Calculus Cholecystitis Complicated with Variations of Extrahepatic Bile Duct: Clinical Experience and Aeromedical Analysis of 3 Cases in Aviation Pilots Open Access

Cholecystitis is highly predominant in Chinese mainland, where it has a prevalence of up to 15% in adults [1]. In fact, cholecystitis is not always associated with gallstones, and although this type is more prevalent in children, it can be seen in adults with similar pathophysiological features [2]. Correspondingly, cholecystitis is also one of the most common diseases in medical examination of aviation personnel. Due to the potential risks to flight safety, cholecystitis, especially with gallstones formation, often requires surgical intervention once diagnosed in pilots whether symptomatic or asymptomatic. Cholecystitis and related surgical treatment in aviation personnel have been known for long time. Because the overall incidence of acute cholecystitis within aircrew would not be changed by aeromedical cholecystectomy being performed on aviators with incidentally detected asymptomatic cholelithiasis, and postoperative convalescence may pose special problems even leading to waiver requests, for aviators, much effort has been put on the adjustment for risk factors of cholecystitis (including body weight, cigarette smoking, physical activity, and metabolic abnormalities) to avoid cholecystectomy [3, 4]. In recent years, the prevalence of calculous cholecystitis in aviation personnel as well as the incidence of laparoscopic cholecystectomy (LC) tends to decrease [5]. But another reverse trend, that is, long-term post-cholecystectomy syndrome (PCS) associated with aerophysiology lasting more than 3 months, seems more apparent [6]. For aviators diagnosed with calculous cholecystitis, more than 70% of the expenditure, including time and economic costs, occurs in the treatment of long-term PCS [7].

Since computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) are most used imaging tools for the medical examination of aviation pilots, the clinical significance of anatomic variations of bile duct has gradually been attached more attention, because the variations seem to play some special role in the formation of gallstone and development of PCS under aerophysiological environment. In this article, we present 3 consecutive cases of aviation pilots who developed long-term PCS in recent 5 years because of anatomical variations of extrahepatic bile duct. The purpose of this article was to elucidate the possible mechanisms of gallstone formation and the development of long-term PCS caused by variations of extrahepatic bile duct, as well as choice of surgical treatments, just in this particular group of aviation personnel.

From January 1, 2019, to December 31, 2023, 7 aviators underwent LC because of calculous cholecystitis in Chinese PLA Air Force Medical Center. Three of them (42.9%) developed long-term PCS within 6 months after surgery, and the main clinical and laboratory features of these 3 patients are shown in Table 1. Summaries of the treatment and outcome characteristics in these cases are presented below.

Enhanced CT of the upper abdomen and MRCP were routinely performed for all these 3 cases before operation. Detailed visualization of intra- and extrahepatic bile duct was attained with CT using axial 5.0-mm slices, as well as MRCP using coronal 1.0-mm slices of T2-weighted images. Surgical planning and LC were performed with a goal of avoiding any iatrogenic injury of bile duct. During operation, a 15-mm incision was made in the umbilicus, a 12-mm trocar was inserted by an open method, and 2- or 3.5-mm trocars were placed in the right upper quadrant. After operation, flurbiprofen, a nonsteroidal anti-inflammatory analgesic, was administered intravenously (50 mg) as necessary during the fasting period, and then loxoprofen (60 mg), also a nonsteroidal anti-inflammatory analgesic, was orally administrated for 1–3 days if necessary. No opioids were administered. All aviators were scheduled for temporary suspension of flight for 2 months during which regular follow-up was conducted every 3 weeks to assess the recovery of the body. Long-term PCS in this article was defined as abdominal pain, dyspepsia, and other abdominal symptoms that occurred in aviation personnel after cholecystectomy and lasted for more than 3 months [5].

A 41-year-old male pilot presented with intermittent dull pain in the right upper quadrant. CT and MRI disclosed an atrophied gallbladder filled with stones and mild dilation of the adjacent intrahepatic bile duct in S5 (the inferior segment of the right anterior liver lobe). The dilated bile duct gave a uniformly low-dense signal on CT and T1-weighted images, a markedly hyperintense signal on T2-weighted images, and showed no contrast enhancement (Fig. 1). MRCP showed the junction of cystic duct (CD) into right hepatic duct (RHD) (Fig. 2). The diagnosis of cholecystolithiasis and atrophic cholecystitis with suspicious presence of the right accessory extrahepatic bile duct was established. During the course of LC, no definite right accessory extrahepatic bile duct branch was found. However, very small amount of bile within the gallbladder fossa was identified, and absorbable ligature clips of poly-p-dioxanone for hemostasis were used where the accessory extrahepatic bile duct might be present until no bile leakage identified. During ground observation after the temporary suspension from flight, this pilot had several episodes of epigastric dull pain after training of flight simulations. Three weeks after surgery, training of flight simulations was suspended because of the enveloped fluid in the gallbladder fossa revealed by ultrasound. Then, percutaneous drainage guided by ultrasound was performed, and a total of 50 mL bile was drained out after 6 days of continuous negative pressure suction. Then, no complications or side effects were met, and the pilot resumed training of flight simulations 6 weeks after surgery. But he still felt epigastric dull pain repeatedly and occasionally a burning sensation behind the sternum. These symptoms were mild and did not interrupt the training. Gastroscopy revealed mild bile regurgitation 3 months after surgery. This pilot was then treated with compound azintamide in combination with rabeprazole and hydrotalcite for 8 weeks, and the effect was remarkable. Flight suspension was waived 6 months after surgery.

A 38-year-old male pilot presented because of gallstones revealed by physical examination of ultrasound but asymptomatic for 3 months. He was admitted to our center for LC because of potential risk during flight. CT revealed the accumulation of sediment-like stones in gallbladder and atrophic cholecystitis (Fig. 3a). MRCP showed the mildly dilated RHD, but did not show clear images of the gallbladder (Fig. 3b). Laparoscopic exploration revealed that the CD was absent, and the gallbladder constituted part of the RHD, forming a diverticulum-like structure on the wall of RHD. After complete removal of the atrophied gallbladder, the defect on the wall of RHD was sutured with 4-0 absorbable suture and an abdominal drainage tube was placed near the gallbladder bed. Slight bile leakage happened within 3 days after surgery, which delayed the removal of the abdominal drainage tube until 1 week after surgery. Although the training of flight simulations on ground was resumed 1 months after surgery, the training was interrupted many times because of intermittent abdominal dull pain or sparse stool. Repeated ultrasound and CT examination showed no obvious fluid accumulation in the gallbladder fossa and no dilation of intrahepatic bile duct. He gradually recovered with a low-fat diet and the oral therapy of small dose of omeprazole and ursodeoxycholic acid for 3 months, and flight suspension was finally waived 7 months after surgery.

A 34-year-old male pilot presented with dull pain of the right upper quadrant after fat diets. Abdominal examination revealed Murphy’s sign was positive. CT disclosed a slightly enlarged gallbladder with multiple stone formations and the gallbladder wall thickening. The CD joined the RHD with abnormal conjunction of left and right hepatic bile ducts on coronal plane of MRCP images (Fig. 4a). Based on the characteristics of clinical symptom and imaging examination, the diagnosis of calculous cholecystitis was established and LC was performed. The anomalous confluence of the CD and the RHD as well as the absence of common hepatic duct was demonstrated intraoperatively (Fig. 4b). No complications or side effects were met. The pilot developed abdominal dull pain and diarrhea several times during the 1-month recovery period, and these symptoms could be released after oral treatment of loxoprofen and loperamide. However, such symptoms were significantly worse when he resumed training of light simulations on ground at the 6th week after surgery and could be relieved soon after training without medication. Training of light simulations had to be suspended and resumed after 3 months of low-fat diet combined with oral azintamide and probiotics. Although he returned to flying 8 months after operation, he continued to experience diarrhea during flight. After 1 year of psychological counseling to relieving mental stress, he gradually returned to normal flight intensity and frequency.

Cholecystitis contributes to nontrained hospitalization rate among military service members much as it has in the civilian population [8]. In general population, the main risk factors associated with gallstone formation include advanced age, female gender (mainly related to pregnancy and oral contraceptive use), obesity, fast weight loss, and family history, and different environmental factors have additional effects [9]. In fact, except family history or genetic effect, none of these factors could explain the gallstone formation for such a small and special group of the aviation personnel. This suggests that specific predisposing factors may exist in gallstone formation in aviation pilots. The main mechanism for gallstone formation could be defined as biliary cholesterol supersaturation, excess pronucleating proteins, or shortage of nucleation inhibiting proteins, and factors related to gallbladder hypomotility and bile stasis [10]. Sipahi et al. [11] firstly reported the significant effect of variation and anatomical characteristic of bile duct to the motility and stasis of gallbladder, and they found that as the sisto-choledochal angle (SCA, defined as the angle between CD and common bile duct) increased, the incidence of gallstone formation increased accordingly. As there were plica spiralis and spiral folds in the lumen of CD acting as a valve, the increment in SCA could lead to enhanced resistance to bile flow, resulting in longer duration of residue saturated bile in the gallbladder, and the decrement of bile drainage through CD into the choledoc promoted the formation of gallstones [12]. Recent studies showed that decreased expression of cholecystokinin (CCK) receptor A and cholesterol 7-alpha-hydroxylase was closely connected with gallstone formation, and lack of mucin secretion originated from the epithelia of the gallbladder neck could lead to cholesterol crystal nucleation and stone formation [13]. Shi et al. [14] of our center also revealed in experimental rats that the aerophysiological environment such as positive acceleration (+Gz) and hypoxia could lead to decreased expression of CCK receptor A and cholesterol 7-alpha-hydroxylase as well as decreased mucin secretion in gallbladder tissue.

In our series, increased SCA associated with variation of extrahepatic bile ducts could be confirmed in all these 3 cases with long-term PCS. In our center, LC has been performed following standard procedures and was correctly performed with sufficient care in this series study. The minimally invasive nature of LC surgery (operation duration controlled in 60 min and blood loss less than 10 mL) determined the rapid recovery of these 3 pilots to daily routine life. Therefore, we think the possibility of surgical factors causing PCS is very small. Although the correct diagnosis of bile duct variation should depend on direct contrast examinations, the obvious variations of extrahepatic bile duct in these 3 pilots could be correctly diagnosed owing to CT scanning of 1.0-mm-thin slice and the coronal imaging of MRCP, which were also directly confirmed by intraoperative findings. In case 1, the presence of the right accessory extrahepatic bile duct originating from the intrahepatic bile duct of S5 increased the volume and internal pressure of the gallbladder, while the increased SCA (90°, calculated as the angle between CD and RHD because of the absence of common bile duct) blocked bile emptying from the gallbladder, thus leading to gallstone formation. In case 2, because of the absence of CD, the gallbladder formed part of the RHD and SCA was calculated as the angle between the gallbladder axis and the right hepatic bile duct (110°). In case 3, SCA was also calculated as the angle between CD and RHD because of the absence of common bile duct (90°). Although our study has unavoidable limitations in selecting the participants, we do not think the increased SCA due to anatomical variations of extrahepatic biliary system in these 3 aviators only a coincidence, considering that only 7 pilots have undergone LC in 5 years. In fact, the increased SCA (≥90°) could be found in other 2 pilots because of the increased length of CD, and the total incidence of 71.4% (5/7) suggests that the increased SCA may be an important reason for gallstone formation in aviation personnel. Further studies based on large numbers of aviators will be needed to confirm our hypothesis.

The incidence of PCS after LC varies widely in literature between 12% and 65% [15]. But due to the limited volume of LC being performed in such particular group of aviation personnel, there are very little data worldwide on the incidence, presentation, and management of related PCS. One earlier study had followed up 40 pilots prospectively for 1 year and reported an incidence of 25.6%, and recent study from Chinese Society of Aerospace Medicine (CSAM) reported an incidence of 28.3% [4, 16]. In a broad sense, any symptom after cholecystectomy can be labeled as PCS, but after an initial high incidence, only less than 10% remained symptomatic after 3 months in general population [17]. From one opinion, the early and temporary nature of PCS reflects some degree of cholestasis or underlying sphincter dysfunction that is temporarily overwhelmed after cholecystectomy and manifests in the early postoperative period as symptoms, settling over time once the choledochus adjusts to increased bile flow through it [18]. Another opinion believes that this fall in the incidence of symptoms after cholecystectomy might reflect the psychological adjustments within the body following loss of the reservoir function of the gallbladder, as well as the tissue response after dissection in Calot’s triangle [19]. Various studies have shown that PCS has no relationship with the duration of preoperative symptoms, the surgery performed (LC or conversion), and the duration of postoperative admission. Only two constant factors, previous attacks of acute cholecystitis and presence of comorbid illnesses, with two temporary factors, elevated preoperative alkaline phosphatase and prior abdominal surgery, could significantly affect the development of PCS [17‒19]. Just as there is no clear and effective way to prevent PCS, which has serious impact on the quality of life in 2%–8% of those after cholecystectomy, and need long-term aggressive therapy, the best approach is still to be cautious in making decisions of cholecystectomy, especially for those asymptomatic [20]. However, this approach contradicts the management principle of gallstone in most aviators although the incidence of PCS seems more higher and the symptoms seemed to last longer in them. Because of the serious potential risks for flight safety, the indication of cholecystectomy in aviation pilots was wider than general population, and the vast majority of pilots who underwent LC were diagnosed as asymptomatic. For aviation personnel, the rigorous medical examination can ensure that they will not suffer from the comorbid illness, mainly diabetes, which is closely associated with gastric dysmotility as well as biliary dyskinesia as a result of autonomic dysfunction after LC [21]. According to the same logic, the factors of elevated preoperative alkaline phosphatase and prior abdominal surgery rarely occur in those pilots and, therefore, can be ruled out as predisposing factors to inducing long-term PCS.

Although the symptoms of PCS can be classified into biliary (nausea, vomiting, food intolerance, and dull pain), dyspeptic (flatulence, heartburn, and belching), and intestinal (abdominal cramps and diarrhea), from our experience, long-term PCS in aviators is characterized by dull pain in the upper abdomen accompanied by diarrhea. After cholecystectomy, pressure in the biliary tract will lose its buffering effect. Tanaka [22] reported that the pressure in common bile duct increased significantly when Oddi sphincter contracted after LC, resulting in intermittent dull pain in the right upper quadrant but without symptoms of infection. We also proved the objective correlation between the aviation environment and the occurrence of PCS. On a vivo rabbit model after cholecystectomy, we found biliary pressure in common bile duct increased accordingly with +Gz but without bile secretion changing, and +Gz could increase the frequency of burst of spike potentials in Oddi sphincter, suggesting that +Gz was an important external factor leading to the biliary physiology disorder and could induce obvious symptoms in those with individual susceptibility [23]. In this series, the initial symptom of bile leak happened in case 1 because of the existence of accessory extrahepatic bile duct, from where bile leaked under +Gz training of flight simulations on the ground. As the training continued, the symptom of epigastric dull pain aggravated in all these 3 cases. We hypothesize that the increased SCA or anatomic variations of bile duct improve the pressure-regulating function of gallbladder in the extrahepatic bile duct system (gallbladder even becoming part of the RHD in case 2), so that endocrine disorders associated with psychiatric stress factors can lead to elevated biliary pressure, reflecting a weakening of the psychological adjustments within those aviation personnel after LC under aviation environment. Literature reported that CCK increased after cholecystectomy especially under mental stress, causing frequent contractions of Oddi sphincter and increased pressure in the common bile duct, and paroxysmal epigastric pain then happened [24]. Although bile reflux was an important factor in the occurrence of long-term PCS in case 1, we think it caused by gastrointestinal dyskinesia, which was closely associated with bile leakage and intra-abdominal adhesion. From our experience, bile reflux rarely happened in pilots after LC and the clinical manifestations were relatively mild. Another predominant symptom for long-term PCS is diarrhea or sparse stool. Possibly diarrhea is mainly caused by the increased bile entering the colon which leads to irritation to the colon. However, most reports are based on the normal biliary anatomy and probably do not reflect the situation of those aviation pilots completely. Present studies have reported that postoperative dilation of the common bile duct was in association with decreased diarrhea after cholecystectomy which could slow the flow of bile through Oddi sphincter [25]. For case 2 and case 3, increased SCA may restrict the normal physiological dilatation of after cholecystectomy because of the anatomic variation of biliary tract (CD joins only with RHD and leads to absent common bile duct), thus unable to regulate the passage of bile through Oddi sphincter into the intestine. Under the simulated physiological environment of aviation, the secretion and flow rate of bile both increased and led to diarrhea or sparse stool, which has been verified by our animal models [23]. Therefore, it should be kept in mind that aviation pilots who have preoperative SCA or bile duct variations but normal diameter of common bile ducts after cholecystectomy tend to develop long-term PCS when resuming flight. This might help in counseling those pilots preoperatively or in relieving apprehensions after surgery.

Anatomical variation of bile duct is not rarely met in aviation personnel with calculous cholecystitis, and long-term PCS remains apparent although much effort has been put on the precaution of gallstone formation and reducing cholecystectomy. Increased SCA induced by variation of bile duct may be an important potential risk for gallstone formation and development of long-term PCS with the cause of probable decrement of bile drainage under the physiological environment of aviation. Dietary adjustment and oral antispasmodic or cholagogic drug therapy, combined with preoperative counseling and relieving apprehensions after surgery, can help pilots recover from PCS and resume flight after cholecystectomy. There is a need for larger number of cases to understand in a better way, the physiology of altered bile flow, and cause of long-term symptoms in those particular patients of aviation personnel. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546233).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). This study protocol was reviewed and approved by the Chinese PLA Air Force Medical Center, Approval No. 2017AGA-024. Written informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

There is no funding for this study.

Conception and design and administrative support: Cheng-Li Liu and Ya-Lin Kong. Provision of study materials or patients: Wen-Bing Li, Zeng Xue, and Wei Shi. Collection and assembly of data: Lu-Bing Wang, Xiao-Jun He, Cheng Wang, Gang Zhao, Ling-Hong Kong, and Meng Pu. Data analysis and interpretation: Wen-Bing Li and Zeng Xue. Manuscript writing and final approval of manuscript: all authors.

Wen-Bing Li and Zeng Xue contributed equally to this work.

All relevant data are within the manuscript and its additional files. Further inquiries can be directed to the corresponding author.