Gallstones and their associated complications
Cholelithiasis, the presence of gallstones in the gallbladder, is estimated to occur in 10 – 15% of the adult population
in the United States.1 In New Zealand, a small study estimated that 20% of the New Zealand population aged
30 to 75 years had cholelithiasis.2 Most people with cholelithiasis are asymptomatic, but over a ten year-period
approximately one-third will develop symptoms.3 Symptoms are usually caused by blockage of the cystic duct
by a gallstone or by migration of a gallstone into the common bile duct. Blockage of the cystic duct causes pressure within
the gallbladder to rise, resulting in symptomatic cholelithiasis that is usually accompanied by a distinctive pattern
of abdominal pain, referred to as biliary colic. Blockage of the common bile duct causes a similar pain, but may be accompanied
by jaundice, pancreatitis or cholangitis.
Approximately 70% of gallstones are cholesterol stones, i.e. more than half the stone is formed from cholesterol.4 These
stones form when bile becomes supersaturated with cholesterol, following increased secretion of cholesterol from the liver
or when production of bile salt or lecithin (an emulsifying fatty substance) decreases.4 Cholesterol microcrystals
then precipitate from biliary sludge within the gallbladder.1 Black pigment stones are the other significant
type of gallstone found among people in Western countries.4 These are made up of calcium bilirubinate and
are related to haemolytic disorders with an increased bilirubin load, and occasionally cirrhosis.
Cholelithiasis is formally diagnosed by abdominal ultrasound, and in symptomatic patients, is treated surgically with
cholecystectomy.4 Patients with uncomplicated episodes of biliary colic can generally be managed in the community
with analgesics and lifestyle advice while they wait for surgery.
Risk factors for gallstone formation
Factors associated with an increased risk of cholelithiasis include:4
- Increasing age
- Increasing body mass
- Female gender
- Pregnancy (see: “Cholelithiasis in women who are pregnant”)
- Medicines, e.g. oral contraceptives, fibrates
- Family history
- Rapid weight loss, e.g. following bariatric surgery
- Haemolytic disorders, e.g. haemolytic anaemia
Gallstones are more prevalent in people who are obese because increasing body mass is associated with an increased production
of cholesterol by the liver.4 Periods of rapid weight loss are also associated with gallstone formation and
people are more likely to become symptomatic during this time. This is possibly due to an increase in the relative amount
of cholesterol in the gallbladder and reduced gallbladder contractility.4 In contrast, people who take statins
long-term are less likely to undergo surgery for biliary colic. One study found that statin use for periods of five years
or more was associated with a decreased risk of cholecystectomy.5 Exercise can also reduce a patient’s likelihood
of developing gallstones and moderate physical activity is reported to prevent gallstone formation independently of body
The higher prevalence of cholelithiasis among females is most likely related to oestrogen increasing biliary secretion
of cholesterol and progesterone reducing bile acid secretion by increasing gallbladder stasis.7 The risk of
gallstone formation in females is increased by taking oral contraceptives.8
People who have a first-degree relative with cholelithiasis are almost 4.5 times more likely to develop gallstones.9 Diabetes,
hypertriglyceridaemia, Crohn’s disease, cirrhosis and conditions that cause the bile duct to become blocked, or procedures
that cause bile salt loss, e.g. ileal resection, are also associated with cholelithiasis.4
Diagnosing biliary colic
Biliary colic typically refers to a steady pain, rather than a series of “colicky” waves that might be expected from
the term.4 The pain originates in the right upper quadrant or epigastric area and can radiate around to the
subscapular region.8 The pain will typically last for more than 30 minutes with an upper limit of six hours,
and is unaffected by movement, body position or defaecation.4 The patient will often be nauseated and may
vomit.8 Episodes of biliary colic often occur following a meal or at night, and after an initial episode,
recurrence is common and may occur within hours.4 In some patients, however, recurrence may occur years later.4
Atypical symptoms of biliary colic are not unusual and include: chest pain, belching (eructation), rapid satiety, dyspepsia
and non-specific abdominal pain.4
Choledocholithiasis (see glossary) can cause pain that is indistinguishable from biliary colic but may be accompanied
by obstructive jaundice, cholangitis or acute pancreatitis.11 The risk of bacteraemia is also increased in
patients with choledocholithiasis as increased biliary pressure can force bacteria from the bile duct into the blood stream
of the liver.10
Consider differential diagnoses
As gallstones are prevalent, and most people who have them are asymptomatic, their presence does not necessarily mean
that a patient’s abdominal pain is due to cholelithiasis.
Gastro-oesophageal reflux disease (GORD), peptic ulcer disease, non-ulcer dyspepsia, hepatitis, right-sided pyelonephritis,
nephrolithiasis, appendicitis, pancreatitis, bowel obstruction, bowel ischaemia, right-sided pneumonia, abnormal aortic
dissection and an atypical presentation of ischaemic heart disease are among the many conditions that may cause upper
abdominal pain. Irritable bowel syndrome should also be considered, particularly in patients with a longer history of
symptoms who report pain that is relieved by defaecation and pain that is more constant over 24 hours.8 Colorectal
cancer should be considered in patients, particularly those aged over 50 years and those with a family history of this
For further information, see: “Surveillance
of people at increased risk of colorectal cancer”, BPJ 44 (May, 2012).
Examining the patient
Patients with uncomplicated biliary colic will typically display pain in the right upper quadrant and epigastrium, and
on examination may display voluntary guarding.4 Severe and ongoing pain and rebound tenderness on examination
suggest that the patient has developed acute cholecystitis, the suspicion of which should be increased if the patient
displays a positive Murphy’s sign.
To assess for a positive Murphy’s sign ask the patient to inspire deeply while palpating the right subcostal region.
Increased discomfort in patients with a positive sign is due to inflammation of the peritoneum overlying the gallbladder
and therefore palpation causes the patient to “catch” their breath. However, a negative sign does not necessarily exclude
cholecystitis and should be interpreted with caution, particularly in older patients.12
Ascending cholangitis is a dangerous condition identified clinically by Charcot’s triad of jaundice, fever and right
upper abdominal pain.10 Mirizzi syndrome is usually diagnosed after imaging a patient with long-term gallstone
disease. The presentation of Mirizzi syndrome can vary greatly but usually includes jaundice or abnormal liver function
tests (LFTs), associated with dilated intra-hepatic ducts on ultrasound with a large stone in Hartman’s pouch.
Investigating biliary colic
Routine testing of patients with suspected biliary colic should include:
- Full blood count (FBC)
- Liver function tests (LFTs)
- Serum creatinine
- Serum amylase
- Urine dipstick
In patients with uncomplicated biliary colic, FBC, LFTs and markers of pancreatic injury, i.e. serum amylase, should
be within the normal range.4 Leukocytosis and an elevated CRP are typical in patients with acute cholecystitis,
but liver enzymes are either normal or only marginally elevated. Markedly elevated liver enzymes are suggestive of choledocholithiasis,
which may be complicated by acute pancreatitis (elevated serum amylase) or cholangitis, indicated by Charcot’s triad.
Gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) levels will be raised in 94% and 91% respectively of
patients with choledocholithiasis.10 Serum amylase is elevated transiently in the majority of patients with
acute pancreatitis. Transient elevation of aspartate aminotransferase (AST) and ALT in combination with acute biliary
pain and elevated amylase is strongly suggestive of passage of a bile duct stone. If the patient has atypical chest pain
then an ECG should be performed and a troponin test requested to help exclude a cardiac cause for the pain.
Ultrasound is the gold-standard diagnostic test for biliary colic
Abdominal ultrasound is used to confirm a diagnosis of biliary colic in all patients before a laparoscopic cholecystectomy
is performed. Local guidelines may vary, but usually recommend a prompt abdominal ultrasound (within five days) for patients
- Jaundice and abnormal LFTs
- Significant, persistent or recurrent upper quadrant pain
A routine ultrasound (within four weeks) should be arranged for patients with characteristic abdominal pain and laboratory
results that are normal or mildly abnormal, but without jaundice.
Red-flags for acute referral to hospital for surgical assessment include:
- Biliary colic that cannot be effectively controlled with analgesia
- Obstructive jaundice
- Suspected acute cholecystitis
- Acute pancreatitis
Abdominal ultrasound can detect approximately 95% of gallstones as well as being able to detect complications
of gallstones, e.g. inflammation of the gallbladder wall or obstruction of the common bile duct.4 Ultrasound
can also identify biliary sludge in some patients, which is seen as layering within the gallbladder.
The sensitivity of ultrasound for detecting gallstones decreases as the patient’s body mass increases and may also be
affected by increased bowel gas, which can occur in patients with acute complications, such as pancreatitis. The sensitivity
of ultrasound for bile duct stones is approximately 60% and patients with dilated bile ducts or other suspicious features
on ultrasound will usually require further investigation.
Magnetic resonance imaging (MRI) will detect bile duct stones in approximately 90% of patients with choledocholithiasis.10
Endoscopic retrograde cholangiopancreatography (ERCP) may be used to diagnose and treat common bile duct stones and
to clear the common bile duct prior to or after laproscopic cholecystectomy in patients with cholelithiasis complicated
by choledocholithiasis.14 ERCP requires the patient to be sedated and involves fluoroscopy and may include
Managing biliary colic in primary care
Patients who have had an episode of uncomplicated biliary colic may be managed in the community while they wait for
a definitive diagnosis and surgical assessment. During this time recurrent bouts of biliary colic may occur.17
The patient’s dietary history may indicate foods that are triggers for biliary colic which can then be avoided, e.g.
fatty food and high-fat dairy products. A high-fibre diet that contains nuts and is low in saturated fat is associated
with a reduced risk of gallstone formation and it is possible that making dietary changes will improve the patient’s symptoms.6 Paradoxically,
for patients on a low-calorie diet the consumption of 10 g of fat per day has been shown to prevent gallstone formation,
most likely by promoting gallbladder emptying.6 Coffee and moderate amounts of alcohol have also been suggested
by some researchers to have a protective effect against biliary colic.6 Coffee is known to affect a number
of processes involved in gallstone formation, including enhancing gallbladder contractility and decreasing cholesterol
crystalisation in bile.18
NSAIDs are the first-line analgesic
NSAIDs are generally the preferred class of analgesia for biliary colic in patients with severe pain and those treated
in the Emergency Department. However, there are a limited number of studies assessing the comparative effectiveness of
analgesics in the treatment of biliary colic. In particular there are no studies assessing the effectiveness of combinations
of analgesics, e.g. NSAIDs with opioids or NSAIDs with anti-spasmodics. In practice it may be necessary to provide multiple
analgesics to patients who are in severe pain.3
Before prescribing NSAIDs for upper abdominal pain consider if the patient’s pain may have another cause, e.g. peptic
ulcer disease, for which NSAIDs are contraindicated.
Diclofenac injectable preparation is indicated for rapid onset pain relief in patients with biliary
- This can be given as diclofenac 75 mg (3 mL) injection, deep into the upper outer quadrant of the gluteal muscle,
repeated once (may be given 30 minutes later if required, in the contralateral muscle)
- It may also be combined with oral diclofenac, 75 mg, to a maximum total dose of 150 mg, daily, for a maximum of two
- Diclofenac suppositories may be considered as an alternative route of administration for patients unable to tolerate
the oral or intramuscular route
Diclofenac is often the first-line NSAID for patients with biliary colic because
of its speed of onset, when given intramuscularly, and its availability. Ten diclofenac 50 mg suppositories and five 75
mg injections are available fully subsidised on a PSO for general practices to have available for acute administration.
Oral ibuprofen, 200 – 400 mg, three to four times daily, or naproxen 250 – 500 mg, twice daily, may
be considered as an alternative for subsequent bouts of biliary colic in some patients as these NSAIDs are associated
with a lower cardiovascular risk than diclofenac.15, 19 For example, diclofenac is contraindicated in patients
who have had a myocardial infarction in the past 12 months.19
A review of eleven studies involving over 1000 patients found that NSAIDs (mainly diclofenac 50 – 75 mg) were more effective
at controlling the pain of biliary colic than anti-spasmodic medicines, e.g. hyoscine butylbromide, and were equally as
effective as opioids (mainly pethidine).3 NSAIDs may also halt the progression of biliary colic to cholecystitis
and other complications by limiting the production of prostaglandins.6 NSAIDs were found to reduce the overall
risk of short-term complications, i.e. jaundice, acute cholangitis, acute cholecystitis and acute pancreatitis, by approximately
half compared to placebo.3 Patients who were potentially at increased risk of the adverse effects of NSAIDs
were excluded from this study, e.g. patients aged over 65 years, patients with diabetes or other systemic co-morbidities.3
NSAIDS may not be the most appropriate analgesic for some patients with biliary colic, e.g. patients with a history
of peptic ulcer. For these patients other analgesics such as codeine and paracetamol or morphine may need to be considered.
For further information see: “Non-steroidal anti-inflammatory drugs
(NSAIDs): Making safer treatment choices”, BPJ 55 (Oct, 2013).
Codeine and paracetamol may be superior to NSAIDs for moderate pain
Codeine and paracetamol may be an effective alternative to NSAIDs in patients with moderate biliary colic. A combination
product of paracetamol 500 mg with codeine 30 mg, was found to provide superior pain relief to tramadol, oral or intramuscular
diclofenac, ibuprofen and hyoscine in a survey of patients with biliary colic.17 However, for the 79% of patients
with severe pain it was found that NSAID analgesia was the most effective.17
Codeine is available fully subsidised in New Zealand in 15 mg, 30 mg and 60 mg tablets which can be prescribed in addition
to paracetamol. Combination medicines containing both paracetamol, 500 mg, and codeine, 8 – 15 mg, are available in New
Zealand, but only the 8 mg formulation is fully subsidised.
Opioids are an alternative to NSAIDs for severe pain
Morphine 5 – 10 mg, IM, is an alternative treatment to NSAIDs for acute pain management in patients with severe pain
due to biliary colic and for patients when an NSAID is unsafe or fails to provide effective pain relief.15 Antiemetics
can be prescribed “as needed” if nausea occurs with the use of morphine.
Morphine is generally preferred over pethidine in New Zealand. Historically, morphine has been avoided in the treatment
of acute biliary colic and pancreatic pain because it was thought to induce spasm in the sphincter of Oddi to a greater
degree than other opioids. Pethidine has therefore traditionally been used in preference. However, a systematic review
found that all narcotics increased biliary pressure to a similar degree and that there was no outcome-based evidence to
support the use of pethidine over morphine.20 Furthermore, it was concluded that morphine may be of more benefit
to patients with acute pancreatitis than pethidine as it provides longer pain relief and a lower risk of seizures.20 Pethidine
is still suggested by some international guidelines for pain control in patients with acute cholecystitis while waiting
for hospital admission, e.g. pethidine intramuscularly, 25 – 100 mg, which may be repeated after four hours.15, 19
Antispasmodic medicines may be combined with NSAIDs or opioids
Antispasmodic medicines, e.g. hyoscine butylbromide, are reported to produce effective analgesia in some patients with
biliary colic, however, other patients may not gain any benefit.8 If hyoscine butylbromide is prescribed to
patients with biliary colic, it is recommended that it is used in combination with an NSAID or opioid.
Hyoscine butylbromide is available in 10 mg tablets at a recommended dose of 20 mg, four times daily.15 Hyoscine
butylbromide is also available in a 20 mg/mL injectable formulation which can be given by intramuscular or subcutaneous
injection, 20 mg, repeated after 30 minutes if necessary, to a maximum of 100 mg, daily.15
Antiemetics may be required for some patients
Nausea is a common symptom in patients with biliary colic and may also be experienced by patients taking opioids. For
some patients with biliary colic their nausea will be relieved once an analgesic has been administered. For patients that
experience ongoing nausea once their pain has been controlled, antiemetics such as metoclopramide, cyclizine and ondansetron
(see NZF for dosing details) may be considered. Some patients may need
to trial more than one antiemetic before they achieve effective symptom control.
Surgical management of biliary colic
Patients with biliary colic should be referred for consideration of laparoscopic cholecystectomy to prevent future episodes.
This surgical procedure takes approximately 60 – 90 minutes and requires an average hospital stay of one to three days.11 Laparoscopic
cholecystectomy is associated with a similar level of risk as open cholecystectomy but with less post-operative pain and
faster recovery. Evidence supports early surgical intervention for patients with acute cholecystitis and the majority
of these patients can be managed laparoscopically.21 Patients with severe acute cholecystitis, whose health
is too fragile to undergo surgery, can be managed through the acute episode with percutaneous drainage of the gallbladder,
plus antibiotics. In all patients the individual risks and benefits of the choice of procedure will need to be balanced.
Patients with severe co-morbidities may be unfit to undergo elective cholecystectomy.
Patients will be asked to consent to both laparoscopic and open procedures before surgery is performed. Conversion to
open surgery generally occurs in less than 5% of patients, but is higher in patients treated acutely or in those with
previous abdominal surgery. Wound complications, e.g. haemorrhage, infection and incisional hernia, bile leaks, diarrhoea
and the rare but important complication of bile duct injury can occur after laparoscopic or open cholecystectomy.11 Incomplete
surgical removal of stones, injury or scarring can result in patients experiencing long-term, post-operative symptoms.
Bile duct exploration to remove common bile duct stones can be performed during laparoscopic or open cholecystectomy
and is necessary if ERCP is unavailable or has failed. A Cochrane review found both surgical and endoscopic approaches
to bile duct stone removal to be equally safe and effective.22 The choice of approaches will be influenced
by local availability and expertise.
The long-term consequences of gallstones and cholecystectomy
Gallstones are a risk factor for gallbladder cancer. Although 85% of people with gallbladder cancer have gallstones,
only 3% of people with gallstones have gallbladder cancer.23 The age-adjusted incidence rates of gallbladder
cancer in New Zealand are reported to be 1 case per 245 000 people in males and 1 case per 135 000 people in females,
which compares to an approximate incidence rate of 1 case per 2 500 people for colorectal cancer.24, 25
Following cholecystectomy, patients who make positive dietary changes will improve their general health, but there are
no specific dietary recommendations for patients who undergo this procedure.
Gallstones and subsequent cholecystectomy are associated with a small increased risk of cancer throughout the digestive
tract. In a large study of over 236 000 patients with primary cancer in the United States, gallstones were associated
with an increased risk (odds ratio) of: liver cancer (OR 2.35), small intestine carcinoid (OR 1.27), pancreatic cancer
(OR 1.24) and non-cardia gastric cancer (OR 1.21).26 In the same study cholecystectomy was associated with
an increased risk of: small intestine carcinoid (OR 1.78), non-cardia gastric cancer (OR 1.26), liver cancer (OR 1.26)
and pancreatic cancer (OR 1.23).26 It has been suggested that this increased risk of malignancy is due to
enhanced exposure of the stomach and small intestine to bile following cholecystectomy. This suggestion was supported
by a reduced risk of colorectal cancer occurring in the colon with increasing distance from the common bile duct.26