1.
Obeticholic acid for severe bile acid diarrhea with intestinal failure: A case report and review of the literature.
Hvas, CL, Ott, P, Paine, P, Lal, S, Jørgensen, SP, Dahlerup, JF
World journal of gastroenterology. 2018;(21):2320-2326
Abstract
Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequestrants, such as colestyramine and colesevelam, which may be given in combination with the opioid receptor agonist loperamide. Some patients are refractory to conventional treatments. We report the use of the farnesoid X receptor agonist obeticholic acid in a patient with refractory bile acid diarrhea and subsequent intestinal failure. A 32-year-old woman with quiescent colonic Crohn's disease and a normal terminal ileum had been diagnosed with severe bile acid malabsorption and complained of watery diarrhea and fatigue. The diarrhea resulted in hypokalemia and sodium depletion that made her dependent on twice weekly intravenous fluid and electrolyte infusions. Conventional therapies with colestyramine, colesevelam, and loperamide had no effect. Second-line antisecretory therapies with pantoprazole, liraglutide, and octreotide also failed. Third-line treatment with obeticholic acid reduced the number of stools from an average of 13 to an average of 7 per 24 h and improved the patient's quality of life. The fluid and electrolyte balances normalized. The effect was sustained during follow-up for 6 mo with treatment at a daily dosage of 25 mg. The diarrhea worsened shortly after cessation of obeticholic acid. This case report supports the initial report that obeticholic acid may reduce bile acid production and improve symptoms in patients with bile acid diarrhea.
2.
ACOX2 deficiency: An inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia.
Monte, MJ, Alonso-Peña, M, Briz, O, Herraez, E, Berasain, C, Argemi, J, Prieto, J, Marin, JJG
Journal of hepatology. 2017;(3):581-588
Abstract
BACKGROUND & AIMS Acyl-CoA oxidase (ACOX2) is involved in the shortening of C27 cholesterol derivatives to generate C24 bile acids. Inborn errors affecting the rest of peroxisomal enzymes involved in bile acid biosynthesis have been described. Here we aimed at investigating the case of an adolescent boy with persistent hypertransaminasemia of unknown origin and suspected dysfunction in bile acid metabolism. METHODS Serum and urine samples were taken from the patient, his sister and parents and underwent HPLC-MS/MS and HPLC-TOF analyses. Coding exons in genes of interest were amplified by high-fidelity PCR and sequenced. Wild-type or mutated (mutACOX2) variants were overexpressed in human hepatoblastoma HepG2 cells to determine ACOX2 enzymatic activity, expression and subcellular location. RESULTS The patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates, mainly tauroconjugated trihydroxycholestanoic acid (THCA). Genetic analysis of enzymes potentially involved revealed a homozygous missense mutation (c.673C>T; R225W) in ACOX2. His only sister was also homozygous for this mutation and exhibited similar alterations in bile acid profiles. Both parents were heterozygous and presented normal C24 and C27 bile acid levels. Immunofluorescence studies showed similar protein size and peroxisomal localization for both normal and mutated variants. THCA biotransformation into cholic acid was enhanced in cells overexpressing ACOX2, but not in those overexpressing mutACOX2. Both cell types showed similar sensitivity to oxidative stress caused by C24 bile acids. In contrast, THCA-induced oxidative stress and cell death were reduced by overexpressing ACOX2, but not mutACOX2. CONCLUSION ACOX2 deficiency, a condition characterized by accumulation of toxic C27 bile acid intermediates, is a novel cause of isolated persistent hypertransaminasemia. LAY SUMMARY Elevation of serum transaminases is a biochemical sign of liver damage due to multiplicity of causes (viruses, toxins, autoimmunity, metabolic disorders). In rare cases the origin of this alteration remains unknown. We have identified by the first time in a young patient and his only sister a familiar genetic defect of an enzyme called ACOX2, which participates in the transformation of cholesterol into bile acids as a cause of increased serum transaminases in the absence of any other symptomatology. This treatable condition should be considered in the diagnosis of those patients where the cause of elevated transaminases remains obscure.
3.
[Infant with 3β-hydroxy-Δ(5)-C27 steroid dehydrogenase deficiency: report of two cases and literatures review].
Li, X, Huang, Z, Wang, H
Zhonghua er ke za zhi = Chinese journal of pediatrics. 2015;(5):360-5
Abstract
OBJECTIVE To study the clinical characteristics and early diagnosis of children with 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase (3β-HSD) deficiency. METHOD Data related to clinical characteristics, serum biochemistry, liver pathology, gene mutations and treatment of two children with 3β-HSD deficiency were analyzed and relevant literature was reviewed. Fifty-three cases of 3β-HSD deficiency were reported since 1993 in the world. RESULT (1) Both patients showed neonatal cholestasis, blood biochemical examination of patient one showed alanine aminotransferase 292 U/L, aspartate aminotransferase 458 U/L, serum bile acids 1.8 µmol/L, total bilirubin 125.6 µmol/L, direct bilirubin 93.8 µmol/L, γ-glutamyl endopeptidase 43 U/L, bile biochemical test revealed bile acid 17.4 µmol/L, no itching; another patient showed alanine aminotransferase 812 U/L, aspartate aminotransferase 819 U/L, serum bile acids 4.9 µmol/L, total bilirubin 151.3 µmol/L, direct bilirubin 108.8 µmol/L, γ-glutamyl endopeptidase 50 U/L, bile biochemical test revealed bile acid 66.0 µmol/L, there was no itching. Both patients were confirmed by HSD3B7 gene mutation analysis. One patient had a homozygous mutation: 130_131insA, a novel mutation had not been reported, the other had compound heterozygous mutations: 544insG and 790C>C/A; The electron microscopic findings included bile pigment granules, fat droplets deposited in the cytoplasm of hepatocytes, glycogen granules increased, bile ductular dilatation or proliferation, bile plugs in canaliculus, biliary epithelial microvilli reduced, chronic inflammatory cell infiltration; (2) 53 cases were diagnosed by urine gas chromatography mass spectrometry (GC/MS) or fast atom bombardment mass spectrometry (FAB-MS), while 33 cases were diagnosed by HSD3B7 gene mutation analysis. All the patients had cholestatic jaundice, 22 cases of hepatomegaly, fats and fat-soluble vitamin malabsorption in 14 cases, blood γ-GT normal or decreased in 53 cases, normal or decreased serum bile acid in 53 cases, 49 cases had no skin itching. Two children were not treated before the age of 5, 1 child before the age of 13 were not treated in time, progressed to cirrhosis. CONCLUSION 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase is the most common bile acid synthetic defects described to date. The clinical presentation of this disorder include neonatal cholestasis, low or normal serum total bile acid concentration and a normal serum γ-GT concentration, bile acid significantly reduced in the bile. Definitive diagnosis can be achieved by gene analysis; Prompt diagnosis and early treatment are essential, primary bile acid treatment leads to clinical and biochemical control and prevents chronic liver disease.