INVESTIGATIONS INTO PHENOTYPE & GENOTYPE OF ATYPICAL PRIMARY HYPEROXALURIA

高草酸尿症的原因是多方面的。其临床表现包括更良性的情况，如特发性高草酸尿，以及更恶性的原发性高草酸尿综合征。在原发性高草酸尿症中，参与草酸代谢的肝酶缺乏，以常染色体隐性遗传的方式，导致草酸蓄积。这些疾病中显著的草酸过量的表型表现为草酸肾结石、进行性肾功能衰竭和全身性草酸中毒。原发性高草酸尿症I型的特征是肝脏特异性丙氨酸-乙醛转氨酶(AGT)的缺陷。在原发性高草酸尿症II型中，丙氧基酸还原酶(GR)和/或甘油脱氢酶(GDH)均缺失。自从对人肝活检标本进行免疫细胞学酶学评估以来，已经发现了一组表型相似的患者(明显的高草酸尿伴肾结石)，但AGT和GDH水平正常(非典型的高草酸尿)。肾脏草酸过多的病因是一个可能的原因。另一个可能的原因是由于肝酶途径尚未确定而导致的代谢过量。我们建议测量非典型高草酸尿症患者的肠道草酸盐吸收。之前确定的梅奥诊所经历的六个家庭将作为研究对象，并与健康成年人和年龄匹配的对照对象进行比较。一种特别准备的草酸盐粉，由20毫克13C标记的草酸盐组成，将被摄入，并通过气相色谱/质谱仪测量尿中13C-草酸盐的排泄量。由于从肠道吸收的大部分草酸可以在尿液中恢复，即它既不被分解也不被吸收，因此尿草酸水平是外源性草酸的有用标志。如果在这些患者中发现肠道高吸收，未来的研究可以指向发现胃肠道草酸盐吸收的途径，从而瞄准潜在的改变生命的干预措施。

The causesof hyperoxaluria are manyfold. The spectrum of its clinical manifestations encompasses the more benign conditions such as idiopathic hyperoxaluria to the more malignant syndromes of primary hyperoxaluria. In primary hyperoxaluria, deficiencies of hepatic enzymes involved in oxalate metabolism, inherited in an autsomal recessive manner, lead to accumulation of oxalate. The phenotypic expression of the marked oxalate overproduction in these disorders is oxalate nephrolithiasis, progressive renal failure and systemic oxalosis. primary hyperoxaluria type I is characterized by a defect of liver-specific alanine-glyoxylate transaminase (AGT). In primary hyperoxaluria type II there is an absence of either gyoxylate reductase (GR) and/or glycerate dehydrogenase (GDH). Since the availability of immunocytologic enzymatic evaluation of human liver biopsy specimens, a subgroup of patients with similar phenotypic features (marked hyperoxaluria with nephrolithiasis) but with normal AGT and GDH levels has been identified (atypical hyperoxaluria). The etiology of the excessive renal oxalate is one possible cause. Metabolic overproduction due to an yet undefined hepatic enzyme pathway is another possible cause. We propose to measure enteric oxalate absorption in patients with atypical hyperoxaluria. The six previously identified families of the Mayo Clinic experience will serve as study subjects and compared to healthy adults and age-matched control subjects. An especially prepared oxalate meal consisting of 20 mg of 13c-labeled oxalate will be ingested and urinary 13c-oxalate excretion measured via gas chromatography/mass spectroscopy. Since the majority of oxalate that is absorbed from the gut can be recovered in the urine, i.e., it is neither catabolized nor absorbed, urinary oxalate levels are useful markers for exogenously-derived oxalate. If enteric hyperabsorption is found in these patients, future inquiry can be directed towards discovering pathways of oxalate absorption in the GI tract thus targeting potential life-chaging interventions.