1.1 Epidemiology of the disease

More than 98% of all bile duct disorders result from gallstones. Cholelithiasis is one of the most high-risk gastrointestinal disorders which has high health care costs (~6.5 billion dollars/year). About 10%–15% of gallstone patients have both gallbladder and CBD stones.⁸

Geography and ethnicity have a significant effect on the prevalence of gallstones and stone-type formation.¹¹ Gallstones are highly prevalent in developed countries, affecting 10%–15% of the population of America and developed countries¹² and 10% of the population in Asian countries and 4%–12% in the Middle East have gallstones. The prevalence of asymptomatic gallstones is reported as 0.8% in North of Iran, 4.7% in southern Iran, and 4.4% in eastern Iran.¹³

The history of asymptomatic gallstones suggests that a large number of affected individuals will remain asymptomatic throughout life, and 10%–25% will develop symptoms such as colic. The annual risk of pain is 2%–3% and for severe complications is 1%–2%.¹² Although 0.6% of deaths are caused by the gallbladder, the high burden of the disease indicates alarming mortality. It was estimated that 1092 deaths due to gallstones occurred in the United States in 2004. Nowadays, cholecystostomy is the most common elective abdominal surgery, and more than 750,000 surgeries are performed annually in the United States.¹¹ Although the mortality rate of this disease is low, its high rate of complications imposes a financial burden. According to the results of studies, 21%–34% of CBD stones move spontaneously, and these stones increase the risk of pancreatitis or cholangitis if the distal duct is blocked. Given that biliary pancreatitis and cholangitis may be life-threatening conditions, it is generally recommended to remove the CBD stones.^{14, 15}

Screening and identifying people who need to be treated or followed up clinically is achieved by physicians and general practitioners. Surgical procedures and consultation for treatment are performed and coordinated with internal medicine specialists and gastroenterologists. Clinical guidelines with strong expertise can be used to help standardize health care in this field. The clinical guide seeks to determine general and important policies for this disease and to modify its screening, diagnostic, and managerial approaches.

To date, no systemized guidelines are found for gallstones with severe complications, for its diagnosis, treatment, and management. Commonly invasive procedures like endoscopy or exploratory laparotomy, in some cases, are performed for diagnosis and surgery for the treatment, however, guidelines regarding the timing of these procedures remain questioned.

2.1 Keywords under study

Gallstone, CBD stone, CBD stones, Cholelithiasis, Choledocholithiasis, Guideline Extraction of recommendations and clinical solutions were done based on different guidelines and each was localized according to the specific situation and conditions of the target population and the conditions in which the solution should be operational and executive conditions such as health, cultural and economic conditions. Then, all the recommendations and solutions in the field of diagnostic and treatment methods were presented based on consultation sessions with experts and finally the consensus of experts consisting of members of the Isfahan Association of Gastroenterology & Liver.

After the final approval of the clinical guide, it was necessary to hold a meeting with the partner team every 2 years to research and review the resources. The duty of the partner team in this meeting was to provide the latest evidence and scientific information and make changes if approved by the other members. After the work was completed, the clinical guide was reviewed by three experienced liver gastroenterologists from other universities (Table 3a–f).

2.2 Diagnosis

Initial assessment of a patient with suspected gallstones and CBD stones is performed based on history, physical examination, laboratory test, and ultrasound. These tests and ultrasounds are available cheaply and widely. Also, these tests are recommended for patients with abdominal and gastrointestinal symptoms who have not responded to treatment, as these patients are suspected of stones.

2.3 History and physical examination (H&P)

Most patients suffer from CBD stone pain in the epigastrium or RUQ accompanied by nausea and vomiting. The pain is often longer than typical biliary colic (biliary colic pain usually resolves within 6 h) and resolves when the stone either passes spontaneously or is removed. Patients may have icterus and Courvoisier's sign on examination (palpably enlarged gallbladder, followed by gallbladder obstruction due to obstruction, which is more common in malignancies).^{3, 17}

Also, anorexia, nausea or vomiting, fever, jaundice, and positive reaction to analgesics should be considered in reviewing patient H&P. Symptoms of ascending cholangitis include fever, jaundice, and abdominal pain (Charcot's cholangitis triad) caused by biliary and bacterial infections of the bile duct and should be cleared up immediately with intravenous antibiotics and endoscopic retrograde cholangiopancreatography (ERCP). Acute Choledocholithiasis is an inflammation of the gallbladder caused by gallbladder obstruction. The disease should be suspected in patients with fever, RUQ pain, or Murphy signs. In a morphological examination to confirm acute choledocholithiasis, the examiner touches the patient's right rib deeply with the right hand and asks the patient to take a deep breath. The sudden cessation of inspiration due to pain characterizes a positive “Murphy sign.” Patients with gallstone pancreatitis due to obstruction at the level of the edema sphincter are usually associated with epigastric pain.^{3, 18}

2.4 Laboratory test

All patients with suspected gallstones should be evaluated based on laboratory tests, including complete blood count, liver test, aminotransferases, amylase, and lipase. In choledocholithiasis, aseptic bile duct obstruction usually occurs with biliary pain, elevated liver enzymes, normal amylase and lipase, and normal white blood cell counts. Cholangitis, as an infectious complication, is associated with obstruction of the biliary tract and is usually associated with a left-shift leukocytosis, elevated liver tests with cholestatic pattern (increased ALP and GGT), elevated levels of bilirubin (more than 2 times), and increased aminotransferase levels up to 2000 and natural amylase and lipase.

Pancreatitis, inflammation of the pancreas, can cause amylase and lipase levels to increase up to 3 times normal. Elevated values of serum alanine aminotransferase level (ALT) indicate that the origin of pancreatitis may be gallstones. The amount of bilirubin and white blood cells can be normal or abnormal, depending on the location and severity of the blockage and the amount of infection. Leukocytosis is also common in acute choledocholithiasis where total bilirubin is usually normal or slightly elevated, unless in co-choledocholithiasis.¹⁸

2.5 Transabdominal ultrasound

Ultrasound of RUQ and epigastrium should be performed in patients who are suspected of stones. The accuracy of transabdominal ultrasound in the detection of gallstones is more than 95%. Elderly patients with unusual abdominal pain, immune-compromised patients with unknown sites of infection, or patients suspected of sepsis due to abdominal problems may also be evaluated by transabdominal ultrasound, due to the possible presence of gallstones. The stones appear as echogenic focus with a posterior shadowing without a signal on transabdominal ultrasound. Also, polyps and bile sludge in ultrasound are seen as echogenic foci without shadowing. The only difference is that biliary sludge moves but the polyp is fixed. For this reason, the patient's ultrasound is performed in different positions such as lying on his back, turning to the left, or standing.³ No gallstones are seen in imaging, in up to 20% of the patients with symptoms typical of biliary colic, possibly because of the small size or composition of the stone.¹

2.6 Useful predictive factors of CBD stones

There are three predictive factors of CBD stones categorized as very strong, strong, and moderate predictive factors (Table 4). Very strong predictive factors include CBD stone seen on transabdominal ultrasound/ascending cholangitis, bilirubin >4 mg/dL. Strong predictive factors are enlarged CBD stones in transabdominal ultrasound (more than 6 mm on trans-abdominal ultrasound) or bilirubin between 1.8 and 4 mg/dL and moderate predictive factors are abnormal liver test (AST, ALP, and ALT) excluding bilirubin or age over 55 or pancreatitis caused by gallstones.^{10, 19, 20}

The results of tests and ultrasound classify patients into three categories: high, moderate, and low probability of having common gallstones (Table 4). Patients with a high probability (i.e., more than 50% likely to have common gallstones) have a very strong predictive factor or two strong predictive factors that direct ERCP must be performed on these patients. Patients with a moderate probability (i.e., a 10%–50% chance of having a CBD stone) have a strong predictive factor or at least a moderate predictive factor in which magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) should be performed for better diagnosis. Patients with a low probability (i.e., less than a 10% chance of having a CBD stone) refer to those for whom there is no predictive factor and should undergo cholecystectomy without further evaluation^{18, 21} (Table 5).

2.7 MRCP and EUS

It is necessary to perform EUS or MRCP in case of strong clinical suspicion of gallstones and normal abdominal ultrasound.³ In the second stage of diagnosis, MRCP or EUS is also performed where the presence of the enlarged CBD in ultrasound or the liver test results are abnormal. The diagnostic accuracy of EUS and MRCP for CBDs has been high in studies (sensitivity and specificity above 90%). Different considerations should be considered to choose one of these two methods. Some of the most important advantages of MRCP include being Noninvasive, no need for sedation, and showing biliary tree anatomy.

One of the most important advantages of EUS over MRCP is that if a person has a CBD stone, ERCP can be performed in the same session after EUS. Other advantages of EUS include the ability to perform for patients with intracranial aneurysm clips, pacemakers, mechanical heart valves, and obese patients with claustrophobia. However, it is more aggressive than MRCP and requires sedation, and a skilled specialist to perform it.^{2, 6, 22}

According to the guideline, MRCP is safer and more acceptable than EUS in most cases. Also, EUS, like MRCP, is not available everywhere.²² Patients with CBD stones with positive EUS or MRCP should undergo ERCP or surgery for the removal of CBD stones, and there is no need for invasive tests for people with negative EUS or MRCP. However, cost, the prevalence of CBD stones, center resources, and specialist skills must be considered.²¹

2.8 ERCP

ERCP is an endoscopic technique in which an upper endoscope with a side view is inserted through the mouth and then guided into the duodenum that allows instruments to be transferred to the bile duct and pancreas. ERCP is considered a gold standard for the diagnosis and is more aggressive than MRCP and requires sedation. The benefits of ERCP over surgical treatment are well documented; however, there are significant risks of short-term complications such as pancreatitis, bleeding following sphincterotomy, infection, and perforation. Due to the associated complications and costs, ERCP should be performed in patients with a high probability (Table 6) of CBD stones.^{15, 21}

ERCP is often associated with bacteremia, which is typically transient. Antibiotic prophylaxis can reduce bacteremia. It is considered unnecessary to prescribe antibiotic prophylaxis to all patients undergoing ERCP, unless there is cholangitis, pancreatic cysts, patient is immunodeficient, or incomplete biliary drainage is predicted. All patients undergoing ERCP should receive prophylactic drugs such as indomethacin or rectal diclofenac after ERCP due to the risk of pancreatitis.^{10, 12}

2.9 Treatment of gallstones and CBD stones

Pain relief is targeted during an acute biliary colic attack. NSAIDs are used to start treatment, and opioids can be used if significant pain relief is not achieved or there is a contraindication. The pain usually subsides within 10–30 min and the patient can be discharged with oral analgesia, and if it recurs, cholecystectomy is performed for the patient. The patient is hospitalized if the pain does not subside within 4 h, as the patient is more likely to have complications.²³ There is no need for treatment for the majority of asymptomatic patients and the expected treatment is used. Unless there are the following cases, which increase the risk of fatal complications: (1) Cases in which the risk of cancer increases, such as gallbladder anomalies, gallbladder adenomas, and porcelain gallbladder; (2) Gallstones larger than 3 cm.²⁴

2.9.3 Surgery

• A.

  Cholecystectomy: Laparoscopic cholecystectomy is recommended currently as standard procedure for all patients with CBD stones and symptomatic gallbladder, except for those who are not candidates for surgery (such as gallbladder cancer, anesthesia, and coagulation-related problems).²² In industrialized countries, cholecystectomy is considered the most common abdominal surgery, so about 900,000 surgeries are performed in Europe and the United States per year.^{1, 9} According to the results of comparison of open cholecystectomy and laparoscopy, laparoscopy is generally expected to reduce pain in incision sites, length of hospital stay, shorten recovery period, and improve the quality of life.²⁶

• B.

  It is recommended to perform cholecystectomy for cases where surgery is possible. It should be performed in the same hospital or if the patient is discharged within 2 weeks thereafter, immediately after elimination of acute pancreatitis caused by gallstones.^{22, 27} The time of surgery is expressed as early cholecystectomy (EC) or delayed cholecystectomy (DC) in patients with acute choledocholithiasis. EC should be performed within 24, 48, or 72 h or 1 week of the onset of symptoms, and DC should be performed within 6 weeks of the onset of symptoms.^{2, 18, 26} Also, choledocholithiasis is performed in patients with co-occurrence of gallstones and CBD stones. Primary laparoscopic cholecystectomy should be performed within 72 h after ERCP.³ Surgical risk should be calculated in patients with acute cholecystitis-containing stones. Emergency surgery is required in a small number of patients. These include:

• 1.

  Complicated cholecystitis: This includes perforated gallbladder, gangrenous gallbladder with necrosis, and emphysema. The patient may die if emergency surgery is not performed in these cases. It is difficult to diagnose necrosis and gangrene by imaging the gallbladder.²⁷ Gangrene and necrosis should be suspected in these cases: old age, male gender, coronary heart disease, diabetes mellitus, presence of abdominal tachycardia on examination, leukocytosis, increased CRP, increased bilirubin, urea, and creatinine, increase the thickness of the gallbladder and the accumulation of fluid around the gallbladder in Imaging.

• 2.

  In cases where the disease progresses and the person becomes ill during supportive treatment, including severe pain that does not respond to analgesic therapy, fever, and unstable hemodynamics.²⁸

• C.

  Diagnosis of stones after cholecystectomy: CBD stones after cholecystectomy can be caused by the movement of the stone from the gallbladder, an undiagnosed stone during surgery, or usually a stone that has just formed in the CBD. The diagnosis of choledocholithiasis is slightly different in patients with previous cholecystectomy. Patients with choledocholithiasis are very unlikely to have normal aminotransferases and ultrasound. The incidence of choledocholithiasis after initial evaluation is from 33% to 43%. For the diagnosis of choledocholithiasis in this group of patients, MRCP and EUS are preferred over ERCP due to their low side effects.^{3, 10}

• 3.

  Stenting: Biliary and pancreatic stents are plastic tubular devices, composed of polyethylene, polyurethane, or Teflon. Stent French diameter and length range from 5 to 12 Fr and 1 to 18 cm, respectively. Pancreatic plastic stents are made of polyethylene and have a French diameter of 3–11.5 and a length of 2–25 cm. There are side holes in most plastic stents to help maintain bile or pancreatic flow if the end of the stent is blocked by bile or food, however, side holes along the stent axis can cause sludge formation. Plastic stents are found in three forms of Amsterdam, single pigtail or double pigtail (Figure 1). Metal stents were developed to increase the diameter of the stent, leading to a shorter stent opening time and more frequent stent occlusion. Metal stents are used for patients with biliary or pancreatic cancer who cannot have surgery. Metal stent diameter and length vary from 6 to 10 mm and 4 to 12 cm, respectively (Figure 2). These stents are composed of stainless steel or a variety of metal alloys, such as nitinol. These stents can be used in benign and malignant biliary diseases, bile leakage, pancreatic leakage or fistula, pancreatic stenosis, chronic pancreatitis, bile duct stones, and pancreatitis after ERCP^{29, 30} (Figure 2).

A biliary stent, also known as a bile duct stent, is used for biliary drainage as a temporary treatment or procedure until endoscopy or surgery if bile duct cleansing has not been performed by ERCP.^{2, 6} A common finding in patients with CBD stones is bacterial infection of the gallbladder, and incomplete bile duct clearance that may put patients at risk for cholangitis, therefore, the use of short-term stents in this group of patients is of utmost importance. The use of pancreatic stents is recommended in addition to rectal NSAID administration in patients at high risk for pancreatitis after ERCP due to frequent cannulation of the pancreatic duct. Long-term biliary stents as the only treatment for CBD stones should be used only for a group of patients with low life expectancy or high surgical risk.^{22, 31}