Characteristics and Outcome of Hepatocellular Carcinoma in Patients With NAFLD Without Cirrhosis

Bonnie Bengtsson; Per Stål; Staffan Wahlin; Niklas K. Björkström; Hannes Hagström


Liver International. 2019;39(6):1098-1108. 

In This Article

Abstract and Introduction


Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is a growing cause of hepatocellular carcinoma (HCC). In NAFLD, HCC occurs more commonly in the absence of cirrhosis compared with other liver diseases; yet, patients with non-cirrhotic NAFLD-HCC are poorly characterized. Here, we characterized a large cohort of HCC cases and assessed the outcomes of patients with non-cirrhotic NAFLD-HCC.

Methods: We identified all cases of HCC treated at the Karolinska University Hospital, Stockholm, Sweden from 2004 to 2017. Patient charts were manually reviewed for variable extraction. Cases were followed passively for all-cause and HCC-related mortality until the end of April 2018. Cox regression was performed to estimate mortality rates and identify mortality risk factors in patients with non-cirrhotic NAFLD-HCC.

Results: Totally, 1562 cases with HCC were identified. Of these, 225 (14.4%) had NAFLD-HCC, of which 83 (37%) did not have cirrhosis. Compared with patients with cirrhotic NAFLD-HCC, patients with non-cirrhotic NAFLD-HCC were older (74 vs 70 years, P < 0.001), had a lower prevalence of type 2 diabetes (T2DM) (66% vs 80%, P = 0.02), larger tumours, less frequently underwent liver transplantation (0% vs 11%, P = 0.002), but more frequently underwent resection (35% vs 8%, P < 0.001). Mortality was similar (aHR for non-cirrhotic NAFLD-HCC vs cirrhotic NAFLD-HCC 0.93, 95% CI 0.58-1.51, P = 0.78). Parameters independently associated with increased mortality included the Barcelona Clinic Liver Cancer stage, number of tumours, lower albumin and presence of T2DM.

Conclusions: Patients with non-cirrhotic NAFLD-HCC differ from those with cirrhosis in age, tumour size and allocated treatments. Despite these differences, survival is similar.


The incidence of liver cancer is increasing and currently listed as the sixth most common cancer worldwide and the third most common cause of cancer-related death.[1] Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers.[2] A majority (80%-90%) of patients diagnosed with HCC have cirrhosis.[3] For decades, viral hepatitis and alcoholic liver disease (ALD) have been the most common causes of cirrhosis and HCC.[4] The increased prevalence of obesity and type 2 diabetes (T2DM) and treatment with new antiviral agents for hepatitis C are rapidly changing the epidemiology of cirrhosis and HCC. Non-alcoholic fatty liver disease (NAFLD), affecting about 25% of the global population,[5,6] has emerged as one of the leading causes of cirrhosis and HCC.[7–9]

HCC is associated with poor survival, especially in later stages of the disease.[10,11] Screening with hepatic ultrasound biannually to detect early forms of HCC when curative treatment is still an option is therefore recommended.[2,12] Several studies have found that NAFLD-HCC occurs more frequently in the absence of cirrhosis compared with other liver diseases.[13–15] However, given the large number of individuals affected by NAFLD, it is not feasible to perform HCC surveillance for all non-cirrhotic NAFLD patients.

There are limited data to shed light on what characterizes patients with non-cirrhotic NAFLD-HCC.[14,16,17] This study therefore aimed to describe NAFLD-HCC patients, with and without cirrhosis in a large cohort. A further aim was to evaluate whether the incidence of NAFLD-HCC is increasing in our geographic area with a generally lower prevalence of obesity and T2DM compared with many other countries. A third goal was to determine whether patients with NAFLD-HCC have cirrhosis less often than patients with other liver diseases. Finally, we sought to compare the prognosis of non-cirrhotic NAFLD-HCC patients to that of cirrhotic NAFLD-HCC and other patients with HCC as well as to identify mortality risk factors in patients with non-cirrhotic NAFLD-HCC.