MetabolismBlood testsDiagnosticsHealth

High bilirubin: is hepatitis always the root cause?

Bilirubin test has been used for diagnostics for decades and many know that high bilirubin accomponies jaundice. Some people even make a diagnosis on the spot: "if bilirubin level is high, it means hepatitis". Actually, elevated bilirubin level may as well be caused by a number of factors external to the liver.


Metabolism of bilirubin
Metabolism of bilirubin

Bilirubin is a product of blood hemoglobin processing. It is constantly being generated in the body as part of red blood cells (RBCs) renewal.

Most of bilirubin in the body is in two forms:

  • indirect bilirubin
  • direct bilirubin

Total bilirubin does not exist as a chemical compound, but represents a total amount of direct and indirect bilirubin. Initially just indirect bilirubin is formed. This process occurs in liver, bone marrow, spleen. Then liver transforms an indirect bilirubin into direct and excretes it with bile into the intestine.

High level of bilirubin in blood plasma is called hyperbilirubinemia. Significantly elevated level of both indirect and direct bilirubin may reveal itself in jaundice.


mg/dL µmol/L
total bilirubin 0.3 - 1.2 5.1 - 21
direct bilirubin 0 - 0.3 0 - 5.1

Normal bilirubin ranges may vary slightly, in case the tests are done at different labs. This is due to use of different equipment.


4 "bottlenecks" of bilirubin metabolism
4 "bottlenecks" of bilirubin metabolism

From the point of generation up to excretion into the intestine bilirubin travels long and difficult path.

There are potential "bottlenecks" on it, where buildup of bilirubin and jandice progression may be triggered. Depending on what stage of metabolism "bottleneck" appears at, either direct or indirect bilirubin is increased more.

There are 4 of such conditions:

  1. Hemolysis (massive destruction of red blood cells).
    Cause: In this case nothing is wrong with bilirubin metabolism itself, just its overproduction takes place. That is why even entirely disease-free liver cannot take on its excretion.
    Effect: elevated level of indirect bilirubin.
  2. Blocking of indirect-to-direct bilirubin transformation in liver (bilirubin conjugation).
    Primary causes: certain hereditary diseases, medications overdose.
    Effect: elevated level of indirect bilirubin.
  3. Stopping of transport of direct bilirubin from liver cell to bile.
    Primary causes: hepatitis, cirrhosis.
    Effects: elevated level of direct, and, to a lesser extent, indirect bilirubin.
  4. Obstruction of biliary truct.
    Primary causes: cholelithiasis, strictures of common bile duct.
    Effect: high direct bilirubin.


To correctly identify the cause of high bilirubin, it is important to specify a type, through which it has increased. The situation is clear, if only one of them is elevated, while another one is within the normal range. Not so if it's both. It is wrong to just compare two numbers (indirect and direct bilirubin levels) and pick what is higher. In such a case the ratio should be calculated. If indirect bilirubin level constitutes 90% or more of total level, then the total increase stems principally from indirect bilirubin excessive buildup, otherwise it's direct bilirubin.


Taking all available tests and symptoms into account besides bilirubin concentration measurements can help to discern what stage of metabolism involves bilirubin buildup that may set off jandice.

pre-hepatic indirect bilirubin buildup hepatic indirect bilirubin buildup hepatic direct bilirubin buildup post-hepatic direct bilirubin buildup
main causes hemolytic anemia Gilbert's syndrome hepatitis, cirrhosis cholelithiasis, tumors
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 disorder of direct bilirubin transport from hepatic cells to bile, stoppage of bile flow in intrahepatic bile ducts obstruction of extrahepatic bile ducts by gallstones, strictures
Signs of anemia: fatigueness, dizziness, paleness yes no no no
splenomegaly (enlargement of spleen) yes no no no
feces discoloration no no possible (total or partial) yes
indirect bilirubin high high normal or slighly elevated normal
direct bilirubin normal normal high high
hemoglobin low normal normal normal
reticulocytes in blood high normal normal normal
transaminase (ALT, AST) normal normal high normal
alkaline phosphatase (ALP) normal or low normal normal or moderately elevated extraelevated
bilirubin in urine no no yes yes
urobilinogen in urine high normal high or absent absent