Pathogenesis of gallstones
Robert Coben, MD
By the end of this lecture you should be familiar with:
1. Pathogenesis of gallstones.
2. Clinical manifestations of gallstones.
3. Approach to the diagnosis of Gallstones
and their related morbidity.
4. Treatment modalities for gallstone disease.
are a major cause of morbidity worldwide. In the United States over 10% of the
total population have gallstones. Each year 1,000,000 new patients are diagnosed.
Performance of 500,000 cholecystectomies leads to an annual expense of more than $5
billion in direct costs. Gallstone prevalence varies with age, sex and ethnic group.
Ultrasound surveys show a female: male ratio of 2:1 in the younger population and an
increasing prevalence in both sexes with age. After the age of 60, 10-15% men and 20-40%
women have gallstones. Childbearing, estrogen-replacement therapy, and oral
contraceptives increase the risk of developing gallstones.
Gallstone prevalence is especially high in certain populations and regions of the world. Some of the highest incidence of
gallstone disease are seen in the Scandinavian countries, Chile and among Native
Americans. The incidence is also higher in markedly obese individuals and in those who lose
weight rapidly. Gallstones are more frequent among patients with certain diseases such as :
regional enteritis (Crohn's disease), cirrhosis of the liver and chronic hemolytic conditions.
While they are widely prevalent, gallstones are asymptomatic in the majority of cases. The
management of gallstone disease has evolved considerably during the past decade: it is now
generally agreed that in most situations patients with gallstones require no treatment until
they become symptomatic.
Pathogenesis of Gallstones
The reemergence of oral dissolution therapy has increased the clinical relevance of gallstone
composition. Gallstones are made mainly of cholesterol, bilirubin and calcium salts, with
smaller amounts of protein and other materials. In Western Countries essentially all
gallstones, whether cholesterol or pigmented, arise in the gallbladder, while in the Orient a
significant fraction of pigmented stones originate in the bile ducts. In Western Countries
cholesterol is the principal constituent of more than three quarters of gallstones. In the
simplest sense, cholesterol gallstones form when the cholesterol concentration in bile
exceeds the ability of bile to hold cholesterol in solution. Non-cholesterol stones are
categorized as black or brown pigment stones, consisting of calcium salts of bilirubin. In
normal individuals only about 1% the bilirubin in gallbladder bile is unconjugated. When the
percentage of unconjugated bilirubin increases so does the risk of developing bilirubin
1. Black pigment stones (bilirubin stones)
a. consist of polymers of bilirubin, with large amounts of mucoprotein.
b. usually contain less than 10% cholesterol.
c. contain 30-60% unconjugated bilirubin by weight. Unconjugated bilirubin is not water
soluble, while conjugated bilirubin is water soluble.
d. 50% are radiopaque, 50% are radiolucent (stones that are more than 4% calcium by
weight are radiopaque).
e. are common in patients with cirrhosis and chronic hemolytic conditions, such as the
thalassemias and possibly sickle cell anemia, in which bilirubin excretion is increased.
2. Brown pigment stones
a. are made of Ca salts of unconjugated bilirubin, with variable amounts of protein and
b. are usually primary biliary stones
c. are usually associated with biliary infection. Bacteria in the biliary system release
glucuronidases, which hydrolyze glucuronic acid from conjugated bilirubin. The
resulting unconjugated bilirubin precipitating as its calcium salt.
d. are more prevalent in Asians, associated with decreased secretory IgA
3. Cholesterol stones
a. 75-80% of gallstones in this country are classified as cholesterol (non-pigmented)
stones. Almost all cholesterol stones are radiolucent. Cholesterol is the major
component (usually greater than 70% by weight).
b. Cholesterol-saturated bile is a prerequisite for the formation of cholesterol gallstones,
and the incidence of gallstones within a population is correlated with the prevalence
of saturated bile. In both experimental models and young people at high risk,
precipitation of cholesterol follows saturation.
c. The solubility of cholesterol is determined primarily by the relative proportions of bile
acids, lecithin, and cholesterol in the bile. Thus, anything that causes a decrease in
bile salts, an increase in cholesterol, or a decrease in lecithin will create a relative
insolubility of cholesterol in solution.
d. It has also been shown that most patients with gallstones have a smaller pool of bile
acid than matched controls without stones.
Stages in Cholesterol Gallstone Formation:
1. Formation of saturated bile: The most critical factor is the ratio of cholesterol/bile acids.
In general the likelihood of stone formation is increased by anything that raises
cholesterol level or lowers bile acid levels, such as:
a. Impaired bile salt return: Seen with ileal disease (Crohn's), ileal resection or bypass.
Drugs that bind bile acids in the gut, such as cholestyramine could also theoretically
cause this problem, but new synthesis of bile acids by the liver usually suffices to
compensate for the losses.
b. Oversensitive feedback mechanism to turn off Cholesterol-7-hydroxylase, the
key regulatory enzyme in bile acid synthesis. Evidence for this is the existence of a
group of gallstone patients who have a small bile acid pool but normal rate of bile
c. Excessive cholesterol synthesis in the face of a normal bile acid pool. HMG-
CoA reductase, the rate limiting step in cholesterol synthesis, is stimulated by insulin
and food intake, both increased in obesity.
d. Combination of mechanisms: endogenous and exogenous estrogen's appear to
both increase cholesterol secretion and decrease chenodeoxycholate secretion. This
is associated with estrogen treatment in women, Native American ethnic group, and
the formation of gallstones in some patients with a lean body mass.
2. Nucleation: The next step in cholesterol gallstone formation is nucleation of cholesterol
into crystals, followed by agglomeration of crystals and growth of the microlith into
Nucleation promoters: Even when supersaturated with cholesterol, fresh bile from
subjects without gallstones rarely contains cholesterol crystals. The same bile, when
incubated, forms crystals very slowly (up to 15 days). Bile of patients with cholesterol
gallstones, on the other hand, usually does contain cholesterol crystals, and its
nucleation time, when incubated, is much more rapid (mean of 2.9 days). Nucleation of
cholesterol occurs far more rapidly from gallbladder bile of patients with cholesterol
gallstones than from hepatic bile in the same patients, even when hepatic bile samples
are supersaturated with cholesterol. The addition of even small amounts of gallbladder
bile to the hepatic bile samples causes rapid nucleation. These observations have led to
the isolation of proteins in the gallbladder that promote or retard the nucleation of
cholesterol crystals. At least five proteins have been identified as putative nucleation
promoters, in addition to gallbladder mucoprotein. High doses of aspirin reduce the
incidence of gallstones in a prairie-dog model, perhaps by inhibiting the synthesis of a
nucleation promoter. Success in other species has been variable.
3. Growth: The crystal acquires additional cholesterol to form a visible stone. Cholesterol
stones often contain alternating layers of cholesterol crystals and mucoprotein. Pure
cholesterol crystals are quite soft. Protein adds strength to the stone. This stage of
stone formation is largely influenced by gallbladder stasis. In theory, microscopic
cholesterol crystals would be regularly ejected from the gallbladder if its contractions were
effective enough. Gallstones forming in patients with high spinal cord injury or treated
with the somatostatin analog Octreotide have been largely associated with impaired
4. Gallbladder sludge, or thickened gallbladder mucoprotein with tiny entrapped cholesterol
crystals, is thought to be the usual precursor of gallstones. Sludge may also occur in
asymptomatic patients with prolonged fasting and can be seen on standard
ultrasonography of the gallbladder. Sludge can sometimes cause biliary pain,
cholecystitis, or acute pancreatitis, but may also resolve without treatment. The antibiotic
ceftriaxone can precipitate in the gallbladder and bile ducts as sludge.
Bile Duct Stones
Primary bile duct stones are stones formed in the biliary tree as the result of bile stasis, e.g.
above a stricture, around foreign material such as a suture, or in association with infection.
They are often earthy, muddy stones that can reach large dimensions, and are composed
predominantly of calcium bilirubinate and minor amounts of cholesterol or fatty acids. These
stones do not dissolve well in lipid solvents and may be found in the intrahepatic or
extrahepatic bile ducts.
Secondary bile duct stones are found in the bile ducts in association with gallbladder stones,
either having migrated out of the gallbladder or having formed concomitantly in the bile ducts.
Their matrix reflects the composition of gallbladder stones, i.e. predominantly cholesterol in
~80%, and black pigment in ~20% of cases. Black pigment stones are usually idiopathic, but
may be associated with chronic hemolysis or cirrhosis. Bacterial infection is not thought to be
important in the pathogenesis of either type of secondary stones.
Clinical manifestations of gallstones
Asymptomatic gallstones: 80% of people harboring gallstones are asymptomatic at any
given point in time. Asymptomatic gallstones should be managed expectantly in the majority
of patients. There are some exceptions such as patients with sickle cell anemia (symptoms of
gallstones may mimic those of sickle cell crisis, and elective cholecystectomy is much safer
than urgent operations in this group), patients in remote locations where urgent medical care
is not possible, and patients with gallstones and calcification of the gallbladder wall which is
considered a premalignant condition.
Symptomatic gallstones need to be treated in a time frame that is appropriate for the
seriousness of the clinical presentation, and the patient's general health. Recurrent biliary
pain (or colic) is the most common indication for treatment.
Biliary colic is a term that has persisted despite the understanding that biliary
disease does not involve the colon or colic. The term "colic" is actually misleading, as the
pain does not wax and wane; rather, it is felt as a steady, severe aching or pressure-type
sensation. Usually the pain is felt in the epigastrium or right upper quadrant, and often
radiates to the infrascapular area or right scapula. It is thought that0 sudden obstruction of
the cystic duct by a calculus produces increased intraluminal pressure and distention of the
gallbladder, leading to a visceral-type pain. Discrete attacks may be precipitated by meals, or
may occur at any time of the day or night. The frequency of episodes may vary from weeks
Characteristically, biliary pain begins suddenly and persists for 1 to 3 hours, although it may
last as little as 15 minutes or as long as 6 hours. The pain is not intensified by moving about.
In fact, most patients are restless and pace the floor, attempting but failing to find a position
that affords relief. A narcotic is often required for analgesia, and a residual aching discomfort
may persist for a day or so. The pain may subside gradually or rapidly after a stone becomes
disimpacted or passes through the cystic duct. Nausea is common and vomiting occurs
occasionally. Results of hepatic chemistry determinations usually are normal.
Acute cholecystitis. Persistent obstruction of the cystic duct, in contrast to the transient
obstruction that produces biliary pain, results in acute cholecystitis. Acute inflammation of the
gallbladder is caused by calculous obstruction of the cystic duct in >90% of cases (some
patients may present with acalculous cholecystitis). The inflammation is thought to be caused
mechanically by increased intraluminal pressure and ischemia, or chemically by release of
lysolecithin by phospholipase activity. Bacterial infection may supervene; enteric organisms
have been cultured from 75% of patients with acute cholecystitis. Bile acids, deconjugated
by the bacteria, also may contribute to the inflammation.
It is estimated that 30% of patients with acute cholecystitis admitted for cholecystectomy have
had no previous symptoms suggestive of cholelithiasis. Approximately 50% have had
symptoms of acute cholecystitis for at least 48 hours prior to admission, and therefore are
febrile and dehydrated and may have an ileus in addition to abdominal pain. Biliary colic may
precede or, less often, accompany or follow acute cholecystitis. In contrast to biliary colic,
acute cholecystitis causes a parietal-type epigastric or right upper-quadrant pain that
increases with jarring or respiration. The patient prefers to remain motionless. Nausea is
common and vomiting occurs occasionally.
The fever usually is low grade (averaging about 38 o C), and shaking chills do not occur. The
gallbladder is generally enlarged, but local guarding of the abdomen hinders effective
palpation in more than half of the patients. Local cutaneous hyperesthesia is not
uncommon. Deep inspiration during palpation of the right upper quadrant produces
increased tenderness and inspiratory arrest (Murphy's sign). Tenderness in the scapular area
(Boas' sign) is less common. Hepatomegaly occurs in 25% of patients, but the peripheral
stigmata of chronic liver disease are absent. Splenomegaly may be found when pigment
stones are associated with hemolytic disease.
A leukocyte count of 10,000 to 15,000/mm 3 with a shift to the left is usual. In a large series
of patients with acute cholecystitis elevation of the following values were reported: serum
bilirubin (almost never more than 5 mg/100 ml in the absence of concomitant bile duct
obstruction) in 37%, alkaline phosphatase (usually to less than twice normal) in 31% and
transaminases (usually to less than five times normal) in 41% of patients. Values typically
returned to normal within 1 week after resolution of symptoms.
In up to 75% of patients with acute cholecystitis, symptoms resolve spontaneously within 72
hours after onset, after the stone presumably disimpacts or passes through the cystic duct. In
the remaining 25%, the inflammation progresses to necrosis, perforation or empyema of the
gallbladder unless intervention occurs. Clinical indications of progression are persistent
symptoms; signs of peritonitis; or rising temperature, pulse rate and white blood cell count. In
elderly or diabetic patients or in patients treated with corticosteroids for other reasons, mild signs
and symptoms may belie the severity of the inflammation. When surgery is not performed,
cholecystitis recurs in 25% of patients within the first year of follow-up and in 60% of patients
within 6 years.