Hemolytic jaundice, also known as prehepatic jaundice, is a type ofjaundice arising fromhemolysis or excessive destruction of red blood cells, when the byproductbilirubin is not excreted by thehepatic cells quickly enough.^[1] Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, theliver does not contribute to this type of jaundice.^[1]

As one of the three categories ofjaundice, the most obvious sign of hemolytic jaundice is the discolouration or yellowing of thesclera and theskin of the patient, but additional symptoms may be observed depending on the underlying causes ofhemolysis. Hemolytic causes associated with bilirubin overproduction are diverse and include disorders such assickle cell anemia,^[2]hereditary spherocytosis,^[3]thrombotic thrombocytopenic purpura,^[4]autoimmune hemolytic anemia,^[5] hemolysis secondary to drug toxicity,^[6]thalassemia minor,^[7] andcongenital dyserythropoietic anemias.^[8]Pathophysiology of hemolytic jaundice directly involves themetabolism ofbilirubin, where overproduction ofbilirubin due tohemolysis exceeds the liver's ability toconjugate bilirubin toglucuronic acid.^[9]

Diagnosis of hemolytic jaundice is based mainly on visual assessment of the yellowing of the patient'sskin andsclera, while the cause ofhemolysis must be determined using laboratory tests.^[10] Treatment of the condition is specific to the cause ofhemolysis, but intensephototherapy andexchange transfusion can be used to help the patient excrete accumulatedbilirubin.^[11] Complications related to hemolytic jaundice includehyperbilirubinemia andchronic bilirubin encephalopathy, which may be deadly without proper treatment.^[12][13]

The signs and symptoms additional to the development of a yellowish colour in thesclera andskin are specific to the causes ofhemolysis.

For example, if the patient has hemolyticjaundice resulting fromsickle cell disease, vaso-occlusive phenomena like acute vaso-occlusive pain andacute chest syndrome may be observed in the acute phases, while inanemia, neurologic deficits and variouspulmonary conditions may manifest in thechronic phase.^[2]

Regardless of the causes, laboratory-confirmed elevation is predominantly seen in unconjugatedbilirubin.^[10] Serumbilirubin concentration rarely exceeds 4 mg/dL, unless the patient has concurrent liver disease.^[14]

The underlying causes of hemolytic jaundice, as its name suggests, are disorders associated withhemolysis. Such disorders are manifold and the common causes include:

• 

  Sickle cell disease, in which a mutation in theglobin gene causes the formation of sicklehemoglobin.^[2] This disease is marked by the manifestation of chronic compensatedhemolytic anemia, with laboratory findings not limited to unconjugatedhyperbilirubinemia but also elevated serumlactate dehydrogenase and low serumhaptoglobin.^[2]
• Thrombotic thrombocytopenic purpura, in which the reduced activity of the von Willebrand factor-cleaving proteaseADAMTS13 causes athrombotic microangiopathy.^[4] This disease, acquired or hereditary, is marked by very severemicroangiopathic hemolytic anemia, with laboratory findings including extremely high serumlactate dehydrogenase and negative anti-RBC antibodies andCoombs test.^[4] Clinically, dark urine fromhemoglobinuria may be observed because the hemolysis is intravascular (see Pathophysiology below).^[4]

  

• Autoimmune hemolytic anemia (AIHA), in which autoantibodies react with self red blood cells and cause their destruction.^[5] This disease is marked by increased extravascular hemolysis, with laboratory findings including increasedlactate dehydrogenase and decreased or absenthaptoglobin in both warm and cold AIHA, and positiveCoombs test.^[5] Clinically, jaundice or dark urine present in approximately one-third of the cases, and most of the symptoms are related to anemia.^[5]

Other less commonly observed causes of hemolysis include:

• Hemolysis secondary to drug toxicity^[15]
• Thalassemia minor^[16]
• Congenital dyserythropoietic anemia^[17]

The above list is not exhaustive, and rare causes ofhemolysis such asBartonella infection,^[18]hemolysis due totransfusion reactions,^[19] andmicroangiopathic hemolytic anemia^[20] should be suspected when symptoms specific to those causes manifest.

The mechanisms by whichbilirubin is overproduced in hemolytic jaundice can be understood in relation to the two major sites ofhemolysis: intravascular and extravascular.

Duringintravascular hemolysis, red blood cells are broken down within thevasculature, allowinghemoglobin from the rupturedred blood cells to form haptoglobin-hemoglobin complexes withhaptoglobin, which will be internalized and degraded byhepatocytes and thespleen.^[21] If the degree ofhemolysis is abnormally high, the unboundhemoglobin is converted tomethemoglobin from which theheme moiety is bound tohemopexin or toalbumin, and both heme-hemopexin and heme-bound albumin are internalized by hepatocytes and subsequently degraded tobilirubin.^[22][10]

Duringextravascular hemolysis,red blood cells are destroyed byphagocytosis bymacrophages in thereticuloendothelial system and digested byphagosomes.^[23] Hemoglobin within red blood cells are then degraded to releaseheme, which will be converted bymicrosomal heme oxygenase toiron,carbon monoxide andbiliverdin, and are immediately reduced to unconjugatedbilirubin bybiliverdin reductase and released into the plasma.^[24]

In both settings ofhemolysis mentioned above, only low levels of conjugatedbilirubin 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 throughglomerular filtration and it binds to theelastic tissue of theskin andsclera, where highalbumin content can be found.^[25] This explains the yellow discolouration observed in these tissues in hemolytic jaundice.

Symptoms ofjaundice can be observed superficially, thus visual methods are used to identify the condition.^[27] However, underlying causes ofjaundice must be diagnosed through laboratory testing.^[28]

In both newborns and adults, yellowing of the skin is a marker for jaundice.^[27] As most cases ofjaundice are observed in newborns, healthcare workers use visual methods to identify the presence of this condition.^[29] A clinicaljaundice 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 serumbilirubin 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 thesclera, 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 diagnosejaundice, but results of different parameters must be compared to determine itsetiology.^[10]

When a patient shows signs ofjaundice such as the yellowing of theskin andsclera, aurine test is performed to check the levels ofurobilinogen present.^[32] The presence ofurobilinogen and its increased levels indicate that there are more than normal amounts ofbilirubin in theintestine, showing thatjaundice observed is not due to the blockage of bile flow, and is of pre-hepatic or hepatic causes.^[32] Normal colour of the patient'surine indicates the absence of unconjugatedbilirubin.^[27]

Results from the urine test should be confirmed by acomplete blood count (CBC) and serum testing for total serum bilirubin and fractionated bilirubin.^[32] Increasedreticulocytes and the presence ofschistocytes in theblood smear of the patient observed during CBC indicateshemolysis.^[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 ofalkaline phosphatase,aspartate transaminase, andalanine 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 aninfant is suspected to have hemolytic jaundice, abnormalmorphologies oferythrocytes can be analyzed to find out the causes ofhemolysis.^[34] ACoomb's test should be performed, and end-tidalcarbon monoxide concentration should be monitored to understand the rate ofhemolysis in the infant's body.^[35] If chronic hemolytic jaundice is diagnosed in a newborn, development ofanemia and bilirubin cholelithiasis should be monitored as well.^[34]

If other symptoms of anemia is present, the amount of serumhaptoglobin in the patient can be measured to test forhemolysis.^[36] Duringhemolysis,hemoglobin inblood dissociates and forms complexes withhaptoglobins in the plasma, which are then catabolized.^[37] Low levels ofhaptoglobin resulting from the test shows that there are large amounts offree hemoglobin in theblood to be bound, acting as an indicator ofhemolysis.^[36]

Asjaundice is not common in adults, most treatment methods for this condition are centered aroundneonates, of which 50% developjaundice.^[27][38]

Intensivephototherapy at saturation dose is used as a first-line clinical treatment which decreases the amount of accumulated unconjugatedbilirubin in the infant's serum by the addition ofoxygen, thus allowing it to dissolve inwater so theliver can more easily convert it into products which can beexcreted without furthermetabolism.^[38] For infants with hemolytic jaundice, severe and prolonged cases ofhyperbilirubinemia, or high serumbilirubin that does not decrease afterphototherapy,blood exchange transfusion is carried out at theumbilical venous catheter to mechanically removebilirubin.^[38][39][40] In cases of immune hemolytic jaundice,intravenous immunoglobulin therapy may be used to treat the condition.^[41] Administration ofintravenous immunoglobulin can block monocyteFc-receptors, preventing or reducing furtherhemolysis.^[11]

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

In cases where patients receive poor or no treatment ofjaundice, neurodevelopmental complications may follow the condition, eventually leading tohearing loss,visual impairment, and in severe cases, mortality.^[38]

Hyperbilirubinemia may be observed whenhemolysis produces too muchbilirubin through the excessive breakdown ofred blood cells, and thebilirubin builds up in the patient'sblood andtissue fluids without properexcretion.^[43] Untreated or inadequately treatedhyperbilirubinemia will lead to other complications such askernicterus.^[12]

Chronic bilirubin encephalopathy, also known askernicterus, is a brain-damaging complication associated with bothpreterm andfull term infants withjaundice, where the large amounts of unconjugatedbilirubin in the infants becomeneurotoxic.^[39][44]Kernicterus affects mainly thebasal ganglia, and its effects can spread to thehippocampus,geniculate nuclei, andcranial nerve nuclei.^[13] Symptoms ofkernicterus includeathetoid cerebral palsy and in severe cases, may lead to death of the patient.^[39] Most cases ofkernicterus develop in infants following early hospital discharge fromphototherapy.^[44]

• Symptoms and signs: Digestive system and abdomen
• Haemorrhagic and haematological disorders of fetus and newborn
• Disorders originating in the perinatal period
• Blood disorders

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