Bile Acid Synthesis Disorders in Arabs: A 10-year Screening Study

Al–Hussaini, Abdulrahman; Setchell, Kenneth D.R.; Alsaleem, Badr; Heubi, James E.; Lone, Khurram; Davit–Spraul, Anne; Jacquemin, Emmanuel

doi:10.1097/mpg.0000000000001734

Cited by 19 publications

(13 citation statements)

References 38 publications

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“…The bile acid profiles of 14 patients with 17 variants assigned as VUS were consistent with HSD3B7 deficiency which is important information for the pathogenicity assessment of these variants if they are detected in future patients. In two patients with the remaining two variants of uncertain significance (c.968 C > T and c.484_485delinsCC), serum TBA concentrations (measured by enzyme immunoassay) were low (< 10µmol/L) and consistent with expectations for a bile acid synthesis disorder [ 20 ]. Elevated atypical urinary bile acids and low serum TBA (measured when off UDCA therapy) enabled us to make the final diagnosis and to prove that these 19 novel variants of uncertain significance are likely pathogenic.…”

Section: Discussionmentioning

confidence: 84%

Genetic spectrum and clinical characteristics of 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency in China

Zhao

Setchell

Gong

et al. 2021

Orphanet J Rare Dis

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Background Biallelic variants in HSD3B7 cause 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, a life-threatening but treatable liver disease. The goal of this study was to obtain detailed information on the correlation between the genotype and phenotype of HSD3B7 deficiency and to report on responses to primary bile acid therapy. Methods The medical records of a cohort of 39 unrelated patients with genetically and biochemically confirmed HSD3B7 deficiency were examined to determine whether there exist genotype-phenotype relationships in this bile acid synthesis disorder. Results In all, 34 of the 44 variants identified in HSD3B7 were novel. A total of 32 patients presented early with neonatal cholestasis, and 7 presented after 1-year of age with liver failure (n = 1), liver cirrhosis (n = 3), cholestasis (n = 1), renal cysts and abnormal liver biochemistries (n = 1), and coagulopathy from vitamin K1 deficiency and abnormal liver biochemistries (n = 1). Renal lesions, including renal cysts, renal stones, calcium deposition and renal enlargement were observed in 10 of 35 patients. Thirty-three patients were treated with oral chenodeoxycholic acid (CDCA) resulting in normalization of liver biochemistries in 24, while 2 showed a significant clinical improvement, and 7 underwent liver transplantation or died. Remarkably, renal lesions in 6 patients resolved after CDCA treatment, or liver transplantation. There were no significant correlations between genotype and clinical outcomes. Conclusions In what is the largest cohort of patients with HSD3B7 deficiency thus far studied, renal lesions were a notable clinical feature of HSD3B7 deficiency and these were resolved with suppression of atypical bile acids by oral CDCA administration.

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Section: Discussionmentioning

confidence: 84%

Genetic spectrum and clinical characteristics of 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency in China

Zhao

Setchell

Gong

et al. 2021

Orphanet J Rare Dis

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“…[15][16][17] In Saudi Arabia, 2.7% of patients with cholestasis in infancy were found to have BASD. [18] In Japan, our bile acid analyses in 1010 infants with cholestasis lacking obvious cause between 1996 and 2017 showed a BASD prevalence of 0.7%, with equal numbers of cases for 3β-HSD deficiency and 5β-reductase deficiency. Our experience as well as previous reports from East Asia suggests that 3β-HSD deficiency is less prevalent in East Asia than in Europe or the US.…”

Section: Discussionmentioning

confidence: 87%

“…However, CA monotherapy is insufficient for 5β-reductase deficiency. [18] UDCA treatment is used initially until a diagnosis of 5β-reductase deficiency is made. In early infancy, 5β-reductase deficiency may be exacerbated by CA.…”

Section: Discussionmentioning

confidence: 99%

“…In consideration of reported mortality, CDCA typically is used in combination with CA to increase the therapeutic effect. [17,18,24] In Japan, CDCA is used instead of CA for treatment of BASD, since the latter is not available for clinical use in Japan; the same is true for China. [25] We have obtained a reliable therapeutic effect from CDCA, and believe that a low dose of CDCA (5 to 10 mg/kg/day) can obtain sufficient benefit.…”

Section: Discussionmentioning

confidence: 99%

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Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment

et al. 2021

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Background: We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) over 21 years between 1996 and 2017. Diagnoses were made by bile acid and genetic analyses. We gave lowdose, 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 5βreductase (5β-reductase) 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 now remains healthy after discontinuation of treatment. A patient with oxysterol 7αhydroxylase deficiency developed liver failure and fully recovered after successful liver transplantation. We used clinical records to clarify long-term outcome and value of CDCA in the other patients. Efficacy of CDCA treatment was evaluated in the 5 patients given a low dose (5 to 10 mg/kg/day) for a long term.Results: Medians with ranges of current patient ages and duration of CDCA treatment are10 years (8 to 43) and 10 years (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.Conclusions: We concluded that low-dose CDCA treatment is effective in 3β-HSD deficiency and 5βreductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term, low-dose CDCA treatment.We have no financial support.

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“…PT was prolonged and not corrected by parenteral vitamin K in seven patients. A routine sTBA was not included in the initial battery of tests in some patients, which may have a delayed diagnosis because a low or normal sTBA when combined with a low serum GGT can be a helpful indicator of a possible bile acid synthesis disorder[27], particularly in the case of the HSD3B7 and AKR1D1 deficiencies. Most of our patients had been placed on UDCA therapy for their cholestasis prior to referral for evaluation, and it is worth cautioning that routine sTBA measurements in UDCA treated patients are of little guidance, or may even mislead, as these will be elevated due to cross-reactivity in the assay from UDCA and its metabolites.…”

Section: Discussionmentioning

confidence: 99%

Δ4-3-oxosteroid-5β-reductase deficiency: Responses to oral bile acid therapy and long-term outcomes

Zhang

Setchell

Zhao

et al. 2019

WJG

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BACKGROUND Disorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5β-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China. AIM To evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA. METHODS Twelve patients with AKR1D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1D1 , were treated with differing doses of CDCA or ursodeoxycholic acid (UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters, notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry. RESULTS Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA. CONCLUSION The primary bile acid CDCA is effective in treating AKR1D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.

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Bile Acid Synthesis Disorders in Arabs: A 10-year Screening Study

Abstract: BASDs are rare but treatable causes of metabolic liver disease in Saudi Arabia. BASD should be considered in infants with cholestasis and low or normal serum total bile acid concentrations.

Cited by 19 publications

References 38 publications

Genetic spectrum and clinical characteristics of 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency in China

Genetic spectrum and clinical characteristics of 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency in China

Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment

Δ4-3-oxosteroid-5β-reductase deficiency: Responses to oral bile acid therapy and long-term outcomes

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