Clin Mol Hepatol > Volume 29(2); 2023 > Article
Teng, Tan, Ng, and Huang: Hepatocellular carcinoma surveillance in non-alcoholic fatty liver disease – who and how?
Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing cause of hepatocellular carcinoma (HCC) globally [1]. The burden of NAFLD-related HCC is predicted to increase further, in tandem with the obesity epidemic [2]. NAFLD encompasses a spectrum of histological severity, ranging from non-alcoholic fatty liver to non-alcoholic steatohepatitis (NASH), which can consequently progress to liver fibrosis and cirrhosis [3]. One of the strongest risk factors for NAFLD-HCC is fibrosis stage [4,5], and a prospective multi-centre study found that incidence of HCC per 100 person-years increased with fibrosis stage [6].
Surveillance is associated with early detection of HCC and a higher likelihood of receiving curative treatment [7]. Patients with early HCC are more likely to be eligible for curative treatment such as ablation, surgical resection, or liver transplantation, with 5-year survival rates of >70% [8,9]. As such, surveillance is linked with improved overall survival [7]. Despite the rise in the incidence of NAFLD-HCC [10], key questions remain regarding HCC surveillance in NAFLD patients–namely who to survey, and how to survey these patients.
In a recent issue of Clinical and Molecular Hepatology, El Dahan et al. [11] highlight that HCC surveillance should be limited to NAFLD patients with cirrhosis, and there is currently no consensus regarding HCC surveillance in NAFLD patients without cirrhosis. Currently, the American Gastroenterology Association (AGA) and the European Association for the Study of the Liver (EASL) suggest that HCC surveillance may be considered selected non-cirrhotic NAFLD patients [12,13]. The AGA clinical practice update recommends the consideration of HCC surveillance in patients with advanced ≥F3 fibrosis, and proposes specific cut-offs on non-invasive tests (NITs) for consideration of surveillance–specifically, liver stiffness measurement of 16.1 kPa on vibration-controlled transient elastography (VCTE) and 5 kPa on magnetic resonance elastography (MRE) are cut-off values at which patients should consider HCC surveillance [12]. EASL guidelines recommend that HCC surveillance may be considered in patients with advanced fibrosis diagnosed either on biopsy or elastography and acknowledge that surveillance in non-cirrhotic NAFLD patients remains unclear [13].
To improve HCC surveillance in NAFLD, further efforts are needed to improve assessment of fibrosis stage, and identify NAFLD patients with advanced fibrosis at elevated risk of HCC. At present, AGA and EASL advocate a sequential approach using NITs (fibrosis-index 4 [FIB-4] followed by VCTE) to identify NAFLD patients with advanced fibrosis [14]. A prospective study involving 5 tertiary European centres showed that this strategy was able to predict risk of liver-related events, which included both complications of cirrhosis and HCC [15]. Longitudinal assessment of NITs has also been proposed as a method of monitoring changes in fibrosis over time and could facilitate early detection of progression to advanced fibrosis or cirrhosis [16,17]. Additionally, there are emerging data that NITs have potential for HCC risk stratification in NAFLD patients. Several studies in Asia and Europe have found that elevated FIB-4 was associated with a substantially increased risk of HCC over a median follow-up of 7–10 years [18-20]. More research is required to evaluate whether i) other NITs such as VCTE and MRE and ii) longitudinal information on NITs are correlated with HCC risk.
Next, HCC surveillance should be individualised in NAFLD patients without cirrhosis. Restricting HCC surveillance in NAFLD to patients with cirrhosis could miss a significant proportion of NAFLD patients who develop HCC. Compared to HCC of other etiologies, a higher percentage of NAFLD-HCC patients were non-cirrhotic (38.5% vs. 14.6%) [10]. This may have contributed to lower HCC surveillance rates among NAFLDHCC patients, as nearly 40% of NAFLD-HCC patients would not have had an indication for routine surveillance based on current guidelines. However, extending existing society recommendations to all non-cirrhotic NAFLD patients has major implications. The incidence of HCC in patients with non-cirrhotic NAFLD is low at approximately 0.1–1.3 per 1,000 person- years [2]. HCC surveillance in thislarge and rising population of NAFLD patients is neither feasible nor cost-effective.
There is a wide heterogeneity of HCC risk in non-cirrhotic NAFLD patients–apart from degree of fibrosis, other factors such as genetic polymorphisms, age, gender, obesity, and type 2 diabetes have been associated with HCC risk [4]. It would be more accurate to assess HCC risk directly, rather than extrapolating HCC risk from fibrosis stage. Several genomewide association studies have identified single nucleotide polymorphisms (SNPs) such as patatin-like phospholipase domain-containing protein 3 (PNPLA3) which could be linked to increased risk of HCC [21]. Polygenic risk scores including these SNPs have been found to improve detection of HCC particularly in individuals with dysmetabolism, and was able to predict HCC independently of presence of severe fibrosis in NAFLD patients [22]. It has been suggested that risk factors and estimates of fibrosis stage could also be combined into risk calculators or risk prediction models to identify NAFLD patients at higher risk of HCC who would benefit from surveillance [4,11]. A HCC risk calculator comprising 7 parameters derived from clinical characteristics and serum lab tests has previously been developed in patients with NAFLD cirrhosis to estimate HCC risk [23], although this has not been externally validated. Another novel risk prediction model comprising age, platelet count, serum aspartate aminotransferase, and liver stiffness based on VCTE has demonstrated utility in prediction of HCC risk in NAFLD patients [24].
El Dahan et al. [11] comment that the current method most often utilized for HCC surveillance, ultrasound (US) +/- alphafetoprotein (AFP), is inadequate for early detection of HCC. US has a relatively poor sensitivity of <50% for early detection of HCC [25]. Furthermore, patients with NASH cirrhosis were found to be more likely to have limited visualisation on ultrasound [26,27]. Surveillance failure could be attributed to the presence of subcutaneous fat, focal fatty infiltration, and heterogeneity of liver parenchyma, which hinder the identification of smaller lesions [28]. The AGA clinical practice update advises that the adequacy of ultrasound for HCC surveillance should be documented, and if inadequate, other imaging modalities such as computed tomography (CT) scan or magnetic resonance imaging (MRI) should be considered [12]. As mentioned by El Dahan et al. [11], numerous alternative imaging techniques such as abbreviated MRI protocols have been proposed, but at present, data on their utility and cost-effec-tiveness is lacking.
Both AGA and American Association for the Study of Liver Disease (AASLD) support US +/- AFP, whereas EASL supports US alone for HCC surveillance [12,13,29]. A meta-analysis found that pooled sensitivity for detection of early HCC improved from 45% with US alone to 63% with addition of AFP to US [25]. EASL also mentions that combining AFP and US leads to a modest 6–8% increase in detection of HCC [13]. Given the inadequate visualisation on US in NAFLD patients, the addition of AFP to US should be considered to maximise the possibility of detection of HCC. El Dahan et al. [11] discuss alternative biomarker-based surveillance tools such as GALAD and other novel biomarkers. Recent evidence suggests that liquid biopsy techniques such as methylation profiling of circulating tumour DNA have the potential to improve detection rates and transform the future of surveillance [30].
In conclusion, a multi-pronged strategy is required to optimise HCC surveillance in NAFLD patients. Improved risk stratification of NAFLD patients who might warrant HCC surveillance, as well as the adoption of more accurate biomarker- or imaging-based surveillance modalities may help address the challenges of HCC surveillance in NAFLD.

FOOTNOTES

Authors’ contributions
Conceptualisation and Design: Margaret LP Teng, Daniel Q. Huang. Acquisition of Data, Analysis and Interpretation of Data: All authors Writing – original draft: Margaret LP Teng, Daniel Q. Huang. Writing – revision and final approval of version to be published: All authors.
Conflicts of Interest
The authors have no conflicts to disclose.

Abbreviations

NAFLD
non-alcoholic fatty liver disease
HCC
hepatocellular carcinoma
NASH
non-alcoholic steatohepatitis
AGA
American Gastroenterology Association
EASL
European Association for the Study of the Liver
NITs
non-invasive tests
VCTE
vibration-controlled transient elastography
MRE
magnetic resonance elastography
FIB4
fibrosis-index 4
SNPs
single nucleotide polymorphisms
US
ultrasound
AFP
alphafetoprotein
CT
computed tomography
MRI
magnetic resonance imaging
AASLD
American Association for the Study of Liver Disease

REFERENCES

1. Huang DQ, Singal AG, Kono Y, Tan DJH, El-Serag HB, Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab 2022;34:969-977.e2.
crossref pmid pmc
2. Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021;18:223-238.
crossref pmid pmc pdf
3. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, et al.; Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021;27:363-401.
crossref pmid pmc pdf
4. Ioannou GN. Epidemiology and risk-stratification of NAFLDassociated HCC. J Hepatol 2021;75:1476-1484.
crossref pmid
5. Ng CH, Lim WH, Hui Lim GE, Hao Tan DJ, Syn N, Muthiah MD. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2022 May 2. doi: 10.1016/j.cgh.2022.04.014.
crossref pmid
6. Sanyal AJ, Van Natta ML, Clark J, Neuschwander-Tetri BA, Diehl A, Dasarathy S, et al.; NASH Clinical Research Network (CRN). Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med 2021;385:1559-1569.
crossref pmid pmc
7. Singal AG, Zhang E, Narasimman M, Rich NE, Waljee AK, Hoshida Y, et al. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis. J Hepatol 2022;77:128-139.
crossref pmid
8. Koh JH, Tan DJH, Ong Y, Lim WH, Ng CH, Tay PWL, et al. Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria: a meta-analysis of 18,421 patients. Hepatobiliary Surg Nutr 2022;11:78-93.
crossref pmid pmc
9. Reveron-Thornton RF, Teng MLP, Lee EY, Tran A, Vajanaphanich S, Tan EX, et al. Global and regional long-term survival following resection for HCC in the recent decade: A meta-analysis of 110 studies. Hepatol Commun 2022;6:1813-1826.
crossref pmid pmc pdf
10. Tan DJH, Ng CH, Lin SY, Pan XH, Tay P, Lim WH, et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol 2022;23:521-530.
crossref pmid pmc
11. El Dahan KS, Daher D, Singal AG. Hepatocellular carcinoma surveillance in patients with non-alcoholic fatty liver disease. Clin Mol Hepatol 2023;29(Suppl):S207-S219.
crossref pmid pmc pdf
12. Loomba R, Lim JK, Patton H, El-Serag HB. AGA Clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: Expert review. Gastroenterology 2020;158:1822-1830.
crossref pmid pmc
13. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018;69:182-236 Erratum in: J Hepatol 2019;70:817.
crossref
14. Stern C, Castera L. Identification of high-risk subjects in nonalcoholic fatty liver disease. Clin Mol Hepatol 2023;29(Suppl):S196-S206.
crossref pmid pmc pdf
15. Boursier J, Hagström H, Ekstedt M, Moreau C, Bonacci M, Cure S, et al. Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events. J Hepatol 2022;76:1013-1020.
crossref pmid
16. Cholankeril G, El-Serag HB. Current challenges and future direction in surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. Semin Liver Dis 2023;43:89-99.
crossref pmid
17. Yu JH, Lee HA, Kim SU. Noninvasive imaging biomarkers for liver fibrosis in nonalcoholic fatty liver disease: current and future. Clin Mol Hepatol 2023;29(Suppl):S136-S149.
crossref pmid pmc pdf
18. Kim GA, Lee HC, Choe J, Kim MJ, Lee MJ, Chang HS, et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol 2018;68:140-146.
crossref pmid
19. Younes R, Caviglia GP, Govaere O, Rosso C, Armandi A, Sanavia T, et al. Long-term outcomes and predictive ability of noninvasive scoring systems in patients with non-alcoholic fatty liver disease. J Hepatol 2021;75:786-794.
crossref pmid
20. Loosen SH, Kostev K, Keitel V, Tacke F, Roderburg C, Luedde T. An elevated FIB-4 score predicts liver cancer development: A longitudinal analysis from 29,999 patients with NAFLD. J Hepatol 2022;76:247-248.
crossref pmid
21. Truong E, Noureddin M. Hepatocellular carcinoma surveillance in non-alcoholic fatty liver disease patients. Hepatoma Res 2022;8:40.
crossref
22. Bianco C, Jamialahmadi O, Pelusi S, Baselli G, Dongiovanni P, Zanoni I, et al. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J Hepatol 2021;74:775-782.
crossref pmid pmc
23. Ioannou GN, Green P, Kerr KF, Berry K. Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLDrelated cirrhosis for risk stratification. J Hepatol 2019;71:523-533.
crossref pmid pmc
24. Lee JS, Sinn DH, Park SY, Shin HJ, Lee HW, Kim BK, et al. Liver stiffness-based risk prediction model for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. Cancers (Basel) 2021;13:4567.
crossref pmid pmc
25. Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: A metaanalysis. Gastroenterology 2018;154:1706-1718 e1.
crossref pmid pmc
26. Simmons O, Fetzer DT, Yokoo T, Marrero JA, Yopp A, Kono Y, et al. Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis. Aliment Pharmacol Ther 2017;45:169-177.
crossref pmid pmc pdf
27. Schoenberger H, Chong N, Fetzer DT, Rich NE, Yokoo T, Khatri G, et al. Dynamic changes in ultrasound quality for hepatocellular carcinoma screening in patients with cirrhosis. Clin Gastroenterol Hepatol 2022;20:1561-1569 e4.
crossref pmid
28. Younes R, Bugianesi E. Should we undertake surveillance for HCC in patients with NAFLD? J Hepatol 2018;68:326-334.
crossref pmid
29. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723-750.
crossref pmid pdf
30. von Felden J, Garcia-Lezana T, Schulze K, Losic B, Villanueva A. Liquid biopsy in the clinical management of hepatocellular carcinoma. Gut 2020;69:2025-2034.
crossref pmid

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: cmh_journal@ijpnc.com
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 606
TOTAL : 2149486
Close layer