Introduction
The etiology of hepatocellular carcinoma (HCC) is complex. The main risk factors for HCC are viral hepatitis, diabetes, obesity, and alcoholic and non-alcoholic fatty liver disease. Additional factors include smoking, exposure to toxins and genetic factors. In chronic liver disease, repeated damage and regeneration of the organ may lead to fibrosis, cirrhosis and the development of HCC. HCC can also arise in the non-cirrhotic liver [1, 2]. In the non-alcoholic fatty liver disease (NAFLD) population, the incidence of HCC in the non-cirrhotic liver is significantly higher than in other etiologies of liver disease [3]. The annual incidence of HCC in patients with NAFLD (1-2%) is lower than in the case of viral cirrhosis (3-5%), but the increase in the incidence of NAFLD, especially in developed countries, such as Western Europe or the United States, causes metabolic processes to become an important risk factor for HCC [4, 5]. The incidence of HCC in patients with metabolic-associated steatotic liver disease (MASLD) as the only etiological factor increased over 15 years from 50.4% to 77.3%. Patients with HCC of MASLD origin, compared to patients with HCC of other etiologies, were older, a greater percentage of them were men, and the coexistence of clinically significant portal hypertension was less common. The diagnosis of HCC was less often the result of oncological surveillance tests, and the cancer was more often more advanced (larger tumor size and extrahepatic metastases) [6].
Metabolic dysfunction-associated steatotic liver disease
According to the position of the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD), the European Association for the Study of Obesity (EASO), and the expert consensus, MASLD replaces the previous term non-alcoholic fatty liver disease (NAFLD) and is part of the new consensus definition of steatotic liver disease (SLD) [7, 8]. NAFLD is defined in most guidelines and publications as the presence of steatosis in > 5% of hepatocytes, in the absence of significant alcohol consumption (< 20 g/day in women and < 30 g/day in men) and the absence of other known causes of liver disease. The definition of NAFLD includes NAFLD and non-alcoholic steatohepatitis (NASH), in which progressive hepatocyte damage is associated with a higher risk of developing fibrosis, cirrhosis and, consequently, HCC [9].
Metabolic-associated steatotic liver disease is characterized by excessive hepatic triglyceride storage in the presence of one or more cardiometabolic risk factors, in the absence of harmful alcohol intake, and without any other apparent cause. The spectrum of MASLD disease includes isolated fatty liver disease (simple steatosis), metabolic-related steatohepatitis (MASH, formerly NASH), fibrosis, cirrhosis, and MASH-related HCC.
Clinical aspects of the diagnosis of MASLD
Hepatic steatosis in imaging or histological examination of a liver section.
Presence of 1 metabolic risk factor:
– body mass index (BMI) ≥ 25 kg/m2 or waist circumference ≥ 94 cm in men and ≥ 80 cm in women (or above normal depending on ethnicity),
– blood pressure ≥ 130/85 mm Hg or treatment for hypertension,
– serum triglyceride concentration ≥ 1.7 mmol/l (150 mg/dl) or treatment for hypertriglyceridemia,
– serum high density lipoprotein (HDL) cholesterol concentration ≤ 1.0 mmol/l (40 mg/dl) in men and ≤ 1.3 mmol/l (50 mg/dl) in women or treatment for hypercholesterolemia,
– fasting glucose ≥ 5.6 mmol/l (100 mg/l) or 2 h after glucose load ≥ 7.8 mmol/l (140 mg/dl) or HbA1c ≥ 5.7% (39 mmol/mol) or type 2 diabetes, or treatment for type 2 diabetes.
MASH criteria: MASLD with steatosis ≥ 5% of hepatocytes, lobular and portal inflammation, and balloon degeneration of hepatocytes [7, 8].
A systematic review of studies on the epidemiology of MASLD concluded that it affects approximately 30% of people worldwide and its incidence is increasing [10]. MASLD/NAFLD is caused by excessive accumulation of lipids in the liver, especially free fatty acids [11]. Lipotoxicity mediated by non-esterified fatty acids and diacylglycerol promotes insulin resistance and endoplasmic reticulum dysfunction, leading to chronic inflammation, subsequent fibrosis, liver cirrhosis, and ultimately hepatocarcinogenesis [12, 13].
Remodeling of adipose tissue, changes in the intestinal microbiome and endoplasmic reticulum, and oxidative stress contribute to insulin resistance and the transformation of NAFLD/MASLD into NASH/MASH. This is the basis for the development of HCC of metabolic etiology. In obese patients, adipocyte inflammation and hypoxia occur. Oxidation of free fatty acids induces the production of reactive oxygen species (ROS) in overloaded mitochondria and the release of pro-inflammatory cytokines, which become readily released. Under these conditions, insulin resistance induced by pro-inflammatory cytokines, adhesion molecules and transcription factors create conditions for the development of NASH. Obesity additionally induces an increase in interleukin (IL)-6 and tumor necrosis factor (TNF), which increases chronic inflammation and activates STAT3, an oncogenic transcription factor.
ROS-mediated impaired mitochondrial function contributes to the selective death of CD4 T cells, reducing immune surveillance. IgA+ cells accumulate in NASH, inhibiting CD8 T cells and accelerating hepatocarcinogenesis. Loss of protective gut bacteria and dysregulated farnesoid X receptor (FXR) signaling in NAFLD increases intestinal permeability, leading to the release of inflammatory factors produced by the gut microbiome. These factors cause further liver damage and ultimately induce the progression of NASH, and dietary factors and ROS additionally induce epigenetic changes that contribute to cell proliferation and carcinogenesis. It is possible that genetic factors related to lipid metabolism and inflammation (e.g. single nucleotide polymorphisms – SNPs, patatin-like phospholipase domain containing 3 – PNPLA3, transmembrane 6 superfamily member 2 – TM6SF2, hydroxysteroid 17β dehydrogenase – HSD17B13) act as risk factors for the development of NASH and HCC in the course of metabolic disease [14, 15].
Systemic treatment of hepatocellular carcinoma
Systemic treatment is used in patients with HCC who cannot undergo surgical or local treatment. Disease stage is determined according to the Barcelona Clinic Liver Cancer (BCLC) classification, which takes into account, in addition to the size and number of lesions and the presence of metastases outside the liver, the patient’s performance status and organ function (according to the Child-Pugh score, ALBI score, α-fetoprotein [AFP] level, and MELD score). Patients with unresectable HCC at stages BCLC B and BCLC C are eligible for systemic treatment [16] (Table 1).
Table 1
BCLC 2022 staging and treatment strategy
In recent years, there has been progress in the systemic treatment of HCC. Published data from clinical trials on the effectiveness of immunotherapy and tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib) and anti-angiogenic antibodies (ramucirumab, bevacizumab) have changed the standard of care. Immune checkpoint inhibitors used alone or in combination (atezolizumab + bevacizumab, ipilimumab + nivolumab, durvalumab + tremelimumab, nivolumab and pembrolizumab as monotherapy) extended the survival time of patients with HCC [17].
Despite the improvement in the effectiveness of treatment, thanks to the registration of new drugs, the heterogeneous nature of HCC (etiopathogenesis, diversity of mutations, multi-stage process of tumorigenesis) requires further research aimed at developing new therapies [18]. It is equally important to precisely determine prognostic and predictive factors which will allow individualization of treatment and the selection of the most effective first-line treatment method, as well as the sequence of systemic treatment.
Hepatocellular carcinoma in steatotic liver disease associated with metabolic disorders MASLD-HCC/non-alcoholic fatty liver disease NAFLD-HCC – systemic treatment
It is estimated that one quarter of the world’s population suffers from NAFLD, and the incidence of NASH will increase by over 50% in the coming years. NAFLD is already the fastest growing cause of HCC in Western countries. Globally, the incidence of NAFLD/MASLD-related HCC is likely to increase as the obesity epidemic continues. The estimated annual incidence of HCC ranges from 0.5% to 2.6% among patients with NASH cirrhosis. The incidence of HCC among NAFLD patients without cirrhosis is lower than in HCC of other etiologies. However, an increasing number of people have metabolic disorders leading to NAFLD/MASLD, and therefore the number of patients with HCC may be higher in this group than in patients with other chronic liver diseases [15].
Features considered in stratifying HCC patients include demographic and clinical factors. Patients differ in terms of age, sex, race, fitness level, liver function, AFP value, etiology of liver disease, presence of vascular invasion, infiltration and/or thrombosis in the main branch of the portal vein, occurrence of metastases and their location (liver, lymph nodes, bones, lungs, adrenal glands), stage in the Barcelona classification, symptoms (jaundice, ascites, encephalopathy, sarcopenia), comorbidities, cirrhosis, and previous therapy. Each of these factors is assessed for its usefulness as a prognostic or predictive factor.
In clinical trials that assessed the effectiveness of immunotherapy, subgroup analyses based on the etiology of HCC included a division into viral and non-viral causes of the disease. The HIMALAYA study showed longer survival in non-viral patients treated with the STRIDE regimen (tremelimumab 1 course + durvalumab) compared to sorafenib. The effectiveness of immunotherapy in overall survival in patients with HCC caused by hepatitis B infection (HBV-related HCC) has been proven in phase 3 studies (KEYNOTE 240, IMbrave150, HIMALAYA, COSMIC-312, LEAP-002, CARES-310).
The results of a meta-analysis of eight randomized clinical trials of systemic therapy for advanced HCC based on immune checkpoint inhibitors (ICIs), divided into subgroups according to the etiology of the disease, indicate a survival advantage in the group of patients with HCC of HBV viral etiology (HR = 0.70, 95% CI: 0.62-0.80), HCV (HR = 0.78, 95% CI: 0.62-0.98) and non-viral etiology (HR = 0.87, 95% CI: 0.78-0.98) [19].
None of the studies planned to assess the effectiveness of treatment in NAFLD/MASLD-dependent HCC. The analysis included a division into viral and non-viral etiology of cancer, without distinguishing the cause of non-infectious liver damage in subgroups (alcoholic, metabolic, toxic, inflammatory). The number of patients with NAFLD was provided in the supplement in the COSMIC-320 study, and in the post-hoc analysis of the IMbrave150 study, where 47 patients with HCC-NAFLD were identified by excluding the cause of liver disease based on the interview and additional tests – negative tests for HBV and HCV, no history of consumption alcohol, exposure to toxins, other liver diseases – which allowed to determine the OS for this group as 19.2 months [20]. In the design of further clinical trials, it is worth considering the cause of non-viral HCC before starting therapy and enabling a more precise determination of patient survival in individual groups. At the same time, it should be remembered that data from subgroup analyses are not sufficient to draw final conclusions. Their aim is to determine whether there are differences in the effectiveness of interventions in a given group and to formulate research hypotheses [21] (Table 2 [22-33]).
Table 2
Efficacy of immunotherapy in hepatocellular carcinoma (HCC) in phase 3 clinical trials. Subgroup analysis taking into account etiology of HCC
| Study (line of treatment) | Treatment | HCC etiology | Number of patients | Median OS (months) | Median OS, depending on etiology (months) | HR (95% CI) for OS depending on etiology |
|---|---|---|---|---|---|---|
| CheckMate 459 [22, 23] (first line) | Nivolumab vs. sorafenib | Viral | 203 | 16.4 vs. 14.7 | HBV: 16.1 vs. 10.4 HCV: 17.5 vs. 12.7 | HBV: 0.79 (0.59-1.07) HCV:0.72 (0.51-1.02) |
| Non-viral | 168 | – | 0.95 (0.74-1.22) | |||
| NAFLD/NASH | Not available | – | Not available | |||
| Keynote 240 [24] (second line) | Pembrolizumab vs. placebo | Viral | 115 | 13.9 vs. 10.6 | – | HBV: 0.57 (0.35-0.94) HCV: 0.96 (0.48-1.92) |
| Non-viral | 163 | – | 0.88 (0.64-1.20) | |||
| NAFLD/NASH | Not available | Not available | Not available | |||
| IMbrave150 [25-27] (first line) | Atezolizumab + bevacizumab vs. sorafenib | Viral | 236 | 19.2 vs. 13.4 | HBV: 19.0 vs. 12.4 HCV: 24.6 vs. 12.6 | HBV: 0.58 (0.40-0.83) HCV: 0.43 (0.25-0.73) |
| Non-viral | 100 | 17.0 vs. 18.1 | 1.05 (0.68-1.63) | |||
| NAFLD/NASH | 47 | 19.2 | Not available | |||
| Himalaya [28, 29] (first line) | Tremelimumab + durvalumab vs. sorafenib | Viral | 232 | 16.4 vs. 13.8 | – | HBV: 0.68 (0.51-0.83) HCV: 0.94 (0.68-1.29) |
| Non-viral | 161 | – | 0.75 (0.59-0.96) | |||
| NAFLD/NASH | Not available | Not available | Not available | |||
| COSMIC-312 [30] (first line) | Cabozantinib + atezolizumab vs. sorafenib | Viral | 263 | 15.4 vs. 15.5 | HBV: 18.2 vs. 14.9 HCV: 13.6 vs. 14.0 | HBV: 0.53 (0.33-0.87) HCV: 1.10 (0.72-1.68) |
| Non-viral | 169 | 15.2 vs. NE | 1.18 (0.78-1.79) | |||
| NAFLD/NASH | 58 | – | Not available | |||
| LEAP-002 [31] (first line) | Lenvatinib + pembrolizumab vs. lenvatinib + placebo | Viral | 247 | 21.2 vs. 19.2 | – | HBV: 0.75 (0.58-0.97) HCV: 0.86 (0.70-1.03) |
| Non-viral | 148 | – | 0.86 (0.66-1.13) | |||
| NAFLD/NASH | 30 | Not available | Not available | |||
| CARES-310 [32] (first line) | Camrelizumab + rivoceranib vs. sorafenib | Viral | 230 | 22.1 vs. 15.2 | – | HBV: 0.66 (0.50-0.87) HCV: 0.45 (0.18-1.16) |
| Non-viral | 42 | – | 0.71 (0.37-1.36) | |||
| NAFLD/NASH | Not available | Not available | ||||
| RATIONALE 301 [33] (first line) | Tislelizumab vs. sorafenib | Viral | 260 | 15.9 vs. 14.1 | – | HBV: 0.91 (0.73-1.14) HCV: 0.64 (0.38-1.08) |
| Non-viral | 82 | – | 0.78 (0.55-1.12) | |||
| NAFLD/NASH | Not available | Not available | Not available |
Treatment of MASLD by non-pharmacological and pharmacological methods
The goal of MASLD treatment is to slow down and stop the unfavorable processes leading to liver damage. As a result, improving liver function helps avoid the metabolic health consequences of fatty liver disease.
Non-pharmacological therapies
Adult patients with MASLD who are overweight or obese should be advised to change their lifestyle, including weight loss using individually planned dietary therapy with energy restriction and increasing physical activity, as well as behavioral therapy. Weight loss leads to improvements in liver enzymes, steatosis, inflammation (MASH) and liver fibrosis. Sustained weight loss of ≥ 5% reduces body fat, 7-10% reduces inflammation, and ≥ 10% reduces liver fibrosis. Weight loss is necessary to improve liver steatosis indicators, and the greater weight loss in an obese patient, the more effective the health effect. However, it should be noted that diet and exercise are most effective when used together [34-37].
According to observational studies, incorrect dietary habits in patients increase the risk of MASLD. It is recommended for these people to follow the principles of the Mediterranean diet or a similar diet, limiting the consumption of highly processed food, i.e. rich in sugars and saturated fatty acids. This way of eating includes the consumption of a variety of vegetables, fruits, whole grains, and fats of good nutritional quality along with the reduction of refined carbohydrates, saturated fats, and highly processed foods, including red and processed meat. The implementation of the Mediterranean diet reduces the risk of developing MASLD by 23% and leads to a reduction in cardiovascular risk and insulin resistance [34, 38-42]. It is worth noting that physical exercises should be adapted to the individual preferences and capabilities of the patient in terms of duration and intensity. They should be used regularly [34, 40, 41] (Table 3).
Table 3
Non-pharmacological recommendations in treatment of MASLD (based on EASL–EASD–EASO 2024 recommendations)
Treatment of MASLD: drug therapies
Currently, the only effective drug in MASH with-out cirrhosis is resmetirom. In the phase 3 MAESTRO-NAFLD trial, resmetirom was superior to placebo in resolving NASH without worsening or with improvement in liver fibrosis. Treatment with resmetirom may be considered in people with MASLD who do not have cirrhosis and have confirmed advanced fibrosis or are at risk of steatohepatitis with significant fibrosis. MASH-targeted drug therapy cannot currently be recommended for adults with cirrhosis. The drug is registered by the FDA, but there is no registration in Poland [34, 43]. Due to the criteria for diagnosing MASLD, it is particularly important to assess the presence of comorbidities. Medical history should include obesity, diabetes, hypertension, lipid metabolism disorders, cardiovascular disease (CVD), and obstructive sleep apnea. The coexistence of these diseases increases the cardiovascular risk, which is one of the main causes of death among people with NAFLD and/or NASH. Therefore, coexisting metabolic diseases should be actively treated [40]. However, it should be emphasized that there is insufficient evidence to recommend antidiabetic or lipid-lowering drugs in the direct treatment of MASH/MASLD. GLP-1 receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, metformin, and statins are safe for use in MASH/MASLD (including compensated cirrhosis) and should be used in appropriate indications (type 2 diabetes, heart failure, lipid metabolism disorders) to effectively treat comorbidities to prevent cardiovascular events and reduce the risk of MASLD/MASH and liver fibrosis, as well as to reduce the risk of liver decompensation, mortality, and HCC in people with liver cirrhosis [34, 44-49] (Table 4).
Table 4
Pharmacological recommendations in treatment of MASLD (based on EASL–EASD–EASO 2024 recommendations)
In conclusion, current clinical challenges and problems in the management of patients with NAFLD/MASLD include the development of appropriate prevention and effective NAFLD/NASH treatment methods that will reduce the risk of HCC; identification of NAFLD patients without cirrhosis who are also at risk of developing HCC; and detecting HCC as early as possible to increase the chances of complete cure or improve progression-free survival and overall survival. Further clinical studies are necessary to prospectively determine predictive factors for systemic treatment and optimal management in the group of patients with MASLD/HCC.
