A recent study (AA Al-Hussaini et al. JPGN 2017; 65: 613-20) showed that serum (total) bile acids is effective in screening for bile acid synthesis disorders. In this prospective study from Saudi Arabia, with 626 patients and 450 with infantile cholestasis, the authors identified bile acid synthetic disorder (BASD) in 2.7% of infantile cholestasis patients. Among the 15 cases, 11 were due to 3β-hydroxyl-Δ5-C27 steroid oxidoreductase dehydrogenase deficiency (HSD3B7). In these conditions, serum bile acids are low or normal (< 10 μmol/L) in the setting of cholestasis; most cholestatic conditions have elevated bile acids. In addition, all of their patients with bile acid synthetic disorders had a normal or low GGT.
Cholic acid is the “only effective therapy” for bile acid synthetic disorders. It has a high cost of “$31,000 yer year in Europe” (50 mg per day).
My take: While the authors provide a diagnostic algorithm (figure 3) for diagnosis of bile acid synthetic disorders, this will likely change with the emergence of genetic screening panel. At this time, in infants/children with cholestasis along with a normal/low GGT and normal/low serum bile acids, one should check urine for fast atom bombardment mass spectrometry.
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Bright Angel Trail, Grand Canyon
JE Heubi et al (JPGN 2017; 65: 321-6) performed a phase 3, open-label, nonrandomized trial on the efficacy and safety of oral cholic acid for patients with Zellweger Spectrum disorders (n=20) and patients with bile acid synthesis disorders (BASD) (n=50). Cholic acid dosing: 10-15 mg/kg/day. Most common BASD were 3β-HSD (n=35), and 5β-reductase (n=10). Based on this work, cholic acid is an FDA-approved agent.
- Urine bile acid metabolite scores improved (P<0.0001) with cholic acid
- Transaminases improved (AST, ALT) (P<0.0001)
- Growth parameters, improved with weight gain reaching statistical significance
- “Liver biopsies showed either stable findings or histologic improvement in all parameters except bridging fibrosis”
- No study drug-related serious adverse events were noted
- With Zellweger spectrum disorders, it is important to note that “there is no evidence that treatment with cholic acid has any impact on the extrahepatic disease.”
My take: Cholic acid helps the liver in these disorders which is particularly important for BASD. It is unclear if this improves outcomes in patients with Zellweger spectrum disorders as it has not been shown to improve extrahepatic disease.
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There is significant variability in the presentation of the most common inborn error of bile acid metabolism, 3β-hydroxy-Δ5-C27-steroid oxidoreductase (3β-HSD) deficiency (Molho-Pessach V et al, Hepatology 2012; 55: 1139-45).
This report investigated a 24-year-old women from Iran with idiopathic cirrhosis and a strong family history of idiopathic cirrhosis, as well as a 32-year-old first-cousin who had a self-limited liver disease (resolved at age 9). A genome-wide analysis of 2.4 million single nucleotide polymorphisms was performed in the patient and cousin and compared to a healthy relative. The investigators were able to identify regions of homozygosity that was present in the proband and cousin but not the healthy relative; one of these regions corresponded to a gene encoding 3β-HSD. Subsequent, sequence analysis revealed a specific frameshift mutation and high levels of 3β-hydroxy-Δ5 using mass spectrometry.
For me, this report has two take home points:
- As with a lot of diseases, 3β-HSD can have variable phenotypic expression and may present beyond infancy. Its diagnosis remains important because a timely diagnosis allows effective treatment with bile acid replacement.
- More ‘idiopathic’ diseases will be unmasked with new molecular tools, especially when investigators combine these tools with careful history-taking and family history.
- w/u for bile acid defects: FAB-MS fast atom bombardment mass spectrometry
**stop URSO 5 days before test
- http://www.orpha.net/data/patho/Pro/en/InbornErrorsBileAcidMetabolism-FRenPro11194v01.pdf. Online review article from Heubi JE, et al, reprinted with permission from Thieme Medical Publishers (Seminars Liver Dis. 2007 Aug;27(3):282-294) Homepage at www.thieme.com.“At the Cincinnati Children‘ Hospital Medical Center, more than 130 patients have been identified with defects, accounting for 1% to 2% of the cases of unexplained liver disease in infants and children.”
- -Gastroenterology 2009; 137: 1310. Long-term good efficacy of cholic acid for primary defects in bile acid synthesis.
- -Hepatology 2009; 39: 1403. Review defects in bile acid synthesis.