Impact of cholecystectomy on Metabolic dysfunction-Associated Steatotic Liver Disease and metabolic syndrome: a 6-month prospective cohort study

Abstract

Background

Cholecystectomy, a common surgery, may cause metabolic changes linked to bile acid metabolism. Early studies suggest a possible link between cholecystectomy and Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) and metabolic syndrome, but findings are inconclusive. This 6-month study aimed to assess how elective cholecystectomy affects metabolic syndrome development and MASLD progression in a Middle Eastern population.

Methods

Participants included 51 patients undergoing elective cholecystectomy and 49 matched controls. MASLD grade and metabolic syndrome status were assessed at baseline and six months post-intervention using ultrasonography and standard clinical criteria.

Results

A total of 100 patients were included in the present study, with 51 assigned to the cholecystectomy group and 49 to the control group. Over a six-month follow-up period, individuals in the cholecystectomy group experienced a significant decrease in body mass index (BMI) (p < 0.05) and fasting blood sugar (FBS) levels (p < 0.05). However, this group also exhibited a significant increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (p < 0.05). In contrast, the control group showed significant improvements in FBS (p < 0.05) and HDL cholesterol levels (p < 0.05). Logistic regression analysis revealed that undergoing cholecystectomy was linked to a higher likelihood of developing metabolic syndrome (OR = 9.63, p < 0.05).

Conclusions

Our findings highlight the potential metabolic implications of cholecystectomy. Cholecystectomy was associated with reduced BMI and improved fasting glucose but significantly increased blood pressure over 6 months. Highlighting the need for careful metabolic monitoring post-surgery.

Introduction

Cholecystectomy is a surgical procedure to remove the gallbladder, and among the most frequent abdominal surgeries globally [1, 2]. The gallbladder’s role in bile storage and concentration is critical for lipid digestion and absorption [3, 4]. Therefore, its removal alters bile flow dynamics, potentially leading to long-term metabolic consequences, like a higher risk of metabolic syndrome and MASLD [5–7].

MASLD affects an estimated 25–30% of the global population, with prevalence rates reaching up to 40% in the Middle East, reflecting the region’s growing burden of obesity and metabolic syndrome [8]. The condition includes a range of liver diseases, from simple steatosis to more dangerous conditions such as non-alcoholic steatohepatitis (NASH) or cirrhosis [9]. MASLD is closely associated with metabolic syndrome, which affects 20–25% of adults worldwide [5, 10]. Metabolic syndrome is directly related to a higher risk of developing type 2 diabetes mellitus and cardiovascular disease, both of which are significant contributors to global morbidity and mortality [11]. As the prevalence of these conditions continues to increase, understanding the factors that influence their progression is essential for developing effective prevention and management strategies. Metabolic syndrome is defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, requiring at least three of the following: elevated waist circumference, high triglycerides, low HDL cholesterol, elevated blood pressure, and high fasting glucose.

Cholecystectomy induces physiological changes, particularly in bile acid metabolism, that may impact lipid and glucose homeostasis [12–14]. Beyond their digestive functions, bile acids serve as signaling molecules that regulate key metabolic pathways via nuclear receptors such as the farnesoid X receptor (FXR) [15]. Alterations in bile acid signaling are hypothesized to contribute to insulin resistance and lipid dysregulation, potentially aggravating components of MASLD and metabolic syndrome.

Although the biological plausibility of these associations is well-established, clinical evidence remains inconsistent. Some retrospective studies suggest an increased risk of MASLD and metabolic syndrome following cholecystectomy, while others report no significant association or even protective effects [5, 12, 14]. These conflicting findings likely stem from variations in study design, population demographics, follow-up durations, and the extent to which confounding factors were accounted for. More research is needed to clarify these relationships and identify underlying mechanisms.

The primary aim of this study was to investigate the impact of cholecystectomy on the severity of MASLD and the prevalence of metabolic syndrome over six months in a Middle Eastern population. Secondary objectives involved examining changes in body mass index (BMI), blood pressure, waist circumference, lipid profiles, and glycemic parameters.

Materials and methods

Study design

This prospective cohort study was conducted at two tertiary care hospitals in Karaj, Iran—Imam Ali Hospital and Madani Hospital—between July 2023 and June 2024. Participants were followed for 6 months after enrollment, with outcomes assessed at the beginning and end of the study period. The institutional review board approved the study of each hospital (IR.ABZUMS.REC.1402.087), and informed consent was secured from all patients in compliance with the Declaration of Helsinki.

The study included patients aged 18–65 who were undergoing elective laparoscopic cholecystectomy for conditions like symptomatic cholelithiasis, biliary colic, or gallbladder polyps without signs of cancer. Eligible participants were adults within this age range. The intervention group consisted of patients scheduled for elective gallbladder removal, while the control group included age- and sex-matched individuals visiting the same hospitals for routine health checks without gallbladder issues. Indications for cholecystectomy included symptomatic gallstone disease, recurrent biliary colic, and gallbladder polyps without malignancy. Exclusion criteria included alcohol use, viral hepatitis, autoimmune liver diseases, recent abdominal surgeries within the past 6 months, pregnancy, chronic inflammatory diseases, use of medications causing fatty liver or managing hypertension, and those who declined participation, missed follow-up visits post-surgery, were receiving chemotherapy, or had anemia. Patients who died during the study, including those with hemochromatosis or kidney problems, were also excluded. Furthermore, patients with grade 3 MASLD at baseline or severe metabolic syndrome were not included.

Participants were recruited consecutively from outpatient clinics. A propensity score matching approach was utilized to ensure comparability between the groups regarding age, sex, and baseline metabolic parameters.

Outcomes

The study’s primary outcomes were changes in MASLD grade and metabolic syndrome status over a six-month follow-up period. MASLD grade was assessed using abdominal ultrasonography and categorized as normal, mild (Grade 1), moderate (Grade 2), or severe (Grade 3). MASLD was diagnosed using standardized abdominal ultrasonography based on echogenicity and hepatorenal contrast. Fibroscan was not utilized due to resource constraints. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) was used as the criteria for Metabolic syndrome.

Secondary outcomes encompassed BMI and waist circumference changes, SBP and DBP, HDL, cholesterol, triglycerides, and FBS and HbA1c.

Physical activity levels were also measured as a confounding variable.

Data collection

At baseline and follow-up, anthropometric measurements, laboratory assessments, and ultrasonography were conducted.

Fasting blood samples were collected to measure HDL cholesterol, triglycerides, FBS, and HbA1c following standard laboratory protocols. Abdominal ultrasonography was performed by radiologists blinded to group allocation, who received standardized training to ensure consistent grading of MASLD. Participants self-reported their physical activity levels as “no change,” “more active,” or “less active” compared with baseline.

Efforts to minimize bias included consecutive recruitment, blinding laboratory and ultrasonography personnel to participant group allocation, and using a uniform data collection process. To account for potential confounding variables, propensity score matching based on sex, age, BMI, and baseline metabolic syndrome components was performed. Additionally, statistical models were adjusted for these covariates.

Statistical analysis

Baseline characteristics were summarized using descriptive statistics. Continuous variables were expressed as mean ± standard deviation, while categorical variables were represented as frequencies and percentages. Differences between the cholecystectomy and control groups at baseline were analyzed using independent t-tests for continuous data and chi-square tests for categorical data.

Within-group changes in metabolic parameters over time were assessed using paired t-tests for continuous variables and McNemar’s test for categorical outcomes. Between-group comparisons of changes over the follow-up period were conducted using independent t-tests.

Logistic regression was employed to explore the relationship between metabolic syndrome at follow-up and key predictors, including group assignment, gender, age, baseline BMI, waist circumference, and triglyceride levels. Model performance was evaluated using Nagelkerke’s R², and predictor significance was determined based on adjusted odds ratios (ORs) with 95% confidence intervals (CIs).

SPSS v27 software was used to perform all statistical analyses. Significance threshold was considered as p < 0.05.

Results

This cohort study included 100 patients. 51 were assigned to the cholecystectomy group, and 49 were placed in the control group (Fig. 1). The mean age of the patients was 43.7 ± 8.7 years, and 74% of the participants were female. Patient characteristics had no significant differences (Table 1).

Fig. 1.

CONSORT 2010 flow diagram illustrating the assignment process

Table 1.

Baseline characteristics of patients

Characteristic	Total n = 100	Cholecystectomy Group n = 51	Control Group n = 49	P-value
Age, years	43.7 ± 8.7	43.5 ± 9.1	43.9 ± 8.3	0.852
Gender
Male	26 (26.0)	16 (31.4)	10 (20.4)	0.211
Female	74 (74.0)	35 (68.6)	39 (79.6)
BMI, kg/m²	27.3 ± 4.5	27.9 ± 5.3	26.7 ± 3.4	0.175
Waist Circumference, cm	95.9 ± 10.3	97.8 ± 12.2	93.9 ± 7.3	0.056
HDL Cholesterol, mg/dL	40.6 ± 9.4	40.1 ± 9.9	41.0 ± 8.9	0.640
Triglycerides, mg/dL	130.3 ± 74.4	139.6 ± 82.9	120.6 ± 63.9	0.247
Fasting Blood Sugar, mg/dL	94.1 ± 14.8	95.2 ± 18.1	92.9 ± 10.3	0.823
HbA1c, %	5.2 ± 0.8	5.1 ± 0.7	5.2 ± 0.9	0.320
Systolic BP, mmHg	113.9 ± 11.9	114.5 ± 13.1	113.3 ± 10.7	0.530
Diastolic BP, mmHg	76.6 ± 9.3	76.5 ± 9.2	76.8 ± 9.6	0.878
Grade of fat infiltration
Normal	44 (44.0)	24 (47.1)	20 (40.8)	0.156
Grade 1	50 (50.0)	22 (43.1)	28 (57.1)
Grade 2	6 (6.0)	5 (9.8)	1 (2.0)
Metabolic Syndrome, n (%)	35 (35.0)	19 (37.3)	16 (32.7)	0.630

The changes after 6 months were evaluated for patients in both groups. Patients in the control group exhibited no significant changes in BMI, waist circumference, blood pressure, triglyceride, and HbA1c levels after 6 months. However, the mean fasting blood sugar decreased (p < 0.05) and HDL levels increased at the second follow-up in this group (p-value < 0.001).

Patients who underwent cholecystectomy surgery demonstrated lower BMI levels after 6 months; however, waist circumferences did not change significantly (p-values > 0.05). SBP and DBP increased after 6 months in the cholecystectomy group (p < 0.05), while FBS decreased (p < 0.05). HDL, TG, and HbA1c levels did not change significantly after the follow-up period in this group (p-values > 0.05).

Comparing the mean differences of these variables after 6 months between the cholecystectomy and control group demonstrated that the SBP and DBP changes are significantly different, with the patients in the cholecystectomy group demonstrating higher blood pressure at the 6-month follow-up (p < 0.05). Also, the mean difference in HDL levels was higher in the control group (p < 0.05). However, the mean differences in BMI, waist circumference, triglyceride, FBS, and HbA1c between the two study groups were not statistically significant after six months (Fig. 2).

Fig. 2.

Changes in SBP, DBP, FBS, and HDL levels among groups

The McNemar-Bowker test revealed a statistically significant difference in the distribution of grades over time (χ² = 10.895, df = 2, p < 0.05), suggesting a shift in the grades of fatty liver after the follow-up time. However, after the intervention, the cholecystectomy group showed no significant changes in their fatty liver grade (p-value = 0.817).

Metabolic syndrome prevalence among patients in the control group decreased from 32.7 to 18.4% after the 6-month follow-up; however, the decrease was not statistically significant according to McNemar’s test (p-value = 0.064). In contrast, the metabolic syndrome rate increased from 37.7 to 54.9% after the intervention in the cholecystectomy group, yet this change was not statistically significant (p-value = 0.065) (Table 2).

Table 2.

Changes in MASLD grade and metabolic syndrome over 6 months

Outcome	Cholecystectomy group (n = 51)		P-value	Control group (n = 49)		P-value
	Baseline	Follow-up		Baseline	Follow-up
MASLD grade, n (%):			0.817
Normal	24 (47.1)	23 (45.1)		20 (40.8)	33 (67.3)
Mild (Grade 1)	22 (43.1)	25 (49.0)		28 (57.1)	13 (26.5)
Moderate (Grade 2)	4 (7.8)	2 (3.9)		1 (2.0)	3 (6.1)
Severe (Grade 3)	1 (2.0)	1 (2.0)		0 (0)	0 (0)
Metabolic syndrome, n(%)	19 (37.7)	28 (54.9)	0.064	16 (32.7)	9 (18.4)	0.065

MASLD Metabolic dysfunction-Associated Steatotic Liver Disease

Logistic regression was conducted to evaluate the association with metabolic syndrome status after follow-up and a range of independent variables, including case-control status, gender, age, waist circumference, BMI, and triglyceride levels before the intervention. The overall model was statistically significant (χ² = 60.298, df = 15, p < 0.05), explaining 62.2% of the variance in metabolic syndrome status (Nagelkerke R² = 0.622) and correctly classifying 84.8% of cases. Significant predictors included case-control status, with cases having 9.63 times higher odds of metabolic syndrome compared to controls (OR = 9.63, 95% CI: 2.21–41.92, p < 0.05), and male sex, which was associated with a 6.93-fold increase in odds (OR = 6.93, 95% CI: 1.04–46.10, p < 0.05). Additionally, higher triglyceride levels were linked to significantly higher odds of developing metabolic syndrome (OR = 1.012, 95% CI: 1.002–1.023, p < 0.05). Other variables, including age, BMI, and HDL cholesterol, did not exhibit significant relations.

Discussion

This study examined how cholecystectomy affects metabolic and clinical parameters over a 6-month follow-up compared to a control group. Our results show that patients who underwent cholecystectomy had notable increases in systolic and diastolic blood pressure, while fasting blood sugar levels significantly decreased. Conversely, the control group significantly improved HDL cholesterol levels throughout the study. Additionally, although there were no significant differences in BMI, waist circumference, triglycerides, and HbA1c between the two groups, logistic regression analysis indicated that those in the cholecystectomy group had markedly higher odds of developing metabolic syndrome. These results suggest a possible link between cholecystectomy and negative metabolic changes, emphasizing the importance of closely monitoring patients who undergo this procedure. The improvements in FBS and HDL in the control group may reflect lifestyle modifications, spontaneous behavioral changes, or regression to the mean. Although no treatment was administered, participants may have adopted healthier behaviors during follow-up.

Pathophysiological perspective, the gallbladder is part of the liver-gallbladder-intestine axis, essential for maintaining systemic balance of triglycerides, fatty acids, bile acids (BAs), and cholesterol. BAs serve as signaling molecules that regulate enterohepatic and systemic metabolism and influence gallbladder motility. Changes in gallbladder movement can lead to gallstone disease (GSD) but can also offer protective effects in certain conditions through BA sequestration and composition changes. The gallbladder also controls insulin resistance (IR) sensitivity by regulating signaling factors from its mucosa, especially FGF15/19, which is stimulated by BAs via FXR activation. FGF15/19 modulates hepatic BA synthesis and maintains homeostasis of BAs, carbohydrates, and lipids in tissues like the liver and fat. Disruptions in FGF15/19, such as after cholecystectomy, may cause metabolic disorders including fatty liver, IR, T2D, and gastrointestinal problems. FGF19 also affects energy expenditure and insulin sensitivity; lower serum levels are associated with a higher risk of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Altered BA circulation impacts liver lipid metabolism through receptors like FXR and TGR5, contributing to MASLD development. Additionally, cholecystectomy increases BA recirculation, which can raise the risk of NAFLD, cirrhosis, and small bowel cancer, regardless of gallstones [16].

A reduction in body mass index (BMI) was observed in the cholecystectomy group, consistent with prior studies suggesting weight changes following this procedure [17]. However, the absence of significant changes in waist circumference challenges the assumption that cholecystectomy uniformly improves all anthropometric measures. This finding suggests that the observed BMI reduction may reflect overall weight loss rather than a specific decrease in abdominal fat, warranting further investigation into the mechanisms driving these variable effects.

The observed increases in both SBP and DBP in the cholecystectomy group stand in contrast to the expected cardiovascular benefits typically associated with weight loss. This apparent paradox may result from post-surgical physiological adaptations or alterations in bile acid metabolism, as suggested in previous research [18, 19]. Changes in lipid profiles and glycemic indices revealed a mixed outcome. While fasting blood sugar levels decreased significantly in both groups, the cholecystectomy group showed no significant changes in HDL cholesterol, triglycerides, or HbA1c levels, indicating a limited effect of the surgery on these metabolic markers within the study period. In contrast, the control group experienced increased HDL levels, likely reflecting the influence of non-surgical interventions such as lifestyle modifications or pharmacological treatments.

The improvement in MASLD grades observed in the control group, as demonstrated by the McNemar-Bowker test, highlights the potential efficacy of conservative management strategies in modifying disease progression. In contrast, the absence of significant improvement in the cholecystectomy group emphasizes the need to disentangle the direct effects of the surgery from other confounding variables.

a longitudinal cohort study by Huh et al. (2023) investigated the association between cholecystectomy and the chances of developing metabolic syndrome in a large Korean population [20]. They demonstrated that cholecystectomy is related to a 20% higher risk of developing metabolic syndrome, regardless of other risk factors. The most affected metabolic syndrome components were high triglycerides, high blood pressure, and low HDL cholesterol. Younger, metabolically healthier individuals were particularly vulnerable [20].

Trends in metabolic syndrome further illustrate the complexity of post-surgical outcomes. Although not statistically significant, the increased prevalence of metabolic syndrome in the cholecystectomy group raises concerns about potential risks linked to the surgery. In the control group, the non-significant decrease in metabolic syndrome prevalence points to the potential of conservative management to reduce these risks. However, its effectiveness remains limited within the study timeframe.

This study has certain limitations. The brief follow-up duration may have limited the observation of long-term metabolic and cardiovascular alterations. Although the sample size was adequate for preliminary comparisons, it affects the wider applicability of the results. Future research should address these issues by including larger groups and longer follow-up periods, as well as considering confounding factors like diet and medication use. A 6-month follow-up might not fully reveal chronic metabolic impacts; longer studies are needed to evaluate ongoing risks. Moreover, the observational design and lack of randomization may limit causal inferences.

Conclusion

Our findings highlight the potential metabolic implications of cholecystectomy. While the procedure was associated with a reduction in BMI and improved fasting blood sugar levels, it also significantly increased SBP and DBP over a follow-up period of 6 months. Additionally, logistic regression analysis revealed that patients undergoing cholecystectomy had considerably higher odds of developing metabolic syndrome compared to controls. These findings emphasize the need for careful monitoring of metabolic health in patients after cholecystectomy and suggest that the procedure may have unintended effects on metabolic parameters. Clinicians should monitor metabolic parameters, including blood pressure and lipid profiles, in patients undergoing cholecystectomy—particularly those at risk for metabolic syndrome.

Authors’ contributions

All authors contributed to the study’s conception and design. S.N., J.Zb, R.Bm, and H.B. collected the data. S.N. and H.A. conducted the analysis, and S.N. and M.Mt. wrote the manuscript. All authors read and approved the final manuscript.

Funding

This study was financially supported by the Vice-Chancellor for Research and Technology, Alborz University of Medical Sciences, Karaj, Iran, under Grant number [ABZUMS 4829].

Data availability

All data are available by reasonable requests via corresponding author.

Declarations

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.