PHYSIOLOGY OF LIVER

http://biomed.brown.edu/Courses/BI108/BI108_2002_Groups/liver/webpage/Nor
malLiver.htm
The liver, weighing roughly 1.2-1.6 kg, performs many of the functions necessary
for staying healthy. It is located in the right side of the body under the lower ribs
and is divided into four lobes of unequal size. Two large vessels carry blood to the
liver. The hepatic artery comes from the heart and carries blood rich in oxygen.
The portal vein brings the liver blood rich in nutrients absorbed from the small
intestine. These vessels divide into smaller and smaller vessels, ending in
capillaries. These capillaries end in the thousands of lobules of the liver. Each
lobule is composed of hepatocytes, and as blood passes through, they are able to
monitor, add, and remove substances from it. The blood then leaves the liver via
the hepatic vein, returns to the heart, and is ready to be pumped to the rest of the
body.
Among the most important liver functions are:
Removing and excreting body wastes and hormones as well as drugs and
other foreign substances These substances have entered the blood supply either
through production by metabolism within the body or from the outside in the form
of drugs or other foreign compounds. Enzymes in the liver alter some toxins so
they can be more easily excreted in urine.
Synthesizing plasma proteins, including those necessary for blood
clotting Most of the 12 clotting factors are plasma proteins produced by the liver.
If the liver is damaged or diseased, it can take longer for the body to form clots.
Other plasma proteins produced by the liver include albumin which binds many
water-insoluble substances and contributes to osmotic pressure, fibrogen which is
key to the clotting process, and certain globulins which transport substances such
as cholesterol and iron.
Producing immune factors and removing bacteria, helping the body fight
infection The phagocytes in the liver produce acute-phase proteins in response to
microbes. These proteins are associated with the inflammation process, tissue
repair, and immune cell activities.
Other important but less immediate functions include:
Producing bile to aid in digestion Bile salts aid in fat digestion and absorption.
Bile is continuously secreted by the liver and stored in the gallbladder until a meal,
when bile enters the beginning of the small intestine. Bile production ranges from
250 mL to 1 L per day depending of amount of food eaten.

 Excretion of bilirubin Bilirubin is one of the few waste products excreted in bile.
Macrophages in the liver remove worn out red blood cells from the blood.
Bilirubin then results from the breakdown of the hemoglobin in the red blood cells
and is excreted into bile by hepatocytes. Jaundice results when bilirubin cannot be
removed from the blood quickly enough due to gallstones, liver disease, or the
excessive breakdown of red blood cells.
Storing certain vitamins, minerals, and sugars The liver stores enough glucose
in the form of glycogen to provide about a day's worth of energy. The liver also
stores fats, iron, copper, and many vitamins including vitamins A, D, K, and B12.
Processing nutrients absorbed from digestive tract The liver converts glucose
into glycogen, its storage form. This glycogen can then be transformed back into
glucose if the body needs energy. The fatty acids produced by the digestion of
lipids are used to synthesize cholesterol and other substances. The liver also has the
ability to convert certain amino acids into others.
Despite the wide variety of functions performed by the liver, there is very little
specialization among hepatocytes (liver cells). Aside from the macrophages called
Kupffer cells in the liver, hepatocytes all seem to be able to perform the same wide
variety of tasks.
One of the liver's most interesting abilities is self-repair and the regeneration of
damaged tissues. In clearing the body of toxins, the liver is damaged by exposure
to harmful substances, demonstrating why this capability is important. It also gives
hope that if a failing liver can be supported for a certain period of time, it might
regenerate and allow the patient to survive and regain a normal life.

Hemostasis

Synthesis

Storage

glucose
proteins
fat and cholesterol
hormones
vitamins, in particular fat-soluble ones (A, D, E, K)
proteins including the clotting factors (~50g/day)
bile acids (important in fat digestion)
heparin (anti-coagulant)
somatomedins (homones that promote growth in bone, soft
tissues)
estrogen
angiotensinogen
cholesterol
acute phase proteins
vitamins
glycogen
cholesterol
iron, copper
fats

Excretion

Filtering

Immune

cholesterol, bile acids, phospholipids

bilirubin
drugs
poisons including heavy metals
hormones
poisons
nutrients including amino acids, sugars, and fats
bilirubin, bile acids
IgA
drugs
dead or damaged cells in circulatory system
excretes IgA into digestive tract
Kupffer cells (macrophages) filter out antigens

Digestion
The liver plays an active role in the process of digestion through the production
of bile. Bile is a mixture of water, bile salts, cholesterol, and the pigment
bilirubin. Hepatocytes in the liver produce bile, which then passes through the
bile ducts to be stored in the gallbladder. When food containing fats reaches the
duodenum, the cells of the duodenum release the hormone cholecystokinin to
stimulate the gallbladder to release bile. Bile travels through the bile ducts and is
released into the duodenum where it emulsifies large masses of fat. The
emulsification of fats by bile turns the large clumps of fat into smaller pieces that
have more surface area and are therefore easier for the body to digest.

Bilirubin present in bile is a product of the livers digestion of worn out red blood
cells. Kupffer cells in the liver catch and destroy old, worn out red blood cells and
pass their components on to hepatocytes. Hepatocytes metabolize hemoglobin,
the red oxygen-carrying pigment of red blood cells, into the components heme
and globin. Globin protein is further broken down and used as an energy source
for the body. The iron-containing heme group cannot be recycled by the body
and is converted into the pigment bilirubin and added to bile to be excreted from
the body. Bilirubin gives bile its distinctive greenish color. Intestinal bacteria
further convert bilirubin into the brown pigment stercobilin, which gives feces
their brown color.

Metabolism
The hepatocytes of the liver are tasked with many of the important metabolic
jobs that support the cells of the body. Because all of the blood leaving the

digestive system passes through the hepatic portal vein, the liver is responsible
for metabolizing carbohydrate, lipids, and proteins into biologically useful
materials.

Our digestive system breaks down carbohydrates into the monosaccharide

glucose, which cells use as a primary energy source. Blood entering the liver
through the hepatic portal vein is extremely rich in glucose from digested food.
Hepatocytes absorb much of this glucose and store it as the macromolecule
glycogen, a branched polysaccharide that allows the hepatocytes to pack away
large amounts of glucose and quickly release glucose between meals. The
absorption and release of glucose by the hepatocytes helps to maintain
homeostasis and protects the rest of the body from dangerous spikes and drops
in the blood glucose level. (See more about glucose in the body.)

Fatty acids in the blood passing through the liver are absorbed by hepatocytes
and metabolized to produce energy in the form of ATP. Glycerol, another lipid
component, is converted into glucose by hepatocytes through the process of
gluconeogenesis. Hepatocytes can also produce lipids like cholesterol,
phospholipids, and lipoproteins that are used by other cells throughout the body.
Much of the cholesterol produced by hepatocytes gets excreted from the body as
a component of bile.

Dietary proteins are broken down into their component amino acids by the
digestive system before being passed on to the hepatic portal vein. Amino acids
entering the liver require metabolic processing before they can be used as an
energy source. Hepatocytes first remove the amine groups of the amino acids
and convert them into ammonia and eventually urea. Urea is less toxic than
ammonia and can be excreted in urine as a waste product of digestion. The
remaining parts of the amino acids can be broken down into ATP or converted
into new glucose molecules through the process of gluconeogenesis.

Detoxification
As blood from the digestive organs passes through the hepatic portal circulation,
the hepatocytes of the liver monitor the contents of the blood and remove many
potentially toxic substances before they can reach the rest of the body. Enzymes
in hepatocytes metabolize many of these toxins such as alcohol and drugs into
their inactive metabolites. And in order to keep hormone levels within
homeostatic limits, the liver also metabolizes and removes from circulation
hormones produced by the bodys own glands.

Storage
The liver provides storage of many essential nutrients, vitamins, and minerals
obtained from blood passing through the hepatic portal system. Glucose is
transported into hepatocytes under the influence of the hormone insulin and
stored as the polysaccharide glycogen. Hepatocytes also absorb and store fatty
acids from digested triglycerides. The storage of these nutrients allows the liver
to maintain the homeostasis of blood glucose. Our liver also stores vitamins and
minerals - such as vitamins A, D, E, K, and B12, and the minerals iron and copper
- in order to provide a constant supply of these essential substances to the
tissues of the body.

Production
The liver is responsible for the production of several vital protein components of
blood plasma: prothrombin, fibrinogen, and albumins. Prothrombin and
fibrinogen proteins are coagulation factors involved in the formation of blood
clots. Albumins are proteins that maintain the isotonic environment of the blood
so that cells of the body do not gain or lose water in the presence of body fluids.

Immunity
The liver functions as an organ of the immune system through the function of the
Kupffer cells that line the sinusoids. Kupffer cells are a type of fixed macrophage
that form part of the mononuclear phagocyte system along with macrophages in
the spleen and lymph nodes. Kupffer cells play an important role by capturing
and digesting bacteria, fungi, parasites, worn-out blood cells, and cellular debris.
The large volume of blood passing through the hepatic portal system and the
liver allows Kupffer cells to clean large volumes of blood very quickly.

The spleen has a number of functions:

It filters the blood removing ageing erythrocytes and antigens

It stores erythrocytes and platelets

Secondary lymphoid organ

Erythrocytes & Platelets

In the foetus the spleen also has a role in haematopoiesis when it becomes the
main erythrocyte producing organ during the haematopoietic transitional phase.

In the developed animal the red pulp is involved in the removal of aged, damaged or
abnormal erythrocytes (along with the liver and bone marrow). As erythrocytes age they become
less supple and this causes them to become damaged when they pass through the very narrow
capillaries of the spleen, after which they are phagocytised by splenicmacrophages. If a
splenectomy is performed the number of aged erythrocytes in circulation increases.
The red pulp also acts as a storage site for erythrocytes. The degree of storage is variable
between species but is particularly notable in horses which, during exercise under sympathetic
activity, can contract their spleen to increase the concentration of circulating erythrocytes. In
some species such as cats and rodents the red pulp acts as a storage site for platelets and
contains megakaryocytes.

Lymphoid
Blood flows through the marginal sinus. This means that most antigens present in the blood
come into contact with the B lymphocytes and dendritic cells in the spleen. Dendritic cells in the
marginal sinus and red pulp take up antigens from the blood and transport them to the primary
follicles in the white pulp. If the antigen activates the B lymphocytesthen a germinal centre will
form in the primary follicle and this is called a splenic nodule. Antibody producing cells then
migrate to the red pulp and marginal zone.
Following splenectomy this doesnt occur and animals are predisposed to septicaemia and
infection with blood protozoa.

Structure and Function

Normal length 8-13cm (>14cm usually palpable); weight 250g (can be up to 2kg)

5% cardiac output enters the spleen

Blood brought into the spleen via the splenic artery that then divides into the trabecular
arteries which then branch into the central arteries, which are sited in the white pulp

The central arteries run in the central axis of the periarteriolar lymphatic sheaths

These give off many arterioles and capillaries some of which terminate in the white pulp whilst
others enter the red pulp

Blood enters sinuses in the red pulp which are lined by endothelial cells and adventitial cells with a
basement membrane

The sinuses are connected by cords (Bilroth cords) which consist of a fibroblast-like reticular
meshwork containing numerous macrophages and erythrocytes.

A few arteries enter the sinuses directly and connect via the collecting vein to the trabecular system

Thus there is both rapid transit (1-2min) and slow transit (particularly when there is splenomegaly
(30-60min or longer)

Plasma skimming occurs by which the plasma and leukocytes pass preferentially into the white
pulp while the red cells remain in the axial stream of the central artery

Passage of cells into the sinuses is assisted by the contraction of the reticular cells

Red cells that are inflexible or have inclusions remain in the cords and are either destroyed or
conditioned for delayed transit

Spleen has 3 actions:

Sequestration cells temporarily trapped by adhesion to the reticular meshwork of the cords
on their passage th

Phagocytosis irreversible uptake of damaged or antibody coated cells as well as particulate

matter

Pooling

Increased amount of blood in the spleen in continuous exchange with the circulation

Since plasma passes freely through the spleen there is an increase in intrasplenic
heamatocrit

The presence of metabolically active macrophages and densely packed red cells leads to
reduced oxygen and glucose, which increased red cell rigidity

Siderotic granules, Howell-Jolly bodies, nuclear remnants and Heinz bodies are removed during
temporary sequestration and the red cells are then returned to the circulation

Reticulocytes can be retained in the spleen for up to 3 days while they lose their intracellular
inclusion bodies, alter the lipid composition of their membrane and reduce in size.

Antibody coated red cells loose pieces of their membrane becoming more spherical and less
flexible each time they traverse the spleen.

It is not clear that the spleen has any special role in the removal of senescent red cells (more likely
that the general reticuloendothelial system does this especially the bone marrow).

Blood pooling
Normal red cell content of the spleen is around 70mL (5% of circulating red cells)

 When the spleen enlarges up to 40% of the red cell mass may be pooled in the spleen
This functionally excludes a large volume of red cells from the circulation and results in functional
anaemia (will give a falsely normal red cell mass result)
Important in myelofibrosis and hairy cell as well as portal hypertension
In splenomegaly due to cellular infiltration the pool is less prominent

Granulocyte pooling
30-50% of the bodies circulating granulocytes are stored in the spleen, with a mean transit time of
around 10min
Neutropenia may occur with hypersplenism
Up to 40% of platelets are also pooled in the spleen and the pool increases when the spleen is enlarged

Immunological functions
White pulp is the largest single accumulation of lymphoid tissue in the body.
Contains 25% of T cells (in the periarteriolar sheaths) and 10% of B cells (in germinal centres in the
white pulp)
During the primary immune response CD8+ T cells act in association with macrophages to stimulate
removal by phagocytosis of blood-borne bacteria
Circulating immune complexes are removed by macrophage phagocytosis if they are large and B cells if
they are small
These are important mechanisms for protection against N. meningitides, H. influenzae B, and strep
pneumoniae
Also important in protection against viral infection and parasites such as plasmodium

Coagulation factors
Spleen can make VIII
Also functions as a reserve pool for platelets

Extramedullary haemopoiesis
Two possible circumstances when the spleen can regain haemopoiesis
1.

Severe anaemia as in chronic haemolysis, megaloblastic anaemia or thalassaemia

2.

Myelofibrosis and occasionally secondary carcinomatosis when there is myeloid metaplasia

Mechanism not entirely clear

Growth factors
Entrapment of circulating stem cells in the red pulp when they have escaped the bone marrow when
the marrow expands (as in severe anaemia)

Causes of splenomegaly
Haematological
Acute leukaemia
CML
CLL
Lymphoma
Myelofibrosis (chronic)
PV / ET
Hairy cell leukaemia
Gauchers disease, Niemann-Pick disease
Thalassaemia / Sickle cell / HbSC
Haemolytic anaemia
Megaloblastic anaemia

Systemic
Viral (EBV, CMV, HIV)
Bacterial (TB, typhoid, SBE)
Parasitic (Malaria, leishmaniasis, schistosomiasis, trypanosomiasis)
Autoimmune (SLE, Rheumatoid)
Amyloidosis
Sarcoidosis

Congestion
Portal hypertension
Cardiac failure
Splenic / portal / hepatic vein obstruction

Physiology of spleen

The spleen is useful for the production antibodies against antigen present in
blood and its the only organ that performs such functions. Other organs may
produce antibodies against antigens seen or present in tissue.

The spleen produces large amounts of B and T lymphocytes through its white
pulp.

It is the largest site for macrophage aggregations and phagocytic function in the
body. It therefore removes old or bad blood cells and platelets.

It destroys bacteria and foreign organisms by a process of opsonization and also

phagocytosis to include its function of producing antibodies

It stores about 33% of all platelets in the entire body.

It is involved in hematopoiesis in the fetus and may be implicated in

extramedullary hematopoesis in certain disease conditions in the adult.

The spleen serves in many lower animals, and to a little extent in man a
reservoir for storing up blood which may then be released into circulation when it
is required, as in sudden loss of blood etc.

Microcirculation in the spleen

The open system suggests that there is no continuity between the ellipsoids and
the sinusoids. Blood from the ellipsoids are discharged into the reticulum of the
spleen from where they are absorbed into the sinusoids.

The compromise theory which suggests that both mechanisms take place.

The sinusoids make up the red pulp of the splenic pulp. They are connected to
the venules as per any of the mechanisms above and from the venules they
discharge their blood into the splenic vein. The sinusoids are lined by special
endothelial cells which are babana shaped and contain myofibrils that allow
them to contract thereby opening up channels by which blood is discharged into
the splenic substance. They are called stave cells. Red blood cell pass through
the sinusoidal spaces. When they are old, they are unable to pass across and
they are then destroyed by the splenic macrophagic system.

Possible risks of blood transfusions

Although blood transfusions can be life-saving, they are not without risks. Infections were once the
main risk, but they have become extremely rare with careful testing and donor screening. Transfusion
reactions and other non-infectious problems are now more common.
When you are getting a transfusion of any kind, its very important that you let your nurse know right
away if you notice any changes in how you feel, such as itching, shivering, headache, chest or back

pain, throat tightness, nausea, dizziness, trouble breathing, or other problems. You should report any
that happen in the next few days, too.

Transfusion reactions
Blood transfusions sometimes cause transfusion reactions. There are several types of reactions and
some are worse than others. Some reactions happen as soon as the transfusion is started, while
others take several days or even longer to develop.
Many precautions are taken before a transfusion is started to keep reactions from happening. The
blood type of the unit is checked many times, and the unit is cross-matched to be sure that it matches
the blood type of the person who will get it. After that, both a nurse and blood bank lab technician look
at the information about the patient and the information on the unit of blood (or blood component)
before its released. The information is double-checked once more in the patients presence before the
transfusion is started.

Allergic reaction
This is the most common reaction. It happens during the transfusion when the body reacts to plasma
proteins or other substances in the donated blood. Usually the only symptoms are hives and itching,
which can be treated with antihistamines like diphenhydramine (Benadryl). In rare cases these
reactions can be more serious.

Febrile reaction
The person gets a sudden fever during or within 24 hours of the transfusion. Headache, nausea,
chills, or a general feeling of discomfort may come with the fever. Acetaminophen (Tylenol) may help
these symptoms.
These reactions are often the bodys response to white blood cells in the donated blood. They are
more common in people who have had transfusions before and in women who have been pregnant
several times. Other types of reaction can also cause fever, and further testing may be needed to be
sure that the reaction is only febrile.
Patients who have had febrile reactions or who are at risk for them are usually given blood products
that areleukoreduced (loo-ko-re-DUCED). This means that the white blood cells have been removed
by filters or other means.

Transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a rare, but very serious transfusion reaction. It can
happen with any type of transfusion, but those that contain more plasma, such as fresh frozen plasma
or platelets, seem more likely to cause it. It often starts within 1 to 2 hours of starting the transfusion,
but can happen anytime up to 6 hours after a transfusion. Theres also a delayed TRALI syndrome,
which can begin up to 72 hours after the transfusion is given.
The main symptom of TRALI is trouble breathing, which can become life-threatening. If TRALI is
suspected during the transfusion, the transfusion should be stopped right away.

Doctors now believe that several factors are involved in this illness, and medicines dont seem to help.
Many of the patients who get TRALI have had recent surgery, trauma, cancer treatment, transfusions,
or have an active infection. Most of the time, TRALI goes away within 2 or 3 days if breathing and
blood pressure are supported, but even with support it is deadly in 5% to 10% of cases. TRALI is
more likely to be fatal if the patient was already very ill before the transfusion. Most often a patient will
need oxygen, fluids, and sometimes support with a breathing machine.
Delayed TRALI has a higher risk of death, with one expert finding a death rate as high as 40%. If a
patient who has had TRALI needs red blood cells, doctors may try to prevent future problems by
removing most of the plasma from the red blood cells using a diluted salt water solution. Researchers
are working on other ways to reduce this risk with careful donor selection and testing.

Acute immune hemolytic reaction

An acute hemolytic (he-mo-LIT-ik) reaction is the most serious type of transfusion reaction, but its
very rare. It happens when donor and patient blood types do not match. The patients antibodies
attack the transfused red blood cells, causing them to break open (hemolyze) and release harmful
substances into the bloodstream.
Patients may have chills, fever, chest and lower back pain, and nausea. The kidneys may be badly
damaged, and dialysis may be needed. A hemolytic reaction can be deadly if the transfusion is not
stopped as soon as the reaction starts.

Delayed hemolytic reaction

This type of reaction happens when the body slowly attacks antigens (other than ABO antigens) on
the transfused blood cells. The blood cells are broken down days or weeks after the transfusion.
There are usually no symptoms, but the transfused red blood cells are destroyed and the patients red
blood cell count falls. In rare cases, the kidneys may be affected, and treatment may be needed.
People dont usually have this type of reaction unless they have had transfusions in the past. Those
who do have this reaction need special blood tests before any more blood can be transfused. Units of
blood that do not have the antigen that the body is attacking must be used.

Graft-versus-host disease
Graft-versus-host disease (GVHD) occurs when a person with a very weak immune system gets white
blood cells in a transfused blood product. The white cells in the transfusion attack the tissues of the
patient who got the blood.
This is more likely if the blood comes from a relative or someone who has the same tissue type (this is
different from blood type) as the patient. The patients immune system doesnt recognize the white
blood cells in the transfused blood as foreign. This allows the white blood cells to survive and attack
the patients body tissues.
Within a month of the transfusion, the patient may have fever, liver problems, rash, and diarrhea.
To prevent white blood cells from causing GVHD, donated blood can be treated with radiation before
transfusion. (Radiation stops white blood cells from working but does not affect red blood cells.)
These are called irradiated blood products. They are often used for people with cancer who might
have weakened immune systems.

Infections
Blood transfusions can transmit infections caused by bacteria, viruses, and parasites. The chance of
getting an infection from blood in the United States is extremely low, but the exact risk for each type of
infection varies. Testing units of blood for germs that can cause infection has made the blood supply
very safe, but no test is 100% accurate.

Bacterial contamination
Rarely, blood gets contaminated with tiny amounts of skin bacteria during donation. Platelets are the
most likely blood component to have this problem. Because platelets must be stored at room
temperature, these bacteria can grow quickly. (Other components are refrigerated or frozen.) Patients
who get these platelets may develop a serious illness minutes or hours after the transfusion starts.
Blood banks routinely test platelets and destroy units of blood that are likely to cause harm. The tests
are still being refined, but today fewer cases of illness are caused by platelets. Also, more hospitals
use single donor platelets, which have a lower risk of bacterial contamination than pooled platelets.

Hepatitis B and C
Viruses that attack the liver cause these forms of hepatitis. Hepatitis is the most common disease
transmitted by blood transfusions. A 2009 study on hepatitis B in donated blood suggested that the
risk is about 1 in every 800,000 units or less. About 1 blood transfusion in 1.6 million may transmit
hepatitis C.
Work continues to be done to reduce the risk of these infections even further. In most cases there are
no symptoms, but hepatitis can sometimes lead to liver failure and other problems.
Several steps are routinely taken to reduce the risk of hepatitis from blood transfusion. People who
are getting ready to donate blood are asked questions about hepatitis risk factors and symptoms of
hepatitis. Donated blood is also tested to find hepatitis B virus, hepatitis C virus, and liver problems
that could be signs of other types of hepatitis.

Human immunodeficiency virus

Human immunodeficiency virus (HIV) causes acquired immune deficiency syndrome (AIDS). Testing
each unit of donated blood for HIV began in 1985, and all donated blood is now tested for HIV.
With improved testing for HIV, the number of transfusion-related AIDS cases continues to drop. The
risk of HIV transmission from a transfusion is about 1 in 2 million. Along with testing, the risk is
reduced by asking donors questions about HIV risk factors and symptoms.

Other infections
Along with the tests noted above, all blood for transfusion is tested for syphilis, as well as HTLV-I and
HTLV-II (viruses linked to human T-cell leukemia/lymphoma). Since 2003, donated blood has been
tested for the West Nile virus, too. In 2007, blood banks also began testing for Chagas disease
(common in South and Central America).

Diseases caused by certain bacteria, viruses, and parasites, such as babesiosis, malaria, Lyme
disease, and others can also be spread by blood product transfusions. But because potential donors
are screened with questions about their health status and travel, such cases are very rare.