An Interview with George Ioannou, MD, MS

VA’s Attention Turns to a New Risk Factor for Hepatocellular Carcinoma

George Ioannou, MD, MS

SEATTLE — The VA’s unparalleled success in treating and curing hepatitis C infections (HCV) in veterans changed the leading risk factors for hepatocellular carcinoma in the nation’s largest health care system. To understand the impact of the VA’s eradication effort and the changes in surveillance driven by declining rates of HCV and the increasing prevalence of other contributors to HCC, U.S. Medicine caught up with George Ioannou, MD, MS, director of hepatology at VA Puget Sound Health Care System and professor of medicine at the University of Washington. This interview has been lightly edited for clarity.

USM: What change have you seen in the VA recently in the causes of cirrhosis/fibrosis and HCC?

GI: We have observed a decline in the cases of cirrhosis and hepatocellular carcinoma (HCC) that are caused by chronic hepatitis C. This is an anecdotal observation but also supported by our publication in JAMA,¹ which demonstrated a reduction in HCV-related HCC in the VA after 2016. This was preceded by massive HCV elimination effort in the VA in 2014 to 2016 after the introduction of direct-acting antivirals, as a result of which the VA achieved HCV eradication of the vast majority of its case load of HCV way ahead of the rest of the country as a whole. In addition, there is a depletion over time in the “baby boomer cohort”, persons born between 1945-1965, who comprise most of the cases of HCV in the VA (and in the U.S. as a whole).

In addition to the sharp decline in HCV-related cirrhosis and HCC, there has been a slower but steady increase in NAFLD-related cirrhosis and HCC for a number of years now, related to the epidemics of obesity, diabetes and overnutrition in the VA and nationally.

USM: Is the same surveillance protocol for HCC used for veterans with all advanced liver disease, regardless of cause?

GI: The VA generally adopts the guidelines of the American Association for the Study of Liver Diseases (AASLD), which recommend screening patients with cirrhosis, irrespective of etiology, with abdominal ultrasonography with or without serum alpha-fetoprotein.

USM: How many veterans (or what percentage) have or are at risk of NAFLD?

GI: This is an impossible estimate to make because it depends on exactly how one defines non-alcoholic fatty liver disease (NAFLD). However, it is reasonable to consider that anywhere from 10% to 30% of veterans, have or are at risk of NAFLD.

USM: What percentage of patients with NAFLD progress to HCC without treatment?

This depends on how advanced NAFLD is, specifically the stage of fibrosis and whether the patient has cirrhosis or not. It also depends on other well recognized risk factors such as male sex, Hispanic ethnicity, older age, diabetes, obesity, and a number of genetic polymorphisms.

The incidence of HCC in veterans with NAFLD who do not have cirrhosis of the liver is very low. It was estimated to be only  0.08 per 1,000 patient-years in a population-based VA study.² In contrast, the incidence of HCC in veterans with NAFLD-cirrhosis is much higher, between 10-15 per 1,000 person-years (or around 1 to 1.5% per year). 2-5 This means that if you follow 1,000 patients with NAFLD-cirrhosis over a year, approximately 10-15 of them will develop HCC.

Of note, even though the risk of HCC in patients with NAFLD who do not have cirrhosis is very low, we still see a lot of HCCs in patients with pre-cirrhotic NAFLD, because the denominator is so large (i.e., there are so many patients with NAFLD)! In fact, in most studies, NAFLD is the leading cause of HCC in the absence of cirrhosis.

USM: Have other risk factors for HCC increased at the VA besides fatty liver?

GI: The main risk factors that have been increasing in the VA and worldwide are obesity, insulin resistance and diabetes. These happen to be both risk factors for NAFLD and risk factors for HCC. Such risk factors are therefore enriched in patients with NAFLD.

USM: How is NAFLD treated?

The cornerstone of NAFLD treatment is healthy diet and exercise, ideally also aiming to achieve some weight loss. Studies suggest that weight loss of about 5% of body weight results in reductions in hepatic steatosis (i.e. the amount of fat in the liver) whereas loss of about 10% of body weight can also result in a reduction in hepatic fibrosis (i.e. the amount of “scar tissue” or collagen in the liver). We know that the stage of fibrosis in NAFLD is the most important determinant of adverse long-term outcomes so reduction in fibrosis is the holy grail of NAFLD treatment. Incidentally, bariatric surgery that can achieve dramatic reductions in weight can also results in amelioration of hepatic steatosis and fibrosis.

There are no pharmacotherapies that are FDA approved to treat non-alcoholic steatohepatitis (NASH). We do use certain medications to treat NASH, for which there are studies that support improvements in liver inflammation or fibrosis. It is difficult to summarize these in a short space, but there are two important points to note: First, these treatments are only used to treat NASH, i.e., the more advanced form of NAFLD which manifests with inflammation and varying degrees of fibrosis of the liver in addition to excess fat; second, these treatments are not “cures” but rather they only work while the patient is being treated and the benefits, if any, start reversing when the patient stops taking the treatment.

USM: Is NAFLD reversible? 

GI: NAFLD is reversible. The liver has a remarkable ability to remodel, to remove fat from liver cells and break down fibrosis. The only condition that as far as we now know is not reversible is advanced cirrhosis of the liver. Even early cirrhosis of the liver has been shown to reverse.

USM: Do patients with NAFLD  exhibit symptoms that could alert them to a health problem?

GI: Unfortunately, NAFLD (as well as most chronic liver diseases) are “silent.” NAFLD causes little or no symptoms in and of itself and there are no pain fibers inside the liver. There are nerve fibers in the capsule that covers the liver which respond to stretch and theoretically if the liver is enlarged because of excess fat deposition this may be experienced as a feeling of fullness or discomfort. However, this is very nonspecific.

In the majority of cases, NAFLD is discovered “incidentally” because a person has elevated liver transaminase levels in their blood or because an imaging study (ultrasound, CT or MRI) demonstrates fat deposition in the liver. Therefore, a high index of suspicion is required. There are also discussions of screening certain high-risk populations for NAFLD, such as patients with type 2 diabetes mellitus (this is recommended by the American Diabetes Association and the European Association for the Study of Diabetes).

USM: At what stage are most NAFLD patients diagnosed?

GI: The vast majority of patients with NAFLD are diagnosed at early stages, especially in a comprehensive healthcare system such as the Veterans Health Administration, where abnormal blood tests (serum transaminases or “liver enzymes”) or imaging studies trigger further work-up. However, it is also not uncommon unfortunately for patients to present for the first time when they get diagnosed with cirrhosis or even HCC.

USM: Is there a way to apply the methods that were successful in treating HCV in the VA to treating NAFLD?

GI: The simple answer is “no” because we do not have a treatment that can eradicate NAFLD forever with a short course of treatment (8 or 12 weeks) like we do for hepatitis C!

The more nuanced answer is that we can definitely apply the lessons and the experiences that we acquired in eradicating HCV in the VA ahead of any other healthcare system, organization or country, to the management of NAFLD. The most important of these lessons in my opinion are the following:

• Get data, set SMART (Specific, Measurable, Attainable, Relevant, and Time-Bound) goals and track results. The VA can use the strength of its comprehensive nationwide EHR systems and analytic capabilities, to identify patients with NAFLD (by VISN and station), and set SMART goals related to the detection or management of NAFLD in these patients and track results.
• Organizational Infrastructure. The VA developed an incredible organizational infrastructure at the VISN [Veterans Integrated Service Network] and facility level to address hepatitis C, cirrhosis and liver cancer. This infrastructure can be repurposed for the management of NAFLD. The Hepatic Innovation Teams, which were critical in improving testing and treatment for hepatitis C across the VA, are now addressing ways to improve surveillance for HCC (with ultrasound with/without AFP) and for esophageal varices (with endoscopy) among patients with cirrhosis. 
• Multidisciplinary teams. Perhaps even more important than in the management of hepatitis C, cirrhosis and liver cancer, multidisciplinary teams are going to be key in the management of NAFLD.

1. Beste LA, Green P, Berry K, Belperio P, Ioannou GN. Hepatitis C-Related Hepatocellular Carcinoma Incidence in the Veterans Health Administration After Introduction of Direct-Acting Antivirals. JAMA. 2020;324:1003-1005.
2. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342-1359 e2.
3. Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, Richardson PA, Li L, Desiderio R, Thrift AP, Asch SM, Chu J, El-Serag HB. Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease. Gastroenterology. 2018;155:1828-1837 e2.
4. Ioannou GN, Green P, Lowy E, Mun EJ, Berry K. Differences in hepatocellular carcinoma risk, predictors and trends over time according to etiology of cirrhosis. PLoS One. 2018;13:e0204412.
5. Ioannou GN, Green P, Kerr KF, Berry K. Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification. J Hepatol. 2019;71:523-533.