155. Approach to Newborn with Suspected Liver Disease

Question 1

Key feature of Neonatal Cholestasis

What enzyme conjugates bilirubin?

Answer 1

Newborn liver dyxfx assoc with failure of biliary excretion and conjugated hyperbilirubinemia

Jaundice: frequent and EARLY sign in neonatal liver disease (late sign in adults)

UGT1A1 conjugates bilirubin to water soluble form

Question 2

What are 3 complications of cholestasis?

Answer 2

1. Vitamin Deficiency: no bile salt excretion = no fat soluble vitamin absorption
   ADEK = night blindness, bone disease, neuropathy/rash, coagulopathy
2. Portal HTN: ascites (shunting blood from portal system), varices (shunted blood to esophageal anastamoses)
3. Neonatal Jaundice
   - most infants have high serum bilirubin in first week of life, jaundice progresses head to toe
   Cause: high bili production: more hemolysis (maternal blood group incompatibilities, extravascular blood, polycythemia, RBC abnormalities, labor induction);
   less bili excretion (high enterohepatic bili circulation, breast feeding, inborn errors of metabolism, hormones/drugs, prematurity, hepatic hypoperfusion, cholestatic syndromes, biliary tree obstruction
   Combined high production, low excretion: sepsis, intrauterine infection, congenital cirrhosis
   - abnormal if: develops before 36hours age or persists after 10 days, serum bili >12mg/dl, elevation of conj (direct) bilirubin to >2mg/dL at any time

Question 3

Gilbert’s Syndrome

• what is it
• sx
• clinical course

Answer 3

2-10% entire population have it
Alteration in Promoter region for bili UDP-GT gene (TATA Box)
causes mild indirect hyperbilirubinemia (less conjugation)
benign clinical course

Question 4

Crigler-Najjar Syndrome

- Type I vs Type 2

Answer 4

Type 1: SEVERE form - COMPLETE ABSENCE of UDP-GT
very high bilirubinemia
tx: continuous phototherapy, frequent exchange transfusions
Kernicterus (brain damage from bili) may occur at any time

Type 2: less severe, PARTIAL ACTIVITY of UDP-GT
hyperbilirubinemia observed, responsive to CYP inducers (Ex: phenobarbital)

Question 5

Dubin Johnson Syndrome

- what is it

Answer 5

Genetic Deficiency in cMOAT/MRP2 gene - canalicular transporter of conjugated bili

causes: mild conjugated hyperbilirubinemia w/ no evidence of hepatocellular/canalicular injury
dx: gene test or preponderance of isoform I in urinary coprophyrin analysis

Question 6

Idiopathic Neonatal Hepatitis

• histo
• RF
• sx
• dx
• prognosis

Answer 6

Histo: multinucleated giant cells
RF: premature and infants small for gestational age
sx: jaundice/hepatosplenomegaly in first week of age
dx: exclusion of other causes of biopsy
prog: 70-80% recover in 6-8mo, 20% develop chronic liver disease and portal HTN

Question 7

Gestational Alloimmune Liver Disease

• what is it
• histo
• cause
• sx
• tx

Answer 7

Neonatal hemochromatosis - severe liver disease assoc with extrahepatic siderosis (Fe deposition) in similar pattern of hereditary hemochromotosis (most dx at autopsy - poor survival)
Histo: extrahepatic Fe deposits (look blue) and liver necrosis
Cause: maternal antibody cross placenta and attack neonatal liver
sx: jaundice, hepatic synthetic dyfx, normal liver enzymes (b/c liver already destroyed)
tx: IVIG to mother before birth to eliminate bad antibody

Question 8

Alpha 1 Antitrypsin Deficiency

• what is it
• sx
• assoc
• histo

Answer 8

A1AT: protease inhibitor
Homozygous: PiZZ
Heterozygous: PiSZ, PiMZ - less severe disease
sx: neonatal cholestasis, juvenile cirrhosis, chronic hepatitis, HCC
Assoc with emphysema in young adulthood

Histo: round inclusion bodies/granules of A1AT in liver - resistant inclusions causing injury

Question 9

Progressive Familial Intrahepatic Cholestasis (PFIC)
PFIC-1 vs. PFIC-2 vs. PFIC-3
tx

Answer 9

All transporters that move bile salts from hepatocyte to bile canaliculi
All severe cholestasis causing

PFIC-1: Byler’s disease - deficiency of FIC-1
normal GGT
Characteristic granular bile on electron microscopy

PFIC-2: BSEP disease - deficiency of BSEP
normal GGT
assoc with increased risk of HCC

PFIC-3: deficiency of hepatocyte membrane transporter MDR3
ELEVATED GGT

Tx: partial external biliary diversion: interpose jejunum from gallbladder out of skin to drain bile - interrupt bile circulation to remove bile acids and prevent systemic spillover

Question 10

Galactosemia

• what is it
• sx
• tx

Tyrosinemia

• what is it
• sx
• dx
• risk
• tx

Answer 10

Defect in galactose-1-p uridyl transferase = accumulation in gal-1-p and galactitol

sx: lethargy, vomiting, acidosis, cataracts, FTT, jaundice, UTI, Gram Neg Sepsis, Hemolytic anemia
tx: dietary avoidance

Tyr: deficiency of fumaryacetoacetate hydrolase (last enzyme in Tyr pathway) AR disorder
sx: acute liver dyxfx, jaundice, hepatomegaly, FTT, anorexia, ascites, coagulopathy, Rickett’s, hemolytic anemia, renal tubule dysfx
Dx: elevated urinary succinyl acetone (alt tyr pathway), high serum tyrosine and methionine
Risk of HCC!
Tx: NTBC - shunts tyrosine down different path preventing toxic metabolite buildup; dietary avoidance

Question 11

Alagille’s Syndrome

• what is it
• sx
• imaging
• histo

Answer 11

Reduced small interlobular bile ducts and other organ problems
gene defect: Jagged1 gene on Ch20 - disrupts NOTCH signaling path
sx: neonatal jaundice, conjugated hyperbilirubinemia, xanthomas, vascular anomalies (cause higher mortality), cirrhosis/liver failure risk, characteristic facies (wide nasal bridge, shaped eyes)
imaging: butterfly vertebrae
Histo: paucity of bile ducts - cannot see them in portal triad

Question 12

CF

- histo

Answer 12

mucin plugs in bile ducts - blockages in large cholangiocytes and large bile ducts

Question 13

Choledochal cyst

• epidemiology
• imaging
• sx
• dx
• risk

Answer 13

Epi: F>M, more prevalent in Asians
Imaging: outpouching cyst in bile duct
CP: 38% in 1st year, 34% ages 1-6, 28% 6yrs+
Sx: triad of abd pain, jaundice, palpable RUQ mass
sx: fever, N/V, pancreatitis
Dx: Ultrasound best
Risk: Cholangiocarcinoma!! (why you need to remove cyst)

Question 14

Biliary Atresia

• what is it
• sx
• types
• histo
• tx
• complication

Answer 14

extrahepatic obstruction of bile ducts = cholestasis, cirrhosis, liver failure
most common cause of liver tx
Progressive fibrosis of large bile ducts
sx: neonatal jaundice, pale stools
types: 1. Embryonic Origin: splenic malformation; 2. Perinatal: perinatal viral infection directs inflammation against bile ducts

Histo: bile duct plugs and increased small bile duct proliferation to try to increase flow

tx: kasai hepatic portoenterostomy to restore bile flow within first 2-3 months of life
dx before 60 days = kasai
dx after 120 days = early liver tx
total bilirubin > 2 at 3 mo old is strong predictor of transplant
complication: portal htn, liver tx (PELD Score, 50% transplanted by age of 2)