MASLD: an emerging factor in the pathophysiology and clinical management of ICC
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Abstract
This article explores the emerging role of metabolic dysfunction-associated steatotic liver disease (MASLD) in the pathophysiology of intrahepatic cholangiocarcinoma (ICC). Despite advances in public health, ICC incidence has risen, suggesting overlooked risk factors. Recent studies indicate a significant association between MASLD and ICC, though causality remains unproven. The article reviews current research, highlighting limitations such as retrospective designs and small sample sizes. It emphasizes the need for comprehensive investigations into MASLD’s role in ICC pathogenesis, prognosis, and management. Future research should focus on integrating advanced methodologies to identify novel biomarkers and therapeutic strategies, aiming to improve patient outcomes and develop tailored prevention and treatment approaches.
Keywords
INTRODUCTION
Previous studies have identified chronic inflammation caused by viruses, parasites, biliary obstruction, or stones as the most significant risk factor for intrahepatic cholangiocarcinoma (ICC). Despite advances in public health, living standards, medical technology, and vaccine distribution, the incidence of ICC has not only stabilized but has increased sharply by 140% over the past 40 years. This trend suggests that current research does not entirely elucidate the mechanisms underlying ICC and that some potential risk factors may be overlooked.
Recent findings indicate that diabetes and obesity significantly elevate the risk of ICC, illustrating the critical role of metabolic diseases in its pathophysiology. Metabolic dysfunction-associated steatotic liver disease (MASLD), which is associated not only with hepatitis and liver fibrosis but also with various metabolic disorders, has seen a dramatic rise in prevalence, affecting over 30% of the global population. This suggests that MASLD may be an emerging factor in the pathophysiology of ICC.
There is currently a significant gap in research exploring the association between MASLD and ICC. Given MASLD’s high prevalence and severity, overlooking its role in the pathogenesis of ICC could hinder early intervention efforts and worsen both ICC incidence and the global burden of liver disease. Therefore, thorough investigations into the relationship between MASLD and ICC are essential.
This study aims to provide a concise review of current research on MASLD and ICC while laying the groundwork for further exploration in this important area.
MASLD IS A LATENT RISK FACTOR
Research overview
The relevant research began in 2007. Welzel et al. identified an increasing incidence of ICC in the United States, contrasting with stable rates of extrahepatic cholangiocarcinoma (eCCA)[1]. This observation led to the hypothesis that unknown risk factors, potentially including MASLD, might contribute to ICC pathogenesis. Their subsequent investigations utilizing the SEER-Medicare database indicated a significant association, with an odds ratio (OR) of 3.0 (95%CI: 1.2-7.3). However, it is crucial to note that these findings, while suggestive, do not establish causation.
In 2016, Kinoshita et al. further explored this potential link, noting a higher prevalence of metabolic dysfunction-associated steatohepatitis (MASH) in ICC patients without known risk factors compared to those with liver metastatic carcinoma[2]. They formally proposed MASLD as a risk factor associated with ICC.
Meta-analyses and cohort studies, such as those by Wongjarupong et al. in 2017, have reinforced the hypothesis of an increased risk, reporting an OR of 2.22 (95%CI: 1.52-3.24) for cholangiocarcinoma (CCA)[3]. Similarly, Petrick et al.’s randomized controlled study suggested a more than threefold increase in risk (OR = 3.52, 95%CI: 2.87-4.32) for ICC[4]. Despite these findings, the absence of prospective data means that the role of MASLD as a risk factor remains speculative.
In addition to these studies, numerous scholars have investigated the relationship between MASLD and ICC in depth [Table 1]. In conclusion, while the current evidence indicates a potential link between MASLD and ICC, it is premature to draw definitive conclusions about causality.
Research on MASLD and the risk of ICC
| Authors | Year of publication | Country | Related conclusions |
| Zhou et al.[5] | 2009 | China | MASLD may be a risk factor for ICC |
| Reddy et al.[6] | 2013 | USA | MASH may affect up to 20% of patients with resectable ICC |
| Nkontchou et al.[7] | 2013 | French | The incidence of MASH was higher (19%) in ICC patients with no other known risk factors |
| Chang et al.[8] | 2013 | Taiwan, China | MASLD increases the risk of CCA |
| Choi et al.[9] | 2016 | USA | MASLD is not a risk factor for CCA (OR = 1.40, 95%CI: 0.94-2.09) |
| Xiong et al.[10] | 2018 | China | Metabolic syndrome was significantly associated with a 1.86-fold increased risk of CCA |
| Sirica et al.[11] | 2019 | USA | MASLD and MASH are risk factors for HCC and ICC |
| De Lorenzo et al.[12] | 2020 | Italy | MASH is a risk factor for ICC, MASLD is not |
| Corrao et al.[13] | 2021 | Italy | MASLD is significantly correlated with the progress of ICC, not eCCA |
| Ghidini et al.[14] | 2021 | Italy | MASLD and MASH are associated with a high risk of CCA, especially ICC |
Critical re-examination
Current research on the association between MASLD and the risk of ICC is constrained by several limitations, including retrospective designs, small sample sizes, and single-center cohort studies. These limitations contribute to weak evidence, potential biases, and significant heterogeneity in research outcomes, making it challenging to draw consistent conclusions. Several specific issues warrant further attention:
(1) Temporal Relevance: The incidence of MASLD has increased dramatically over the past decade[15], yet many studies rely on data from the late 20th century. This temporal disconnect, coupled with inadequate control of confounding factors, compromises the accuracy of research findings. Future studies should utilize up-to-date, comprehensive datasets and account for time effects and potential confounders.
(2) Geographic and Ethnic Considerations: The influence of regional and ethnic factors cannot be overlooked. While MASLD was traditionally considered a Western disease[16], its prevalence in Asia, the Middle East, and North Africa has surged over the past three decades, with related mortality rates surpassing those in Europe and the United States[17]. The predominance of studies based on European and American populations may introduce bias due to genetic, environmental, and lifestyle differences across regions and ethnicities. Moreover, the current data inadequately represent the baseline characteristics and disease patterns of Asian populations, potentially leading to misinterpretation of the MASLD-ICC association in these groups.
(3) Metabolic Syndrome Features: A critical oversight in current research is the insufficient focus on the individual components of metabolic syndrome, namely obesity and diabetes, as these factors may play pivotal roles in the observed association between MASLD and ICC. Obesity, a proinflammatory state, can exacerbate liver pathology, possibly accelerating the progression from MASLD to ICC. Similarly, diabetes, through its systemic metabolic effects, might influence carcinogenic pathways, thereby increasing ICC risk. Future studies must employ a multifaceted approach to address this issue: (a) Comprehensive patient profiling: Researchers should conduct detailed metabolic assessments, including body mass index (BMI), waist circumference, lipid profiles, fasting glucose levels, and insulin resistance markers; (b) Stratified analysis: Studies should stratify patients based on the presence and severity of individual metabolic syndrome components to isolate their effects on ICC risk; (c) Longitudinal designs: Long-term follow-up studies are needed to track the progression of metabolic syndrome features and their temporal relationship with ICC development; (d) Molecular investigations: Research should explore potential molecular mechanisms linking specific metabolic abnormalities to cholangiocarcinogenesis, such as examining the role of adipokines, proinflammatory cytokines, and insulin signaling pathways; (e) Dose-response relationships: Investigations into whether the severity or duration of metabolic syndrome features correlates with ICC risk could provide valuable insights.
By meticulously accounting for these factors, future research can more accurately evaluate the independent contribution of MASLD to ICC risk, potentially uncovering complex interactions between metabolic syndrome components and liver pathology in cholangiocarcinogenesis.
PATHOGENESIS OF MASLD-RELATED ICC
Research overview
Research on the pathogenesis of MASLD and ICC remains limited. To date, only two articles address this topic [Figure 1]. The first article[18] focuses on the genetic factors, offering an in-depth examination of the role of MASLD in the initiation and proliferation of ICC. The second article[19] analyzes the impacts of metabolic syndrome (MetS) and fibrosis on inflammation and the mechanism that promotes cholangiocyte cancer, framed within the context of systemic metabolism. Together, these studies not only provide valuable insights for future research but also underscore the pressing need for comprehensive investigations and expansions within this domain.
Figure 1. Potential pathogenesis of MASLD-related ICC. MASH: Metabolic dysfunction-associated steatohepatitis; MetS: metabolic syndrome; HC: hepatic cells; YAP 1: yes-associated protein 1; SOX 9: SRY-box transcription factor 9; OPN: osteopontin; TnC: tenascin-C; POSTN: periostin; ICC: intrahepatic cholangiocarcinoma.
High expression of YAP1 and SOX9 promotes ICC progression
In 2020, Hu et al. reported that over 90% of ICC patients exhibited alterations in YAP1 and/or SOX9[18]. Utilizing dual tissue microarray chips and a preclinical ICC mouse model, their findings included: (a) Nuclear levels of SOX9 and YAP1 were elevated in over 90% of human CCA samples (n = 108). Additionally, the expression of p-AKT, SOX9, and YAP1 was significantly upregulated in the hepatic cells of mice with MASH or primary sclerosing cholangitis (PSC); (b) The deletion of either YAP1 or SOX9 alone led to ICC pathogenesis, which was characterized by high expression levels of the remaining gene. In contrast, concurrent deletion of both genes completely inhibited ICC pathogenesis; (c) YAP1 deficiency impeded the reprogramming of hepatic cells to biliary epithelial cells (BECs) and tumor cell proliferation. In contrast, SOX9 deficiency solely inhibited tumor cell proliferation. Based on these observations, the authors propose a model of MASLD-related ICC pathogenesis. This model suggests that steatohepatitis in MASLD patients promotes elevated expression of YAP1 and SOX9 in liver cells, facilitating the transdifferentiation of hepatic cells to BECs and subsequent tumor cell proliferation.
The biological heterogeneity of ICC significantly impacts the efficacy of surgical and chemotherapeutic interventions. This is primarily due to the diverse origins of ICC cells[20]. This study not only underscores the complex interplay between MASLD, HCC, and ICC but also advocates for a comprehensive approach to hepatobiliary diseases, avoiding isolated disease analyses. Furthermore, the study highlights common features of ICC heterogeneity, offering novel insights for the development of broad-spectrum therapeutic strategies for advanced ICC and improving prognosis.
Osteopontin overexpression is a prominent feature of ICC patients with MetS
In 2023, Cadamuro et al. highlighted recent epidemiological evidence suggesting that MetS is frequently associated with MASLD or MASH, positioning it as a potential risk factor for ICC[3,14,19]. Concurrently, studies have demonstrated that ICC typically involves the deposition and remodeling of a dense extracellular matrix (ECM)[21-23], with ECM remodeling identified as a critical mechanism underlying cardiovascular mortality in patients with MetS and MASLD[19]. Thus, the authors hypothesize that ECM remodeling driven by MetS is a key pathological mechanism in MASLD that may precipitate ICC.
In their study, Cadamuro et al. analyzed 44 ICC patients with MetS and 22 without, focusing on the levels of osteopontin (OPN), tenascin-C (TnC), and periostin (POSTN) within the ECM to assess changes in its composition and impact on ICC cell biology[19].
Their findings revealed that: (a) Enhanced deposition of OPN, TnC, and POSTN was observed in the tumors of the 44 ICC patients with MetS compared to adjacent non-tumorous tissue; (b) Significantly greater OPN accumulation was observed in MetS-afflicted ICC patients relative to those without MetS; (c) OPN, TnC, and POSTN markedly promoted cell viability and a cancer stem cell-like phenotype in human ICC cell lines; (d) Differences in the distribution and composition of fibrosis between MetS and non-MetS ICC patients are likely due to OPN-mediated recruitment of cancer-associated fibroblasts.
The study concluded that de novo expression of OPN, TnC, and POSTN was significantly associated with the promotion of motility of malignant cholangiocytes. At the same time, fibrosis can promote tumor progression. The overexpression of OPN is a significant feature of ICC with MetS and a key effector of fibrosis.
This investigation provides a foundational analysis of the pathophysiological links between MetS, ECM remodeling, and ICC, offering crucial insights for monitoring MetS and MASLD patients’ risk of progressing to ICC. This work also establishes a theoretical basis for early prevention, precise diagnosis, and the development of novel ICC treatment strategies. However, further investigation is required to elucidate the specific roles and mechanisms of various OPN isoforms (including OPNa, OPNb, OPNc, OPN4 and OPN5) in ICC progression, suggesting substantial opportunities for future research in this domain.
Future perspective
MASLD-related ICC represents a complex disease trajectory originating from metabolic disorders and culminating in malignancy. Current research into its pathogenesis remains sparse, and existing studies fall short of providing a comprehensive understanding of the disease’s overall mechanistic blueprint. However, revisiting the literature from the perspectives of origin and outcome offers valuable insights.
Origin perspective
From the origin standpoint, existing studies have delved into the mechanisms by which metabolic disorders such as diabetes and obesity contribute to CCA. These studies highlight key features such as hepatic steatosis, insulin resistance, and the subsequent upregulation of genes promoting cell turnover in the pathogenesis of CCA [Table 2]. Given that MASLD shares commonalities with these metabolic disorders, it is anticipated that MASLD-related ICC will exhibit similar characteristics. Future research can build upon these findings by investigating:
Metabolic factors affect the pathophysiology of ICC
| Metabolic factor | Proposed mechanism | Reference |
| Leptin | Overexpression enhances cholangiocarcinoma cell growth | [24] |
| Adipose tissue inflammation | Chronic hepatic inflammation and fibrosis due to IL-6 and TNFα release | [25] |
| Insulin resistance | Compensatory hyperinsulinemia and increased IGF-1 production, promoting cell proliferation and survival | [4,26-28] |
| Hyperinsulinemia | Direct stimulation of cholestatic cell proliferation; increased IGF-1 and insulin receptor expression in tumor cells | [29-33] |
| Hyperglycemia | STAT3 activation leading to aggressive CCA phenotypes; NF-κB glycosylation and nuclear localization promoting aggressive phenotype | [31,34,35] |
| Low APN levels | Reduced AdipoR expression leading to APN insensitivity; impaired activation of anti-neoplastic pathways (MAPK, mTOR, STAT-3, etc.) | [36-40] |
(1) The specific molecular pathways linking MASLD to hepatic steatosis, insulin resistance, and altered gene expression in cholangiocytes.
(2) The potential synergistic effects of various metabolic derangements commonly observed in MASLD (e.g., dyslipidemia, hyperglycemia, and altered adipokine profiles) on ICC development.
(3) The role of genetic predisposition and epigenetic modifications in modulating the susceptibility of individuals with MASLD to ICC.
Outcome perspective
From the outcome perspective, the pathogenesis of ICC, including MASLD-related ICC, involves intricate physiological systems and metabolic processes. The convergence of pathological progression in ICC, regardless of the initial causative factors, suggests shared mechanisms that warrant further exploration. In general, the investigation of ICC pathogenesis can be divided into three main categories: (a) Studies of metabolic-related pathways: for instance, the association between the overexpression of ErbB family receptor tyrosine kinases in the bile of ICC patients and the origin of ICC[41]; (b) Investigations at the cellular and molecular levels, including mutations in PTEN, TP53, KRAS, CXCL12, and other genes in ICC cell lines and tissue[42-44], as well as the promoting effects of multiple uncontrolled miRNA expressions on the progression of ICC[45,46]; (c) Analysis of related signaling pathways: the potential roles of C-JNK, Wnt/β-catenin, and JAK-STAT signaling pathways in the proliferation and metastasis of ICC. Building on these established research foundations, we can delve deeper into the key genes and signaling pathways upstream or downstream of MASLD-related ICC to uncover its unique pathological processes and provide new insights for developing treatment strategies.
Inflammation as a central element
Inflammation is a critical factor linking MASLD to ICC, given its close association with hepatic steatosis. Extensive research has demonstrated the role of inflammation in ICC pathogenesis [Figure 2][47,48], with inflammatory mediators like IL-6 and TNFα activating pathways such as JAK-STAT, p38 MAPK, and Akt, which enhance cell growth, survival, and proliferation. The upregulation of COX-2 and Mcl-1 due to inflammation confers resistance to apoptosis, further promoting oncogenesis. Understanding the pivotal role of inflammation in the pathophysiological process of MASLD-related ICC is essential for unraveling its pathogenesis. Future studies should focus on delineating the inflammatory pathways and mediators that serve as critical links between MASLD and ICC, providing a foundation for targeted therapeutic strategies.
Figure 2. The molecular pathogenesis of ICC induced by inflammation. IL-6: Interleukin-6; TNF-α: tumor necrosis factor alpha; Wnt: wingless/integrated; EGFR: epidermal growth factor receptor; ErbB2: Erb-B2 receptor tyrosine kinase 2; IL-6R: interleukin-6 receptor; TNFR: tumor necrosis factor receptor; LPR: low-density lipoprotein receptor-related protein; FZD: frizzled; iNOS: inducible nitric oxide synthase; COX2: cyclooxygenase-2; miR: microRNA; IncRNA: long non-coding RNA; NO: nitric oxide; Notch: notch signaling pathway; p38: p38 mitogen-activated protein kinase; MAPK: mitogen-activated protein kinase; MAP3K8: mitogen-activated protein kinase kinase kinase 8; DNMT1: DNA methyltransferase 1; JAK-STAT3: janus kinase-signal transducer and activator of transcription 3; p44/42 MAPK: p44/p42 mitogen-activated protein kinase (also known as ERK1/ERK2); P21: cyclin-dependent kinase inhibitor 1; SOCS3: suppressor of cytokine signaling 3; Mid-1: midline 1; P16: cyclin-dependent kinase inhibitor 2A; RASSF1A: RAS-association domain family 1, isoform A; NF2: neurofibromatosis type 2; AJID: atypical junctional intercellular domain; TCF: T-cell factor; CEF: cell-free extract.
Additional insights and revelations
Recent studies have indicated that certain ICCs share a common progenitor cell origin as HCC[49,50]. This finding underscores the importance of adopting a holistic approach to hepatobiliary diseases and highlights the necessity of a unified metabolic interpretation. It also reveals a significant correlation between MASLD-related ICC and the broader spectrum of existing MASLD diseases. As research progresses, the MASLD disease spectrum may be refined, with eventual outcomes potentially extending beyond HCC to include ICC.
Furthermore, it is important that MASLD without cirrhosis has been associated with HCC or ICC[51,52]. This association suggests that certain elements of the MASLD disease progression may not always manifest as traditionally expected. Therefore, in investigating the pathogenesis of MASLD-related ICC, it is crucial to elucidate this phenomenon and transcend the limitations of conventional progression models in order to expand the scope of research perspectives.
PROGNOSIS OF MASLD-RELATED ICC
Research overview
The prognosis of patients is a critical factor in predicting the course of progression and provides an essential basis for treatment decisions by healthcare providers. Recent studies on the prognosis of MASLD-related ICC have primarily focused on differences between ICC patients with and without MASLD, yielding varied conclusions that warrant further investigation.
Reddy et al. reported no significant differences in tumor-free survival and overall survival between ICC patients with or without MASLD[6]. Conversely, De Lorenzo et al. found that the median survival of patients with MASLD (38.5 months) was significantly shorter than that of patients without traditional risk factors including HBV, HCV, alcohol, and environmental toxins (48.1 months, P = 0.003), and was comparable to that of patients with traditional risk factors (31.9 months, P = 0.948)[12]. Yu et al. observed that, in comparison to HBV-associated ICC, MASLD-related ICC patients exhibited a lower 5-year overall survival rate (24.0% vs. 48.9%), a higher 5-year recurrence rate (80.9% vs. 55.0%), and a higher early recurrence rate (58.5% vs. 30.0%) (all P < 0.01)[53].
In conclusion, the results of current cohort studies on the prognosis of MASLD-related ICC patients are inconclusive. Meta-analyses are challenging due to the limited number of studies and diverse research objectives. Further investigation is needed to elucidate the role of MASLD in the onset and progression of ICC and its impact on quality of life. A clear understanding of the prognosis of MASLD-related ICC patients can facilitate more accurate disease progression assessment and subsequent treatment adjustments, such as the introduction of new adjuvant therapies or postoperative radio-chemotherapy, with the aim of enhancing patient prognosis.
Critical re-examination
The prognosis of MASLD-related ICC patients is closely related to the treatment. Currently, the treatment strategy is mostly referred to the general ICC patients, but the surgical procedure has been updated in recent years. New adjuvant chemotherapies have been recommended as first-line treatments for locally advanced ICC[54-56]. Additionally, the role of lymph node dissection in surgery has gained focus[57,58], with the latest treatment guidelines advocating for its widespread application during surgical intervention[59].
However, due to the extensive time span of samples included in relevant studies, the underutilization of novel adjuvant chemotherapies and lymph node dissection in earlier cases may lead to a pessimistic prognosis assessment for MASLD-related ICC. Therefore, further studies are necessary to determine the prognosis and optimal treatment strategies for MASLD-related ICC patients.
CLINICAL MANAGEMENT
Early intervention
Malignant tumors, both intrahepatic and extrahepatic, rank as the second most common cause of death among patients with MASLD, following cardiovascular events. Large cohort studies[60] have identified a significant link between MASLD and an elevated cancer risk. Further investigations[61] have revealed that all histological stages of MASLD are significantly associated with increased overall mortality. This risk intensifies with the histological progression of MAFLD (HR = 1.71, 95%CI: 1.64-1.79 for simple steatosis; HR = 2.14, 95%CI: 1.93-2.38 for MASH; HR = 2.44, 95%CI: 2.22-2.69 for non-cirrhotic fibrosis; HR = 3.79, 95%CI: 3.34-4.30 for cirrhosis). Consequently, the early identification of MAFLD patients at high risk of malignancy and timely intervention to obstruct disease progression is crucial for optimizing the management of MAFLD-related ICC.
Key intervention[62] targets connecting MASLD and ICC include metabolic function, inflammation, insulin resistance, and liver fibrosis, making them essential focal points for early intervention strategies. Current research primarily focuses on evaluating the effects of pharmacological interventions on these aspects of MASLD. Two main approaches have emerged: one investigates the repurposing of existing drugs for other metabolic disorders (such as hyperlipidemia and diabetes) for use in MASLD[62,63] [Table 3]; the other concentrates on the development of new drugs specifically targeting MASLD. Recently, phase 3 clinical trial data for the new drug Rezdiffra demonstrated a significant improvement in liver fibrosis among MASH patients with moderate to severe non-cirrhotic fibrosis[64]. As a result, Rezdiffra was approved, marking a milestone as the first drug sanctioned for MASH treatment, effectively addressing a long-standing therapeutic gap.
Effects of drugs on hepatic steatosis, inflammation and fibrosis, and cardiovascular events
| Drug | Liver | Cardiovascular system |
| Vitamin E | Improves non-T2DM fatty liver and hepatocyte ballooning/inflammation, does not improve fibrosis | Increases the risk of heart failure in T2DM patients |
| Obeticholic acid | Improves liver fibrosis, prevents the progression of NASH | No effect |
| Statins | Prevent the progression of MASLD, reduce the risk of HCC | Reduce cardiovascular risk |
| Metformin | Prevents the progression of MASLD, reduce the risk of HCC | No effect |
| Pioglitazone | Reduces liver fat content in DM patients, alleviates NASH | Reduces the risk of cardiovascular events in T2DM and NASH patients |
| GLP-1RA | The effect on improving fatty liver, liver enzyme levels, and liver fibrosis in NASH patients needs further research | Reduces the risk of cardiovascular events in T2DM patients |
| SGLT-2i | The effect on improving fatty liver in T2DM patients, and liver fibrosis in NASH patients needs further research | Reduces the risk of cardiovascular and kidney events in T2DM patients |
| DPP-4i | Cannot alleviate fatty liver and fibrosis in overweight T2DM patients | Reduces the risk of cardiovascular events in T2DM patients |
Additionally, some scholars have argued[65] that new drug development should focus on the broader “metabolic dysfunction” rather than solely aiming to ameliorate inflammation and fibrosis pre- and post-liver biopsy. Reducing the risk of malignancy and improving patient quality of life should be key objectives in pharmacotherapy.
Looking ahead, the future of MASLD management is promising, with innovative approaches under exploration. These include targeting the gut-liver axis via microbiome modulation, leveraging incretin-based therapies, and investigating epigenetic modifications in disease progression[66]. Furthermore, precision medicine approaches utilizing genetic and metabolomic profiling may enable more personalized and effective interventions.
Treatment and challenges
Currently, the U.S. National Comprehensive Cancer Network’s 2023 CCA Guidelines[59] do not specify distinct treatment protocols for patients with MASLD-related ICC. Consequently, these patients typically receive standard ICC treatments, which encompass a range of modalities depending on disease stage and patient factors.
For resectable tumors, surgical resection remains the gold standard, offering the best chance for long-term survival. However, only 30%-40% of patients are candidates for this approach at diagnosis[67]. Additionally, the presence of MASLD can complicate surgical outcomes due to impaired liver function and regenerative capacity.
For unresectable cases, systemic therapy is the mainstay of treatment. The current first-line regimen consists of gemcitabine plus cisplatin, which has shown improved overall survival compared to gemcitabine alone[68]. In addition, recent studies have proposed new regimens such as TOPAZ-1[69] and KEYNOTE-966[70], which can benefit patients more than traditional first-line regimens. Recent advancements in targeted therapies, such as FGFR2 inhibitors for FGFR2 fusion-positive ICC, have opened new avenues for personalized treatment[71]. However, the efficacy of these regimens in MASLD-related ICC is not well-documented, and the potential for increased toxicity due to underlying liver dysfunction warrants careful consideration.
Locoregional therapies play a crucial role in managing ICC, particularly for patients with limited hepatic disease[71,72]. These include radiofrequency ablation (RFA), microwave ablation (MWA), and transarterial chemoembolization (TACE). Stereotactic body radiation therapy (SBRT) has also shown promise in local tumor control. However, the radiosensitivity of MASLD-affected liver tissue and the risk of radiation-induced liver disease necessitate precise planning and dose management. In addition, the altered vascular architecture and regenerative limitations in MASLD may impact their effectiveness and safety.
Liver transplantation, while a potential curative option for select patients with MASH-related end-stage liver disease and early-stage ICC[66], poses significant challenges in the context of MASLD. The increased risk of postoperative complications, including the risk of developing recurrent or de novo MASLD, graft dysfunction, and cardiovascular events[73], highlights the need for stringent candidate selection and comprehensive perioperative management.
Despite these options, the unique pathophysiology of MASLD-related ICC presents distinct challenges. The altered hepatic microenvironment, chronic inflammation, and metabolic dysregulation associated with MASLD may influence treatment efficacy and tolerability. This underscores a significant gap in current oncological practice, highlighting the need for tailored approaches that consider the specific biological context of MASLD-related ICC.
Perioperative management
Recent studies[74] have demonstrated that patients with MetS, MASLD, or MASH face significantly increased risks of postoperative complications such as cardiovascular events, infections, and renal insufficiency following liver resection or transplantation. A meta-analysis by Meijer et al. indicated that both MASLD and MASH are independent risk factors for postoperative complications after hepatectomy, with risks escalating alongside disease severity[75]. Neal et al. suggested that only MASH was associated with increased complication risks, but the majority of studies highlight the need for intensive perioperative management due to elevated surgical risks in MASLD patients[76]. Mechanistic studies by Veteläinen et al. and McCuskey et al. have demonstrated that MASH can exacerbate postoperative inflammatory responses, impair hepatocyte function, diminish liver regenerative capacity, and lead to microvascular dysfunction[77,78]. Collectively, these factors reduce surgical tolerance and increase the risk of postoperative mortality in these patients.
Therefore, for patients with MASLD, irrespective of disease stage, enhanced perioperative management is crucial. Poon et al. recommend comprehensive preoperative liver function assessments, preoperative interventions such as portal vein embolization, and meticulous surgical techniques to minimize liver injury[79]. Cauchy et al. and Reddy et al. noted that even patients with latent or mild MASLD are at increased risk of postoperative complications[80,81]. Cauchy et al. further emphasized that the reduced liver regenerative capacity associated with MASH necessitates combining tumor treatment with minimally invasive techniques during surgery[82].
In conclusion, detailed and comprehensive treatment and management strategies should be emphasized for MASLD-related ICC patients to mitigate surgical risks and reduce the incidence of complications regardless of their stage of MASLD. Additionally, specific treatment options for this subgroup have not received adequate attention, underscoring the need for further research to fundamentally improve prognosis for these patients.
DEFINITION UPDATE
MASLD represents a novel conceptualization of non-alcoholic fatty liver disease (NAFLD), establishing more precise diagnostic criteria. It is crucial to recognize that MASLD should not be viewed exclusively as the hepatic manifestation of metabolic syndrome. Instead, it encompasses a broader spectrum of intra- and extrahepatic complications, including insulin resistance and alcoholic liver disease[15]. The recent consensus to further rename NAFLD to MASLD underscores the pivotal role of metabolic cardiovascular risk factors in its pathogenesis[83]. This refinement in terminology allows for a more nuanced diagnosis: patients with fatty liver disease and a normal BMI without diabetes can be diagnosed with MASLD based on a single metabolic cardiovascular risk factor, while those with multiple risk factors require at least two for diagnosis.
These terminological shifts emphasize the need for a more comprehensive understanding of the disease, particularly highlighting the central role of metabolic dysfunction in its initiation and progression. This evolving conceptualization is crucial for developing more targeted therapeutic interventions. Moreover, it underscores the importance of categorizing MASLD alongside other metabolic disorders such as diabetes, chronic kidney disease, and cardiovascular disease, facilitating a more integrated approach to treatment and management.
The relationship between MASLD and NAFLD has been a subject of debate in recent literature. Some researchers argue that these should be considered distinct disease entities. In a meta-analysis involving 980,867 patients, Ayada et al. compared the definitions of the two diseases[84]. The study found that 79.9% of patients with fatty liver met the criteria for both conditions, 4.0% met only the NAFLD criteria, and 15.1% met the MASLD criteria. Notably, patients diagnosed with MASLD exhibited a higher prevalence of liver fibrosis progression than those with NAFLD or overlapping conditions. Alharthi et al. considered MASLD a superior name compared with NAFLD, and the transformation in name and definition from NAFLD to MAFLD represents an important milestone, which indicates significant tangible progress toward a more inclusive, equitable, and patient-centered approach to addressing the profound challenges of this disease[85].
However, other studies suggest a high degree of overlap between MASLD and NAFLD, indicating that they may be more similar than different. Younossi et al. found that only 5.29% of patients with NAFLD do not fulfill MASLD criteria in their database and the National Health and Nutrition Examination Survey of 6,429 patients[86]. Similarly, a study by Suzuki et al. reported that 96.7% of MASLD patients in their database met NAFLD criteria[87]. Zou et al. further corroborated these findings, suggesting that insights from NAFLD research remain largely applicable to MASLD[88]. These studies collectively argue that the clinical characteristics, diagnostic criteria, and research findings for NAFLD can be largely applied to MASLD, indicating a high degree of continuity between the two concepts.
In conclusion, while the shift from NAFLD to MASLD represents a significant advancement in our understanding of fatty liver disease, the high degree of overlap between these concepts suggests that much of our existing knowledge remains relevant. However, the more precise and inclusive nature of MASLD criteria may lead to better identification and management of patients at risk for metabolic liver disease. As we move forward, a balanced approach that acknowledges both the continuity and the refinements brought by the MASLD concept will be crucial for advancing our understanding and treatment of this increasingly prevalent condition.
LEAN MASLD
Obesity is a well-established risk factor and diagnostic criterion for MASLD. The increasing prevalence of MASLD over recent decades can largely be attributable to an obesogenic environment characterized by high-calorie food intake and physical inactivity[89,90]. However, it is important to note that obesity is not present in all MASLD patients. Global studies have identified that individuals with a normal BMI (18.5-25 kg/m²) who present with at least two associated risk factors - such as increased waist circumference, hypertension, low HDL-C levels, hypertriglyceridemia, impaired fasting glucose, insulin resistance, and chronic subclinical inflammation - can also develop MASLD. These cases, often termed “lean MASLD,” account for 15% to 50% of all MASLD cases[91].
While some studies suggest that lean MASLD patients may share similar morphological characteristics with their non-lean counterparts[92] or even exhibit better histological and metabolic profiles[93], long-term prognostic data often indicate worse outcomes. Meta-analyses have demonstrated that lean MASLD is associated with a higher risk of various extrahepatic complications[94] and increased all-cause mortality compared to non-lean MASLD patients[95-97]. Nonetheless, some studies report no significant survival differences between these groups. Despite the limited and somewhat conflicting prognostic data, outcomes for lean MASLD patients tend to be poorer than those of healthy individuals and may be similar to or worse than those of non-lean MASLD patients. Therefore, there is a critical need for targeted management strategies aimed at slowing disease progression and improving prognosis in lean MASLD patients.
Recent research has highlighted the role of metabolic adaptation in the pathogenesis of lean MASLD, which may explain why lean MASLD patients have similar or worse long-term outcomes compared to their non-lean counterparts. Initially, lean MASLD patients exhibit adaptive metabolic responses characterized by increased serum bile acids and elevated Farnesoid X Receptor (FXR) activity[98,99]. This adaptation appears to mitigate hepatic inflammation in the early stages of the disease. However, as the disease progresses, this adaptive response wanes, leading to a failure to attenuate hepatic inflammatory responses and contributing to disease progression. The impaired bile acid signaling, driven by alterations in the macrophage epigenome and increased expression of proinflammatory cytokines, underscores the complexity of lean MASLD pathophysiology.
Currently, no specific guidelines exist for managing lean MASLD due to a paucity of research evidence. Nevertheless, some studies indicate that weight loss can effectively mitigate fatty liver disease, with a dose-dependent relationship observed[100]. Additionally, poor diet quality is a principal modifiable risk factor for worsening metabolic health[101]. Therefore, it is important to provide all MASLD patients, particularly those with metabolically unhealthy profiles, with personalized dietary guidance and encourage physical activity (while reducing sedentary behavior) to optimize metabolic function and maintain cardiovascular health.
FUTURE INSIGHTS
The intricate interplay between metabolic dysregulation, chronic inflammation, and biliary carcinogenesis warrants further investigation. Our preliminary search on ClinicalTrials.gov using the terms “MASLD” and “intrahepatic cholangiocarcinoma” did not yield any ongoing or completed trials. Expanding the search to “metabolism” and “primary liver cancer” identified 13 relevant clinical trials, providing insights into the current research landscape on metabolic dysfunction and liver cancer.
These trials [Table 4] predominantly investigate the metabolic reprogramming of cancer cells, the impact of lifestyle factors such as diet and obesity on liver cancer, and the exploration of metabolic markers for early diagnosis and prognosis of HCC. For instance, trial NCT06278701 examines dietary interventions on liver function recovery post-hepatectomy, while NCT05794048 aims to identify metabolic markers for optimizing patient care. Trials such as NCT03663062 and NCT03356535 explore links between obesity, metabolic syndrome, and liver cancer risk, emphasizing the complex relationship between metabolic health and liver carcinogenesis.
Clinical trials of metabolism and PLC
| NCT number | Country | Focus | Objective |
| NCT06278701 | China | Dietary intervention | Evaluate the effects of late-evening snacks on nutritional status, liver function recovery, complication rate, quality of life, and metabolic patterns in HCC patients post-hepatectomy |
| NCT05794048 | France | Metabolic profiling | Characterize metabolic signatures of HCC and pancreatic tumors to identify prognostic and theranostic markers |
| NCT06315361 | Italy | Diabetes and NAFLD | Investigate the clinical impact of NAFLD in diabetic patients and assess the applicability of non-invasive fibrosis scores in this high-risk population |
| NCT05623150 | France | Alcohol-related liver disease and metabolic syndrome | Identify metabolic, immune, and imaging factors associated with HCC development in patients with alcohol-related liver disease or non-alcoholic steatohepatitis |
| NCT04371042 | Italy | NAFLD and metabolic syndrome | Establish an observational cohort of NAFLD patients at different stages and a comparative cohort without NAFLD to characterize clinical phenotypes and collect biological samples for future omics-based studies |
| NCT03663062 | UK | Obesity and liver disease | Assess the link between body weight, fatty liver disease, and colorectal adenomas in a UK population undergoing colonoscopy |
| NCT02730611 | USA | Metabolic syndrome and bile acid metabolism | Investigate the relationship between bile acid profiles, metabolic syndrome, and the efficacy of vertical sleeve gastrectomy in obese patients, with a focus on HCC and cholangiocarcinoma risk |
| NCT03356535 | France | Lifestyle and metabolic signatures | Identify metabolic signatures associated with healthy lifestyle behaviors and assess their relationship with HCC risk using data from a large European cohort |
| NCT01798173 | France | Metabolic syndrome and HCC in cirrhosis | Identify metabolic signatures associated with healthy lifestyle behaviors and assess their relationship with HCC risk using data from a large European cohort |
| NCT01342705 | France | Iron overload and HCC risk | Assess the effect of phlebotomy on HCC risk in patients with compensated alcoholic cirrhosis and hepatic iron overload |
| NCT04649671 | China | Exercise and insulin resistance | Investigate the impact of a mobile health-based exercise program on insulin resistance in HCC patients |
| NCT02561546 | China | Gene therapy and diabetes in HCC | Evaluate the preliminary efficacy of p53 gene therapy in treating diabetes in patients with HCC |
| NCT06072287 | UK | Psychological distress in chronic diseases | Develop and validate a new measure of illness-related distress for individuals living with long-term health conditions, including liver diseases |
Given that ICC and HCC both fall under PLC and share common progenitor cell origins, future clinical research on MASLD-related ICC should leverage insights from these existing studies. Looking ahead, we propose several key directions for MASLD-related ICC:
(1) Prospective Cohort Studies: Large-scale studies are needed to delineate the natural history and specific risk factors of MASLD-related ICC. Incorporating advanced imaging techniques, such as those in NCT05794048, may help identify early radiological signatures of ICC in MASLD patients.
(2) Metabolomic and Proteomic Approaches: Methods used in trials like NCT04371042 and NCT03356535 should be applied to ICC research to discover novel biomarkers for early detection and prognosis.
(3) Interventional Studies on Lifestyle Modifications: Adapt strategies from trials such as NCT06278701 (late-evening snack strategy) and NCT04649671 (mobile health-based exercise program) for MASLD patients at high risk of ICC.
(4) Innovative Therapeutic Approaches: Explore novel treatments like p53 gene therapy investigated in NCT02561546 in the context of MASLD-related ICC to open new avenues for targeted therapy.
By addressing these priorities, we anticipate significant advancements in our understanding of MASLD-related ICC. Development of tailored screening protocols, identification of novel therapeutic targets, and ultimately improved outcomes for at-risk or diagnosed patients are expected. Interdisciplinary collaboration and integration of cutting-edge technologies will be pivotal in unraveling the complex interplay between metabolic dysfunction and cholangiocarcinogenesis, paving the way for personalized prevention and treatment strategies in the precision medicine era.
CONCLUSION
In general, it is evident that MASLD is an emerging factor in the pathophysiology of ICC. Despite the increasing prevalence of MASLD and its potential role in ICC progression, significant research gaps remain, particularly concerning the pathogenesis, prognosis, and optimal management strategies for MASLD-related ICC. Current studies are limited by retrospective designs, small sample sizes, and regional biases, necessitating large-scale, multicenter prospective cohort studies to elucidate the natural history and specific risk factors of MASLD-related ICC. Additionally, the intricate interplay between metabolic disorders, inflammation, and genetic factors in ICC pathogenesis warrants further exploration. Future research should focus on integrating advanced imaging, metabolomic, and proteomic approaches to identify novel biomarkers for early detection and prognosis. Moreover, interventional studies on lifestyle modifications and targeted therapeutic strategies are crucial for improving patient outcomes. Addressing these gaps will not only enhance our understanding of MASLD-related ICC but also pave the way for more effective prevention and treatment paradigms.
DECLARATIONS
Authors’ contributions
Conceptualized the review, conducted the literature review, and contributed to the writing and editing of the manuscript: Li ZL, Tang ZH
Assisted in the literature review: Chen JL, Tang Y, Qin DL
Availability of data and materials
Not applicable.
Financial support and sponsorship
National Natural Science Foundation of China (81772521); Hospital-level Clinical Research Cultivation Fund of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (17CSK06); Multicenter Clinical Study of Shanghai Jiao Tong University School of Medicine (DLY201807).
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
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Li, Z. L.; Chen J. L.; Tang Y.; Qin D. L.; Tang Z. H. MASLD: an emerging factor in the pathophysiology and clinical management of ICC. Hepatoma. Res. 2024, 10, 41. http://dx.doi.org/10.20517/2394-5079.2024.63
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