15. Jaundice

Page created on February 12, 2019. Last updated on April 16, 2020 at 14:40

Bilirubin

Bilirubin is the breakdown product of the heme part of haemoglobin. It is the culprit of the yellowness of urine and of the brownness of feces. Bilirubin is toxic, so the liver keeps its level low by eliminating it. The normal serum level is <17 µmol/L.

As red blood cells are at the end of their lifespan of around 120 days they are phagocytosed by macrophages in the spleen. This breaks down haemoglobin in to heme and globin. Globin is broken down into amino acids, while heme is broken down into iron and protoporphyrin. Protoporphyrin is then converted into unconjugated bilirubin (UCB), also called indirect bilirubin.

UCB is lipid-soluble and therefore not water-soluble. It’s transported from the spleen to the liver by binding to albumin. When inside the liver the unconjugated bilirubin is taken up by hepatocytes. Inside the hepatocytes will the UCB undergo biotransformation, just like any drug would. The biotransformation of unconjugated bilirubin involves an enzyme called uridine glucuronosyltransferase, or UGT for short. UGT conjugates the unconjugated bilirubin with glucuronic acid, making it conjugated bilirubin (CB), also called direct bilirubin.

Conjugated bilirubin is water-soluble, so the hepatocyte secretes it into the bile canaliculi where it is led to the gallbladder and stored in bile. When you eat will the gallbladder contract and release the bile into the duodenum. Inside the duodenum will bacteria convert the conjugated into urobilinogen, which is quickly spontaneously converted into stercobilin, which is then excreted with the feces. It is the stercobilin that gives feces the brown colour.

Not all urobilinogen is converted into stercobilin and excreted. Some of it is reabsorbed by the intestines into the blood as part of the enterohepatic circulation. Some of the reabsorbed urobilinogen is converted into urobilin and excreted via the kidney, which gives urine the yellow colour. The rest of the urobilinogen travels to the liver, is converted back into conjugated bilirubin and is excreted into the bile again.

If any part of this metabolism is impaired can the level of either unconjugated, conjugated bilirubin or both be elevated in the blood, called hyperbilirubinaemia. We distinguish unconjugated hyperbilirubinaemia and conjugated hyperbilirubinaemia depending on which form of bilirubin that is accumulating.

Jaundice

Jaundice, or icterus, is the condition where the bilirubin levels in the blood is so high that the skin and sclera turn yellowish. When there is elevation of bilirubin in the blood but no clinical evidence of jaundice the condition is called subicterus.

The rate-limiting step of bilirubin metabolism is the UGT enzyme in the hepatocytes that conjugate bilirubin. If an excessive number of RBCs are haemolysed will excessive amounts of unconjugated bilirubin be produced. The UGT enzyme is bottlenecked and can’t keep up with the increased workload, causing unconjugated bilirubin to accumulate in the plasma.

If something is wrong with the UGT enzyme or the hepatocytes themselves will the livers capacity to conjugate unconjugated bilirubin also decrease. This also causes unconjugated hyperbilirubinaemia.

If there is an obstruction of bile flow will the pressure increase inside the bile duct proximal to the obstruction. This causes bile to be forced into the blood, causing conjugated hyperbilirubinaemia.

Because of the extensive process to metabolise heme are there many pitfalls where the metabolism may be disrupted. We therefore classify jaundice based on the underlying reason of the jaundice:

• Prehepatic (haemolytic) jaundice – due to increased haemolysis
• Intrahepatic (hepatocellular) jaundice – due to problems with hepatocytes or UGT
• Posthepatic (obstructive) jaundice – due to obstruction of bile outflow

Prehepatic jaundice

Prehepatic jaundice is caused by anything that causes an increased rate of haemolysis. The UGT enzyme bottlenecks the bilirubin metabolism, causing unconjugated bilirubin to accumulate in the blood.

It can occur due to haematomas or haemolytic conditions. Increased haemolysis occurs in diseases where the RBCs are fragile like thalassaemia, sickle cell anaemia, G6PD deficiency or in hypersplenism.

In prehepatic jaundice will a lot of conjugated bilirubin be produced and excreted into the gut, where it is converted into urobilinogen and causes the feces to become darker than normal. Increased urobilinogen in the gut means increased reabsorption of urinobilinogen, which is converted into urobilin and excreted via the kidney.

In prehepatic jaundice:

• is the colour of the urine normal – as there is no conjugated bilirubin in it
• is the feces darker – due to increased amount of stercobilin
• the urine contains no bilirubin – as the excess bilirubin in the blood is unconjugated and therefore not water-soluble
• the blood contains more unconjugated bilirubin

Some teachers may claim that the urine is dark in prehepatic jaundice due to increased urobilin content, but urobilin doesn’t cause the urine to darken; only conjugated bilirubin does. My sources for this are Oxford Handbook of Clinical Diagnosis page 312 and Harrison’s Principles of Internal Medicine page 733.

While urobilinogen don’t darken the urine, haemoglobin can. Prehepatic jaundice is often caused by extensive haemolysis, which can release large amounts of haemoglobin. Some of this haemoglobin might escape reabsorption in the proximal tubules and darken the urine.

Intrahepatic jaundice

Intrahepatic jaundice is caused by any problem with the UGT enzyme or the hepatocytes themselves. It can occur due to:

• Neonatal physiological jaundice – infants have decreased levels of UGT
• Gilbert syndrome – genetic deficiency of UGT
• Hepatitis
• Cirrhosis
• Liver tumor
• Crigler Najjar syndrome type I and II
• Breast milk jaundice – breast milk contains compounds that inhibit UGT

Neonates have only about 1% of the UGT activity that adults have. It’s therefore not uncommon that neonates develop a slight jaundice. This is physiological. The decreased UGT activity does however predispose them to damage due to hyperbilirubinaemia if there is another factor in play.

The low neonatal activity of UGT isn’t helped by the fact that breast milk contains compounds that inhibit their UGT activity further.

People with Gilbert syndrome have a genetic deficiency of UGT and/or the uptake of unconjugated bilirubin. Their UGT activity is approximately 30% of that of the normal population. People suffering from it may develop jaundice in periods of stress, during exercise or during menstruation. It normally does not cause any symptoms and does not need treatment. In fact do people with Gilbert syndrome have much lower incidence of cardiovascular disease!

Crigler Najjar syndrome is similar to Gilbert in that there is a genetic deficiency of UGT, however in Crigler Najjar is there basically no UGT activity at all. The disease is mostly fatal.

When the normal function of the hepatocytes is decreased, as during cirrhosis, hepatitis or cancer will unconjugated bilirubin accumulate in the blood.

In intrahepatic jaundice the liver conjugates less bilirubin than normally, causing less stercobilin to be formed in the gut. The stool therefore has a lighter colour than normal. The stool is also pale because it contains more fat.

The reabsorbed urobilinogen from the intestines can’t be converted back to conjugated bilirubin by the liver, so it’s instead converted into urobilin and excreted through the urine (but it does not affect the urine colour, see above). The urine is darker due to increased conjugated bilirubin in the urine.

In all cases of intrahepatic jaundice will there be unconjugated hyperbilirubinaemia. In those cases where the liver cells are damaged, like hepatitis and cirrhosis, will the damaged hepatocytes be unable to excrete all the conjugated bilirubin to the bile, causing some conjugated bilirubin to return to the blood. In those cases will there be both conjugated and unconjugated hyperbilirubinaemia.

In intrahepatic jaundice:

• is the urine darker – as it contains more conjugated bilirubin
• is the feces lighter – as less bilirubin reaches the gut
• the urine contains large amounts of conjugated bilirubin
• the blood contains more unconjugated bilirubin and often more conjugated bilirubin as well

Posthepatic jaundice

In posthepatic jaundice is there a problem with excreted bilirubin into the bile canaliculi. Most commonly will an occlusion of the biliary tract cause increased pressure inside the biliary tract. Broken bile canaliculi will allow bile to leak back into the blood. It can be caused by:

• Rotor syndrome
• Dubin-Johnson syndrome
• Intrahepatic cholestasis
• Cholelithiasis

The Rotor and Dubin-Johnson syndromes are conditions where there is no mechanical obstruction, however the hepatocytes can’t excrete conjugated bilirubin into the bile canaliculi due to transport protein deficiencies.

Intrahepatic cholestasis can occur due to drugs, pregnancy or after surgery. It can also occur in hepatitis and primary biliary cholangitis.

When the bile duct is mechanically obstructed, most commonly due to a stone, will the pressure in the duct increase proximal to the obstruction. The increased pressure damages bile canaliculi which allows backleak of bile into the blood. Not only conjugated bilirubin but bile acids will enter the blood. Bile acids in the blood causes pruritus (itching).

No bilirubin enters the gut, causing the stool to be pale. Large amounts of conjugated bilirubin is found in the urine, but no urobilin.

In posthepatic jaundice:

• is the urine darker – as it contains more conjugated bilirubin
• is the feces pale – as no bilirubin reaches the gut
• does the blood contain more conjugated bilirubin and bile acids
• is itching often a symptom

Bilirubin toxicity

Why is hyperbilirubinaemia dangerous? Bilirubin itself is an antioxidant and might therefore be useful in low concentrations.

It’s mostly the unconjugated bilirubin that is dangerous. Due to its lipid-solubility can it cross the blood-brain barrier and damage the basal ganglia, a condition called kernicterus. Neonates are especially predisposed to this as they have a weaker blood-brain barrier.

Kernicterus is treated with phototherapy, where the patient is exposed to special blue light that convert unconjugated bilirubin into a more water-soluble form that can be excreted with the urine.

Summary

Type	Color of stool	Indirect bilirubin	Direct bilirubin	Bilirubin in urine	Urinary urobilinogen	Common cause
Prehepatic jaundice	Dark	Increased	Normal	Normal	Increased	Haemolytic conditions
Intrehepatic jaundice	Pale, acholic	Increased	Increased	Increased (dark urine)	Normal or increased	Cirrhosis
Posthepatic jaundice	Pale, acholic	Normal	Increased	Increased (dark urine)	Absent	Cholelithiatis