8.

A 46-year-old obese woman presents with a 6-hour history of moderate steady pain in the
RUQ that began after eating dinner and radiates through to her back. This pain gradually
increased before becoming constant over the last few hours. She has had previous episodes of
similar pain for which she has not sought medical advice. Her vital signs are normal. The
pertinent findings on physical examination are tenderness to palpation in the right upper
quadrant with no guarding or rebound.

Definition

Cholelithiasis is the presence of solid concretions in the gallbladder. Gallstones form in the
gallbladder but may exit into the bile ducts (choledocholithiasis). Symptoms ensue if a stone
obstructs the cystic or the bile duct.

Epidemiology

Cholelithiasis occurs in approximately 10% to 15% of adults in the US and Europe. [3] The
highest prevalence of cholelithiasis arises in Native American populations; Hispanic people
experience a somewhat lower prevalence. [4] Age, obesity, and female sex hormones are
important aetiological factors.[3] [5] The prevalence rates are relatively low in Africa and
Asia. [6] The current epidemic of obesity will undoubtedly escalate the frequency of gallstones.

Despite its high prevalence, cholelithiasis is generally asymptomatic in >80% of

people. [7] Biliary pain, however, will develop annually in 1% to 2% of individuals previously
asymptomatic. [8] [9] [10] Those with a history of biliary colic are more likely to experience
recurrent pain and are at increased risk of complications. Major complications (i.e., acute
cholecystitis, cholangitis, and acute pancreatitis) occur at an annual rate of 0.1% to 0.3% among
asymptomatic individuals harbouring stones. [10] [11] Such complications make gallstones the
most common gastrointestinal disease requiring hospitalisation in the US, resulting in
approximately 700,000 cholecystectomies being performed yearly.

Aetiology

Cholelithiasis transpires as a result of 3 principal defects: bile supersaturated with cholesterol,

accelerated nucleation, and gallbladder hypomotility retaining this abnormal bile. Cholesterol
supersaturation of gallbladder bile occurs primarily when the liver secretes excessive amounts
of cholesterol, compared to its solubilising agents, bile salts and lecithin. The next stage is
precipitation of cholesterol microcrystals in the gallbladder, initiated by the presence of
nucleating agents (primarily biliary glycoproteins such as mucin). [13] Impaired gallbladder
contractility then facilitates retention, providing time for these microcrystals to agglomerate in a
mucin scaffold and grow into overt gallstones.

Ninety percent of gallstones are composed of cholesterol; these form in the

gallbladder. [1] Some risk factors for the development of cholesterol gallstones are modifiable,
 such as obesity, total parenteral nutrition, rapid weight loss after bariatric surgery, and
medications (e.g., oestrogen, octreotide, clofibrate, ceftriaxone). Others, such as
age, [14] genetic factors, [15] [16] and female sex, are immutable. These cholesterol stones that
form in the gallbladder can migrate into the common bile duct, as occurs in 10% to 15% of
patients presenting for cholecystectomy.

Approximately 2% of all gallstones are black pigment stones. [17] The pigment material consists
of polymerised calcium bilirubinate. Patients with chronic haemolytic anaemia, cirrhosis, cystic
fibrosis, and ileal diseases are at highest risk of developing black pigment stones.

Brown pigment gallstones form de novo in bile ducts as a result of stasis and infection. They
consist of calcium bilirubinate, calcium salts of long-chain fatty acids, cholesterol, and mucin
(glycoproteins primarily from bacterial biofilms). Bacterial infection, biliary parasites (Clonorchis
sinensis, Opisthorchis species, and Fasciola hepatica), and stasis (from partial biliary obstruction)
are key factors, particularly in Asian people. In developed countries, such bile duct stones more
commonly result from biliary strictures, either inflammatory or neoplastic.

Pathophysiology

Symptoms and complications of cholelithiasis result when stones obstruct the cystic and/or bile
ducts. Transient obstruction of the cystic duct results in biliary pain. More persistent obstruction
leads to acute cholecystitis. Uncommonly (in 1% of cholecystectomies), a large gallstone
becomes impacted in the cystic duct or the neck of the gallbladder, compresses the common
bile duct, and causes obstruction and jaundice.

If gallstones pass into the bile ducts causing obstruction, the result can be biliary pain and,
importantly, cholangitis. Stone passage through the distal bile duct can culminate in obstruction
at the ampulla. Acute biliary pancreatitis results from the consequent increase in pancreatic
ductal pressure and reflux of pancreaticobiliary secretions into the pancreatic duct. Multiple
small stones (<5 mm), a dilated cystic duct, and a properly emptying gallbladder are risk factors
for acute biliary pancreatitis. [18] [19] [20]

If a gallstone erodes through the gallbladder wall, a cholecystoenteric fistula can develop and
lead to duodenal obstruction (Bouveret's syndrome) or obstruction in the narrowest segment of
an otherwise healthy bowel causing gallstone ileus. Erosion of a stone into the common duct
produces a biliary fistula, another form of Mirizzi's syndrome.

Classification

Types of stones in the biliary tract

Cholesterol gallstones

Approximately 85% to 90% of gallstones are composed of cholesterol. These form in the
gallbladder. [1] The multiple risk factors for their development include genetics (family history),
diet (obesity, sudden weight reduction), age, and female sex hormones.
 Black pigment gallstones

Less than 15% of all gallstones consist of polymerised calcium bilirubinate. [2] Risk factors for
these black pigment stones are age, chronic haemolytic anaemia, cirrhosis, cystic fibrosis, and
ileal disease.

Brown pigment stones (ductal stones)

These stones form in the bile ducts as a result of stasis and infection. They consist of
unconjugated bilirubin and calcium salts of long-chain fatty acids. Bile duct strictures or parasitic
infestation represent the major risk factors.

Primary prevention

Patients (with an in situ gallbladder) who have undergone bariatric surgery and are experiencing
rapid weight loss, [36] those receiving parenteral nutrition, and those requiring long-term use of
somatostatin are at high risk of gallstones. Primary prevention of gallstone formation entails
lifestyle modification: a diet high in fibre, low in saturated fat, and maintenance of a normal
body weight, coupled with moderate physical activity. [2]Preventative medical therapy employs
ursodeoxycholic acid (UDCA) to lower cholesterol saturation in bile and so lessen the short-term
risk of stone formation in obese individuals undergoing rapid weight loss through dietary caloric
restriction or bariatric surgery. [36] UDCA has limited value for dissolving established gallstones
because of limited success and a high recurrence rate. [37] This agent is best reserved for the
occasional non-surgical candidate with small gallstones who is truly symptomatic.

History & examination

Key diagnostic factors

presence of risk factors (common)

Key factors include female sex, obesity (BMI 30), Native American/Hispanic
ethnicity, [47] positive family history, dietary insufficiencies, use of certain medications (e.g.,
exogenous oestrogen, octreotide, clofibrate, ceftriaxone), terminal ileum disease, pregnancy,
and diabetes.

RUQ or epigastric pain (lasting >30 minutes) (common)

Constant pain typically increases in intensity and lasts for several hours (biliary colic).

Other diagnostic factors

postprandial pain (common)

Onset of pain may be after a meal.

 RUQ or epigastric tenderness (common)

Suggestive of symptomatic cholelithiasis.

nausea (uncommon)

Often accompanies pain in patients with biliary pain or acute cholecystitis.

jaundice (uncommon)

Uncommon in simple biliary colic and acute cholecystitis. Jaundice develops primarily in patients
with choledocholithiasis, and is characteristic of cholangitis.

Risk factorshide all

Strong

increasing age

The frequency of gallstones rises noticeably after the age of 40 years to become 4 to 10 times
more likely in older individuals and peaking at 70 to 79 years. [2] [14] Age correlates positively
with increased cholesterol secretion and saturation; yet the stone type found in advanced age
tends to be pigment.

female sex

Women have 2 to 3 times higher incidence of gallstones than men.[21] The basis may be
increased cholesterol secretion into bile.

Hispanic and Native-American ethnicity

In the US, these populations have the highest prevalence of gallstones, reaching rates of 50%
among men and 70% among women >50 years of age. [4] [22] [23]

FHx of gallstones

There is increased prevalence of gallstones in some families. [15]Monozygotic twin studies show
a higher concordance for gallstone disease than dizygotic twins. [16]

gene mutations

Genome-wide association studies have so far revealed 2 susceptibility genes for cholesterol
gallstone disease: ABCG8 p.D19H (increasing cholesterol excretion), and UGT1A1 in male
carriers of the Gilbert's syndrome variant rs6742078 (presumably the secreted bilirubin pigment
functioning as the nucleating agent).[24]

pregnancy/exogenous oestrogen
 Increasing levels of oestrogen heighten cholesterol saturation of bile, making women more
prone to developing sludge and gallstones. [25] Higher levels of progesterone also cause
gallbladder hypomotility.

Use of exogenous oestrogen for contraceptive or hormone replacement increases the risk of
gallstones as a result of increased cholesterol secretion into bile. [26]

obesity

Augmented hepatic cholesterol synthesis and secretion into bile is the postulated mechanism
for gallstone development in people with an elevated BMI >30. [27] [28]

prolonged fasting/rapid weight loss

Prolonged fasting causes gallbladder hypomotility. The resulting bile stasis increases the risk for
developing gallstones.

Patients undergoing bariatric surgery are also at increased risk of developing gallstones due to
cholesterol supersaturation of bile from enhanced cholesterol mobilisation accompanied by
decreased bile acid secretion. Bariatric surgery commonly causes formation of biliary sludge;
most disappears but some evolves into gallstones that persist. [29]

total parenteral nutrition (TPN)

TPN is employed in conditions often with marked weight loss and causes gallbladder
hypomotility and stasis. Both increase the risk for stone formation.

octreotide

This somatostatin analogue impairs gallbladder and small intestinal motility. The resultant
gallbladder stasis and heightened secondary bile acid production leads to cholesterol stone
formation.

ceftriaxone

Has been associated with gallstone development.

terminal ileum disease or resection

Crohn's disease most commonly affects the terminal ileum and is associated with an increased
risk of gallstones. [30] The basis is bile salt malabsorption creating a deficiency, such that the
bile becomes overly saturated with cholesterol. A more important component is excessive bile
salts escaping into the colon to increase the solubility of bilirubin pigment, thus enhancing its
absorption and return to the liver. The resultant excessive secretion of bile pigment produces
black pigment stones. [31]

haemoglobinopathy

Sickle cell disease and beta-thalassaemia are hereditary haemolytic anaemias. The increased
haemolysis releases increased bilirubin leading to pigment stone formation. Such black pigment
 stones present at younger ages and typically require cholecystectomy, especially in sickle cell
disease because of confounding symptoms of abdominal pain.

diabetes and the metabolic syndrome

The metabolic syndrome (diabetes, abdominal obesity, hypertension, and dyslipidaemia)

promotes stone formation. [32]The basis is elevated hepatic cholesterol secretion, depressed
bile salt synthesis, and/or impairing gallbladder motility.

Weak

low-fibre diet

The role of specific diets is not clear. Those high in refined carbohydrates and fat (triglycerides)
and low in fibre are associated with gallstones.

Diagnostic investigations

1st investigations to order

Test

FBC

For biliary pain with or without fever, elevated WBC suggests inflammation from a complication of cholelithiasis:
acute cholecystitis, cholangitis, or pancreatitis.

serum LFTs

For biliary pain with or without jaundice. Elevated alkaline phosphatase, with or without an elevated gamma-GT
suggests obstruction of the cystic or bile duct. Passage of a common duct stone may be revealed by a transiently
elevated ALT.

serum lipase and amylase

For pain located primarily in the epigastric area, with or without radiation to the back. Serum lipase is the
preferred test.

abdominal ultrasound

For biliary pain. This is the best single test for cholelithiasis and sludge in the gallbladder, a key to diagnosis.

Low sensitivity for choledocholithiasis. If stones are detected in the gallbladder with pericholecystic fluid and
gallbladder wall thickening, consider acute cholecystitis. [39] View imageView image
EUS is more sensitive for microlithiasis (small gallstones <3mm).

Investigations to consider

Test

magnetic resonance cholangiopancreatography (MRCP)

For suspected choledocholithiasis that is not confirmed by abdominal ultrasound. MRCP has limited value for de
stones (<5 mm). [41] [48]

endoscopic ultrasound scan (EUS)

For suspected choledocholithiasis that is not confirmed by abdominal ultrasound, particularly in patients who ca
MRCP (claustrophobia, implanted devices) or to confirm choledocholithiasis in high-risk patients prior to a therap

Value of EUS is dependent on local expertise.

endoscopic retrograde cholangiopancreatography (ERCP)

Is the preferred intervention for patients with high risk of bile duct stones (positive imaging, symptoms, and/or b
its therapeutic capability to remove an obstructing stone.

Differential diagnosis

Condition Differentiating signs/symptoms

Peptic ulcer May have hx of Helicobacter pylori infection, NSAID use, smoking, increased
disease (PUD) age, or positive family history of PUD. Presents with burning or gnawing
Condition Differentiating signs/symptoms

pain in the upper abdomen, particularly with food consumption and often
improved with antacids.

Gallbladder Can present with painless jaundice and/or weight loss, although often
cancer presents late with upper abdominal pain.

Gallbladder Often found incidentally on imaging for other conditions.

polyps

Acalculous Positive Murphy's sign (tenderness suddenly becomes worse during deep
cholecystitis inspiration, and produces inspiratory arrest). In ICU setting, findings are
often subtle.

Sphincter of Oddi Postcholecystectomy biliary pain.

dysfunction (SOD)

Non-biliary acute History is helpful in identifying alcohol use, possible offending medications,
pancreatitis or recent biliary tract endoscopy/surgery.