How bilirubin is formed
The catabolism of pigments begins in the cells of the reticuloendothelial system (RES). The initial substrate is heme, which is released predominantly from hemoglobin, as well as from myoglobin and tissue cytochromes.
Stages of transformation:
- Under the influence of the enzyme heme oxygenase (and microsomal oxidases), heme is converted into biliverdin.
- The enzyme biliverdin reductase reduces biliverdin to unconjugated (indirect) bilirubin.
Subsequently, having undergone conjugation in the liver, the pigment becomes direct (conjugated) bilirubin. It acquires water solubility, detaches from albumin, and actively reacts with the Ehrlich diazo reagent. In this form, it is secreted into the bile ducts and sent to the small intestine.
Classification of jaundice
Depending on the localization of the primary injury, all disorders of pigment metabolism are divided into two broad groups.
- Hepatic jaundice. Based on primary damage to the hepatocytes themselves. These include hepatocellular (parenchymal) and enzymopathic forms (various enzymopathies).
- Non-hepatic (symptomatic) jaundice. Not primarily associated with damage to the hepatic parenchyma. This includes hemolytic (suprahepatic) jaundice, where the problem lies in the excessive breakdown of erythrocytes, and obstructive (subhepatic) jaundice caused by impaired bile outflow.
Stages of hepatocellular jaundice
When the liver parenchyma is damaged, both bile formation and bile excretion processes are disrupted. The dynamics of these disorders are clearly traced in three stages of the pathological process.
I. Pre-icteric stage Characterized by initial alteration of hepatocyte membranes and a drop in the activity of enzymes that break down urobilinogen. Due to cytolysis, hepatic transaminases (ALT, AST) and potassium enter the bloodstream. Urobilinogenemia and urobilinogenuria develop.
II. Icteric stage A malfunction of the "bilirubin conveyor" occurs (the ligandin protein and the enzyme glucuronyl transferase suffer). Due to inflammation and edema, bile capillaries are compressed. Direct bilirubin and bile acids are regurgitated back into the systemic circulation. Laboratory signs: bilirubinemia, cholemia, appearance of direct bilirubin in the urine (beer-colored urine). The level of urobilinogen drops, and stool becomes lighter due to a decrease in stercobilinogen.
III. Final stage Severe functional liver failure occurs with total suppression of conjugation. Progressive depression of glucuronyl transferase leads to a rapid surge in indirect bilirubin in the blood, while the level of direct bilirubin drops. Urobilinogen and stercobilinogen almost completely disappear from excreta.
Clinical manifestations
The visual manifestation of any jaundice is a change in skin color. The skin tone directly depends on the severity and nature of hyperbilirubinemia.
Shade options in jaundice:
- Light lemon
- Orange-yellow
- Green
- Olive-yellow
In addition to the cosmetic defect, an excess of bile components in the blood (cholemia) provokes systemic disorders: the central nervous system, hemostasis system, and cardiovascular activity suffer.
Briefly: answers to topical questions
What specific substance does indirect bilirubin bind to in hepatocytes during the conjugation process?
In hepatocytes, indirect bilirubin binds to glucuronic acid. This process is catalyzed by a special enzyme that converts the pigment into a soluble form.
- Glucuronic acid (or UDP-glucuronic acid) is the substance attached to bilirubin.
- Glucuronyl transferase is the enzyme with whose participation conjugation occurs.
As a result of this reaction, conjugated (direct) bilirubin, specifically bilirubin diglucuronide, is formed in the cytoplasm of liver cells, which is then actively secreted into the biliary tract.
What changes in urine and stool parameters are characteristic of obstructive (subhepatic) jaundice?
Obstrutive (subhepatic) jaundice is characterized by the appearance of very dark urine and complete discoloration of excrement due to impaired bile outflow.
| Parameter | Characteristics of changes |
|---|---|
| Urine | Acquires the color of beer (due to the high concentration of direct bilirubin). Urobilinogens are completely absent in the urine during complete obturation. |
| Stool | Becomes completely discolored (acholic). Stercobilinogens (stercobilin) are absent due to the blockade of bile flow into the intestine. |
What is the detailed pathogenesis of hemolytic (suprahepatic) jaundice development?
The leading mechanism in the development of hemolytic (suprahepatic) jaundice is the hyperproduction of indirect bilirubin due to massive erythrocyte breakdown.
Pathogenesis includes the following key links:
- Enhanced hemolysis — accelerated destruction of erythrocytes leads to the formation of a huge amount of free pigment by macrophages.
- Functional block — normal hepatocytes do not have time to capture and conjugate (convert into the direct form) the excessive amount of incoming indirect bilirubin.
As a result, the amount of generated indirect bilirubin exceeds the liver's capacity to metabolize it, leading to its accumulation in the blood and tissues.
Properties of direct bilirubin: "Straight into water" — it is water-soluble, reacts directly with the Ehrlich reagent, and is easily filtered by the kidneys (hence bilirubinuria).
Class and exam questions
It received its name because it actively and directly reacts with Ehrlich's diazo reagent, unlike unconjugated bilirubin.
It received its name because it actively and directly reacts with Ehrlich's diazo reagent in laboratory tests.
What happens to enzymes in the final stage of hepatic jaundice?
In the third stage, a profound depression of glucuronyl transferase occurs. Due to the blockade of this enzyme, glucuronidation (conjugation) of bilirubin ceases, direct bilirubin is not formed, and toxic indirect bilirubin accumulates in the blood.
How do stool and urine change in the second (icteric) stage?
Urine acquires a "beer" color due to the excretion of water-soluble direct bilirubin, and stool becomes light (acholic) due to a decrease in bile flow into the gut and a drop in stercobilinogen levels.
What else to study on this topic
- Pathogenesis of hemolytic (suprahepatic) jaundice
- Mechanism of development of obstructive (subhepatic) jaundice
- Enzymopathic jaundice: Gilbert and Crigler-Najjar syndromes
- Effect of cholemia on the circulatory system and hemostasis
- Cytolysis syndrome: diagnostic significance of ALT and AST
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