Gallstones are common disease affecting 5–22% of the adult Western population and 10%–15% of the Chinese population.1, 2, 3 However, only 13–22% of the patients with gallstones presented symptomatically during their lifetime.4, 5 Cholecystectomy is a common and well established procedure for treatment of complicated and uncomplicated gallstone disease. More than 800,000 cholecystectomies are performed annually in the United States1, 6Since 1990s laparoscopic cholecystectomy was more and more performed instead of the open procedure, the cholecystectomy rate has been increased significantly probably due to lower threshold for tolerance of gallstone associated symptoms from both patients and doctors sides.7, 8
The common symptoms related to gallstones are upper abdominal pain (UAP) and some other atypical discomfort in upper abdominal region. Complete relief of UAP following cholecystectomy was presented in 66–91% of the patients, while some patients complained unrelieved or persistent UAP after surgery.9, 10, 11, 12, 13, 14 Therefore, it is important to investigate the causes of persistent UAP following cholecystectomy. Several previous studies have identified certain preoperative factors predicting UAP relief following cholecystectomy, e.g. UAP frequency, duration, nocturnal pattern, and some concomitant morbidity, etc.15, 16, 17, 18 Therefore, it is recommended that determining preoperatively whether the gallstones are the cause of upper abdominal symptoms or merely an incidental finding are critical for avoiding unnecessary cholecystectomy and persistent symptoms after surgery.9, 10
However, what exactly constitutes biliary-like abdominal pain and associated symptoms still remains unclear. Therefore, it is still difficult to completely avoid unnecessary cholecystectomy.10 Although some clinical features were found to be related to postoperative UAP relief, the possible causes of postoperative UAP following cholecystectomy remains unclarified, which were thought to be more complicated. The present study aims at investigating the risk factors for persistent UAP using a face-to-face and telephone call-based questionnaire after cholecystectomy.
Patients and methods
We enrolled all the 2567 consecutive patients undergoing single cholecystectomy from January 2013 to December 2014. 198 patients diagnosed as pure gallbladder polypus or gallbladder carcinoma were excluded. Among the 2369 patients with uncomplicated gallstones, 345 patients with no obvious preoperative symptoms were excluded from the study, and 2024 patients with preoperative UAP were included. During follow up, 310 patients complained abdominal symptoms and diagnosed with biliary stones, stricture or fistula, or some other abdominal conditions, and then underwent endoscopic, laparoscopic or open biliary, gastrointestinal tracts, and/or liver surgeries after cholecystectomy, which were then excluded from the study. Finally, 1714 patients with completion of the questionnaire were all included into the present study (Fig. 1).
The indication of cholecystectomy was definite diagnosis of gallstones, upper biliary-like abdominal pain, and/or some atypical upper abdominal symptoms, which included dyspepsia, nausea, vomit, flatulence, bloating, heartburn, etc. And patient’s intention for cholecystectomy would also be considered by physicians, since they might complain some slight discomfort when eating or sleeping. The type of abdominal symptoms, time, frequency and duration of UAP, other concomitant disease were clearly recorded at admission. All the laboratory and imaging studies were performed 24–48 h before the surgery. Most cholecystectomies were performed laparoscopically, but few were converted to open procedure when necessary. Open surgery was indicated in patients with previous open upper abdominal surgeries, and suspected gangrenous or perforated cholecystitis by some surgeons but not all.
All the patients were scheduled for the first regular follow up one month after surgery in outpatient department. They were evaluated for any presented symptoms in short term after surgery, and examined by ultrasound, routine blood tests and liver function tests when necessary. When the upper abdominal symptoms persisted but no abnormal findings presented in surgical sites, the patients would be recommended for further noninvasive examination first, e.g. magnetic resonance cholangiopancreatography (MRCP), upper gastrointestinal and colonic imaging. Endoscopic examination was only performed in patients with abnormal findings by imaging examinations. The patients with severe condition necessitating surgical/endoscopic treatments would be excluded from the study, since the postoperative symptoms of these patients were known to be related to the observed disease after cholecystectomy. Therefore, we enrolled only the patients with persistent UAP due to unknown causes after cholecystectomy. However, for the patients with persistent postoperative UAP but no significant clinical findings would be treated empirically for symptomatic control, e.g. analgesic, antiacid, choleretic, and/or anti-inflammatory treatments, etc. Choleretic drug included ursodeoxycholic acid (UDCA) and/or traditional Chinese herbs pair with mainly Capillaris (Yinchen), Gardenia (Zhizi), Scutellaria (Huangqi), Rhubarb(Daihuang), Bupleurum (Chaihu), Desmodium (Jinqiancao), Dandelion (Pugongying), Gentian (Longdan), Turmeric (Jianghuang), Honeysuckle (Jinyinhua), etc.
All the patients were asked to complete a biliary symptom questionnaire in October 2016. The questionnaire was started with whether or not the patient had obvious postoperative UAP occurred intermittently three months after cholecystectomy. If not, the patients would be categorized as no postoperative UAP group. The patients presenting with UAP three months after cholecystectomy would be further evaluated for average frequency of postoperative UAP (less or more than once per day), duration of each episode of UAP (less or more than 30min), severity of the pain, and any treatment medications. For measurement of pain, we used 0–10 scales and defined as recommended previously 1–3 (mild pain, being adaptable but does not interfere with most activities), 4–6 (moderate pain, interferes with many activities, and patient is unable to adapt to pain but remains independent), and 7–10 (severe pain, patient is disabled and unable to function independently).19
Quantitative data were expressed as median and range, while qualitative variables were expressed as number (proportions, %). The difference of qualitative variables between different groups was evaluated by the Chi-Square test or Fisher’s exact. The potential factors relevant to postoperative UAP and its relief were assessed. The factors with p value less than 0.1 by univariate analysis were enrolled into multivariate analysis, and hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated using logistic regressionmodel. Statistical analysis was carried out using SPSS 22.0 (SPSS Inc., Chicago, IL). p < 0.05 was considered statistically significant.
As shown in Table 1, the age of the patients ranged from 14 to 90 years old, with predominantly female patients (66.1%). Most of the patients had a history of UAP for longer than one month (65.3%). 925 (54.0%) patients presented with one or more of other atypical abdominal symptoms, including nausea, vomit, jaundice, dyspepsia, flatulence, bloating, heartburn, regurgitation, etc.
|Variables||Median (range)/number (%)|
|Age (years)||54 (14–90)|
|Female gender||1133 (66.1%)|
|Concurrent abdominal symptoms|
|UAP history longer than one month||1120 (65.3%)|
|Clinical jaundice||240 (14.0%)|
|Alanine aminotransferase (U/L)||21.0 (2.7–994.7)|
|Aspartate transaminase (U/L)||20.7 (3.8–1116.6)|
|Alkaline phosphatase (U/L)||72.4 (12.1–1978.0)|
|Gamma-glutamyl transferase (U/L)||24.6 (3.6–3021.0)|
|Total bilirubin (μmol/L)||12.3 (3.0–171.2)|
|Direct bilirubin (μmol/L)||4.1 (0.7–133.7)|
|Albumin (g/L)||40.5 (21.2–57.3)|
|White blood cell count (×109/L)||5.9 (1.3–25.3)|
|Neutrophil granulocyte ratio (%)||61.5 (28.2–96.4)|
|Hemoglobin (g/L)||133.0 (56.0–199.0)|
|Maximum stone diameter ≥ 10 mm||1222 (71.3%)|
|Multiple stones in gallbladder||1282 (74.8%)|
|Laparoscopic converted to open||3 (0.2%)|
|Surgery time (min)||28 (10–150)|
|Laparoscopic cholecystectomy (min)||27 (10–100)|
|Open cholecystectomy (min)||40 (15–150)|
1532 (89.4%) patients underwent laparoscopic cholecystectomy, 3 (0.2%) were converted from laparoscopic to open surgery, and 179 (10.4%) underwent open cholecystectomy. The median time of surgery was 28 min, which, however, shorter when performed laparoscopically than openly (27 min vs. 40 min). Most of the patients showed large (≥1 cm) and multiple gallstones (71.3% and 74.8%, respectively).
Risk factors associated with postoperative UAP
However, persistent UAP symptom was still present in 172 (10%) patients after cholecystectomy but with no obvious clinical findings in surgical sites (sludge, stones or stricture in biliary tract). We then evaluated the potential risk factors associated with occurrence of persistent postoperative UAP (Table 2). By univariate analysis, females were more likely to develop postoperative UAP than male counterparts (11.4% vs. 7.4%, OR, 1.6, 95% CI, 1.1–2.3, p = 0.010, Table 2). Moreover, preoperative UAP history longer than one month and lasting more than 30 min every time were both found to be risk factors correlated with postoperative UAP (12.5% vs. 8.8%, OR = 1.5, 95% CI, 1.1–2.0, p = 0.018; and 17.7% vs. 8.9%, OR = 2.2, 95% CI, 1.5–3.2, p < 0.001, Table 2). And the most recent episode of UAP presented more than 24 h before hospitalization seemed to be associated with higher risk of postoperative UAP, compared with preoperative UAP presented within 24 h before hospitalization of the patients (11.6% vs. 7.8%, p = 0.055, Table 2). In multivariate analysis, female gender, preoperative UAP occurring more than 24 h before admission, and each episode of UAP longer than 30 min were selected as independent risk factors associated persistent postoperative UAP (OR = 1.6, 1.4 and 3.2, and p = 0.007, 0.027 and <0.001, respectively, Table 2). However, other atypical abdominal symptoms including fever, nausea, vomit, jaundice, dyspepsia and flatulence were not correlated with postoperative UAP (all p > 0.1, Table 2). The type and duration of the cholecystectomies were not found any relation with postoperative UAP (both p > 0.1, Table 2). Moreover, 134 (7.8%) patients complained other obvious abdominal symptoms after cholecystectomy including nausea, vomit, dyspepsia, fat intolerance, diarrhea, constipation and flatulence, etc.
|Variables||Proportion (%) with postsurgical UAP||Univariate analysis||Multivariate analysis|
|OR (95% CI)||Pvalue||OR (95% CI)||Pvalue|
|Age (years)||1.2 (0.8–1.6)||0.364|
|Gender||1.6 (1.1–2.3)||0.010||1.7 (1.2–2.4)||0.007|
|UAP history >1 months||1.5 (1.1–2.0)||0.018||1.4 (1.0–2.0)||0.071|
|UAP onset||1.4 (1.0–2.1)||0.055||1.7 (1.1–2.7)||0.027|
|≤24 h at admission||38/486 (7.8)|
|>24 h at admission||134/1228 (11.6)|
|UAP duration||2.2 (1.5–3.2)||<0.001||3.2 (2.1–5.1)||<0.001|
|≤30 min||134/1499 (8.9)|
|>30 min||38/215 (17.7)|
|Clinical Jaundice||0.8 (0.5–1.3)||0.417|
|Any nonpain symptoms||0.9 (0.7–1.2)||0.573|
|Surgery procedure||0.7 (0.4–1.3)||0.298|
|Surgery time (min)||0.8 (0.6–1.2)||0.377|
|Surgery time (min) of LC||0.9 (0.6–1.3)||0.499|
|Surgery time (min) of OC||0.8 (0.3–2.5)||0.789|
UAP, upper abdominal pain; LC, laparoscopic cholecystectomy; OC, open cholecystectomy.
Clinical factors associated with relief of postoperative UAP
Till the end time of follow up (October 2016), 132 out of 172 (76.7%) patients reported significant relief of postoperative UAP. We further investigated any clinical features correlated with relief of postoperative UAP (Table 3). Preoperative UAP occurring within 24 h at admission seemed to be positively associated with postoperative UAP relief (OR = 2.4, 95% CI, 1.1–5.3, p = 0.035, Table 3). The surgery type and duration did not affect postoperative UAP relief. Moreover, less frequent postoperative UAP (≤1 episode per day) was more likely to be relieved compared with frequent pain (85% vs. 63.1%, OR = 3.3, 95% CI, 1.6–6.9, p = 0.001, Table 3). Interestingly, moderate and severe postoperative UAP seemed to be more likely relieved than slight pain (OR = 2.9 and 2.4, p = 0.028). Administration of choleretic medications were found to significantly relieve postoperative UAP (yes vs. no, 86.3% vs. 64.9%, OR = 3.4, 95% CI, 1.6–7.2, p = 0.003). The average duration of postoperative UAP were unrelated to relief of the symptom. However, by multivariate analysis, preoperative UAP occurring within 24 h at admission, postoperative UAP less than 1 episode per day and choleretic medication use were independently associated with the relief of postoperative UAP (OR = 2.5, 2.5 and 2.6, p = 0.038, 0.020 and 0.018, respectively, Table 3).
|Variables||Proportion (%) with postsurgical UAP relief||Univariate analysis||Multivariate analysis|
|OR (95% CI)||Pvalue||OR (95% CI)||Pvalue|
|Age (years)||0.6 (0.3–1.1)||0.107|
|Preoperative UAP history >1 months||1.8 (0.8–3.8)||0.125|
|Preoperative UAP onset||2.4 (1.1–5.3)||0.035||2.5 (1.1–6.1)||0.038|
|≤24 h at admission||34/38 (89.5)|
|>24 h at admission||98/134 (73.1)|
|Preoperative UAP duration||1.0 (0.4–2.3)||0.944|
|≤30 min||103/134 (76.9)|
|>30 min||29/38 (76.3)|
|Any preoperative nonpain symptoms||1.0 (0.5–2.0)||0.913|
|Surgery procedure||0.7 (0.2–2.5)||0.741|
|Surgery time (min)||1.3 (0.6–3.0)||0.548|
|Postoperative UAP frequency (/day)||3.3 (1.6–6.9)||0.001||2.5 (1.2–5.4)||0.020|
|Postoperative UAP duration||1.4 (0.7–3.1)||0.346|
|≤30 min||96/122 (78.7)|
|>30 min||36/50 (72.0)|
|Postoperative UAP severity||0.028|
|Slight (1–3/10)||64/93 (68.8)||1||1|
|Moderate (4–6/10)||52/60 (86.7)||2.9 (1.2–7.0)||0.014||1.9 (0.7–4.9)||0.203|
|Severe (7–10/10)||16/19 (84.2)||2.4 (0.7–8.9)||0.186||1.5 (0.4–5.8)||0.593|
|Choleretic drug use||3.4 (1.6–7.2)||0.003||2.6 (1.2–5.7)||0.018|
UAP, upper abdominal pain.
Possible causes of postoperative UAP
Totally, 1542 out of 1714 (90%) patients presenting with preoperative UAP were relieved from the UAP symptoms following cholecystectomy. However, 172 (10%) patients with preoperative UAP complained persistent postoperative UAP. Most of the cholecystectomized patients were routinely followed up with no significant abnormal findings in surgical sites. The causes of postoperative UAP following cholecystectomy might be complex. Some other concomitant disorders could cause similar upper abdominal symptoms, which might be confused with gallstones symptoms before surgery and then lead to no relief of UAP after surgery. Viral or fatty hepatitis, cardiovascular disease (coronary intervention previously), gastroesophageal reflux disease (GERD) and gastritis(diagnosed with endoscopy), severe chronic obstructive pulmonary diseasemight be potential causes of postoperative UAP respectively in 13 patients, 9 patients, 15 patients, and 1 patient. Although all the patients were consistently treated for the concomitant disease above before and after cholecystectomy, the abdominal symptoms were not significantly relieved after cholecystectomy. Moreover, there were still 94 (5.5%) patients presented with both preoperative and postoperative UAP, the causes of which remained unknown.
Cholecystectomy is a designed procedure to relieve UAP and associated symptoms due to gallstones. However, postoperative UAP was still persistent in 10%–33% of the patients with mostly unknown causes.9, 10, 11, 12, 13, 14Most of these studies are from Western countries. In the present study from a large Eastern institute, we enrolled all the symptomatic patients undergoing cholecystectomy for UAP, and some of them presented nonspecific abdominal symptoms concomitantly. However, 10% patients still complained postoperative UAP for about two years. Patients with gallstones often have other disorders which produce symptoms similar to gallstones, making it to be confused whether the symptoms are caused by gallstones or other concomitant disease. Although differential diagnosis of gallstones from other disorders has been routinely made before proceed with cholecystectomy, a tendency of preconceived association between gallstones and upper abdominal symptoms from both patients and physicians makes unnecessary cholecystectomy unavoidable completely. Even though, some clinical researchers have endeavored to identify preoperative symptoms which could well predict complete relief of preoperative UAP after cholecystectomy. Several characteristics of the preoperative UAP were demonstrated positively correlated with postoperative relief of UAP, e.g. UAP frequency less than once per month, onset shorter than one year, episodic UAP, UAP lasted for hours rather than days or longer, and nocturnal patter of UAP, etc.11, 12, 13, 14, 15, 20 Our results were mostly consistent with previous studies that shorter history and duration of preoperative UAP might be positively related to the relief of preoperative UAP. However, it still remains obscure what are the causes of persistent UAP after cholecystectomy.
Although postoperative UAP might be a sign of potential complications of cholecystectomy, some patients were found no abnormal display in surgery sites. In our study, 310 patients undergoing other surgeries after cholecystectomy were excluded for potential confounding factors related to postcholecystectomy symptoms. The remaining 172 patients complaining postoperative UAP after cholecystectomy were demonstrated no significant abnormal findings during the follow up. The symptoms of these patients after cholecystectomy might be called “postcholecystectomy syndrome (PCS)”. As previously defined, PCS includes a large number of disorders originated in both biliary and extra-biliary organs.21, 22 However, nowadays, PCS mostly imply the symptoms related to functional changes in hepato-biliary-cholecysto-pancreatico-duodeno-gastro-esophageal region after cholecystectomy.23 It has been reported that in 5% of the patients undergoing cholecystectomy (5.5% in our study), the reason for postoperative UAP remains unknown.21, 24 The possible mechanism of functional PCS was proposed in Fig. 2. Presence of normal gallbladder and functional sphincter of Oddi maintains certain intraluminal pressure in the common bile duct (CBD) and pancreatic duct (PD) and controls the rhythm of bile and pancreatic juice excretion into the duodenum (Fig. 2a). However, absence of gallbladder leads to direct passage of hepatic bile juice into duodenum, thus functional biliary hypertension and CBD dilation, biliopancreatic reflux, and finally dysfunction of the sphincter of Oddi (mostly hypotonus). Some functional disorders might occur due to dysfunction of the sphincter of Oddi, such as duodenogastroesophageal reflux and alkaline reflux gastritis due to surplus bile juice into the duodenum, refluxing cholangitis and cholestatic hepatitisdue to intestinal contents reflux into the CBD, and chronic biliary pancreatitisdue to biliopancreatic reflux (Fig. 2b).
Although persistent UAP after cholecystectomy has been frequently addressed in some reports, treatments of postcholecystectomy UAP with no obvious clinical findings are rarely available. Totally, 132 out of 172 (76.7%) patients reported relief of postoperative UAP after conservative treatments. Notably, onset of preoperative UAP within 24 h was negatively related to occurrence of postoperative UAP but positively related to relief of postoperative UAP. Therefore, postoperative UAP is unlikely to occur in patients with acute calculous cholecystitis and more likely to relieve once occurred, which might advocate early cholecystectomy with definite diagnosis of gallstones and surgery indications. Also, less frequent postoperative UAP is more likely to be controlled as we identified. Although most patients might take more than a single type of medication, choleretic medications were mostly administrated when there was no contraindication. 95 patients who complained postoperative UAP in our study have taken UDCA and/or traditional Chinese herbs, and 86.3% of them reported significant relief of the postoperative UAP (versus 64.9% of the patients without choleretic medication). UDCA is a hydrophilic hepatoprotective bile acid. It helps in dissolving the cholesterol monohydrate crystals and biliary sludge in the biliary tract, preventing development of choledocholithiasis, duodenogastric reflux, chronic gastroduodenitis and chronic biliary pancreatitis.25, 26, 27, 28 Although they are more complex in the components, some botanicals have been proved to possess choleretic and hepatoprotective effect in patients and animal models,29, 30, 31, 32 and therefore commonly used in selected patients in China, Japan and Korea. Although facing unimaginable complexity of multi-herb formula, many researchers in not only China but some other Asian countries are working on unveiling active components and the underlying mechanism of the traditional Chinese medicine formula to make it modernization and globalization.
In conclusion, because of the highly subjective report of UAP, it is important to differentiate whether UAP is a manifestation of gallstones or some other concomitant disorders before cholecystectomy. Although organic periampullary disease is the most common causes, functional disorder of the sphincter of Oddi after cholecystectomy is not an uncommon reason for persistent UAP after cholecystectomy. Female gender, onset of the most recent UAP longer than 24 h before admission and each episode of UAP more than 30 min are risk factors of persistent postcholecystectomy UAP. Choleretic medications including UDCA and traditional Chinese herbs are effective in relieving the postoperative UAP in most of the patients due to functional postcholecystectomy syndrome.
Study conception and design: Zhang XF, Lv Y; Acquisition of data: Zhang J, Lu Q, Ren YF, Dong J, Mu YP; Analysis and interpretation of data: Zhang J, Zhang XF; Drafting of manuscript: Zhang XF; Critical revision: Lv Y, Zhang XF.
This study was supported in part by National Natural Science Foundation(NO. 81372582), “New-Star” Young Scientists in Shaanxi Province Programme(2014kjxx-30), and the Fundamental Research Funds for the Central Universities.
Conflict of interest