Characteristics, Aetiologies and Trends of Hepatocellular Carcinoma in Patients Without Cirrhosis

A United States Multicentre Study

Samer Gawrieh; Lara Dakhoul; Ethan Miller; Andrew Scanga; Andrew deLemos; Carla Kettler; Heather Burney; Hao Liu; Hamzah Abu-Sbeih; Naga Chalasani; Julia Wattacheril


Aliment Pharmacol Ther. 2019;50(7):809-821. 

In This Article

Abstract and Introduction


Background: Limited data exist on the burden and features of non-cirrhotic hepatocellular carcinoma (HCC) in the United States.

Aim: To evaluate characteristics, aetiologies, trends and outcomes of non-cirrhotic HCC from 2000 to 2014 at five large US centres

Methods:Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria.

Results: Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non-cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P < .001 for all). Among non-cirrhotic patients, non-alcoholic fatty liver disease (NAFLD) was the most common liver disease (26.3%), followed by hepatitis C virus (HCV) (12.1%) and hepatitis B virus (HBV) (10%) infections. As of 2014, there was increased percentage of cirrhotic HCC and a decline in non-cirrhotic HCC mainly due to significant annual increases in cirrhotic HCC due to HCV (0.96% [P < .0001]) and NAFLD (0.66% [P = .003]). Patients with non-cirrhotic HCC had larger tumours (8.9 vs 5.3 cm), were less frequently within Milan criteria (15% vs 39%), more frequently underwent resection (43.6% vs 8%) (P < .001 for all) and had better overall survival than cirrhotic HCC patients (median 1.8 vs 1.3 years, P = .004).

Conclusions: Nearly 12% of HCCs occurred in patients without underlying cirrhosis. NAFLD was the most common liver disease in these patients. During the study, the frequency of non-cirrhotic HCC decreased, whereas that of cirrhotic HCC increased. Although non-cirrhotic patients presented with more advanced HCC, their survival was better.


Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, causing more than 700 000 deaths per year.[1] HCC incidence rates have significantly increased in the US, surpassed only by thyroid cancer.[2–5] Furthermore, HCC mortality rate is the highest of all cancers in the US.[4]

While viral hepatitis and alcohol have traditionally been the main liver diseases driving the occurrence of HCC,[6,7] the new millennium has witnessed the emergence of non-alcoholic fatty liver disease (NAFLD) as a major contributor to the burden of HCC, not only in the US and Western countries but also at the global level.[8–11] Over the past two decades, NAFLD cirrhosis has been increasingly recognised as an important cause of HCC.[12–18] Recent studies based on national data have shown a significant and recent increase in NAFLD contribution to the HCC burden and mortality in the US.[8,10,19,20] In a study of United Network for Organ Sharing (UNOS) registry from 2002 to 2012, liver transplantation for HCC related to NAFLD has increased four-fold compared to a two-fold increase for HCC related to hepatitis C virus (HCV), making NAFLD the most rapidly growing indication for liver transplantation for HCC in the US.[19] Between 2001 and 2013, HCV followed by NAFLD were the major contributors to the increasing rates of cirrhosis and HCC among the US veterans.[10] In a study of the Surveillance, Epidemiology and End Results (SEER) registries with Medicare-linkage files for HCC between 2004 and 2009, a 9% annual increase in NAFLD-related HCC was observed, exceeded only by a 13% annual increase in HCV-related HCC. However, whether NAFLD contribution to the expanding HCC burden is exclusively via the cirrhosis-carcinogenesis pathway was not clear from these studies.

The development of HCC in a non-cirrhotic setting has long been recognised as an uncommon event in patients with chronic liver disease, occurring primarily in the setting of hepatitis B virus (HBV) infection.[21,22] Accumulating data from different case reports and studies over the past two decades have shown that the same phenomenon occurs in the setting of non-cirrhotic NAFLD.[23–28] The mechanisms of carcinogenesis in the setting of non-cirrhotic NAFLD are not entirely clear, but the chronic inflammatory state associated with obesity and commonly seen with NAFLD, insulin resistance and lipotoxicity may alter hepatocyte proliferation and different modes of hepatocyte death, thus promoting a carcinogenic milieu.[29–32]

There seems to be geographical differences in the frequency of non-cirrhotic HCC in the setting of NAFLD; only 15% of patients with NAFLD and HCC were not cirrhotic in an Australian study,[33] compared to 27% in a single-centre US study,[34] and up to 50% in European and Japanese studies.[35–38] However, besides population differences, some of these studies were based on data from single centres, had small study size, lacked specific criteria to define the non-cirrhotic status or included only patients referred for surgical resection. The proportion of non-cirrhotic HCC in the US has not been adequately quantified.

While the trends of HCC related to specific underlying liver diseases in select populations in the US have been recently described based on the UNOS, Veterans Administration (VA) and SEER databases, these studies relied on International Classification of Diseases (ICD) codes for identifying the underlying liver diseases or presence of obesity or diabetes to infer the presence of NAFLD.[8,10,19] No other large-scale data with direct ascertainment of the underlying aetiology of liver disease and cirrhotic status are yet available in the US to allow for high-resolution evaluation of all comers with HCC. With the limitations in current literature,[39] it is unclear whether the rising incidence of NAFLD in the US has resulted in higher number of non-cirrhotic HCC. If this was true, it would have a major public health impact as the proportion of HCC linked to NAFLD is anticipated to be on the rise with the global and growing epidemic of obesity and metabolic syndrome.

To address these questions, we studied 5144 patients with HCC seen at five major liver centres across the US over a 14.5-year period between 2000 and 2014. The primary objectives of this study were to (a) characterise the frequency and characteristics of non-cirrhotic HCC, (b) assess the trends of percentage of non-cirrhotic HCC over the study period and (c) determine the contribution of NAFLD to the burden of non-cirrhotic HCC. As secondary objectives, we report on the treatment modalities these patients received and their survival compared to cirrhotic patients with HCC.