Neonatal giant cell hepatitis: a case study.
Bilirubin is a tetrapyrrole produced primarily by the normal breakdown of heme from haemoglobin following the removal of red cells by the spleen. It is transported to the liver bound to plasma albumin where it undergoes conjugation by the hepatocytes forming the more water soluble form, conjugated bilirubin, and is then released into the bile. Bile is a fluid made by the liver that serves two main functions: carrying toxins and waste products out of the body, including bilirubin, and facilitating the emulsification and digestion of fats. It is also important for absorption of the fat-soluble vitamins A, D, E, and K (1). Bile flow is the key mechanism for bilirubin excretion.
Accumulation of bilirubin in the body produces jaundice (icterus), which is characterized by high plasma bilirubin levels and deposition of yellow bilirubin pigments in the skin, sclera, mucous membranes, and other less visible tissues (1,2). Jaundice due to conjugated hyperbilirubinemia is less common in neonates than that due to unconjugated (albumin bound) hyperbilirubinemia. In neonatal hepatitis and biliary atresia inflammation of bile ducts soon after birth results in obstructive jaundice, and presents with elevated concentrations of conjugated bilirubin. Bile is retained in the liver where it starts damaging and scarring liver cells and if not treated in early stages can lead to end stage liver failure (3).
Possible etiologies for biliary atresia include infections such as cytomegalovirus, Reo virus III, Epstein-Barr virus, rubella virus, as well as alpha-1-antitrypsin deficiency, Down syndrome, and congenital atresia which has been associated with certain chromosome disorders. Acquired biliary atresia may be due to autoimmune inflammation (1). Giant cell hepatitis, however, is usually caused by various degrees of insults to the immature liver, or can be idiopathic. In some cases it may be caused by maternal viral hepatitis (4).
As high levels of unconjugated bilirubin can cause neurological damage (kernicterus) due to its high fat solubility, it is very important to identify the cause for jaundice in neonates (1). High conjugated bilirubin however, can damage liver cells eventually leading to cirrhosis and end stage liver failure if bilirubin is not drained from the liver (5). Both scenarios need timely management.
A twenty-five day old male baby presented to the community laboratory for a bilirubin test. Neonatal bilirubin at LabTests was analysed by a Roche COBAS-501 colorimetric assay. Results are summarised in Table 1. In an attempt to identify babies with biliary atresia early, the laboratory reflex test-adds direct bilirubin to all total bilirubin requests for babies < 1 year old.
The baby was born at 37 weeks weighing 2.3 Kg to an 18-year old mother. He had meconium exposure at birth and several episodes of neonatal hypoglycemia requiring intra-venous dextrose until day 6 of life. The baby was being investigated for prolonged jaundice, had light pale green stools, and a rash. The mother had reported that the jaundice worsened after feeding six-month-old cow's milk formula. No vomiting or fever was reported.
The chest X-ray was unremarkable. Abdominal ultrasound showed a normal size gallbladder with soft markers for increased vascularity and peri-portal echogenicity. Results did not confirm nor exclude biliary atresia. Follow up ultrasound after 3-4 months was advised.
A subsequent liver biopsy showed no cirrhosis, two bile ducts were observed, bile plugging was observed in ductules. Parenchyma showed marked intracellular and extracellular cholestasis with lobular inflammation. Iron deposits were identified in the hepatocytes, peri-portal associated proteins, hepatocyte giant cell transformation, and ballooning degeneration with scattered necrotic individual hepatocytes were observed. These findings were consistent with giant cell neonatal hepatitis.
Laboratory tests for CMV, Enterovirus, Epstein Barr virus, and Parvovirus were negative (not detected). Hepatitis and HIV screen tests were negative and an alpha-1- antitrypsin test was normal.
The baby was prescribed a special milk formula and closely monitored. Bilirubin levels eventually normalized and he eventually gained weight. He is currently well and thriving.
This case shows the importance of testing of conjugated bilirubin in neonates with persistent jaundice. Symptoms of pathological and physiological jaundice can be quite similar but the pathophysiology is different. It is very important to distinguish neonatal hepatitis from biliary atresia as biliary atresia requires surgical therapy but neonatal hepatitis does not. Table 2 summarises causes of neonatal jaundice.
In this case the direct bilirubin concentration was high which indicated pathological jaundice. This could have indicated hepatitis, cholestasis, or some another critical condition such as biliary atresia, giant cell neonatal hepatitis, toxoplasmosis, and intra or extra hepatic obstruction.
X-ray and scan results on day 28 suspected hepatitis but biliary atresia was not excluded. Conjugated hyperbilirubinaemia may be due to decreased secretion of conjugated bilirubin into canaliculi or due to a blockage compromising the drainage of conjugated bilirubin. The baby was prescribed a special milk formula but the mother fed the baby with six-week old cow's milk formula as she ran out of the prescribed formula (Pepti Junior Formula, normally given to babies with cow's milk and soya milk allergies). This could have insulted the immature liver and led to further complications and liver inflammation, necrosis and possibly plugged bile ducts.
Biliary atresia is a life-threatening condition in infants in which the bile ducts inside or outside the liver do not have normal openings. Bile ducts in the liver, also called hepatic ducts, carry bile from the liver to the gallbladder for storage and then to the small intestine for use in digestion (9). Biliary atresia is the most common cause of pediatric end-stage liver failure. Kasai procedure, a surgical which by-passes the bile ducts in neonates, aims to restore biliary flow to the intestine and with this treatment survival rates are 80 to 90% at 4 years. However, if untreated, this disease lead to end stage liver failure and death by age of 3 years (5).
Nutrition and special diet therapy is very important for hepatitis as in the absence of bile acids protein and fats absorption is impaired (6). After three weeks the baby was doing well and had a weight gain of 4.0 Kg (birth weight: 2.3 Kg) and the total bilirubin was significantly lower (40 [micro]mol/L).
In conclusion, neonatal giant cell hepatitis is common in neonates but rare in the adult population. Radiological investigations, liver biopsy, and series of biochemical tests are needed to differentiate biliary atresia from this disorder.
Vanita Patil, BMLSc MSc, Senior Scientist  Samarina Musaad, PGDipPH FAACB FRCPA, Pathologist [1,2]
 Department of Biochemistry, Labtests, Auckland
 Department of Chemical Pathology, LabPlus, Auckland
Correspondence: Vanita Patil. Email: firstname.lastname@example.org
[1.] Hartley JL, Davenport M, Kelly DA . Biliary atresia. Lancet 2009: 374: 1704-1713.
[2.] Fieldman AG, Sokol RJ. Neonatal cholestasis. Neoreviews 2013:14: e63-e73.
[3.] Tietz Textbook of Clinical Chemistry and Molecular Diagnosis. (Fifth edition). 2012. Elsevier, St Louis, USA.
[4.] Collins DL. Neonatal hepatitis; including case associated with maternal hepatitis during pregnancy. Can Med Assoc J 1956:15: 828-832.
[5.] Lam L, Mussad S, Kyle C, Mouat S. Utilization of reflex testing for direct bilirubin in the early recognition of biliary atresia. Clin Chem 2017: 63: 973-979.
Vanita Patil  and Samarina Musaad [1,2]
 Labtests and  LabPlus, Auckland
Caption: Table 2. Physiological classification of jaundice.
Table 1. Laboratory results. Analyte 31/7/2017 1/8/2017 17/8/2017 Labtests LabPlus LabPlus [Na.sup.+] mmol/L 140 141 [K.sup.+] mmol/L 4.6 4.7 [Cl.sup.-] mmol/L 105 103 Creatinine [micro]mol/L <20 <20 Total bilirubin [micro]mol/L 176 167 156 Direct bilirubin [micro]mol/L 151 145 161 Total protein g/L 49 50 Albumin g/L 27 31 ALT IU/L 289 215 Alkaline phosphatase IU/L 697 1133 Gamma glutamyl transferase IU/L 57 94 AST IU/L 654 586 Analyte Reference range [Na.sup.+] mmol/L 135-145 [K.sup.+] mmol/L 3.3-5.4 [Cl.sup.-] mmol/L 95-110 Creatinine [micro]mol/L <20 Total bilirubin [micro]mol/L up to 24 hrs <150; 24 to 48 hrs <200; 48 to 72 hrs <250; 3 to 7 days <300; 7 to 3 weeks <100; 3 to 4 weeks <50; 4 weeks to adult <25 Direct bilirubin [micro]mol/L one month <25; adult <5 Total protein g/L < one month: 45-65 Albumin g/L 0 to 3 month: 25-40 ALT IU/L <45 Alkaline phosphatase IU/L male 0-10 years: 80-350 Gamma glutamyl transferase IU/L <150 AST IU/L <80
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|Title Annotation:||CASE STUDY|
|Author:||Patil, Vanita; Musaad, Samarina|
|Publication:||New Zealand Journal of Medical Laboratory Science|
|Article Type:||Case study|
|Date:||Aug 1, 2018|
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