Risk Factors for Cholecystectomy After Laparoscopic Roux-En-Y Gastric Bypass

We conducted a retrospective case-control study at the Medical Center (MC) Slotervaart (Amsterdam, the Netherlands). The local medical ethics committee confirmed that the Dutch Medical Research Involving Human Subjects Act did not apply to the current study and that an official approval was not required. All patients who underwent bariatric surgery in our institution have signed an informed consent form stating that their anonymized data can be used for scientific research. The electronic medical record system was searched to identify all patients (18–65 years) who underwent primary LRYGB between January 2013 and December 2015. Patients who underwent cholecystectomy because of postoperative biliary symptoms were defined as cases. Postoperative biliary symptoms consisted of biliary colic, cholecystitis, choledocholithiasis, cholangitis, or biliary pancreatitis (see “Study outcome” for the extensive definition of postoperative biliary symptoms). Only cases who developed biliary symptoms within 2 years after LYRGB were included, irrespective of the timing of the cholecystectomy. For each case, two patients who underwent LRYGB after that specific case and who remained free of biliary symptoms and cholecystectomy were consecutively selected as controls. The minimum period of follow-up was 24 months for all control patients. Exclusion criteria were prior or concomitant gallbladder surgery, prior bariatric surgery, another type of bariatric surgery than LRYGB, or the development of symptomatic gallstones more than 2 years after LRYGB. In our institute, an ultrasound is not regularly performed pre- or postoperatively and a concomitant cholecystectomy is only performed in case of symptomatic gallstone disease prior to bariatric surgery.

We collected preoperative data on demographics (age, gender, ethnicity, body mass index (BMI), physical activity; only for women: fertility, offspring, use of birth control pills), presence of comorbidity (hypertension, type 2 diabetes (T2D), and pain syndrome), and the preoperative use of medication. In addition, information on weight loss was gathered 12 months postoperative (window 6–18 months). In our outpatient clinic, weight loss is assessed during planned visits regularly at 6, 12, and 24 months after LRYGB. Percent total weight loss was calculated by the following formula: %TWL = [(Initial Weight) – (Postoperative Weight)]/Initial Weight × 100. Physical activity was determined according to the Dutch activity guide line for adults [18]. Hypertension was defined as known hypertension, use of antihypertensive medication, a systolic blood pressure ≥ 140 mm/Hg, or a diastolic blood pressure ≥ 90 mm/Hg; T2D as known T2D, use of antidiabetics, or HbA1c ≥ 53 mmol/mol at preoperative blood testing; fertile as age ≤ 50 years or use of birth control pills; and preoperative pain syndrome as patients with a medical history of irritable bowel syndrome (IBS), fibromyalgia, or complex regional pain syndrome (CRPS). The individual potency of each statin was determined according to the meta-analysis by Law et al. [19, 20]. Four subgroups were defined for statin use: no statin use, low intensity (less than 1.6 times reduction in low-density lipoprotein cholesterol (LDL-C)), moderate intensity (1.6 times reduction, e.g., most widely prescribed dose of simvastatin 40 mg daily), or high intensity (more than 1.6 times reduction in LDL-C).

Primary outcome was the need for cholecystectomy because of postoperative biliary symptoms. Postoperative biliary symptoms consisted of biliary colic, cholecystitis, choledocholithiasis, cholangitis, or biliary pancreatitis. Biliary colic was defined as upper abdominal pain lasting at least 30 min with gallstones visible on abdominal imaging, according to the Rome criteria. Acute cholecystitis was defined according to the diagnostic criteria of the Tokyo Guidelines (TG18/TG13); there must be at least one local sign of inflammation: (1) Murphy’s sign and (2) right upper quadrant mass/pain/tenderness, and at least one systemic sign of inflammation: (1) fever, (2) elevated C-reactive protein; (3) and elevated white blood cell count [21]. Choledocholithiasis was defined as the presence of stones in the intra- or extrahepatic bile ducts. Cholangitis was also defined according to the diagnostic criteria of the Tokyo Guidelines (TG18/TG13): signs of systematic inflammation, cholestasis, and evidence on imaging must be present [22]. Furthermore, acute biliary pancreatitis was diagnosed when the following features were present: (1) upper abdominal pain, (2) increased serum lipase or amylase levels, and (3) gallstones and/or sludge or a dilated common bile duct on imaging or elevated alanine aminotransferase (ALT) levels. The studied risk factors are shown in Table 1.

The same procedure was performed in two subsets of the study population. The first subset consisted of cases who developed biliary symptoms within 9 months and controls since we hypothesized that we would observe a stronger association between potential risk factors and the occurrence of cholecystectomy in patients who developed biliary symptoms shortly after bariatric surgery. The second subset of patients consisted of female cases and controls in which we studied female-associated factors (fertility, offspring, use of birth control pills).

To test for a dose-effect relationship between the intensity of preoperative statin and cholecystectomy, the categorical variable “preoperative use of statins (no, low, moderate, high)” was entered as a continuous variable in our logistic regression models.

Kaplan-Meier curves were constructed to explore the “time to onset of biliary symptoms” and “time to cholecystectomy,” separately. Time to onset of biliary symptoms or cholecystectomy was defined as the period from the date of bariatric surgery to the onset of biliary symptoms or date of cholecystectomy.

In the uni- and multivariable analyses we replaced/recoded missing values by using the mean of the values of the case or control group for numerical variables and “no” for categorical variables. In case the specific dates of the development of biliary symptoms or cholecystectomy were missing, they were estimated based on the visits of the outpatient clinic.

Between January 2013 and December 2015, 1780 primary LRYGBs were performed at the MC Slotervaart. We identified 233 (13.1%) cases who underwent a cholecystectomy because of biliary symptoms within 2 years after LRYGB. These cases were compared with 466 controls. Demographic and clinical characteristics of the study population are summarized in Table 1. The mean age (± standard deviation (SD)) of cases was 39.8 ± 10.6 and the mean age of controls was 43.8 ± 10.5 years. In both groups, most patients were female (91.8% versus 80.7%) and the majority were Caucasian (88.8% versus 82.4%). Preoperative BMI (± SD) was similar (43.4 ± 5.1 and 43.4 ± 5.0 kg/m²).

During the first 24 postoperative months, cases developed biliary symptoms after a median (IQR) follow-up of 9 (5–14) months, and cholecystectomy was performed after a median follow-up of 12 (8–17) months (Figs. 1 and 2). The most common indication for cholecystectomy was biliary colic (67.4%). Other indications were suspicion on biliary colic according to the treating surgeon, but not fitting the Rome criteria (10.3%), cholecystitis (7.7%), biliary pancreatitis (1.7%), choledocholithiasis (0.9%), and for 12% of the patients the indication was not specified.

The results of the univariate logistic regression analysis of all patients are shown in Table 1. Female gender (odds ratio (OR) 95% confidence interval (95% CI) 2.70 (1.60–4.55)), Caucasian ethnicity (OR (95% CI) 1.70 (1.06–2.73)), higher %TWL (OR (95% CI) 1.08 (1.06–1.11)), and the existence of a preoperative pain syndrome (OR (95%CI) 3.26 (1.76–6.06)) were significantly associated with an increased risk for subsequent cholecystectomy. Older age (OR (95% CI) 0.97 (0.95–0.98)), hypertension (OR (95% CI) 0.59 (0.43–0.82)), T2D (OR (95% CI) 0.51 (0.33–0.79)), and the use of statins preoperatively (OR (95% CI) 0.35 (0.21–0.60)) were significantly associated with a reduced risk. When further exploring the intensity of statins, we observed a dose-effect relationship (overall p value = 0.003). As compared to no preoperative statin use, the use of low-intensity statin was not statistically significantly associated (OR (95% CI) 0.58 (0.26–1.32)), while moderate-intensity statin (OR (95% CI) 0.38 (0.18–0.81)) or high-intensity statin (OR (95%CI) 0.07 (0.01–0.52)) was associated with cholecystectomy. Testing for a trend confirmed the dose-effect relationship (p < 0.001). Preoperative physical activity and BMI were not associated with the risk for cholecystectomy.

The results of the multivariable logistic regression analysis in all patients are shown in Table 2. In the final model, four factors were associated with cholecystectomy after LRYGB: female gender (OR (95% CI) 1.83 (1.06–3.17)), Caucasian ethnicity (OR (95%) 1.82 (1.10–3.02)), %TWL at 12 months (OR (95%CI) 1.06 (1.04–1.09)), and pain syndrome (OR (95%CI) 2.72 (1.43–5.18)). Older age (OR (95%CI) 0.98 (0.96–0.99)) was found to be a protective factor, while preoperative statin use (OR (95% CI) 0.56 (0.31–1.00)) almost reached statistical significance.

The dose-effect relationship of preoperative statin use and cholecystectomy was also established in the multivariable model, although not significant (overall p value = 0.125). (Supplementary Table 1). Testing for a trend in this model confirmed the dose-effect (p = 0.013).

Table 3 summarizes the results of the multivariable analysis of cases who developed biliary symptoms within 9 months (median) after LRYGB. In this subgroup, preoperative use of statins was significantly associated (OR (95% CI) 0.27 (0.09–0.78)), besides age, gender, %TWL, and the existence of pain syndrome.

In the female population, female-associated factors (fertility, offspring, and the use of birth control pills) were not associated with cholecystectomy in the multivariable analysis (Supplementary Table 2). On the other hand, preoperative use of statins was associated, along with age, Caucasian ethnicity, %TWL, and pain syndrome.