Section1: Epidemiology and aetiology
More than 80% of gallstones result from precipitation of cholesterol crystals within the gallbladder, which aggregate with other constituents of bile to form biliary sludge and calculi.
Increased secretion of cholesterol into the bile and reduced motility of the gallbladder are important factors that contribute to the formation of gallstones. Once present, they can migrate via the cystic duct into the common bile duct.
Cholesterol stones should be differentiated from pigment stones, which may form within the biliary system as a consequence of bile duct infections, haemolytic anaemia, small bowel disease such as Crohn's disease, or cystic fibrosis.
Risk factors for the development of cholesterol stones include increasing age, female sex, family history, obesity, dyslipidaemia and oestrogen therapy. Exercise and moderate alcohol consumption appear to be protective.1,2,3
Risk factors for biliary sludge include pregnancy, drugs (such as ceftriaxone, octreotide and thiazide diuretics), total parenteral nutrition and fasting.4
The genetic factors that predispose to stone formation remain the subject of continuing study.5
Common bile duct stones are estimated to be present in 10-20% of individuals with symptomatic gallstones. Recent studies of patients undergoing cholecystectomy also report a prevalence of around 10%.6,7 It should be noted that among patients where there is no clinical suspicion of ductal stones prior to surgery the incidence is significantly lower, and likely to be less than 5%.8,9,10,11 This is especially likely in those who have a normal bilirubin and normal calibre bile ducts on transabdominal ultrasound.9
Some 2-4% of individuals with stones within the gallbladder will develop symptoms over the course of a year.12,13 This is important because in most cases, biliary colic heralds the beginning of recurrent problems.
Unfortunately the natural history of stones within the common bile duct is less well understood. A large number of patients spontaneously pass ductal stones into their duodenum before or after laparoscopic cholecystectomy.8,14,15,16 Others will experience full or partial obstruction of the bile and/or pancreatic duct. The consequences can include pain, jaundice, sepsis (cholangitis), acute pancreatitis and, if left untreated, liver cirrhosis.12
Section 2: Making the diagnosis
Certain clinical presentations are highly suggestive of common bile duct stones. For example, in the context of right upper quadrant pain, fever and jaundice, ductal stones are very likely to be present. However, in many cases the patient will have pain in the absence of overt biliary obstruction.
In this setting, the doctor needs to decide whether the pain described by the patient is likely to have a biliary origin. Biliary colic typically manifests as an ache arising in the epigastrium and/or right upper quadrant of the abdomen. Onset after eating supports the diagnosis. Symptoms are episodic and last hours to days.
Having established that the patient has suspected biliary colic, the initial differential diagnosis is of stones contained exclusively in the gallbladder versus stones that are also, or solely, present in the common bile duct. It should be noted that patients can present with problems secondary to ductal stones years after a cholecystectomy has been performed.
Before investigating, the referring clinician should be mindful of alternative diagnostic possibilities, including peptic ulcer disease, pancreatic cancer and cholangiocarcinoma. Although the latter conditions typically present as painless jaundice, history alone can be misleading.
In particular, the clinician should be wary of attributing pain to stone disease if it is unremitting, radiates through to the back, or is associated with significant weight loss.
Conversely, it should be noted that although it is unusual for ductal stones to cause biliary obstruction without pain, this can occur, particularly in the older patient.
Transabdominal ultrasound and liver function tests are cheap, widely available and safe. They are therefore useful initial tests for patients who have not undergone previous assessment for possible common bile duct stones.17,18,19,20,21
Unlike gallbladder stones, common bile duct stones can be difficult to visualise on transabdominal ultrasound. However, a combination of biliary colic with a dilated bile duct on ultrasound and/or abnormal LFTs is suggestive of the diagnosis.
Clinicians should be aware of the danger of over-analysing the pattern of LFT abnormality. Whilst alkaline phosphatase (ALP) is often raised, normal levels can be seen. In the context of acute biliary obstruction the dominant abnormality can be an alanine transferase (ALT) of several hundred international units or higher.
When there is a persistent suspicion of common bile duct stones and results are non-diagnostic, further investigation may be necessary.
For patients with symptomatic stones within the gallbladder, additional tests such as intraoperative cholangiography or laparoscopic ductal ultrasound can be performed at the same time as laparoscopic cholecystectomy.
For patients requiring assessment before or after gallbladder removal, other options include magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound. Both are sensitive and specific tests which avoid the risks associated with the gold standard investigation endoscopic retrograde cholangiopancreatography (ERCP), which is now generally reserved for therapeutic intervention.22
It should be recognised that a minority of patients have troublesome symptoms consistent with biliary colic in the absence of demonstrable anatomical abnormality. Many patients in this group will have functional abdominal pain, and pain modulating medications such as low dose amitriptyline can be helpful in this setting.
However consideration should also be given to gallbladder and sphincter of Oddi dysfunction. In the former group, there is evidence of delayed gallbladder emptying on radionuclide (HIDA) scanning. Cholecystectomy can be effective for a proportion of these patients. In the latter there is typically evidence of elevated pressures in the sphincter at the end of the common bile duct (sphincter of Oddi), which have been postulated to cause episodic bile duct obstruction.
Sphincter of Oddi dysfunction is a controversial diagnosis for two reasons. Firstly, the test required to make a diagnosis (manometry of the sphincter of Oddi during ERCP) is restricted to a few tertiary centres and can cause acute pancreatitis in 20% or more of cases.23
Secondly, evidence that the recommended treatment of biliary sphincterotomy results in benefit is mixed, with a recent randomised control trial failing to demonstrate a sustained improvement in pain and disability.24 Investigation for sphincter of Oddi dysfunction should therefore only be considered in patients with severe symptoms that have not responded to medical therapy.
Section 3: Managing the condition
Stones in the gallbladder can be managed conservatively if they are not causing the patient pain, but most clinicians would offer to remove stones in the common bile duct regardless of presenting symptoms. This is consistent with current NICE guidance.16
In patients who have already undergone cholecystectomy, the treatment of choice is ERCP. This can typically be performed as a day case procedure, either under conscious sedation or general anaesthetic.
Therapeutic ERCP entails identifying the orifice of the common bile duct (the major duodenal papilla, or ampulla of Vater) where it enters the duodenum, using a flexible video endoscope passed via the oesophagus.
The duct is then cannulated and cholangiography undertaken. Following this, a biliary sphincterotomy is performed, whereby the papilla is cut using electrocautery.
Stones can then be removed using a balloon catheter or metal basket.
In settings where stone extraction is incomplete, the endoscopist will insert a plastic stent into the duct to prevent biliary obstruction, and as a precursor to further intervention.
Where duct clearance proves impossible despite one or more ERCPs, a number of specialised techniques can be deployed, such as electrohydraulic lithotripsy, extracorporeal shock wave lithotripsy and percutaneous radiological intervention. Open surgery also remains an important option for the patient with complex stone disease.
ERCP is associated with some significant risks. Acute pancreatitis is historically the most common complication and occurs more frequently in young female patients. However the incidence can be reduced by the use of non-steroidal anti-inflammatory medications at the time of intervention. Other complications include bleeding, perforation and sepsis.23
Although most adverse events settle with supportive management, there is a small mortality rate associated with the procedure of <0.5%.25
This means that careful case selection, good operator technique and thorough discussion with the patient are essential.
In patients who have common bile duct stones that have arisen from an in-situ gallbladder, the clinician needs to consider removal of the gallbladder in conjunction with bile duct clearance. Given that open surgery is avoided for routine cases, two options are available for these patients.
The patient can undergo a single-stage procedure involving laparoscopic common bile duct exploration and cholecystectomy. Alternatively, the surgeon can arrange for an ERCP to be performed before or after laparoscopic gallbladder removal.
There is no evidence of a difference in overall efficacy, morbidity or mortality when these approaches are compared.26 As a result, management strategies are usually determined by the availability of local expertise and resources.
Sepsis and pancreatitis
Special considerations apply to patients presenting with sepsis (cholangitis) or severe pancreatitis as a consequence of an obstructing common bile duct stone.
In these patients, timing of ERCP can be important, with emergency intervention in those individuals who are more seriously unwell being a potentially life-saving procedure.13 Jaundiced patients who present with fever, rigors or severe pain should therefore be referred to secondary care for same day assessment, and possible hospital admission.
Section 4: Prognosis
Prognosis in patients with common bile duct stones is generally excellent if the condition is recognised and the stones are successfully removed.
This can be achieved in most cases, regardless of whether ERCP or surgical extraction is selected. 23,27 Recurrent problems following duct clearance, or cholecystectomy, can occur but are uncommon.
Risks and outcomes
The overall risks of ERCP and surgery are comparable; both have a mortality rate of less than 1%.23, 27 However, it is important to recognise that some subgroups of patients may have more severe problems and a worse outcome.
For example, 20% of patients with bacterial cholangitis fail to respond to antibiotic therapy. Even with urgent ERCP and supportive medical therapy, the 30-day mortality rate in this group may be as high as 10%.28
Moreover, management of large or intrahepatic ductal stones can be very challenging, particularly when associated with multiple comorbidities.
Intervention in patients who have had previous gastroduodenal surgery can also be difficult and require specialised techniques.
Management of incidental findings
With increased use of imaging, the clinician is occasionally confronted with an elderly patient who has been found incidentally to have ductal stones, despite the absence of symptoms and normal biochemistry. There are no studies describing the natural history of such patients if stones are left in situ. Care in this setting has to be individualised, though in keeping with advice above, removal should be considered. This is on the basis that complications from stone disease can be severe and ERCP in the older patient is usually well tolerated.
Section 5: Case study
A normally well 83-year-old woman presented to her GP with six weeks of intermittent abdominal pain.
She had a distant history of cholecystectomy and was taking dabigatran for AF. On examination she looked well.
Mild right upper quadrant discomfort was elicited on palpation of the abdomen. LFTs revealed a bilirubin of 28 micromol/L, ALT of 96 IU/L, AP of 200 IU/L and gamma GT of 288 IU/L. Clotting screen revealed a normal INR of 1.1 (normal range 0.86 – 1.14). Creatinine was 62 micromol/L.
An ultrasound was organised by her doctor, along with referral to gastroenterology for an urgent outpatient assessment.
The patient was reviewed by a gastroenterologist with the results of her ultrasound.
This showed a maximum common bile duct diameter of 10mm, but no intrahepatic duct dilation, no obvious stone in the duct and a normal-looking pancreas. Her pain had settled since visiting her GP and repeat LFTs showed normalisation.
At this point, the gastroenterology team suspected she had passed a common bile duct stone. An outpatient MR cholangiogram was performed, which identified a 5mm filling defect in the distal common bile duct consistent with a retained stone.
The patient was assessed for day case ERCP. Having been counselled regarding the risks of the procedure, she discussed her options with her family and then agreed to proceed.
To minimise the risk of bleeding, her dabigatran was stopped three days before admission noting that it has a half-life of 12-14 hours and exerts a maximum anticoagulation effect within 2-3 hours after ingestion. The INR was not checked as it has no role in monitoring dabigatran therapy or other direct thrombin inhibitors, and a normal result is not indicative of normal clotting in this setting.
At ERCP, the presence of a common bile duct stone was confirmed on cholangiography. Biliary sphincterotomy was performed and the calculus was removed with a 10mm balloon catheter.
The patient recovered quickly from conscious sedation and was discharged six hours later, with instructions to restart her anticoagulation, and to present to A&E if she developed any pain, fever, black stools or other symptoms post-procedure. She was well at follow up one month later.
This case illustrates several points. First, pain in the context of abnormal LFTs should always raise the suspicion of ductal stones.
Second, ultrasound can be diagnostic if it visualises a stone in the duct, but more commonly, this procedure will simply demonstrate common bile duct dilatation.
Finally, ERCP can be safely performed in older patients, but it is important for the patient to be adequately assessed before the procedure is undertaken.
Morbidities that influence the outcome should be identified and the patient should understand the potential risks and benefits of undergoing ERCP. Purely diagnostic procedures should be avoided.
It should be noted that all patients need to be screened for coagulopathy because this is a common finding before ERCP, either as a result of prescribed medication or vitamin K deficiency secondary to biliary obstruction. Where this is identified, steps to correct blood clotting are usually undertaken to minimise the risk of bleeding following sphincterotomy. 22 Physicians should be aware newer anticoagulant drugs (NOACs) have different pharmacokinetics to warfarin and their effect cannot be measured using INR.
|SUGGESTED FURTHER CPD ACTIVITIES|
- Dr Earl Williams is consultant gastroenterologist, Royal Bournemouth Hospital, Dorset.
- Dr Ghassan El Sayed is ERCP and EUS fellow, Royal Bournemouth Hospital, Dorset.
- Afamefuna S, Allen SN. Gallbladder disease: Pathophysiology, diagnosis and treatment. US Pharmacist. 2013; 38(3): 33-41
- Leitzmann MF, Giovannucci EL, Stampfer MJ, et al. Prospective study of alcohol consumption patterns in relation to symptomatic gallstone disease in men. Alcohol Clin Exp Res. 1999; 23: 835–41
- Department of Health. At least five a week. 2004.
- Stinton LM, Shaffer EA. Epidemiology of Gallbladder Disease: Cholelithiasis and Cancer. Gut Liver. 2012; 6(2): 172–187
- Marschall HU, Einarsson C. Gallstone disease. J Intern Med 2007; 261(6): 529-42.
- Balandraud P, Biance N, Peycru T et al. Fortuitous discovery of common bile duct stones: results of a conservative strategy. Gastroenterol Clin Biol 2008; 32: 408-12.
- Videhult P, Sandblom G, Rasmussen IC. How reliable is intraoperative cholangiography as a method for detecting common bile duct stones? Surg Endosc 2009 ; 23: 304-12.
- Yousefpour AS, Kalbasi H, Setayesh A et al. Predictive value and main determinants of abnormal features of intraoperative cholangiography during cholecystectomy. Hepatobiliary Pancreat Dis Int 2011; 10: 308-12
- Collins C, Maguire D, Ireland A et al. A prospective study of common bile duct calculi in patients undergoing laparoscopic cholecystectomy: natural history of choledocholithiasis revisited. Ann Surg 2004; 239: 28-33.
- Nebiker CA, Baierlein SA, Beck S et al. Is routine MR cholangiopancreatography (MRCP) justified prior to cholecystectomy? Langenbecks Arch Surg 2009; 394: 1005-10.
- Lill S, Rantala A, Pekkala E et al. Elective laparoscopic cholecystectomy without routine intraoperative cholangiography: a retrospective analysis of 1101 consecutive cases. Scand J Surg 2010; 99: 197-200.
- Attili AF, De Santis A, Capri R et al. The natural history of gallstones: the GREPCO experience. The GREPCO Group. Hepatology 1995; 21: 655-60.
- Halldestam I, Enell EL, Kullman E et al. Development of symptoms and complications in individuals with asymptomatic gallstones. Br J Surg 2004; 91: 734-8.
- Tse F, Yuan Y. Early routine endoscopic retrograde cholangiopancreatography strategy versus early conservative management strategy in acute gallstone pancreatitis. Cochrane Database Syst Rev 2012
- Lefemine V, Morgan RJ. Spontaneous passage of common bile duct stones in jaundiced patients. Hepatobiliary Pancreat Dis Int 2011; 10: 209-13.
- NICE. Gallstone disease: diagnosis and initial management. 2014
- Pourseidi B, Khorram-Manesh A. Triple non-invasive diagnostic test for exclusion of common bile ducts stones before laparoscopic cholecystectomy. World J Gastroenterol 2007; 13: 5745-9.
- Jovanovic P, Salkic NN, Zerem E et al. Biochemical and ultrasound parameters may help predict the need for therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in patients with a firm clinical and biochemical suspicion for choledocholithiasis. Eur J Intern Med 2011; 22: e110-e114.
- Nathan T, Kjeldsen J, Schaffalitzky de Muckadell OB. Prediction of therapy in primary endoscopic retrograde cholangiopancreatography. Endoscopy 2004; 36: 527-34.
- Onken JE, Brazer SR, Eisen GM et al. Predicting the presence of choledocholithiasis in patients with symptomatic cholelithiasis. Am J Gastroenterol 1996; 91: 762-7.
- Trondsen E, Edwin B, Reiertsen O et al. Prediction of common bile duct stones prior to cholecystectomy: a prospective validation of a discriminant analysis function. Arch Surg 1998; 133: 162-6.
- Williams EJ, Green J, Beckingham I et al. Guidelines on the management of common bile duct stones (CBDS). Gut 2008; 57(7): 1004-21.
- Freeman ML, Nelson DB, Sherman S et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996; 335: 909-18
- Cotton PB, Durkalski V, Romagnuolo J. Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial. JAMA. 2014 May;311(20):2101-9.
- Angelo Andriulli MD, Silvano Loperfido MD. Incidence Rates of Post-ERCP Complications: A Systematic Survey of Prospective Studies. The American Journal of Gastroenterology 2007; 102: 1781–1788
- E.S. J Clayton, S. Connor. Meta-analysis of endoscopy and surgery versus surgery alone for common bile duct stones with the gallbladder in situ. Br J Surg. 2006; 93(10) 1185-91
- Alexakis N, Connor S. Meta-analysis of one- vs. two-stage laparoscopic/endoscopic management of common bile duct stones. HPB (Oxford) 2012; 14(4): 254-9.
- Lai EC, Mok FP, Tan ES et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med 1992; 326: 1582-6.