SOURCES OF BILIRUBIN:
Hemoglobin metabolism - accounts for 80% of all bilirubin production, with each gm of Hb producing 35mg of bilirubin by the action of biliverdin reducatse.
Ineffective or shunt Hb
Lysis of precursor cells in bone marrow
FACTORS RESPONSIBLE FOR INCREASED BILIRUBIN PRODUCTION IN NEONATES:
Neonatal bilirubin production is upto thrice that of adults, with neonatal production being 6-10mg/kg/day compared to adult bilirubin being 3mg/kg/day. The contributing factors include:
Increased RBC mass
Shortened RBC lifespan (70-90days)
BILIRUBIN - DIRECT AND INDIRECT:
- Bilirubin produced by Hb metabolism is UN-CONJUGATED, and reacts as an INDIRECT agent in Van Den Bergh test. It is lipid soluble, thus easily crosses the BBB, and causes damage to brain cells. For the same reason, it can not be readily excreted in urine. For travelling in the blood stream, it binds to albumin ( 1gm albumin - 8.5 gm bilirubin). Free fatty acids and sulfasoxazole can displace bilirubin from albumin.
- Bilirubin is CONJUGATED on reaching teh hepatocyte, when it dissociates from albumin and binds to Y-ligandin, forming bilirubin diglucoronide. It acts as a DIRECT reagent in Van den Bergh test. This is water soluble and maybe readily excreted in urine and bile. UDP glucoronyl transferase and quantity of Ligandin Y are the detreminants of this reaction of conjugation. Most of this conjugated bilirubin is excreted into the small intestines in bile, some hydolyses back to unconjugated variiety and reabsorbed in the enterohepatic circulation, while the remaining is converted to urobilinogen and stercobilinogen by intestinal flora to be excreted in urine and feces, respectively.
UNCONJUGATED / INDIRECT HYPERBILIRUBINEMIA
ETIOLOGY:
1. PHYSIOLOGICAL CAUSES:
a. Physiologic Jaundice
b. Breast Milk Jaundice
2. PATHOLOGICAL CAUSES:
Hemolytic
a. Crigler Najjar Syndrome
b. Gilbert Disease
c. Blood group incompatibility
d. Infection
e. G6PD deficiency
f. Thalassemia
g. Spherocytosis
Non-Hemolytic
h. Polycythemia
i. Internal hemorrhage
j. Infant of Diabetic Mother
k. Pyloric stenosis
l. Hypothyroidism
m. Immune thrombocytopenia
1a. PHYSIOLOGIC JAUNDICE - commonest cause of hyperbilirubinemia, yet a diagnosis of exclusion. Occurs due to Increased bilirubin due to increased RBC mass, shortened RBC lifespan, and hepatic immaturity. Peak bilirubin in term infants occurs on day 3, and on day 5 in premature ones. Levels in breats fed infants may rise upto 15-17mg/dl, while in non-breastfed ones stay till 12mg/dl.
1b. BREAST MILK JANDICE - no evidence of hemolysis is seen, occurs in 1st to 2nd week of life, indirect bilirubin may go upto 20mg/dl.Interruptiopn of breast feeding for a day or 2 significantly reduces teh levels, which don't rise again on resumption of breast feeding.
PATHOLOGICAL JAUNDICE:
- if presents on 1st day of life
- if bilirubin increases by > 0.5mg/dl/hour
- if bilirubin is >13mg/dl in term infants
- if direct bilirubin is >1.5mg/dl
- if hepatosplenomegaly is present
- if anemia is present
2a. CRIGLER NAJJAR SYNDROME - permanent deficiency of UDP glucoronyl transferase. Autosomal dominant variety responds to enzyme induction by phenobarbital, while autosomal recessive doesn't, resulting in kernicterus.
2b. GILBERT DISEASE - mutation of promoter region of UDP glucoronyl transferase, produces mild indirect hyperbilirubinemia.
2c. BLOOD GROUP INCOMATIBILITY - Due to abo, Rh, Kell and Duffy antibodies, hemolysis occurs resulting in hyperbilirubinemia.
2d. INFECTIONs
2e. INTERNAL HEMORRHAGE - cephalhematoma, splenic or hepatic hematoma
EXAMINATION:
Physical signs are visible on bilirubin levels of 5-10mg/dl, compared to adult ones on 2mg/dl.
INVESTIGATIONS:
a. INDIRECT AND DIRECT BILIRUBIN LEVELS
b. BLOOD TYPING
c. Coombs test
d. Complete blood count
e. blood smear
f. RETICULOCYTE COUNT
TREATMENT:
a. Phototherapy: effective and safe method. BLue and white lights both are good, but white is preferred as blue may conceal cyanotic changes, if any. Phototherapy converts the water-insoluble 4Z, 15Z bilirubin IX into water soluble, 4Z, 15E bilirubin IX which maybe excreted in bile. It also results in formation of LUMIRUBIN,which is water soluble and excreted in urine too.
Complications of phototherapy include increased insensible water loss, diarrhea, dehydration, maculopapular red rash, lethargy, masking of cyanosis, nasal obstruction by eye pads and possibility of retinal hemorrhage.
b. Exchange Transfusion: reserved for infants at risk of kernicterus, at a level of 20mg/dl for term infants weighing over 2kg (at bilirubin levels in mg/dl 10% of body weight in g). Assymptomatic infants with physiologgical jaundices may not require it until bilirubin is 25mg/dl or more. Amount of blood exchanged is equal to twice the infant's blood volume, determined by : weught in kg x 85ml/kg x 2. This amount removes 85% of infants RBCs, maternal antibodies, and exchangeable indtect bilirubin. Performed through umblical venous catheter placed in inferior vena cava. Complications include transfusion reaction, metabolic instability, infection, vessel perforation or hemorrhage, hypotension, necrotizing enterocolitis, thrombocytopenia and GVHD.
c. Heme Oxygenase Inhibitors: tin mesoporphyrin may reduce indirect hyperbilirubinemia and need for phototherapy.
CONJUGATED / DIRECT HYPERBILIRUBINEMIA
ETIOLOGY:
a. hyperalimentation cholestasis
b. CMV infection
c. TORCH infection
d. inspissated bile from prolonged hemolysis
e. neonatal hepatitis
f. sepsis
g. cystic fibrosis
h. biliary atresia
INVESTIGATIONS:
a. Liver enzymes
b. Bacterial and viral cultures
c. Metabolic screening tests
d. Hepatic ultrasound
e. Sweat ch;loride test
TREATMENT:
specific treatment for underlying cause
no exchange transfusion required / helpful.
note : bilirubin produced in fetus is transferred to maternal blood through placenta and is metabolized by maternal liver. The fetal bilirubin only mildly elevates in presence of severe hemolysis, inspissated bile stasis and conjugated hyperbilirubinemia.