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Download Infant Jaundice 9/6/12 Continuity Lecture
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Jaundice in the newborn is a common problem for the general pediatrician – occurs in 2/3 of all newborn in 1st week of life Jaundice is defined as the presence of a yellow/yellow green hue to the skin, sclerae and mucous membranes due to an elevated serum bilirubin Jaundice usually becomes apparent at a total serum bilirubin of 5 mg/dl Bilirubin Production Bilirubin is a product of heme catabolism in the reticuloendothelial system Approximately 80 to 90 percent of bilirubin is produced during the breakdown of hemoglobin from red blood cells or from ineffective erythropoesis The remaining 10 to 20 percent is derived from the breakdown of other heme-containing proteins, such as cytochromes and catalase Bilirubin Production Bilirubin is formed in two steps The enzyme heme oxygenase catalyzes the breakdown of heme, resulting in the formation of carbon monoxide and biliverdin Biliverdin is then converted to unconjugated bilirubin by the enzyme biliverdin reductase Unconjucated bilirubin can cross the blood brain barrier Bilirubin clearance Hepatic uptake Circulating unconjugated bilirubin binds to albumin and is transported to the liver Albumin saturation or presence of medications (ie. Ceftriaxone, ibuprofen) can displace bilirubin Bilirubin dissociates from albumin and is taken up by hepatocytes, where it is processed for excretion Bilirubin Conjugation Conjugation — Occurs in hepatocytes Uridine diphosphogluconurate glucuronosyltransferase (UGT) catalyzes the conjugation of bilirubin with glucuronic acid UGT produces bilirubin diglucuronides and bilirubin monoglucuronides Levels of UGT increase in the first few weeks after birth (start at 1% of the adult levels) Conjugated bilirubin is more water soluble than unconjugated bilirubin and is excreted in bile Bilirubin Conjugation Conjugated bilirubin is more water soluble than unconjugated bilirubin Conjugated bilirubin is excreted into bile via an active process and then into digestive tract Conjugated bilirubin cannot be reabsorbed by the intestinal epithelial cells, it is broken down in the intestine by bacterial enzymes and then reabsorbed Newborn Bilirubin At birth, infant's GI tracts are essentially sterile, therefore very little conjugated bilirubin is reduced to urobilinogen Infants have beta-glucuronidase in the intestinal mucosa, which helps deconjugate the conjugated bilirubin The unconjugated bilirubin is then reabsorbed through the intestinal wall and recycled into the circulation (enterohepatic circulation of bilirubin) Evaluation Begins prenatally with maternal blood type, coombs test, isoimmune antibodies (anti Jk, K, D); baby blood type Determine whether the jaundice is due to conjugated (direct) or unconjugated (indirect) hyperbilirubinemia Most infants will have unconjugated hyperbilirubinemia, usually of a benign and physiologic nature Elevated direct bilirubinemia > 1 mg/dl if TSB <5mg/dl or direct bili >20% of the TSB NEVER physiologic and implies a pathologic state Differential of Unconjugated Hyperbilirubinemia Increased Bilirubin Production Hemolytic disease Isoantibodies: ABO, Rh, Minor Antibodies Enzyme defects: G6PD, Pyruvate Kinase Deficiency, Congenital Porphyria Structural defects: Spherocytosis, elliptocystosis Birth Trauma Cephalohematoma, Bruising Polycythemia Macrosomia, IDM Differential of Unconjugated Hyperbilirubinemia Impaired Bilirubin Conjugation Gilbert Crigler-Najjar, Type I & II Decreased Bilirubin Excretion Biliary obstruction- Biliary Atresia, Choledocal cyst, Dubin Johnson Syndrome, Rotor Syndrom Differential of Unconjugated Hyperbilirubinemia Asian Prematurity Metabolic Disorders Hypothyroid Galactosemia IDM Infection Sepsis UTI Breastfeeding Drugs Physiologic Jaundice Occurs after DOL 1 Peak is at day 3-5 days Elevated hct and short life span of RBC increased bilirubin production Deficiency of hepatic UGT poor excretion Increase in enterohepatic circulation of bilirubin Physiologic Jaundice These normal physiologic alterations generally result in a mild unconjugated hyperbilirubinemia that occurs in most newborns In Caucasian and African-American infants, the mean peak total bili occurs at 48 to 96 hours of life and is 7 to 9 mg/dL (In Asian infants, mean TSB peak is 10mg/dL) Resolves within the first one to two weeks after birth Peak total bili is later in premature infants Breastfeeding Jaundice Breast Milk Jaundice Within the first week of life Begins 3-5 DOL Inadequate intake and milk production Peaks within 2 weeks Dehydration Decreased bilirubin elimination and increased enterohepatic circulation of bilirubin May take up to 12 weeks to resolve Caused by an unknown factor in human milk that promotes an increase in intestinal absorption of bilirubin ABO Incompatibility Major blood groups: A, B, AB , O and Rh Biggest risk factor is mother O and baby A, B or AB All women should be screened during pregnancy If Rh negative, rhogam given prenatally and postnatally (based on baby blood type) Minor blood groups: Kell, Duffy , E Previous transfusion, pregnancy or exposure to bacteria or viruses Degree of hemolytic disease varies with antibody-may need to monitor closely G6PD Most common and clinically significant red cell enzyme defect X linked defect, so males have full enzyme deficiency Common in Mediterranean population, but found in 11-13% of the African American population in the US Common cause of kernicterus in the US (~30%) Treatment of Unconjugated Hyperbilirubinemia Phototherapy Goal is to bypass liver conjugation Converts bilirubin into lumirubin (more soluble substance than bilirubin) which is excreted without conjugation into bile and urine Converts the stable 4Z,15Z bilirubin isomer to the 4Z,15E isomer, which is more polar and less toxic and excreted into bile without conjugation Photo-oxidation reactions convert bilirubin to a colorless polar compound that is excreted in urine Nomogram for designation of risk in 2840 well newborns at ≥36 weeks’ gestational age with birth weight of ≥2000 g or ≥35 weeks’ gestational age and birth weight of ≥2500 g based on the hour-specific serum bilirubin values. Maisels M J et al. Pediatrics 2009;124:1193-1198 ©2009 by American Academy of Pediatrics Guidelines for phototherapy in hospitalized infants ≥35 weeks’ gestation. Maisels M J et al. Pediatrics 2009;124:1193-1198 Use total bilirubin Risk factors=isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, albumin <3.0 g/dl ©2009 by American Academy of Pediatrics Helpful link www.bilitool.org Treatment of Unconjugated Hyperbilirubinemia Exchange transfusion Removes bilirubin from the circulation when intensive phototherapy fails or in infants with signs of bilirubininduced neurologic dysfunction (BIND) Moost effective method for removing bilirubin rapidly Decreases the total bili by 50% Treatment of Unconjugated Hyperbilirubinemia IVIG IVIG can reduce the need for exchange transfusion in infants with hemolytic disease caused by Rh or ABO incompatibility IVIG (dose 0.5 – 1 g/kg over two hours); may repeat once after 12 hours IVIG Indications: rise in total bilirubin inspite of intensive phototherapy or within 2 or 3 mg/dL of the threshold for exchange transfusion Mechanism of action is uncertain ? Block hemolysis by blocking antibody receptors on RBC’s Red Flags of Neonatal Jaundice Jaundice in the first 24 hours of life Rate of total bili rise greater than 0.2 mg/dL per hour Jaundice in a term newborn after 2 weeks of age Direct (conjugated) hyperbilirubinemia You are evaluating a FT 4 day old infant in your office. Birth history unremarkable. Mother reports he has become more jaundice since discharge. He is strictly breastfeeding, with normal stooling and urine output. She is vigorous and exam is normal except for jaundice. Serum bilirubin is 12mg/dL. What is the most appropriate management Admit for phototherapy Continue breastfeeding Discontinue breastfeeding for 3 days, then resume Supplement with water Supplement with formula Guidelines for phototherapy in hospitalized infants ≥35 weeks’ gestation. Maisels M J et al. Pediatrics 2009;124:1193-1198 Use total bilirubin Risk factors=isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, albumin <3.0 g/dl ©2009 by American Academy of Pediatrics A 4 day old is brought to your office for evaluation of jaundice. She was born at 37 weeks gestation. MBT and BBT are A+. She is breastfeeding exclusively with normal stooling and urination. She is vigorous, has jaundice and appears well hydrated. At what serum bilirubin would you initiate phototherapy? 10mg/dL 12mg/dL 15mg/dL 17mg/dL 20mg/dL Guidelines for phototherapy in hospitalized infants ≥35 weeks’ gestation. Maisels M J et al. Pediatrics 2009;124:1193-1198 4 day old. 37 weeks gestation. MBT and BBT are A+. Where would you initiate therapy? 10 mg/dL, 12mg/dL, 15mg/dL, 17mg/dL, 20mg/dL What if she was 39 weeks old? ©2009 by American Academy of Pediatrics Clinical Manifestations of Unconjugated Hyperbili Bilirubin is a potential neurotoxin The brain regions most often affected include the basal ganglia and the brainstem nuclei for oculomotor and auditory function Clinical Manifestations of Unconjugated Hyperbilirubinemia Severe hyperbilirubinemia (Total bili >25 to 30 mg/dL) is associated with an increased risk for bilirubin-induced neurologic dysfunction (BIND) Bilirubin-Induced Neurologic Dysfunction occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue Acute Bilirubin Encephalopathy (ABE) - acute manifestations of BIND Kernicterus - chronic and permanent sequelae of BIND Acute Bilirubin Encephalopathy Early phase Sleepy, lethargic, but arousable Slight hypotonia, decreased movement Poor suck, high pitched cry Intermediate phase Less arousable, increased lethargy, Irritable Variable tone, increasing tone; start to see retrocollis opisthotonos Poor feeding, high pitched cry Advanced phase Deep stupor to coma Hypertonia- backward arching of the neck (retrocollis) and trunk (opisthotonos) with stimulation No feeding, shrill cry, inconsolable Kernicterus Develops during the first year after birth Cognitive function is relatively spared The major features: Choreoathetoid cerebral palsy (chorea, tremor and dystonia) Sensorineural hearing loss commonly manifesting as auditory neuropathy Gaze abnormalities, especially limitation of upward gaze Dental enamel dysplasia Conjugated Hyperbilirubinemia Pathologic condition of cholestasis Incidence of neonatal liver disease manifesting cholestasis: 1:2500 live births Differential of Conjugated Hyperbilirubinemia Extrahepatic disorders Biliary atresia Choledochal cyst Congential bile duct cyst Spontaneous perforation of the bile duct Common bile duct stone/sludge Choledochocele (anomaly of pancreaticobiliary junction) Intrahepatic disorders Idiopathic neonatal hepatitis Byler’s disease Alagille syndrome Sclerosing cholangitis Anatomic disorders Congenital hepatic fibrosis with polycystic kidney and liver Caroli disease (cystic dilation of intrahepatic biliary tree) Differential of Conjugated Hyperbilirubinemia Infectious Toxoplasmosis Syphilis Rubella CMV HSV Varicella Hepatitis B Hepatitis C TB Coxsackie Parvovirus B19 Differential of Conjugated Hyperbilirubinemia Toxins/drugs Chromosomal/syndromic abnormalities TPN Gram negative sepsis (UTI, NEC) Medications (TMP-SMX, anticonvulsants) Trisomy 17, 18, 21 Turner syndrome Polysplenic syndrome (heterotaxy) Systemic disease Post shock/asphyxia Congestive heart failure Hypoplastic left heart syndrome Metabolic disorders Disorders of carbohydrate metabolism (galactosemia) Disorders of lipid metabolism Gaucher disease Niemann-Pick, Wolman disease Disorders of amino acid metabolism (tyrosinemia) Alpha-1-antitrypsin deficiency CF Hypopituitary Differential of Conjugated Hyperbilirubinemia Long list of etiologies…. Most common Biliary atresia Idiopathic neonatal hepatitis Infectious/TORCH Alpha 1 antitrypsin deficiency Alagille syndrome Progressive familial intrahepatic cholestasis (PFIC) TPN A 2 week old infant is here for her well child visit. She was born FT, NSVD. MBT B+, BBT O+, coombs negative. She has been jaundiced since DOL 2, peak bilirubin at DOL 5 was 13 mg/dL. She is strictly breastfed. She has had normal urine output and is stooling normally. She is gaining 30 grams daily. On exam all is normal except jaundice. What do you do next? Fractionated bilirubin Hemoglobin is 13 g/dl, total bilirubin is 8.9 mg/dL with direct fraction of 6.1mg/dL What is the likely cause? Alagille Sydrome Biliary Atresia Physiologic Jaundice Breastmilk Jaundice ABO incompatibility Biliary Atresia Most common disorder causing neonatal cholestasis Congenital disorder resulting in common bile duct between the liver and the small intestine being blocked or absent Etiology unknown, ? of intrauterine viral infection Signs and symptoms are indistinguishable from physiologic jaundice to start and usually begin to develop at 1-6 weeks of age Usually thriving infant May present with acholic stools, hepatomegaly, splenomegaly Biliary Atresia Labs show an elevated direct bili and may show a mild transaminitis and elevated GGT An ultrasound should be done to look for an anatomic abnormality and to attempt to view the gall bladder A hepatobiliary scan that does not demonstrate excretion of tracer from the biliary tree into the small bowel is concerning for biliary atresia and prompts further work up Biliary Atresia Liver biopsy will demonstrate interlobular bile duct proliferation The gold standard for diagnosis is an intra-op cholangiogram If no definitive extrahepatic bilary ducts can be demonstrated on cholangiogram, a Kasai procedure is proformed (hepatoportoenterostomy) Kasai Procedure Dissect and excise the fibrotic remnants of the extrahepatic bile ducts up to the hilum of the liver and its junction with the hepatic parenchyma. Jejunojejunostomy (Rouxen-y anastomosis) is constructed and the free limb is brought up to and sutured to the exposed small biliary branches present at the resection line in the hilum Biliary Atresia If the infant has a Kasai procedure before 2 months of age, bile flow may be established in up to 90% of patients Delayed diagnosis and Kasai procedure worsens prognosis 57-80% of post Kasai patients will progress to liver transplant A 2 week old infant is here for her well child visit. She was born FT, NSVD. MBT B+, BBT O+, coombs negative. PNL negative. She has been jaundiced since DOL 2, peak bilirubin at DOL 5 was 13 mg/dL. She is strictly breastfed. She has had normal urine output and is stooling normally. She is gaining 30 grams daily. On exam all is normal except jaundice. Hemoglobin is 13 g/dl, total bilirubin is 8.9 mg/dL with direct fraction of 6.1mg/dL. What would you do next? Direct and indirect Coombs test Liver Biopsy Abdominal ultrasound Referral to surgeon for exploratory laparotomy and intraoperative cholangiography Serology for TORCH infections Alagille Syndrome Autosomal dominant disorder Paucity of the interlobular bile ducts Jaundice, Extrahepatic biliary hypoplasia, Pulmonary outflow tract abnormalities (PPS most common), Butterfly vertebrae, Bone abnormalities, Developmental delay Characteristic facies (prominent forehead, small pointed chin, hypertelorism) Alagille Syndrome Associated with a Jag-1 mutation It is important to distinguish Alagille syndrome from biliary atresia to prevent an unnecessary surgery Treatment is symptomatic usually with urosodiol to prevent pruritis and with fat soluble Vitamin supplements Some patients progress to cirrhosis and liver failure and may require transplant Alpha-1-antitrypsin deficiency Most common inherited metabolic cause of neonatal cholestasis Protease inhibitor (Pi) ZZ results in jaundice 75% of patients with Alpha-1-antitrypsin deficiency will have their jaundice resolve by 7 months of age Mild transaminitis usually persists Periodic acid schiff positive diastase resistant inclusions accumulate within hepatocytes and cause of liver injury Alpha-1-antitrypsin deficiency Alpha-1-antitrypsen deficiency is associated with chronic obstructive pulmonary disease, specifically emphysema Clinical manifestations of lung disease are generally not seen in pediatric patients Counseling regarding no exposure to tobacco is necessary There is no specific treatment for alpha-1-antitrypsin deficiency A 9 month old presents with FTT since 1 month of age. Mother states he is becoming increasingly jaundiced since his 6month visit. His birthweight was 3.1 kg and is now 6.2kg. On exam you note he has dysmorphic facies, broad forehead and wide spaced eyes. He has scleral icterus. You note a soft systolic murmur on exam. His liver edge is firm and palpated 2cm below right costal margin. Serum bili is 6.8mg/dL with a direct fraction of 5.1 mg/dL. Which of the following is most likely? Alpha 1 antitrypsin deficiency Alagille Syndrome Choledocal Cyst Biliary Atresia Idiopathic Neonatal Hepatitis Galactosemia Galactose is presented to the liver and the rest of the body in several ways A majority of ingested galactose is found as a component of lactose in milk (lactose is broken down by lactose into glucose and galactose) Galactose is absorbed into the bloodstream and proceeds to the liver Galactosemia We’ll skip the complicated major and minor catabolic pathways for galactose in the liver…but defects lead to problems with glycogen synthesis The “classic” clinical presentation is an infant with jaundice, hepatic dysfunction, hepatomegaly, unconjugated hyperbili, FTT and E coli sepsis. Cataracts may be present at birth or develop early Positive urine reducing substances with the above symptoms is concerning for galactosemia Galactosemia Symptoms of galactosemia may not develop until the patient is exposed to galactose (baby initially on soy and then gets lactose containing formula or milk at 1 year of age) Galactosemia is part of the newborn screen and usually diagnosed at birth Untreated galactosemia is a potential life threatening disorder Treatment is a lactose and galactose free diet Summary Neonatal jaundice is common Jaundice, lasting longer than 2 weeks make sure you confirm unconjugaed bilirubin!!!! Elevated direct bili > 1 mg/dl if TSB <5mg/dl or direct bili >20% of the TSB NEVER physiologic and implies a pathologic state Thoughtful evaluation and work up will avoid unnecessary tests and procedures References American Academy of Pediatrics Subcommitee on Hyperbilrubinemia. Management of hyperbilirubinemia in the newborn infant 35 weeks or more weeks of gestation. Pediatrics. 2004; 114: 297-316 Lauer BJ, Spector ND. Hyperbilirubinemia in the Newborn. Pediatrics in Review. 2011; Vol 32: 31-349 Maisels, MJ. Neonatal Jaundice. Pediatrics in Review. 2006; Vol 27: 443452 Suchy, F. Neonatal Cholestasis. Pediatrics in Review. 2004; Vol 25: 388-396
