Masanori Kawachi

Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII

To identify the mechanism of hyperuricemia in glycogen storage diseases (glycogenoses) that affect muscle, we studied the effects of exercise and prolonged rest on purine metabolism in two patients with glycogenosis type III (debrancher deficiency), one patient with type V (muscle phosphorylase deficiency), and one patient with type VII (muscle phosphofructokinase deficiency). All had hyperuricemia except for one patient with glycogenosis type III. Plasma concentrations of ammonia, inosine, and hypoxanthine increased markedly in all the patients after mild leg exercise on a bicycle ergometer. The plasma urate concentrations also increased, but with a delayed response. Urinary excretion of inosine, hypoxanthine, and urate increased greatly after exercise, consistently with the increases in plasma levels. Hypoxanthine and urate concentrations were extremely high in the plasma and urine of the patient with glycogenosis type VII. With bed rest, the plasma hypoxanthine level returned to normal within a few hours, and the plasma urate concentration decreased from 18.6 to 10.6 mg per deciliter (1106 to 630 mumol per liter) within 48 hours. Similarly, the urinary excretion of these purine metabolites was reduced by bed rest. These findings indicate that muscular exertion in patients with glycogenosis types III, V, and VII causes excessive increases in blood ammonia, inosine, and hypoxanthine due to accelerated degradation of muscle purine nucleotides. These purine metabolites subsequently serve as substrates for the synthesis of uric acid, leading to hyperuricemia.

Influence of daily drinking habits on ethanol-induced hyperuricemia

We examined the influence of alcohol drinking habits on the serum uric acid level after the ingestion of a small amount of ethanol. Subjects were divided into two groups according to their alcohol drinking habits--regular drinkers, who consume more than 60 g ethanol every day, and nondrinkers/occasional drinkers, who consume less than 20 g ethanol occasionally. Drinking 0.5 g ethanol/kg increased serum uric acid levels in regular drinkers by 52.6 +/- 26.3 mumol/L (0.8 +/- 0.4 mg/dL), whereas it did not in nondrinkers/occasional drinkers. Urinary excretion of uric acid was unaltered in both groups. Hypoxanthine and xanthine in both plasma and urine and serum acetate were increased more in regular drinkers than in nondrinkers/occasional drinkers. Accelerated adenine nucleotide degradation secondary to enhanced ethanol oxidation likely explains the ethanol-induced hyperuricemia in regular drinkers.

Metabolism of pyrazinamide and allopurinol in hereditary xanthine oxidase deficiency

The metabolism of pyrazinamide and allopurinol was studied in three xanthinuric patients from two families with hereditary xanthinuria to determine whether both substrates were oxidized only by xanthine oxidase or by other oxidases as well. One xanthinuric patient could neither metabolize pyrazinamide into 5-hydroxypyrazinamide nor allopurinol into oxypurinol. Two xanthinuric patients could metabolize both pyrazinamide into 5-hydroxypyrazinamide and allopurinol into oxypurinol but could not oxidize pyrazinoic acid to 5-hydroxypyrazinoic acid. These findings suggest that xanthinuria comprises at least two subgroups.

Glycogenosis Type V (McArdle’s Disease) with Hyperuricemia

A 28-year-old male with glycogenosis type V associated with continuous hyperuricemia during mild daily activities is reported. An aerobic exercise test using a bicycle ergometer revealed that purine metabolites, i.e., ammonia, inosine, hypoxanthine and xanthine, were transiently increased by the exercise and that a subsequent increment in uric acid continued until the following day. The accelerated purine degradation by the muscle exercise was thus shown to be able to cause the overt hyperuricemia in a patient with glycogenosis type V. Therapeutic use of fructose for glycogenosis was disappointing due to fructose-induced hyperuricemia. A search for myogenic hyperuricemia is essential for therapeutic trials.

Decreased renal clearance of xanthine and hypoxanthine in a patient with renal hypouricemia: a new defect in renal handling of purines

Renal handling of urate, xanthine and hypoxanthine was studied in a hypouricemic patient who had increased plasma concentrations of xanthine and hypoxanthine. The patient, a 50-year-old man, had been suffering from Parkinsons disease, while neither systemic disorders nor particular renal diseases known to affect plasma purine levels were found. His serum urate level was 58 +/- 6 mumol/l (healthy controls for males, 310 +/- 48 mumol/l, mean +/- SD) and the renal uric acid clearance was 3 times higher than that of the controls, establishing a diagnosis of renal hypouricemia. Xanthine and hypoxanthine concentrations in the plasma were elevated to 1.3 +/- 0.1 mumol/l (controls, 0.5 +/- 0.3) and 5.9 +/- 3.5 mumol/l (controls, 1.6 +/- 0.4), respectively. Both renal xanthine and hypoxanthine clearance was only half the value of the controls, indicating reduced urinary excretion of xanthine, and hypoxanthine appears to be responsible for their elevation in plasma. A probenecid loading test revealed no response of urinary urate excretion but normal responses of xanthine and hypoxanthine excretion. However, urinary excretion of urate, xanthine or hypoxanthine did not respond at all to pyrazinamide administration. These findings indicate that the patient had a defective renal handling of xanthine and hypoxanthine as well as urate.

Low glucose-1, 6-bisphosphate and high fructose-2, 6-bisphosphate concentrations in muscles of patients with glycogenosis types VII and V

The level of glucose-1, 6-bisphosphate, a potent allosteric activator of phosphofructokinase, was markedly decreased in muscles of patients with glycogenosis type VII (muscle phosphofructokinase deficiency) and type V (muscle phosphorylase deficiency). Glucose-1-phosphate kinase activity in muscle was virtually absent in a patient with glycogenosis type VII, whereas it was normal in a patient with type V glycogenosis. Glucose-1-phosphate level was increased in type VII glycogenosis, whereas it was decreased in type V glycogenosis. Another activator of phosphofructokinase, fructose-2, 6-bisphosphate was increased in muscles of patients with both types of glycogenosis although it was much higher in type VII than in type V. This finding may be partly related to the difference of fructose-6-phosphate concentrations. The results suggest that phosphofructokinase would contribute to the major glucose-1-phosphate kinase activity in normal human muscle and would also form a kind of self-activating system.

A genetic defect in muscle phosphofructokinase deficiency, a typical clinical entity presenting myogenic hyperuricemia.

Myogenic hyperuricemia is a common pathophysiologic feature of muscle glycogenoses1. Type VII glycogenosis is the one which lacks catalytic activity of phosphofructokinase, a key enzyme of glycolysis, in muscle (PFK-M)2. Energy crisis in the exercising muscles of the patient results in the abnormal purine degradation leading to a typical manifestation of myogenic hyperuricemia1,3. As a step to clarify the molecular basis of this abnormal purine metabolism, we have reported the cloning of full-length human PFK-M cDNA4. The sequence data enabled us to reconfirm the gene duplication mechanism as hypothesized in rabbit PFK-M gene5,6,7. We have also elucidated the existence of the alternative splicing and the alternative promoter system of human PFK-M gene8,9. In addition, we have recently reported the complete structure of human PFK-M gene10. In this paper, we report on the genetic defect in a patient with PFK-M deficiency as the typical clinical entity presenting myogenic hyperuricemia.

Renal Hypouricemia Associated with Hyperoxypurinemia due to Decreased Renal Excretion of Oxypurines: a New Defect in Renal Purine Transport

A decrease in uric acid level associated with an increase in oxypurine (xanthine and hypoxanthine) level in both plasma and urine is known as a principal feature of hereditary xanthinuria due to a defect of xanthine oxidase (EC. 1.2.3.2) (Holmes and Wyngaarden, 1989). In this paper, we report a case of renal hypouricemia associated with increased plasma levels of oxypurines caused by renal tubular dysfunction. We examined renal handling of urate and oxypurines by loading probenecid and pyrazinamide. The results suggest that the renal handling of oxypurines as well as urate is affected in this patient.

Autoantibodies to the insulin receptor impair clearance of plasma endogenous insulin

Plasma insulin clearance was studied in a patient with autoantibodies to the insulin receptor, manifesting persistent hyperinsulinemia associated with alternating hyper- and hypoglycemia. In the postabsorptive period, the plasma glucose level gradually decreased. To prevent the development of hypoglycemia, glucose was infused and the glycemic level was clamped at 50 mg/dl without insulin infusion. The plasma C-peptide level was below the detectable range during the clamp, indicating no appreciable secretion of insulin. The plasma insulin level declined exponentially with a markedly prolonged disappearance rate (half-time: 3.0 h) during the study. These results indicate that hyperinsulinemia in the postabsorptive period in this patient is attributable to the impairment of plasma insulin clearance through receptor-mediated mechanisms, and also confirm that the receptor plays the principal role in plasma insulin removal.

57 STUDIES ON THE METABOLISM OF PYRAZINAMIDE AND ALLOPURINOL IN PATIENTS WITH HEREDITARY XANTHINURIA

The aim of this study was to examine whether pyrazinamide and allopurinol were metabolized in three xanthinuric patients of two families of hereditary xanthinuria lacking xanthine oxidase because we were interested in whether both pyrazinamide and allopurinol were oxidized only by xanthine oxidase or by other kinds of oxidase. A xanthinuric patient, the propositus of a family of xanthinuria could neither metabolize pyrazinamide into 5-hydroxypyrazinamide nor allopurinol into oxypurinol. Two xanthinuric patients, the propositus of the other family of xanthinuria and his elder brother could metabolize both pyrazinamide into 5-hydroxypyrazinamide and allopurinol into oxypurinol. These results suggests that xanthinuria consists of at least two subgroups; one does not possess pyrazinamide-allopurinol oxidizing enzyme(s) other than xanthine oxidase or possesses a variant form of xanthine oxidase which can neither metabolize oxypurines nor pyrazinamide or allopurinol, and the other possesses pyrazinamide-allopurinol oxidizing enzyme(s) or possesses the other variant form of xanthine oxidase which can not metabolize oxypurines but can do both pyrazinamide and allopurinol.