Metabolic links between metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis

Abstract

Primary biliary cholangitis (PBC) and metabolic dysfunction-associated steatotic liver disease (MASLD) increasingly coexist in the same patient against the backdrop of a global epidemic of metabolic disorders. A growing body of evidence points to profound pathogenetic intersections between autoimmune damage to the biliary tract and systemic metabolic dysfunction. These interactions involve key mechanisms: Immune regulation, lipid metabolism, adipokine profile, and gut microbiota function. In comorbid cases, these processes do not simply add up, but may give rise to a qualitatively distinct clinical-pathogenetic variant. A recent study conducted by Koky et al published in World Journal of Hepatology provides important information about this comorbidity, demonstrating that patients with PBC and concomitant MASLD have a specific adipokine imbalance characterized by decreased adiponectin and increased leptin levels, resulting in an elevated leptin/adiponectin ratio. This editorial summarizes current understanding of the pathogenetic links between PBC and MASLD and discusses the implications for clinical practice and future research.

Key Words: Primary biliary cholangitis; Metabolic dysfunction-associated steatotic liver disease; Adipokines; Adiponectin; Leptin; Immunometabolism; Gut microbiota; Oxidative stress; Mitochondrial dysfunction; Leptin/adiponectin ratio

Core Tip: The increase in metabolic disorders has led to the comorbidity of primary biliary cholangitis (PBC) and metabolic dysfunction-associated steatotic liver disease (MASLD) becoming increasingly common. Beyond simple comorbidity, these conditions cause complex immunometabolic cross-talk involving common pathways of immune dysregulation, lipid metabolism alterations, adipokine imbalance, and gut microbiota dysfunction. Recent data suggest that in patients with PBC, concomitant MASLD disrupts the characteristic hyperadiponectinemia associated with cholestasis, leading to a specific adipokine profile with an elevated leptin/adiponectin ratio. This Editorial summarizes current understanding of the pathogenetic relationships between PBC and MASLD, analyzes new clinical data on their bidirectional effects, and identifies critical gaps in knowledge. Understanding these interactions is important for developing personalized therapeutic approaches and improving treatment outcomes for patients with this increasingly recognized dual pathology.

This editorial refers to “Adipokine profiles reflect metabolic dysfunction but not fibrosis in patients with primary biliary cholangitis” by Koky et al, 2026; https://doi.org/10.4254/wjh.v18.i2.113685.

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INTRODUCTION

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease of autoimmune origin characterized by progressive destruction of small intrahepatic bile ducts, leading to cholestasis, fibrosis, and ultimately cirrhosis of the liver. The disease is associated with the presence of specific antimitochondrial antibodies (AMA) directed against the E2 subunit of the pyruvate dehydrogenase complex and predominantly affects middle-aged women. Metabolic dysfunction-associated steatotic liver disease (MASLD), in turn, is a hepatic manifestation of systemic metabolic syndrome. Formerly known as non-alcoholic fatty liver disease (NAFLD), MASLD is diagnosed when liver steatosis is present in combination with at least one cardiometabolic risk factor in the absence of significant alcohol consumption. The spectrum of MASLD ranges from simple steatosis to steatohepatitis, fibrosis, and cirrhosis.

The prevalence of MASLD has reached epidemic proportions globally, inevitably increasing its comorbidity with other chronic liver diseases, including PBC. A recent study showed that the prevalence of MASLD in patients with PBC was 24.0%[1], underscoring that this combination is no longer coincidental and requires close attention, as the data indicate mutual aggravation of the course and prognosis. While PBC is traditionally considered a model of organ-specific autoimmunity and MASLD a manifestation of systemic metabolic dysfunction (Figure 1), their coexistence may have more complex pathogenetic associations[2,3]. It is important to note that there is still insufficient clinical data to assess the characteristics of the comorbid course of both diseases. A recent study by Koky et al[4] published in World Journal of Hepatology was an important step in the study of this comorbidity, demonstrating that in patients with PBC, the presence of concomitant MASLD or metabolic syndrome is associated with a specific imbalance of adipokines. This study highlights the complex pathways of metabolic and immune regulation in combined forms of liver damage. The aim of this Editorial is to synthesize current evidence on the pathogenetic intersections of PBC and MASLD and to discuss their implications for clinical practice and future research directions.

Figure 1 Key pathogenetic links in primary biliary cholangitis and metabolic dysfunction-associated steatotic liver disease.

PATHOGENETIC BASIS OF PBC AND MASLD OVERLAP

Dyslipidemia

Dyslipidemia is characteristic of both diseases, but its pattern differs. MASLD is associated with an atherogenic lipid profile, including elevated triglycerides, small dense low-density lipoprotein particles, and reduced high-density lipoprotein. This profile is directly associated with an increased risk of cardiovascular disease[5,6]. PBC develops a unique cholestatic dyslipidemia. It is characterized by a significant increase in total cholesterol and low-density lipoprotein. However, unlike atherosclerotic dyslipidemia, PBC is often associated with an increase in high-density lipoprotein. The key difference is the formation of lipoprotein-X, an abnormal particle rich in phospholipids and non-esterified cholesterol, which is formed in plasma due to bile lipid reflux during cholestasis. Lipoprotein-X is generally considered non-atherogenic. This profile, along with often elevated adiponectin levels, explains the well-known cardiovascular paradox of PBC, in which, despite marked hypercholesterolemia, patients do not have a proportionally increased risk of atherosclerotic events[7-12].

Immune dysregulation and microbial-immune interactions

Despite fundamental differences in pathogenesis, the diseases share some common immunological mechanisms. Both diseases are characterized by chronic inflammation mediated by innate immunity. Proinflammatory cytokines (tumor necrosis alpha, interleukin-6, interleukin-1β) play a key role and can be induced both in response to metabolic stress (lipotoxicity, endoplasmic reticulum stress in hepatocytes in MASLD) and as a result of autoimmune damage to the bile ducts in PBC. Macrophages and Kupffer cells are activated in both diseases. In MASLD, they respond to excess lipids and damage-associated molecular patterns, and in PBC, they respond to apoptosis of bile duct epithelial cells, leading to chronic cholangitis[13-15]. A growing body of evidence also points to the important role of adaptive immunity in the pathogenesis of PBC and MASLD. In this regard, these various disrupted immune mechanisms represent a promising therapeutic target in both diseases[16-19].

Gut microbiota dysbiosis is recognized as a common link, but its specific manifestations and consequences vary[17]. In MASLD, it contributes to endotoxemia and activation of the toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells pathway, exacerbating insulin resistance and inflammation[20-24]. Dysbiosis in PBC may be associated with impaired enterohepatic circulation of bile acids due to cholestasis. Another important aspect is the theory of “molecular mimicry”. It is believed that some intestinal bacteria (e.g., Novosphingobium aromaticivorans, Escherichia coli) express proteins homologous to the mitochondrial autoantigen pyruvate dehydrogenase complex-E2 (PDC-E2). The immune response to these bacterial antigens in the intestine may cross-react with the cholangiocytes' own proteins, triggering or maintaining the autoimmune process[25-27]. Comorbidity potentially combines both harmful effects: Systemic inflammation caused by endotoxemia and impaired immune tolerance.

Mitochondrial dysfunction and oxidative stress

Mitochondrial dysfunction is a common end result, but it is caused by different factors. In MASLD, it is secondary to metabolic stress in hepatocytes and leads to increased production of reactive oxygen species[28-30]. In PBC, the key event is a specific autoimmune reaction against the mitochondria of cholangiocytes, directed against the PDC-E2. Circulating AMA, a serological marker of PBC, are primarily directed against the PDC-E2. The uniqueness of the process lies in the preservation of the immunogenic form of PDC-E2 on apoptotic bodies, which makes the antigen available for presentation to the immune system. Activation of immune cells and damage to cholangiocytes, in turn, lead to the development of oxidative stress[31,32].

Changes in adipokine profile

PBC is often associated with elevated levels of adiponectin, an anti-inflammatory and cardioprotective hormone produced by adipose tissue[33,34]. This may be a compensatory response to chronic inflammation. In MASLD, on the contrary, hypoadiponectinemia is characteristic, exacerbating insulin resistance and inflammation[35,36]. This difference may explain the different cardiovascular profiles in patients with the two diseases, despite the presence of dyslipidemia in both cases.

A study conducted by Koky et al[4] demonstrated a specific imbalance of adipokines in patients with a combination of PBC and MASLD or metabolic syndrome. These patients showed a statistically significant decrease in adiponectin levels and a sharp increase in leptin levels. As a result, the leptin/adiponectin (L/A) ratio was significantly higher. A similar, albeit less pronounced, pattern was observed in patients with PBC and metabolic syndrome. It is noteworthy that, unlike MASLD, the association of the L/A ratio with metabolic syndrome in regression analysis was not independent of body mass index. At the same time, adipokine levels and the L/A ratio were not associated with the severity of fibrosis (F3-F4) and showed no significant differences between patients with and without complete biochemical response. These findings challenge the classical view of hyperadiponectinemia as a hallmark of isolated PBC[36-39]. The data obtained may indicate that in patients with PBC, additional metabolic effects manifest themselves in endocrine disorders of adipose tissue typical of MASLD. The current study shows that in patients with PBC and MASLD, metabolic dysfunction overlaps this cholestatic signal, leading to a decrease in adiponectin. Thus, adiponectin levels in PBC may reflect a balance between two opposing influences: An increasing (cholestasis) and a decreasing (metabolic dysfunction) one. The most important difference from isolated MASLD is that the identified adipokine imbalance in comorbid PBC was not associated with advanced fibrosis. Leptin is believed to act as a profibrogenic molecule, while adiponectin has strong antifibrotic properties[40]. It is important to note the differences in the pathogenesis of fibrogenesis in both diseases: In MASLD, adipokines (leptin) directly activate hepatic stellate cells[41-46], whereas in PBC, fibrosis is primarily caused by chronic cholangitis and bile acid toxicity[47], and the role of adipokines in this process in patients with PBC has not been sufficiently studied.

Despite the importance of these new observations, the data must be interpreted with caution, given the limitations of the original study, which include a design that does not allow for the establishment of a causal relationship between metabolic dysfunction and changes in the adipokine profile, the absence of all necessary control groups, and the small sample size. The small number of participants may have been insufficient to identify a true association between fibrosis and adipokines, potentially leading to false negative results. Therefore, these conclusions require cautious interpretation and validation in larger, well-designed studies.

CLINICAL ASPECTS OF THE OVERLAP BETWEEN PBC AND MASLD

In addition to pathophysiological differences, PBC and MASLD are clinically distinct diseases. MASLD is usually asymptomatic for a long time and is detected during routine examinations. Complaints are usually nonspecific and may include fatigue, heaviness, or discomfort in the right upper quadrant. In contrast, PBC is characterized by more pronounced symptoms, including severe fatigue, skin itching, and extrahepatic autoimmune manifestations. AMA are a reliable serological differential diagnostic marker: They are negative in MASLD and positive in 90%-95% of patients with PBC. As noted earlier, the nature of dyslipidemia and the adipokine profile also differ fundamentally. Instrumental and histological diagnostics also reveal characteristic differences. The main instrumental difference is that MASLD is dominated by signs of steatosis, while PBC is dominated by damage to the small bile ducts.

The clinical consequences of the pathogenetic overlap between PBC and MASLD remain poorly understood and controversial. Key questions about the impact of comorbidity on fibrosis progression, response to therapy, and extrahepatic outcomes also remain unresolved[48]. Multivariate analysis, for example, has shown that diabetes mellitus is associated with more severe liver fibrosis and increases the risk of developing cirrhosis in PBC[49]. This opens up new avenues for understanding the complex immune and metabolic interactions between PBC, MASLD, and other metabolic diseases.

In addition, there are other differences in the results of various studies. It has previously been shown that PBC is more severe in overweight patients. In particular, it has been established that non-alcoholic steatohepatitis and body mass index ≥ 25 are associated with severe bile duct damage and fibrosis in patients with PBC. It has been suggested that body mass index be considered as a tool for predicting progressive fibrosis in PBC[50]. Another retrospective single-center study showed that concomitant NAFLD does not adversely affect the activity, severity, and progression of PBC[51]. Another recent retrospective study showed that patients with PBC and concomitant NAFLD (diagnosed by ultrasound) had a comparable response to ursodeoxycholic acid (UDCA) therapy but were associated with less severe fibrosis markers and higher estimated survival rates. The authors suggest that this pattern may be related to the formation of a specific immune phenotype or the beneficial effect of UDCA[1]. Pharmacotherapy itself may represent a critical modifier of these immune-metabolic relationships. Some evidence suggests that UDCA, in addition to its hepatoprotective and anti-cholestatic effects, may also exert mild beneficial effects on metabolic parameters: Improving insulin sensitivity, attenuating hepatic steatosis, and reducing cholesterol and triglyceride levels[52-56]. Assessment of clinical associations may also be complicated by differences in MASLD diagnostic methods used in different studies.

Thus, the impact of comorbid MASLD on the course of PBC and vice versa requires further clarification. Likely, key roles are played by specific phenotypes of metabolic dysfunction, genetic predisposition and the timing of therapy. To date, active screening for metabolic disorders and their correction in all patients with PBC appears to be a reasonable clinical tactic.

CONCLUSION

Thus, metabolic and immune links between MASLD and PBC form a complex network of interactions. The pathogenetic pathways of these diseases are linked through common immune mechanisms, gut microbiota dysfunction, and adipokine dysregulation. Their interaction appears to create not simply the sum of two pathologies, but a qualitatively different clinical-pathogenetic variant with unique characteristics. Adipokine imbalance, in particular an elevated L/A ratio may serve as an indicator of metabolic dysfunction in PBC, though this requires validation in larger studies. However, further prospective and interventional studies are needed to confirm the mechanisms, causal relationships, and practical implementation of this and other biomarkers. Future studies should also include comorbidities and other biomarkers characterizing the features of the comorbid course of MASLD and PBC in the analysis. An important condition for new studies is also an increase in the patient sample size, thereby enabling a more comprehensive analysis that accounts for potential confounders overlooked in smaller studies.