Navigation

Bilirubinuria and urobilinogenuria

Автор: ,

Understanding Bilirubinuria

Bilirubinuria refers to the detectable presence of bilirubin in the urine. Bilirubin is a yellowish pigment that represents an end product of the metabolism of heme, a component of hemoglobin found in red blood cells, as well as other heme-containing proteins like myoglobin, cytochromes, and catalase. Under normal physiological conditions, bilirubin is not found in urine. Its appearance in urine, specifically in its conjugated form, is typically preceded by an elevation of conjugated bilirubin levels in the blood (hyperbilirubinemia).

 

Bilirubin Metabolism Overview

Bilirubin metabolism is a multi-step process:

  1. Formation: Bilirubin is primarily formed in the reticuloendothelial system (RES), mainly in the spleen, liver, and bone marrow, from the breakdown of aged or damaged red blood cells and the heme they contain.
  2. Transport in Plasma: This newly formed bilirubin, known as unconjugated bilirubin (also called free, or indirect bilirubin), is lipid-soluble and water-insoluble. It binds tightly to albumin in the plasma for transport to the liver. This albumin-bilirubin complex is too large to pass through the renal glomerulus, hence unconjugated bilirubin is not normally excreted in urine.
  3. Hepatic Uptake and Conjugation: Unconjugated bilirubin is taken up by hepatocytes (liver cells). Within the hepatocyte, it undergoes conjugation, primarily with glucuronic acid, catalyzed by the enzyme UDP-glucuronosyltransferase. This process forms bilirubin monoglucuronide and bilirubin diglucuronide, collectively referred to as conjugated bilirubin (BC) or direct bilirubin.
  4. Properties of Conjugated Bilirubin: Conjugated bilirubin is water-soluble and less tightly bound to albumin. This water solubility allows it to be filtered by the renal glomeruli if its concentration in the blood becomes significantly elevated.
  5. Biliary Excretion: Conjugated bilirubin is actively secreted by hepatocytes into the bile canaliculi, then flows through the bile ducts into the gallbladder (for storage and concentration) and finally into the small intestine (duodenum) as a component of bile.
  6. Intestinal Transformation: In the small intestine and colon, conjugated bilirubin is further transformed by bacterial enzymes. It is first deconjugated and then reduced to form a group of colorless compounds collectively known as urobilinogens (including urobilinogen, mesobilirubinogen, mesobilirubin, and stercobilinogen).
  7. Enterohepatic Circulation of Urobilinogen: A portion of urobilinogen formed in the duodenum is reabsorbed by enterocytes and returns to the liver via the portal vein blood flow. In a healthy liver, this reabsorbed urobilinogen is almost completely taken up by hepatocytes and re-excreted into bile, or oxidized to dipyrroles and other colorless products. Only a very small amount normally escapes hepatic uptake and enters the systemic circulation to be filtered by the kidneys.
  8. Formation and Excretion of Stercobilinogen: The majority of urobilinogen derivatives continue to the colon, where intestinal flora further convert them into stercobilinogen. Most stercobilinogen is oxidized to stercobilin, the pigment that gives feces its brown color, and is excreted in the feces.
  9. Renal Excretion of Urobilinogen/Stercobilinogen: A small fraction of stercobilinogen formed in the colon is absorbed into the bloodstream, primarily through the hemorrhoidal veins, bypassing the portal circulation to some extent. This portion enters the systemic circulation via the inferior vena cava, reaches the kidneys, and is excreted in the urine.
Urinalysis is a urine test commonly used to detect urinary tract infections, kidney issues, or diabetes.

Thus, normal urine contains only trace amounts of urobilinogen (derived from both enterohepatic circulation and colonic absorption of stercobilinogen). For clinical purposes, the stercobilinogen detected in urine is usually referred to as urobilinogen (or its oxidized form, urobilin), because standard laboratory methods do not typically differentiate between stercobilinogen and urobilinogen.

 

Mechanism and Significance of Bilirubinuria

Conjugated bilirubin appears in the urine (bilirubinuria) when its concentration in the blood rises to a level that exceeds the renal threshold for its filtration. This typically occurs when serum conjugated bilirubin levels reach approximately 30-34 µmol/L (about 1.8-2.0 mg/dL). At this concentration of conjugated bilirubin in the blood, clinical jaundice (yellowness of the mucous membranes and sclera of the eyes) usually becomes apparent. Therefore, bilirubinuria is a key indicator of elevated conjugated hyperbilirubinemia and often points to hepatobiliary disease (liver or bile duct problems).

An increase in stercobilin (in feces, leading to dark stools) and urobilinogen/stercobilinogen (in urine, leading to dark urine upon standing as it oxidizes to urobilin) can be possible with:

  • Increased intravascular or extravascular hemolysis of erythrocytes (e.g., hemolytic anemias).
  • Resorption of massive hematomas (large bruises).
  • Certain diseases of the colon that might lead to increased reabsorption of stercobilinogen.

 

Pathogenetic Mechanisms of Bilirubin Metabolism Disorders

Disruptions in bilirubin metabolism can lead to hyperbilirubinemia (elevated bilirubin in the blood), bilirubinuria, urobilinogenuria, and clinical jaundice. There are several primary pathogenetic mechanisms underlying these disorders:

  1. Increased Bilirubin Production: Primarily due to increased destruction of erythrocytes (hemolysis), either intravascularly or extravascularly (intracellularly within the RES). This leads to an overproduction of unconjugated bilirubin, which can overwhelm the liver's capacity for conjugation.
  2. Impaired Hepatic Uptake or Conjugation: Damage to the liver parenchyma (from any etiology, such as viral hepatitis, alcoholic liver disease, cirrhosis, drug-induced liver injury) or congenital (hereditary) defects in the enzymes responsible for bilirubin uptake and conjugation (e.g., Gilbert's syndrome, Crigler-Najjar syndrome). This leads to an accumulation of unconjugated bilirubin or a mix of unconjugated and conjugated bilirubin.
  3. Impaired Biliary Excretion (Cholestasis): Obstruction of the bile ducts, either intrahepatic (within the liver, e.g., primary biliary cholangitis, drug-induced cholestasis) or extrahepatic (outside the liver, e.g., gallstones in the common bile duct, pancreatic cancer compressing the bile duct). This leads to a buildup of conjugated bilirubin, which then regurgitates into the bloodstream.
  4. Acquired Defects in Bile Pigment Exchange: Besides the above, other acquired conditions can affect specific steps in bilirubin processing.

 

Understanding Urobilinogenuria

Urobilinogenuria refers to the presence of an increased amount of urobilinogen in the urine. As mentioned, normal urine contains trace amounts of urobilinogen. Elevated levels are clinically significant and indicate an abnormality in bilirubin metabolism or liver function.

 

Formation and Excretion of Urobilinogen/Stercobilinogen

Recapping the urobilinogen pathway: Conjugated bilirubin excreted into the intestine is converted by gut bacteria into urobilinogens (including stercobilinogen). A significant portion of this urobilinogen is reabsorbed into the portal circulation and returned to the liver (enterohepatic circulation). A healthy liver efficiently extracts almost all of this reabsorbed urobilinogen, re-excreting it into bile or metabolizing it further (e.g., oxidizing it to dipyrroles). Only a small fraction bypasses the liver, enters the systemic circulation, and is filtered by the kidneys into the urine. Another small portion of stercobilinogen formed in the colon is also absorbed directly into the systemic circulation and excreted by the kidneys.

 

Causes of Increased Urobilinogen/Stercobilinogen in Urine

An increase in stercobilinogen (clinically detected as urobilinogen or urobilin upon oxidation) in feces and urine can be observed due to conditions causing increased intracellular hemolysis of erythrocytes. The excessive breakdown of red blood cells leads to increased production of unconjugated bilirubin. This unconjugated bilirubin, upon entering the intestine after hepatic conjugation, results in the formation of large amounts of stercobilinogen. A larger quantity of this stercobilinogen is then absorbed into the bloodstream and subsequently passes into the urine.

 

Urobilinogenuria as an Indicator of Liver Dysfunction

Urobilinogenuria can be an early and sensitive sign of liver parenchymal damage (hepatocellular dysfunction). When liver cells are damaged, their ability to efficiently extract reabsorbed urobilinogen from the portal blood is impaired. Consequently, more urobilinogen remains in the systemic circulation and is excreted by the kidneys. This can be detected even before other signs of liver damage, such as jaundice or significant elevations in liver enzymes, become apparent. For example, urobilinogenuria is often detected during the prodromal (early) phase of infectious hepatitis (e.g., viral hepatitis A or B) or serum hepatitis.

 

Urobilinogenuria in Hemolytic States and Shunt Hyperbilirubinemia

Increased urobilinogen in urine is a characteristic finding in hemolytic states, where there is excessive breakdown of red blood cells. The liver conjugates the increased load of bilirubin, leading to more bilirubin entering the gut and thus more urobilinogen being formed and reabsorbed. The healthy liver may be overwhelmed by the sheer amount of reabsorbed urobilinogen, allowing more to pass into the urine.

Urobilinuria can also develop when the "direct" pathway of bilirubin formation is enhanced, a phenomenon known as shunt hyperbilirubinemia. This involves the premature destruction of erythroid precursors in the bone marrow (ineffective erythropoiesis) or the rapid turnover of non-hemoglobin heme proteins in the liver, leading to bilirubin production that bypasses the circulation of mature red blood cells. Conditions where this can occur include:

  • Pernicious anemia (Vitamin B12 deficiency)
  • Congenital erythropoietic porphyria (Gunther's disease)
  • Thalassemias
  • Aplastic anemia
  • Lead poisoning
  • Significant internal hemorrhages (resorption of large hematomas also increases bilirubin load)

Physiological jaundice of newborns is also accompanied by an increase in stercobilinogen (urobilin) in urine and feces. This is caused by high hemolysis of excess fetal erythrocytes after birth and the transient immaturity of hepatocyte enzyme systems, particularly insufficient activity of UDP-glucuronosyltransferase, which is needed for bilirubin conjugation.

A similar pathogenetic mechanism (overwhelmed conjugation capacity leading to increased bilirubin flow to the gut) is observed in conditions like polycythemia vera (erythremia) and certain forms of dysmyelopoiesis (ineffective erythropoiesis). In these situations, high glucuronyltransferase activity is required for the conjugation of the large amounts of unconjugated bilirubin formed. If the liver's conjugating capacity is exceeded, it results in hyperbilirubinemia, an increase in stercobilinogen in feces, and its appearance in the urine as urobilinogen.

 

Urobilinogenuria in Impaired Hepatic Bilirubin Uptake/Conjugation

An increase in stercobilinogen in feces and urine (urobilinogenuria) can also be observed as a result of an impaired ability of hepatocytes to take up or conjugate blood bilirubin, even with normal bilirubin production. In these cases, unconjugated bilirubin levels in the blood are typically mildly elevated, sometimes leading to subicteric sclera (slight yellowing of the whites of the eyes). The mechanism often involves a deficiency in the enzyme systems responsible for the capture and transport of bilirubin across the hepatocyte cell membrane or for its conjugation. Examples include:

  • Post-hepatitis hyperbilirubinemia (e.g., Kalk's hyperbilirubinemia)
  • Congenital conditions like Gilbert's syndrome (mild UDP-glucuronosyltransferase deficiency or impaired uptake)
  • Crigler-Najjar syndrome (more severe UDP-glucuronosyltransferase deficiency; Type II may have some urobilinogen, Type I typically has absent conjugated bilirubin and thus no urobilinogen).

In these conditions, although conjugation may be impaired, some bilirubin still reaches the gut to form urobilinogen. If liver function is otherwise relatively preserved for urobilinogen uptake from portal blood, urobilinogenuria might be less prominent than in frank hepatocellular damage or hemolysis unless there's a coexisting issue.

 

Clinical Significance and Diagnostic Approach

The detection of bilirubinuria and abnormal levels of urobilinogenuria provides valuable clues for diagnosing and differentiating various types of jaundice and liver diseases.

  • Bilirubinuria: Almost always indicates the presence of conjugated hyperbilirubinemia. This points towards either hepatocellular disease (where the liver can conjugate bilirubin but cannot excrete it properly into bile) or biliary obstruction (where bile flow is blocked, causing conjugated bilirubin to back up into the blood). Bilirubinuria is typically absent in pre-hepatic jaundice (e.g., pure hemolytic anemia where the excess bilirubin is unconjugated and cannot pass the renal filter).
  • Urobilinogenuria:
    • Increased levels: Suggestive of hemolysis (increased bilirubin turnover) or hepatocellular disease (impaired hepatic clearance of reabsorbed urobilinogen).
    • Absent or very low levels: Strongly suggests complete biliary obstruction, as no bilirubin reaches the intestine to be converted into urobilinogen. It can also be seen in severe hepatocellular damage where bile production itself is minimal, or with broad-spectrum antibiotic use that alters gut flora.

A standard urinalysis dipstick test can detect both bilirubin and urobilinogen. Further investigations typically include liver function tests (LFTs), serum bilirubin fractionation (total, direct/conjugated, indirect/unconjugated), complete blood count (CBC) to assess for hemolysis, and imaging studies (ultrasound, CT, MRI/MRCP) if biliary obstruction or liver pathology is suspected.

 

Differential Diagnosis of Jaundice Based on Urine Findings

The pattern of bilirubin and urobilinogen in the urine can help differentiate the types of jaundice:

Type of Jaundice Urine Bilirubin Urine Urobilinogen Common Causes
Pre-hepatic (Hemolytic) Jaundice Absent (Negative) Increased (+++) Hemolytic anemias, ineffective erythropoiesis, resorption of large hematomas.
Hepatic (Hepatocellular) Jaundice Present (Positive, + to +++) Normal or Increased (++)
(May be decreased in severe damage/cholestasis)		 Viral hepatitis, alcoholic liver disease, cirrhosis, drug-induced liver injury, Gilbert's syndrome (bilirubin often absent), Crigler-Najjar.
Post-hepatic (Obstructive/Cholestatic) Jaundice Present (Positive, ++ to +++) Absent or Markedly Decreased (Trace or Negative)
(if obstruction is complete)		 Gallstones in common bile duct, pancreatic cancer, biliary atresia, tumors of bile duct/ampulla, primary biliary cholangitis, drug-induced cholestasis.

Note: The "Normal" urine urobilinogen level refers to the usual trace amounts detected. The degree of increase (e.g., +, ++, +++) is relative.

 

When to Consult a Physician

The appearance of dark urine (which could be due to bilirubin or high levels of urobilin), jaundice (yellowing of skin or eyes), or persistent unexplained changes in urine or stool color warrants prompt medical evaluation. These can be signs of underlying liver disease, biliary tract disorders, or hemolytic conditions that require diagnosis and management by a healthcare professional. Urinalysis findings of bilirubinuria or significantly increased urobilinogenuria should always be followed up with further medical investigation.

References

  1. Berk PD, Noyer C. Bilirubin metabolism and its disorders. In: Zakim D, Boyer TD, eds. Hepatology: A Textbook of Liver Disease. 3rd ed. WB Saunders; 1996:241-301.
  2. Sherlock S, Dooley J. Diseases of the Liver and Biliary System. 11th ed. Blackwell Science; 2002. (Chapter on Jaundice and Bilirubin Metabolism).
  3. Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):555-71.
  4. Kuntz E, Kuntz HD. Hepatology: Principles and Practice. 2nd ed. Springer; 2006. (Section on Bile Pigments).
  5. McPherson RA, Pincus MR. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Elsevier; 2017. (Chapter on Liver Function).
  6. Wallach J. Interpretation of Diagnostic Tests. 9th ed. Lippincott Williams & Wilkins; 2011. (Section on Urinalysis - Bilirubin and Urobilinogen).
  7. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. (Resource for drug effects on liver and bilirubin).