Liver disease in infancy caused by oxysterol 7α-hydroxylase deficiency: successful treatment with chenodeoxycholic acid
Liver disease in infancy caused by oxysterol 7α-hydroxylase deficiency: successful treatment with chenodeoxycholic acid
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DOI：
10.1007/s10545-014-9695-6
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发表时间：
2014-09-01
影响因子：
4.2
通讯作者：
Clayton, Peter T.
中科院分区：
文献类型：
--
作者：
Dai, Dongling;Mills, Philippa B.;Clayton, Peter T.
一名巴基斯坦血统近亲父母的孩子在第 5 周时出现黄疸，然后在第 3 个月时出现烦躁、凝血酶原时间延长、白蛋白低和低血糖发作。研究显示丙氨酸转氨酶升高，而γ-谷氨酰转肽酶正常。通过电喷雾电离串联质谱 (ESI-MS/MS) 对尿液进行分析表明，主峰为 m/z 480（牛磺酸缀合的 3β-羟基-5-胆烯酸）和 m/z 453（硫酸化 3β-羟基-5-胆烯酸）。通过气相色谱-质谱法（GC-MS）对血浆进行的分析显示，3β-羟基-5-胆烯酸、3β-羟基-5-胆烯酸和27-羟基胆固醇的浓度增加，表明氧化甾醇7α-羟化酶缺乏。该患者的 CYP7B1 突变 (c.1249C > T) 是纯合子，该突变改变了氧化甾醇 7 α-羟化酶 (p.R417C) 中高度保守的残基 - 先前在一个患有 5 型遗传性痉挛性截瘫的家族中报道过。在接受熊去氧胆酸 (UDCA) 治疗时，他的病情恶化，但在接受鹅去氧胆酸 (CDCA) 治疗时，15 mg/kg/d，他进步很快。活检（CDCA 两周后）显示巨细胞肝炎、进展中的微结节性肝硬化和脂肪变性。 CDCA 治疗后肝功能的改善与 3β-羟基-Delta(5) 胆汁酸的血浆浓度和尿排泄量下降有关，而 3β-羟基-Delta(5) 胆汁酸被认为具有肝毒性。 5岁时（接受CDCA，6毫克/公斤/天），他的肝功能正常。除了有绊倒的倾向外，神经系统发育正常。检查发现有高弓足，但没有上运动神经元体征。该病例的研究结果表明，CDCA 可以降低胆固醇 27-羟化酶的活性，这是胆汁酸合成酸性途径的第一步。
A child of consanguineous parents of Pakistani origin developed jaundice at 5 weeks and then, at 3 months, irritability, a prolonged prothrombin time, a low albumin, and episodes of hypoglycaemia. Investigation showed an elevated alanine aminotransferase with a normal gamma-glutamyl-transpeptidase. Analysis of urine by electrospray ionisation tandem mass spectrometry (ESI-MS/MS) showed that the major peaks were m/z 480 (taurine-conjugated 3 beta-hydroxy-5-cholenoic acid) and m/z 453 (sulphated 3 beta-hydroxy-5-cholenoic acid). Analysis of plasma by gas chromatography-mass spectrometry (GC-MS) showed increased concentrations of 3 beta-hydroxy-5-cholenoic acid, 3 beta-hydroxy-5-cholestenoic acid and 27-hydroxycholesterol, indicating oxysterol 7 alpha-hydroxylase deficiency. The patient was homozygous for a mutation (c.1249C > T) in CYP7B1 that alters a highly conserved residue in oxysterol 7 alpha-hydroxylase (p.R417C) - previously reported in a family with hereditary spastic paraplegia type 5. On treatment with ursodeoxycholic acid (UDCA), his condition was worsening, but on chenodeoxycholic acid (CDCA), 15 mg/kg/d, he improved rapidly. A biopsy (after 2 weeks on CDCA), showed a giant cell hepatitis, an evolving micronodular cirrhosis, and steatosis. The improvement in liver function on CDCA was associated with a drop in the plasma concentrations and urinary excretions of the 3 beta-hydroxy-Delta(5) bile acids which are considered hepatotoxic. At age 5 years (on CDCA, 6 mg/kg/d), he was thriving with normal liver function. Neurological development was normal apart from a tendency to trip. Examination revealed pes cavus but no upper motor neuron signs. The findings in this case suggest that CDCA can reduce the activity of cholesterol 27-hydroxylase - the first step in the acidic pathway for bile acid synthesis.