STUDY - Technical - New Dacian's Medicine
Jaundice
(1)
Translation Draft
Here's an extra job... I feel that I have to finish presenting the signs of the disease as soon as possible because allopathic medicine seems (literally) quite ineffective and boring, as an argument (which is why I decided to leave its accumulations/observations in the approach of New Medicine)... But we will only discuss this when I make an epilogue of the signs of the disease (I hope that it "comes" as soon as possible)... Get to work!
The accumulation of bilirubin in the bloodstream causes yellow pigmentation of the plasma, leading to the coloration of richly infused tissues. Serum bilirubin levels increase when its production from hem exceeds its metabolism and excretion. The imbalance between production and "metabolization" can come either from the excessive release of bilirubin precursors into the bloodstream or from physiological processes that prevent the hepatic take-over, metabolism or excretion of this metabolite.
Clinically, hyperbilirubinemia occurs as jaundice, yellow pigmentation of the skin and sclerosing. Jaundice can usually be detected when serum bilirubin levels exceed 34-43 micromol/ l or approximately double the upper limit of normal values, but can be detectable at lower levels of bilirubin in patients with light skin and severe anaemia. Conversely, jaundice is frequently masked in individuals with dark skin or edema.
Scleral tissue is rich in elastin, which has a high affinity for bilirubin, so scleral jaundice is usually a more sensitive sign of hyperbilirubinemia than generalized jaundice. An equally early sign of hyperbilirubinemia is the darkening of urine, resulting from renal excretion of bilirubin in the form of bilirubin-glucuronide. In pronounced jaundice, the skin may take a greenish tinge due to oxidation of part of the circulating bilirubin to biliverdine.
This effect is more common in conditions with conjugated, accentuated or long-lasting hyperbilirubinemia, such as cirrhosis. Other causes of yellow skin coloration include caroteneemia, usually aresultion as a result of ingestion and absorption of large amounts of betacarotene and related pigment compounds. Unlike hyperbilirubinemia, however, caroteneemia does not cause scleral jaundice.
To better understand the mechanisms of jaundice it is time to discuss the production and metabolism of bilirubin starting with the sources and chemical characterization of serum bilirubin. Normal serum concentrations of bilirubin range from 5 to 17 micromoles/ l. More than 90% of serum bilirubin in normal individuals is in unconjugated form, with a non-polar molecule circulating as an albumin-related complex.
The rest is conjugated with a polar group (especially glucuronide) which makes it hydrosoluble and thus capable of being filtered and excreted by the kidneys. When measured by routine clinical trials, the direct or conjugated fraction is frequently overestimated, leading to reported normal values of 1,7-8,5 micromoles/ l. Approximately 80% of circulating bilirubins derive from aging erythrocytes. When circulating erythrocytes reach the end of their normal life of about 120 days they are destroyed by reticuloendothelial cells.
Oxidation of the half of hem dissociated from hemoglobin in these cells generates biliverdine, which is then metabolized to bilirubin. Approximately 15-20% of circulating bilirubin derives from other sources, including 1. ineffective erythropoiesis from the destruction of maturing erythrocytes in the bone marrow and 2. from the metabolism of other hem-containing proteins, the most well-known of which are hepatic cytochromes, muscle myoglobin and widespread hem-containing enzymes. Unconjugated bilirubin released into plasma is closely bound, but non-covalently, to albumin.
Certain organic anions, such as sulfonamides and salicylates, compete with bilirubin for albumin binding sites, allowing the released pigment to enter the tissues. In the neonatal period, brain cells, especially those in the basal ganglia, have an affinity for unconjugated bilirubin, facilitating its retention in the brain. This phenomenon may explain the neurotoxic effects of neonatal hyperbilirubinemia. Conjugated bilirubin is bound to albumin in two forms, reversible and irreversible. Non-covalent, reversible binding is similar to that of unconjugated bilirubin, although the complex is less stable.
When present in serum for long periods of time (e.g. cholestasis, long-evolving biliary obstruction or chronic active hepatitis), conjugated bilirubin may form an irreversible covalent complex with albumin called delta bilirubin or biliprotein. Due to the irreversibility of the link, this complex is not excreted by the kidneys. This delta bilirubin has a serum half-life similar to that of albumin (15-20 days) and thus remains detectable in serum until a few weeks after the release of the bile duct or during convalescence after hepatocellular diseases. Bilirubin is present in body fluids (joint fluids, pleural fluid, cerebrospinal fluid) proportional to their albumin content and is absent in true secretions such as tears, saliva and pancreatic juice. The appearance of jaundice is also influenced by blood flow and edema, with paralyzed and edematous extremities tending to remain uncolored.
And so, it was time to present the liver metabolism of bilirubin. The liver plays a central role in the metabolism of bile pigments. This process can be divided into three distinct phases: 1. hepatic take-over/capture (unconjugated albumin-related bilirubin is presented to the liver cell, where the complex dissociates and nonpolar bilirubin enters the hepatocyte by diffusion or transport through the plasma membrane.
Subsequent hepatocytic capture and storage of bilirubin involves the binding of bilirubin to cytoplasmic proteins binding anions, in particular ligandin/ glutathione-S-transferase B which preventbilirubin eflux back into plasma), 2. conjugation (Unconjugated bilirubin is insoluble in water unless combined with an amphyth molecule such as albumin. Because albumin is missing from the bile, bilirubin should be converted into a hydrosoluble derivative before bile excretion. This process is mainly accomplished by conjugating bilirubin with glucuronic acid, generating bilirubin-glucuronide.
The conjugation reaction occurs in the endoplasmic reticulum of hepatocytes and is catalyzed by bilirubin-glucuronyl transfers in a two-stroke reaction) and 3. excretion into the bile (Under normal conditions, only conjugated bilirubin can be excreted in the bile. Although the overall process is not fully understood, bilirubin excretion appears to be an energy-dependent process limited to the canaliculary membrane. Excretion is the speed-limiting stage in the liver metabolism of this pigment.
Deficient excretion leads to low concentrations of bilirubin and concomitant eflow of bilirubin conjugated through the sinusoidal membrane of the hepatocyte into the bloodstream. The role of intracellular protein trafficking and membrane transport processes in normal and abnormal bilirubin excretion is still insufficiently understood). Of these three phases, excretion appears to be the stage that limits the rhythm and most likely to be undermined when the liver cell is affected. I'm going to go a little bit into presenting some details about these phases.
As for the intestinal phase of bilirubin metabolism, after secretion in the bile, conjugated bilirubin is transported through the bile ducts into the duodenum. Conjugated bilirubin is not resorbed by the intestinal mucosa. It is either excreted unchanged in the stool or metabolized by oleal and colonic bacteria in urobilinogen and related products. Urobilinogen can be reabsorbed from the small intestine and colon and enters the portal circulation. Some of the portal urobilinogen is taken up by the liver and re-excreted into the bile, while the rest bypasses the liver and is excreted by the kidneys. Under normal conditions, the daily urinary excretion of urobilinogen does not exceed 4 mg.
When hepatic uptake and excretion of urobilinogen is affected (e.g. in hepatocellular diseases) or bilirubin production is greatly increased (e.g. in hemolysis), daily urinary excretion of urobilinogen may increase significantly. On the contrary, extrahepatic bile collection or obstruction interferes with the intestinal phase of bilirubin metabolism and leads to much low urobilinogenic urinary production and excretion. Measuring urinary urobilinogen can thus be a useful tool in distinguishing the possible causes of hyperbilirubinemia.
We've reached the renal excretion of bilirubin. Urine does not normally contain bilirubin detectable by regular clinical tests, although traces can be detected by sensitive spectrophotometric processes. Unconjugated bilirubin, being closely related to albumin, is not filtered by renal glomerules. Since there is no tubular secretion process for bilirubin, unconjugated bilirubin is not excreted in the urine. On the contrary, conjugated bilirubin is a polar molecule less closely related to albumin. A significant fraction circulates unbound, is filtered by renal glomerules and appears in the urine. The presence of bilirubin in the urine is evidence of conjugated hyperbilirubinemia and can be a unique, early point of differentiation in the evaluation of jaundice.
Bile salts increase glomerular filtration of conjugated bilirubin and in diseases associated with elevated circulating bile salts (e.g. cholestasis, extrahepatic biliary obstruction) renal excretion of bilirubin is significantly intensified. This increased renal excretion may explain the observation that serum conjugated bilirubin tends to reach a plateau at levels below 510-680 micromol/ l in patients with severe hepatocellular lesions.
I will complete this post by addressing the physiopathological consequences of hyperbilirubinemia. In most cases, hyperbilirubinemia itself has insignificant physiopathological effects. Unlike circulating bile salts whose levels are also high in cholestasis and biliary obstruction, bilirubin will not be stored in skin tissues and does not produce itching. However, unconjugated plasma bilirubin that is not related to albumin may cross the blood-brain barrier. Under conditions such as neonatal jaundice or Crigler-Najjar syndrome type I or II, very high concentrations of unconjugated bilirubin may accumulate, and the resulting diffusion of bilirubin in the central nervous system can cause encephalopathy (nuclear jaundice) and permanent impairment of nerve function. The risk of nuclear jaundice is increased by conditions that favour increased circulating levels of unbound, unconjugated bilirubin, such as hemolysis, hypoalbuminemia, acidosis and increased levels of compounds competing with bilirubin for albumin binding, such as free fatty acids and medicines.
High concentrations of unconjugated bilirubin can be decreased by removing these favouring factors and facilitating the bile excretion of unconjugated bilirubin. Exposure to blue light causes conformation changes in unconjugated bilirubin, making it more polar and water-soluble. These photoisomers are taken over and excreted by the liver and kidneys, without the need for conjugation. Intense blue light treatment may provide sufficient isomerization of unconjugated bilirubin circulating freely through the skin to prevent nuclear jaundice in patients with neonatal jaundice.
I think I have at least two more jaundice posts... So, I hope to pull hard to finish faster...
Here's an extra job... I feel that I have to finish presenting the signs of the disease as soon as possible because allopathic medicine seems (literally) quite ineffective and boring, as an argument (which is why I decided to leave its accumulations/observations in the approach of New Medicine)... But we will only discuss this when I make an epilogue of the signs of the disease (I hope that it "comes" as soon as possible)... Get to work!
The accumulation of bilirubin in the bloodstream causes yellow pigmentation of the plasma, leading to the coloration of richly infused tissues. Serum bilirubin levels increase when its production from hem exceeds its metabolism and excretion. The imbalance between production and "metabolization" can come either from the excessive release of bilirubin precursors into the bloodstream or from physiological processes that prevent the hepatic take-over, metabolism or excretion of this metabolite.
Clinically, hyperbilirubinemia occurs as jaundice, yellow pigmentation of the skin and sclerosing. Jaundice can usually be detected when serum bilirubin levels exceed 34-43 micromol/ l or approximately double the upper limit of normal values, but can be detectable at lower levels of bilirubin in patients with light skin and severe anaemia. Conversely, jaundice is frequently masked in individuals with dark skin or edema.
Scleral tissue is rich in elastin, which has a high affinity for bilirubin, so scleral jaundice is usually a more sensitive sign of hyperbilirubinemia than generalized jaundice. An equally early sign of hyperbilirubinemia is the darkening of urine, resulting from renal excretion of bilirubin in the form of bilirubin-glucuronide. In pronounced jaundice, the skin may take a greenish tinge due to oxidation of part of the circulating bilirubin to biliverdine.
This effect is more common in conditions with conjugated, accentuated or long-lasting hyperbilirubinemia, such as cirrhosis. Other causes of yellow skin coloration include caroteneemia, usually aresultion as a result of ingestion and absorption of large amounts of betacarotene and related pigment compounds. Unlike hyperbilirubinemia, however, caroteneemia does not cause scleral jaundice.
To better understand the mechanisms of jaundice it is time to discuss the production and metabolism of bilirubin starting with the sources and chemical characterization of serum bilirubin. Normal serum concentrations of bilirubin range from 5 to 17 micromoles/ l. More than 90% of serum bilirubin in normal individuals is in unconjugated form, with a non-polar molecule circulating as an albumin-related complex.
The rest is conjugated with a polar group (especially glucuronide) which makes it hydrosoluble and thus capable of being filtered and excreted by the kidneys. When measured by routine clinical trials, the direct or conjugated fraction is frequently overestimated, leading to reported normal values of 1,7-8,5 micromoles/ l. Approximately 80% of circulating bilirubins derive from aging erythrocytes. When circulating erythrocytes reach the end of their normal life of about 120 days they are destroyed by reticuloendothelial cells.
Oxidation of the half of hem dissociated from hemoglobin in these cells generates biliverdine, which is then metabolized to bilirubin. Approximately 15-20% of circulating bilirubin derives from other sources, including 1. ineffective erythropoiesis from the destruction of maturing erythrocytes in the bone marrow and 2. from the metabolism of other hem-containing proteins, the most well-known of which are hepatic cytochromes, muscle myoglobin and widespread hem-containing enzymes. Unconjugated bilirubin released into plasma is closely bound, but non-covalently, to albumin.
Certain organic anions, such as sulfonamides and salicylates, compete with bilirubin for albumin binding sites, allowing the released pigment to enter the tissues. In the neonatal period, brain cells, especially those in the basal ganglia, have an affinity for unconjugated bilirubin, facilitating its retention in the brain. This phenomenon may explain the neurotoxic effects of neonatal hyperbilirubinemia. Conjugated bilirubin is bound to albumin in two forms, reversible and irreversible. Non-covalent, reversible binding is similar to that of unconjugated bilirubin, although the complex is less stable.
When present in serum for long periods of time (e.g. cholestasis, long-evolving biliary obstruction or chronic active hepatitis), conjugated bilirubin may form an irreversible covalent complex with albumin called delta bilirubin or biliprotein. Due to the irreversibility of the link, this complex is not excreted by the kidneys. This delta bilirubin has a serum half-life similar to that of albumin (15-20 days) and thus remains detectable in serum until a few weeks after the release of the bile duct or during convalescence after hepatocellular diseases. Bilirubin is present in body fluids (joint fluids, pleural fluid, cerebrospinal fluid) proportional to their albumin content and is absent in true secretions such as tears, saliva and pancreatic juice. The appearance of jaundice is also influenced by blood flow and edema, with paralyzed and edematous extremities tending to remain uncolored.
And so, it was time to present the liver metabolism of bilirubin. The liver plays a central role in the metabolism of bile pigments. This process can be divided into three distinct phases: 1. hepatic take-over/capture (unconjugated albumin-related bilirubin is presented to the liver cell, where the complex dissociates and nonpolar bilirubin enters the hepatocyte by diffusion or transport through the plasma membrane.
Subsequent hepatocytic capture and storage of bilirubin involves the binding of bilirubin to cytoplasmic proteins binding anions, in particular ligandin/ glutathione-S-transferase B which preventbilirubin eflux back into plasma), 2. conjugation (Unconjugated bilirubin is insoluble in water unless combined with an amphyth molecule such as albumin. Because albumin is missing from the bile, bilirubin should be converted into a hydrosoluble derivative before bile excretion. This process is mainly accomplished by conjugating bilirubin with glucuronic acid, generating bilirubin-glucuronide.
The conjugation reaction occurs in the endoplasmic reticulum of hepatocytes and is catalyzed by bilirubin-glucuronyl transfers in a two-stroke reaction) and 3. excretion into the bile (Under normal conditions, only conjugated bilirubin can be excreted in the bile. Although the overall process is not fully understood, bilirubin excretion appears to be an energy-dependent process limited to the canaliculary membrane. Excretion is the speed-limiting stage in the liver metabolism of this pigment.
Deficient excretion leads to low concentrations of bilirubin and concomitant eflow of bilirubin conjugated through the sinusoidal membrane of the hepatocyte into the bloodstream. The role of intracellular protein trafficking and membrane transport processes in normal and abnormal bilirubin excretion is still insufficiently understood). Of these three phases, excretion appears to be the stage that limits the rhythm and most likely to be undermined when the liver cell is affected. I'm going to go a little bit into presenting some details about these phases.
As for the intestinal phase of bilirubin metabolism, after secretion in the bile, conjugated bilirubin is transported through the bile ducts into the duodenum. Conjugated bilirubin is not resorbed by the intestinal mucosa. It is either excreted unchanged in the stool or metabolized by oleal and colonic bacteria in urobilinogen and related products. Urobilinogen can be reabsorbed from the small intestine and colon and enters the portal circulation. Some of the portal urobilinogen is taken up by the liver and re-excreted into the bile, while the rest bypasses the liver and is excreted by the kidneys. Under normal conditions, the daily urinary excretion of urobilinogen does not exceed 4 mg.
When hepatic uptake and excretion of urobilinogen is affected (e.g. in hepatocellular diseases) or bilirubin production is greatly increased (e.g. in hemolysis), daily urinary excretion of urobilinogen may increase significantly. On the contrary, extrahepatic bile collection or obstruction interferes with the intestinal phase of bilirubin metabolism and leads to much low urobilinogenic urinary production and excretion. Measuring urinary urobilinogen can thus be a useful tool in distinguishing the possible causes of hyperbilirubinemia.
We've reached the renal excretion of bilirubin. Urine does not normally contain bilirubin detectable by regular clinical tests, although traces can be detected by sensitive spectrophotometric processes. Unconjugated bilirubin, being closely related to albumin, is not filtered by renal glomerules. Since there is no tubular secretion process for bilirubin, unconjugated bilirubin is not excreted in the urine. On the contrary, conjugated bilirubin is a polar molecule less closely related to albumin. A significant fraction circulates unbound, is filtered by renal glomerules and appears in the urine. The presence of bilirubin in the urine is evidence of conjugated hyperbilirubinemia and can be a unique, early point of differentiation in the evaluation of jaundice.
Bile salts increase glomerular filtration of conjugated bilirubin and in diseases associated with elevated circulating bile salts (e.g. cholestasis, extrahepatic biliary obstruction) renal excretion of bilirubin is significantly intensified. This increased renal excretion may explain the observation that serum conjugated bilirubin tends to reach a plateau at levels below 510-680 micromol/ l in patients with severe hepatocellular lesions.
I will complete this post by addressing the physiopathological consequences of hyperbilirubinemia. In most cases, hyperbilirubinemia itself has insignificant physiopathological effects. Unlike circulating bile salts whose levels are also high in cholestasis and biliary obstruction, bilirubin will not be stored in skin tissues and does not produce itching. However, unconjugated plasma bilirubin that is not related to albumin may cross the blood-brain barrier. Under conditions such as neonatal jaundice or Crigler-Najjar syndrome type I or II, very high concentrations of unconjugated bilirubin may accumulate, and the resulting diffusion of bilirubin in the central nervous system can cause encephalopathy (nuclear jaundice) and permanent impairment of nerve function. The risk of nuclear jaundice is increased by conditions that favour increased circulating levels of unbound, unconjugated bilirubin, such as hemolysis, hypoalbuminemia, acidosis and increased levels of compounds competing with bilirubin for albumin binding, such as free fatty acids and medicines.
High concentrations of unconjugated bilirubin can be decreased by removing these favouring factors and facilitating the bile excretion of unconjugated bilirubin. Exposure to blue light causes conformation changes in unconjugated bilirubin, making it more polar and water-soluble. These photoisomers are taken over and excreted by the liver and kidneys, without the need for conjugation. Intense blue light treatment may provide sufficient isomerization of unconjugated bilirubin circulating freely through the skin to prevent nuclear jaundice in patients with neonatal jaundice.
I think I have at least two more jaundice posts... So, I hope to pull hard to finish faster...
Have a good week,
everyone!
Dorin, Merticaru