Persistent = Neonatal=20 Jaundice

&n= bsp; =20 Kulkarni A*, Sibal A**

* Consultant = Neonatologist, Academic Coordinator, Apollo Centre for Advanced = Pediatrics,=20 Indraprastha Apollo Hospital

**Consultant = Pediatric=20 Gastroenterologist and Hepatologist, Medical Director. Indraprastha = Apollo=20 Hospital

Address = for Correspondence:

Dr. Anjali = Kulkarni

36 Ishwar = Nagar

Mathura = Road

New Delhi, = 110065

Email:=20 kulkarnianjali@hotmail.com

Persistent Neonatal Jaundice

Definition

Persistent neonatal jaundice is defined as = visible=20 jaundice that persists beyond 14 days of life in a term infant or 21 = days in a=20 preterm infant.^{1, 2} The urgency to investigate a baby with = prolonged=20 neonatal jaundice is to rule out treatable causes for a favorable long- = term=20 outcome. The important rectifiable reasons are usually hypothyroidism,=20 extrahepatic biliary atresia, hypopitutarism, galactosemia and urinary = tract=20 infection.³

Physiologic jaundice (unconjugated = hyperbilirubinemia)=20 typically resolves by 14 days of age. Nonetheless, between 2.4 and 15 = percent of=20 newborns are jaundiced at two weeks of age. ^{4, 5}The majority = of=20 these infants have breast milk jaundice. Even though it is estimated = that=20 between 60 and 375 jaundiced infants will need to be tested at two weeks = of age=20 to detect one case of neonatal cholestasis,³ such testing is = recommended because it is possible that some of these infants may not = have=20 another health care visit until they are two months old (an important = prognostic=20 threshold for infants with biliary atresia)

Approach to baby with prolonged jaundice

In a well child, = the first=20 step is to examine the stools and urine. If the stools are pale and the = urine=20 contains bilirubin (i.e. a history of nappy staining yellow) the child = needs=20 urgent referral to a Paediatric Gastroenterologist to exclude biliary = atresia=20 and other causes of portal tract obstruction (for e.g. Choledochal = cyst). The=20 second step is to confirm whether the prolonged jaundice is due to an = elevation=20 of conjugated or unconjugated bilirubin in the plasma and classify it as = conjugated or unconjugated hyperbilirubinemia.

Unconjugated=20 Hyperbilirubinaemia

If the estimation = of=20 bilirubin indicates that > 85% is unconjugated, then breast milk = jaundice or=20 another cause of unconjugated hyperbilirubinaemia is likely (Table 1). Appropriate = further=20 investigations should include:

Full blood count, including reticulocytes=20
Examination of blood film
Thyroid function tests
GALT assay =96 i.e. red cell = galactose-1-phosphate=20 uridyl transferase

Table=20 1:

Causes of=20 unconjugated hyperbilirubinaemia

Breast Milk Jaundice =
Haemolysis
- Blood group incompatibilities (ABO = &=20 Rhesus)
Polycythaemia
Extravasated Blood
Increased Enterohepatic Circulation=20
- Pyloric stenosis
- Bowel obstruction =
Endocrine/Metabolic (also cause = conjugated=20 hyperbilirubinaemia)
- Hypothyroidism
- Hypopituitarism
- Hypoadrenalism
- Galactosaemia=20

Conjugated=20 Hyperbilirubinemia or neonatal cholestasis

It is defined as = prolonged=20 conjugated hyperbilirubinemia that occurs in the newborn period and = results from=20 diminished bile flow and/or excretion, which can be caused by a number = of=20 disorders. Conjugated bilirubin concentration is greater than 1.0 mg/dL = (17.1=20 =B5mol/L) if the total bilirubin is <5.0 mg/dl (85.5 =B5mol/L) or = more than 20=20 percent of the total bilirubin if the total bilirubin is >5.0 mg/dl = (85.5=20 =B5mol/L). ³Neonatal cholestasis affects approximately one = in 2,500=20 births.⁶Neonatal = cholestasis=20 constitutes 30% of hepatobiliary disorders in=20 India.

The North American = Society=20 for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) = guideline=20 for the evaluation of cholestatic jaundice in infants recommends that = any infant=20 noted to be jaundiced at the two-week well child visit should be = evaluated for=20 cholestasis.³

The evaluation of neonatal cholestasis may = appear=20 complicated because of the large number of potential diagnoses, the = similar=20 clinical presentations of a variety of conditions (table 2) and the = non-specificity of=20 diagnostic tests. Neonatal hepatitis and biliary atresia, which = typically occur=20 in term infants, account for 70 to 80 percent of cases, ^{6 =}alpha-1=20 antitrypsin deficiency accounts for another 5 to 15 percent of = cases.^6,=20
7 In premature infants, cholestasis more frequently results from = total=20 parenteral nutrition (TPN) or sepsis.

Table=20 2:

Idiopathic neonatal hepatitis=20 (Infection)

Viral = (CMV,=20 rubella, Herpes, HIV, parvovirus B19, ECHO, adenovirus)

Bacterial=20 (UTI, sepsis,=20 syphilis)

Bile duct = obstruction=20

Extrahepatic biliary duct=20 atresia

Choledochal cyst

Non syndromic paucity of intrahepatic = biliary=20 ducts

Inspissated bile/ mucus = plug

Cholelithiasis/ biliary=20 sludge

Tumours/ masses (intrinsic and=20 extrinsic)

Neonatal sclerosing cholangitis=20

Congenital hepatic fibrosis or = caroli=92s=20 disease

Cholestatic = syndromes

Arteriohepatic dysplasia (alagille=20 syndrome)

Byler syndrome

Progressive familial intrahepatic = cholestasis type=20 1-3

Bile acid synthesis = defects

Toxins=20

Drugs

Total parenteral nutrition=20

Metabolic diseases =

Alpha 1 antitrypsin=20 deficiency

Cystic fibrosis

Tyrosinemia

Gaucher disease

Niemann Pick = disease

Wolman disease

Arginase = deficiency

Galactosemia

Fructosemia

Type 4 glycogen storage=20 disease

Peroxisomal = disorders

Zellweger syndrome

Hypopitutarism

Hypothyroidism

Neonatal = hemochromatosis

Miscellaneous

Shock, hypoperfusion, intestinal = obstruction,=20 erythrophagocytic lymphohistiocytosis, neonatal=20 lupus

The initial step is rapid diagnosis and early = initiation=20 of therapy of treatable disorders. Conditions such as sepsis, = hypothyroidism,=20 panhypopituitarism, and inborn errors of metabolism (eg, galactosemia) = must be=20 recognized and treated promptly to avoid significant progression of the = illness.=20 For infants in whom these disorders are excluded, consultation with a = pediatric=20 gastroenterologist is warranted. Extrahepatic biliary atresia must be=20 differentiated from neonatal hepatitis because early surgical = intervention (ie,=20 before two-months of age) results in a better outcome.^{3 =}Additional=20 testing is directed at the diagnosis of specific conditions and = evaluation of=20 associated complications, such as coagulopathy. Pertinent points in = history that=20 may be helpful in narrowing the differential diagnosis of neonatal=20 cholestasisare:

=D8 =20 Congenital = infections=20 (microcephaly, skin lesions, chorioretinitis on funduscopy, = thrombocytopenia,=20 cataract, congenital heart lesions)

=D8 =20 Consanguinity = (increases=20 the risk of an autosomal recessive disorder)

=D8 =20 Prenatal = ultrasonography=20 and results (eg, presence of choledochal cyst or bowel=20 anomalies)

=D8 =20 Isoimmune = hemolysis (3=20 percent of infants with severe ABO incompatibility have conjugated=20 hyperbilirubinemia that may persist until two weeks of=20 age⁸

=D8 =20 Neonatal = infection,=20 particularly urinary tract infection

=D8 =20 Dietary history = (eg,=20 breast milk or galactose-containing formula)

=D8 =20 Weight gain = (neonatal=20 hepatitis and metabolic disease may cause failure to=20 thrive)

=D8 =20 Vomiting (may = occur in=20 metabolic disease, bowel obstruction, pyloric = stenosis)

=D8 =20 Stooling pattern = (delayed=20 stooling may occur in cystic fibrosis, hypothyroidism; diarrhea may = occur in=20 infection, metabolic disease, progressive familial intrahepatic=20 cholestasis)

=D8 =20 Stool color = (persistent=20 clay colored stools are specific, but not necessarily sensitive for = biliary=20 obstruction) ⁹

=D8 =20 Urine color = (dark urine=20 suggests conjugated hyperbilirubinemia)

=D8 =20 Excessive = bleeding=20 (coagulopathy, vitamin K deficiency leading to clotting factors=20 deficiency)

=D8 =20 Infant's = disposition=20 (irritability in case of metabolic diseases or sepsis; lethargy may = indicate=20 metabolic disease, sepsis, hypothyroidism,=20 panhypopituitarism)

=D8 =20 A history of = similar=20 problems in the parents or siblings suggests a heritable disorder (eg, = cystic=20 fibrosis, alpha-1-antitrypsin deficiency, progressive familial = intrahepatic=20 cholestasis, Alagille syndrome)

Important aspects of the physical examination=20 include:³

=D8 =20 Measurement of = vital signs=20 and growth parameters

=D8 =20 Assessment of = general=20 health (ill-appearance may indicate infection or metabolic disease, = whereas=20 infants with biliary atresia typically appear = well)

=D8 =20 General = appearance=20 (infants with Alagille syndrome may exhibit characteristic facial = appearance=20 with a broad nasal bridge, triangular facies, and deep set=20 eyes)

=D8 =20 General = assessment of=20 infant's vigor, tone, and symmetry

=D8 =20 Funduscopic = examination=20 (congenital infection, storage disease (cherry red spot), posterior = embryotoxon=20 in alagille syndrome, cataract)

=D8 =20 Cardiac murmur = or signs of=20 heart failure (may be present in biliary atresia or Alagille=20 syndrome)

=D8 =20 Abdominal = examination=20 (presence of ascites; abdominal wall veins; liver size, position, and=20 consistency; spleen size and consistency; abdominal masses; umbilical=20 hernia)

=D8 =20 Direct = examination of the=20 urine and stool to evaluate color (dark urine suggests conjugated=20 hyperbilirubinemia; light stools suggest = cholestasis)

=D8 =20 Bruising or = petechiae or=20 frank bleeding (coagulopathy)

Laboratory=20 studies help to delineate the = extent of=20 hepatobiliary dysfunction and help to identify the etiology. Assessment = of liver=20 cell injury and biliary disorders should include total and conjugated = bilirubin,=20 serum alanine aminotransferase (ALT) and aspartate aminotransferase = (AST), serum=20 alkaline phosphatase, and gamma-glutamyl transpeptidase (GGTP). Serum = bile acid=20 concentration (cholic and chenodeoxycholic acids and their conjugates), = which is=20 not routinely measured, is often elevated prior to the rise in serum=20 bilirubin.

Despite wide variability in serum GGTP=20 concentrations,¹⁰ GGTP is helpful in the evaluation of = neonatal=20 cholestasis. Compared to age-specific norms, elevated serum GGTP is seen = in many=20 forms of neonatal liver disease, but raises the concern for biliary = atresia or=20 other diseases that damage bile ducts,^{11, 12} whereas low GGTP = concentration is suggestive of progressive familial intrahepatic = cholestasis=20 type 1 or 2, or a bile acid synthesis defects. Hepatic=20 technetium-99m-mebrofenin iminodiacetate (99mTc-mebrofenin IDA) scans = and serum=20 gamma-glutamyl transpeptidase (GGTP) have high sensitivity for = extrahepatic=20 biliary atresia (EHBA). Of the various clinical, biochemical and imaging = parameters that were significantly different between patient groups, = sensitivity=20 for EHBA was: serum GGTP > or =3D 150 IU l(-1) (100%), = 99mTc-mebrofenin IDA=20 scans (100%), pale stools (82.8%) and total serum bilirubin > or =3D = 12 mg=20 dl(-1) (66%). However, specificity ranged from 48.5 to 79%.=20 ¹³

The biosynthetic capacity of the liver is = assessed by=20 prothrombin and partial thromboplastin times (PT, PTT), which require = clotting=20 factors produced in the liver, and serum albumin and glucose = concentrations.=20 Blood ammonia concentration may be elevated if the liver's ability to = clear=20 endogenous substances from the circulation is = impaired.

Other studies include a complete blood count = with=20 platelet count, urinalysis with testing for reducing substances (to = evaluate=20 galactosemia), urinary aminoacidogram, thyroid function tests, bacterial = cultures of urine and blood, alpha-1-antitrypsin, and screening for = cystic=20 fibrosis (sweat chloride or mutation analysis), urinary succinyl acetone = for=20 tyrosinemia, viral serology to rule out hepatitis B and C. Acid-base = status with=20 arterial lactate should be assessed as an initial step in the evaluation = for=20 metabolic disease and glycogen storage disease.

Imaging = studies = help in the=20 diagnosis of patients with neonatal cholestasis. These include abdominal = ultrasonography, hepatobiliary scintigraphy (HIDA scan), magnetic = resonance=20 cholangiopancreatography (MRCP), and rarely endoscopic retrograde=20 cholangiopancreatography (ERCP).

Ultrasonography: As a = general=20 rule, abdominal ultrasonography commonly is used as the initial test = because it=20 is non-invasive, easily available, and can identify structural = abnormalities of=20 the hepatobiliary tract.³ It is most helpful in the diagnosis = of=20 choledochal cysts but can also suggest the diagnosis of biliary atresia; = suggestive findings for the latter are the inability to visualize the=20 gallbladder and the presence of the triangular cord sign (triangular or = bandlike=20 periportal echogenic density >3 mm in thickness).^{14, =
15} In one ultrasound study of 331 = infants=20 with an identifiable gallbladder, an irregular shape to the gallbladder = and=20 irregular wall had positive and negative predictive values for biliary = atresia=20 of 75 and 97 percent, respectively, when calculated from the same = population of=20 infants.¹⁵ The sensitivity and specificity of a small or = absent=20 gallbladder in detecting obstruction ranges from 73 to 100 percent and = 67 to 100=20 percent, respectively when correlated with pathologic, surgical, and = subsequent=20 clinical examinations.³

Scintigraphy: = Hepatobiliary=20 scintigraphy with technetium-labeled iminodiacetic acid analogs can be = helpful=20 for distinguishing biliary atresia from neonatal hepatitis and other = causes of=20 cholestasis. The test depends upon adequate hepatocellular function and = patency=20 of the biliary tract. Infants with biliary atresia usually have normal = uptake of=20 the isotope but absent excretion of the bile in the intestine, whereas = those=20 with neonatal hepatitis typically have delayed uptake but appropriate=20 excretion.However, nonvisualization of the gallbladder or = lack of=20 excretion can occur in patients without biliary atresia.¹⁷=20 Pretreatment for five days with phenobarbital=20 (5 mg/kg per day) increases the accuracy of this test by enhancing = isotope=20 excretion.¹⁸ The sensitivity and specificity of scintigraphy = in=20 detecting obstruction ranges from 83 to 100 percent and 33 to 100 = percent=20 respectively.³ Scintigraphy adds little to the routine = evaluation of=20 the cholestatic infant, but may be of value in determining patency of = the=20 biliary tract, thereby excluding biliary atresia.=20 Pretreatment with UDCA significantly improves the specificity of = hepatobiliary=20 scintigraphy in ruling out extrahepatic biliary atresia as a cause of = prolonged=20 neonatal jaundice.¹⁹

MRCP =97 = Magnetic=20 resonance cholangiopancreatography (MRCP) may be another helpful = modality in=20 evaluating infants with neonatal cholestasis. Results from initial = studies are=20 encouraging.^20,21,22,23 In two studies, the negative and = positive=20 predictive values of MRCP in detection of biliary atresia were 91 to 100 = percent=20 and 75 to 96 percent, respectively indicating that although it may aid = in=20 excluding the diagnosis, it should not be relied upon exclusively to = identify=20 infants with biliary atresia. In addition, it requires deep sedation or = general=20 anesthesia. MRI evaluation with SQUID sequences can be used to evaluate = hepatic=20 iron load as in cases with neonatal hemochromatosis where quantitative = iron=20 assessment on biopsy is difficult.

ERCP:=20 Endoscopic retrograde cholangiopancreatography (ECRP) is a promising = technique=20 available only at a few select tertiary care centers.³It = involves=20 endoscopic intubation of the biliary and pancreatic ducts through the = ampulla of=20 Vater with a small catheter and injection of contrast material for = radiologic=20 visualization of the ductal systems. ERCP appears to be a sensitive and = specific=20 means of detecting biliary obstruction. Its utility in neonates is = limited by=20 the scarce availability of appropriately sized endoscopes, the need for = deep=20 sedation or general anesthesia in most cases, and the lack of = validation. In=20 select circumstances, ERCP can clarify the etiology of neonatal = cholestasis and=20 reduce the need for laparotomy.

Additional = tests

Liver biopsy =97 = Percutaneous=20 liver biopsy is generally needed in the evaluation of neonatal = cholestasis,=20 particularly when biliary tract obstruction is high on the differential=20 diagnosis. Percutaneous liver biopsy can be performed safely in young = infants=20 and may be helpful in establishing a definitive diagnosis of cholestatic = jaundice.³ The NASPGHAN guideline recommends that a = percutaneous=20 liver biopsy be performed in most infants with undiagnosed = cholestasis.³⁼²⁰The biopsy should be interpreted by a pathologist with expertise = in=20 pediatric liver disease. Biopsy is recommended before performing a = surgical=20 procedure to diagnose biliary atresia as findings on histopathology are = quite=20 specific. In case the results are equivocal and biopsy was performed = when the=20 infant was <6 weeks of age, repeat biopsy may be necessary.=20

Duodenal = aspirate =97=20 Duodenal aspirate analysis is an alternative to scinitigraphy for = assessing=20 excretion of bile into the intestine.^{3, 25} In this test, = fluid is=20 obtained from the duodenum (either by placing a tube or string into the=20 duodenum) and analyzed for bilirubin. Fluoroscopy may be required for = correct=20 tube placement. If the bilirubin concentration in the aspirate is less = than or=20 equal to that in the serum suggests biliary atresia. The sensitivity and = specificity of duodenal aspirate analysis in detecting obstruction = ranges from=20 91 to 100 percent and 43 to 100 percent, respectively.³

Summary = and=20 recommendations =97 Infants with neonatal cholestasis usually = are=20 initially detected by their primary care providers who note prolonged = jaundice=20 or abnormal stool or urine color. The evaluation of these infants should = be=20 undertaken in a staged approach as denoted in the figure=20 1.²⁵ The initial step is rapid diagnosis and = initiation of=20 therapy of treatable disorders (eg, sepsis, hypothyroidism, inborn = errors of=20 metabolism). The next step is to distinguish extrahepatic biliary = atresia from=20 neonatal hepatitis because early surgical intervention for extrahepatic = biliary=20 atresia results in improved outcome. Finally, additional testing is = directed at=20 the diagnosis of specific conditions and evaluation of associated = complications=20 (eg, coagulopathy).

Figure=20 1: staged approach to a baby with neonatal=20 cholestasis

The NASPGHAN guideline for the evaluation of = cholestatic=20 jaundice in infants between two and eight weeks of age makes the = following=20 recommendations regarding the evaluation: = ³

Any infant who is noted to be jaundiced at = two weeks=20 of age should be evaluated for cholestasis by measuring total serum = bilirubin=20 and conjugated (direct) bilirubin. The evaluation of breastfed infants = who=20 have a normal physical examination, normally colored stools and urine, = and can=20 be closely monitored may be delayed until they are three weeks of=20 age.=20
Conjugated hyperbilirubinemia is defined as = conjugated=20 bilirubin concentration greater than 1.0 mg/dL (17.1 =B5mol/L) if the = total=20 bilirubin is <5.0 mg/dL (85.5 =B5mol/L) or more than 20 percent of = the total=20 bilirubin if the total bilirubin is >5.0 mg/dL (85.5=20 =B5mol/L).=20
Infants in whom a treatable condition is = diagnosed=20 (eg, urinary tract infection, galactosemia) and treated and in whom = jaundice=20 fails to resolve should be reevaluated.=20
Referral to a pediatric gastroenterologist = is=20 recommended for all infants with cholestasis.=20
Ultrasound and liver biopsy is recommended = for most=20 infants with cholestasis.=20
Scintigraphy and duodenal aspirate are not = routinely=20 recommended but may be useful in situations in which other tests are = not=20 readily available.=20
MRCP and ERCP are not routinely recommended, = although=20 ERCP may be useful in experienced hands.

Management:

First step in = management is=20 to treat the underlying cause.

=95 =20 Biliary atresia = and=20 choledochal cyst- early surgical management before irreversible = cirrhosis sets=20 in.

=95 =20 Galactosemia- = lactose free=20 diet

=95 =20 Hypothyroidism- = thyroxine=20 replacement

=95 =20 Sepsis and UTI- = treat with=20 antibiotics

=95 =20 Congenital = infections- treat=20 appropriately

=95 =20 Panhypopopitutarism- to=20 provide needed hormone replacements

General management = of=20 neonatal cholestasis is summarized in table=20 3:

Clinical=20 impairement

Management=20

Malnutrition = related=20 to malabsorbtion of dietary long chain fatty acids=20

Replace with = dietary=20 formula or supplements containing medium- chain fatty=20 acidS

Fat soluable = vitamin=20 malabsorbtion:

1) =20 vitamin A=20 deficiency

2) =20 vitamin E=20 deficiency

3) =20 vitamin D=20 deficiency

4) =20 vitamin K=20 deficiency

Replace with = 10,000-=20 15,000 IU/ day as Aquasol A

Replace with = 50- 400=20 IU/ day as oral ά-tocopherol

Replace with = 5000 -=20 8000 IU/ day of vitamin D2 or 3-5 μ/kg/d of 25- OH=20 cholecalciferol

Replace with = 2.5- 5 mg=20 of parenteral vitamin K alternate=20 day.

Micronutrient=20 deficiency

Supplement = calcium,=20 phosphate and Zinc

Water = soluable vitamin=20 deficiency

Supplement = with twice=20 the recommended dietary = allowances

Retention of = biliary=20 constituents e.g. cholesterol (leading to itching and=20 xanthomas)

Administer = choleretic=20 bile salts and ursodeoxycholic acid, 15-=20 20mg/kg/day

Progressive = liver=20 disease; portal hypertension, spontaneous bacterial peritonitis=20 (SBP)

Control = bleeding, salt=20 restriction, spironolactone, appropriate management with = antibiotics and=20 supportive care

End- stage = liver=20 disease

Liver=20 transplantation

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