Approach to a case of Neonatal Cholestasis Ira Shah (Co-Incharge, Consultant Pediatrician, Pediatric Liver Clinic) Gunjan Narkhede (Resident in Pediatric Liver Clinic) Pediatric Hepatobiliary Clinic, B.J.Wadia Hospital For Children, Mumbai. Email: irashah@pediatriconcall.com Introduction: Neonatal cholestasis accounts for almost 30% of pediatric hepatobiliary diseases. It requires prompt evaluation and management as some of the causes are fatal in early life if untreated whereas others cause substantial morbidity by causing chronic liver disease. It is defined as prolonged elevation of conjugated bilirubin beyond 14 days of life (i.e. the conjugated fraction >20% of total bilirubin.). Conjugated Jaundice that appears within 3 months of life is called as neonatal cholestasis. History of jaundice with high coloured urine (often noted as yellow staining of diapers), clay coloured /light stools with or without hepatomegaly is suggestive of cholestasis. Thus any jaundice that persists beyond 2 weeks of life, progresses after this time or does not regress by this time get a serum bilirubin done with a conjugated fraction. Etiology: The cause of neonatal cholestasis can be genetic, metabolic, infectious or undefined causing - mechanical obstruction of bile flow e.g. Biliary atresia or bile acid secretion or functional impairment of hepatic excretory e.g. Congenital infections. The common causes of Neonatal cholestasis include: 1. Obstructive causes: Biliary Atresia, Choledochal cysts 2. Infections TORCH infections, Reo virus and Group C rotavirus infections 3. Metabolic Tyrosinemia, Fructosemia, galactosemia, Hypothyroidism, Panhypopituitarism 4. Genetic Alagille syndrome, Progressive familial intrahepatic cholestasis (PFIC), bile acid defects, Cystic fibrosis 5. Storage Niemann Pick Disease C. 6. Idiopathic Why is neonatal cholestasis an emergency? Neonatal cholestasis is an emergency as timely intervention can prevent liver cirrhosis and death. Biliary atresia is an emergency as prognosis depends on age of presentation, age of operation, expertise of the surgeon and the bile duct size at the time of porta. At our center, incidence of Biliary Atresia amongst neonatal cholestasis syndrome is 36.4%. We see about 45-50 new patients of neonatal cholestasis syndrome per year in our Pediatric Liver Clinic. The mean age of presentation of patients with biliary atresia is 89 days + 55.8days. (almost 3 months). Those with bile duct sizes >200microns had better prognosis than those with sizes 100-200 microns (Odd s ratio=1.8) and <100microns (Odd s ratio=3). Operation before 3 months had a better prognosis as compared to operation after 3 months of age. (Odd s ratio = 2). (1) Other conditions such as Galactosemia and metabolic disorders are also urgent as timely intervention can prevent irreversible liver damage. At our center, common causes of neonatal cholestasis have included Biliary atresia, CMV infection, galactosemia, alagille syndrome, PFIC and idiopathic causes. Thus urgent diagnosis becomes essential in these conditions.
Investigations Lets take a short overview of the investigations helpful in diagnosis. Investigations of preference depend on the clinical presentation of the patient. Usual investigations done are : Test Serum bilirubin fractionation Liver function tests including GGTP and alkaline phosphatase Assessment of stool colour Implication Confirms cholestasis High GGTP with high alkaline phosphatase suggests obstruction Low GGTP with high alkaline phosphatase suggests PFIC Normal GGTP and normal alkaline phosphatase may suggest non-obstructive causes Indicates bile flow into intestine. Clay coloured stools suggests obstruction Urine/serum bile acid measurement Confirms cholestasis USG HIDA scan Suggests/excludes choledochal cyst, may show triangular cord sign suggestive of biliary atresia. Confirms flow of bile into the intestine though absence of same does not confirm atresia- can occur in severe hepatitis. Depends on the liver function and low uptake of the tracer by liver due to poor function can lead to poor excretion and false sense of obstructions Specific investigations: Thyroxine and TSH Sweat chloride Urine/plasma amino acids,urine reducing substance TORCH titres Hypothyroidism, panhypopituitarism Cystic fibrosis Metabolic liver disease For congenital infections 2 D Echo For Alagille syndrome and congenital infections Hearing and Ophthalmology examination Liver biopsy Intra operative cholangiogram For hearing loss and chorioretinitis respectively for congenital infections Most valuable- Biliary atresia- bile ductular proliferation,portal/perilobular fibrosis, BUT BAISC ARCHITECTURE INTACT; Neonatal hepatitis- severediffuse hepatocellular disease,distortion OF LOBULAR ARCHITECTURE,marked infiltration with inflammatory cells,focal hepatocellular necrosis. A low threshold should be kept for IOC in patients with clay stools without waiting for HIDA as HIDA is very often
inconclusive. How to differentiate biliary atresia from non-obstructive causes? This simple table will help to differentiate between obstructive and non-obstructive causes. However it may not be the same all the time and thus an individual based approach will be essential. Obstructive causes Non-obstructive causes Full term Normal birth weight No ANC/PNC complications CLAY COLOURED STOOLS Growing well Usually isolated hepatomegaly Preterm/Full term AGA/LBW ANC- fever, rash, lymphnodes Yellow stools Failure to thrive Hepatosplenomegaly Approach to Neonatal Cholestasis: Consensus Report on Neonatal Cholestasis Syndrome by Pediatric Gastroenterology Subspecialty Chapter of Indian Academy of Pediatrics (Indian Pediatrics 2000;37: 845-851) has suggested the following algorithm for approach to Neonatal cholestasis. (2)
* Babies with NCS due to infections of Herpes, Toxoplasmosis and rarely CMV may be sick, look for their extra hepatic manifestations. Stop milk feeds till galactosemia is ruled out. In febrile babies, look for malarial parasite, sepsis and UTI. ** This is to look for galactose in urine while on milk feeds. If reducing substances are positive, check urine samples with glucose stick. If negative, most likely reducing substances in urine are due to galactose. Treat as galactosemia. GALI-PUT should be done to confirm the diagnosis. However there may be instances where liver biopsy may be inconclusive due to improper reporting or due to evolving disease and in such instances either serial liver biopsies or urgent cholangiogram may be needed to find out the cause. (3). Thus based on our clinical experience of over 200 patients, where the only clinical marker for biliary atresia was clay stools (4) we have modified our approach to neonatal cholestasis as follows: Approach to Neonatal Cholestasis (Wadia Protocol)
* Liver biopsy and Intraoperative cholangiogram are done depending on the reports of the tests in patients with yellow stools. Conclusion: Neonatal cholestasis syndrome is a hepatobiliary emergency and timely referral is essential to avoid irreversible liver damage. References: 1. Sanghai Saket, Shah Ira, Bhatnagar Sushmita. Incidence and Prognostic factors associated with Biliary Atresia in Western India. Annals Hepatol. 2009; 8: 120-122. 2. Pediatric Gastroenterology Subspecialty Chapter of Indian Academy of Pediatrics. Consensus Report on Neonatal Cholestasis Syndrome. Indian Pediatrics 2000;37: 845-851 3. Sweta Mohanty, Ira Shah, Sushmita Bhatnagar. Evolving Biliary Atresia With Cytomegalovirus. Accepted For Publication In Indian Pediatrics. 2010 4. Ira Shah, Sushmita Bhatnagar. Clinical and Laboratory Markers predictive of Biliary Atresia. Mahapedicon 2008, Mahabaleshwar, 14-15 th November 2008.