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CASE REPORT
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Neonatal giant cell hepatitis secondary to extrahepatic biliary atresia associated with choledochal cyst


 Department of Pathology, K S Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, Karnataka, India

Date of Submission22-May-2020
Date of Decision21-Sep-2020
Date of Acceptance29-Sep-2020

Correspondence Address:
Shubha P Bhat,
Department of Pathology, K S Hegde Medical Academy, Nitte Deemed to be University, Mangalore - 575 018, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_273_20

  Abstract 


Neonatal hepatitis (NH) and biliary atresia (BA) are the most common causes of cholestasis in infancy. NH is a nonobstructive type of neonatal cholestatic syndrome manifesting with hepatitis. BA is an obstructive inflammatory syndrome of the extrahepatic biliary tract. BA accounts for 40% of cholestasis in infancy, and NH accounts for 10%–15% cases of neonatal cholestasis. Choledochal cyst is a congenital abnormality characterized by cystic dilatation of the biliary tree. The clinical presentation of these two conditions is very much similar and hence poses a challenge for diagnosis. Radiological studies are beneficial for the preliminary diagnosis of BA and choledochal cyst. BA and choledochal cyst are amenable to surgical treatment, while NH is not. Histopathological examination of the liver biopsy helps differentiate BA from NH.

Keywords: Biliary cirrhosis, choledochal cyst, extrahepatic biliary atresia, neonatal giant cell hepatitis



How to cite this URL:
Hidangmayum A, Bhat SP, Teerthanath S, Kishan Prasad H L, Sajitha K. Neonatal giant cell hepatitis secondary to extrahepatic biliary atresia associated with choledochal cyst. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Feb 28]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=308998




  Introduction Top


Neonatal hepatitis (NH) is best considered a clinicopathological syndrome and does not represent a distinct pathologic disease entity. Neonatal giant cell hepatitis (NGCH) and idiopathic neonatal hepatitis (INH) are used synonymously in infant cholestatic disorders.[1] NH accounts for about 10%–15% of cholestasis.[2] Potential etiologies include intrauterine infections such as TORCH; endocrinal causes such as hypothyroidism, hypopituitarism, and inherited diseases such as α1-antitrypsin deficiency; metabolic disorders such as glycogen storage disease, tyrosinemia, and disorders of glycolipid and lipid metabolism; and chromosomal anomalies such as trisomy 18 and trisomy 21.[3] Histologically, NGCH is characterized by cholestasis with the varying transformation of hepatocytes into multinucleated giant cells and extramedullary hematopoiesis.[4] In later stages, periportal fibrosis can be seen, ultimately resulting in biliary cirrhosis. Biliary atresia (BA) refers to complete or partial obstruction of the extrahepatic biliary tree. The reported incidence is high in Taiwan, accounting for 1 in 5600 live births, to as low as 1 in 18,000 live births in Europe.[5],[6] There are two clinical patterns of BA – a perinatal (or acquired) form and an embryonic form. The perinatal form of BA is asymptomatic and anicteric at birth and develops jaundice during the first postnatal weeks, whereas the infants with the embryonic form are icteric at birth.[7] Helpful investigations are liver function tests, coagulation profile, and Ultrasonography (USG) of the abdomen to exclude the presence of an extrahepatic biliary tract anomaly such as a choledochal cyst. Liver biopsy and histopathological examination are the cornerstones for the diagnosis. Histological features of BA include ductular reaction, portal edema, and fibrosis with hepatocanalicular cholestasis. Around 35% of the BA shows giant cell transformation of hepatocytes. The primary treatment of BA is always surgical.[4],[5] Overall, the 5-year and 10-year survival rates are about 50% and 30%, respectively. Herein, we present a case of NGCH with biliary cirrhosis, secondary to extrahepatic BA and choledochal cyst in a neonate.


  Case Report Top


A 44-day-old female baby was brought to our hospital for the management of enteric duplication cyst, diagnosed during the antenatal period. The baby was a term baby, born by vaginal delivery. The postnatal period was uneventful. On examination, there was icterus. There was no staining of diaper or history of dark stools. Per-abdominal examination revealed an enlarged, palpable liver, 4 cm below the right costal margin. The liver span was 9 cm and was firm in consistency. Preliminary laboratory investigations revealed a hemoglobin value of 9.8 gm%, total bilirubin of 6.89 mg/dl, direct bilirubin of 3.21 mg/dl, deranged coagulation profile with prolonged prothrombin time (PT) of 81.1 s, international normalized ratio of 8.1, and activated partial thromboplastin time (APTT) of 87.8 s. Ultrasonography (USG) of the abdomen showed a well-defined thin-walled cystic lesion in the region of porta hepatis measuring 1.4 cm × 1.8 cm, anterior to the portal vein, communicating superiorly with common hepatic duct and inferiorly extending posteriorly to the first part of the duodenum. The liver was 7.2 cm in size and mildly enlarged. The cyst had a beak-like extension into porta hepatis with a suspicious communication with the cystic duct. A provisional diagnosis of choledochal cyst Type I was performed and advised magnetic resonance cholangiopancreatography (MRCP). MRCP revealed dilatation of the entire extrahepatic duct measuring 13 mm in diameter [Figure 1]. The baby was stabilized with Vitamin K and other supportive measures.

During laparotomy, a choledochal cyst of Type 1 was noted. Distal to the cyst, the common bile duct (CBD) was blind-ending and fibrous, and proximal to the cyst was a fibrotic band. The gallbladder was pale and atretic with no bile. Right and left hepatic ducts were fibrosed and cord-like with no lumen. The liver appeared to be cirrhotic. Kasai's procedure could not be done as the CBD was blind-ending and fibrous. Cholecystectomy with excision of choledochal cyst and resection of the fibrosed right and left hepatic ducts along with a biopsy of the liver was done. The specimen of the gallbladder along with a choledochal cyst, a resected fibrosed confluence of the hepatic duct, and a liver biopsy [Figure 2] was received for histopathological examination. The gallbladder was atretic, measuring 1.5 cm × 0.6 cm. The outer surface of the gallbladder at the one end appeared to be dilated with no bile within. The choledochal cyst measured 2.5 cm × 1.5 cm × 1 cm and had a smooth inner wall. The hepatic ducts measured 1.5 cm × 0.6 cm × 0.4 cm, which on cutting through had a thickened fibrotic wall with a narrowed lumen. The liver biopsy specimen consisted of bile-stained liver tissue measuring 0.6 cm × 0.4 cm × 0.3 cm.
Figure 1: Magnetic resonance cholangiopancreatography showing dilatation of the extrahepatic duct (arrow)

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Figure 2: Gross specimen of the atretic gallbladder (arrow) along with choledochal cyst (arrowhead), fibrosed confluence of the hepatic duct (asterisk)

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Microscopy of the choledochal cyst showed denuded mucosa lined by the granulation tissue. Subepithelial tissue showed glands. The wall showed loose fibrocollagenous tissue and congested capillaries [Figure 3]. The atretic gallbladder showed columnar epithelium with attenuation at places. Subepithelium showed scattered lymphocytes and congested blood vessels in the serosa [Figure 4]. The bile duct showed denuded mucosa. The wall showed glands and dense fibrosis. Separately sent right and left hepatic duct showed duct with near-total occlusion of the lumen lined focally by columnar epithelium with denudation. Subepithelium showed congested blood vessels and glands surrounded by lymphoplasmacytic. The wall was fibrotic [Figure 5]. Sections studied from the liver biopsy showed liver tissue showing lobular disarray [Figure 6] with hepatocytes transformed into syncytial multinucleated giant cells containing bile pigment in the cytoplasm [Figure 7]. Residual hepatocytes showed features of ballooning degeneration. Sinusoids were dilated and congested. The portal tract showed ductular proliferation with fibrosis and scattered lymphocytic infiltrate. Bridging fibrosis was seen [Figure 8]. Reticulin stain showed intense staining of the fibrotic bands, which divide the liver parenchyma into nodules [Figure 9]. Features were suggestive of NH with biliary cirrhosis secondary to extrahepatic BA with Type 1 choledochal cyst.
Figure 3: Microscopy of choledochal cyst, with denuded mucosa and wall showing loose fibrocollagenous tissue and congested capillaries (H and E, ×10)

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Figure 4: Microscopy showing atretic gallbladder lined by columnar epithelium with attenuation at places (H and E, ×10)

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Figure 5: Microscopy of the hepatic duct with near-total occlusion of the lumen caused due to dense fibrotic wall (H and E, ~10)

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Figure 6: Microscopy of the liver biopsy showed lobular disarray and congested sinusoids (H and E, ×10)

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Figure 7: Hepatocytes transformed into syncytial multinucleated giant cells containing bile pigment in the cytoplasm (H and E, ×40)

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Figure 8: Portal tract showing ductular reaction with bridging fibrosis and scattered lymphocytic infiltrate (H and E, ×10)

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Figure 9: Reticulin stain showed intense staining of the fibrotic bands dividing the liver parenchyma into nodules, ×10

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As the liver was in the cirrhotic stage, the parents were counseled regarding the urgent need for liver transplantation. They were referred to a higher center for liver transplantation and further management. However, transplantation could not be done, and the baby succumbed to the disease 4 months postsurgery.


  Discussion Top


NGCH clinically presents within the first 3 months of life as jaundice due to conjugated hyperbilirubinemia. It encompasses a constellation of symptoms and signs associated with infections and metabolic and genetic diseases, thus directing clinicians to search for underlying specific etiology for cholestasis. If no underlying cause can be detected, the term “INH” is used.[8] The necessary investigations should include serum bilirubin levels, Coomb's test, and serology for toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes simplex, hepatitis A, B, and C, and human immunodeficiency virus.[9] In our case, the child had conjugated hyperbilirubinemia along with elevated PT and APTT. Furthermore, an abdominal USG of the abdomen must be done to look for any structural anomaly of the liver and the biliary tree. The histopathological findings in the liver biopsy tissue usually reveal cholestasis with the varying transformation of hepatocytes into multinucleated giant cells and extramedullary hematopoiesis. Occasionally, parenchymal siderosis, intralobular fibrosis, and increasing perivenular, pericellular, and periportal fibrosis are seen that may eventually evolve into cirrhosis. A mild ductular reaction may be seen. Large multinucleated hepatocytes with or without bile pigment are common findings in infants with liver disease, regardless of the etiology, and thus, are considered a nonspecific reactive change. Multinucleated hepatocytes are formed as a result of the breakdown of the syncytial cell-to-cell borders with the canalicular aspects of the cell membrane partially preserved. These giant cells exhibit multiple nuclei, either scattered throughout the cytoplasm or clustered toward one pole of the cell. Multinucleated giant cell change is unusual in adult liver cell injury.[8] The management of infants with INH is supportive, which includes adequate nutrition. The prognosis for NH syndrome is generally considered favorable when the liver disease resolves over the 1st year of life, with the mortality rate being 13%–25%. Predictors of a poor clinical outcome include severe or prolonged (>6 months) jaundice, acholic stools, familial occurrence, and persistent hepatomegaly.[9]

BA presents as a progressive obstructive cholangiopathy affecting extrahepatic ducts, leading to cholestasis, fibrosis, and cirrhosis. It is classified based on the extent of biliary damage as – Type I BA that affects the CBD with a cystic proximal duct; Type II that affects the common hepatic duct; and Type III being the most common that involves the entire extrahepatic biliary tree.[10] There are two clinical phenotypes of BA: a perinatal (or acquired) form seen in 80% of affected infants and an embryonic form often associated with congenital anomalies such as preduodenal portal vein, midline symmetric liver, intestinal malrotation, situs inversus, asplenia, and polysplenia.[11] The etiology of BA remains unknown. Defects in morphogenesis, immunological dysregulation, and viral infections such as cytomegalovirus, reovirus, and rotavirus, resulting in autoimmune-mediated bile duct injury, have been proposed.[12] Infants with BA typically have normal gestational age and birth weight with cholestatic jaundice as the primary clinical presentation. Investigations show hyperbilirubinemia, altered liver function test, and an abdominal USG showing a small or absent gallbladder.[13] In our case, BA was an intraoperative finding which showed atretic gallbladder and bile ducts. The right and left hepatic ducts were fibrosed and cord-like with no lumen. Histopathological findings of liver biopsy exhibit proliferation of the bile ducts, portal edema, and fibrosis and hepatocanalicular cholestasis.[6] In later stages, periportal fibrosis can be seen, ultimately resulting in biliary cirrhosis. Around 35% of the cases show a giant cell transformation of hepatocytes. The primary treatment of BA is always surgical, which includes hepatic portoenterostomy or Kasai's operation with resection of the obliterated extrahepatic ducts.[4] In our case, Kasai's procedure could not be done as the CBD was blind-ending and fibrous. Biliary cirrhosis occurs if there is cholestasis for >2 months. Other complications include recurrent episodes of ascending cholangitis or sepsis due to the immediate proximity of the bowel segment to the porta hepatis of the residual biliary tree, growth failure, malnutrition, deficiencies of lipid-soluble vitamins, and altered protein-energy and nutrient utilization.

In our case, liver biopsy tissue sections showed features of BA as well as NGCH. There was lobular disarray with hepatocytes transformed into syncytial multinucleated giant cells containing bile pigment in the cytoplasm along with ballooning degeneration of the residual hepatocytes. In addition, the portal tract showed a ductular reaction with fibrosis and scattered lymphocytic infiltrate. Bridging fibrosis causing parenchymal nodules supported by reticulin stain was also seen. Hepatic ducts and bile ducts showed fibrosis of the wall along with atretic gallbladder tissue. Findings were suggestive of NGCH with biliary cirrhosis secondary to extrahepatic BA.

Choledochal cyst is a rare congenital abnormality characterized by cystic dilatation of the biliary tree. It is of unknown etiology, commonly seen in females than males. The estimated incidence in the Western population is one in 100–150 thousand live births. It can present anytime between birth to 16 years, with a median age of 2.2 years.[14] Clinical manifestations include jaundice, abdominal pain, or mass. The Todani classification of bile duct cysts divides choledochal cysts into five groups – Type 1 to Type V of which Type I accounts for 80%–90% of cases. Type I choledochal cyst is characterized by fusiform dilation of the extrahepatic bile duct. It has been subclassified as – Ia: dilatation of entire extrahepatic bile duct; Ib: focal segmental dilatation of extrahepatic bile duct; and Ic: dilatation of the CBD portion of the extrahepatic bile duct. These cysts are formed as a result of the reflux of pancreatic secretions into the bile duct through an anomalous pancreaticobiliary junction. Type II arises from the supraduodenal extrahepatic bile duct or the intrahepatic bile ducts. Type III also is known as a choledochocele and represents protrusion of a focally dilated, intramural segment of the distal CBD into the duodenum. Type IV is characterized by multiple communicating intra- and extrahepatic duct cysts. Type V, also known as Caroli disease, is a rare form of congenital biliary cystic disease manifested by cystic dilations of intrahepatic bile ducts. The choledochal cyst can be discovered by antenatal USG as early as 16 weeks of gestation.[13] Radical cyst excision and reconstruction with a Roux-en-Y hepaticojejunostomy are now established as the treatment of choice for choledochal cyst. Histologically, there will be chronic inflammation of the wall, and the epithelial lining is often denuded, intact, or absent. Infants usually have an intact columnar epithelium and scant inflammation.


  Conclusion Top


There are many causes of cholestasis in infants, of which the two most common causes are BA and NH. Both have a similar clinical presentation, and thus, diagnosis can be challenging at times. The workup protocol of such patients should include a detailed history, liver function test, and coagulation profile, along with other imaging modalities such as USG and MRCP. Liver biopsy is the cornerstone of diagnosis. The histologic spectrum of NH includes giant cell change of hepatocytes, intralobular cholestasis, and necrosis of hepatocytes. BA shows ductular proliferation, periportal inflammation, and fibrosis with or without the histological features of NH. Around 35% of the cases show a giant cell transformation of hepatocytes. Hence, histopathological examination of liver tissue supported by radiological findings is useful in diagnosis.

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  References Top

1.
Correa KK, Nanjundiah P, Wirtschafter DD, Alshak NS. Idiopathic neonatal giant cell hepatitis presenting with acute hepatic failure on postnatal day one. J Perinatol 2002;22:249-51.  Back to cited text no. 1
    
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Kheir AE, Ahmed WM, Gaber I, Gafer SM, Yousif BM. Idiopathic neonatal hepatitis or extrahepatic biliary atresia? The role of liver biopsy. Sudan J Paediatr 2016;16:58-62.  Back to cited text no. 2
    
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Lai MW, Chang MH, Hsu SC, Hsu HC, Su CT, Kao CL, et al. Differential diagnosis of extrahepatic biliary atresia from neonatal hepatitis: A prospective study. J Pediatr Gastroenterol Nutr 1994;18:121-7.  Back to cited text no. 3
    
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Arroyo M, Crawford JM. Pediatric liver disease and inherited, metabolic, and developmental disorders of the pediatric and adult liver. In: Odze R, Goldblum J, editors. Surgical Pathology of the Gi Tract, Liver, Biliary Tract and Pancreas. Philadelphia: Saunders; 2009. p. 1245-90.  Back to cited text no. 4
    
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Feldman AG, Mack CL. Biliary atresia: Clinical lessons learned. J Pediatr Gastroenterol Nutr 2015;61:167-75.  Back to cited text no. 5
    
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Yoon PW, Bresee JS, Olney RS, James LM, Khoury MJ. Epidemiology of biliary atresia: A population-based study. Pediatrics 1997;99:376-82.  Back to cited text no. 6
    
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Lamps LW. Liver: Non-neoplastic diseases. In: Goldblum JR, Mckenney JK, Myers JL. editors. Rosai and Ackerman's Surgical Pathology. 11th ed. Philadelphia: Elsevier; 2011. p. 764-5.  Back to cited text no. 7
    
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Theise ND. Liver and bile ducts. In: Kumar V, Abbas AK, Jon C, editors. Robbins and Cotran Pathologic Basis of Disease: South Asia Edition. 9th ed. India: Elsevier; 2015. p. 856-8.  Back to cited text no. 8
    
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Andrianov MG, Azzam RK. Cholestasis in infancy. Pediatr Ann 2016;45:e414-9.  Back to cited text no. 9
    
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Siew AM, Kelly DA. The liver in the neonate, in infancy and childhood. In: Dooley JS, Lok AS, Garcia-Tsao G, Pinzani M, editors. Sherlock's Diseases of the Liver and Biliary System. 13th ed. Hoboken, NJ: Blackwell; 2018. p. 599-607.  Back to cited text no. 10
    
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Lamps LW. Gall bladder and extrahepatic duct. In: Goldblum JR, Mckenney JK, Myers JL, editors. Rosai and Ackerman's Surgical Pathology. 11th ed. Philadelphia: Elsevier; 2011. p. 845-7.  Back to cited text no. 11
    
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Verkade HJ, Bezerra JA, Davenport M, Schreiber RA, Mieli-Vergani G, Hulscher JB, et al. Biliary atresia and other cholestatic childhood diseases: Advances and future challenges. J Hepatol 2016;65:631-42.  Back to cited text no. 12
    
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Stringer MD, Dhawan A, Davenport M, Mieli-Vergani G, Mowat AP, Howard ER. Choledochal cysts: Lessons from a 20 year experience. Arch Dis Child 1995;73:528-31.  Back to cited text no. 13
    
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Bancroft JD, Bucuvalas JC, Ryckman FC, Dudgeon DL, Saunders RC, Schwarz KB. Antenatal diagnosis of choledochal cyst. J Pediatr Gastroenterol Nutr 1994;18:142-5.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]



 

 
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