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Exacerbation of familial intrahepatic cholestasis in conjunction with COVID-19 vaccination

      Abbreviations:

      BRIC (benign recurrent intrahepatic cholestasis), ULN (upper limit of normal), PFIC (progressive familial intrahepatic cholestasis)
      To the Editor:
      The devastating global impact of the COVID-19 pandemic led to the fast development of efficient anti-COVID-19 vaccines. These have in rare instances been associated with side effects including autoimmune hepatitis.
      • Shroff H.
      • Satapathy S.K.
      • Crawford J.M.
      • Todd N.J.
      • VanWagner L.B.
      Liver injury following SARS-CoV-2 vaccination: a multicenter case series.
      ,
      • Tun G.S.Z.
      • Gleeson D.
      • Dube A.
      • Al-Joudeh A.
      Immune-mediated hepatitis with the Moderna vaccine, no longer a coincidence but confirmed.
      Herein, we report the case of a 53-year-old man presenting in our emergency department with jaundice and pruritus. Within 48 hours following BTN162b2 Pfizer-BioNTech mRNA COVID-19 vaccination he felt fatigued, developed nausea, severe ubiquitous pruritus and a temperature (37.5-38°C). Progressive jaundice occurred within 72 h post vaccination. He denied consuming drugs, rarely drank alcohol, had no allergies and had no history of suspicious travel nor contact with animals. SARS-CoV-2 infection was repeatedly excluded (positive SARS-CoV-2 spike-antibodies [17.7 U/ml]; negative SARS-CoV-2 nucleocapsid-antibodies [0.107 COI]). He reported having been diagnosed with benign recurrent intrahepatic cholestasis (BRIC, Summerskill-Walshe-Tygstrup-Syndrome) in early childhood, as had 4 of his 13 siblings.
      The clinical examination showed jaundice and excoriations. Vital signs and neurology were normal. An abdominal examination revealed no tenderness, a normal liver and spleen and no ascites. Upon admission, laboratory tests revealed hyperbilirubinemia (total bilirubin 480 μmol/L, upper limit of normal [ULN] 24 μmol/L), elevated alkaline phosphatase (412 U/L, ULN 130 U/L), bile acids (232.7 μmol/L, ULN 8 μmol/L), ALT 99 U/L (ULN 59 U/L), and AST 61 U/L (ULN 34 U/L). GGT, INR, albumin and creatinine were initially normal (Fig. 1A). An extensive workup showed no evidence for viral (HAV, HBV, HCV, HEV), autoimmune hepatitis or Wilson’s disease and no signs of mechanical bile duct obstruction or cirrhosis. A presumptive diagnosis of cholestatic disorder was confirmed by liver histopathology showing marked canalicular and intracytoplasmic cholestasis in all zones, predominantly zone III, with mild predominantly portal immune cell infiltration, particularly of macrophages, and minimal signs of portal fibrosis (Fig. 1B). Based on the above, he was diagnosed with an exacerbation of BRIC and a therapy with colestyramine 4 g b.i.d. and ursodeoxycholic acid 250 mg t.i.d., followed by rifampicin 150 mg b.i.d. and phototherapy was initiated. Subsequently the patient deteriorated, developing acute kidney injury (AKI, creatinine max. 353 μmol/L [ULN 97 μmol/L]) due to bile-cast nephropathy (bilirubin max. 665 μmol/L; bilirubin-casts in urinary sediment). He was transferred to intensive care for temporary continuous veno-venous haemofiltration in combination with a Cytosorb® filter. Under this treatment clinical symptoms and renal function improved. Bilirubin levels peaked 8 weeks following vaccination and normalised within 16 weeks (Fig. 1A). The case was reported to the Swiss authority for drugs and therapeutic products (Swissmedic); causality was assessed as “possible” according to WHO criteria.
      Figure thumbnail gr1
      Fig. 153-year-old patient with benign recurrent intrahepatic cholestasis.
      (A) The levels of bilirubin, bile acids and creatinine over the course of the BRIC exacerbation. On the x axis depicted is the time in months from the onset of BRIC exacerbation; an asterisk indicates the time over 5 days of continuous veno-venous haemofiltration (cvvHF) treatment. (B) Liver histology (H&E stain) of the index patient exhibiting a BRIC exacerbation. Marked canalicular and intracytoplasmic cholestasis in all liver zones, predominantly in Zone III with mild immune cell infiltration, magnification 200x. BRIC, benign recurrent intrahepatic cholestasis.
      Genetic testing of the entire coding and flanking intronic sequence of the associated genes ATP8B1, ABCB11 and ABCB4 by next-generation sequencing revealed a rare, likely pathogenic homozygous missense variant in the ATP8B1 gene in the patient. The detected variant c.749T>A (reference sequence NM_005603; chr18: g.55362714 (hg19)) is expected to result in an amino acid exchange of the highly conserved leucine to histidine at position 250 of the protein (p.(Leu250His)), which is predicted to have a deleterious effect on protein function by automated online prediction tools (SIFT, PolyPhen2, MutationTaster, CADD). The variant has no allele frequency in the population (e.g. not observed in gnomAD v2.1) and was just recently reported in a compound heterozygous constellation with another variant in a patient with familial intrahepatic cholestasis type 1 deficiency.
      • van Wessel DBE
      • Thompson R.J.
      • Gonzales E.
      • Jankowska I.
      • Shneider B.L.
      • Sokal
      • et al.
      Impact of genotype, serum bile acids, and surgical biliary diversion on native liver survival in FIC1 deficiency.
      No other potentially pathogenic variant was detected in ATP8B1, ABCB11 and ABCB4. Genetic testing by Sanger sequencing in 9 of his available siblings prove the variant c.749T>A p.(Leu250His) to segregate with the BRIC phenotype in the homozygous state (3 affected homozygous siblings, 5 heterozygous and one non-mutated unaffected sibling). Of note, one affected sister received COVID-19 vaccination without experiencing a BRIC manifestation. The reasons for the different clinical evolution remain unknown. Potential factors such as her advanced age, variable gene expression or other genetic factors may have contributed.
      The typical temporal relationship in the absence of other possible triggers suggests that BRIC exacerbation in this patient likely resulted from COVID-19 vaccination. Yet, direct causality cannot be definitively established. This is, to our knowledge, the first report of BRIC exacerbation developing post COVID-19 vaccination. The WHO database on adverse drug effects has reported no case of progressive familial intrahepatic cholestasis (PFIC) in combination with a COVID-19 vaccination to date (04 APR 2022, BRIC is not a search term). The underlying mechanism remains unclear, it is possible that immune responses and cytokine release triggered cholestasis similar to immune responses following infection. Previously, BRIC exacerbation was reported to occur following hepatitis A vaccination.
      • Folvik G.
      • Hilde O.
      • Helge G.O.
      Benign recurrent intrahepatic cholestasis: review and long-term follow-up of five cases.
      We do not intend to discourage COVID-19 vaccination. Nonetheless, this severe manifestation of cholestasis complicated by AKI requiring intensive care in a patient with BRIC1 related to a homozygous ATP8B1 variant should arouse our awareness of unknown hepatic responses to COVID-19 vaccination.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors' contributions

      YG, MD & CB, clinical care of the patient; YG & CB, drafting of the manuscript; JV, histopathological evaluation; AJ, genetic data analysis and interpretation. JV, MD, AJ & CB, critical revision of the manuscript;

      Data availability statement

      Additional data is available upon request to the corresponding author.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      We acknowledge the whole patients’ family who participated in the genetic family testing. Moreover, we acknowledge Julia Laube and Dr. Markus Zweier from the Institute of Medical Genetics at the University of Zurich for performing the sequencing analyses.

      Supplementary data

      The following are the supplementary data to this article:

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