Figure 1. The glyoxylate pathway in the human hepatocyte. Alanine:glyoxylate aminotransferase (AGT). Glyoxylate reductase: hydroxypyruvate reductase (GR/HPR). Glycolate oxidase (GO). Lactate dehydrogenase (LDH). D-amino acid oxidase (DAO). Pyridoxal phosphate (PLP). Deficiency or mistargeting of AGT* (PHI) results in buildup of glyoxylate and increased oxalate production. Deficiency of a protein with dual GR and HPR ** activities (PHII) gives rise to increased hydroxypyruvate and glyoxylate, precursors of L-glycerate and oxalate, respectively.
Figure 1. The glyoxylate pathway in the human hepatocyte.
The primary hyperoxalurias are autosomal recessive disorders of glyoxylate metabolism characterized by excessive production and urinary excretion of oxalate and glycolate (Primary Hyperoxaluria type II, PH2) (see Figure 1).
The term "primary hyperoxaluria" was first used by Archer and colleagues in 1957 to specifically denote a suspected metabolic origin for the marked hyperoxaluria, recurrent urolithiasis and renal and extra-renal calcium oxalate crystal deposition that characterized affected children. The urine oxalate excretion rate in affected patients is typically 3 to 6 times normal with severe clinical consequences. Kidney stones and/or calcification of the kidney occur in childhood or adolescence. Renal injury due to oxalate and consequences of the stones often leads to renal failure. Loss of renal function, if not addressed promptly by transplantation, leads to markedly increased plasma concentrations of oxalate with deposition of calcium oxalate in body tissues. Resulting organ system dysfunction including ischemic ulcers of the skin, metabolic bone disease, refractory anemia, cardiomyopathy, and cardiac conduction system abnormalities are the cause of severe morbidity and mortality. Historically, the median age at death was only 36 years.
These rare diseases (PH1 and PH2) can be caused by defects in at least 2 glyoxylate-metabolizing enzymes (see Figure 1). Since pyridoxine (vitamin B6) is a cofactor for the causative enzyme in PH1, administration of this vitamin can reduce urine oxalate levels in some PH1 patients. Recently, a third group of patients has been identified with an as-yet-unknown genetic cause of hyperoxaluria. Untreated, PH patient outcome is often poor, with death from renal failure and systemic oxalosis the norm.However, there is wide variability in outcome amongst patients, and with careful and aggressive treatment patient survival with preserved renal function to middle age (or older) is possible. The important factors that influence improved patient survival are currently poorly understood.
However, in all cases, care by a dedicated physician who is familiar with treatment of PH is essential to minimize complications, and maximize quality of life. Treatment strategies include careful dietary advice to minimize oxalate ingestion and maximize fluid intake, carefully titrated doses of pyridoxine for those patients in whom it is effective and neutral phosphate and/or citrate to reduce urinary saturation with calcium oxalate. Renal function must be monitored vigilantly and renal replacement therapy should be initiated promptly if renal clearance falls below a critical threshold, in order to prevent body-wide deposition of calcium oxalate. Kidney transplantation alone or combined kidney-liver transplantation is clearly the preferred treatment of renal failure for PH patients. Current evidence is split regarding which patients benefit the most from the riskier combined kidney-liver transplant. If transplantation is not possible, patients must be aggressively dialyzed, often 6 or 7 days per week and/or using a combination of modalities, in order to remove enough oxalate to prevent body-wide oxalosis.