Hemolytic jaundice

The mechanisms by which bilirubin is overproduced in hemolytic jaundice can be understood in relation to the two major sites of hemolysis: intravascular and extravascular.

Process of heme breakdown that leads to the production of bilirubin, in extravascular hemolysis.

During intravascular hemolysis, red blood cells are broken down within the vasculature, allowing hemoglobin from the ruptured red blood cells to form haptoglobin-hemoglobin complexes with haptoglobin, which will be internalized and degraded by hepatocytes and the spleen.[21] If the degree of hemolysis is abnormally high, the unbound hemoglobin is converted to methemoglobin from which the heme moiety is bound to hemopexin or to albumin, and both heme-hemopexin and heme-bound albumin are internalized by hepatocytes and subsequently degraded to bilirubin.[22][10]

Zones of cephalocaudal jaundice progression according to the Kramer's scale.

During extravascular hemolysis, red blood cells are destroyed by phagocytosis by macrophages in the reticuloendothelial system and digested by phagosomes.[23] Hemoglobin within red blood cells are then degraded to release heme, which will be converted by microsomal heme oxygenase to iron, carbon monoxide and biliverdin, and are immediately reduced to unconjugated bilirubin by biliverdin reductase and released into the plasma.[24]

In both settings of hemolysis mentioned above, only low levels of conjugated bilirubin may accumulate in the serum, with the amount falling within the normal limits of 4 percent of total bilirubin as conjugated bilirubin can be efficiently excreted in bile through being secreted across canalicular membrane.[25] Increased levels of conjugated bilirubin will only be observed with coexisting hepatobiliary abnormalities. Only when the canalicular excretion capacity is exceeded, conjugated bilirubin will accumulate in the plasma.[26] As unconjugated bilirubin has a high affinity to albumin, at high level it is not efficiently cleared through glomerular filtration and it binds to the elastic tissue of the skin and sclera, where high albumin content can be found.[25] This explains the yellow discolouration observed in these tissues in hemolytic jaundice.

In both newborns and adults, yellowing of the skin is a marker for jaundice.[27] As most cases of jaundice are observed in newborns, healthcare workers use visual methods to identify the presence of this condition.[29] A clinical jaundice scale, an adapted version of the Kramer's scale, is used to quantify the severity of jaundice through the spread of skin discoloration from zone 1, the head, to zone 5, the palms and soles of the neonate's body.[29][30] Cephalocaudal progression of jaundice to zone 4 and 5 of the Kramer's scale shows a significant positive correlation with serum bilirubin concentration of at least 11.0 mg per 100 ml, indicating the need for treatment.[29]

Conjunctival icterus can be quantified by the Jaundice Eye Colour Index (JECI) through digital photography of the sclera, where a JECI of 0 indicates a white colour, and a JECI of 0.1 indicates an intense yellow colour, which is a sign of hemolytic jaundice.[31]

Multiple tests can be used to diagnose jaundice, but results of different parameters must be compared to determine its etiology.[10]

When a patient shows signs of jaundice such as the yellowing of the skin and sclera, a urine test is performed to check the levels of urobilinogen present.[32] The presence of urobilinogen and its increased levels indicate that there are more than normal amounts of bilirubin in the intestine, showing that jaundice observed is not due to the blockage of bile flow, and is of pre-hepatic or hepatic causes.[32] Normal colour of the patient's urine indicates the absence of unconjugated bilirubin.[27]

Results from the urine test should be confirmed by a complete blood count (CBC) and serum testing for total serum bilirubin and fractionated bilirubin.[32] Increased reticulocytes and the presence of schistocytes in the blood smear of the patient observed during CBC indicates hemolysis.[28] If the patient has hemolytic jaundice, serum testing will show that conjugated bilirubin will only account for less than 15% of the total serum bilirubin due to the increase of unconjugated bilirubin.[33]

Analysis of liver biopsies will show the levels of alkaline phosphatase, aspartate transaminase, and alanine transaminase in the patient, which has a negative correlation with liver function.[27] Normal levels of these enzymes indicate that there is no significant hepatocellular damage.[27]

When an infant is suspected to have hemolytic jaundice, abnormal morphologies of erythrocytes can be analyzed to find out the causes of hemolysis.[34] A Coomb's test should be performed, and end-tidal carbon monoxide concentration should be monitored to understand the rate of hemolysis in the infant's body.[35] If chronic hemolytic jaundice is diagnosed in a newborn, development of anemia and bilirubin cholelithiasis should be monitored as well.[34]

If other symptoms of anemia is present, the amount of serum haptoglobin in the patient can be measured to test for hemolysis.[36] During hemolysis, hemoglobin in blood dissociates and forms complexes with haptoglobins in the plasma, which are then catabolized.[37] Low levels of haptoglobin resulting from the test shows that there are large amounts of free hemoglobin in the blood to be bound, acting as an indicator of hemolysis.[36]

Phototherapy for newborns with jaundice.

Intensive phototherapy at saturation dose is used as a first-line clinical treatment which decreases the amount of accumulated unconjugated bilirubin in the infant's serum by the addition of oxygen, thus allowing it to dissolve in water so the liver can more easily convert it into products which can be excreted without further metabolism.[38] For infants with hemolytic jaundice, severe and prolonged cases of hyperbilirubinemia, or high serum bilirubin that does not decrease after phototherapy, blood exchange transfusion is carried out at the umbilical venous catheter to mechanically remove bilirubin.[38][39][40] In cases of immune hemolytic jaundice, intravenous immunoglobulin therapy may be used to treat the condition.[41] Administration of intravenous immunoglobulin can block monocyte Fc-receptors, preventing or reducing further hemolysis.[11]

In adults, hemolytic jaundice is uncommon, and medical treatment methods should be determined by recognizing the underlying causes of hemolysis in the patient.[42]

Hyperbilirubinemia may be observed when hemolysis produces too much bilirubin through the excessive breakdown of red blood cells, and the bilirubin builds up in the patient's blood and tissue fluids without proper excretion.[43] Untreated or inadequately treated hyperbilirubinemia will lead to other complications such as kernicterus.[12]

Chronic bilirubin encephalopathy, also known as kernicterus, is a brain-damaging complication associated with both preterm and full term infants with jaundice, where the large amounts of unconjugated bilirubin in the infants become neurotoxic.[39][44] Kernicterus affects mainly the basal ganglia, and its effects can spread to the hippocampus, geniculate nuclei, and cranial nerve nuclei.[13] Symptoms of kernicterus include athetoid cerebral palsy and in severe cases, may lead to death of the patient.[39] Most cases of kernicterus develop in infants following early hospital discharge from phototherapy.[44]