Biochemical functions of liver. Metabolism of
porphyrins: metabolism of bile pigments, biochemistry of jaundices. Biotransformation of
xenobiotics and endogenous toxins in the liver: microsomal oxidation, cytochrome Ð-450.
Urine formation function of
kidney. Physical-chemical properties and chemical composition of normal urine.
Pathobiochemistry of kidney.
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 glicogen. Content in the liver –
70-100g. After eating amount of glicogen in the liver increase up to 150g.
After 24 hours of starvation content of glicogen 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 glicogen 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.
ransport 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. The major protein of HDL is apo A.
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 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.
Kidney – the couple organ, which is responsible for
excriting of final products of metabolism and for homeostasis. They regulate
water and mineral metabolism, acid-base balance, excriting of nitrogenous
slags, osmotic pressure. Also they regulate arterial pressure and
erhythropoesis.
Kidney
functions in organism:
a)
excretion of final metabolic products;
b)
maintaining of acid-base balance;
c)
water-salts balance regulation;
d)
endocrine function.(The
kidneys secrete a variety of hormones, including erythropoietin,
and the enzyme renin. Erythropoietin is
released in response to hypoxia (low
levels of oxygen at tissue level) in the renal circulation. It stimulates erythropoiesis (production
of red blood cells) in the bone marrow. Calcitriol,
the activated form of vitamin D, promotes intestinal absorption
of calcium and
the renalreabsorption of phosphate.
Part of the renin-angiotensin-aldosterone system,
renin is an enzyme involved
in the regulation of aldosterone levels.)
The
kidney participates in whole-body homeostasis,
regulating acid-base balance, electrolyte concentrations, extracellular fluid volume,
and regulation of blood pressure. The kidney
accomplishes these homeostatic functions both independently and in concert with
other organs, particularly those of the endocrine
system. Various endocrine hormones coordinate these endocrine
functions; these include renin, angiotensin
II, aldosterone, antidiuretic hormone,
and atrial natriuretic peptide,
among others.
Many of
the kidney's functions are accomplished by relatively simple mechanisms of
filtration, reabsorption, and secretion, which take place in the nephron.
Filtration, which takes place at therenal
corpuscle, is the process by which cells and large proteins
are filtered from the blood to make an ultrafiltrate that eventually becomes
urine. The kidney generates
http://www.youtube.com/watch?v=6x5pVoMb_vI&feature=related
Physical and chemical
characteristics and components of urine:
a)
volume, physical and chemical properties of urine;
b)
inorganic components of urine;
c)
organic components of urine.
Key words and phrases:
http://www.youtube.com/watch?v=glu0dzK4dbU
Nephron – is the structural and functional unit of kidney.
Urine – fluid with different organic and inorganic
compouds, which must be excreted (excess of water, final products of nitrogen
metabolism, xenobiotics, products of protein’s decay, hormones, vitamins and
their derivates). Most of them present in urine in a bigger amount than in
blood plasma. So, urine formation – is not passive process (filtration and
diffusion only).
In basis of urine formation
lay 3 processes: filtration, reabsorbtion and secretion.
Glomerulal filtration.
Water and low weight molecules go to the urine with help of following powers:
blood hydrostatic pressure in glomerulas (near
Hydrostatic
pressure depends from correlation between opening of a. afference and a.
efference.
Primary
urine formed in result of filtration (about
For
evaluate of filtration used clearance
(clearance for some substance – it is a amount of blood plasma in ml, which is
cleaned from this substance after 1 minute passing through kidney).
Drugs
which stimulate blood circulation in kidney (theophyllin), also stimulate
filtration. Inflammatory processes of renal tissue (nephritis) reduce
filtration, and azotaemia occurred (accumulation of urea, uric acid, creatinin,
and other metabolic final products).
Reabsorbtion.
Lenght of renal tubules is about
All
substances can be divided into 3 group:
1.
Actively reabsorbed substances.
2.
Substances, which are reabsorbed in a little amount.
3.
Non-reabsorbed substances.
To
the first group belong Na+, Cl-, Mg2+, Ca2+,
H2O, glucose and other monosaccharides, amino acids, inorganic phosphates,
hydrocarbonates, low-weight proteins, etc.
Na+
reabsorbed by active transport to the epitelium cell, then – into the
extracellular matrix. Cl- and HCO3- following
Na+ according to the electroneutrality principle, water – according to
the osmotic gradient. From extracellular matrix substances go to the blood
vessels. Mg2+ and Ca2+ are reabsorbed with help of
special transport ATPases. Glucose and amino acids use the energy of Na+
gradient and special carriers. Proteins are reabsorbed by endocytosis.
Urea
and uric acid are little reabsorbable substances.
Creatinin,
mannitol, inulin and some other substances are non-reabsorbable.
Henle’s
loop play important role in the reabsobtion process. Its descendent and
ascendent parts create anti-stream system, which has big capacity for urine
concentration and dilution. Fluid which passes from proximal part of renal
tubule to the descendent part of Henle’s loop, where concentration of osmotic
active substances higher than in kidney cortex. This concentration is due to
activity of thick ascendent part of Henle’s loop, which is non-penetrated for
water and which cells transport Na+ and Cl- into the
interstitium. Wall of descendent part is penetrated for water and here water
pass into the interstitium by osmotic gradient but osmotic active substances
stay in the tubule. Ascendent part continue to reabsorb salt hypertonically,
even in the absence of aldosteron, so that fluid entering the distal tubule
still has a much lower osmolality than does interstitial fluid.
The kidney is responsible for maintaining a balance of
the following substances:
Substance |
Description |
||||
If glucose is not reabsorbed by the kidney, it
appears in the urine, in a condition known as glycosuria.
This is associated
with diabetes mellitus.[3] |
reabsorption (almost 100%) viasodium-glucose transport proteins(apical)
and GLUT (basolateral). |
– |
– |
– |
|
All are reabsorbed nearly completely.[5] |
reabsorption |
– |
– |
– |
|
Regulation of osmolality.
Varies with ADH[6][7] |
reabsorption
(50%) via passive transport |
secretion |
– |
reabsorption in medullary collecting ducts |
|
Uses Na-H antiport,
Na-glucose symport, sodium ion channels (minor)[8] |
reabsorption
(65%, isosmotic) |
reabsorption (25%, thick ascending, Na-K-2Cl symporter) |
reabsorption
(5%, sodium-chloride symporter) |
reabsorption (5%, principal cells), stimulated by aldosterone via ENaC |
|
Usually follows sodium.
Active (transcellular) and passive (paracellular)[8] |
reabsorption |
reabsorption (thin ascending, thick ascending, Na-K-2Cl symporter) |
reabsorption
(sodium-chloride symporter) |
– |
|
absorbed osmotically along with solutes |
reabsorption
(descending) |
– |
reabsorption (regulated by ADH, via arginine vasopressin receptor 2) |
||
Helps maintain acid-base balance.[9] |
reabsorption
(80–90%) [10] |
reabsorption
(thick ascending) [11] |
– |
||
Uses vacuolar H+ATPase |
– |
– |
– |
secretion
(intercalated cells) |
|
Varies upon
dietary needs. |
reabsorption
(65%) |
reabsorption (20%, thick ascending, Na-K-2Cl symporter) |
– |
secretion (common, via Na+/K+-ATPase,
increased by aldosterone),
or reabsorption (rare, hydrogen potassium ATPase) |
|
reabsorption |
reabsorption (thick ascending) via passive transport |
– |
– |
||
Calcium and magnesium compete, and an excess of one
can lead to excretion of the other. |
reabsorption |
reabsorption
(thick ascending) |
reabsorption |
– |
|
Excreted as titratable acid. |
reabsorption (85%) viasodium/phosphate cotransporter.[4]Inhibited
by parathyroid hormone. |
– |
– |
– |
|
|
reabsorption
(100%[12]) viacarboxylate transporters. |
– |
– |
– |
The body
is very sensitive to its pH.
Outside the range of pH that is compatible with life, proteins are denatured
and digested, enzymes lose their ability to function, and the body is unable to
sustain itself. The kidneys maintain acid-base homeostasis by
regulating the pH of the blood
plasma. Gains and losses of acid and base must be balanced.
Acids are divided into "volatile acids" and "nonvolatile
acids".[14] See
also titratable acid.
The major homeostatic control
point for maintaining this stable balance is renal excretion. The kidney is
directed to excrete or retain sodium via the action of aldosterone, antidiuretic hormone(ADH,
or vasopressin), atrial natriuretic peptide (ANP),
and other hormones. Abnormal ranges of the fractional excretion of sodium can
imply acute tubular necrosis or glomerular dysfunction.
Some
substances (K+, ammonia and other) are secreted into urine in the distal part of tubules. K+ is
changed to Na+ by the activity of Na+-K+ATPase.
Renin-Angiotensin mechanism
The renin–angiotensin
system (RAS) or the renin–angiotensin–aldosterone system (RAAS)
is a hormone system that
regulates blood pressure and water (fluid) balance.
When blood volume is low, juxtaglomerular cells in the
kidneys secrete renin directly
into circulation. Plasma renin then carries out the
conversion of angiotensinogen released by
the liver to angiotensin I.
Angiotensin
I is subsequently converted to angiotensin
II by the enzyme angiotensin converting enzyme found
in the lungs. Angiotensin II is a potent vaso-active peptide that causes blood
vessels to constrict, resulting in increased blood pressure. Angiotensin II
also stimulates the secretion of the hormone aldosterone from
the adrenal cortex. Aldosterone causes
the tubules of the kidneys to increase the reabsorption of sodium and water
into the blood. This increases the volume of fluid in the body, which also
increases blood pressure.
If the
renin–angiotensin–aldosterone system is abnormally active, blood pressure will
be too high. There are many drugs that interrupt different steps in this system
to lower blood pressure. These drugs are one of the main ways to control high
blood pressure (hypertension), heart
failure,kidney failure, and harmful effects
of diabetes.
The
system can be activated when there is a loss of blood volume or a drop in blood
pressure (such as in hemorrhage).
This loss of pressure is interpreted by baroreceptors in
the carotid sinus. In alternative fashion,
a decrease in the filtrate NaCl concentration and/or decreased filtrate flow
rate will stimulate the macula densa to signal the juxtaglomerular cells to
release renin.
·
If the perfusion of the juxtaglomerular apparatus in
the kidney's macula densa decreases, then
the juxtaglomerular cells (granular cells, modified pericytes in the glomerular
capillary) release the enzyme renin.
·
Renin cleaves a zymogen,
an inactive peptide,
called angiotensinogen, converting it
into angiotensin
I.
·
Angiotensin I is then converted to angiotensin
II by angiotensin-converting enzyme (ACE),[5] which
is thought to be found mainly in lung capillaries.
One study in 1992 found ACE in all blood vessel endothelial cells.[6]
·
Angiotensin II is the major bioactive
product of the renin-angiotensin system, binding to receptors on intraglomerular mesangial cells,
causing these cells to contract along with the blood vessels surrounding them
and causing the release of aldosterone from
the zona glomerulosa in the adrenal
cortex. Angiotensin II acts as an endocrine, autocrine/paracrine,
and intracrinehormone.
Cardiovascular
effects
It is believed that
angiotensin I may have some minor activity, but angiotensin II is the major
bio-active product. Angiotensin II has a variety of effects on the body:
·
Throughout the body, it is a potent vasoconstrictor of arterioles.
·
In the kidneys, it constricts glomerular arterioles,
having a greater effect on efferent arterioles than
afferent. As with most other capillary beds in the body, the constriction of afferent arterioles increases
the arteriolar resistance, raising systemic arterial blood pressure and
decreasing the blood flow. However, the kidneys must continue to filter enough
blood despite this drop in blood flow, necessitating mechanisms to keep
glomerular blood pressure up. To do this, angiotensin II constricts efferent
arterioles, which forces blood to build up in the glomerulus, increasing
glomerular pressure. The glomerular filtration rate(GFR)
is thus maintained, and blood filtration can continue despite lowered overall
kidney blood flow. Because the filtration fraction has increased, there is less
plasma fluid in the downstream peritubular capillaries. This in turn leads to a
decreased hydrostatic pressure and increased oncotic pressure (due to
unfiltered plasma proteins) in the peritubular capillaries. The effect of
decreased hydrostatic pressure and increased oncotic pressure in the
peritubular capillaries will facilitate increased reabsorption of tubular
fluid.
·
Angiotensin II decreases medullary blood
flow through the vasa recta. This decreases the washout of NaCl and urea in the
kidney medullary space. Thus, higher concentrations of NaCl and urea in the
medulla facilitate increased absorption of tubular fluid. Furthermore,
increased reabsorption of fluid into the medulla will increase passive
reabsorption of sodium along the thick ascending limb of the loop of Henle.
·
Angiotensin II stimulates Na+/H+ exchangers
located on the apical membranes (faces the tubular lumen) of cells in the
proximal tubule and thick ascending limb of the loop of Henle in addition to Na+ channels
in the collecting ducts. This will ultimately lead to increased sodium
reabsorption
·
Angiotensin II stimulates the
hypertrophy of renal tubule cells, leading to further sodium reabsorption.
·
In the adrenal
cortex, it acts to cause the release of aldosterone.
Aldosterone acts on the tubules (e.g., the distal convoluted tubules and
the cortical collecting
ducts) in the kidneys, causing them to reabsorb more sodium and
water from the urine. This increases blood volume and, therefore, increases blood
pressure. In exchange for the reabsorbing of sodium to blood, potassiumis
secreted into the tubules, becomes part of urine and is excreted.
·
Release of anti-diuretic hormone (ADH), also
called vasopressin – ADH is made in
the hypothalamus and released from the posterior pituitary
gland. As its name suggests, it also exhibits
vaso-constrictive properties, but its main course of action is to stimulate
reabsorption of water in the kidneys. ADH also acts on the central nervous system to
increase an individual's appetite for salt, and to stimulate the sensation of thirst.
These effects directly act in concert to increase blood pressure.
Locally
expressed renin-angiotensin systems have been found in a number of tissues,
including the kidneys, adrenal
glands, the heart, vasculature and nervous
system, and have a variety of functions, including local
cardiovascular regulation, in association or independently of the systemic
renin-angiotensin system, as well as non-cardiovascular functions. Outside
the kidneys, renin is predominantly picked up from the circulation but may be
secreted locally in some tissues; its precursor prorenin is highly expressed in
tissues and more than half of circulating prorenin is of extrarenal origin, but
its physiological role besides serving as precursor to renin is still
unclear.Outside the liver, angiotensinogen is picked up from the circulation or
expressed locally in some tissues; with renin they form angiotensin I, and
locally expressed angiotensin converting enzyme, chymase or
other enzymes can transform it into angiotensin II. This process can be
intracellular or interstitial.
In the adrenal
glands, it is likely involved in the paracrine regulation
of aldosterone secretion,
in the heart and vasculature, it may be involved in remodeling or vascular
tone, and in the brain where
it is largely independent of the circulatory RAS, it may be involved in local
blood pressure regulation. In addition, both the central and peripheral nervous
systems can use angiotensin for sympathetic neurotransmision. Other places
of expression include the reproductive system, the skin and digestive organs.
Medications aimed at the systemic system may affect the expression of those
local systems, beneficially or adversely.[
|
Peculiarities of biochemical processes in kidney.
Kidney
have a very high level of metabolic processes. They use about 10 % of all O2,
which used in organism. During 24 hours through kidney pass 700-
Metabolism
of proteins also present in kidney in high level. Especially, glutamine deaminase
is very active and a lot of free ammonia formed. In kidney take place the first
reaction of creatin synthesis.
Kidney
have plenty of different enzymes: LDG (1, 2, 3, 5), AsAT, AlAT. Specific for
kidney is alanine amino peptidase, 3rd isoform.
Utilization
of glucose in cortex and medulla is differ one from another. Dominative type of
glycolysis in cortex is aerobic way and CO2 formed in result. In
medulla dominative type is anaerobic and glucose converted to lactate.
Two
sources contribute to the renal ammonia: blood ammonia (is about one-third of
excreted ammonia), and ammonia formed in the kidney. The predominant source for
ammonia production within the kidney is glutamine, the most abundant amino acid
in plasma, but a small amount may
originate from the metabolism of other amino acids such as asparagine, alanine,
and histidine. Ammonia is secreted into the tubular lumen throughout the entire
length of the nephron. Secretion occurs both during normal acid-base balance
and in chronic acidosis.Metabolic acidosis is accompanied by an adaptive
increase in renal ammonia production with a corresponding increase in urinary
ammonium excretion.
Kidney
cortex like liver appear to be unique in that it possess the enzymatic
potential for both glucose synthesis from noncarbohydrate precursors
(gluconeogenesis) and glucose degradation via the glycolytic pathway.
Gluconeogenesis is important when the dietary supply of glucose does not
satisfy the metabolic demands. Under these conditions, glucose is required by the
central nervous system, the red blood cells, and possibly other tissues which
cannot obtain all their energy requirements from fatty acids or ketone body
oxidation. Also, gluconeogenesis may be important in the removal of excessive
quantities of glucose precursors from the blood (lactate acid after severe
exercise for example). Although the biosynthetic pathways are similar, there
are several important differences in the factors which regulate gluconeogenesis
in the two organs. 1) The liver utilizes predominately pyruvate, lactate and
alanine. The kidney cortex utilizes pyruvate, lactate, citrate,
α-ketoglutarate, glycine and glutamine. 2) Hydrogen ion activity has
little effect upon hepatic gluconeogenesis, but it has marked effects upon
renal gluconeogenesis. Thus, when intracellular fluid pH is reduced (metabolic
acidosis, respiratory acidosis or potassium depletion), the rates of
gluconeogenesis in slices of renal cortex are markedly increased. The ability
of the kidney to convert certain organic acids to glucose, a neutral substance,
is an example of a nonexcretory mechanism in the kidney for pH regulation.
Regulation of urine formation.
Na-uretic
hormone (produced in heart) decrease reabsorbtion of Na+, and
quantity of urine increased.
Aldosteron
and some other hormones (vasopressin, renin, angiotensin II) increase
Na-reabsorbtion and decrease quantity of
urine.
Role of kidney in acid-base balance regulation.
The kidneys have
two important roles in the maintaining of the acid-base balance: to reabsorb
bicarbonate from and to excrete hydrogen ions into urine. 4500 mmol of
bicarbonate are filtered into the primary filtrate of urine daily, but only 2
mmol of it are finally excreted. 70-80% of bicarbonate is reabsorbed in the
first part of proximal tubule, 10-20% in the loop of Henle and 5-10% in the
distal tubule and collecting ducts. (Jalanko & Holmberg 1998)
Carbonic
anhydrase plays an important role in the reabsorption in the proximal tubule.
Disturbance in the reabsorption of bicarbonate in the proximal tubule leads to
metabolic acidosis, hyperchloremia and alkalotic urine. This disease is named
as "type II renal tubular acidosis" (N25.8). (Jalanko & Holmberg
1998)
Renal tubules
actively secrete hydrogen ions. Most of this takes place in the distal part of
the nephron, but active transport of hydrogen ions occurs in the proximal
tubule, too. The H-ATPase of the apical cell membrane secretes hydrogen ions
into urine. For each hydrogen ion secreted, one bicarbonate molecule is
transported to the interstitial fluid, from there it diffuses into the
bloodstream. Fifty mmol of hydrogen ions are normally excreted daily. (Jalanko
& Holmberg 1998)
If the hydrogen
ions are not properly secreted into the collecting ducts, the result is
metabolic acidosis, hypokalemia, hypocalcemia, nephrocalcinosis and an
alkalotic urine. This disease is called "type I renal tubular
acidosis" (N25.8). (Jalanko & Holmberg 1998)
The maximal
hydrogen ion gradient, against which the transport mechanism can secrete H+ ions,
corresponds to a urine pH of
The source of
the hydrogen ions secreted by the tubular cells is not completely certain. It
is probably produced by dissociation of H2CO3. The
acid-secreting cells contain carbonic anhydrase, which facilitates the rapid
formation of H2CO3 from CO2 and
water. The renal acid secretion is mainly regulated by the changes in the
intracellular pCO2, potassium concentration, carbonic anhydrase
activity and adrenocortical hormone concentration. (Ganong 1991)
Kidney
have some mechanisms for maintaining acid-base balance. Na+
reabsorbtion and H+ secretion play very important role.
1.
Primary urine has a lot of Na2HPO4 (in dissociated form).
When Na+ reabsorbed, H+ secreted into urine and NaH2PO4
formed.
2.
Formation of hydrocarbonates. Inside renal cells carboanhydrase forms from CO2
and H2O H2CO3, which dissociated to H+
and HCO3-. H+ excreted from cell into urine (antiport
with Na+) and leaded with urine. Na+ connect with HCO3-,
NaHCO3 formed and go to the blood, thereupon acidity decreased.
3.
Formation of free ammonia. NH3 used for formation of NH4+
(H+ ion associted), and different acid metabolites excreted as
ammonia salts.
Physical and chemical
characteristics of urine.
Urine amount (diures) in healthy people is 1000-2000
ml per day. Day-time diures is in 3-4 times more than night-time.
Normal colour of urine is yellow (like hay or
amber), what is due to presence of urochrom (derivate of urobilin or
urobilinogen). Some another colour substances are uroerythrin (derivate of
melanine), uroporphyrines, rybophlavine and other. Colour depends from urine
concentration.
Urine varies in appearance, depending principally upon a body's level of hydration, as well as other factors. Normal
urine is a transparent solution ranging from colorless to amber but is usually
a pale yellow. In the urine of a healthy individual the color comes primarily
from the presence of urobilin.
Urobilin in turn is a final waste product resulting from the breakdown of heme from hemoglobin during the destruction of aging blood
cells.
Colorless urine indicates over-hydration, generally preferable to
dehydration (though it can remove essential salts from the body). Colorless
urine in drug tests can suggest an attempt to avoid detection of illicit drugs
in the bloodstream through over-hydration.
·
Dark yellow urine is often indicative of
dehydration.
·
Yellowing/light orange may be caused by
removal of excess B vitamins from the bloodstream.
·
Certain medications such as rifampin and phenazopyridine can cause orange urine.
·
Bloody urine is termed hematuria,
a symptom of a wide variety of medical conditions
·
Dark orange to brown urine can be a
symptom of jaundice, rhabdomyolysis, or Gilbert's
syndrome.
·
Black or dark-colored urine is referred
to as melanuria and may be caused by a melanoma.
·
Pinkish urine can result from the
consumption of beets.
·
Greenish urine can result from the
consumption of asparagus.
·
Reddish or brown urine may be caused by porphyria (not to be confused with the harmless,
temporary pink or reddish tint caused by beeturia).
·
Blue urine can be caused by the
ingestion of methylene blue, e.g. in medications
·
Blue urine stains can be caused by blue diaper
syndrome
Urine is transparent. This characteristic depends
from amount of different salts (oxalates, urates, phosphates), amount of
present epitelium cells and leucocytes.
Density of urine depends from concentration of soluble
substances. Borders of variation are from 1002 to 1035 g/l. Near 60-
The pH of urine can vary between 4.6 and 8,
with neutral (7) being norm. In persons with hyperuricosuria, acidic urine can
contribute to the formation of stones of uric acid in
the kidneys, ureters, or bladder. Urine pH can be monitored by a physician or at home.
A diet high in citrus, vegetables, or dairy can increase urine pH (more basic).
Some drugs also can increase urine pH, including acetazolamide, potassium
citrate, and sodium bicarbonate.
A diet high in meat can decrease urine pH (more acidic). Cranberries, popularly thought to
decrease the pH of urine, have actually been shown not to acidify urine. Drugs that can decrease urine pH
include ammonium chloride, chlorothiazide
diuretics, and methenamine mandelate.[14][15]
In normal conditions urine has acid or weak acid
reaction (pH=5,3-6,8). This depends from presence of NaH2PO4
and KH2PO4.
Fresh urine has a specific smell, which is due to
presence of flying acids. But a lot of microorganisms, which are present in
urine, split urea and free ammonia formed.
Exhaustive detailed description of the composition of human urine can be found
in NASA Contractor Report No. NASA CR-1802, D. F. Putnam, July 1971. That report provided detailed chemical
analyses for inorganic and organic constituents, methods of analysis, chemical
and physical properties and its behavior during concentrative processes such as
evaporation, distillation and other physiochemical operations. Urine is an
aqueous solution of greater than 95% water, with the remaining constituents, in
order of decreasing concentration urea 9.3 g/L, chloride 1.87 g/L, sodium 1.17 g/L, potassium 0.750 g/L, creatinine 0.670 g/L and other dissolved ions,
inorganic and organic compounds.
Urine is sterile until it reaches the urethra, where epithelial cells lining the urethra are colonized by facultatively
anaerobic Gram negative
rods and cocci. Subsequent to elimination from the body, urine can
acquire strong odors due to bacterial action, and in particular the release of ammonia from the breakdown of urea.
Some diseases
alter the quantity and consistency of urine, such as diabetes introducing sugar.
Consuming beets can result in beeturia (pink/red urine containing betanin)
for some 10–14% of the popu Urine is a liquid produced by the kidneys to remove
waste products from the bloodstream. Human urine is yellowish in color and
variable in chemical composition, but here is a list of its primary components.
Human urine consists primarily of
water, with organic solutes including urea, creatinine, uric acid, and trace
amounts of enzymes, carbohydrates, hormones, fatty acids, pigments, and mucins,
and inorganic ions such as sodium (Na+), potassium (K+),
chloride (Cl-), magnesium (Mg2+), calcium (Ca2+),
ammonium (NH4+), sulfates (SO42-),
and phosphates (e.g., PO43-). A representative chemical
composition would be:
water 95%
urea 9.3 g/l
chloride 1.87 g/l
sodium 1.17 g/l
potassium 0.750 g/l
creatinine 0.670 g/l
Organic compounds of urine.
Proteins.
Healthy people excretes 30 mg of proteins per day. As a rule these are low
weight proteins.
Urea.
This is main part of organic compounds in urine. Urea nitrogen is about 80-90 %
of all urine nitrogen. 20-
Uric
acid. Approximately 0,6-1,0 g of uric acid is excreted
per day in form of different salts (urates), mainly in form of sodium salt. Its
amount depends from food.
Creatinin
and creatin. Near 1-
Amino
acids. Per day healthy person excretes 2-
Couple
substances. Hypuric acid (benzoyl glycine) is excreted in
amount 0,6-
Indican
(potassium salt of indoxylsulfuric acid). Per day
excrition of indican is about 10-
Organic
acids. Formic, acetic, butyric, β-oxybutyric,
acetoacetic and some other organic acids are present in urine in a little
amount.
Vitamines.
Almost all vitamines can be excreted via kidney, especially, water-soluble.
Approximately 20-30 mg of vit C, 0.1-0.3 mg of vit B1, 0.5-0.8
mg of vit B2 and some products of vitamine’s metabolism. These data
can be used for evaluating of supplying our organism by vitamines.
Hormones.
Hormones and their derivates are always present in urine. Their amount depends
from functional state of endocrinal glands and liver. There is a very wide used
test – determination of 17-ketosteroids in urine. For healthy man this index is
15-
Urobilin.
Present in a little amount, gives to urine yellow colour.
Bilirubin.
In normal conditions present in so little amount that cannot be found by
routine methods of investigations.
Glucose.
In normal conditions present in so little amount that cannot be found by
routine methods of investigations.
Galactose.
Present in the newborn’s urine, when digestion of milk or transformation of
glalactose into glucose in the liver are violated.
Fructose.
It is present in urine very seldom, after eating a lot of fruits, berries and
honey. In all other cases it indicates about
liver’s disorders, diabetes mellitus.
Pentoses.
Pentoses are excreted after eating a lot of fruits, fruit juices, in case of
diabetes mellitus and steroid diabetes, some intoxications.
Ketone
bodies. In normal conditions urine contains 20-50 mg of
ketone bodies and this amount cannot be found by routine methods of clinical
investigations.
Porphyrines.
Urine of healthy people contains a few I type porphyrines (up to 300 mkg per
day).
Inorganic
compounds of urine.
Urine of healthy people contains 15-
NaCl.
Per day near 8-
Potassium.
Twenty-four hours urine contains 2-
Different drugs can change excretion of Na and K.
For example, salicylates and cortikosteroids keep Na and amplify excretion of
K.
Calcium.
Twenty-four hours urine contains 0.1-
Magnesium.
Content of magnesium in urine is 0.03-
Iron.
Amount of iron in urine is about 1 mg per day.
Phosphorus.
In urine are present one-substituted phosphates of potassium and sodium. Their
amount depends from blood pH. In case of acidosis two-substituted phosphates
(Na2HPO4) react with H+ and one-substituted
phosphates (NaH2PO4) formed. In case of alkalosis
one-substituted phosphates react with bases and two-substituted phosphates
formed. So, in both cases amount of phosphates in urine increases.
Sulfur.
Amount of sulfur in twenty-four hours urine is 2-
Ammonia.
Ammonia is excreted in ammonium sulfates and couple substances. Ammonium salts
make up 3-6 % of all nitrogen in urine. Their amount depends from
character of food and blood pH.
Urine
analysis infers valuable information in a variety of
ailments. Physical characteristics of urine have been used as
diagnostic and prognostic tool from the time immemorial by the health
physicians. We know that the major functions of kidneys are:
·
Removal of water not needed by the body
fluids, the amount depending on the balance between glomerular filtrate and he
degree of tubular reabsorption;
·
The excretion of certain substances
normally present in the plasma when their concentration rises above a certain
level;
·
The selective reabsorption of substances
such as glucose which are of value to the body;
·
The excretion of useless substances; and
·
Regulation of acid base balance.
Disordered
renal function may lead to a change in the volume of the
urine excreted per day along with remarkable changes in its physical and
chemical properties and microscopic contents. Urine analysis is
the very first investigation of diagnostic importance not only in renal
disorders but also in other diseases like diabetes, liver disease, jaundice
etc. In diagnostic pathology the extent of abnormalities could only be
understood in comparison with the reference values obtained from similar
investigations in normal individuals. Hence, it is important to have an
understanding of normal parameters of physical and
chemical characteristics of urine.
Characteristics
of normal urine:
·
Quantity: The
quantity averages 1500 to 2000 ml in an adult man daily. It may vary with the
amount of fluid taken. In fact it is linked with the protein metabolism; higher
is the protein intake higher will be the urinary output since the urea produced
from the protein needs to be flushed out from the body. Higher is the urea
production in the body, the higher is the volume of urine to excrete it.
·
Color: The color
should be clear pale amber without any deposits. However, a light flocculent
cloud of mucus may sometimes be seen floating in the normal urine.
·
Specific gravity: It
varies from 1.010 to 1.025. Specific gravity is determined with urinometer.
·
Odor: The odor
is aromatic.
·
Reaction: The
reaction of normal urine is slightly acidic with an average pH of 6.0.
Composition
of normal urine: Urine is mainly composed of water, urea
and sodium chloride. I an adult taking about
·
Water: Near about 96%
·
Solids: About 4%
(urea 2% and other metabolic products 2%. Other metabolic products include: uric
acid, creatinine, electrolytes or salts such as sodium chloride, potassium
chloride and bicarbonate).
§
Urea is one of
the end products of protein metabolism. It is prepared from the deaminated
amino-acid in the liver and reach the kidneys through blood
circulation (The normal blood urea level is 20-40 mg/dl). About
§
Uric Acid: The normal
level of uric acid in blood is 2 to 6 mg/dl and about 1.5 to
§
Creatinine: Creatinine
is the metabolic waste of creatin in muscle. Purine bodies, oxalates,
phosphates, sulphates and urates are the other metabolic products.
§
Electrolytes or salts such
as sodium chloride and potassium chloride are also excreted in the urine to
maintain the normal level in blood. These are the salts which are the part of
our daily diet and are always taken in excess and need to be excreted to
maintain normal physiological balance.
Proteinuria may be a sign of renal (kidney)
damage. Since serum proteins are readily reabsorbed from urine, the presence of
excess protein indicates either an insufficiency of absorption or impaired
filtration. Diabetics may suffer from damaged nephrons and develop proteinuria. The most common
cause of proteinuria is diabetes, and in any person with proteinuria and
diabetes, the etiology of the underlying proteinuria should be separated into
two categories: diabetic proteinuria versus the field.
With severe
proteinuria, general hypoproteinemia can develop
which results in diminished oncotic pressure.
Symptoms of diminished oncotic pressure may include ascites, edema andhydrothorax.
Conditions with proteinuria as a sign
Proteinuria may be a feature of the following conditions:
·
Nephrotic
syndromes (i.e.
intrinsic renal failure)
·
Toxic lesions of kidneys
·
Amyloidosis
·
Collagen vascular diseases (e.g.
systemic lupus
erythematosus)
·
Dehydration
·
Glomerular diseases, such as membranous
glomerulonephritis, focal segmental glomerulonephritis,
minimal change disease (lipoid nephrosis)
·
Strenuous exercise
·
Stress
·
Benign orthostatic (postural)
proteinuria
·
Focal
segmental glomerulosclerosis (FSGS)
·
IgA nephropathy (i.e. Berger's disease)
·
Membranoproliferative
glomerulonephritis
·
Diabetes mellitus (diabetic
nephropathy)
·
Drugs (e.g. NSAIDs, nicotine, penicillamine, lithium carbonate, gold and other heavy metals, ACE inhibitors, antibiotics, or opiates (especially heroin)[16]
·
Infections (e.g. HIV, syphilis, hepatitis,
poststreptococcal infection, urinary schistosomiasis)
·
Hypertensive
nephrosclerosis
·
Organ rejection: Kidney transplant patients
may have gamma-globulins in their urine if the kidneys start to reject.[17]
·
Familial
Mediterranean fever
·
Systemic
lupus erythematosus
·
Rheumatoid arthritis
·
Glycogen
storage disease type 1[18]
·
A urinary tract infection which has
spread to the kidney(s)
This list is incomplete;
you can help by expanding it.
·
Waldenstrom's
macroglobulinemia
·
Chronic
lymphocytic leukemia
·
Malignancies (e.g., lymphoma, other
cancers)
There are three main
mechanisms to cause proteinuria:
·
Due to disease in glomerulus
·
Because of increased quantity of
proteins in serum (overflow
proteinuria)
·
Due to low reabsorption at proximal tubule (Fanconi syndrome)
Proteinuria can also be caused by certain biological agents, such as bevacizumab (Avastin) used in cancer treatment, or
by excessive fluid intake (drinking in excess of
Glucosuria is the excretion of glucose into the urine.
Ordinarily, urine contains no glucose because the kidneys are able to reclaim
all of the filtered glucose back into the bloodstream. Glycosuria is nearly
always caused by elevated blood glucose levels, most commonly due to untreated diabetes mellitus. Rarely, glycosuria is
due to an intrinsic problem with glucose reabsorption within the kidneys
themselves, a condition termed renal glycosuria. Glycosuria leads to
excessive water loss into the urine with resultant dehydration, a process
called osmotic diuresis.
Glycosuria refers to sugar in the urine. Less than 0.1% of
glucose normally filtered by the glomeruli appears in the urine, and less than
130 mg should appear in the urine over a 24-hour period. Glucose is present in
glomerular filtrate but is reabsorbed by the kidney's proximal tubule. If the
blood glucose level exceeds the capacity of the tubules to reabsorb all the
glucose present in the glomerular filtrate, the renal threshold is reached and
glucose spills into the urine. A finding of glycosuria indicates that the
person is hyperglycemic or has a lowered renal threshold for glucose. The renal
threshold for glucose is approximately 160 to 190mg/dl of blood; glucose does
not appear in the urine until the blood glucose rises above this level.
Occasionally,
glycosuria may be a normal finding, such as after eating a heavy meal or during
times of emotional stress. Some individuals have a benign condition in which
they have a lower than usual renal threshold for glucose, but have normal blood
glucose levels. In pregnancy, the renal threshold for glucose may be lowered so
that small amounts of glycosuria may be present. Patients on hyperalimentation
may have glycosuria if the carbohydrate solution is being infused faster than
the pancreas can produce insulin. The most common reason for glycosuria is
diabetes mellitus. Urine glucose tests are used to screen for diabetes, to
confirm a diagnosis of diabetes, or to monitor diabetic control.
Renal glycosuria, also known as renal
glucosuria, is a rare condition in which the simple sugar
glucose is excreted in the urine despite
normal or low blood glucose levels. With normal kidney (renal) function,
glucose is excreted in the urine only when there are abnormally elevated levels
of glucose in the blood. However, in those with renal glycosuria, glucose is
abnormally elevated in the urine due to improper functioning of the renal
tubules, which are primary components of nephrons, the filtering
units of the kidneys.
Hematuria, or haematuria, is the presence
of red blood cells
(erythrocytes) in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a
kidney stone or a tumor
in the urinary tract (kidneys, ureters, urinary bladder, prostate, and urethra), ranging from trivial to lethal.
If white blood cells
are found in addition to red blood cells, then it is a signal of urinary tract
infection.
Microscopic hematuria
Occasionally "hemoglobinuria"
is used synonymously, although more precisely it refers only to hemoglobin in the urine.
Red discoloration of the urine can have various causes:
o
Microscopic
hematuria (small amounts of blood, can be seen only on urinalysis or light microscopy)
o
Macroscopic hematuria (or
"frank" or "gross") hematuria
·
Hemoglobin (only the red pigment, not the red blood cells)
·
Other pigments
o
Myoglobin in myoglobinuria
o
Porphyrins in porphyria
o
Drugs such as Rifampicin and Phenazopyridine
Acute hematuria due to trauma.
Often, the diagnosis is made on the basis of the medical history and some blood tests—especially in young people in
whom the risk of malignancy is negligible and the symptoms are generally
self-limiting.
Ultrasound investigation of the renal tract
is often used to distinguish between various sources of bleeding. X-rays
can be used to identify kidney stones,
although CT scanning
is more precise.
In older patients, cystoscopy with biopsy of suspected lesions is often employed to
investigate for bladder cancer.
If combined with pain, it may be loin pain hematuria syndrome.[1]
The most common causes of hematuria[2]
are:
·
Urinary tract infection with viruses,[2]
other sexually transmitted diseases
(particularly in women)[2]
or some bacterial species including strains of EPEC and Staphylococcus saprophyticus
·
Kidney stones
or ureter stones
·
Benign prostatic hyperplasia, in older
men, especially those over 50
Other, less common causes of hematuria include:
·
IgA
nephropathy ("Berger's disease") - occurs during viral
infections in predisposed patients
·
Trauma (e.g., a blow to the kidneys)
·
Tumors and/or cancer in the urinary
system,[2]
for example bladder cancer or renal cell carcinoma
·
Kidney diseases
·
Urinary Schistosomiasis
(caused by Schistosoma haematobium) - a major
cause for hematuria in many African and Middle-Eastern countries;
·
Prostate infection or inflammation (prostatitis)
Rare causes include:
·
Paroxysmal nocturnal hemoglobinuria
- a rare disease
where hemoglobin
of hemolyzed
cells is passed into the urine
·
Sickle cell
trait can precipitate large amounts of red blood cell discharge, but
only a small number of individuals endure this problem
·
Arteriovenous malformation of the kidney
(rare, but may impress like renal cell carcinoma on scans as both are highly
vascular)
·
Nephritic syndrome (a condition associated with
post-streptococcal and rapidly progressing glomerulonephritis)
·
Fibrinoid necrosis of the Glomeruli (as a
result of malignant hypertension)
·
Vesical varices may rarely
develop secondary to obstruction of the inferior vena cava
·
Allergy
may rarely cause episodic gross hematuria in children
·
Left renal vein
hypertension,
also called "nutcracker phenomenon" or
"nutcracker syndrome," is a rare vascular abnormality responsible for
gross hematuria
·
Ureteral Pelvic Junction Obstruction
(UPJ) is a rare condition beginning from birth in which the ureter is blocked between
the kidney and bladder. This condition may cause blood in the urine [6]
·
March hematuria
secondary to repetitive impacts on the body, usually the feet
·
Athletic nephritis secondary to strenuous
exercise
·
Medications can cause red discoloration
of the urine, but not hematuria. Some examples include: sulfonamides,
quinine,
rifampin,
phenytoin