Rethinking metabolic risk in primary biliary cholangitis: The prognostic impact of lean type 2 diabetes mellitus

Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by progressive immune-mediated destruction of the intrahepatic bile ducts and lymphocytic cholangitis. It can progress to cirrhosis and hepatic failure and increase mortality risk. Emerging evidence highlights the role of metabolic abnormalities in the progression of chronic liver diseases, with glucose metabolism disorders and insulin resistance contributing to hepatic inflammation and fibrosis. Notably, lean type 2 diabetes mellitus (T2DM) represents a distinct phenotype characterized by β-cell dysfunction and increased cardiometabolic risk despite a normal body mass index (BMI). We read with great interest the study by Yin et al, which demonstrated that lean T2DM is an independent predictor of mortality in patients with PBC, with a synergistic adverse effect observed in patients with both low BMI and diabetes. These findings challenge the assumption that a normal BMI confers metabolic protection. Mechanistically, metabolic dysfunction may promote disease progression through insulin resistance, inflammation, and oxidative stress, independent of body weight. However, reverse causality related to sarcopenia and advanced disease should be considered. This opinion review examines the role of lean T2DM as a prognostic modifier in PBC and highlights the need to incorporate metabolic assessment into current risk stratification strategies.

Key Words: Type 2 diabetes mellitus; Primary biliary cholangitis; Body mass index; Mortality; Metabolic dysfunction

Core Tip: Primary biliary cholangitis presents marked clinical heterogeneity that is not fully explained by the current prognostic models. These models are primarily based on the biochemical response to ursodeoxycholic acid and the fibrosis stage. Emerging evidence suggests that metabolic dysfunction, particularly type 2 diabetes mellitus in lean individuals, is an underrecognized modifier of disease progression and mortality. Recent findings indicate synergistic adverse effects between the thin phenotype and diabetes, which challenges traditional body mass index-based assumptions regarding metabolic risk in patients with primary biliary cholangitis. Thus, beyond weight, comprehensive metabolic assessment should be incorporated into risk stratification strategies. In addition, future prospective studies should evaluate whether integrating lean type 2 diabetes mellitus into existing prognostic models can improve individualized patient management.

INTRODUCTION

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by progressive destruction of the interlobular bile ducts, driven by a T-cell-mediated lymphocytic response. If untreated or inadequately controlled, this process can lead to cirrhosis, hepatic failure, and increased mortality[1]. The disease is typically defined by persistent cholestatic liver enzyme elevation, particularly alkaline phosphatase and gamma-glutamyl transpeptidase, along with the presence of anti-mitochondrial antibodies and PBC-specific antinuclear antibodies[2]. Although PBC is often described as a slowly progressive condition, its clinical course is highly heterogeneous. While many patients achieve biochemical control with first-line therapy using ursodeoxycholic acid (UDCA), a substantial proportion exhibit an incomplete biochemical response and remain at increased risk of fibrosis progression, hepatic decompensation, and liver-related mortality[3]. Accordingly, identifying reliable predictors of disease progression has become a central component of contemporary PBC management. Baseline factors such as younger age at diagnosis, male sex, advanced fibrosis or cirrhosis, elevated bilirubin levels, and specific autoantibody profiles (e.g., anti-gp210 and anti-sp100 antibodies) are linked to more aggressive disease and poorer outcomes[4]. However, prognostic assessment in PBC is becoming increasingly understood as a dynamic process in which long-term risk is largely determined by the biochemical response to UDCA. Validated models, including the GLOBE and UK-PBC scores, incorporate on-treatment biochemical parameters to refine the prediction of clinical outcomes[5].

Despite the robustness of these prognostic frameworks, accumulating evidence suggests that they may not fully capture all the modifiers of disease progression. In particular, metabolic dysfunction has emerged as an important yet incompletely integrated determinant of liver disease outcomes. Patients with PBC frequently exhibit metabolic abnormalities, which are known to contribute to hepatic inflammation, fibrogenesis and increased cardiovascular risk[6]. The overlap between PBC and metabolic dysfunction-associated steatotic liver disease (MASLD) further highlights this interaction, with recent data demonstrating that a considerable proportion of patients with PBC present with concomitant hepatic steatosis and metabolic dysfunction. Whether similar mechanisms affect outcomes in patients with autoimmune cholestatic disorders is unclear[7]. These observations suggest that metabolic factors may influence disease trajectory beyond traditional cholestatic and immunological mechanisms.

In clinical practice, body mass index (BMI) is typically used as an alternative measure of metabolic risk; however, it does not adequately reflect body composition, visceral adiposity, or the presence of sarcopenia, all of which may significantly influence metabolic health and disease progression[8]. Importantly, metabolic dysfunction is not restricted to individuals who are overweight or obese. Type 2 diabetes mellitus (T2DM), a heterogeneous disorder traditionally associated with excess adiposity, is being increasingly recognized in individuals with a normal or low BMI. This lean phenotype is characterized by more pronounced β-cell dysfunction, distinct metabolic profiles, and, paradoxically, increased cardiovascular morbidity and mortality[9]. Moreover, growing evidence indicates that T2DM is independently associated with fibrosis progression and adverse outcomes across multiple chronic liver diseases, underscoring its potential role as a key modifier of hepatic disease severity. In the context of PBC, nonetheless, the prognostic implications of lean T2DM remain insufficiently defined. Current risk stratification models primarily incorporate cholestatic biochemistry, fibrosis stage, and treatment response, without systematically accounting for metabolic phenotyping or body composition parameters[10].

The study by Yin et al[11] provides important insights by demonstrating that lean T2DM is an independent predictor of mortality in patients with PBC, with a synergistic adverse effect observed in individuals with both low BMI and diabetes. These findings challenge the conventional assumption that normal body weight confers metabolic protection and suggest that BMI alone is insufficient for risk stratification in this population. In this opinion review, we critically examine the emerging evidence supporting lean T2DM as a prognostic modifier in PBC, explore its biological plausibility as a disease modifier, and discuss its potential in current risk stratification models.

METABOLIC DYSFUNCTION AND BMI AS MODIFIERS OF DISEASE SEVERITY AND OUTCOMES IN PATIENTS WITH PBC

Accumulating evidence indicates that metabolic factors, including obesity, T2DM, and MASLD, influence both the susceptibility to PBC and its clinical course. Although PBC is classically defined as an autoimmune cholestatic liver disease, patients frequently present with metabolic comorbidities and systemic immune-mediated conditions, suggesting a broader and more complex pathophysiological framework[2]. In this context, metabolic disturbances have emerged as clinically relevant modifiers of disease trajectory and its long-term outcomes. Epidemiologic and genetic data highlight a clinically relevant association between T2DM and disease progression, reinforcing the concept that metabolic dysfunction contributes to disease severity in patients with PBC[12]. Furthermore, chronic liver inflammation itself may also contribute to impaired glucose tolerance and insulin resistance, highlighting the bidirectional relationship between hepatic injury and metabolic dysregulation[13]. Bile acid signaling pathways, particularly those mediated by the farnesoid X receptor (FXR), further link cholestasis with lipid and glucose homeostasis; therefore, these pathways serve as mechanistic links between cholestasis and metabolic dysfunction in PBC[2].

Among metabolic determinants, BMI has been widely used as a potential marker of metabolic risk. A high BMI is associated with an increased prevalence of hepatic steatosis and coexisting T2DM in patients with PBC; these conditions may be accompanied by high alanine aminotransferase levels and advanced histological findings. Additionally, MASLD with a coexisting elevated BMI has been linked to poor biochemical response to therapy, although its impact on fibrosis progression remains inconsistent across studies[3]. Mendelian randomization analyses further suggest a causal relationship between higher BMI and increased risk of PBC, supporting a role for adiposity-related immune dysregulation in disease pathogenesis[14]. However, these findings should be interpreted cautiously, as BMI does not fully capture the complexity of metabolic health.

As a single measure of metabolic risk, BMI has significant limitations. It does not distinguish between lean mass and adiposity, nor does it reflect fat distribution or the presence of sarcopenia. Visceral adiposity, rather than total body weight, is more strongly associated with insulin resistance and adverse cardiometabolic outcomes[15]. Adipose tissue itself functions as an active endocrine organ, modulating systemic inflammation and metabolic signaling through the release of cytokines and adipokines that can directly influence hepatic fibrogenesis[16]. These limitations are particularly relevant in chronic liver disease, where alterations in body composition may occur independently of BMI. The so-called “obesity paradox”, in which individuals with chronic diseases who are overweight or obese may exhibit better survival, further underscores the inadequacy of BMI as a standalone prognostic marker[13,17].

The complex relationship between metabolic dysfunction and PBC is further illustrated by the overlap between PBC and MASLD. Patients with coexisting PBC and MASLD represent a clinically distinct subgroup characterized by worse biochemical responses to standard therapy and higher rates of liver-related complications, including liver transplantation and mortality[7]. In these patients, metabolic factors such as steatosis, dyslipidemia, and fibrosis stage independently contribute to adverse outcomes. Nevertheless, the relationship remains complex, as not all studies consistently demonstrate an effect of steatosis on fibrosis progression, suggesting heterogeneity in disease mechanisms and patient phenotypes. Moreover, while dyslipidemia is highly prevalent in patients with PBC, it does not uniformly translate to increased cardiovascular risk, emphasizing the need for nuanced metabolic assessment[18]. Importantly, metabolic dysfunction is not confined to individuals with elevated BMI. Lean metabolic phenotypes, including lean MASLD and lean T2DM, illustrate that significant metabolic dysfunctions may occur even in individuals with normal body weight. In PBC, emerging evidence suggests that metabolic abnormalities in lean individuals may also influence disease severity and progression. For example, Himoto et al[13] demonstrated that apoptosis inhibitor of macrophages levels were associated with markers of disease severity independent of obesity or insulin resistance, indicating that metabolic risk may be underrecognized in this population[15]. Similarly, lean T2DM has been associated with adverse outcomes in metabolic liver disease, supporting the concept that disturbances in glucose metabolism may contribute to disease progression irrespective of BMI[19].

From a clinical perspective, these observations indicate the importance of comprehensive metabolic evaluation in all patients with PBC, regardless of body weight. Reliance on BMI alone may lead to an underestimation of risk in metabolically unhealthy but nonobese individuals. Instead, a more integrated approach incorporating metabolic profiling, lifestyle assessment, and body composition analysis may better capture disease heterogeneity and improve risk stratification. Such an approach aligns with the evolving paradigm of precision medicine in PBC, where early identification of high-risk phenotypes may enable more individualized management strategies and improved long-term outcomes[10].

Critical appraisal of lean T2DM as a prognostic factor in patients with PBC

In their retrospective cohort study, Yin et al[11] demonstrated that lean T2DM is an independent predictor of mortality in patients with PBC, with a synergistic adverse effect observed in individuals with both low BMI and diabetes. These findings provide a novel perspective on metabolic risk stratification in PBC, challenging the conventional assumption that normal body weight confers metabolic protection. However, several methodological considerations should be addressed when these results are interpreted. First, despite multivariable adjustment, the retrospective and single-center design intrinsically restricts causal inference and raises the possibility of selection bias, information bias and residual confounding. Consideration should also be given to the notion of “lean” BMI, which may fluctuate among populations and ethnic groups. Furthermore, differentiating between lean metabolic dysfunction and other clinical conditions linked to low BMI is difficult because of the lack of comprehensive metabolic phenotyping, which includes measurements of insulin resistance, visceral adiposity, and body composition.

An important consideration in studies evaluating lean phenotypes in patients with chronic liver disease is the potential for reverse causality. Patients with advanced liver disease frequently develop weight loss, malnutrition, and sarcopenia, resulting in a reduction in BMI that may reflect disease severity rather than a distinct metabolic phenotype[20]. In this context, low BMI may act as a surrogate marker of advanced disease rather than an independent risk factor, potentially confounding the observed association between lean T2DM and adverse outcomes. The lack of systematic assessment of muscle mass or nutritional status in this study further limits the ability to disentangle these effects. This phenomenon has been well described in chronic liver disease, where sarcopenia is independently associated with increased mortality and worse clinical outcomes[21]. Despite these limitations, the study by Yin et al[11] highlights an important and underrecognized clinical concept: Metabolic risk in PBC is not restricted to individuals with overt obesity. Rather, patients with lean T2DM may represent a distinct high-risk subgroup characterized by adverse metabolic profiles that are not captured by BMI alone. This observation is consistent with evidence across chronic liver diseases demonstrating that T2DM is associated with fibrosis progression and adverse outcomes, independent of body weight[22,23].

From a clinical standpoint, these findings raise important questions regarding risk stratification and patient management. Current prognostic models for PBC, including the GLOBE and UK-PBC scores, primarily rely on biochemical response to treatment with UDCA and fibrosis stage, without incorporating metabolic variables or body composition metrics[24,25]. The identification of lean T2DM as a potential prognostic modifier suggests that a more comprehensive metabolic assessment may be warranted, particularly in patients with normal or low BMI who may otherwise be considered at lower risk. However, before integration into clinical practice, these findings require validation in prospective, multicenter cohorts with standardized definitions of lean phenotypes and detailed metabolic characterization. To better contextualize these findings, it is important to consider the established determinants of disease progression in PBC beyond metabolic factors.

Established prognostic determinants in PBC beyond BMI

Beyond BMI and metabolic phenotyping, prognosis in patients with PBC is determined by a well-established set of biochemical, clinical, and histological factors that remain central to risk stratification. Among these, the biochemical response to UDCA is consistently recognized as one of the strongest predictors of long-term outcomes. Contemporary treatment goals increasingly emphasize the normalization of alkaline phosphatase and bilirubin levels, as these parameters are closely associated with transplant-free survival and a reduced risk of disease progression[26-28]. Patients who fail to achieve an adequate biochemical response represent a high-risk subgroup and may require early therapeutic escalation and closer monitoring[29]. Prognostic models have further refined outcome prediction by integrating treatment response with baseline clinical characteristics. The UK-PBC and GLOBE are widely validated tools that demonstrate strong discriminative performance for predicting liver-related outcomes, including hepatic decompensation and mortality. Comparative analyses confirm that these models outperform older scoring systems and highlight the dynamic nature of prognosis in PBC, which evolves over time and is influenced by treatment response[30].

Assessment of fibrosis burden also plays a critical role in determining prognosis. Noninvasive modalities, particularly vibration-controlled transient elastography and magnetic resonance elastography, have emerged as reliable predictors of disease progression and clinical outcomes[31,32]. These techniques provide incremental prognostic value beyond biochemical markers, particularly in identifying patients with subclinical fibrosis progression who may otherwise be classified as low risk. In addition to biochemical and structural markers, immunological factors contribute to disease heterogeneity. The presence of specific autoantibodies, such as anti-gp210, has been associated with more aggressive disease phenotypes, a reduced response to therapy, and poor survival[33-35]. These findings suggest that immunological profiling may offer additional prognostic insight beyond conventional laboratory parameters. Finally, therapeutic response patterns and evolving treatment strategies further influence outcomes. Advances in second-line therapies, including peroxisome proliferator-activated receptor agonists, highlight the importance of early identification of patients with inadequate response to UDCA and the need for personalized treatment approaches[36]. Collectively, these established determinants underscore that prognosis in PBC is multifactorial, reflecting the interplay between cholestatic severity, fibrosis progression, treatment response, and immune-mediated mechanisms. Integrating these traditional predictors with emerging metabolic factors may ultimately provide a more comprehensive and clinically meaningful framework for risk stratification.

Mechanistic links between lean T2DM and disease progression in patients with PBC

The biological plausibility of lean T2DM as a modifier of disease progression in PBC is supported by multiple interconnected metabolic and inflammatory pathways. Although PBC is primarily driven by autoimmune-mediated bile duct injury, increasing evidence suggests that metabolic dysfunction can amplify hepatic inflammation and fibrogenesis through mechanisms that overlap with those observed in other chronic liver diseases. Insulin resistance represents a central mechanism linking metabolic dysfunction to liver injury. Even in individuals with a normal BMI, impaired insulin signaling can promote hepatic steatosis, increased free fatty acid flux, and the activation of proinflammatory pathways. At the cellular level, insulin resistance enhances hepatic stellate cell activation and collagen deposition, contributing directly to fibrogenesis[37,38]. In addition, hyperglycemia and altered glucose metabolism induce oxidative stress through increased production of reactive oxygen species, which further exacerbates hepatocellular injury and promotes fibrotic remodeling[39].

Chronic low-grade inflammation is another key pathway through which lean T2DM may influence disease progression. Elevated levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, have been implicated in both insulin resistance and liver fibrosis. These cytokines not only perpetuate systemic metabolic dysfunction but also contribute to hepatic immune activation and cholangiocyte injury, processes that are central to the pathogenesis of PBC[40,41]. Importantly, these inflammatory pathways may be present even in the absence of overt obesity, reinforcing the concept of BMI-independent metabolic risk. Adipose tissue dysfunction also plays a critical role, even in lean individuals. Alterations in the secretion of adipokines, including decreased adiponectin levels and increased leptin levels, can promote insulin resistance, inflammation, and fibrogenesis. Leptin, in particular, has been shown to activate hepatic stellate cells and increase collagen synthesis, whereas adiponectin exerts antifibrotic and anti-inflammatory effects[42,43]. These alterations may occur independently of total fat mass, particularly in individuals with increased visceral adiposity or ectopic fat deposition.

The gut-liver axis represents an additional mechanistic link between metabolic dysfunction and liver disease progression. Dysbiosis and increased intestinal permeability can lead to the translocation of bacterial products, such as lipopolysaccharides, which activate hepatic immune responses and promote inflammation and fibrosis[44]. In patients with metabolic dysfunction, these processes may further amplify the underlying autoimmune-mediated injury characteristic of PBC. Finally, bile acid signaling pathways provide a direct interface between metabolic regulation and cholestatic liver disease. The FXR plays a central role in regulating bile acid homeostasis, lipid metabolism, and glucose metabolism. Dysregulation of FXR signaling has been associated with both metabolic disorders and cholestatic liver injury, suggesting that a shared mechanistic pathway may contribute to disease progression in patients with PBC and metabolic dysfunction[45,46]. Collectively, these mechanisms support the concept that lean T2DM is not a benign phenotype but rather a metabolically active state capable of promoting inflammation, fibrosis, and adverse outcomes in patients with PBC (Figure 1). Importantly, these pathways operate independently of body weight, reinforcing the limitations of BMI as a surrogate marker of metabolic risk and highlighting the need for more comprehensive metabolic assessment in this population.

Figure 1 Metabolic dysfunction as a modifier of disease progression in primary biliary cholangitis. Lean type 2 diabetes mellitus, obesity-associated insulin resistance, and overlap with metabolic dysfunction-associated steatotic liver disease may contribute to disease progression in primary biliary cholangitis through mechanisms that are not adequately captured by body mass index alone. Shared pathways include insulin resistance, chronic inflammation, oxidative stress, adipokine dysregulation, gut-liver axis alterations, and disrupted bile acid signaling. These processes may promote immune-metabolic crosstalk, hepatic stellate cell activation, fibrogenesis, and impaired hepatic homeostasis, ultimately contributing to fibrosis progression, an incomplete response to ursodeoxycholic acid, cirrhosis, and mortality. Low body mass index may also reflect sarcopenia or advanced disease, highlighting the potential role of reverse causality in the interpretation of lean phenotypes. MASLD: Metabolic dysfunction-associated steatotic liver disease; BMI: Body mass index; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; FXR: Farnesoid X receptor; PBC: Primary biliary cholangitis; ECM: Extracellular matrix; UDCA: Ursodeoxycholic acid; ROS: Reactive oxygen species.

Clinical implications, current limitations, and future directions

The recognition of metabolic dysfunction as a modifier of disease progression in PBC has important implications for clinical practice. Current management strategies focus primarily on the biochemical response to UDCA and fibrosis stage; however, these approaches may not fully capture the heterogeneity of disease progression[24,25]. The identification of lean T2DM as a potential high-risk phenotype suggests that metabolic evaluation should be incorporated into routine risk stratification, even in patients with a normal or low BMI. In this context, screening for glucose metabolism disorders, insulin resistance, and cardiometabolic risk factors may allow earlier identification of patients at increased risk of adverse outcomes. Importantly, lean individuals with T2DM may be incorrectly classified as low risk solely on the basis of their BMI, potentially delaying closer monitoring or therapeutic escalation. Integrating metabolic variables into existing prognostic models could improve risk prediction and support more individualized management strategies (Table 1)[47,48]. This approach aligns with current recommendations emphasizing comprehensive assessment and personalized care of patients with PBC[49-51]. Furthermore, lifestyle interventions, including dietary modification and physical activity, may play a relevant role in modulating metabolic dysfunction and disease progression. Emerging evidence suggests that adherence to healthy dietary patterns and increased physical activity are associated with improved metabolic profiles and potentially better liver-related outcomes[52,53]. Therefore, structured metabolic and lifestyle assessments should be considered as part of routine clinical evaluation in patients with PBC.

Table 1 Metabolic determinants of disease progression in primary biliary cholangitis.

Factor	Mechanism	Clinical impact in PBC	Ref.
Type 2 diabetes mellitus	Insulin resistance, chronic inflammation, profibrogenic signaling	Fibrosis progression ↑, mortality ↑	[17,25]
Lean type 2 diabetes mellitus	β-cell dysfunction, metabolic dysregulation independent of adiposity	Underrecognized high-risk phenotype, mortality ↑	[11]
Obesity/high BMI	Visceral adiposity, adipokine imbalance, systemic inflammation	Steatosis, altered biochemical profile, variable fibrosis impact ↑	[14]
MASLD overlap	Lipotoxicity, oxidative stress, mitochondrial dysfunction	Response to UDCA ↓, liver-related complications ↑	[7]
Visceral adiposity	Cytokine release, insulin resistance	Cardiometabolic risk, fibrosis progression ↑	[47]
Sarcopenia/Low BMI	Reduced muscle mass, frailty, metabolic dysregulation	Associated with worse outcomes, potential reverse causality	[20,21]
Dyslipidemia in PBC	Altered bile acid metabolism, lipid abnormalities	High prevalence but variable CV risk impact	[48]
Adipose tissue dysfunction	Cytokines, endocrine signaling	Promotes inflammation and fibrogenesis	[18]

BMI: Body mass index; MASLD: Metabolic dysfunction-associated steatotic liver disease; PBC: Primary biliary cholangitis; UDCA: Ursodeoxycholic acid; CV: Cardiovascular.

Despite growing interest in the role of metabolic dysfunction in PBC, several limitations remain. The definition of lean metabolic phenotypes is not standardized. Variability in BMI cutoffs across populations and the lack of consistent assessment of body composition complicate the interpretation and comparison of findings across studies. BMI alone is an imperfect surrogate of metabolic health, as it does not account for visceral adiposity, ectopic fat deposition, or sarcopenia, all of which may significantly influence prognosis in patients with chronic liver disease[54,55]. Additionally, the potential role of reverse causality must be carefully considered. In advanced liver disease, weight loss and sarcopenia are common and are independently associated with poor clinical outcomes. As such, a low BMI may reflect disease progression rather than a protective or distinct metabolic phenotype[20,21]. The absence of a systematic evaluation of muscle mass and nutritional status in most studies limits the ability to differentiate between true lean metabolic dysfunction and disease-related cachexia. Finally, current prognostic models for PBC do not incorporate metabolic or body composition variables. Although tools such as the GLOBE and UK-PBC demonstrate strong predictive performance, they primarily rely on biochemical parameters and treatment response, potentially overlooking clinically relevant modifiers of disease progression[24,56].

Future research should focus on integrating metabolic phenotyping into the prognostic framework of PBC. Prospective, multicenter studies with standardized definitions of lean phenotypes and comprehensive metabolic assessment, including insulin resistance, body composition, and visceral adiposity, are needed to validate the role of lean T2DM as an independent risk factor. Advanced methods for body composition analysis, such as imaging-based assessment and bioelectrical impedance, may provide more accurate characterization of metabolic risk beyond BMI[57,58]. In addition, longitudinal studies evaluating the dynamic interaction between metabolic dysfunction and disease progression are essential to clarify causality and identify potential therapeutic targets. The incorporation of metabolic variables into predictive models represents a promising avenue for improving risk stratification.

Emerging approaches, including machine learning and artificial intelligence-based models, may facilitate the integration of complex clinical, biochemical, and metabolic data to increase prognostic accuracy[59]. From a therapeutic perspective, targeting metabolic dysfunction may represent an adjunct strategy for improving outcomes in patients with PBC. Pharmacological interventions aimed at insulin resistance, inflammation, and bile acid signaling, alongside lifestyle modification, could mitigate disease progression, although this approach requires further investigation in dedicated clinical trials[60]. Overall, a shift toward a more comprehensive and individualized approach that integrates metabolic health, body composition, and traditional disease markers may improve the management and long-term outcomes of patients with PBC.

The paradigm of risk stratification in patients with PBC is evolving from a predominantly biochemical and treatment–response-based approach toward a more comprehensive framework that incorporates metabolic health. The identification of lean T2DM as a potential prognostic modifier challenges the traditional reliance on BMI as a surrogate of metabolic risk and highlights the limitations of current models that do not account for metabolic heterogeneity. Recent evidence suggests that metabolic dysfunction, even in the absence of overt obesity, can contribute to hepatic inflammation, fibrogenesis, and adverse clinical outcomes. In this context, lean T2DM may represent a clinically relevant high-risk phenotype that remains underrecognized in routine practice. However, the interpretation of these findings requires caution, given the potential influence of reverse causality and the lack of standardized definitions of lean metabolic phenotypes. Future efforts should focus on integrating metabolic profiling, body composition assessment, and traditional prognostic markers into more refined risk stratification tools. Prospective, multicenter studies are needed to validate the role of lean T2DM and clarify its mechanistic contribution to disease progression. Ultimately, a more individualized and multidimensional approach to patient evaluation, encompassing metabolic, immunologic, and biochemical factors, may improve the prediction of outcomes and guide more personalized management strategies in patients with PBC.

CONCLUSION

The paradigm of risk stratification in patients with PBC is evolving from a predominantly biochemical and treatment-response-based approach toward a more comprehensive framework that incorporates metabolic health. The identification of lean T2DM as a potential prognostic modifier challenges the traditional reliance on BMI as a surrogate of metabolic risk and highlights the limitations of current models that do not account for metabolic heterogeneity. Recent evidence suggests that metabolic dysfunction, even in the absence of overt obesity, can contribute to hepatic inflammation, fibrogenesis, and adverse clinical outcomes. In this context, lean T2DM may represent a clinically relevant high-risk phenotype that remains underrecognized in routine practice. However, the interpretation of these findings requires caution, given the potential influence of reverse causality and the lack of standardized definitions of lean metabolic phenotypes. Future efforts should focus on integrating metabolic profiling, body composition assessment, and traditional prognostic markers into more refined risk stratification tools. Prospective, multicenter studies are needed to validate the role of lean T2DM and clarify its mechanistic contribution to disease progression. Ultimately, a more individualized and multidimensional approach to patient evaluation, encompassing metabolic, immunologic, and biochemical factors, may improve the prediction of outcomes and guide more personalized management strategies in patients with PBC.