The liver is the largest gland in the body and performs an astonishingly large number of tasks that impact all
body systems. One consequence of this complexity is that hepatic disease has widespread effects on virtually
all other organ systems. At the risk of losing sight of the forest by focusing on the trees, we will focus on three fundamental roles of the liver:
The latter is the only one of the three that directly affects digestion - the liver, through its biliary tract,
secretes bile acids into the small intestine where they assume a critical role in the digestion and
absorption of dietary lipids. However, understanding the vascular and metabolic functions of the liver
is critical to appreciating the gland as a whole.
Bile is a complex fluid containing water, electrolytes and a battery of organic molecules including
bile acids, cholesterol, phospholipids and bilirubin that flows through the biliary tract into the small
There are two fundamentally important functions of bile in all species:
Adult humans produce 400 to 800 ml of bile daily, and other animals proportionately similar amounts. The secretion of bile can be considered to occur in two stages:
Secretion into bile is a major route for eliminating cholesterol. Free cholesterol is virtually insoluble in aqueous solutions, but in bile, it is made soluble by bile acids and lipids like lethicin. Gallstones, most of which are composed predominantly of cholesterol, result from processes that allow cholesterol to precipitate from solution in bile.
Gallstones are concretions that form in the biliary system, usually the gallbladder. Although rarely recognized in animals, they affect a large number of people. In the US alone, it is estimated that about 20 million people have gallstones at any given time, resulting in expenditures of about $5 billion for diagnosis and treatment. A majority of cases are asymptomatic, but signs in clinically affected patients range from mild abdominal pain or minor "indigestion" to excruciating pain, often manifest at night. There are two major types of gallstones, which seem to form due to distinctly different pathogenetic mechanisms.
About 90% of gallstones are of this type.
These stones can be almost pure cholesterol
or mixtures of cholesterol and substances such
as mucin. Stones recovered at surgery range
from about 5 mm to greater than 25 mm in
The key event leading to formation and progression of cholesterol stones is precipitation of cholesterol in bile. Unesterified cholesterol is virtually insoluble in aqueous solutions and is
kept in solution in bile largely by virtue of the detergent-like effect of bile salts. This is
however a rather precarious situation and
several factors can tip the balance in favor of precipitation, including:
Roughly 10% of human gallstones are
pigment stones composed of large quantities
of bile pigments, along with lesser amounts
of cholesterol and calcium salts. The most
important risk factor for development of these stones is chronic hemolysis from almost any
cause - this makes sense considering that
bilirubin is a major constituent of these stones. Additionally, some forms of pigment stones are associated with bacterial infections. Apparently, some bacteria release glucuronidases that deconjugate bilirubin, leading to precipitation
as calcium salts.
There are clearly important genetic determinants for cholesterol stone
For example, the prevalence of the disease
in descendants of Chilean Indians and in
American Indians is extraordinarily high and
not accounted for by environment.
There is also an important sex bias in
development of stones - the prevalence in
adult females is two to three times that seen
in males and use of contraceptive steroids is
a risk factor for development of gallstones.
This sex difference is likely the manifestation
of differences in sex steroids: progesterone
and also probably estrogen impair gall bladder emptying and are associated with hyper secretion
of cholesterol into bile. Additionally, estrogen treatment reduces synthesis of bile acids.
These pro-precipitation factors peak during
late pregnancy when the levels of these steroid hormones are highest, then dissipate rapidly