**1. Introduction**

Neonatal hyperbilirubinemia is defined as a total serum bilirubin level >5 mg/dL (86 μmol/L). This is a frequently encountered problem during the first week of life that affects approximately 60% of term and 80% of preterm babies [1, 2]. About 10% of breastfed babies are still jaundiced at 1 month of age [1]. The yellowish coloration results from deposition of unconjugated bilirubin pigment into the skin and mucous membranes [2]. Generally, neonatal jaundice is considered a transitional phenomenon without noticeable clinical impact, related to hepatic, red cell, and gastrointestinal immaturity [1, 3]. However, hyperbilirubinemia in the newborn period can be associated with severe illnesses such as hemolytic disease, metabolic and endocrine disorders, anatomic abnormalities of the liver, and infections [2]. Acute bilirubinassociated neuropathy caused by a dangerous rise of the total serum bilirubin level can often progress into a chronic neurologic condition characterized as kernicterus.

The latter is characterized by a severe athetoid cerebral palsy, auditory and visual problems, dental enamel dysplasia, and, less frequently, intellectual and other dysfunctions [1, 2, 4, 5]. Neonatal hyperbilirubinemia develops as an interaction between environmental and genetic factors; however, growing attention is turned to the genetically determined conditions. Gene variants related with neonatal hyperbilirubinemia are those that encode the erythrocyte enzyme glucose-6-phosphate dehydrogenase (G6PD), the hepatic isoenzyme uridine diphosphate (UDP) glucuronosyl transferase 1A1 (UGT-1A1), as well as the hepatic solute carrier organic anion transporter 1B1 [6–8].

#### **1.1 Pathophysiology of jaundice**

Neonatal hyperbilirubinemia results from a predisposition to a higher production of bilirubin in newborn infants and their limited ability of bilirubin excretion [9].

Newborns, especially preterm newborns, have higher rates of bilirubin production than adults, because they have a higher red cell turnover and a shorter life span. Newborns produce bilirubin at a rate of approximately 6–8 mg per kg per day which is more than twice the production rate in adults [2].

Other limitations that are evident in newborn infants are decreased hepatic uptake of bilirubin from plasma due to decreased ligandin and limited ability to conjugate bilirubin due to decreased activity of the hepatic conjugating enzyme UDP glucuronosyl transferase (UGT-1A1) [9, 10]. The products of the conjugation reaction are transferred via the bile into the intestines. In the newborns' intestines, considerable amount of the conjugated bilirubin is hydrolyzed back to unconjugated bilirubin. This reaction is catalyzed by the enzyme beta glucuronidase. The unconjugated bilirubin is reabsorbed back into the bloodstream by means of the enterohepatic circulation, thus adding an additional bilirubin load to the alreadyoverstretched liver. Hence, enterohepatic circulation of bilirubin represents an important contributor to neonatal jaundice [10].

All the abovementioned features in the newborn infants' bilirubin metabolism contribute concurrently to the appearance of physiologic neonatal jaundice.

Physiologic jaundice refers to the transient increase of the serum bilirubin in term infants during the first week of life, followed by a constant decrease over the next few weeks to normal levels found in adults. Average peak serum bilirubin levels (TSB) found in physiologic jaundice vary between 5 and 6 mg/dL (86 and 103 μmol/L). Exaggerated form of physiologic jaundice is considered when levels of TSB extend to values of 7–17 mg/dL (104–291 μmol/L) [9]. And, when serum bilirubin levels increase above 17 mg/dL (291 μmol/L) in term infants, a pathologic cause of jaundice should be pursued [2, 9].

#### **1.2 Etiology of pathologic jaundice**

According to the mechanism of accumulation of bilirubin, causes of neonatal indirect hyperbilirubinemia are classified into three categories (**Table 1**).

1.*Bilirubin overproduction* ensues with hemolytic causes of disease such as Coombspositive blood group incompatibilities in the ABO, rhesus, or minor blood group systems. On the other side of the hemolytic spectrum are the Coombs-negative disease causes such as erythrocyte membrane or enzyme defects, defects of hemoglobin (Hb) synthesis, sepsis, and some drugs. Bilirubin overproduction is also a mechanism of bilirubin accumulation in non-hemolytic disease causes such as cephalohematoma, bruising, central nervous system (CNS) hemorrhage, polycythemia, and exaggerated enterohepatic circulation [2, 9, 10].

**3**

*Neonatal Hyperbilirubinemia in Newborns of the Republic of North Macedonia*

**conjugation**

and 2

Physiologic jaundice Crigler-Najjar syndrome types 1

Gilbert syndrome Hypothyroidism Breast-milk jaundice G6PD deficiency

**Impaired bilirubin excretion**

Biliary atresia, choledochal cyst, primary sclerosing cholangitis, gallstones, neoplasm, Dubin-Johnson syndrome, Rotor's syndrome

Sepsis, urinary tract infection, syphilis, toxoplasmosis, tuberculosis, hepatitis,

Alpha-1-antitrypsin deficiency, cystic fibrosis, galactosemia, tyrosinemia, glycogen storage disease, Gaucher's disease, hypothyroidism, Wilson's disease, Niemann-Pick disease • Chromosomal abnormality

Turner's syndrome, trisomy 18 and 21

Aspirin, acetaminophen, sulfonamides, alcohol, rifampin, erythromycin, corticosteroids, tetracycline

• Biliary obstruction

• Infection

rubella, herpes • Metabolic disorder

syndromes • Drugs

2.*Decreased bilirubin conjugation* is present in etiologies such as in physiologic jaundice, breast-milk jaundice, Crigler-Najjar syndrome types 1 and 2, hypothyroidism, Gilbert syndrome, and glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency). Hemolysis was traditionally considered the pathophysiological mechanism of jaundice in G6PD deficiency, and indeed some known hemolysis triggers such as menthol or Chinese remedies applied to the umbilicus for antisepsis have been described in association with this etiology of jaundice. Moreover, other assumed triggers of hemolysis, such as fava transmitted through human breast milk, chemical cleansers, bacterial and viral infections, and henna applied to the newborn's skin in some cultures of the Middle East, have been described into association with G6PD deficiency-linked neonatal hyperbilirubinemia. However, the hematological markers of hemolysis such as hemoglobin and hematocrit (Hct) values and reticulocyte count have only occasionally been reduced in infants with G6PD

*Classification of neonatal jaundice based on the mechanism of accumulation.*

*DOI: http://dx.doi.org/10.5772/intechopen.87045*

Hemolytic causes • Positive Coombs test ABO incompatibility, rhesus incompatibility, other blood group

incompatibilities • Negative Coombs test Red blood cell membrane defects (spherocytosis, elliptocytosis, pyropoikilocytosis,

stomatocytosis)

Drugs (vitamin K)

Non-hemolytic causes • Extravascular sources

• Polycythemia

transfusion

circulation

**Table 1.**

Cephalohematoma, bruising, CNS hemorrhage, swallowed blood

Fetal-maternal transfusion, delayed cord clamping, twin-twin

• Exaggerated enterohepatic

Cystic fibrosis, intestinal atresia, pyloric stenosis, Hirschsprung's disease, breast-milk jaundice *Information from Refs. [2, 10].*

Sepsis

Red blood cell enzyme defects (G6PD deficiency, pyruvate kinase deficiency, other deficiencies) Hemoglobinopathies (alpha thalassemia, beta thalassemia) Unstable hemoglobins: congenital Heinz body hemolytic anemia

**Increased bilirubin load Decreased bilirubin** 


#### **Table 1.**

*Update on Critical Issues on Infant and Neonatal Care*

transporter 1B1 [6–8].

**1.1 Pathophysiology of jaundice**

is more than twice the production rate in adults [2].

important contributor to neonatal jaundice [10].

cause of jaundice should be pursued [2, 9].

**1.2 Etiology of pathologic jaundice**

The latter is characterized by a severe athetoid cerebral palsy, auditory and visual problems, dental enamel dysplasia, and, less frequently, intellectual and other dysfunctions [1, 2, 4, 5]. Neonatal hyperbilirubinemia develops as an interaction between environmental and genetic factors; however, growing attention is turned to the genetically determined conditions. Gene variants related with neonatal hyperbilirubinemia are those that encode the erythrocyte enzyme glucose-6-phosphate dehydrogenase (G6PD), the hepatic isoenzyme uridine diphosphate (UDP) glucuronosyl transferase 1A1 (UGT-1A1), as well as the hepatic solute carrier organic anion

Neonatal hyperbilirubinemia results from a predisposition to a higher production of bilirubin in newborn infants and their limited ability of bilirubin excretion [9]. Newborns, especially preterm newborns, have higher rates of bilirubin production than adults, because they have a higher red cell turnover and a shorter life span. Newborns produce bilirubin at a rate of approximately 6–8 mg per kg per day which

Other limitations that are evident in newborn infants are decreased hepatic uptake of bilirubin from plasma due to decreased ligandin and limited ability to conjugate bilirubin due to decreased activity of the hepatic conjugating enzyme UDP glucuronosyl transferase (UGT-1A1) [9, 10]. The products of the conjugation reaction are transferred via the bile into the intestines. In the newborns' intestines, considerable amount of the conjugated bilirubin is hydrolyzed back to unconjugated bilirubin. This reaction is catalyzed by the enzyme beta glucuronidase. The unconjugated bilirubin is reabsorbed back into the bloodstream by means of the enterohepatic circulation, thus adding an additional bilirubin load to the alreadyoverstretched liver. Hence, enterohepatic circulation of bilirubin represents an

All the abovementioned features in the newborn infants' bilirubin metabolism

Physiologic jaundice refers to the transient increase of the serum bilirubin in term infants during the first week of life, followed by a constant decrease over the next few weeks to normal levels found in adults. Average peak serum bilirubin levels (TSB) found in physiologic jaundice vary between 5 and 6 mg/dL (86 and 103 μmol/L). Exaggerated form of physiologic jaundice is considered when levels of TSB extend to values of 7–17 mg/dL (104–291 μmol/L) [9]. And, when serum bilirubin levels increase above 17 mg/dL (291 μmol/L) in term infants, a pathologic

According to the mechanism of accumulation of bilirubin, causes of neonatal

1.*Bilirubin overproduction* ensues with hemolytic causes of disease such as Coombspositive blood group incompatibilities in the ABO, rhesus, or minor blood group systems. On the other side of the hemolytic spectrum are the Coombs-negative disease causes such as erythrocyte membrane or enzyme defects, defects of hemoglobin (Hb) synthesis, sepsis, and some drugs. Bilirubin overproduction is also a mechanism of bilirubin accumulation in non-hemolytic disease causes such as cephalohematoma, bruising, central nervous system (CNS) hemorrhage,

indirect hyperbilirubinemia are classified into three categories (**Table 1**).

polycythemia, and exaggerated enterohepatic circulation [2, 9, 10].

contribute concurrently to the appearance of physiologic neonatal jaundice.

**2**

*Classification of neonatal jaundice based on the mechanism of accumulation.*

2.*Decreased bilirubin conjugation* is present in etiologies such as in physiologic jaundice, breast-milk jaundice, Crigler-Najjar syndrome types 1 and 2, hypothyroidism, Gilbert syndrome, and glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency). Hemolysis was traditionally considered the pathophysiological mechanism of jaundice in G6PD deficiency, and indeed some known hemolysis triggers such as menthol or Chinese remedies applied to the umbilicus for antisepsis have been described in association with this etiology of jaundice. Moreover, other assumed triggers of hemolysis, such as fava transmitted through human breast milk, chemical cleansers, bacterial and viral infections, and henna applied to the newborn's skin in some cultures of the Middle East, have been described into association with G6PD deficiency-linked neonatal hyperbilirubinemia. However, the hematological markers of hemolysis such as hemoglobin and hematocrit (Hct) values and reticulocyte count have only occasionally been reduced in infants with G6PD

deficiency-associated hyperbilirubinemia [11, 12]. It has been shown that inadequate conjugation capacity of the liver mainly contributes to development of neonatal jaundice in G6PD-deficient infants [12–14]. This has been proven by significantly lower total serum bilirubin level as well as mono- and di-conjugated bilirubin fractions in G6PD-deficient newborns that developed hyperbilirubinemia than the non-hyperbilirubinemic G6PD-deficient newborns [13]. Research that further supports the report that the decreased bilirubin conjugation is the main element of jaundice in G6PD-deficient newborns has shown varying shortening of red cell life span, which could only partially contribute to the jaundice [11, 13]. Moreover, the problem of jaundice is potentiated in cases of inherited UDP glucuronosyltransferase promoter polymorphism associated with Gilbert syndrome [14, 15]. The combination of the two gene mutations has been shown to significantly increase the incidence of hyperbilirubinemia in a dose-dependent manner [15].

3.And finally, the third mechanism of jaundice marked by *impaired bilirubin excretion* causes direct (conjugated) hyperbilirubinemia [2, 9, 10, 16]. Neonatal sepsis can be featured by both indirect and direct hyperbilirubinemia [2, 16].
