STUDY - Technical - New Dacian's Medicine
Jaundice
(2)
Translation Draft
Of the chemical tests for bile pigments in serum, the most widely used is the van den Bergh reaction. Bilirubin pigments are exposed to sulphanilic acid to produce diazoconjugations, and chromogeneproducts are measured colorimetrically. The van den Bergh reaction can be used to distinguish unconjugated bilirubin from conjugated bilirubin due to the different solubility of pigments.
When the reaction is carried out in aqueous environment, hydrosoluble conjugated bilirubin reacts directly with sulphanilic acid, giving a positive direct van den Bergh reaction. When the reaction is carried out in methanol, the intramolecular hydrogen bonds of unconjugated bilirubin are broken (thus, both conjugated and unconjugated pigment react, giving a measure of total bilirubin levels). The indirect value, representing the fraction of unconjugated bilirubin, is estimated by subtracting the fraction that reacts directly from the measured total bilirubin.
The ability of the direct van den Bergh reaction to distinguish between conjugated and unconjugated bilirubin depends on the duration of the reaction. If the reaction is allowed to continue for more than one minute, a small amount of unconjugated pigment will react in the aqueous environment, giving a false lysted estimate of the fraction reacting directly (conjugated). This observation underlines the importance of considering these reactions as approximations rather than as actual measurements of conjugated and unconjugated fractions.
More accurate measurements of bilirubin fractions in biological fluids show that normal serum contains predominantly unconjugated bilirubin (more than 96%). This observation confirms the old suspicion that the small amount of bilirubin reacting directly, measured in normal serum by the van den Bergh method, is an overestimation of the actual amount present. Qualitative determination of bilirubin in urine can be achieved by specific reaction with Ictotest or dipstick tablets.
The foam test is also a simple qualitative test. When normal urine is shaken vigorously in a test tube, the foam is absolutely white. In the case of urine containing bilirubin, the foam will be yellow. This difference can be subtle, becoming apparent only after comparison with a similar agitated sample from a normal individual. With the exception of concentrated urine, the most common cause of intense yellow-brown urine or dark urine is bilirubin.
However, other causes of dark urine should be considered, including yellow or orange urine due to medicinal products (e.g. sulfasalazine, rifampicin, thiamine), red urine due to porphyria, hemoglobinuria, myoglobinuria or medicinal products (e.g. pyridium) and dark brown or black urine due to homogentic acid (in ocrazone) or melanin (from melanoma).
I will now proceed to address etiological considerations in jaundice. Once jaundice is clinically or chemically recognized, it is important to determine whether it is predominantly due to unconjugated or conjugated hyperbilirubinemia. In the absence of available chemical determinations, a simple approach is to determine whether bilirubin is present in urine. Its absence in the urine suggests unconjugated hyperbilirubinemia, as this pigment is not filtered by renal glomerules (the presence indicating conjugated hyperbilirubinemia).
When chemical analysis (van den Bergh reaction) indicates 80-85% of total serum bilirubin as unconjugated, the patient is considered to have mainly unconjugated hyperbilirubinemia. A patient with more than 50% serum bilirubin (conjugated) is considered to have predominantly conjugated hyperbilirubinemia. Disorders of bilirubin metabolism can occur through any of these four mechanisms: 1. overproduction, 2. low hepatic capture, 3. low hepatic conjugation and 4. low excretion of bilirubin in the bile (either due to intrahepatic dysfunction or extrahepatic mechanical obstruction). Jaundice can also be described on the basis of pathogenic mechanisms or pathological processes leading to increased levels of bilirubin.
Thus, the terms hemolytic jaundice, hepatocellular jaundice and obstructive or cholestatic jaundice are commonly used. Although these classifications are useful, in any patient can operate more than one isolated disorder of bilirubin metabolism, and more than one "type" of jaundice, isolated, may be present. For example, a patient with cirrhosis may have not only impaired liver cell function (and hence hepatocellular jaundice), but also hemolysis. Furthermore, as indicated above, obstructive jaundice or cholestasis may be due to either mechanical obstruction of the bile ducts or damage to the functional liver excretion of bilirubin.
To begin the description of jaundice with predominantly unconjugated bilirubinemia resulting from the overproduction of bilirubin. An increased amount of hemoglobin released from senescent or hemolyzed erythrocytes leads to increased production of bilirubin. Erythrocytic destruction leading to hyperbilirubinemia most commonly results from intravascular hemolysis (e.g. autoimmune, microangiopathic or associated with hemoglobinopathy) or resorption of a voluminous hematoma.
Excessive production of bilirubin is reflected in serum levels of bilirubin increased to 51-68 micromol/ l, with the predominance of unconjugated bilirubin. In the case of liver capture of bilirubin, as shown above, the taking of bilirubin by hepatocytes requires the dissociation of the nonpolar pigment molecule from albumin, transport through the cell membrane and binding to ligandine. In rare cases of drug-induced jaundice (e.g. flavaspidic acid) and possibly in some patients with Gilbert syndrome, there may be a disorder of this bilirubin capture phase.
In the case of glucuronic conjugation, deficiency in glucuronyl-transferase activity may occur as a result of both genetic and acquired defects. In the fetus and newborn, the activity of glucuronyl-transferase is normally low and immature hepatocyte has an increased ability to secretion unconjugated bilirubin. Although transient, these deficiencies together with increased neonatal intestinal absorption of unconjugated bilirubin contribute to the development of neonatal jaundice, which occurs between the second and fifth days of life.
The significance of inherited glucuronyl-transferase deficits depends on the degree of residual enzyme activity. Gilbert syndrome, associated with a slight decrease in activity, produces mild, asymptomatic unconjugated hyperbilirubinemia. Moderately low activity occurs in Crigler-Najjar syndrome type II (this enzyme is totally lacking in Crigler-Najjar syndrome type I, an autosomal-recessive disorder associated with nuclear jaundice and infant mortality through CNS dysfunction). Defects acquired in the activity of glucuronyl-transferase may be induced by drugs (i.e. by direct enzyme inhibition) or generally associated with liver disease. However, in most hepatocellular disorders, bilirubin excretion is affected to a greater extent than bilirubin conjugation, leading to mainly conjugated hyperbilirubinemia.
In the case of jaundice with predominant conjugated bilirubinemia I will start with impaired hepatocytic excretion of bilirubin. Interference with bile excretion of conjugated bilirubin by hepatocytes leads to a re-entry of this pigment into the systemic circulation, leading to a predominant conjugated hyperbilirubinemia and consecutive bilirubinuria. The mechanism of this spills is unknown, although it is likely that the affected ducticulal excretion leads to increased intracellular levels of conjugated bilirubin, which diffuses or is transported through the sinusoidal membrane into the blood.
In addition, hepatocellular necrosis can contribute to the rupture of the bile ducts, leading to direct reflux of bile into the liver sinusoids. Several mechanisms have been postulated to explain the low secretion of bilirubin conjugated in hepatocellular disease and hepatic cholestatic disease: 1. occlusion of the ducts by thickened bile, 2. ducticulary occlusion by swollen hepatocytes, 3. obstruction of the terminal intrahepatic bile ducts (cholangioles) of inflammatory cells, 4. modified hepatocellular permeability, allowing the reuptake of the excreted pigment and 5. specific inhibition of membranary transport proteins.
Hepatocellular disorders in which jaundice may be associated with an obstructive or cholestatic phase include: 1. drug reactions, in particular those due to chlorpromazine or anabolic steroids, 2. alcoholic hepatitis and fatty infiltration of the liver induced by alcohol, 3. jaundice in the last trimester of pregnancy, 4. certain types of postoperative jaundice, 5. recurrent benign intrahepatic cholestasis, 6. Dubin-Johnson and Rotor syndromes and 7. occasional cases of viral or autoimmune hepatitis.
Damage to bilirubin excretion is common in cirrhosis of any cause in the late stage. It occurs much earlier in the course of primitive bile cirrhosis and in rare cases of biliary cirrhosis occurring secondary to chronic, recurrent choledocolithiasis or cholangitis. In the case of extrahepatic bile obstruction we are dealing with complete and partial obstruction. Complete obstruction of the extrahepatic bile ducts causes jaundice and predominantly conjugated hyperbilirubinemia, associated with marked bilirubinuria and acholic stools. As shown above, the concentration of bilirubin increases progressively and reaches a plateau at 510-680 micromol/ l. Partial obstruction of the extrahepatic bile ducts can also cause jaundice if the clearance of bilirubin in the duodenum is unable to balance the level of depigment production.
In such cases, the intabile pressure is usually increased (at levels reaching 250 mmHg). This increased pressure interferes with the hepatocytic secretion of bilirubin, further exaggerating the imbalance between bilirubin production and clearance. In partial biliary obstruction, the degree of jaundice and bilirubinuria depends on many factors, including the presence of simultaneous hepatocellular disease or colangitis, which can exacerbate the impairment of bilirubin hepatocytic excretion.
The functional reserve of the liver is so large that the occlusion of the intrahepatic bile ducts does not cause jaundice unless the bile drainage of a large segment (greater than 75%) is interrupted. of the parenchyma. In many patients, either of the two main liver ducts or a large number of secondary ducts may be blocked without the appearance of jaundice. On the contrary, diffuse narrowing of the intrahepatic bile ducts, even without complete obstruction, can produce jaundice in a way analogous to partial obstruction of the extrahepatic ducts.
That's enough for today! Tomorrow (I hope to be able to return to my daily posts) I will try to complete the jaundice (starting with the jaundice assessment) to move forward as quickly as possible... So, as the end of the month and semester and in an attempt to organize further, at the signs of the disease I still have to present about 1. abdominal distension and ascites completing gastrointestinal disorders and I will open presentations on renal and electrolyte disorders with 2. main manifestations of kidney disease, then 3. disorders of motion, incontinence and bladder pain, 4. imbalances of fluids and electrolytes, 5. acidosis and alkalose, then I'll start a new group, that of urogenital disorders, starting with 6. impotence, 7. menstrual disorders and other common gynecological disorders, 8. hirsutism and virilization, then a new group, that of the skin signs starting with 9. approach of the patient with skin disorders, 10. eczema, psoriasis, skin infections, acne and other common skin conditions, 11. drug-induced skin reactions, 12. skin manifestations of diseases, 13. photosensitivity and other reactions to light, a new group, that of haematological signs, starting with 14. anemia, then 15. haemorrhage and thrombosis, 16. adenopathies and splenomegalia, 17. pathological changes in granulocytes and monocytes, another group of cancer, starting with 18. presentation of neoplastic patients, solid tumours in adults, 19. evaluation of breast nodules in both sexes and, no more signs of disease.
As far as I can assess at this time I will have to post daily to complete until the August (August 15th) holiday... I'll try... In parallel I hope to be able to "let go" of working on the section "New Medicine" on my old site dorinm.ro (this month "has" 15 years of existence – Lord, how time passes...)
Of the chemical tests for bile pigments in serum, the most widely used is the van den Bergh reaction. Bilirubin pigments are exposed to sulphanilic acid to produce diazoconjugations, and chromogeneproducts are measured colorimetrically. The van den Bergh reaction can be used to distinguish unconjugated bilirubin from conjugated bilirubin due to the different solubility of pigments.
When the reaction is carried out in aqueous environment, hydrosoluble conjugated bilirubin reacts directly with sulphanilic acid, giving a positive direct van den Bergh reaction. When the reaction is carried out in methanol, the intramolecular hydrogen bonds of unconjugated bilirubin are broken (thus, both conjugated and unconjugated pigment react, giving a measure of total bilirubin levels). The indirect value, representing the fraction of unconjugated bilirubin, is estimated by subtracting the fraction that reacts directly from the measured total bilirubin.
The ability of the direct van den Bergh reaction to distinguish between conjugated and unconjugated bilirubin depends on the duration of the reaction. If the reaction is allowed to continue for more than one minute, a small amount of unconjugated pigment will react in the aqueous environment, giving a false lysted estimate of the fraction reacting directly (conjugated). This observation underlines the importance of considering these reactions as approximations rather than as actual measurements of conjugated and unconjugated fractions.
More accurate measurements of bilirubin fractions in biological fluids show that normal serum contains predominantly unconjugated bilirubin (more than 96%). This observation confirms the old suspicion that the small amount of bilirubin reacting directly, measured in normal serum by the van den Bergh method, is an overestimation of the actual amount present. Qualitative determination of bilirubin in urine can be achieved by specific reaction with Ictotest or dipstick tablets.
The foam test is also a simple qualitative test. When normal urine is shaken vigorously in a test tube, the foam is absolutely white. In the case of urine containing bilirubin, the foam will be yellow. This difference can be subtle, becoming apparent only after comparison with a similar agitated sample from a normal individual. With the exception of concentrated urine, the most common cause of intense yellow-brown urine or dark urine is bilirubin.
However, other causes of dark urine should be considered, including yellow or orange urine due to medicinal products (e.g. sulfasalazine, rifampicin, thiamine), red urine due to porphyria, hemoglobinuria, myoglobinuria or medicinal products (e.g. pyridium) and dark brown or black urine due to homogentic acid (in ocrazone) or melanin (from melanoma).
I will now proceed to address etiological considerations in jaundice. Once jaundice is clinically or chemically recognized, it is important to determine whether it is predominantly due to unconjugated or conjugated hyperbilirubinemia. In the absence of available chemical determinations, a simple approach is to determine whether bilirubin is present in urine. Its absence in the urine suggests unconjugated hyperbilirubinemia, as this pigment is not filtered by renal glomerules (the presence indicating conjugated hyperbilirubinemia).
When chemical analysis (van den Bergh reaction) indicates 80-85% of total serum bilirubin as unconjugated, the patient is considered to have mainly unconjugated hyperbilirubinemia. A patient with more than 50% serum bilirubin (conjugated) is considered to have predominantly conjugated hyperbilirubinemia. Disorders of bilirubin metabolism can occur through any of these four mechanisms: 1. overproduction, 2. low hepatic capture, 3. low hepatic conjugation and 4. low excretion of bilirubin in the bile (either due to intrahepatic dysfunction or extrahepatic mechanical obstruction). Jaundice can also be described on the basis of pathogenic mechanisms or pathological processes leading to increased levels of bilirubin.
Thus, the terms hemolytic jaundice, hepatocellular jaundice and obstructive or cholestatic jaundice are commonly used. Although these classifications are useful, in any patient can operate more than one isolated disorder of bilirubin metabolism, and more than one "type" of jaundice, isolated, may be present. For example, a patient with cirrhosis may have not only impaired liver cell function (and hence hepatocellular jaundice), but also hemolysis. Furthermore, as indicated above, obstructive jaundice or cholestasis may be due to either mechanical obstruction of the bile ducts or damage to the functional liver excretion of bilirubin.
To begin the description of jaundice with predominantly unconjugated bilirubinemia resulting from the overproduction of bilirubin. An increased amount of hemoglobin released from senescent or hemolyzed erythrocytes leads to increased production of bilirubin. Erythrocytic destruction leading to hyperbilirubinemia most commonly results from intravascular hemolysis (e.g. autoimmune, microangiopathic or associated with hemoglobinopathy) or resorption of a voluminous hematoma.
Excessive production of bilirubin is reflected in serum levels of bilirubin increased to 51-68 micromol/ l, with the predominance of unconjugated bilirubin. In the case of liver capture of bilirubin, as shown above, the taking of bilirubin by hepatocytes requires the dissociation of the nonpolar pigment molecule from albumin, transport through the cell membrane and binding to ligandine. In rare cases of drug-induced jaundice (e.g. flavaspidic acid) and possibly in some patients with Gilbert syndrome, there may be a disorder of this bilirubin capture phase.
In the case of glucuronic conjugation, deficiency in glucuronyl-transferase activity may occur as a result of both genetic and acquired defects. In the fetus and newborn, the activity of glucuronyl-transferase is normally low and immature hepatocyte has an increased ability to secretion unconjugated bilirubin. Although transient, these deficiencies together with increased neonatal intestinal absorption of unconjugated bilirubin contribute to the development of neonatal jaundice, which occurs between the second and fifth days of life.
The significance of inherited glucuronyl-transferase deficits depends on the degree of residual enzyme activity. Gilbert syndrome, associated with a slight decrease in activity, produces mild, asymptomatic unconjugated hyperbilirubinemia. Moderately low activity occurs in Crigler-Najjar syndrome type II (this enzyme is totally lacking in Crigler-Najjar syndrome type I, an autosomal-recessive disorder associated with nuclear jaundice and infant mortality through CNS dysfunction). Defects acquired in the activity of glucuronyl-transferase may be induced by drugs (i.e. by direct enzyme inhibition) or generally associated with liver disease. However, in most hepatocellular disorders, bilirubin excretion is affected to a greater extent than bilirubin conjugation, leading to mainly conjugated hyperbilirubinemia.
In the case of jaundice with predominant conjugated bilirubinemia I will start with impaired hepatocytic excretion of bilirubin. Interference with bile excretion of conjugated bilirubin by hepatocytes leads to a re-entry of this pigment into the systemic circulation, leading to a predominant conjugated hyperbilirubinemia and consecutive bilirubinuria. The mechanism of this spills is unknown, although it is likely that the affected ducticulal excretion leads to increased intracellular levels of conjugated bilirubin, which diffuses or is transported through the sinusoidal membrane into the blood.
In addition, hepatocellular necrosis can contribute to the rupture of the bile ducts, leading to direct reflux of bile into the liver sinusoids. Several mechanisms have been postulated to explain the low secretion of bilirubin conjugated in hepatocellular disease and hepatic cholestatic disease: 1. occlusion of the ducts by thickened bile, 2. ducticulary occlusion by swollen hepatocytes, 3. obstruction of the terminal intrahepatic bile ducts (cholangioles) of inflammatory cells, 4. modified hepatocellular permeability, allowing the reuptake of the excreted pigment and 5. specific inhibition of membranary transport proteins.
Hepatocellular disorders in which jaundice may be associated with an obstructive or cholestatic phase include: 1. drug reactions, in particular those due to chlorpromazine or anabolic steroids, 2. alcoholic hepatitis and fatty infiltration of the liver induced by alcohol, 3. jaundice in the last trimester of pregnancy, 4. certain types of postoperative jaundice, 5. recurrent benign intrahepatic cholestasis, 6. Dubin-Johnson and Rotor syndromes and 7. occasional cases of viral or autoimmune hepatitis.
Damage to bilirubin excretion is common in cirrhosis of any cause in the late stage. It occurs much earlier in the course of primitive bile cirrhosis and in rare cases of biliary cirrhosis occurring secondary to chronic, recurrent choledocolithiasis or cholangitis. In the case of extrahepatic bile obstruction we are dealing with complete and partial obstruction. Complete obstruction of the extrahepatic bile ducts causes jaundice and predominantly conjugated hyperbilirubinemia, associated with marked bilirubinuria and acholic stools. As shown above, the concentration of bilirubin increases progressively and reaches a plateau at 510-680 micromol/ l. Partial obstruction of the extrahepatic bile ducts can also cause jaundice if the clearance of bilirubin in the duodenum is unable to balance the level of depigment production.
In such cases, the intabile pressure is usually increased (at levels reaching 250 mmHg). This increased pressure interferes with the hepatocytic secretion of bilirubin, further exaggerating the imbalance between bilirubin production and clearance. In partial biliary obstruction, the degree of jaundice and bilirubinuria depends on many factors, including the presence of simultaneous hepatocellular disease or colangitis, which can exacerbate the impairment of bilirubin hepatocytic excretion.
The functional reserve of the liver is so large that the occlusion of the intrahepatic bile ducts does not cause jaundice unless the bile drainage of a large segment (greater than 75%) is interrupted. of the parenchyma. In many patients, either of the two main liver ducts or a large number of secondary ducts may be blocked without the appearance of jaundice. On the contrary, diffuse narrowing of the intrahepatic bile ducts, even without complete obstruction, can produce jaundice in a way analogous to partial obstruction of the extrahepatic ducts.
That's enough for today! Tomorrow (I hope to be able to return to my daily posts) I will try to complete the jaundice (starting with the jaundice assessment) to move forward as quickly as possible... So, as the end of the month and semester and in an attempt to organize further, at the signs of the disease I still have to present about 1. abdominal distension and ascites completing gastrointestinal disorders and I will open presentations on renal and electrolyte disorders with 2. main manifestations of kidney disease, then 3. disorders of motion, incontinence and bladder pain, 4. imbalances of fluids and electrolytes, 5. acidosis and alkalose, then I'll start a new group, that of urogenital disorders, starting with 6. impotence, 7. menstrual disorders and other common gynecological disorders, 8. hirsutism and virilization, then a new group, that of the skin signs starting with 9. approach of the patient with skin disorders, 10. eczema, psoriasis, skin infections, acne and other common skin conditions, 11. drug-induced skin reactions, 12. skin manifestations of diseases, 13. photosensitivity and other reactions to light, a new group, that of haematological signs, starting with 14. anemia, then 15. haemorrhage and thrombosis, 16. adenopathies and splenomegalia, 17. pathological changes in granulocytes and monocytes, another group of cancer, starting with 18. presentation of neoplastic patients, solid tumours in adults, 19. evaluation of breast nodules in both sexes and, no more signs of disease.
As far as I can assess at this time I will have to post daily to complete until the August (August 15th) holiday... I'll try... In parallel I hope to be able to "let go" of working on the section "New Medicine" on my old site dorinm.ro (this month "has" 15 years of existence – Lord, how time passes...)
Have a fruitful, kind
week, full of understanding, love and gratitude!
Dorin, Merticaru