HIGH BILIRUBIN or HYPERBILIRUBINEMIA: symptoms and causes

There bilirubin it is a waste substance of the organism, which derives from degradation hemoglobin. A high bilirubin can result from having problems with the liver (hepatitis, cirrhosis) or alle biliary tract (obstruction or infection of gallbladder and bile ducts, cause direct hyperbilirubinemia). A increase in indirect bilirubin instead it is frequently associated with an increased destruction of red blood cells, as in haemolytic anemia. The main symptom of high bilirubin isjaundice cutaneous (yellow skin) and sleral jaundice (yellow eyes). Other frequent symptoms of hyperbilirubinemia are the presence of I made clear and of very dark urine, itching and nausea with loss of appetite.

High bilirubin

There bilirubin is a waste substance that derives from the degradation of the hemoglobin molecule, present within Red blood cells and in charge of the transport of oxygen from the lungs to the body tissues. Bilirubin is primarily responsible for the green color of bile. Once produced, bilirubin is transported to the liver, transformed and eliminated with the bile in the intestine. Part of the bile is then reabsorbed and returns to the blood and from there to the liver, repeating the same path. It is important to measure the blood levels of total bilirubin (bilirubinemia), and its two components direct bilirubin (i.e. bilirubin already processed by the liver and linked toglucuronic acid) and the indirect or free bilirubin (bilirubin not yet processed in the liver and therefore still insoluble). Indirect bilirubin can be obtained with the simple formula:
Indirect bilirubin = Total bilirubin - direct bilirubin.
There total and fractional bilirubinemia allows us to indirectly understand the health of the liver and biliary tract.

High bilirubin values

  • Total bilirubin: it is high when it exceeds 1 mg / dL or 17 mmol / L (1 milligram per deciliter or 17 millimoles per liter)
  • Direct Bilirubin: it is high if it exceeds i 0.3 mg / dL or 5.1 mmol / L  (0.3 milligrams per deciliter or 5.1 millimoles per liter)
  • Indirect bilirubin: is high when it exceeds 0.8 mg / dL or 12 mmol / L (0.8 milligrams per deciliter or 12 millimoles per liter)

Bilirubin: what it is and how it is formed

Bilirubin is a pigment, that is a colored substance, present in bile and in numerous compounds of our organism, such as hemoglobin (of which it is a degradation product), myoglobin, cytochromes, catalases and peroxidases, which are enzymes involved in the metabolism of cells . Chemically, bilirubin is the hemoglobin deprived of the iron atom and the protein part (globin) which has the transport function. The name bilirubin derives directly from the color that characterizes it, red, and from the liquid in which it is present in high concentrations, bile.

There bilirubin it mostly results (about 80%) from the normal destruction of red blood cells at the end of their life cycle, which is 120 days; the remainder is produced by the catabolism, ie the degradation, of other compounds such as the aforementioned proteins present in the serum (myoglobin, cytochromes, etc.). It is the products of bilirubin catabolism that give the urine its typical light yellow color and the stools the normal brown color.

The main functions of bilirubin

Bilirubin is primarily a waste product but some studies have revealed that it is also a powerful antioxidant; probably, bilirubin also has the function of reducing the oxidative damage caused by free radicals against cells, which is the cause of premature aging, cell death and some types of tumors.
Despite being a waste product of metabolism, bilirubin is very useful for verifying the correct functionality of the liver, an organ that deals with part of its degradation; the dosage of its two forms (direct and indirect) provides the doctor with useful information on liver function and the functioning of the normal process of destruction of red blood cells.

How bilirubin is eliminated: conjugation, hepatic and renal elimination

Bilirubin is the product of degradation of hemoglobin contained in red blood cells. When the red blood cells, at the end of their life, are destroyed in the spleen, the majority of their components are recycled and used to form new molecules. In the early stages of hemoglobin catabolism, the biliverdin, which in turn (by some specific enzymes) is converted into bilirubin. This bilirubin is called live is it is not soluble in water: to reach the liver through the bloodstream, it must be bound by a protein called albumin.
The albumin-bilirubin complex indirectly reaches the liver, where it is broken down by specialized cells and an enzyme (called UDPGT) binds bilirubin toglucuronic acid: this form of conjugated bilirubin is called direct. Direct bilirubin is soluble, so it escapes from the liver cells and enters the bile, from where it passes into the small intestine and then into the large intestine. In the colon and ileum, an enzyme (beta-glucuronidase) operates the reverse process, that is, it splits direct bilirubin into bilirubin and glucuronic acid. Here, part of the bilirubin is broken down by the bacteria present in the intestine into urobilinogen, while a small amount of bilirubin (20%) and urobilinogen are absorbed by the intestinal mucosa and put back into circulation.
Once back in the blood, urobilinogen can follow two paths: it can return to the bile or be filtered by the kidneys, oxidized to urobilin and excreted in the urine. However, urobilinogen 80% is transformed by the bacteria of the large intestine into stercobilin and excreted with the fecal material.

Causes of high bilirubin

High levels of bilirubin in the blood (hyperbilirubinemia) can be caused by:

  • Liver problems (pathologies affecting the liver such as viral hepatitis, cirrhosis, cancers)
  • Increased destruction (haemolysis) of red blood cells with consequent increase in the degradation of hemoglobin, from which bilirubin derives. This is the case of haemolytic anemia due to transfusion reactions, drug reactions, favism (susceptibility to cellular oxidation due to an enzyme defect), sickle cell anemia.
  • Obstruction of the bile ducts because of calculations to the gallbladder or bile ducts (the main bile duct site of stones is the choledochus
  • Obstruction of the bile ducts due to narrowing as occurs in autoimmune diseases such as sclerosing cholangitis and primary biliary cholangitis
  • Presence of large hematomas healing
  • Genetic diseases be rare (Crigler-Najjar syndrome, Rotor syndrome, Dubin Johnson syndrome) both common and benign (Gilbert's syndrome).

After having diagnosed a high level of bilirubin in the blood, it is necessary to check which form it is, that is to distinguish between direct bilirubin and indirect bilirubin and calculate the ratio between the two forms, which is normally 1: 4 in favor of the indirect. Laboratory tests generally show the wording of fractionated bilirubin, i.e. they indicate the amount of direct bilirubin, indirect bilirubin and the total.

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There bilirubin can be high in pregnancy due to cholestasis gravidarum, caused by the permanence of bile acids in the liver which, produced in excess, lead to an increase in bilirubin present in the blood.

High direct bilirubin

There direct bilirubin is the amount of bilirubin that is conjugated to glucuronic acid and which, after exiting the liver, passes into the small intestine and large intestine in the form of urobilinogen. L' direct hyperbilirubinemia it is usually caused by liver problems (viral hepatitis, drug reaction, cirrhosis or alcoholic hepatitis) or bile duct obstruction. Also some genetic diseases, such as Rotor syndrome and Dubin Jonhson syndrome, can cause an increase in the conjugated bilirubin level; these are usually benign syndromes that do not require any medical treatment.

High indirect bilirubin

There indirect bilirubinemia it is the amount of bilirubin that derives directly from the catabolism of hemoglobin and to a small extent from the degradation of other serum hemoproteins. Indirect hyperbilirubinemia, therefore, is a symptom of the liver's inability to manage too high levels of unconjugated bilirubin, which can result from massive haemolysis (destruction of red blood cells), as in the case of haemolytic anemia, transfusion reactions, syndrome Gilbert's disease (very common but harmless, caused by a defect in the enzyme that captures bilirubin making it soluble) and Crigler-Najjar syndrome (defect in the enzyme glucuronyl-transferase).
In infants, indirect hyperbilirubinemia is the cause ofneonatal jaundice. In fact, during fetal life the newborn produces more red blood cells than are needed outside the womb; at birth, excess red blood cells are rapidly eliminated, producing a high proportion of bilirubin which can take a few days to dispose of by the liver and causes the symptoms of jaundice. In some cases, hemolysis can be caused by an immune reaction of the mother against the newborn, due to the diversity of the Rh factor exposed on the red blood cells (Rh negative mother and Rh positive baby).
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High bilirubin: symptoms

High blood bilirubin can be caused by a number of conditions and diseases, but the main symptom that can usually be seen is the same, namely jaundice. Jaundice, ie the yellow color of the skin and sclera (the white part) of the eyes, is directly related to the high percentage of bilirubin that is deposited in the epidermal layers. Jaundice is a consequence of an excess of bilirubin in the blood, both direct and indirect. Other symptoms are related to the elevated form of bilirubin.

Symptoms of direct hyperbilirubinemia

If the excess bilirubin is direct, i.e. conjugated to glucuronic acid, some symptoms may appear (in addition to jaundice) that direct the doctor in the diagnosis. A symptom is pale (yellow or brownish) stools which can be caused by the difficulty of the bile in reaching the small intestine and transforming into stercobilin, or by a defect in the bacterial flora of the colon which has the task of transforming bilirubin into urobilinogen.
Along with light stools, dark brown or red urine may be noted; this abnormal tone is caused by direct bilirubin which, being water-soluble, is filtered more by the kidney and ends up in the urine, changing its color. Another symptom of direct hyperbilirubinemia is pruritus, caused by excess bile and an increase in bile salts in the blood, which cause an accumulation in the skin.

Symptoms of indirect hyperbilirubinemia

Symptoms caused by an excess of indirect bilirubinemia mainly result from the underlying causes of the hyperbilirubinemia, such as massive hemolysis or a transfusion reaction. In addition to jaundice, asthenia (extreme weakness), pallor (often covered by jaundice), tachycardia (increased heart rate), hepatosplenomegaly (palpable enlargement of the liver and spleen that attempt to metabolize hemoglobin and bilirubin in excess).
Fever and dark urine may be present, and in severe cases disseminated intravascular coagulation (SCID), or massive blood clotting, may occur, especially in the case of transfusion reactions
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