BIOCHEMICAL FUNCTIONS OF LIVER. PORPHYRINS AND BILE PIGMENTS. PATHOBIOCHEMISTRY OF JAUNDICE. METABOLISM OF XENOBIOTICS IN THE
LIVER: MICROSOMAL OXIDATION, CYTOCHROME Ð-450.
What are the functions of the
liver?
http://www.youtube.com/watch?v=tat0QYxlCbo&feature=related
Liver’s functions:
• It is responsible for the
production of bile which is stored in the gallbladder and released when required
for the digestion of fats.
• The liver stores glucose in
the form of glycogen which is converted back to glucose again when needed for
energy.
• It also plays an important role in the metabolism of
protein and fats. It stores the vitamins A, D, K, B12 and folate and
synthesizes blood clotting factors.
• Another important role is as
a detoxifier, breaking down or transforming substances like ammonia, metabolic
waste, drugs, alcohol and chemicals, so that they can be excreted. These may
also be referred to as "xenobiotic" chemicals. If we examine the
liver under a microscope, we will see rows of liver cells separated by spaces
which act like a filter or sieve, through which the blood stream flows. The
liver filter is designed to remove toxic matter such as dead cells,
microorganisms, chemicals, drugs and particulate debris from the blood stream.
The liver filter is called the sinusoidal system, and contains specialized
cells known as Kupffer cells which ingest and breakdown toxic matter.
http://www.youtube.com/watch?v=nXRWkorYFXc
Role of the liver in carbohydrate metabolism.
From intestine glucose pass into the liver, where most
part of it undergone the phosphorillation. Glucose-6-phosphate formed in result
of this reaction, which catalyzed by two enzymes – hexokinase and glucokinase.
When level of glucose in blood of v. porta and in the hepatocytes is normal
activity of glucokinase is low. After eating activity of this enzyme increase
and blood level of glucose decrease because glucose-6-phosphate cannot pass
through membrane.
http://www.youtube.com/watch?v=ejJRYozvuaw&feature=related
http://www.youtube.com/watch?v=nKgUBsC4Oyo&feature=related
Fructose and galactose also transformed into
glucose-6-phosphate in the liver.
Glucose-6-phosphate is a key product of carbohydrates
metabolism. In the liver this substance can metabolized into different ways
depend of liver’s and whole organism’s necessity.
1. Synthesis of glycogen. Content in the liver – 70-100g.
After eating amount of glycogen in the liver increase up to 150g. After 24
hours of starvation content of glycogen in the liver decreases to zero and
glukoneogenesis started.
2. Glucose-6-phosphatase catalize dephosphorillation
of glucose-6-phosphate and free glucose formed. This enzyme is present in the
liver, kidney and small intestine. This process keep normal level of glucose in
the blood.
3. Excess of glucose-6-phosphate, which not used for
synthesis of glycogen and forming of free glucose, decomposites in glycolysis
for pyruvate and for acetyl-CoA, which are used for fatty acids synthesis.
4. Glucose-6-phosphate decomposites for H2O and CO2,
and free energy for hepatocytes formed.
5. Part of glucose-6-phosphate oxidized in
pentosophosphate cycle. This way of glucose decomposition supplyes reducted NADPH,
which is necessary in fatty acid synthesis, cholesterin synthesis, and also
pentosophosphates for nucleic acids. Near 1/3 of glucose in liver used for this
pathway, another 2/3 – for glycolisis.
The Hexokinase Reaction:
The ATP-dependent phosphorylation of glucose to form
glucose 6-phosphate (G6P)is the first reaction of glycolysis, and is catalyzed
by tissue-specific isoenzymes known as hexokinases. The phosphorylation
accomplishes two goals: First, the hexokinase reaction converts nonionic glucose
into an anion that is trapped in the cell, since cells lack transport systems
for phosphorylated sugars. Second, the otherwise biologically inert glucose
becomes activated into a labile form capable of being further metabolized.
Four mammalian isozymes of hexokinase are known (Types
I - IV), with the Type IV isozyme often referred to as glucokinase. Glucokinase
is the form of the enzyme found in hepatocytes. The high Km of glucokinase for
glucose means that this enzyme is saturated only at very high concentrations of
substrate.
Comparison of the activities of hexokinase and
glucokinase. The Km for hexokinase is significantly lower (0.1mM) than that of
glucokinase (10mM). This difference ensures that non-hepatic tissues (which
contain hexokinase) rapidly and efficiently trap blood glucose within their
cells by converting it to glucose-6-phosphate. One major function of the liver
is to deliver glucose to the blood and this in ensured by having a glucose
phosphorylating enzyme (glucokinase) whose Km for glucose is sufficiently
higher that the normal circulating concentration of glucose (5mM).
This feature of hepatic glucokinase allows the liver
to buffer blood glucose. After meals, when postprandial blood glucose levels
are high, liver glucokinase is significantly active, which causes the liver
preferentially to trap and to store circulating glucose. When blood glucose
falls to very low levels, tissues such as liver and kidney, which contain
glucokinases but are not highly dependent on glucose, do not continue to use
the meager glucose supplies that remain available. At the same time, tissues
such as the brain, which are critically dependent on glucose, continue to
scavenge blood glucose using their low Km hexokinases, and as a consequence
their viability is protected. Under various conditions of glucose deficiency,
such as long periods between meals, the liver is stimulated to supply the blood
with glucose through the pathway of gluconeogenesis. The levels of glucose
produced during gluconeogenesis are insufficient to activate glucokinase,
allowing the glucose to pass out of hepatocytes and into the blood.
The regulation of hexokinase and glucokinase
activities is also different. Hexokinases I, II, and III are allosterically
inhibited by product (G6P) accumulation, whereas glucokinases are not. The
latter further insures liver accumulation of glucose stores during times of
glucose excess, while favoring peripheral glucose utilization when glucose is
required to supply energy to peripheral tissues.
Hepatocytes content full set of gluconeogenesis
necessary enzymes. So, in liver glucose can be formed from lactate, pyruvate,
amino acids, glycerine. Gluconegenesis from lactate takes place during
intensive muscular work. Lactate formed from glucose in muscles, transported to
the liver, new glucose formed and transported to the muscles (Kori cycle).
http://www.youtube.com/watch?v=qF3ylhC0VeQ
http://www.youtube.com/watch?v=CkwQJCtq6sE&feature=related
Regulation of
Blood Glucose Levels
If for no other reason, it is because of the demands of
the brain for oxidizable glucose that the human body exquisitely regulates the
level of glucose circulating in the blood. This level is maintained in the
range of 5mM.
Nearly all carbohydrates ingested in the diet are
converted to glucose following transport to the liver. Catabolism of dietary or
cellular proteins generates carbon atoms that can be utilized for glucose
synthesis via gluconeogenesis. Additionally, other tissues besides the liver
that incompletely oxidize glucose (predominantly skeletal muscle and
erythrocytes) provide lactate that can be converted to glucose via
gluconeogenesis.
Maintenance of blood glucose homeostasis is of paramount
importance to the survival of the human organism. The predominant tissue
responding to signals that indicate reduced or elevated blood glucose levels is
the liver. Indeed, one of the most important functions of the liver is to
produce glucose for the circulation. Both elevated and reduced levels of blood
glucose trigger hormonal responses to initiate pathways designed to restore
glucose homeostasis. Low blood glucose triggers release of glucagon from
pancreatic -cells.
High blood glucose triggers release of insulin from pancreatic -cells.
Additional signals, ACTH and growth hormone, released from the pituitary act to
increase blood glucose by inhibiting uptake by extrahepatic tissues.
Glucocorticoids also act to increase blood glucose levels by inhibiting glucose
uptake. Cortisol, the major glucocorticoid released from the adrenal cortex, is
secreted in response to the increase in circulating ACTH. The adrenal medullary
hormone, epinephrine, stimulates production of glucose by activating
glycogenolysis in response to stressful stimuli.
Glucagon binding to its' receptors on the surface of
liver cells triggers an increase in cAMP production leading to an increased
rate of glycogenolysis by activating glycogen phosphorylase via the
PKA-mediated cascade. This is the same response hepatocytes have to epinephrine
release. The resultant increased levels of G6P in hepatocytes is hydrolyzed to
free glucose, by glucose-6-phosphatase, which then diffuses to the blood. The
glucose enters extrahepatic cells where it is re-phosphorylated by hexokinase.
Since muscle and brain cells lack glucose-6-phosphatase, the
glucose-6-phosphate product of hexokinase is retained and oxidized by these
tissues.
In opposition to the cellular responses to glucagon (and
epinephrine on hepatocytes), insulin stimulates extrahepatic uptake of glucose
from the blood and inhibits glycogenolysis in extrahepatic cells and conversely
stimulates glycogen synthesis. As the glucose enters hepatocytes it binds to
and inhibits glycogen phosphorylase activity. The binding of free glucose
stimulates the de-phosphorylation of phosphorylase thereby, inactivating it.
Why is it that the glucose that enters hepatocytes is not immediately
phosphorylated and oxidized? Liver cells contain an isoform of hexokinase
called glucokinase. Glucokinase has a much lower affinity for glucose than does
hexokinase. Therefore, it is not fully active at the physiological ranges of
blood glucose. Additionally, glucokinase is not inhibited by its product G6P,
whereas, hexokinase is inhibited by G6P.
One major response of non-hepatic tissues to insulin is
the recruitment, to the cell surface, of glucose transporter complexes. Glucose
transporters comprise a family of five members, GLUT-1 to GLUT-5. GLUT-1 is
ubiquitously distributed in various tissues. GLUT-2 is found primarily in intestine,
kidney and liver. GLUT-3 is also found in the intestine and GLUT-
Hepatocytes, unlike most other cells, are freely
permeable to glucose and are, therefore, essentially unaffected by the action
of insulin at the level of increased glucose uptake. When blood glucose levels
are low the liver does not compete with other tissues for glucose since the extrahepatic
uptake of glucose is stimulated in response to insulin. Conversely, when blood
glucose levels are high extrahepatic needs are satisfied and the liver takes up
glucose for conversion into glycogen for future needs. Under conditions of high
blood glucose, liver glucose levels will be high and the activity of
glucokinase will be elevated. The G6P produced by glucokinase is rapidly
converted to G1P by phosphoglucomutase, where it can then be incorporated into
glycogen.
Diabetes mellitus –
general term referring to all states characterized by hyperglycemia.
For
the disease characterized by excretion of large amounts of very dilute urine,
see diabetes insipidus. For diabetes mellitus in pets, see diabetes in cats and
dogs.
Diabetes
mellitus (IPA pronunciation: is a metabolic disorder characterized by
hyperglycemia (high blood sugar) and other signs, as distinct from a single
illness or condition.
The
World Health Organization recognizes three main forms of diabetes: type 1, type
2, and gestational diabetes (occurring during pregnancy),[ which
have similar signs, symptoms, and consequences, but different causes and
population distributions. Ultimately, all forms are due to the beta cells of
the pancreas being unable to produce sufficient insulin to prevent
hyperglycemia Type 1 is usually due to autoimmune destruction of the pancreatic
beta cells which produce insulin. Type 2 is characterized by tissue-wide
insulin resistance and varies widely; it sometimes progresses to loss of beta
cell function. Gestational diabetes is similar to type 2 diabetes, in that it
involves insulin resistance; the hormones of pregnancy cause insulin resistance
in those women genetically predisposed to developing this condition.
Types 1 and 2
are incurable chronic conditions, but have been treatable since insulin became
medically available in 1921, and are nowadays usually managed with a
combination of dietary treatment, tablets (in type 2) and, frequently, insulin
supplementation. Gestational diabetes typically resolves with delivery.
Diabetes can cause many complications. Acute
complications (hypoglycemia, ketoacidosis or nonketotic hyperosmolar coma) may
occur if the disease is not adequately controlled. Serious long-term
complications include cardiovascular disease (doubled risk), chronic renal
failure (diabetic nephropathy is the main cause of dialysis in developed world
adults), retinal damage (which can lead to blindness and is the most
significant cause of adult blindness in the non-elderly in the developed
world), nerve damage (of several kinds), and microvascular damage, which may
cause erectile dysfunction (impotence) and poor healing. Poor healing of
wounds, particularly of the feet, can lead to gangrene which can require
amputation — the leading cause of non-traumatic amputation in adults in the
developed world. Adequate treatment of diabetes, as well as increased emphasis
on blood pressure control and lifestyle factors (such as smoking and keeping a
healthy body weight), may improve the risk profile of most
aforementioned complications.
Role of the liver in lipid metabolism.
In the liver all processes of lipid
metabolism take place. Most important of them are following:
1. Lipogenesis (synthesis of fatty acids and lipids).
Substrate for this process – acetyl-CoA, formed from glucose and amino acids,
which are not used for another purposes. This process is very active when the
person eats a lot of carbohydrates. Liver more active than another tissues
synthesizes saturated and monounsaturated fatty acids. Fatty acids then used
for synthesis of lipids, phospholipids, cholesterol ethers.
Glycerol-3-phosphate, which is necessary for lipids synthesis, formed in liver
in result of two processes: from free glycerol under influence of
glycerolkinase, or in reducing of dioxiacetone phosphate under influence of
glycerolphosphate dehydrogenase. Active form of fatty acids interact with
glycerol-3-phosphate and phosphatidic acid formed, which used for synthesis of
triacylglycerines and glycerophospholipids.
http://www.youtube.com/watch?v=hRx_i9npTDU&feature=related
2. Liver play a central role in synthesis of
cholesterin, because near 80 % of its amount is synthesized there. Biosynthesis
of cholesterin regulated by negative feedback. When the level of cholesterin in
the meal increases, synthesis in liver decreases, and back to front. Besides
synthesis regulated by insulin and glucagon. Cholesterin used in organism for
building cell membranes, synthesis of steroid hormones and vitamin D. Excess of
cholesterin leads out in the bile to the intestine. Another part of cholesterin
used for bile acids synthesis. This process regulated by reabsorbed bile acids
according to negative feedback principles.
http://www.youtube.com/watch?v=hRx_i9npTDU&feature=related
3. Liver is a place of ketone bodies synthesis. These
substances formed from fatty acids after their oxidation, and from liver
transported to another tissues, first of all to the heart, muscles, kidneys and
brain. These substances are main source of energy for many tissues of our
organism excepting liver in normal conditions (heart) and during starvation
(brain).
http://www.youtube.com/watch?v=mLi9SEIrbuc&feature=related
Transport
forms of lipids
Certain lipids
associate with specific proteins to form lipoprotein systems in which the
specific physical properties of these two classes of biomolecules are blended.
In these systems the lipids and proteins are not covalently joined but are held
together largely by hydrophobic interactions between the nonpolar portions of
the lipid and the protein components.
Transport lipoproteins of blood plasma. The plasma
lipoproteins are complexes in which the lipids and proteins occur in a relatively
fixed ratio. They carry water-insoluble lipids between various organs via the
blood, in a form with a relatively small and constant particle diameter and
weight. Human plasma lipoproteins occur in four major classes that differ in
density as well as particle size. They are physically distinguished by their
relative rates of flotation in high gravitational fields in the
ultracentrifuge.
The blood lipoproteins serve to transport water-insoluble triacylglycerols
and cholesterol from one tissue to another. The major carriers of
triacylglyeerols are chylomicrons and
very low density lipoproteins (VLDL).
The triacylglycerols of the chylomicrons and VLDL are digested in capillaries
by lipoprotein lipase. The fatty acids that are produced are utilized for
energy or converted to triacylglycerols and stored. The glycerol is used for
triacylglycerol synthesis or converted to DHAP and oxidized for energy, either
directly or after conversion to glucose in the liver. The remnants of the chylomicrons are
taken up by liver cells by the process of endocytosis and are degraded by
lysosomal enzymes, and the products are reused by the cell.
VLDL is converted to intermediate
density lipoproteins (IDL), which is
degraded by the liver or converted in blood capillaries to low density lipoproteins LDL by further digestion of
triacylglycerols. LDL is taken up by various tissues and provides cholesterol,
which the tissue utilize
High density lipoproteins (HDL) which is synthesized by the liver, transfers apoproteins to
ehylomicrons and VLDL.
HDL picks up cholesterol from cell membranes or from other lipoproteins.
Cholesterol is converted to cholesterol esters by the lecithin:cholesterol
acyltransferase (LCAT) reaction. The cholesterol esters may be transferred to
other lipoproteins or carried by HDL to the liver, where they are hydrolyzed to
free cholesterol, which is used for synthesis of VLDL or converted to bile
salts.
Composition
of the blood lipoproteins
The
major components of lipoproteins are triacylglycerols, cholesterol, cholesterol
esters, phospholipids, and proteins. Purified proteins (apoproteins) are
designated A, B, C, and E.
Chylomicrons
are the least dense of the blood lipoproteins because they have the most
triacylglycerol and the least protein.
VLDL is more
dense than chylomicrons but still has
a high content of triacylglycerol.
IDL, which is derived from VLDL, is more dense than chylomicrons
but still has a high content of triacylglycerol.
LDL has less triacylglycerol and more
protein and, therefore, is more dense than the IDL from which it is derived.
LDL has the highest content of cholesterol and its esters.
HDL is the most dense lipoprotein. It
has the lowest triacylglycerol and the highest protein content.
http://www.youtube.com/watch?v=XLLBlBiboJI&feature=related
Metabolism
of Chylomicrons
Chylomicrons are synthesized in intestinal epithelial cells. Their
triacylglycerols are derived from dietary lipid, and their major apoprotein is
apo B-48.Chylomicrons travel through the lymph into the blood. In peripheral tissues, particularly
adipose and muscle, the triacylglyerols are digested by lipoprotein lipase.The
chylomicron remnants interact with receptors on liver cells and are taken+ up
by endocytosis. The
contents are degraded by lysosomal
enzymes, and the products (amino acids, fatty acids, glycerol, and cholesterol)
are released into the cytosol and reutilized.
Metabolism of VLDL
VLDL is
synthesized in the liver, particularly after a
high-carbohydrate meal. It is formed from triacylglycerols that are package
with cholesterol, apoproteins (particularly apo B-100), and phospholipids and it
is released into the blood.
In peripheral tissues, particularly
adipose and muscle, VLDL triacylglycerols are digested by lipoprotein lipase,
and VLDL is converted to IDL.
IDL returns
to the liver, is taken up by endocytosis, and is degraded by lysosomal enzymes.
IDL
may also be further degraded by lipoprotein lipase, forming LDL.
LDL reacts with receptors on various cells, is
taken up by endocytosis and is digested by
lysosomal enzymes.
Cholesterol,
released from cholesterol esters by a lysosomal esterase, can be used for the
synthesis of cell memmbranes or bile salts in the liver or steroid hormones in
endocrine tissue.
http://www.youtube.com/watch?v=XPguYN7dcbE
Metabolism of HDL.
HDL
is synthesized by the liver and released into the blood as disk-shaped
particles.
HDL
cholesterol, obtained from cell membranes or from other lipoproteins, is
converted to cholesterol esters. As cholesterol esters accumulate in the core
of the lipoprotein, HDL particles become spheroids.
HDL
particles are taken up by the liver by endocytosis and hydrolyzed by lysosomal
enzymes. Cholesterol, released from cholesterol esters may be packaged by the
liver in VLDL and released into the blood or converted to bile salts and
secreted into the bile.
However, there is also considerable awareness that
abnormal levels of certain lipids, particularly cholesterol (in hypercholesterolemia) and, more recently, trans fatty acids, are risk factors for heart disease and other diseases. We need fats in our
bodies and in our diet. Animals in general use fat for energy storage because
fat stores 9 KCal/g of energy. Plants, which don’t move
around, can afford to store food for energy in a less compact but more easily
accessible form, so they use starch (a carbohydrate, NOT A LIPID) for energy
storage. Carbohydrates and proteins store only 4 KCal/g of energy, so fat
stores over twice as much energy/gram as other sources of energy.
We
need fats in our bodies and in our diet. Animals
in general use fat for energy storage because fat stores 9 KCal/g of energy.
Plants, which don’t move around, can afford to store food for energy in a less
compact but more easily accessible form, so they use starch (a carbohydrate,
NOT A LIPID) for energy storage. Carbohydrates and proteins store only 4
KCal/g of energy, so fat stores over twice as much energy/gram as fat. By the way,
this is also related to the idea behind some of the high-carbohydrate weight
loss diets.
The
human body burns carbohydrates and fats for fuel in a given proportion to each
other. The theory behind these diets is that if they supply carbohydrates but not
fats, then it is hoped that the fat needed to balance with the sugar will be
taken from the dieter’s body stores. Fat is
also is used in our bodies to a) cushion vital organs like the kidneys and b)
serve as insulation, especially just beneath the skin.
Role of the liver in protein metabolism.
Liver has full set of enzymes, which
are necessary for amino acids metabolism. Amino acids from food used in the
liver for following pathways:
1. Protein synthesis.
2. Decomposition for the final products.
3. Transformation to the carbohydrates and lipids.
4. Interaction between amino acids.
5. Transformation to the different substances with
amino group.
6. Release to the blood and transport to another
organs and tissues.
The high speed of protein synthesis and decomposition
is typical for the liver. Hepatocytes catch different protein from blood (from
hemolysated RBC, denaturated plasma proteins, protein and peptide hormones) and
decomposite them to the free amino acids which used for new synthesis. When
organism does not get necessary quantity of amino acids from food, liver
synthesizes only high necessary proteins (enzymes, receptors).
Liver syntesizes 100 % of albumines, 90 % of
α1-globulines, 75 % of α2-globulines, 50 % of β-globulines,
blood clotting factors, fibrinogen, protein part of blood lipoproteins, such
enzyme as cholinesterase. The speed of these processes is enough high, for
example, liver synthesizes 12-16g of albumines per day.
Amino acids, which are not used for protein synthesis,
transformed to another substances. Oxidative decomposition of amino acids is
main source of energy for liver in normal conditions.
Liver can synthesize non-essential amino acids.
Liver synthesizes purine and pyrimidine nucleotides,
hem, creatin, nicotinic acid, cholin, carnitin, polyamines.
The decomposition of hemoglobin in
tissues, bile pigments formation.
After
a life span of about 120 days the erythrocytes die. The dead erythrocytes are
taken up by the phagocytes of the reticuloendothelial system of the body. About
1. The protein (globin)
part is utilized partly as such or along with other body proteins.
2. The iron is stored in
the reticuloendothelial cells and is reused for the synthesis of Hb and other
iron containing substances of the body.
3. The porphyrin part is
converted to bile pigment, i.e. bilirubin which is excreted in bile.
The
several stages, which are involved in the formation of bile pigment from Hb and
the farther fate of this pigment, are given below:
1.
Hemoglobin dissociates into heme and globin.
2.
Heme in the presence of the enzyme, heme oxygenase, loses one molecule
of CO and one atom of iron in Fe3+ form producing biliverdin. In
this reaction, the porphyrin ring is cleaved by oxidation of the alpha methenyl
bridge between pyrrole rings. The enzyme needs NADPH+H+ and O2.
Biliverdin
which is green in color is the first bile pigment to be produced; it is reduced
to the yellow-colored bilirubin, the main bile pigment, by the enzyme biliverdin
reductase requiring NADPH+H+.
Bilirubin
is non-polar, lipid soluble but water insoluble. Bilirubin is a very toxic
compound. For example, it is known to inhibit RNA and protein synthesis and
carbohydrate metabolism in brain. Mitochondria appear to be especially
sensitive to its effect. Bilirubin formed in reticuloendothelial cells
then is associated with plasma protein albumin to protect cells from the toxic
effects. As this bilirubin is in complex with plasma proteins, therefore it
cannot pass into the glomerular filtrate in the kidney; thus it does not appear
in urine, even when its level in the blood plasma is very high. However, being
lipid soluble, it readily gets deposited in lipid-rich tissues specially the
brain.
This
bilirubin is called indirect bilirubin or free bilirubin or
unconjugated bilirubin.
The
detoxication of indirect bilirubin takes place in the membranes of
endoplasmatic reticulum of hepatocytes. Here bilirubin interact with UDP-glucuronic
acid and is converted to the water soluble form -bilirubin mono- and
diglucoronids. Another name of bilirubin mono- and diglucoronids is conjugated
bilirubin or direct bilirubin or bound bilirubin. This reaction is
catalized by UDP-glucoroniltransferase.
Conjugated
bilirubin is water soluble and is excreted by hepatocytes to the bile.
Conjugated (bound) bilirubin undergoes degradation in the intestine through the
action of intestinal microorganisms. Bilirubin is reduced and, mesobilirubin
is formed. Then mesobilirubin is reduced again and mesobilinogen is
formed. The reduction of mesobilinogen results in the formation of stercobilinogen
(in a colon). Stercobilinogen is oxidized and the chief pigment
(brown color) of feces stercobilin is formed. A part of mesobilinogen
is reabsorbed by the mucous of intestine and via the vessels of vena
porta system enter liver. In hepatocytes mesobilinogen is splitted
to pyrol compounds which are excreted from the organism with bile. If
the liver has undergone degeneration mesobilinogen enter the blood and is
excreted by the kidneys. This mesobilinogen in urine is called urobilin, or
true urobilin. Thus, true urobilin can be detected in urine only
in liver parenchyma disease.
Another
bile pigment that can be reabsorbed in intestine is stercobolinogen.
Stercobolinogen is partially reabsorbed in the lower part of colon into the
haemorroidal veins. From the blood stercobolinogen pass via the
kidneys into the urine where it is oxidized to stercobilin. Another name
of urine stercobilin is false urobilin.
As
mentioned above, the conversion of bilirubin to mesobilirubin occurs under the influence
of intestinal bacteria. These bacteria are killed or modified when
broad-spectrum antibiotics are administered. The gut is sterile in the newborn
babies. Under these circumstances, bilirubin is not-converted to urobilinogen,
and the feces are colored yellow due to bilirubin. The feces may even become
green because some bilirubin is reconverted to green-colored biliverdin by
oxidation.
The total bilirubin content in the blood serum is
1,7-20,5 micromol/l, indirect (unconjugated) bilirubin content is 1,7-17,1
micromol/l and direct (conjugated) bilirubin content is 0,86-4,3 micromol/l.
Differentiation
between unconjugated and conjugated bilirubin. Direct and indirect bilirubin.
Diazo
reagent which is a mixture of sulfanilic acid, HCI and NaN02 is
added to the serum. The conjugated bilirubin gives a reddish violet color with
it and the maximum color intensity is obtained within 30 seconds; this is
called direct test.
The
unconjugated bilirubin does not give the direct test; however, it gives
indirect test in which alcohol or caffeine is also added which sets free the
bilirubin frum its complex with plasma proteins. Due to this difference in the
type of diazo reaction given by these two forms of bilirubin, the term direct
and indirect forms of bilirubin are also used to describe conjugated
and unconjugated forms of bilirubin.
Some
other differences between these two forms of bilirubin are given below:
|
Property |
Unconjugated
|
Conjugated |
|
1.
Solubility |
Soluble
in lipid, insoluble in water |
Soluble
in water, insoluble in lipid |
|
2.
Excretion in urine |
No |
Yes |
|
3.
Deposition in hram |
Yes |
No |
|
4.
Plasma level is increased in jaundice |
Pre-hepatic
jaundice |
Hepatic and posthepatic |
The mechanism of jaundice
development, their biochemical characteristic.
Jaundice
or icterus is the orange-yellow discoloration
of body tissues which is best seen in the skin and conjunctivae; it is caused
by the presence of an excess of bilirubin in the blood plasma and tissue
fluids. Depending upon the cause of an increased plasma bilirubin level,
jaundice can be classified as
1)
pre-hepatic,
2)
hepatic and
3)
post-hepatic
Pre-hepafic jaundice. This
type of jaundice is due to a raised plasma level of unconjugated bilirubin. It
is due to an excessive breakdown of red cells which leads to an increased
production of uncongugated bilirubin; it is also called haemolytic jaundice.
As the liver is not able to excrete into the bile all the bilirubin
reaching it, the plasma bilirubin level rises and jaundice results. This type
of jaundice was in the past called acholuric jaundice because the unconjugated
bilirubin, being bound to plasma proteins, is not excreted in the urine despite
its high level in the plasma; the urine is also without bile salts. Prehepatic
jaundice is also seen in neonates (physiological jaundice) especially in the
premature ones because the enzyme UDP-glucuronyl transferase is deficient.
Moreover relatively more bilirubin is produced in-the neonates because of
excessive breakdown of red blood cells.
Hepatic jaundice.This
is typically seen in viral hepatitis. Several viruses are responsible for viral
hepatitis and include hepatitis A, B, C and D viruses. The liver cells are
damaged: inflammation produces obstruction of bile canaliculi due to swelling
around them. This cholestasis causes the bile to regurgitate into the blood
through bile canaliculi. The blood contains abnormally raised amount both of
conjugated and unconjugated bilirubin and bile salts which are excreted in the
urine.
Post hepatic jaundice. This
results when there is extrahepatic cholestasis due to an obstruction in the
biliary passages outside the liver. In this way, the bile cannot reach the
small intestine and therefore the biliary passages outside as well as inside
the liver are distended with bile. This leads to damage to the liver and bile
regurgitates into the blood. The conjugated bilirubin and the bile salt levels
of the blood are thus greatly raised and both of these are excreted in the
urine. Liver function tests will vary according to the degree of obstruction,
i.e complete or incomplete. If the obstruction is complete, the stools become
pale or clay-colored and the urine does not have any stercobilin. The
absorption of fat and fat soluble vitamins also suffers due to a lack of bile
salts. Excess of bile salts in the plasma produces severe pruritus (itching).
Hemolytic jaundice is
characterized by
1.
Increase mainly of unconjugated bilirubin in the blood serum.
2.
Increased excretion of urobilinogen with urine.
3.
Dark brown colour of feces due to high content of stercobilinogen.
Hepatic jaundice is
characterized by
1.Increased levels of conjugated and unconjugated
bilirubin in serum.
2.Dark coloured urine due to the excessive excretion
of bilirubin and urobilinogen.
3.Pale, clay coloured stools due to the absence
of stercobilinogen.
4.Increased activities of alanine and aspartate
transaminases.
Obstructive (post
hepatic ) jaundice is characterized by
1.Increased concentration mainly of conjugated
bilirubin in serum.
2.Dark coloured urine due to elevated excretion of
bilirubin and clay coloured feces due to absence of stercobilinogen.
Role of the liver in detoxification processes.
A xenobiotics is a compound that is foreign to the
body. The principal classes of xenobiotics of medical relevance are drugs, chemical
cancerogens, and various compounds that have found their way into our
environment by one route or another (insecticides, herbicides, pesticides, food
additions, cosmetics, domestic chemical substances). Most of these compounds
are subject to metabolism (chemical alteration) in the human body, with the
liver being the main organ involved; occasionally a xenobiotics may be excreted
unchanged.
Some internal substances also have toxic properties
(for example, bilirubin, free ammonia, bioactive amines, products of amino
acids decay in the intestine). Moreover, all hormones and mediatores must be
inactivated.
Reactions of detoxification take place in the liver.
Big molecules like bilirubin excreted with the bile to intestine and leaded out
with feces. Small molecules go to the blood and excreted via kidney with urine.
The metabolism of xenobiotics has 2 phases:
In phase 1,
the major reaction involved is hydroxylation, catalyzed by members of a class
of enzymes referred to as monooxygenases or cytochrome P-450 species. These
enzymes can also catalyze deamination, dehalogenation, desulfuration,
epoxidation, peroxidation and reduction reaction. Hydrolysis reactions and
non-P-450-catalyzed reactions also occur in phase 2.
In phase 2,
the hydroxylated or other compounds produced in phase 1 are converted by
specific enzymes to various polar metabolites by conjugation with glucuronic
acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation.
The overall purpose of metabolism of xenobiotics is to
increase their water solubility (polarity) and thus facilitate their excretion
from the body via kidney.Very hydrophobic xenobiotics would persist in adipose
tissue almost indefinitely if they were not converted to more polar forms.
In certain cases, phase 1 metabolic reaction convert
xenobiotics from inactive to biologically active compounds. In these instances,
the original xenobiotics are referred to as prodrugs or procarcinogens. In
other cases, additional phase 1 reactions convert the active compounds to less
active or inactive forms prior to conjugation. In yet other cases, it is the
conjugation reactions themselves that convert the active product of phase 1 to
less active or inactive species, which are subsequently excreted in the urine
or bile. In a very few cases, conjugation may actually increase the biologic
activity of a xenobiotics.
Hydroxylation is the chief reaction involved in phase
1. The responsible enzymes are called monooxygenases or cytochrome P-450
species. The reaction catalyzed by a monooxygenase is:
RH + O2 + NADPH + H+ → R-OH + H2O
+ NADP
RH above can represent a very widee variety of drugs,
carcinogens, pollutants, and certain endogenous compounds, such as steroids and
a number of other lipids. Cytochrome P-450 is considered the most versatile
biocatalyst known. The importance of this enzyme is due to the fact that
approximately 50 % of the drugs that patients ingest are metabolized by species
of cytochrome P-450. The following are important points concerning cytochrome
P-450 species:
http://www.youtube.com/watch?v=3DgxjDalZW0
1. Like hemoglobin, they are hemoproteins.
2. They are present in highest amount in the membranes
of the endoplasmic reticulum (ER) (microsomal fraction) of liver, where they
can make up approximately 20 % of the total protein. Thay are also in other
tissues. In the adrenal, they are found in mitochondria as well as in the ER;
the various hydroxylases present in that organ play an important role in cholesterol
and steroid biosynthesis.
3. There are at least 6 closely related species of
cytochrome P-450 present in liver ER, each with wide and somewhat overlapping
substrate specificities, that act on a wide variety of drugs, carcinogens, and
other xenobiotics in addition to endogenous compounds such as certain steroids.
4. NADPH, not NADP, is involved in the reaction
mechanism of cytochrome P-450. The enzyme that uses NADPH to yield the reduced
cytochrome P-450 is called NADPH-cytochrome P-450 reductase.
5. Lipids are also components of the cytochrome P-450
system. The preferred lipid is phosphatidylcholine, which is the major lipid
found in membranes of the ER.
6. Most species of cytochrome P-450 are inducible. For
instance, the administration of phenobarbital or of many other drugs causes a
hypertrophy of the smooth ER and a 3- to 4-fold increase in the amount of
cytochrome P-450 within 4-5 days. Induction of this enzyme has important
clinical implications, since it is a biochemical mechanism of drug interaction.
7. One species of cytochrome P-450 has its
characteristic absorption peak not at 450 nm but at 448 nm. It is often called
cytochrome-448.This species appears to
be relatively specific for the metabolism of polycyclic aromatic hydrocarbons
(PAHs) and related molecules; for this reason it is called aromatic hydrocarbon
hydroxylase (AHH). This enzyme is important in the metabolism of PAHs and in
carcinogenesis produced by this agents.
8. Recent findings have shown that individual species of
cytochrome P-450 frequently exist in polymorphic forms, some of which exhibit
low catalytic activity. These observation are one important explanation for the
variations in drug responses noted among many patients.
http://www.youtube.com/watch?v=3DgxjDalZW0
In phase 1 reactions, xenobiotics are generally
converted to more polar, hydroxylated derivates. In phase 2 reactions, these
derivates are conjugated with molecules such as glucuronic acid, sulfate, or
glutatione. This renders them even more water-soluble, and they are eventually
excreted in the urine or bile.
There are at least 5 types of phase 2 reactions:
1.
Glucuronidation. UDP-glucuronic acid is the glucuronyl donor, and
a variety of glucuronyl transferases, present in both the ER and cytosol, are
the catalysts. Molecules such as bilirubin, thyroxin, 2-acetylaminofluorene (a
carcinogen), aniline, benzoic acid, meprobromate (a tranquilizer), phenol,
crezol, indol and skatol, and many steroids are excreted as glucuronides. The
glucuronide may be attached to oxygen, nitrogen, or sulfur groups of
substrates. Glucuronidation is probably the most frequent conjugation reaction.
Glucuronidation,
the combining of glucuronic acid with toxins, requires the enzyme UDP-glucuronyl
transferase (UDPGT). Many of the commonly prescribed drugs are detoxified
through this pathway. It also helps to detoxify aspirin, menthol, vanillin
(synthetic vanilla), food additives such as benzoates, and some hormones. Glucuronidation
appears to work well, except for those with Gilbert's syndrome--a
relatively common syndrome characterized by a chronically elevated serum
bilirubin level (1.2-3.0 mg/dl). Previously considered rare, this disorder is
now known to affect as much as 5% of the general population. The condition is
usually without serious symptoms, although some patients do complain about loss
of appetite, malaise, and fatigue (typical symptoms of impaired liver
function). The main way this condition is recognized is by a slight yellowish
tinge to the skin and white of the eye due to inadequate metabolism of
bilirubin, a breakdown product of hemoglobin. The activity of UDPGT is
increased by foods rich in the monoterpene limonene (citris peel, dill weed
oil, and caraway oil). Methionine, administered as SAM, has been shown to be
quite beneficial in treating Gilbert's syndrome.
2. Sulfation.
Some alcohols, arylamines, and phenols are sulfated. The sulfate donor in these
and other biologic sulfation reactions is adenosine
3´-phosphate-5´-phosphosulfate (PAPS); this compound is called
active sulfate.
Sulfation
is the conjugation of toxins with sulfur-containing compounds. The sulfation
system is important for detoxifying several drugs, food additives, and,
especially, toxins from intestinal bacteria and the environment. In addition to
environmental toxins, sulfation is also used to detoxify some normal body
chemicals and is the main pathway for the elimination of steroid and thyroid
hormones. Since sulfation is also the primary route for the elimination of
neurotransmitters, dysfunction in this system may contribute to the development
of some nervous system disorders.
Many
factors influence the activity of sulfate conjugation. For example, a diet low
in methionine and cysteine has been shown to reduce sulfation. Sulfation is
also reduced by excessive levels of molybdenum or vitamin B6 (over
about 100 mg/day). In some cases, sulfation can be increased by supplemental
sulfate, extra amounts of sulfur-containing foods in the diet, and the amino
acids taurine and glutathione.
Sulfoxidation
is the process by which the sulfur-containing molecules in drugs and foods are
metabolized. It is also the process by which the body eliminates the sulfite
food additives used to preserve many foods and drugs. Various sulfites are
widely used in potato salad (as a preservative), salad bars (to keep the
vegetables looking fresh), dried fruits (sulfites keep dried apricots orange),
and some drugs. Normally, the enzyme sulfite oxidase metabolizes sulfites
to safer sulfates, which are then excreted in the urine. Those with a
poorly functioning sulfoxidation system, however, have an increased ratio of
sulfite to sulfate in their urine. The strong odor in the urine after eating
asparagus is an interesting phenomenon because, while it is unheard of in
China, 100% of the French have been estimated to experience such an odor (about
50% of adults in the U.S. notice this effect). This example is an excellent
example of genetic variability in liver detoxification function. Those with a
poorly functioning sulfoxidation detoxification pathway are more sensitive to
sulfur-containing drugs and foods containing sulfur or sulfite additives. This
is especially important for asthmatics, which can react to these additives with
life-threatening attacks. Molybdenum helps asthmatics with an elevated ratio of
sulfites to sulfates in their urine because sulfite oxidase is dependent upon
this trace mineral.
3.
Conjugation with Glutathione. Glutathione (γ-glutamylcysteinylglycine)
is a tripeptide consisting of glutamic acid, cysteine, and glycine. Glutathione
is commonly abbreviated to GSH; the SH indicates the sulfhydryl group of its
cysteine and is the business part of the molecule. A number of potentially
toxic electrophilic xenobiotics (such as certain carcinogens) are conjugated to
the nucleophilic GSH. The enzymes catalyzing these reactions are called
glutathione S-transferases and are present in high amounts in liver cytosol and
in lower amounts in other tissues. glutathione conjugates are subjected to
further metabolism before excretion. The glutamyl and glycinyl groups belonging
to glutathione are removed by specific enzymes, and an acetyl group (donated by
acetyl-CoA) is added to the amino group of the remaining cystenyl moiety. The
resulting compound is a mercapturic acid, a conjugate of L-acetylcysteine,
which is then excreted in the urine.
Glutathione is also an
important antioxidant. This combination of detoxification and free radical protection,
results in glutathione being one of the most important anticarcinogens and
antioxidants in our cells, which means that a deficiency is cause of serious
liver dysfunction and damage. Exposure to high levels of toxins depletes
glutathione faster than it can be produced or absorbed from the diet. This
results in increased susceptibility to toxin-induced diseases, such as cancer,
especially if phase I detoxification system is highly active. Disease states
due to glutathione deficiency are not uncommon.
A
deficiency can be induced either by diseases that increase the need for
glutathione, deficiencies of the nutrients needed for synthesis, or diseases
that inhibit its formation. Smoking increases the rate of utilization of
glutathione, both in the detoxification of nicotine and in the neutralization
of free radicals produced by the toxins in the smoke. Glutathione is available
through two routes: diet and synthesis. Dietary glutathione
(found in fresh fruits and vegetables, cooked fish, and meat) is absorbed well
by the intestines and does not appear to be affected by the digestive
processes. Dietary glutathione in foods appears to be efficiently absorbed into
the blood. However, the same may not be true for glutathione supplements.
In
healthy individuals, a daily dosage of 500 mg of vitamin C may be sufficient to
elevate and maintain good tissue glutathione levels. In one double-blind study,
the average red blood cell glutathione concentration rose nearly 50% with 500
mg/day of vitamin C. Increasing the dosage to 2,000 mg only raised red blood
cell (RBC) glutathione levels by another 5%. Vitamin C raises glutathione by
increasing its rate of synthesis. In addition, to vitamin C, other compounds
which can help increase glutathione synthesis include N-acetylcysteine
(NAC), glycine, and methionine. In an effort to increase
antioxidant status in individuals with impaired glutathione synthesis, a
variety of antioxidants have been used. Of these agents, only microhydrin,
vitamin C and NAC have been able to offer some possible benefit.
Over
the past 5-10 years, the use of NAC and glutathione products as antioxidants
has become increasingly popular among nutritionally oriented physicians and the
public. While supplementing the diet with high doses of NAC may be beneficial
in cases of extreme oxidative stress (e.g. AIDS, cancer patients going through
chemotherapy, or drug overdose), it may be an unwise practice in healthy
individuals.
4. Acetylation.
These reactions is represented by X +
Acetyl-CoA → Acetyl-X + CoA, where X represents a xenobiotic. These
reactions are catalyzed by acetyltransferases present in the cytosol of various
tissues, particularly liver. The different aromatic amines, aromatic amino
acids, such drug as isoniazid, used in the treatment of tuberculosis, and
sulfanylamides are subjects to acetylation. Polymorphic types of
acetyltransferases exist, resulting in individuals who are classified as slow
or fast acetylators, and influence the rate of clearance of drugs such as
isoniazid from blood. Slow acetylators are more subject to certain toxic
effects of isoniazid because the drug persists longer in these individuals.
Conjugation
of toxins with acetyl-CoA is the primary method by which the body eliminates
sulfa drugs. This system appears to be especially sensitive to genetic
variation, with those having a poor acetylation system being far more
susceptible to sulfa drugs and other antibiotics. While not much is known about
how to directly improve the activity of this system, it is known that
acetylation is dependent on thiamine, pantothenic acid, and vitamin C.
5. Methylation.
A few xenobiotics (amines, phenol, tio-substances, inorganic compounds of
sulphur, selen, mercury, arsenic) are subject to methylation by
methyltransferases, employing S-adenosylmethionine as methyl donor. Also
catecholamines and nicotinic acid amid (active form of vitamin PP) are
inactivated due to methylation.
Very important way of detoxification is ureogenes
(urea synthesis). Free ammonia, which formed due to metabolism of amino acids,
amides and amines, removed from organism in shape of urea.
Methylation
involves conjugating methyl groups to toxins. Most of the methyl groups
used for detoxification come from S-adenosylmethionine (SAM). SAM is
synthesized from the amino acid methionine, a process which requires the
nutrients choline, vitamin B12, and folic acid. SAM is able to
inactivate estrogens (through methylation), supporting the use of methionine in
conditions of estrogen excess, such as PMS. Its effects in preventing
estrogen-induced cholestasis (stagnation of bile in the gall bladder)
have been demonstrated in pregnant women and those on oral contraceptives. In
addition to its role in promoting estrogen excretion, methionine has been shown
to increase the membrane fluidity that is typically decreased by estrogens,
thereby restoring several factors that promote bile flow. Methionine also
promotes the flow of lipids to and from the liver in humans. Methionine is a major
source of numerous sulfur-containing compounds, including the amino acids
cysteine and taurine.
Are there
things that support liver detoxification?
Nutritional factors
Antioxidant
vitamins like vitamin C, beta-carotene, and vitamin E are obviously quite
important in protecting the liver from damage as well as helping in the
detoxification mechanisms, but even simple nutrients like B-vitamins, calcium,
and trace minerals are critical in the elimination of heavy metals and other
toxic compounds from the body. The lipotropic agents, choline, betaine,
methionine, vitamin B6, folic acid, and vitamin B12, are
useful as they promote the flow of fat and bile to and from the liver.
Lipotropic formulas have been used for a wide variety of conditions by
nutrition-oriented physicians including a number of liver disorders such as
hepatitis, cirrhosis, and chemical-induced liver disease. Lipotropic
formulas appear to increase the levels of SAM and glutathione. Methionine,
choline, and betaine have been shown to increase the levels of SAM.
Botanical medicines
There is a
long list of plants which exert beneficial effects on liver function. However,
the most impressive research has been done on silymarin, the flavonoids
extracted from silybum marianum (milk thistle). These compounds exert a
substantial effect on protecting the liver from damage as well as enhancing
detoxification processes. Silymarin prevents damage to the liver through
several mechanisms: by acting as an antioxidant, by increasing the synthesis of
glutathione and by increasing the rate of liver tissue regeneration. Silymarin
is many times more potent in antioxidant activity than vitamin E and vitamin C.
The protective effect of silymarin against liver damage has been demonstrated
in numerous experimental studies. Silymarin has been shown to protect the liver
from the damage produced by such liver-toxic chemicals as carbon
tetrachloride, amanita toxin, galactosamine, and praseodymium nitrate.
One of the
key mechanisms by which silymarin enhances detoxification is by preventing the
depletion of glutathione. Silymarin not only prevents the depletion of
glutathione induced by alcohol and other toxic chemicals, but has been shown to
increase the level of glutathione of the liver by up to 35%, even in normals.
Inhuman studies, silymarin has been shown to have positive effects in treating
liver diseases of various kinds, including cirrhosis, chronic hepatitis, fatty
infiltration of the liver, and inflammation of the bile duct. The standard dosage
for silymarin is 70-210 mg three times/day.
Amino acid conjugation
Several amino
acids (glyucine, taurine, glutamine, arginine, and ornithine) are
used to combine with and neutralize toxins. Of these, glycine is the most
commonly utilized in phase II amino acid detoxification. Patients suffering
from hepatitis, alcoholic liver disorders, carcinomas, chronic arthritis,
hypothyroidism, toxemia of pregnancy, and excessive chemical exposure are
commonly found to have a poorly functioning amino acid conjugation system. For
example, using the benzoate clearance test (a measure of the rate at
which the body detoxifies benzoate by conjugating it with glycine to form
hippuric acid, which is excreted by the kidneys), the rate of clearance in
those with liver disease is 50% of that in healthy adults.
Even in
apparently normal adults, a wide variation exists in the activity of the
glycine conjugation pathway. This is due no only to genetic variation, but also
to the availability of glycine in the liver. Glycine, and the other amino acids
used for conjugation, become deficient on a low-protein diet and when chronic
exposure to toxins results in depletion.
Dietary Changes
Adding
certain supplements to your diet can stimulate detoxification. Fiber, vitamin C
and other antioxidants, chlorophyll, and glutathione (as the amino acid
L-cysteine) will all help. Herbs such as garlic, red clover, echinacea, or
cayenne may also induce some detoxification. Saunas, sweats, and niacin therapy
have been used to cleanse the body.
Simply
increasing liquids and decreasing fats will shift the balance strongly toward
improved elimination and less toxin buildup. Changes might include increased
consumption of filtered water, herb teas, fruits, and vegetables, as well as
reducing fats, especially fried food, meat and milk products. In general,
moving from an acid-generating diet to a more alkaline one will aid the process
of detoxification. Acid-forming foods, such as meats, milk products, breads and
baked goods, and especially the refined sugar and carbohydrate products, will
increase body acidity and lead to more mucus production and congestion, whereas
the more alkaline vegetarian foods enhance cleansing and clarity in the
body.
A deeper
level of detoxification diet is made up exclusively of fresh fruits and
vegetables, either raw and cooked, and whole grains, both cooked and sprouted.
This diet keeps fiber and water intake high and helps colon detoxification.
Most people can handle this well and make the shift from their regular diet
with a few days transition. Some people do well on a brown rice fast (a more
macrobiotic plan), usually for a week or two, eating three to four bowls of
rice daily along with liquids such as teas."
Role of liver
in excretion.
Bile is an important vehicle for bile acid and
cholesterol excretion, but it also removes many drugs, toxins, bile pigments,
and various inorganic substances such as copper, zinc, and mercury.
Evaluating of liver’s functions.
Different methods are used for evaluating of liver’s
functions. Base for some of them is role of liver in proetin metabolism (e.g.
thymol’s test), for another – role of liver in detoxification (indican’s test)
or in excretion (checking of bilirubin level in blood). In all cases physician
must make a conclusion about disorder of liver’s functions after complex
investigation, because, as mentioned above, all metabolic ways are present in
liver.
The
liver filter can remove a wide range of microorganisms such as bacteria, fungi,
viruses and parasites from the blood stream, which is highly desirable, as we
certainly do not want these dangerous things building up in the blood stream
and invading the deeper parts of the body. Infections with parasites often come
from the contaminated water supplies found in large cities, and indeed other
dangerous organisms may find their way into your gut and blood stream from
these sources. This can cause chronic infections and poor health, so it is
important to protect your liver from overload with these microorganisms. The
safest thing to do is boil your water for at least 5 minutes, or drink only
bottled water that has been filtered and sterilized. High loads of unhealthy
microorganisms can also come from eating foods that are prepared in conditions
of poor hygiene by persons who are carrying bacteria, viruses or parasites on
their skin. Foods, especially meats that are not fresh or are preserved, also
contain a higher bacterial load, which will overwork the liver filter if they
are eaten regularly.
Recently,
it has become very fashionable for people to detoxify their bodies by various
means, such as fasting or cleansing the bowels with fiber mixtures. Fasting can
by its extreme nature, only be a temporary method of cleansing the body of
waste products, and for many people causes an excessively rapid release of
toxins which can cause unpleasant, acute symptoms. The liver filter, like any
filter, needs to be cleansed regularly, and it is much easier and safer to do
it everyday. This is easily and pleasantly achieved by adopting a daily eating
pattern that maintains the liver filter in a healthy clean state. By following
the methods and guidelines on this site, you will be able to keep the liver
filter healthy and clean. Although it is important to keep the intestines
moving regularly and to sweep their walls with high fiber and living foods, it
is important to remember that the bowels are really a channel of elimination
and not a cleansing organ per se. In other words the bowels cannot cleanse,
filter or remove toxic wastes from the blood stream.
The liver is the most important organ in
detoxification, as it is the body's premier cleansing organ. All the blood in
the body passes through the liver, which removes toxins, impurities, and debris
from the bloodstream.
The
liver stores fat-soluble substances; these can include chemicals, which can be
stored in the liver for years. Using enzymes, the liver transforms these
chemicals into water-soluble substances that can be excreted though the kidneys
or the gastrointestinal tract.
Hormones
are metabolized by the liver. Estrogen produced by the body and from hormone
replacement therapies is broken down. If estrogen is not adequately processed,
excess estrogen can result in endometriosis; high blood pressure; PMS; and
breast, uterine, and vaginal cancer.
The
liver also manufactures bile to digest fats; chemically changes many foods into
vitamins and enzymes; converts carbohydrates and proteins into glucose for
brain fuel and glycogen for muscular energy; and stores nutrients to be
secreted as needed by the body to build and maintain cells.
If
the liver cannot perform these jobs well, you may exhibit a number of symptoms.
These include gas; constipation; a feeling of fullness; loss of appetite; nausea
after fatty meals; an oily taste in the mouth; revulsion to fatty foods;
frequent headaches not related to stress; weak ligaments, tendons, and muscles;
skin problems; and emotional excesses.
What Can
Affect the Liver?
Briefly
put, living. What you eat, where you live, and what you do all can affect the
liver's performance. If you consume a lot of processed foods, the additives can
eventually affect the liver. If you live in an area that is highly polluted,
exposure to chemicals in the air and water affects the liver. All of this can
hurt the liver's performance.
An impaired
liver does not process food or detoxify substances as rapidly or as completely
as a healthy liver. If the liver is not producing enough bile, it cannot adequately
digest fats. If the liver is detoxifying more slowly than it should, it can
result in more toxic substances circulating in the body.
If toxins
continue to accumulate, the liver may not be able to work fast enough to clean
the blood. It is like being on a treadmill that is going a little too fast: try
as you might, you cannot go forward, but instead are swept back into greater
toxicity. Instead of being converted into something useful or being eliminated,
toxins remain unchanged. They are eventually stored in fatty body tissue and in
the cells of the brain and central nervous system. The stored toxins may be
slowly released to recirculate in the blood, contributing to many chronic
illnesses.
A toxin is
basically any substance that creates irritating and/or harmful effects in the
body; stressing and undermining one's biochemical health and organ function.
Toxins can come from by products of normal cell metabolism or from the outside
environment e.g. pollution, drugs, pesticides, dyes, chemicals, microbes, heavy
metals, tobacco smoke and so on.
Toxicity
occurs when we take in more then we can utilize and eliminate. Toxic chemicals
can be a real problem, since after years of exposure to these substances the
body’s ability to eliminate them can slow down. They can get recirculated into
the bloodstream or stored in the liver, body fat or other parts of the body.
These types of buildups and problems throughout the body can contribute to the
development of serious illnesses. Many chemicals are so widespread that we are
unaware of them. But they have worked their way into our bodies faster than
they can be eliminated, and are causing allergies and addictions in record
numbers. The body's built in detoxification apparatus include the respiratory,
gastrointestinal, urinary, skin and lymphatic systems.
Symptoms
of Toxicity
Cancer and
cardiovascular disease are two of the main toxicity-related diseases.
Arthritis, allergies, obesity, and many skin problems are others. In addition,
a wide range of symptoms, such as headaches, fatigue, pains, coughs,
gastrointestinal problems and problems from immune weakness can all be related
to toxicity.
Common
indications of toxicity include frequent, unexplained headaches, back or joint
pain, tight or stiff neck, arthritis, chronic respiratory or sinus problems,
asthma, abnormal body odor, bad breath, coated tongue, food allergies, poor
digestion, chronic constipation with intestinal bloating or gas, brittle nails
and hair, psoriasis, adult acne, unexplained weight gain over
Detoxification
is the process of clearing toxins from the body or neutralizing them. Energy
balancing and detoxification herbal baths prompt the body to eliminate toxins
from specific areas of the body. As these toxins are released from the
areas where they have been stored, they move into the blood, lymph and other
body fluids out of the body through the urinary, gastrointestinal, lymphatic
and respiratory systems and the skin. The period of detoxification can be
a few days, a few weeks or a months depending on the extent, location and
type of the toxins in the body. As a person is detoxifying they may
experience uncomfortable symptoms including depression, mood changes, nausea,
diarrhea , foggy head, fatigue, lack of energy, bad breathe, foul urine odour,
foul perspiration odour, body odour, sores, rashes, acne, cold or flu like
symptoms, headaches or any other symptom. This period where symptoms may
seem to worsen is sometimes called a healing crisis, but is actually just the
body's reacting to the presence of the toxins in the bloodstream and the
movement of the toxins out of the body. .
How does the
body get rid of toxins?
"The
liver is one of the most important organs in the body when it comes to
detoxifying or getting rid of foreign substances or toxins. The liver plays a
key role in most metabolic processes, especially detoxification. The liver
neutralizes a wide range of toxic chemicals, both those produced internally and
those coming from the environment. The normal metabolic processes produce a
wide range of chemicals and hormones for which the liver has evolved efficient
neutralizing mechanisms. However, the level and type of internally produced
toxins increases greatly when metabolic processes go awry, typically as a
result of nutritional deficiencies. These non-end-product metabolites have
become a significant problem in this age of conventionally grown foods and poor
diets.
Many of the
toxic chemicals the liver must detoxify come from the environment: the content
of the bowels and the food, water, and air. The polycyclic hydrocarbons
(DDT, dioxin, 2,4,5-T, 2,3-D, PCB, and PCP), which are components of various
herbicides and pesticides, are an example of chemicals that are now found in
virtually all fat tissues measured. Even those eating unprocessed organic foods
need an effective detoxification system because all foods contain naturally occurring
toxic constituents.
The liver
plays several roles in detoxification: it filters the blood to remove large
toxins, synthesizes and secretes bile full of cholesterol and other fat-soluble
toxins, and enzymatically disassembles unwanted chemicals. This enzymatic
process usually occurs in two steps referred to as phase I and phase
II. Phase I either directly neutralizes a toxin, or modifies the toxic
chemical to form activated intermediates which are then neutralized by one of
more of the several phase II enzyme systems.
Proper
functioning of the liver's detoxification systems is especially important for
the prevention of cancer. Up to 90% of all cancers are thought to be due to the
effects of environmental carcinogens, such as those in cigarette smoke, food,
water, and air, combined with deficiencies of the nutrients the body needs for
proper functioning of the detoxification and immune systems. The level of
exposure to environmental carcinogens varies widely, as does the efficiency of
the detoxification enzymes, particularly phase II. High levels of exposure to
carcinogens coupled with slow detoxification enzymes significantly increases
susceptibility to cancer.
How does the
liver remove toxins from the body?
One of
the liver's primary functions is filtering the blood. Almost
Bile
Excretion
The liver's
second detoxification process involves the synthesis and secretion of bile.
Each day the liver manufactures approximately
What
happens when excretion of bile is inhibited?
When the
excretion of bile is inhibited (i.e. cholestasis), toxins stay in the
liver longer. Cholestasis has several causes, including obstruction of the bile
ducts and impairment of bile flow within the liver. The most common cause of
obstruction of the bile ducts is the presence of gallstones. Currently, it is
conservatively estimated that 20 million people in the U.S. have gallstones.
Nearly 20% of the female and 8% of the male population over the age of 40 are
found to have gallstones on biopsy and approximately 500,000 gall bladders are
removed because of stones each year in the U.S. The prevalence of gallstones in
this country has been linked to the high-fat, low-fiber diet consumed by the
majority of Americans.
Impairment of
bile flow within the liver can be caused by a variety of agents and conditions.
These conditions are often associated with alterations of liver function in
laboratory tests (serum bilirubin, alkaline phosphatase, SGOT, LDH, GGTP,
etc.) signifying cellular damage. However, relying on these tests alone to
evaluate liver function is not adequate, since, in the initial or subclinical
stages of many problems with liver function, laboratory values remain normal.
Among the symptoms people with enzymatic damage complain of are:
Fatigue; general
malaise; digestive disturbances; allergies and chemical sensitivities;
premenstrual syndrome; constipation
Perhaps the
most common cause of cholestasis and impaired liver function is alcohol
ingestion. In some especially sensitive individuals, as little as
Oranges and
tangerines (as well as the seeds of caraway and dill) contain limonene,
a phytochemical that has been found to prevent and even treat cancer in animal
models. Limonene's protective effects are probably due to the fact that it is a
strong inducer of both phase I and phase II detoxification enzymes that
neutralize carcinogens.
Are there
things that inhibit detoxification?
Grapefruit juice decreases the rate of elimination of drugs from the
blood and has been found to substantially alter their clinical activity and
toxicity.
Curcumin, the
compound that gives turmeric its yellow color, is interesting because it inhibits
phase I while stimulating phase II. This effect can be very useful in
preventing certain types of cancer. Curcumin has been found to inhibit
carcinogens, such as benzopyrene (found in charcoal-broiled meat), from
inducing cancer in several animal models. It appears that the curcumin exerts
its anti-carcinogenic activity by lowering the activation of carcinogens while
increasing the detoxification of those that are activated. Curcumin has also
been shown to directly inhibit the growth of cancer cells.
As most of
the cancer-inducing chemicals in cigarette smoke are only carcinogenic during
the period between activation by phase I and final detoxification by phase II, curcumin
in the turmeric can help prevent the cancer-causing effects of tobacco. Those
exposed to smoke, aromatic hydrocarbons, and other environmental
carcinogens will probably benefit from the frequent use of curry or turmeric.
The activity
of phase I detoxification enzymes decreases in old age. Aging also decreases
blood flow through the liver, further aggravating the problem. Lack of the
physical activity necessary for good circulation, combined with the poor
nutrition commonly seen in the elderly, add up to a significant impairment of
detoxification capacity, which is typically found in aging individuals. This
helps to explain why toxic reactions to drugs are seen so commonly in the
elderly.
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Liver
failure, or hepatic failure, is severe deterioration of liver function
resulting from extensive damage of liver cells. The syndrome respresents a
severe clinical condition and is associated with high mortality; therefore, a
great challenge to intensive care management. Causes Symptoms Pathobiochemistry
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Jaundice
is a cause for concern and there are many misconceptions associated with it. Dr
Vikram Ananthakrishnan (M.S., F.R.C.S) answers some frequently asked questions
about this common ailment and about the liver.
Jaundice
can be broadly classified as infective and obstructive jaundice.
A
virus called Hepatitis A, is a common cause of infective jaundice. This virus
is transmitted through water and food. Children are often affected.
The
other viruses such as Hepatitis B and Hepatitis C viruses are transmitted through
blood. Viruses responsible for these infections spread through the body
secretions like saliva, sweat, semen, vaginal fluids of infected persons. Close
contact and sexual intercourse are important factors in spread. Homosexuals
contract these infections more easily. Blood, blood products, contaminated
needles and tattooing, are also important sources through which infection
spreads. These viruses are more resistant to the various methods of
sterilisation than the AIDS virus. They are a major cause for concern as they
spread rapidly. There are more people infected by Hepatitis B virus in the
world than the AIDS virus.
Hepatitis
B and Hepatitis C infections can lead to chronic liver diseases, cirrhosis and
eventually liver cancer & liver failure.
The
other viruses associated with jaundice are Hepatitis D and E. Hepatitis E
infection can be acquired from contaminated water.
Diseases
like Leptospirosis can also cause jaundice.
Stones
or growths, blocking the pathway of bile, cause a type of jaundice called
obstructive jaundice. Occasionally, drugs can also cause jaundice.
How
is Leptospirosis transmitted and how is it treated?
This
is an infection caused by water or food contaminated with rats’ urine. Patients
develop fever and later jaundice and eventually (renal) kidney failure. If left
unrecognised leptospirosis can be fatal. The infection is treated with
antibiotics like penicillin and doxycycline.
Amongst
the different types of infective jaundice, which is worse?
Hepatitis
C is the most dangerous type of jaundice. Like Hepatitis B it also leads to
chronic liver disease.
Which
form of jaundice requires surgery?
Sometimes
stones & growths block the pathway of bile drainage from the liver (where it
is made) to the small intestine (where it acts on the food to digest and break
down fats). This can also cause jaundice. Stones in the bile pathway usually
originate in the gall bladder. This often requires removal of the gall bladder
along with the stones in the biliary pathway. Growths may require major surgery
for their removal. In case they are very advanced, a bypass operation may need
to be done to relieve the jaundice.
What
are the tests (investigations) done for jaundice?
These
can be broadly classified as blood tests, scans and endoscopy.
Blood
tests are done to assess the overall function of the liver. These tests are
collectively called Liver Function Tests.
These
tests will show if there is on going destruction of the liver. Blood tests will
help identify the type of jaundice.
They
will show whether the synthetic function of the liver is good. The various
clotting tests can be done to see if the liver is producing adequate proteins
for clotting purposes.
Ultrasound
scan is done to see if there are any gross architectural abnormalities in the
liver. What cannot be captured by ultrasound can be done by CT scan and the
MRI. M.R.I has now become the gold standard in looking for abnormalities in the
liver and the surrounding organs when there is obstructive jaundice.
Endoscopy
may be performed to look at the oesophagus (food pipe), stomach and the first
few inches of the small intestine. A special variety of endoscope may also be
used wherein a dye can be injected into the bile ducts and the pancreatic ducts
and pictures can be taken. This gives complete visualisation of the pathway
that bile takes to drain into the small intestine. It also studies the ducts of
the pancreas. It is called E.R.C.P. (endoscopic retrograde cholangio
pancreaticogram).
What
is the diet recommended for jaundice patients?
Foods
that are rich in glucose are recommended in jaundice. These help the liver
cells to regenerate and also provide the required nourishment for the body.
Fats are to be taken in reduced quantities. Deep fried foods & alcohol are
to be avoided.
What
is the treatment for Jaundice?
The treatment for jaundice depends upon the
type of jaundice. For viral hepatitis, causing jaundice, there is no definitive
treatment. Only supportive measures are given. The virus is slowly eliminated
from the body with the help of the immune system.
In
case it is jaundice caused by blockage to the pathway of bile, surgery may be
needed.
What
is the role of immunisation in Jaundice?
Hepatitis
B is one of the common causes of jaundice that can have serious consequences.
Immunising a person can prevent this viral infection and its consequences. The
vaccine is easily available and is usually given in three doses either at
monthly intervals or two doses are given at monthly intervals and the third six
months after the first dose. Immunisation with the vaccine now begins from the
infant period itself. A single booster dose is required once every five years
to maintain the protection.
What
is the role of Herbs in treating Jaundice?
The
common herb used is Keezhanelli. Its role in treatment is not fully proven.
The
liver has a variety of functions. Its two main functions are synthesising and
detoxifying.
Synthesising:
It
helps to break down and store various nutrients like carbohydrates, proteins
and fat.
Whenever
there is excess glucose in the blood, it converts it to fat and stores it.
If
the blood glucose levels are low it breaks down fat and protein into glucose.
It
stores vitamins A, D, K , B12, Folate.
Liver
is responsible for a variety of protein syntheses. It helps in the synthesis of
substances for clotting of blood, as well as albumin (the most important
protein).
Detoxyfying
It
breaks down drugs, alcohol and poisons absorbed from the intestines.
It
is said that, “Liver failure is power failure.”
What
is the relation between alcohol and Liver disease?
The
liver takes up alcohol from the blood stream. (One of the main functions of the
liver is to clean up the blood of various poisons and the intestines from
invading organisms.) The liver breaks down alcohol (metabolises) and thus bears
the brunt of this poison. Intake of 3 units of alcohol or more in men and 2 or
more units in women for more than five years causes disease.
What
is cirrhosis of the liver?
Cirrhosis
of the liver is the end result of various insults on the liver. The insults
could be poisons or viruses. It is a process wherein the normal liver tissue is
replaced by non-functioning fibrous tissue. This alters the blood flow within
the liver causing other pathways to open thus resulting in various
complications.
What
are the complications of cirrhosis liver?
Complications
are:
Fluid
retention causing large and distended abdomen.
This
retention of fluids with a reduction in the synthesis of proteins can lead on
to swelling of the legs (Oedema).
There
can be Anaemia (low Haemoglobin) and susceptibility to infections.
The
blood flow through the liver could be blocked causing alternate pathways to
open up. This leads to dilatation of veins especially in the lower end of the
food pipe (oesophagus). These veins can rupture causing massive bleeding. The
liver can fail in its function of removing various poisons in the body causing
altered behaviour patterns and eventually coma and death.
Biochemistry
of Liver Function
In
the past, the liver has been referred to as the center of courage, passion,
temper, and love and even as the center of the soul. it was once believed to
produce "yellow bile" necessary for good health. Today, the liver is
a complex organ responsible for many major metabolic functions in the body.
More than 100 tests measuring these diverse functions have existed in the
clinical laboratory at one time. However, many were abandoned in favor of those
that have proven to be most clinically useful.
The
liver performs several hundred functions each day. These function can be
classified into the following:
1.Excretory
Function
2.
Synthetic Function
3.
Detoxification Function
1.
Excretory Function
One
of the more important liver functions, and one that is disturbed in a large
number of hepatic disorders, is the excretion of bile.
The
excretion of bile:
Bile
comprises bile salts, bile acids, bile pigments (primarily bilirubin),
cholesterol, and other substances extracted from the blood. Total bile production
averages about
Bile
acids: The primary bile acids are cholic acid and chenodcoxycholic acid. They
are formed in the liver from cholesterol. The bile acids are conjugated with
the amino acids glycine or taurine, forming bile salts. Bile salts (conjugated
bile acids) are excreted into the bile canaliculi by means of a carriermediated
active transport system. During fasting and between meals, a major portion of
the bile acid pool is concentrated up to 10-fold in the gallbladder. Bile acids
reach the intestine when the gallbladder contracts after each meal.
Approximately 500-600 mL of bile enter the duodenum each day.
Bile
salts help in the digestion and absorption of lipids. When the conjugated bile acids
(salts) come into contact with bacteria in the terminal ileum and colon,
dehydration to secondary bile acids (deoxycholic and lithocolic) occurs, and
these secondary bile acids are subsequently absorbed. The absorbed bile acids
enter the portal circulation and return to the liver, where they are
reconjugated and reexcreted. The enterohepatic circulation of bile occurs 2-5
times daily.
Bilirubin
is the principal pigment in bile. It is formed by the breakdown of hemoglobin
when red blood cells are phagocytized by the reticuloendothelial system. The
reticuloendothelial system is mainly in the spleen, liver, and bone marrow.
About 80% of the bilirubin formed daily comes from the degradation of
hemoglobin. The remainder comes from destruction of hemecontaining proteins
(myoglobin, cytochromes, catalase) and catabolism of heme. When hemoglobin is
destroyed, the protein portion -globin- is reused by the body. The iron enters
the body's iron stores and is also reused.
The
porphyrin ring is changed to biliverdin, which is easily reduced to bilirubin.
Bilirubin is transported to the liver in the bloodstream bound to albumin. This
bilirubin is referred to as unconjugated bilirubin or indirect bilirubin.
At
the liver, unconjugated bilirubin is separated from the albumin and taken up by
the hepatic cells. Two nonalbumin proteins, isolated from liver cell cytoplasm
and designated Y and Z, account for the intracellular binding and transport of
bilirubin. Conjugation of bilirubin occurs in the hepatocytes. An enzyme, uridyldiphosphate
glucuronyl transferase (UDPGT), transfers glucuronic acid molecules to
bilirubin, converting bilirubin into a diglucuronide ester. This product,
bilirubin diglucuronide, is referred to as conjugated bilirubin or direct
bilirubin. Conjugated bilirubin is water soluble. It is secreted from the
hepatic cell into the bile canaliculi and then into larger bile ducts and
eventually into the intestine. In the colon, the bile pigments are acted on by
enzymes of the intestinal bacteria. The first product of this reaction is
mesobilirubin, which is reduced to form mesobilirubinogen. This produces
urobilinogen which is a colorless product. The oxidation of urobilinogen
produces the red-brown pigment urobilin, which is excreted in the stool.
A
small portion of the urobilinogen is reabsorbed into the portal circulation and
returned to the liver, where it is again excreted with the bile into the
intestine. This is called enterohepatic circulation of bile pigments. However,
a small quantity of urobilinogen remains in the blood. This urobilinogen, which
is colorless, is ultimately filtered by the kidney and excreted in the urine.
A
total of 200-300 mg of bilirubin is produced daily in the healthy adult. A
normally functioning liver is required to eliminate this amount of bilirubin
from the body. This excretory function requires that bilirubin be in the
conjugated form; that is, the water-soluble diglucuronide. Almost all the
bilirubin formed is eliminated in the feces, and a small amount of the
colorless product urobilinogen is excreted in the urine.
Reference
Value of Bilirubins:
•
Total bilirubin 0.2 - 1.0 mg/dL
•
Direct (Conjugated) 0.0 - 0.2 mg/dL
•
Indirect (Unconjugated) 0.2 - 0.8 mg/dL
2.
Synthetic Function
The
liver is the main site of synthesis of:
Proteins:
The
liver plays an important role in production of albumin and the majority of the
α and β-globulins. All the blood-clotting factors (except VIII) are
synthesized in the liver. Deamination of glutamate in the liver is the primary
source of ammonia, which is converted to urea.
Carbohydrates:
The
synthesis and metabolism of carbohydrates is centered in the liver. Glucose is
converted to glycogen (Glycogenesis), a portion of which is stored in the liver
and later reconverted to glucose (Glycogenolysis) as necessary. An additional
important liver function is gluconeogenesis from amino acids.
Lipids:
Fat
is formed from carbohydrates in the liver (Lipogenesis) when nutrition is
adequate and the demand for glucose is being met from dietary sources. The
liver also plays a key role in the metabolism of fat. It is the major site for
the
-
removal of chylomicron remnants
-
the conversion of acetyl- CoA to fatty acids, triglycerides, and cholesterol.
-
metabolism of cholesterol into bile acids
-
Synthesis of Very-low-density lipoproteins
-
Synthesis of high-density lipoproteins
-
Synthesis of phospholipids.
The
formation of ketone bodies occurs in the liver. When the demand for
gluconeogenesis depletes oxaloacetate and acetyl-CoA cannot be converted
rapidly enough to citrate, acetyl-CoA accumulates and a ,decyclase in the liver
liberates ketone bodies into the blood .
The
liver is the storage site for all fat-soluble vitamins (A, D, E, and K) and
several water-soluble vitamins, such as B12. Another vitamin-related function
is the conversion of carotene into vitamin A.
The
liver is the source of somatomedin (an insulin-like factor that mediates the
activity of growth hormone) and angiotensinogen, and is a major site of
metabolic clearance of many other hormones. As the source of transferrin,
ceruloplasmin, and metallothionein, the liver plays a key role in the
transport, storage, and metabolism of iron, copper, and other metals .
Many
enzymes are synthesized by liver cells. Those enzymes that have been found useful
in the diagnosis of hepatobiliary disorders include aspartate amino transferase
(AST, or serum glutamic-oxaloacetic transaminase [SGOT]) and alanine amino
transferase (ALT, or serum glutamic pyruvic transaminase [SGPT]), alkaline
phosphatase (ALP) and 5'-nucleotidase (5NT), and γ-glutamyltransferase
(GGT).
3.
Detoxification Function
Because
the liver is interposed between the splanchnic circulation and the systemic
blood, it serves to protect the body from potentially injurious substances
absorbed from the intestinal tract and toxic by-products of metabolism.
The
most important mechanisms of detoxification includ oxidation, reduction,
hydrolysis, hydroxylation, carboxylation, and demethylation. Detoxification
mechanisms convert many toxic or insoluble compounds into less toxic or more
water-soluble compounds and, therefore, excretable by the kidney. For example,
ammonia, a toxic substance arising in the large intestine through bacterial
action on amino acids, is carried to the liver by the portal vein and converted
by hepatocytes into the innocuous compound urea.
Conjugation
with compounds, such as glycine, glucuronic acid, sulfuric acid, glutamine,
acetate, cysteine, and glutathione, occurs mainly in the cytosol. This
mechanism is the mode of bilirubin and bile acid excretion.