Best Management of neonatal cholestasis (NC) 2024

Management of neonatal cholestasis (NC)

INVESTIGATIONS
The principal diagnostic concerns are to differentiate hepatocellular diseases from anatomical disorders, and diseases that are managed medically from those requiring surgical intervention. The initial evaluation of an infant with neonatal cholestasis includes a complete liver function test (LFT), thyroid function test, and a sepsis screen followed by specific radiological and histopathological tests.

The most important initial investigation is to establish cholestasis by
Serum bilirubin (total and differential) levels
Prothrombin time or international normalized ratio (INR) and serum albumin.
The severity of liver dysfunction can be measured by estimating the prothrombin time or international normalized ratio (INR) and serum albumin.
Serum transaminase
The serum transaminases are sensitive indicators of hepatocellular injury but lack specificity and prognostic value.
Alkaline phosphatase
Biliary obstruction may show high alkaline phosphatase levels, however, this finding has little specificity.
Gamma-glutamyl transpeptidase (GGTP)
The biliary obstruction marker gamma-glutamyl transpeptidase (GGTP) is raised in the majority of cholestatic illnesses; yet, low or normal levels are reported in patients with progressive familial intrahepatic cholestasis (PFIC) and disorders of bile acid production.
Ultrasonography of abdomen
May provide findings suggestive of Biliary atresia(BA). The triangular cord sign, abnormal gallbladder morphology (not visualized or length 1.9 cm or lack of smooth/complete echogenic mucosal lining with an indistinct wall or irregular/lobular contour), lack of gallbladder contraction after oral feeding, and non-visualized common bile duct (CBD) are characteristics abdominal ultrasonography findings in BA. However, a proximal BA with a distal patent bile duct and a mucus-filled gallbladder is still possible even in the presence of a dilated gallbladder. It is advised that ultrasounds be performed after four hours of fasting. USG can also be used to confirm the existence of other surgically treatable conditions like choledochal cysts, inspissated bile plug syndrome, and choledocholithiasis.
Hepatobiliary-imino-di-acetic acid (HIDA) scan
It plays little role in determining whether a child has neonatal cholestasis , particularly if the baby has clearly apparent pale or pigmented feces. Limitations include the time needed (5-7 days) for priming before the scan, particularly in patients who are referred late.  postponing the liver biopsy in order to obtain a high-quality HIDA scan was not necessary because it may not be possible everywhere in our nation. A liver biopsy can be performed quickly, and a HIDA scan is optional. However, HIDA is helpful in the detection of unusual causes such as spontaneous bile duct perforation. Intra-operative cholangiogram (IOC) remains the gold standard for the diagnosis of BA.
Liver biopsy
A liver biopsy is an essential investigation in the evaluation of neonatal cholestasis. Early recognition of BA by liver biopsy can avoid unnecessary laparotomy. The characteristic histopathology features of BA are bile duct proliferation, bile plugs in ducts, fibrosis, and lymphocytic infiltrates in the portal tracts. If done by qualified medical professionals, a percutaneous liver biopsy within the first few months of life under local anesthesia and sedation is a safe technique
FOR METABOLISM DISORDER
In galactosemia, urine is positive for non-glucose-reducing substances while the infant is on lactose feeds. E. coli sepsis in the presence of liver cell dysfunction is very characteristic of galactosemia. An assay of the Galactose-1 phosphate uridyl transferase (GALT) enzyme is used for confirmation. Mutational analysis of the GALT gene from Indian subjects has revealed heterogeneity in the structure of the gene and the presence of novel mutations. Hereditary fructose intolerance (HFI) is not an uncommon cause of neonatal cholestasis in our country as there are many states where sugar water continues to be given to newborns until lactation is fully established. It should be considered in clinical settings where sucrose or fruit juices have been given to babies. An assay of aldolase B enzyme in liver biopsy sample confirms HFI. The Fructose challenge test can make the child very ill and is now obsolete. Plasma tyrosine levels are unreliable in the diagnosis of tyrosinemia. Measurement of urinary succinylacetone and succinyl acetoacetate or assay of the FAH gene is diagnostic. Markedly raised serum ferritin and uncorrected coagulopathy are suggestive of hemochromatosis that may be confirmed by a buccal mucosal biopsy.
FOR INFECTION
Among the congenital infections, cytomegalovirus (CMV) is most commonly implicated. Serum IgM level is unreliable in diagnosis and should not be used. Assay of pp65 antigen and CMV polymerase chain reaction (PCR) are more specific and reliable if the biochemical tests and histology are consistent with the diagnosis.     
General Medical Management
Most infants with neonatal cholestasis are underweight and will need nutritional support. The goal is to provide adequate calories to compensate for steatorrhea and to prevent/ treat malnutrition. The calorie requirement is approximately 125% of the recommended dietary allowance (RDA) based on ideal body weight. In breastfed infants, breastfeeding should be encouraged, and medium-chain triglyceride (MCT) oil should be administered in a dose of 1-2 mL/kg/d in 2-4 divided doses in expressed breast milk. In older infants, a milk-cereal-mix fortified with MCT is preferred. Adding puffed rice powder and MCT to milk can make feeds energy-dense. Essential fatty acids should constitute 23% of the energy provided. Vegetable protein at 2-3 g/kg/ d is recommended.
Vitamin and mineral supplementation
Infants with neonatal cholestasis require supplementation with fat-soluble vitamins administered orally as water-soluble preparations. In the treatment of vitamin deficiencies, standard deficiency protocols should be followed. 1,25 dihydroxy Vitamin D3 (0.05-0.2 ug/kg/d) is recommended in the presence of significant bone changes or in patients having severe cholestasis. Vitamin K is administered at a dose of 5 mg intramuscular, subcutaneously, or intravenously, at diagnosis to correct the coagulopathy.
Vitamin A
Vitamin D
Vitamin E
Vitamin K
Oral Calcium
Phosphorus
Zinc Magnesium
If the INR is markedly prolonged, intramuscular injections should be avoided. Vitamin supplementation should be continued till 3 months after resolution of jaundice .
Specific treatment
Special infant formula and diets are recommended for children with specific diagnoses (galactosemia, fructosemia, and tyrosinemia). However these formulae are currently not available in India. The group feels that steps must be taken to make them available at the earliest. Treatment with nitisinone (1 mg/kg/d) in addition to dietary restriction leads to rapid reduction of toxic metabolites in tyrosinemia. Specific therapy is recommended for patients with CMV (associated neurological involvement), herpes, and toxoplasmosis-related cholestasis. There is no role for steroids in idiopathic neonatal hepatitis.
Treatment of pruritus
In infants with pruritus due to severe cholestasis, the group recommended, in the following order: Ursodeoxycholic acid (UDCA) (20 mg/kg/d), rifampicin (5-10 mg/kg/d), and phenobarbitone (5–10 mg/kg/d). A symptom chart should be made for pruritus. Depending on the severity and response to the previous agent, an add-on drug can be considered. Appropriate antibiotics depending on the site of infection and culture sensitivity reports need to be administered in patients with bacterial sepsis.
Surgical option
Kasai’s PE consists of removal of the atretic extrahepatic tissue and a Roux-en-Y jejunal loop anastomosis to the hepatic hilum. PE may be considered successful if serum bilirubin normalizes after surgery.In general, over half the patients normalize their bilirubin after Kasai’s PE if performed within 6 months . About 20% of all patients undergoing Kasai’s PE during infancy survive into adulthood with their native liver . In children with progressive familial intrahepatic cholestasis (PFIC) without decompensated cirrhosis, external and internal biliary diversion has been shown to be of benefit. Surgery gives excellent results for choledochal cysts and should be performed as soon as the diagnosis is made. 
Liver transplantation
Standard therapy for 1)Decompensated cirrhosis due to any cause, is now well established in India as well. 2)Any baby with Kasai’s PE and the bilirubin remaining>6 mg/dL, three months after surgery, should be referred to a transplant center. Babies with BA who present with decompensated cirrhosis (low albumin, prolonged INR, ascites) are not likely to improve with a Kasai PE and should be referred for liver transplantation.
FAQ
Is there a cure for neonatal cholestasis?

What is neonatal cholestasis (NC)?

Is percutaneous liver biopsy safe in neonatal cholestasis?

How is cholestasis evaluated in a jaundiced infant?

What is infant jaundice?

How is cholestasis evaluated in a jaundiced infant?