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CASE REPORT  
Year : 2021  |  Volume : 64  |  Issue : 5  |  Page : 146-148
Benign recurrent intrahepatic cholestasis - 2 (BRIC-2)/ABCB11 deficiency in a young child – Report from a tertiary care center in South India


1 Department of Pathology, Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Thiruvananthapuram, Kerala, India
2 Department of Gastrosurgery, Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Thiruvananthapuram, Kerala, India

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Date of Submission25-Mar-2020
Date of Decision30-Apr-2020
Date of Acceptance08-Jun-2020
Date of Web Publication7-Jun-2021
 

   Abstract 


ABCB11 deficiency, formerly benign recurrent intrahepatic cholestasis (BRIC) is a very rare hereditary disorder characterized by the recurrent and intermittent episodes of cholestasis, jaundice, and pruritus. We report the case of a 12-year-old boy presenting with recurrent episodes of jaundice and severe pruritis since childhood. An extensive workup was done to rule out all the possible etiologies. Liver biopsy was done and histopathology was consistent with intrahepatic cholestasis. Immunohistochemistry, enzyme studies, and genetic testing confirmed the diagnosis. The patient was treated with Ursodeoxycholicacid and is on regular follow-up. We report this case due to the rarity of the disease in South India and to highlight the importance of genetic testing, which is the gold standard for diagnosis as well as for the classification of the disease. These patients should be under regular follow-up as those with fibrosis progression are at a risk for cholangiocarcinoma and hepatocellular carcinoma.

Keywords: ABCB11, Benign Recurrent Intrahepatic Cholestasis, cholestasis, cirrhosis, jaundice

How to cite this article:
Kalaranjini K V, Glaxon JA, Vasudevan S, Arunkumar M L. Benign recurrent intrahepatic cholestasis - 2 (BRIC-2)/ABCB11 deficiency in a young child – Report from a tertiary care center in South India. Indian J Pathol Microbiol 2021;64, Suppl S1:146-8

How to cite this URL:
Kalaranjini K V, Glaxon JA, Vasudevan S, Arunkumar M L. Benign recurrent intrahepatic cholestasis - 2 (BRIC-2)/ABCB11 deficiency in a young child – Report from a tertiary care center in South India. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Jun 23];64, Suppl S1:146-8. Available from: https://www.ijpmonline.org/text.asp?2021/64/5/146/317907





   Introduction Top


Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive disorder characterized by intermittent episodes of severe cholestatic jaundice.[1],[2],[3] Earlier, pediatric intrahepatic cholestatic liver diseases were classified by phenotype into BRIC or progressive familial intrahepatic cholestasis (PFIC) based on whether the elevated bilirubin levels were episodic or persistent, with the persistent form more strongly associated with fibrosis and progression. The advent of improved genetic-based understanding has led to the reclassification based on underlying genetics.[1] The published data on BRIC from India is in the form of case reports and small case series with only a single case reported from South India.[4]


   Case Report Top


A 12-yr-old male child presented with fever, itching, and jaundice since 3 weeks duration. There is similar past history starting at the age of 3 months with recurrent episodes of jaundice, which lasted for about 2 months followed by a symptom-free period, each lasting for about 1 year. During the above episodes, he was treated with cholerectics, which offered temporary relief. During these episodes, there was no abdominal pain, distension, bleeding, or loss of weight. There is no history suggestive of similar illness in the family or siblings.

On examination, he was icteric, with shiny nails, and scratch marks over the body. He had a regular pulse rate of 78/min with a blood pressure of about 90/60 mm Hg. His abdominal examination was normal with no tenderness or organomegaly. All other systemic examinations were normal. Investigations [Table 1] revealed prominent conjugated hyperbilirubinemia, markedly elevated alkaline phosphatase, and deranged international normalized ratio (INR) with normal levels of hepatic transaminases and gamma-glutamyl transpeptidase (GGT). An abdominal ultrasonogram done showed mild hepatomegaly. All viral markers for hepatitis A, B, and C were negative. Workup for autoantibodies like anti-nuclear, anti-mitochondrial, and anti-smooth muscle antibodies was negative. Serum copper levels were normal. Based on clinical and laboratory findings, the possibility of recurrent intrahepatic cholestasis was considered, and liver biopsy was performed.
Table 1: Investigations done

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Two cores of liver tissue were received with hepatocytes showing marked hepatocellular and canalicular cholestasis [Figure 1] and [Figure 2] and portal tracts showing mild periportal fibrosis, highlighted by using special stain Trichrome, [Figure 3] and mild mixed inflammatory infiltrate. No evidence of giant cell transformation was seen. No steatosis, glycogenated nuclei, or Mallory–Denk bodies seen in the biopsy and Orcein stain showed no copper associated protein. Based on the history of recurrent episodes of jaundice, clinical features, biochemical values, and biopsy findings, a diagnosis of BRIC/PFIC was suggested, and immunohistochemistry (IHC) and genetic testing were advised for confirmation. Following this IHC was done, which showed multi drug resistant protein (MDR3) and bile salt export protein (BSEP) positivity in canaliculi. Genetic testing [Figure 4] done showed homozygous missense variation in exon 26 of ABCB11 gene, which encodes the human bile salt export pump (BSEP); thereby confirming the diagnosis of ABCB11 deficiency (BRIC-2).
Figure 1: Photomicrograph with hepatocytes showing marked hepatocellular and canalicular cholestasis (H and E x 10)

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Figure 2: Photomicrograph to better appreciate the hepatocellular and canalicular cholestasis (H and E x 40)

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Figure 3: Photomicrograph with portal tracts showing mild periportal fibrosis, highlighted by Trichrome (Trichrome x 40)

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Figure 4: DNA Test Report showing variation in exon 26 of ABCB11 gene

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   Discussion Top


BRIC is a rare disorder first described in 1959 by Summerskill and Walshe who reported two unrelated patients with recurrent intrahepatic cholestasis.[5] In the following year, Tygstrup described the condition in two distantly related 15-year-old boys living in a small village in Faroe Island.[6] Hence BRIC was also formerly known as Summerskill-Walshe-Tygstrup syndrome. With the advent of advanced genetic testing, familial causes of pediatric intrahepatic cholestatic liver diseases have been classified broadly based on the three major gene mutations – ATP8B1, ABCB11, and ABCB4. However, there remains a small proportion of cases that do not have mutations in these three genes, suggesting that other genes remain yet to be identified.[1],[2]

ATP8B1 deficiency tends to have more episodic patterns of injury (formerly called BRIC1) than persistent patterns of injury (formerly called PFIC1) while ABCB11 deficiency has more cases with persistent bilirubin elevations and fibrosis progression (formerly called PFIC2) than the more indolent episodic pattern (formerly called BRIC2), and ABCB4 deficiency (formerly called PFIC3) is associated with elevated bilirubin levels and elevated GGT.[1]

A diagnostic criteria for BRIC has been proposed by Luketic and Shiffman, which includes: (a) At least two episodes of jaundice with asymptomatic interval of months to years; (b) Laboratory investigations suggestive of intrahepatic cholestasis; (c) Cholestasis induced severe pruritus; (d) Cholangiography showing normal intra and extrahepatic bile ducts; (e) Liver histology suggesting centrilobular cholestasis; (f) Absence of other causes of cholestasis.[7] Our patient fulfilled all these above-mentioned criteria. The same authors proposed dropping the adjective “benign” because of the profound effect that the disease has on the long-term quality of life of patients.[3],[7]

ABCB11 gene codes for the bile salt export pump (BSEP) protein. Mutations in this gene lead to impaired canalicular transport of bile salts. IHC for BSEP proteins showing reduced or absent staining supporting a diagnosis of ABCB11 defiency, but a normal BSEP staining pattern does not completely exclude ABCB11 deficiency since some mutations affect the protein function and not its overall expression.[1],[2]

Conditions like Wilson's disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, and chronic viral hepatitis are to be considered in the differential diagnosis.[4] All viral markers for hepatitis A, B, and C were negative. Workup for autoantibodies like anti-nuclear, anti-mitochondrial, and anti-smooth muscle antibodies was negative. No evidence of giant cell transformation seen. No steatosis, glycogenated nuclei, or Mallory–Denk bodies were seen in the biopsy and Orcein stain showed no copper associated protein. Hence, ruling out all the above-mentioned differential diagnosis.

In our case, the patient is a 12-year-old child who fulfilled all the criteria for the diagnosis of BRIC laid down by Luketic and Shiffman. Laboratory investigations showed normal GGT. Histologically, liver biopsy showed marked hepatocellular and canalicular cholestasis and mild periportal fibrosis. IHC was done, which showed MDR3 and BSEP positivity in canaliculi. Further genetic testing was done, which showed a mutation in ABCB11 gene hence confirming the diagnosis of ABCB11 deficiency (BRIC-2).


   Conclusion Top


Detailed and relevant investigations should be done in all cases of pediatric intrahepatic cholestatic liver disease to exclude all other causes of cholestasis. The knowledge of this entity is crucial for early detection. Genetic testing is also of importance to categorize the patients based on the mutations. Individuals with ABCB11 deficiency are at an increased risk for cholelithiasis and those with fibrosis progression (as in our case) are at risk for cholangiocarcinoma and hepatocellular carcinoma.[1],[2] Hence, the patient should be under regular follow-up for monitoring the course and progression of this disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Torbenson M. Paediatric Cholestatic Liver Disease. In: Epstein J, editor. Biopsy Interpretation of the Liver. 1st ed. Philadelphia: Wolters Kluwer; 2015. p. 229-34.  Back to cited text no. 1
    
2.
Gupta N. Cholestatic Pediatric Diseases. In: Gupta N, editor. Liver Biopsy Made Easy. 1st ed. New Delhi: Jaypee; 2017. p. 195-6.  Back to cited text no. 2
    
3.
Richard J, Bernard C, Eve A. Genetic and metabolic Liver disease. In: Burt A, Portmann B, Ferrell L, editors. MacSween's Pathology of the Liver. 6th ed. Edinburgh: Churchill Livingstone; 2012. p. 210-2.  Back to cited text no. 3
    
4.
Geethalakshmi S, Mageshkumar S. Benign recurrent intrahepatic cholestasis: A rare case report. Int J Sci Stud 2014;2:222-4.  Back to cited text no. 4
    
5.
Summerskill WHJ, Walshe JM. Benign recurrent intrahepatic obstructive jaundice. Lancet 1959;274:686-90.  Back to cited text no. 5
    
6.
Tygstrup N. Intermittent possibly familial intrahepatic cholestatic jaundice. Lancet 1960;1:1171-2.  Back to cited text no. 6
    
7.
Luketic VA, Schiffman ML. Benign recurrent intrahepatic cholestasis. Clin Liver Dis 1999;3:509-28.  Back to cited text no. 7
    

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Correspondence Address:
Jinu A Glaxon
Department of Pathology, Sree Gokulam Medical College and Research Foundation, Venjaramoodu - 695 607, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_254_20

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