Hyperlipoproteinemia has been thought to be a major risk factor for coronary arterial disease, which is frequently associated with patients with primary gout. In the previous study we demonstrated that type IIb and IV hyperlipoproteinemia coexist frequently in gouty patients. In the present study we investigated qualitative changes in LDL particles in 34 gouty patients. The 34 gouty patients were divided into 22normolipidemic (NL-G group) and 12 hypertriglyceridemic (≥150mg/dl) men (HTG-G group). The 22 nongouty subjects were divided into 12 normolipidemic and 10 hypertriglyceridemic men (NL-C and HTG-C group, respectively). Serum cholesterol and triglyceride levels were not changed between gout and control in normolipidemic or hypertriglyceridemic group. High-density lipoprotein cholesterol values were higher in HTG-G group than those in HTG-C group (p <0.05), and similar tendency was shown between NL-G and NL-C groups. LDL-cholesterol and LDL-apoB concentrations in gout were different form those in nongout (HTG-G υs HTG-C, and NL-G υs NL-C). However, LDL-apoB/LDL-cholesterol ratio in gout was significantly higher than in nongout [0.75±0.10(Mean±SD)in NL-G υs 0.67±0.05 in NL-C, p&lｔ;0.05; 0.90±0.07 in HTG-G υs 0.83±0.08 in HTG-C, P<0.05]. Analysis of LDL particle size by high performance liquid chromatography demonstrated that LDL from gouty patient is smaller than LDL from nongout. LDL particles form gouty patients with high ratio of LDL- apoB/LDLcholesterol were extremely small. In conclusion, LDL from gouty patients was apoBrich (cholesterol-poor) and small as compared with normal LDL. These changes in LDL particle of gout may be responsible at least in part for the development of atherosclerosis in this disease, since apoB-rich LDL has been reported to be more atherogenic than normal LDL.
Uric acid levels in contused cerebral tissue were measured by high-performance liquid chromatography with an electrochemical detector in 11 patients with severe closed head injury. The concentration of uric acid appeared to increased with the severity of the contusion. To clarify these findings, the following experiment was done. Cold injury was produced on right cerebral hemisphere in rats. Uric acid was measured in the injured and contralateral cerebral hemispheres from 1 hour to 1 week after injury. The cerebral uric acid level was significantly increased at 48 hours. We analyzed the changes of the cerebral uric acid level after administration of allopurinol, a specific inhibitor of xanthine oxidase, in rats with cold injury Allopurinol markedly suppressed the increase of uric acid 3 hours after injury. These results suggest that in injured brain tissue, uric acid is generated from xanthine or hypoxanthine by xanthine oxidase. Thus, the end-product of purine degradation in mammalian brain is considered to be uric acid.
Family members of two brothers with hereditary xanthinuria (xanthine oxidase deficiency) were studied. The xanthine oxidase activities in the duodenal mucosa from the parents were about half that of normal subjects (father 9.3 and mother 12.8mU/g tissue vs. controls 20.6±6.5mU/g tissue, Mean±SD), suggesting they were heterozygotes. In the parents, plasma xanthine and hypoxanthine concentrations were normal, while urinary xanthine and hypoxanthine excretions were significantly higher, than those of normal subjects (xanthine: father 11.6 and mother 18.2mg/g creatinine υs. normal value 6.7 to 10.3mg/g creatinine, hypoxanthine 9.4 and 11.0mg/g creatinine vs.4.1 to 6.9mg/g creatinine). Similar findings were obtained in the daughter of the elder brother and in the aunt. These indicated that a metabolic blockage existed at the step of xanthine oxidase in the parents and other heterozygotes. Although the urate synthesis was impaired at the xanthine oxidase step, the father had hyperuricemia (9.1mg/dl) due to the decreased renal excretion of urate and gout.
In 221 patients with primary gout, we studied urinary N-acetyl-β-D-glucosaminidase (NAG) as an index of tubular injury with respect to associated disorders such as nephropathy, hypertension and diabetes mellitus. Gouty patients had elevated urinary NAG excretion, compared with age-matched controls. Urinary NAG was not correlated with β2-microglobulin excretion. The elevation of NAG was highest in gouty patients with uncontrolled hyperuricemia. Serial measurements of NAG showed that gouty patients with uncontrolled hyperuricemia of more than 10 years duration had increased urinary NAG excretion, compared with well controlled patients. However, aged gouty patients did not have higher urinary NAG excretion. Gouty patients with nephropathy, hypertension or diabetes mellitus showed markedly elevated NAG excretion. Thus, urinary NAG excretion appears to be a useful index of early tubular damage or nephropathy caused by disorders associated with gout.
Hiroto MASHIBA and Shoji NAKAMOTO To evaluate the incidence and mechanism of hypouricemia ( <2mg), we studied serum uric acid concentrations of 1,220 in - patients and 3,258 out - patients. Hypouricemia was noted in 2.54% of in - patients and 0.37% of out - patients. All hypouricemia of in - patients, which seemed to be induced by diseases or drugs, were transient and secondary. Idiopathic renal hypouricemia was noted in four cases of the out - patients. One of these patients had a defect of presecretory reabsorption and two had a defect of postsecretory reabsorption and one had an enhanced secretion of uric acid in the renal tubule. In one of the four patients, idiopathic renal hypouricemia was considered to be hereditary and in two, it was associated with urolithiasis. In conclusion, the incidence of hypouricemia was higher in in - patient than in out patients because there were many secondary hypouricemia in in - patients. And idiopathic renal hypouricemia was often noted in hereditary cases and associated with urolithiasis.
Routine laboratory examihation revealed hypouricemia(0.98±0.02mg/dl, Mean±SE)in a 50 - year - old male suffering from Parkinsonism. Consanguinity was recognized in his family, and additional three members were Parkinsonian. The 24 - hour urate excretion was within normal range, and the ratio of renal urate clearance to creatinine clearance (CuA/Ccr)was increased (31.4±1.2%). The renal handling of urate was examined by means of pyrazinamide, probenecid and benzbromarone loading tests. Pyrazinamide did not suppress CuA /Ccr, and no increment of CuA /Ccr was observed during either probenecid or benzbromarone loading test. These data indicate that renal hypouricemia in this case is based on tubular reabsorption defect with impaired response to pyrazinamide. On the other hand, serum hypoxanthine and xanthine levels were elevated, suggesting partial metabolic blockage at xanthine oxidase step or impaired renal transport of oxypurine.
A 55 - year - old man was admitted to the hospital because of pulmonary emphysema and benign prostatic hypertrophy. During the administration of chlormadinone acetate (50mg per day ), serum uric acid level was decreased from 4.0mg/dl to 1.9mg/dl and fractional uric acid clearance was high, but daily urinary excretion of uric acid was within normal range. In addition, probenecid loading test showed an increase in fractional uric acid clearance from 16.6% to 61.5% and pyrazinamide suppression test showed a marked decrease in fractional uric acid clearance to 2.3%. Serum uric acid level returned to normal after the cessation of chlormadinone acetate. These results suggest that the cause of hypouricemia is renal origin and chlormadinone acetate acts on the site of tubular secretion in the renal handling of uric acid.
Enhancement of platelet function has been reported as one of the factors of vascular disorders in patients with gout. Thus, we studied (1) platelet function in patients with gout but no complications; (2) PRP additive tests in healthy subjects and (3)therapeutic effects of antiplatelets in patients with gout and hyperuricemia. In study 1, no significant difference was seen between control and patients with gout in the ADP aggregation, PF4 or β-TG, but collagen aggregation was significantly higher in the gouty patients. In study 2, platelet aggregation was measured by adding uric acids, allopurinol, oxipurinol, sulfinpyrazone, ticlopidine and aspirin to PRP in healthy subject. As a result, aggregation of ADP and collagen was significantly inhibited by aspirin, but no platelet function were significantly inhibited by other drugs. In study 3, the patienth with gout and hyperuricemia were divided into a non - treated serum uric acid group and a treated group before platelet function was measured using ticlopidine. No significant changes were noted in the TXB2, PF4 or β-TG levels in either group, but platelet aggregation was markedly decreased in both groups after in the presence of ticlopidine. Our findings revealed a higher enhancement of platelet function in the patients with gout and hyperuricemia. Nonetheless, this enhancement of platelet functions was not considerd to be associated with serum uric acid. On the other hand, the platelet aggregation in the patients with gout and hyperuricemia was significantly inhibited by ticlopidine.
After 135 patients with gout or asymptomatic hyperuricemia were divided into group A (84 patients) taking both CG - 120 and Benzbromarone, a uricosuric agent, and group B (51 patients) taking Benzbromarone alone, the combined effects of CG - 120and Benzbromarone on their clinical courses were observed for a period of 24 weeks, and the following findings were obtained. 1) Since urinary pH in group A was significantly higher than that in group B, CG -120 was proved highly effective in urine alkalization. 2) However, CG - 120 was not effective in the excretion of uric acid, since no significant difference was noted between the two groups in the serum uric acid, excretion of urinary uric acid or uric acid clearance. 3) Although no significant difference was recognized between the two groups in creatinine clearance or urine - concentrating capacity, the incidence of albumiuria and hematuria in group A was appreciably lower than that in group B for the period. 4) No significant difference was recognized between the two groups in the incidence of side effects and abnormal laboratory test results. Nonetheless, the medication was discontinued due to hematuria, hepatic disturbances, a decline of urinary pH, etc. in 4 patients in group B, but was discontinued in none of the patients group A. 5) From the above mentioned findings, it was concluded that combined use of CG -120 and Benzbromarone was considered superior to the use of Benzbromarone alone in treating patients with gout or asymptomatic hyperuricemia.