Studies on urinary excretion of 5-Hydroxyindoleacetic acid
In man and other mammals, the conversion of serotonin(5-hydroxytryptamine) to 5-hydroxyindoleacetic acid(5-HIAA) seems to be the final step in its metabolism, and monoamine oxidase(MAO) is probably responsible for its osidative deamination(Sjoerdsma, 1959). Since it was shown that 85 to 100 per cent of serotonin administered orally was excreted in the urine within several hours as 5-HIAA, interest has centered on the urinary excretion rate of 5-HIAA, in view of the possibility that this compound may serve as an indicator for serotonin metabolism. Udenfriend et al., (1955)suggested that quantitative determination of urinary 5-HIAA is valuable for detecting the presence of the malignant carcinoid.
Numerous investigators have examined the normal daily excretion of 5-HIAA and agree that the amount of urinary 5-HIAA appears to be relatively constant in each individual but varies considerably between individuals. Udenfriend et al.(1955), Snow et al.(1955), Borges et al.(1955) and Dick et al.(1956) have reported that the
normal range of urinary 5-HIAA excretion in the United States of America is 2 to 9 mg for 24 hours. Despite of numerous investigations of urinary excretion of 5-HIAA in a large number of the occidental people, such data in the oriental people is lacking.
The present study was undertaken in order to know the normal level of urinary 5-HIAA excretion, in both Korean and Chinese peoples. Such information is important for comparing the levels of urine examples among various ethnic groups, and will provide a necessary baseline for the comparion of urinary 5-HIAA levels in certain pathological conditions.
The possibility of the involvement of serotonin in mental diseases has received considerable attention since the initial suggestions made by Wooley and Shaw(1956), and by Gaddum and Hameed(1954). As discussed by Kety(1959), however, the considerable amount of available data have not been resolved into a single logical pattern which would allow the delineation of the physiological role of serotonin. At the present time, therefore, neither the normal role of serotonin in the brain metabolism nor its possible abberant action in mental disease has been defined.
Experimental results indicating serotonin deficiency as well as serotonin excess in schizophrenia have been reported and each was considered as an etiological factor. Likewise, conflicting results have been obtained from tryptophan loading test which
measures the influence of an increased tryptophan ingestion on the level of urinary 5-HIAA excretion. In the present work, the object was to determine the 5-HIAA excretion rates among schizophrenic patients and to compare the results with the
normal values. In addition, tryptophan loading tests were also carried out.
Current interest in the role of amines in mental disease and in the development of tranquilizing agents have served to focus attention on serotonin. Those reserpine alkaloids which have a tranquilizing effect presumably release brain serotonin from bound to free state. On the other hand, chlorpromazine, another
tranquilizer, inhibits the formation of 5-HIAA from secrotonin and presumably have a serotonin-sparing action. Most of the data on which this postulation is based, were obtained in animal experiments using relatively large doses of drugs. the dose
used was 5mg per kg of the body weight which is 50 to 100 times the therapeutic dose in man.
The additional purpose of this study was to discover andy changes of serotonin metabolism in mental patients receiving therapeutic dose of these psychiatric drugs.
In view of the high incidence of peptic ulcer among patients suffering from certain forms of malignant carcinoid (Blackman et al. 1956, MacDonald, 1956). The surinary 5-HIAA was also determined in patients suffering from gastic or duodenal ulcer.
Twenty-four hour urine specimens were collected from 114 normal Korean adults(75 males and 29 females) and 177 normal Chinese adults(172 males and 5 females) ranging in age from 17 to 61. Korean adults were selected from medical students and University employees. Chinese adults were selected from the employees of NAMRU-2 in Taipei, Taiwan. In addition, 43 primary school students(20 males and 23 females) ranging in age from 5 to 12 year s were studied. All subjects were well nourished, normal individuals, eating a typical Korean or Chinese diet, and had no overt signs of renal, hepatic or gastrointestinal disease. No dietary restrictions were imposed on these subjects, with the exception that bananas and pineapples were restricted from diet for at least 12 hours prior to the begining of urine collection.
Twentyfour-hour urine samples were collected from 116 chronic schizophrenic patients(107 males and 9 females) ranging in age from 18 to 62. The duration of the condition ranged from 1 to 19 years. And none were on drug therapy at the time of the test.
Tryptophan loading test was carried out by administration of 50mg of 1-tryptophan per kg of body weight to each subject as a single dose. Urine samples for 5-HIAA analysis were collected at certain intervals before and after tryptophan ingestion.
The urinary excretion of 5-HIAA in thirteen other chronic schizophrenic 0patients was determined before, during and after oral administration of the usual therapeutic dose of tranquilizer. A twenty-fur hour urine sample was tested for
5-HIAA every five days. A daily dose of 75 to 150 mag of chlorpromazine was given orally in 6 schizophrenic patients of reserpine for 40 days. Another 6 patients received orally 1 to 2 mg. of reserpine a day for 30 days. During administration of these agents, 20 mg. per kg of body weight of 1-tryptophan a days was also given in both groups. After discontinuing the adminitration of the tranquilizer, each group continue to receive the same doses of tryptophan alone for another 3 weeks.
One hundred and ten patients suffering from peptic ulcer (67 with duodenal ulcer, 36 with gastric ulcer, and 7 patients with gastric and duodenal ulcer) were also included in this investigation. The ages of patients ranged from 16 to 68 years.
The diagnosis of peptic ulcer was made by typical clinical symptoms, gastric analysis, stool test for occult blood, and roentgenological studies for the upper gastointestinal tract. None of these patients had been on antacids, anticholinergic
drugs, tranquilizers or sedatives for at least a week prior to the test. A simultaneous determination of gastric acidity and urinary excretion of 5-HIAA was performed in 78 normal subjects and in 100 patients with peptic ulcer.
The collected urines were kept frozen until the time of chemical determination.
The amount of 5-HIAA in 24-hour urine specimens was determined according to the method of pierce(1958). The method used for the measurement of gastric acidity was Rehfuss's fractional gastric analysis(1914) and the acidity was expressed by means of clinical units as adopted by Bockus(1946).
1. Urinary excretion of 5-HIAA in normal oriental peoples:
Urinary excretion of 5-HIAA was determined in 114 normal Korean adults and in 177 normal Chinese adults. The amount of urinary 5-HIAA excreted during a period of 24 hours is fairly constant in each individual but varies widely between individuals.
The mean daily output of urinary 5-HIAA in normal Korean adults and in normal Chinese adults are 1.93±0.86(S.D) mg. and 2.09±0.94(S.D.) mg., respectively which yeild similar value each other. It was found that some normal oriental peoples excrete relatively small amount of 5-HIAA as compared to Americans and most Europeans. For 43 children, the daily urinary excretion of 5-HIAA found were 1.31±0.56(S.D.)mg. No significant differences between ages, sexes and different races in the oriental people were found.
Ⅱ. Urinary excretion of 5-HIAA in schizophrenic patients:
Among the 116 chronic schizophrenic cases tested, the daily mean value for urinary 5-HIAA excretion was 1.51±0.84 mg per day, with a range of 0.37 to 3.85. There was no evidence of difference among catatonic, paranoid, simple, or undifferentiated types of schizophrenic patients with respect to 5-HIAA excretion.
There was no statistically significant difference between mean values for urinary 5-HIAA excretion in normal subjects and in schizophrenic patients (P>0.05).
Ⅲ. The tryptophan loading test in normal adults and schizophrenic patients:
The tryptophan loading test produced an increased urinary 5-HIAA excretion in both normal adults and schizophrenic patients. The increase was most marked in the first few hours and it returns to normal level within the 24∼48 hour period following tryptophan ingestion. However, it is apparent that the tryptophan loading produced an increased rate of 5-HIAA excretion in the urine of both normal and schizophrenic subjects; the changes were more marked and prolonged in schizophrenic patients.
Ⅳ. Utinary excretion of 5-HIAA after long term administration of certain tranquilizers with tryptophan:
Urinary excretion of 5-HIAA following simultaneous administration of chlorpromazine and tryptophan is not significantly different from that before drugs. In additonal groups, administered reserpine and tryptophan were administerd
Simultaneously, the value of urinary 5-HIAA is also unchanged from it without drugs.
Ⅴ. Urinary excretion of 5-HIAA in patients with peptic ulcer:
In patients with peptic ulcer, the mean value of 5-HIAA excretion during a period of 24 hour is 1.82 mg. ranged 0.20 to 3.60 mg. The difference between the urinary excretion of 5-HIAA in normal subjects and in patients with petic ulcer is not significant(PO>0.1). Of those 110 patients, 67 had duodenal ulcers, 36 had gastric ulcers and 7 had both gastric and duodenal ulcers. The mean urinary output of 5-HIAA in patients with each type of peptic ulcer is not significantly different from that in normal adults. It may be concluded that the daily excretion of 5-HIAA in the urine is neither affected by the presence of ulcer nor by the type of peptic ulcer.
Ⅵ. Gastric acidity and urinary excretion of 5-HIAA:
Furthermore, it appears that there is no significant relationship between the gastric acidity and the daily urinary excretion of 5-HIAA in subjects with or without peptic ulcer. From the above results, one may presume that there is no changes in serotonin metabolism in patients with peptic ulcer.