Introduction
The relationship between lifestyle-related conditions and fatty liver disease has attracted considerable attention in recent years. In June 2023, the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), and the Latin American Association for the Study of Liver Diseases jointly announced a change in the disease name and classification of fatty liver disease. The aim was to avoid potentially discriminatory terms such as “alcoholic” and “fatty”. In Japan, “fatty liver” was changed to “steatotic liver disease” by the Japanese Society of Gastroenterology and the Japanese Society of Hepatology in August 2024; “non-alcoholic fatty liver disease (NAFLD)” was changed to “metabolic syndrome-associated steatotic liver disease (MASLD)”, and “non-alcoholic steatohepatitis (NASH)” was renamed “metabolic dysfunction associated steatohepatitis”. It has been reported that 96-98% of patients who are diagnosed with conventional NAFLD also meet the criteria for MASLD [1, 2]. Therefore, NAFLD can be considered largely equivalent to MASLD. The importance of testing to distinguish high-risk patients with lifestyle-related liver diseases from those with chronic viral- or alcohol-induced hepatitis is increasing. The incidence of non-viral hepatocellular carcinoma (HCC) increased significantly, with a higher proportion of patients having obesity or diabetes compared to those with viral hepatitis. These epidemiological trends of increasing HCC incidence in Japan persisted over the past 24 years (1996-2019) [3]. This review outlines the treatment approaches currently being used for fatty liver disease, aiming to prevent its progression to HCC and inhibit cardiovascular disease (CVD) complications.
Metabolic risk factors of liver carcinogenesis
Chronic hepatitis is characterized by the continuous inflammation and destruction of liver cells. However, with the advent of direct-acting antivirals, the hepatitis C virus (HCV) can now be fully eliminated from the body. As a result, the incidence of liver cancer caused by viral hepatitis is decreasing – although its incidence from other causes has been steadily increasing [3]. Although HCC was thought to be declining with the remission of viral hepatitis over the years, a recent worldwide analysis revealed it to be among the top three causes of cancer-related deaths in 46 countries, and both its incidence and associated mortality rate are projected to increase substantially [4]. More specifically, the incidence of liver cancer is projected to increase by 55% over the next 20 years, with 1.4 million new cases diagnosed by 2040. In addition, an estimated 1.3 million deaths are projected by 2040, representing an increase of 56.4%. This latest projection underscores the need to urgently strengthen “measures to reduce alcohol consumption in the population and control the rising prevalence of diabetes and obesity”, along with current liver cancer prevention measures such as immunization and testing and treatment for both hepatitis B and HCV infection – all of which have been shown to be effective in reducing the risk of liver cancer. Therefore, the prevention and treatment of fatty liver disease associated with diabetes and obesity are a critical priority to lower the future incidence of HCC [4].
Hepatic function reserve as a guide to treatment of HCC
The natural history of HCC indicates the importance of hepatic function reserve, as it facilitates continued treatment of the malignancy [5]. The Japanese Society of Hepatology proposed the Nara Declaration in 2023. Additionally, a report from the 2009 Japan Public Health Center-based Prospective Study, conducted by the country’s Ministry of Health, Labor and Welfare, highlighted the risk of hepatocarcinogenesis with alanine transaminase (ALT) > 30. A total of 19,812 men and women aged 40-69 years were followed up for 12 years, and the relationship between baseline ALT levels and the risk of hepatocarcinogenesis was investigated. The results showed that, even among the 18,576 patients who were not infected with the hepatitis virus, the risk of hepatocarcinogenesis was 6.5× higher in the group with ALT levels of 30-69 IU/l compared to those with levels ≤ 29 IU/l, and 60.5× higher in the group with ALT levels ≥ 70 IU/l. Therefore, it can be concluded that patients with ALT levels ≥ 30 IU/l require treatments aimed at suppressing potential hepatocarcinogenesis, regardless of hepatitis virus infection [6].
Relationship between fatty liver disease and hepatic function reserve
A random-effects meta-analysis of 20 countries examining type 2 diabetes and its association with NAFLD/NASH found that the estimated prevalence of NAFLD in patients with type 2 diabetes was 55.5% overall (n = 49,419) and 52.0% in the East Asia subset |(n = 33,911) [7]. NAFLD is present in 25% of the general population, 80% of individuals with obesity, and 65% of patients with type 2 diabetes [8]. The NASH-NAFLD 2022 guideline also recommends assessing the Fib-4 index [9]. This index is a formula that incorporates the blood test parameters, including aspartate aminotransferase, ALT, platelet count, and age, and is based on low (< 1.3), intermediate (1.3-2.66), and high (> 2.67) values. Higher values indicate a greater risk of liver fibrosis, which in turn increases the risk of liver cancer. Higher Fib-4 values also indicate a greater likelihood of early cirrhosis; hence, detailed examinations are recommended for intermediate or higher values. However, the role of age in this index remains unclear, and a re-examination of the utility of the Fib-3 index has been planned in a multicenter study involving our department [10]. The albumin-bilirubin (ALBI) score has also been recently recognized as a measure of hepatic function reserve [11]. It is calculated using two parameters – albumin and total bilirubin – and evaluated in three grades. Although there are many such testing methods, a “single-marker” diagnosis, in which only one test value is needed to accurately identify the disease, is also sought. The Child-Pugh classification represents the most widely used method worldwide for evaluating hepatic reserve capacity [12]. Recently, Mac-2 binding protein glycosylation isomer (M2BPGi) has emerged as a glycan marker used to noninvasively evaluate liver fibrosis [13]. M2BPGi is considered a prognosis factor for liver disease; however, its relationship with hepatic reserve and nutritional status has not been fully analyzed, and its cutoff value may vary depending on the underlying liver disease. In a study of 743 patients with NASH/NAFLD [14], M2BPGi showed a cut-off value of 0.68 for predicting modified albumin-bilirubin (mALBI) grade 1 vs. grades 2-3.
Relationship between fatty liver disease and diabetes mellitus
The NASH-NAFLD guidelines suggest the administration of sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with NAFLD/NASH who have type 2 diabetes mellitus to improve liver function and histology. However, this recommendation is categorized as weak due to a low level of evidence (C), despite a 100% agreement rate. Our group investigated the effects of SGLT2 inhibitors on diabetes mellitusassociated NAFLD, using computed tomography (CT). Before and after the treatment, the ALT values in the cohort were 40.89 ±40.07 U/l and 22.08 ±16.38 U/l, respectively, and those for ferritin were 128.09 ±115.16 ng/mg and 77.70 ±74.02 ng/mg, respectively. The visceral fat area (VFA) also improved from 51.04 ±18.92 cm2/m2 before SGLT2 inhibitor treatment to 44.04 ±20.07 cm2/m2 afterward (p = 0.0001). Treatment with SGLT2 inhibitors also improved the liver/spleen (L/S) ratios, as well as ALT, ferritin, and VFA levels – suggesting that SGLT2 inhibitors may be useful for mitigating the pathogenesis of NAFLD in patients with diabetes mellitus [15]. However, some patients have been reported to rebound during long-term treatment with SGLT2Is and become treatment nonresponders. The current consensus on the utility of incretin-related drugs, such as GLP-1 analogs and DPP-4 inhibitors, for treating NAFLD/NASH yields a weak recommendation (100% agreement), with a level of evidence of C.
One study assessed the efficacy of combination therapy with SGLT2I and GLP-1A for improving outcomes in patients with diabetes. The study investigated NAFLD by examining changes in body composition via CT imaging, alongside an assessment of the drug’s clinical efficacy. Patients with diabetes mellitus-associated NAFLD who had not responded to SGLT2Is and were treated with GLP-1A combination therapy were followed up via CT. Changes in liver function, liver CT values, visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI) were also assessed. The GLP-1A combination improved hemoglobin A1c (HbA1c) (from 6.5% to 6.2%), fasting blood sugar (from 119.0 to 104.0 mg/dl), body composition (body mass index [BMI], from 25.2 to 23.5), waist size (from 88.0 to 85.7 cm), VATI (from 51.5 to 48.3) and SATI (from 66.1 to 56.6) compared to SGLT2I use alone. In patients with diabetes mellitus and NAFLD, combination therapy with SGLT2I and GLP-1A improved liver function, body composition, and glycemic control [16].
Relationship between fatty liver disease and dyslipidemia
NAFLD is a phenotype of metabolic syndrome in the liver. Patients with dyslipidemia often have an increased risk of NAFLD-related complications. The NAFLD/NASH practice guidelines were revised in 2020, and statins are now recommended for dyslipidemia-associated NAFLD [17]. However, the diagnostic criteria for MASLD include the triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels, but exclude low-density lipoprotein cholesterol (LDL-C). Although no clear definition has been formalized for either EASL or AASLD, TG synthase inhibition has been reported to exacerbate fatty liver in murine experiments [18]. Moreover, LDL-C may be low in patients with hypertriglyceridemia, and fibrates reduce HDL-C levels (with LDL-C levels possibly transiently elevated) [19]. TG levels may therefore be more reflective of hepatic pathophysiology. MASLD corresponds to the condition of increased hepatic fat levels, which is the leading cause of hepatic failure and carcinoma. It is also an independent risk factor for CVD and mortality [20].
The development and progression of MASLD have a strong genetic component, involving genes primarily contributing to hepatic lipid processing. The most robust of these associations is with a single nucleotide polymorphism of the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, as the G allele in PNPLA3 (rs738409[G]), encoding the I148M protein variant, was strongly correlated with increased hepatic fat levels [21]. A genetic variant in PNPLA3 has been associated not only with liver fat accumulation but also with susceptibility to steatohepatitis, fibrosis, cirrhosis, and HCC [22, 23]. Hence, the main contributors to CVD risk in patients with MASLD remain conventional cardiometabolic risk factors, which are more prominent in metabolic syndrome-associated MASLD than in genetically driven MASLD [24]. Based on these findings, it appears that the first step in preventing CVD is to treat metabolic syndrome.
Serum lipidomic studies have delineated three distinct metabolic phenotypes, or “metabotypes” in MASLD. Of these, two primary metabolites, MASLD-A and MASLD-C, are particularly relevant to CVD risk. MASLD-A is characterized by lower very low-density lipoprotein (VLDL) secretion and TG levels, which are associated with a reduced risk of CVD. In contrast, MASLD-C exhibits increased VLDL secretion and TG levels, correlating with an elevated CVD risk [25]. Notably, CVD remains the primary cause of mortality in MASLD [26, 27], underscoring the importance of identifying these distinct metabotypes.
Observational data from prospective cohort studies showed an association between elevated TGs and CVD [28–31]. Demonstrating that lowering TGs with a conventional fibrate (a peroxisome proliferator-activated receptor alpha [PPARα] agonist) reduced cardiovascular events in high-risk patients has been challenging [32, 33]. Conventional fibrates have relatively weak PPARα agonistic potency and can cause reversible elevation in serum creatinine (with fenofibrate) [34, 35]. Furthermore, they may elevate liver enzymes, especially when combined with a statin [36]. Therefore, alternative PPARα agonists were sought that may offer improved selectivity, potency, and tolerability. This effort yielded the selective peroxisome proliferator-activated modulator α (SPPARMα) pemafibrate, which has shown greater potency for PPARα activation (> 2,500 times vs. fenofibric acid, the active form of fenofibrate) and improved specificity compared to conventional fibrates [37–39]. Consequently, SPPARα pemafibrate is now available for patients with dyslipidemia. Many groups in Japan have reported on the effectiveness of pemafibrate, including its role in reducing the risk of HCC and improving liver function in NAFLD [40–48]. Our group recently investigated whether pemafibrate was effective for improving NAFLD via CT – assessing changes in body composition – in patients with dyslipidemia. The subjects were 67 patients who had been taking pemafibrate continuously for ≥ 6 months and had undergone ≥ 2 follow-up CT examinations over the study period. Changes in liver function, liver CT values, VATI, and SATI were evaluated. The changes before and after the pemafibrate treatment were as follows: mean and interquartile range (IQR), ALT ranged from 42.0 (34.5-55.0) to 18.0 (14.5-24.0) (IU/l) (p < 0.001), alkaline phosphatase from 251.5 (194.3-339.8) to 159.4 (123.6-218.1) (IU/l) (p < 0.001), γ-GTP from 31.0 (17.0-49.5) to 18.0 (12.5-29.0) (IU/l) (p < 0.001), TG from 168.5 (127.5-213.0) to 130.8 (94.3-170.2) (mg/dl) (p < 0.001), M2BPGi from 0.73 (0.46-1.02) to 0.61 (0.44-0.86) (p < 0.010), and ALBI score from –3.02 (–3.13-–2.88) to –3.20 (–3.34-–3.02) (p < 0.001). In terms of CT body composition, VATI did not change, while SATI decreased from 62.20 (46.75-90.24) to 60.96 (41.13-89.14) (p < 0.001). Liver CT values before pemafibrate administration were classified into two groups – Group A (< 50) and Group B (> 50) – and the changes before and after treatment were compared. Platelet count was +1.86 ±11.02 ×103/µl in Group A and +1.66 ±2.93 ×103/µl in Group B (p = 0.010); total bilirubin was –0.10 ±0.20 (mg/dl) in Group A and –0.02 ±0.20 (mg/dl) in Group B (p = 0.098); and the L/S ratio was +0.02 ±0.31 in Group A and –0.13 ±0.31 in Group B (p = 0.012) [49]. Pemafibrate improves liver function in patients with dyslipidemia-associated NAFLD/NASH and may be particularly useful in those with low liver CT values. Further studies are warranted to determine whether pemafibrate also improves long-term VATI outcomes [49]. Hence, the PROMINENT (Pema--fibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) trial was conducted to determine whether lowering TG is beneficial in terms of preventing CVD [50]. This trial indicated a possible benefit with pemafibrate in MASLD. Pemafibrate significantly reduced any hepatic adverse event (incidence per 100 person-years, 1.35 vs. 1.64; hazard ratio [HR] = 0.83, 95% CI: 0.69-0.99, p = 0.04), as well as investigator-reported MASLD events (referred to as NAFLD in the trial) (incidence per 100 person-years, 0.95 vs. 1.22; HR = 0.78, 95% CI: 0.63-0.96, p = 0.02) [50]. However, the PROMINENT trial did not demonstrate a reduction in CVD events despite the use of a potent triglyceride-lowering, fibric-acid derivative. Nevertheless, an improvement in hypertriglyceridemia-associated metabolic complications was observed with pemafibrate as well as with another potent triglyceride-lowering therapy. Although the PROMINENT trial did not demonstrate a significant benefit of pemafibrate as a triglyceride-lowering therapy in a specific population, it does not necessarily negate the potential benefits of treating hypertriglyceridemia in reducing CVD events. It is necessary to explore appropriate populations that could benefit from this therapy. An ongoing trial is investigating combination treatment with pemafibrate and an SGLT2 inhibitor in patients with non-alcohol-related steatohepatitis and liver fibrosis, the more severe presentation of MASLD, with results anticipated in 2025 (ClinicalTrials.gov Identifier NCT05327127).
Conclusions
The recent global increase in NAFLD/NASH (MASLD), a phenotype of lifestyle-related diseases in the liver (particularly metabolic syndrome such as obesity and type 2 diabetes), is expected to cause a steady rise in the incidence of non-B, non-C HCC. Early identification and effective treatment of high-risk individuals are crucial because MASLD-related HCC has a propensity for advanced-stage detection and carries a poor short-term prognosis. Diagnostic strategies such as M2BPGi and parameters assessing hepatic function reserve may prove to be non-invasive yet promising tools to ascertain the severity of liver diseases. According to the Nara Declaration, MASLD-related liver cancer is associated with a high rate of diabetes mellitus and thus requires regular screening and therapeutic intervention akin to strategies employed for patients with ALT levels of > 30 IU/l or viral hepatitis. Treatment methods, including SGLT2 inhibitors, may be useful for mitigating the pathogenesis of NAFLD in patients with diabetes mellitus. Combination therapy of SGLT2 and GLP-1A must be explored further as promising improvements in liver function, body composition, and glycemic index have been reported in NAFLD patients. SPPARMα pemafibrate shows potential for improving liver function in NAFLD in patients with dyslipidemia. Hence, recognizing MASLD as a systemic disease necessitates developing preventive strategies targeting CVDs for its proper management and to mitigate future risks of MASLD-associated HCC.
