Pathogenesis of gallstones

[Guest guest]

Pathogenesis of gallstones

Coben, MD

http://jeffline.tju.edu/CWIS/DEPT/GI/education/pdfs/gallstones.pdf

Educational Goals

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.

Gallstones

Gallstones 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 gallstones.

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 cholesterol.

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 acid synthesis.

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 macroscopic gallstones.

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 gallbladder motility.

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.

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 to years.

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 ('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.