Factors influencing the cure of pseudolithiasis: a retrospective study of 264 patients

Abstract

Objective

To identify independent predictors of complete resolution in patients with pseudobiliary calculi and evaluate the effectiveness of different therapeutic strategies.

Methods

Clinical data were retrospectively analyzed from 264 patients with pseudobiliary calculi admitted to The First Hospital of Lanzhou University between January 2018 and December 2019. Patients were categorized into complete resolution group (n = 43) and persistent group (n = 221) based on discharge CT findings. Univariate and multivariate logistic regression analyses were performed to assess the impact of demographic characteristics, laboratory parameters, comorbidities, and therapeutic interventions on prognosis.

Results

Among 264 enrolled patients, 43 (16.29%) achieved complete resolution while 221 (83.71%) showed persistent calculi. Univariate analysis revealed significant differences between groups in gender (χ² = 4.738, P = 0.030), concurrent cholecystitis (χ² = 24.424, P < 0.001), cholangitis (P = 0.001), viral hepatitis (χ² = 3.957, P = 0.047), decompensated cirrhosis (χ² = 6.827, P = 0.009), Age Groups (t=-2.232, P = 0.030), AST/ALT ratio (t = 6.340, P < 0.001), and white blood cell count (t=-3.103, P = 0.002). Therapeutic interventions, including ceftazidime (χ² = 11.21, P = 0.001), mezlocillin (P = 0.014), ornidazole (χ² = 6.317, P = 0.012), and iodinated contrast media (χ² = 5.271, P = 0.022), showed statistically significant differences between groups. Multivariable logistic regression analysis shows that acute cholecystitis [OR = 0.237, 95% CI (0.106–0.529), P < 0.001], cholangitis [OR = 0.258, 95% CI (0.075–0.889), P = 0.032], and elevated white blood cell count [OR = 0.876, 95% CI (0.806–0.953), P = 0.002] are negatively associated with the resolution of pseudolithiasis. In contrast, the increase in the AST/ALT ratio [OR = 5.132, 95% CI(2.063–12.766), P < 0.001] and the use of iodinated contrast agents [OR = 3.944, 95% CI(1.262–12.33), P = 0.018] are continuously positively correlated with pseudolithiasis.In addition, the use of ceftazidime [OR = 0.291, 95% CI (0.121–0.701), P = 0.006] and mezlocillin [OR = 0.045, 95% CI (0.004–0.531), P = 0.014] has a significant promoting effect on the resolution of pseudolithiasis. These findings provide a systematic analysis of potential predictive factors associated with the complete resolution of pseudobiliary stones, offering preliminary evidence for further optimization of personalized treatment strategies.

Conclusion

Our research indicates that, unlike chronic cholelithiasis, pseudolithiasis exhibits uniqueness and temporality. The underlying inflammatory gallbladder diseases and their treatments may facilitate the rapid resolution of pseudolithiasis, while factors such as viral hepatitis and decompensated cirrhosis may affect liver function and bile composition but do not appear to directly contribute to the occurrence of pseudolithiasis. Furthermore, differences in sex hormone levels may result in a higher rate of short-term resolution of pseudolithiasis in male patients compared to females. These findings provide preliminary evidence for the prevention and management strategies of pseudolithiasis.

Introduction

Pseudocholelithiasis, also known as false gallstones, is a unique clinical phenomenon first reported by Schaad and colleagues in 1986 as a reversible gallbladder precipitate occurring during treatment with ceftriaxone [1]. This phenomenon has garnered widespread attention from clinicians, prompting in-depth studies into its pathological mechanisms and clinical characteristics [2, 3]. Epidemiological studies indicate that high doses or prolonged use of ceftriaxone significantly increase the risk of developing pseudocholelithiasis, with prevalence rates ranging from 15–46% [4, 5]. Recent multicenter studies have shown significant differences in incidence among different populations, with children and elderly patients exhibiting higher susceptibility compared to adults [6, 7].

Previous research on pseudocholelithiasis has primarily focused on pediatric and geriatric populations, which are more sensitive to certain medications that may lead to the condition. However, the management of pseudocholelithiasis varies significantly across different geographical regions and healthcare systems, influenced by factors such as resource availability, diagnostic practices, and treatment strategies. For instance, high-income countries typically have access to advanced diagnostic tools and medications, while resource-limited areas may rely more on conservative management approaches [8]. Understanding these differences is crucial for translating research findings into global clinical practice and developing standardized management strategies.

Although pseudocholelithiasis often resolves spontaneously, clinical observations indicate that active intervention may be necessary in certain cases to prevent complications [9]. Without timely intervention, pseudocholelithiasis can lead to complex complications, with mechanisms involving various factors, including the patient’s underlying conditions, drug interactions, and alterations in biliary system function [10, 11]. Molecular biology studies have identified that polymorphisms in the UGT1A1 gene, which lead to decreased UDP-glucuronosyltransferase (UDPG) function, may play a critical role in disease progression [12]. Additionally, recent research suggests that changes in bile composition, impaired gallbladder contraction, and the release of inflammatory mediators may also promote the occurrence and development of pseudocholelithiasis [13, 14].

Despite some progress in research, current clinical studies on prognostic factors for pseudocholelithiasis primarily focus on the dosage and duration of ceftriaxone treatment [15, 16], with relatively few systematic studies on other potential influencing factors. Specifically, there is a lack of large-scale clinical evidence regarding comorbidities, laboratory test abnormalities, and other drug interventions affecting the prognosis of pseudocholelithiasis [17]. A deeper understanding of these factors is essential for optimizing clinical treatment strategies and preventing complications.

This study aims to systematically analyze the factors influencing the complete resolution of pseudocholelithiasis in hospitalized patients, addressing the gaps in existing research. By comparing the baseline characteristics, underlying diseases, and medication regimens of patients with complete resolution of false gallstones during hospitalization to those in whom they persisted at discharge, we explored the potential impact of these factors on the resolution of pseudocholelithiasis. The findings revealed that gallbladder-related inflammatory diseases and the use of specific antimicrobial agents are key influencing factors, with the noteworthy observation that the use of iodinated contrast agents may also contribute to the persistence of pseudocholelithiasis. These characteristics provide important evidence for the differential diagnosis and clinical treatment strategies for pseudocholelithiasis.

Materials and methods

Study population

This single-center retrospective cohort study was conducted at The First Hospital of Lanzhou University, a tertiary care academic medical center. We screened consecutive patients who received CT-confirmed diagnosis of pseudolithiasis between January 1, 2018, and December 31, 2019. Inclusion criteria encompassed: (1) radiologically confirmed new-onset pseudolithiasis, biliary sludge, or high-density gallbladder content on computed tomography; (2) availability of comprehensive clinical documentation, including demographic parameters, laboratory investigations, and therapeutic interventions; and (3) presence of comparative CT imaging documentation demonstrating gallbladder changes in pre- and post-ceftriaxone administration phases.

Patients were excluded if they met any of the following criteria: (1) documented history of cholelithiasis or prior cholecystectomy; (2) lack of baseline CT examination prior to ceftriaxone initiation or absence of follow-up CT imaging within the9-week post-treatment period; (3) incomplete clinical documentation or absence of essential data points; or (4) loss to follow-up during the study period.

Research methodology

We employed a standardized data collection protocol to conduct a comprehensive retrospective analysis. Clinical data were systematically extracted and evaluated according to predetermined criteria, covering demographics and baseline characteristics, including age groups, gender, and comorbidities. The imaging assessment involved detailed computed tomography (CT) scans performed at admission and discharge, with a focus on analyzing changes in gallbladder morphology. These analyses included measurements of gallbladder size, wall thickness assessment, quantitative analysis of sediment density, and evaluation of its distribution patterns. Laboratory parameters were systematically recorded, primarily including liver function indicators (AST/ALT ratio), hematological parameters (white blood cell count), and fasting blood glucose levels. Additionally, medication usage records included information on antimicrobial therapy and the use of contrast agents (iodinated contrast media and gadolinium-based contrast agents).

To further explore the mechanisms influencing the resolution of pseudolithiasis and identify potential related factors, we included key clinical indicators closely associated with pathophysiological mechanisms, such as cholecystitis, cholangitis, and decompensated liver cirrhosis. These indicators are closely related to inflammatory responses in the gallbladder, biliary flow obstruction, and liver function impairment, and they hold significant implications for the occurrence, progression, and prognosis of pseudolithiasis.

Data extraction was completed using standardized electronic forms within the hospital’s electronic medical record system. To ensure the integrity and accuracy of the data, all extracted data were verified by two independent researchers. In cases of disagreement, discrepancies were resolved by reviewing original records and reaching a consensus. This process ensured the quality of the data and the reliability of the research findings.To ensure data integrity and accuracy, two independent researchers conducted verification of all extracted information.

CT findings of pseudolithiasis

Currently, there are no globally unified or authoritative guidelines for the CT diagnostic criteria of pseudolithiasis. However, based on published literature, several characteristic CT imaging features have been summarized. The diagnostic criteria for gallbladder stones on CT typically involve the presence of well-defined focal areas within the gallbladder, where the density differs significantly from that of normal gallbladder contents, facilitating detection. These stones generally appear as distinctly round or oval structures. In contrast, pseudolithiasis is characterized by high-density areas that lack a rounded shape, often appearing as smaller or dispersed punctate high-density spots, typically in a non-clustered pattern [17].

The resolution of pseudolithiasis is defined as the point at which the density within the gallbladder becomes nearly equivalent to that of normal bile. The density of pseudoliths was assessed by averaging measurements independently obtained by two radiologists. Any discrepancies in measurements were resolved through consensus.

Radiological assessments were conducted independently by two senior radiologists, each with over 10 years of experience, using a double-blind methodology. Inter-observer disagreements were resolved through consensus meetings to ensure accuracy and reliability.

Statistical analysis

The normality of continuous variables was assessed through visual inspection of Q-Q plots, a widely used method for detecting deviations from normality. For significantly skewed variables, data transformations were applied to meet parametric analysis assumptions. Specifically, the Box-Cox transformation was used to correct positive skewness and stabilize variance, while logarithmic transformation reduced the impact of extreme values and improved data symmetry.

All statistical analyses were conducted using SPSS 23.0 software (IBM Corporation, Armonk, New York, USA).Normally distributed data are presented as mean ± standard deviation (Mean ± SD) and analyzed using independent samples t-test for intergroup comparisons; non-normally distributed data are presented as median and interquartile range [M(Q1, Q3)] and analyzed using the Mann-Whitney U test. Categorical variables are summarized as frequency and percentage [n(%)] and for intergroup comparisons, Pearson’s chi-square test is used when the expected frequency is ≥ 5, while Fisher’s exact test is used when the expected frequency is < 5.

The identification of prognostic factors employed a two-stage analytical approach. First, potential predictive factors were screened through univariate analysis, with variables having a P value < 0.05 included in subsequent multivariate analysis. Then, a multivariate logistic regression model was utilized to analyze these variables, quantifying the strength and direction of the association between the variables and the outcomes using odds ratios (OR) and their 95% confidence intervals (95% CI).

All statistical tests were two-sided, and a significance level of P < 0.05 was considered statistically significant.

Results

Data transformations for normality

Box-Cox transformation was applied to the continuous variable age, and logarithmic transformations were used for the continuous variables white blood cell count and blood glucose to ensure they met the assumptions of parametric analyses. After transformation, all continuous variables satisfied normality assumptions, as confirmed by Q-Q plots showing approximately normal distributions (Figs. 1, 2, 3 and 4).

Fig. 1

Normality Assessment via Q-Q Plot of Age Data (Box-Cox Transformation)

Fig. 2

Normality Assessment of AST/ALT Ratio via Q-Q Plot

Fig. 3

Normality Assessment of Log-Transformed Glucose via Q-Q Plot

Fig. 4

Normality Assessment of Log-Transformed Leukocyte Counts via Q-Q Plot

Clinical characteristics of the participants

This study included a total of 264 patients with false gallstones, who were divided into a complete resolution group (43 cases, 16.29%) and a persistent group (221 cases, 83.71%) based on the results of CT examinations at the time of discharge.

Results of univariate analysis

Demographic characteristics and underlying diseases

The clinical and laboratory characteristics of the subjects are detailed in Table 1. The proportion of males in the complete remission group was significantly higher than that in the persistent group (67.4%, 29/43 vs. 49.3%, 109/221, χ² = 4.738, P = 0.030). There was also a significant difference in age distribution between the two groups. For clinical relevance, age was categorized into three groups: 0–14 years (assigned a value of 1), 15–64 years (assigned a value of 2), and ≥ 65 years (assigned a value of 3). The analysis showed that the mean age Groups value in the complete remission group was significantly higher than that in the persistent group (2.4 ± 0.5 vs. 2.2 ± 0.5, t=-2.232, P = 0.030); Compared to the sustained group, the proportion of patients with viral hepatitis (4.7% vs. 16.3%, χ² = 3.957, P = 0.047) and decompensated cirrhosis (2.3% vs. 18.1%, χ² = 6.827, P = 0.009) in the complete remission group was significantly lower.

Table 1 Comparing clinical characteristics between complete resolution patients and persistent pseudolithiasis patients

Laboratory examination indicators

The AST/ALT ratio in the complete remission group (0.905 ± 0.316) was significantly lower than that in the persistent group (1.488 ± 1.165) (t = 6.340, P < 0.001); the white blood cell count in the complete remission group ((8.951 ± 3.995)×10⁹ L^− 1) was higher than that in the persistent group ((6.906 ± 3.940)×10⁹ L^− 1) (t=-3.103, P = 0.002).

Drug usage

The analysis of antimicrobial drug usage revealed that the usage rate of ceftazidime in the complete remission group was significantly higher than that in the persistent group (30.2% vs. 10.9%, χ² = 11.210, P = 0.001). The usage rates of mezlocillin and ornidazole were also significantly higher in the complete remission group (mezlocillin: 7.0% vs. 0.5%, Fisher’s exact test, P = 0.014; ornidazole: 30.2% vs. 14.5%, χ² = 6.317, P = 0.012).

In terms of contrast agent usage, the rate of iodine contrast agent use was significantly lower in the complete remission group compared to the persistent group (9.3% vs. 25.3%, χ² = 5.271, P = 0.022). The usage rate of gadolinium contrast agents was also lower in the complete remission group than in the persistent group (2.3% vs. 12.2%, Fisher’s exact test, P = 0.050), although this result only demonstrated borderline statistical significance.

Other clinical indicators

There were no significant differences between the two groups of patients in terms of multiple underlying diseases and interventions (P > 0.05). Analysis of underlying diseases showed that the incidence rates of hypertension (18.6% vs. 14.5%, χ² = 0.476, P = 0.490), diabetes (7.0% vs. 8.6%, P = 1.000), coronary heart disease (2.3% vs. 1.4%, P = 0.511), and acute severe pancreatitis (14.0% vs. 17.6%, χ²=0.347, P = 0.556) did not differ significantly between the two groups. Similarly, the incidence rates of liver failure (51.2% vs. 47.1%, χ² = 0.243, P = 0.622) and obstructive jaundice (16.3% vs. 7.2%, P = 0.073) showed no statistically significant difference, although the rate of obstructive jaundice was slightly higher in the complete remission group, it did not reach statistical significance.

Regarding continuous variables, there was no significant difference in fasting blood glucose levels between the two groups (7.074 ± 3.060 vs. 6.243 ± 2.840 mmol L^− 1, t=-1.729, P = 0.085).

In terms of treatment measures, the usage rates of ceftriaxone (2.3% vs. 3.6%, P = 1.000) and somatostatin (9.3% vs. 16.7%, χ²=1.519, P = 0.218) also showed no statistically significant differences between the two groups.

Multivariate logistic regression analysis

The results of the logistic regression analysis are shown in Tables 2 and 3. In the univariate analysis, variables with P < 0.050 were selected for inclusion in the multivariate logistic regression model, and a stepwise regression method was employed for analysis. The results indicate that the independent factors associated with the prognosis of pseudolithiasis are as follows: the presence of cholecystitis significantly reduced the risk of persistent pseudolithiasis (OR = 0.237, 95% CI: 0.106–0.529, P < 0.001), and cholangitis was also confirmed as a protective factor (OR = 0.258, 95% CI: 0.075–0.889, P = 0.032). Conversely, an elevated AST/ALT ratio significantly increased the risk of persistent pseudolithiasis (OR = 5.132, 95% CI: 2.063–12.766, P < 0.001), while a higher white blood cell count exhibited a protective effect (OR = 0.876, 95% CI: 0.806–0.953, P = 0.002). Regarding the use of antimicrobial agents, the administration of ceftazidime (OR = 0.291, 95% CI: 0.121–0.701, P = 0.006) and mezlocillin (OR = 0.045, 95% CI: 0.004–0.531, P = 0.014) significantly reduced the risk of persistent pseudolithiasis. However, the use of iodinated contrast agents significantly increased the risk of persistent pseudolithiasis (OR = 3.944, 95% CI: 1.262–12.330, P = 0.018).

Table 2 Multifactorial logistic regression of clinical factors in pseudolithiasis

Table 3 Multifactorial logistic regression of medication factors in pseudolithiasis

Comprehensive analysis suggests that cholecystitis, cholangitis, elevated white blood cell count, and the use of certain antimicrobial agents may play a protective role in the prognosis of pseudolithiasis, while an abnormal increase in the AST/ALT ratio and the use of iodinated contrast agents may be risk factors for poor prognosis.

Additionally, other significant factors identified in univariate analysis, such as gender, age, viral hepatitis, decompensated cirrhosis, the use of ornidazole, and the use of gadolinium contrast agents, did not demonstrate independent prognostic significance in multivariate logistic regression analysis (P > 0.050).

Discussion

This study conducted a retrospective analysis of 264 patients with pseudolithiasis to explore the influencing factors and short-term prognosis. The results indicated that only 43 patients (16.29%) experienced symptom relief, while 221 patients (83.71%) still had symptoms at the time of discharge. The following is a discussion of the main findings of the study and their significance, along with an analysis of possible mechanisms based on previous literature, as well as an acknowledgment of the study’s limitations and future directions.

The influence of age and gender

Previous studies have indicated that age (> 18 years), gender, and renal impairment are significant factors influencing the occurrence of pseudolithiasis. The results of the univariate analysis in this study align with these findings, suggesting that the observed gender differences may be related to the higher estrogen levels in females. Research by Wang et al. [18]. points out that estrogen regulates the expression of genes associated with cholesterol metabolism and bile acid synthesis through nuclear receptors ESR1 and ESR2, leading to increased cholesterol secretion from the liver, elevated bile saturation, and reduced gallbladder contraction function. Furthermore, the risk of gallstones in women who use oral contraceptives is significantly increased, with this risk positively correlated with the duration and dosage of hormone use [19]. These mechanisms may enhance the susceptibility of females to the formation and persistence of pseudolithiasis.

In contrast, male androgens may promote the natural resolution of stones by enhancing biliary dynamics and reducing bile viscosity. This gender difference is consistent with research findings on gallstones, where men typically exhibit a lower risk of chronic biliary pathology, which may provide an explanation for the male advantage in the resolution of pseudolithiasis. The aforementioned findings suggest that hormone levels related to gender may play a crucial role in the occurrence and resolution of pseudolithiasis. This understanding not only offers direction for further research into the endocrine mechanisms underlying gender differences but may also provide a theoretical basis for the development of personalized treatment strategies for pseudolithiasis.

In terms of age, this study categorized patients into three stages (1: 0–14 years, 2: 15–65 years, and 3: 66 years and older). The results indicated that the average age of the remission group (2.4 ± 0.5) was significantly higher than that of the persistent group (2.2 ± 0.5, P = 0.030). This difference may be related to variations in gallbladder function, bile flow, and inflammatory response capabilities among different age groups. Children may experience remission from pseudolithiasis more easily due to better gallbladder function and bile dynamics; adults may face more obstacles due to metabolic diseases or lifestyle-related factors; while elderly individuals, despite diminished gallbladder function, may achieve stone remission linked to compensatory inflammatory mechanisms.

Based on this result, management should be stratified according to the patient’s age: pediatric patients may adopt a strategy of close observation to minimize unnecessary interventions; adults should focus on early screening and intervention for metabolic diseases; elderly patients require special attention to inflammatory responses and gallbladder function, with personalized treatment plans developed accordingly.

This study provides important evidence for the stratified management of pseudolithiasis, while also offering new research directions for further exploring the physiological differences of the gallbladder among different age groups and their impact on stone resolution. These findings not only deepen the understanding of the mechanisms underlying the occurrence and resolution of pseudolithiasis but also lay the groundwork for optimizing treatment strategies and developing precise intervention measures.

The relationship between inflammation and related indicators and the relief of pseudolithiasis

In terms of inflammatory markers, this study found that elevated levels of cholecystitis, cholangitis, and white blood cell count (WBC) were significantly associated with the resolution of pseudolithiasis (OR < 1). The reduction in WBC levels, as an indicator of inflammation improvement, was significantly correlated with the resolution of pseudolithiasis, suggesting that controlling the inflammatory response may contribute to the natural course of the disease under specific conditions. The results indicated a statistically significant correlation between the decrease in WBC levels and the regression of pseudolithiasis [OR = 0.876, 95%CI(0.806–0.953), P = 0.002], suggesting that for each unit decrease in WBC levels, the likelihood of pseudolithiasis regression increases by approximately 12.4%. As a systemic marker of infection and systemic inflammation, the dynamic changes in WBC may not only reflect the control of local inflammation in the gallbladder or bile ducts but also indicate an improvement in the systemic inflammatory state, potentially playing a positive role in bile dynamics and the local biliary environment.

Interestingly, although inflammation itself may exacerbate the formation of pseudolithiasis by interfering with bile flow and reducing gallbladder function, patients in this study who received anti-infective treatment exhibited improvements in acute inflammation and related changes in bile flow. This may partially explain the correlation between elevated inflammatory markers and the resolution of pseudolithiasis, suggesting a potential positive role for antimicrobial treatment in specific patients. This finding emphasizes the connection between inflammation resolution and the regression of pseudolithiasis, but the mechanisms and specific impacts require further investigation. Exploring how targeted interventions on inflammation and bile flow can optimize the natural course of pseudolithiasis is also worthy of deeper exploration in future research.

Relationship between liver function status and the resolution of pseudolithiasis

In patients with decompensated liver cirrhosis, this study found no significant association with the occurrence or resolution of pseudolithiasis. This may be related to the long-term chronic disruption of bile secretion dynamics in these patients, which affects the condition in a milder or less reversible manner, resulting in a weaker correlation with the resolution of pseudolithiasis in the short term. However, the dynamic changes in liver function status may still play a potential role in bile metabolism, particularly through the liver function abnormalities reflected by the AST/ALT ratio. The results of this study indicate a significant association between changes in the AST/ALT ratio and the resolution of pseudolithiasis [OR = 5.132, 95%CI(2.063–12.766), P < 0.001]. This finding suggests that patients with an elevated AST/ALT ratio are more likely to experience regression of pseudolithiasis compared to the control group, potentially reflecting the critical role of improved bile flow in this process. This observation is consistent with previous studies, such as that by Li et al. [20], which indicated that dynamic changes in liver function abnormalities may contribute to the formation or resolution of gallstones by influencing bile composition and biliary dynamics; however, the specific mechanisms underlying pseudolithiasis still require further investigation.

The effect of contrast agents on the resolution of pseudolithiasis

This study systematically evaluated the impact of iodine contrast agents on pseudolithiasis for the first time, revealing that iodine contrast agents are an independent risk factor for the persistence of pseudolithiasis (OR = 3.944, P = 0.018). This provides new evidence that iodine contrast agents may interfere with the natural resolution of pseudolithiasis through various mechanisms. On one hand, their unique physicochemical properties (high iodine content, hydrophilicity, hypertonicity, and high viscosity) may form insoluble complexes by binding with bile salts or calcium ions in the gallbladder, adhering to previously formed bile sludge or the surface of pseudolithiasis, thereby inhibiting their natural dissolution. On the other hand, their hypertonicity and high viscosity may further hinder the clearance of pseudolithiasis by altering gallbladder contraction function and bile dynamics. These physicochemical characteristics provide a biological rationale for iodine contrast agents being a risk factor for the persistence of pseudolithiasis, although the specific mechanisms require further investigation.

Furthermore, some studies indicate that iodine-based contrast agents may affect bile metabolism through compensatory excretion pathways in patients with impaired renal function, while the adverse reactions associated with gadolinium-based contrast agents are primarily limited to mild allergic responses [21–22]. This suggests that iodinated contrast agents may have a stronger potential impact on the biliary system due to their unique physicochemical properties. Future research should delve deeper into the specific effects of iodine-based contrast agents on bile secretion, excretion, and bile acid metabolism through in vitro experiments and animal models, in order to comprehensively elucidate their mechanisms and provide more precise evidence for clinical practice.

Particularly in the management of patient risk stratification, there should be further optimization in the selection of low-osmolarity, low-viscosity iodinated contrast agents, especially in high-risk patients with impaired renal function or reduced gallbladder function, in order to minimize the occurrence or persistent risk of pseudolithiasis as much as possible. This finding provides important reference for the individualized selection of contrast agents in imaging examinations.

The impact of antimicrobial agents on the resolution of pseudolithiasis

Ceftriaxone is one of the common causes of pseudo-cholelithiasis, and its mechanism may be closely related to its high concentration distribution in bile and its physicochemical properties [23]. As a broad-spectrum antibiotic, approximately 40–50% of ceftriaxone is excreted through bile. When its concentration exceeds solubility, it easily binds with calcium ions in bile to form insoluble complexes, which can deposit in the gallbladder and may further alter the physicochemical properties of bile, such as reducing bile acid concentration and bile salt solubility, thereby promoting the formation of biliary sludge or pseudo-cholelithiasis. These effects are particularly significant in patients receiving high doses or long-term treatment with ceftriaxone. However, this study did not find a significant association between ceftriaxone and the persistence of pseudo-cholelithiasis (P > 0.050). This may be related to the lower dosage of ceftriaxone used and the shorter treatment duration in the study population. A prospective study indicated that when the cumulative dose exceeds 19 g, the risk of inducing pseudo-cholelithiasis significantly increases. Notably, these types of stones are usually reversible, with most resolving spontaneously after discontinuation of the drug, without the need for special treatment.

Furthermore, this study found that ceftazidime and mezlocillin may have a positive effect on the alleviation of pseudolithiasis, possibly related to their anti-inflammatory and antibacterial properties. By reducing the pathogenic bacterial load in bile and alleviating biliary inflammation, these medications may, to some extent, inhibit the progression of pseudolithiasis and promote its resolution. It is noteworthy that the resolution of pseudolithiasis is a complex and multifactorial process, potentially influenced by bile composition, gallbladder motility, and concomitant treatments. Individual differences among patients, such as gallbladder function and bile metabolism characteristics, may further alter the specific effects of antibiotics on pseudolithiasis, introducing a degree of uncertainty into clinical outcomes. Therefore, these findings emphasize the multifactorial nature of pseudolithiasis formation and resolution, indicating that, in addition to ceftriaxone, other intrinsic and extrinsic variables may also play significant roles in determining clinical outcomes.

Future research should integrate in vitro experiments, animal models, and dynamic monitoring technologies to further explore the specific effects of different antibiotics on bile composition, bile dynamics, and the biliary environment. Additionally, large-scale prospective studies should clarify the risk stratification criteria for high-risk patients and optimize antibiotic selection strategies, particularly assessing the potential application value of ceftazidime and mezlocillin in the management of pseudolithiasis. More comprehensive mechanistic studies and the establishment of individualized treatment plans will provide a more precise theoretical basis and practical guidance for the diagnosis and treatment of pseudolithiasis.

Analysis of the mechanism of pseudolithiasis formation and clinical management implications

Previous studies on pseudolithiasis have primarily focused on the occurrence of pseudolithiasis resulting from long-term use of high-dose ceftriaxone. There have also been case reports concerning infants and elderly patients developing pseudolithiasis [24–25]. The mechanisms underlying the formation of pseudolithiasis mainly involve two aspects: (1) drug-related factors, as molecular biology research indicates that ceftriaxone can bind with bile or calcium ions to form insoluble precipitates; (2) gallbladder dysfunction, with reduced gallbladder contraction considered a significant risk factor for the formation of pseudolithiasis [26]. These mechanisms suggest that the effects of the drug and short-term changes in gallbladder dynamics may play a critical role in the formation of pseudolithiasis.

This study further explores the factors related to the formation and regression of pseudolithiasis. The results indicate that, although there are significant differences in gender, age, and certain comorbidities between the regression group and the persistent group, not all comorbidities are associated with pseudolithiasis. For instance, the presence of viral hepatitis, decompensated cirrhosis, and elevated fasting blood glucose levels did not show a significant correlation with the formation or regression of pseudolithiasis (P > 0.05). This finding suggests that, while viral hepatitis and decompensated cirrhosis may influence the biliary environment by impairing liver function and altering bile composition, they may not directly determine the formation or regression of pseudolithiasis. Similarly, although fasting blood glucose has been confirmed to be associated with the formation of gallstones (possibly through insulin resistance mechanisms), it did not exhibit a similar significant association in the context of pseudolithiasis. These findings indicate that, compared to chronic metabolic abnormalities or structural biliary damage, the formation and regression of pseudolithiasis may be more driven by short-term and reversible factors, such as medication use, bile stasis, or acute inflammation.

The above results suggest that there may be significant pathophysiological differences between pseudolithiasis and chronic cholelithiasis. Chronic cholelithiasis is typically associated with long-term metabolic abnormalities (such as insulin resistance) or structural biliary damage, whereas the formation and resolution of pseudoliths appear to be more dependent on short-term variations in bile flow or gallbladder motility. This distinction has clinical implications, indicating that the management of pseudolithiasis should focus on the identification and resolution of short-term triggers, such as bile stasis and acute inflammation, rather than the control of long-term metabolic diseases. Furthermore, this finding underscores the importance of stratified management in diagnosis and treatment; by differentiating pseudolithiasis from chronic cholelithiasis, more targeted intervention strategies can be developed.

Limitations of the study

This study is a single-center retrospective analysis, with subjects primarily drawn from hospitalized patients in a specific geographic area. Consequently, the findings may be influenced by regional differences, hospital practice patterns, and patient characteristics. Caution should be exercised when applying the study conclusions to broader populations or different healthcare settings. For instance, variations in diagnostic criteria, treatment strategies, and accessibility of medical resources across different regions may affect the applicability of the predictive factors and treatment effects identified in this study.

Furthermore, the sample size of the intervention group in this study is relatively small (n = 43), which may reduce the robustness of the statistical analysis and increase the uncertainty of the results. After optimizing the model and calculating statistical power, key variables were confirmed to have sufficient efficacy to support the study’s conclusions. However, considering the limitations posed by the low event occurrence rate, future research should prioritize multi-center, large-sample prospective study designs to further validate the findings of this study and enhance the external generalizability and reliability of the conclusions, as well as to further verify the stability and practical significance of low-efficacy variables.

The follow-up period of this study was limited to the duration of hospitalization, which restricts the assessment of the long-term prognosis of pseudolithiasis. Over time, important clinical outcomes may have been overlooked, such as recurrence, sustained remission, or late complications. Therefore, the conclusions of this study primarily apply to the short-term progression of pseudolithiasis during hospitalization, rather than long-term outcomes. Additionally, the lack of extended follow-up may underestimate certain key results (such as late recurrence or long-term complete remission rates), thereby affecting the generalizability of the conclusions. To address this issue, future research should incorporate an extended follow-up period, including post-discharge monitoring or long-term observational designs, to more comprehensively evaluate the clinical outcomes of pseudolithiasis. Despite these limitations, this study provides important insights into the short-term progression of pseudolithiasis during hospitalization and its predictive factors, laying the groundwork for broader future research.

Imaging assessments also have certain limitations: the detection rate of multi-slice spiral CT for homogeneous dense stones is relatively low, which may lead to missed diagnoses; at the same time, the interpretation of CT density images has a degree of subjectivity, and the involvement of different observers may affect the reliability of the results, Future research could utilize AI diagnostic systems to reduce human error.

Furthermore, this study did not adequately incorporate the impact of potential diseases on the development of pseudolithiasis, which represents a limitation of this research. Existing evidence suggests that metabolic disorders (such as liver and kidney dysfunction) can influence the occurrence and progression of pseudolithiasis through various mechanisms, such as altering bile composition (cholesterol or bile salt concentrations) or gallbladder dynamics, increasing the risk of bile sludge or gallstone formation, and potentially reducing the resolution of pseudolithiasis. Future research will comprehensively collect data related to biliary system function and metabolic disorders (such as cholecystitis, acute liver injury, lipid metabolism abnormalities, and relevant medical history) and employ multivariable analysis to assess the impact of these factors on the risk of occurrence and resolution of pseudolithiasis.

Future research directions

To overcome the aforementioned limitations, future research should focus on the following efforts:

Multicenter prospective studies: Expand the sample size and include a more diverse patient population to enhance the reliability and generalizability of the conclusions.

Extended follow-up duration: Incorporate post-discharge monitoring or long-term observational designs to comprehensively assess the long-term outcomes of pseudolithiasis.

Standardized imaging assessments: Introduce artificial intelligence-assisted diagnostic systems to improve diagnostic accuracy and reduce human error.

In-depth mechanistic studies: Focus on exploring the specific mechanisms by which iodinated contrast agents, cefoperazone, and other medications affect bile metabolism and the formation of pseudolithiasis, providing a basis for the development of preventive strategies or targeted therapies.

Summary

In conclusion, the findings suggest that, compared to chronic metabolic abnormalities or structural biliary injuries, the formation and resolution of pseudolithiasis are more likely driven by short-term and reversible factors, such as drug usage, bile stasis, or acute inflammation. These results indicate significant pathophysiological differences between pseudolithiasis and chronic gallstones. While chronic gallstones are typically associated with long-term metabolic disturbances (e.g., insulin resistance) or structural biliary damage, the formation and resolution of pseudolithiasis appear to depend more on transient alterations in bile flow or gallbladder motility. This distinction provides new insights into the prevention and management of pseudolithiasis and highlights potential avenues for further investigation into the pathological mechanisms of gallstone disease.