BIOCHEMICAL FUNCTIONS OF LIVER. PORPHYRINS AND BILE PIGMENTS. PATHOBIOCHEMISTRY OF JAUNDICE. METABOLISM OF XENOBIOTICS IN THE nLIVER: MICROSOMAL OXIDATION, CYTOCHROME Р-450.
What are the functions of the nliver?
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Liver’s functions:
• It is responsible for the nproduction of bile which is stored in the gallbladder and released wherequired for the digestion of fats.
n• The liver stores glucose in the form of glycogen which nis converted back to glucose again wheeeded for energy.
n• It also plays an important role in the metabolism of nprotein and fats. It stores the vitamins A, D, K, B12 and folate and nsynthesizes blood clotting factors.
n• Another important role is as a detoxifier, breaking ndown or transforming substances like ammonia, metabolic waste, drugs, alcohol nand chemicals, so that they can be excreted. These may also be referred to as n”xenobiotic” chemicals. If we examine the liver under a microscope, nwe will see rows of liver cells separated by spaces which act like a filter or nsieve, through which the blood stream flows. The liver filter is designed to nremove toxic matter such as dead cells, microorganisms, chemicals, drugs and nparticulate debris from the blood stream. The liver filter is called the nsinusoidal system, and contains specialized cells known as Kupffer cells which ningest 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 npart of it undergone the phosphorillation. Glucose-6-phosphate formed in result nof this reaction, which catalyzed by two enzymes – hexokinase and glucokinase. nWhen level of glucose in blood of v. porta and in the hepatocytes is normal nactivity of glucokinase is low. After eating activity of this enzyme increase nand blood level of glucose decrease because glucose-6-phosphate cannot pass nthrough membrane.
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Fructose and galactose also transformed into nglucose-6-phosphate in the liver.
Glucose-6-phosphate is a key product of carbohydrates nmetabolism. In the liver this substance can metabolized into different ways ndepend of liver’s and whole organism’s necessity.
1. Synthesis of glicogen. Content in the liver – n70-100g. After eating amount of glicogen in the liver increase up to 150g. nAfter 24 hours of starvation content of glicogen in the liver decreases to zero nand glukoneogenesis started.
2. Glucose-6-phosphatase catalize dephosphorillatioof glucose-6-phosphate and free glucose formed. This enzyme is present in the nliver, kidney and small intestine. This process keep normal level of glucose ithe blood.
3. Excess of glucose-6-phosphate, which not used for nsynthesis of glicogen and forming of free glucose, decomposites in glycolysis nfor pyruvate and for acetyl-CoA, which are used for fatty acids synthesis.
4. Glucose-6-phosphate decomposites for H2O and CO2, nand free energy for hepatocytes formed.
5. Part of glucose-6-phosphate oxidized ipentosophosphate cycle. This way of glucose decomposition supplyes reducted nNADPH, which is necessary in fatty acid synthesis, cholesterin synthesis, and nalso pentosophosphates for nucleic acids. Near 1/3 of glucose in liver used for nthis pathway, another 2/3 – for glycolisis.
The Hexokinase Reaction:
The ATP-dependent phosphorylation of glucose to form nglucose 6-phosphate (G6P)is the first reaction of glycolysis, and is catalyzed nby tissue-specific isoenzymes known as hexokinases. The phosphorylatioaccomplishes two goals: First, the hexokinase reaction converts nonionic nglucose into an anion that is trapped in the cell, since cells lack transport nsystems for phosphorylated sugars. Second, the otherwise biologically inert nglucose becomes activated into a labile form capable of being further metabolized. n
Four mammalian isozymes of hexokinase are known (Types nI – IV), with the Type IV isozyme often referred to as glucokinase. Glucokinase nis the form of the enzyme found in hepatocytes. The high Km of glucokinase for nglucose means that this enzyme is saturated only at very high concentrations of nsubstrate.
Comparison of the activities of hexokinase and nglucokinase. The Km for hexokinase is significantly lower (0.1mM) than that of nglucokinase (10mM). This difference ensures that non-hepatic tissues (which ncontain hexokinase) rapidly and efficiently trap blood glucose within their ncells by converting it to glucose-6-phosphate. One major function of the liver nis to deliver glucose to the blood and this in ensured by having a glucose nphosphorylating enzyme (glucokinase) whose Km for glucose is sufficiently nhigher that the normal circulating concentration of glucose (5mM).
This feature of hepatic glucokinase allows the liver nto buffer blood glucose. After meals, when postprandial blood glucose levels nare high, liver glucokinase is significantly active, which causes the liver preferentially nto trap and to store circulating glucose. When blood glucose falls to very low nlevels, tissues such as liver and kidney, which contain glucokinases but are nnot highly dependent on glucose, do not continue to use the meager glucose nsupplies that remain available. At the same time, tissues such as the brain, nwhich are critically dependent on glucose, continue to scavenge blood glucose nusing their low Km hexokinases, and as a consequence their viability is nprotected. Under various conditions of glucose deficiency, such as long periods nbetween meals, the liver is stimulated to supply the blood with glucose through nthe pathway of gluconeogenesis. The levels of glucose produced during ngluconeogenesis are insufficient to activate glucokinase, allowing the glucose nto pass out of hepatocytes and into the blood.
The regulation of hexokinase and glucokinase nactivities is also different. Hexokinases I, II, and III are allosterically ninhibited by product (G6P) accumulation, whereas glucokinases are not. The nlatter further insures liver accumulation of glucose stores during times of nglucose excess, while favoring peripheral glucose utilization when glucose is nrequired to supply energy to peripheral tissues.
Hepatocytes content full set of gluconeogenesis necessary nenzymes. So, in liver glucose can be formed from lactate, pyruvate, amino nacids, glycerine. Gluconegenesis from lactate takes place during intensive nmuscular work. Lactate formed from glucose in muscles, transported to the nliver, new glucose formed and transported to the muscles (Kori cycle).
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Regulation of Blood Glucose Levels
If for no other reason, it is because of the demands of nthe brain for oxidizable glucose that the human body exquisitely regulates the nlevel of glucose circulating in the blood. This level is maintained in the nrange of 5mM.
Nearly all carbohydrates ingested in the diet are nconverted to glucose following transport to the liver. Catabolism of dietary or ncellular proteins generates carbon atoms that can be utilized for glucose nsynthesis via gluconeogenesis. Additionally, other tissues besides the liver nthat incompletely oxidize glucose (predominantly skeletal muscle and nerythrocytes) provide lactate that can be converted to glucose via ngluconeogenesis.
Maintenance of blood glucose homeostasis is of paramount nimportance to the survival of the human organism. The predominant tissue nresponding to signals that indicate reduced or elevated blood glucose levels is nthe liver. Indeed, one of the most important functions of the liver is to nproduce glucose for the circulation. Both elevated and reduced levels of blood nglucose trigger hormonal responses to initiate pathways designed to restore nglucose homeostasis. Low blood glucose triggers release of glucagon from npancreatic -cells. nHigh blood glucose triggers release of insulin from pancreatic -cells. nAdditional signals, ACTH and growth hormone, released from the pituitary act to nincrease blood glucose by inhibiting uptake by extrahepatic tissues. nGlucocorticoids also act to increase blood glucose levels by inhibiting glucose nuptake. Cortisol, the major glucocorticoid released from the adrenal cortex, is nsecreted in response to the increase in circulating ACTH. The adrenal medullary nhormone, epinephrine, stimulates production of glucose by activating nglycogenolysis in response to stressful stimuli.
Glucagon binding to its’ receptors on the surface of nliver cells triggers an increase in cAMP production leading to an increased nrate of glycogenolysis by activating glycogen phosphorylase via the nPKA-mediated cascade. This is the same response hepatocytes have to epinephrine nrelease. The resultant increased levels of G6P in hepatocytes is hydrolyzed to nfree glucose, by glucose-6-phosphatase, which then diffuses to the blood. The nglucose enters extrahepatic cells where it is re-phosphorylated by hexokinase. nSince muscle and brain cells lack glucose-6-phosphatase, the nglucose-6-phosphate product of hexokinase is retained and oxidized by these ntissues.
In opposition to the cellular responses to glucagon (and nepinephrine on hepatocytes), insulin stimulates extrahepatic uptake of glucose nfrom the blood and inhibits glycogenolysis in extrahepatic cells and conversely nstimulates glycogen synthesis. As the glucose enters hepatocytes it binds to nand inhibits glycogen phosphorylase activity. The binding of free glucose nstimulates the de-phosphorylation of phosphorylase thereby, inactivating it. nWhy is it that the glucose that enters hepatocytes is not immediately nphosphorylated and oxidized? Liver cells contain an isoform of hexokinase ncalled glucokinase. Glucokinase has a much lower affinity for glucose than does nhexokinase. Therefore, it is not fully active at the physiological ranges of nblood glucose. Additionally, glucokinase is not inhibited by its product G6P, nwhereas, hexokinase is inhibited by G6P.
One major response of non-hepatic tissues to insulin is nthe recruitment, to the cell surface, of glucose transporter complexes. Glucose ntransporters comprise a family of five members, GLUT-1 to GLUT-5. GLUT-1 is nubiquitously distributed in various tissues. GLUT-2 is found primarily in intestine, nkidney and liver. GLUT-3 is also found in the intestine and GLUT-
Hepatocytes, unlike most other cells, are freely npermeable to glucose and are, therefore, essentially unaffected by the actioof insulin at the level of increased glucose uptake. When blood glucose levels nare low the liver does not compete with other tissues for glucose since the extrahepatic nuptake of glucose is stimulated in response to insulin. Conversely, when blood nglucose levels are high extrahepatic needs are satisfied and the liver takes up nglucose for conversion into glycogen for future needs. Under conditions of high nblood glucose, liver glucose levels will be high and the activity of nglucokinase will be elevated. The G6P produced by glucokinase is rapidly nconverted to G1P by phosphoglucomutase, where it can then be incorporated into nglycogen.
Diabetes mellitus – general term referring to all states characterized nby hyperglycemia.
For the disease characterized by excretion of large amounts of very ndilute urine, see diabetes insipidus. For diabetes mellitus in pets, see ndiabetes in cats and dogs.
Diabetes mellitus (IPA pronunciation: is a metabolic disorder ncharacterized by hyperglycemia (high blood sugar) and other signs, as distinct nfrom a single illness or condition.
The World Health Organization recognizes three main forms of diabetes: ntype 1, type 2, and gestational diabetes (occurring during pregnancy),[ which have nsimilar signs, symptoms, and consequences, but different causes and populatiodistributions. Ultimately, all forms are due to the beta cells of the pancreas nbeing unable to produce sufficient insulin to prevent hyperglycemia Type 1 is nusually due to autoimmune destruction of the pancreatic beta cells which nproduce insulin. Type 2 is characterized by tissue-wide insulin resistance and nvaries widely; it sometimes progresses to loss of beta cell function. Gestational ndiabetes is similar to type 2 diabetes, in that it involves insulin resistance; nthe hormones of pregnancy cause insulin resistance in those women genetically npredisposed to developing this condition.
Types 1 and n2 are incurable chronic conditions, but have been treatable since insulibecame medically available in 1921, and are nowadays usually managed with a ncombination of dietary treatment, tablets (in type 2) and, frequently, insulisupplementation. Gestational diabetes typically resolves with delivery.
Diabetes can cause many complications. Acute ncomplications (hypoglycemia, ketoacidosis or nonketotic hyperosmolar coma) may noccur if the disease is not adequately controlled. Serious long-term ncomplications include cardiovascular disease (doubled risk), chronic renal nfailure (diabetic nephropathy is the main cause of dialysis in developed world nadults), retinal damage (which can lead to blindness and is the most nsignificant cause of adult blindness in the non-elderly in the developed nworld), nerve damage (of several kinds), and microvascular damage, which may ncause erectile dysfunction (impotence) and poor healing. Poor healing of nwounds, particularly of the feet, can lead to gangrene which can require namputation — the leading cause of non-traumatic amputation in adults in the ndeveloped world. Adequate treatment of diabetes, as well as increased emphasis non blood pressure control and lifestyle factors (such as smoking and keeping a nhealthy body weight), may nimprove the risk profile of most aforementioned complications.
Role of the liver in lipid metabolism.
In the liver all processes of lipid metabolism take nplace. Most important of them are following:
1. Lipogenesis (synthesis of fatty acids and lipids). nSubstrate for this process – acetyl-CoA, formed from glucose and amino acids, which nare not used for another purposes. This process is very active when the persoeats a lot of carbohydrates. Liver more active than another tissues synthesizes nsaturated and monounsaturated fatty acids. Fatty acids then used for synthesis nof lipids, phospholipids, cholesterol ethers. Glycerol-3-phosphate, which is nnecessary for lipids synthesis, formed in liver in result of two processes: nfrom free glycerol under influence of glycerolkinase, or in reducing of ndioxiacetone phosphate under influence of glycerolphosphate dehydrogenase. nActive form of fatty acids interact with glycerol-3-phosphate and phosphatidic nacid formed, which used for synthesis of triacylglycerines and nglycerophospholipids.
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2. Liver play a central role in synthesis of ncholesterin, because near 80 % of its amount is synthesized there. Biosynthesis nof cholesterin regulated by negative feedback. When the level of cholesterin ithe meal increases, synthesis in liver decreases, and back to front. Besides nsynthesis regulated by insulin and glucagon. Cholesterin used in organism for nbuilding cell membranes, synthesis of steroid hormones and vitamin D. Excess of ncholesterin leads out in the bile to the intestine. Another part of cholesteriused for bile acids synthesis. This process regulated by reabsorbed bile acids naccording to negative feedback principles.
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3. Liver is a place of ketone bodies synthesis. These nsubstances formed from fatty acids after their oxidation, and from liver ntransported to another tissues, first of all to the heart, muscles, kidneys and nbrain. These substances are main source of energy for many tissues of our norganism excepting liver iormal conditions (heart) and during starvatio(brain).
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Transport forms of lipids
Certain lipids associate with specific proteins nto form lipoprotein systems in which the specific physical properties of these ntwo classes of biomolecules are blended. In these systems the lipids and nproteins are not covalently joined but are held together largely by hydrophobic ninteractions between the nonpolar portions of the lipid and the proteicomponents.
ransport lipoproteins of blood plasma. The plasma nlipoproteins are complexes in which the lipids and proteins occur in a nrelatively fixed ratio. They carry water-insoluble lipids between various norgans via the blood, in a form with a relatively small and constant particle ndiameter and weight. Human plasma lipoproteins occur in four major classes nthat differ in density as well as particle size. They are physically ndistinguished by their relative rates of flotation in high gravitational nfields in the ultracentrifuge.
The blood lipoproteins serve to transport nwater-insoluble triacylglycerols and cholesterol from one tissue to another. nThe major carriers of triacylglyeerols are chylomicrons nand very low density lipoproteins (VLDL).
The triacylglycerols of the chylomicrons and VLDL are ndigested in capillaries by lipoprotein lipase. The fatty acids that are nproduced are utilized for energy or converted to triacylglycerols and stored. nThe glycerol is used for triacylglycerol synthesis or converted to DHAP and noxidized for energy, either directly or after conversion to glucose in the nliver. The remnants of the chylomicrons are ntaken up by liver cells by the process of endocytosis and are degraded by nlysosomal enzymes, and the products are reused by the cell.
VLDL is converted to intermediate density lipoproteins (IDL), which is degraded by the liver or nconverted in blood capillaries to low ndensity lipoproteins LDL by further digestion of triacylglycerols. LDL is ntaken up by various tissues and provides cholesterol, which the tissue utilize
High density nlipoproteins (HDL) which is synthesized by the liver, transfers apoproteins to ehylomicrons nand VLDL.
HDL picks up cholesterol from cell membranes or from nother lipoproteins. Cholesterol is converted to cholesterol esters by the nlecithin:cholesterol acyltransferase (LCAT) reaction. The cholesterol esters nmay be transferred to other lipoproteins or carried by HDL to the liver, where nthey are hydrolyzed to free cholesterol, which is used for synthesis of VLDL or nconverted to bile salts.
Composition of the blood lipoproteins
The major components of lipoproteins are ntriacylglycerols, cholesterol, cholesterol esters, phospholipids, and proteins. nPurified proteins (apoproteins) are designated A, B, C, and E.
Chylomicrons are the least dense of the blood lipoproteins because nthey 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 nof triacylglycerol.
LDL has less triacylglycerol and more proteiand, therefore, is more dense than the IDL from which it is derived. LDL has the nhighest content of cholesterol and its esters.
HDL is the most dense lipoprotein. It has the nlowest triacylglycerol and the highest protein content.
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Metabolism of Chylomicrons
Chylomicrons nare synthesized in intestinal nepithelial cells. Their triacylglycerols are derived from dietary lipid, and ntheir major apoprotein is apo B-48.Chylomicrons travel through the lymph into nthe blood. In peripheral tissues, nparticularly adipose and muscle, the triacylglyerols are digested by lipoproteilipase.The chylomicron remnants interact with receptors on liver cells and nare taken+ up by endocytosis. The contents are degraded by lysosomal enzymes, and the products n(amino acids, fatty acids, glycerol, and cholesterol) are released into the ncytosol and reutilized.
Metabolism nof VLDL
VLDL is synthesized in the liver, particularly after a nhigh-carbohydrate meal. It is formed from triacylglycerols that are package nwith cholesterol, apoproteins (particularly apo B-100), and phospholipids and nit is released into the blood.
In peripheral tissues, nparticularly adipose and muscle, VLDL triacylglycerols are digested by lipoproteilipase, and VLDL is converted to IDL.
IDL returns to the liver, is taken up by endocytosis, and is degraded by nlysosomal enzymes.
IDL may also be further degraded by lipoproteilipase, forming LDL.
LDL reacts with nreceptors on various cells, is taken up by endocytosis and is digested by lysosomal enzymes.
Cholesterol, released from cholesterol esters by a nlysosomal esterase, can be used for the synthesis of cell memmbranes or bile nsalts in the liver or steroid hormones in endocrine tissue.
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Metabolism nof HDL.
HDL is synthesized by the liver and released into the nblood as disk-shaped particles. The major protein of HDL is apo A.
HDL cholesterol, obtained from cell membranes or from nother lipoproteins, is converted to cholesterol esters. As cholesterol esters naccumulate in the core of the lipoprotein, HDL particles become spheroids.
HDL particles are taken up by the liver by endocytosis nand hydrolyzed by lysosomal enzymes. Cholesterol, released from cholesterol nesters may be packaged by the liver in VLDL and released into the blood or nconverted to bile salts and secreted into the bile.
However, nthere is also considerable awareness that abnormal levels of certain lipids, nparticularly cholesterol (in hypercholesterolemia) and, more recently, trans fatty acids, are risk factors for heart disease and other diseases. We need fats in our nbodies and in our diet. Animals in general use fat for energy storage because nfat stores 9 KCal/g of energy. Plants, which don’t move naround, can afford to store food for energy in a less compact but more easily naccessible form, so they use starch (a carbohydrate, NOT A LIPID) for energy nstorage. Carbohydrates and proteins store only 4 KCal/g of energy, so fat nstores over twice as much energy/gram as other sources of energy.
We need fats nin our bodies and in our diet. Animals igeneral use fat for energy storage because fat stores 9 KCal/g of energy. nPlants, which don’t move around, can afford to store food for energy in a less ncompact but more easily accessible form, so they use starch (a carbohydrate, nNOT A LIPID) for energy storage. Carbohydrates and proteins store only 4 nKCal/g of energy, so fat stores over twice as much energy/gram as fat. By the nway, this is also related to the idea behind some of the high-carbohydrate nweight loss diets.
The nhuman body burns carbohydrates and fats for fuel in a given proportion to each other. nThe theory behind these diets is that if they supply carbohydrates but not nfats, then it is hoped that the fat needed to balance with the sugar will be ntaken from the dieter’s body stores. Fat is nalso is used in our bodies to a) cushion vital organs like the kidneys and b) nserve as insulation, especially just beneath the skin.
Role of the liver in protein metabolism.
Liver has full set of enzymes, which are necessary for namino acids metabolism. Amino acids from food used in the liver for following npathways:
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 namino group.
6. Release to the blood and transport to another norgans and tissues.
The high speed of protein synthesis and decompositiois typical for the liver. Hepatocytes catch different protein from blood (from nhemolysated RBC, denaturated plasma proteins, protein and peptide hormones) and ndecomposite them to the free amino acids which used for new synthesis. Wheorganism does not get necessary quantity of amino acids from food, liver synthesizes nonly high necessary proteins (enzymes, receptors).
Liver syntesizes 100 % of albumines, 90 % of nα1-globulines, 75 % of α2-globulines, 50 % of β-globulines, nblood clotting factors, fibrinogen, protein part of blood lipoproteins, such nenzyme as cholinesterase. The speed of these processes is enough high, for nexample, liver synthesizes 12-16g of albumines per day.
Amino acids, which are not used for protein synthesis, ntransformed to another substances. Oxidative decomposition of amino acids is nmain source of energy for liver iormal conditions.
Liver can synthesize non-essential amino acids.
Liver synthesizes purine and pyrimidine nucleotides, nhem, creatin, nicotinic acid, cholin, carnitin, polyamines.
The decomposition of hemoglobin itissues, bile pigments formation.
After na life span of about 120 days the erythrocytes die. The dead erythrocytes are ntaken up by the phagocytes of the reticuloendothelial system of the body. About n
1. The nprotein (globin) part is utilized partly as such or along with other body nproteins.
2. The niron is stored in the reticuloendothelial cells and is reused for the synthesis nof Hb and other iron containing substances of the body.
3. The nporphyrin part is converted to bile pigment, i.e. bilirubin which is excreted nin bile.
The nseveral stages, which are involved in the formation of bile pigment from Hb and nthe farther fate of this pigment, are given below:
1. nHemoglobin dissociates into heme and globin.
2. nHeme in the presence of the enzyme, heme oxygenase, loses one molecule nof CO and one atom of iron in Fe3+ form producing biliverdin. Ithis reaction, the porphyrin ring is cleaved by oxidation of the alpha methenyl nbridge between pyrrole rings. The enzyme needs NADPH+H+ and O2.
Biliverdiwhich is green in color is the first bile pigment to be produced; it is reduced nto the yellow-colored bilirubin, the main bile pigment, by the enzyme biliverdireductase requiring NADPH+H+.
Bilirubiis non-polar, lipid soluble but water insoluble. Bilirubin is a very toxic ncompound. For example, it is known to inhibit RNA and protein synthesis and ncarbohydrate metabolism in brain. Mitochondria appear to be especially nsensitive to its effect. Bilirubin formed in reticuloendothelial cells nthen is associated with plasma protein albumin to protect cells from the toxic neffects. As this bilirubin is in complex with plasma proteins, therefore it ncannot pass into the glomerular filtrate in the kidney; thus it does not appear nin urine, even when its level in the blood plasma is very high. However, being nlipid soluble, it readily gets deposited in lipid-rich tissues specially the nbrain.
This nbilirubin is called indirect bilirubin or free bilirubin or nunconjugated bilirubin.
The ndetoxication of indirect bilirubin takes place in the membranes of nendoplasmatic reticulum of hepatocytes. Here bilirubin interact with UDP-glucuronic nacid and is converted to the water soluble form -bilirubin mono- and ndiglucoronids. Another name of bilirubin mono- and diglucoronids is conjugated nbilirubin or direct bilirubin or bound bilirubin. This reaction is ncatalized by UDP-glucoroniltransferase.
Conjugated nbilirubin is water soluble and is excreted by hepatocytes to the bile. nConjugated (bound) bilirubin undergoes degradation in the intestine through the naction of intestinal microorganisms. Bilirubin is reduced and, mesobilirubiis formed. Then mesobilirubin is reduced again and mesobilinogen is nformed. The reduction of mesobilinogen results in the formation of stercobilinoge(in a colon). Stercobilinogen is oxidized and the chief pigment n(brown color) of feces stercobilin is formed. A part of mesobilinogeis reabsorbed by the mucous of intestine and via the vessels of vena nporta system enter liver. In hepatocytes mesobilinogen is splitted nto pyrol compounds which are excreted from the organism with bile. If nthe liver has undergone degeneration mesobilinogen enter the blood and is nexcreted by the kidneys. This mesobilinogen in urine is called urobilin, or ntrue urobilin. Thus, true urobilin can be detected in urine only nin liver parenchyma disease.
Another nbile pigment that can be reabsorbed in intestine is stercobolinogen. nStercobolinogen is partially reabsorbed in the lower part of colon into the nhaemorroidal veins. From the blood stercobolinogen pass via the nkidneys into the urine where it is oxidized to stercobilin. Another name nof urine stercobilin is false urobilin.
As nmentioned above, the conversion of bilirubin to mesobilirubin occurs under the ninfluence of intestinal bacteria. These bacteria are killed or modified whebroad-spectrum antibiotics are administered. The gut is sterile in the newborbabies. Under these circumstances, bilirubin is not-converted to urobilinogen, nand the feces are colored yellow due to bilirubin. The feces may even become ngreen because some bilirubin is reconverted to green-colored biliverdin by noxidation.
The total bilirubin content in the blood serum is n1,7-20,5 micromol/l, indirect (unconjugated) bilirubin content is 1,7-17,1 nmicromol/l and direct (conjugated) bilirubin content is 0,86-4,3 micromol/l.
Differentiation between unconjugated and conjugated bilirubin. Direct nand indirect bilirubin.
Diazo nreagent which is a mixture of sulfanilic acid, HCI and NaN02 is nadded to the serum. The conjugated bilirubin gives a reddish violet color with nit and the maximum color intensity is obtained within 30 seconds; this is called ndirect test.
The nunconjugated bilirubin does not give the direct test; however, it gives nindirect test in which alcohol or caffeine is also added which sets free the nbilirubin frum its complex with plasma proteins. Due to this difference in the ntype of diazo reaction given by these two forms of bilirubin, the term direct nand indirect forms of bilirubin are also used to describe conjugated nand unconjugated forms of bilirubin.
Some nother 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 ndevelopment, their biochemical characteristic.
Jaundice nor icterus is the orange-yellow discoloration of nbody tissues which is best seen in the skin and conjunctivae; it is caused by nthe presence of an excess of bilirubin in the blood plasma and tissue fluids. nDepending upon the cause of an increased plasma bilirubin level, jaundice cabe classified as
1) n pre-hepatic,
2) n hepatic and
3) n post-hepatic
Pre-hepafic jaundice. This ntype of jaundice is due to a raised plasma level of unconjugated bilirubin. It nis due to an excessive breakdown of red cells which leads to an increased productioof uncongugated bilirubin; it is also called haemolytic jaundice. As the nliver is not able to excrete into the bile all the bilirubin reaching it, the nplasma bilirubin level rises and jaundice results. This type of jaundice was ithe past called acholuric jaundice because the unconjugated bilirubin, being nbound to plasma proteins, is not excreted in the urine despite its high level nin the plasma; the urine is also without bile salts. Prehepatic jaundice is nalso seen ieonates (physiological jaundice) especially in the premature ones nbecause the enzyme UDP-glucuronyl transferase is deficient. Moreover relatively nmore bilirubin is produced in-the neonates because of excessive breakdown of nred blood cells.
Hepatic jaundice.This nis typically seen in viral hepatitis. Several viruses are responsible for viral nhepatitis and include hepatitis A, B, C and D viruses. The liver cells are ndamaged: inflammation produces obstruction of bile canaliculi due to swelling naround them. This cholestasis causes the bile to regurgitate into the blood nthrough bile canaliculi. The blood contains abnormally raised amount both of nconjugated and unconjugated bilirubin and bile salts which are excreted in the nurine.
Post hepatic jaundice. This nresults when there is extrahepatic cholestasis due to an obstruction in the nbiliary passages outside the liver. In this way, the bile cannot reach the nsmall intestine and therefore the biliary passages outside as well as inside nthe liver are distended with bile. This leads to damage to the liver and bile nregurgitates into the blood. The conjugated bilirubin and the bile salt levels nof the blood are thus greatly raised and both of these are excreted in the nurine. Liver function tests will vary according to the degree of obstruction, ni.e complete or incomplete. If the obstruction is complete, the stools become npale or clay-colored and the urine does not have any stercobilin. The nabsorption of fat and fat soluble vitamins also suffers due to a lack of bile nsalts. Excess of bile salts in the plasma produces severe pruritus (itching).
Hemolytic jaundice is ncharacterized by
1. nIncrease mainly of unconjugated bilirubin in the blood serum.
2. nIncreased excretion of urobilinogen with urine.
3. nDark brown colour of feces due to high content of stercobilinogen.
Hepatic jaundice is ncharacterized by
1.Increased levels of conjugated and unconjugated nbilirubin in serum.
2.Dark coloured urine due to the excessive excretioof bilirubin and urobilinogen.
3.Pale, clay coloured stools due to the absence nof stercobilinogen.
4.Increased activities of alanine and aspartate ntransaminases.
Obstructive (post nhepatic ) jaundice is characterized by
1.Increased concentration mainly of conjugated nbilirubin in serum.
2.Dark coloured urine due to elevated excretion of nbilirubin 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 nbody. The principal classes of xenobiotics of medical relevance are drugs, nchemical cancerogens, and various compounds that have found their way into our nenvironment by one route or another (insecticides, herbicides, pesticides, food nadditions, cosmetics, domestic chemical substances). Most of these compounds nare subject to metabolism (chemical alteration) in the human body, with the nliver being the main organ involved; occasionally a xenobiotics may be excreted nunchanged.
Some internal substances also have toxic properties n(for example, bilirubin, free ammonia, bioactive amines, products of amino nacids decay in the intestine). Moreover, all hormones and mediatores must be ninactivated.
Reactions of detoxification take place in the liver. nBig molecules like bilirubin excreted with the bile to intestine and leaded out nwith feces. Small molecules go to the blood and excreted via kidney with urine.
The metabolism of xenobiotics has 2 phases:
In phase 1, nthe major reaction involved is hydroxylation, catalyzed by members of a class nof enzymes referred to as monooxygenases or cytochrome P-450 species. These nenzymes can also catalyze deamination, dehalogenation, desulfuration, nepoxidation, peroxidation and reduction reaction. Hydrolysis reactions and nnon-P-450-catalyzed reactions also occur in phase 2.
In phase 2, nthe hydroxylated or other compounds produced in phase 1 are converted by nspecific enzymes to various polar metabolites by conjugation with glucuronic nacid, sulfate, acetate, glutathione, or certain amino acids, or by methylation.
The overall purpose of metabolism of xenobiotics is to nincrease their water solubility (polarity) and thus facilitate their excretiofrom the body via kidney.Very hydrophobic xenobiotics would persist in adipose ntissue almost indefinitely if they were not converted to more polar forms.
In certain cases, phase 1 metabolic reaction convert nxenobiotics from inactive to biologically active compounds. In these instances, nthe original xenobiotics are referred to as prodrugs or procarcinogens. Iother cases, additional phase 1 reactions convert the active compounds to less nactive or inactive forms prior to conjugation. In yet other cases, it is the nconjugation reactions themselves that convert the active product of phase 1 to nless active or inactive species, which are subsequently excreted in the urine nor bile. In a very few cases, conjugation may actually increase the biologic nactivity of a xenobiotics.
Hydroxylation is the chief reaction involved in phase n1. The responsible enzymes are called monooxygenases or cytochrome P-450 nspecies. The reaction catalyzed by a monooxygenase is:
RH + O2 + NADPH + H+ n→ R-OH + H2O + NADP
RH above can represent a very widee variety of drugs, carcinogens, npollutants, and certain endogenous compounds, such as steroids and a number of nother lipids. Cytochrome P-450 is considered the most versatile biocatalyst nknown. The importance of this enzyme is due to the fact that approximately 50 % nof the drugs that patients ingest are metabolized by species of cytochrome nP-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 nof the endoplasmic reticulum (ER) (microsomal fraction) of liver, where they ncan make up approximately 20 % of the total protein. Thay are also in other ntissues. In the adrenal, they are found in mitochondria as well as in the ER; nthe various hydroxylases present in that organ play an important role icholesterol and steroid biosynthesis.
3. There are at least 6 closely related species of ncytochrome P-450 present in liver ER, each with wide and somewhat overlapping nsubstrate specificities, that act on a wide variety of drugs, carcinogens, and nother xenobiotics in addition to endogenous compounds such as certain steroids.
4. NADPH, not NADP, is involved in the reactiomechanism of cytochrome P-450. The enzyme that uses NADPH to yield the reduced ncytochrome P-450 is called NADPH-cytochrome P-450 reductase.
5. Lipids are also components of the cytochrome P-450 nsystem. The preferred lipid is phosphatidylcholine, which is the major lipid nfound in membranes of the ER.
6. Most species of cytochrome P-450 are inducible. For ninstance, the administration of phenobarbital or of many other drugs causes a nhypertrophy of the smooth ER and a 3- to 4-fold increase in the amount of cytochrome nP-450 within 4-5 days. Induction of this enzyme has important clinical nimplications, since it is a biochemical mechanism of drug interaction.
7. One species of cytochrome P-450 has its ncharacteristic absorption peak not at 450 nm but at 448 nm. It is often called ncytochrome-448.This species appears to nbe relatively specific for the metabolism of polycyclic aromatic hydrocarbons n(PAHs) and related molecules; for this reason it is called aromatic hydrocarbohydroxylase (AHH). This enzyme is important in the metabolism of PAHs and icarcinogenesis produced by this agents.
8. Recent findings have shown that individual species nof cytochrome P-450 frequently exist in polymorphic forms, some of which nexhibit low catalytic activity. These observation are one important explanatiofor the variations in drug responses noted among many patients.
http://www.youtube.com/watch?v=3DgxjDalZW0
In phase 1 reactions, xenobiotics are generally nconverted to more polar, hydroxylated derivates. In phase 2 reactions, these nderivates are conjugated with molecules such as glucuronic acid, sulfate, or nglutatione. This renders them even more water-soluble, and they are eventually nexcreted in the urine or bile.
There are at least 5 types of phase 2 reactions:
1. nGlucuronidation. UDP-glucuronic acid is the glucuronyl donor, and na variety of glucuronyl transferases, present in both the ER and cytosol, are nthe catalysts. Molecules such as bilirubin, thyroxin, 2-acetylaminofluorene (a ncarcinogen), aniline, benzoic acid, meprobromate (a tranquilizer), phenol, ncrezol, indol and skatol, and many steroids are excreted as glucuronides. The nglucuronide may be attached to oxygen, nitrogen, or sulfur groups of nsubstrates. Glucuronidation is probably the most frequent conjugation reaction.
Glucuronidation, nthe combining of glucuronic acid with toxins, requires the enzyme UDP-glucuronyl ntransferase (UDPGT). Many of the commonly prescribed drugs are detoxified through nthis pathway. It also helps to detoxify aspirin, menthol, vanillin (synthetic nvanilla), food additives such as benzoates, and some hormones. Glucuronidatioappears to work well, except for those with Gilbert’s syndrome–a nrelatively common syndrome characterized by a chronically elevated serum nbilirubin level (1.2-3.0 mg/dl). Previously considered rare, this disorder is nnow known to affect as much as 5% of the general population. The condition is nusually without serious symptoms, although some patients do complain about loss nof appetite, malaise, and fatigue (typical symptoms of impaired liver nfunction). The main way this condition is recognized is by a slight yellowish ntinge to the skin and white of the eye due to inadequate metabolism of bilirubin, na breakdown product of hemoglobin. The activity of UDPGT is increased by foods nrich in the monoterpene limonene (citris peel, dill weed oil, and caraway oil). nMethionine, administered as SAM, has been shown to be quite beneficial itreating Gilbert’s syndrome.
2. Sulfation. nSome alcohols, arylamines, and phenols are sulfated. The sulfate donor in these nand other biologic sulfation reactions is adenosine n3´-phosphate-5´-phosphosulfate (PAPS); this compound is called nactive sulfate.
Sulfatiois the conjugation of toxins with sulfur-containing compounds. The sulfatiosystem is important for detoxifying several drugs, food additives, and, nespecially, toxins from intestinal bacteria and the environment. In addition to nenvironmental toxins, sulfation is also used to detoxify some normal body nchemicals and is the main pathway for the elimination of steroid and thyroid nhormones. Since sulfation is also the primary route for the elimination of nneurotransmitters, dysfunction in this system may contribute to the development nof some nervous system disorders.
Many nfactors influence the activity of sulfate conjugation. For example, a diet low nin methionine and cysteine has been shown to reduce sulfation. Sulfation is nalso reduced by excessive levels of molybdenum or vitamin B6 (over nabout 100 mg/day). In some cases, sulfation can be increased by supplemental nsulfate, extra amounts of sulfur-containing foods in the diet, and the amino nacids taurine and glutathione.
Sulfoxidatiois the process by which the sulfur-containing molecules in drugs and foods are nmetabolized. It is also the process by which the body eliminates the sulfite nfood additives used to preserve many foods and drugs. Various sulfites are nwidely used in potato salad (as a preservative), salad bars (to keep the nvegetables looking fresh), dried fruits (sulfites keep dried apricots orange), nand some drugs. Normally, the enzyme sulfite oxidase metabolizes sulfites nto safer sulfates, which are then excreted in the urine. Those with a npoorly functioning sulfoxidation system, however, have an increased ratio of nsulfite to sulfate in their urine. The strong odor in the urine after eating nasparagus is an interesting phenomenon because, while it is unheard of iChina, 100% of the French have been estimated to experience such an odor (about n50% of adults in the U.S. notice this effect). This example is an excellent nexample of genetic variability in liver detoxification function. Those with a npoorly functioning sulfoxidation detoxification pathway are more sensitive to nsulfur-containing drugs and foods containing sulfur or sulfite additives. This nis especially important for asthmatics, which can react to these additives with nlife-threatening attacks. Molybdenum helps asthmatics with an elevated ratio of nsulfites to sulfates in their urine because sulfite oxidase is dependent upothis trace mineral.
3. nConjugation with Glutathione. Glutathione n(γ-glutamylcysteinylglycine) is a tripeptide consisting of glutamic acid, ncysteine, and glycine. Glutathione is commonly abbreviated to GSH; the SH nindicates the sulfhydryl group of its cysteine and is the business part of the nmolecule. A number of potentially toxic electrophilic xenobiotics (such as ncertain carcinogens) are conjugated to the nucleophilic GSH. The enzymes ncatalyzing these reactions are called glutathione S-transferases and are npresent in high amounts in liver cytosol and in lower amounts in other tissues. nglutathione conjugates are subjected to further metabolism before excretion. nThe glutamyl and glycinyl groups belonging to glutathione are removed by nspecific enzymes, and an acetyl group (donated by acetyl-CoA) is added to the namino group of the remaining cystenyl moiety. The resulting compound is a nmercapturic acid, a conjugate of L-acetylcysteine, which is then excreted ithe urine.
Glutathione is also aimportant antioxidant. This combination of detoxification and free radical nprotection, results in glutathione being one of the most important nanticarcinogens and antioxidants in our cells, which means that a deficiency is ncause of serious liver dysfunction and damage. Exposure to high levels of ntoxins depletes glutathione faster than it can be produced or absorbed from the ndiet. This results in increased susceptibility to toxin-induced diseases, such nas cancer, especially if phase I detoxification system is highly active. nDisease states due to glutathione deficiency are not uncommon.
A ndeficiency can be induced either by diseases that increase the need for nglutathione, deficiencies of the nutrients needed for synthesis, or diseases nthat inhibit its formation. Smoking increases the rate of utilization of nglutathione, both in the detoxification of nicotine and in the neutralizatioof free radicals produced by the toxins in the smoke. Glutathione is available nthrough two routes: diet and synthesis. Dietary glutathione n(found in fresh fruits and vegetables, cooked fish, and meat) is absorbed well nby the intestines and does not appear to be affected by the digestive nprocesses. Dietary glutathione in foods appears to be efficiently absorbed into nthe blood. However, the same may not be true for glutathione supplements.
Ihealthy individuals, a daily dosage of 500 mg of vitamin C may be sufficient to nelevate and maintain good tissue glutathione levels. In one double-blind study, nthe average red blood cell glutathione concentration rose nearly 50% with 500 nmg/day of vitamin C. Increasing the dosage to 2,000 mg only raised red blood ncell (RBC) glutathione levels by another 5%. Vitamin C raises glutathione by increasing nits rate of synthesis. In addition, to vitamin C, other compounds which cahelp increase glutathione synthesis include N-acetylcysteine (NAC), glycine, nand methionine. In an effort to increase antioxidant status iindividuals with impaired glutathione synthesis, a variety of antioxidants have nbeen used. Of these agents, only microhydrin, vitamin C and NAC have nbeen able to offer some possible benefit.
Over nthe past 5-10 years, the use of NAC and glutathione products as antioxidants nhas become increasingly popular among nutritionally oriented physicians and the npublic. While supplementing the diet with high doses of NAC may be beneficial nin cases of extreme oxidative stress (e.g. AIDS, cancer patients going through nchemotherapy, or drug overdose), it may be an unwise practice in healthy nindividuals.
4. Acetylation. nThese reactions is represented by X + nAcetyl-CoA → Acetyl-X + CoA, where X represents a xenobiotic. These nreactions are catalyzed by acetyltransferases present in the cytosol of various ntissues, particularly liver. The different aromatic amines, aromatic amino nacids, such drug as isoniazid, used in the treatment of tuberculosis, and nsulfanylamides are subjects to acetylation. Polymorphic types of nacetyltransferases exist, resulting in individuals who are classified as slow nor fast acetylators, and influence the rate of clearance of drugs such as nisoniazid from blood. Slow acetylators are more subject to certain toxic neffects of isoniazid because the drug persists longer in these individuals.
Conjugatioof toxins with acetyl-CoA is the primary method by which the body neliminates sulfa drugs. This system appears to be especially sensitive to ngenetic variation, with those having a poor acetylation system being far more nsusceptible to sulfa drugs and other antibiotics. While not much is known about nhow to directly improve the activity of this system, it is known that nacetylation is dependent on thiamine, pantothenic acid, and vitamin C.
5. Methylation. nA few xenobiotics (amines, phenol, tio-substances, inorganic compounds of nsulphur, selen, mercury, arsenic) are subject to methylation by nmethyltransferases, employing S-adenosylmethionine as methyl donor. Also ncatecholamines and nicotinic acid amid (active form of vitamin PP) are ninactivated due to methylation.
Very important way of detoxification is ureogenes n(urea synthesis). Free ammonia, which formed due to metabolism of amino acids, namides and amines, removed from organism in shape of urea.
Methylatioinvolves conjugating methyl groups to toxins. Most of the methyl groups nused for detoxification come from S-adenosylmethionine (SAM). SAM is nsynthesized from the amino acid methionine, a process which requires the nnutrients choline, vitamin B12, and folic acid. SAM is able to ninactivate estrogens (through methylation), supporting the use of methionine iconditions of estrogen excess, such as PMS. Its effects in preventing nestrogen-induced cholestasis (stagnation of bile in the gall bladder) nhave been demonstrated in pregnant women and those on oral contraceptives. Iaddition to its role in promoting estrogen excretion, methionine has been showto increase the membrane fluidity that is typically decreased by estrogens, nthereby restoring several factors that promote bile flow. Methionine also npromotes the flow of lipids to and from the liver in humans. Methionine is a nmajor source of numerous sulfur-containing compounds, including the amino acids ncysteine and taurine.
Are there things that support liver detoxification?
Nutritional factors
Antioxidant nvitamins like vitamin C, beta-carotene, and vitamin E are obviously quite nimportant in protecting the liver from damage as well as helping in the ndetoxification mechanisms, but even simple nutrients like B-vitamins, calcium, nand trace minerals are critical in the elimination of heavy metals and other ntoxic compounds from the body. The lipotropic agents, choline, betaine, nmethionine, vitamin B6, folic acid, and vitamin B12, are nuseful as they promote the flow of fat and bile to and from the liver. nLipotropic formulas have been used for a wide variety of conditions by nnutrition-oriented physicians including a number of liver disorders such as nhepatitis, cirrhosis, and chemical-induced liver disease. Lipotropic nformulas appear to increase the levels of SAM and glutathione. Methionine, ncholine, and betaine have been shown to increase the levels of SAM.
Botanical medicines
There is a nlong list of plants which exert beneficial effects on liver function. However, nthe most impressive research has been done on silymarin, the flavonoids nextracted from silybum marianum (milk thistle). These compounds exert a nsubstantial effect on protecting the liver from damage as well as enhancing ndetoxification processes. Silymarin prevents damage to the liver through several nmechanisms: by acting as an antioxidant, by increasing the synthesis of nglutathione and by increasing the rate of liver tissue regeneration. Silymariis many times more potent in antioxidant activity than vitamin E and vitamin C. nThe protective effect of silymarin against liver damage has been demonstrated niumerous experimental studies. Silymarin has been shown to protect the liver nfrom the damage produced by such liver-toxic chemicals as carbotetrachloride, amanita toxin, galactosamine, and praseodymium nitrate.
One of the nkey mechanisms by which silymarin enhances detoxification is by preventing the ndepletion of glutathione. Silymariot only prevents the depletion of nglutathione induced by alcohol and other toxic chemicals, but has been shown to nincrease the level of glutathione of the liver by up to 35%, even iormals. nInhuman studies, silymarin has been shown to have positive effects in treating nliver diseases of various kinds, including cirrhosis, chronic hepatitis, fatty ninfiltration of the liver, and inflammation of the bile duct. The standard ndosage for silymarin is 70-210 mg three times/day.
Amino acid nconjugation
Several amino nacids (glyucine, taurine, glutamine, arginine, and ornithine) are nused to combine with and neutralize toxins. Of these, glycine is the most ncommonly utilized in phase II amino acid detoxification. Patients suffering nfrom hepatitis, alcoholic liver disorders, carcinomas, chronic arthritis, nhypothyroidism, toxemia of pregnancy, and excessive chemical exposure are commonly nfound to have a poorly functioning amino acid conjugation system. For example, nusing the benzoate clearance test (a measure of the rate at which the nbody detoxifies benzoate by conjugating it with glycine to form hippuric acid, nwhich is excreted by the kidneys), the rate of clearance in those with liver ndisease is 50% of that in healthy adults.
Even iapparently normal adults, a wide variation exists in the activity of the nglycine conjugation pathway. This is due no only to genetic variation, but also nto the availability of glycine in the liver. Glycine, and the other amino acids nused for conjugation, become deficient on a low-protein diet and when chronic nexposure to toxins results in depletion.
Dietary Changes
Adding ncertain supplements to your diet can stimulate detoxification. Fiber, vitamin C nand other antioxidants, chlorophyll, and glutathione (as the amino acid nL-cysteine) will all help. Herbs such as garlic, red clover, echinacea, or ncayenne may also induce some detoxification. Saunas, sweats, and niacin therapy nhave been used to cleanse the body.
Simply nincreasing liquids and decreasing fats will shift the balance strongly toward nimproved elimination and less toxin buildup. Changes might include increased nconsumption of filtered water, herb teas, fruits, and vegetables, as well as nreducing fats, especially fried food, meat and milk products. In general, nmoving from an acid-generating diet to a more alkaline one will aid the process nof detoxification. Acid-forming foods, such as meats, milk products, breads and nbaked goods, and especially the refined sugar and carbohydrate products, will nincrease body acidity and lead to more mucus production and congestion, whereas nthe more alkaline vegetarian foods enhance cleansing and clarity in the body. n
A deeper nlevel of detoxification diet is made up exclusively of fresh fruits and nvegetables, either raw and cooked, and whole grains, both cooked and sprouted. nThis diet keeps fiber and water intake high and helps colon detoxification. nMost people can handle this well and make the shift from their regular diet nwith a few days transition. Some people do well on a brown rice fast (a more nmacrobiotic plan), usually for a week or two, eating three to four bowls of nrice daily along with liquids such as teas.”
Role of liver in excretion.
Bile is an important vehicle for bile acid and ncholesterol excretion, but it also removes many drugs, toxins, bile pigments, nand various inorganic substances such as copper, zinc, and mercury.
Evaluating of liver’s functions.
Different methods are used for evaluating of liver’s nfunctions. Base for some of them is role of liver in proetin metabolism (e.g. nthymol’s test), for another – role of liver in detoxification (indican’s test) nor in excretion (checking of bilirubin level in blood). In all cases physiciamust make a conclusion about disorder of liver’s functions after complex ninvestigation, because, as mentioned above, all metabolic ways are present iliver.
The nliver filter can remove a wide range of microorganisms such as bacteria, fungi, nviruses and parasites from the blood stream, which is highly desirable, as we ncertainly do not want these dangerous things building up in the blood stream nand invading the deeper parts of the body. Infections with parasites often come nfrom the contaminated water supplies found in large cities, and indeed other ndangerous organisms may find their way into your gut and blood stream from nthese sources. This can cause chronic infections and poor health, so it is nimportant to protect your liver from overload with these microorganisms. The nsafest thing to do is boil your water for at least 5 minutes, or drink only nbottled water that has been filtered and sterilized. High loads of unhealthy nmicroorganisms can also come from eating foods that are prepared in conditions nof poor hygiene by persons who are carrying bacteria, viruses or parasites otheir skin. Foods, especially meats that are not fresh or are preserved, also ncontain a higher bacterial load, which will overwork the liver filter if they nare eaten regularly.
Recently, nit has become very fashionable for people to detoxify their bodies by various nmeans, such as fasting or cleansing the bowels with fiber mixtures. Fasting caby its extreme nature, only be a temporary method of cleansing the body of nwaste products, and for many people causes an excessively rapid release of ntoxins which can cause unpleasant, acute symptoms. The liver filter, like any nfilter, needs to be cleansed regularly, and it is much easier and safer to do nit everyday. This is easily and pleasantly achieved by adopting a daily eating npattern that maintains the liver filter in a healthy clean state. By following nthe methods and guidelines on this site, you will be able to keep the liver nfilter healthy and clean. Although it is important to keep the intestines nmoving regularly and to sweep their walls with high fiber and living foods, it is nimportant to remember that the bowels are really a channel of elimination and nnot a cleansing organ per se. In other words the bowels cannot cleanse, filter nor remove toxic wastes from the blood stream.
The liver is the most important organ in detoxification, nas it is the body’s premier cleansing organ. All the blood in the body passes nthrough the liver, which removes toxins, impurities, and debris from the nbloodstream.
The nliver stores fat-soluble substances; these can include chemicals, which can be nstored in the liver for years. Using enzymes, the liver transforms these nchemicals into water-soluble substances that can be excreted though the kidneys nor the gastrointestinal tract.
Hormones nare metabolized by the liver. Estrogen produced by the body and from hormone nreplacement therapies is broken down. If estrogen is not adequately processed, nexcess estrogen can result in endometriosis; high blood pressure; PMS; and nbreast, uterine, and vaginal cancer.
The nliver also manufactures bile to digest fats; chemically changes many foods into nvitamins and enzymes; converts carbohydrates and proteins into glucose for nbrain fuel and glycogen for muscular energy; and stores nutrients to be nsecreted as needed by the body to build and maintain cells.
If nthe liver cannot perform these jobs well, you may exhibit a number of symptoms. nThese include gas; constipation; a feeling of fullness; loss of appetite; nnausea after fatty meals; an oily taste in the mouth; revulsion to fatty foods; nfrequent headaches not related to stress; weak ligaments, tendons, and muscles; nskin problems; and emotional excesses.
What Can Affect the Liver?
Briefly nput, living. What you eat, where you live, and what you do all can affect the nliver’s performance. If you consume a lot of processed foods, the additives caeventually affect the liver. If you live in an area that is highly polluted, nexposure to chemicals in the air and water affects the liver. All of this cahurt the liver’s performance.
An impaired nliver does not process food or detoxify substances as rapidly or as completely nas a healthy liver. If the liver is not producing enough bile, it cannot nadequately digest fats. If the liver is detoxifying more slowly than it should, nit can result in more toxic substances circulating in the body.
If toxins ncontinue to accumulate, the liver may not be able to work fast enough to cleathe blood. It is like being on a treadmill that is going a little too fast: try nas you might, you cannot go forward, but instead are swept back into greater ntoxicity. Instead of being converted into something useful or being eliminated, ntoxins remain unchanged. They are eventually stored in fatty body tissue and ithe cells of the brain and central nervous system. The stored toxins may be nslowly released to recirculate in the blood, contributing to many chronic nillnesses.
A toxin is nbasically any substance that creates irritating and/or harmful effects in the nbody; stressing and undermining one’s biochemical health and organ function. nToxins can come from by products of normal cell metabolism or from the outside nenvironment e.g. pollution, drugs, pesticides, dyes, chemicals, microbes, heavy nmetals, tobacco smoke and so on.
Toxicity noccurs when we take in more then we can utilize and eliminate. Toxic chemicals ncan be a real problem, since after years of exposure to these substances the nbody’s ability to eliminate them can slow down. They can get recirculated into nthe bloodstream or stored in the liver, body fat or other parts of the body. nThese types of buildups and problems throughout the body can contribute to the ndevelopment of serious illnesses. Many chemicals are so widespread that we are nunaware of them. But they have worked their way into our bodies faster thathey can be eliminated, and are causing allergies and addictions in record nnumbers. The body’s built in detoxification apparatus include the respiratory, ngastrointestinal, urinary, skin and lymphatic systems.
Symptoms nof Toxicity
nCancer and cardiovascular disease are two of the main toxicity-related diseases. nArthritis, allergies, obesity, and many skin problems are others. In addition, na wide range of symptoms, such as headaches, fatigue, pains, coughs, ngastrointestinal problems and problems from immune weakness can all be related nto toxicity.
Common indications nof toxicity include frequent, unexplained headaches, back or joint pain, tight nor stiff neck, arthritis, chronic respiratory or sinus problems, asthma, nabnormal body odor, bad breath, coated tongue, food allergies, poor digestion, nchronic constipation with intestinal bloating or gas, brittle nails and hair, npsoriasis, adult acne, unexplained weight gain over
Detoxificatiois the process of clearing toxins from the body or neutralizing them. Energy nbalancing and detoxification herbal baths prompt the body to eliminate toxins nfrom specific areas of the body. As these toxins are released from the nareas where they have been stored, they move into the blood, lymph and other nbody fluids out of the body through the urinary, gastrointestinal, lymphatic nand respiratory systems and the skin. The period of detoxification can be na few days, a few weeks or a months depending on the extent, location and ntype of the toxins in the body. As a person is detoxifying they may nexperience uncomfortable symptoms including depression, mood changes, nausea, ndiarrhea , foggy head, fatigue, lack of energy, bad breathe, foul urine odour, nfoul perspiration odour, body odour, sores, rashes, acne, cold or flu like nsymptoms, headaches or any other symptom. This period where symptoms may nseem to worsen is sometimes called a healing crisis, but is actually just the nbody’s reacting to the presence of the toxins in the bloodstream and the nmovement of the toxins out of the body. .
How does the body get rid of toxins?
“The nliver is one of the most important organs in the body when it comes to ndetoxifying or getting rid of foreign substances or toxins. The liver plays a nkey role in most metabolic processes, especially detoxification. The liver nneutralizes a wide range of toxic chemicals, both those produced internally and nthose coming from the environment. The normal metabolic processes produce a nwide range of chemicals and hormones for which the liver has evolved efficient nneutralizing mechanisms. However, the level and type of internally produced ntoxins increases greatly when metabolic processes go awry, typically as a result nof nutritional deficiencies. These non-end-product metabolites have become a nsignificant problem in this age of conventionally grown foods and poor diets.
Many of the ntoxic chemicals the liver must detoxify come from the environment: the content nof the bowels and the food, water, and air. The polycyclic hydrocarbons n(DDT, dioxin, 2,4,5-T, 2,3-D, PCB, and PCP), which are components of various nherbicides and pesticides, are an example of chemicals that are now found ivirtually all fat tissues measured. Even those eating unprocessed organic foods nneed an effective detoxification system because all foods contaiaturally noccurring toxic constituents.
The liver nplays several roles in detoxification: it filters the blood to remove large ntoxins, synthesizes and secretes bile full of cholesterol and other fat-soluble ntoxins, and enzymatically disassembles unwanted chemicals. This enzymatic nprocess usually occurs in two steps referred to as phase I and phase nII. Phase I either directly neutralizes a toxin, or modifies the toxic nchemical to form activated intermediates which are theeutralized by one of nmore of the several phase II enzyme systems.
Proper nfunctioning of the liver’s detoxification systems is especially important for nthe prevention of cancer. Up to 90% of all cancers are thought to be due to the neffects of environmental carcinogens, such as those in cigarette smoke, food, nwater, and air, combined with deficiencies of the nutrients the body needs for nproper functioning of the detoxification and immune systems. The level of nexposure to environmental carcinogens varies widely, as does the efficiency of nthe detoxification enzymes, particularly phase II. High levels of exposure to ncarcinogens coupled with slow detoxification enzymes significantly increases susceptibility nto cancer.
How does the liver remove toxins from the body?
One of nthe liver’s primary functions is filtering the blood. Almost
Bile Excretion
The liver’s nsecond detoxification process involves the synthesis and secretion of bile. nEach day the liver manufactures approximately
What nhappens when excretion of bile is inhibited?
When the nexcretion of bile is inhibited (i.e. cholestasis), toxins stay in the nliver longer. Cholestasis has several causes, including obstruction of the bile nducts and impairment of bile flow within the liver. The most common cause of nobstruction of the bile ducts is the presence of gallstones. Currently, it is nconservatively estimated that 20 million people in the U.S. have gallstones. nNearly 20% of the female and 8% of the male population over the age of 40 are nfound to have gallstones on biopsy and approximately 500,000 gall bladders are nremoved because of stones each year in the U.S. The prevalence of gallstones ithis country has been linked to the high-fat, low-fiber diet consumed by the nmajority of Americans.
Impairment of nbile flow within the liver can be caused by a variety of agents and conditions. nThese conditions are often associated with alterations of liver function ilaboratory tests (serum bilirubin, alkaline phosphatase, SGOT, LDH, GGTP, netc.) signifying cellular damage. However, relying on these tests alone to nevaluate liver function is not adequate, since, in the initial or subclinical nstages of many problems with liver function, laboratory values remaiormal. nAmong the symptoms people with enzymatic damage complain of are:
Fatigue; general nmalaise; digestive disturbances; allergies and chemical sensitivities; npremenstrual syndrome; constipation
Perhaps the nmost common cause of cholestasis and impaired liver function is alcohol ningestion. In some especially sensitive individuals, as little as
Oranges and ntangerines (as well as the seeds of caraway and dill) contain limonene, na phytochemical that has been found to prevent and even treat cancer in animal nmodels. Limonene’s protective effects are probably due to the fact that it is a nstrong inducer of both phase I and phase II detoxification enzymes that nneutralize carcinogens.
Are there things that inhibit detoxification?
Grapefruit juice decreases the rate nof elimination of drugs from the blood and has been found to substantially nalter their clinical activity and toxicity.
Curcumin, nthe compound that gives turmeric its yellow color, is interesting because it inhibits nphase I while stimulating phase II. This effect can be very useful ipreventing certain types of cancer. Curcumin has been found to inhibit ncarcinogens, such as benzopyrene (found in charcoal-broiled meat), from ninducing cancer in several animal models. It appears that the curcumin exerts nits anti-carcinogenic activity by lowering the activation of carcinogens while nincreasing the detoxification of those that are activated. Curcumin has also nbeen shown to directly inhibit the growth of cancer cells.
As most of nthe cancer-inducing chemicals in cigarette smoke are only carcinogenic during nthe period between activation by phase I and final detoxification by phase II, ncurcumin in the turmeric can help prevent the cancer-causing effects of ntobacco. Those exposed to smoke, aromatic hydrocarbons, and other environmental ncarcinogens will probably benefit from the frequent use of curry or turmeric.
The activity nof phase I detoxification enzymes decreases in old age. Aging also decreases nblood flow through the liver, further aggravating the problem. Lack of the physical nactivity necessary for good circulation, combined with the poor nutritiocommonly seen in the elderly, add up to a significant impairment of ndetoxification capacity, which is typically found in aging individuals. This nhelps to explain why toxic reactions to drugs are seen so commonly in the nelderly.
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Liver failure, or hepatic failure, is severe deterioration of liver functio resulting from extensive damage of liver cells. The syndrome respresents a severe clinical condition and is associated with high mortality; therefore, a great challenge to intensive care management. Causes Symptoms Pathobiochemistry |
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Jaundice nis a cause for concern and there are many misconceptions associated with it. Dr nVikram Ananthakrishnan (M.S., F.R.C.S) answers some frequently asked questions nabout this common ailment and about the liver.
Jaundice ncan be broadly classified as infective and obstructive jaundice.
A nvirus called Hepatitis A, is a common cause of infective jaundice. This virus nis transmitted through water and food. Children are often affected.
The nother viruses such as Hepatitis B and Hepatitis C viruses are transmitted nthrough blood. Viruses responsible for these infections spread through the body nsecretions like saliva, sweat, semen, vaginal fluids of infected persons. Close ncontact and sexual intercourse are important factors in spread. Homosexuals ncontract these infections more easily. Blood, blood products, contaminated nneedles and tattooing, are also important sources through which infectiospreads. These viruses are more resistant to the various methods of nsterilisation than the AIDS virus. They are a major cause for concern as they nspread rapidly. There are more people infected by Hepatitis B virus in the nworld than the AIDS virus.
Hepatitis nB and Hepatitis C infections can lead to chronic liver diseases, cirrhosis and neventually liver cancer & liver failure.
The nother viruses associated with jaundice are Hepatitis D and E. Hepatitis E ninfection can be acquired from contaminated water.
Diseases nlike Leptospirosis can also cause jaundice.
Stones nor growths, blocking the pathway of bile, cause a type of jaundice called nobstructive jaundice. Occasionally, drugs can also cause jaundice.
How nis Leptospirosis transmitted and how is it treated?
This nis an infection caused by water or food contaminated with rats’ urine. Patients ndevelop fever and later jaundice and eventually (renal) kidney failure. If left nunrecognised leptospirosis can be fatal. The infection is treated with nantibiotics like penicillin and doxycycline.
Amongst nthe different types of infective jaundice, which is worse?
Hepatitis nC is the most dangerous type of jaundice. Like Hepatitis B it also leads to nchronic liver disease.
Which nform of jaundice requires surgery?
Sometimes nstones & growths block the pathway of bile drainage from the liver (where nit is made) to the small intestine (where it acts on the food to digest and nbreak down fats). This can also cause jaundice. Stones in the bile pathway nusually originate in the gall bladder. This often requires removal of the gall nbladder along with the stones in the biliary pathway. Growths may require major nsurgery for their removal. In case they are very advanced, a bypass operatiomay need to be done to relieve the jaundice.
What nare the tests (investigations) done for jaundice?
These ncan be broadly classified as blood tests, scans and endoscopy.
Blood ntests are done to assess the overall function of the liver. These tests are ncollectively called Liver Function Tests.
These ntests will show if there is on going destruction of the liver. Blood tests will nhelp identify the type of jaundice.
They nwill show whether the synthetic function of the liver is good. The various nclotting tests can be done to see if the liver is producing adequate proteins nfor clotting purposes.
Ultrasound nscan is done to see if there are any gross architectural abnormalities in the nliver. What cannot be captured by ultrasound can be done by CT scan and the nMRI. M.R.I has now become the gold standard in looking for abnormalities in the nliver and the surrounding organs when there is obstructive jaundice.
Endoscopy nmay be performed to look at the oesophagus (food pipe), stomach and the first nfew inches of the small intestine. A special variety of endoscope may also be nused wherein a dye can be injected into the bile ducts and the pancreatic ducts nand pictures can be taken. This gives complete visualisation of the pathway nthat bile takes to drain into the small intestine. It also studies the ducts of nthe pancreas. It is called E.R.C.P. (endoscopic retrograde cholangio npancreaticogram).
What nis the diet recommended for jaundice patients?
Foods nthat are rich in glucose are recommended in jaundice. These help the liver ncells to regenerate and also provide the required nourishment for the body. nFats are to be taken in reduced quantities. Deep fried foods & alcohol are nto be avoided.
What nis the treatment for Jaundice?
The treatment for jaundice depends upon the ntype of jaundice. For viral hepatitis, causing jaundice, there is no definitive ntreatment. Only supportive measures are given. The virus is slowly eliminated nfrom the body with the help of the immune system.
Icase it is jaundice caused by blockage to the pathway of bile, surgery may be nneeded.
What nis the role of immunisation in Jaundice?
Hepatitis nB is one of the common causes of jaundice that can have serious consequences. nImmunising a person can prevent this viral infection and its consequences. The nvaccine is easily available and is usually given in three doses either at nmonthly intervals or two doses are given at monthly intervals and the third six nmonths after the first dose. Immunisation with the vaccine now begins from the ninfant period itself. A single booster dose is required once every five years nto maintain the protection.
What nis the role of Herbs in treating Jaundice?
The ncommon herb used is Keezhanelli. Its role in treatment is not fully proven.
The nliver has a variety of functions. Its two main functions are synthesising and ndetoxifying.
Synthesising:
It nhelps to break down and store various nutrients like carbohydrates, proteins nand fat.
Whenever nthere is excess glucose in the blood, it converts it to fat and stores it.
If nthe blood glucose levels are low it breaks down fat and protein into glucose.
It nstores vitamins A, D, K , B12, Folate.
Liver nis responsible for a variety of protein syntheses. It helps in the synthesis of nsubstances for clotting of blood, as well as albumin (the most important nprotein).
Detoxyfying
It nbreaks down drugs, alcohol and poisons absorbed from the intestines.
It nis said that, “Liver failure is power failure.”
What nis the relation between alcohol and Liver disease?
The nliver takes up alcohol from the blood stream. (One of the main functions of the nliver is to clean up the blood of various poisons and the intestines from invading norganisms.) The liver breaks down alcohol (metabolises) and thus bears the nbrunt of this poison. Intake of 3 units of alcohol or more in men and 2 or more nunits in women for more than five years causes disease.
What nis cirrhosis of the liver?
Cirrhosis nof the liver is the end result of various insults on the liver. The insults ncould be poisons or viruses. It is a process wherein the normal liver tissue is nreplaced by non-functioning fibrous tissue. This alters the blood flow withithe liver causing other pathways to open thus resulting in various ncomplications.
What nare the complications of cirrhosis liver?
Complications nare:
Fluid nretention causing large and distended abdomen.
This nretention of fluids with a reduction in the synthesis of proteins can lead oto swelling of the legs (Oedema).
There ncan be Anaemia (low Haemoglobin) and susceptibility to infections.
The nblood flow through the liver could be blocked causing alternate pathways to nopen up. This leads to dilatation of veins especially in the lower end of the nfood pipe (oesophagus). These veins can rupture causing massive bleeding. The nliver can fail in its function of removing various poisons in the body causing naltered behaviour patterns and eventually coma and death.
Biochemistry nof Liver Function
Ithe past, the liver has been referred to as the center of courage, passion, ntemper, and love and even as the center of the soul. it was once believed to nproduce “yellow bile” necessary for good health. Today, the liver is na complex organ responsible for many major metabolic functions in the body. nMore than 100 tests measuring these diverse functions have existed in the nclinical laboratory at one time. However, many were abandoned in favor of those nthat have proven to be most clinically useful.
The nliver performs several hundred functions each day. These function can be nclassified into the following:
1.Excretory nFunction
2. nSynthetic Function
3. nDetoxification Function
1. nExcretory Function
One nof the more important liver functions, and one that is disturbed in a large nnumber of hepatic disorders, is the excretion of bile.
The nexcretion of bile:
Bile ncomprises bile salts, bile acids, bile pigments (primarily bilirubin), ncholesterol, and other substances extracted from the blood. Total bile productioaverages about
Bile nacids: The primary bile acids are cholic acid and chenodcoxycholic acid. They nare formed in the liver from cholesterol. The bile acids are conjugated with nthe amino acids glycine or taurine, forming bile salts. Bile salts (conjugated nbile acids) are excreted into the bile canaliculi by means of a carriermediated nactive transport system. During fasting and between meals, a major portion of nthe bile acid pool is concentrated up to 10-fold in the gallbladder. Bile acids nreach the intestine when the gallbladder contracts after each meal. nApproximately 500-600 mL of bile enter the duodenum each day.
Bile nsalts help in the digestion and absorption of lipids. When the conjugated bile nacids (salts) come into contact with bacteria in the terminal ileum and colon, ndehydration to secondary bile acids (deoxycholic and lithocolic) occurs, and nthese secondary bile acids are subsequently absorbed. The absorbed bile acids nenter the portal circulation and return to the liver, where they are nreconjugated and reexcreted. The enterohepatic circulation of bile occurs 2-5 ntimes daily.
Bilirubiis the principal pigment in bile. It is formed by the breakdown of hemoglobiwhen red blood cells are phagocytized by the reticuloendothelial system. The nreticuloendothelial system is mainly in the spleen, liver, and bone marrow. nAbout 80% of the bilirubin formed daily comes from the degradation of nhemoglobin. The remainder comes from destruction of hemecontaining proteins n(myoglobin, cytochromes, catalase) and catabolism of heme. When hemoglobin is ndestroyed, the protein portion -globin- is reused by the body. The iron enters nthe body’s iron stores and is also reused.
The nporphyrin ring is changed to biliverdin, which is easily reduced to bilirubin. nBilirubin is transported to the liver in the bloodstream bound to albumin. This nbilirubin is referred to as unconjugated bilirubin or indirect bilirubin.
At nthe liver, unconjugated bilirubin is separated from the albumin and taken up by nthe hepatic cells. Two nonalbumin proteins, isolated from liver cell cytoplasm nand designated Y and Z, account for the intracellular binding and transport of nbilirubin. Conjugation of bilirubin occurs in the hepatocytes. An enzyme, nuridyldiphosphate glucuronyl transferase (UDPGT), transfers glucuronic acid nmolecules to bilirubin, converting bilirubin into a diglucuronide ester. This nproduct, bilirubin diglucuronide, is referred to as conjugated bilirubin or ndirect bilirubin. Conjugated bilirubin is water soluble. It is secreted from nthe hepatic cell into the bile canaliculi and then into larger bile ducts and neventually into the intestine. In the colon, the bile pigments are acted on by nenzymes of the intestinal bacteria. The first product of this reaction is nmesobilirubin, which is reduced to form mesobilirubinogen. This produces nurobilinogen which is a colorless product. The oxidation of urobilinogeproduces the red-brown pigment urobilin, which is excreted in the stool.
A nsmall portion of the urobilinogen is reabsorbed into the portal circulation and nreturned to the liver, where it is again excreted with the bile into the nintestine. This is called enterohepatic circulation of bile pigments. However, na small quantity of urobilinogen remains in the blood. This urobilinogen, which nis colorless, is ultimately filtered by the kidney and excreted in the urine.
A ntotal of 200-300 mg of bilirubin is produced daily in the healthy adult. A nnormally functioning liver is required to eliminate this amount of bilirubifrom the body. This excretory function requires that bilirubin be in the nconjugated form; that is, the water-soluble diglucuronide. Almost all the nbilirubin formed is eliminated in the feces, and a small amount of the ncolorless product urobilinogen is excreted in the urine.
Reference nValue of Bilirubins:
• nTotal bilirubin 0.2 – 1.0 mg/dL
• nDirect (Conjugated) 0.0 – 0.2 mg/dL
• nIndirect (Unconjugated) 0.2 – 0.8 mg/dL
2. nSynthetic Function
The nliver is the main site of synthesis of:
Proteins:
The nliver plays an important role in production of albumin and the majority of the nα and β-globulins. All the blood-clotting factors (except VIII) are nsynthesized in the liver. Deamination of glutamate in the liver is the primary nsource of ammonia, which is converted to urea.
Carbohydrates:
The nsynthesis and metabolism of carbohydrates is centered in the liver. Glucose is nconverted to glycogen (Glycogenesis), a portion of which is stored in the liver nand later reconverted to glucose (Glycogenolysis) as necessary. An additional nimportant liver function is gluconeogenesis from amino acids.
Lipids:
Fat nis formed from carbohydrates in the liver (Lipogenesis) wheutrition is nadequate and the demand for glucose is being met from dietary sources. The nliver also plays a key role in the metabolism of fat. It is the major site for nthe
– nremoval of chylomicron remnants
– nthe conversion of acetyl- CoA to fatty acids, triglycerides, and cholesterol.
– nmetabolism of cholesterol into bile acids
– nSynthesis of Very-low-density lipoproteins
– nSynthesis of high-density lipoproteins
– nSynthesis of phospholipids.
The nformation of ketone bodies occurs in the liver. When the demand for ngluconeogenesis depletes oxaloacetate and acetyl-CoA cannot be converted nrapidly enough to citrate, acetyl-CoA accumulates and a ,decyclase in the liver nliberates ketone bodies into the blood .
The nliver is the storage site for all fat-soluble vitamins (A, D, E, and K) and nseveral water-soluble vitamins, such as B12. Another vitamin-related functiois the conversion of carotene into vitamin A.
The nliver is the source of somatomedin (an insulin-like factor that mediates the nactivity of growth hormone) and angiotensinogen, and is a major site of nmetabolic clearance of many other hormones. As the source of transferrin, nceruloplasmin, and metallothionein, the liver plays a key role in the ntransport, storage, and metabolism of iron, copper, and other metals .
Many nenzymes are synthesized by liver cells. Those enzymes that have been found nuseful in the diagnosis of hepatobiliary disorders include aspartate amino ntransferase (AST, or serum glutamic-oxaloacetic transaminase [SGOT]) and nalanine amino transferase (ALT, or serum glutamic pyruvic transaminase [SGPT]), nalkaline phosphatase (ALP) and 5′-nucleotidase (5NT), and nγ-glutamyltransferase (GGT).
3. nDetoxification Function
Because nthe liver is interposed between the splanchnic circulation and the systemic nblood, it serves to protect the body from potentially injurious substances nabsorbed from the intestinal tract and toxic by-products of metabolism.
The nmost important mechanisms of detoxification includ oxidation, reduction, nhydrolysis, hydroxylation, carboxylation, and demethylation. Detoxificatiomechanisms convert many toxic or insoluble compounds into less toxic or more nwater-soluble compounds and, therefore, excretable by the kidney. For example, nammonia, a toxic substance arising in the large intestine through bacterial naction on amino acids, is carried to the liver by the portal vein and converted nby hepatocytes into the innocuous compound urea.
Conjugatiowith compounds, such as glycine, glucuronic acid, sulfuric acid, glutamine, nacetate, cysteine, and glutathione, occurs mainly in the cytosol. This nmechanism is the mode of bilirubin and bile acid excretion.
