Alkaline phosphatase isoenzyme activities in

Transcription

1 nnls of the Rheumtic Diseses 1993; 52: Deprtment of nesthesiology (Pin Clinic), Niigt University School of Medicine, Niigt, Jpn S id Correspondence to: Dr S id, Deprtment of nesthesiology, Niigt University School of Medicine, shimchi, Niigt 951, Jpn. ccepted for publiction 4 Mrch 1993 lkline phosphtse isoenzyme ctivities in rheumtoid rthritis: heptobiliry enzyme dissocition nd reltion to disese ctivity Sumihis id bstrct Objectives-Hyperphosphtsemi hs been observed occsionlly in ptients with rheumtoid rthritis (R), nd it hs been suggested tht the serum lkline phosphtse (LP) level is relted to the ctivity of the disese. Therefore, the reltionship between serum LP nd R ws studied. Methods-The serum ctivities of heptobiliry enzymes (LP isoenzymes, y-glutmyltrnspeptidse (GTP), leucine minopeptidse (LP), sprtte minotrnsferse (ST), nd lnine minotrnsferse (LT)), immunoglobulins, R hemgglutinin test (RH), C rective protein (CRP), nd erythrocyte sedimenttion rte (ESR) were observed in 288 ptients with rheumtoid rthritis. Results-Serum biliry LP (LP1) ctivity ws detected in 31.6% of the ptients. In ptients positive for LP1 the respective vlues of totl LP (LPt) (p<1), liver LP (LP2) (p<-1), bone LP (LP3) (p<5), y-gtp (p<oool), LP (p<1), immunoglobulins IgG (p<1), Ig (p<1), nd IgM (p<1), RH (p<1), CRP (p<1), ESR (p<1), nd rticulr index (p<1) were significntly higher thn in ptients who did not hve LP1. Significnt Spermn's rnk correltions (rs) were demonstrted between serum LP2 level nd the respective vlues of LPt (rs=9128, p<-1), LP, (rs= 4443, p<.1), LP3 (rs=5898, p<1), y-gtp (rs=293, p<1), LP (rs=393, p<1), Ig (rs=22995 p<-1), IgM (rs=17735 p<5), RH (rs=242, p<1), CRP (rs= p<1), ESR (rs=.418, p<1), nd the rticulr index (rs=465 p<-1). However, no significnt difference or correltion ws noted for either ST or LT. In mny ptients who showed bnorml hyperphosphtsemi, heptobiliry enzyme dissocition ws observed: levels oflpt (in 12-8%), LP1 (in 31.6%)/ LP2 (18.8%)/ -y-gtp (in 4.3%), nd LP (in 19.3%) were bnormlly high, but both ST nd LT were within norml limits. Conclusion-These findings re considered to be chrcteristic of R, nd suggest the existence of ltent or subclinicl heptobiliry involvement nd n ssocition between the expnsion of heptobiliry involvement nd the mechnism of disese ctivtion. Thus mesurement of the serum levels of LP nd its isoenzymes in R is considered to be importnt. (nn Rheum Dis 1993; 52: ) The level of serum lkline phosphtse (LP) in ptients with rheumtoid rthritis (R) is thought to be within norml limits. Hyperphosphtsemi hs been observed occsionlly in ptients with R, however, despite the bsence of ny clinicl heptobiliry disorder.' 1-2 Comprison between ptients with R nd osteorthritis hs shown higher serum LP level in R These reports suggest n increse of the bseline serum LP level in R, lthough the underlying mechnism remins uncertin. Most reports hve described tht the rised serum LP ctivity origintes in the liver or bone, or both, from observtions of LP isoenzymes.i" Roslki, Foo, nd Tnner" reported detection of serum biliry LP isoenzyme (LP1) ctivity, which is mcromoleculr nd is thought to be detectble only in cholestsis.'3-15 Recently, observtion of serum smples from ptients with R suggested tht LP1 ctivity ws detectble t high prevlence of bout 3%./12 Furthermore, this report suggested tht serum levels of liver LP (LP2) nd bone LP (LP3) isoenzymes, s well s totl LP (LPt) in ptients with R, were higher thn in those with osteorthritis, nd tht these levels in ptients with R who were LP1 positive were higher thn those who were negtive. No LP1 ctivity ws detectble in serum smples from ptients with osteorthritis. Bsed on these findings, serum heptobiliry enzyme ctivities in R were observed in the present study. It is suggested tht the serum LP level is relted to R disese ctivity The reltion between serum LP nd R disese ctivity ws lso studied, therefore, bsed on observtions of immunoglobulins, C rective protein (CRP), erythrocyte sedimenttion rte (ESR), nd rticulr index.'6 Mterils nd methods Two hundred nd eighty eight ptients with R (226 women nd 62 men; men ge, 54

2 512 id Tble 1 Cses demonstrting bnorml hyperphosphtsemi (more thn 3 IUll) Ptient ge Sex LPt* LP,* LP,* LP,* y-gtp* LP* ST* L7* No (IU/i) (IU/I) (IU/I) (IU/I) (U) (U) (U) (U) 1 55 F F F F F F F NR F F M F NR F F F F M NR F F F F (SE 1) yers), dignosed ccording to the revised criteri of the mericn Rheumtism ssocition, 17 were entered into the present study. They hd been receiving tretment for R t our pin clinic from 1985 to The rticulr index ws scored ccording to the method of Ritchie et l."5 No other dignosed -Z '- L -i J -J ) ) 1l LPt LP3 LP, o o o o O o o 12 (1756) * j it I 6 Tble 2 Comprison between ptients with rheumtoid rthritis with nd without biliry lkline phosphtse ctivity LP,-positive LP,-negtive LPt (IU/l)*** 255(2) (n=91) 162(3) (n= 197) LP, (IU/1)*** 149(1) (n=91) 9(2) (n=197) LP, (IU/l)* 73(5) (n=91) 62(2) (n= 197) ST(U) 17 1(-8) (n=88) 16-4(-5) (n= 17) LT (U) 14-8(1-) (n=88) 13-2(-6) (n=17) y-gtp (U)*** 44(8) (n=86) 14(1) (n=167) LP (U)*** 27(2) (n=74) 14(2) (n=149) IgG (g/l)*** 21-1(-6) (n=91) 19-1(-4) (n= 197) Ig (g/l)*** 5-3( 3) (n=91) 3-8( 1) (n=197) IgM (g/l)*** 2-8(-1) (n=91) 2-4(-1) (n=197) RH (/I)*** 196(173) (n=91) 272(41) (n=197) CRP (mg/l)*** 51(4) (n=91) 17(1) (n= 197) ESR (mn/h)*** 83(5) (n=91) 42(2) (n=197) rticulr index*** 16 2(1-2) (n=91) 6-5( 4) (n= 197) LPt=totl lkline phosphtse; LP,=biliry LP; LP,=liver LP; LP3=bone LP; y-gtp=-y-glutmyltrnspeptidse; LP=leucine minopeptidse; ST=sprtte minotrnsferse; LT=lnine minotrnsferse. *Norml rnge: LPt=7-26 IU/l; LP, = IU/l; LP, 14 IU/l; LP3-11 IU/1; y-gtp=- 6 U; LP=13-19 U; ST=5-4 U; LT=5-35 U. lthough bnorml vlues re seen in LPt, LP,, LP,, -ygtp, nd LP, both ST nd LT re pproximtely within norml limits. LP ws mesured by Bessey, Lowry nd Brock's method.' The sum of LP,, LP,, nd LP, is not equl to the vlue of LPt in some cses becuse intestinl LP is not shown. LP,=biliry lkline phosphtse; LPt=totl LP; LP,liver LP; LP3=bone LP; ST=sprtte minotrnsferse; LT=lnine minotrnsferse; y-gtp=yglutmyl trnspeptidse; LP=leucine minopeptidse; RH=rheumtoid rthritis hemgglutinin test; CRP=C rective protein; ESR=erythrocyte sedimenttion rte. LP ws mesured by Bessey, Lowry, nd Brock's method.'8 *p<.5, ***p<.1 between ptients positive or negtive for LP, by the Mnn-Whitney U test. Vlues re given s men (SE). disorders were cliniclly evident in these ptients, such s biliry, heptic, skeletl, intestinl, or uterine diseses, nd there ws no overlp with other utoimmune or connective tissue diseses, such s systemic lupus erythemtosus, or primry biliry cirrhosis. Non-steroidl nti-inflmmtory drugs, corticosteroids, or disese modifying ntirheumtic drugs hd been given to ll ptients. D - CY) o 1' 13 1 y-gtp IlI ll 11 r log(lp2) (lu/l) log(lp2) (IU/I) Figure1 Left: reltion between liver lkline phosphtse (LP2) nd totllp (LPt), biliry LP (LP), or bone LP (LP). Significnt Spermn's rnk correltion (rs) ws demonstrted between LP2 nd ech vlue oflpt (,; rs= 9128; p< 1), LP, (U,LI; rs=o4443; p<1), or LP3 (,; rs= 5898; p< 1). Right: reltion between LP2 nd y-glutmyl trnspeptidse (y-gtp) (rs= 293; p< 1), or leucine minopeptidse (LP) (rs= 393; p< 1). Open symbols represent ptients positiveforlp, ndfilled symbols, ptients who hd no LP, ctivity. The br grph below the broken line (left) shows LP2 in these ptients negtive for LP,. The vlues for ptients positive for LP, re distributed to the upper right. 6 I I I I I LP 1l IiI H 1' r

3 ! - P lkline phosphtse isoenzyme ctivities in R I I L 8 - * * L *% * * * v* t 8-6- IZ: <2 * ;L g L ** * *. Figure 2 Reltion between liver lkline phosphtse (LP2) nd Ig, IgM, or rheumtoid rthritis hemgglutinin test (RH). Significnt Spermn's rnk correltions (rs) were demonstrted between LP2 nd ech vlue of Ig (rs)= 2299; p< 1), IgM (r-1 773; p<-5), or RH (rs= 242; p< 1). Open tringles represent ptients positive for biliry LP (LP) ndfiled circles, ptients with no LP ctivity. The vlues ofptients with LP, ctivity re distributed to the upper right. L - *^#~~* * L O Le & * * * *. * * io2 L* * h..m * -"* I (LT) (IFCC method), nd CRP (immunonephelometry). ESR ws obtined by - Westergren's method. The resuslts were expressed s men nd stndrd error of the men (men (SE)). Dt were nlysed sttisticlly using the Mnn- Whitney U test, or Spermn's rnk correltion coefficient (rs). Differences t p<5 were considered significnt. Results Serum LP, ctivity ws detected in 91 out of (32%) ptients with R nd ws undetectble in the remining 198 ptients. - Vlues of LP, vried from 2 to 497 IU/1, but 279 (97%) were less thn 5 IU/l (tble 1). In - the ptients positive for LP1 the respective vlues of LPt (p< 1), LP2 (p<1 ), - LP3 (p< 5), y-gtp (p<.l), LP (p<-l), IgG (p<-l), Ig (p<-l), IgM I - (p<1), RH (p<-l), CRP (p<-l), ESR (p< l), nd the rticulr index (p< l) were significntly higher, by the Mnn-Whitney U test, thn in those without LP1 ctivity. No significnt differences were noted in either ST or LT (tble 2). On the other hnd, significnt Spermn's rnk correltions were demonstrted between the serum LP2 level nd the respective vlues of LPt (rs=9l28, p<1l), LP, (rs=4443, p<l), LP3 (rs=5898, p<o-oo1), y-gtp (rs=293, p<l), LP - (rs=393, p<l), Ig (rs=2299, p<oo1), IgM (r= 1773, p<5), RH l)3 (rs=242, p<o-l), CRP (rs=3532, p<1), ESR (rs=418, p<-1), nd the log(lp2) (lu/l) rticulr index (rs=46, p<l). The vlues of these prmeters in ptients positive for LP, were distributed to the upper right, s shown in figs 1-3. Mny ptients demonstrting heptobiliry enzyme dissocition were noted: high vlues of LPt, LP1, LP2, y-gtp, nd LP were seen in mny ptients, wheres the vlues of ll clinicl ssessments of rticulr indewx both ST nd LT were pproximtely within nd lbortory dt were performed s norml limits in ll the ptients tested (tbles routine clinicl exmintion on the erliest 1 nd 3). No jundice ws observed in ny of consulttion dy fter the strt of thlis the ptients. Tble 1 shows the clinicl dt for investigtion in 1985, when informed conse nt 2 ptients who demonstrted bnormlly high ws obtined. LPt ctivity ws mesured t:y serum LPt ctivity (more thn 3 IU/1). the method of Bessey, Lowry, nd Brock,"8 nid Tbles 1 nd 3 suggest tht heptobiliry LP isoenzymes were seprted by electr o- enzyme dissocition ws demonstrted phoresis on cellulose cette membrn es frequently for LP, (31 6%), often for LPt (Helen Lbortories, Urw, Jpnl). (128%)), LP2 (18-8%), nd LP (19-3%), Immunoglobulins (IgG, Ig, nd IgM) were nd occsionlly for y-gtp (4.3%). However, determined by single rdil immunodiffusic)n four ptients showing bnorml hyper- phosphtsemi but LP1 negtivity were (Hoechist Jpn, Tokyo, Jpn). Rheumtoid rthritis hemgglutintion test (RH) ws lso noted. In these cses, the increse of LPt performed by the microtitre method (Ft,iji ws not so severe, nd LP3 elevtion ws seen Reibo, Tokyo, Jpn). n utonlyser dominntly (tble 1). (Hitchi 736-6, Hitchi Medico, Tokyo, In few cses pttern considered to Jpn) nd Clinimte kits (Diichi Pure indicte binding to immunoglobulin ws Chemicls, Tokyo, Jpn) were used for found. These cses showed electrophoretic mesurements of LPt, -y-glutmyl trnspepiti- ptterns quite different from those of ptients dse (-y-gtp) (y-glutmyl CP substn ce positive for LP1 (fig 4), nd were in method), leucine minopeptidse (L] P) greement with the results obtined by (Tuppy, Wiesbuer nd Wintersbergerr's Mekw, Sudo, nd Kno.2 Significnt method"9), sprtte minotrnsferse (S-r) reltions between the immunoglobulin binding (IFCC method), lnine minotrnsferise nd heptobiliry enzymes were not noted. 513

4 514 x ) c :3 C) E 8 C - n w X\% \ * ~~ ~ ~~~~~~~~~~~~~~~4~ * 16 - oo~ _~ ~ ~ ~ ~ ~ ~ *; 16 && 12 & i.*. _ ~~~~~~~~~~~~~~~~~4 o * 8 4 O 1 2 log(lp2) (lu/1) Figure 3 Reltion between liver lkline phosphtse (LP2 nd the rticulr index, Tble 3 Heptobiliry enzyme dissocition Discussion Hyperphosphtsemi in ptients with hs been observed on occsion. I-12 Seve LPr LP, LP, y-gtp LP ST LT (n=288) (n=288) (n=288) (n=253) (n=223) (n=258) (n=2' Csesshowed (n) highvlue (%) * -8 Rnge (LU/1) (LU/1) (IU/1) (U) (U) (U) (U) LPt=totl lkline phosphtse; LP,=biliry LP; LP,=liver LP; y-gtp=y-glutm trnspeptidse; LP=leucine minopeptidse; ST=sprtte minotrnsferse; LT=lnine minotrnsferse. lthough high vlues re demonstrted in LPt, LP,, LP,, -y-gtp, nd LP of mny ptie with R, both ST nd LT re pproximtely within norml limits. *Vlues of ST were less thn 4 U in ll ptients. increses in -y-gtpl or 5'-nucleotidse,2 4 - or both, but norml ST nd LT levels.' On the other hnd, it hs been reported tht serum LP1 ctivity is detectble in ptients with R." 12 In the present study serum LP, ctivity ws detectble in 31-6% of ptients exmined. This prevlence rte is thought to be very high, becuse serum LP, ctivity is usully detectble only in biliry disorders, s the internl pressure of the bile cpillries increses. 135 In the present study high serum vlues of heptobiliry enzymes were evident in mny ptients (tbles 1 nd 3). Significnt correltions between LP2 nd the respective vlues of LPt, LP,, LP2, LP3, y-gtp, nd LP were demonstrted (fig 1), nd these - vlues were higher in those ptients positive for LP, thn in those who hd no LP, ctivity. - These findings indicte the probble existence of subclinicl heptobiliry involvement in R. This involvement is supported by the histopthologicl observtions by Kendll, Cockel, nd Hwkins,2 Webb et l,5 Lefkovits nd Frrow,"'2 nd Dietrichson et l,27 indicting tht the histology of the liver in R is nonspecific, nd includes findings of Kupffer cell hyperplsi, ftty infiltrtion, nd infiltrtion of peripherl res with mononucler cells.28 Neither ST nor LT ws high, however, even in ptients who showed bnormlly high levels of LPt, LP,, LP,, y-gtp, nd LP in the present study (tbles 1-3). These phenomen re considered to indicte heptobiliry enzyme dissocition. 13 In the previous study,'2 the bseline serum LP2 level ws significntly rised, even in ptients without LP,, in comprison with C ptients with osteorthritis. In the ptients rective protein (CRP) or erythrocyte sedimenttion rte (ESR). Significnt Spermn 's positive for LP,, the respective vlues of rnk correltions (rq were demonstrted between LP, nd ech vlue of the rticulr index (rs=46; p<1), CRP (rs=o3532; p<1) or ESR (rs=418; LPt, LP2, -y-gtp, nd LP were p<ooo1). Open tringles represent ptients positive for biliry LP (LP) nd filled significntly higher thn in ptients without circles, ptients with no LP, ctivity. The vlues ofptients with LP, ctivity re LP, ctivity (tble 2). These results distributed suggest to the upper right. more frequent underlying subclinicl heptobiliry involvement in R thn is generlly Intestinl LP isoenzyme ctivity ws seen in ssumed. Becuse the serum levels of these the serum of type B or blood, but t: his enzymes re known to increse more in biliry ctivity, 2 (SE 2) IU/1, ws considered to be trct disorders thn in heptocellulr physiologiclly norml.2' No other ] LP injury," 212 this involvement seems to strt from isoenzyme ctivity ws seen. the biliry cpillries t the ltent stge. s involvement of the bile cpillries proceeds further, LP, leks into serum nd the serum LP, ctivity my be detectble. R Concomitntly, the LP2 level still rises. The rl lekge seems not to be ttributble to n uthors hve recorded rise of L.P2 increse in internl pressure of the bile ctivity ccompnied by concurre nt cpillries but to n increse in the permebility of the bile cpillries in R. If the pressure hd incresed, jundice would ccompny the presence of LP,. Even in the cse showing very high level of LPt tht 58) is, 1756 IU/l (LP,, 497; LP2, 787 IU/1), id jundice ws not observed. Thus LP2_ y-gtp, nd LP increse considerbly, s shown in fig 1, but remin t subclinicl levels in most cses (tble 2). Considering the norml iyle levels of both ST nd LT t this stge, therefore, heptocellulr injury is thought to be nts slight. When the involvement expnds to heptocytes, obvious heptitis, such s tht

5 lkline phosphtse isoenzyme ctivities in R C + \- + Figure 4 Electrophoretic ptterns of serum lkline phosphtse in ptients with rheumtoid rthritis. : norml pttern. B: pttern considered to indicte binding to immunoglobulin. C nd D: bility LP (LP) ctivity is evident. LP, hs moved towrds the node side. B D reported by Job-Deslnde et l,'9 my become cliniclly evident. Of course, the levels of ST nd LT would then increse. However, Job- Deslnde et l'9 demonstrted tht increses in serum bilirubin (1-63,umol/l), ST (54-92 U), nd LT ( U) were mild in heptitis during R, nd jundice ws present in two of six cses. These fcts re thought to support the results of the present study. Therefore, it is thought tht we observed the ltent or subclinicl involvement of R s heptobiliry enzyme dissocition. Such dissocition, which is considered to be chrcteristic of R, ws observed frequently for LP,, sometimes for LPt, LP2, nd LP, nd occsionlly for y-gtp, nd becme more frequent in the ptients positive for LP, (tbles 1 nd 3). The number nd level of prmeters showing bnorml vlues re thought to indicte the grde nd intensity of heptobiliry involvement. connection between serum LP nd R disese ctivity hs lredy been shown by severl uthors.' In the present study significnt correltion between LP2 nd the respective vlues of Ig, IgM, RH, CRP, ESR, nd the rticulr index ws demonstrted (figs 2 nd 3), nd IgG, Ig, IgM, RH, CRP, ESR, nd the rticulr index in ptients positive for LP, were ll significntly rised compred with ptients without LP, ctivity (tble 2). These fcts suggest reltion between the two phenomen in heptobiliry involvement nd disese ctivtion. It is known tht promotion of disese ctivity induces more ctive bone resorption.3 32 ctivted bone resorption is ccompnied by concomitnt bone formtion nd rise in serum LP3."2 Therefore, severl uthors' hve considered tht disese ctivity in R is relted to the level of LP3. reltion between R disese ctivity nd LP3 might not be wholly denied. The higher LP3 level in ptients with R, however, is 515 considered to be produced by the ctivted bone formtion: this is to sy, rise of LP3 is not cuse but result of disese ctivtion. Therefore, significnt correltion between LP2 nd LP3 ws considered to be present (fig 1). In four ptients negtive for LP, showing bnorml hyperphosphtsemi, however, the LP3 level ws considerbly rised (ptients 1-4 in tble 1). From these fcts, the existence of other disese ctivtion mechnisms, which re not ssocited with heptobiliry enzyme dissocition, is lso suggested. In ctul cses, both mechnisms would work concurrently. Whichever mechnism opertes, serum LPt ctivity my hve to increse in prllel with disese ctivity in R. In fct, three of these four ptients lso hd high LP2 level (tble 1). Therefore, LP,, LP2, nd LP3 re considered importnt for the evlution of disese ctivtion. To determine whether the disese ctivity is ssocited with LP ctivities, however, other mrkers tht directly indicte the disese ctivity should be monitored in the long term. There is lso possibility tht rises in LP, y-gtp, nd LP re due to liver toxicity resulting from tretment with non-steroidl nti-inflmmtory drugs, disese modifying ntirheumtic drugs, or corticosteroids. In the present study, however, no pthologicl increse of ST nd LT ws observed in ny subject even though tretment with these drugs ws continued. The previous study"2 lso showed tht this ws unlikely, s LP isoenzyme ctivities did not differ mong ptients treted with these drugs. Doube et l3 lso reported tht non-steroidl ntiinflmmtory drugs hd no influence on LP ctivity in ptients with R. Therefore, rises in these enzymes re considered to be ttributble to R itself. Webb et l,' Spooner et l,8 nd Knthri nd Woolf'3 demonstrted cses of R nd primry biliry cirrhosis overlpping. In the present study, however, ptients with pprent heptobiliry disorders, such s cirrhosis or heptitis, were excluded nd both ST nd LT were t norml levels. Thus the present findings indicte tht serum biliry enzymes, expecilly LPt, LP,, nd LP2, re relted closely to the ctivity of R nd subclinicl heptobiliry involvement by R, which is observed in the ltent nd subclinicl stges s heptobiliry enzme dissocition. 1 Frnk Von, Klemmyer K. Die lklische Serumphosphtse bei Erkrnkungen des rheumtischen Formenkreises unt ihre Beeinflussung druch Kortikosteroide. ZRheumforsch 1968; 27: Kendll M J, Cockel R, Hwkins C F. Rised lkline phosphtse in rheumtoid rthritis. n index of liver dysfunction? nn Rheum Dis 197; 29: Perlik F, Kuitov M. The evlution of bone chnges in ptients with rheumtoid rthritis. Z Rheumtol 1983; 42: Thompson P W, Houghton B J, Clifford C, Jones D D, Whitcker K B, Moss D W. The source nd significnce of rised serum enzymes in rheumtoid rthritis. Q_ Med 199; 76: Webb J, Whley K, McSween R N M, Nuki G, Dick W C, Buchnn W W. Liver disese in rheumtoid rthritis nd Sjogren's syndrome. nn Rheum Dis 1975; 34: 7-81.

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