Hepatocellular carcinoma in non-alcoholic fatty liver disease-a review of an emerging challenge facing clinicians

Abstract

Importance: Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of chronic liver disease and is becoming a leading cause of hepatocellular carcinoma (HCC) in many developed countries. This presents major challenges for the surveillance, diagnosis and treatment of HCC.

Objective: To discuss the clinical challenges faced by clinicians in managing the rising number of NAFLD-HCC cases.

Evidence review: MEDLINE, PubMed and Embase databases were searched using the keywords; NAFLD, HCC, surveillance, hepatectomy, liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE), selective internal radiotherapy treatment (SIRT) and sorafenib. Relevant clinical studies were included.

Findings: Current HCC surveillance programmes are inadequate because they only screen for HCC in patients with cirrhosis, whereas in NAFLD a significant proportion of HCC develops in the absence of cirrhosis. Consequently NAFLD patients often present with a more advanced stage of HCC, with a poorer prognosis. NAFLD-HCC patients also tend to be older and to have more co-morbidities compared to HCC of other etiologies. This limits the use of curative treatments such as liver resection and orthotopic liver transplantation (OLT). Evidence suggests that although NAFLD-HCC patients who undergo liver resection or OLT have worse perioperative and short-term outcomes, overall long-term survival is comparable to HCC of other etiologies. This highlights the importance of careful patient selection, pre-habilitation and perioperative planning for NAFLD-HCC patients being considered for surgical treatment. Careful consideration is also important for non-surgical treatments, although the evidence supporting treatment selection is frequently lacking, as these patients tend to be poorly represented in clinical trials. Locoregional therapies such as percutaneous ablation and TACE may be less well tolerated and less effective in NAFLD patients with obesity or diabetes. The tyrosine kinase inhibitor sorafenib may also be less effective.

Conclusions and relevance: This review highlights how international guidelines, for which NAFLD traditionally has made up a small part of the evidence base, may not be appropriate for all NAFLD-HCC patients. Future guidelines need to reflect the changing landscape of HCC, by making specific recommendations for the management of NAFLD-HCC.

Keywords: Non- alcoholic fatty liver disease (NAFLD); catheter ablation; hepatectomy; hepatocellular carcinoma (HCC); liver transplantation; population surveillance; sorafenib.

Figure 1

Hepatocellular carcinoma staging and treatment. The EASL guidelines recommend the BCLC algorithm for the management of patients with HCC (45). Patients are classified based on tumour stage, liver function and performance status into four categories (A-D) (blue boxes), with treatments ranging from resection, transplantation and ablation in fitter patients with early disease (BCLC-A), to supportive care in those with advanced HCC in association with poor liver function and/or performance status (BCLC-D) (green boxes). In the populations where HCV cirrhosis is highly prevalent (orange boxes), up to half the patients are suitable for curative or locoregional therapies, with 40% suitable for 1^st line medical therapy. In regions where NAFLD is the commonest cause of HCC, the majority of treatable patients are classed BCLC-C (13) and may have age or metabolic syndrome co-morbidities less suitable for medical therapies (yellow boxes). The recent updated EASL guideline supports ECOG-PS stage being attributed to cancer associated symptoms only, potentially enabling an allocation of a patient with physical restrictions impacting performance to BCLC-A or BCLC-B categories, if they have preserved liver function and an earlier stage cancer. In reality, there is little evidence supporting the use of locoregional therapies in these patients. Neither are there evidence based guidelines directing therapies in the absence of cirrhosis. Medical therapies should be considered, but neither elderly patients nor NAFLD patients have been well represented in the clinical trials of medical therapies. HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic for Liver Cancer; EASL, European Association for the Study of the Liver; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; TACE, transarterial chemoembolization; SIRT, selective internal radiotherapy treatment; NAFLD, non-alcoholic fatty liver disease.

Figure 2

HCC MDT care in a centre with high prevalence of metabolic syndrome and NAFLD. In Newcastle upon Tyne, UK, NAFLD is the commonest cause of HCC and over two thirds of patients have the metabolic syndrome irrespective of their underlying liver disease etiology. NAFLD patients are more likely to present in the absence of cirrhosis and require biopsy confirmation of their HCC and liver disease stage. The BCLC algorithm guides treatment strategies in cirrhotic patients and in non-cirrhotic patients, liver function may be better preserved and more radical surgical approaches may be appropriate in those that are fit enough. In NAFLD patients classed as BCLC-C, medical therapies may not be ideal (e.g., restricted mobility, renal or cardiac impairment). Selective TACE may be better tolerated and preferable to supportive care in some instances. This figure summaries the modified BCLC pathway (yellow boxes) directed by the Newcastle upon Tyne Hepatopancreatobiliary multidisciplinary team (HPB MDT), with # noting those areas where the evidence base is lacking and research or service improvement audits are necessary to inform future modifications to clinical practice. HPB, hepatobiliary; MDM, multidisciplinary meeting; HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic for Liver Cancer; TNM, tumor node metastasis; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; HCC, hepatocellular carcinoma; MDT, multidisciplinary team; SIRT, selective internal radiation therapy; DEB-TACE, drug-eluting bead transarterial chemoembolization; NAFLD, non-alcoholic fatty liver disease.