Primary hyperoxaluria type 1: pathophysiology and genetics

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare genetic form of calcium oxalate kidney stone disease. It is caused by a deficiency in the liver-specific enzyme, alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5'-phosphate (PLP)-dependent enzyme involved in the metabolism of glyoxylate. The excessive endogenous synthesis of oxalate that ensues leads to hyperoxaluria, and the crystallization of the poorly soluble calcium salt of oxalate is responsible for a severe kidney stone disease, which can progress to end-stage renal disease, systemic deposition of oxalate and death. Knowledge about metabolic precursors of glyoxylate and oxalate, molecular pathology of AGT and analytical methods for diagnosis and clinical assessment have allowed a better understanding of the mechanisms underlying PH1 and opened the door to new therapeutic strategies.

Keywords: alanine:glyoxylate aminotransferase; glycolate; glyoxylate; kidney stones; oxalate; primary hyperoxaluria; urolithiasis.

FIGURE 1:

Metabolism of oxalate in the hepatocyte and consequences in PH1. AGT, alanine:glyoxylate aminotransferase (AGT is also SPT, serine:pyruvate aminotransferase); GO, glycolate oxidase; PLP/PMP, pyridoxal phosphate/pyridoxamine phosphate, the two B6 vitamers interacting with AGT as coenzymes; GR, glyoxylate reductase; LDH, lactate dehydrogenase. The metabolism of hydroxyproline involves multiple steps, finishing with 4-hydroxy-2-oxoglutarate aldolase (HOGA1). PH1 is caused by a deficiency in AGT, PH2 by a deficiency in GR and PH3 by a deficiency in HOGA1.