Neonatal Cholestasis

Definition

Increased Direct Bilirubin >2mg/dL or >20% of the total bilirubin level
Cholestasis is an impairment of bile formation or flow, intrahepatic or extrahepatic in origin, that causes retention of bile acids, bilirubin, and lipids in the liver and bloodstream with clinical consequences including jaundice, pruritus, malabsorption of fat soluble vitamins, and progressive hepatic injury if not corrected.

Etiology

Anatomical, Infectious, Metabolic, Genetic, Endocrinopathy

Anatomical

Choledochal Cyst

5 subtypes (1 and 4 most common)

Type 1 - saccular dilation of extrahepatic bile duct
Type 4 - saccular dilation of intra- and extrahepatic biliary tree

Jaundice, acholic stool, palpable RUQ mass

Dx - Ultrasound
Tx - Surgery (resection), if not treated - risk cholangiocarcinoma

Inspissated Bile syndrome

Impaired Bile flow leading to cholestasis
Risk factors: TPN or severe intestinal disease
Dx - Ultrasound --> Bile Sludge (often seen)
Tx - Ursodeoxycholic acid can improve flow

recalcitrant cases - surgical flush of biliary tree with saline

Biliary Atresia (Must Dx within first 60 days of life)

Obliteration of extrahepatic biliary tree
Presents at ~3wks
Leads to fibrosis --> Cirrhosis within 1st few months of life
approx 100% mortality by age 2 if not treated
Dx - Intraoperative cholangiogram (gold standard)

Supportive - Ultrasound with absent or poorly defined gallbladder
Liver Bx - proliferation of bile ductsm bile plugs of intrahepatic bile ducts, fibrosis, cirrhosis (late)
Labs - Increased AST,ALT,GGT,AlkPhos,Direct Bili
Exclude other diagnoses i.e. A1AT deficiency

Tx - Kasai portoenterostomy

needs to be performed within the 1st 60 days of life
Effective bile drainage with resolution of jaundice in

70% if surgery performed within 60 days of life

40-50% if performed within 60-90 days of life
25% if performed within 90-120 days of life
10-20% if performed at 120 days of life

Nutrition

Breast milk or MCT (med-chain triglyceride) containing formula to promote adequate fat absorption
ADEK
Zinc Supplementation

Pruritis

Hydroxyzine for sx relief
Ursodeoxycholic acid may help improve bile flow

Post-Kasai Complications

Cholangitis

Fever, irritability, jaundice, acholic stools
Increased AST, ALT, D bili, AlkPhos, and GGT
+/- bactermia usually with neg Bld Cx
Bile lakes - risk infection
Tx - Abx

Portal Hypertension (pHTN)

Splenomegaly , decreased WBC, Plt's
Eso or gastric varices
Ascites

Med management - diuretics
Intermittent paracentesis
Risk - spontaneous bacterial peritonitis

Cirrhosis or end stage liver disease

Infectious

TORCH

Toxoplasmosis
Other
Syphilis
Rubella
CMV
Herpes / HIV

Herpes can present with fulminant liver failure

Metabolic

A1AT deficiency (Autosomal recessive)

One of the Most Common Causes
Buildup of A1AT in ER in hepatocytes
Variable Course

mild disease to fibrosis to liver transplantation
PHTN suggests worse prognosis

Dx - A1AT level and phenotype

MM - normal
ZZ - deficiency
MZ/MS: heterozygote (carrier - no disease)

Tx - no FDA approved therapy

Counsel against smoking and 2nd hand smoke exposure (pulm disease may develop in adulthood)

Inborn errors of metabolism

Hypoglycemia and splenomegaly should make you think inborn errors of metabolism

Galactosemia

E Coli sepsis, absent red reflexes or cateracts

Dx - Newborn screen (NBS)

Decreased RBC galactose-1-phosphate uridylyltransferase level (gold standard)

Tyrosinemia

can present as fulminant liver failure
Coagulopathy "out of proportion" to mild increase in aminotransferases
Dx - increased urine succinylacetone
Tx - NTBC inhibits enzyme in degradation pathway

Fructosemia

Bile acid synthesis defects (BASDs)

defects in enzymes involved in bile acid synthesis leading to cholestasis
Dx - bile acids below normal while other causes of cholestasis increase serum bile acids

if low, confirm by measuring individual bile acid levels
GGT usually not elevated

Tx - Oral bile acid supplementation

Genetic Disorders

Alagille syndrome (Autosomal dominant)

variable penetrance - Jagged 1 gene on chromosome 20
Cholestasis --> paucity of intrahepatic bile ducts seen on liver Bx

early proliferation, later paucity

Physical exam

abnormal facies with deep set eyes and pointed chin, can see pulm stenosis
Ophtho - posterior embryotoxon
Cardiac - defects with pulm stenosis most common
skeletal - butterfly or hemivertebrae
Renal - disease common

Cystic Fibrosis (CF)

5% of CF patients have neonatal cholestasis
NBS - increased immunoreactive trypsinogen
Sweat Cl and genetic testing for mutations in CF transmembrane regulator
Pancreastic insuficiency (decreased fecal elastase)

Progressive familial intrahepatic cholestasis (PFIC)

3 types

PFIC 1 defect of canalicular surface protein FIC1

low to normal GGT
Growth failure and diarrhea
neonates or older children

PFIC 2 bile salt export pump (BSEP) disease

low to normal GGT
pruritis - can be severe
Risk -hepatocellular carcinoma HCC

PFIC 3 MDR3 deficiency

affecting phosphatidylcholine secretion into bile canaliculus

High GGT
can present later in life

Endocrinopathies

Hypothyroidism

NBS can be normal

Panhypopituitarism

Persistent hypoglycemia in neonate
Septo-optic dysplasia / optic nerve hypoplasia
if undiagnosed --> adrenal crisis
Dx - AM cortisol, TSH, T4, glucose

MRI to eval pituitary gland

Evaluation

Obtain Direct Bilirubin in:

All breastfed infants who remain jaundiced at 3wks of life
All formula-fed infants who remain jaundiced a 2wks of life

Tier 1 evalauation

CMP (ALT, AST, Alk Phos, Albumin, Total Protein)
Direct Bili
GGT
PT/INR

*Note: INR and Albumin assess synthetic function)

Imaging

Abdominal US - to visualize the gallbladder and evaluate for structural abnormalities (Choledocal cyst, etc...)

Physical Exam findings:

Situs inversus or dextrocardia --> Biliary atresia esp if polysplenia present
Pulmonary stenosis or other congenital heart defects --> Alagille syndrome
Abnormal Facies (deep set eyes/pointed chin) --> Alagille syndrome
Large anterior fontanelle --> hypothyroidism
Hepatosplenomegaly --> metabolic disorders
Absent red reflexes --> glactosemia
Acholic stools --> obstructive process e.g. biliary atresia

Tier 2 evaluation

Metabolic tests

Reducing subs (carbohydrate metabolism disorders)
Urine organic acids (see green table below) -organic acidemias, mitochondrial defects, others
Plasma AA (see blue table below)
NH3 (see differential here)
Acylcarnitine profile (ACP) - Fatty acid oxidation defects
Serum Bile acids and urine for bile salt species profiling
Fat Soluble Vitamins
F/u NBS prior to obtaining/sending metabolic studies

Tier 3 Evaluation

Cholestasis Genetic Panel (Cholestasis Chip)
+/- Liver Bx (if clinically indicated)

Recommendations
- Start / Continue Ursodiol
- Start / Continue ADEK as there is typically malabsorption of fat soluble vitamins in the setting of liver disease and cholestasis
- Follow up CMP, Total and Direct Bili, GGT, INR weekly

If patient has only been off of PN for xxx months, would recommend holding off on Genetic testing (jaundice chip) for PFIC, Alagille, etc. If the cholestasis persists or worsens over the next few weeks, this can be re-evaluated

Metabolic Disorders Tables

Disorders Detected by Urine Organic Acid Analysis
Disorder	Key Metabolite(s)	Notes
Tyrosinemia Type I	↑ Succinylacetone	Pathognomonic; confirms diagnosis
Maple Syrup Urine Disease (MSUD)	↑ Ketoacids (e.g., 2-ketoisocaproic acid)	Branched-chain amino acid metabolism defect
Methylmalonic acidemia (MMA)	↑ Methylmalonic acid	Vitamin B12-related or enzyme defect
Propionic acidemia	↑ 3-hydroxypropionic acid, methylcitric acid	Severe acidosis, neutropenia
Isovaleric acidemia	↑ Isovalerylglycine	"Sweaty feet" odor; leucine metabolism defect
Glutaric acidemia Type I	↑ Glutaric acid, 3-hydroxyglutaric acid	Associated with dystonia and brain atrophy
Multiple carboxylase deficiency	↑ 3-hydroxyisovaleric acid, lactic acid	Biotin-responsive disorder
MCAD deficiency	↑ Hexanoylglycine, suberylglycine	Fatty acid oxidation defect
Lactic acidosis	↑ Lactic acid, pyruvate	Seen in mitochondrial disorders or severe liver dysfunction
3-Methylcrotonyl-CoA carboxylase deficiency	↑ 3-methylcrotonylglycine	Biotin-related disorder

Metabolic Disorders Detected by Plasma Amino Acid Analysis
Disorder	Key Amino Acid Abnormality	Notes
Phenylketonuria (PKU)	↑ Phenylalanine	Deficiency of phenylalanine hydroxylase
Maple Syrup Urine Disease (MSUD)	↑ Leucine, Isoleucine, Valine	Branched-chain ketoacid dehydrogenase defect
Homocystinuria	↑ Homocysteine, Methionine	Cystathionine β-synthase deficiency
Tyrosinemia Type I	↑ Tyrosine, Succinylacetone (urine)	FAH enzyme defect; succinylacetone is diagnostic
Histidinemia	↑ Histidine	Often benign, but detectable
Citrullinemia	↑ Citrulline	Urea cycle defect (argininosuccinate synthetase deficiency)
Argininosuccinic aciduria	↑ Argininosuccinate	Urea cycle defect
Nonketotic hyperglycinemia	↑ Glycine (plasma and CSF)	Glycine cleavage system defect
Hartnup disease	Abnormal neutral amino acids in urine	Defect in renal/intestinal transport of neutral amino acids
Ornithine transcarbamylase deficiency	↓ Citrulline, ↑ Orotic acid (urine)	Urea cycle defect
Carbamoyl phosphate synthetase I deficiency	↓ Citrulline, ↑ Ammonia	Urea cycle defect
Arginase deficiency	↑ Arginine	Urea cycle defect
Galactosemia	Secondary amino acid abnormalities	Due to liver dysfunction
Lysinuric protein intolerance	↓ Lysine, arginine, ornithine in plasma; ↑ in urine	Defect in amino acid transport

Neonatal Cholestasis with Low GGT

Neonatal cholestasis with low or normal gamma-glutamyl transferase (GGT) is an important diagnostic clue that points toward specific genetic and metabolic disorders, distinct from the more common high-GGT causes like biliary atresia or Alagille syndrome. Early recognition is critical for targeted therapy and transplant planning.

Key Causes

Condition	Gene(s)	Key Features
PFIC Type 1 (Byler disease)	ATP8B1	Pruritus, hepatomegaly, diarrhea, normal bile ducts, low GGT
PFIC Type 2	ABCB11	Severe cholestasis, early liver failure, low GGT
Bile Acid Synthesis Defects	HSD3B7, AKR1D1, CYP7A1, etc.	Fat-soluble vitamin deficiency, normal/low GGT, responds to bile acid therapy
ARC Syndrome	VPS33B, VIPAS39	Arthrogryposis, renal dysfunction, cholestasis, failure to thrive
TJP2 Deficiency	TJP2	Cholestasis, liver fibrosis, low GGT
Smith-Lemli-Opitz Syndrome	DHCR7	Dysmorphic features, developmental delay, cholesterol synthesis defect
Transaldolase Deficiency	TALDO1	Hepatosplenomegaly, coagulopathy, low GGT
Zellweger Spectrum Disorders	PEX genes	Hypotonia, seizures, craniofacial dysmorphism, cholestasis
Mitochondrial Hepatopathies	DGUOK, POLG	Liver failure, neurologic symptoms, low GGT