Document DvDVQ1wYoxqYeJE0j6xn2q15M

INFORMATION INTERSCIENCE INCORPORATED Folia Medics XLVIII (7): 544-556, 1965 A FURTHER CONTRIBUTION TO THE STUDY OF THE BEHAVIOR OF .SEBUM AND URINARY 6-ALA IN SUBJECTS EXPOSED TO THE PROLONGED TOXIC ACTION OF LEAD W. Balbo, G. Gualdi, V. Marucci COMPANY N 27039 -4X.iOO>os Folia Medica XLVIII (7): 544-556, 1965 Institute of Legal Medicine and Insurances of the University of Rome Director: Prof. G. Gerin A FURTHER CONTRIBUTION TO THE STUDY OF THE BEHAVIOR OF SERUM AND URINARY J*r-ALA IN SUBJECTS EXPOSED TO THE PROLONGED TOXIC ACTION OF LEAD (*) W. Balbo, G. Gualdi, V. Marucci (*) A communication on the' subj ect was presented at the VI International Congress of the Academy of Legal Medicine and of ..Social Medicine (Parigi, September 22-26, 1964) DUP04Q007139 .the- Importance of delta-aminolevulinic acid (6-ALA) as an intermediate, stage In tke . s7ntl1e.ais of the. porphyf;n ring has Been demonstrated' or some time. hy. several authors, As is well-knowu, this compound-, derives, from the synthesis .of'. glycine wfth' succiSly*l'>- eoenzyme A and is the', precursor of pro*phobilinogen, Hany investigators, thefefoje, have studied the behavior of 6-ALA in the alterations of porphyrin metabolism which lead tq the elimination of both coproporphyrin and porphobilinogen. Because .lead exerts its toxic ..action by producing, among other things, an increase of the porphyrins in every stage of their biosynthesis, it has been possible even in an experimental way, to show the significance of the level of hematic and urinary <$-ALA far the diagnosis of saturnism. Several investigations have been conducted by Italian and foreign authors on the urinary elimination of 5-ALA. A constant increase of the level of this metabolite in subjects affected by acute or chronic lead poisoning has been observed unanimously (Chiesura and Brugnone; Griggs and Harris; Haeger-Aronsen; Ruhino, Teso and Rasetti; Saia and Morco; Schwartz; Tishkoff, Graville, Rosen and Dameshek) as well as in subjects, simply exposed for professional reasons, but not poisoned (Baiba and Marucei). Concerning the normal values of hematic .6-ALA, the following are data which are inferable from the literature, la 5.0 male blood donors Haeger-Aronsen observed an average value of 19 4 yg %/cc of serum, Rasetti and Parigi have taken a concentration of 20-3Q yg %/ee of serum as the normal value. Danielij Sengiprgl and Masetti..found a quantity.of finALA equal to 24. 4.6 pg %/cc'in-the'serum of normal subjects (the number'of 'observations is not specified). -1- DUP040007140 txi 20'. normal vsubjects Chiesura. and - Srugnoae observed an. ays^aga. concen tration of serum-6-ALA'equal to`-7..S5 yg Z, with a pmximal value of'1CL6Q ug Z/cc and a minimal value, of 4,. 25 pg Z/'cc," P'ecbfa, fati-, Mole, Balletta and Daniele have taken 46- pg Z/cc. of plasma as the maximal normal value. This value--was deduced'after'haying assayed 6-AIA in 20. normal subject and repeating the investigation some, days later. Saifa and Morco, found values of serum 6-ALA up to 0.026 mg Z/cc. in a group of normal subjects Cthe'number was not stated). These values of hematic Sr-ALA have consistently turned out to he increased in acute and chronic lead poisoning. In a study carried out on 34 'workers who were exposed to the risk, of saturnism., Haeger-Aronsen found an elevation of the serum 6-ALA level with values up to 0,048 mg Z/cc in 12 of them. In addition, he found a parallel trend between the con centrations of serum and urinary 6-ALA, The same author also observed elevated levels of 6-ALA, from 0,025 mg to Q.2Q0 mg Z/cc of serum in 20 rabbits acutely poisoned with lead acetate 0-00-200 mg per Kg of body weight). In all 28 subjects affected by saturnism, Danieli, Sangiorgi and Masetti noted an increase of the serum 6-ALA with values ranging from 38 jug to 152 pg Z/cc. At the same time, increased urinary excretion of the metabolite with values between .3,8 and 58.Q mg in 24 hours 'was found in 26 of the subjects. The aforesaid authors also assayed serum and urinary 6-ALA in patients affected by carcinoma., idiopathic porphyria, hepatic cirrhosis, chronic and acute pblogosis, chronic renal insufficiency, collageaQpatM.es, or erythropathlea, They found a simultaneous increase, of serum and urinary levels in 11Z of the' cases. Ac cording to the' authors, this finding) places some restriction on the asserted -2 DUP040007141 specificity..of elevated - pteyiqu^iy, Dani^li, . in. collalboratipn'TSTitii Sajdos 'and Sa3d.qsiI9.rQ6., pointed put .the'early, constant and considerable increase of serum and > urinary values' of 5-ALA in human and experimental saturnism. Pecora, fati, Mole, Balletta and Daniele observed an increase in urinary 5-ALA in 30 of 36 subjects affected by chronic lead poisoning, in 29 of 1^'v' these 30 cases, there was an alevatijan of plasma 5-ALA. ..at the same time. The authors noted that the only subject with plasma 5-ALA level within normal limits presented only slightly increased urinary excretion of the metabolite. These authors also studied the behavior of other fractions of porphyrin meta holism, of lead in the blood and urine, and have observed a clear parallelism only 'between the increase of urinary and plasma <5-ALA and that of the erythrocytic free protoporphyrins. On the other hand, in experimental poisoning, they found an increase in all values; especially elevated were the urinary- and plasma 5-ALA, the erythrocytic free protoporphyrins and the urinary coproporphyrins. The experimental part was conducted on a group of 2Q rabbits which were administered 2 cc of 20% lead acetate by gastric route every day for 52 days. In 20 subjects exposed to lead, Rasetti and Parlgi observed an average concentration of serum 5-ALA equal to 83 pg %/cc. with a minimum of 31 pg %/cc and a maximum of 148 p g %/cc, They also found a close correlation between serum and urinary levels of 5 -ALA, The authors explain the high, serum and urinary levels as a consequence of an accumulation of the metabolite through the enzymatic blockage exerted by lead on ALA-dehydraae. Chiesura and Brugnone observed a considerable increase of serum 5 -ALA in 23-subjects' affected'by- saturnism and 18 workers exposed to.the toxic action -3- DUP040007142 of lead (in. tile'.former maximal values -wera greater than 9Q-Pg %/ee and in the latter'the values'were up to'.-SQ-'pg %/g c )1. The increase.usually $$$ directly proportional to. the urinary eli&inatipaiof ' fr-ALA, Bearing this result in mind, the authors maintain that the kidney does not seem to play an active role in the. urinary elimination' of S-ALA, verifying this through, glomerular filtration with little or no tubular reabsorption., it should be mentioned y incidentally that similar behavior is typical of porphobilinogen also (Goldberg and kimington)* Saita and Morco assayed serum and urinary <5-ALA in 1$ subjects with satur nism (8 in the florid phase) both before and during several cycles of ehelant therapy with Caite^EDTA, They found clearly elevated values of serum .5-ALA in saturnine subjects in the florid phase (from Q..055 mg %/cc to 0.128 mg %/cc, with an average value of 0.097 mg %/cc). Values higher than normal - but less elevated than the preceding ones ** were found for the remaining subjects (from 0.037 mg to 0,096 mg %/cc with an average value of 0,050 mg %/cc), A rapid and clear reduction of the serum A-ALA level during the ehelant therapy was ob served in the cases of florid saturnism. This reduction was less marked in the other cases. The behavior of urinary d-ALA turned out to be similar. However, it should be noted that the drop Id senna 5-ALA values during treatment with CaNa^EDTA, was more rapid compared to the urinary 5-ALA. The authors believe that this occurs through the resolution of the renal arteriolar spasm which is caused by lead, with the consequent elimination of .serum 5-ALA through the urines through the partial yielding of the enzymatic block at the expense of ALA-dehydrase as a result of the chelation of the. circulating lead; through normalization'.of the permeability of'the erythrocytic ..membrane produced by the removal of the lead ions. -4 DUP040007143 PERSONAL OBSERVATIONS 3?- i^8j8lye4-t&e'-ars?9 and wijWfy -S-ALA-in 50 Workers exposed, for professional reasons, to:the prolonged toxic action-; of lead j^pundrynien, printers! and in 30 malie control-subjects who were not exposed:. The aforesaid workers were subjected .to . clinical verifications for sus-^ y .s pected saturnism at the. hearrby Medical-legal Center of Occupational Toxicology, annex of the Institute of Legal Medicine and Insurances of the University of Rome,, Our study involved male persons varying in age from ,22 to .60 years. In M the data of the verifications all of the workers explained their- normal occu pational activities. In addition, we took into account the values of lead in the blood, and in the urine, and the values of the coproporphyrinuria; these factors indicated the degree' of toxic impregnation in the organism. The determination of lead in the bipod was done by the method of Sandell from the finger. Lead in the urine was assayed polarographieally by the method of Proctor and pester. The level of coproporphyrinuria was determined specttophotQmetrically by the method of Schwartz, Zieve and Natson. The values usually found by these methods in subjects nqt exposed to the toxic substance, vary from Q..6QQ mg %/g fqr lead in the bipod, up to 0.095 mg/liter for lead in tbe urine, and up to Q.16Q mg/lfter for- coproporphyrinuria. .For the determinationof -'urinary &-ALA, the method of Mauzerall and Gr.ani.ck was used.. As the average normal value we took the figure indicated by our preceding study (Balho and Maruccij, to be., exact , Q, 235 mg o.f 6-ALA per 10Q cc of urine which'equals an average daily elimination of 3.4,25-mg . -5- DUP040007144 For tlxe,4eterminatioii of .aerwri 5-ALA, the;.method described.,by Hanger - Aronsen in Supplement 4-7 of'Scan, J.,-..Clih;; Lab. invest ,/4.2 * I9.6Q wns used. The.; values:, for serum 5-ALA. of eachnf'the 3Q cqnttol subjects and the total average concentration of the metabolite. are reported in Table 1. In Table It are shown the number .of the series , the" number of the elini* v.. - ' / cal chart, thename. and age of the individuals exposed to the action of lead, their profession, the'duration of .exposure, ` the serum and urinary values of 5-ALA, the levels of lead in the blood and urine and urinary coprop.orphyrins, As regards the urinary 5-ALA, for both, the control subjects that those exposed' to lead, the assay was carried out on 24 -hour urine specimens.. CONSUMMATIONS AND CONCLUSIONS The data' obtained' from our study of 30 control subjects who were not ex posed to lead, allow us to indicate a figure of 0.0293 mg %/cc as an average normal, value of serum 5 -ALA,. As: we have already said, we will assume 0.235 mg %/cc of urine as the average normal Value for urinary 5-ALA. With regard to the studies conducted on 50 exposed subjects, the level of lead in the blood exceeded normal values in 4 cases (32, 34, 42 and 45) ; values for lend in the urine were higher than normal in 4 cases (34, 35, 42 and 45); and for coproporphyrinuria in 21 cases (1, 6, 8, 9, 15, 16, 32, 34, 35, 36, 38, 40-49). Urinary 5-ALA exceeded the average, normal values in 4.Q cases (1,3,5-12,14-1.6, 17,19,21-27,29-38,40-49) while in 48. cases. (23 and 26 excluded.) the. concentra tions of .serum 5--ALA exceeded the normal. It appears from a comparison of the aforesaid data that in subjects exposed to the prolonged'toxic action of lead, the increase of serum 5-ALA' (96% of the cases.) and urinary- &-ALA (80% of the'cases) shows a considerably greater frequency - 6- DUP040007145 table- ! . Control subjects not - exposed.to. lead. Number Name 1 2 3 '' 4 5 6 7 8 9 IQ 11 12 13 14 IS 16 17 18 19 20 21 22 M.l, S,V. R,S. G.G. H.G. C,fl. P.1, A,M> A.3, s,c. 3?. A, P.A. M, S. D.A.S. a.i. G.G. A.H. B,R. AG. a,p. D * J) S* R.Q. - 7 *- Serum- 6^-ALA mg , %/cc. 0,034 0,026 0,031 0,019 0.021 0,037 0.026 0,015 0.010 0.021 0,031 0.005 0.024 0.037 0.005 0,010 0,028 0.026 0,028 0,053 0.071 0.023 DUP040007146 table I (cent' d) Number 23 24 25 26 27 28 29 3.0 Name Sepum fi-ALA ..... ................ (mg,- %7ec,::............ s.o. Q.Q63 c.v\ 0.0,24 S,G.C. 0.021 c.p. Q.Q23 L.L, 0.055 O.G. 0.060 B.C, 0.024 ............ ......ByN.......... ..........................................0.Q28 Average concentration 0,0293 mg Z/cc of serum than the. increase of the levels of lead in the blood (8% of the cases) and of lead in the urine (8% of the cases). Of particular significance is a clear relationship between the levels of coproporphyrinuria and those of serum and urinary 5-ALA. In fact, in 21 sub jects who presented with hypercoproporphyrinuria, an increase of serum 5-ALA. This fact, already absorbed by us in previous researches (Balbo and Marucci) confirms the idea that lead exerts its toxic action at the level of various fractions of porphyrin metabolism, causing accumulation and elimination in every stage of their biosynthesis.. Then by- comparing the number of subjects who showed increased urinary and serum <$-ALA' (40 and 48 cases) with those with elevated'CQpropbrphyfinuria (24 cases) , it-appears that delta-aminolevulinic acid is more sensitive to lead toxicity than are the coproporphyrins. 8- DUP040007147 6 Number Chart H h"* CO id h-* H* 0 VO CP s ON Ui 4> Co td H* co LJ LO co co Id CO Id CO CO CO CO Co .dv- ON ON S M H* ON ON .ON NO o VO SO 03 . -*4 Ov SI VO VO ON vo 50 o ON tn 45- H* 45- 45- Id f-* 0 H1 to 01 0 W m s O >n 0 > a IS o *CS * s>0 > 0 > < 2S w 00 a 0 0 * .* * ui j -* csn o 4> ho 45vo Cd -> co p\ Ul t-* to Ui hd 'o CO 4> Ul u> 45- M H* 3 O rt si *0 HCO it {3*. {13 J- w 0 n h- H* 3 o rt `"O H* <0 rt {3* rt H* h* .rt h- 3* 0 VS H4 a H* H" vs 3 3 *o H- 0 3 0 o o 0 0 *3 0 j rt ft 1 rt 0 s e tte r CO vs SI VS H n> w o rt H- F* rt CO CO in a> rf rt rf H 1-* M p > H* H- 0 3 3 H* o o *o rt rt V! 0 H W F* H* (0 m rt rf - 0 R o* CD H ho M Id O H* SI CO h-4 H1 s* H* o CO CO H* H* H* ON Id Ui oO o o0Oo o0oo0 0 t . 4 Ul .* ' o . o o o o o 0 0 O o .45- o n Ul Ul 45* ON CO 4> id Co h- CO CO I'd h* CO 00 45- id i-l id s td u* o o > O o . oo . oO .* o o o O * 0 Id Id to CO 45- Id Ul Id 45*. Id si H* *> o i> o o -fc* ON Id 45- VO to Ut o o 0 CO o\ Ut Ui Co CO VO vo -d oo .<> O o * o - O .<* o . :.m o . O o 0 . hO 4> co CO 45* 45* CO J-* CO LO Ui U> .o -*4 o Ul CO ON - S SI OP 4?* Id to O is? ON s o M M O si CO 00 O 00 oo o oo O O oOo0 o > . * * * ji .* 0 oo o o o O 0 0 co .id hr* Id Id Ul ho CO id >-* CO CO -*4 o Id Ul o Ui On CO Id Ul h-4 Ul o o o o Oo o Oo ooo <> . .* o o CO * O o o H* >a .45- VO Ul ON ON -si Id -d H* H CO 45* Id Ul o o o h-* Ul Ul Sc| CD rt :CD> -o 0 3 3-3 Hi 0 cr* 0 ffl 00 . irt rf tS' : SB O rf -^3 3 M- O. O. O H- J : 00 flQ J fe irr 0 :s <=f OQ I i> . : 6^ O .9 O* J*1OQ H S3' -O b mv 03 UQ H - 'Si* -h4HSl .CD V H T3 p- 3? 3 *3 >. H H* B3 OQ 3 *> 1 P* Lead in Coproppr Serum Urinary Lead Duration Name, age Occupation DUP040007148 - ot - - I-1 F4 F4 M - S-J P pi 45- : co ;CO OJ W : >4 *0 -4 H H O. 6 : CO IO >4 oi > sn a c j * - - w w CO a i> .Pd * : to to to Vi to -> to P* * n> M : 'W : : rt . v. F* P* H* CD {3 JF O *d rt r(Dt H, xo rt p* CD F4 *XJ rIDt * f 0 D* H- 2J O 0 0* 3S EJ* H (O' rf rj a 8J' s to .# t poi 0 n 0 c ti 0 ' rf . 0H* 3 H 0 K0* Hw O 0 rf eu ; Co : CO CO Cn to :o 0 O 0 -* . - O 0 P P : OJ Cn 4> 45- : 4*- CO to to :O .p O -# : fO 45* to : -5> 00 to : O to co O to 0 -P- : -O * p O P . to bo M to SI CO 0 Cn CO CO F* :O .* O O Cn 0O - QO to to 0 Cn 0 * 0 CO Co m rt a> <0 O CD e p1 c f* c rt P* 0 H 03 . 0 xo rf -rf R rf 0. O rf*b 'H* 0 K O. 0. O b ->* i0 O <* ,3 Pj C/3 00 & *> F* g i> 0 .3 c m cj t o 1 rs : p-i-h r1 0 0 Oc H O -Vj 3 0* H- c* TO M 0 ro 00 s^.o 0. -*>> pu TO > 3 t-< TO ft tO H* 0 H* 0 G. O .0 O - : O F* F4 ON VO VO J-* Cn Cn O s F4 F* O H 13 O H- 0* O : *5 *0 * rf p. O S 0 10 TOGO 1H H* 1 DUP040007149 It should .beiabsexvedthal: In, 48 :subjects..elevated serum 4-at .A an increase of urinary 6-ALA wag simultaneously present In .'38'. of: them. believe that the. Ipwef frequency of increased:urinapy 6-ALA compared' to.serum 6-AT.A is due to the' renal artepiplaf spasm caused by lead and this-hinders the elimina tion ;Qftb.e metabolite through, the urine,. This hypothesis of ours is supported , by investigations carried out by Salta' and Mprco in 1363 on 19 saturnine sub jects treated'with chelant therapy; the .authors attributed the more rapid fall of serum 6-ALA values compared' to urinary 6-ALA to the resolution of the renal arterial spasm which had been produced by the toxic substance. No relationship was observed between the course of urinary and serum g-ALA and the years of exposure to lead. In summary, the researches conducted by us allow us to state the following conclusive data: 1) an increase of serum and urinary g-ALA levels ha.B been absorbed in 96% and 80%, respectively, of subjects exposed to the toxic action of lead; 2) no parallelism was observed between the course of levels of serum and urinary 6-ALA. and levels of lead in the blood and urine; 3) in 38% of those exposed to saturnine risk., the simultaneous increase in tbe levels of serum and urinary 6-ALA and in Coproporphyrinuria was ob served; this is an expression of the toxic action of lead at the level of more fractions of porphyrin metabolism; 4) a greater frequency of elevated values of serum 6-ALA C96% of the cases) and of urinary 6-ALA (801 of the cases) compared to coproporphyrlnuria values. (42% qf the cases) was. shown; this, indicates a greater sensitiyity qn the part of 6-ALA to the action-of lead; - 11 - DUP040007150 5) finally; a more frequent iactaaae :i,n the le^el.qf ..parm 5-ALA (96% Qf 'th.e' ca$es): uQTkpared tq-urinary 5-A1A'(SO% of the cases) was noted* thj.? is refferable to. .an obstacle for the elimination of the metabolite at the renal level (arteriolar spasm). -SBMtfARI The authors assayed the serum and urinary- 5-ALA levels in 40 subjects exposed, for professional reasons, to the' prolonged toxic action of lead. They also assayed the serum 5-ALA level in 30 control subjects Who were not exposed. In addition, they determined the levels of lead in the blood .and urine, and of Coproporphyfinuria, which are indicative of the degree of toxic impregnation of the organism. The results of the investigations carried out on the unexposed group of per sons allow us to state the figure 0,0293 mg as the average normal value of 5-ALA per 100 cc of serum. As concerns the average normal value of urinary 5-ALA, the authors took the figure 0,235 mg/100 cc of urine; this value was determined in a previous study (Balbo and Marucci). In 4/50 expose subjects the level of lead in the blood appeared to be increased ; eoproporphyrinuria was found in 21/50 cases, while concentrations of serum and urinary 5-ALA exceeded the norm in 4$ and 40 cases, respectively. Ho relationship was observed between the course of serum and urinary 6-ALA and the years of exposure to the toxic action of lead. Neither was a parallel course found between serum and urinary levels of 6 -ALA and the levels of leadin the.', blood and urine.. On the other hand, evidence was presented for a simultaneous increase of - 12 - DUP040007151 coprOparphyrinuria and serum and urinary 6-ALA values in 38% qf the cases; tills is referable to the. toxic actionexerted by lead at the. level of .more fract ions of' porphyrin metabolism. In additipn, a greater frequency! of increased urinary- and serum 6-ALA values compared'to cpproporph.yrinur.ia . values Was .observed, ibis is an index /' of the greater' sensitivity- of the metabolite to the action of lead,. finally, a greater frequency of elevation of serum <5 -ALA levels compared to levels of urinary 5-ALA was found, The authors maintain that this is due to the renal arteriolar spasm caused'by lead which hindered the elimination of the metabolite through the urine. -13 - DUP040007152 DUP04G007153 i pijqr i /e.t-'iwr L-V.U( {JJ[ 6nvS5by/Y-i !1 .FOLIA MF.P1CA ISTITLfTO 01 ilEUlCfXA V.EGAl.E K DEU.E ASSICURAZIO.S'1 DELL'Cit.IVKli?iTA" B1 ROMA Direltiirc; l'r,.r. C, GEIUX CKXTKO UniCo-UCtLE Ul TOSSICOI.OCIA BEL LAYOjRD: SOItO At. ItAlttOTXATO BEU.'l.X.A.I.I,, ULTER10RE CONTRIBETo ALLO STUDIO DEL COIMPORTAMENTO DEL c-ALA S1ERIC0 ED DR1KARJ0 IK SOGGETTI ESPQSTl ALL'AZIOKE TOSSICA PROTRATTA DEL PIOMBO (*) W. BALED . G. GUALDI V.. MA1UICCI JL'importanza dcU acido delta--amino--Iev.ulinico (c-ALA) conic Lap pa 'intermedia nella sinlesi delFa.nello porfirinice c stala da tempo messa in evidenza da inimerosi Aulori. Tale eomposlo. come nolo, deriya dall:i sintesi della glieoeolla eon il succinil-cocnzlma A ed e il preeursore del porfobiliuogeno; molti ricerealori hau.no studiato, perlanlo, il comporla- menlo del 2--ALA nelle allerazipni del mctabolismo porfirinjeo elie por tano alia ejemianzipne sia di eopropor/inae sia di porfobilinogcno. Poiehe il piombo esercita la sua azione tossica rletenmnaudb, Ira Taltro, un aumenlo dclle porfiriuc in ogni stadio della loro lnalurazione, e stato possibile dimoslrare,, anohe in via spcrimentale, PimpcrrUmza del dosaggro della 5--ALA ematico qd nrinano ai /ini della diagnosi di satnrnismo, .Sulla eliminazione urinaria del 5-ALA numerose ricercbe sonp slate' condottc da Autori italiain e'stranieri. E' stato coneordemente rjlerato un costante aumepto del lasso di tale metabolita in soggclli affetti da intossicazione acuta o eronica da piombo (Chiesura e Brugnone; Griggs e Harris; Haeger--Aronson; Ilubino, Teso e Raselti; Saia .e Moreo; Schwartz; Tishkoff, Gravillc, Rosen c Damcsliek) ovvero in saggelli semplicementc esposti, per ragiopi professional!, ma non inlossieali (Bidbo e Mamcci), * Per qudntp riguarcla i valor! norinuli del 5--ALA ematico i Halt desumibili dalla Jctteratura sono i seguenti- (*) Una cotnnnirazmni: sull'nrininif'iiln t* stala .pri'seiitala al 'VI CmigrcSso dcR'Ai-faili-mva mlcrnir/imtafr di mril'irina legiiU* e (H inrilu'irta socialt* (PariifU 22_2<j ^ptU'mlirc 1961}. .VI.!* sTO ST I tpicssa hilla dpi nia- por- tra one, del 1 di tale veto i da 'SS3 reo; *et.d lead dad rrfcso ITIjSl, FOLIA MF.D1CA 515. ITacgcr--Aronsen ha osservato, in 50 donatori di sanguc di esso maschile, nn valore medio di jig 19 -1% cp di sicro, Rasclli e Parigi hanno assunto come valorc ixornialo una concentra- zione di jig 20-30% cc di sicro. Danicli, Sanglorgi c Masetli hanno trovato, nel sicro di soggetli norniali, una quandta di 2-ALA pari a tig 21 di .1,0% ee (non b preei- sulo.il numcro dcllc osservazioni). ' ., Chiesura c Bruguonc, in 20 soggelti nornndi, hanno .osservato una poncentrazione media di 5--ALA nel sicro pari a jig 7,95% cc, con va- lore nxassimo di jig 10,60% ec e luintnio di jig 1,21% co. Pecora, Fad, Mole, Balletla e Panicle hanno assunto come valore massimo normale jig 16% cc di plasma, Q.ucslo valore e stato desunto dopo aver dosato il 2--ALA in 20 soggeld norniali, ripetendo. I'indagine a '.distanza di alcuni giorni. Saita e Moreo, in un gntppo di soggelti liormali (non e prcc.isa.to il xiumevo), hanno vLscontrato valori di 2-ALA sierico fino a mg 0,0.26% ce. Tali valori di c-ALA cmaLico soixo risultad eostantemente aumentad nella ixifossicazione acuiia c cronica da piombo. Haegcr-Aronsen, in. una hulagine svolt.a su 31 operai espostL a rischio saturnino, ha trovnto, in 12 di essi, un iitnalzameiilo del tasso di 5--ALA sierico eon valori fino a nig 0,013 % cc ed ha riseontrato, ixiol- tre, un audamciito parallelo tra 1c eoucenirazipni di 2--ALA sierico ed urlnario. La stessa Ilaeger--Aronscn ha osservato tassi elevad di 2--ALA, da mg 0,025 a mg 0,200 .% cc di sicro, in 20 eonigli intossieati acuta- mente con acetato di piombo (mg 100--200 pro kg di peso corporco). . Danicli, Sangiorgi e Masetti, ill 23 soggctt.i affetti da saturnisnvo, hanno notato -- in tutti i casi -- axunento del 2-ALA sierico con va lori oscilianti da jig 33 a jig 15.2% ce, cd in 26 di essi eontemporaneo aumento dell'cscrezioue urinaria del xnetabolila, con Valori oscillated da mg" 3,8 a mg 58,0 xicllc 21 ore, I suddetti Autori hanno dosato il 2-ALA sierico ed urinario anchc in spggetti afield da eare.inoma, pprfiria idiopa- tica, cirrosi epatica, flogosi acute e cvoiiiche, iiisuflicienza renalc cronica, eollagenopatic, critropadc: hanno riseontrato un aumento contcmppranco dei tassi sierici ed xirinari iicll'11% dei casi. Tale doto, sccondo gli Au tori, pone .qualchc Umiliaziope alia asscrita spccificita della clevazioue dei tassi del 2--ALA nel satrunlsmo. In precedenza lo stesso Danicli, in col- laihoi-azionc con Gajdos c Gajdos-Torok, aveva segnalato il preeoce, eo- staiite e xiotevole aumento (Jet valori sierico ed urlnario del 2--ALA nel saturnisnxo umiuio e speriinentale. - 516- FOLU MEDIC,! Pecora, Fall, Mole, BalleUa c Dunicle, -su 36 soggetlj affell I da in tpssieazioo.e crOiiica da piombo, Ji.nuno osservato, in .30 easl, aumenlo- del.2-ALA urinario c, in 29 di questi uliiini, conlcmporoecp innalzanicnto del lasso di 2-ALA plasma tico. Gli Aulori fanno nolare die Punlco soggetto con 2-ALA plasmafico nci lintili della norma, presunlava uiia escrczioiic urinaria del melabolila solo licvemcnle aumcnlala. I inedosimi Aulori lianno studialo il eomportamenlo unchc di allre frarioni del me tabolismo porfirina, della pioinbemia c della pioraburia, cd .lrannp psservato nil cbiaro parnllelismo sollnnfco Ira rauinonlo del S-ALA plasnialieo ed urinario e quello dcllc protojiorfirinc libere cj-ilrocilane. Ndriutossicazione spcrimenLalc, inveec, hanno risconlralo an aumento di iulli i valori: parlicolarmcntc elevati il 2-ALA plasmalico e nrinario, le protoporfirine libere critrocilarie c le coproporfirine urinnric. La parte sperinientaJc e stata condoltn.su di un. gruppo di 20 conigli a cui ei'ano somministrati quolidinnamente, pur via gaslriea, 2 cc di acetato di piombo al 20% per un periodo di 52 giorni- Rasclli e Parigi hajino notaLo, in 20 soggelli e.-posLi al piombo, -ana conccnlrazione media di 2-ALA sierico pari a pg 83% cc, eon un miniino di jig 31 %. ce c an massimo di pg 118% ce, ed inoltre una slvctta corrcJazione tra i tassi sierico ed nrinario del 2--ALA. Gli Autori spiegauo gli alti lirclli sieriei ed urinari come conscgucnza di in* aeeiimulo del lnctabolta per ii bloceo enzimatico cscrcilalo dal piombo suit'ALA--deidrasi- - Chiesura e Brugnonc lianno eonslatato, in 23 soggelti snLurnini cd in 18 operai esposti alTaziouc tossica deli piombo, un aumento notevole del 5--ALA sierico (nci primi con valori massimi supmiori a pg 90% .ce e nei second! eon valori tsina a pig 60%, cc); Fauinento era di solito dirett'amentc proporzionale allVliminazione urinaria del 2--ALA stessft. Tenuto presente lale dato, gli Aulori affermpno qhe il reap non sembra intervenire con molo altivo ncirdiminazionc urinaria del 2--ALA, verificandosi, questa, per filtrazione glomerulare, Cori .scarso o nitllp riassorbimento tubidarc. Da ricordare sia della pcv^inciso --- cbe un comportamento analogo q proprio andie del porfogilinogeno (Goldberg c R1minglon). Saiita e Moreo hanno dosato il 2-ALA sierico ed urinario in 19 soggetti satrUnini (di eui 8 in fase flprida), sia prinia sia durante pin cicli di lerapia chclantc con CaNiuEDTA. Essi hanno rjscontrato valori netiamenlc elevati di 2--ALA sierico nei soggelli saturnini In fase flprida (da mg 0,055 a ing 0,128% ee, cpn yalorft medio di mg 0,09?% ce); va lori superior! alia norma -- ma mono elevati dei precedent! -- nci re- DUP040007156 FOf.lA MKD1CA 3-17 stanli soggellt (.da mg 0,0.37 a mg 0,036% c.c, con valorc medio .di mg 0,050% cc). Nci casi di saturnismo flcrida si e verificala una rapid;! e liella dimirmzionc del tasso di S-ALA .sierieo durante da terapia chelante; talc diminuzione e stata nicno marcata negli allri casi. Analogo c risultato J1 comportamenlo del S-ALA urinario. Da nolarc, pero, chc la cadnta doi valori di --ALA sierieo, durante il traltamcnto coil CaNa2EDTA, c stata pin rapida rispcLto al 2--ALA urinario. Gli Autori rileiigono chc cib avvenga per xisoluzionc dcllo spasmo artcriolave renale provocato dal piombo, con conseguente elimiuazionc del 2--ALA sierieo attraverso Ie urine; per parzialc cediiucnto del blocco' enzimatico a carico dell'ALA-- dcidrasi in seguito alia cbelazione del piombo circolante; per normalise zazioue della pexmeabilita della membrana eritrocitaria determinafa dalI'allontamcnto degli ioni piombo. OsSERVAZJOM PERSONAL!. Abbiamo dosato il S^-ALA. sierieo ed irrinario in .50 operai esposti, per ragioni professional'!, alt'a/.ionc tossica protxalta del piombo (fonditori e tipografi) ed in 30 soggelii di contralto, di.sesso maseliile, non esposti. . .At . I suddelti operai sono stali da noi sottoposti ad n'ceertnmcnti clinici, per'sospettp satitrnismo, presso il Centro mcdico-Iegale. di tossicologia .del iasvoro, anhesSo aiPIstituto di medicina legale e delle ,assic.Ui:azioui deirUnjversita di Iloma. Si trattava di individui di essso maseliile e di eta variabile dai 22 :ai 60 anni. L'esposizione al tossico era compresa tra .2 e 40 anni. Alla data degli aceertamenti tutti gli operai esplieavano la loro normale at tivita lavoraliva. Inoltre abbiamo preso in considerazione i valori piombemia, della piombjuria e della eoprop.orfiriimria, qua 15 elementi indieatjvi del grado di impregnazione tossica dcll'organismo. La pioinbemia e stata determinata con il metodo di Sandell al ditizone. La piomburia e stata dosata polarogrnficamente con il metodo di Proctor e Oester,. Il tasso della coproporfirintiria c stato determinatp alio spettrofoto- ftietco eon il metodo di Schwartz, Zieye o Watson. I valori cpmunemciite riscontrabili eon questc met.odiehc, in sog- getti non esposti at tossico, oseillatjo lino a mg 0.600%o g per la piomhe- TAi]111.A 1. -- Soggriti di cotilrtdlu non csposli at piomho. Xn.uo :: 3`Am1g`A7s, i*l`nV" i M. T. 0,034 2 S. V. 0,020 3 R. S. 0,0.31 * ' 4 5 G. G, SI. G, 0,019 0,021 6 C. N.. 0,0.37 7 P-. I. ' 0,02o ,8 A. M. 0,015 9 A. S. 0,01.0 . % 10 11 12 S, C. F. A. P. A. 0,02.1 0,031 0,005 13 SI, S. ' 0,021 14 D. A. S. 0,037 15 :M, T. 0,005 .16 G, G. 0,010 It A. M. 18 - B. R. 0,028 ` 0,02b .19 A, G. 0,028 ,20 B. P. 0,053 21 ii 22 D, D. S. R. Q. 0,071 .0,023 .23 S. 0, 0,063 ... 24 ' C. V. 0,024 25 S, G. C, 0,021 26 C. P. 0,023 27 L. L. 0,055 28 0, G. 29 B. C. 0,060 0,024 30 ----- *---------*-*------^----;------------Cmtccpttazione media ' B, N. 0,028 ---------^-------- ------------- --------- ---------- .____ ^ Jug 0,0293% ct di sic.ro DUP040007158 FOMA .MEDIC* 5-f9 nria, fino a nig 0,095/litro per lap iomburia e fino a mg 0,160/Iitro per la eoproporflrinuria. Per la cletermliiazioiic del 2-ALA urinario e state adoperalo il nielodo di MauzcraU e Granick. Come valorc medio norniaie abb'iniijo as- sunlo la eifi'a indicate in una nostra prccedqntc indagiue (Balbo e Manicci), e preeisamcnlc mg 0,235 di 2-ALA per 100 cc di urine pari ad una cliuiinazione media gior.nnliera di mg 3,125. Per la determinazione del 2-ALA sierico e state usato il metodo dc- scritlo di Haeger-Aronsen nel supplemcnte -17 dello Sean,. J. Clin. Lab. Invest., 12, 1960. Nclla Tabclla I sono riportati i valori del 2-ALA sierico pci- ciascuno dei 30 soggetti di controilo e la coricentruzione. media glo.bale del meta- bolita. Nclla tabclla II sono indicatl il .n umer d'ordine, il num.ero della eartella clinica (CC), il nome e Pejt'a degli individui esposti alPazioiie del piombo, il loro mestiere, la durata dcli'csposizione, i valori sierici ed urinari del 2--ALA, i tassi della piombemia, della piomburia e delle coproporfMne urinarie. Per quanto riguarda il 2-ALA, ,i .tassi della piombemia, della piomburia e delle copvoporfirinc urinarie. Per quanto riguarda il 2--ALA urinario, il dosaggio, si a per i sog getti di controilo sia per quelll esposti, e stato eseguito su urine delie 24 ore. .. - - CoNSIDF.BAZIOSI E CONCLUStOtS'I. I dati da noi riscontrati nei 30 soggetti di controilo, non esposti al piombo, eoiiscutono di indicare, come valorc medio normalc di 2--ALA sierico, la eifra di mg 0,0293% cc,- Come abbiamo gia detto, per il 2--ALA urinario assumiamo il valorc medio norjnale di nig 0,235% ce di urine. Per quanto riguarda le ricercbc praficate nei 50 soggetti esposti, la piombemia ha sitpcrato i valori novmali in 4 easi (3.2, 34, 42, 45); la piomburia iu 4 easi (34, 35, 42, 4.5); In .coproporfirmuria hi 21 easi (I, 6, 8, 9, 15, 16, 32, 34, 35, 36, 38, 40-49). II O--ALA urinario ba snperoto i! valore medio normale in 4-0 easi (1, 3, 5-12, 14-16, 17, 19, 21-27, 29-38, 41-49), mc.Urc In 48 east (ccecttuali, eioe, i iin.' 23 e 26) sono state osservate coneen.trazioni di 8--ALA sierico cceedenti la norma. ' t-r* 6s 15 W >-* cs -4 c* cn 03 to H CO 03 co CO CO CO CO 03 Co Ki co M to 03 03 CO 03 -4 pa -*41 fcO s> o .) p MS c OV S3 p p S3 O O S3 O* Cv 03 *4 p -4 4* f^ <->j .& MS bo _l4* O* SC o cr p- O' MS is r3 yi P p 03 p P j - P >=3 P > sPp i*J TJl \n > hi 0 b > 0 > < 'Z -M > pP 00 to .Vi k9 lo lo W o. t4> r- p -. o 4v CO 14 .'3 4* CO C* 14 yl IO S3 CO .*?! CO .o .o Q a ,o o co co vi to -W4, o*- -*c3b -4 CO j *o-- -c <e!* oc .-CrN- Cbi W O O CS "G <3p O O , p O CS OOV S -* a w,.* ^. .OOc. r C C< s O*o O> '. CO in . ** ,,j . o SSI .4*.* *. c* ci - to- CO T- cs 4^ .33 10 to C3 M H -O CO 05 * to to tc .to v p p p GO p MA 4a. 'C3 MM N3 03 t8 O M US -4 -F* o- "bo ** y-i >- .fo. .<-? .4O- v Zj * O* 4w O ' .cs os v* c* CO rtoi *O4- sC>-!. t*o CO +G *4 . ? p p p < CO -* 14 43*M M !3 Ul 'f* w w *4 vO O 03 O r4 O V cc * j* ~ -O c-Oo >c-s C4=O. c1-o0 uM ->* 0^ -- 0 -4 C* CC CS o o o o o o GO M U W -->' . S& "o CO N3 to co M -- CO ii <yj >3 Ctf <3 era c o p .to cr> cn o cs 14 V h c c ' %* V '%. p p p p p . < --* ' ~s* t-* " v~* ' O To p'J-.ow- VyO* SvOi Mo vinj >-*./ Ov ccor\ *-* o t*--o c-/i **-* >V-<I CCOS OOk b I: 3 i I i i | iy r \ i r l DUP040007160 o os w CM cc ,09 K9 t94 w0 0t3.1 t4sSf CM t5 (4 >-* 0 t-- >o c= ' 1w .O NO O 03 fc* -05 oOsv .CIttSooO 0= O-4' . .03 tO\3V C4M to CM to -- -C4M NO 03 t--4 Cn CM o% cc CC cn <! 9 fcQ J-M .2! zn 25 p P P s > p M 9 > >. in p P p P 4< iH r ? P -Cl ' era .e0ra 03 to 1C-C9 Mb W 03 03 .0033 wt .OOn Mb .Q ,4V. 14 --t.0o? w *4 _ ' * T & *? 0 r -? > ts M >>--l 3 tr >=3 > S' . Tfi -rs** o -o2 $ .3 3 t.-5' ,tHr` t5-** -!5 . . 6 i a> :* 3 : 5" 5'X cr. ^ S2 3 >-t o /5A n n * -W5*. -5.' x % Vj 'IT 5S '3 .! i to os. -a CM VI .CM w w tsS ^ v* 3 .> .0 to H O' CM :K5 * . o " V p .0 p p p O <3 p -C p p G *** * 4* to cr* Ca <i> C/ . *- i|S *~Jco e .0 co 03 .0 GO > SO *4 'C .o a ,|<tCn3J p*cJ* w w p p >- pp . 0 0 O t *4 CM !to M M >. w |3 lO tO O Vi ti tO - os .4 to CM o O' *>3 *--* CM >4 .Os pi u ji, CO O O to CO ^ to O' ps cn ^ . C\ sj p Os .0 V p to oto Cs3 oto dera *p.9 vo oVs pcn pOS tOo 'oos <o3s -o00 CBP ^ W -4 -- 03 tr* ^o H C d w cc -o to .O O j-- 03 so CS &ry tn era VS 4* M 4* C K O 5a %> "= o > r ---\ *3 * f 000 p o O -3 .0 p p p p 0 Va O O O *0 O VO CJS to era co o 00 10 CM co o Mb os ` O CCoo Ct/Sl o 'CnI tCoC sS Cn *v Os >0 .era <3 4 .O' o to 1 m 1 P P p .0 O O P 00<TS<3 P<3 oe c4m^ o to- o -oost *c--n' ods eOra oK-** Sb'tr# P e--ra* >V-s >-- 1ti O C6 os --. Ots ^C3o O m tri G e o .0 o .0 I DUP040007161~' 3815 15. 15. 30 L im .tijiistn "X 4- j*. 4" J4 4- <0 0= -J pv 6* . 6s t9 3. to to .6a tlS " 6a ' O ip .05 -4 ,pv-`. 6* -0* t3 t fc3 O) bid W 6 to w i--* c*a .6a os op 03 -ce An ^4 .cc J -4 vO .-j -~4 .j o o 4 SO vO CO 03 03 W Its Ov Wf ep 03 30 -6? to ta * -4 j ' 4 SMS !v- j P p PV < e < < p ^3 :> J0 tio -a A. p p _r- > a *s c. p p tg > p` Cr W ** >- tl ?o -4 \w 'IP v- <3S A ' A1Pi U O' 3 M CO. ' fc ' O' '3 _ o ' * p * r n "4 n :g r r (f y o hi,> (4 ^ ^ W 3 -- -3 3 V s "? j j ^2 X* ~ ** S' 3 S' = `5* ift* *Z `I' =2 2.. S' I- O*3 r .p " ? -i t-- t*3 >--* t--> o O cn -o ^ .pv <ya P"o p ss O > t>3 $n co o 1-0 hd 32 0,037 0,198 0,133 0,040 0.( 95 DUP040007162 t'Of.U MEDlCil 553 Dal eonfronip tlci dati suddeUi risulla die net foggclli esposti alJ'azione lossica protratla del pionibo raumenlo del 2-A.LA sierico (96% tlci easi) c di qucllo urinario (8t)% dci cast) presenta unn frequenza notevolnu'nte superiore rispcllo aU'aicnienCo dci tassi della piombemia (8% del casi) c del la piomburia (3% dci easi). E' di parlicolarc importanza il rilievo di uii chiiirp rappprtp tra i Hvelli della coproporfiriuuria e quelli del 2--ALA sierico ed urinario. Inlatti, nci 21 soggetti che presentavano ipcrcoprpporfirinuria e stats risconlrato costantc aumento del c-ALA sierico cd in 19 di jfcssi aumento del 2-ALA urinario. Questo dafo, gia da noi rilevato Sir precedenti rjcerche (Dalbo e Marticci), confcrma la nozionc che II pintnbb eseveita la sua azione tossiea a livello di varie frazioui del metabolismo porfirinico,. deterininandone raecimiulo e la eliminazione in ogni loro stadio di maturazionc. Dal confroulo. poi, tra il numerp dei soggetti che presentavano au* rneijtp del 2--ALA sierico .ed urinario {-18 e -1:0 easi) e .quell! eon eop.roporlirinuria elcrata (21 easi) si rileva la maggiore sensibilita dcll'acido delta--aniiino-levulinieo alia tossic.ita del piojnbo rispetlo idle coproporfirine. Da rilevare che nei 18 soggetti eon 2--ALA sierico elevate era pre sente uti Contempo ranch aiunentp del 2-ALA urinario In 38 di essi. Riteniainp die la minore frequenza dell'auhicnto del 2--ALA urinario rispetto a quello sierico sia dovuta alio spasnio arteriolare renale provocato dal piomho e che pstacola la cluuhiazione del jnelabolita altraversp le urine. Questa nostra ipotesi e eonfortata dalle ricerclie eflcttuate da Saita e Moireo nel 1963 in 19 soggetti eaturnini traltnti con tcrapia ehelante; glj Autori attribn|.rono hi piii rapida eaduta dei yalori di 2--ALA sierico rispetto a quelli di c-ALA urinario alia risoluzione ddlo spagmo artcrialare renale ehe era .stato provocato dal tossico. Non e stato osspr.valo alcun rapporto tra ra.ndainento del 2--ALA sierico ed urinario e gli anni di esposiziouc al piombo. In defini.tiva, le ricerche da noi effeLtuatc ei pcrmetlouo cli enunciare i segue.nti dati concTusivi: ' 1) si e constatato faumento dei live Hi del 2--ALA sierico nel 96% c del c-ALA urinario nell`80% dei soggetti esposti ali'azioue tossiea del piotiibo; 2) non e stato rilevato un parallclismo tra I'andamento del tassi del 2--ALA sierico ed urinario e quell! della piombemia c della pioniburia; 3) nei 38% degli esposti al rischio saturnino si e osservato I'a.u- DUP040007163 FI>U.\ MKBICA mento euntcmpoi-anoo rlci lassi del o-ALA sierico, clcl 2-ALA uririario e della copropoi firi n u ria, quale csprcssipi ip dell'axiom: tpssica del piomijo a llivello di piu frazjoni del mctabolisnio porfirinieo; 4) e stata messa in evidenza u;.ia maggiorc frequenzu di valori elevati del 2-ALA sierico (96% dci casi) e del S-ALA itriiiario (80% dci casi) rispetto ai valori della; coproporfirimiria (12% dci casi): Indice, questo, di una maggiorc scnsiliilila del o-ALA all'azionc del piombo; 5) si c nolafo, inline, nn piu frequeule uumenlo del lasso del 2--ALA sierico (96% del casi) rispetto a quelli del o-ALA urinario (80% dei casi), riferibiJe ad eu ostacolo alia elimiijazione del metabolita a livello renale (spasmo arteriolarc). ! M.ASS.UNTO Gli Ajilori linnno donato il S-ALA sierico eil urinaria in 40 sOggetli esposii, per ragi.onl professionali, eH'azionc Joasira p.rolralla (lei pioiuLo ed il SrALA sierico in 30 soggetli di cpnlrnitn, .non esposli. Inotlrp liarmo cleternrinaio i tassi delta piomticmia, delta pinmljuriia c della ebpropnrliriiuicia, quail elcmenli in- dicativi del grado di inipjegnaaioue tossiea dcH'organismo. I risultati dclle ricerclis eseguile sill gruppo di indivijui non csposli lianno i perntesso di assumere, come valore medio nonnaic, la eifra di Wg 0,0293 di 5-ALA per 100 cc di siero. i Per quanju riguarda il valore medio normale del O-ALA jurinario, gli anlnri .K lianno assunlu la eifra di mg 0,2i,.i per IfiO cc di urine; tale valore era stalo determinalo in una prceedcnte indagine (Ball)o e Manieei). Nei 50 soggetli esposti la pioinbomi.a e rUultata aumentala it) 4 cast, la pim- buria in 4ciisi, la cpproporfirinuria in .21 easi, inentre sono state osservale con- cenlrazioui di 5-ALA sierico cd uriuario eecedcnti Ja uornia in 48 e, rlspettiva- jnente, in 4.0 casi. 1 Non c stale no lalo alcun rapporto Ira i'amlamenlo del 5-ALA sierico .ed uri- uario c gli aniii di esposizion.c .airarione tossiea del piomLo. Neppure e state rt- 1 4 sconlrato un aiula inenlo parallelo tra 1 lassi del 5-ALA sierico ed urihario e quelli della piomliemla e della piomburui. E' stalo messo in evidenza, invece, un ron.temporanco atimenlo dei valori della coproporllriiiuria c del O-ALA sierico cd urinario nel 38% dei casi, rifert- b'Ue dell azionc tossica cscrcilata dal pionibo a livello di pin frazioni del meta* bolismo porfirinieo, W stata osscrvatii, inoltrr, una maggiore frequenza dciranmento dci valori del 5-ALA sierico ed urinario rispctlp a quelli della coproporfirinviriii; questo ifatto .e indice di una iuaggiore scnslbilita del metaWlUii airazionc del pimnbo. E* stata xtleviita, infine, una niaggiore freeptenza neirinualzaniento dri tiu^si del- 5-ALA sierico rispetto a quelli del 5-ALA urmarlo. CU autort ritengivno clic cio sla doyulo ..a)lo spasirto arteriolarc renale provneato dal piontbo clip os.ta.eola - la eltminarioive del inctalmlila attraverso 1e urine. t DUF040007164 *