Lecture sevenNeonatal hyperbilirubinemia
Neonatal hyperbilirubinemia is a condition characterized by an excessive concentration of bilirubin in the blood .there are two types of neonatal hyperbilirubinemia ( unconjugated ) which can be physiological or pathologic in origin and (conjugated ) which always stems from pathologic cause . both types may lead to jaundice . neurotoxic concentration of unconjugated bilirubin can cause kernicterus .
Normal bilirubin metabolism : bilirubin is a bile pigment formed from the degradation of heme that is mainly derived from red blood cell destruction 75% but also from ineffective red blood cell production 25% .
Bilirubin is poroduced by the catabolism of hemoglobin in the reticuloendotheelial system . the tetrapyrole ring of the heme is cleaved by heme oxygenase to form equivalent quantities of biliverdin and carbine monoxide . biliverdin is converted to bilirubin by bilivedin reductase . one gram of hemoglobin produce 35 mg of bilirubin compared with adult newborn have two to three fold greater rate of bilirubin production (6-10 mg/kg/day vs.3mg/kg/day ) this increased production is caused in part by increased RBC mass and short half life of erythrocyte 70-90 days compared to 120 days in adult .Bilirubin produced after hemoglobin catabolism is lipid soluble and unconjugated and react as un indirect reagent in the van den bergh test .indirect –reacting unconjugated bilirubin is toxic to the central nervous system and is insoluble in water ,limiting its excretion . unconjugated bilirubin binds to albumin on specific bilirubin binding sites , one gram of albumin binds 8.5 mg of bilirubin in the newborn .if the binding sites become saturated or if a competitive compound binds at the site displacing bound protein , free bilirubin becomes available to enter the central nervous system .organic acids and and drugs like sulfisoxazole can displace bilirubin from its binding sites on albumin .Bilirubin dissociates from albumin at the hepatocyte and become bound to a cytoplamic liver protein Y ligandin . hepatic conjugation result in the production of bilirubin diglucuronide , which is water suloble and capable of biliary and renal excretion . the enzyme glucuronosyl transferase represents the rate – limiting step off bilirubin conjugation . the concentration of ligandin and glucuronosyl transferase are lower in newborn particularly in premature than in older children .Conjugated bilirubin gives a direct reaction in the van den bergh test . most conjugated bilirubin is excreted through the bile into the small bowel and eliminated in the stool .some bilirubin may undergo hydrolysis back to the unconjugated fraction by intestinal glucuronidase , however and may be reabsorbed (enterohepatic recirculation ) . in addition , bacteria in the neonatal intestine covert bilirubin to urobilinogen and stercobilinogen which are excreted in urine and stool and usually limit bilirubin reabsorbtion . delayed passage of meconium which contain bilirubin , also may contribute to the enterohepatic recirculation of bilirubin .maternal indirect hyperbiliruninemia also may increase fetal bilirubin level .
Physiological jaundice :
Physiological jaundice is a common cause of hyperbilirubinemia among newborn it is a diagnosis of exclusion made after careful evaluation has ruled out more serious causes of jaundice such as hemolysis , infection and metabolic diseases .
Physiological jaundice as opposed to pathological jaundice is characterized by :
Clinical jaundice appearing after first day .
An increase in the total serum bilirubin concentration of less than 5mg/dl/day
A total serm bilirubin concentration of less than 13 mg/dl in term and less than 15mg/dl in preterm and direct bilirubin of less than 1.5-2 mg/dl .
Persistence of clinical jaundice for less than one week .
Pathological jaundice :Jaundice and underling hyperbilirubinemia are considered pathological if the time of appearance ,duration ,or pattern varies rom that of physiological jaundice .the greatest risk associated with indirect hyperbilirubinemia is the development of bilirubin induced neurological toxicity which typically occurs with high indirect bilirubin levels , the development of kernicterus depends on :
Level of indirect bilirubin .
Duration of exposure to bilirubin elevation .
The cause of jaundice .
The infants well-being .
specific causes of nonphysiological indirect hyperbilirubinemia include :
(i) – hemolytic diseases of immune etiology .(fetomaternal blood group incompatibilities RH and ABO as well as non immune like spherocytosis , hemoglobenopathies red blood cell enzyme deficiency .
(ii)- extravascular blood loss and accumulation ( cephalhematoma ) .
(iii)- increased enterohepatic circulation due to intestinal obstruction .
(iv)- breast feeding associated with poor intake .
( v)- disorder of bilirubin metabolism like Gilpert syndrome and Crigler-Najjar syndrome.
(vi) – metabolic disorder like hypothyroidism .
Jaundice associated with breast –feeding :Significant elevation in indirect bilirubin (breast milk jaundice ) develops in term infants after the seven day with maximum concentration as high as 10-30 mg/dl reached during the 2nd -3rd wk .and may persist for 3-10 wk at a lower level if the breast feeding discontinued for one or two days the serum level fall rapidly. although uncommon kernicterus can occur .the cause of breast milk jaundice is unclear but may be due to glucuronidase in some breast milk .
The late jaundice associated with breast feeding should be distinguished from early onset known as breast feeding jaundice which occur in the 1st wk and may be a result of decreased milk intake or dehydration .
Crigler –najjar syndrome :Is a serious rare autosomal recessive , permanent deficiency of glucuronosyltransferase that result in severe indirect jaundice . type ll respond to enzyme induction by Phenobarbital producing elevted enzyme and reduce bilirubin .type l does not respond to Phenobarbital and manifest as persist indirect jaundice often leeding to kirnicterus in absence of hemolysis .
Gilbert disease : is caused by a mutation of the promoter region of glucuronosyltransferase and result in mild indirect jaundice and usually occur after puberty and not need treatment .
Causes of jaundice in the first wks ( physiological jaundice , ABO and Rh –incompatibility , concealed hemorrhage , congenital infection , sepsis ,breast feeding jaundice , Crigler –Najjar syndrome ,urinary tract infection , polycythemia ) .
Causes of jaundice after first wks ( beast milk jaundice , septicemia , bile duct atresia , hepatitis , galactosemia , hypothyroidisim , CF ,inborn error of metabolism ) .
Kernicterus ;Kernicterus is a severe neurological condition associated with very high levels of unconjucated bilirubin in the blood . kernicterus is characterized by yellow staining of the basal ganglia and hippocampus ,which is accompanied by wide spread of cerebral dysfunction .
Causes . kernicterus occurs when free bilirubin crosses the blood brain barrier and enter the brain cell .
(i)- normally unconjugated bilirubin is bound tightly to albumin which prevent bilirubin from crossing the blood brain barrier .free bilirubin exists when ths amount of unconjugated bilirubin exeeds the binding capacity of albumin.
(ii)- bilirubin also may enter the brain at a low concentration owing toe displacement from the albumin binding site by another compound ( e.g. sulfa drugs). Which lead to increased free bilirubin concentration or because of disruption of the blood brain barrier by sepsis , asphyxia , acidosis , or infusion of hyperosmolar solutions .
Kernicterus causes a complex of neurologic symptoms including the earliest clinical manifestation as lethargy ,hypotonia , irritability poor moro response and poor feeding . later signs include bulging fontanelle , opisthotonic posturing , pulmonary hemorrhage ,fever and seizure .
Infants with severe cases of kernicterus die in the neonatal period , survived infants may developed nerve deafness . choreosthetoid cerebral palsy , mental retardation and discoloration of the teeth .
Kernicterus can be prevented by avoiding high indirect bilirubin levels and avoiding condition and drugs that may displace bilirubin from albumin .
Early signs occasionally may be reversed by immediately exchange transfusion .
Treatment of jaundice :
Regardless the cause the goal of therapy is to prevent neurotoxicity related to indirect –reacting bilirubin .
(1)--Phototherapy : is an effective and safe method for reducing indirect bilirubin particularly when initiated before serum bilirubin increased to levels associated with kernicterus . in term infants phototherapy is begun when indirect levels are between 16- 18 mg/dl . in premature infants when bilirubin is at lower levels . blue and white lights are effective in reducing bilirubin levels .
Phototherapy causes a photochemical reaction producing the reversible , more water soluble isomers of indirect bilirubin this isomr can be excreted bypassing the liver conjugation system or excreted in urine .
Because phototherapy may require 6-12 hrs to have a measurable effect it must be started at bilirubin level below those indicated for exchange transfusion . the therapeutic effect of phototherapy depend on :
Light energy and effective wavelength 425-to475 nm wavelength .
The distance between the light and infant 15-20 cm .
The surface area of exposed skin .
Rate of hemolysis and metabolisim and excretion of bilirubin .
Complications of phototherapy include :
Increased insensible water loss and dehydration .
Macular –papular skin rash .
Lethargy and masking of cyanosis .
Nasal obstruction by eye pads and potential retinal damage .
Loose stool .
Bronze baby syndrome in infants with direct jaundice .
(2)- intravenous immunoglobulin in jaundice caused by isoimmune hemolyric disease and can be used if phototherapy not effective and bilirubin approaching exchange level .
(3)- metalloporphyrins a single i.m dose on the first day of life may reduce the need for subsequent phototherapy . the proposed mechanism is competitive enzymatic inhibition of the rate – limiting conversion of heme protein to biliverdin .
(4)- exchange transfusion : is used principally in hemolytic disease or when the bilirubin concentration is very high . this procedure directly remove the bilirubin from the intravascular space . unbound antibodies that initiate the hemolytic process and affected red blood cell also are removed beside correction of anemia .
Exchange transfusion usually is performed when the serum bilirubin concentration is 20 mg/dl or more . the specific bilirubin concentration that requires treatment varies with gestational age , the cause of jaundice and the presence of medical complications (e.g. sepsis , acidosis ).
As the rule of thumb alevel of 20 mg/dl for bilirubinnis te exchange number for infantwith hemolysis who weigh more than 2000g .asymptomatic infant with physiological or breast milk jaundice may not require exchange transfusion unless indirect bilirubin level exceed 25 mg/dl .the exchangeable level of bilirubin for other infants may be estimated by calculating 10% of birth weight in grams , so the level in an infants weighing 1500g would be 15mgdl .
The exchange transfusion is usually performed umbilical catheter in vein to a distance no greater than 7 cm in a full term .the exchange should be carried out over 45-60 min.with aspiration of 20 ml of infant blood alternating with infusion of 20 ml of donor blood , 5-10 ml may be indicated in sick or premature infants .
Rh hemolytic disease of the newborn need O Rh negative RBCs do not have major blood group antigen so they are not memolysed by maternal antibodies that may still be present in the infants circulation .if RBC are made available before delivery of the sensitized infant the RBCs must be O Rh negative and cross matched against the mother . if the RBCs are sourced after delivery the RBCs must be cross matched against infant .
ABO incompatibility : use group O , Rh specific RBCs . these RBCs contained low levels of antibodies and lack antigens that could trigger any circulating maternal antibodies in th newborn .
Estimated double volume to be exchange :
Term/preterm=85ml x 2 x weight(kg)= 170 ml x weight (kg) .
The infants stomach should be emptied before transfusion to prevent aspiration and body temperature should be maintained and vital signs monitored .
After exchange transfusion the bilirubin level must be determined at frequent intervals every 4-8 hrs because bilirubin may rebound within hrs as a result of continued hemolysis and redistribution of bilirubin from tissue store .
Acute complications include ( transient bradicardia , cyanosis ., transient vasospasim , thrombosis , apnea , infections necrotizing enterocolitis , vessel perforation or hemorrhage , metabolic instability ).
Late complications ( late anemia GVH reaction , inspissated bile syndrome , portal vein thrombosis ) .
Conjugated or direct hyperbilirubinemiaDirect jaundice defined as direct bilirubin level > 2mgdl or > 20% of the total bilirubin is never physiological . direct bilirubin is not neurotoxic to the infant but signifies a serious underling disorder involving cholestasis or hepatocellular injury .
Causes of direct jaundice :
TORCH infection ( toxoplasmosis ,rubella,cytomegalovirus ,herpes simplex)
Metabolic disorders ( e.g. galactosemia ).
Bacterial sepsis .
Obstructive jaundice ( e.g. biliary atresia ) .
Prolonged administration of intravenous protein solution .
Neonatal hepatitis , alpha one antitrypsin deficiency , cystic fibrosis .
Inspissated bile from prolonged hemolysis .
diagnosis : is based on conjugated fraction of the bilirubin level and ( liver enzymes ,bacterial and viral culture , metabolic screen , hepatic ultrasound sweet chloride and possible liver biopsy ) . therapy : is directed to the underlying cause of direct jaundice .