1、What is the Differential Diagnosis of Neonatal What is the Differential Diagnosis of Neonatal Unconjugated Hyperbilirubinemia?Unconjugated Hyperbilirubinemia? Patient Presentation Patient Presentation A 3A 3- -dayday- -old female came to clinic withold female came to clinic with jaundice. She was a
2、39 week infant born by spontaneous vaginal delivery without complications who was discharged on day 2 of life with a transcutaneous bilirubin of 10.0 mg/dL. She had been breastfeeding well, with several stools and many voids. The past medical historypast medical history shows she was born to a G2 P2
3、 caucasian mother with blood type B+ with normal screening maternal laboratories and no problems during pregnancy or delivery. Birth weight was 3080 grams. The family historyfamily history was negative for hematological, gastrointestinal or genetic problems. The review of systems review of systems w
4、as negative. The pertinent physical exam pertinent physical exam showed her vital signs to be normal with a current weight of 2990 grams (10-25%). She was alert and active with no distress. She was jaundiced from her head to her upper thighs. She had scleral icterus. Her abdominal examination was no
5、rmal with no hepatosplenomegaly. The lalaboratory evaluation boratory evaluation showed a total bilirubin of 17.3 mg/dL and a direct bilirubin of 0.3 mg/dL. The diagnosis ofdiagnosis of of neonatal unconjugated hyperbilirubinemia was made and she was admitted for phototherapy. The patients clinical
6、coursepatients clinical course showed her to improve after 24 hours of phototherapy and continuation of breastfeeding. She had many voids and stools during that time also. Her bilirubin decreased to 14.6 mg/dL with the phototherapy. Six hours after discontinuing the phototherapy, it had decreased to
7、 13.4 mg/dL. She was discharged to home with routine followup. DiscussionDiscussion Bilirubin is a metabolite of heme degradation. Heme is oxidized to biliverdin which is then reduced to bilirubin. Bilirubin is then taken up into the liver and conjugated; conjugated bilirubin is then excreted throug
8、h the gastrointestinal tract. Bilirubin can also be converted by a blue light at wavelength 450 nm into a water-soluble compound called lumirubin which is then excreted through the kidneys. HyperbilirubinemiaHyperbilirubinemia occurs because of an increase in hemoglobin metabolites, decreased hepati
9、c uptake, decreased hepatic conjugation and/or decreased excretion. Unconjugated hyperbilirubinemia in the newborn is a normal occurance. After birth the infant must rely on its own relatively immature liver to detoxify metabolites, the infants gastrointestinal tract also is not yet working as well
10、for excretion, the infant is usually slightly fluid deficient before breastfeeding and/or bottle feeding are well established, and there is increased breakdown of red blood cells as the fetus has a higher hemoglobin than an infant and thus an infant is relatively hemoconcentrated. If the infant is a
11、lso further stressed because of intrapartum or post-partum complications such as hypoxia, infection, shock or other problems, the hyperbilirubinemia can be exacerbated. The total bilirubin rises from 1.5 mg/dL to 6.5 mg/dL (+ or - 2.5 mg/dL) over the first 3-4 days of life. Premature infants because
12、 of the relative immaturity of the liver usually have a higher maximum bilirubin that is 30-50% more than full-term infants. Visible jaundice (the yellowish staining of the skin and mucous membranes) on day 1 of life or a rate of total bilirubin rising 5.0 mg/dL/24 hours is not normal and requires e
13、valuation. Evaluation for a possible pathological process usually includes: total bilirubin and indirect bilirubin (looking for total amounts and elevated unconjugated hyperbilirubinemia), complete blood count with blood smear (to look for evidence of hemolysis), reticulocyte count (to look for evid
14、ence of physiological response), direct Coombs test (to look for antibodies), and blood and Rh type (to compare for blood group incompatabilities). Other tests depending on the clinical situation may include an APT test, sepsis evaluation, Glucose-6-phosphate deficiency screening, hemoglobin electro
15、phoresis, prothrombin time, partial thromboplastin time, and thyroid function testing. Treatment for hyperbilirubinemia may be necessary to prevent kernicterus or the staining of the basal ganglia, hippocampus and subthalamic nucleus of the brain. This in turn causes damage to the central nervous sy
16、stems with signs of hyper- and hypo-tonia, seizures, abnormal deep tendon reflexes and other reflexes, developmental delay, cranial nerve deficits and movement abnormalities. The level of bilirubin to begin treatment depends on gestation age, chronological age in hours/days, total bilirubin level an
17、d other risk factors such as acidosis, asphyxia, hypoalbuminemia (3.0 g/dL), Glucose-6-phosphate deficiency, isoimmune hemolytic disease, lethargy, sepsis, and temperature instability. Infants with lower weights are also at increased risk of hyperbilirubinemia requiring treatment. Phototherapy is us
18、ed most frequently for treatment. After phototherapy is begun, total bilirubin is checked within 4-6 hours looking for a 1-2 mg/dL decline (with total amount always remaining below the threshold for exchange transfusion). Sometimes exchange transfusions are necessary if phototherapy is failing or ev
19、en before a trial of phototherapy if the bilirubin is very high. Nomograms that assist in determining hyperbilirubinemia risk and possible treatment (phototherapy or exchange transfusion) are available from the American Academy of Pediatrics (see To Learn MoreTo Learn More below). Conjugated hyperbi
20、lirubinemia is defined as the direct bilirubin being 2.0 mg/dL or 10% of the total serum bilirubin. Learning PointLearning Point Causes of unconjugated hyperbilirubinemiaCauses of unconjugated hyperbilirubinemia include: Transient jaundice o Normal physiologic jaundice o Breast-feeding jaundice (usu
21、ally occurs in first week of life) o Breast-milk jaundice (usually occurs in weeks 2-3 of life) o Reabsorption of extravascular blood - severe caput or cephalohematoma o Polycythemia - twin-to-twin transfusion Gastrointestinal problems o Increased enterohepatic circulation secondary to intestinal ob
22、struction Cystic fibrosis Hirschsprung disease Ileal atresia Pyloric stenosis Other causes of intestinal obstruction o Bilirubin metabolism problems Crigler-Najjar syndrome Gilbert syndrome Hypothyroidism Hypoxia Lucey-Driscoll syndrome Hematological problems o ABO incompability o Rh incompatability
23、 o Clotting disorders o Autoimmune disease o Hemoglobinopathies o Microangiopathies o Red cell enzyme defects - Glucose-6-phosphate deficiency, pyruvate kinase deficiency o Red cell membrane defects - spherocytosis, elliptocytosis Miscellaneous o Acidosis o Dehydration o Hypoalbuminemia o Infant of
24、a diabetic mother o Medication o Sepsis o Swallowed maternal blood Questions for Further DiscussionQuestions for Further Discussion 1. What are the advantages and disadvantages of using a transcutaneous bilimeter to measure bilirubin levels? 2. What is the differential diagnosis of conjugated hyperb
25、ilirubinemia? 3. When is supplemental breast milk, formula or intravenous fluids indicated as part of treatment for hyperbilirubinemia? Related CasesRelated Cases Disease Jaundice Symptom/Presentation Jaundice Specialty Gastroenterology General Pediatrics Neonatology Age Newborn To Learn MoreTo Lear
26、n More To view pediatric review articles on this topic from the past year check PubMed. Information prescriptions for patients can be found at MedlinePlus for this topic: Jaundice and at Pediatric Common Questions, Quick Answers for this topic: Jaundice. To view current news articles on this topic c
27、heck Google News. To view images related to this topic check Google Images. Bakerman P, Strausbauch P. Bakermans ABCs of Interpretive Laboratory Data. 4th edit. Interpretive Laboratory Data, Scottsdale, AZ. 2002. pp 92-94. Rudolph CD, et.al. Rudolphs Pediatrics. 21st edit. McGraw-Hill, New York, NY.
28、 2003:164-169. American Academy of Pediatrics Clinical Practice Guideline. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics 2004:114;297-316. Available from the Internet at: http:/aappolicy.aappublications.org/cgi/content/full/pediatrics;114/1/297 (rev
29、. July 2004, cited 2/25/08). Robertson J, Shilkofski N. The Harriet Lane Handbook. 17th. Edit. Mosby Publications: St. Louis. 2005:314-317, 467-470. ACGME Competencies Highlighted by CaseACGME Competencies Highlighted by Case Patient Care 1. When interacting with patients and their families, the hea
30、lth care professional communicates effectively and demonstrates caring and respectful behaviors. 2. Essential and accurate information about the patients is gathered. 3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scienti
31、fic evidence, and clinical judgment is made. 4. Patient management plans are developed and carried out. 7. All medical and invasive procedures considered essential for the area of practice are competently performed. 8. Health care services aimed at preventing health problems or maintaining health ar
32、e provided. Medical Knowledge 10. An investigatory and analytic thinking approach to the clinical situation is demonstrated. 11. Basic and clinically supportive sciences appropriate to their discipline are known and applied. Practice Based Learning and Improvement 13. Information about other populat
33、ions of patients, especially the larger population from which this patient is drawn, is obtained and used. nsitivity and responsiveness to patients culture, age, gender, and disabilities are demonstrated. Systems Based Practice 24. Cost-effective health care and resource allocation that does not com
34、promise quality of care is practiced. Patient Presentation Patient Presentation A 4A 4- -dayday- -old male was transferred to a regional childrens hospital old male was transferred to a regional childrens hospital for direct hyperbilirubinemia. The infant was full term, was discharged at 2 days of l
35、ife, and returned that morning to his private medical doctors office for routine followup. Mother reports that he had been breastfeeding sluggishly, was urinating well and had stools that were yellow-colored. The past medical historypast medical history showed a normal pregnancy and delivery. The fa
36、mily historyfamily history was negative for congenital, metabolic, or gastrointestinal abnormalities. The review of systems review of systems was negative. The pertinent physical exam pertinent physical exam showed a jaundiced infant with a slightly protuberant abdomen. The vital signs and growth pa
37、rameters were normal. He was jaundiced over the entire body including the eyes and he had no prominent cutaneous abdominal vasculature. His liver was palpable 2-3 cm below the right costal margin and there was no splenomegaly or obvious masses. The laboratory evaluation laboratory evaluation showed
38、a total bilirubin of 17.1 mg/dL with a direct bilirubin of 7.1 mg/dL. The gamma-glutamyltransferase was elevated at 580 U/L (normal up to 94 U/L). Alanine aminotransferase was 46 (normal up to 35 U/L) and the aspartate aminotransferase was 87 (normal up to 35 U/L). Coagulation studies were normal. H
39、e had a normal complete blood count, electrolytes, and neonatal screen. Later blood and urine cultures were negative including for cytomegalovirus and toxoplasmosis. Other testing was negative including a sweat test for cystic fibrosis, syphilis, hepatitis A and B and alpha-1-anti-trypsin levels. Th
40、e radiologic evaluation radiologic evaluation of an ultrasound of the right upper quadrant showed a small gallbladder and a normal intra and extrahepatic biliary tree, and hepatobiliary scan revealed no excretion of radiotracer into the biliary tree or bowel. He had a liver biopsy that showed modera
41、te to severe fibrosis with proliferation of the bile ducts that was compatible with the diagnosis diagnosis ofof of biliary atresia. The patients clinical coursepatients clinical course showed that he underwent a Kasai procedure (i.e. hepatoportal enterostomy) at 10 days of life. He had some hepatom
42、egaly until 18 months of age which then resolved. At 3 years of life he is doing well without hepatomegaly, jaundice or abnormal growth. “02-09-09Figure70BiliaryAtresiaUS.jpg” Figure 70 - Transverse ultrasound image of the liver at the level of the main portal vein shows the liver and intrahepatic a
43、nd extrahepatic biliary tree to be unremarkable. The gall bladder (not shown) was small and collapsed, although the patient had been fasting for 12 hours before the exam. “02-09-09Figure71BiliaryAtresiaHIDA.jpg” Figure 71 - Serial images from a hepatobiliary scan obtained up to 5 minutes after the i
44、njection of radiotracer show prompt uptake of radiotracer by the liver but no excretion of radiotracer into the biliary tree, gall bladder, or bowel. “02-09-09Figure72BiliaryAtresiaHIDA24Hours.jpg” Figure 72 - Delayed image from a hepatobiliary scan obtained at 24 hours after injection of radiotrace
45、r again fails to show excretion of radiotracer into the biliary tree, gall bladder, or bowel. A diagnosis of biliary atresia was therefore made. DiscussionDiscussion Biliary atresiaBiliary atresia occurs in 1 in 5000 - 12,000 live births worldwide. Its cause is unknown. Biliary atresia was universal
46、ly fatal until the Kasai procedure was introduced. Liver transplantation can be used if the Kasai fails. Patients that have surgery early ( 2.0 mg/dL and is 10% of the total bilirubin. Age at presentation, appearing well or ill, and other associated signs such as hepatomegaly or elevated gamma-gluta
47、myltransferase can assist in the prioritization of the differential diagnosis. The differential diagnosis of direct hyperbilirubinemia includes: Structural abnormalities o Alagille syndrome o Biliary atresia o Choledochal cyst o Gallstones Genetic/Metabolic abnormalities o Alpha-1-anti-trypsin defic
48、iency o Cystic fibrosis o Fructose intolerance o Galactosemia o Glycogen storage disease o Gauchers disease o Niemann Pick o Neonatal hemochromatosis o Porphyria o Tyrosinemia o Wolman disease Infectious diseases o Intrauterine infection o Urinary tract infection o Sepsis o Adenovirus o Coxsackie vi
49、rus o Cytomegalovirus o Hepatitis B o Herpes o Listeriosis o Rubella o Syphilis o Toxoplasmosis Other o Autoimmune hepatitis o Bile plug syndrome o Dubin-Johnson syndrome o Rotor syndrome o Hypopituitarism o Hypothyroidism o Idiopathic neonatal/giant cell hepatitis o Total parenteral nutrition To review the differential diagnosis of indirect or unconjugated hyperbilirubinemia see What is the Differential Diagnosis of Neonatal Unconjugated H
