Urinary excretion of succinylacetone and δ-aminolevulinic acid in patients with hereditary tyrosinemia

Succinylacetone was excreted in the urine from four patients with hereditary tyrosinemia i.e., two patients with the severe infantile type with fatal outcome and two patients with a less severe juvenile form. In the urine from two patients with neonatal transient tyrosinemia and from normal individuals succinylacetone was not detectable.The urinary excretion of δ-aminolevulinic acid was also increased in all patients with hereditary tyrosinemia compared to patients with neonatal transient tyrosinemia and to normal individuals.The results presented support the hypothesis of a deficiency of fumarylacetoacetase in hereditary tyrosinemia.Furthermore an analytical method for the quantitative determination of succinylacetone in urine using GC-MS is described.     

Human urinary protein with high calcium affinity

The purpose of this study was to determine if the excretion of catecholamines and their metabolites is altered in patients with the carcinoid syndrome. We found no correlation between the urinary excretion of 5-hydroxyindoleacetic acid and the excretion of 3-methoxy-4-hydroxymandelic acid, homovanillic acid or norepinephrine. There was a positive correlation between the urinary excretion of 5-hydroxyindoleacetic acid and epinephrine. An earlier report of decreased excretion of 3-methoxy-4-hydroxymandelic acid in the carcinoid syndrome can be attributed to 5-hydroxyindoleacetic acid interfering with the analytical method used for the measurement of 3-methoxy-4-hydroxymandelic acid. Patients with elevated excretion of catecholamines and their metabolites (pheochromocytoma and neuroblastoma) have normal levels of urinary 5-hydroxyindoleacetic acid. The methods used for the measurement of catecholamine metabolites in patients with the carcinoid syndrome, should not be affected by the elevated levels of urinary 5-hydroxyindoleacetic acid found in this condition.     

Plasma uric acid concentration related to the urinary excretion of aldosterone and of electrolytes in normal subjects.

1. The relations between the concentration of plasma uric acid and urinary excretion of aldosterone, sodium and potassium, were studied in ten healthy males on a diet containing 160 mmol of sodium and 90 mmol of potassium per day. 2. Plasma uric acid correlated positively with aldosterone excretion and this correlation was statistically independent of sodium and potassium excretion. 3. Plasma uric acid correlated positively with potassium excretion and negatively with the urinary sodium/potassium ratio. There was no significant simple correlation with sodium excretion but the partial correlation of plasma uric acid and sodium excretion was negative and significant when excretion of aldosterone and potassium were held constant.     

Sex differences in salicylic acid metabolism in streptozotocin induced diabetes in rats

The metabolism of salicylic acid was studied in male and female streptozotocin-induced diabetic Wistar rats. Results obtained showed that in both sexes there was a significant increase in urinary excretion of salicyluric acid in diabetic rats when compared to controls (P less than or equal to 0.001). Within the diabetic groups, there was a significant increase in the urinary excretion of salicyluric acid in the female in comparison to the male rats (P less than or equal to 0.01). A statistically significant increase was observed in urinary excretion of salicyl-glucuronic acid in diabetic female compared to control female rats (P less than or equal to 0.01) while comparison of diabetic male to control male showed a significant decrease in urinary excretion of salicyl-glucuronic acid (P less than or equal to 0.01). Comparison of the diabetic female and male groups showed a high statistically significant difference in urinary excretion of salicyl-glucuronic acid. The diabetic ration, ie diabetic/control was significantly higher in female than in male rats with respect to salicyl-glucuronic acid (P less than or equal to 0.001) and total urinary excretion (P less than or equal to 0.01). The diabetic ratio may likely reflect the true significance of the roles played by the two metabolic pathways. The results suggest sex differences in the metabolism of salicylic acid; this may also be the case in other disease states.     

Contrasting effects of lovastatin and cholestyramine on low-density lipoprotein cholesterol and 24-hour urinary mevalonate excretion in patients with heterozygous familial hypercholesterolemia

To further validate the usefulness of quantitative measurements of urinary mevalonic acid excretion as an indicator of rates of cholesterol biosynthesis, we have determined the 24-hour urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolemia treated with drugs that have opposing effects on cholesterol biosynthesis. In patients with familial hypercholesterolemia treated with the bile acid sequestrant cholestyramine (16 gms/day), urinary mevalonate excretion increased by 28%, whereas low-density lipoprotein cholesterol concentrations decreased by 21%. In patients with familial hypercholesterolemia treated with the 3-hydroxy 3-methyl glutaryl coenzyme A reductase inhibitor lovastatin (80 mg/day), concentrations of low-density lipoprotein cholesterol and the urinary excretion of mevalonate both decreased (by 40% and 34%, respectively). When cholestyramine was used in combination with lovastatin, low-density lipoprotein cholesterol levels decreased by an additional 14% as compared to monotherapy with lovastatin; urinary mevalonate excretion rose by (25%), but the magnitude of this increase was not statistically significant. We conclude that rates of excretion of urinary mevalonic acid (which may reflect rates of whole body cholesterol biosynthesis) in patients with FH decrease on therapy with lovastatin and increase in response to cholestyramine treatment. When used in combination, these drugs counteract each other's effects on cholesterol synthesis, but low-density lipoprotein cholesterol concentrations decrease further. Measurement of urinary mevalonate excretion affords a practical means of assessing the comparable effects of different dietary or pharmaceutical manipulations on cholesterol biosynthesis in human beings.     

Clinical test of renal guanidinoacetic acid metabolism by oral citrulline and creatine loading.

We devised a clinical test of renal metabolism based on the synthesis of guanidinoacetic acid from citrulline in the proximal convoluted tubule. Intravenous administration of a citrulline/creatine solution to rats with modified levels of renal glycine amidinotransferase activity revealed a strong correlation (r = 0.921) between this activity and urinary guanidinoacetic acid excretion. Citrulline (1.75 g) and creatine (1.50 g) were administered orally to healthy individuals and patients with chronic glomerulonephritis. In the healthy individuals, urinary guanidinoacetic acid excretion increased 5-fold by 2 h after dosing (15.1 +/- 2.2 vs. 2.8 +/- 1.1 mg/h). In the glomerulonephritis patients, blood clearance of citrulline decreased as the creatinine clearance decreased and urinary guanidinoacetic acid excretion also decreased. Of 56 patients with glomerulonephritis or diabetes mellitus, one had increased urinary guanidinoacetic acid excretion associated with an excess of adrenal androgens. This test appears a useful, noninvasive and simple method for examining the metabolic activity of the renal proximal convoluted tubules.     

Effect of clavulanic acid on inactivated amoxicillin excretion in urinary tract infection

Oral amoxicillin was taken with and without clavulanic acid by normal subjects and by patients with chronic complicated urinary tract infection to examine the in vitro protective effect of clavulanic acid on amoxicillin degradation. When amoxicillin alone was taken, urinary excretion of the penicilloic acid of amoxicillin in bacteria-positive patients was higher than that in bacteria-negative patients and in normal subjects. There was no comparable change in urinary penicilloic acid excretion in the presence of clavulanic acid. There were significant in vitro protective effects of clavulanic acid on beta-lactamases in the urine.     

Serum concentrations and excretion of bile acids in cirrhosis.

Bile acid concentrations in serum, and urinary and faecal excretion of bile acids have been studied in ten patients with liver cirrhosis as a consequence of alcohol abuse. Eight of the patients were categorized as Child group A, whereas the remaining two patients comprised Child group C. Individual bile acids were isolated and identified by gas chromatography coupled to mass spectrometry. Total fasting serum bile acid concentrations were elevated in all patients, but not correlated to conventional tests of liver function. Eight of the patients had increased urinary excretion of bile acids. Faecal bile acid-excretion was highly variable between patients, and also between Child's group A and C patients. Total fasting serum bile acid concentrations were not correlated to either urinary, faecal, or total bile acid excretion (= synthesis of bile acids) or to the ratio between urinary and faecal excretion of bile acids. The daily synthesis of bile acids showed a large overlap between Child's group A and C patients. The percentage of chenodeoxycholic acid and its metabolites relative to total daily excretion of bile acids did not correlate, indicating that the synthesis pathways for the primary bile acids does not systematically change in relation to the rate of synthesis. We conclude that even in mild cirrhosis, serum bile acid concentrations are elevated. However, no consistent changes in synthesis of bile acids or synthesis pathways was observed in such patients.     

Effect of ACTH on renal excretion of purine bases in a patient with isolated ACTH deficiency

We investigated the renal transport of purine bases (uric acid, hypoxanthine and xanthine) after rapid and continuous ACTH loading tests in a patient with isolated ACTH deficiency, a rare cause of secondary adrenocortical insufficiency. Plasma uric acid concentration and the urinary ratio of uric acid/creatinine did not change in the rapid ACTH test, which did not increase plasma cortisol concentration. In the continuous ACTH loading test, the plasma concentration of uric acid and oxypurines (hypoxanthine and xanthine) decreased, and the urinary excretion and fractional clearance of them increased as well as the plasma concentrations and urinary excretion of cortisol. These findings suggest that glucocorticoid directly affects the common renal transport pathway for uric acid, hypoxanthine, and xanthine.     

The influence of dietary purines and pyrimidines on purine

Allopurinol-induced orotaciduria is reduced by dietary ribonucleic acid (RNA), RNA hydrolysate and different nucleotides. These findings are compatible with feedback regulation of pyrimidine biosynthesis by dietary nucleotides. Serum uric acid and urinary uric acid excretion on a purine-free isoenergetic diet reach a minimum after about 10 days and remain constant thereafter. When purines from different biochemical sources are added to such a diet there is always a linear relationship between dietary purines and serum uric acid level and urinary uric acid excretion. The findings suggest that dietary purines play a minor role if any in the regulation of purine biosynthesis in man.     

Equilibration of labelled and endogenous bile acids in patients with liver cirrhosis after administration of (24-14C)cholic and chenodeoxycholic acids

On separate occasions (24-14C)cholic acid and (24-14C)chenodeoxycholic acid were administered intravenously to patients with liver cirrhosis and the isotope excretion in urine and faeces monitored. Bile acids in serum, urine and faeces were extracted and separated into unconjugated bile acids, glycine- and taurine conjugates, glucuronides and sulphates. Individual bile acid conjugates were separated by high-performance liquid chromatography (HPLC) and the unconjugated bile acids were separated by gas-liquid chromatography (GLC) and identified by gas chromatography-mass spectrometry (GC-MS). Individual bile acid conjugates were quantified and their isotope contents determined. In serum, isotope contents declined rapidly during the first day, followed by a markedly slow rate of reduction. In accordance with this, the excretion of isotope from the patients was found to be very slow and the routes of bile acid excretion were changed, which resulted in an increased ratio of urine/faeces isotope excretion. Studies of the ratio of labelled to endogenous bile acid conjugates indicated that a continuous transformation of the labelled compounds occurred during the period of study. As judged from serum bile acids, conjugation to glycine- or taurine conjugates was rapid. The specific activities of labelled sulphate esters were consistently lower than for other conjugates during the 300-min observation period. During the first day, the urinary bile acids contained a high proportion of unconjugated labelled bile acids, which gradually disappeared. Labelled primary bile acids were slowly converted into microbial products, mainly 7-alpha dehydroxylated derivatives. The observed slow transformations resulted in a much delayed equilibration of labelled and endogenous bile acid derivatives, which invalidates isotope techniques for calculation of kinetic data of bile acid turnover. However, the observed very slow turnover of labelled bile acids in cirrhosis, owing to the persistent high rate of intestinal absorption and low capacity for urinary excretion, makes it possible for the intestinal flora to markedly change the composition of the bile acids in the pool. Studies of endogenous urinary and faecal bile acid excretion revealed the changed route of bile acid excretion with a high urinary/faeces ratio and the decreased synthesis of bile acids in cirrhosis.     

Urinary serotonin in the diagnosis of carcinoid tumors

To determine whether measurement of serotonin in urine would give useful complementary information to the usual measurement of 5-hydroxyindoleacetic acid (5-HIAA) in urine and platelet serotonin in platelets, I measured these analytes in 75 consecutive patients with carcinoid tumors, and found that 75% had above-normal urinary 5-HIAA excretion, 64% had above-normal serotonin excretion, and 64% had above-normal platelet serotonin concentration. Six patients had increased urinary serotonin, but 5-HIAA excretion and platelet serotonin concentration were normal. Only two of a further 50 patients with solid noncarcinoid tumors--and none of 55 patients with flushing or diarrhea, who did not prove to have a carcinoid tumor--had increased urinary serotonin. Ingestion of four bananas (a food rich in serotonin) increased urinary 5-HIAA but not urinary serotonin excretion of seven normal subjects. Evidently, measurement of urinary serotonin excretion is helpful in the evaluation of patients with suspected carcinoid tumors.     

Effects of exercise and grape juice ingestion in combination on plasma concentrations of purine bases and uridine

BACKGROUND: Since grape juice contains considerable amounts of fructose, which may increase the plasma concentration of urate, the combination of exercise and grape juice may increase the plasma concentration of urate to a greater degree than grape juice or exercise alone. METHODS: We performed 3 experiments with 6 healthy male Japanese. The first was exercise alone (exercise alone experiment), the second was grape juice ingestion alone (grape juice alone experiment), and the third was a combination of exercise and grape juice ingestion (combination experiment). RESULTS: In the exercise alone experiment, the concentrations of purine bases and uridine in plasma, and lactate in blood, as well as the urinary excretion of oxypurines were increased, whereas the urinary excretion of uric acid and fractional excretion of purine bases were decreased. In the grape juice alone experiment, the concentrations of purine bases and uridine, as well as lactate in blood were increased, whereas the fractional excretion of uric acid was decreased. In the combination experiment, the concentrations of purine bases and uridine in plasma, and lactate in blood, as well as the urinary excretion of oxypurines were increased, whereas the urinary excretion of uric acid and fractional excretion of hypoxanthine, xanthine, and uric acid were decreased. The increase in plasma concentration of urate by the combination of exercise and grape juice was greater than that by each alone, though it was not significantly different from the sum of increases in those 2 experiments. CONCLUSION: Increases in adenine nucleotide degradation and lactic acid production caused by both exercise and grape juice ingestion play an important role in the increase in plasma concentration of urate, while those in combination have an additive effect on that concentration.     

Renal excretion of urobilinogen in the dog

The renal excretion of urobilinogen was studied in dogs by standard clearance techniques. The use of radiochemically pure tritiated mesobilirubinogen as a representative urobilinogen afforded much greater analytical precision than can be obtained with the usual colorimetric and fluorimetric techniques which are only semiquantitative. With constant plasma levels of urobilinogen, raising urinary pH from 5 to 8 increased urobilinogen excretion from about 30% to up to 200% of the filtered load. When urinary pH was kept constant, changes in blood pH had no effect on urobilinogen excretion. Increases in urinary flow had no effect on urobilinogen excretion when the urine was alkaline but increased excretion markedly during aciduria. Probenecid did not influence urobilinogen excretion by the kidney. It is concluded that urobilinogen is excreted by a three-component system of glomerular filtration, active secretion, and pH-dependent nonionic diffusion in the distal nephron. Urobilinogen is a weak acid, and this mode of excretion is similar to that of other weak, organic acids, such as salicylates. These results indicate that urinary pH and flow must be considered in the clinical interpretation of measurements of urinary urobilinogen.     

Prostaglandin precursor fatty acids in cirrhosis with ascites: effect of linoleic acid infusion in functional renal failure

1. Functional renal failure (FRF) in cirrhosis with ascites could be related to an inappropriately low renal prostaglandin (PG) production. To investigate whether the impaired renal PG synthesis in these patients is related to a PG precursor fatty acid deficiency, serum levels of linoleic and arachidonic acids and the urinary excretion of PGE2, 6-keto-PGF1 alpha and thromboxane B2 (TxB2) were measured in 10 normal subjects, 17 non-azotaemic cirrhotic patients with ascites and 10 cirrhotic patients with ascites and FRF. 2. Serum linoleic acid levels were similar in the three groups studied. Both groups of cirrhotic patients showed lower arachidonic acid levels than normal subjects; however, non-azotaemic cirrhotic patients and patients with FRF did not differ in relation to serum arachidonic acid. 3. Non-azotaemic cirrhotic patients had higher urinary PGE2, 6-keto-PGF1 alpha and TxB2 excretion than normal subjects and cirrhotic patients with FRF. Patients with FRF showed similar urinary PGE2 and TxB2 and lower urinary 6-keto-PGF1 alpha than normal subjects. In all cirrhotic patients no significant correlation was found between serum linoleic and arachidonic acid levels and urinary PGs. 4. In seven patients with FRF an acute intravenous infusion of linoleic acid induced a marked increase in serum levels of this fatty acid. However, no increase in serum arachidonic acid levels and urinary PG excretion and no improvement in renal function was observed. 5. This study suggests that an arachidonic acid deficiency is present in cirrhotic patients with ascites but that this abnormality is not a major determinant of renal function and PG production in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Porphyrin Precursors in Sulfanilamidopyrimidin Treatment

Thirty apparently healthy individuals were treated with 5-methoxi-2-sulfanilamidopyrimidin for five days. The 24-hour urinary excretion of delta-aminolaevulic acid (ALA) and porphobilinogen (PBG) was determined before and after treatment. A significant increase in the urinary ALA excretion and decrease in the PBG excretion was found.     

Pathogenesis of abnormal acid-base balance in the young spontaneously hypertensive rat

1. We have previously reported reduced blood pH and plasma bicarbonate in young Okamoto-Aoki spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto rats (WKY). Acid loading with 1.5% (w/v) NH4Cl as the sole drinking fluid produced identical falls in blood pH, the difference remaining significant. 2. The ability of SHR to excrete acid and alkaline loads was compared with that of WKY under metabolic cage conditions. The effects of such manipulations on urinary sodium, potassium, calcium and phosphate excretion were also determined. 3. No difference was found in the ability to excrete an acid load or to reduce urine pH. Neither total urinary ammonium ion nor titratable acid differed significantly between the strains under either baseline or acid-loading conditions. 4. Baseline urinary bicarbonate excretion was not significantly different between strains but intraperitoneal administration of NaHCO3 at 2.0 mmol/kg body weight resulted in enhanced excretion in the SHR (SHR vs WKY: 625.2 +/- 71.5 vs 381.8 +/- 40.6 mumol 24 h-1 kg-1 body weight, P less than 0.01, mean +/- SEM). 5. No difference in urinary sodium or potassium excretion was observed between SHR and WKY, but basal calcium and phosphate excretion were reduced in SHR (P less than 0.05). 6. Increased urinary bicarbonate excretion in the presence of significantly reduced plasma bicarbonate suggests reduced tubular reabsorption of bicarbonate, which may contribute to the mild metabolic acidosis in young SHR.     

Erythrocyte metabolism in purine nucleoside phosphorylase deficiency after enzyme replacement therapy by infusion of erythrocytes.

Purine nucleoside phosphorylase deficiency is associated with a severely defective T-cell immunity. A patient with purine nucleoside phosphorylase deficiency was treated with transfusions of irradiated erythrocytes and plasma. This resulted in a remarkable correction of the metabolic disturbances in the patient. The urinary excretion of inosine, deoxyinosine, guanosine, and deoxyguanosine decreased, whereas uric acid excretion as well as serum uric acid concentration increased. It could be shown that the enzyme activity of the circulating erythrocytes correlated inversely with the urinary excretion of nucleosides and directly with the excretion of uric acid. As a consequence of the therapy, several glycolytic intermediates of the erythrocytes were increased, especially 2,3-diphosphoglycerate. The high 2,3-diphosphoglycerate level caused a shift to the right of the oxygen dissociation curve (P50 = 32.9 mm Hg). The immunological status of the patient showed definite improvement after the enzyme replacement therapy.     

Evaluation of lead, zinc, and copper excretion in chronic moonshine drinkers

To assess the usefulness of various routine and inexpensive tests widely used in the detection of an increased body lead load, the whole blood lead value, the 24-hour urinary excretion of lead, delta-aminolevulinic acid (DALA) and coproporphyrin, the presence of basophilic stippling and the whole blood osmotic fragility test were compared to a 24-hour urinary lead excretion after a calcium disodium edetate (EDTA) mobilization test in 20 chronic moonshine drinkers. Of these tests, only urinary lead excretion after EDTA mobilization was a sensitive indicator of excessive body burden, though a reference value of 650 micrograms urine lead excretion per 24 hours may have excluded some patients with increased lead loads. The reason for increased zinc and copper excretion before and after EDTA mobilization is not known but raises the possibility of their concomitant contamination of moonshine whiskey.     

Hyperuricemia in glycogen storage disease type I. Contributions by hypoglycemia and hyperglucagonemia to increased urate production.

Studies were performed to determine whether hypoglycemia or the glucagon response to hypoglycemia increases uric acid production in glycogen storage disease type I (glucose-6-phosphatase deficiency). Three adults with this disease had hyperuricemia (serum urate, 11.3-12.4 mg/dl) and reduced renal clearance of urate (renal urate clearance, 1.1-3.1 ml/min). These abnormalities were improved in one patient by intravenous glucose infusion for 1 mo, suggesting a role for hypoglycemia and its attendant effects on urate metabolism and excretion. A pharmacologic dose of glucagon caused a rise in serum urate from 11.4 to 13.0 mg/dl, a ninefold increase in urinary excretion of oxypurines, a 65% increase in urinary radioactivity derived from radioactively labeled adenine nucleotides, and a 90% increase in urinary uric acid excretion. These changes indicate that intravenous glucagon increases ATP breakdown to its degradation products and thereby stimulates uric acid production. To observe whether physiologic changes in serum glucagon modulate ATP degradation, uric acid production was compared during saline and somatostatin infusions. Serum urate, urinary oxypurine, radioactivity, and uric acid excretion increased during saline infusion as patients became hypoglycemic. Infusion of somatostatin suppressed these increases despite hypoglycemia and decreased the elevated plasma glucagon levels from a mean of 81.3 to 52.2 pg/ml. These data suggest that hypoglycemia can stimulate uric acid synthesis in glucose-6-phosphatase deficiency. Glucagon contributes to this response by activating ATP degradation to uric acid.