Hepatocellular carcinoma is 10 times more likely to develop in the setting of nonalcoholic steatohepatitis than in simple fatty liver disease

A dangerous and growing problem

Overindulgence in the Western diet has led to an enormous increase in caloric consumption and obesity in the United States. Overall, 36.5% of Americans are obese, and obesity affects more than 40% of Americans aged 40 to 59 years.

Obesity is the primary driver of nonalcoholic fatty liver disease (NAFLD) and is estimated to impact a staggering 100 million Americans. Globally, the prevalence of NAFLD is more than 25%, making it the most prevalent liver disease worldwide.

In some patients NAFLD can progress to nonalcoholic steatohepatitis (NASH), which may in turn lead to a substantial number of cases of deadly hepatocellular carcinoma, or HCC, even in the absence of cirrhosis.

• Alarmingly, as many as 12% of adult Americans have NASH, putting them at increased risk for HCC

Current HCC surveillance guidelines do not account for NAFLD and NASH in the absence of cirrhosis

In addition to obesity, other metabolic comorbidities—particularly diabetes—occurring in the setting of NAFLD in the absence of cirrhosis can lead to HCC. However, these conditions are not factored into HCC surveillance guidelines, as patients who have NAFLD or NASH are not sufficiently represented in the clinical trials that support such guidelines. This clinical reality presents a challenge to surveillance programs for HCC that currently focus on patients who have cirrhosis.

The link between NAFLD and HCC took decades to establish

Foie gras, or fatty liver, was described by the French pathologist Pierre-Charles-Alexandre Louis in 1825. Thomas Addison introduced the term into the English language in 1836. The underlying clinical difference between the two forms of the disease—alcoholic fatty liver disease and NAFLD—is the patient’s heavy use of alcohol in alcoholic fatty liver disease. The histologic difference, however, was not characterized until liver biopsies had become common in the late 1950s, possibly delaying the clinical acceptance of NAFLD. In 2002, the risk of HCC developing in the setting of NAFLD was established by the results of two independent, seminal studies reported by Bugianesi et al and Marrero et al.

Metabolic risk factors for HCC and their population attributable fractions

The metabolic risk factors for HCC often occur in combination (cofactors) with dramatic effect. For example, new research has shown that the four horsemen of the “hepatocalypse”—diabetes, obesity, dyslipidemia, and hypertension—amplify the risk of HCC 2.6-fold among patients who have NAFLD when they are compared with patients who have NAFLD in the absence of such cofactors.

Population-attributable fraction of risk

Strong associations between metabolic risks and the development of HCC have been established in the last decade by examining the population-attributable fraction (PAF) of risk. Population-attributable fractions account for the strength of the association between exposure to an individual risk and outcome and the prevalence of the risk factor. Although the risk factors for HCC have been widely reported, it wasn’t until 2013 that PAFs were determined for HCC in the United States. In a study that year, nearly 7,000 patients who had a diagnosis of HCC were compared with more than 255,000 random control patients over a period from 1973 to 2007.

The study found that among individual risk factors for HCC, diabetes and obesity had the greatest PAF (36.6%), followed by chronic alcohol abuse (23.5%), hepatitis C virus (HCV) infection (22.4%), hepatitis B virus infection (6.3%), and genetic disorders (3.2%).

More recently, a study of PAFs for HCC in the United States confirmed these initial findings and found that the PAF for metabolic disorders, including diabetes and obesity, accounted for a remarkable 32% of the total HCC burden. Moreover, the metabolic disorder PAF increased from 26% to 36% over the course of the study. The runner-up PAF was chronic HCV infection, accounting for 20.5% of the HCC burden.

Overall HCC PAFs 2000 to 2011

HBV, hepatitis B virus; HCV, hepatitis C virus; PAF, population-attributable fraction.

These data reveal that the highest PAFs for developing HCC are metabolic. With upwards of 70 million Americans living with NAFLD, many of whom are likely to have metabolic comorbidities, it should not be surprising that we now face a dangerous and growing problem.

In the context of these warnings and the enormous explosion of obesity, the lack of clinical attention paid to the metabolic risks for HCC and the absence of recommendations by scientific societies for the surveillance of HCC in the setting of NAFLD are striking.

Should surveillance for HCC be expanded to include more at-risk patients?

Several studies (reviewed by F. Negro and J. Debes) have confirmed that HCC can develop in patients who have fatty liver disease. These studies also confirm that HCC can develop in the absence of cirrhosis in patients who have fatty liver disease and associated metabolic traits.

Importantly, the study results revealed that the risk of HCC developing in the absence of cirrhosis was 5 times higher in patients who have HCC and NAFLD or metabolic syndrome than in patients who have HCV-related HCC.

Kanwal et al recently investigated the independent and combined effects of diabetes, hypertension, dyslipidemia, and obesity on the risk of cirrhosis or HCC developing among patients who had NAFLD. For both cirrhosis and HCC, disease progression occurred least in patients who had none or only one of the comorbidities; a stepwise progression of disease was found with each additional comorbidity. The results also establish that among patients who have NAFLD, diabetes had the strongest association with progression to HCC, whether cirrhosis was evident or not.

Currently, only patients who have cirrhosis are recommended for HCC surveillance, but that guideline may need to be expanded. All in all, the emerging studies underscore the need to include patients who have one or more metabolic comorbidities and NAFLD in the absence of cirrhosis in surveillance programs for HCC.

The implications of NAFLD and NASH on the surveillance of HCC

Because surveillance is not yet recommended for most patients who do not have cirrhosis, and the rate of adherence to current guideline-recommended surveillance is less than 30%, the challenge of adding in yet another population of at-risk patients may be daunting.

• A possible future approach to surveillance for HCC could be predicated on prioritizing patients who do not have cirrhosis but do have NAFLD and diabetes or a combination of several metabolic comorbidities. This approach to surveillance in the absence of cirrhosis is analogous to that suggested in international guidelines for patients infected with HBV who are at risk for HCC

Current surveillance methods are inadequate

Contributing to the surveillance challenge, the current primary surveillance tool (ultrasonography) performs poorly in patients who are obese or have NASH; therefore, an improved method of HCC surveillance that is simple to use and highly sensitive could benefit these and other patients at high risk for HCC.

“The ideal surveillance tool should be highly reproducible, not operator dependent (unlike abdominal ultrasonography), have good accuracy, and easy to implement in different clinical settings.” —Llovet, et al. Nature Reviews, 2021.