Saudi Journal of Gastroenterology
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Year : 2017  |  Volume : 23  |  Issue : 5  |  Page : 303-305
Intrahepatic cholestasis in two omani siblings associated with a novel homozygous ATP8B1 mutation, c.379C>G (p.L127V)

1 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, United Arab Emirates
2 Department of Pediatrics, Tawam Hospital, United Arab Emirates
3 Institute of Liver Studies, King's College Hospital, London SE5 9RS, England, United Kingdom; Institut für Pathologie, Medizinische Universität Graz, 8036 Graz, Austria

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Date of Web Publication18-Sep-2017


We report two Omani brothers with intrahepatic cholestasis that resolved with supportive care. In one, cholestasis began in infancy; in the other, only at the age of 18 months. Whole exome sequencing identified a novel homozygous variant, c.379C>G (p.L127V) in ATP8B1. Those attending patients with cholestasis from the Arabian peninsula should be aware of this mutation and of the variation in its phenotypic effects.

Keywords: ATP8B1, benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, whole exome sequencing

How to cite this article:
Narchi H, Alhefeiti S, Althabahi F, Hertecant J, Knisely A S, Souid AK. Intrahepatic cholestasis in two omani siblings associated with a novel homozygous ATP8B1 mutation, c.379C>G (p.L127V). Saudi J Gastroenterol 2017;23:303-5

How to cite this URL:
Narchi H, Alhefeiti S, Althabahi F, Hertecant J, Knisely A S, Souid AK. Intrahepatic cholestasis in two omani siblings associated with a novel homozygous ATP8B1 mutation, c.379C>G (p.L127V). Saudi J Gastroenterol [serial online] 2017 [cited 2022 May 17];23:303-5. Available from:

   Introduction Top

Progressive familial intrahepatic cholestasis (PFIC) is a clinical designation for several autosomal recessive disorders often apparent in infancy.[1],[2],[3] In PFIC1, hepatic dysfunction manifests as malabsorption with failure to thrive, pruritus, and cholestatic jaundice. It ultimately develops into severe and permanent liver disease with progressive fibrosis. Patients with less severe manifestations and without liver fibrosis are said to have “benign” recurrent intrahepatic cholestasis (BRIC1).

One form of PFIC1/BRIC1 is caused by defects in familial intrahepatic cholestasis 1 (FIC1) protein, expressed in the apical membrane of a variety of epithelial cells, including hepatocytes, and is encoded by ATP8B1. It is an aminophospholipid transporter responsible for the enrichment of the inner leaflet of the plasma membrane in phosphatidylserine and phosphatidylethanolamine. Functional deficiency of FIC1 results in disordered membrane composition, with instability and disturbed function of various membrane proteins. Deafness, diarrhea, pancreatitis, elevated sweat electrolyte concentrations, and hypothyroidism are among the extrahepatic sequelae of ATP8B1 disease. Distinct ATP8B1 mutations cause PFIC1 in particular demes: in Amish [c.923G>T (p.G308V)], Inuit and Athabascan [c.1660G>A (D554N)] and Indian children (c.[589_592inv; 592_593insA]) or BRIC in northern European children and adults [c.1982T>C (p.I661T)].[4],[5],[6] The full range of mutations associated with PFIC1/BRIC1 remains undescribed in the various populations of the Middle East and Arabian peninsula.

We report two Omani brothers in whom intrahepatic cholestasis was associated with the novel homozygous c.379C>G (p. L127V) mutation in ATP8B1. We describe the clinical phenotype associated with that mutation, with mild, resolving disease suggestive of BRIC1.

   Case Reports Top

Case 1

A previously healthy 18-month-old Omani boy, born at term to healthy consanguineous parents, presented with several weeks' history of worsening jaundice, dark-colored urine, and frequent large, pale, smelly, and greasy stools, accompanied by reported itching.

During pregnancy, complicated by gestational diabetes managed by diet, no pruritus was reported. His birth weight was 3.1 kg; the neonatal period was uneventful and without hyperbilirubinemia. His growth and developmental milestones were appropriate. On examination, his weight was 11 kg (25th percentile), height 83 cm (50th percentile), and head circumference 47 cm (25th percentile). He was mildly jaundiced and had cutaneous scratch marks. Abdominal organomegaly was not found. Laboratory test results included total bilirubin 27 μmol/L (expected, 5–22), direct bilirubin 15.3 μmol/L (1.7–8.6), alkaline phosphatase 789 IU/L (110–302), gamma-glutamyl transpeptidase (GGT) 8 IU/L (6–16), aspartate aminotransferase 112 IU/L (22–58), alanine aminotransferase 98 IU/L (11–39), prothrombin time 27.6 s (8.1–12.3), and international normalized ratio 2.76 (0.88–1.24), without hypoproteinemia. The absence of elevated serum GGT activity despite jaundice with conjugated hyperbilirubinemia and pruritus, in conjunction with the family history (see Case 2), led to the presumptive diagnosis of familial intrahepatic cholestasis. Serum and urine bile acids analyses were not performed. Liver biopsy was not done. Medium-chain triglyceride formula was added to the diet and therapy was started with ursodeoxycholic acid (300 mg/day), fat-soluble vitamins E, D, K, and A daily supplements, and weekly subcutaneous injections of 2.5 mg vitamin K. During the first 4 weeks of treatment, jaundice and itching worsened, total and direct bilirubin values rose but progressively declined into expected ranges, and coagulopathy normalized. By the age of 20 months, jaundice and itching resolved completely and urine and stool color normalized. Serum GGT activity always remained within expected range.

Case 2

An older brother, now 15 years old, developed intrahepatic cholestasis during infancy. The information available in his chart was incomplete because of frequent loss to follow-up. Light microscopy of a liver-biopsy specimen obtained at age 6 months found intralobular cholestasis, mainly canalicular, and mild portal-tract fibrosis with focal portal-portal bridging fibrosis [Figure 1]a. GGT normally outlines all bile canaliculi crisply. Expression of GGT was deficient [Figure 1]b, suggestive of ATP8B1 disease.[7] Intrahepatic cholestasis lasted until 4 years of age, and was managed with supportive care. Resolution was spontaneous; he has remained well.
Figure 1: Liver biopsy specimen of the proband's older sibling at the age of six months. (a) Intralobular cholestasis, mainly canalicular; mild portal-tract fibrosis with focal portal-portal bridging fibrosis. Chromotrope aniline blue stain. (Magnification, ×100). (b) Deficiency of canalicular expression of gamma-glutamyl transpeptidase (GGT); the canalicular network marks only in immediately periportal regions. Anti-GGT antibody, diaminobenzidine chromogen, hematoxylin counterstain. (Magnification, ×200)

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Whole exome sequencing

Whole exome sequencing (Baylor Miraca Genetics Laboratories, Houston, TX) revealed that both brothers were homozygous for the novel ATP8B1 variant c.379C>G (p. L127V), predicted by SIFT/PolyPhen2 analysis to be tolerated but possibly damaging. Sanger sequencing confirmed the mutation. Each parent was a heterozygote for the variant, supporting autosomal recessive Mendelian inheritance. Another brother and sister were both heterozygotes for this mutation. They complain occasionally of pruritus, but icterus and clinical-biochemistry abnormalities, including hypercholanemia, have not been documented.

   Discussion Top

We report intrahepatic cholestasis in two Omani brothers homozygous for the novel c.379C>G (p. L127V) variant in ATP8B1. Although the clinical course of the older brother is not well documented, mild liver fibrosis at age 6 months: precludes BRIC. Yet cholestasis remitting around the age of 4 years is atypical for PFIC1. The phenotype appears to be an intergrade. Disease in the younger brother, with remission after a briefer bout of cholestasis, appears clinically to represent BRIC1 but without confirmatory clinicopathologic criteria in the absence of liver histopathology. The mutation common to both brothers thus appears, in homozygous form, to be associated with mild, resolving disease more suggestive of BRIC1. Given both clinical courses, this mutation seems to be associated with a favorable prognosis, although long-term consequences cannot yet be assessed.

Many mutations in ATP8B1 have been described.[4],[5],[6] The mutation type sometimes predicts the cholestasis phenotype. For example, nonsense and frame-shift mutations are more often detected in PFIC1, whereas missense mutations are more frequently identified in BRIC1.[4] However, phenotypic presentation varies greatly even among patients with the same mutation.[8] BRIC1 and PFIC1 caused by ATP8B1 mutation are therefore considered part of a clinical continuum spectrum of intrahepatic-cholestasis disorders and are therefore preferably referred to as ATP8B1 deficiency disease.[7],[9],[10] Variation in background (coexistent mutation in other genes predisposing to cholestasis) may contribute to phenotypic variation, but without clear explanation so far.[4],[8],[9],[10]

The c.379C>G (p. L127V) variant in ATP8B1 in our patient and sibling has not been previously reported. Comprehensive studies of ATP8B1 in patients with BRIC1 or PFIC1 from the Middle East are lacking. Until more variants are reported from the Middle East, expensive whole genome sequencing studies will be needed for individual patients. Only when results of such studies are shared, collated, and coordinated with tribal and regional origin can diagnosis and screening be conducted more rapidly and cheaply.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Jacquemin E. Progressive familial intrahepatic cholestasis. Genetic basis and treatment. Clin Liver Dis 2000;4:753-63.  Back to cited text no. 1
Baussan C, Cresteil D, Gonzales E, Raynaud N, Dumont M, Bernard O, et al. Genetic cholestatic liver diseases: The example of progressive familial intrahepatic cholestasis and related disorders. Acta Gastroenterol Belg 2004;67:179-83.  Back to cited text no. 2
Hori T, Nguyen JH, Uemoto S. Progressive familial intrahepatic cholestasis. Hepatobiliary Pancreat Dis Int 2010;9:570-8.  Back to cited text no. 3
Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004;40:27-38.  Back to cited text no. 4
Liu LY, Wang XH, Wang ZL, Zhu QR, Wang JS. Characterization of ATP8B1 gene mutations and a hot-linked mutation found in Chinese children with progressive intrahepatic cholestasis and low GGT. J Pediatr Gastroenterol Nutr 2010;50:179-83.  Back to cited text no. 5
Sharma A, Poddar U, Agnihotry S, Aggarwal R. A novel truncation mutation in ATP8B1 gene in progressive familial intrahepatic cholestasis. Indian Pediatr 2016;53:1099-101.  Back to cited text no. 6
Paulusma CC, Groen A, Kunne C, Ho-Mok KS, Spijkerboer AL, Rudi de Waart D, et al. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology 2006;44:195-204.  Back to cited text no. 7
van Mil SW, Klomp LW, Bull LN, Houwen RH. FIC1 disease: A spectrum of intrahepatic cholestatic disorders. Semin Liver Dis 2001;21:535-44.  Back to cited text no. 8
van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH. Familial cholestasis: Progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol 2010;24:541-53.  Back to cited text no. 9
van Ooteghem NA, Klomp LW, van Berge-Henegouwen GP, Houwen RH. Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: Low GGT cholestasis is a clinical continuum. J Hepatol 2002;36:439-43.  Back to cited text no. 10

Correspondence Address:
Hassib Narchi
Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain PO Box 17666
United Arab Emirates
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/sjg.SJG_178_17

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