Two Case Reports of Successful Treatment of Cholestasis With Steroids in Patients With PFIC-2

Engelmann, Guido; Wenning, Daniel; Herebian, Diran; Sander, Oliver; Dröge, Carola; Kluge, Stefanie; Kubitz, Ralf

doi:10.1542/peds.2014-2376

Cited by 17 publications

(9 citation statements)

References 30 publications

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“…For example, dogs receiving a high dosage of hydrocortisone (5 mg/kg) showed a significant increase in bile flow [ 99 ]. Engelmann et al reported that steroids effectively ameliorated cholestatic itches and reduced the serum level of bile salts and bilirubin in two PFIC2 patients carrying missense mutations in BSEP [ 100 ].…”

Section: Main Textmentioning

confidence: 99%

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

et al. 2018

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BackgroundJaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.Main bodyThe major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.Short conclusionUnderstanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

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Section: Main Textmentioning

confidence: 99%

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

et al. 2018

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“…For example, glucocorticoids have been described to interfere with transcription and mRNA processing on different levels, including alternative promoter usage 53 , induction of shortened protein variants 54 or inhibition of pre-mRNA splicing 55 . Interestingly, child 2 of our study was successfully treated by glucocorticoids 16 . His second mutation p.R832C is clearly associated to PFIC-2 9 .…”

Section: Discussionmentioning

confidence: 72%

“…Additionally, p.V444A and p.A1028A as well as four other intronic variants in a distance ≥15 nucleotides from the splice-sites were detected ( Supplementary Table S1 ). Child 2 was listed for liver transplantation but was removed from the list two years later because cholestasis was effectively controlled by budesonide 16 .…”

Section: Resultsmentioning

confidence: 99%

Exon-skipping and mRNA decay in human liver tissue: molecular consequences of pathogenic bile salt export pump mutations

Dröge

Schaal

Engelmann

et al. 2016

Sci Rep

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The bile salt export pump BSEP mediates bile formation. Over 150 BSEP mutations are associated with progressive familial intrahepatic cholestasis type 2 (PFIC-2), with few characterised specifically. We examined liver tissues from two PFIC-2 patients compound heterozygous for the splice-site mutation c.150 + 3A > C and either c.2783_2787dup5 resulting in a frameshift with a premature termination codon (child 1) or p.R832C (child 2). Splicing was analysed with a minigene system and mRNA sequencing from patients’ livers. Protein expression was shown by immunofluorescence. Using the minigene, c.150 + 3A > C causes complete skipping of exon 3. In liver tissue of child 1, c.2783_2787dup5 was found on DNA but not on mRNA level, implying nonsense-mediated mRNA decay (NMD) when c.2783_2787dup5 is present. Still, BSEP protein as well as mRNA with and without exon 3 were detectable and can be assigned to the c.150 + 3A > C allele. Correctly spliced transcripts despite c.150 + 3A > C were also confirmed in liver of child 2. In conclusion, we provide evidence (1) for effective NMD due to a BSEP frameshift mutation and (2) partial exon-skipping due to c.150 + 3A > C. The results illustrate that the extent of exon-skipping depends on the genomic and cellular context and that regulation of splicing may have therapeutic potential.

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“…Engelmann et al proposed steroid treatment has a positive effect on disease course of PFIC 2 [27]. Recently new choleretic agents such as resveratrol, retinoid X, farnesoid X receptor agonists and tauroursodeoxycholate are investigated in the treatment of cholestasis.…”

Section: Treatmentmentioning

confidence: 99%

Progressive familial intrahepatic cholestasis in children

Sevinç¹,

Ağın²,

Doğan³

2018

Ann Gastroenterol Dig Syst

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Two Case Reports of Successful Treatment of Cholestasis With Steroids in Patients With PFIC-2

Cited by 17 publications

References 30 publications

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

Exon-skipping and mRNA decay in human liver tissue: molecular consequences of pathogenic bile salt export pump mutations

Progressive familial intrahepatic cholestasis in children

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