STUDIES ON THE MATABOLISM OF PANTOTHENIC ACID IN LIVER DAMAGE

Transcription

1 THE JOURNAL OF VITAMINOLOGY 4, (1958) STUDIES ON THE MATABOLISM OF PANTOTHENIC ACID IN LIVER DAMAGE PANTOTHENIC ACID TREATMENT IN PATIENTS WITH LIVER DISEASE TATSUYUKI UESHIMA, HIROSHI UNNO, YUKIO SHIGETA, MASAHISA WADA, KIICHI OJI AND TUNEO YOSHIDA Yoshida Clinics of Internal Medicine, School of Medicine, Osaka University, Fukushima, Osaka (Received April 18, 1958) In a previous study (1) concerning the metabolism of pantothenic acid (PaA) in patients with various liver diseases, it was found that the deficiency of PaA frequently existed. In severe cases disturbance of the utilization of PaA was found. Correlation was found between PaA excretion and various liver func tions, especially, thymol turbidity test (TTT), serum cholesterol ester ratio, hippuric acid synthesis and blood pyruvate level. These metabolic disturban ces of PaA in liver damage might be expected to cause an impairment of liver function in hippuric acid synthesis, metabolism of ƒ -keto acids and cholesterol. The present study deals with the effect of PaA treatment in patients with liver disease. EXPERIMENTAL Materials and Methods 1. Test of Acetylating Activity After supper, 0.5g of p-aminobenzoic acid (PABA) was administered to the patients. From that time urine was collected for 12 hours and the percentage of acetylated PABA was measured using the method of Bratton and Marshall (2). The cases showing a recovery of less than 70 per cent were excluded. The results of the acetylating activity was compared with urinary PaA content. 2. ƒ -Keto Acid Test Hourly urine specimens were collected separately for many hours before and after the intravenous administration of 20ml of 20 per cent fructose solu tion. The urinary content of pyruvic acid (PyA) and ƒ -ketoglutaric acid (KGA) was measured using the method of Shimizu and Shimazono (3). The content of these acids in the first and second hour specimens after administra tion was compared with that one hour before administration. The coefficient of increase of these acids was calculated and was used as a measure of com parison (Sawada's method) (4).

2 3. The Urinary PaA Level, Liver Function Tests, Blood Levels of Cholesterol and PaA These were measured as described in a previous report (1). 4. Experiments in Patients with Liver Diseases 20mg of calcium pantothenate (Ca-PaA) was administered intramuscularly daily for 1-4 weeks to 30 cases with various liver diseases. No drug other than PaA was used during the experiment. RESULTS 1. Effects on Clinical Signs It was found that PaA was effective in improving anorexia, fatiguability, pareschesias and nervousness. It was especially effective in various nervous complaints in the tested patients. In some cases PaA was effective in reduc ing the abdominal distention and tenderness (5). 2. Effects on Various Liver Function Tests Serum Colloidal Reactions-After PaA treatment, TTT was slightly lowered in cases of acute hepatitis while the zinc sulfate test (ZST) was lowered in chronic hepatitis. In severe liver cirrhosis, no significant improvement was noted. Icteric Index-In patients with acute or chronic hepatitis and liver cir rhosis jaundice was found to be slightly improved after treatment. Hippuric Acid Synthesis Test-PaA treatment improved hippuric acid synthesis in all cases, except in severe cirrhosis. Most remarkable improve ment was found in patients with chronic hepatitis. 3. Influence on Various Metabolic Functions PaA Content in Urine and Serum-In most cases, PaA level in urine and serum returned to normal after treatment. In patients with severe liver cir rhosis, the increase of PaA content in the urine following PaA administration was remarkable. This fact might be due to disturbed utilization of PaA in these cases. Acetylation Test-The average acetylating activity in the patients with liver disease was found to be 76.6 }6 per cent (mean }standard deviation) in contrast to 89.6 }2.8 per cent in normal adults. After PaA treatment, the acetylating activity was improved in most cases. Cholesterol Metabolism-After PaA treatment, serum cholesterol-ester ratio was found to be increased, especially in cases where the ester ratio was de creased before treatment. Blood PyA Level-High PyA level in the blood was often seen in cir rhosis and in some cases of acute or chronic hepatitis. PaA treatment was found to be effective in reducing the abnormally elevated PyA level toward normal except in those cases with severe liver cirrhosis. Keto Acid Test-The urinary excretion of PyA and KGA in the fasting state was slightly increased in liver diseases over the values found in

3 Vol. 4 MATABOLISM OF PANTOTHENIC ACID 151 Acetylating Activity FIG. 1 Influence of PaA Treatment upon Acetylating Activity and Coefficient of In crease of ƒ -Keto Acids Following Fructose Administration in Patients with Liver Disease Cofficient of Increase of ƒ -Keto Acids adults, but this difference was not statistically significant. After intravenous administration of fructose, ƒ -keto acids increased both in liver disease and in normal adults. In the first hour the coefficient of increase of PyA and KGA in normal adults was 1.47 and 1.26 respectively, but in liver disease it was 1.8 and In the second hour the coefficient of these acids returned to the base line in normal adults, but remained at a level of 1.85 and 1.51 in liver disease. As shown in Fig. 1, PyA increase coefficient (PIC) and KGA increase coefficient (KIC) were improved in most cases after PaA treatment. Correlation between Urinary Con tent of PaA and the Test of Acetyl ating Activity-As shown in Fig. 2, significant correlation was found between urinary content of PaA and acetylating activity. FIG. 2 Urinary Excretion of PaA and Acetylating Activi

4 DISCUSSION Lipmann et al. (6) demonstrated that biosynthesis of coenzyme A (CoA) from PaA occurs chiefly in the liver and that CoA plays an important role in the metabolism of carbohydrate, protein and fat. Numerous reports have shown that the liver is important in metabolism as well as in storage of various vitamins. Actually, in liver damage, the metabolism of thiamine, riboflavin and nicotinic acid was found to be disturbed. The therapeutic usefulness of these B-complex vitamins in liver disease has been demonstrated by many workers. However, there have been few reports about the therapeutic use of PaA in liver disease (7, 8). Previous studies concerning the metabolism of PaA in patients and animals with liver damage indicated that deficiency of PaA frequently existed. Therefore, in the present study, various liver func tion tests before and after PaA treatment were studied in patients with liver disease. It was found that anorexia and various nervous complaints including pares thesias were often improved by PaA treatment. This effect is interesting as others have reported that nervous disturbances appeared in animals and humans with experimentally induced PaA deficiency (9, 10). Takaoka (11) observed that in patients with chronic hepatitis having various nervous complaints treat ment using cocarboxylase (CoC) was also very effective. According to these results, treatment using PaA with or without CoC seems to be indicated in liver disease cases who have paresthesias and neuralgia. Best and Taylor (12) reported that PaA was more effective than thiamine in improving loss of ap petite and atony of the gastrointestinal tract in patients with thiamine deficiency. It was found that the PaA content of the serum was 260 }95mƒÊg/ml in nor mal adults. This shows close agreement with the report of Pearson (13). Mali et al. (14) who reported that in the blood of patients with ariboflavinosis and beriberi PaA was often decreased. We observed that the PaA content of the serum in patients with liver disease frequently decreased. After PaA treatment, the level of serum PaA was increased to normal in these patients. In most cases with moderate to severe liver damage, no marked improve ment was found in routine liver function tests with the exception of rapid and remarkable increase in hippuric acid synthesis. CoA may be a limiting factor here (15, 16). PaA was ineffective in improving hippuric acid synthesis in a few cases with severe liver cirrhosis. The prognosis of such cases was gen erally unfavorable. Beiglbock and Kahle (17) reported in 8 cases of liver disease that hippuric acid synthesis was increased by the administration of 1.0g of PaA 30 minutes before the sodium benzoate injection. Lipmann and his associates (18) demonstrated that acetyl CoA was necessary for the acetylation of PABA, sulfanilamides and other related substances and that there was a close relation between the acetylation and oxidation of PyA and acetate. Therefore, acetylating activity was expected to be a valuable aid in evaluating abnormalities in the metabolism of ƒ -keto acids. Gershberg (19) reported that acetylation of PABA was not disturbed in a few patients with liver cirrhosis. However, his study was performed in patients treat

5 Various Liver Function Tests and the Influence of PaA Treatment in Patients with Liver Disease Pr>20% was not mentioned. The figures of tests are given in average value

6 with various vitamins. In the present study, disturbance of acetylating acti vity was found in the majority of patients with untreated liver disease. It is known that patients with various liver diseases, especially those with acute hepatitis and cirrhosis, have abnormalities in biological oxidation (20). Markees (21) reported that CoC was effective in the treatment of patients with liver disease showing disturbance of metabolism of ƒ -keto acids. The authors found abnormal blood levels of PyA and a high coefficient of increase of ƒ -keto acids in the first and second hour urine specimens after intravenous administration of 20ml of 20 per cent fructose solution in patients with liver disease. Such a tendency was most marked in cases with severe liver cirrho sis showing disturbance of PaA utilization. Both the decreased acetylating activity and abnormalities of biological oxidation were improved by PaA treat ment in most cases. Our data suggest that disturbed PaA metabolism caused a disturbance in acetylating activity and PyA oxidation in patients with liver disease. PaA treatment was found to improve cholesterol metabolism, causing in crease in both total and ester cholesterol, and restoring the ester ratio to normal. In the biosynthesis of CoA, ƒà-mercaptoethylamine and ATP are necessary as well as PaA. Simultaneous administration of methionine would seem in dicated for the proper utilization of PaA in most cases. No side effect was noted in our experiment of administrating 20mg of PaA daily far 1-4 weeks. Welsh (22) and Gershberg (19, 23) also reported that no untoward effects were observed in patients taking Ca-PaA orally SUMMARY Twenty mg of calcium pantothenate was administered intramuscularly daily for 1-4 weeks to patients with various liver diseases. Improvement in hip puric acid synthesis, serum cholesterol ester ratio, acetylating activity and ƒ -keto acid metabolism was observed. However, other tests of liver function were not improved or only slightly it at all. Favorable effects upon fatiguability, anorexia and nervous complaints including paresthesias were also observed. REFERENCES

7 Vol. 4 MATABOLISM OF PANTOTHENIC ACID Bean, W. B., Hodges, R. E. and Daum, K., Bradbury, J. T., Gunning, R., Manresa, J., Murray, W., Oliver, P., Routh, J. I., Schedl, H. P., Townsend, M., and Tung, I. C., J. Clin. Invest. 34, 1073 (1955). 11. Takaoka, T., Vitamins 13, 281, 12. Best, C. H. and Taylor, N. B. The Physiological Basis of Medical Practice. 5th Ed. p The Williams and Wilkins Co., Baltimore 13. Pearson, P. B., J. Biol. Chem. 140, Spies, T. D., Stanbery, M. A., Williams, R. J., Jukes, T. H., and Babcock, S. H. J. Am. Med. Assoc., 115, 292, Chantrenne, H., J. Biol. Chem., 189, Schachter, D., and Taggart, J. V., ibid., 204, Beiglbock, W., and Kahle, R., Klin. Wschr., 33, Lipmann, F., Kaplan, N. O., Novelli, G. D., Tuttle, L. C., and Guirard, B. M., J. Biol. Chem., 167, Gershberg, H., and Kuhl, W. J., J. Clin. Invest., 29, Davis, H. A., and Bauer, F. K., Arch. Surg. 48, Markees, S., Deut. Med. Wschr., 78, Welsh, A. L., Arch. Dermatol. Syphilol., 65, Gershberg, H., Rubin, S. H., and Ralli, E. P., J. Nutrition 39, 107