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:

• Vascular functions, including formation of lymph and the hepatic phagocytic system.
• Metabolic achievements in control of synthesis and utilization of carbohydrates, lipids and proteins.
• Secretory and excretory functions, particularly with respect to the synthesis of secretion of bile.                      

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
intestine. 


There are two fundamentally important functions of bile in all species:

• Bile contains bile acids, which are critical for digestion and absorption of fats and fat-soluble vitamins                in the small intestine.
• Many waste products, including bilirubin, are eliminated from the body by secretion into bile and                        elimination in feces.

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:

• Initially, hepatocytes secrete bile into canaliculi, from which it flows into bile ducts.                                               This hepatic bile contains large quantities of bile acids, cholesterol and other organic molecules.                                                                
• As bile flows through the bile ducts it is modified by addition of a watery, bicarbonate-rich                                   secretion from ductal epithelial cells.                                                                                                                              
• The gall bladder stores and concentrates bile during the fasting state.                                                  Typically, bile is concentrated five-fold in the gall bladder by absorption of water                                                 and small electrolytes - virtually all of the organic molecules are retained.

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
diameter.

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:

• Hyper secretion of cholesterol into bile due to such things as obesity, acute         high calorie intake, chronic polyunsaturated fat diet, contraceptive steroids or pregnancy, diabetes mellitus.
•                            
• Hypo secretion of bile salts due to such things as impaired bile salt synthesis and abnormal intestinal loss of bile salts (e.g. recirculation failure due to ideal disease).
• Impaired gallbladder function with incomplete emptying or stasis is seen in late pregnancy and with oral contraceptive use, in patients on total parenteral nutrition and due to unknown causes, perhaps associated with neuroendocrine dysfunction.

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
formation. 

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
after birth.