Effect of lysine infusion on urea cycle in lysinuric protein intolerance.

Poor intestinal absorption and excessive renal loss of dibasic amino acids result in low plasma concentrations in patients with lysinuric protein intolerance (LPI). Arginine and ornithine deficiency impair the function of the urea cycle and cause hyperammonemia after protein intake, while chronic lysine deficiency may cause growth failure and lead to reduced bone density in such patients. Since high lysine concentrations inhibit several enzymes of the urea cycle in the liver, lysine supplementation may induce hyperammonemia in LPI. We thus studied how LPI patients tolerate high plasma lysine by intravenous (IV) infusion of 3.3 mmol/kg lysine hydrochloride over 90 minutes in 6 adult patients and 4 healthy controls. The plasma lysine concentration (mean +/- SD, range) peaked in the patients (9,114 +/- 1,864, 7,156 to 12,044 micromol/L) and controls (10,185 +/- 2,253, 7,714to 13,122 micromol/L) at 90 minutes. Urinary lysine excretion peaked in the second 2-hour urine collection in the patients (4,582 +/- 1,276, 3,018 to 6,315 micromol/m2 body surface area per hour) and in the first 2-hour collection in the controls (5,373 +/- 1,766, 3,551 to 7,286 micromol/m2/h). Two patients had mild nausea but no hyperammonemia and one patient had moderate hyperammonemia (peak, 112 micromol/L) at the end of the infusion. Orotic acid excretion increased in 2 subjects with a peak excretion rate of 33 and 251 micromol/m2/h in the third 2-hour collection after starting the load. All other subjects remained asymptomatic and showed no change in plasma ammonia or urinary orotic acid excretion. We thus conclude that an acute increase in plasma lysine caused minimal clinical or biochemical untoward effects in patients with LPI. Moderate increases in plasma lysine after low-dose oral supplementation with lysine or well-absorbed lysine derivatives are probably well tolerated in LPI.