BIOCHEMICAL FUNCTIONS OF LIVER. PORPHYRINS AND BILE PIGMENTS. PATHOBIOCHEMISTRY OF JAUNDICE. METABOLISM OF XENOBIOTICS IN THE LIVER: MICROSOMAL OXIDATION, CYTOCHROME Đ-450.
What are the functions of the liver?
• 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.
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.
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).
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.
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.
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).
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.
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.
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.
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:
Soluble in lipid, insoluble in water
Soluble in water, insoluble in lipid
2. Excretion in urine
3. Deposition in hram
4. Plasma level is increased in 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
2) hepatic and
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:
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.
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.
Antioxidant vitamins like vitamin C, beta-carotene, and vitamin E are obviously quite important in protecting the liver from damage as well as helping in the detoxification mechanisms, but even simple nutrients like B-vitamins, calcium, and trace minerals are critical in the elimination of heavy metals and other toxic compounds from the body. The lipotropic agents, choline, betaine, methionine, vitamin B6, folic acid, and vitamin B12, are useful as they promote the flow of fat and bile to and from the liver. Lipotropic formulas have been used for a wide variety of conditions by nutrition-oriented physicians including a number of liver disorders such as hepatitis, cirrhosis, and chemical-induced liver disease. Lipotropic formulas appear to increase the levels of SAM and glutathione. Methionine, choline, and betaine have been shown to increase the levels of SAM.
There is a long list of plants which exert beneficial effects on liver function. However, the most impressive research has been done on silymarin, the flavonoids extracted from silybum marianum (milk thistle). These compounds exert a substantial effect on protecting the liver from damage as well as enhancing detoxification processes. Silymarin prevents damage to the liver through several mechanisms: by acting as an antioxidant, by increasing the synthesis of glutathione and by increasing the rate of liver tissue regeneration. Silymarin is many times more potent in antioxidant activity than vitamin E and vitamin C. The protective effect of silymarin against liver damage has been demonstrated in numerous experimental studies. Silymarin has been shown to protect the liver from the damage produced by such liver-toxic chemicals as carbon tetrachloride, amanita toxin, galactosamine, and praseodymium nitrate.
One of the key mechanisms by which silymarin enhances detoxification is by preventing the depletion of glutathione. Silymarin not only prevents the depletion of glutathione induced by alcohol and other toxic chemicals, but has been shown to increase the level of glutathione of the liver by up to 35%, even in normals. Inhuman studies, silymarin has been shown to have positive effects in treating liver diseases of various kinds, including cirrhosis, chronic hepatitis, fatty infiltration of the liver, and inflammation of the bile duct. The standard dosage for silymarin is 70-210 mg three times/day.
Several amino acids (glyucine, taurine, glutamine, arginine, and ornithine) are used to combine with and neutralize toxins. Of these, glycine is the most commonly utilized in phase II amino acid detoxification. Patients suffering from hepatitis, alcoholic liver disorders, carcinomas, chronic arthritis, hypothyroidism, toxemia of pregnancy, and excessive chemical exposure are commonly found to have a poorly functioning amino acid conjugation system. For example, using the benzoate clearance test (a measure of the rate at which the body detoxifies benzoate by conjugating it with glycine to form hippuric acid, which is excreted by the kidneys), the rate of clearance in those with liver disease is 50% of that in healthy adults.
Even in apparently normal adults, a wide variation exists in the activity of the glycine conjugation pathway. This is due no only to genetic variation, but also to the availability of glycine in the liver. Glycine, and the other amino acids used for conjugation, become deficient on a low-protein diet and when chronic exposure to toxins results in depletion.
Adding certain supplements to your diet can stimulate detoxification. Fiber, vitamin C and other antioxidants, chlorophyll, and glutathione (as the amino acid L-cysteine) will all help. Herbs such as garlic, red clover, echinacea, or cayenne may also induce some detoxification. Saunas, sweats, and niacin therapy have been used to cleanse the body.
Simply increasing liquids and decreasing fats will shift the balance strongly toward improved elimination and less toxin buildup. Changes might include increased consumption of filtered water, herb teas, fruits, and vegetables, as well as reducing fats, especially fried food, meat and milk products. In general, moving from an acid-generating diet to a more alkaline one will aid the process of detoxification. Acid-forming foods, such as meats, milk products, breads and baked goods, and especially the refined sugar and carbohydrate products, will increase body acidity and lead to more mucus production and congestion, whereas the more alkaline vegetarian foods enhance cleansing and clarity in the body.
A deeper level of detoxification diet is made up exclusively of fresh fruits and vegetables, either raw and cooked, and whole grains, both cooked and sprouted. This diet keeps fiber and water intake high and helps colon detoxification. Most people can handle this well and make the shift from their regular diet with a few days transition. Some people do well on a brown rice fast (a more macrobiotic plan), usually for a week or two, eating three to four bowls of rice daily along with liquids such as teas."
Role of liver in excretion.
Bile is an important vehicle for bile acid and cholesterol excretion, but it also removes many drugs, toxins, bile pigments, and various inorganic substances such as copper, zinc, and mercury.
Evaluating of liver’s functions.
Different methods are used for evaluating of liver’s functions. Base for some of them is role of liver in proetin metabolism (e.g. thymol’s test), for another – role of liver in detoxification (indican’s test) or in excretion (checking of bilirubin level in blood). In all cases physician must make a conclusion about disorder of liver’s functions after complex investigation, because, as mentioned above, all metabolic ways are present in liver.
The liver filter can remove a wide range of microorganisms such as bacteria, fungi, viruses and parasites from the blood stream, which is highly desirable, as we certainly do not want these dangerous things building up in the blood stream and invading the deeper parts of the body. Infections with parasites often come from the contaminated water supplies found in large cities, and indeed other dangerous organisms may find their way into your gut and blood stream from these sources. This can cause chronic infections and poor health, so it is important to protect your liver from overload with these microorganisms. The safest thing to do is boil your water for at least 5 minutes, or drink only bottled water that has been filtered and sterilized. High loads of unhealthy microorganisms can also come from eating foods that are prepared in conditions of poor hygiene by persons who are carrying bacteria, viruses or parasites on their skin. Foods, especially meats that are not fresh or are preserved, also contain a higher bacterial load, which will overwork the liver filter if they are eaten regularly.
Recently, it has become very fashionable for people to detoxify their bodies by various means, such as fasting or cleansing the bowels with fiber mixtures. Fasting can by its extreme nature, only be a temporary method of cleansing the body of waste products, and for many people causes an excessively rapid release of toxins which can cause unpleasant, acute symptoms. The liver filter, like any filter, needs to be cleansed regularly, and it is much easier and safer to do it everyday. This is easily and pleasantly achieved by adopting a daily eating pattern that maintains the liver filter in a healthy clean state. By following the methods and guidelines on this site, you will be able to keep the liver filter healthy and clean. Although it is important to keep the intestines moving regularly and to sweep their walls with high fiber and living foods, it is important to remember that the bowels are really a channel of elimination and not a cleansing organ per se. In other words the bowels cannot cleanse, filter or remove toxic wastes from the blood stream.
The liver is the most important organ in detoxification, as it is the body's premier cleansing organ. All the blood in the body passes through the liver, which removes toxins, impurities, and debris from the bloodstream.
The liver stores fat-soluble substances; these can include chemicals, which can be stored in the liver for years. Using enzymes, the liver transforms these chemicals into water-soluble substances that can be excreted though the kidneys or the gastrointestinal tract.
Hormones are metabolized by the liver. Estrogen produced by the body and from hormone replacement therapies is broken down. If estrogen is not adequately processed, excess estrogen can result in endometriosis; high blood pressure; PMS; and breast, uterine, and vaginal cancer.
The liver also manufactures bile to digest fats; chemically changes many foods into vitamins and enzymes; converts carbohydrates and proteins into glucose for brain fuel and glycogen for muscular energy; and stores nutrients to be secreted as needed by the body to build and maintain cells.
If the liver cannot perform these jobs well, you may exhibit a number of symptoms. These include gas; constipation; a feeling of fullness; loss of appetite; nausea after fatty meals; an oily taste in the mouth; revulsion to fatty foods; frequent headaches not related to stress; weak ligaments, tendons, and muscles; skin problems; and emotional excesses.
Briefly put, living. What you eat, where you live, and what you do all can affect the liver's performance. If you consume a lot of processed foods, the additives can eventually affect the liver. If you live in an area that is highly polluted, exposure to chemicals in the air and water affects the liver. All of this can hurt the liver's performance.
An impaired liver does not process food or detoxify substances as rapidly or as completely as a healthy liver. If the liver is not producing enough bile, it cannot adequately digest fats. If the liver is detoxifying more slowly than it should, it can result in more toxic substances circulating in the body.
If toxins continue to accumulate, the liver may not be able to work fast enough to clean the blood. It is like being on a treadmill that is going a little too fast: try as you might, you cannot go forward, but instead are swept back into greater toxicity. Instead of being converted into something useful or being eliminated, toxins remain unchanged. They are eventually stored in fatty body tissue and in the cells of the brain and central nervous system. The stored toxins may be slowly released to recirculate in the blood, contributing to many chronic illnesses.
A toxin is basically any substance that creates irritating and/or harmful effects in the body; stressing and undermining one's biochemical health and organ function. Toxins can come from by products of normal cell metabolism or from the outside environment e.g. pollution, drugs, pesticides, dyes, chemicals, microbes, heavy metals, tobacco smoke and so on.
Toxicity occurs when we take in more then we can utilize and eliminate. Toxic chemicals can be a real problem, since after years of exposure to these substances the body’s ability to eliminate them can slow down. They can get recirculated into the bloodstream or stored in the liver, body fat or other parts of the body. These types of buildups and problems throughout the body can contribute to the development of serious illnesses. Many chemicals are so widespread that we are unaware of them. But they have worked their way into our bodies faster than they can be eliminated, and are causing allergies and addictions in record numbers. The body's built in detoxification apparatus include the respiratory, gastrointestinal, urinary, skin and lymphatic systems.
Cancer and cardiovascular disease are two of the main toxicity-related diseases. Arthritis, allergies, obesity, and many skin problems are others. In addition, a wide range of symptoms, such as headaches, fatigue, pains, coughs, gastrointestinal problems and problems from immune weakness can all be related to toxicity.
of toxicity include frequent, unexplained headaches, back or joint pain, tight
or stiff neck, arthritis, chronic respiratory or sinus problems, asthma,
abnormal body odor, bad breath, coated tongue, food allergies, poor digestion,
chronic constipation with intestinal bloating or gas, brittle nails and hair,
psoriasis, adult acne, unexplained weight gain over
Detoxification is the process of clearing toxins from the body or neutralizing them. Energy balancing and detoxification herbal baths prompt the body to eliminate toxins from specific areas of the body. As these toxins are released from the areas where they have been stored, they move into the blood, lymph and other body fluids out of the body through the urinary, gastrointestinal, lymphatic and respiratory systems and the skin. The period of detoxification can be a few days, a few weeks or a months depending on the extent, location and type of the toxins in the body. As a person is detoxifying they may experience uncomfortable symptoms including depression, mood changes, nausea, diarrhea , foggy head, fatigue, lack of energy, bad breathe, foul urine odour, foul perspiration odour, body odour, sores, rashes, acne, cold or flu like symptoms, headaches or any other symptom. This period where symptoms may seem to worsen is sometimes called a healing crisis, but is actually just the body's reacting to the presence of the toxins in the bloodstream and the movement of the toxins out of the body. .
"The liver is one of the most important organs in the body when it comes to detoxifying or getting rid of foreign substances or toxins. The liver plays a key role in most metabolic processes, especially detoxification. The liver neutralizes a wide range of toxic chemicals, both those produced internally and those coming from the environment. The normal metabolic processes produce a wide range of chemicals and hormones for which the liver has evolved efficient neutralizing mechanisms. However, the level and type of internally produced toxins increases greatly when metabolic processes go awry, typically as a result of nutritional deficiencies. These non-end-product metabolites have become a significant problem in this age of conventionally grown foods and poor diets.
Many of the toxic chemicals the liver must detoxify come from the environment: the content of the bowels and the food, water, and air. The polycyclic hydrocarbons (DDT, dioxin, 2,4,5-T, 2,3-D, PCB, and PCP), which are components of various herbicides and pesticides, are an example of chemicals that are now found in virtually all fat tissues measured. Even those eating unprocessed organic foods need an effective detoxification system because all foods contain naturally occurring toxic constituents.
The liver plays several roles in detoxification: it filters the blood to remove large toxins, synthesizes and secretes bile full of cholesterol and other fat-soluble toxins, and enzymatically disassembles unwanted chemicals. This enzymatic process usually occurs in two steps referred to as phase I and phase II. Phase I either directly neutralizes a toxin, or modifies the toxic chemical to form activated intermediates which are then neutralized by one of more of the several phase II enzyme systems.
Proper functioning of the liver's detoxification systems is especially important for the prevention of cancer. Up to 90% of all cancers are thought to be due to the effects of environmental carcinogens, such as those in cigarette smoke, food, water, and air, combined with deficiencies of the nutrients the body needs for proper functioning of the detoxification and immune systems. The level of exposure to environmental carcinogens varies widely, as does the efficiency of the detoxification enzymes, particularly phase II. High levels of exposure to carcinogens coupled with slow detoxification enzymes significantly increases susceptibility to cancer.
the liver's primary functions is filtering the blood. Almost
second detoxification process involves the synthesis and secretion of bile.
Each day the liver manufactures approximately
What happens when excretion of bile is inhibited?
When the excretion of bile is inhibited (i.e. cholestasis), toxins stay in the liver longer. Cholestasis has several causes, including obstruction of the bile ducts and impairment of bile flow within the liver. The most common cause of obstruction of the bile ducts is the presence of gallstones. Currently, it is conservatively estimated that 20 million people in the U.S. have gallstones. Nearly 20% of the female and 8% of the male population over the age of 40 are found to have gallstones on biopsy and approximately 500,000 gall bladders are removed because of stones each year in the U.S. The prevalence of gallstones in this country has been linked to the high-fat, low-fiber diet consumed by the majority of Americans.
Impairment of bile flow within the liver can be caused by a variety of agents and conditions. These conditions are often associated with alterations of liver function in laboratory tests (serum bilirubin, alkaline phosphatase, SGOT, LDH, GGTP, etc.) signifying cellular damage. However, relying on these tests alone to evaluate liver function is not adequate, since, in the initial or subclinical stages of many problems with liver function, laboratory values remain normal. Among the symptoms people with enzymatic damage complain of are:
Fatigue; general malaise; digestive disturbances; allergies and chemical sensitivities; premenstrual syndrome; constipation
most common cause of cholestasis and impaired liver function is alcohol
ingestion. In some especially sensitive individuals, as little as
Oranges and tangerines (as well as the seeds of caraway and dill) contain limonene, a phytochemical that has been found to prevent and even treat cancer in animal models. Limonene's protective effects are probably due to the fact that it is a strong inducer of both phase I and phase II detoxification enzymes that neutralize carcinogens.
Curcumin, the compound that gives turmeric its yellow color, is interesting because it inhibits phase I while stimulating phase II. This effect can be very useful in preventing certain types of cancer. Curcumin has been found to inhibit carcinogens, such as benzopyrene (found in charcoal-broiled meat), from inducing cancer in several animal models. It appears that the curcumin exerts its anti-carcinogenic activity by lowering the activation of carcinogens while increasing the detoxification of those that are activated. Curcumin has also been shown to directly inhibit the growth of cancer cells.
As most of the cancer-inducing chemicals in cigarette smoke are only carcinogenic during the period between activation by phase I and final detoxification by phase II, curcumin in the turmeric can help prevent the cancer-causing effects of tobacco. Those exposed to smoke, aromatic hydrocarbons, and other environmental carcinogens will probably benefit from the frequent use of curry or turmeric.
The activity of phase I detoxification enzymes decreases in old age. Aging also decreases blood flow through the liver, further aggravating the problem. Lack of the physical activity necessary for good circulation, combined with the poor nutrition commonly seen in the elderly, add up to a significant impairment of detoxification capacity, which is typically found in aging individuals. This helps to explain why toxic reactions to drugs are seen so commonly in the elderly.
Liver failure, or hepatic failure, is severe deterioration of liver function resulting from extensive damage of liver cells. The syndrome respresents a severe clinical condition and is associated with high mortality; therefore, a great challenge to intensive care management.
Jaundice is a cause for concern and there are many misconceptions associated with it. Dr Vikram Ananthakrishnan (M.S., F.R.C.S) answers some frequently asked questions about this common ailment and about the liver.
Jaundice can be broadly classified as infective and obstructive jaundice.
A virus called Hepatitis A, is a common cause of infective jaundice. This virus is transmitted through water and food. Children are often affected.
The other viruses such as Hepatitis B and Hepatitis C viruses are transmitted through blood. Viruses responsible for these infections spread through the body secretions like saliva, sweat, semen, vaginal fluids of infected persons. Close contact and sexual intercourse are important factors in spread. Homosexuals contract these infections more easily. Blood, blood products, contaminated needles and tattooing, are also important sources through which infection spreads. These viruses are more resistant to the various methods of sterilisation than the AIDS virus. They are a major cause for concern as they spread rapidly. There are more people infected by Hepatitis B virus in the world than the AIDS virus.
Hepatitis B and Hepatitis C infections can lead to chronic liver diseases, cirrhosis and eventually liver cancer & liver failure.
The other viruses associated with jaundice are Hepatitis D and E. Hepatitis E infection can be acquired from contaminated water.
Diseases like Leptospirosis can also cause jaundice.
Stones or growths, blocking the pathway of bile, cause a type of jaundice called obstructive jaundice. Occasionally, drugs can also cause jaundice.
How is Leptospirosis transmitted and how is it treated?
This is an infection caused by water or food contaminated with rats’ urine. Patients develop fever and later jaundice and eventually (renal) kidney failure. If left unrecognised leptospirosis can be fatal. The infection is treated with antibiotics like penicillin and doxycycline.
Amongst the different types of infective jaundice, which is worse?
Hepatitis C is the most dangerous type of jaundice. Like Hepatitis B it also leads to chronic liver disease.
Which form of jaundice requires surgery?
Sometimes stones & growths block the pathway of bile drainage from the liver (where it is made) to the small intestine (where it acts on the food to digest and break down fats). This can also cause jaundice. Stones in the bile pathway usually originate in the gall bladder. This often requires removal of the gall bladder along with the stones in the biliary pathway. Growths may require major surgery for their removal. In case they are very advanced, a bypass operation may need to be done to relieve the jaundice.
What are the tests (investigations) done for jaundice?
These can be broadly classified as blood tests, scans and endoscopy.
Blood tests are done to assess the overall function of the liver. These tests are collectively called Liver Function Tests.
These tests will show if there is on going destruction of the liver. Blood tests will help identify the type of jaundice.
They will show whether the synthetic function of the liver is good. The various clotting tests can be done to see if the liver is producing adequate proteins for clotting purposes.
Ultrasound scan is done to see if there are any gross architectural abnormalities in the liver. What cannot be captured by ultrasound can be done by CT scan and the MRI. M.R.I has now become the gold standard in looking for abnormalities in the liver and the surrounding organs when there is obstructive jaundice.
Endoscopy may be performed to look at the oesophagus (food pipe), stomach and the first few inches of the small intestine. A special variety of endoscope may also be used wherein a dye can be injected into the bile ducts and the pancreatic ducts and pictures can be taken. This gives complete visualisation of the pathway that bile takes to drain into the small intestine. It also studies the ducts of the pancreas. It is called E.R.C.P. (endoscopic retrograde cholangio pancreaticogram).
What is the diet recommended for jaundice patients?
Foods that are rich in glucose are recommended in jaundice. These help the liver cells to regenerate and also provide the required nourishment for the body. Fats are to be taken in reduced quantities. Deep fried foods & alcohol are to be avoided.
What is the treatment for Jaundice?
The treatment for jaundice depends upon the type of jaundice. For viral hepatitis, causing jaundice, there is no definitive treatment. Only supportive measures are given. The virus is slowly eliminated from the body with the help of the immune system.
In case it is jaundice caused by blockage to the pathway of bile, surgery may be needed.
What is the role of immunisation in Jaundice?
Hepatitis B is one of the common causes of jaundice that can have serious consequences. Immunising a person can prevent this viral infection and its consequences. The vaccine is easily available and is usually given in three doses either at monthly intervals or two doses are given at monthly intervals and the third six months after the first dose. Immunisation with the vaccine now begins from the infant period itself. A single booster dose is required once every five years to maintain the protection.
What is the role of Herbs in treating Jaundice?
The common herb used is Keezhanelli. Its role in treatment is not fully proven.
The liver has a variety of functions. Its two main functions are synthesising and detoxifying.
It helps to break down and store various nutrients like carbohydrates, proteins and fat.
Whenever there is excess glucose in the blood, it converts it to fat and stores it.
If the blood glucose levels are low it breaks down fat and protein into glucose.
It stores vitamins A, D, K , B12, Folate.
Liver is responsible for a variety of protein syntheses. It helps in the synthesis of substances for clotting of blood, as well as albumin (the most important protein).
It breaks down drugs, alcohol and poisons absorbed from the intestines.
It is said that, “Liver failure is power failure.”
What is the relation between alcohol and Liver disease?
The liver takes up alcohol from the blood stream. (One of the main functions of the liver is to clean up the blood of various poisons and the intestines from invading organisms.) The liver breaks down alcohol (metabolises) and thus bears the brunt of this poison. Intake of 3 units of alcohol or more in men and 2 or more units in women for more than five years causes disease.
What is cirrhosis of the liver?
Cirrhosis of the liver is the end result of various insults on the liver. The insults could be poisons or viruses. It is a process wherein the normal liver tissue is replaced by non-functioning fibrous tissue. This alters the blood flow within the liver causing other pathways to open thus resulting in various complications.
What are the complications of cirrhosis liver?
Fluid retention causing large and distended abdomen.
This retention of fluids with a reduction in the synthesis of proteins can lead on to swelling of the legs (Oedema).
There can be Anaemia (low Haemoglobin) and susceptibility to infections.
The blood flow through the liver could be blocked causing alternate pathways to open up. This leads to dilatation of veins especially in the lower end of the food pipe (oesophagus). These veins can rupture causing massive bleeding. The liver can fail in its function of removing various poisons in the body causing altered behaviour patterns and eventually coma and death.
Biochemistry of Liver Function
In the past, the liver has been referred to as the center of courage, passion, temper, and love and even as the center of the soul. it was once believed to produce "yellow bile" necessary for good health. Today, the liver is a complex organ responsible for many major metabolic functions in the body. More than 100 tests measuring these diverse functions have existed in the clinical laboratory at one time. However, many were abandoned in favor of those that have proven to be most clinically useful.
The liver performs several hundred functions each day. These function can be classified into the following:
2. Synthetic Function
3. Detoxification Function
1. Excretory Function
One of the more important liver functions, and one that is disturbed in a large number of hepatic disorders, is the excretion of bile.
The excretion of bile:
comprises bile salts, bile acids, bile pigments (primarily bilirubin),
cholesterol, and other substances extracted from the blood. Total bile production
Bile acids: The primary bile acids are cholic acid and chenodcoxycholic acid. They are formed in the liver from cholesterol. The bile acids are conjugated with the amino acids glycine or taurine, forming bile salts. Bile salts (conjugated bile acids) are excreted into the bile canaliculi by means of a carriermediated active transport system. During fasting and between meals, a major portion of the bile acid pool is concentrated up to 10-fold in the gallbladder. Bile acids reach the intestine when the gallbladder contracts after each meal. Approximately 500-600 mL of bile enter the duodenum each day.
Bile salts help in the digestion and absorption of lipids. When the conjugated bile acids (salts) come into contact with bacteria in the terminal ileum and colon, dehydration to secondary bile acids (deoxycholic and lithocolic) occurs, and these secondary bile acids are subsequently absorbed. The absorbed bile acids enter the portal circulation and return to the liver, where they are reconjugated and reexcreted. The enterohepatic circulation of bile occurs 2-5 times daily.
Bilirubin is the principal pigment in bile. It is formed by the breakdown of hemoglobin when red blood cells are phagocytized by the reticuloendothelial system. The reticuloendothelial system is mainly in the spleen, liver, and bone marrow. About 80% of the bilirubin formed daily comes from the degradation of hemoglobin. The remainder comes from destruction of hemecontaining proteins (myoglobin, cytochromes, catalase) and catabolism of heme. When hemoglobin is destroyed, the protein portion -globin- is reused by the body. The iron enters the body's iron stores and is also reused.
The porphyrin ring is changed to biliverdin, which is easily reduced to bilirubin. Bilirubin is transported to the liver in the bloodstream bound to albumin. This bilirubin is referred to as unconjugated bilirubin or indirect bilirubin.
At the liver, unconjugated bilirubin is separated from the albumin and taken up by the hepatic cells. Two nonalbumin proteins, isolated from liver cell cytoplasm and designated Y and Z, account for the intracellular binding and transport of bilirubin. Conjugation of bilirubin occurs in the hepatocytes. An enzyme, uridyldiphosphate glucuronyl transferase (UDPGT), transfers glucuronic acid molecules to bilirubin, converting bilirubin into a diglucuronide ester. This product, bilirubin diglucuronide, is referred to as conjugated bilirubin or direct bilirubin. Conjugated bilirubin is water soluble. It is secreted from the hepatic cell into the bile canaliculi and then into larger bile ducts and eventually into the intestine. In the colon, the bile pigments are acted on by enzymes of the intestinal bacteria. The first product of this reaction is mesobilirubin, which is reduced to form mesobilirubinogen. This produces urobilinogen which is a colorless product. The oxidation of urobilinogen produces the red-brown pigment urobilin, which is excreted in the stool.
A small portion of the urobilinogen is reabsorbed into the portal circulation and returned to the liver, where it is again excreted with the bile into the intestine. This is called enterohepatic circulation of bile pigments. However, a small quantity of urobilinogen remains in the blood. This urobilinogen, which is colorless, is ultimately filtered by the kidney and excreted in the urine.
A total of 200-300 mg of bilirubin is produced daily in the healthy adult. A normally functioning liver is required to eliminate this amount of bilirubin from the body. This excretory function requires that bilirubin be in the conjugated form; that is, the water-soluble diglucuronide. Almost all the bilirubin formed is eliminated in the feces, and a small amount of the colorless product urobilinogen is excreted in the urine.
Reference Value of Bilirubins:
• Total bilirubin 0.2 - 1.0 mg/dL
• Direct (Conjugated) 0.0 - 0.2 mg/dL
• Indirect (Unconjugated) 0.2 - 0.8 mg/dL
2. Synthetic Function
The liver is the main site of synthesis of:
The liver plays an important role in production of albumin and the majority of the α and β-globulins. All the blood-clotting factors (except VIII) are synthesized in the liver. Deamination of glutamate in the liver is the primary source of ammonia, which is converted to urea.
The synthesis and metabolism of carbohydrates is centered in the liver. Glucose is converted to glycogen (Glycogenesis), a portion of which is stored in the liver and later reconverted to glucose (Glycogenolysis) as necessary. An additional important liver function is gluconeogenesis from amino acids.
Fat is formed from carbohydrates in the liver (Lipogenesis) when nutrition is adequate and the demand for glucose is being met from dietary sources. The liver also plays a key role in the metabolism of fat. It is the major site for the
- removal of chylomicron remnants
- the conversion of acetyl- CoA to fatty acids, triglycerides, and cholesterol.
- metabolism of cholesterol into bile acids
- Synthesis of Very-low-density lipoproteins
- Synthesis of high-density lipoproteins
- Synthesis of phospholipids.
The formation of ketone bodies occurs in the liver. When the demand for gluconeogenesis depletes oxaloacetate and acetyl-CoA cannot be converted rapidly enough to citrate, acetyl-CoA accumulates and a ,decyclase in the liver liberates ketone bodies into the blood .
The liver is the storage site for all fat-soluble vitamins (A, D, E, and K) and several water-soluble vitamins, such as B12. Another vitamin-related function is the conversion of carotene into vitamin A.
The liver is the source of somatomedin (an insulin-like factor that mediates the activity of growth hormone) and angiotensinogen, and is a major site of metabolic clearance of many other hormones. As the source of transferrin, ceruloplasmin, and metallothionein, the liver plays a key role in the transport, storage, and metabolism of iron, copper, and other metals .
Many enzymes are synthesized by liver cells. Those enzymes that have been found useful in the diagnosis of hepatobiliary disorders include aspartate amino transferase (AST, or serum glutamic-oxaloacetic transaminase [SGOT]) and alanine amino transferase (ALT, or serum glutamic pyruvic transaminase [SGPT]), alkaline phosphatase (ALP) and 5'-nucleotidase (5NT), and γ-glutamyltransferase (GGT).
3. Detoxification Function
Because the liver is interposed between the splanchnic circulation and the systemic blood, it serves to protect the body from potentially injurious substances absorbed from the intestinal tract and toxic by-products of metabolism.
The most important mechanisms of detoxification includ oxidation, reduction, hydrolysis, hydroxylation, carboxylation, and demethylation. Detoxification mechanisms convert many toxic or insoluble compounds into less toxic or more water-soluble compounds and, therefore, excretable by the kidney. For example, ammonia, a toxic substance arising in the large intestine through bacterial action on amino acids, is carried to the liver by the portal vein and converted by hepatocytes into the innocuous compound urea.
Conjugation with compounds, such as glycine, glucuronic acid, sulfuric acid, glutamine, acetate, cysteine, and glutathione, occurs mainly in the cytosol. This mechanism is the mode of bilirubin and bile acid excretion.