2. Approach to Neonatal Cholestasis
DR. MUHAMMAD SALMAN KHOSO
Mbbs, Fcps ( Paeds Med), Fcps ( Paeds Gastroenterology, Hepatology & Nutrition)
Consultant Pediatric Gastroenterology, Hepatology & Nutrition
Dow University Of Health Sciences (DUHS)
3. OBJECTIVES
What is neonatal cholestasis
Differential diagnosis for neonatal cholestasis.
Understand how to approach to the neonate with conjugated hyperbilirubinemia.
Know the therapeutic management of neonates with cholestasis.
4. Bile
Bitter-tasting, dark green to yellowish brown fluid
Water (85%), bile salts (10%),
( Cholic, chenodeoxycholic, deoxycholic, and lithocholic acid)
Pigments (3%), bile pigments e.g bilirubin glucuronide
Fats (1%), such as Phospholipids (lecithin) , cholesterol.
0.7% inorganic salts.
Hepatic bile: pH 7.4, colour is golden yellow ,
Gall Bladder bile: pH 6.8, color is green dark to yellow (darker)
5. Water - 97.5%
Solids - 2.5%
Inorganic- Na, K, Cl, Ca, HCO3
Organic – Constituents
Bile acids
Primary BA
Cholic acid
Chenodeoxy cholic acid
Secondary BA
Deoxycholic acid
Lithocholic acid
Bile salts -Bile acids + Na/K + Glycine
/ taurine
Bile pigments
Bilirubin
Biliverdin
Cholesterol
Lecithin
Fatty acids
6. Function of Bile
Digestion of fats
It is by emulsification of fats i.e to make insoluble fats soluble in water
Breaking fat globules in minute particles
Decreasing surface tension of fats particles
Absorption of fats
Combining with emulsified lipids and making Micelles
Choleretic function
It stimulates further bile secretion from Liver
7. Cholagogue action
It stimulates gall bladder contraction for bile expulsion
Laxative action
It stimulates peristaltic movements of intestine helps in defecation
Prevention of gall stone formation
Keeping cholesterol & lecithin in solution forms
In absence of bile salts – the cholesterol & lecithin may be precipitated & may
form gallstones
8. Definitions
Cholestasis – Defined as an impairment in the excretion of bile.
Intrahepatic production of bile,
Transmembrane transport of bile, or
Mechanical obstruction to bile flow.
Conjugated hyperbilirubinemia – the terms "conjugated bilirubin" and "direct bilirubin" are often used
interchangeably
Conjugated bilirubin can be estimated by the "direct" reaction with a diazo reagent (van den bergh reaction)
Direct-reacting bilirubin includes both the conjugated bilirubin and the delta fraction, which represents
bilirubin covalently bound to albumin
9. Introduction
Neonatal cholestasis is defined as prolonged direct/ conjugated hyperbilirubinemia
beyond the first 14 days of extra-uterine life
At birth
Within 3 months
Direct hyperbilirubinemia, typically defined as a direct/total
bilirubin ratio of more than 15–20%, or a direct bilirubin level above
1.0 mg/dl, is collectively defined as cholestasis
Guideline for the Evaluation of Cholestatic Jaundice in Infants. JPGN Volume 64, Number 1, January 2017
10. Introduction cont…
Cholestasis is defined as disturbances in bile flow caused by diseases either in the
hepatocytes, intrahepatic bile ducts or extra hepatic biliary system
The biochemical features of cholestasis reflect the retention of components of bile
in the serum (eg, bilirubin, bile acids, and/or cholesterol)
The pattern and severity of each of these abnormalities vary with the underlying
disorder
Cholestatic liver disorders are unique to children and cholestatic diseases
have been central in the development of Pediatric Hepatology
11. Epidemiology
Neonatal cholestasis lasting more than two weeks affects approximately 1 in 2500
births
J Pediatr Gastroenterol Nutr 39(2):115-128
No prevalence from Pakistan because of lack of epidemiological studies
The Children’s Hospital, Lahore data-NC constitute 30.2% of all hepatobiliary disorders
Pak Pediatr J 2017; 41(1): 42-48
In India, NC constitutes approximately 27-33% of hepatobiliary disorders in India
Clinical Medicine Insights: Pediatrics, 2018; 12: 1–6
12. Epidemiology cont…
Biliary atresia is yet considered the most common cause worldwide followed by
monogenic disorders and others
With the availability of genetic analysis the number of idiopathic neonatal
hepatitis is decreasing consistently
13. Most common cause of cholestasis in an infant
what does the world say
30% BA in USA
Mónica D’Amato G.,
MD,1Patricia Ruiz N., Susana
Gómez Rojas, MD.3 Bogotá
Columbia
Most common
cause NNH and
infection
Most common cause is BA in Europe
Frontier in pediatrics, doi: 10.3389/fped.2014.00065
14. Most common cause of cholestasis in an
infant what does the world say
30% BA in Iran
Iran J Pediatre
doi: 10.5812/ijp.65409
Saudi Data
BA is around 16%
Ahmed et al. BMC Gastroenterol (2021) 21:118
https://doi.org/10.1186/s12876-021-01699-4
30 %of NCS in India reported to
have BA
15. Cholestatic children seen in Year 2020
at CHL
Genetic cholestasis, 62, 40%
Metaboilc liver disease, 35, 22%
NNH, 36, 23%
Biliary atresia, 23, 15%
Year 2020
17. Cholestasis, understanding the homeostasis of bile acid pool
The homeostasis of bile acids is tightly controlled by the de novo synthesis of bile acids and the
expression of transporters that affect hepatocellular bile acid levels
The key regulating molecules are farnesoid X receptor (FXR, NR1H4)
FXR downregulates the expression of bile acid synthesis enzymes (mainly CYP7A1) and the
sinusoidal uptake transporter of NTCP
FXR upregulates the expression of the bile acid efflux transporter BSEP to reduce intracellular bile
acid concentrations
Through FXR, bile is controlled via a negative feedback loop
18. Clinical presentation
Jaundice/ scleral icterus
High colored urine
Pigmented/ acholic stools (must be seen by physician)
Dysmorphism and congenital anomalies
Growth parameters
Measurement and consistency of liver and
spleen, any ascites
Relevant systemic examination
19. Cholestatic disorders in children
Significantly affect the health and well being of the child
Debilitating pruritus and failure to thrive are extremely distressing for the parents
They itch till they draw blood
No good medical therapies for ameleriotion of symptoms
No cure medically
20. Initial screening
First step in jaundiced infant --> Serum concentrations of both total and conjugated
bilirubin.
If the infant has conjugated hyperbilirubinemia
Serum conjugated bilirubin concentration greater than 1.0 mg/dL (17.1
micromol/L) if the total bilirubin is <5.0 mg/dL, or
Greater than 20% of the total bilirubin if the total bilirubin is >5.0 mg/dL.
Serum direct bilirubin > 2.0 mg/dl in infants with intestinal failure-associated liver
disease,
21. Neonatal cholestasis – the term "neonatal cholestasis" is often used to refer to cholestatic liver
disease that is present at birth and/or develops within the first few months of life
In clinical practice, these disorders usually become apparent within the first three months of life.
However, similar diagnostic considerations apply for infants whose cholestasis is identified after
three months of age.
Neonatal cholestasis lasting more than two weeks affects approximately 1 in 2500 births.
22. History
Birth history
Prenatal ultrasonography and results
Birth weight and gestational age
Newborn screen results
Isoimmune hemolysis
Maternal infections (TORCH)
Complications of pregnancy
Family history
Consanguinity
History of similar problems in the family
Stool characteristics
Stool color
Diet and gastrointestinal symptoms
Dietary history
Vomiting
Other symptoms
Urine color
Excessive bleeding (eg, after
circumcision)
Infant's behavior
Neonatal infection
23. On Examination
Vital signs
General health and vigor
Growth parameters
Facies and appearance
Ophthalmologic examination
Cardiac examination
Abdominal examination
Ascites
Abdominal wall veins
Liver size, Liver consistency
Spleen
Skin
Urine
Stool
24. Physical Examination
Specific components of the physical examination may be useful in narrowing the
differential diagnosis and are outlined in the table.
Key features include:
Infants with biliary atresia are generally well-appearing, except for jaundice, and stools
are often acholic.
Infants who present late (>90 days of age) with biliary atresia may have features of
advanced liver disease including failure to thrive, ascites, and hepatosplenomegaly.
By contrast, infants who are ill-appearing or failing to thrive are more likely to have
infection or metabolic disease.
25. GOALS OF EVALUATION
Diagnose and treat known medical and/or life-threatening conditions.
Identify disorders amenable to surgical therapy within an appropriate time-frame.
26. Investigations
Total and conjugated bilirubin
ALT and AST
Alkaline phosphatase and GGTP
Total protein and albumin
Electrolytes, bicarbonate, glucose
CBC with differential
PT/INR and PTT
Cultures of blood, urine, CSF
TORCH titers,
Urine-reducing substances
Serum bile acids
Alpha-1 antitrypsin concentration
Protease inhibitor phenotype (PI type)
TSH, T4
Urine bile acid analysis by FAB-MS
Metabolic testing
Genetic testing
27. All other neonatal cholestasis are high GGT cholestatic conditions
Normal/ Low GGT
All PFIC except type 3
BASD
ARC Syndrome
Pan-hypopituitarism
Lymphoedema cholestasis syndrome 1 (LCS1/Aagenese syndrome)
Smith-Lemli-Opitz syndrome
CALFAN Syndrome
28. Radiological evaluation
Ultrasonography
Patient should be NPO to increase likelihood of visualizing the gallbladder
Feeding with exam may demonstrate a functioning gallbladder
Hepatobiliary scintigraphy (HIDA)
34. Most common causes of neonatal cholestasis
Diagnosis
Proportion of young infants with
conjugated hyperbilirubinemia
Extrahepatic biliary atresia 25% (range 2 to 55%)
Idiopathic neonatal hepatitis 25% (range 4 to 45%)
Infectious hepatitis (eg, cytomegalovirus) 11%
Parenteral nutrition-associated 6%
Metabolic disease (eg, galactosemia, tyrosinemia) 4%
Alpha-1 antitrypsin deficiency 4%
Alagille syndrome 1%
Progressive familial intrahepatic cholestasis 1%
35. Biliary Atresia
It is progressive obliterative inflammatory process involving bile ducts,resulting in
obstruction of bile flow leading to cholestasis ,hepatic fibrosis and eventually cirrhosis.
Generally acholic stools with onset at about 2 weeks-old
Average birth weight
Hepatomegaly with firm to hard consistency
Female predominance
36. Normal uptake on radionucleotide scan with absent excretion
Biopsy shows bile duct proliferation, bile plugs, portal or perilobular fibrosis and
edema, and intact lobular structure
37. Kasai Procedure
Performed for biliary atresia that is not surgically correctable with excision of a distal atretic segment.
Roux-en-Y portoenterostomy
Bile flow re-established in 80-90% if performed prior to 8 weeks-old.
Bile flow re-established in less than 20% if performed after 12 weeks-old
Success of the operation is dependent on the presence and size of ductal remnants, the extent of the
intrahepatic disease, and the experience of the surgeon.
Complications are ascending cholangitis and re-obstruction as well as failure to re-establish bile flow.
Biliary atresia is the most common indication for transplant and may be the initial treatment when detected
late.
38. INTRAHEPATIC CHOLESTASIS
Neonatal Hepatitis:
The term neonatal hepatitis implies intrahepatic cholestasis , which has various forms.
Idiopathic neonatal hepatitis, which can occur in either a sporadic or a familial form,
is a disease of unknown cause. Patients with the sporadic form presumably have a
specific yet undefined metabolic or viral disease. Familial forms, on the other hand,
presumably reflect a genetic or metabolic aberration; in the past, patients with α1-
antitrypsin deficiency were included in this category.
39. GALACTOSEMIA
Deficiency of enzymes GALT,GALK,GAL epimerase
Symptoms presents usually few days after birth and includes
Feeding intolerance, vomitings, diarrhea,
Jaundice, hepatomegaly, coagulopathy, hypoglycemia, cataracts, developmental
delay.
Cataracts may be present at birth but usually found after 2 weeks.it is formed due
to accumulation of GALACTITOL in lense (lenticular cataract).
40. Diagnosis
Urine positive for non glucose reducing substances while on lactose feeds.
Raised galactose-1-P in RBCs is a typical finding.
Confirmation by enzyme assay of Galactose 1 phosphatase uridyl transferase in
RBCs.
Genetic Mutation analysis .
Treatment is with lactose free formula milk and exclusion of lactose from diet.
41. Progressive Familial Intrahepatic Cholestasis
Group of familial cholestatic conditions
Defect in epithelial transporters.
Five known types
Autosomal recessive.
42. PFIC-1
“Byler’s disease” PFIC-1 is severe form of IHC
First described in Amish child, Jacob Byler
Chromosome 18q12 ,Gene FIC1 (ATP8B1)
Present with diarrhea ,secretory diarrhea may persist after liver transplantation
Short stature, sensorineural deafness, pancreatitis
Low GGT is typical finding.
43. PFIC 2
Chromosome 2q24,Mutations in ABCB11, gene
Bile salt export pump, or BSEP.
Retention of bile salts within hepatocytes
Causes hepatocellular damage and cholestasis.
Risk of developing hepatocellular carcinoma
44. PFIC 3
Mutations in ABCB4, gene encoding multidrug resistance protein 3 (MDR3)
The free or "unchaperoned" bile acids in bile of patients with MDR3 deficiency
cause a cholangitis.
Markedly elevated GGT.
45. Treatment of PFIC
Ursodeoxycholic acid (20-30 mg/kg/d),
It improves bile flow.
UDCA is generally used as first line therapy for pruritus due to cholestasis
Rifampin acts by inhibiting the bile acid uptake by the hepatocytes and also
induces the hepatic microsomal enzymes.
Cholestyramine, an anion exchange resin, binds bile acids in the intestinal lumen,
blocking the enterohepatic circulation and excretion.
Liver transplantation.
46. Bile Acid Synthesis Defect
Hypothesis is that inborn errors in bile acid biosynthesis lead to absence of normal
trophic or choleretic primary bile acids and accumulation of atypical (hepatotoxic)
metabolites.
Inborn errors of bile acid biosynthesis cause acute and chronic liver disease; early
recognition allows institution of targeted bile acid replacement, which reverses the
hepatic injury.
47. Disorders of bile acid metabolism — Primary disorders of bile acid synthesis are
caused by inherited defects in the enzymes that are necessary for synthesis of the
two main bile acids (cholic acid and chenodeoxycholic acid).
Severe cholestatic jaundice from birth and progressive liver failure, sometimes
with stools that are loose, fatty (steatorrhea), or pale-colored (acholic), and
occasionally with pruritus.
Milder forms may present in anicteric school-aged children as fat-soluble vitamin
deficiency, pruritus, and/or neurologic disease with less prominent liver disease.
48. Laboratory testing typically reveals conjugated hyperbilirubinemia and elevated
aminotransferase activity (alanine transaminase [ALT] and aspartate transaminase
[AST]), with paradoxically normal or low GGTP.
49. Alagille Syndrome
Genetics and clinical features – Alagille syndrome is inherited in an autosomal dominant
fashion, with mutations in the JAG1 gene responsible for Alagille syndrome in more than 90
percent of patients; a small percentage have mutations in the NOTCH2 gene.
Tthe paucity of interlobular bile ducts
Hepatic manifestations:
Chronic cholestasis
Jaundice
Cirrhosis
Pruritus
Xanthomas
Cardiac murmur or anomalies – Most commonly peripheral pulmonic stenosis; also tetralogy of
Fallot, ductus arteriosus, septal defects, or co-arctation of the aorta
Butterfly vertebrae
50. Triangular, with a prominent forehead, deep-set eyes, a pointed chin, and a straight nose with a bulbous tip.
51. Diagnosis
Conjugated hyperbilirubinemia, other laboratory findings include elevations of serum aminotransferases, and
gamma-glutamyl transpeptidase (GGTP), which is often disproportionally increased.
The clinical diagnosis of Alagille syndrome in the infant with cholestasis includes the characteristic clinical
features
Liver biopsy demonstrating reduced number of the interlobular bile ducts.
In patients with clinical characteristics suggestive of Alagille syndrome, the diagnosis can also be made or
confirmed by the finding of a JAG1 or NOTCH2 gene mutation.
The histologic finding of paucity of interlobular bile ducts found in Alagille syndrome also may be observed
in, including alpha-1 antitrypsin deficiency, cystic fibrosis, infection (CMV, syphilis), mitochondrial
disorders, PFIC1 and PFIC2, or ARC cholestasis syndrome
52. Neonatal iron storage disease (neonatal
hemochromatosis)
It is a rapidly progressive disease characterized by increased iron deposition in the liver, heart, and endocrine
organs without increased iron stores in the reticuloendothelial system.
Patients have multi-organ failure and shortened survival.
This is an alloimmune disorder with maternal antibodies directed against the fetal liver.
Laboratory findings include hypoglycemia, hyperbilirubinemia, hypoalbuminemia, elevated ferritin and
profound hypoprothrombinemia.
Serum aminotransferase levels may be high
The diagnosis is usually confirmed by buccal mucosal biopsy or MRI demonstrating extrahepatic siderosis.
The prognosis is poor; however, liver transplantation can be curative.
53. Treatment of Neonatal Cholestasis.
Medical management
Nutritional support
Treatment of pruritus
Choleretics and bile acid-binders
Management of portal hypertension and its consequences
54. Nutritional support
Adequate calories and protein
Supplement calories with medium chain triglycerides(MCT)
Maintain levels of essential long-chain fatty acids
Treatment and/or prophylaxis for fat-soluble vitamin deficiencies (vitamins A,
D, E, and K)
55. Treatment of pruritus
Bile acid-binders: cholestyramine, cholestipol
Ursodeoxycholic acid
Phenobarbital as a choleretic
Rifampin
Ondensterone
56. Management of portal hypertension and its consequences
Variceal bleeding
Fluid resuscitation
Blood products
Sclerotherapy
Balloon tamponade
Porto-venous shunting
Propanolol
57. Management of portal hypertension and its consequences (cont.)
Ascites
Sodium restriction
Diuretics: spironolactone, furosemide
Albumin
Paracentesis
Thrombocytopenia managed with platelet infusions when clinically indicated
Ultimately LIVER TRANSPLANTATION.
