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Table of Contents
CASE REPORT
Year : 2021  |  Volume : 15  |  Issue : 2  |  Page : 176-180

Progressive familial CD10 deficient ductopenic disorder; Hitherto an unnamed entity! - A case report


1 Department of Histopathology, SRL Ltd., Fortis Escorts Heart Institute, New Delhi, India
2 Department of Hepatology, SRL Ltd., Fortis Escorts Heart Institute, New Delhi, India
3 Department of Liver Transplant Surgery, SRL Ltd., Fortis Escorts Heart Institute, New Delhi, India

Date of Submission07-Apr-2020
Date of Decision07-Sep-2020
Date of Acceptance28-Nov-2020
Date of Web Publication30-Jun-2021

Correspondence Address:
Dr. Nalini Bansal
Department of Histopathology, SRL Ltd., Fortis Escorts Heart Institute, Okhla, New Delhi - 110 025
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_29_20

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  Abstract 

Inherited liver disorders are group of genetic diseases that cause early liver involvement many of them progressing to early cirrhosis. Of the familial cholestatic disorders most widely studied are progressive familial intrahepatic cholestatic disorders. These disorders are caused by defects in enzymes involved with the formation and excretion of bile constituents. They are, however, not associated with ductopenia. We herein report the first case of a familial cholestatic disorder in three female siblings resident of Lahore, Pakistan presenting as chronic cholestasis all progressing to cirrhosis before 10 years of age. The first two female siblings underwent liver transplants for chronic cholestasis. The third sibling underwent liver biopsy for the evaluation of cholestasis and later liver transplant for same. There are no other associated cardiac or skeletal anomalies in any of the sisters. The findings of biopsy and explant tissue were similar in all three sibling sisters. There are features of advanced fibrosis, significant ductopenia, bile ductular reaction at the porto-parenchymal interface, cholestasis, increased copper stores on rhodanine stain no loss of bile salt export pump, and multi-drug resistant 3 protein (MDR3), and the absence of CD10 from canaliculi. The findings raised differentials for progressive familial intrahepatic cholestasis (PFIC) type 3, Alagille syndrome, and variant of familial cholestatic disorder. PFIC 3 causes cholestasis, but the presence of MDR3 stain, ductopenia, and deficient CD10 are not seen in PFIC 3. Familial ductopenic disorders have been identified in the adult population called as idiopathic adulthood ductopenia and had autosomal dominant pattern of inheritance. The argument against Alagille syndrome is the absence of any other syndromic features of Alagille and autosomal recessive mode of inheritance. These findings led us to conclude if there is a need to redefine a new entity of progressive familial CD10 deficient ductopenic disorder. The findings though limited by genetic studies give way for further research on the subject.

Keywords: Bile salt export pump, CD10 deficient, multi-drug resistant 3 protein, progressive familial CD10 deficient ductopenic disorder, progressive familial intrahepatic cholestasis


How to cite this article:
Bansal N, Rastogi M, Vij V. Progressive familial CD10 deficient ductopenic disorder; Hitherto an unnamed entity! - A case report. Indian J Transplant 2021;15:176-80

How to cite this URL:
Bansal N, Rastogi M, Vij V. Progressive familial CD10 deficient ductopenic disorder; Hitherto an unnamed entity! - A case report. Indian J Transplant [serial online] 2021 [cited 2021 Jul 24];15:176-80. Available from: https://www.ijtonline.in/text.asp?2021/15/2/176/319884


  Introduction Top


Progressive familial intrahepatic cholestasis is a group of heterogeneous familial disorders characterized by progressive cholestasis.[1] Three types of progressive familial cholestasis have been identified by molecular and genetic testing. A spectrum of progressive cholestasis remains to be identified. Describing a family of three girls all presenting with similar features of progressive cholestasis but with distinct phenotypes not yet described in literature.


  Case Report Top


Baby 1–4-year-old female, developed jaundice 1 month after her birth which was slowly progressive and associated with generalized pruritis which was disturbing the child from sleep. She had intermittent episodes of nasal bleed. She had an episode of upper gastrointestinal bleed at 2½ years of age for which endoscopy and esophageal variceal ligation were done. She had recent onset of abdominal distension along with fever suggestive of spontaneous bacterial peritonitis (SBP). She also had episodes of irritability in between along with altered behavior. Her blood group was O+. She had delayed milestones and is vaccinated for the age. She was born of cesarean section of a consanguineous marriage. She had a history of congenital talipes equinovarus right foot at 6 months of age with uneventful surgery. Her weight and height were 15 kg and 93 cm. Blood pressure was 108/64 mmHg. On presentation, her liver function profile (LFT) profile was bilirubin direct 16.63/14.45 (0.00–1.00 mg/dl/0.00–0.30 mg/dl), serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT)-303/221 (15–37 U/L/30–65 U/L), serum alkaline phosphatase (SAP)/gamma-glutamyl transferase (GGT) 1123/126 (50–136 U/L/5–85 U/L), total protein 6.8 (6.4–8.2 g/dl), and albumin 2.2 (3.4–5 g/dl). Kidney function test was normal. Lipid profile showed total cholesterol 167, DL/LDL -14/142, and very-low-density lipoprotein/triglyceride (VLDL/TG) 20.8/104 mg/dl. Thyroid profile was normal. Serum ceruloplasmin 0.31 and IgG level were mildly elevated 19.4 (4–15.9 g/l). Her autoimmune and viral markers were negative. Tumor markers for carcinoembryonic antigen/CA19.9/alpha-fetoprotein were normal. Two-dimensional (2D) Echo showed situs solitus, A-V, V-A concordance, pulmonary venous drainage, normal biventricular systolic function, sepate were intact, trace TR, and pulmonary artery systolic pressure (PASP) approximately. 25, pulmonary vascular resistance approximately. 1.1. On computed tomography liver showed hepatosplenomegaly with irregular nodular liver margins with shunts seen in the perigastric region extending superiorly to the posterior mediastinum and in the left lienorenal region suggestive of chronic liver disease (CLD). Body and tail of the pancreas were not visualized? agenesis. Small hypodense area (10 HU) seen in lower pole of the right kidney possibily small cyst. Atelectatic changes seen in both lower lobes of the lung. She underwent liver transplant for same.

Baby 2–5-year-old girl presented with complaints of jaundice since birth with delayed developmental milestones. There was associated progressive pruritis and loss of appetite for the past 2 years. The parents also gave history of macrocephaly at the age of 6 months, which on evaluation was found to be infective communicating hydrocephalus. She underwent VP shunt for the same at the age of 9 months. On evaluation for hematemesis at the age of 2 years, she was found to be having CLD. She underwent upper gastrointestinal endoscopy which revealed grade III esophageal varices; EST was done for same. Immunization was complete till date. No history of Hepatic encephalopathy, Hepatorenal syndrome, spontaneous bacterial peritonitis/Ascites. PELD 13, CTP 10, Child's C. Her weight and height were 15 kg and 93 cm. BP was 108/64 mmHg. On presentation, her LFT profile was bilirubin direct 13.38/12.09 (0.00–1.00 mg/dl/0.00–0.30 mg/dl), SGOT/SGPT-230/247 (15–37 U/L/30–65 U/L), SAP/GGT 1850/653 (50–136 U/L/5–85 U/L), total protein 7.6 (6.4–8.2 g/dl), and albumin 2.5 (3.4–5 g/dl). Lipid profile showed total cholesterol 568, HDL/LDL-13/625, and VLDL/TG 32/160 mg/dl. Thyroid profile was normal. Serum ceruloplasmin 0.31 units and IgG level were mildly elevated 18.5. Her autoimmune and viral markers were negative. 2D Echo showed situs solitus with levocardia, AV and VA concordance; normal pulmonary and systemic drainage, normally related great vessels, normal cardiac chambers and valves, no intracardiac shunt, PASP 17 mmHg, and normal aortic arch. CT of the liver angio showed hepatosplenomegaly with irregular nodular liver margins. There was enlarged caudate lobe encasing the IVC. She underwent liver transplant for same.

Baby 3–6-year-old female presented with features of cholestasis. In view of family history underwent liver biopsy for same. She had a history of itching since the age of 4 months progressively increasing, poor weight gain, and had yellow-colored urine at the age of 2 months. She had a history of diarrhea. She had decreased appetite. She was vaccinated as per the age. She was born by cesarean section out of 3rd degree consanguineous marriage. She had a history of surgery for congenital foot abnormality at 6 months of age. There was no history of abdominal distension. There was no history of decreased urine. Her weight and height were 19 kg. BP was 110/70 mmHg. On presentation, her LFT profile was Bilirubin direct 2.85/2.42 (0.00–1.00 mg/dl/0.00–0.30 mg/dl), SGOT/SGPT - 202/306 (15–37 U/L/30–65 U/L), SAP/GGT 981/355 (50–136 U/L/5–85 U/L), total protein 7.9 (6.4-8.2 g/dl), and albumin 2.5 (3.4–5 g/dl). Lipid profile showed total cholesterol 423, HDL/LDL-15/525, and VLDL/TG 35/165. Thyroid profile was normal. Serum ceruloplasmin 0.31 units and IgG level were mildly elevated 15 units. Her USG of the abdomen showed hepatomegaly with coarse echo pattern and irregular liver margin suggestive of CLD, Child 6 Grade A cirrhosis. She also later underwent liver transplant for same.

We report a case of three female siblings who presented from Lahore, Pakistan with features of progressive cholestasis. The age of the patients were 4, 5, and 6 years. The clinical features and liver function tests are described in [Table 1] and [Table 2]. All three siblings had raised GGT and on histology, there was ductopenia in all three of them [Figure 1]. Histology from all explants and one liver biopsy showed significant ductopenia with absent CD 10 immunostain from canaliculi. IHC for bile salt export pump (BSEP) and multi-drug resistant 3 protein (MDR3) was positive in all three siblings. There was no giant cell transformation of hepatocytes. Based on the histology and clinical features with raised GGT possible consideration for Progressive familial intrahepatic cholestasis (PFIC) 3 was made. However, MDR3 was preserved in all three siblings on immunostain. There was significant ductopenia noted in all three biopsies. Differential of Alagille syndrome and idiopathic adulthood ductopenia (IAD) were thus kept. However, on complete evaluation, no other syndromic features of Alagille were noted in any of the patients examined. CD 10 deficiency though has been described in Alagille syndrome is not seen in IAD.
Table 1: Clinical features of three siblings

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Table 2: Liver function test of three siblings

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Figure 1: Baby 1-(a) Histology showing cirrhotic liver (H and E, ×10). (b) Histology showing cirrhotic liver (MT, ×10) (c) IHC CK7 showing ductopenia with hepatocytes showing regenerative hepatobiliary phenotype. (d) IHC CD10 negative in canaliculi. Baby 2-(e) Histology showing cirrhotic liver (H and E, ×10). (f) Histology showing cirrhotic liver (MT, ×10). (g) IHC CK7 showing ductopenia with hepatocytes showing regenerative hepatobiliary phenotype. (h) IHC CD10 negative in canaliculi Baby 3-(i) Histology showing cirrhotic liver (H and E, ×10). (j) Histology showing cirrhotic liver (MT, ×10). (k) IHC CK7 showing ductopenia with hepatocytes showing regenerative hepatobiliary phenotype. (l) IHC CD10 negative in canaliculi

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Family history with the familial history features of progressive cholestasis together with associated ductopenia and deficient CD10 leads to speculation if this is new variant of PFIC or a novel un-named entity.


  Discussion Top


PFIC refers to heterogeneous group of autosomal recessive disorders of childhood in which bile formation is disrupted. The disorder is familial and often presents in the neonatal period or 1st year of life and leads to death from liver failure at ages usually ranging from infancy to adolescence.[1],[2]

Three types of PFIC's have been identified based on molecular and genetic testing. PFIC1 is caused by defects in ATP8B1 encoding the FIC1 protein and PFIC2 is caused by defect in ABCB11 encoding the BSEP protein. Defects in ABCB4, encoding the MDR3, impair biliary phospholipid secretion resulting in PFIC3.[3] Possibility of other unidentified genotypes has been postulated by several authors.[4]

Serum GGT activity is normal in PFIC1 and PFIC2 patients but is elevated in PFIC3 patients.

Immunohistochemistry by MDR3 and BSEP is a useful aid for identifying patients with PFIC 2 and 3 and absent canalicular staining for BSEP is seen in cases of PFIC 2 while absent MDR3 staining is seen in cases of PFIC 3.[5],[6] The immunostain for BSEP and MRD3 were positive in all 3 siblings' liver tissue.

Because of ductopenia and cholestasis, the differentials included were Alagille syndrome, alpha1antitrypsin deficiency, and IAD [Table 3].
Table 3: Comparison of clinical and histological features with differential diagnosis

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Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder. The disease occurs due to defects in components of the Notch signaling pathway, most commonly due to mutation in JAG1 (ALGS type 1), but in a small proportion of cases mutation in NOTCH2 (ALGS type 2).[7]

Classic criteria for Allagile syndrome included liver histology showing bile duct paucity and three of five major clinical features: cholestasis, ophthalmologic abnormalities (commonly posterior embryotoxon), characteristic facial features (prominent forehead, deep-set eyes with moderate hypertelorism, pointed chin, and straight nose with a bulbous tip), cardiac defect (commonly stenosis of the peripheral/pulmonary arteries), and skeletal abnormalities (commonly butterfly vertebrae).[8]

Other than histological finding of ductopenia no other abnormality was noted in any of the three siblings. Furthermore, Alagille syndrome is an autosomal dominant disease.

IAD was first proposed as a condition characterized by chronic cholestasis by Ludwig et al. in 1988.[9] IAD has an adult or adolescent-onset, biochemical evidence of cholestatic liver disease, evidence of ductopenia by liver biopsy with normal cholangiography, and an unknown etiology. Youngest patient described for IAD is a 15-year-old male.[10] In our cases, though ductopenia was seen, all three siblings were younger than 6 years of age, and CD10 deficiency is not described in IAD.

There were no PAS–D globules within hepatocytes and IHC for Alpha1 antitrypsin was also negative.

The findings led us to conclude that the above family is different from those of other familial cholestasis as had been described previously. Progressive familial CD10 deficient ductopenic disorder is thus considered as a distinct entity that remains to be explored by adequate genetic testing.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Jacquemin E. Progressive familial intrahepatic cholestasis. Genetic basis and treatment. Clin Liver Dis 2000;4:753-63.  Back to cited text no. 1
    
2.
Van Mil SW, Houwen RH, Klomp LW. Genetics of intrafamilial cholestasis syndromes. J Med Genet 2005;42:449-63.  Back to cited text no. 2
    
3.
Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 2009;4:1.  Back to cited text no. 3
    
4.
Ortiz D, Arias IM. MDR3 mutations: A glimpse into Pandora's Box and the future of canalicular pathophysiology. Gastroenterology 2001;120:1549-52.  Back to cited text no. 4
    
5.
Evason K, Bove KE, Finegold MJ, Knisely AS, Rhee S, Rosenthal P, et al. Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): Correlation with genetic and immunohistochemical studies. Am J Surg Pathol 2011;35:687-96.  Back to cited text no. 5
    
6.
Colombo C, Vajro P, Degiorgio D, Coviello DA, Costantino L, Tornillo L, et al. Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations. J Pediatr Gastroenterol Nutr 2011;52:73-83.  Back to cited text no. 6
    
7.
Turnpenny PD, Ellard S. Alagille syndrome: Pathogenesis, diagnosis and management. Eur J Hum Genet 2012;20:251-7.  Back to cited text no. 7
    
8.
Alagille D, Estrada A, Hadchouel M, Gautier M, Odièvre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): Review of 80 cases. J Pediatr 1987;110:195-200.  Back to cited text no. 8
    
9.
Ludwig J, Wiesner RH, LaRusso NF. Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis. J Hepatol 1988;7:193-9.  Back to cited text no. 9
    
10.
Park BC, Park SM, Choi EY, Chae HB, Yoon SJ, Sung R, et al. A case of idiopathic adulthood ductopenia. Korean J Intern Med 2009;24:270-3.  Back to cited text no. 10
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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