Definition

Neonatal cholestasis refers to conjugated hyperbilirubinemia >1.5–2 mg% in a newborn/infant with passage of high coloured urine with or without clay stools, commonly presenting as jaundice with dark urine with deep yellow staining of the nappy and light colored or white stools. It occurs with a frequency of 1 in 2500 live births.

In neonates who present with cholestasis it is very important to quickly differentiate between medical and surgical causes, so that an early decision can be made for surgical intervention as delay beyond 6–8 weeks of age is associated with adverse outcome. Features which point towards medical causes of cholestasis are low birth weight or growth restricted babies, signs of sickness in for of features of sepsis, encephalopathy, failure to thrive, exposure to potentially toxic substances, prolonged parenteral nutrition and stigmata of intrauterine infections. Some of them may have history of consanguinity and dysmorphic features. Babies with of surgical causes cholestasis are usually full term healthy neonates at birth, thrive well till they develop complications related to liver failure. Many have hepatomegaly with or without splenomegaly.

What is the need for Early Diagnosis?

Prompt identification and diagnostic assessment of infant with cholestasis is most essential.

For early surgical intervention e.g. Extra epatic biliary atresia (EHBA). The success of surgical correction of biliary atresia (Kasai's operation) is significantly reduced if it is performed after 6–8 weeks of age.

To recognize disorders amenable to specific medical therapy e.g. sepsis/galactosemia/hypothyroidism etc. so to prevent neurodevelopmental delay.

To institute early conservative/empiric management.

Etiology

Neonatal cholestasis results from intrahepatic and extrahepatic causes. Intrahepatic causes could be further divided into hepato cellular and paucity of intra hepatic ducts. Figure 1 depicts the etiology of neonatal cholestasis. Figure 1Etiology of Neonatal cholestasis

Approach to a Case of Neonatal Cholestasis

History A detailed history regarding current illness including information on

Dark colored urine and clay colored stool

Birth weight & gestation

Antenatal history for intrauterine infections

Family history

Exposure to toxins and drugs e.g. TPN

A child with biliary atresia is usually a term baby with normal birth weight and accepting feeds well. Pigmented stools do not rule out biliary atresia, upto 30% of biliary atresia stools are yellow in the early weeks.

Clinical Evaluation One can get important clues from clinical evaluation:

A sick baby is usually secondary to sepsis, UTI, congenital infections and metabolic disorders.

Dysmorphic features - Down's syndrome, Alagille's syndrome etc.

Increased incidence of associated anomalies like polysplenia, situs inversus, cardiac anomalies, malrotation of gut etc. with EHBA.

Examination of the eye and the fundus e.g. cataract in galactosemia, chorioretinitis in TORCH infections, posterior embryotoxon in Alagille's syndrome, cherry red spot in lipid storage disorders, etc.

InvestigationsAims

To identify treatable conditions

To differentiate between medical and surgical conditions

Recognize complications

Early referral

First Phase Investigations Prothrombin time, Blood counts, Liver function tests, Electrolytes, Blood culture, Urine culture, Urine microscopy, Urine reducing substances, Random blood glucose (Pre feed), Ascitic tap (if ascites) and Thyroid function tests (TSH, Free T₄).

Raised prothrombin time usually responds to vitamin K unless there is advanced liver disease with liver failure or cirrhosis. Liver failure is more commonly seen in galactosemia, tyrosinemia, neonatal hemachromatosis, sepsis or later in course of biliary obstructions.

Standard LFTs are usually abnormal with modestly raised levels of AST, ALT, and alkaline phosphatase.

GGT is raised in all cases of cholestasis except in one of the bile acid synthetic defects and progressive faimilial intrahepatic cholestasis type 1 and 2. Markedly raised GGT is seen more often in biliary atresia.

Serum albumin does not fall till late.

None of the biochemical tests differentiate neonatal hepatitis from biliary atresia and at best reflect the degree of damage to liver.

Subsequent Investigations At this juncture the treating clinician must try to differentiate between medical and surgical jaundice. If the baby is sick then the tests should be directed towards infective and metabolic causes. However, simultaneously one must investigate to rule out EHBA. As per the clinical suspicion one may proceed with following investigations.

Second Phase Investigations to rule out medical causes TORCH, VDRL, Hepatitis B/C, HIV, Hbs Ag, HCV Ab, T4, TSH, Serum cortisol, Galactose 1 Phosphate Uridyl transferase (to r/o galactosemia), Urinary succinyl acetone (to r/o tyrosinemia), Cholesterol, triglycerides, S. iron and ferritin levels (to r/o neonatal hemachromatosis), alpha 1AT levels and genotype. Bone marrow aspiration (Storage disorders like Niemanpick's, Gauchers). Skin biopsy, muscle biopsy, white cell or skin fibroblast enzyme assay. Serum lactate/pyruvate/ammonia levels, very long change fatty acids, urinary branched chain amino acids and urinary organic acids (to rule out metabolic diseases like mitochondrial defects, glycogen storage defects, urea cycle disorders etc.)

Second Phase Investigations to rule out surgical causes Tests that help to differentiate between neonatal hepatitis and biliary atresia include ultrasound abdomen, HIDA scan and liver biopsy.

Figure 2 depicts the algorithmic approach to evaluation and management of a case with neonatal cholestasis. Figure 2Algorithmic approach to evaluation and management of a case with Neonatal cholestasis.

Role of USG

It is the first non-invasive investigations which can exclude choledochal cyst, any focal leisons, dilated CBD, anomalies of viscera or portal hypertension. This should be done with the baby fasting for at least 4 hours. A normally distended gall bladder on fasting which contracts on feeding, virtually rules out biliary atresia.

Role of HIDA scan

Hepatobiliary scintigraphy basically rules out total from partial cholestasis. It is a sensitive (approx. 97%) test for diagnosis of EHBA but it is not very specific for it (50 – 80%) i.e. failure of excretion of dye in biliary tree could result from EHBA or marked intrahepatic cholestasis, but visualization of the tracer in intestinal tract (esp. within 4 hours) virtually rules out biliary atresia.

Priming the patient with phenobarbitone (5 mg/kg) for 5 days prior to the test enhances hepatic uptake and excretion of the dye, thereby improving accuracy of the test.

Role of Liver Biopsy

Paucity of intrahepatic ducts

Etiology of neonatal hepatitis e.g. alpha 1 AT deficiency, CMV hepatitis, storage disorders etc.

Helps to prognosticate as it can grade and stage liver disease.

Where liver biopsy is inconclusive a per-operative cholangiography is performed to confirm or rule out biliary atresia.

Role of MRCP and ERCP in newborns to rule out biliary atresia is still limited.

Treatment

On suspicion of cholestatic liver disease, vitamin-K is started along with supplementation of other fat soluble vitamins (A,D,E,). Supportive management along with treatment of underlying cause if any is the main stay of treatment. Therefore treatment is aimed at improving nutritional status, reducing discomfort, early diagnosis and management of complications.

For surgical jaundice e.g. Extra epatic biliary atresia (EHBA) or cholecochal cyst, definitive surgical procedures like Kasai's operation should be performed before 6–8 weeks of age.

Liver Transplantation

This may remain the only option for infants with decompensated liver disease (ascites and/or encephalopathy) or failed portoenterostomy. Biliary Atresia is the commonest cause of liver transplantation in young children. There has been a dramatic increase in the survival rates through out the 1990’s with most international centres reporting one year survival rates of between 85%–90% and a 5–8 years survival rates of more than 80%.

Conclusion

New born babies having jaundice beyond 14 days of age with dark urine with or without acholic/pale stools should be investigated further without delay. The investigations need to be carried out on an emergency basis to identify treatable causes of neonatal cholestasis, both medical conditions like galactosemia, tyrosinaemia, hypothyroidism and infections etc. and surgical ones especially EHBA wherein the success of definitive medical management or surgery is significantly reduced if it is performed after 6 – 8 weeks of age.

Jaundice when it becomes surgical: Approach and management