Fetal and Pediatric Pathology, Early Online:1–7, 2015 C Informa Healthcare USA, Inc. Copyright ISSN: 1551-3815 print / 1551-3823 online DOI: 10.3109/15513815.2014.999393
ORIGINAL RESEARCH
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Can Neonatal Hepatitis Be More Fatal than Biliary Atresia? Gulden Diniz,1 Hulya Tosun Yildirim,2 Sebnem Calkavur,3 Cigdem Ecevit,4 Ozgur Olukman,3 Ozlem Bekem Soylu,4 and Safiye Aktas5 1
Department of Pathology, Tepecik Research Hospital, Izmir, Turkey; 2 Department of Pathology, Dr. Behcet Uz Children’s Hospital, Izmir, Turkey; 3 Department of Neonatology, Dr. Behcet Uz Children’s Hospital, Izmir, Turkey; 4 Department of Pediatric Gastroenterology, Dr. Behcet Uz Children’s Hospital, Izmir, Turkey; 5 Department of Pathology, Basic Oncology, Dokuz Eylul University Oncology Institute, Izmir, Turkey
Background/Aims: The basic problem in diagnosis of neonatal cholestasis (NC) is to differentiate biliary atresia (BA) from other non-obstructive disorders. Because if bile flow cannot be provided by surgery, BA leads to cirrhosis and death within the first year of life. The aim of the present study is to determine histopathological features that may help to differentiate BA from neonatal hepatitis (NH). Material and Methods: This retrospective study was carried out on 105 liver biopsy specimens of 74 infants with NC who were diagnosed between 2003 and 2012. Results: The mean age was 76.5 ± 40.64 days. The most valuable biopsy findings for the discrimination between NH and BA, in decreasing order of importance, were ductular proliferation (p < 0.001), cholestasis in neoductuli (p < 0.001), fibrosis (p = 0.002), and extramedullar hematopoiesis (p = 0.02). While Kasai operations were performed in 19 cases, liver transplantation was performed in 10 cases. Survival rate among the death cases with BA was longer than the survival time of the death cases with NH (p = 0.023). Currently more children live with a close to normal quality of life with portoenterostomy and/or liver transplantation. On the contrary, NH can be more fatal with associated disorders such as growth retardation, specific infections, respiratory distress, and metabolic or endocrine diseases. Keywords: biliary atresia, neonatal hepatitis, differential diagnosis
INTRODUCTION Neonatal cholestasis (NC) is characterized by conjugated hyperbilirubinemia with dark urine, and acholic stool persisting more than 2 weeks during the first month of life. The frequency of NC is difficult to evaluate with certainty, but varies between 1:500 and 1:5000 live births [1, 2]. The initial approach in the diagnosis of NC is to distinguish extrahepatitic obstructive causes from non-obstructive intrahepatitic disorders [3]. Biliary atresia (BA) is an idiopathic inflammatory process involving the bile ducts, resulting in obstruction of biliary tract, chronic cholestasis, progressive fibrosis, and eventually biliary cirrhosis. The basic etiology of the disease is still not clear. The Received 7 November 2014; Revised xxxx; accepted 14 December 2014. Address correspondence to Gulden Diniz, Department of Pathology, Tepecik Research Hospital, Izmir, Turkey. E-mail:
[email protected]
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G. Diniz et al.
differential diagnosis of BA includes other disorders of NC such as idiopathic neonatal hepatitis (NH), paucity of the interlobular bile ducts (PIBD), specific infections like rubella, cytomegalovirus infections, toxoplasmosis, and various congenital metabolic disorders like galactosemia, alpha-1-antitrypsin (A1AT) deficiency, hypopituitarism, and others [4]. Because of the similarity of the clinical presentation of NH and BA, many cases of NH are misdiagnosed as BA, resulting in unnecessary exploratory surgery [1–5]. On the other hand, misdiagnosing BA as NH may result in progressive cirrhosis. Therefore, diagnostic accuracy is very important as portoenterostomy, known as Kasai operation, should be performed as early as possible in order to prevent progressive hepatic failure in infants with BA [3]. In the light of this data, the aim of this present study was to assess hepatic histopathological variables that correlate best with the diagnosis of BA, and help distinction from other non-obstructive causes. The second aim was to determine the association between early diagnosis and survival rate of infants with NC. MATERIALS AND METHODS This retrospective study involved 74 newborn infants, 38 (51.4%) with NH and 36 (48.6%) with BA whose diagnoses were confirmed by laparotomy or by follow-up until 1 year of age. The cases were diagnosed, treated, and followed in a Dr. Behcet Uz Children’s Hospital between 2003 and 2012. The inclusion criteria consisted of jaundice beginning at first month of life with hepatic biopsy during the first 6 months of life. Differential diagnosis was done by clinical and physical examination, laboratory findings, ultrasonography, cholescintigraphy, and liver biopsy. A total of 105 liver specimens from 74 patients were evaluated blindly by 2 pathologists (GD and HTY), and 25 patients had both percutaneous and surgical liver biopsy. Several biopsy examinations were required in five patients with non-obstructive cholestasis. The formalin-fixed and paraffin-embedded tissue sections of liver biopsies (needle or wedge) were stained with H&E, Gomori’s reticulin, Gomori’s trichrom, Pearl’s Prussian blue, periodic acid-Schiff (PAS) and PAS with diastase digestion (dPAS). The studied histopathological parameters included parenchymal cholate degeneration, inflammation, ductular proliferation, cholestasis, portal edema, fibrosis, multi-nucleate giant cell transformation, reticular network, Kupffer cell proliferation, extramedullar hematopoiesis and hemosiderin deposits. All histological findings were correlated with clinical features such as gender, age, presence of special diagnosis, survival and treatment modalities. The final diagnosis of the patients were confirmed by laparotomy, necropsy, genetic molecular tests or for idiopathic NH, by the complete resolution of clinical and biochemical parameters on follow-up. Categorical variables were compared by the Pearson’s chi-square test. Comparisons of the continuous variables were performed with the Mann–Whitney U test. A p value