new updates BY NEDAL ELASAD

2. Introduction
Jaundice is a common finding in the first 2 weeks of life
Mostly jaundice is caused by ↑indirect bilirubin, usually due to physiological cause
In infants who continue to have jaundice beyond 2 weeks of age, hepatomegaly, pale stool or diarrhea serum
bilirubin and fraction into direct/indirect should be obtained

3. Definition
.Neonatal cholestasis is generally defined as conjugated hyperbilirubinemia that occurs in the newborn period
Direct > 1mg/dL when total < 5mg/dL or direct > 20% when total bilirubin > 5mg/dL
Studies now suggest – in the first 5 days of life, direct > 0.3-0.4 mg/dL or direct > 10% of total
Cholestasis results from diminished bile formation and/or excretion, which can be caused by a number of
disorders

4. Etiology
Neonatal cholestasis can be divided into
-
Extrahepatic etiologies
-
Intrahepatic etiologies

5. Extrahepatic
Biliary atresia
Choledochal cyst
Cholelithiasis
Biliary sludge
Inspissated bile
CBD spontaneous
perforation
Tumor

6. Intrahepatic
Infections
Toxins
Endocrine
Genetic and inborn
error of metabolism
Others
TORCH
Bacterial
sepsis
Viruses
Drugs associated cholestasis
TPN associated cholestasis
Hypothyroidism
Panhypopituitarism
A1AT deficiency
Galactosemia
Alagille syndrome
CF

7. Clinical aspect
-Jaundice & scleral icterus
-Pale stool
-Dark urine
-Hepatomegaly
-Signs of coagulopathy
-Other signs and symptoms depend on the specific disease process

8. Evaluation of neonatal cholestasis
*Basic evaluation
-history and physical examination ( identify red flags ) .
-CBC and reticulocyte count .
-Total and direct bilirubin
-Electrolytes, BUN, creatinine, calcium, phosphate.
-AST , ALT , GGT , alkaline phosphatase.
-Total protein,INR, albumin, cholesterol.
-Comprehensive metabolic panel .
-A1AT level .

9. Evaluation of neonatal cholestasis

10. Evaluation of neonatal cholestasis

11. Evaluation of neonatal cholestasis
However , this single-test , single result approach was timely and expensive.
> New method for evaluation of neonatal cholestasis :
-TGP ( target genetic panels ).
-WES( whole-exome sequencing).
-WGS ( whole-genome sequencing ) .
those testing has rapid results , cost effective manner and can identify all knowns gene mutation associated
with cholestatic disease also uncover new genetic abnormalities .

12. Evaluation of neonatal cholestasis
> Imaging :
-Abdominal ultrasonography
All infants with cholestasis should undergo abdominal ultrasonography as part of their initial evaluation to
assess liver structure , size , ascites , and identify finding of extrahepatic obstructive lesion ( choledochal cyst ,
gallstone , obstructive sludge ) , absence of gallbladder .
none of this finding are diagnostic for BA , and conversely some infant with BA have normal hepatobiliary
ultrasonography .
-HIDA scan :
Was used to assess biliary patency and rule out BA . however the specify of a HIDA is low ( 33%-80% ) , non
excretion by HIDA scan is observed not only in infant with BA , can seen in ALGS and INH .
-cholangiogram:
cholangiogram is ultimately required to establish the diagnosis of biliary atresia and is the most commonly
performed as an intraoperative .

13. Evaluation of neonatal cholestasis
>Liver biopsy:
Liver biopsy remain a critical tool in evaluating neonatal cholestasis .
Several studies have found that a diagnosis of BA was correctly suggested by liver biopsy histology in 85% to
95% of case.
It is important to remember that non-BA causes of cholestasis can mimic the histological appearance of BA ,
and IOC is needed to confirm the diagnosis of BA .
In addition , several cholestatic process are evolving over time and may not be diagnostic in initial liver biopsy if
done before age 4-6 weeks .

14. Evaluation of neonatal cholestasis
>Novel biomarkers :
Recent studies have suggested that elevated serum levels of matrix metalloproteinase 7 (MMP7) at 1 to 2
months of age may reliably discriminate BA from other causes of cholestasis.
In addition , high level of MMP 7 can prognostics which infant will ultimately need liver transplantation .

15. Selected disorders resulting in neonatal cholestasis
Biliary atresia
BA is fibroinflammatory disease leads to complete obstruction of part or entire extrahepatic biliary tree and
progressive biliary cirrhosis .
BA is the leading cause of neonatal cholestasis and the most frequent indication for pediatric liver
transplantation .
Infants with BA typically are well-appearances at birth and will develop persistent jaundice with acholic stool
around 3 to 6 weeks of age . At time of diagnosis HPE procedure is performed.
The success of HPE is dependent on the age , if done before 45 days of age the success rate is up to 80% and if
performed after 90 days the success rate is up to 20% .
Approximately 50 % of children with BA require a liver transplant before 2 years of age , and 75% by 20 years
of age .

16. Selected disorders resulting in neonatal cholestasis
A1AT deficiency
A1AT deficiency is an autosomal recessive disorder , affecting approximately 1 in 2000-5000 live birth which
can lead to hepatocyte injury and cirrhosis .
Infant with A1AT :
-40% will be asymptomatic
-40% will have abnormal liver biochemical test results
-10-20% will have cholestatic .
Of all children with A1AT deficiency 7% will develop cirrhosis and 17% will require a transplant .

17. Selected disorders resulting in neonatal cholestasis
Alagille syndrome
ALGS is an autosomal dominant disorder occurring in approximately 1 in 70,000 live births.
mutation in the JAGGED 1 gene are identified in over 90% of individuals with ALGS , mutation in NOTCH2 are
reported in 4% ,
ALGS has phenotypic variability that can include :
-Neonatal cholestasis.
-Congenital right heart disease (88%) .
-Dysmorphic facies > triangular face , broad forehead , deep-set eyes (85%) .
-Ocular posterior embryotoxon .
-Butterfly vertebrae (39%).
-Renal anomalies.
By the age 20 , 40% will develop portal hypertension , and only 24% survive to adulthood with their native
liver.

18. Selected disorders resulting in neonatal cholestasis
PN-associated cholestasis
One of the most common complication in infants receiving PN is PNAC.
In study of 1,366 infant who received PN for more than 14 days shows PANC occurred in :
-14% of infant who receive PN for 14-28 days , 43% for 29-56 days and 85% if more than 100 days .
The pathogenesis of PNAC :
-Biological and toxin factors from PN will activate innate inflammation in the liver .
- Suppresses expression of bile leads to cholestasis.
Risk factors :
-Patient-related : prematurity , sepsis , dilated small bowel , lack on enteral intake .
-PN related : type and amount , lack of PN cycling , duration of PN infusion and lack of antioxidant in PN .

19. Selected disorders resulting in neonatal cholestasis
Progressive familial intrahepatic cholestasis
PFIC consists of several autosomal recessive hereditary disorder caused by mutation in 1 of the genes that
response for bile acid transport.
> PFIC type 1 and 2 have normal GGT , patient with type 1 may also experience severe pruritus, diarrhea ,
pancreatitis and hearing loss , patient with type 2 at risk for the development of HCC .
>PFIC type 3 have high GGT and less dever pruritus .

20. Treatment of neonatal cholestasis
All infants with cholestasis require careful attention to their nutrition , growth and vitamin levels .
>Oral feeding is prefered , if infant unable to feed and tolerate the required volume nasogastric tube or PN .
>Most cholestatic infants require the addition of MCT ( medium chain triglyceride) .
>Increase caloric count up to 125%-140%.
> Fat soluble vitamins (AKED) .
>All age appropriate immunization , in some cases must be given early > e.g MMR+V vaccine may given at 6
months instate of 1 year.
>Medication for pruritus as UDCA , rifampicin or cholestyramine .
>Infants with PFIC1 , PFIC2 or ALGS who have not develop cirrhosis , a partial biliary surgical diversion to help
improve pruritus and cholestasis .

21. SCREENING AND PREVENTION
Despite the clear importance of early diagnosis and HPE before age 30 to 45 days for infant with BA , the
median age for HPE in united state remain more than 60 days .
Screening tool to help identify infants with BA earlier
-National stool colour : in Taiwan , japan and Switzerland this program has significantly reduced the average
age at diagnosis and time of HPE .
-Direct bilirubin measurement before discharge from the hospital , BA are elevated within the first 72 hours
after birth , so can be diagnosis before discharge from hospital .
-MMP7 : can be used to identified BA among infants with cholestasis , which appears in the initial studies to be
95%-99% sensitive and 93%-95% specific for identifying infants with BA.

22. CONCLUSIONS
-Over the past 2 decades, much has been elucidated about the molecular mechanisms and genetic defects that
result in neonatal cholestasis, as well as the pathophysiology of PNAC. However, the etiology of BA still
remains enigmatic.
-In preterm infant the etiology can be multifactorial, and usually resolves with advanced feeding .
-late identification of BA continues to be a challenge in many countries and BA remain the primary indication
for pediatric liver transplant .
-there is an urgent need for national programs to identify infants with cholestasis , particularly those with BA.