PHYSIOLOGY OF LIVER

Although the liver has been examined by the anatomist for many centuries, a
knowledge of its function is relatively modern. Claude Bernard was the first to
demonstrate its importance in carbohydrate metabolism and was responsible for
identification and naming of glycogen. In 1922, Mann and his colleagues, by perfecting a
technique of experimental total hepatectomy in dogs, were able to give the first full
account of liver function.
Within few hours of total hepatectomy the sugar concentration falls rapidly, and a
hypoglycaemia develops, there is increasing weakness followed convulsions coma and
death. When the state first develops, it can be rapidly reversed by administering glucose.
A few hours later a somewhat similar state occurs but accompanied by vomiting, ataxia
and apparent loss of sight and hearing. This final state is uninfluenced by giving glucose,
and so is not hypoglycaemic in origin. The storage of glycogen in muscle only a little even
when the animal is dying of hypoglycaemia, and it is concluded that liver is responsible
solely for replenishing the liver sugar.
The importance of the liver in the formation of urea was suspected before
experimental hepatectomy was became practicable. The liver was known to have a higher
urea content than other tissues and it was also known that the fluid perfused through the
liver acquire a higher urea content in transit. If the liver is removed from the animal, the
blood urea concentration falls to almost zero after about 24 hours, but remains stable if
the kidneys have also been removed. Blood urea rises progressively in animals with an
intact liver with bilateral nephrectomy, and it follows that the urea formation is dependent
on liver.
Hepatectomised dogs become increasingly jaundiced throughout the period of their
survival. The plasma bilirubin begins to rise early and yellow colour of plasma is visible to
naked eye with in about three hours. The sclera are jaundiced in dogs which survive about
16 hours and at the post mortem the fat through out the body is found to be stained. The
formation of bilirubin is not prevented by removing all the abdominal viscera including the
liver and spleen and extra bilirubin is still formed after the injection of haemoglobin. It can
be concluded that the liver is not only the organ formation of bilirubin but it is the principal
organ of the bilirubin excretion.
The functions include formation of bile, carbohydrate storage, ketone body formation,
and other functions in control of carbohydrate metabolism: reduction and conjugation of
adrenal and gonadal steroid hormones; detoxifictions of many drugs and toxins;
manufacture of plasma proteins; inactivation of polypeptide hormones; urea formation and
many important functions in the metabolism of fat.
CARBOHYDRATE METABOLISM
The liver occupies a key position in the carbohydrate metabolism. It stores
carbohydrates as glycogen, a condensation product of many molecules of glycogen.
Glycogen can be formed from monosaccharides in the portal venous blood (glycogenesis),
from the glycerol of fat, and from deaminated amino acids (neoglycogenesis). The stored
glycogen is converted into glucose (glycogenolysis) as required to maintain blood glucose
concentration at constant level.
The formation of glycogen and its release as glycogen is under the influence of
hormones. Insulin favours the laying down of glycogen and retards the liberation of
glucose, while the hormones of the anterior pituitary, the adrenal cortex and the thyroid
favours the break down of glycogen and the liberation of glucose. Glucagon and
adrenaline also liberate glucose from the glycogen.
The liver glycogen is the only readily available reserve of the glucose for maintaining
the concentration of the blood sugar; muscle glycogen is not available for this purpose, as
shown by experiments in totally hepatectomised animals where hypoglycaemic death
occurred before very much glycogen had disappeared from muscles.
The average adult liver contains about 100 grams of glycogen. The store is exhausted
by about 24 hours of starvation after which the whole body requirement for glucose must
be met by the formation of glucose from body fat and protein. This process at its normal
speed results in the liberation of small amounts of ketone bodies, and the ketosis of
starvation represents the normal process carried to excess. In children the reserve of the
liver glycogen is similar and the metabolic rate higher, and the ketosis of starvation begins

correspondingly earlier.
Glycogen in addition to its fundamental role in carbohydrate metabolism, protects the
liver from damage by many poisons, of which chloroform is the classical example.
The liver is also the site of metabolism to glucose of other monosaccharides, such as
fructose, and of lactic pyruvic and ketoglutaric acids produced by the utilisation of glucose
in muscle and other tissues 12.
AMINO ACID METABOLISM: FORMATION OF UREA.
The liver is concerned in breakdown of food and body protein and particularly in the
deamination of the amino acids. The amino acids set free by digestion of protein are
absorbed by the small intestine, pass into portal blood to the liver and some pass through
the liver into the systemic blood. The average concentration of the amino acids in the
blood is 3-4 mg/dl, but this may rise to 10 mg/dl after a meal rich in protein. The absorbed
amino acids together with those released by the breakdown of body protein from the
amino acid pool which is available for the re-synthesis into protein or for combustion as a
source of energy. The amino acid pool is in a continual state of flux, with amino acids
being added, transformed or removed all the time.
Many of the 20 amino acids can be synthesised in the body by transformation from
other amino acids, or by the amination of the carbohydrates but there is a group of 8
amino which cannot be synthesised and are termed essential since they must be supplied
in diet.
Oxidative deamination occurs principally in the liver. The reaction involves the
transformation of the amino acid (e.g. alanine) to the corresponding keto-acid (pyruvic
acid) and the liberation of ammonia. The keto- acid can be used for synthesising other
compounds or burned as a source of energy. Most of the ammonia released in the process
of deamination is converted to urea and excreted in the urine, and the reminder is used in
the synthesis of other amino acids (reamination). Oxidative deamination occurs in the
tissues other than the liver, but urea formation is probably a hepatic function only. The
formation of urea CO(NH2)2 requires the union of carbon dioxide and ammonia with the
elimination of water:
CO2 + 2NH3 ---> CO(NH2)2 + H2O
Deamination of amino acids may also be coupled with the simultaneous amination of
a ketoacid, the enzymes facilitating these reactions being termed transaminases. The
result is the transference of the NH 2 group from one amino acid and its use to synthesise
another as in the formation of glutamic acid from alinine facilitated by alanine amino
transferase (ALT).
The amino transferases are intracellular enzymes but small quantities are normally
present in the circulation. When significant cellular damage occurs in an organ, their
serum concentration rises an example of which is increase in ALT following damage to
liver.
PROTEIN METABOLISM: The liver manufacture albumin and the proteins concerned with
blood clotting (fibrinogen, prothrombin, and factors V, VII, IX, and X). Furthermore the
hepatic Kupffer cells able to synthesise a and b-globulin, and remove g-globulin, and to
remove g-globulin from portal blood.
The evidence that the liver is the major source of plasma albumin is both
experimental and clinical. In dogs after total hepatectomy, there is slow but progressive
fall in the concentration of the plasma albumin, suggesting albumin is being slowly utilised
without replacement. In man, the ability to make albumin is reduced in liver failure and
hepatic cirrhosis, and the plasma concentration of albumin is often much less than the
normal value of 40-50g/l.
The characteristic change in the chronic liver disease is a fall in the serum albumin
accompanied by a rise in serum g-globulin. It is therefore necessary to measure fractions
as total value may be within the normal range. It should be noted that the serum albumin
and g-globulin concentrations measure different hepatic functions: the albumin is formed
in the liver whereas gglobulin is formed in extrahepatic reticuloendothelial system and
removed from the circulation by hepatic Kupffer cells.
BLOOD COAGULATION: As indicated above the liver is the site of synthesis of the
coagulation factors V, VII, IX, and X as well as fibrinogen and prothrombin is dependent on
the presence of vitamin K from intestine. Synthesis of many of the coagulation factors may

thus be impaired either by extensive parenchymatous disease or damage or by failure to

absorb vitamin K from gut and may cause the development of significant bleeding
tendency. Lack of labile factor V occurs with severe liver disease and never with vitamin K
deficiency.
The problem is most often associated with resection for injury when the bleeding
tendency is caused by large quantities of stored blood which is deficient in factor. The liver
is the only site for synthesis of fibrinogen but impaired formation is rare even in severe
hepatic failure. The only common cause of fibrinogen lack is increased fibrinolysis which
may occur in all forms of liver disease and especially in patients with cirrhosis.
Tests for defect in blood coagulation include the one stage prothrombin time and this
should be measured in all patients with hepatobiliary disease. A prolonged prothrombin
time may indicate deficient prothrombin synthesis, especially in the presence of
obstructive jaundice. Operation and such procedures as splenic venography or liver biopsy
should be postponed until the patient has responded to treatment with vitamin K given
parentally. Failure to respond promptly to vitamin K may be an index of synthesis,
however, reflecting severe hepatocellular dysfunction.
FAT METABOLISM
The liver plays an important role in the metabolism of fat and is concerned not only
with the digestion and absorption of fat by virtue of secreting bile salts into the duodenum
but also in the removal of fat from the blood stream after absorption has taken place.
The bile salts assist in the intestinal absorption of dietary fat by breaking up fat
globules into a fine emulsion thus allowing greater contact with lipases for hydrolysis and
also a reduction in particle size; they also form water soluble complexes (micelles) with
lipids which promotes their absorption. The products of hydrolysis (free fatty acids,
monoglycerides and to a lesser extent diglycerides and triglycerides) and probably
absorbed as a mixture by the mucosal cells of the intestine. Long chain fatty acids are
converted into triglycerides, enter the lymphatic and pass by way of thoracic duct to the
systemic vein together with the particulate fat. Short chain fatty acids are water soluble
and enter the portal blood and pass to the liver some is metabolised and some continues
to be deposited in the body fat depots.
Fatty infiltration impairs the live function and interferes with the detoxication of
barbiturates and makes dangerous the administration of fat-soluble anaesthetics such as
ether chloroform, methoxyflurane, enflurane or halothane.
DETOXICATION
The liver protects the body against many endogenous and exogenous toxic
substances. The substances are dealt with by conjugation, by destructive oxidation or by a
combination of these processes. The method of dealing with toxin appears to be
fortuitous, depending on the resemblance of the toxin to the physiological compounds.
Conjugation may be with amino-acids glucuronic acids sulphates or ascetic acid.
Oxidative destruction is the method of dealing with many compounds foreign to the body.
The alkaloid, strychnine and nicotine and the short lasting barbiturates are destroyed in
this way. Liver disease or damage may make a patient unduly susceptible to the agents
normally conjugated or destroyed in the liver and this often influences the drug dosage in
these conditions.
RETICULO-ENDOTHELIAL FUNCTION
The hepatic Kupffer cells which are found lining the sinusoids are an important part of
the reticulo-endothelial (mononuclear phagocytic) system, the remainder being located in
the bone marrow, lymph nodes and spleen. These hepatic cells are able to ingest colloidal
particles, their main function is ingestion of bacteria and bacterial products such as
endotoxin the removal of g-globulin, the destruction of erythrocytes and the extraction of
injected colloids from the circulation.
By the ingestion of bacteria the phagocytic cells are concerned in the defence of the
body against infection they greatly increase in number resulting in enlargement of the
organs rich in globulins.

Anatomy and Physiology of the liver

Human liver development begins during the third week of gestation and does not acheive
mature architecture until about 15 years of age. It reaches its largest relative size, 10% of
fetal weight, around the ninth week. It is about 5% of body weight in the healthy neonate.
The liver is about 2% of body weight in the adult. It weighs around 1400g in an adult
female and about 1800g in the male.*
The liver is located in the right upper quadrant of the abdomen, just below the diaphragm.
It is almost completely behind the rib cage but the lower edge may be palpated along the
right costal margin during inspiration. A connective tissue layer called Glisson's capsule
covers the surface of the liver. The capsule extends to invest all but the smallest the
vessels within the liver. * The falciform ligament attaches the liver to the abdominal wall
and diaphragm and divides the liver into a larger right lobe and a smaller left lobe.

In 1957, the french surgeon Claude Couinaud described 8 liver segments. Since then,
radiographic studies describe an average of twenty segments based on distribution of
blood supply*. Each segment has its own independent vascular and biliary branches.
Surgeons utilize these independent segments when performing liver resection for tumor or
transplantation. There are at least three reasons why segmental resection is superior to
simple wedge resection. First, segmental resection minimizes blood loss because vascular
density is reduced at the borders between segments. Second, it results in improved tumor
removal for those cancers which are disseminated via intrasegmental branches of the
portal vein. Third, segmental resection spares normal liver allowing for repeat partial
hepatectomy*.

Each segment of the liver is further divided into lobules. Lobules are usually represented
as discrete hexagonal aggregations of hepatocytes. The hepatocytes assemble as plates
which radiate from a central vein. Lobules are served by arterial, venous and biliary

vessels at their periphery. This model is useful for teaching purposes but more closely
resembles the adult pig lobule than the human. Human lobules have little connective
tissue separating one lobule from another. The paucity of connective tissue makes it more
difficult to identify the portal triads and the boundaries of individual lobules. Central veins
are easier to identify due to their large lumen and because they lack connective tissue
that invests the portal triad vessels.

Lobules consist of hepatocytes and the spaces between them. Sinusoids are the spaces
between the plates of hepatocytes. Sinusoids receive blood from the portal triads. About
25% of total cardiac output enters the sinusoids via terminal portal and arterial vessels.
Seventy-five percent of the blood flowing into the liver comes through the portal vein; the
remaining 25% is oxygenated blood that is carried by the hepatic artery. The blood mixes,
passes through the sinusoids, bathes the hepatocytes and drains into the central vein.
About 1.5 liters of blood exit the liver every minute.
The liver is central to a multitude of physiologic functions, including:

Clearance of damaged red blood cells & bacteria by phagocytosis

Nutrient management
Synthesis of plasma proteins such as albumin, globulin, protein C, insulin-like
growth factor, clotting factors etc.
Biotransformation of toxins, hormones, and drugs
Vitamin & mineral storage

Phagocytosis
Red blood cell (RBC) lifespan is about 120 days. Reticuloendothelial (macrophage) cells in
the spleen, liver and bone marrow are primarily responsible for clearing pathogens and
debris. Kupffer cells are reticuloendothelial cells resident in the liver sinusoids that
scavange damaged RBCs and bacteria as they pass through. Hundreds of millions of RBCs
are removed by the reticuloendothelial system every minute. Kupffer cells, like other
reticuloendothelial macrophages, lyse RBCs into heme and globin. Globin is further
catabolized into polypeptide components for reuse. Heme is broken into biliverdin and
iron. Biliverdin is converted to bilirubin. Iron is transported by transferrin to the liver and
spleen for storage and to the bone for hematopoiesis.
About 85% of bilirubin is derived from lysis of RBCs, the rest comes from the breakdown of
other hemoproteins like myoglobin, cytochromes and peroxidases. Kupffer cells like other
reticuloendothelial macrophages release bilirubin into the blood. In the blood, bilirubin
binds to albumin. The albumin/bilirubin compound is small enough to pass through the
endothelial fenestrae and into the space of Disse where it contacts the hepatocyte.
Hepatocytes cleave bilirubin from albumin and absorb the bilirubin. In the hepatocyte
cytoplasm, bilirubin is conjugated to glucouronic acid. Bilirubin uridine diphosphate
glucuronyl transferase (UDPGT) catalyzes the bonding of glucuronic acid and bilirubin to
produce water-soluble bilirubin. Water soluble conjugated bilirubin is secreted into
canaliculi along with water, electrolytes, bicarbonate, bile acids, salts, cholesterol and
phospholipids. This combination is called bile and serves as a detergent to keep bile
soluble in the biliary tract. Bile drains from the canaliculi>canal of Hering>bile
ducts>common hepatic duct>gallbladder>common bile duct>ampulla of
vater>duodenum.*

In the duodenum, bile salts attach to fat globules forming smaller micelles that collect
fatty acids and glycerol. The micelles travel to the jejunum where they deliver their cargo
to the intestinal epithelium. Inside the epithelial cells glycerol and fatty acids are rejoined
to form triglycerides. Finally triglycerides are joined to cholesterol and proteins are added
to the surface; creating a chylomicron.
Lipid management*
The liver receives a variety of lipid forms including: chylomicrons remnants, very low
density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL)
and fatty acids. Large lipoprotein molecules are broken into smaller units by the lytic
action of lipoprotein lipase (LPL) expressed on endothelium of vessels. Circulating
lipoproteins small enough to enter the space of Disse attach to receptors on the
hepatocyte. These lipoprotein remnants are held near the heptocyte surface and exposed
to hepatic lipase compounds. Low Density Lipoprotein receptors transfer the lipoprotein
fragments into the hepatocyte by the process of endocytosis.

Chylomicrons are the product of intestinal packaging of dietary fats. Chylomicrons

are produced in the duodenal villi and secreted into the lymph lacteals for delivery
to the thoracic duct>subclavian vein>superior vena cava>right
ventricle>lungs>Left ventricle>aorta>hepatic artery>sinusoid. Chylomicrons range
from 75-1200nm in diameter. They contain 98% lipids and 2% protein. Chylomicrons
are degraded in the blood by contact with LPL. Chylomicrons become smaller and
more dense as fatty acids are stripped off. Loss of fatty acids results in chylomicron
remnants of various sizes and density when they finally reach the liver. Hepatic
lipase expressed by the hepatic sinusoidal endothelium and hepatocytes continues
the remnant degradation.
Very low density lipoproteins (VLDL) are synthesized primarily in the hepatocyte.
VLDLs range from 30-80nm. They contain 90% lipids and 10% protein.Their purpose
is to transport triglycerides made in the liver into plasma for use or storage outside
the liver.
Low density lipoprotein (LDL) is formed from VLDLs in the plasma by the action of
lipase. LDL diameter is about 20nm. They contain 70% lipids and 30% protein. LDLs
distribute cholesterol throughout the body. Cholesterol is an important constituent
of: VLDL, cell membranes, hormones, bile etc.
High density lipoprotein (HDL) are small lipoprotein particles (5-15nm) formed in the
liver and intestine. They range from 5-15nm in diameter. They contain 50% lipids
and 50% protein. HDLs collect cholesterol & lipoprotein fragments from the blood
and blood vessel plaques and return them to the liver for repurposing.

Fatty acids are linear hydrocarbon chains that are the major constituents of dietary
lipoproteins (triglycerides). The liver degrades lipoproteins with hepatic lipase or
synthesizes fatty acids from carbohydrate sources. When carbohydrate energy
sources are low fatty acids are oxidized for energy.

Carbohydrate management:
When energy intake exceeds energy output the body stores the surplus glucose as
glycogen or triglyceride. When energy output exceeds energy intake the body reacts by
releasing stored energy as glucose and fatty acids.
Glucose is the preferred energy source for most tissues but the body maintains very
limited supplies of free circulating glucose. Certain tissues like the brain, RBCs, lens and
cornea use glucose almost exclusively. To supply these tissues when blood glucose drops
the liver lyses glycogen. Glycogen is a complex molecule composed of thousands of
glucose units. Hepatocytes and myocytes store glucose as intracellular glycogen granules.
The liver is central to blood glucose management because the liver is the only organ that
can store and release glucose into the blood for use by other organs. After a meal the liver
removes excess blood glucose and stores up to 8% of its weight as glycogen. Myocytes
can store about 1-2% of total muscle mass as glycogen but once glucose enters a myocyte
it must be used or stored by that myocyte. Myocytes lack the enzyme necessary to
release glucose into the circulation.
The liver uses three metabolic processes to manage carbohydrates and insure adequate
blood glucose:

Glycogenesis - excess glucose, fructose, and galactose are converted to glycogen

and stored in the liver.
Glycogenolysis - when blood glucose falls, the liver breaks down stored glycogen to
raise blood glucose levels
Gluconeogenesis - the liver can synthesize glucose from lactic acid, some amino
acids and glycerol. When glucose is low the liver can derive energy from the
metabolism of fatty acids which can conserve available glucose.

Protein management:
Dietary protein is denatured by stomach acids and digested into amino acids in the small
intestine. Amino acids are absorbed by the small intestine and delivered to the liver via
the portal circulation. Up to 50% of the livers' energy requirements can be supplied by
amino acid oxidation. Oxidative deamination breaks amino acids into keto acid and an
ammonia molecule. The keto acid is used in the Kreb's cycle to produce ATP. The liver
combines ammonia with CO2 to form urea and H2O.
The liver also uses dietary amino acids and those released during normal tissue
breakdown to produce its own proteins and enzymes as well as plasma proteins. Plasma
proteins produced by hepatocytes include: albumin, fibrinogen, prothrombin, afetoprotein, a2-macroglobin, hemopexin, transferrin, complenent components C 3,C6 andC1,
a1-antitrypsin, caeruloplasmin.*

Albumin is only produced by the liver and equals about 50% its total protein
synthesis. About 12 grams of albumin are synthesized by the normal liver daily.*
Patients with decompensated cirrhosis produce only about 4 g per day. About 40%
of total albumin is intrascular.
a-fetoprotein peaks about 16 weeks gestation and disappears a few weeks after
birth. It may reappear in association with chronic hepatitis and a number of
carcinomas
a1-antitrysin deficiency is inherited
a2-macroglobin functions as a protease inhibitor. It is active in the inhibition of
thrombin and plasmin.
hemopexin transports heme in the plasma protecting tissues from the actions of

heme.
transferrin is globulin that transports heme to bone marrow for incorporation into
erythroid precursors.
complement components assist the immune system to raise an immune response.
caeruloplasmin is the major copper carrying plasma protein.

Biotransformation
Hepatocytes protect the body from injury by biotransforming toxins and drugs and by
deactivating hormones. The liver employs enzymes to make substances more water
soluble, so they can be excreted from the body in the urine and feces. In Phase 1
biotransformations the cytochrome P450 enzymes alter the target molecule by adding or
exposing functional groups such as -OH or -COOH. Phase 2 biotransformation enzymes
add sugars, amino acids, sulfates or acetyl groups to the functional group which makes
them more water soluble.
Vitamins
The liver also plays an important role in vitamin and mineral (iron & copper) storage.
About 80% of the body's vitamin A stores are concentrated in fat droplets within the
stellate cells of the liver. In pathological conditions like hepatic fibrosis or liver cirrhosis the
stellate cells lose vitamin A, transform into fibroblasts or myofibroblasts and begin
producing large amounts of collagen and adhesive glycoproteins.* Normal vitamin A
reserves are enough to prevent a deficiency for about 10 months. The liver also contains
about a year supply of B12. Vitamin D stores equal about 3-4 months. Small amounts of
Vitamins E and K and Vitamin C are stored in the liver to facilitate liver functions.