Case Presentation: One month-old with conjugated hyperbilirubinemia

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Case PresentationOne month-old with conjugated
hyperbilirubinemia
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Case Presentation

• Male infant first noted to have hypoglycemia
  (D-stick in 40s) at 2 hours of life
• Developed a conjugated hyperbilirubinemia
• Feeding and growing well
• Pigmented stools
• No fevers

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Past History

• Born at 38 weeks via C-section
• IUGR (birth weight 2130 g)
• Mom G2P2. Labs B pos, RPR neg, Hep B neg, HIV
  neg, Rubella immune, GC/CT neg

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Physical exam

• Weight 3.0 kg (25th ile)
• Generally well-appearing
• Non-dysmorphic
• No murmur
• Liver, spleen not enlarged
• Normal genitalia

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Laboratory Studies, part 1

• Normal electrolytes, CBC
• Total bili 6.8, direct 5.3
• ALT 164, AST 335
• Alk phos 750, GGT 282
• PT 12, PTT 43
• Normal T4, TSH, GH, insulin, cortisol

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Differential Diagnosis
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The evaluation of cholestasis in the infant

• The most interesting differential in medicine.
  Period.

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One way to think about it
I. Extrahepatic disorders A. Biliary
atresia B. Bile duct stricture (?neonatal
sclerosing cholangitis) C. Choledochal cyst
D. Anomalies of choledochopancreaticoductal
junction E. Spontaneous perforation of the
bile duct F. Mass (neoplasia, stone) II.
Intrahepatic disorders A. Idiopathic 1.
Idiopathic neonatal hepatitis 2.
Intrahepatic cholestasis, persistent a.
Arteriohepatic dysplasia (Alagilles syndrome)
b. Nonsyndromic paucity of intrahepatic
ducts c. Severe intrahepatic
cholestasis with progressive
hepatocellular disease (see Table 527) 3.
Intrahepatic cholestasis, recurrent a.
Benign recurrent intrahepatic cholestasis
b. Hereditary cholestasis with lymphedema
(Aagenaes) B. Anatomic 1. Congenital
hepatic fibrosis or infantile polycystic disease
(of liver and kidney) 2. Carolis
disease (cystic dilation of intrahepatic ducts)
C. Metabolic or endocrine disorders 1.
Disorders of amino acid metabolism a.
Tyrosinemia 2. Disorders of lipid
metabolism a. Wolmans
disease/cholesterol ester storage disease
b. Niemann-Pick disease c. Gauchers
disease 3. Disorders of carbohydrate
metabolism a. Galactosemia b.
Fructosemia c. Glycogen storage
disease, Type IV 4. Disorders of bile acid
metabolismprimary a. 3 -hydroxysteroid
.5 -C27 steroid dehydrogenase/isomerase
b. .5 -3-oxosteroid 5 -reductase 5.
Disorders of bile acid metabolismsecondary
a. Zellwegers syndrome (cerebrohepatorenal
syndrome) b. Specific peroxisomal
enzymopathies
6. Mitochondrial hepatopathies 7. Metabolic
disease in which the defect is uncharacterized
a. a 1-antitrypsin deficiency b. Cystic
fibrosis c. Idiopathic hypopituitarism
d. Hypothyroidism e. Neonatal iron storage
disease (perinatal hemochromatosis) f.
Infantile copper overload g. Familial
erythrophagocytic lymphohistiocytosis (FELS)
h. Arginase deficiency 8. Toxic a.
Cholestasis associated with parenteral
nutrition D. Cholestasis associated with
infection 1. Sepsis with possible endotoxemia
(urinary tract infection, gastroenteritis)
2. Syphilis 3. Toxoplasmosis 4. Listeriosis
5. Congenital viral infection a.
Cytomegalovirus (CMV) b. Herpes virus (HSV
and HHV-6) c. Coxsackie virus d. ECHO
virus e. Rubella virus f. Hepatitis B
virus (Hepatitis C virus and other non-A,
non-B viruses?) g. Human immunodeficiency
virus (HIV) h. Parvovirus B19 E. Genetic or
chromosomal 1. Trisomy E 2. Down syndrome
3. Donahues syndrome (leprechaunism) F.
Miscellaneous 1. Langerhans cell
histiocytosis 2. Shock or hypoperfusion 3.
Intestinal obstruction 4. Neonatal lupus From
Walker et al., Pediatric Gastrointestinal
Disease, 3rd ed.
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1. The big bad six

• Extrahepatic biliary atresia
• Galactosemia
• Tyrosinemia
• Sepsis
• Urosepsis
• Hypothyroidism

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2. Easy fix/freebies

• Choledochal cyst
• Biliary sludge
• Cholelithiasis
• Extrinsic masses

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3. Cant fix now, but maybe someday

• Alpha-1 antitrypsin deficiency
• Cystic fibrosis
• Alagille syndrome
• Progressive familial intrahepatic cholestasis
  syndromes
• Congenital hepatic fibrosis/infantile polycystic
  kidney disease

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4. Can treat, but wont go away

• TORCH infections
• Hepatitis B, C
• HIV
• Tuberculosis
• Bile acid synthetic disorders
• Urea cycle disorders
• Hereditary fructose intolerance

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5. Uh-oh

• Niemann-Pick disease
• Zellweger syndrome
• Neonatal iron storage disorder
• Autosomal trisomies
• Gauchers disease
• Leprechaunism

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6. Hey, no problem (maybe)

• Many viruses
• TPN cholestasis
• Idiopathic neonatal cholestasis

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What would you do?
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First step of the workup

• Liver function tests, including fractionated
  bilirubin, aminotransferases, GGT, albumin,
  PT/PTT, glucose, (ammonia)
• Urine and blood cultures
• Urine reducing substance
• Urine succinylacetone
• Ultrasound
• Thyroid function tests
• DISIDA

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Case Laboratory studies

• Normal neogen screen
• Alpha-1 antitrypsin MM
• Urine succinylacetone negative
• Urine CMV and serum IgM negative

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Diagnostic studies

• Abdominal U/S negative
• Head U/S negative
• Ophthalmologic exam normal
• DISIDA showed no excretion at 24 hours

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And then?

• The patient was referred to CHOP for second
  opinion and possible liver biopsy
• A diagnostic test was obtained.

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UTI

• Urine culture grew gt100,000 cfu Citrobacter
• Repeat DISIDA on antibiotics was normal
• Most recent bili, 1 month after discharge, is 1.6

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Second phase of the workup

• Check newborn screen
• Alpha-1 antitrypsin PI typing
• Screen for Alagille syndrome, with x-ray to look
  for butterfly vertebrae, eye exam for posterior
  embryotoxon, etc.
• Sweat test

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Whats on the newborn screen?

• Hypothyroidism
• PKU
• Sickle cell disease
• MSUD
• Galactosemia
• Cystic Fibrosis
• Congenital adrenal hyperplasia

• Acylcarnitine profile
• Amino acid profile
• Biotinidase deficiency
• G6PD deficiency

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Third phase of the workup

• TORCH serologies
• HIV test
• Other serologies

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Fourth phase of the workup

• Liver biopsy, EM
• Bile and/or urine for bile acid analysis
• Genetic tests for specific disorders
• Intraoperative cholangiogram