HYPERBILIRUBINEMIA Fatima c. Dela cruz

Jaundice Yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration) 1st week of life 60% term and 80% preterm infants Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). The serum bilirubin level required to cause jaundice varies with skin tone and body region, but jaundice usually becomes visible on the sclera at a level of 2 to 3 mg/dL (34 to 51 μmol/L) and on the face at about 4 to 5 mg/dL (68 to 86 μmol/L). With increasing bilirubin levels, jaundice seems to advance in a head-to-foot direction, appearing at the umbilicus at about 15 mg/dL (258 μmol/L) and at the feet at about 20 mg/dL (340 μmol/L). Slightly more than half of all neonates become visibly jaundiced in the first week of life.

Jaundice Accumulation in skin of unconjugated, non-polar, lipidsoluble bilirubin pigment formed from Hgb by the action of heme oxygenase, biliverdin reductase, & non-enzymatic reducing agents in the reticuloendothelial cells May also be due in part to deposition of the pigment after it has been converted in the liver cell microsome by the enzyme uridine diphosphoglucuronic acid (UDP)-glucuronyl transferase to the polar, water-soluble ester glucuronide of bilirubin (direct reacting)

Jaundice Indirect Bilirubin (Unconjugated, B1) Non-polar Reversibly, but tightly bound to albumin Does not cross the BBB Free bilirubin: the form of indirect bilirubin that crosses the BBB

Jaundice Direct Bilirubin (Conjugated, B2) Always pathologic Water soluble, polar Excreted into the bile & into the small intestine and filtered into the kidney

The serum bilirubin level required to cause jaundice Face - 4 to 5 mg/dL (68 to 86 μmol/L Umbilicus - 15 mg/dL (258 μmol/L) Feet- 20 mg/dL (340 μmol/L)

Risk Factors for Hyperbilirubinemia in Newborns Maternal factors Blood type ABO or Rh incompatibility Breastfeeding Drugs: diazepam (Valium), oxytocin (Pitocin) Ethnicity: Asian, Native American Maternal illness: gestational diabetes

Risk Factors for Hyperbilirubinemia in Newborns Neonatal factors Birth trauma: cephalohematoma, cutaneous bruising, instrumented delivery Drugs: sulfisoxazole acetyl with erythromycin ethylsuccinate (Pediazole), chloramphenicol (Chloromycetin) Excessive weight loss after birthInfections: TORC Infrequent feedings Male gender Polycythemia Prematurity Previous sibling with hyperbilirubinemia

Mechanisms of hyperbilirubinemia Increased production Decreased hepatic uptake Decreased conjugation Impaired excretion Impaired bile flow (cholestasis) Increased enterohepatic circulation

Physiologic hyperbilirubinemia Shorter neonatal RBC life span increases bilirubin production deficient conjugation due to the deficiency of UGT decreases clearance low bacterial levels in the intestine combined with increased hydrolysis of conjugated bilirubin increase enterohepatic circulation. Bilirubin levels can rise up to 18 mg/dL by 3 to 4 days of life (7 days in Asian infants) and fall thereafter Physiologic hyperbilirubinemia occurs in almost all neonates. Shorter neonatal RBC life span increases bilirubin production; deficient conjugation due to the deficiency of UGT decreases clearance; and low bacterial levels in the intestine combined with increased hydrolysis of conjugated bilirubin increase enterohepatic circulation. Bilirubin levels can rise up to 18 mg/dL by 3 to 4 days of life (7 days in Asian infants) and fall thereafter.

Breastfeeding jaundice  develops in one sixth of breastfed infants in the first week of life. Breastfeeding increases enterohepatic circulation of bilirubin in some infants who have decreased milk intake and who also have dehydration or low caloric intake. The increased enterohepatic circulation also may result from reduced intestinal bacteria that convert bilirubin to nonresorbed metabolites.

Breast milk jaundice develops after the first 5 to 7 days of life peaks at about 2 weeks thought to be caused by an increased concentration of β-glucuronidase in breast milk, causing an increase in the deconjugation and reabsorption of bilirubin. Breastfeeding jaundice develops in one sixth of breastfed infants in the first week of life. Breastfeeding increases enterohepatic circulation of bilirubin in some infants who have decreased milk intake and who also have dehydration or low caloric intake. The increased enterohepatic circulation also may result from reduced intestinal bacteria that convert bilirubin to nonresorbed metabolites.

Determine the cause of jaundice if: Jaundice appears in the first 24-36 h of life Total serum bilirubin (TSB) rises by > 5 mg/dL/day Serum bilirubin >12 mg/dL term and 10-14 mg/dL in preterm infants Jaundice persists after 10-14 days of life Direct-reacting bilirubin >2 mg/dL at any time Pathologic hyperbilirubinemia in term infants is diagnosed if Jaundice appears in the first 24 h, after the first week of life, or lasts > 2 wk Total serum bilirubin (TSB) rises by > 5 mg/dL/day TSB is > 18 mg/dL Infant shows symptoms or signs of a serious illness Some of the most common pathologic causes are Immune and nonimmune hemolytic anemia G6PD deficiency Hematoma resorption Sepsis Hypothyroidism

Some of the most common pathologic causes Immune and nonimmune hemolytic anemia G6PD deficiency Hematoma resorption Sepsis Hypothyroidism

Mechanism Causes Increased enterohepatic circulation Breast milk (breast milk jaundice) Breastfeeding failure (breastfeeding jaundice) Drug-induced paralytic ileus (Mg sulfate or morphine ) Fasting or other cause for hypoperistalsis Hirschsprung's disease Intestinal atresia or stenosis, including annular pancreas Meconium ileus or meconium plug syndrome Pyloric stenosis* Swallowed blood

Neonatal Hyperbilirubinemia Mechanism causes Overproduction Breakdown of extravascular blood (eg, hematomas; petechiae; pulmonary, cerebral, or occult hemorrhage) Polycythemia due to maternofetal or fetofetal transfusion or delayed umbilical cord clamping

Neonatal Hyperbilirubinemia mechanis causes Overproduction due to hemolytic anemia Certain drugs and agents in neonates with G6PD deficiency (eg, acetaminophen ,alcohol,antimalarials, aspirin ,bupivacaine ,corticosteroids, diazepam,nitrofurantoin , oxytocin  penicillin, phenothiazine, sulfonamides) Maternofetal blood group incompatibility (eg, Rh, ABO) RBC enzyme deficiencies (eg, of G6PD or pyruvate kinase) Spherocytosis Thalassemias (α, β–γ)

Neonatal Hyperbilirubinemia mechanis causes Undersecretion due to biliary obstructio α1-Antitrypsin deficiency* Biliary atresia* Choledochal cyst* Cystic fibrosis* (inspissated bile) Dubin-Johnson syndrome and Rotor's syndrome* Parenteral nutrition Tumor or band* (extrinsic obstruction)

Neonatal Hyperbilirubinemia mechanis causes Undersecretion due to metabolic-endocrine conditions Crigler-Najjar syndrome (familial nonhemolytic jaundice types 1 and Drugs and hormones Gilbert syndrome Hypermethioninemia Hypopituitarism and anencephaly Hypothyroidism Lucey-Driscoll syndrome Maternal diabetes Prematurity Tyrosinosis

Neonatal Hyperbilirubinemia mechanis causes Mixed overproduction and undersecretion Asphyxia Intrauterine infections Maternal diabetes Respiratory distress syndrome Sepsis Severe erythroblastosis fetalis Syphilis TORCH infections

Evaluation History History of present illness should note age of onset and duration of jaundice Important associated symptoms include lethargy and poor feeding (suggesting possible kernicterus), which may progress to stupor, hypotonia, or seizures and eventually to hypertonia Patterns of feeding can be suggestive of possible breastfeeding failure or underfeeding. 

Evaluation Review of systems symptoms of causes, including respiratory distress, fever, and irritability or lethargy (sepsis); hypotonia and poor feeding (hypothyroidism, metabolic disorder); and repeated episodes of vomiting (intestinal obstruction).

Evaluation Past medical history focus on maternal infections (toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex [TORCH] infections) disorders that can cause early hyperbilirubinemia (maternal diabetes) maternal Rh factor and blood group (maternofetal blood group incompatibility) history of a prolonged or difficult birth (hematoma or forceps trauma)

Evaluation Physical examination Overall clinical appearance and vital signs are reviewed. The skin is inspected for extent of jaundice. Gentle pressure on the skin can help reveal the presence of jaundice. Also, ecchymoses or petechiae (suggestive of hemolytic anemia) are noted. The physical examination should focus on signs of causative disorders

Evaluation The general appearance is inspected for plethora (maternofetal transfusion) macrosomia (maternal diabetes) lethargy or extreme irritability (sepsis or infection) and any dysmorphic features such as macroglossia (hypothyroidism) flat nasal bridge or bilateral epicanthal folds (Down syndrome)

Evaluation Head and neck examination Lungs Abdomen any bruising and swelling of the scalp consistent with a cephalohematoma are noted Lungs are examined for rales, rhonchi, and decreased breath sounds (pneumonia) Abdomen is examined for distention, mass (hepatosplenomegaly), or pain (intestinal obstruction) Neurologic examination should focus on signs of hypotonia or weakness (metabolic disorder, hypothyroidism, sepsis)

Treatment Treatment is directed at the underlying disorder

Treatment Breastfeeding jaundice increasing the frequency of feedings If the bilirubin level continues to increase > 18 mg/dL in a term infant with early breastfeeding jaundice, a temporary change from breast milk to formula may be appropriate reastfeeding jaundice may be prevented or reduced by increasing the frequency of feedings. If the bilirubin level continues to increase > 18 mg/dL in a term infant with early breastfeeding jaundice, a temporary change from breast milk to formula may be appropriate; phototherapy also may be indicated at higher levels. Stopping breastfeeding is necessary for only 1 or 2 days, and the mother should be encouraged to continue expressing breast milk regularly so she can resume nursing as soon as the infant's bilirubin level starts to decline. She also should be assured that the hyperbilirubinemia has not caused any harm and that she may safely resume breastfeeding. It is not advisable to supplement with water or dextrose because that may disrupt the mother's production of milk.

Treatment Definitive treatment  Phototherapy Exchange transfusion

Treatment Phototherapy standard of care, most commonly using fluorescent white light. (Blue light is most effective for intensive phototherapy.) Photoisomerize unconjugated bilirubin into forms that are more water-soluble and can be excreted rapidly by the liver and kidney without glucuronidation provides definitive treatment of neonatal hyperbilirubinemia and prevention of kernicterus Phototherapy is an option when unconjugated bilirubin is > 12 mg/dL (> 205.2 μmol/L) and may be indicated when unconjugated bilirubin is > 15 mg/dL at 25 to 48 h, 18 mg/dL at 49 to 72 h, and 20 mg/dL at > 72 h Phototherapy: This treatment remains the standard of care, most commonly using fluorescent white light. (Blue light is most effective for intensive phototherapy.) Phototherapy is the use of light to photoisomerize unconjugated bilirubin into forms that are more water-soluble and can be excreted rapidly by the liver and kidney without glucuronidation. It provides definitive treatment of neonatal hyperbilirubinemia and prevention of kernicterus. Phototherapy is an option when unconjugated bilirubin is > 12 mg/dL (> 205.2 μmol/L) and may be indicated when unconjugated bilirubin is > 15 mg/dL at 25 to 48 h, 18 mg/dL at 49 to 72 h, and 20 mg/dL at > 72 h (see Fig. 1: Metabolic, Electrolyte, and Toxic Disorders in Neonates: Risk of hyperbilirubinemia in neonates ≥ 35 wk gestation.). Phototherapy is not indicated for conjugated hyperbilirubinemia. Because visible jaundice may disappear during phototherapy, though serum bilirubin remains elevated, skin color cannot be used to evaluate jaundice severity. Blood taken for bilirubin determinations should be shielded from bright light, because bilirubin in the collection tubes may rapidly photo-oxidize

Treatment Exchange transfusion  This treatment can rapidly remove bilirubin from circulation and is indicated for severe hyperbilirubinemia, which most often occurs with immune-mediated hemolysis Small amounts of blood are withdrawn and replaced through an umbilical vein catheter to remove partially hemolyzed and antibody-coated RBCs as well as circulating Igs These then are replaced with uncoated donor RBCs.

Neonatal Hyperbilirubinemia IV immunoglobulin can be effective adjunct to phototherapy in immune hemolytic disease Phenobarbital 5-8mg/kg/d (takes days to work) Metalloporphyrins (experimental) Sn-Mesoporphyrin (6umol/kg IM x 1), an inhibitor of bilirubin production, was effective at reducing need for photo therapy, compared with "usual care"

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