Large Analysis Sheds Light on Risk Factors for Non-Cirrhotic NASH-Associated HCC

About one quarter of patients with nonalcoholic steatohepatitis-associated hepatocellular carcinoma present without cirrhosis at diagnosis, suggesting a crucial subset of patients for future research with implications for HCC screening and surveillance.

Ju Dong Yang, MD, MSc

About one quarter of patients (26%) with nonalcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) present without cirrhosis at diagnosis, suggesting a crucial subset of patients for future research with implications for HCC screening and surveillance, according to Ju Dong Yang, MD, MSc, at the 10th Annual Conference of the International Liver Cancer Association (ILCA).1

In a multivariate analysis of retrospective data for 4,734 patients, hypertension and cigarette smoking were independently associated with non-cirrhotic NASH-related HCC. The odds ratio (OR) for non-cirrhotic NASH HCC was 2.52 for those with hypertension (P = 006) and 2.27 for those who smoked (P = .007). Diabetes was inversely related with having non-cirrhotic NASH HCC (multivariate OR, 0.34; P = .002).

“We identified potential risk factors for the development of HCC in the absence of cirrhotic liver disease in patients with NASH,” said Yang, an associate faculty member, Division of Gastroenterology and Hematology, Mayo Clinic College of Medicine in Rochester, Minnesota, in an interview with OncLive. “Our data proposed that potentially we can put liver cancer surveillance, for example, [in place] for a patient who has smoked in the past or is currently smoking because they may be at high risk of developing liver cancer, even in the absence of cirrhotic liver disease.”

NASH, a form of non-alcoholic fatty liver disease, is one of the major causes of HCC in Western countries. In the United States, NASH is the most rapidly growing etiology of HCC and second leading cause of liver transplantation.

The idea that cirrhosis is not present in all patients with NASH-associated HCC has been shown previously; however, Yang and his colleagues set out to confirm these findings in a larger analysis. For this study, researchers looked at data from 4,734 patients who were part of the longitudinal BRIDGE study.2

This study found that males had a 1.61-fold increased risk of non-cirrhotic HCC, while Hepatitis B was associated with a 3.15-fold increased risk and hypertension was associated with a 1.60-fold increased risk. Most importantly, Yang pointed out, NASH was associated with a 3.57-fold increased risk of non-cirrhotic HCC.

“Our study confirmed that patients with NASH, which is a common cause of liver disease in the US, may develop liver cancer in the absence of cirrhosis,” Yang said, noting that previous studies were performed in a small number of patients.

To identify risk factors associated with non-cirrhotic HCC in patients with NASH, the retrospective study also looked at data from just over 312 patients from the BRIDGE study with NASH—82 did not have cirrhosis while 230 did. A number of factors were significantly different between arms, namely male gender (78% non-cirrhotic vs 65% cirrhotic), diabetes (65% vs 83%, respectively), hypertension (78% vs 65%), smoking (67% vs 50%), albumin (4.0 vs 3.6), platelets (248 vs 132), and tumor size in centimeters (6.5 vs 4.0).

There were some differences between the groups in regard to treatment: patients with non-cirrhotic NASH HCC more commonly received surgical resection compared with their cirrhotic NASH HCC counterparts (36% vs 9%), though they were less likely to receive liver transplantation (0% vs 18%). The groups were treated with curative intent at the same rate (49% for non-cirrhotic patients vs 45% for cirrhotic patients) and overall survival was similar (HR, 0.8; 0.6-1.2; P = .25).

With the increasing prevalence of NASH in the general population, NASH-associated HCC will increase too, Yang noted, so researchers should have some sense of urgency—though there is still important work to be done.


  1. Yang J, Harmsen WS, Therneau TM, et al. Comparison of Clinical Features of NASH Associated HCC With Versus Without Liver Cirrhosis. Presented at: 10th Annual Conference of the International Liver Cancer Association; Vancouver, Canada, September 9-11, 2016.
  2. Park JW, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015 Sep;35(9):2155-66. Doi: 10.1111/liv.12818.

“The associations seen in the current study between cigarette smoking, hypertension, and non-cirrhotic HCC may help to guide HCC risk stratification, but they should be further validated in a future study,” Yang concluded.


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