Best evidence topic: Should patients with asymptomatic choledocholithiasis be treated differently from those with symptomatic or complicated disease?

Choledocholithiasis is a common finding in clinical practice, with presentation varying from asymptomatic to life-threatening complications. In symptomatic patients, there is no doubt that treatment to clear the bile duct is indicated, but there is still a debate regarding the treatment of patients with silent common bile duct stones (CBDS). The question addressed by this best evidence topic is whether patients with asymptomatic CBDS should be managed in the same way as patients with symptoms or complications. The search strategy yielded 609 articles, from which 8 articles found to be relevant to this topic. We also summarised the most notable societal guidelines recommendations, regarding this topic. We tabulated the article title, author, year, country, study type, outcomes, results, and comments. We concluded that patients with asymptomatic CBD stones should be offered endoscopic treatment If they are fit, after discussion of the potential risks and benefits of both options of conservative and interventional treatment with the patients.


Introduction
This BET was designed using a framework outlined by the International Journal of Surgery [1]. This format was used because a preliminary literature search suggested that the available evidence is of insufficient quality to perform a meaningful meta-analysis. A BET provides evidence-based answers to common clinical questions, using a systematic approach of reviewing the literature.
Choledocholithiasis is a common complication of gallstone disease that presents to clinicians in a variety of modes ranging from being incidentally discovered silent CBDS to life-threatening complications such as pancreatitis. There is a general consensus that symptomatic patients with CBDS should be offered treatment which in most clinical settings will be ERCP. However, the treatment of silent CBDS remains a matter of debate. This can be explained by the paucity of evidence regarding the natural history of CBD stones. In this topic we attempted to answer the question of whether silent CBD stones should be managed differently from symptomatic disease, by looking at data on the natural history of silent CBD stones, and the outcome of their management in asymptomatic patients.

Clinical scenario
A 70 years old female patient, undergoing investigations for change in bowel habit with a Computed Tomography (CT) colonography. The scan didn't reveal any colonic abnormality, but showed a CBD stone measuring 7 mm. She denied having any symptoms related to gallstone disease, and her Liver function tests are normal. She had undergone laparoscopic cholecystectomy 2 years earlier. You wonder whether she should be referred for ERCP or managed conservatively.

Three part question
(1) Should patients with asymptomatic CBD stones [2] offered the same treatment as symptomatic patients or [3] Should they be managed conservatively.

Search strategy
Medline search from 1978 to 2020, limited to English language articles.

Inclusion criteria
• Studies on the natural history of CBD stones.
• Studies comparing treatment of CBDS in symptomatic and symptomatic patients. • Review articles and guideline papers on the management of CBDS.

Exclusion criteria
• Studies comparing different treatment modes (Endoscopic, Surgical) • Studies on paediatric population. • Irrelevant articles.

Search outcome
• The search outcome yielded 609 results, which were filtered one by one by going through the title and the summary in order to look for the relevant articles. This yielded 23 papers which were further filtered by reading through the main paper. 3 duplicate articles were excluded and 12 articles were found relevant. The rest were irrelevant to the topic and were excluded. • 8 study articles were found relevant to the topic, summarised in Table 1. • 4 relevant guidelines articles were found and summarised in Table 2.

Discussion
Choledocholithiasis is one of the common complications of gallstone disease, defined as the presence of stones within the common bile duct. This presence can be secondary to passing of a stone from the gallbladder into the bile duct, which is the most common type, or less commonly be formed de-novo inside the CBD. The presentation of CBD stones can vary from being asymptomatic, to life-threatening complications such as jaundice, cholangitis, pancreatitis.
There is a wide agreement among clinicians that patients with symptoms or complications from CBD stones should be offered treatment to clear the duct. The type of treatment will be influenced by several factors, including the timing when the diagnosis is made e.g. preoperative, during cholecystectomy, or postoperative, anatomical factors, e.g. previous gastric surgery, or congenital anomalies, and local expertise. Whatever the modality, the goal is to clear the bile duct of all stones, and provide adequate biliary drainage. This is strongly recommended by the most notable national guidelines [10,11,14].
This consensus turns into debate and disagreement in case of silent CBD stones, that may be discovered during cholecystectomy by using IOUS or IOC, or found on abdominal imaging done for other reasons. Although some of the national guidelines recommend offering duct clearance to asymptomatic patients if they are fit for the procedure, the evidence for this is of low quality, and there is still no consensus on managing these patients. These guidelines also agree that further research on the natural history of CBD stones is still needed. Surgeons and gastroenterologists managing these patients, are often faced with an important question: Does the benefit of having ERCP and duct clearance outweigh the risks associated with the procedure?
In order to answer this question, we need to have knowledge of the natural history of asymptomatic CBD stones, and what are the consequences If they are left alone, and the benefits and risks of ERCP in these patients.
There is paucity of data on the natural history of asymptomatic CBD stones. There are few retrospective cohort studies exploring the outcome of patients with silent CBD stones discovered during cholecystectomy using IOC, and even fewer studies looking at those that were discovered during imaging for other reasons.
One of these studies was conducted by Collins et al. [3] on 34 patients diagnosed with CBD stones discovered during laparoscopic cholecystectomy by routine IOC which was done for all patients with or without evidence of choledocholithiasis. When found, a trans-cystic catheter was left in place for 6 weeks. It was found that, after 6 weeks of follow-up, one third of these patients had asymptomatic spontaneous duct clearance, while the remaining had persistent filling defects on cholangiogram and underwent ERCP. The author concluded that It's reasonable to manage the asymptomatic patients conservatively in the short term. Another study by Ammori et al. found that only 4 out of 14 patients with small CBD stones (<5 mm) became symptomatic during follow-up and needed ERCP [4]. They concluded that patients with asymptomatic small CBD stones can be managed expectantly, and only treated when they develop symptoms or complications.
In a recent retrospective cohort study by Hakuta et al. [2] in 2019, comparison between expectant and endoscopic treatment of asymptomatic CBD stones, showed cumulative incidence of complications in the expectant group to be 6.1%, 11%, and 17% at 1,3-and 5-years follow-up respectively, while the complication rate in the intervention group was 32% including 4 patients with severe pancreatitis. These figures imply that the natural history of silent CBD stones may favour wait-and-see management approach as an alternative to endoscopic treatment in asymptomatic patients.
On the other hand, data from the Swedish registry on 3828 patients that had cholecystectomy with CBD stones found on IOC, showed unfavourable outcome in 25.3%, which was significantly high, compared to 12.7% risk in those patients who had and form of treatment to clear the duct during surgery [5]. However, it's important to note that the unfavourable outcomes rate in this study also included post ERCP complications for patients that became symptomatic after surgery and had to have endoscopic treatment. We can argue that in the last scenario, these post intervention complications should be taken out of the equation, or even be included in the outcomes from intervention rather than wait-and-see group, which can change the results. This study also showed that there is a statistically significant association between increased CBD stone size and increased rate of symptomatic patients.
In the study by Yamashita et al. [9], multivariate analysis showed that CBD dilatation (>10 mm) was the only factor associated with increased risk of cholangitis requiring emergent endoscopic biliary drainage in both symptomatic and asymptomatic patients. Hence, they concluded that all patients; symptomatic and asymptomatic with CBD stones and dilated CBD (>10 mm) should undergo endoscopic treatment.
The aforementioned studies attempted to explore the natural history of silent CBD stones and If there was a difference in the outcome between interventional and wait-and-see treatment. What about the outcome from endoscopic treatment in these two groups? Is there a difference? Our search found three studies [6][7][8]  patients) that compared ERCP treatment in symptomatic and asymptomatic groups. The main focus of these studies is to compare the risk of post-ERCP complications and particularly PEP in both groups. All of these studies showed higher risk of pancreatitis after ERCP for the asymptomatic than the symptomatic group. This higher incidence is suggested to be secondary to nondilated CBD, with small ampullary orifice, and prolonged cannulation time in asymptomatic group.
Measures to reduce the incidence of PEP include the use of rectal non-steroidal anti-inflammatory drugs immediately before or after Small sample size ERCP, and prophylactic pancreatic stenting are advised in various guidelines [15,16]. These measures may be of particular importance in asymptomatic patients with higher risk of PEP. Another crucial factor in reaching a decision on treatment of these patients, is considering their thoughts and opinions. Asymptomatic patients usually have higher expectations, and may be less tolerant to complications, as the procedure in their case is essentially prophylactic. After giving them all the necessary information, including the increased risk of endoscopic treatment, as well as the consequences of wait-andsee management, these discussions should be clearly documented in the patients' notes. This becomes especially important in an increasingly litigious society.

Clinical bottom line
The current guidelines still recommend offering treatment to clear the CBD in asymptomatic patients, however the evidence for this is of low quality. There are data to suggest that wait-and-see can be a viable option, especially in high risk, or short life expectancy patients. Informed consent and discussion with patients about the potential benefits and potential higher risks is recommended in order to reach a management decision. When performed for asymptomatic patients, ERCP should be done by experienced endoscopists, and PEP preventative measures may be considered.
This study is limited by the paucity of studies on the natural history of CBDS, and the absence of controlled studies comparing interventional and conservative management of asymptomatic patients with CBDS. Further research on the natural history of CBD stones and controlled studies comparing various approaches to management of these patients is still required to reach a high-quality evidence.

Ethical approval
Not Applicable.

Source of funding
None.

Author contribution
HN: Conducted the literature search and wrote the paper. RI: Assisted in the literature search and writing of paper. SA: Assisted in writing of paper. AA: Assisted in the literature search, editing of writing.