Abstract
We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency (n = 3), Δ4-3-oxosteroid 5β-reductase (5β-reductase) deficiency (n = 3), and oxysterol 7α-hydroxylase deficiency (n = 1) over 21years between 1996 and 2017. We aimed to clarify long-term outcome in the 7 patients with BASD as well as long-term efficacy of chenodeoxycholic acid (CDCA) treatment in the 5 patients with 3β-HSD deficiency or 5β-reductase deficiency. Diagnoses were made from bile acid and genetic analyses. Bile acid analysis in serum and urine was performed using gas chromatography-mass spectrometry. Clinical and laboratory findings and bile acid profiles at diagnosis and most recent visit were retrospectively obtained from medical records. Long-term outcome included follow-up duration, treatments, growth, education/employment, complications of treatment, and other problems. Medians with ranges of current patient ages and duration of CDCA treatment are 10 years (8 to 43) and 10years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted. We concluded that CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment.
Highlights
In frequency are 5β-reductase deficiency (OMIM 235555), caused by mutations in SRD5B1 (AKR1D1) and oxysterol 7α deficiency (OMIM 603711) due to mutations in CYP7B1.[12]. These 3 disorders often present in the first few months of life as cholestasis with conjugated hyperbilirubinemia and elevated transaminases, usually progressing to cirrhosis if untreated
Absence of pruritus and normal serum γglutamyltransferase (GGT) and normal or low serum total bile acids (TBA) using 3α-hydroxysteroid dehydrogenase enzyme method concentrations have been emphasized as characteristic findings in bile acid synthesis disorders (BASD), such as 3β-hydroxy-Δ -C -steroid dehydrogenase/isomerase (3β-HSD) deficiency, 5β-reductase deficiency, and oxysterol 7α deficiency.[1,2,3, 12]
One patient with 5β-reductase deficiency was treated with ursodeoxycholic acid (UDCA) only during her first year, while early in life another patient who had oxysterol 7α deficiency required liver transplantation, which was successful
Summary
Since 1987, 6 bile acid synthesis disorders (BASD) caused by single-enzyme defects, including 3βhydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency, Δ4-3-oxosteroid 5β-reductase (5βreductase) deficiency, oxysterol 7α-hydroxylase (oxysterol 7α) deficiency, sterol 27 hydroxylase deficiency, bile acid-CoA ligase deficiency, and bile acid-CoA: amino acid N-acyltransferase deficiency have been reported.[1,2,3,4,5,6] The first known Japanese BASD patient, who had 3β-HSD deficiency, was reported in 1998. [7, 8] Subsequently Japanese 5β-reductase deficiency and oxysterol 7α deficiency cases have been reported, but neither sterol 27 hydroxylase deficiency (except in adults or older children with cerebrotendinous xanthomatosis) nor amidation defects are known to have arisen in Japan.[9,10,11] No standard samples for unusual bile acids such as 3β-hydroxy-Δ5, 3-oxo-Δ4 and allo-bile acids were available, while a few pediatricians with an interest in neonatal cholestasis may have made a delayed diagnosis of BASD in Japan.BASD are rare autosomal recessive inherited disorders. Since 1987, 6 bile acid synthesis disorders (BASD) caused by single-enzyme defects, including 3βhydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency, Δ4-3-oxosteroid 5β-reductase (5βreductase) deficiency, oxysterol 7α-hydroxylase (oxysterol 7α) deficiency, sterol 27 hydroxylase deficiency, bile acid-CoA ligase deficiency, and bile acid-CoA: amino acid N-acyltransferase deficiency have been reported.[1,2,3,4,5,6] The first known Japanese BASD patient, who had 3β-HSD deficiency, was reported in 1998. Long-term chenodeoxycholic acid (CDCA) treatment to 5 of the patients, who had 3β-hydroxy-Δ 5 -C 27 -steroid dehydrogenase/isomerase (3β-HSD) deficiency (n=3) or Δ 4 -3-oxosteroid 5β-reductase (5βreductase) deficiency (n=2). Another patient with the latter diagnosis whose bile acid analyses had mitigating features was maintained on ursodeoxycholic acid according to parental preferences and remains healthy after discontinuation of treatment. Efficacy of CDCA treatment was evaluated in the 5 patients given a low dose (5 to 10 mg/kg/day) for a long term
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