes. “Some patients may not have a safe place to walk or experience food insecurity, which is why it’s so important to get a good history first,” Wattacheril says. If needed, she can refer them to a nutritionist who provides education and guidance in developing a plan to make changes.

Early intervention is also the goal of a project led by Dr. Jessica Hawng, a professor of general internal medicine at The University of Texas MD Anderson Cancer Center in Houston. In August 2019, her team received $2.4 million in funding from the Cancer Prevention & Research Institute of Texas to screen 1,000 patients for liver cancer risk factors including hepatitis B, hepatitis C and alcohol use and metabolic conditions such as obesity and diabetes. The participants are patients at Hope Clinic in Houston, a health center for low-income, uninsured

and underinsured people.

The patients will undergo a FibroScan with the ultrasound imaging machine that detects fat, stiffening (fibrosis) and hardening (cirrhosis) of the liver. The researchers will analyze the data to determine which risk factors predict fibrosis and then develop a risk tool to help primary care providers and specialists deter- mine which patients have a high likelihood of developing NAFLD and NASH.

“The future of fatty liver disease hinges upon diagnosis, but right now there are no clear screening recommendations for physicians,” Hwang says. “We hope to change that problem with the risk tool that would be developed in our study.”

A STEALTHY CONDITION

One of the challenges in the effort to reduce liver cancer is the fact that patients with underlying liver disease that can lead to cancer typically experience no symptoms until the disease has progressed. “The earlier stages of liver disease usually get detected only if patients are having a liver blood test or an abdominal imaging test for some other health issue,” Friedman says.

Tony Villiotti, 73, is trying to raise awareness about the silent disease because his NAFLD progressed to NASH, cirrhosis and ultimately liver cancer. In 2018, he founded NASH Knowledge, a nonprofit organization that provides information and resources related to liver disease, including a link to a documentary Villiotti produced to share his story. He got a diagnosis of NAFLD in 2005 at the age of 59, but his doctor didn’t raise any concerns. “He encouraged me to lose some weight, but I had been told that many times in my life,” says Villiotti, who also has type 2 diabetes. “I didn’t realize high BMI could increase my risk of developing NASH.”

After a routine blood test nine years later, Villiotti was told that his liver enzymes were highly elevated, and an MRI showed that his condition had progressed to cirrhosis. “My first reaction was that cirrhosis was a drinker’s disease, so I thought they had the wrong person,” says Villiotti, who lives in Pittsburgh. “I felt fine, and my diabetes was under control.” He started seeing a hepatologist, who suggested that he consider getting a transplant, but Villiotti resisted the idea because he had heard that people with diabetes had difficulty tolerating the anti-rejection drugs.

In 2017, he was told he had liver cancer. He also started experiencing cirrhosis symptoms, including hepatic encephalopathy, or mental confusion caused by excess toxins in his blood. “I had a foggy brain, so I couldn’t drive or read a book, and sometimes I wandered around in the middle of the night,” Villiotti says.

He was ready to join the national transplant waiting list but unsure whether he would get a donor liver before it was too late. In March 2018, his doctor called with the good news that a liver was available. Villiotti was weak for the first few months after the trans- plant, but now he has more energy than he had in 15 years.

“I wish I had known more about this disease earlier,” he says. “Now I’m trying to help others understand that they need to talk to their doctors about NAFLD.”

EMERGING TREATMENTS FOR LIVER DISEASE

Research also suggests that, along with obesity, diabetes and high cholesterol, certain gene variations can increase the chances of developing fatty liver disease. One of the earliest studies that revealed a genetic risk was the 2008 Dallas Heart Study, which included 6,000 residents of Dallas County ages 18 to 65.

The researchers found that the PNPLA3 variant was associated with steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Forty-nine percent of Hispanics in the study had the gene compared with 17% of African Americans and 23% of European Americans, and these findings prompted researchers to explore drugs that target this variant.

“It’s important to understand that there may be other ancestry groups with undetected variants that have not yet been studied,” Wattacheril says. “Patients who are thin, seemingly fit and do not have diabetes may still be at risk of NAFLD.” For example, South Asians and East Asians tend to accumulate fat in the liver at a lower BMI, yet these groups have not been studied systematically, according to Wattacheril. “The need for longitudinal studies in diverse populations is critical,” she says.

Standard treatments for liver cancer include surgery, transplant, embolization, radiation and medications such as chemotherapy or targeted drugs.

Doctors may also have a new option for treating patients who have NASH. Recent phase 3 clinical trial results were encouraging for participants who took Ocaliva (obeticholic acid), a drug that reduces inflammation in the liver. Participants took either a placebo or 10 or 25 milligrams of the medication daily for 18 months, and fibrosis improved more frequently in the groups that took the drug. “I’m excited about these results because many trials of other drugs targeting the liver have not worked,” McCullough says.

Even patients who progress to liver cancer have more treatment options than ever, says Dr. Ghassan Abou- Alfa, a medical oncologist specializing in liver cancer at Memorial Sloan Kettering Cancer Center in New York City. Tyrosine kinase inhibitors, for example, block proteins that help tumor cells grow or form new blood vessels, and the Food and Drug Administration approved three of these medications to treat liver cancer within the past few years, and another in 2007.

In 2017, the agency approved the first immunotherapy treatment for liver cancer, Opdivo (nivolumab); Keytruda (pembrolizumab) got the OK a year later. “Now we are finding that if you combine two forms of treatment, such as immunotherapy with a biologic or two immunotherapies, patients are having good outcomes,” Abou-Alfa says.

Although the number of treatments is rising, hepatologists like Dr. Sonali Paul, of The University of Chicago Medicine, are eager to, when possible, prevent liver cancer from developing. That’s why education should start early, she says. NAFLD has become the most common cause of chronic liver disease among children and adolescents, which comes as no surprise to Paul, because the obesity epidemic also affects youth.

“For now, there is no pill to treat fatty liver, and it is best to talk to patients about the risks before scarring takes effect,” she says. “If we explain to kids and adults that their livers are sick, they have a chance to change their eating and exercise habits for the long run.”