Pediatric Diseases of Liver and Pancreas

Question 1

Crigler Najjar Type 1

Answer 1

• Absent/ extremely low UDGTP for conjugating bilirubin –> accumulate unconjugated bilirubin
• Presentation - neonatal jaundice that does not improve and kernicterus (irreversible brain damage; variable acute and chronic, posturing, hypotonia, sz, fevers, hearing loss, spasticity, cog dysfunction)
• Dx
  
  • Labs - persistent elevated unconjugated bilirubin w/ no detectable conjugated bilirubin; normal liver tests
  • May confirm w/ genotyping
  • No conjugated bilirubin in bile either
• Liver Histology - normal
• Tx
  
  • Phototherapy 10-16 hrs/ day; photoisomerize bilirubin –> lumirubin –> excreted in urine
  • Avoid drugs like Bactrim that displace bilirubin from albumin
  • Liver transplant and viral gene therapy to give normal enzyme?

Question 2

Tyrosinemia

Answer 2

• Inborn error in tyrosine breakdown/catabolism due to def FAH –> accummulation of intermediate metabolites
  
  • Malelyllacetoacetate / fumarylacetoacetate
  • Succinylacetone - effects porphyrin metabolism –> porphyria-like disease
• Present w/ liver failure or later porphyria (paresthesias, autonomic dysfunction, paralysis)
• Labs - elevated metabolites (esp succinylacetone) + often high alpha fetoprotein + prolonged prothrombin time (shows dysfunction)
• Histology
  
  • Micro-nodular cirrhosis
  • Nonspecific “neonatal hepatitis”
  • Dysplasia and/or HCC
  • Reversion to normal due to mutagenesis and survival adv of hepatocytes w/ normal enzymes
• Dx - plasma AA (suggestive) or urine succinylacetone (diagnostic); can meas enzyme in skin fibroblasts; genotyping
  
  • In PA newborn screen
• Tx
  
  • NTBC - blocks path proximal to accumulation of toxic metabolite
  • Monitor for HCC (ultrasound and alpha fetoprotein) even w/ NTBC tx
  • Avoid high protein diet b/c then tyrosine accumulation esp in cornea
  • Liver transplant is successful

Question 3

Alpha 1 Antitrypsin Def

Answer 3

-If abnormal A1AT then accumulates in liver (variable expression of disease based on if second mutation in processing of abnormal protein is present)

• Presentation
  
  • Neonatal cholestasis
  • Chronic hepatitis
  • Cirrhosis
• Labs
  
  • Neonates w/ inc AST/ALT and inc conjugated bilirubin
  • May have dec WBCs and platelets from cirrhosis (cannot make) or hypersplenism (trapped in spleen)
• Histology
  
  • Non-specific neonatal hepatitis
  • PAS pos globules in hepatocytes
  • EM shows accumulation of polymerized protein in ER
• Dx - low serum A1AT + serum electrophoresis to show ZZ phenotype + genotyping
• Tx
  
  • Avoid smoking (for emphysema)
  • No specific lung tx
  • Screen for HCC (ultrasound and fetal alphaprotein)
  • Liver transplant is successful

Question 4

Maple Syrup Urine Disease

Answer 4

• Inborn error of BCAA; def in branch-chain alpha-ketoacid dehydrogenase complex (BCKD) –> accumulation of BCAA (Leucine, isoleucine and valine)
• Presentation
  
  • Neonatal irritability, poor feeding, apnea, movement disorders, coma, resp failure
  • Maple urine smell in ear wax and then urine
  • Neuro crisis secondary to illnesses that lead to protein catabolism; coma due to cerebral edema
  • If prolonged … ADHD, anxiety, panic disorder, depression, mental retardation
• Labs - elevated BCAAs (leucine, isoleucine, valine) + elevated allo-isoleucine + urinary excretion of BCAAs and ketones
• Histology - normal
• Dx
  
  • Plasma BCAAs or allo-isoleucine
  • Can meas enzymes in skin fibroblasts or lymphocytes
  • Genotyping
  • Can access severity by leucine tolerance test
• Tx
  
  • Low protein diet w/ essential AA supplementation as needed
  • Careful monitoring when concurrent disease that leads to protein catabolism
  • Liver transplant; domino effect (can donate their liver to someone w/ normal BCKD expression)

Question 5

Bile Acid Synthesis Defects

Answer 5

• Mult poss inborn errors
• Causes hepatocyte injury b/c accumulation of intermediates AND causes cholestasis b/c no bile salts made
• Presentation
  
  • Liver injury - manifests as jaundice (dec ability to conjugate) and eventually cirrhosis
  • No bile salts - dec fat absorption
    
    • Failure to thrive in infants b/c cannot absorb long chain fats
    • Vit A def - night blindness
    • Vit D def - rickets
    • Vit E def
    • Vit K def - coagulopathy
• Labs - chronic inc AST/ALT and bilirubin
• Histology - nonspecific neonatal hepatitis and
  hepatocyte findings of cholestasis w/o obstruction to flow
• Dx - mass spect of urine bile acid metabolites
• Tx
  
  • Primary bile acid replacement
  • Vit A, D, E, K replacement
  • Liver transplant if not systemic disease w/ neuro involvement

Question 6

3 Types of Biliary Atresia

Answer 6

• 1- Biliary atresia w/ lateral malformation (10%)
  
  • Mult problems including asplenia or polysplenia, intestinal malrotation, situs inversus, interruption of IVC, cardiac malformation
• 2- Biliary atresia w/ at least 1 malformation (5-10%)
  
  • Usually cardiac, GU or GI
• 3- Biliary atresia w/o major malformation (80%)
  
  • No other birth defects

Question 7

Biliary Atresia Dx

Answer 7

• Should make dx in first 30-60 days of life for best prognosis
• 1- If jaundice persists then fractionate bilirubin
• 2- If inc conjugated bilirubin then r/o other causes (PE, blood and urine tests for infection/UTI, review newborn screen)
• 3- US of gallbladder and liver, HIDA scan, liver biopsy, cholangiogram

Question 8

Biliary Atresia Tx and Prognosis

Answer 8

• SURGERY (hepatoportoenterostomy - HPE or Kasai) - attach small intestine directly to liver then Roux-en-Y connection of rest of intestine
• *Restoration of bile flow by HPE dep on age of diagnosis (younger <60 days better)
• Treat complications
  - Nutrition esp fat soluble vitamins
  - Treat ascites, hyperammonia, varices, etc
• Liver transplant indicated if… (80%)
  - Late dx (3-4 months old), failure to re-establish bile flow 3 mo after HPE, fibrosis/cirrhosis in older kids, portal HTN or end stage liver disease in older kids

Question 9

Alagille’s (genetics and manifestations)

Answer 9

• Hepatic - hepatomegaly, cholestasis (jaundice, pruritus, xanthomas), splenomegaly, portal HTN, cirrhosis, synthetic disease
• Vascular - aneurysm, AVM, intracranial
• Cardiac - murmur, pulmonary artery stenosis, often cardiac congenital anomalies
• Skeletal - butterfly vertebrae, clubbing, spina bifida, shortened phalanges, rickets, no 12th rib, etc
• Occular - posterior embryotoxon (see Schwalbe’s line), keratopathy, glaucoma, strabismus, etc
• Facial - prominent forehead, deep eyes, flat profile, straight nose, prominent ears, pointed chin

Genetics = JAG1 auto dominant mutation (notch ligand) in 94% of cases

Question 10

Alagille’s Dx

Answer 10

• HISTO (bile duct paucity - inc portal tract:bile duct) AND 3/5
  
  • Cholestasis
  • Cardiac defect (often pulm artery stenosis)
  • Skeletal abnormality (often butterfly vert on CXR)
  • Opth abnormality (often posterior embryotoxon)
  • Characteristic facial feature

Question 11

Alagille’s Complications, Tx, Prognosis,

Answer 11

TX

- UDCA to dec bile acid
- Ursodiol, rifampin, bile acid sequesterants for pruritus
- Liver transplant if progressive liver disease

• Prognosis - dep on extra-hepatic problems (60% at 30 yrs)
• Complications
  • Nutrition/ fat soluble vit def –> growth fail, fractures
  • Portal HTN and end stage liver disease
  • Pruritus and cholangitis

Question 12

Shwachan Diamond Syndrome

Answer 12

• 2nd most common inherited cause of exocrine insufficiency behind CF
• Acinar cell hypoplasia but ducts intact
• Genetics - SBDS gene
• Presentation
  
  • Pancreatic exocrine insufficiency - fat replacement
  • Short stature
  • Heme - neutropenia, thrombocytopenia, anemia
  • Recurrent infections
  • Skeletal - short/flared ribs, clinodactyly, delayed bone age, metaphyseal chondrodysplasia
  • Periportal fibrosis and elevated AST/ALT
  • Psychomotor retardation
  • Dental abnormalities
  • Dry, scaly, thick skin

Question 13

Johnson Blizzard Syndrome

Answer 13

• Pancreatic acini replaced by connective tissue –> pancreatic insufficiency BUT islets and ducts normal
• Presentation
  • Deafness, dental anomalies, nasal hypoplasia (“beak-shaped”)

Question 14

How does acute pancreatitis present in kids?

Answer 14

• Mainly notice ab pain and vomiting; fever, IRRITABILITY and ab distention in babies
• Causes in kids - systemic illness, trauma, congenital anomalies, gallstones, drugs, hereditary pancreatitis, idiopathic
• Systemic illnesses associated w/ acute pancreatitis …
  - Sepsis
  - HUS
  - Collagen vascular disease (SLE, PAN, Kawasaki)
  - Diabetic ketoacidosis
  - Organ transplant
  - Sickle cell
  - Chrons
  - Anorexia

Question 15

How does chronic pancreatitis present in kids?

Answer 15

• Most often due to genetics and obstruction in kids (v. environmental causes in adults)
• CF, Shwachman-Diamond Syndrome, Johanson-Blizzard Syndrome, Jeune syndrome, Pearson’s syndrome
  - Most are genetic (73%)- PRSS1, SPINK1, CFTR, CTRC
  - Obstruction/structural (33%)
• First attack around 7 yo then dx of chronic pancreatitis at 10 yo
• Suspicious if … acute recurrent pancreatitis events, steatorrhea, pain
• Imaging - pancreatic duct dilation, pancreatic atrophy or pancreatic calcifications