Neonatal jaundice or neonatal hyperbilirubinemia results from elevated total serum bilirubin (TSB) and clinically manifests as yellowish discoloration of the skin, sclera, and mucous membrane. The term jaundice derives from the French word “jaune,” which means yellow. It is the most commonly encountered medical problem in the first two weeks of life and a common cause of readmission to the hospital after birth.[rx] Approximately 60% of term and 80% of preterm newborns develop clinical jaundice in the first week after birth.[rx] In most cases, it is a mild, transient, and self-limiting condition and resolves without treatment referred to as “physiological jaundice.” However, it is imperative to distinguish this from a more severe form called “pathological jaundice.” Failure to identify and treat this entity may result in bilirubin encephalopathy and associated neurological sequelae.
There are two distinct types of Neonatal hyperbilirubinemia.
Unconjugated Hyperbilirubinemia(UHB) or Indirect Hyperbilirubinemia
Unconjugated hyperbilirubinemia is the more common type and is either physiological or pathological. Physiological jaundice accounts for 75% of neonatal hyperbilirubinemia and results from a physiological alteration in neonatal bilirubin metabolism. Healthy adults have a normal TSB level of less than 1mg/dl in contrast to neonates, where TSB levels are physiologically higher. Even in healthy full-term newborns, there is an increased bilirubin load owing to increased red blood cell (RBC) mass and a decreased RBC lifespan. Clearance of bilirubin is also compromised due to impaired activity of uridine diphosphate glucuronosyltransferase (UGT), the enzyme needed for bilirubin conjugation. The UGT enzyme in a newborn has an activity of about 1% of the adult level.[rx] Moreover, these infants also have increased enterohepatic circulation, further contributing to elevated TSB levels. Physiological jaundice typically appears after 24 hours of age, peaks at around 48-96 hours, and resolves by two to three weeks in full-term infants.[rx]
Jaundice is considered pathological if it presents on the first day of life, TSB is more than the 95th centile for age based on age-specific bilirubin nomograms, levels rise by more than 5 mg/dL/day or more than 0.2 mg/dL/hour, or jaundice persists beyond 2 to 3 weeks in full-term infants.[rx]
Based on the mechanism of bilirubin elevation, the etiology of unconjugated hyperbilirubinemia can be subdivided into the following three categories:
Increased Bilirubin Production
Immune-mediated hemolysis – Includes blood group incompatibilities such as ABO and Rhesus incompatibility.
Non-immune mediated hemolysis – includes RBC membrane defects like hereditary spherocytosis and elliptocytosis; RBC enzyme defects like glucose-6-phosphate dehydrogenase (G6PD) deficiency; pyruvate kinase deficiency; sequestration like cephalohematoma, subgaleal hemorrhage, Intracranial hemorrhage; polycythemia, and sepsis.
Decreased Bilirubin Clearance
Crigler-Najjar type I & II, and Gilbert syndrome.
Other miscellaneous etiologies include the infant of a mother with diabetes, congenital hypothyroidism, drugs like sulfa drugs, ceftriaxone, and penicillins, Intestinal obstruction, pyloric stenosis, breast milk jaundice, breastfeeding jaundice.
Exaggerated hemolysis, either immune or non-immune mediated, is the most common cause of pathological hyperbilirubinemia in newborns. Immune-mediated hemolysis is seen with blood group incompatibility such as ABO/RH incompatibility and leads to hemolytic disease of newborns (HDN). In HDN, due to ABO incompatibility, preformed maternal anti-A and anti-B antibodies of immunoglobulin (Ig) G subclass cross the placenta and cause hemolysis and UHB in newborns with blood type A, B, or AB. Although the direct Coombs test is used to aid diagnosis, the sensitivity and positive predictive value for predicting severe UHB are low.[rx] ABO incompatibility between mother and fetus exists in about 15% of pregnancies, but HDN due to ABO incompatibility is seen only in 4% of newborns with ABO incompatibility.[rx]
In Rhesus (Rh) incompatibility, an Rh-negative mother who has been previously exposed to Rh-positive RBCs usually from a previous pregnancy or miscarriage becomes sensitized and develops antibodies against the Rh antigen. Initially, sensitization produces IgM antibodies that can not cross the placenta. However, during subsequent pregnancies, the antibody class switch produces IgG antibodies that can cross the placenta, causing RBC hemolysis in the fetus with Rh-positive blood. The Rh antigen is very immunogenic, and the resultant HDN is usually severe, often leading to hydrops in fetuses or severe UHB in newborns. The American College of Obstetricians and Gynecologists (ACOG) has recommended that all Rh-negative pregnant women receive anti-D immune globulin at 28 weeks of gestation and again following delivery if the infant is Rh-positive/unknown.[rx]
Non-immune causes of UHB include RBC enzyme defects, RBC membrane defects, hemoglobinopathies, sepsis, sequestration, and polycythemia. The glucose-6 phosphatase dehydrogenase (G6PD) enzyme deficiency is the most common RBC enzyme defect and is transmitted as an X-linked recessive trait. G6PD protects RBCs against oxidative damage by generating NADPH (nicotinamide adenine dinucleotide phosphate hydrogenase) from NADP (nicotinamide adenine dinucleotide phosphate). When exposed to oxidant stressors like illness, certain medications, dyes, and foods like fava beans, G6PD deficient RBCs are hemolyzed, causing anemia and hyperbilirubinemia. More than 200 different types of mutations are known to cause G6PD deficiency.[rx] The clinical presentation varies depending on the variant, and some newborns may develop severe hyperbilirubinemia and bilirubin encephalopathy. Pyruvate kinase deficiency(PKD) is another enzyme deficiency that causes hemolysis and may present as UHB in newborns. It is an autosomal recessive(AR) disorder caused by a defect in Adenosine triphosphate (ATP) synthesis machinery. In PKD, RBCs and, in particular, young RBCs have shortened life spans resulting in anemia and UHB.[rx]
UHB due to RBC membrane defects includes hereditary spherocytosis (HS) and hereditary elliptocytosis (HE). HS, also known as Minkowski Chauffard disease, is the most common RBC membrane defect caused by mutations in RBC membrane proteins.[rx] Most cases are transmitted as an autosomal dominant (AD) trait and can present in the neonatal period with UHB.[rx] Hereditary elliptocytosis is another type of RBC membrane defect that is mostly asymptomatic but rarely does cause UHB in the neonatal period.[rx] Most cases are transmitted as AD traits caused by mutations in RBC’s structural membrane protein. The elliptical-shaped RBCs in HE are trapped in the spleen leading to extravascular hemolysis and elevated TSB.
RBC sequestrations from cephalohematoma, subgaleal hemorrhage, and Intracranial hemorrhage are also important causes or risk factors for UHB in the neonatal period due to increased bilirubin load. Polycythemia is another entity associated with an increased risk of UHB in newborns. Clinical conditions associated with polycythemia are intrauterine growth restriction (IUGR), infant of diabetic mothers (IDM), large for gestational age (LGA), maternal smoking, high altitude, twin to twin transfusion, and placental transfusion (delayed cord clamping/umbilical cord milking). Studies have shown that placental transfusion reduces the incidence of postnatal anemia and leads to improved neurodevelopmental outcomes among term and preterm infants.[rx][rx] This practice has gained popularity, but at the same time, it may also increase the risk of hyperbilirubinemia.[rx][rx]
Indirect hyperbilirubinemia due to decreased bilirubin clearance usually results from quantitative or qualitative defects in the uridine diphosphate glucuronosyltransferase (UGT) enzyme. Gilbert syndrome, Crigler–Najjar syndrome type 1, and Crigler–Najjar syndrome type 2 are three prototype disorders resulting from an abnormality in the UGT enzyme. Gilbert syndrome is the most common of these and results from a mutation in the UGT1A1 gene resulting in decreased UGT production leading to unconjugated hyperbilirubinemia.[rx] Gilbert syndrome typically presents as mild jaundice at times of stress in the absence of hemolysis or liver dysfunction.[rx] Presentation in the neonatal period is rare and is usually associated with G6PD.[rx] Crigler-Najjar syndrome type 1 is an AR disorder resulting from a complete absence of UGT activity. Affected patients present with severe hyperbilirubinemia in the first days of life, often leading to bilirubin encephalopathy. Patients with Crigler-Najjar syndrome type 2 retain some of the activity of UGT enzymes. As such, the TSB levels are not that high, and patients rarely develop bilirubin encephalopathy.[rx]
Breast milk jaundice and breastfeeding jaundice are two other common etiologies of UHB in newborns. Breastfeeding jaundice, also known as breastfeeding failure jaundice, occurs in the first week of life and is due to inadequate intake of breast milk leading to dehydration and sometimes hypernatremia.[rx] Breastfeeding failure leads to decreased intestinal motility and decreases the elimination of bilirubin in the stool or meconium. Breast milk jaundice occurs late in the first week, peaks in the second, and usually resolves by two weeks of age. It is thought to be mainly due to inhibition of the UGT enzyme by pregnanediol and deconjugation of conjugated bilirubin in the intestines by beta-glucuronidase present in breast milk.[rx][rx]
Other miscellaneous causes of UHB include IDM, gastrointestinal obstruction, congenital hypothyroidism, and certain medications. IDMs often have polycythemia which is mainly responsible for the increased incidence of jaundice in these infants.[rx] UHB in congenital hypothyroidism is related to decreased hepatic uptake of bilirubin, impaired UGT activity, and sluggish gut motility. Gastrointestinal obstruction promotes increased bilirubin recycling by augmenting the enterohepatic circulation. When used in the neonatal period, certain medications may also worsen UHB by displacing bilirubin from albumin, affecting albumin binding.[rx] Sepsis can also predispose a newborn to UHB by causing oxidative damage to RBCs, increasing bilirubin load.[rx]
The majority of infants with clinical UHB have a combination of two or more factors discussed earlier. Furthermore, certain recognized risk factors predispose an infant to jaundice. These risk factors comprise prematurity, a history of jaundice in previous siblings requiring phototherapy, Asian ethnicity, male gender, and exclusive breastfeeding.[rx] Lastly, UHB in premature infants presents a special scenario. It is believed that preterm infants have an increased risk of bilirubin encephalopathy and kernicterus in addition to being at a higher of jaundice. However, at present, there is a dearth of data on the magnitude of the problem as well as consensus guidelines on the management of UHB in preterm infants.[rx][rx] The TSB threshold for initiation of phototherapy and criteria for exchange transfusion is also not clear in this population. Bilirubin is an antioxidant and may have a physiological role in neonates.[rx][rx] Keeping TSB levels low by aggressive treatment in preterm infants may reduce the antioxidant level and potentially worsen the retinopathy of prematurity. Reduced antioxidant status is also associated with chronic lung disease and neurological injury. As such, treatment of UHB in this population is a challenging task in the absence of evidence-based guidelines.[rx]
Conjugated Hyperbilirubinemia(CHB) or Direct Hyperbilirubinemia
Conjugated hyperbilirubinemia, also referred to as neonatal cholestasis, is characterized by elevation of serum conjugated/direct) bilirubin (> 1.0 mg/dL) and is due to impaired hepatobiliary function. Distinguishing CHB from UHB is critical because cholestatic jaundice/CHB is almost always pathologic and warrants prompt evaluation and treatment.[rx]
The causes of neonatal cholestasis/CHB are extensive and can be classified into the following categories:
Obstruction of biliary flow: Biliary atresia, choledochal cysts, neonatal sclerosing cholangitis, neonatal cholelithiasis
Infections: CMV, HIV, rubella, herpes virus, syphilis, toxoplasmosis, urinary tract infection (UTI), septicemia
Genetic causes: Alagille syndrome, alpha-1 anti-trypsin deficiency, galactosemia, fructose mix, Tyrosinemia type 1, cystic fibrosis, progressive familial intrahepatic cholestasis (PFIC), Aagenaes syndrome, Dubin-Johnson syndrome, Bile acid synthesis disorders(BSAD)
Intrinsic causes of hemolysis
- Membrane conditions
- Hereditary elliptocytosis
- Enzyme conditions
- Glucose-6-phosphate dehydrogenase deficiency (also called G6PD deficiency)
- Pyruvate kinase deficiency
- Globin synthesis defect
- sickle cell disease
- Alpha-thalassemia, e.g. HbH disease
Extrinsic causes of hemolysis
- Systemic conditions
- Arteriovenous malformation
- Alloimmunity (The neonatal or cord blood gives a positive direct Coombs test and the maternal blood gives a positive indirect Coombs test)
- Hemolytic disease of the newborn (ABO)
- Rh disease
- Hemolytic disease of the newborn (anti-Kell)
- Hemolytic disease of the newborn (anti-Rhc)
- Other blood type mismatches causing hemolytic disease of the newborn
- Breastfeeding jaundice
- Breast milk jaundice
- Urinary tract infection
- Gilbert’s syndrome
- Crigler–Najjar syndrome
- High GI obstruction (Pyloric stenosis, Bowel obstruction)
- Hepatitis A
- Hepatitis B
- TORCH infections
- Alpha 1-antitrypsin deficiency, which is commonly missed, and must be considered in DDx
- Cystic fibrosis
- Dubin–Johnson syndrome
- Rotor syndrome
- Total parenteral nutrition
- Biliary atresia or bile duct obstruction
- Alagille syndrome
- Choledochal cyst
“Breastfeeding jaundice” (or “lack of breastfeeding jaundice”) is caused by insufficient breast milk intake, resulting in inadequate quantities of bowel movements to remove bilirubin from the body. This leads to increased enterohepatic circulation, resulting in increased reabsorption of bilirubin from the intestines. Usually occurring in the first week of life, most cases can be ameliorated by frequent breastfeeding sessions of sufficient duration to stimulate adequate milk production.
Breast milk jaundice
Whereas breastfeeding jaundice is a mechanical problem, breast milk jaundice is a biochemical occurrence and the higher bilirubin possibly acts as an antioxidant. Breast milk jaundice occurs later in the newborn period, with the bilirubin level usually peaking in the sixth to 14th days of life. This late-onset jaundice may develop in up to one third of healthy breastfed infants.
- The gut is sterile at birth and normal gut flora takes time to establish. The bacteria in the adult gut convert conjugated bilirubin to stercobilinogen which is then oxidized to stercobilin and excreted in the stool. In the absence of sufficient bacteria, the bilirubin is de-conjugated by brush border β-glucuronidase and reabsorbed. This process of re-absorption is called enterohepatic circulation. It has been suggested that bilirubin uptake in the gut (enterohepatic circulation) is increased in breast fed babies, possibly as the result of increased levels of epidermal growth factor (EGF) in breast milk. Breast milk also contains glucoronidase which will increase deconjugation and enterohepatic recirculation of bilirubin.
- The breast-milk of some women contains a metabolite of progesterone called 3-alpha-20-beta pregnanediol. This substance inhibits the action of the enzyme uridine diphosphoglucuronic acid (UDPGA) glucuronyl transferase responsible for conjugation and subsequent excretion of bilirubin. In the newborn liver, activity of glucuronyl transferase is only at 0.1-1% of adult levels, so conjugation of bilirubin is already reduced. Further inhibition of bilirubin conjugation leads to increased levels of bilirubin in the blood. However, these results have not been supported by subsequent studies.
- An enzyme in breast milk called lipoprotein lipase produces increased concentration of nonesterified free fatty acids that inhibit hepatic glucuronyl transferase, which again leads to decreased conjugation and subsequent excretion of bilirubin.
Most infants develop visible jaundice due to elevation of unconjugated bilirubin concentration during their first week. This is called physiological jaundice. This pattern of hyperbilirubinemia has been classified into two functionally distinct periods.
- Phase one
- Term infants – jaundice lasts for about 10 days with a rapid rise of serum bilirubin up to 204 μmol/l (12 mg/dL).
- Preterm infants – jaundice lasts for about two weeks, with a rapid rise of serum bilirubin up to 255 μmol/l (15 mg/dL).
- Phase two – bilirubin levels decline to about 34 μmol/l (2 mg/dL) for two weeks, eventually mimicking adult values.
- Preterm infants – phase two can last more than one month.
- Exclusively breastfed infants – phase two can last more than one month.
Mechanisms involved in physiological jaundice include:
- Relatively low activity of the enzyme glucuronosyltransferase which normally converts unconjugated bilirubin to conjugated bilirubin that can be excreted into the gastrointestinal tract. Before birth, this enzyme is actively down-regulated, since bilirubin needs to remain unconjugated in order to cross the placenta to avoid being accumulated in the fetus. After birth, it takes some time for this enzyme to gain function.
- Shorter life span of fetal red blood cells, being approximately 80 to 90 days in a full term infant, compared to 100 to 120 days in adults.
- Relatively low conversion of bilirubin to urobilinogen by the intestinal flora, resulting in relatively high absorption of bilirubin back into the circulation.[rx]
Miscellaneous: Idiopathic neonatal hepatitis, parenteral nutrition induced cholestasis, gestational alloimmune liver disease/neonatal hemochromatosis, hypotension,
Biliary atresia (BA) is the most common cause of conjugated hyperbilirubinemia in infants.[rx] The incidence of BA varies from region to region. It is reported at a frequency of 1 in 6000 live births in Taiwan, the region with the highest incidence. In the United States, it has an incidence of around 1 in 12,000 live births.[rx] The etiology of BA is not well understood, but genetic factors along with viral infection, toxins, chronic inflammatory and autoimmune injury to bile ducts seem to play a role in its pathogenesis. The disease involves both intra-hepatic and extra-hepatic bile ducts and classically presents around 2 to 4 weeks of life with pale stools and jaundice. The initial evaluation is by ultrasonography which may show an absent gallbladder and the classic “triangular cord” sign.[rx] Early diagnosis is critical to maximizing the response to a Kasai operation (hepatic portoenterostomy).[rx] If the surgery is delayed by 90 days of life, less than 25% of patients are reported to respond, compared to surgery performed within 60 days when more than 70% of patients will establish adequate bile flow.[rx]
Choledochal cysts involve dilation of the intrahepatic and extra-hepatic bile duct. Ultrasonography can detect cysts with normal or dilated intrahepatic bile ducts as opposed to sclerosed ducts in biliary atresia. However, cystic biliary atresia may resemble choledochal cysts.[tx] Neonatal sclerosing cholangitis (NSC) is a rare form of cholangiopathy that often presents in infancy with CHB, hepatosplenomegaly, pale stools, and high serum gamma-glutamyltransferase activity (GGT).[rx] Neonatal cholelithiasis is also a rare entity that can cause significant direct hyperbilirubinemia in neonates.[rx]
Cytomegalovirus (CMV) is the most common congenital infection that manifests in various ways. Most infected newborns are asymptomatic, but hepatomegaly and CHB are the most prominent feature of hepatic involvement.[rx] Syphilis, toxoplasmosis, herpes, and rubella should be included in the differential diagnosis of neonatal cholestasis, especially when other stigmata of congenital infection like growth restriction, coagulopathy, skin rash, and thrombocytopenia are present. Careful evaluation of maternal history along with specific serologies and culture would aid the diagnosis. UTI is also a significant cause of CHB in neonates, and urine culture should be included as part of the diagnostic evaluation. Microcirculatory changes in the liver, a direct effect of bacterial products, and toxins released by bacteria are thought to be the possible mechanism of cholestasis in patients with UTIs.[rx]
Alagille syndrome (ALGS) is an AD disorder caused by mutations in JAG1 or NOTCH2 genes leading to a lack of interlobular bile ducts.[rx] With an incidence of 1 in 30,000 live births, ALGS is the most common cause of familial intrahepatic cholestasis.[rx] Characteristic clinical features in addition to cholestasis are butterfly vertebrae, congenital heart defect (most commonly peripheral pulmonic stenosis), kidney involvement, dysmorphic features (broad forehead, small pointy chin), and posterior embryotoxic of the eye. GGT levels are elevated out of proportion, often up to 20 times their normal value. Interestingly, CHB in patients with ALGS may resolve with age.[rx] Few patients with cystic fibrosis (CF) can present with features of cholestasis because of abnormal bile that plugs the bile ducts.[rx] In developing nations where newborn screening with immunoreactive trypsinogen is unavailable, neonatal cholestasis may be the first clue to the diagnosis.
Alpha-1-antitrypsin deficiency is the most common genetic cause of cholestatic and may mimic biliary atresia in early infancy. Accumulation of anti-trypsin polymers in the endoplasmic reticulum of hepatocytes of a patient with the PiZZ genotype leads to apoptosis of hepatocytes, ultimately resulting in cholestasis and cirrhosis later in childhood.[rx] As with ALGS, cholestasis may also improve with age. Galactosemia, fructose mix, and tyrosinemia type 1 are a few of the inborn errors of metabolism known to cause cholestasis in neonates. Newborns with galactosemia present with cholestatic jaundice, cataracts, hepatomegaly, failure to thrive, renal tubular acidosis, and Escherichia coli sepsis after the ingestion of galactose from milk.[rx] Galactose-1-phosphate uridyl transferase (GALT) deficiency leads to the accumulation of toxic galactose metabolites in multiple organs. The presence of reducing substances in urine suggests galactosemia, and GALT activity in the liver or erythrocytes confirms the diagnosis. Neonatal cholestasis may be a presenting feature in hereditary tyrosinemia type 1, another AR disorder caused by deficiency of enzyme fumarylacetoacetate hydroxylase. Other features of this disorder are renal Fanconi syndrome, hepatomegaly, coagulation abnormality, and the risk of hepatocellular carcinoma in untreated patients.[rx]
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of three genetic disorders that present with cholestasis. They are related to mutations in one of the genes involved in canalicular hepatobiliary transport.[rx] Types 1 and 2 usually manifest in the neonatal period, while type 3 presents later in infancy. Affected patients frequently develop cirrhosis and end-stage liver disease during childhood. GGT level is normal in types 1 and 2 and elevated in type 3 patients. PFIC1 is caused by a mutation in the ATP8B1 gene, which encodes FIC1 protein, whereas PFIC2 is caused by a mutation in the ABCB11 gene, which encodes for the bile salt excretory protein (BSEP). PFIC 3 is caused by a mutation in the ABCB4 gene, which encodes for the multi-drug resistant-3 protein (MDR3).[rx] Agencies syndrome, also known as lymphedema cholestasis syndrome (LCS), is another type of idiopathic familial intrahepatic cholestasis syndrome characterized by neonatal cholestasis and lymphedema in lower extremities. It is transmitted as an AR trait and is mostly seen in individuals of Norwegian descent.[rx] Dubin-Johnson syndrome (DJS) is a rare AR disorder caused by a mutation in the ABCC2 gene, which codes for a non-biliary ion transporter in the liver. A unique feature of DJS is the presence of black liver and excretion of coproporphyrin 1 in urine.[rx] Bile acid synthesis disorder (BASD) results from a deficiency of one of the enzymes involved in synthesizing bile acids from cholesterol. BASDs are an uncommon cause of cholestasis, but many of these are curable with medical therapy alone.
Parenteral nutrition-associated cholestasis (PNAC) is an important iatrogenic cause of cholestasis recognized most commonly in preterm infants managed with parenteral nutrition (PN). PNAC is present in about 20% of neonates who have received PN for more than two weeks.[rx] Duration of PN use and intestinal failure are two independent risk factors for PNAC. The mechanism is not entirely clear and is probably multifactorial.[rx] Abnormal bile salt metabolisms due to prematurity and harmful effects of components of PN are thought to be the main culprit. Other factors such as sepsis, and necrotizing enterocolitis, appear to potentiate liver injury.[rx] Gestational alloimmune liver disease (GALD), which causes almost all neonatal hemochromatosis cases, is a fulminant alloimmune disorder and results from intra-hepatic and extra-hepatic iron deposition resulting in liver failure.[rx]
In GALD, maternal IgG immunoglobulin against fetal hepatocytes crosses the placenta causing complement-mediated damage to fetal hepatocytes. Patients present with signs of liver failure in the form of hypoglycemia, coagulopathy, hypoalbuminemia, cholestatic jaundice, edema, and elevated liver enzymes. The risk of recurrence in subsequent pregnancies is almost 90%, and GALD can result in fetal or neonatal deaths.[rx] The term idiopathic neonatal hepatitis is used when the etiology of neonatal cholestasis cannot be ascertained after an extensive diagnostic workup. The size of this entity is shrinking with advancements in newer diagnostic tools, with more and more causes of neonatal cholestasis being identified that were originally labeled as idiopathic neonatal hepatitis.[rx]
Common symptoms of jaundice include:
- A yellow tinge to the skin and the whites of the eyes, normally starting at the head and spreading down the body
- Pale stools
- Dark urine
Accompanying symptoms of jaundice resulting from low bilirubin levels include:
- Abdominal pain
- Weight loss
- In these cases, yellowing may be more obvious elsewhere, such as:
- On the palms of their hands
- On the soles of their feet
- Inside their mouth
- Not want to feed or not feed as well as usual
- Have dark, yellow pee (it should be colorless)
- Have pale poo (it should be yellow or orange)
The term Kernicterus denotes yellow staining of deeper brain nuclei seen on autopsy specimens on infants with severe unconjugated hyperbilirubinemia. The histopathologic features seen on these autopsies include nuclei that have undergone pyknosis, the presence of vacuolation in the cytoplasm, and fading of the Nissl substance.[rx]
A liver biopsy is often needed for making a definitive diagnosis of cholestasis. It may help differentiate Biliary atresia from idiopathic neonatal hepatitis. Histopathological features of BA include the expansion of the hepatic portal tracts with edema, fibro-dysplasia, bile ductular proliferation, and bile plugs in the ductal lumen. Multinucleate giant cells and hemopoiesis are other features often seen on histopathologic exams of cholestatic liver samples.[rx] Although not diagnostic of any disorder, the prominence of hepatic erythropoiesis is seen more frequently in cholestasis of infectious etiology. The pathognomonic histopathological features of other cholestatic disorders include periodic acid- Schiff (PAS)-positive granules in alpha-1 antitrypsin deficiency, paucity of bile ducts in Alagille syndrome, necrosis, and inflammation around duct seen in sclerosing cholangitis.[rx]
Among familial causes of cholestasis, canalicular cholestasis with a marked absence of ductular proliferation and isolated periportal biliary metaplasia of the hepatocytes is commonly seen in PFIC1 patients. In PFIC2 patients, the histopathology is similar except that altered liver architecture and extensive lobular and portal fibrosis with inflammation are more common.[rx]
History and Physical
The evaluation of the neonate with jaundice starts with a detailed history, including birth history, family history, the onset of jaundice, and maternal serologies. Color of stool and urine presence of pruritis should be assessed for infants evaluated for jaundice and may provide a clue to the type of jaundice. The American Academy recommends universal screening of all newborns for jaundice and identifying risk factors for developing severe hyperbilirubinemia.[rx] Major risk factors in newborns over 35 weeks gestation include pre-discharge bilirubin in the high-risk zone, jaundice observed in the first 24 hours, blood group incompatibility, gestational age 35 to 36 weeks, a previous sibling who received phototherapy, cephalhematoma or significant bruising, exclusive breastfeeding and east Asian race. Prematurity is also a known risk factor for developing severe hyperbilirubinemia.[rx] Minor risk factors are serum bilirubin in the high intermediate-range, macrosomic infant of a diabetic mother, polycythemia, male gender, and maternal age older than 25 years.[rx]
To assess for jaundice, newborns should ideally be examined in daylight. However, the clinical assessment may be unreliable, especially if a newborn has received phototherapy or has dark skin.[rx] Therefore clinically significant jaundice should always be confirmed with a TSB or transcutaneous bilirubin. A focused physical examination to identify the cause of pathologic jaundice should be performed. Evaluation for pallor, petechiae, cephalhematoma, subgaleal bleed, extensive bruising, hepatosplenomegaly, weight loss, and signs of dehydration needs to be done. All infants with jaundice should also be assessed for signs and symptoms of bilirubin encephalopathy that include poor feeding lethargy, altered sleep, abnormal tone, or seizures. It is, however, important to note that up to 15% of neonates with kernicterus are clinically asymptomatic in the newborn period.[rx] As discussed in prior sections, certain etiologies of neonatal cholestasis have multi-system involvement. These signs should be looked for during physical exams that may often provide a clue to diagnosis and aid in directing specific work-up.
Diagnosis of Unconjugated Hyperbilirubinemia
Bilirubin levels can be assessed using a transcutaneous measurement device or blood samples for total serum bilirubin. Transcutaneous estimation of bilirubin reduces the frequency of blood tests, but its utility is limited in infants with dark skin and following phototherapy use.[rx][rx] The serum level should be measured when the transcutaneous bilirubin (TcB) level exceeds the 95th percentile on the transcutaneous nomogram or 75% of the TSB nomogram for phototherapy. Another limitation of relying on TcB is the inability to detect the direct fraction of bilirubin required for diagnosing neonatal cholestasis.
Recommended workups for identifying a hemolytic disease as the cause of unconjugated hyperbilirubinemia include maternal/neonatal blood type, Coombs test, complete blood cell (CBC), reticulocyte count, blood smear, and G6PD. Serum albumin should always be checked, especially if the TSB level approaches near the exchange transfusion levels, as it is considered a surrogate marker for free bilirubin. Free bilirubin is the fraction responsible for bilirubin-induced toxicity.[rx] Bilirubin-albumin ratio(B/A) ratio is, therefore, an additional tool that may predict the risk of kernicterus and may serve as an alternative guide to exchange transfusion.
Radiographic imaging is usually not required for most cases of UCH. Magnetic resonance imaging (MRI) findings have high sensitivity for bilirubin encephalopathy, with posteromedial borders of the globus pallidus being the most sensitive brain region for detecting signal changes. Infants with bilirubin encephalopathy demonstrate hyperintense signals on T1-weighted sequences in the acute stage that eventually becomes hyperintense on T2-weighted sequences as the disease evolves. Magnetic resonance spectroscopy(MRS) shows increased levels of glutamate and decreased levels of N-acetyl-aspartate and choline.[rx] However, the absence of these findings does not exclude the risk of chronic bilirubin encephalopathy.
Diagnosis of Conjugated Hyperbilirubinemia
In patients with conjugated hyperbilirubinemia, the serum aminotransferases should be ordered for evidence of hepatocellular injury, alkaline phosphatase, and GGT levels for evidence of obstruction in biliary channels, prothrombin time/INR, and serum albumin to evaluate for hepatic synthetic function. Additional tests like TORCH titers, urine cultures, viral cultures, serologic titers, Newborn screening results, specific tests for inborn errors of metabolism, alpha-1 antitrypsin phenotype, and specific genetics tests may be needed depending on the scenario.
Radiology is often necessary as part of the workup of neonatal cholestasis. Hepatic ultrasonography may help identify sludging in the biliary tree, gallstones, inspissated bile, and choledochal cysts. Triangular cord sign seen on hepatic ultrasound has high sensitivity and almost 100% specificity for biliary atresia.[rx] Hepatobiliary scintigraphy is another tool increasingly used in evaluating neonatal cholestasis. Decreased excretion of tracer 24 hours after introduction suggests obstruction and further helps in excluding nonobstructive causes of cholestasis.[rx] Prior treatment with phenobarbitone has been shown to improve the sensitivity of this imaging. Finally, liver biopsy is usually considered the gold standard for diagnosing neonatal cholestasis. Histopathological interpretation by an experienced pathologist will help to identify the correct diagnosis in 90% to 95% of cases and may prevent unnecessary interventions in patients with intrahepatic cholestasis.[rx]
Treatment of Unconjugated Hyperbilirubinemia
Phototherapy and exchange transfusion are the mainstay of treatment for patients with unconjugated hyperbilirubinemia.
Phototherapy (PT) remains the first-line treatment for managing pathological unconjugated hyperbilirubinemia. PT is very effective in reducing TSB to safe levels and reduces the risk of bilirubin toxicity and the need for exchange transfusion. Phototherapy is started based on risk factors and the TSB levels on the bilirubin nomogram.[rx] However, guidelines on the indications for PT in preterm infants are lacking, especially in the United States, because of a lack of evidence. As such most hospitals in the U.S have instituted their guidelines for the use of phototherapy and exchange transfusion in preterm infants based on birth weight or gestational age.[rx] The efficacy of phototherapy depends on the dose and wavelength of light used as well as the surface area of the infant’s body exposed to it. Increasing the dose of PT can be achieved by placing phototherapy units at a minimum safe distance from the infant and increasing the number of units used.
Bilirubin absorbs light optimally in the blue-green range (460 to 490 nm). PT works by inducing bilirubin photoisomerization and converting bilirubin into lumirubin, which is the rate-limiting step for bilirubin excretion.[rx] During phototherapy, the eyes of the newborn must be covered to avoid retinal injury. Measures are necessary to expose maximum body surface area to the light and avoid interruptions in PT. It is important to maintain adequate hydration and ensure normal urine output as most bilirubin is excreted in the urine as lumirubin. After phototherapy is discontinued, there is an increase in the total serum bilirubin level known as the” rebound bilirubin.” The “rebound bilirubin” level is usually lower than the level at the initiation of phototherapy and usually does not require reinitiation of phototherapy.[rx] PT has been considered relatively safe, but recent evidence points towards possible long-term side effects. Reported side-effects of PT use include rash, dehydration, hypocalcemia, retinal damage, hemolysis due to oxidative damage, delay in PDA closure in preterm infants, and allergic reactions.[rx]
Few studies have also reported an increased incidence of solid organ tumors and non-lymphocytic leukemias in children treated with phototherapy.[rx][rx] The bronze baby syndrome is another commonly described phenomenon associated with PT and results in irregular pigmentation of the skin, mucous membranes, and urine. It is usually seen in neonates with elevated serum conjugated bilirubin levels. The mechanism is not clear but appears to be related to the accumulation of photoisomers of bilirubin and biliverdin deposition.[rx][rx]
Exchange transfusion (ET), the first successful treatment ever used for jaundice, is currently the second-line treatment for severe unconjugated hyperbilirubinemia.[rx] It is indicated when there is a failure of response to PT, or the initial TSB levels are in the exchange range based on the nomogram. ET rapidly removes bilirubin as well as hemolysis, causing antibodies from circulation. A double volume exchange blood transfusion (160 to 180 ml/kg) is performed, replacing the neonate’s blood in aliquots with crossed-matched blood. Since most of the total body bilirubin lies in the extravascular compartment complications, TSB levels immediately following ET are about 60% of the pre-exchange level that later increase to 70 to 80% of pre-exchange levels as a result of equilibrium with an extravascular moiety of bilirubin. During ET, vitals should be monitored closely, and TSB, CBC, serum calcium, glucose, and electrolytes need to be checked following the procedure. Complications of ET include electrolyte abnormalities like hypocalcemia and hyperkalemia, cardiac arrhythmias, thrombocytopenia, blood-borne infections, portal vein thrombosis, graft versus host disease, and necrotizing enterocolitis (NEC).[rx][rx] Phototherapy should resume after exchange transfusion until the bilirubin reaches a level where it can be safely discontinued.
Intravenous Immunoglobulin (IVIG)
IVIG is used when immune-mediated hemolysis is the cause of UHB jaundice and prevents RBC hemolysis by coating Fc receptors on RBCs.The AAP recommends IVIG infusion in immune-mediated hemolysis if TSB remains within 2 to 3 mg/dl of exchange level despite intensive phototherapy.[rx][rx] However, the evidence that the use of IVIG reduces the need for ET is not very clear. Nonetheless, IVIG is often used in clinical practice to manage unconjugated hyperbilirubinemia.
Treatment of Conjugated Hyperbilirubinemia
Treatment of conjugated hyperbilirubinemia is tailored to the specific etiology. Patients diagnosed with biliary atresia require a Kasai operation (hepatic portoenterostomy) preferably within two months of life for best outcomes.[rx] The Kasai operation involves removing the atretic biliary ducts and fibrous plate and Roux-en-Y anastomosis of jejunum with the remaining ducts to provide an alternative pathway for biliary drainage.[rx] Infectious causes of cholestasis would be treated with specific anti-microbial, whereas treatment with cholic acid and chenodeoxycholic acid is often curative for many BASDs. Metabolic causes of cholestasis would typically respond to the improvement of the primary disorder and liver functions. Patients with GALD appear to respond well to IVIG and double volume exchange transfusion. Liver transplant, when available, is curative but is technically challenging in this age group.[rx] Parenteral nutrition-induced cholestasis is managed with cyclic PN, reducing the duration of exposure and initiating enteral feeds as early as possible. Manganese and copper content of PN should be reduced to minimize liver injury.