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High indirect bilirubin: causes


Breakdowned red blood cell (RBC)
Breakdowned red blood cell (RBC)

The source of indirect bilirubin is hemoglobin, released from broken down senescent red blood cells (RBC). Small quantities of indirect bilirubin are constantly being generated in the body as part of RBCs renewal. There is no way to remove indirect bilirubin out of the system, because it is unsoluble in water. To get rid of bilirubin, our body needs to transform it into water-soluble substance that is direct bilirubin (the process is called conjugation of bilirubin). This metabolic stage takes place in liver. Then direct bilirubin excretes to bile.


High level of indirect bilirubin in blood can be caused by problems at early or final stage of its metabolism:

  1. Hemolysis (massive destruction of RBC). Liver is usually disease-free, but there is too much bilirubin due to its overproduction. The liver just cannot keep up with it.
  2. Blockage of indirect-to-direct bilirubin transformation. It happens in some liver diseases, whether hereditary or acquired.

To illustrate a point, an analogy with supermarket can be made. There may be two causes for checkout lines:

  1. Too many customers, the cashiers are doing their best, but the lines remain huge.
  2. Usual number of customers, but most of the desks are closed: the cashiers are on sick leave; still the same result.


Mechanism of pre-hepatic elevation of indirect bilirubin
Mechanism of prehepatic elevation of indirect bilitubin level: massive breakdown of erythrocytes → excess free hemoglobin → excess indirect bilirubin → even entirely healthy liver cannot keep up with it.

Hemolysis is a massive destruction of red blood cells. Released hemoglobin is a source of substantial amounts of indirect bilirubin. Conditions accomponied with hemolysis have different origins. Their common feature is anemia, given that hemolysis leads to deficiency of red bloos cells and hemoglobin in blood. That is why such conditions are referred to as "hemolytic anemia". Signs of anemia are skin discoloration, weakness and dizziness. The system tries to make up for this low RBCs amount and young unripe RBCs ("reticulocytes") count rises. Spleen is enlarged, considering that it is actively engaged in disposal of destroyed RBCs.

Meanwhile, there may be fully functioning liver and no constraints on bilirubin metabolism. In this case, the problem is the amount of bilirubin itself, because its production outpaces its processing in liver.

The consequence of an extensive accumulation of indirect bilirubin in the body in hemolytic anemia is hemolytic jaundice.

Causes of hemolytic anemia:

  1. Hereditary hemolytic anemia usually reveals itself in permanent or recurring jaundice in young children. Genetic flaws in enzyme systems, cell membranes or hemoglobin underlie these disorders. Red blood cells with such defects have low viability.
    • hereditary spherocytosis
    • glucose-6-phosphate dehydrogenase (G-6-PD) deficiency
    • erythrocyte pyruvate kinase deficiency
    • sickle cell anemia
    • thalassemia
    • paroxysmal nocturnal hemoglobinuria (PNH)
  2. Autoimmune hemolytic anemia. In such conditions the body produces antibodies to its own red blood cells, which results in their breakdown and hemolytic anemia. Autoimmune hemolytic anemia can be idiopatic or be a component of some another disease such as:
    • systemic lupus erythematosus
    • rheumatoid arthritis
    • Hodgkin's disease
    • lymphoid leukemia
  3. Infectious diseases:
    • Malaria
    • Septicemia
  4. Hemolytic disease of the newborn (HDN), or erythroblastosis fetalis. Hemolysis of RBC is due to ummune incompatability between mother and fetus. Most often it is Rh Factor incompatability.
  5. Drug-induced hemolytic anemia. Numerous drugs are capable of triggering hemolysis. Apart from direct toxic damage of RBCs or blocking their enzymes, much more sophisticated mechanism is possible: while adsorbing on RBCs surfaces, drug modifies their immune "passport". Such red blood cells are identified by the immune system as foreign and become the targets. The key feature of such anemia (called drug-induced immune hemolytic anemia) is no improvement even after drug cessation. Medications that can induce hemolytic anemia are those listed below:
    • Cephalosporins
    • Penicillin
    • Nonsteroidal anti-inflammatory drugs (NSAIDs)
    • Nitrofurantoin
    • Levofloxacin
    • Methyldopa
  6. Exposure to hemolytic poisons:
    • Lead and its compounds
    • Arsenic and its compounds
    • Copper salts
    • Nitrobenzene
    • Aniline


Mechanism of hepatic elevation of indirect bilirubin
Mechanism of hepatic elevation of indirect bilirubin: hereditary deficiency of enzyme glucuronyltransferase (UGT)

One indispensable part of bilirubin metabolism is its transformation from indirect to direct form, or conjugation of bilirubin. This process takes place in hepatic cells and requires a presense of a certain set of enzymes. The enzyme most studied is glucuronyltransferase (UGT). Conjugantion of bilirubin slows down, if there is a lack of one of the enzymes or its ability to function normally is lost.

The cause of the failure of enzymes that transform bilirubin may be hereditary or acquired:

  • Gilbert's syndrome. It is very common hereditary disease. By some estimates, up to 5% of the world population suffers from it. Due to a genetic defect synthesis of UGT enzyme is seriously reduced: just 3-10% of its normal amount. Generally, it is enough, but multiple effects of stressors may trigger unconjugated hyperbilirubinemia (elevated level of indirect bilirubin in serum) and jaundice. Among those factors are infections, medications that block AGT, excessive physical activities, alcohol etc. This condition usually manifests itself in adolescence. In the opinion of many specialists, mild forms of Gilbert's syndrome should be considered not as a disease, but rather a variant of norm.
  • Other hereditary diseases. There is no point in listing all of them, because, in contrast to Gilbert's syndrome described above, they are extremely rare. A classic example of such disease is Crigler-Najjar syndrome with less than 300 cases recorded worldwide. It is characterized by almost total absence of AGT and manifests itself in a severe jaundice during neonatal period.
  • Competitive inhibition
    Competitive inhibition is one of the mechanisms of indirect bilirubin buildup in liver: numerous medications require the same enzymes as indirect bilirubin and edge it out of metabolism
  • Drug-induced nonhemolytic jaundice. Drugs containing estradiol, nonsteroidal anti-inflammatory drugs (NSAIDs), X-ray contrast agents and many more medications require the same enzymes as indirect bilirubin does to be hepatically metabolized. At some point, bilirubin cannot sustain a competition anymore and is edged out of the metabolism. If liver is healthy, then this effect appears only in a massive overdosing. But on the background of pathologies already in place there (most often it's Gilbert's syndrome), even regular doses of specified medications may lead to jaundice. Alcohol also can destabilize bilirubin conjugation.


pre-hepatic indirect bilirubin buildup hepatic indirect bilirubin buildup
main causes hemolytic anemia Gilbert's syndrome
mechanism of buildup massive breakdown of red blood cells leads to overproduction of indirect bilirubin disorder of bilirubin conjugation (transformation of indirect to direct form) in hepatic cells
Signs of anemia: fatigueness, dizziness, paleness yes no
splenomegaly (enlargement of spleen) yes no
indirect bilirubin high high
direct bilirubin normal normal
hemoglobin low normal
reticulocytes in blood high normal
transaminase (ALT, AST) normal normal
alkaline phosphatase (ALP) normal or low normal
bilirubin in urine no no
urobilinogen in urine high normal