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Acute intermittent porphyria—another approach to therapy
OO?O-711X
Inr. J. Biochem. Vol. 12. pp. 819 to 822 0 Pergamon Press Ltd 1980 Punted m Great Br~tam
ACUTE
INTERMITTENT APPROACH
80 IlOt-0819502.00,0
PORPHYRIA-ANOTHER TO THERAPY
EVA A. WIDER DE XIFRA, ALCIRA M. DEL C. BATLLE. ANA M&A and SAMUEL MALAMUD
STELLA
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP). Facultad de Cievcias Exactas y Naturales. Universidad de Buenos Aires y Consejo National de lnvestigaciones Cientificas y Tbcnicas (CONICET). Ciudad Universitaria, Pabell6n II, 4to Piso. Ntiiiez. 1428 Buenos Aires, Argentina and Divisi6n de Clinica Midica, Hospital de Agudos “Cosme Argerich”. Municipalidad de la Ciudad de Buenos Aires, Secretaria de Salud Pdblica, Av. Almirante Brown 240. 1155 Buenos Aires, Argentina Abstract-l. Acute Intermittent Porphyria patients in early or acute attacks were treated with folic acid (30 mg/day) adrfiinistered orally for not longer than 10 days. 2. Both clinical and biochemical improvement immediately followed folic acid administration. 3. This is a simple and short-term therapy. which can be used either for treatment or prophylaxis.
INTRODUffION It is well known
that Acute
Intermittent
Porphyria
(AIP) is a genetically determined disease and its relapse might be frequently accompanied by serious consequences. Grand ml seizures can occur during attacks of neurological disfunction, so paralysis and death may ensue. It is generally accepted that there is no cure for AIP and some interesting discussion can be arisen about reliable prevention or treatment of the attacks. AIP therapy either in attack or remission is still difficult. High carbohydrate intake has offered one of the first basic approaches, although the clinical and chemical response to this treatment ranges from spectacular recovery to little or no effect (Welland et al., 1964; Bonkowsky et al., 1976; Brodie et al., 1977). The other therapeutic trial involves intravenous hematin administration (Bonkowsky et al., 1971; Dhar er al., 1975: Peterson et al., 1976; Lamon et a[., 1978). It has been reported that prompt and often dramatic recovery followed hematin infusions. however, hematin administration is less straight forward than high carbohydrate intake and likely more hazardous and it should perhaps be reserved for those patients not responding to carbohydrate infusion. Both of these treatments are dependent on repression of hepatic Aminolevulinate Synthetase (ALA-S), which is enhanced in AIP (Tschudy rt al., 1975). Longterm corticosteroid therapy (Jusic ef al., 1976) and large doses of intravenously administered propanolol (Douer et al.. 1978) have also been used with apparently success; nevertheless the possible side effects of these compounds need to be evaluated and their administration to AIP patients does require continuous monitoring; further. their mechanism of action is still unclear. We now know that the increased ALA-S activity in AIP is actually secondary to a decrease in the activity of Uroporphyrinogen I Synthetase (Deaminase) and Porphobilinogenase (PBGase) the primary genetic abnormality in AIP (Heilmeyer & Clotten, 1969; Strand et al.. 1970: Miyagi et al., 1971: Meyer et al., 1972: Magnussen et al., 1974; Astrup, 1978; Batlle et al., 1978). 819
Tephly (1975) and Piper & Van Lier (1977) have found that pteridine derivatives also stimulated its activity, and might act either as a coenzyme or as a compound controlling enzymic conversion of Porphobilinogen (PBG) into uroporphyrinogens (urogens). Parallely, we have demonstrated, in Euylenu gradis, the existence of a low molecular weight, heatstable factor which activates PBGase, regulating its activity, and that this factor can be replaced by folic acid (Rossetti et al., 1980). These findings prompted us to treat some AIP patients in attack or in early attack with folic acid
(10 mg; 3 times daily) administered orally for 10 days. Results reported here do show that folic administration was followed by both biochemical and clinical recovery, indicating that this simple and short-term treatment seems to be beneficial to control and suppress the acute attacks of AIP and apparently it can also be an effective agent in preventing early attacks. MATERIALS AND METHODS Urinary Aminolevulinate (ALA) and PBG were estimated following Mauzerall & Granick (I 956). Fractionation. identification and quantification of porphyrins from urine were determined by methods described by Rimington (1971) and those reported by Batlle rt a/. (1979). PBGase and Deaminase activities in blood erythrocytes were measured by the procedure of Batlle et al. (1978). Control values for enzyme activities were obtained from 30 healthy subjects although it is always advisable to carry out within family comparisons for a precise diagnosis of AIP. Measurements of enzyme activities: porphyrins, PBG and ALA excretion were performed before, during and after folic acid therapy.
RESULTS AND DISCUSSION
Case 1 A 32-yr-old woman was complaining of colicky abdominal pain of several days duration which radiated to her back. Nausea, vomiting, anxiety and headaches
820
EVA A. WIDERDE XIFRAer uf
accompanied the pains. She also felt tired and somnolent. Immediate urinary ALA, PBG and porphyrins and blood deaminase determinations were performed. ALA and PBG levels in urine were 20 mg/24 hr and 150 mg/24 hr respectively. TotaI free porphyrins were IZOO~g/24 hr. PBGase activity was t 1.8 units/ml RBC (normal 22.5 i 5) and deaminase 27.5 units/ml RBC (normal 55 t_ 10). These data confirmed the diagnosis of AIP. The first time she was admitted to the hospital she was treated with high carbohydrate therapy, following Brodie et cf. {1977) but using IOoi,dextrose in aqueous salution, which was administered by slow parenteral infusion, 360g per day (9Og every 6 hr). Within 1 week clinical improvement was significant; ALA, PBG and porphyrins urinary levels were correspondly reduced, while enzyme activity remained low. After 15 days, dextrose infusions were suspended, she was indicated to keep a diet of IoOg of carbohydrate and IOOg of protein daily, however as she felt well she reduced her carbohydrate intake to avoid weight gain. Six months later, she began to feei the signs of one of her attacks which are preceded by general malaise, abdominai pains and slight nausea. Due to several reasons, among them, her fulltime job, although she responded to the carbohydrate treatment, we decided to try folic acid therapy. Folic acid was administered, orally, 30 mg per day, 10 mg every 8 hr. On the following day, her clinical condition was improved and remission was complete within 3-5 days. There was also a decline in urinary ALA, PBG and porphyrins (Fig. 1); however PBGase and Deaminase activities were within the same values as those determined before initiating treatment. This therapy appeared to results in both symptomatic and bi~hemi~l improvement. After 10 days folic acid intake was suspended, and for some months no other reiapse occurred. However, from time to time, generally coincident with excess eating and drinking, the early symptoms of an attack re-appear, she then has decided by her own to take 10 or 20mg per day dur-
ing 2 or 3 days, and she has told us that her discomfort immediately disappears. This experience suggested that oral intake of folic acid could be an effective treatment for AIP and proves to be successful in the management of early attacks. ense 2 A 1%yr-old woman, complained of acute low abdominal pains, nausea, vomiting, depression, constipation and swallowing difficuities. Palpitations associated with hypertension and tachycardia were also observed. The diagnosis of AIP was made on the basis of ALA, PBG and porphyrins urinary levels: 40 mg/24 hr, 200 mg/24 hr and 1850 ~$124 hr respectively, and reduced activity of PBGase and deaminase: II units/ml RBC and 24.5 units/ml RBC. Folic acid therapy was immediately started, as described for Case I. Rapid remission of the acute symptoms was followed, with a concomitant decrease of porphyrins and precursors urinary excreted (Fig. 2). Case 3 The patient, a 4%yr-old man, was admitted to the hospital after having had an operation, a general anesthetic had been employed for this purpose, which appears to have precipitated an acute attack. On admission he looked very sick and anxious, his blood pressure was 160/IOOmm and had a tachycardia of IO&l lO,/min. He could not walk by himself and complained of weakness and pains in the tegs. The patient was confused, his conciousness was disturbed and during the first 2 days in hospital he had night hallucinations and his mental state was that of an organic psychosis. His speech was difficult and was always most unto-o~rative. AIP was diagnosed on the basis of clinical symptoms, urinary porphyrins and precursors levels and enzymic determinations. The patient was immediately placed on high carbohydrate therapy in the form of continuous parenteral infusion of
Fig. 1. Effect of f&c acid therapy on an AIP patient in early attack on daily urinary excretion of ALA (0). PBG (e) and total porphyrins (a).
Acute
intermittenr poq&&3
dextrose IQ/,aqueoussolution (15 g/br, 360 g/Z4 hr). However no si~~~~t improvement was observed during the first 4 days, except that bbd pressure deW%W2d to ~~~~~rnm. As the high ~r~~~drate treatment seemed to have failed to bring about a satisfactory recovery, it was decided to discontinue its administration and begin with oral folic acid intake (Figp 3). After 6 days of treatment his clinical conditions greatly improved, associated with a significant decline r
821
in the urinary excretion of ALA, PIlG and parphyrins. At the tenth day foiic acid administration was suspended and SQO~ after the patient was dis charged and came back borne, in C&d&a, Argentine @at km from Buenos Airesj.
CONCLUSIONS
From these results, Qral administration of folic acid seems to have a beneficial influence on the manage1;
1s
Fig. 3. Effect of high carbohydrate intake, followed by folic acid oral administration on an AIP patient in attack an daily urinary excretion of ALA (a), PBC (a) and total porphyrins (Ai.
822
EVA A. WIDERDE XIFRAet al.
ment of AIP, resulting in both clinical and biochemical improvement, and could be used either for treatment or prophylaxis. It has the advantage that the agent can be administered orally and its action is rapidly observed. It is a simple and short-term therapy, with very low possibilities of producing any harmful side effects, as it is often the case of most of the treatments claimed to be efficient so far. Further studies, using different doses of folic acid, on AIP and also Porphyria Variegate patients will provide additional information to support the efficacy of this therapy. Finally, we would like to quote Tschudy et al. (1973, to emphasize that.. .“These studies are particularly exciting because they provide an example of how basic biochemical studies are achieving progress towards the goal of metabolic research; that is to iearn to manipulate the chemical controls of the body for therapeutic purposes”. Acknowledgrments-Part of this work was supported with grants from the CONICET and the SECYT. E. A. Wider de Xifra, A. M. del C. Bathe and A. M. Stella hold the post of Scientific Researchers in the CONICET. We wish to thank Dr Ana Adela Juknat de Geralnik and Dr Maria Victoria Rossetti for their valuable help in obtaining venous blood from both patients and healthy volunteers. We are very grateful to Miss Hilda Gasparoli and Mr Francisco Ortega for their technical assistance.
DOUER D.. WEINBERGERA.. PINKHAS J. & ATSMONA. (1978) Treatment of acute intermittent porphyria with large doses of propanolol. J.A.M.A. 240, 766768. HEILMEYERL. & CLOTEN R. (1969) Zur biochemischen Pathogenese der Porphyria Acuta Intermittens. ICIin. ~oc~e~se~r. 47, 71-74. Juste A., SCJSTARKO M. & MAJIC D. (1976) Long-term ACTH and corticosteroid therapy in two siblings with Polyneuropathy due to acute intermittent porphyria. Eur. Neural. 14, 294301. LAMONJ. M., BENNETTM., FRYKHOLMB. C. & TSCHU~Y D. P. (1978) Prevention of acute porphyric attacks by intravenous haematin. Laptcet 2, 492494. MAGNU~~EN C. R,, LEVINJ. P., DOHERTYJ. M., CHEESEMAN J. 0. & TSCHUI~Y D. P. (1974) A red cell enzyme method for the diagnosis of acute intermittent porphyria. Blood 44, 857-868. MAUZERALLD. & GRANICK S. (1956) The occurrence and determination of &amino-levulinic acid and porphobilinogen in urine. J. bid. Chem. 286, 1277-1282. MEYER U. A., STRAND L. J., Doss M., REES A. C. & MARVER H. S. (1972) Intermittent acute porphyriademonstration of a genetic defect in porphobilinogen metabolism. N. Engql.J. Med. 286, 1277-1282. MIYAGIK., CARDINALR., BOSSENMAIER 1. & WATSONC. J. (1971) The serum porphobilinogen and hepatic porphobilinogen deaminase in normal and porphyric individuals. J. Lab. c&z. Med. 78, 683-695. PETERSONA.. BOSSENMAIER I.. CARDINALR. Br WATSON C. J. (1976) Hematin treatment of acute porphyria: early remission of an almost fatal relapse. J.A.M.A. 235, 520-522.
PIPER W. N. & VAN LIER R. 8. L. (1977) Pteridine regulation of inhibition of hepatic uroporphyrinogen- I REFERENCES svnthetase activity by lead chloride. Mot. Pharmac. I3_ l-126-1135 - ASTRUP E. G. (1978) Family studies on the activity of uroRIMINGTONC. (1971) Quantitative determination of porporphyrinogen I synthase in diagnosis of acute intermitphobihnogen and porphyrins in urine and porphyrins in tent porphyria. Clin. Sci. mofec. Med. 54, 251-256. feces and erythrocytes. Ass. Clin. pnthol. 70, 1-9. BATLLE A. M. DEL C., WIDER DE XIPRA E. A. & STELLA A. M. (1978) A simple method for measuring erythrocyte ROSSETT~ M. V., GERALNIKA. A. J. DE & BATLLEA. M. DEL porphobilinogenase and its use in the diagnosis of acute C. (1980) Porphyrin biosynthesis in Euglena gracilis V. intermittent porphyria. Int. J. Biuchem. 9,871-876. Evidence on the existence of a low molecular weight factor which regulates Porphobilinogen~ activity. In BA~LLEA. M. DELC., WIUERDE XIFRAE. A., STELLAA. M., preparation. Busros N. & WITH T. K. (1979) Studies on porphyrin !&RANDJ., FELSCHERB. F., REDEKERA. G. & MARVER biosynthesis and the enzymes involved in bovine conH. S. (1970) Enzymatic abnormalitv in heme biosynthesis genital erythropoietic porphyria. Clin. Sci. molec. Med. in acute iniermikent porphyria: decreased hepaiic con57, 63-70. version of porphobilinogen to porphyrins and increased BONKOWSKY H. L., TSCHUDYD. P., COLLINSA., BOSSENdelta aminolevulinic acid svnthetase activity. Proc. narn. MAIERI.. CARDINALR. & WATSONC. J. (1971) Repression Acad. Sci. U.S.A. 67, 1315-1320. of the overproduction of porphyrin precursors in acute TEPHLYT. (1975) identification of a small molecular weiaht intermittent porphyria by intravenous infusions of hae. substance that protects uro~rphyrinogen I synthetase matin. Proc. natn. Acad. Sri. U.S.A. 68, 2725-2729. from the inhibition by lead. In Porphyrin in Human BONKOWSKYH. L.. MAGNUSSENC. R.. COLLINSA. R.. Diseases-Report of the Discussions (Edited by DOSS M. DOHERTYJ. M.. HESS R. A. & TSCHUDYD. P. (1976) & NAWR~CKIP.). pp. 1288134. Comparative effects of glycerol and dextrose on’ porTSCHUDY D. P., VALSAMIS M. & MAGNUSSEN C. R. (1975) phyrin precursors excretion in acute intermittent porAcute intermittent porphyria: clinical and selected phyria. Metabolism 25, 405414. research aspects. Arm. infern. Med. 83, 851-864. BRODIEM. J., MOORE M. R., THOMPSONG. G. & GOLDWELLANDF. H., HELLMANE. S., COLLINSA., HUNTER BERG A. (1977) The treatment of acute intermittent porphyria with laevulose. Clin. Sci. m&c. Med. 53,365371. G. W. & TSCHUDY D. P. (19641 Factors affecting the excretion of porphyrin precursors by patients with acute DHARG. J., BO~~ENMA~ER 1.. PETRYKAZ. J., CARDINALI. & intermittent porphyria I. The effect of diet. Metabolism WATSONC. J. (1975) Effects of hematin in hepatic por13, 232-250. phyria. Ann. intern. Med. 83, 20-30.
Inr. J. Biochem. Vol. 12. pp. 819 to 822 0 Pergamon Press Ltd 1980 Punted m Great Br~tam
ACUTE
INTERMITTENT APPROACH
80 IlOt-0819502.00,0
PORPHYRIA-ANOTHER TO THERAPY
EVA A. WIDER DE XIFRA, ALCIRA M. DEL C. BATLLE. ANA M&A and SAMUEL MALAMUD
STELLA
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP). Facultad de Cievcias Exactas y Naturales. Universidad de Buenos Aires y Consejo National de lnvestigaciones Cientificas y Tbcnicas (CONICET). Ciudad Universitaria, Pabell6n II, 4to Piso. Ntiiiez. 1428 Buenos Aires, Argentina and Divisi6n de Clinica Midica, Hospital de Agudos “Cosme Argerich”. Municipalidad de la Ciudad de Buenos Aires, Secretaria de Salud Pdblica, Av. Almirante Brown 240. 1155 Buenos Aires, Argentina Abstract-l. Acute Intermittent Porphyria patients in early or acute attacks were treated with folic acid (30 mg/day) adrfiinistered orally for not longer than 10 days. 2. Both clinical and biochemical improvement immediately followed folic acid administration. 3. This is a simple and short-term therapy. which can be used either for treatment or prophylaxis.
INTRODUffION It is well known
that Acute
Intermittent
Porphyria
(AIP) is a genetically determined disease and its relapse might be frequently accompanied by serious consequences. Grand ml seizures can occur during attacks of neurological disfunction, so paralysis and death may ensue. It is generally accepted that there is no cure for AIP and some interesting discussion can be arisen about reliable prevention or treatment of the attacks. AIP therapy either in attack or remission is still difficult. High carbohydrate intake has offered one of the first basic approaches, although the clinical and chemical response to this treatment ranges from spectacular recovery to little or no effect (Welland et al., 1964; Bonkowsky et al., 1976; Brodie et al., 1977). The other therapeutic trial involves intravenous hematin administration (Bonkowsky et al., 1971; Dhar er al., 1975: Peterson et al., 1976; Lamon et a[., 1978). It has been reported that prompt and often dramatic recovery followed hematin infusions. however, hematin administration is less straight forward than high carbohydrate intake and likely more hazardous and it should perhaps be reserved for those patients not responding to carbohydrate infusion. Both of these treatments are dependent on repression of hepatic Aminolevulinate Synthetase (ALA-S), which is enhanced in AIP (Tschudy rt al., 1975). Longterm corticosteroid therapy (Jusic ef al., 1976) and large doses of intravenously administered propanolol (Douer et al.. 1978) have also been used with apparently success; nevertheless the possible side effects of these compounds need to be evaluated and their administration to AIP patients does require continuous monitoring; further. their mechanism of action is still unclear. We now know that the increased ALA-S activity in AIP is actually secondary to a decrease in the activity of Uroporphyrinogen I Synthetase (Deaminase) and Porphobilinogenase (PBGase) the primary genetic abnormality in AIP (Heilmeyer & Clotten, 1969; Strand et al.. 1970: Miyagi et al., 1971: Meyer et al., 1972: Magnussen et al., 1974; Astrup, 1978; Batlle et al., 1978). 819
Tephly (1975) and Piper & Van Lier (1977) have found that pteridine derivatives also stimulated its activity, and might act either as a coenzyme or as a compound controlling enzymic conversion of Porphobilinogen (PBG) into uroporphyrinogens (urogens). Parallely, we have demonstrated, in Euylenu gradis, the existence of a low molecular weight, heatstable factor which activates PBGase, regulating its activity, and that this factor can be replaced by folic acid (Rossetti et al., 1980). These findings prompted us to treat some AIP patients in attack or in early attack with folic acid
(10 mg; 3 times daily) administered orally for 10 days. Results reported here do show that folic administration was followed by both biochemical and clinical recovery, indicating that this simple and short-term treatment seems to be beneficial to control and suppress the acute attacks of AIP and apparently it can also be an effective agent in preventing early attacks. MATERIALS AND METHODS Urinary Aminolevulinate (ALA) and PBG were estimated following Mauzerall & Granick (I 956). Fractionation. identification and quantification of porphyrins from urine were determined by methods described by Rimington (1971) and those reported by Batlle rt a/. (1979). PBGase and Deaminase activities in blood erythrocytes were measured by the procedure of Batlle et al. (1978). Control values for enzyme activities were obtained from 30 healthy subjects although it is always advisable to carry out within family comparisons for a precise diagnosis of AIP. Measurements of enzyme activities: porphyrins, PBG and ALA excretion were performed before, during and after folic acid therapy.
RESULTS AND DISCUSSION
Case 1 A 32-yr-old woman was complaining of colicky abdominal pain of several days duration which radiated to her back. Nausea, vomiting, anxiety and headaches
820
EVA A. WIDERDE XIFRAer uf
accompanied the pains. She also felt tired and somnolent. Immediate urinary ALA, PBG and porphyrins and blood deaminase determinations were performed. ALA and PBG levels in urine were 20 mg/24 hr and 150 mg/24 hr respectively. TotaI free porphyrins were IZOO~g/24 hr. PBGase activity was t 1.8 units/ml RBC (normal 22.5 i 5) and deaminase 27.5 units/ml RBC (normal 55 t_ 10). These data confirmed the diagnosis of AIP. The first time she was admitted to the hospital she was treated with high carbohydrate therapy, following Brodie et cf. {1977) but using IOoi,dextrose in aqueous salution, which was administered by slow parenteral infusion, 360g per day (9Og every 6 hr). Within 1 week clinical improvement was significant; ALA, PBG and porphyrins urinary levels were correspondly reduced, while enzyme activity remained low. After 15 days, dextrose infusions were suspended, she was indicated to keep a diet of IoOg of carbohydrate and IOOg of protein daily, however as she felt well she reduced her carbohydrate intake to avoid weight gain. Six months later, she began to feei the signs of one of her attacks which are preceded by general malaise, abdominai pains and slight nausea. Due to several reasons, among them, her fulltime job, although she responded to the carbohydrate treatment, we decided to try folic acid therapy. Folic acid was administered, orally, 30 mg per day, 10 mg every 8 hr. On the following day, her clinical condition was improved and remission was complete within 3-5 days. There was also a decline in urinary ALA, PBG and porphyrins (Fig. 1); however PBGase and Deaminase activities were within the same values as those determined before initiating treatment. This therapy appeared to results in both symptomatic and bi~hemi~l improvement. After 10 days folic acid intake was suspended, and for some months no other reiapse occurred. However, from time to time, generally coincident with excess eating and drinking, the early symptoms of an attack re-appear, she then has decided by her own to take 10 or 20mg per day dur-
ing 2 or 3 days, and she has told us that her discomfort immediately disappears. This experience suggested that oral intake of folic acid could be an effective treatment for AIP and proves to be successful in the management of early attacks. ense 2 A 1%yr-old woman, complained of acute low abdominal pains, nausea, vomiting, depression, constipation and swallowing difficuities. Palpitations associated with hypertension and tachycardia were also observed. The diagnosis of AIP was made on the basis of ALA, PBG and porphyrins urinary levels: 40 mg/24 hr, 200 mg/24 hr and 1850 ~$124 hr respectively, and reduced activity of PBGase and deaminase: II units/ml RBC and 24.5 units/ml RBC. Folic acid therapy was immediately started, as described for Case I. Rapid remission of the acute symptoms was followed, with a concomitant decrease of porphyrins and precursors urinary excreted (Fig. 2). Case 3 The patient, a 4%yr-old man, was admitted to the hospital after having had an operation, a general anesthetic had been employed for this purpose, which appears to have precipitated an acute attack. On admission he looked very sick and anxious, his blood pressure was 160/IOOmm and had a tachycardia of IO&l lO,/min. He could not walk by himself and complained of weakness and pains in the tegs. The patient was confused, his conciousness was disturbed and during the first 2 days in hospital he had night hallucinations and his mental state was that of an organic psychosis. His speech was difficult and was always most unto-o~rative. AIP was diagnosed on the basis of clinical symptoms, urinary porphyrins and precursors levels and enzymic determinations. The patient was immediately placed on high carbohydrate therapy in the form of continuous parenteral infusion of
Fig. 1. Effect of f&c acid therapy on an AIP patient in early attack on daily urinary excretion of ALA (0). PBG (e) and total porphyrins (a).
Acute
intermittenr poq&&3
dextrose IQ/,aqueoussolution (15 g/br, 360 g/Z4 hr). However no si~~~~t improvement was observed during the first 4 days, except that bbd pressure deW%W2d to ~~~~~rnm. As the high ~r~~~drate treatment seemed to have failed to bring about a satisfactory recovery, it was decided to discontinue its administration and begin with oral folic acid intake (Figp 3). After 6 days of treatment his clinical conditions greatly improved, associated with a significant decline r
821
in the urinary excretion of ALA, PIlG and parphyrins. At the tenth day foiic acid administration was suspended and SQO~ after the patient was dis charged and came back borne, in C&d&a, Argentine @at km from Buenos Airesj.
CONCLUSIONS
From these results, Qral administration of folic acid seems to have a beneficial influence on the manage1;
1s
Fig. 3. Effect of high carbohydrate intake, followed by folic acid oral administration on an AIP patient in attack an daily urinary excretion of ALA (a), PBC (a) and total porphyrins (Ai.
822
EVA A. WIDERDE XIFRAet al.
ment of AIP, resulting in both clinical and biochemical improvement, and could be used either for treatment or prophylaxis. It has the advantage that the agent can be administered orally and its action is rapidly observed. It is a simple and short-term therapy, with very low possibilities of producing any harmful side effects, as it is often the case of most of the treatments claimed to be efficient so far. Further studies, using different doses of folic acid, on AIP and also Porphyria Variegate patients will provide additional information to support the efficacy of this therapy. Finally, we would like to quote Tschudy et al. (1973, to emphasize that.. .“These studies are particularly exciting because they provide an example of how basic biochemical studies are achieving progress towards the goal of metabolic research; that is to iearn to manipulate the chemical controls of the body for therapeutic purposes”. Acknowledgrments-Part of this work was supported with grants from the CONICET and the SECYT. E. A. Wider de Xifra, A. M. del C. Bathe and A. M. Stella hold the post of Scientific Researchers in the CONICET. We wish to thank Dr Ana Adela Juknat de Geralnik and Dr Maria Victoria Rossetti for their valuable help in obtaining venous blood from both patients and healthy volunteers. We are very grateful to Miss Hilda Gasparoli and Mr Francisco Ortega for their technical assistance.
DOUER D.. WEINBERGERA.. PINKHAS J. & ATSMONA. (1978) Treatment of acute intermittent porphyria with large doses of propanolol. J.A.M.A. 240, 766768. HEILMEYERL. & CLOTEN R. (1969) Zur biochemischen Pathogenese der Porphyria Acuta Intermittens. ICIin. ~oc~e~se~r. 47, 71-74. Juste A., SCJSTARKO M. & MAJIC D. (1976) Long-term ACTH and corticosteroid therapy in two siblings with Polyneuropathy due to acute intermittent porphyria. Eur. Neural. 14, 294301. LAMONJ. M., BENNETTM., FRYKHOLMB. C. & TSCHU~Y D. P. (1978) Prevention of acute porphyric attacks by intravenous haematin. Laptcet 2, 492494. MAGNU~~EN C. R,, LEVINJ. P., DOHERTYJ. M., CHEESEMAN J. 0. & TSCHUI~Y D. P. (1974) A red cell enzyme method for the diagnosis of acute intermittent porphyria. Blood 44, 857-868. MAUZERALLD. & GRANICK S. (1956) The occurrence and determination of &amino-levulinic acid and porphobilinogen in urine. J. bid. Chem. 286, 1277-1282. MEYER U. A., STRAND L. J., Doss M., REES A. C. & MARVER H. S. (1972) Intermittent acute porphyriademonstration of a genetic defect in porphobilinogen metabolism. N. Engql.J. Med. 286, 1277-1282. MIYAGIK., CARDINALR., BOSSENMAIER 1. & WATSONC. J. (1971) The serum porphobilinogen and hepatic porphobilinogen deaminase in normal and porphyric individuals. J. Lab. c&z. Med. 78, 683-695. PETERSONA.. BOSSENMAIER I.. CARDINALR. Br WATSON C. J. (1976) Hematin treatment of acute porphyria: early remission of an almost fatal relapse. J.A.M.A. 235, 520-522.
PIPER W. N. & VAN LIER R. 8. L. (1977) Pteridine regulation of inhibition of hepatic uroporphyrinogen- I REFERENCES svnthetase activity by lead chloride. Mot. Pharmac. I3_ l-126-1135 - ASTRUP E. G. (1978) Family studies on the activity of uroRIMINGTONC. (1971) Quantitative determination of porporphyrinogen I synthase in diagnosis of acute intermitphobihnogen and porphyrins in urine and porphyrins in tent porphyria. Clin. Sci. mofec. Med. 54, 251-256. feces and erythrocytes. Ass. Clin. pnthol. 70, 1-9. BATLLE A. M. DEL C., WIDER DE XIPRA E. A. & STELLA A. M. (1978) A simple method for measuring erythrocyte ROSSETT~ M. V., GERALNIKA. A. J. DE & BATLLEA. M. DEL porphobilinogenase and its use in the diagnosis of acute C. (1980) Porphyrin biosynthesis in Euglena gracilis V. intermittent porphyria. Int. J. Biuchem. 9,871-876. Evidence on the existence of a low molecular weight factor which regulates Porphobilinogen~ activity. In BA~LLEA. M. DELC., WIUERDE XIFRAE. A., STELLAA. M., preparation. Busros N. & WITH T. K. (1979) Studies on porphyrin !&RANDJ., FELSCHERB. F., REDEKERA. G. & MARVER biosynthesis and the enzymes involved in bovine conH. S. (1970) Enzymatic abnormalitv in heme biosynthesis genital erythropoietic porphyria. Clin. Sci. molec. Med. in acute iniermikent porphyria: decreased hepaiic con57, 63-70. version of porphobilinogen to porphyrins and increased BONKOWSKY H. L., TSCHUDYD. P., COLLINSA., BOSSENdelta aminolevulinic acid svnthetase activity. Proc. narn. MAIERI.. CARDINALR. & WATSONC. J. (1971) Repression Acad. Sci. U.S.A. 67, 1315-1320. of the overproduction of porphyrin precursors in acute TEPHLYT. (1975) identification of a small molecular weiaht intermittent porphyria by intravenous infusions of hae. substance that protects uro~rphyrinogen I synthetase matin. Proc. natn. Acad. Sri. U.S.A. 68, 2725-2729. from the inhibition by lead. In Porphyrin in Human BONKOWSKYH. L.. MAGNUSSENC. R.. COLLINSA. R.. Diseases-Report of the Discussions (Edited by DOSS M. DOHERTYJ. M.. HESS R. A. & TSCHUDYD. P. (1976) & NAWR~CKIP.). pp. 1288134. Comparative effects of glycerol and dextrose on’ porTSCHUDY D. P., VALSAMIS M. & MAGNUSSEN C. R. (1975) phyrin precursors excretion in acute intermittent porAcute intermittent porphyria: clinical and selected phyria. Metabolism 25, 405414. research aspects. Arm. infern. Med. 83, 851-864. BRODIEM. J., MOORE M. R., THOMPSONG. G. & GOLDWELLANDF. H., HELLMANE. S., COLLINSA., HUNTER BERG A. (1977) The treatment of acute intermittent porphyria with laevulose. Clin. Sci. m&c. Med. 53,365371. G. W. & TSCHUDY D. P. (19641 Factors affecting the excretion of porphyrin precursors by patients with acute DHARG. J., BO~~ENMA~ER 1.. PETRYKAZ. J., CARDINALI. & intermittent porphyria I. The effect of diet. Metabolism WATSONC. J. (1975) Effects of hematin in hepatic por13, 232-250. phyria. Ann. intern. Med. 83, 20-30.