hemolytic jaundice

File:Jaundice eye new.jpg

The signs and symptoms additional to the development of a yellowish colour in the sclera and skin are specific to the causes of hemolysis.

For example, if the patient has hemolytic jaundice resulting from sickle cell disease, vaso-occlusive phenomena like acute vaso-occlusive pain and acute chest syndrome may be observed in the acute phases, while in anemia, neurologic deficits and various pulmonary conditions may manifest in the chronic phase.

Regardless of the causes, laboratory-confirmed elevation is predominantly seen in unconjugated bilirubin.{{Cite book| vauthors = Brodsky R |title=UpToDate|year=2021|chapter=Diagnosis of hemolytic anemia in adults}} Serum bilirubin concentration rarely exceeds 4 mg/dL, unless the patient has concurrent liver disease.{{Cite book| vauthors = Shaked O |title=UpToDate|year=2020|chapter=Evaluation of jaundice caused by unconjugated hyperbilirubinemia in children}}

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

• File:Sickle Cell Blood Smear.JPGSickle cell disease, in which a mutation in the globin gene causes the formation of sickle hemoglobin. This disease is marked by the manifestation of chronic compensated hemolytic anemia, with laboratory findings not limited to unconjugated hyperbilirubinemia but also elevated serum lactate dehydrogenase and low serum haptoglobin.
• Thrombotic thrombocytopenic purpura, in which the reduced activity of the von Willebrand factor-cleaving protease ADAMTS13 causes a thrombotic microangiopathy. This disease, acquired or hereditary, is marked by very severe microangiopathic hemolytic anemia, with laboratory findings including extremely high serum lactate dehydrogenase and negative anti-RBC antibodies and Coombs test. Clinically, dark urine from hemoglobinuria may be observed because the hemolysis is intravascular (see Pathophysiology below).File:Thrombotic Thrombocytopenic Purpura (TTP).jpg
• Autoimmune hemolytic anemia (AIHA), in which autoantibodies react with self red blood cells and cause their destruction. This disease is marked by increased extravascular hemolysis, with laboratory findings including increased lactate dehydrogenase and decreased or absent haptoglobin in both warm and cold AIHA, and positive Coombs test. Clinically, jaundice or dark urine present in approximately one-third of the cases, and most of the symptoms are related to anemia.

Other less commonly observed causes of hemolysis include:

• Hemolysis secondary to drug toxicity{{cite journal | vauthors = Beutler E | title = Drug-induced hemolytic anemia | journal = Pharmacological Reviews | volume = 21 | issue = 1 | pages = 73–103 | date = March 1969 | pmid = 4887725 | url = https://pubmed.ncbi.nlm.nih.gov/4887725 }}
• Thalassemia minor{{cite journal | vauthors = Galanello R, Origa R | title = Beta-thalassemia | journal = Orphanet Journal of Rare Diseases | volume = 5 | pages = 11 | date = May 2010 | pmid = 20492708 | pmc = 2893117 | doi = 10.1186/1750-1172-5-11 | doi-access = free }}
• Congenital dyserythropoietic anemia{{Cite web|title=Congenital dyserythropoietic anemia - Conditions - GTR - NCBI|url=https://www.ncbi.nlm.nih.gov/gtr/conditions/C0002876/|access-date=2021-04-14|website=www.ncbi.nlm.nih.gov}}

The above list is not exhaustive, and rare causes of hemolysis such as Bartonella infection,{{cite journal | vauthors = Orf K, Cunnington AJ | title = Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection | language = English | journal = Frontiers in Microbiology | volume = 6 | pages = 666 | date = 2015 | pmid = 26175727 | pmc = 4485309 | doi = 10.3389/fmicb.2015.00666 | doi-access = free }} hemolysis due to transfusion reactions,{{cite book | vauthors = Harewood J, Ramsey A, Master SR |title=Hemolytic Transfusion Reaction|date=2021|url=http://www.ncbi.nlm.nih.gov/books/NBK448158/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=28846280|access-date=2021-04-01}} and microangiopathic hemolytic anemia{{cite journal | vauthors = Brain MC | title = Microangiopathic hemolytic anemia | journal = Annual Review of Medicine | volume = 21 | issue = 1 | pages = 133–44 | date = 1970-02-01 | pmid = 4913945 | doi = 10.1146/annurev.me.21.020170.001025 }} should be suspected when symptoms specific to those causes manifest.

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.File:Heme Breakdown.pngDuring 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.{{cite journal | vauthors = Rother RP, Bell L, Hillmen P, Gladwin MT | title = The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease | journal = JAMA | volume = 293 | issue = 13 | pages = 1653–62 | date = April 2005 | pmid = 15811985 | doi = 10.1001/jama.293.13.1653 | doi-access = free }} 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.{{cite journal | vauthors = Berlin NI, Berk PD | title = Quantitative aspects of bilirubin metabolism for hematologists | journal = Blood | volume = 57 | issue = 6 | pages = 983–99 | date = June 1981 | pmid = 7225572 | doi = 10.1182/blood.V57.6.983.983 | doi-access = free }}

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During extravascular hemolysis, red blood cells are destroyed by phagocytosis by macrophages in the reticuloendothelial system and digested by phagosomes.{{cite journal | vauthors = Lang F, Lang E, Föller M | title = Physiology and pathophysiology of eryptosis | journal = Transfusion Medicine and Hemotherapy | volume = 39 | issue = 5 | pages = 308–14 | date = October 2012 | pmid = 23801921 | pmc = 3678267 | doi = 10.1159/000342534 }} 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.{{cite journal | vauthors = Sticova E, Jirsa M | title = New insights in bilirubin metabolism and their clinical implications | journal = World Journal of Gastroenterology | volume = 19 | issue = 38 | pages = 6398–407 | date = October 2013 | pmid = 24151358 | pmc = 3801310 | doi = 10.3748/wjg.v19.i38.6398 | doi-access = free }}

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.{{Cite book| vauthors = Roy-Chowdhury N |title=UpToDate|year=2020|chapter=Bilirubin metabolism}} 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.{{Cite book| vauthors = Roy-Chowdhury N |title=UpToDate|year=2020|chapter=Classification and causes of jaundice or asymptomatic hyperbilirubinemia}} 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. This explains the yellow discolouration observed in these tissues in hemolytic jaundice.

Symptoms of jaundice can be observed superficially, thus visual methods are used to identify the condition. However, underlying causes of jaundice must be diagnosed through laboratory testing.

In both newborns and adults, yellowing of the skin is a marker for jaundice. As most cases of jaundice are observed in newborns, healthcare workers use visual methods to identify the presence of this condition. 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.{{cite journal | vauthors = Hatzenbuehler L, Zaidi AK, Sundar S, Sultana S, Abbasi F, Rizvi A, Darmstadt GL | title = Validity of neonatal jaundice evaluation by primary health-care workers and physicians in Karachi, Pakistan | journal = Journal of Perinatology | volume = 30 | issue = 9 | pages = 616–21 | date = September 2010 | pmid = 20357808 | doi = 10.1038/jp.2010.13 | doi-access = free }} 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.{{cite journal | vauthors = Knudsen A | title = The cephalocaudal progression of jaundice in newborns in relation to the transfer of bilirubin from plasma to skin | journal = Early Human Development | volume = 22 | issue = 1 | pages = 23–8 | date = April 1990 | pmid = 2335140 | doi = 10.1016/0378-3782(90)90022-B }}

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.{{cite journal | vauthors = Leung TS, Outlaw F, MacDonald LW, Meek J | title = Jaundice Eye Color Index (JECI): quantifying the yellowness of the sclera in jaundiced neonates with digital photography | journal = Biomedical Optics Express | volume = 10 | issue = 3 | pages = 1250–1256 | date = March 2019 | pmid = 30891343 | pmc = 6420273 | doi = 10.1364/BOE.10.001250 }}

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

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. 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.{{cite book | vauthors = Greenberg A | chapter = Chapter 4 - Urinalysis and Urine Microscopy|date=2014-01-01 | title = National Kidney Foundation Primer on Kidney Diseases | edition = Sixth |pages=33–41| veditors = Gilbert SJ, Weiner DE |place=Philadelphia|publisher=W.B. Saunders|language=en|doi=10.1016/b978-1-4557-4617-0.00004-2|isbn=978-1-4557-4617-0 }} Normal colour of the patient's urine indicates the absence of unconjugated bilirubin.

Results from the urine test should be confirmed by a complete blood count (CBC) and serum testing for total serum bilirubin and fractionated bilirubin. Increased reticulocytes and the presence of schistocytes in the blood smear of the patient observed during CBC indicates hemolysis. 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.{{cite journal | vauthors = Tisdale WA, Klatskin G, Kinsella ED | title = The significance of the direct-reacting fraction of serum bilirubin in hemolytic jaundice | language = English | journal = The American Journal of Medicine | volume = 26 | issue = 2 | pages = 214–27 | date = February 1959 | pmid = 13617278 | doi = 10.1016/0002-9343(59)90310-9 }}

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. Normal levels of these enzymes indicate that there is no significant hepatocellular damage.

When an infant is suspected to have hemolytic jaundice, abnormal morphologies of erythrocytes can be analyzed to find out the causes of hemolysis.{{cite journal | vauthors = Christensen RD, Yaish HM, Lemons RS | title = Neonatal hemolytic jaundice: morphologic features of erythrocytes that will help you diagnose the underlying condition | language = english | journal = Neonatology | volume = 105 | issue = 4 | pages = 243–9 | date = 2014 | pmid = 24526179 | doi = 10.1159/000357378 | doi-access = free }} 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.{{cite journal | vauthors = Herschel M, Karrison T, Wen M, Caldarelli L, Baron B | title = Evaluation of the direct antiglobulin (Coombs') test for identifying newborns at risk for hemolysis as determined by end-tidal carbon monoxide concentration (ETCOc); and comparison of the Coombs' test with ETCOc for detecting significant jaundice | journal = Journal of Perinatology | volume = 22 | issue = 5 | pages = 341–7 | date = 2002-07-01 | pmid = 12082466 | doi = 10.1038/sj.jp.7210702 | doi-access = free }} If chronic hemolytic jaundice is diagnosed in a newborn, development of anemia and bilirubin cholelithiasis should be monitored as well.

If other symptoms of anemia is present, the amount of serum haptoglobin in the patient can be measured to test for hemolysis. During hemolysis, hemoglobin in blood dissociates and forms complexes with haptoglobins in the plasma, which are then catabolized.{{cite journal | vauthors = Tolosano E, Fagoonee S, Hirsch E, Berger FG, Baumann H, Silengo L, Altruda F | title = Enhanced splenomegaly and severe liver inflammation in haptoglobin/hemopexin double-null mice after acute hemolysis | journal = Blood | volume = 100 | issue = 12 | pages = 4201–8 | date = December 2002 | pmid = 12393471 | doi = 10.1182/blood-2002-04-1270 | doi-access = free }} 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.{{cite journal | vauthors = Shih AW, McFarlane A, Verhovsek M | title = Haptoglobin testing in hemolysis: measurement and interpretation | journal = American Journal of Hematology | volume = 89 | issue = 4 | pages = 443–7 | date = April 2014 | pmid = 24809098 | doi = 10.1002/ajh.23623 | doi-access = free }}

As jaundice is not common in adults, most treatment methods for this condition are centered around neonates, of which 50% develop jaundice.

File:Jaundice phototherapy.jpg

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.{{cite journal | vauthors = Woodgate P, Jardine LA | title = Neonatal jaundice: phototherapy | journal = BMJ Clinical Evidence | volume = 2015 | date = May 2015 | pmid = 25998618 | pmc = 4440981 }} 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.{{cite journal | vauthors = Murki S, Kumar P | title = Blood exchange transfusion for infants with severe neonatal hyperbilirubinemia | journal = Seminars in Perinatology | volume = 35 | issue = 3 | pages = 175–84 | date = June 2011 | pmid = 21641492 | doi = 10.1053/j.semperi.2011.02.013 | series = Newborn Jaundice Technologies | s2cid = 206275955 }}{{cite journal | vauthors = Mishra S, Agarwal R, Deorari AK, Paul VK | title = Jaundice in the newborns | journal = Indian Journal of Pediatrics | volume = 75 | issue = 2 | pages = 157–63 | date = February 2008 | pmid = 18334797 | doi = 10.1007/s12098-008-0024-7 | s2cid = 11031084 }} In cases of immune hemolytic jaundice, intravenous immunoglobulin therapy may be used to treat the condition.{{cite journal | vauthors = Maisels MJ | title = Neonatal jaundice | journal = Pediatrics in Review | volume = 27 | issue = 12 | pages = 443–54 | date = December 2006 | pmid = 17142466 | doi = 10.1542/pir.27-12-443 }} Administration of intravenous immunoglobulin can block monocyte Fc-receptors, preventing or reducing further hemolysis.{{cite journal | vauthors = Ergaz Z, Arad I | title = Intravenous immunoglobulin therapy in neonatal immune hemolytic jaundice | journal = Journal of Perinatal Medicine | volume = 21 | issue = 3 | pages = 183–7 | date = 1993-01-01 | pmid = 8229608 | doi = 10.1515/jpme.1993.21.3.183 | s2cid = 41214946 | doi-access = free }}

In adults, hemolytic jaundice is uncommon, and medical treatment methods should be determined by recognizing the underlying causes of hemolysis in the patient.{{Cite book|url=https://www.worldcat.org/oclc/880898938|title=Ferri's clinical advisor 2015 : 5 books in 1|date=2015|others=Fred F. Ferri|isbn=978-0-323-08430-7|location=Philadelphia, PA|oclc=880898938}}

In cases where patients receive poor or no treatment of jaundice, neurodevelopmental complications may follow the condition, eventually leading to hearing loss, visual impairment, and in severe cases, mortality.

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.{{cite journal | vauthors = Porter ML, Dennis BL | title = Hyperbilirubinemia in the term newborn | journal = American Family Physician | volume = 65 | issue = 4 | pages = 599–606 | date = February 2002 | pmid = 11871676 | url = https://pubmed.ncbi.nlm.nih.gov/11871676 }} Untreated or inadequately treated hyperbilirubinemia will lead to other complications such as kernicterus.{{cite journal | vauthors = Watson RL | title = Hyperbilirubinemia | journal = Critical Care Nursing Clinics of North America | volume = 21 | issue = 1 | pages = 97–120, vii | date = March 2009 | pmid = 19237047 | doi = 10.1016/j.ccell.2008.11.001 | series = The High-Risk Neonate: Part I | s2cid = 243878612 }}

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.{{cite journal | vauthors = Gourley GR | title = Bilirubin metabolism and kernicterus | journal = Advances in Pediatrics | volume = 44 | pages = 173–229 | date = 1997 | doi = 10.1016/S0065-3101(24)00052-5 | pmid = 9265971 | url = https://pubmed.ncbi.nlm.nih.gov/9265971 }} Kernicterus affects mainly the basal ganglia, and its effects can spread to the hippocampus, geniculate nuclei, and cranial nerve nuclei.{{cite journal | vauthors = Hamza A | title = Kernicterus | journal = Autopsy & Case Reports | volume = 9 | issue = 1 | pages = e2018057 | year = 2019 | pmid = 30863731 | pmc = 6394357 | doi = 10.4322/acr.2018.057 }} Symptoms of kernicterus include athetoid cerebral palsy and in severe cases, may lead to death of the patient. Most cases of kernicterus develop in infants following early hospital discharge from phototherapy.

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Category:Symptoms and signs: Digestive system and abdomen

Category:Haemorrhagic and haematological disorders of fetus and newborn

Category:Disorders originating in the perinatal period

Category:Blood disorders