Weighing between 3.17 and 3.66 pounds (lb), or between 1.44 and 1.

66 kilograms (kg), the liver

is reddish-brown with a rubbery texture. It is situated above and to the left of the stomach and
below the lungs.
The skin is the only organ heavier and larger than the liver.
The liver is roughly triangular and consists of two lobes: a larger right lobe and a smaller left
lobe. The lobes are separated by the falciform ligament, a band of tissue that keeps it anchored to
the diaphragm.
A layer of fibrous tissue called Glisson's capsule covers the outside of the liver. This capsule is
further covered by the peritoneum, a membrane that forms the lining of the abdominal cavity.
This helps hold the liver in place and protects it from physical damage.
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. 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.

The liver is an organ only found in vertebrates which detoxifies various metabolites, synthesizes
proteins and produces biochemicals necessary for digestion and growth. In humans, it is located
in the right upper quadrant of the abdomen, below the diaphragm. Its other roles
in metabolism include the regulation of glycogen storage, decomposition of red blood cells and
the production of hormones.
The liver is an accessory digestive organ that produces bile, a fluid containing cholesterol and
bile acids, and an alkaline compound which helps the breakdown of fat. Bile aids in digestion via
the emulsification of lipids. The gallbladder, a small pouch that sits just under the liver, stores
bile produced by the liver which is afterwards moved to the small intestine to complete
digestion. The liver's highly specialized tissue consisting of mostly hepatocytes regulates a wide
variety of high-volume biochemical reactions, including the synthesis and breakdown of small
and complex molecules, many of which are necessary for normal vital functions.

Anatomy
Architecture of Hepatic Tissue
The liver is covered with a connective tissue capsule that branches and extends throughout the
substance of the liver as septae. This connective tissue tree provides a scaffolding of support and
the highway which along which afferent blood vessels, lymphatic vessels and bile ducts traverse
the liver. Additionally, the sheets of connective tissue divide the parenchyma of the liver into
very small units called lobules.
The hepatic lobule is the structural unit of the liver. It consists of a roughly hexagonal
arrangement of plates of hepatocytes radiating outward from a central vein in the center. At the
vertices of the lobule are regularly distributed portal triads, containing a bile duct and a terminal
branch of the hepatic artery and portal vein. Lobules are particularly easy to see in pig liver
because in that species they are well deliniated by connective tissue septae that invaginate from
the capsule.
Functions of the liver

The liver is classed as a gland and associated with many functions. It is difficult to give a precise
number, as the organ is still being explored, but it is thought that the liver carries out 500 distinct
roles. Understanding function and dysfunction of the liver, more than most other organs, depends
on understanding its structure. The major aspects of hepatic structure that require detailed
attention include:
 The hepatic vascular system, which has several unique characteristics relative to other
organs
 The biliary tree, which is a system of ducts that transports bile out of the liver into the
small intestine
 The three dimensional arrangements of the liver cells, or hepatocytes and their
association with the vascular and biliary systems.

The Biliary System

The biliary system is a series of channels and ducts that conveys bile - a secretory and excretory
product of hepatocytes - from the liver into the lumen of the small intestine. Hepatocytes are
arranged in "plates" with their apical surfaces facing and surrounding the sinusoids. The basal
faces of adjoining hepatocytes are welded together by junctional complexes to form canaliculi,
the first channel in the biliary system. A bile canaliculus is not a duct, but rather, the dilated
intercellular space between adjacent hepatocytes.
Hepatocytes secrete bile into the canaliculi, and those secretions flow parallel to the sinusoids,
but in the opposite direction that blood flows. At the ends of the canaliculi, bile flows into bile
ducts, which are true ducts lined with epithelial cells. Bile ducts thus begin in very close
proximity to the terminal branches of the portal vein and hepatic artery, and this group of
structures is an easily recognized and important landmark seen in histologic sections of liver -
the grouping of bile duct, hepatic arteriole and portal venule is called a portal triad.
Small bile ducts, or ductules, anastomose into larger and larger ducts, eventually forming the
common bile duct, which dumps bile into the duodenum. A sphincter known as the sphinter of
Oddi is present around the common bile duct as it enters the intestine.
The gall bladder is another important structure in the biliary system of many species. This is a
sac-like structure adhering to the liver which has a duct (cystic duct) that leads directly into the
common bile duct. During periods of time when bile is not flowing into the intestine, it is
diverted into the gall bladder, where it is dehydrated and stored until needed

Bile production:
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.
In species with a gallbladder (man and most domestic animals except horses and rats), further
modification of bile occurs in that organ. 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
lecithin. Gallstones, most of which are composed predominantly of cholesterol, result from
processes that allow cholesterol to precipitate from solution in bile.
Role of Bile Acids in Fat Digestion and Absorption
Bile acids are derivatives of cholesterol synthesized in the hepatocyte. Cholesterol, ingested as
part of the diet or derived from hepatic synthesis is converted into the bile acids cholic and
chenodeoxycholic acids, which are then conjugated to an amino acid (glycine or taurine) to yield
the conjugated form that is actively secreted into
cannaliculi.
Bile acids are facial amphipathic, that is, they contain
both hydrophobic (lipid soluble) and polar
(hydrophilic) faces. The cholesterol-derived portion of a bile acid has one face that is
hydrophobic (that with methyl groups) and one that is hydrophilic (that with the hydroxyl
groups); the amino acid conjugate is polar and hydrophilic.
Their amphipathic nature enables bile acids to carry out two important functions:
 Emulsification of lipid aggregates: Bile acids have detergent action on particles of dietary
fat which causes fat globules to break down or be emulsified into minute, microscopic
droplets. Emulsification is not digestion per se, but is of importance because it greatly
increases the surface area of fat, making it available for digestion by lipases, which
cannot access the inside of lipid droplets.
 Solubilization and transport of lipids in an aqueous environment: Bile acids are lipid
carriers and are able to solubilize many lipids by forming micelles - aggregates of lipids
such as fatty acids, cholesterol and monoglycerides - that remain suspended in water. Bile
acids are also critical for transport and absorption of the fat-soluble vitamins.
Role of Bile Acids in Cholesterol Homeostasis
Hepatic synthesis of bile acids accounts for the majority of cholesterol breakdown in the body. In
humans, roughly 500 mg of cholesterol are converted to bile acids and eliminated in bile every
day. This route for elimination of excess cholesterol is probably important in all animals, but
particularly in situations of massive cholesterol ingestion.
Interestingly, it has recently been demonstrated that bile acids participate in cholesterol
metabolism by functioning as hormones that alter the transcription of the rate-limiting enzyme in
cholesterol biosynthesis.
Enterohepatic Recirculation
Large amounts of bile acids are secreted into the intestine every day, but only relatively small
quantities are lost from the body. This is because approximately 95% of the bile acids delivered
to the duodenum are absorbed back into blood within the ileum.
Venous blood from the ileum goes straight into the portal vein, and hence through the sinusoids
of the liver. Hepatocytes extract bile acids very efficiently from sinusoidal blood, and little
escapes the healthy liver into systemic circulation. Bile acids are then transported across the
hepatocytes to be resecreted into canaliculi. The net effect of this enterohepatic recirculation is
that each bile salt molecule is reused about 20 times, often two or three times during a single
digestive phase.

It should be noted that liver disease can dramatically alter this pattern of recirculation - for
instance, sick hepatocytes have decreased ability to extract bile acids from portal blood and
damage to the canalicular system can result in escape of bile acids into the systemic circulation.
Assay of systemic levels of bile acids is used clinically as a sensitive indicator of hepatic disease.
Pattern and Control of Bile Secretion
The flow of bile is lowest during fasting, and a majority of that is diverted into the gallbladder
for concentration. When chyme from an ingested meal enters the small intestine, acid and
partially digested fats and proteins stimulate secretion of cholecystokinin and secretin. As
discussed previously, these enteric hormones have important effects on pancreatic exocrine
secretion. They are both also important for secretion and flow of bile:
 Cholecystokinin: The name of this hormone describes its effect on the biliary system -
cholecysto = gallbladder and kinin = movement. The most potent stimulus for release of
cholecystokinin is the presence of fat in the duodenum. Once released, it stimulates
contractions of the gallbladder and common bile duct, resulting in delivery of bile into
the gut.
 Secretin: This hormone is secreted in response to acid in the duodenum. Its effect on the
biliary system is very similar to what was seen in the pancreas - it stimulates biliary duct
cells to secrete bicarbonate and water, which expands the volume of bile and increases its
flow out into the intestine.

Biliary Excretion of Waste Products: Elimination of Bilirubin

The liver is well known to metabolize and excrete into bile many compounds and toxins, thus
eliminating them (usually) from the body. Examples can be found among both endogenous
molecules (steroid hormones, calcium) and exogenous compounds (many antibiotics and
metabolities of drugs). A substantial number of these compounds are reabsorbed in the small
intestine and ultimately eliminated by the kidney.
One of the most important and clinically relevant examples of waste elimination via bile is that
of bilirubin. Additionally, the mechanisms involved in elimination of bilirubin are similar to
those used for elimination of many drugs and toxins.
Bilirubin is a useless and toxic breakdown product of hemoglobin, which also means that it is
generated in large quantities. In the time it takes you to read this sentence aloud, roughly 20
million of your red blood cells have died and roughly 5 quintillion (5 x 10 15) molecules of
hemoglobin are in need of disposal.
Dead, damaged and senescent red blood cells are picked up by phagocytic cells throughout the
body (including Kuppfer cells in the liver) and digested. The iron is precious and is efficiently
recycled. The globin chains are protein and are catabolized and their components reused.
However, hemoglobin also contains a porphyrin called heme that cannot be recycled and must be
eliminated. Elimination of heme is accomplished in a series of steps:
 Within the phagocytic cells, heme is converted through a series of steps into free
bilirubin, which is released into plasma where it is carried around bound to albumin, itself
a secretory product of the liver.
 Free bilirubin is stripped off albumin and absorbed by - hepatocytes. Within hepatocytes,
free bilirubin is conjugated to either glucuronic acid or sulfate - it is then called
conjugated bilirubin.
 Conjugated bilirubin is secreted into the bile canaliculus as part of bile and thus delivered
to the small intestine. Bacteria in the intestinal lumen metabolize bilirubin to a series of
other compounds which are ultimately eliminated either in feces or, after reabsortion, in
urine. The major metabolite of bilirubin in feces is sterobilin, which gives feces their
characteristic brown color.
If excessive quantities of either free or conjugated bilirubin accumulate in extracellular fluid, a
yellow discoloration of the skin, sclera and mucous membranes is observed - this condition is
called icterus or jaundice. Determining whether the excessive bilirubin is free or conjugated can
aid in diagnosing the cause of the problem..

The Hepatic Vascular System

The liver receives approximately 30% of resting cardiac output and is therefore a very vascular
organ. The hepatic vascular system is dynamic, meaning that it has considerable ability to both
store and release blood - it functions as a reservoir within the general circulation.
Unlike most organs, the liver has two major sources of blood. The portal vein brings in nutrient-
rich blood from the digestive system, and the hepatic artery carries oxygenated blood from the
heart.The blood vessels divide into small capillaries, with each ending in a lobule. Lobules are
the functional units of the liver and consist of millions of cells called hepatocytes.
Blood is removed from the liver through three hepatic veins.The liver is grossly divided into two
parts when viewed from above – a right and a left lobe - and four parts when viewed from below
(left, right, caudate, and quadrate lobes). The falciform ligament divides the liver into a left and
right lobe. From below, the two additional lobes are located between the right and left lobes, one
in front of the other. A line can be imagined running from the left of the vena cava and all the
way forward to divide the liver and gallbladder into two halves. This line is called "Cantlie's
line"
Other anatomical landmarks include the ligamentum venosum and the round ligament of the
liver (ligamentum teres), which further divide the left side of the liver in two sections. An
important anatomical landmark, the porta hepatis, divides this left portion into four segments,
which can be numbered starting at the caudate lobe as I in an anticlockwise manner. From this
parietal view, seven segments can be seen, because the eighth segment is only visible in the
visceral view.In the normal situation, 10-15% of the total blood volume is in the liver, with
roughly 60% of that in the sinusoids. When blood is lost, the liver dynamically adjusts its blood
volume and can eject enough blood to compensate for a moderate amount of hemorrhage.
Conversely, when vascular volume is acutely increased, as when fluids are rapidly infused, the
hepatic blood volume expands, providing a buffer against acute increases in systemic blood
volume.
The circulatory system of the liver is unlike that seen in any other organ. Of great importance is
the fact that a majority of the liver's blood supply is venous blood. The pattern of blood flow in
the liver can be summarized as follows:
 Roughly 75% of the blood entering the liver is venous blood from the portal
vein. Importantly, all of the venous blood returning from the small intestine, stomach,
pancreas and spleen converges into the portal vein. One consequence of this is that the
 liver gets "first pickings" of everything absorbed in the small intestine, which, as we will
see, is where virtually all nutrients are absorbed.
 The remaining 25% of the blood supply to the liver is arterial blood from the hepatic
artery.

 Terminal branches of the hepatic portal vein and hepatic artery empty together and mix as
they enter sinusoids in the liver. Sinusoids are distensible vascular channels lined with
highly fenestrated or "holey" endothelial cells and bounded circumferentially by
hepatocytes. As blood flows through the sinusoids, a considerable amount of plasma is
filtered into the space between endothelium and hepatocytes (the "space of Disse"),
providing a major fraction of the body's lymph.
 Blood flows through the sinusoids and empties into the central vein of each lobule.

 Central veins coalesce into hepatic veins, which leave the liver and empty into the vena
cava.
Formation of lymph in the liver
Approximately half of the lymph formed in the body is formed in the liver. Due to the large
pores or fenestrations in sinusoidal endothelial cells, fluid and proteins in blood flow freely into
the space between the endothelium and hepatocytes (the "space of Disse"), forming lymph.
Lymph flows through the space of Disse to collect in small lymphatic capillaries associated with
portal triads (the reason they are not called portal tetrads is because these lymphatic vessels are
virtually impossible to identify in standard histologic sections), and from there in the systemic
lymphatic system.

As you might expect, if pressure in the sinusoids increases much above normal, there is a
corresponding increase in the rate of lymph production. In severe cases the liver literally sweats
lymph, which accumulates in the abdominal cavity as ascitic fluid. What lesions can you
envision that would raise blood pressure in sinusoids, resulting in production of ascites
The Hepatic Phagocytic System
The liver is host to a very important part of the phagocytic system. Lurking in the sinusoids are
large numbers of a type of tissue macrophage known as the Kupffer cell. Kupffer cells are
actively phagocytic and represent the main cellular system for removal of particulate materials
and microbes from the circulation. The image below is a lightly stained section of liver from a
mouse that was injected intravenously with a very small quantity of India ink - Kupffer cells are
clearly visible throughout the section because they have phagocytosed the ink particles and
appear dark black.

Their location just downstream from the portal vein allows Kupffer cells to efficiently scavenge
bacteria that get into portal venous blood through breaks in the intestinal epithelium, thus
preventing invasion of the systemic circulation. The liver is part of the mononuclear phagocyte
system. It contains high numbers of Kupffer cells that are involved in immune activity. These
cells destroy any disease-causing agents that might enter the liver through the gut.

Metabolic Functions of the Liver

Hepatocytes are metabolic overachievers in the body. They play critical roles in synthesizing
molecules that are utilized elsewhere to support homeostasis, in converting molecules of one
type to another, and in regulating energy balances, the major metabolic functions of the liver can
be summarized into several major categories:
Carbohydrate Metabolism
Metabolizing carbohydrates: Carbohydrates are stored in the liver, where they are broken down
into glucose and siphoned into the bloodstream to maintain normal glucose levels. They are
stored as glycogen and released whenever a quick burst of energy is needed.
It is critical for all animals to maintain concentrations of glucose in blood within a narrow,
normal range. Maintainance of normal blood glucose levels over both short (hours) and long
(days to weeks) periods of time is one particularly important function of the liver.
Hepatocytes house many different metabolic pathways and employ dozens of enzymes that are
alternatively turned on or off depending on whether blood levels of glucose are rising or falling
out of the normal range. Two important examples of these abilities are:
 Excess glucose entering the blood after a meal is rapidly taken up by the liver and
sequestered as the large polymer, glycogen (a process called glycogenesis). Later, when
blood concentrations of glucose begin to decline, the liver activates other pathways which
lead to depolymerization of glycogen (glycogenolysis) and export of glucose back into
the blood for transport to all other tissues.
 When hepatic glycogen reserves become exhaused, as occurs when an animal has not
eaten for several hours, do the hepatocytes give up? No! They recognize the problem and
activate additional groups of enzymes that begin synthesizing glucose out of such things
as amino acids and non-hexose carbohydrates (gluconeogenesis). The ability of the liver
to synthesize this "new" glucose is of monumental importance to carnivores, which, at
least in the wild, have diets virtually devoid of starch.
Fat Metabolism
Few aspects of lipid metabolism are unique to the liver, but many are carried out
predominantly by the liver. Major examples of the role of the liver in fat metabolism include:
 The liver is extremely active in oxidizing triglycerides to produce energy. The liver
breaks down many more fatty acids that the hepatocytes need, and exports large
quantities of acetoacetate into blood where it can be picked up and readily metabolized
by other tissues.
 A bulk of the lipoproteins are synthesized in the liver.
 The liver is the major site for converting excess carbohydrates and proteins into fatty
acids and triglyceride, which are then exported and stored in adipose tissue.
 The liver synthesizes large quantities of cholesterol and phospholipids. Some of this is
packaged with lipoproteins and made available to the rest of the body. The remainder is
excreted in bile as cholesterol or after conversion to bile acids.
Protein Metabolism
The most critical aspects of protein metabolism that occur in the liver are:
 Deamination and transamination of amino acids, followed by conversion of the non-
nitrogenous part of those molecules to glucose or lipids. Several of the enzymes used in
these pathways (for example, alanine and aspartate aminotransferases) are commonly
assayed in serum to assess liver damage.
 Removal of ammonia from the body by synthesis of urea. Ammonia is very toxic and if
not rapidly and efficiently removed from the circulation, will result in central nervous
system disease. A frequent cause of such hepatic encephalopathy in dogs and cats are
malformations of the blood supply to the liver called portosystemic shunts.
 Synthesis of non-essential amino acids.
  Production of albumin: Hepatocytes are responsible for synthesis of most of the
plasma proteins Albumin is the most common protein in blood serum. It transports fatty
acids and steroid hormones to help maintain the correct pressure and prevent the leaking
of blood vessels. Albumin, the major plasma protein, is synthesized almost exclusively
by the liver. Also, the liver synthesizes many of the clotting factors necessary for blood
coagulation.
Other functions of the liver include:
Supporting blood clots: Vitamin K is necessary for the creation of certain coagulants that help
clot the blood. Bile is essential for vitamin K absorption and is created in the liver. If the liver
does not produce enough bile, clotting factors cannot be produced.
Vitamin and mineral storage: The liver stores vitamins A, D, E, K, and B12. It keeps
significant amounts of these vitamins stored. In some cases, several years' worth of vitamins is
held as a backup. The liver stores iron from hemoglobin in the form of ferritin, ready to make
new red blood cells. The liver also stores and releases copper.
Helps metabolize proteins: Bile helps break down proteins for digestion.
Filters the blood: The liver filters and removes compounds from the body, including hormones,
such as estrogen and aldosterone, and compounds from outside the body, including alcohol and
other drugs.
Synthesis of angiotensinogen: This hormone raises blood pressure by narrowing the blood
vessels when alerted by production of an enzyme called renin in the kidneys.

Biochemical tests to diagnose liver disease

• A series of special blood tests can often determine whether or not the liver is functioning
properly. These tests can also distinguish between acute and chronic liver disorders and
between hepatitis and cholestasis.
• Serum bilirubin test: An elevated bilirubin level may indicate an impaired bile flow or a
problem with the liver processing bile.
• Serum albumin test) - a decrease in albin levels indicates a violation of the protein-synthesizing
function of the liver.
• Serum Alkaline Phosphatase Test: Alkaline phosphatase is found in many tissues, with the
highest concentrations in the liver, biliary tract and bone. This test can be performed to
evaluate liver function and to identify liver lesions that can cause obstruction of the biliary
tract, such as tumors or abscesses. Serum aminotransferases (transaminases): This enzyme
is released from damaged liver cells.
• Prothrombin time (PTT) test: The prothrombin time test measures how long it takes for blood
to clot. Blood clotting requires vitamin K and a protein that is made by the liver. Prolonged
clotting may indicate liver disease or other deficiencies in specific clotting factors.
• Alanine transaminase (ALT) test: This test measures the level of alanine aminotransferase (an
enzyme found predominantly in the liver) that is released into the bloodstream after acute
liver cell damage. This test may be performed to assess liver function, and/or to evaluate
treatment of acute liver disease, such as hepatitis.
• Aspartate transaminase (AST) test: This test measures the level of aspartate transaminase (an
enzyme that is found in the liver, kidneys, pancreas, heart, skeletal muscle, and red blood
cells) that is released into the bloodstream after liver or heart problems.
• Gamma-glutamyl transpeptidase test: This test measures the level of gamma-glutamyl
transpeptidase (an enzyme that is produced in the liver, pancreas, and biliary tract). This
test is often performed to assess liver function, to provide information about liver diseases,
and to detect alcohol ingestion.
• Lactic dehydrogenase test: This test can detect tissue damage and aides in the diagnosis of liver
disease.
• 5'-nucleotidase test: This test measures the levels of 5'- nucleotidase (an enzyme specific to the
liver). The 5'- nucleotidase level is elevated in persons with liver diseases, especially those
diseases associated with cholestasis (disruption in the formation of, or obstruction in the
flow of bile).
• Alpha-fetoprotein test: Alpha-fetoprotein (a specific blood protein) is produced by fetal tissue
and by tumors. This test may be performed to monitor the effectiveness of therapy in
certain cancers, such as hepatomas.
• Mitochondrial antibodies test: The presence of these antibodies can indicate primary biliary
cirrhosis, chronic active hepatitis, and certain other autoimmune disorders. Cytolysis
syndrome
• Cytolysis syndrome (cytolytic syndrome, hepatocyte integrity disorder syndrome) is a non-
specific reaction of liver cells to the action of damaging factors. The syndrome is based on
a violation of the permeability of cell membranes, their organelles, which leads to the
release of intracellular enzymes into the blood plasma. The cytolytic process can affect a
small number of hepatocytes, but often he more common, captures a huge amount free
cells.
• The following tests are indicators of cytolysis:  alanine aminotransferase (ALT);  aspartate
aminotransferase (AST);  γ-glutamyl transpeptidase (GGPT);  lactate dehydrogenase -
LDH (5th fraction);  glutamate dehydrogenase (GDH);  aldolase, etc.
• It should also be borne in mind that ALT, GGPT, LDH are cytoplasmic enzymes, GDH -
mitochondrial, AST - cytoplasmic-mitochondrial enzyme. This is important to know for an
indirect assessment of severity damage to hepatocytes.
Cholestasis syndrome
• Cholestasis syndrome (violation of excretory liver function)
• Cholestasis - reduction or complete cessation outflow of bile dueto a violation of its formation,
excretion and / or excretion. Thepathological process can be localized anywhere from
thesinusoidal membrane of the hepatocyte to the duodenal papilla.

Liver disease
An organ as complex as the liver can experience a range of problems. A healthy liver functions
very efficiently. However, in a diseased or malfunctioning liver, the consequences can be
dangerous or even fatal.
Examples of liver disease include:
Fascioliasis: This is caused by the parasitic invasion of a parasitic worm known as a liver fluke,
which can lie dormant in the liver for months or even years. Fascioliasis is considered a tropical
disease.
Cirrhosis: This sees scar tissue replace liver cells in a process known as fibrosis. This condition
can be caused by a number of factors, including toxins, alcohol, and hepatitis. Eventually,
fibrosis can lead to liver failure as the functionality of the liver cells is destroyed.
Hepatitis: Hepatitis is the name given to a general infection of the liver, and viruses, toxins, or
an autoimmune response can cause it. It is characterized by an inflamed liver. In many cases, the
liver can heal itself, but liver failure can occur in severe cases.
Alcoholic liver disease: Drinking too much alcohol over long periods of time can cause liver
damage. It is the most common cause of cirrhosis in the world.
Primary sclerosing cholangitis (PSC): PSC is a serious inflammatory disease of the bile ducts
that results in their destruction. There is currently no cure, and the cause is currently unknown,
although the condition is thought to be autoimmune.
Fatty liver disease: This usually occurs alongside obesity or alcohol abuse. In fatty liver disease,
vacuoles of fat build up in the liver cells. If it is not caused by alcohol abuse, the condition is
called non-alcoholic fatty liver disease (NAFLD).
It is usually caused by genetics, medications, or a diet high in fructose sugar. It is the most
common liver disorder in developed countries and has been associated with insulin resistance.
Non-alcoholic steatohepatitis (NASH) is a condition that can develop if NAFLD gets worse.
NASH is a known cause of liver cirrhosis.
Gilbert's syndrome: This is a genetic disorder affecting 3 to 12 percent of the population.
Bilirubin is not fully broken down. Mild jaundice can occur, but the disorder is harmless.
Liver cancer: The most common types of liver cancer are hepatocellular carcinoma and
cholangiocarcinoma. The leading causes are alcohol and hepatitis. It is the sixth most
common form of cancer and the second most frequent cause of cancer death.
Liver failure: Liver failure has many causes including infection, genetic diseases, and excessive
alcohol.
Ascites: As cirrhosis results, the liver leaks fluid (ascites) into the belly, which becomes distended
and heavy.
Gallstones: If a gallstone becomes stuck in the bile duct draining the liver, hepatitis and bile duct
infection (cholangitis) can result.
Hemochromatosis: Hemochromatosis allows iron to deposit in the liver, damaging it. The iron also
deposits throughout the body, causing multiple other health problems.
Primary sclerosing cholangitis: A rare disease with unknown causes, primary sclerosing
cholangitis causes inflammation and scarring in the bile ducts in the liver.
Primary biliary cirrhosis: In this rare disorder, an unclear process slowly destroys the bile ducts in
the liver. Permanent liver scarring (cirrhosis) eventually develops.
Neonatal Jaundice
Jaundice is a relatively common occurance in human infants. As in adults, jaundice is due to
elevated blood concentrations of bilirubin (hyperbilirubinemia). There are at least two significant
processes that predispose normal infants to jaundice:
  The rate of bilirubin production is higher in infants than adults because their red blood cells
have a shorter half-life and turn over more rapidly.
 Infants have a relatively limited ability to conjugate bilirubin, and conjugation in the liver is
necessary for efficient elimination.
Additionally, there are a number of pathologic conditions that can result in neonatal jaundice.
Examples include:
 Conditions that cause accelerated destruction of red cells, which can occur as a result of
immune-mediated hemolysis, certain enzyme deficiencies, or structural abnormalities in red
cells.
 Increased intestinal absorption of bilirubin, which blunts the infant's ability to eliminate this
waste product. Infants that fail to feed well are often deficient in the types of intestinal
bacteria that metabolize bilirubin, and in such cases, significant amounts of bilirubin of
reabsorbed into blood.
 Genetic defects in hepatic uptake of bilirubin (e.g. Gilbert's syndrome) or deficiency in the
enzyme necessary for conjugating bilirubin (uridine diphosphate glucuronosyltransferase).
A large majority of cases of neonatal hyperbilirubinemia are mild and resolve over the first
few weeks of life. However, persistently high concentrations of bilirubin can be
dangerous. Elevated levels of bilirubin interfere with a number of cellular processes, and may be
neurotoxic. Kernicterus is a serious and life-threatening form of neonatal jaundice that reflects the
toxicity of bilirubin to the central nervous system. Kernicterus, in both acute and chronic forms, is
manifest by a variety of neurologic and cognitive deficits ranging from poor suckling and seizures to
low IQ. Clearly, this disorder should be treated without delay.
The standard treatment for neonatal jaundice is phototherapy. Affected infants are placed under
lights, and photons are absorbed by bilirubin as it circulates in skin capillaries. This energy transfer
results in conversion of bilirubin to lumirubin and other products which, in contrast to bilirubin, are
more water-soluble and readily excreted. The rate of bilirubin elimination depends upon both the
wavelength of light used and its dose. Blue light (460 to 490 nm) is the most effective, but such light
causes eye strain in those monitoring the baby, making it difficult to detect other conditions such as
cyanosis. The most frequently used form of phototherapy is standard fluorescent white light.
In severe cases of neonatal jaundice, another effective treatment is exchange transfusion. In this
procedure, small amounts of blood (and hence bilirubin) are removed from the baby and replaced
with donor blood; this procedure is repeated until roughly twice the blood volume has been replaced.
Exchange transfusion also eliminates antibodies against red blood cells, which may be the inciting
factor in development of hyperbilirubinemia.
Neonatal jaundice almost certainly occurs in animals other than humans, but, by it self, is not
recognized as a significant disorder. Immune-mediated hemolytic anemias are relatively common in
foals, calves and piglets, and may lead to jaundice. However, the most serious aspect of this disease
is the anemia, rather than jaundice per se.
Gallstones (Cholelithiasis)
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 expeditures of about $5 billion
for diagnosis and treatment. A majority of cases are asymptomatic, but signs in clinicially affected
patients range from mild abdominal pain or minor "indigestion" to excrutiating pain, often manifest
at night. There are two major types of gallstones, which seem to form due to distinctly different
pathogenetic mechanisms: cholesterol stones and pigment stones. Additional types of gallstones
include calcium stones and mixed stones.
Cholesterol Stones
Roughly 50-90% 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:
 Hypersecretion of cholesterol into bile due to such things as obesity, acute high calorie
intake, chronic polyunsaturated fat diet, contraceptive steroids or pregnancy, diabetes
mellitus and certain forms of familial hypercholesterolemia.
 Hyposecretion 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 ileal 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.
There are clearly important genetic determinants for cholesterol stone formation. For example,
the prevelance of the disease in descendents 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 prevelance 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 hypersecretion 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
hightest, then dissipate rapidly after birth.
The gold standard for treatment is open cholecystectomy, but laparoscopic cholecystecomy is rapidly
becoming the treatment of choice. Medical treatment with bile salts is not extremely useful in the
long term and is expensive.
Pigment Stones
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.

Regeneration of the Liver

The liver has a remarkable capacity to regenerate after injury and to adjust its size to match its
host. Within a week after partial hepatectomy, which, in typical experimental settings entails
surgical removal of two-thirds of the liver, hepatic mass is back essentially to what it was prior to
surgery. Some additional interesting observations include:
 In the few cases where baboon livers have been transplanted into people, they quickly
grow to the size of a human liver.
  When the liver from a large dog is transplanted into a small dog, it loses mass until it
reaches the size appropriate for a small dog.
 Hepatocytes or fragments of liver transplanted in extrahepatic locations remain quiescent
but begin to proliferate after partial hepatectomy of the host.
These types of observations have prompted considerable research into the mechanisms
responsible for hepatic regeneration, because understanding the processes involved will likely
assist in treatment of a variety of serious liver diseases and may have important implications for
certain types of gene therapy. A majority of this research has been conducted using rats and
utilized the model of partial hepatectomy, but a substantial body of confirmatory evidence has
accumulated from human subjects.
The dominant processes leading to regeneration of the liver following removal of tissue (partial
hepatectomy) are compensatory hypertrophy (enlargement of hepatocytes) followed by
hyperplasia (proliferation of hepatocytes). Proliferating hepatocytes also are capable of
transdifferentiating into other cell types such those of the biliary system. Blood borne stem cells
from bone marrow can participate in regeneration but are thought to play a minor role, except
perhaps when hepatocytes are greatly compromised by toxic injury.
Partial hepatectomy leads to proliferation of all populations of cells within the liver, including
hepatocytes, biliary epithelial cells and endothelial cells. DNA synthesis is initiated in these cells
within 10 to 12 hours after surgery and essentially ceases in about 3 days. Cellular proliferation
begins in the periportal region (i.e. around the portal triads) and proceeds toward the centers of
lobules. Proliferating hepatocytes initially form clumps, and clumps are soon transformed into
classical plates. Similarly, proliferating endothelial cells develop into the type of fenestrated cells
typical of those seen in sinusoids.
It appears that hepatocytes have a practically unlimited capacity for proliferation, with full
regeneration observed after as many as 12 sequential partial hepatectomies. Clearly the
hepatocyte is not a terminally differentiated cell.
Changes in gene expression associated with regeneration are observed within minutes of hepatic
resection. An array of transcription factors are rapidly induced and probably participate in
orchestrating expression of a group of hepatic mitogens. Proliferating hepatocytes appear to at
least partially revert to a fetal phenotype and express markers such as alpha-fetoprotein. Despite
what appears to be a massive commitment to proliferation, the regenerating hepatocytes continue
to conduct their normal metabolic duties for the host such as support of glucose metabolism.
The processes and signals involved in shutting down the regenerative response are less well
studied than those that stimulate it. TGF-beta1, which is known to inhibit proliferative responses
in hepatocytes, is one cytokine involved in this process, but undoubtedly several others
participate.
Because of the importance of the liver and its functions, evolution has ensured that it can regrow
rapidly as long as it is kept healthy. This ability is seen in all vertebrates from fish to humans.
The liver is the only visceral organ that can regenerate.
It can regenerate completely, as long as a minimum of 25 percent of the tissue remains. One of
the most impressive aspects of this feat is that the liver can regrow to its previous size and ability
without any loss of function during the growth process.
In mice, if two-thirds of the liver is removed, the remaining liver tissue can regrow to its original
size within 5 to 7 days. In humans, the process takes slightly longer, but regeneration can still
occur in 8 to 15 days - an incredible achievement, given the size and complexity of the organ.
 Over the following few weeks, the new liver tissue becomes indistinguishable from the original
tissue.
This regeneration is helped by a number of compounds, including growth factors and cytokines.
Some of the most important compounds in the process appear to be:
 hepatocyte growth factor
 insulin
 transforming growth factor-alpha
 epidermal growth factor
 interleukin-6
 norepinephrine

Health
Below are some recommendations to help keep your liver working as it should:
Diet: As the liver is responsible for digesting fats, consuming too many can overwork the organ
and disturb it from other tasks. Obesity is also linked to fatty liver disease.
Moderate alcohol intake: Avoid consuming more than two drinks at a time. Drinking too much
alcohol causes cirrhosis of the liver over time. When the liver breaks down alcohol, it produces
toxic chemicals, such as acetaldehyde and free radicals. For serious damage to occur, it takes the
equivalent of a liter of wine every day for 20 years in men. For women, the threshold is less than
half of that.
Avoiding illicit substances: When last surveyed in 2012, close to 24 million people in the
United States had consumed an illicit, non-medical drug within the last month. These can
overload the liver with toxins.
Caution when mixing medications: Some prescription drugs and natural remedies can interact
negatively when mixed. Mixing drugs with alcohol puts significant pressure on the liver. For
example, combining alcohol and acetaminophen can lead to acute liver failure. Be sure to follow
the instructions on any medications.
Protection against airborne chemicals: When painting or using strong cleaning or gardening
chemicals, the area should be well ventilated, or a mask should be worn. Airborne chemicals can
cause liver damage because the liver has to process any toxins that enter the body.
Travel and vaccinations: Vaccination is essential if you are traveling to an area in which
hepatitis A or B might be a concern. Malaria grows and multiplies in the liver, and yellow
fever can lead to liver failure. Both diseases can be prevented by oral medication and
vaccination.
Safe sex: There is no vaccination for hepatitis C, so caution is advised in regards to safe sex,
tattoos, and piercings.
Avoid exposure to blood and germs: Receive medical attention if you are exposed to the blood
of another person. It is also important not to share personal items related to hygiene, such as
toothbrushes, and to avoid dirty needles.
Despite its ability to regenerate, the liver depends on being healthy to do so. The liver can mostly
be protected through lifestyle choices and dietary measures

Detoxification in the liver

The most significant pressures the liver has to deal with come from man-made chemicals such as
petrol, preservatives, pollutants, pesticides, cigarette smoke, recreational drugs and medication.
Almost everything we eat, breathe in or put into our body has to be detoxified by the liver.
The liver has various ways of ways of dealing with toxins, such as breaking them down into safer
substances, eliminating them through bile or repackaging them into a safer form. As a last resort
the liver will even store toxins itself to protect the rest of the body.
The liver filters toxins through the sinusoid channels, which are lined with immune cells called
Kupffer cells. These engulf the toxin, digest it and excrete it. This process is called phagocytosis.
As most chemicals are relatively new it will be thousands of years before our body properly
adapts to them. If the liver cannot figure out what to do with them it simply stores them, often in
fat tissue. This is process is potentially damaging to the fabric of the liver.
There are three major phases of detoxification in the liver

Phase 1 Detoxification

The Phase one detoxification pathway converts a toxic chemical into a less harmful chemical
and is achieved by various chemical reactions such as oxidation, reduction and hydrolysis. This
biotransformation converts the lipophilic compounds into more water-soluble metabolites which
can be efficiently eliminated from the body. During this process free radicals are produced
which, if excessive, can damage the liver cells. Phase 1 is catalyzed by the enzymes of the
cytochrome P450 group. These enzymes are found in the cells of the liver that are called
Hepatocytes.The Cytochrome P450 pathway is induced by the presence of various chemicals and
the production of free radicals, or reactive oxygen species (ROS) is kept in check by
antioxidants. However, if these antioxidants, such as C, E and beta-carotenes are lacking, then
these free radicals are free to do damage to the body. Therefore, an adequate supply of various
antioxidants is necessary to quench these free radicals to prevent tissue damage.

Furthermore, exposures to certain toxic chemicals such as pesticides can disrupt the P-450
enzyme system by causing over activity or what is called ‘induction’ of this pathway. This over
activity results in high levels of ROS which, if not further metabolised by Phase II conjugation,
may cause damage to proteins, RNA, and DNA within the cell.In addition to inducers of the
Cytochrome P450 pathway, there are also those substances that are know to inhibit, such as
naringenin found in grapefruit juice. This has the potential to be dangerous as some drugs can be
left active in the bloodstream and therefore continuing to exert unwanted effects.A
polymorphism, or genetic variability in the Cytochrome P450 can effect how a toxin is
metabolized. The area this can have the greatest effect is upon the metabolism of drugs. It can
cause unexpected side effects dependent upon the drug and enzyme involved and also produce a
therapeutic failure. Interactions with common drugs such as statins, warfarin, antidepressants and
antiepileptic are often associated with the P450 enzymes.

Phase 2 detoxification
 Phase 2 detoxification is referred to as conjugation and this is the process of adding a molecule
to the xenobiotic to make it hydrophilic and therefore theoretically able to be excreted through
the bile or kidneys. The end products of conjugation have increased molecular weight and tend to
be less active than the products of phase 1 reactions.There are six phase 2 detoxification
pathways:Glutathione conjugation,Amino acid conjugation,Acetylation,Methylation,Sulphation
and GlucoronidationThese conjugation molecules join with specific enzymes to catalyze the
reaction process. The liver is then able to turn drugs, hormones, and other various toxins into
substances that are secreted from the body. Any lack of these enzymes or their cofactors will
result in the xenobiotic remaining active and therefore potential to cause damage within the
body.

Phase 3 Detoxification

Latest research has identified a third detoxification pathway; Phase 3 detoxification. It is thought
that through this pathway the now water soluble molecules are excreted. Although a lesser
studied pathway, it is essential to the removal of waste. Often referred to as the antiporter
pathway, within which more than 350 antiporter proteins have been identified, the best known
and most studied is the of which is the the best known and most studied transporter known as P-
glycoprotein.P-glycoprotein is found in the intestinal epithelium where it pumps zenobiotics
back into the intestinal epithelium, the liver where it pumps toxins into the bile ducts, and in the
proximal tubule of the kidney where it pumps toxins back into the urine-conducting ducts. It can
also be found in the blood brain barrier and the blood-testis barrier.The transporters in Phase III
belong to a family of proteins called the ABC transporters, or ATP-binding cassette, as they
require ATP, or energy, to pump toxins through the cell membrane and out of the cell. Phase III
transporters also decrease the effectiveness of pharmaceutical therapies as they increase their
clearance from the body, thus reducing the load on the liver. This is an important note for
chemotherapy drugs, as the transporters enable cancer cells to become resistant.In this day and
age of an ever increasing toxic burden around us it is essential to support and maintain good
detoxification and a balance through all of the pathways. In order to do this a good understanding
of the detoxification processes is required, particularly amongst those in a professional capacity
looking to support those who seek advice and treatment.

Alcohol toxicity
Alcohol is a lethal substance and its danger is identified with the amount and term of alcohol
utilization. It can affect each organ in the body. In the mind, in a solitary drinking scene,
expanding levels of liquor lead at first to incitement (experienced as joy), fervor and garrulity. At
expanding fixations liquor creates sedation prompting uproars of unwinding, afterwards to
slurred discourse, instability, loss of coordination, incontinence, trance state and eventually
Alcohol reliance and unsafe liquor use demise through liquor harming, because of the sedation of
the essential mind works on breathing and flow. The reliance delivering properties of liquor have
been examined widely over the most recent 20 years. Liquor influences a wide scope of synapse
frameworks in the mind, prompting the highlights of liquor reliance. The principle synapse
frameworks influenced by liquor are gamma-aminobutyric corrosive (GABA), glutamate,
dopamine and narcotic. The activity of liquor on GABA is like the impacts of different narcotics,
for example, benzodiazepines and is answerable for liquor’s calming and anxiolytic properties.
Glutamate is a major neurotransmitter responsible for brain stimulation, and alcohol affects
glutamate through its inhibitory action on N-methyl D-aspartate (NMDA)-type glutamate
receptors, producing amnesia (for example, blackouts) and sedation. Chronic alcohol
consumption leads to the development of tolerance through a process of neuroadaptation:
receptors in the brain gradually adapt to the effects of alcohol, to compensate for stimulation or
sedation (Figure 1). This is experienced by the individual as the same amount of alcohol having
less effect over time. This can lead to individual increasing alcohol consumption to achieve the
desired psychoactive effects. The key neurotransmitters involved in tolerance are GABA and
glutamate, with chronic alcohol intake associated with reduced GABA inhibitory function an
increased NMDA-glutamatergic activity.