Is biliary pain exclusively related to gallbladder stones? A controlled prospective study

Patients

Seventy-five GPs in Rotterdam, in The Netherlands, participated in the study. All consecutive patients with upper abdominal pain aged 18 years and older who consulted a participating GP between January 1996 and June 1998, and in whom the GP suspected symptomatic gallbladder stones, were eligible for the study. After obtaining written informed consent, patients were referred to a GP diagnostic service or, in the case of high suspicion of symptomatic gallbladder stones, to the radiology department of one of nine local hospitals for an ultrasound examination of the upper abdomen. Subsequent referral to a surgeon for cholecystectomy was decided on by the GP. All patients with gallbladder stones were preoperatively examined by a surgeon, who indicated further diagnostic investigation, i.e. liver function tests in all patients, and endoscopic examination or barium enema examination whenever applicable. Patients with acute cholecystitis or cholangitis, and patients with bile duct stones (based on the presence of jaundice and the results of liver function tests), were excluded. The surgeon gave the final indication for cholecystectomy. The research ethics committee of the University Hospital Rotterdam approved the study protocol.

Assessments

At inclusion, just before ultrasound examination, the patients were given a structured self-administered questionnaire to complete about the presence or absence of 11 symptoms during the previous month. The questionnaire had been used and validated in a previous randomised controlled trial.8 The symptoms were: biliary pain (defined as: acute, steady, severe or very severe, and upper abdominal pain lasting 1 hour or more),3 upper abdominal pain, upper abdominal pain after fatty food intake, vomiting, nausea, feeling of distension (bloating), belching, acid regurgitation, constipation, diarrhoea, and flatulence. Patients were asked to mark their health status on a visual analogue scale from 0–100. The radiologist was blinded to the answers in the questionnaire.

One year after inclusion, all patients were sent a copy of the same questionnaire by post. Non-responders received a reminder by post and a second reminder by telephone. A structured questionnaire was posted to participating GPs. In this questionnaire the GP was asked about other diagnoses for the initial symptoms of the patients, whether patients had consulted the GP during the 1-year follow-up with symptoms similar to those at inclusion, and whether bile duct stones were detected after cholecystectomy.

Ultrasound examinations were performed by radiologists, senior radiological residents or experienced radiology technicians. All patients were examined in a fasting state with a 3.5 MHz scanner according to a standardised protocol.

Statistical analysis

Likelihood ratios with 95% confidence intervals (CIs) were calculated to estimate the value of gastrointestinal symptoms for discrimination between patients with and without gallbladder stones.

Symptom relief rates after 1-year follow-up were calculated for each symptom. The relief rate was defined as the number of patients in which the symptom had disappeared after 1 year divided by the number of patients exhibiting the symptom at inclusion. Differences in proportions were tested with a χ² test statistic. Differences between means for different groups were tested using a one-way analysis of variance (ANOVA) or a Kruskall–Wallis test where appropriate.

To evaluate the relationship between patient characteristics and relief of upper abdominal pain, a multivariable logistic regression analysis was performed, with the relief rate for upper abdominal pain as the dependent variable. Patient characteristics, group status (without gallbladder stones, with gallbladder stones but not operated on, or with gallbladder stones and operated on), and level of suspicion for the presence of gallbladder stones were entered as ind-ependent variables. For each of the independent variables, adjusted odds ratios (ORs) with asymptomatic 95% CIs were calculated from the regression coefficients. SPSS software was used to perform the analyses.

Symptoms at baseline and relief rates after 1-year follow-up

Tables 4 and 5 give the frequency of symptoms at inclusion and the symptom relief rates after 1 year for the three groups.

At inclusion, patients who were operated on reported biliary pain significantly more often than patients without gallstones and patients with gallstones who were not operated on (65% versus 45% and 46%, respectively, P = 0.017) (Table 4). After 1-year follow-up, however, there was no significant difference in the relief rate of biliary pain between the three patient groups (87%, 83% and 63%, respectively, P = 0.24). Also, upper abdominal pain and upper abdominal pain after fatty food intake were reported more often at inclusion by operated patients, but after 1 year the relief rates for these symptoms were comparable between the three groups (Table 4 and 5).

Of the dyspeptic symptoms, only nausea was reported more often in patients who had been operated on compared with patients without gallstones and patients with gallstones who had not been operated on (81% versus 65% and 73%, respectively, P = 0.05). Of the patients who were operated on, 84% reported three or more dyspeptic symptoms at inclusion; this was comparable to the rates in the other two groups (69% and 77%, P = 0.06) (Table 4).

GP questionnaire

Eleven (15%) GPs did not respond to the follow-up questionnaire. In total, 24 (33%) patients who had been operated on visited their GP with symptoms similar to those before cholecystectomy. The presence of common bile duct stones was not evaluated in any of these patients. In two of these patients a duodenal ulcer was diagnosed, and in one the GP diagnosed functional gastritis.

In the patients without gallstones, 69 (63%) consultations for symptoms similar to those at inclusion resulted in a further diagnosis in 35 patients. Gastritis was diagnosed in 17 patients (this was functional in 12, due to alcohol abuse in three, Helicobacter pylori in one, and viral in one), irritable bowel syndrome in seven patients, and gastro-oesophageal reflux in five. In three patients, other diagnoses were made and in three further patients, the GP reconsidered the diagnosis of cholelithiasis because of the presence of sludge in the gallbladder on ultrasound scanning.

Summary of main findings

We have described 233 patients in whom their GPs suspected gallstone disease. In total, 65% of the patients with gallstones who were operated on reported biliary pain at inclusion, as did 46% of the patients with gallstones who were not operated on and 45% of patients who did not have gallstones. Relief rates for biliary pain after 1 year were comparable in the three patient groups. These findings indicate that gallstones do not exclusively cause severe, steady, upper abdominal pain, nor can symptom relief exclusively be attributed to gallstone removal.

The burden of dyspeptic symptoms in all patients was high; 77% of all patients reported three or more dyspeptic symptoms. Of the patients who were operated on, 84% reported three or more dyspeptic symptoms. None of the gastrointestinal symptoms allowed clinically relevant discrimination between patients with and without gallbladder stones. Likelihood ratios for the presence of gallbladder stones were all close to 1. In contrast, GPs were able to select patients at risk from gallstones for ultrasound examination. A high suspicion for symptomatic gallbladder stones, however, did not predict relief of upper abdominal pain after cholecystectomy.

Comparison with other studies

A clinical suspicion of gallstones arises when a patient presents with so-called ‘biliary pain’. In all definitions of biliary pain the sudden occurrence and severity of the pain were important characteristics. Our definition of biliary pain has underlined these characteristics.

In a systematic literature review biliary pain was consistently related to the presence of gallbladder stones4; however, only 20% of patients with suspected gallbladder stone disease presented with biliary pain. In this study, 35% of the patients who went on to have surgery did not initially report biliary pain according to a widely accepted definition. However, 91% of the patients with gallstones in this study who were operated on did report upper abdominal pain. These findings suggest that either the definition of biliary pain should be adjusted or that the indication for surgery is not always adequate.

Strength and limitations of the study

Only a few studies have used a control group in the evaluation of postoperative symptoms in gallstone disease.9^-11 In these control groups the frequency of symptoms was assessed at one point in time, either retrospectively or in cross section. Subjects in these control groups were either patients suffering from other non-related diseases or healthy volunteers. To our knowledge, no study has prospectively followed a control group when evaluating gastrointestinal symptoms before and after cholecystectomy.

In the present study, patients with and without gallbladder stones consulted their GP with symptoms that caused the GP to suspect symptomatic gallbladder stones. Both groups were followed for a comparable period of time, yet it can be successfully argued that the patients without gallbladder stones are not comparable with patients after cholecystectomy. In addition, the third group of patients with gallbladder stones who had not been operated on was not a perfect control group; in 50% of these patients the reason not to operate was ‘doubt about the relation between symptoms and gallbladder stones’. Although the three patient groups differed significantly, only the presence of comorbidity could be related to a higher relief of upper abdominal pain. A total of 36% of the patients had concomitant cardiac disease, gastric disease (i.e. reflux oesophagitis, gastritis), or other gastrointestinal disease (i.e. irritable bowel syndrome): all these diseases can cause upper abdominal pain. Exclusion of these diseases as a cause of upper abdominal pain before diagnosing symptomatic gallbladder stones may optimise the indication for cholecystectomy and thereby explain the better outcome in patients who had been operated on.

The best control group would have been a group of patients with gallstones randomly selected not to have cholecystectomy; such a study was recently performed.12 In patients with uncomplicated symptomatic gallbladder stone disease, cholecystectomy was compared with ‘watchful waiting’. After a median follow-up of 67 months, gallstone-related complications were less in the watchful-waiting arm compared with postoperative complications in the cholecystectomy arm. In total, 17% of patients in the watchful-waiting arm were referred again because of upper abdominal pain. Relief of symptoms, however, was not systematically assessed in this trial. The authors concluded that expectant management carries a low risk of complications and should be considered for all patients with uncomplicated gallbladder stone disease. Our findings that relief of biliary pain and upper abdominal pain were comparable in the three patient groups suggest that relief of symptoms in patients who have been operated on cannot exclusively be attributed to cholecystectomy. This supports the idea that having the gallbladder removed in the case of upper abdominal pain coinciding with the presence of gallbladder stones may rest on common practice rather than on evidence-based medicine.

Implications for future research and policy

Well designed randomised controlled trials are urgently needed to clarify the indication for elective cholecystectomy. GPs should be aware that, even in the presence of gallbladder stones, biliary pain cannot be attributed exclusively to gallbladder stone disease. Before a diagnosis of symptomatic gallbladder stones is made, other pathology common in general practice; for example, reflux oesophagitis and irritable bowel syndrome, should be excluded.