Cholelithiasis after Weight Loss Surgery: Challenge and Prophylaxis

Cholelithiasis after Weight Loss Surgery: Challenge and Prophylaxis

Ahmed Talha MD, MRCS;1 Ayman Farouk, MD,1 Ihab Hasouna, MD.2

1) Department of Surgery, Medical Research Institute, Alexandria University, Egypt.

2) Department of Internal Medicine, Faculty of Medicine, Alexandria

University, Egypt.

Background: Rapid loss of weight after bariatric surgery is associated with a high incidence of gallstone formation. This study was carried out to detect the efficacy of six months regimen of prophylactic Ursodeoxycholic acid in the prevention of gallstones and to identify the predictive factors for gallstone formation after weight loss surgery.

Methods:  A  randomized  controlled  trial  was  carried  out  involving  108  patients  with a preoperative diagnosis of morbid obesity were subjected to either laparoscopic sleeve gastrectomy (LSG) or greater curve plication (LGCP) with follow-up for a minimum one year; they were divided into two groups; (group A; receiving Ursodeoxycholic acid) and (group B; receiving placebo). Data were collected about: Patient clinical history, baseline characteristics and postoperative follow-up.

Results: The demographic parameters were comparable in the two groups. The incidence of cholelithiasis after surgery was 14.3% (13 cases). The mean %EWL was significantly higher in those who develop gallstones than others (P= 0.045). Also, there was a significant increased cholelithiasis post-LSG than LGCP (P=0.036). There was a significant decrease in the incidence of gallstone formation from 22% in placebo to 6.5% in treated group with Ursodeoxycholic acid (P = 0.041).

Conclusions: The percentage of excess weight loss was the only predictive postoperative factor for gallstone formation. A six months use of Ursodeoxycholic acid is an effective prophylaxis for gallstone formation after weight loss procedures although a larger study is required to reach a definitive conclusion.

Key Words: Obesity; gallstone; bariatric surgery; ursodeoxycholic acid.

Introduction:

Worldwide prevalence of obesity is increasing, and the incidence of obesity in the US has increased from 22.9% between 1988 and 1994, to 34% in 2006.1–3

Obesity is associated with increased risk for hypertension, diabetes, pulmonary disease, hyperlipidemia, cardiomyopathy, malignancy, arthritis, infertility, sleep apnea, gallstone formation and psychosocial impairments. Given the fact that with weight loss improves many of these comorbidities,4  much effort has gone into the development of effective

treatment modalities focused on sustained weight loss. Dietary regimen, behavioral modification, and exercise have been largely unsuccessful in achieving and maintaining long-term results in morbidly obese patients. Therefore, more aggressive treatment is typically required for obese subjects at risk for medical complications of obesity. Surgery has become an attractive alternative because it represents a long-term solution.5

Bariatric surgery is the most effective modality for long-term weight loss and for resolving the associated comorbidities.6 The

primary mechanisms through which bariatric surgery achieves its outcomes are believed to be the mechanical restriction of food intake, reduction   in   the   absorption   of   ingested foods, or a combination of both.7 However, controversies  exist  regarding  the  ideal weight loss metabolic procedure that allowed continuous search for new techniques.

Many operative modalities have been devised, among those most commonly performed nowadays; adjustable gastric banding   (AGB);   Roux-en-Y   gastric bypass (RYGB); biliopancreatic diversion with duodenal switch (BPD); and sleeve gastrectomy (SG) and greater curve plication (GCP) preferably through minimally invasive approach.5–8

Between  35–38%  of  patients  with morbid obesity develop gallstones as they lose weight after bariatric surgery.5,9–11 A routine synchronous cholecystectomy during bariatric surgery is recommended by some centers.9,12 Therefore, a preventive therapy for  gallstone  formation  is  recommended in  several  studies.  Ursodeoxycholic  acid (500 mg/d) is highly effective in preventing gallstone formation in patients undergoing dietary-induced weight reduction.13

This  study  was  carried  out  to  detect the efficacy of six months regimen of prophylactic Ursodeoxycholic acid in the prevention of gallstones and to identify the predictive factors for gallstone formation after weight loss surgery.

Study design:

This was randomized controled trial study, where all patients from age 18 to 60 years, with a preoperative diagnosis of morbid obesity based on the guidelines issued by International Federation for Surgery of Obesity (IFSO)14 underwent either laparoscopic sleeve gastrectomy (LSG) or laparoscopic greater curve plication (LGCP) at the Department of Surgery, Medical Research Institute Hospital, Alexandria University and continued their follow-up for a minimum of one year. 108 patients were divided into two groups; (group A; receiving Ursodeoxycholic acid; 500 mg/d for six months in the immediate postoperative

period) and (group B; receiving placebo), were offered the opportunity to participate in this trial. Informed consent was obtained from all participants and approval was obtained from the ethics committee of our institutions.

The      exclusion      criteria      included the following: American Society of Anesthesiologists (ASA) class IV and V, patients with contraindication for laparoscopy, prior cholecystectomy, presence of gallstones, use of other investigational drugs, pregnancy or refusal.

Randomization method:

Eligible patients were randomized into two groups; (group A; receiving Ursodeoxycholic acid)   and   (group   B;   receiving   placebo) using sealed opaque envelopes containing computer-generated random numbers. The randomization was performed one week before surgery during the preoperative assessment. Data were collected about: Patient clinical    history,    baseline    characteristics and postoperative follow-up evaluating the percentage of excess weight loss (% EWL) and gallstone formation.

Study Protocol:

All   patients   underwent   the   following basic preoperative investigations, including the  following:  (1)  blood  tests:  complete blood count, coagulation profile, renal and liver function tests and hormonal profile including TSH and cortisone levels; (2) radiologic imaging: chest radiograph and ultrasonography of abdomen and pelvis; (3) electrocardiogram; (4) echocardiogram; and (5) respiratory function tests.

Eligible  patients  had  undergone  either LSG or LGCP. Ambulation was encouraged, and chest physiotherapy was started in the immediate postoperative period. An upper gastrointestinal contrast study using water- soluble  contrast  (Gastrograffin)  was  done on the first postoperative day. Clear liquids were started on confirmation of staple-line integrity. The patient was discharged once oral intake of 1,500–2,000 ml/24 h was established. Prokinetics, and proton pump inhibitors were continued for ten days. All

medications  were  given  orally  in  crushed or liquid form. The drain was removed on the second postoperative day. A liquid diet was given for two weeks, a pureed/soft diet for six weeks, and normal diet thereafter. Dietary counseling was provided, and a normal consistency, low-calorie, high protein diet is advised at two months from surgery. Patients were followed up at 1, 3, 6, and

12 postoperative months and then annually. Abdominal Ultrasonography investigation of the gallbladder was performed in all patients at six and twelve postoperative months.

Statistical analysis:

Statistical     analysis     was     performed using the Statistical Package for the Social Sciences (SPSS) version 20 software (SPSS, Inc., Chicago, IL, USA). Significance was set  at  a  P-value  <0.05.  Qualitative  data were described using number and percent. Quantitative   data   were   described   using mean and standard deviation for normally distributed data. Comparison between different groups regarding categorical variables was tested using Chi-square test while for two groups comparison t-test was used for parametric data.

Results:

From March 2010 to October 2013, 134 patients were submitted to bariatric surgery and 108 patients were eligible. 91 patients completed follow-up gallbladder sonography and   were   randomly   classified  into   two groups; 45 to placebo and 46 to 500 mg/d Ursodeoxycholic acid. Twenty six patients refused  to  participate  in  the  study  or  did not meet the inclusion criteria. (Figure I) 66 patients  (72.5%)  patients  underwent  LSG and 25 patients (27.5%) underwent LGCP Table (1).

There were 36 men (39.6%) and 55 women (60.4%). There were no significant differences with respect to age, sex, or preoperative BMI between  those  who  developed  gallstones or not. Table (1) However, the group who formed gallstones have significantly higher mean % EWL in the first postoperative year (P = 0.045). Table (1) Regarding the type of

operation there was a significant difference between those who developed gallstones or not (P = 0.036) as in LSG 10.9% versus 3.3% in LGCP; patients showed a noticeably more rapid weight loss, with significant incident development of gallstone formation Table (1).

Ultrasonography investigation of the gallbladder was performed in all patients. During follow up, 13 of them (14.3%) developed gallstones postoperatively in a range of 6 - 12 months and 78 (85.7%) did not develop gallstones Table (1). Of those developed gallstones 5 cases (38.5%) were symptomatizing and the other 8 cases (61.5%) discovered by routine ultrasonography during follow up. So the incidence of symptomatizing cholelithiasis after surgery in this series was

5.5 % Table (2).

There   were   no   significant  differences with respect to age, sex, preoperative BMI,

%EWL or the type of surgery between those receiving medication and placebo in any of the patient groups.Table (3).

No patient was withdrawn from the study because of a serious adverse drug reaction. No severe side effects from medication were observed. Mild and moderate side effects such as nausea and constipation were equivalent in both groups

Gallstone formation was significantly less frequent (P = 0.041) with Ursodeoxycholic acid than with placebo at 12 months: 6.5% versus 22%, respectively. Table (2). 5 cholecystectomies  were  performed  (mean

14.9 ± 4.3) months after surgery in patients with  symptomatic  cholelithiasis:  1  patient in the Ursodeoxycholic acid group and 4 patients in the placebo group, 2% versus 8.9

%, respectively. (P =0.11) Table (2).

Discussion:

Obesity and rapid weight loss are well known risk factors for cholelithiasis as approximately one third of patients may develop gallstones after bariatric surgery. Furthermore,  10%  to  15%  of  all  patients will require cholecystectomy for complaints related to gallstones.9–13 Some centers routinely       perform       cholecystectomies with    bariatric    procedures    to    prevent

complications of cholelithiasis, prophylactic cholecystectomy is not preferred as the operation may increase the overall operative time and length of hospital stay. In addition, a cholecystectomy after losing weight may be technically easier than during maximum obesity.11–13 Also, Angrisani et al15 reported that laparoscopic cholecystectomy in obese patients was technically more difficult, and required  a  significantly  longer  operating time. In the present study, we excluded patients who had previous cholecystectomy or requiring concomitant cholecystectomy to avoid the debate about this difficulty and the prolonged operative time.

The risk of developing gallstones in obese patients is increased that could be due to a higher cholesterol saturation of gallbladder bile, diminished gallbladder motility with subsequent stasis and increased levels of gallbladder  mucin  promoting  precipitation of cholesterol crystals16 During rapid weight loss produced by weight loss surgery with very low caloric diet, the incidence of gallstone formation increased,17 but the underlying mechanism  is  not  fully  understood,  and some pathogenic mechanisms have been proposed including: increased cholesterol saturation index of bile as a result of cholesterol mobilization from adipose tissues and excretion in bile, increased gallbladder secretion of mucin and calcium, and increased presence of prostaglandins and arachidonic acid.16,18–21

The present study revealed five out of thirteen cases who developed gallstones were symptomatic with the overall symptomatic gallstone  incidence  after  surgery  5.5  % which is lower than the findings as Tucker et al.22 reported incidence of 6%, Portenier et al23  8.1%, Papasavas et al24  6.9%, Villegas et al25 7.3% while Abo-Ryia et al26 reported

8%. This may be because we had two groups one was taking Ursodeoxycholic acid with a lower incidence of gallstone formation, thus, decreasing the overall number of gallstone incidence.

Weight   loss   after   antiobesity   surgery is  maximal  during  the  first  postoperative year,  decreasing  over  time.  The  peak  of

symptomatic gallstone disease at 2 years after surgery.27,28

The higher occurrence of cholelithiasis following   weight   reduction   surgery   was in the phase of greater weight loss that encouraged surgeons to use Ursodeoxycholic acid as prophylaxis in the first 6 postoperative months.9,29

This drug is a bile acid that prevents biliary lithiasis by decreasing cholesterol and mucin concentration, increasing bile acid concentration, decreasing bile saturation, and enhancing gallbladder emptying.9,29,30

Two controlled trials31,32 have shown the

effectivenessofsixmonthsofUrsodeoxycholic acid  treatment  in  lowering  the  incidence of gallstone formation. Cholelithiasis was found  in  22-32%  of  controls  versus  in

2- 3% of treated patients at 6-12 months. Similarly, we found a significant decrease in the incidence of cholelithiasis after bariatric surgery from 22 % in placebo versus 6.5% in patients receiving Ursodeoxycholic acid for six months in the immediate postoperative period.

Age, obesity, female gender and parity are known risk factors for gallstones formation of  are  known,  in  the  general  population which is most likely due to the female sex hormones.33 We tried to identify the risk factors for cholelithiasis after weight loss surgery by comparing the patients who developed  gallstones  during  rapid  weight loss with those who did not. In our study, Age,  gender  and  mean  preoperative  BMI were  not  significant between  both  groups so, not considered as predictors for gallstone formation which is similar to that reported by others.26,27,34 However the mean percent of excess weight loss in the first postoperative year was significantly higher in the group that formed gallstone which is in accordance to the findings of Schmidt et al.35  Ming Li et al.34 Wudel et al.30 Yang et al.28 and Abo- Ryia et al26  In another study, only weight loss of more than 25% was associated with an increased risk of gallstone disease after antiobesity surgery.35

It is accepted that gallstone formation after bariatric surgery is related to weight loss.9

Figure (1): Trial flow sheet showing progress through the phases of the trial.

Table (1): Predictors of cholelithiasis in either group.

BMI; body mass index, SD; standard deviation, %EWL; percentage of excess weight loss

Shiffman et al36 showed that bile cholesterol normalized when the weight stabilized 24 months after gastric bypass. Miller et al37 demonstrate in their prospective study on more than 1000 restrictive procedures that a weight stabilization phase is reached not before 24 months and in another study, a significantly reduced gallstone formation rate of 8% after 24 months compared with 30%

in the placebo group.9 According to Shiffman et al, at 6 months, gallstones had developed in 36% and gallbladder sludge in additional

13% of patients.36  We reported 13 patients

(14.3%)  out  of  91  had  gallstones  at  one year and this short follow-up period could be an explanation of smaller percentage of gallstone formation in our patients.

The bariatric procedure used to achieve

Table 2: Distribution of patients free of gallstone at the time of surgery.

Table (3): Demographic data of both groups

weight  loss  could  influence  the  risk  of

developing symptomatic gallstone disease.37

Patients who had undergone gastric bypass were at a greater risk than those who had undergone a restrictive procedure.37 Previous studies   have   demonstrated   similar   rates of   cholecystectomy   after   gastric   bypass and gastric banding (8.1% and 6.8%, respectively)38–40 In our study, we found a significant difference between both groups as the incidence of gallstone formation was higher in LSG than in LGCP while, Ming Li et al.34 reported insignificant difference regarding the type of operation; Gastric Bypass, Gastric Banding, and Sleeve Gastrectomy.

Conclusion:

The  percentage  of  excess  weight  loss was the only predictive postoperative factor for  gallstone  formation. A six  months  use of Ursodeoxycholic acid is an effective prophylaxis for gallstone formation after weight loss procedures although a larger study

is required to reach a definitive conclusion.

Conflict of Interest: There is no conflict of interest or financial ties to include.

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