Insights from exploring the interrelated dynamics of gallstone disease, non-alcoholic fatty liver disease, and kidney stone disease

Abstract

This article delved into the comprehensive study by Jiang et al, which meticulously examined the bidirectional relationships among gallstone disease, non-alcoholic fatty liver disease, and kidney stone disease through a multicenter study, systematic review, and meta-analysis. The study provides significant evidence supporting these associations, offering valuable insights into the etiology and potential prevention strategies for these interconnected conditions. The clinical significance of these bidirectional relationships is profound, as they underscore the importance of recognizing these conditions not only as isolated diseases but as part of a complex network that can influence each other. These results highlight the critical need for thorough screening and personalized prevention strategies for individuals with these interconnected conditions. Explicit implications for prevention strategies and early screening practices are crucial, as they can lead to early detection and intervention, significantly altering disease progression and outcomes. Furthermore, identifying potential therapeutic targets within these shared pathways may enhance treatment efficacy and patient outcomes, making this research highly relevant to clinical practice. By comprehending the common pathophysiological mechanisms and applying specific interventions, healthcare professionals can greatly enhance patient care and lessen the impact of these widespread diseases on global health.

Key Words: Gallstones; Non-alcoholic fatty liver disease; Kidney calculi; Cross-sectional study; Multidisciplinary screening; Chronic disease prevention; Individualized prevention strategies; Systemic inflammation; Insulin resistance; Shared pathophysiology

Core Tip: This article emphasizes the significant bidirectional associations among gallstone disease, non-alcoholic fatty liver disease, and kidney stone disease as presented in the study by Jiang et al. Through a multicenter cross-sectional study, systematic review, and meta-analysis, the research reveals robust evidence of these interconnections, independent of common risk factors like obesity and insulin resistance. The findings highlight the need for comprehensive screening and individualized prevention strategies for patients diagnosed with any of these conditions. By recognizing the shared pathophysiological mechanisms, healthcare providers can enhance chronic disease prevention, improve patient outcomes, and reduce the socio-economic burden associated with these prevalent diseases.

TO THE EDITOR

Gallstone disease (GSD), non-alcoholic fatty liver disease (NAFLD), and kidney stone disease (KSD) are prevalent conditions that significantly impact global health. GSD affects approximately 10%-20% of adults worldwide[1,2], while NAFLD has a prevalence of 25.2%, with regional variations ranging from 13.5% in Africa to 31.8% in the Middle East[3]. Over the past few decades, the incidence of KSD has shown a continuous increase globally, with prevalence rates varying from 0.1% to 18.5% across different countries[4]. These diseases are known to share common risk factors, including obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, metabolic syndrome, and oxidative stress (OxS), which contribute to their interrelated nature[5-13]. Understanding the bidirectional associations among these diseases is crucial for effective disease prevention and management. Previous studies have consistently highlighted the interrelated nature of these conditions[14,15]. For another example, a landmark study by Taylor et al[14] demonstrated a significant correlation between GSD and NAFLD, suggesting shared metabolic pathways[14]. Another pivotal study by Chang et al[15] provided evidence for the influence of metabolic syndrome on the co-occurrence of NAFLD and KSD. These studies, among others, have laid the groundwork for understanding the complex interactions between these diseases, emphasizing the need for integrated management approaches.

The co-occurrence of GSD and NAFLD illustrates the complexity of their shared metabolic pathways and emphasizes their bidirectional relationship. Metabolic syndrome, comprising risk factors like obesity, insulin resistance, and dyslipidemia, is a dominant contributor to NAFLD development[16]. This syndrome acts as a hepatic manifestation in such conditions, underscoring its significance in NAFLD’s pathogenesis[17]. Notably, genetic factors also play a crucial role in these interactions. Variants like the patatin-like phospholipase domain protein 3-rs738409 are significantly associated with NAFLD susceptibility, highlighting the genetic predisposition that intersects with metabolic traits such as lipid and glucose metabolism[18]. For example, polymorphisms in genes like microsomal triglyceride transfer protein have been identified as potential biomarkers for NAFLD susceptibility in individuals with metabolic syndrome, further evidencing the genetic overlaps[19].

Interestingly, metabolic syndrome exacerbates the effects of NAFLD, with evidence suggesting that NAFLD patients with metabolic syndrome have an increased risk of cardiovascular events and other complications[20]. The influence of metabolic syndrome components on NAFLD highlights the need for an integrated management approach that considers both genetic and metabolic factors[21,22]. Previous research has consistently identified significant interrelationships among GSD, NAFLD, and KSD, emphasizing the need for a comprehensive approach to managing these conditions[23-26]. For instance, bidirectional associations between GSD and KSD have been documented in prospective cohort studies, illustrating how one condition can influence the development of the other[23]. Similarly, reciprocal relationships between GSD and NAFLD have been observed in young and middle-aged Asian populations, highlighting the interconnected nature of these diseases[24]. Additionally, positive associations between NAFLD and KSD have been reported across various populations, including Asian cohorts[25,26]. These findings underscore the novelty and importance of the study by Jiang et al[1], as it builds upon foundational insights to explore new dimensions of these associations.

However, the findings from these studies have shown considerable variability, partly due to differences in sample sizes and study populations[27,28]. This variability underscores the importance of large-scale, multicenter studies to provide more definitive evidence. Notably, there has been a scarcity of such studies focusing on the Chinese population, highlighting a significant gap in the current research landscape. Recognizing the bidirectional connections among GSD, NAFLD, and KSD has significant clinical implications. It enables the development of more comprehensive strategies for chronic disease prevention and control, aiding early intervention efforts. This understanding also broadens the scope for identifying high-risk individuals and tailoring personalized prevention strategies, ultimately improving patient outcomes. Moreover, these insights can provide new perspectives on disease pathogenesis and help identify novel therapeutic targets.

THE BIDIRECTIONAL CONNECTIONS AMONG GSD, NAFLD, AND KSD

The interrelationships among GSD, NAFLD, and KSD are complex, potentially bidirectional, and influenced by shared risk factors and pathophysiological mechanisms. GSD is prevalent worldwide and is closely associated with metabolic disorders such as obesity, insulin resistance, and the metabolic syndrome[27-30]. NAFLD, also related to metabolic syndrome, is a common liver disorder characterized by excessive fat accumulation in the liver unrelated to alcohol consumption[27]. Both conditions share common risk factors including obesity, dyslipidemia, and T2DM[28,29]. The pathogenesis of GSD involves cholesterol supersaturation in bile, gallbladder motility disorders, and biliary microenvironment changes, which are influenced by metabolic syndrome components[30,13]. NAFLD has been linked to systemic inflammation and insulin resistance, which are also critical in GSD development[27]. The concurrent presence of NAFLD and GSD may exacerbate the inflammatory state, contributing to their progression. The association between GSD and KSD is less direct but may involve shared metabolic abnormalities such as obesity and insulin resistance[29]. Gallstones, primarily cholesterol stones, and kidney stones, particularly calcium oxalate stones, have overlapping risk factors, including high body mass index and metabolic syndrome[30]. Both diseases may share pathophysiological pathways involving dyslipidemia and altered bile acid metabolism, potentially leading to a higher incidence of these stones in individuals with metabolic syndrome[30]. NAFLD’s association with CKD is well-documented, driven by shared risk factors like hypertension, obesity, and insulin resistance[27]. NAFLD-induced systemic inflammation and OxS may contribute to renal damage, thereby increasing the risk of kidney stones[27]. The hepatic insulin resistance seen in NAFLD can result in altered renal handling of calcium and uric acid, further influencing kidney stone formation (Table 1)[27]. While GSD, NAFLD, and KSD appear interconnected through shared metabolic and inflammatory pathways, further research is essential to fully understand these associations. Prospective studies focusing on the underlying mechanisms and their clinical implications could pave the way for novel therapeutic strategies targeting these interrelated conditions.

Table 1 Previous studies on the connections among gallstone disease, non-alcoholic fatty liver disease, and kidney stone disease.

Disease connection	Shared risk factors	Pathophysiological mechanisms	Ref.
GSD and NAFLD	Obesity, insulin resistance, metabolic syndrome	Cholesterol metabolism, systemic inflammation	Marcuccilli and Chonchol[27], Di Ciaula et al[28], Chen et al[29]
GSD and KSD	Obesity, metabolic syndrome, dyslipidemia	Dyslipidemia, altered bile acid metabolism	Chen et al[29], Shaffer[30]
NAFLD and KSD	Obesity, hypertension, insulin resistance	Systemic inflammation, oxidative stress, calcium handling	Marcuccilli and Chonchol[27]

GSD: Gallstone disease; NAFLD: Non-alcoholic fatty liver disease; KSD: Kidney stone disease.

KEY FINDINGS AND STATISTICAL INSIGHTS

The study by Jiang et al[1] reveals significant bidirectional associations among GSD, NAFLD, and KSD through a multicenter cross-sectional study involving 640425 subjects and a systematic review and meta-analysis. The multivariable logistic regression analyses indicated that KSD increases the risk of GSD with a pooled odds ratio (OR) of 1.42 [95% confidence interval (CI): 1.16-1.75], and GSD increases the risk of KSD with a pooled OR of 1.48 (95%CI: 1.31-1.67). Similarly, GSD was linked to a higher risk of NAFLD (pooled OR = 1.31, 95%CI: 1.17-1.47) and vice versa (pooled OR = 1.37, 95%CI: 1.26-1.50). Furthermore, NAFLD was associated with an increased risk of KSD (pooled OR = 1.28, 95%CI: 1.08-1.51), and KSD was linked to a higher risk of NAFLD (pooled OR = 1.21, 95%CI: 1.16-1.25). The application of multivariable logistic regressions allowed for the adjustment of confounding variables, thereby providing a more precise estimate of the associations. These regressions were utilized to control for factors such as age, gender, body mass index, and lifestyle factors, ensuring that the observed associations were not confounded by these variables. Additionally, sensitivity analyses were conducted to test the robustness of these findings, including subgroup analyses based on demographic factors and study designs. These sensitivity analyses involved re-analyzing the data excluding certain studies to assess the impact on overall results, confirming the consistency and reliability of the findings. These associations were consistent across different geographic regions and study designs, with the trial sequential analysis confirming the sufficiency and conclusiveness of the evidence, thereby underscoring the robustness and stability of the findings (Figure 1).

Figure 1 Bidirectional association among gallstone disease, non-alcoholic fatty liver disease, and kidney stone disease. KSD: Kidney stone disease; NAFLD: Non-alcoholic fatty liver disease; GSD: Gallstone disease; OR: Odds ratio; CI: Confidence interval.

CLINICAL IMPLICATIONS

The findings of Jiang et al[1] have substantial clinical implications for the management and prevention of GSD, NAFLD, and KSD. Recognizing the significant bidirectional relationships among these three conditions necessitates a paradigm shift in how clinicians approach diagnosis, treatment, and prevention strategies. This study extends previous research by providing robust epidemiologic evidence through a large-scale multicenter cross-sectional study and meta-analysis, specifically highlighting the novel bidirectional associations among these diseases in a Chinese population. This is particularly noteworthy given the scarcity of such studies in this demographic, addressing a significant gap in the research landscape.

Firstly, the evidence of bidirectional associations underscores the importance of comprehensive screening for patients diagnosed with any of these conditions. For example, a patient presenting with GSD should also be evaluated for NAFLD and KSD, considering the elevated risk of these coexisting conditions. Clinicians should implement a structured screening protocol that involves liver function tests, abdominal ultrasounds, and renal function assessments for patients diagnosed with any one of these conditions. This multidimensional screening approach can lead to earlier detection and intervention, thereby improving patient outcomes and reducing the overall disease burden. Secondly, understanding the shared pathophysiological mechanisms, such as obesity, insulin resistance, dyslipidemia, and OxS, enables clinicians to adopt a holistic approach to patient management. Systemic inflammation and insulin resistance act as pivotal shared mechanisms linking these diseases. Insulin resistance can promote pro-inflammatory cytokine signaling and OxS, contributing to the progression of NAFLD and the formation of gallstones and kidney stones. Addressing these common risk factors through lifestyle modifications, such as dietary changes, weight management, and increased physical activity, can simultaneously reduce the risk and severity of GSD, NAFLD, and KSD. For instance, weight reduction has been shown to improve liver function in NAFLD, decrease the formation of gallstones, and reduce the risk of kidney stones. Moreover, the study highlights the need for tailored therapeutic strategies that consider the interconnected nature of these diseases. Pharmacological interventions aimed at managing one condition should be evaluated for their potential impact on the others. For example, targeting the farnesoid X receptor and fibroblast growth factor 19 pathways could offer novel therapeutic opportunities, as dysfunction in these pathways is implicated in the shared pathogenesis of these diseases. The findings also suggested that interdisciplinary collaboration among gastroenterologists, hepatologists, and nephrologists is crucial for optimizing patient care. Multidisciplinary teams can develop comprehensive care plans that address the complexities of managing multiple interrelated diseases. This collaborative approach can enhance patient education, adherence to treatment plans, and overall quality of care.

Furthermore, public health initiatives should incorporate the insights from this study to develop more effective prevention programs. By targeting the shared risk factors and promoting healthy lifestyle choices at the population level, public health campaigns can help reduce the incidence of GSD, NAFLD, and KSD. Screening programs in high-risk populations, such as individuals with obesity, T2DM, or metabolic syndrome, can facilitate early detection and intervention. In conclusion, the bidirectional relationships among GSD, NAFLD, and KSD revealed by Jiang et al[1] have profound clinical implications. A comprehensive, integrated approach to screening, prevention, and treatment is essential to manage these interconnected diseases effectively. By addressing the common underlying risk factors and fostering interdisciplinary collaboration, healthcare providers can improve patient outcomes, reduce the socio-economic burden of these conditions, and pave the way for future research into targeted therapies and prevention strategies.

LIMITATIONS OF THE STUDY

Despite the comprehensive nature of the study, several limitations should be acknowledged. Firstly, the use of ultrasound for disease detection may not distinguish between cholesterol and pigment stones, which have different pathogenesis. This limitation could affect the interpretation of the bidirectional relationships involving GSD. Secondly, significant heterogeneity was observed among the study results, likely due to varying characteristics such as population source, follow-up period, and different disease measurements. Although the researchers employed rigorous statistical methods to adjust for these factors, the inherent variability among studies cannot be entirely eliminated. Thirdly, the cross-sectional nature of the multicenter study limits the ability to establish causal relationships. While the bidirectional associations are compelling, longitudinal studies are necessary to confirm causality and further elucidate the underlying mechanisms. Lastly, the study’s reliance on observational data means it is susceptible to confounding factors and biases, such as sample selection and information biases. Future research should aim to address these limitations by incorporating more diverse populations, employing longitudinal designs, and utilizing advanced diagnostic techniques to improve the accuracy and generalizability of the findings.

CONCLUSION

The study by Jiang et al[1] provides compelling evidence for the bidirectional associations among GSD, NAFLD, and KSD. These findings underscore the importance of comprehensive screening and individualized prevention strategies for patients with these interrelated conditions. By understanding the shared pathophysiological mechanisms and implementing targeted interventions, healthcare providers can significantly improve patient care and reduce the burden of these prevalent diseases on global health.