Chapter 33 - Primary Hyperoxaluria

Abstract

The primary hyperoxalurias (1 and 2) are genetic disorders in glyoxylate metabolism that lead to systemic overproduction of oxalate. This endogenous production of oxalate cannot be managed by restriction of dietary oxalate, although it may be possible to restrict dietary glyoxylate precursors, such as glycolate and hydroxyproline to limit endogenous oxalate production. Glyoxylate produced in the mitochondria or present in the cytoplasm can be converted to glycolate by the glyoxylate reductase (GR) activity of the GRHPR enzyme. This enzyme is present both in the cytoplasm and in the mitochondria. In the absence of GR activity (PH2 patients) the excess glyoxylate is converted to oxalate, presumably in the cytoplasm by lactate dehydrogenase (LDH). In PH2 patients, who lack both GR and hydroxypyruvate reductase (HPR) enzymatic activities, the lack of HPR results in an accumulation of hydroxypyruvate, which is converted to L-glycerate by LDH. Thus, the diagnostic biochemical features of PH2 are high urinary L-glycerate in conjunction with hyperoxaluria. The diagnosis and screening of PH, and the further classification of PH into PH1 and PH2 utilizes biochemical analyte measurements of urine, genetic screening for mutations, and measurements of tissue enzyme functions. A definitive diagnosis of PH1 and PH2 can be obtained by assessments of glyoxylate aminotransferase (AGT) and GRHPR enzymatic activities and immunoreactivity in hepatic tissue (minimum of 2 mg), respectively. Alternatively, the diagnosis can be established at the molecular level in the majority of patients with minimal invasiveness and associated morbidity. Measurement of GR and DGDH activity in liver can be used for definitivediagnosis of PH2.