How do you define unexplained biliary pain?

  • – Patients with gallbladder-type symptoms and gallbladder in situ, but with no gallbladder stones or sludge apparent on imaging, generally with abnormal gallbladder emptying on scintigraphy.

  • – Patients who are postcholecystectomy and have unexplained biliary pain are discussed under the chapter, “Sphincter of Oddi dysfunction.”

Biliary dyskinesia; gallbadder dyskinesia; chronic acalculous cholecystitis (although inflammation is often [1/3 of cases] not proven pathologically, or may be incidental to the pain)

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Acute acalculous cholecystitis generally presents with gallbladder wall thickening on ultrasound/CT, abnormal scintigraphy, and elevated serum inflammatory markers, and is generally different than what is being discussed in this chapter. Risk factors include elderly men, vasculitis, burns, sepsis, trauma/post-surgical, and pregnancy.

Occult sludge and impaired blood flow to the gallbladder are part of the pathophysiology in many cases, with coagulation factors and prostaglandins playing a role. Opportunistic infections, such as in HIV-positive or transplant patients, can occur with cytomegalovirus (CMV), or cryptosporidia. Ebstein-Barr virus (EBV)-related cholecystitis can occur in children as an acute acalculous cholecystitis.

What disease states can produce this sign or symptom?

Alternative diagnoses can include occult cholelithiasis, choledocholithiasis, irritable bowel syndrome (IBS; right colon or duodenal spasms or right-sided visceral hypersensitivity, right-sided stool/constipation), dyspepsia (ulcer and non-ulcer), chronic pancreatitis, atypical reflux/gas, inflammation/stretch of the liver capsule (sometimes seen with fatty liver and other processes), adhesions, scar-related pain, neuropathic pain (e.g., from thoracic disc disease), and costochondral/abdominal muscle musculoskeletal pain (Table I).

Table I.
Other diagnoses Selected differentiating factors
Pain related to bowel movements
Associated constipation, diarrhea, postprandial urgency or other symptoms
IBS Associated bloating
Changing/fleeting location of pain
Response to antispasmodics, neuromodulators
Other risk factors for visceral hypersensitivity, such as longstanding narcotics
Response to antacids, Hp eradication, stopping NSAID, or promotility medications
Nausea-predominant symptoms
Dyspepsia Associated reflux-type symptoms or radiation into chest
Post-prandial distress/bloating
Abnormal EGD
Pain positional
Little to no relationship to meals
Musculoskeletal and neuropathic pain Associated back pains
Physical exam rib tenderness, reproduction with spine percussion, or increase tenderness when muscles tensed
Risk factors for chronic pancreatitis
Centrally located pain, often radiating to the back
Chronic pancreatitis Structural (CT/MRI/EUS/ERCP) or functional (endocrine/exocrine) abnormality in the pancreas
+/- Response to pancreatic enzymes

What urgent or emergent measures should be initiated even before the diagnosis is established?


What is the appropriate initial diagnostic approach to identify the specific underlying disease?

Ruling out occult lithiasis – imaging
Noninvasive biliary imaging

The main alternate diagnosis here is missed gallbladder lithiasis, which will have identical history and physical exam findings. Therefore, the initial test of choice is a gallbladder/RUQ ultrasound. Since this test is somewhat operator-dependent, if normal on one ultrasound, repeating this test in a more experienced center can be helpful. In addition, moving and shaking the gallbladder can be used as part of that procedure. It is less likely that this, and other maneuvers, can be done when a patient is in acute pain; therefore, if the original ultrasound was done during a pain attack, repeating when the pain has settled can allow a more thorough exam.

Although MRCP (magnetic resonance cholangiopancreatography) is well studied for choledocholithiasis, it is not as well studied in gallbladder stones. It is probably inferior to ultrasound for small stones and sludge, except perhaps in those patients with anatomy that limits the sensitivity of conventional RUQ ultrasounds, such as obesity (subcutaneous fat increases the distance from the skin surface to the gallbladder, decreases the movability of the gallbladder, and the fat attenuates ultrasound waves).

Endoscopic ultrasound (EUS) can detect missed lithiasis in up to 80% of patients with biliary pain and a normal RUQ ultrasound in some studies, but the frequency is likely much lower in atypical pain or after high-quality careful RUQ ultrasound. (See Figure 1.)

Figure 1.

Occult lithiasis on EUS, with arrows indicating 1-2 mm nonshadowing echogenicities representing bits of sludge seen to be floating and mobile on real-time imaging.

CT is not a good test for cholelithiasis but can detect wall thickening or pericholecystic fluid or alternate diagnoses in selected cases.

Invasive sampling

Endoscopic retrograde cholangiopancreatography (ERCP) to sample cystic duct or gallbladder bile is too dangerous (post-ERCP pancreatitis) for its low yield, and bile analysis for crystals is not done well enough in most centers anyway. Sampling of bile duct bile is probably not helpful. A study looking at EUS with gallbladder FNA to sample gallbladder bile for crystals was ended early because of a high rate of bile leaks, and this should not be done.

Gallbladder motility testing

After cholelithiasis has been carefully ruled out, the next step is to assess for dysmotility. The classic test for this is a scintigraphy (HIDA or DISIDA) scan to assess gallbladder filling and emptying. Poor emptying (generally <35% [cutoffs used in different studies unfortunately variable, however]), stimulated by cholecystokinin (CCK), is a sign of a motility problem or a problem with the gallbladder wall that affects its distensibility and flexibility, such as inflammation.

An exaggerated ejection fraction, indicating a possibly hyperkinetic/hypercontractile gallbladder, may also indicate a disorder that may respond to cholecystectomy, but that is more controversial.

It is generally thought that these motility tests are only moderately sensitive and specific for this condition and to predict response to therapy.

History and physical exam

Most patients are women (90% in the only randomized trial), just as in SOD, for an unclear reason.

The pains are typically 15 minutes to a few hours in duration, and are often following meals, especially in the evening, similar to symptomatic cholelithiasis. (Central) epigastric and RUQ pain locations are equally likely due to referral of foregut visceral pain to the center of the epigastrium in many people. It is unlikely to cause nausea alone and is unlikely to cause chronic pain; both these presentations can be seen, but response to cholecystectomy may be lower. Weight loss is uncommon but nausea and anticipatory fear of pain can reduce intake and can lead to mild weight changes.

Physical exam can be normal, especially between attacks, but mild to moderate tenderness in the epigastrium and/or RUQ is common. Murphy’s sign is not present. Maneuvers to exclude musculoskeletal causes for pain are useful in selected patients, including palpation with and without tensing of the abdominal wall and percussion of thoracic spine, especially if there is a positional component to the pain (worse when lifting, prolonged standing, bending over, etc.). Laboratory testing, including liver enzymes, is generally normal, but ,because of the prevalence of fatty liver, mild enzyme elevations (unrelated) can be seen. Hepatomegaly should be ruled out.

Atypical pain and nonbiliary testing

For less typical biliary pain (e.g., more chronic pain, associated nausea/bloating, associated constipation, or reflux/chest-pain), a trial of antacid medication and/or antispasmodic and/or osmotic laxative might be reasonable. Nausea-predominant presentations may warrant a gastric emptying study. Patients with partial response to antacid medication may warrant esophageal pH testing prior to resorting to cholecystectomy.

Almost all patients being considered for cholecystectomy for this syndrome should have an upper endoscopy to rule out upper GI pathology. Prior to this, exclusion of NSAIDs (nonsteroidal anti-inflammatory drugs) and/or testing and treating for H. pylori can be tried, as this has a small benefit over placebo in non-ulcer dyspepsia.

With regard to patients with colonic or other IBS-type symptoms, the clinician should consider performing a colonoscopy, especially when the patient is over the age of 50 and especially if gallbladder function testing is normal.

What is the diagnostic approach if this initial evaluation fails to identify the cause?

The presence of sphincter of Oddi dysfunction (SOD) in a patient that still has his/her gallbladder is a very controversial area, as this is generally felt to be a postcholecystectomy pain syndrome. Although referral to a tertiary center to consider an ERCP with manometry can be made, often those centers would prefer not to do that study in patients with a gallbladder (GB) in situ.

Empiric cholecystectomy in patients with a normal functional test and normal structural testing is selectively performed. However, a tertiary opinion should be obtained, other causes should be ruled out, and other empiric therapies exhausted. Patients should understand that it is very possible that gallbladder surgery will not help their pain.

What is the effectiveness of treatment?

Treatment consists of laparoscopic cholecystectomy.

Treatment efficacy varies from study to study but is as low as 30% to 50% in patients with atypical pain, nausea, or dyspepsia; however, the efficacy can be much higher in highly selected patients with typical biliary pain. A small percentage (<0.5%) of patients can have complications such as a bile leak or other duct injury, among others, but mortality is rare. Conversion to open cholecystectomy occurs uncommonly and takes on the risks of that laparotomy – longer recovery time, wound infections, etc.

The efficacy of empiric cholecystectomy in patients with normal gallbladder testing, including ultrasound and HIDA, is not known but anecdotally may be helpful in selected patients.

The efficacy of nonsurgical therapies, such as antispasmodics or neuromodulating drugs, is really unknown and largely unstudied, but these are reasonable to try in selected patients, especially if IBS is the differential.

The efficacy of ERCP with manometry-directed sphincterotomy for possible SOD (generally considered a post-cholecystectomy syndrome) in patients who are not postcholecystectomy is unclear. Limited subgroup analyses, such as using SOD outcome data from Indiana University, have shown some benefit even in patients with gallbladder in situ. This needs further study.

What's the evidence?

Yap, L, Wycherley, AG, Morphett, AD, Toouli, J. “Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy”. Gastroenterology. vol. 101. 1991. pp. 786-93.

Levine, R, Fromm, H. “Acalculous abdominal pain in patients with abnormal cholescintigraphy: is cholecystectomy the answer”. Gastroenterology. vol. 102. 1992. pp. 742-3.

DiBaise, JK, Oleynikov, D. “Does gallbladder ejection fraction predict outcome after cholecystectomy for suspected chronic acalculous gallbladder dysfunction? A systematic review”. Am J Gastroenterol. vol. 98. 2003. pp. 2605-11.

Gurusamy, KS, Junnarkar, S, Farouk, M, Davidson, BR. “Cholecystectomy for suspected gallbladder dyskinesia”. Cochrane Database of Syst Rev. 2009.

Rastogi, A, Slivka, A, Moser, AJ, Wald, A. “Controversies concerning pathophysiology and management of acalculous biliary-type abdominal pain”. Dig Dis Sci. vol. 50. 2005. pp. 1391-40.

Fullarton, GM, Bell, G. “Prospective audit of the introduction of laparoscopic cholecystectomy in the west of Scotland. West of Scotland Laparoscopic Cholecystectomy Audit Group”. Gut. vol. 35. 1994. pp. 1121-6.

Gall, CA, Chambers, KJ. “Cholecystectomy for gall bladder dyskinesia: Symptom resolution and satisfaction in a rural surgical practice”. ANZ J Surg. vol. 72. 2002. pp. 731-4.

Ozden, N, DiBaise, JK. “Gallbladder ejection fraction and symptom outcome in patients with acalculous biliary-like pain”. Dig Dis Sci. vol. 48. 2003. pp. 890-7.

Goncalves, RM, Harris, JA, Rivera, DE. “Biliary dyskinesia: natural history and surgical results”. Am Surg. vol. 64. 1998. pp. 493-8.

Krishnamurthy, GT, Krishnamurthy, S, Brown, PH. “Constancy and variability of gallbladder ejection fraction: impact on diagnosis and therapy”. J Nucl Med. vol. 45. 2004. pp. 1872-7.

Eversman, D, Fogel, EL, Rusche, M. “Frequency of abnormal pancreatic and biliary sphincter manometry compared with clinical suspicion of sphincter of Oddi dysfunction”. Gastrointest Endosc. vol. 50. 1999. pp. 637-41.

Jacobson, BC, Waxman, I, Parmar, K. “Endoscopic ultrasound-guided gallbladder bile aspiration in idiopathic pancreatitis carries a significant risk of bile peritonitis”. Pancreatology. vol. 2. 2002. pp. 26-9.