Neonatal Jaundice and Cholestasis

Educational Objectives

The goal of this program is to improve the diagnosis and management of neonatal jaundice and cholestasis. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize signs and symptoms of jaundice and cholestasis in neonates.
2. Differentiate among conjugated and unconjugated hyperbilirubinemia and associated conditions in infants.
3. Treat various manifestations of liver dysfunction and failure in children.

Summary

Direct (conjugated) vs indirect (unconjugated) bilirubin: direct bilirubin >1 mg/dL or >15% of total bilirubin is abnormal (indicates conjugated hyperbilirubinemia [HBR]; associated with cholestasis); conjugated bilirubin is water-soluble; unconjugated bilirubin is more lipid-soluble

Neonatal unconjugated HBR

Physiologic jaundice (PJ): most common cause; caused by delayed conjugation and increased turnover of heme, an immature secretory system within the liver, and immature excretory system outside the liver; bilirubin rises to 6 to 12 mg/dL by 4 to 6 day; jaundice appears by day 2 or 3; maximum bilirubin is usually ≈15 mg/dL; urine is pale and stools are normal color; causes of exaggerated PJ are prematurity, medications, bruising, inadequate oral intake, delayed stooling, and breastfeeding; indicators include jaundice in the first 36 hr of life, total HBR ≥12 md/dL, persistent HBR >8 days, and elevated conjugated bilirubin >1.0 mg/dL

Breast milk jaundice: multiple proposed mechanisms; continue breastfeeding with increasing frequency; use phototherapy

Hemolytic anemia: production of heme activates heme oxygenase, increasing bilirubin; low neonatal levels of uridine diphosphate (UDP) glucose dehydrogenase leads to slower conjugation (presents in first 36 hr of life; normal-colored urine and stool; various erythroblasts on peripheral smear); caused by incompatibilities in blood groups, hereditary hemolytic syndromes, and neonatal infections

Crigler-Najjar syndrome: 2 types; characterized by absence of UDP-glucuronosyltransferase; presents soon after birth with significant jaundice and photosensitivity; urine is light; stools are grayish in color; kernicterus is common (bilirubin immediately increases on stopping phototherapy); type 2 is responsive to phenobarbital (distinguishes between types); genetic testing is available

Gilbert syndrome: exaggerated elevation of bilirubin under stress; more common in boys; autosomal dominant; normal examination

Cholestasis (conjugated HBR): neonates may not appear jaundiced until bilirubin is >5.0 mg/dL; most cases present within the first month of life; assess conjugated and total bilirubin in neonates jaundiced beyond 2 to 3 wk of age; differential diagnoses — neonatal hepatitis, metabolic diseases, biliary atresia (BA), and intrahepatic (IH) cholestasis; diagnostic evaluation — obtain history of pregnancy, neonatal course, and family history; on physical examination, evaluate for growth, cardiovascular (CV) signs (murmur), hepatosplenomegaly, abdominal distention, and extrahepatic (EH) anomalies; assess stool color; assess fractionated bilirubin (total and conjugated), liver injury tests, liver function tests, complete blood cell count, and platelets; assess urine, blood, cerebrospinal fluid, and skin lesions for suspected infection; ultrasonography is recommended to assess abnormalities of the biliary system and liver; assess serum α-1 antitrypsin (AAT; common form of metabolic disease in infants) and phenotype (MM or ZZ); family history of emphysema or liver failure is a key factor; infectious serologies (eg, herpes) can cause acute liver failure in infants; perform paracentesis for ascites; secondary testing — cholescintigraphy (HIDA scan; hepatic function and excretion); liver biopsy (likely gold standard) allows routine histology, immunohistochemistry, electron microscopy, and viral and bacterial cultures; exploratory laparotomy and intraoperative cholangiogram are recommended for negative workup and suspected BA

Biliary atresia: progressive, sclerosing, inflammatory process; can affect any portion of the EH biliary tract; leads to segmental or complete ductular obliteration; rapid development of end-stage liver disease (LD) caused by persistent IH inflammation; perinatal BA — most common form (65%-90% of cases); obliteration of fully formed bile ducts; infant initially looks healthy; jaundice worsens over several weeks; assessment of conjugated bilirubin at 2 wk shows increasing levels (if >1 mg/dL, consult hepatologist and a transplant hepatologist); biopsy shows remnants of bile duct; may be associated with other anomalies; embryonic BA — accounts for 10% to 35% of cases; early onset; jaundice and conjugated HBR at birth; mild elevation of conjugated bilirubin >1 mg/dL; minimal bile ducts; often associated with other anomalies occurring singly or in combination (eg, poly- or asplenia, CV defects, abdominal situs inversus, intestinal malrotation, portal vein and hepatic artery anomalies)

Outcomes: earlier diagnosis (<2 mo of age) is associated with better outcomes (jaundice resolves in 60% to 70% cases); later diagnosis may have good outcomes from surgery, but success rate is lower; outcomes are improved in surgical centers with physicians who are familiar with pediatric LD and BA; postoperative nutrition is important; proper bile excretion takes time after surgery, leading to fat malabsorption (large proportion of calories; may need to substitute or add medium-chain triglycerides for long-chain triglycerides to meet nutritional goals); do not delay vaccination (progression to liver transplantation can occur rapidly); 70% of infants with BA need liver transplantation by age 20 yr

Vitamin supplementation in cholestatic disorders: fat malabsorption causes deficiency of fat-soluble vitamins (eg, A, D, E, and K); vitamin A deficiency causes corneal damage and night blindness; vitamin D deficiency causes rickets and hypoglycemia; vitamin E deficiency can cause peripheral neuropathy, retinopathy, ataxia, and ophthalmoplegia; vitamin K deficiency may cause coagulopathy; treatment involves large doses of fat-soluble vitamins, but toxicities can develop; excessive vitamin A causes hepatotoxicity, dermatitis, and pseudotumor cerebri; excessive vitamin D can cause hypercalcemia, lethargy, arrhythmias, and nephrocalcinosis

Other causes of EH cholestasis: biliary (choledochal) cyst; choledocholithiasis; spontaneous perforation of the common bile duct — child appears septic; may present with ascites and hepatomegaly; HIDA scan may show biliary leak into the peritoneum; requires surgery

Idiopathic neonatal hepatitis (INH): sporadic — occurs randomly (no family history); 74% of patients recover, ≈7% develop LD, and 19% die; familial — more serious; ≈22% of patients recover, ≈16% develop chronic LD, and ≈63% die; cause not currently known; obtain family history

Neonatal AAT deficiency: LD primarily associated with PiZZ phenotype; association with PiZ null and PiSZ phenotypes is rare; normal phenotype is PiMM; autosomal codominant; ≈15% of children with PiZZ develop LD in first 20 yr of life; if present in neonatal period (jaundice) with PiZZ phenotype, micronodular cirrhosis can develop (50% of cases)

Genetic causes of IH neonatal cholestasis: arthrogryposis-renal dysfunction-cholestasis syndrome (involves neurogenic arthrogryposis multiplex, renal tubular dysfunction, and cholestasis); paucity of IH bile ducts includes syndromic (Alagille) and nonsyndromic forms; progressive familial IH cholestasis (PFIC); many present with severe itching and jaundice; g-glutamyl transferase (hallmark of disease) may be normal

Alagille syndrome: most common paucity syndrome of bile duct; associated anomalies include those of the eye (posterior embryotoxon), heart (eg, pulmonic stenosis, Tetralogy of Fallot), skeleton (eg, butterfly vertebrae, foreshortened fingers, stunted growth), kidney (may require transplantation), and face (prominent forehead and chin, hypertelorism), and growth failure and mental retardation; some abnormalities are associated with side effects of the disease rather than the disease itself (eg, malnourishment and extracardiac disorders); mortality is 17% to 28% (from liver or cardiac disease); LD usually presents within the first year of life; survival after liver transplantation is only ≈75% because of associated lung and renal disease

Gestational alloimmune LD (GALD; neonatal hemochromatosis): noninfectious cause of acute liver failure in newborns; children present with neonatal growth restriction, oligohydramnios, and fetal distress; iron is abnormally distributed in the liver and EH tissues; may present with high levels of ferritin and α-fetoprotein, hypoglycemia, and cholestasis; synthetic failure in the liver leads to prolonged prothrombin and partial thromboplastin times, but normal or low levels of aspartate aminotransferase and alanine aminotransferase; iron deposition occurs in EH tissues (heart, adrenal glands, pancreas) and can be assessed on magnetic resonance imaging or buccal biopsy of the lip; treatment — maternal intravenous immunoglobulin (IVIG) if disease is known or with history of death of a sibling from neonatal hemochromatosis; therapy is given during pregnancy; newborns with highly suspected GALD should be given IVIG and exchange transfusions (mortality rate is high without treatment)

Drug-induced LD: can be caused by prolonged chloral hydrate (used for sedation), drugs passed through maternal breast milk, drugs causing cholelithiasis, and antibiotics that can cause sludging

Vascular causes of cholestasis: congenital diseases; neonatal asphyxia; severe congestive heart failure; Budd-Chiari syndrome (rare in infants); veno-occlusive disease (sinusoidal occlusion disease); neoplasia

Metabolic disorders associated with neonatal cholestasis: family history is useful; assess for enlarged liver or spleen on physical examination and liver biopsies; carbohydrate disorders — galactosemia and fructosemia; glycogen storage disease can be associated with enlarged liver and spleen; type 4 is associated with LD; miscellaneous metabolicdefects — cystic fibrosis, panhypopituitarism (check cortisol), hypothyroidism, copper overload, and Zellweger syndrome; infectious causes — cytomegalovirus, hepatitis A and B, herpes, and bacterial infections

Readings

Amegan-Aho KH et al. Neonatal jaundice: Awareness, perception and preventive practices in expectant mothers. Ghana Med J. 2019 Dec;53(4):267-272.; Anderson NB et al. Neonatal indirect hyperbilirubinemia. Neoreviews. 2020 Nov;21(11):e749-e760. doi: 10.1542/neo.21-11-e749.; Ansong-Assoku B, Ankola PA. Neonatal jaundice. StatPearls Publishing. 2020 Jun 25; Available from: https://www.ncbi.nlm.nih.gov/books/NBK532930/; Bhandari J et al. Crigler Najjar syndrome. StatPearls Publishing. 2020 Nov 23; Bratton S et al. Breast milk jaundice. StatPearls Publishing. 2020 Nov 18; Evans HM et al. Neonatal liver disease. J Paediatr Child Health. 2020 Nov;56(11):1760-1768.; Feldman AG, Whitington PF. Neonatal hemochromatosis. J Clin Exp Hepatol. 2013;3(4):313-320. doi:10.1016/j.jceh.2013.10.004; Lane E, Murray KF. Neonatal cholestasis. Pediatr Clin North Am. 2017;64(3):621-639. doi:10.1016/j.pcl.2017.01.006; Mitra S et al. Neonatal jaundice: Aetiology, diagnosis and treatment. Br J Hosp Med (Lond). 2017 Dec 2;78(12):699-704.; Siddiqui AI et al. Biliary atresia. StatPearls Publishing. 2020 Oct 2; Tripathi N, Jialal I. Conjugated hyperbilirubinemia. StatPearls Publishing. 2020 Aug 25.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Hupertz was recorded exclusively for Audio Digest using virtual teleconference software, in compliance with social-distancing guidelines during the COVID-19 pandemic. Audio Digest thanks the speakers for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PD673101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.