Pediatr Gastroenterol Hepatol Nutr.  2017 Jun;20(2):114-123. 10.5223/pghn.2017.20.2.114.

Early Diagnosis of ABCB11 Spectrum Liver Disorders by Next Generation Sequencing

Affiliations
  • 1Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea. neurobaby79@gmail.com
  • 2Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea.

Abstract

PURPOSE
The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis.
METHODS
Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members.
RESULTS
Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis.
CONCLUSION
ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.

Keyword

Cholestasis; Jaundice; Hyperbilirubinemia; ABCB11; Mutation; High-throughput nucleotide sequencing

MeSH Terms

Biliary Atresia
Choledochal Cyst
Cholestasis
Cholestasis, Intrahepatic
Diagnosis
Early Diagnosis*
Exome
Genetic Counseling
Hepatitis
High-Throughput Nucleotide Sequencing
Humans
Hyperbilirubinemia
Jaundice
Liver Transplantation
Liver*
Metabolic Diseases
Parenteral Nutrition, Total
Syphilis, Congenital

Figure

  • Fig. 1 Pedigrees of two Korean families who were subjected to familial genetic analyses. The open symbol represents an unaffected individual, the filled symbol is affected individuals, the symbol with a dot is an obligate carrier, and the symbol with a vertical line is a non-penetrant carrier. (A) Family with progressive familial intrahepatic cholestasis type 2. (B) Family with benign recurrent intrahepatic cholestasis type 2.

  • Fig. 2 Imaging and histologic findings in the patients. (A) A plain abdominal X-ray of patient II-1 with progressive familial intrahepatic cholestasis type 2 (PFIC2) revealed a markedly distended abdomen with no air-fluid levels or free gas under the diaphragm. (B) Abdominal computed tomography of patient II-1 with PFIC2, which showed multinodular hepatocellular carcinoma and hemoperitoneum due to the ruptured tumor. (C) Small bowel activity was not noted 6 hours after Tc99m injection in a diisopropyl iminodiacetic acid scan of patient II-3 with PFIC2. (D) Percutaneous cholecystocholangiography in patient II-3 with PFIC2 after contrast injection demonstrated a contrast-filled gall bladder and that contrast material was excreted into the small bowel loops. (E-I) Histologic and electron microscopic findings after liver biopsy of patient II-3 with PFIC2 revealed mild portal inflammation and lobular disarray (E), mild portal and focal periportal fibrosis by Masson's trichrome stain (F), mild bile canalicular and lobular cholestasis with a mild ballooning change and focal lobular inflammation and apoptosis (G), distended canaliculi with loss of microvilli (H), and filamentous bile (I). Coarse granular bile was seen with PFIC1 and filamentous bile was distinctive in PFIC2. (J, K) Electron microscopic findings after liver biopsy of patient II-2 with benign recurrent intrahepatic cholestasis type 2 showed similar findings with those of patient II-3, specifically distended canaliculi with loss of microvilli (J) and filamentous bile (K).

  • Fig. 3 Identification of novel mutations. (A) Identification of causative novel heterozygous mutations in the progressive familial intrahepatic cholestasis type 2 patient and his parents. Sequencing chromatograms of c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp) in ABCB11 (NM_003742.2). The patient inherited c.11C>G (p.Ser4*) from the mother and c.1543A>G (p.Asn515Asp) from the father. (B) ABCB11 p.Val444Ala was homozygous in the benign recurrent intrahepatic cholestasis type 2 patient and his sister, and heterozygous in the parents. ABCB11 c.3084A>G, p.Ala1028Ala was heterozygous in the patient, sister, and father, but homozygous in the mother.


Cited by  1 articles

Benign Recurrent Intrahepatic Cholestasis Type 2 in Siblings with Novel ABCB11 Mutations
Min Ji Sohn, Min Hyung Woo, Moon-Woo Seong, Sung Sup Park, Gyeong Hoon Kang, Jin Soo Moon, Jae Sung Ko
Pediatr Gastroenterol Hepatol Nutr. 2019;22(2):201-206.    doi: 10.5223/pghn.2019.22.2.201.


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