Cholelithiasis: Is the presence of gallstones in the gallbladder

Causes

Ethnicity, gender, age, genetics, dietary considerations, and presence of certain comorbidities are
major risk factors in the development of cholelithiasis and associated complications.

 Ethnicity: Prevalence rates of cholelithiasis are highest among western Caucasian,

Hispanic, and Native American populations. Eastern European, African American, and Asian
populations are less afflicted.
 Age: Advancing age is a major risk factor for gallbladder disease; gallstones are
exceedingly rare in children.
 Gender: The prevalence rate of cholelithiasis is higher in women of all age groups. The
difference is attributed to increased levels of estrogens and progesterone, which ultimately promote
the formation of gallstones. Estrogens increase cholesterol formation, which supersaturate the bile,
leading to precipitation of cholesterol stones; progesterone inhibits gallbladder motility leading to
biliary stasis and stone formation. Pregnancy contributes to the female preponderance in prevalence
due to increases in circulating sex steroids in the gravid state.
 High-fat diet: Historically, but not statistically, high-fat diet is associated with the formation
of gallstones and symptoms associated with gallstones. Estrogen therapy, in similar fashion, is
associated with higher risk of cholelithiasis.
 Genetics: Studies in family history suggest that genetics have a significant role in
development of gallstones.
 Dietary considerations: Obesity, high-fat diet, and hypertriglyceridemia are strongly
associated with the formation of gallstones and arising complications. Additional dietary risk factors
include decreased oral intake, rapid weight loss, and use of parenteral nutrition. Diosgenin-rich
beans, particularly associated with a South American diet, increase cholesterol secretion and
gallstone formation.
 Bariatric surgery: More than one third of the patients develop gallstones after bariatric
surgery. Weight loss greater than 25% is the best predictor for the gallstone formation. Rapid weight
loss mobilizes tissue cholesterol stores and increases the saturation of bile.3
 Comorbidities
o Diabetes mellitus is associated with an increased risk of gallstone, though the
mechanism is unclear; once symptomatic, patients with diabetes are prone to more severe
complications.
o Crohn disease, ileal resection, or other diseases of the ileum decrease bile salt
reabsorption and increase the risk of gallstone formation.
o Hemolytic diseases, including sickle cell disease and spherocytosis, promote the
formation of pigmented stones.
o Bacterial or parasitic infections from organisms that contain B -glucuronidase, an
enzyme that deconjugates bilirubin glucuronide, increase the risk for pigmented stones.
o Cirrhosis carries major multifactorial risks for gallstone formation and gallbladder
disease. Reduced hepatic synthesis and transport of bile salts, hyperestrogenemia, impaired
 gallbladder contraction and increased biliary stasis, among other factors, contribute to the formation
of gallstones (typically pigment stones) in cirrhosis.

Risk Factors

 Chronic overnutrition with carbohydrate  Ineffective erythropoiesis (vitamin B12

and triglyceride-rich, low-fiber diet and folate deficiencies)
 Obesity  Liver cirrhosis
 Positive family history  TPN
 Native American descent  Severe Crohn disease of the ileum
 Female gender and/or ileal resection
 Pregnancy/Parity  Anatomical abnormalities (biliary
 Chronic hemolysis (sickle cell disease, stricture, duodenal diverticulum)
thalassemia, spherocytosis, malaria).  Medications (estrogens, octreotide,
clofibrate, furosemide, cyclosporine,
ceftriaxone)

Etiology

Cholelithiasis occurs as a result of 3 principle defects: cholesterol supersaturation, accelerated

nucleation, and gallbladder hypomotility. Cholesterol supersaturation of gallbladder bile can occur
primarily as a result of hepatic hypersecretion of cholesterol, or sometimes as a result of
hyposecretion of bile salts or lecithin. The aggregated cholesterol crystals form microcrystals in the
presence of kinetic proteins such as mucin. Impaired gallbladder motility allows for the formation of
macroscopic gallstones and is seen in high-risk patients, such as those with obesity, diabetes, on
total parenteral nutrition, and those with rapid weight loss.

Around 90% of gallstones are composed of cholesterol and these form in the gallbladder. There are
multiple risk factors for the development of cholesterol gallstones including age, genetic factors,
dietary factors (low-fiber, high-carbohydrate, and high-fat), and medication (e.g., estrogen, octreotide,
clofibrate, ceftriaxone).

Approximately 2% of all gallstones are black pigment stones. These consist of polymerized calcium
bilirubinate. Patients with hemolytic anemia, cirrhosis, and ileal diseases are at highest risk of
developing black pigment stones.

Brown pigment gallstones occur infrequently and usually 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.
Patients with duodenal diverticula, bile duct strictures, or parasitic disease are at increased risk.

Clinical Presentations
The clinical presentation of gallstone-induced complications varies. Differentiating features such as
pain site and duration, presence or absence of a mass, fever and laboratory parameters can assist in
establishing the correct diagnosis (Table 2).

TABLE 2
Differentiating Features of Gallstone-Induced Complications*

Acute Chronic
Feature Biliary colic cholecystitis cholecystitis Cholangitis Pancreatitis

Pain site Epigastrium RUQ RUQ RUQ Epigastric

Pain duration <3 hours > 3 hours Variable Variable Variable

Mass No masses RUQ mass No masses ± ±

Fever ± ± ± ±

Increased ± ± ± ±
WBC

Increased Normal ± ± +
amylase level

RUQ = right upper quadrant; WBC = white blood cell count; + = present; = absent; ± = present or
absent.
*--These characteristics may not always be present.

Biliary Colic
As many as one third of patients with gallstones will develop symptoms (Table 3). It is thought that
the pain of biliary colic is caused by the functional spasm of the cystic duct when obstructed by
stones, whereas pain in acute cholecystitis is caused by inflammation of the gallbladder wall.6 Pain
often develops without any precipitating symptoms. Typically, the pain has a sudden onset and
rapidly increases in intensity over a 15-minute interval to a
plateau that can last as long as three hours. The pain may
radiate to the interscapular region or to the right shoulder.

It is worthwhile to clarify some misconceptions about Biliary colic pain develops

suddenly, rapidly increases in
biliary pain. First, biliary colic is a misnomer, because intensity over 15 minutes and
the pain is steady, not colicky. Second, the pain site is can last as long as three hours.
primarily in the epigastrium, and it is incorrect to
interpret pain located in the epigastrium as nonbiliary.
Third, fat intolerance is not a feature of biliary colic.

Acute Cholecystitis
The most common cause of acute cholecystitis is obstruction of the cystic duct by gallstones,
resulting in acute inflammation. Approximately 90 percent of cases of acute cholecystitis are
associated with cholelithiasis. The clinical features of acute cholecystitis may include symptoms of
local inflammation (e.g., right upper quadrant mass, tenderness) and systemic toxicity (e.g., fever,
leukocytosis). Most patients with acute cholecystitis have had previous attacks of biliary pain. The
pain of acute cholecystitis typically lasts longer than three hours and, after three hours, shifts from
the epigastrium to the right upper quadrant. This sequence of clinical features includes visceral
pain from ductal impaction by stones, progressing to inflammation of the gallbladder with parietal
pain.

In elderly patients, localized tenderness may be the only presenting sign; pain and fever may be
absent.7 In 30 to 40 percent of patients, the gallbladder and adherent omentum can be perceived as a
palpable mass. Jaundice is noted in approximately 15 percent of patients with acute cholecystitis,
even without choledocholithiasis. The pathogenesis may involve edema and inflammation secondary
to the impacted stone in the cystic duct. This leads to the compression of the common hepatic duct or
the common bile duct (Mirizzi's syndrome).
 In the event of delayed diagnosis in the setting of acute
cholecystitis, the cystic duct remains obstructed, and the
lumen may become distended with clear mucoid fluid
TABLE 3 (hydrops of the gallbladder). Although rare, a large
Complications of Gallstones*
gallstone in the gallbladder will sometimes erode
through the gallbladder wall into an adjacent viscus,
usually the duodenum. Subsequently, the stone may
Complication Percentage become impacted in the terminal ileum (small bowel
obstruction) or in the duodenal bulb/pylorus, causing
gastric outlet obstruction (Bouveret's syndrome).
Patients with chronic cholecystitis usually have had
Biliary colic 70 to 80†
repeated attacks of biliary pain or acute cholecystitis.
Acute cholecystitis 10 This results in a thickened and fibrotic gallbladder that
may not be palpable in these patients.
Emphysematous <1‡
cholecystitis Acute cholecystitis may present as an acalculous
disorder in 5 to 10 percent of patients. Acalculous
Mirizzi's syndrome <1‡ cholecystitis typically affects critically ill, older men in the
setting of major surgery, critical illness, total parenteral
Hydrops of the <1‡
nutrition, extensive trauma or burn-related injury. The
gallbladder
pathogenesis probably involves a combination of biliary
Small bowel obstruction 1‡ stasis, chemical inflammation and ischemia.
(gallstone ileus) Complications develop more frequently in acalculous
cholecystitis than in calculous cholecystitis.
Gastric outlet obstruction <1‡
(Bouveret's syndrome) Rarely, infectious agents can cause acute cholecystitis.
Cytomegalovirus and cryptosporidia can result in
Perforation of gallbladder 12‡
cholecystitis and cholangitis in immunocompromised
Acute biliary pancreatitis -- persons. Salmonella can colonize the gallbladder
epithelium without eliciting inflammation, creating a
Acute -- carrier state.
suppurative/obstructive
cholangitis Choledocholithiasis
Acute suppurative cholangitis is a common complication
of choledocholithiasis. The usual clinical presentation,

*--One third of patients with gallstones occurring in 70 percent of the cases of

develop symptoms. choledocholithiasis, consists of pain, jaundice and chills
†--Percentage incidence in patients with (i.e., Charcot's triad). Refractory sepsis characterized by
symptomatic gallstones.
‡--Percentage incidence in patients with altered mentation, hypotension and Charcot's triad
acute cholecystitis. constitutes Raynold's pentad. Depending on the
progression of the illness, endotoxemia with shock or
multiple liver abscesses may be noted. On the other hand, cholangitis may be a short, self-limited
illness complicating choledocholithiasis. The most commonly found organisms are Escherichia coli,
Klebsiella, Pseudomonas and enterococci, with a 15 percent contribution by anaerobes.

Acute biliary pancreatitis is another potential complication of choledocholithiasis.8 Differentiating acute

pancreatitis from cholecystitis can be difficult because both conditions produce tenderness in an
overlapping area. Although acute cholecystitis alone can be associated with hyperamylasemia,
pancreatitis often has higher enzyme levels. Also, cholecystitis and pancreatitis may coexist.