Titration of Bile Acid Supplements in 3β‐Hydroxy‐Δ5‐C27‐Steroid Dehydrogenase/Isomerase Deficiency

Riello, Laura; D’Antiga, Lorenzo; Guido, Maria; Alaggio, Rita; Giordano, Giuseppe; Zancan, Lucia

doi:10.1097/mpg.0b013e3181b97bd2

Cited by 20 publications

(14 citation statements)

References 20 publications

(23 reference statements)

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“…UDCA, a potent choleretic widely used in the treatment of cholestatic liver diseases, has been used to treat some patients with the HSD3B7 deficiency[8,11,35]. It stimulates bile flow, lowers serum transaminases, and may improve liver histology[11,30].…”

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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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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“…Liver injury in 3β‐HSD deficiency is the result of a lack of normal primary bile acids that are required to stimulate bile flow, combined with the presence of increased production of 3β‐hydroxy‐Δ 5 bile acids that accumulate due to the enzyme defect 26. Replacement therapy with oral administration of the primary bile acid, cholic acid, reduces the levels of 3β‐hydroxy‐Δ 5 bile acids through negative feedback inhibition on endogenous bile acid synthesis and this leads to a normalization of the clinical symptoms, liver function tests, and liver histology if initiated prior to development of significant cirrhosis 3, 7, 10, 14, 18, 19. Prolonged treatment with cholic acid (>15 years) is both safe and efficacious 7, 18, 21…”

Section: Discussionmentioning

confidence: 99%

“…Patients with 3β‐HSD deficiency can differ widely in presenation. Some patients present with signs of liver disease (jaundice, hepatosplenomegaly), others with fat soluble vitamin deficiencies (hypocalcemia, rickets, coagulopathy) or fat malabsorption as a result of cholestasis, or a combination of these features 2, 3, 6‐16, 18. The proband in our family did not have clinical evidence of cholestasis at presentation, although her bilirubin level was mildly elevated.…”

Section: Discussionmentioning

confidence: 99%

“…The diagnosis was established by measuring bile acids in the urine using mass spectrometry in a consanguineous Saudi Arabian family in which several family members presented as neonates with giant cell hepatitis and bridging cirrhosis 5. Over 50 patients with this disorder from at least 40 unrelated families have subsequently been reported 3, 6‐1617 and 21 different mutations have been described that cause 3β‐HSD deficiency 3, 6, 7, 12, 13…”

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Homozygosity mapping identifies a bile acid biosynthetic defect in an adult with cirrhosis of unknown etiology

et al. 2012

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The most common inborn error of bile acid metabolism is 3β-hydroxy-Δ5-C27-steroid oxidoreductase (3β-HSD) deficiency, a disorder that usually presents in early childhood with hepatic dysfunction. Timely diagnosis of this disorder is crucial since it can be effectively treated with primary bile acid replacement. Here we describe a 24-year-old woman from Iran with cirrhosis of unknown etiology. Her sister and a first cousin died of cirrhosis (ages 19 and 6 years) and another 32-year old first cousin had a self-limited liver disorder in childhood that resolved at age 9 years. The family history was consistent with the notion that affected family members were homozygous for a mutant allele inherited identical-by-descent. A genome-wide analysis of 2.5 million single nucleotide polymorphisms (SNP) was performed to identify regions of homozygosity that were present in the proband and the 32-year old first cousin, but not in a healthy relative. One of these regions contained the gene encoding 3β-HSD (HSD3B7). Sequence analysis of HSD3B7 revealed that the proband and her 32-year old cousin were homozygous for a frame shift mutation (c.45_46del AG, p.T15Tfsx27) in exon 1. The diagnosis of 3β-HSD deficiency was confirmed by documenting high levels of 3β-hydroxy-Δ5 bile acids in the serum of the first cousin using mass spectrometry. To our knowledge, the 32-year old relative in this family represents the oldest asymptomatic patient with this disorder. Conclusion: This study highlights the clinical utility of homozygosity mapping in diagnosing autosomal recessive metabolic disorders. This family illustrates the wide variation in expressivity that occurs in 3β-HSD deficiency and underscores the need to consider a bile acid synthetic defect as a possible cause of liver disease in adults.

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“…Provided that the liver damage is not too advanced at the time of diagnosis, we can expect normalisation of liver function tests (LFT's), improvement in the liver biopsy appearances, correction of fat soluble vitamin malabsorption and improved growth and weight gain. This has been achieved with chenodeoxycholic acid alone (Subramaniam 360 380 400 420 440 460 480 500 520 540 560 580 600 620 640 660 680 (Subramaniam et al 2010), with ursodeoxycholic acid plus chenodeoxycholic acid (Riello et al 2010) and with cholic acid alone (Gonzales et al 2009). Treatment can be monitored by suppression of urinary excretion of unsaturated bile acids (Ichimiya et al 1991;Riello et al 2010;Gonzales et al 2009).…”

Section: Diagnostic Testsmentioning

confidence: 99%

Disorders of bile acid synthesis

Clayton

2011

J of Inher Metab Disea

134

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Inborn errors of bile acid synthesis can produce life-threatening cholestatic liver disease (which usually presents in infancy) and progressive neurological disease presenting later in childhood or in adult life. Both types of disease can often be treated very effectively with bile acid replacement therapy and it is therefore important to diagnose these disorders as early as possible. The cholestatic disease in infancy is characterised by conjugated hyperbilirubinaemia with raised transaminases but normal γ-glutamyl transpeptidase and a biopsy showing a giant cell hepatitis. There is usually evidence of fat-soluble vitamin malabsorption. The neurological presentation often includes signs of upper motor neurone damage (spastic paraparesis). The most useful screening test for many of these disorders is analysis of urinary cholanoids (bile acids and bile alcohols); this is usually now achieved by electrospray ionisation tandem mass spectrometry. The disorders that are discussed in this review are: 3β-hydroxysteroid-Δ5-C27-steroid dehydrogenase deficiency, Δ4-3-oxosteroid 5β-reductase deficiency, sterol 27-hydroxylase deficiency (cerberotendinous xanthomatosis, CTX), oxysterol 7α-hydroxylase deficiency (including one form of hereditary spastic paraparesis) and the amidation defects, bile acid-CoA: aminoacid N-acyltransferase (BAAT) deficiency and bile acid-CoA ligase deficiency. The disorders of peroxisome biogenesis and peroxisomal β-oxidation that affect bile acid synthesis will be covered in the review by Ferdinandusse et al.

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Titration of Bile Acid Supplements in 3β‐Hydroxy‐Δ5‐C27‐Steroid Dehydrogenase/Isomerase Deficiency

Cited by 20 publications

References 20 publications

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

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

Homozygosity mapping identifies a bile acid biosynthetic defect in an adult with cirrhosis of unknown etiology

Disorders of bile acid synthesis

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