Quantitative liver function tests: A realizable goal?

REVIEW

Quantitative liver function tests: A realizable goal?

DFNIS J Ml)Rl,AN, MP! IAR1'1, Pl ,n. SL 'SAN L E1uc1n, MB,BS, FRAC!', l lANY ( •I !ABRIAi, BSc, r, ,n, RWl lr\RI) A S1'1AI I WOl)I), Ml), FRACT

DJ MORGAN, SL ELLIOTI, H GHABRIAL, RA SMALLWOOD. Quantitative liver function tests: A realizable goal? Can J Gastrocnterol 1991 ;5(2):77-81. A variety of tests has been used to assess liver function and predicL hep,nic functional reserve in patients with liver disease. These tests comprise clinical assessment, simple hiochemical measurements and so-called 'quantitative' tests of liver function, ie, elimination rate measuremen ts of cxogenou~ markers ~uch as drugs and ocher compounds. So far no single test or group of test" has proved to be a ~uffic iently sensit ive and accurate measure of overall hepatic function across the whole spectrum of liver disease. This may he due to diversity in the hepatic handling of these compounds and in changes in architecture, hemoJynamics and cell function in li ver disease. The absence of a satisfactory test emphasizes the value of clinical assessments (cg, the Child-Turcotte or ChildPugh classifications), because of their relative simplicity.

Key Words: Liver disease, Liver function, Quantitative tests

Epreuves fonctionnelles hepatiques quantitatives: Un objectif realisable?

RESUME: Diverses epreuves permettenr d'evaluer la fonction hepatique ct de predire les reserves fonctionnellcs des patient~ porteurs d'affecrions hcpatiques. Parmi ccs tests figurent !'examen clinique, lcs simples mcsures biochimiqucs ct !es epreuves ditcs "quantitativcs" de la fonction hcpatique (qui mcsurent le caux d'eliminacion des marqueurs exogcnes tels que lcs medicaments et autres substances) . Jusqu'a present, ii n'existe aucune epreuve unique ou groupe de tests suffisamment sensibles ou exacts pour mesurer la fonccion heparique pour toute la gamme d'affeccions du foie. La situation peut ccre anribuable a la diversite des mecanismes hepaciques a !'oeuvre ct aux divers changements qui affectent ('architecture, l'hemodynamisme ec la fonction hepatocellulaire. Le fa it qu'on nc dispose pas d'epreuves sarisfa isantes augmenre encore la valeur des examens cliniques (ex: !cs classifications de Child-Turcotte ou de Chi ld-Pugh) , a cause de leur relative simplicicc.

\'1rnman College of Plumrwcy, Melhuume, illlct U11wcrsi1y of Mdhourne, IJc/llmmcm oj Med1cme, l<e/1amwion (;enernl f--lm/nwl, / leiclelher,g, Vicwna, A11.\!ralia

Corres()()mlence imd re/mnr.~: Dr IJJ lvfnri:1m, Vicwrnm Colle!!e of Ph1m1111t)', {8 / Ro:,-al Parade, Park1•ille, Vicrori11, Aw,rrnlw 305 2

Received for /mhlicm1Cm ( )cwl>er Ii, J 990. Affc/Hect Fehnwry 13, / 991

CAN J GA~"fRl )!·NT! Rl )I Vlll 5 Nt, 2 M,\llt'l 1/Al'IUI 1991

C l IR.l)Nll' I IVl:R !)!Sr.ASE l'OMl'RISb

an a,,nnment of disorders in which chere may he \'tlrymg degree~ of change rn urgnn ,truLture, hemndynam1cs ,tnd L~·ll funttion. Over the ye,1rs nwny d1fferen1 methods have been prnpo,ed fur nhiaining quant ira(1\'e informat1nn regarding the extent of liver dysfunclllm and prngre~sinn of the disease. ldcally, wh,1t 1, required 1s a hepatologist's coun1 crpan to crcat mine clearance, which ma111ta111s a rcliahle and predictahle re lari,m,hip m renal funcunnnl reserve throughout the course t1f progrL·ss1ve renal 1mpa1rmcnt. It is therefore poss1hle to predict with rca,onahlc ,lCturacy when renal d1alyw, <)r tran,planiamm wi ll hecome ncces, :,ary.

The first mea~ures adopted to a:.sess hepn tk funttion 1n patie nt , with c hronic liver disease were based on clinical features and rouune hiochemical tests. Development of tests with n·rta111 ex,)genous :.uhsrance:, - such a, g,llacto;.c and indlicyaninc green followed. More recently there ha~ heen 1 nterest 111 selected drugs for mea,urmg hepatic funuinn ( 1,2), ,mce hepc1t 1c drug d 1111imHHl11 may he 1mpa1red 111

patients with e,rnhlhhcd l1wr disease

0.4). Thc introduction nt liver tr,tnsplan

tatHm ha, highlightcd the need f,)r a MHtsfactnry quanr1tac1ve test of hepatu.:

77

MUR<;AN r1 al

funcno nal rc,crve, in orJcr to hcucr Jefine when l rnnsplant will he required. The course of chronic Ii vcr J isease often makes the timing of trnnsplantat io n Jifficulr, since it can he erratic and punctuated hy pe ri od s of sudd e n dete rioratio n due tO interc urrent gastro int eM inal hleeding, infection or an alcoholic hinge. In chi, article the various approac hes to .:.ssessing liver function in chronic liver<lisease will he reviewed, with emphasis on the socalled 'quantitati ve' tests.

FACTORS AFFECTING ELIMINATION OF

SUBSTRATES BY THE LIVER Hepatic elimination requires initia l

upwke of the wbstance into the live r cell from sinuwidal hlood via the space of Disse, followed hy transport within the hepacocyte, and fina lly metabolism by hepatic enzymes or secretion of the unchanged compound into hilc. Impairment of hepat ic elimination may invo lve one or more of these steps, bur it is the final step which is normally rate limiting. The capac ity nf th is final elimination process ( 1e, metabol ism or biliary xcrction) is very high for some substances and very low for others. If the capacity is very high, then hepatic clearance will be largely dependent on hepatic blondflow and independent of e limination capaci ty (intrinsic c leara nce). lf the elimination capacity is low, hepatic clearance will be independent nf hepatic hloodflow but will depend on intrins ic clearance ( 5 ). F1ir compo unds in this la tt er cmegory that arc highly hound to plasma proteins, hepat ic clearance will also depend on the degree of protein hmding (6).

These considerntions indicate that there arc se veral po tential mechanism~ by which hepatic elimination cou ld he c hanged.

PA THOPHYSIOLOGY OF CHRONIC LIVER DISEASE There b a variety of functional and

structural changes that may occur m chronic liver disease (7). The synthetic function of rhc liver may he compromised, with impa ired production of export proteins such as a lbumin, alpha-I acid glycoprme in and clotting factors.

78

A reduction in plasma concentratiom of a lbumin and alpha-I acid glycopmtein leads to a reduction in the extent of plasma prote in binding of o therwise highly protein bound drugs and othe r compounds (8,9).

There is a lso a reduction in the various metabolic functions of the live r. Of special interest are the he patic mixed function oxidasc enzymes, which are responsible for the oxidation of many drugs and a wide va riety of other compounds. The re is a reduction in the hepatic content of cytoch rome P450, an essential component of the mixed function oxidase system (1 0-13 ). Thb is reflected in reduced in vitro oxidation rates of many subs trates ( I 0, l l ). However, it is now recognized that cytoc hrome P450 is a family of isoenzymcs, and that the effect of cirrhosis on t he hepat ic content of each isoenzymc is nor necessarily the same ( 11 ).

A n o th er important c h a n ge in c hronic liver disease is alteration of the liver's mic rocirculation. ln the healthy liver, the endothelial cells lining the sinusoi<ls arc perforated by a multitude of fcnestrae, which allow free access of solutes and part icles to the space of Oissc, and thus to rhe liver cell. In chronic liver disease one finds a striking reduction in the number of fenestrae, deposit io n of collagen in the space of Dissc and formation of a basal lamina beneath the endothelial cells (14-16). These c h a n ges transform ed the sinusoids into capillary- like strucwres with decreased access of s mall molecules into t he space of Oisse, and hinde red uptake by the liver ( 17-20).

Finally, functiona l hepatic bloodnow may be reduced as a result of intrao r exrrnhepa tic shunting of blood, wh ic h the reby reduces the delivery of substances in blood to the liver cell (7).

CLINICAL INDICES AND CONVENTIONAL LIVER

FUNCTION TESTS The simplest assessment of liver

function involves a comhinar ion of clinical features (cg, neurological state, presence cif ascite~) and simple bioc hem ica l tests (cg, serum bilirubin, scru m a lbumin , prothromhin time) (21,22). TlllS approach is not e ntirely

sat isfactory hccau~e of observer error, a lack of i ndcpcndcncc among individual variables (2 3) and a dependence on other fac tors unrelated to the liver. Moreover, certnin va riable~ (cg, tramaminase enzymes) may he norma l even though Ii ver d iseasc is advanced. T hese indices, while pmviding a means of standardiz ing scverit y to permit comparison of different pm ient groups, have been considered tno imp recise for determ ining the timing of liver tram,· plantation in the indiv idual patient.

To predict prognos is more rel iably, models have hcen dcvbcd which apply stat istical mctholb ro comhi nat ions of' convenuonal clinical, hiochcmical and histological data to form a prognost il index. These mathematical models have been app lied to severa l diseases, in particu lar to primary bilimy cirrhosb (24-26) and primary sclerusmg cholangitis (27). They have all used 1he Cnx p ro portiona l hazards mult ivariau: regression procedure for da ta obtained from clinical triab (28). Not surprisingly, the models use similar ri~k variables (age a nd scrum hilirubin are common to

.i ll and seem to have the grea test impact). Two models for rrimary bi liary cirrhosis have hecn tested a nd found to

be highly correlated in their assessment o( patie nt risk (r=0.92) (25,26). However, even within specific disease groups, the models do not yield a precise prognosis for a given individua l (29).

A disadvantage of each of these models is char rhcy use data recorded at only one time period in what is usually a long d isea~e course. A I t hough the overall course of cholestaric diseases such as primary hil iary cirrhosis and primary sclcrosing ch olangi tis is one of progressive decline, it may occur in a 'stepwise' manner rathe r than as a smooch decline. Accordingly, as suggested by C hristensen (29), the prcdict i vc rower of a mod el cou ld he increased if it encompassed follow-up data in its analysis.

QUANTITATIVE LIVER FUNCTION TESTS

A possible a lternat ive to the~c indirect statistical ana lyses is the use of so-called 'quan titative' liver function tests, ie, tests of th e capacity of the liver

CAN J GASTRl)ENTEROL V OL 5 No 2 MARCI I/APRIL 1991

to eliminate marker compounds. Some of these tests use exogenous test compounds such as galactose ( 30-3 3), indocyani ne green ( 1,34,35), bile acids (36- 38) and sorbitol (39). The compound is injected either as a bolus or as a prolonged infusion, and measuremenr is made of a single plasma concencrat ion of substrate or of several conccntrat iom over an appropriate period. Even more s imply, in the case of bile acids the postprandia l plasma concentration of endogenous bile acids is measured (38).

A II l)f these substances are characterized by high hepatic clearance at the low doses used , so chat their elimination rates pred l)minantly reflect h epatic hlnodflow rather than the capacity d the el1m1narion process. They have found widespread application, therefore, as indices of hep,nic hloodflow (30,33-3 5,39-42). At high doses suffi c ient ro saturate hepatic elim ination processes, galactose and indocyanine green have also hcen used as measures of elimination capacity, hecause at n high dose, elimination depends more o n e l imination capacity than o n bloodflow (l ,3 l .40). Each of these test subst a n ces d e pe nds on a different process for its hepnric elimination, eg, galactosc depends on the cyrosolic enzyme ga lactokinr1sc, and indocyanine green and hile ac ids depend on biliary excretion mechanisms.

Severn l drugs have been used as quantitative markers of liver function . These in c lude antipyrine (43 -45) , aminopyrine (46,47), caffeine (48 ), phenacetin (49) anddiazepam (50). All are e liminated entirely hy hepatic metabolism, ox idation being the main path way. They have lo w hepati c clearance; therefore, their elimination rates reflect the capacity of hepatic drug oxidation systems rather than hepatic blood£low. The test may be perfo rmed by measuring systemic clearance of the drug by collecting multiple blood or saliva samples after ingestion of a single oral dose. A lternatively, carbon- 14-label led drug may be administered and the excretion rate of 14C02 in expired air used as a measure of the rate of hepatic metaboli:.m (46,49-52).

The metabolism of these drugs is carried out by different hepatic enzymes.

The principal enzyme system rcspon, sible, cy tochrome P450, is a family of at least 20 separate isocnzymes ( 53 ). Even the ox idation of a single drug docs not usually reflect the activity of a single isocnzyme. For example, c;1ffeinc is metabolized to at least 11 metabolites, and numerous cytochrome P450 isoenzymes arc involved (54).

Moreover, the metabolism of these drugs is not representative of othe r major metaholic pathways in the liver, for example, drug conjugation proce,ses. Conjugation seems tn he much less affected in li ver disease than oxidation ( 55 ).

A further complicating factor is the wide variahility in the handling of drugs even in healthy persPns with no rmal livers. There may be a several lOO-fold difference among normal indiv iduals in the ir ahility to metabolize a g iven drug (56).

EVALUATION OF QUANTIT A Tl VE LIVER

FUNCTION TESTS The effect of liver disease on the

hepatic disposition of many drugs and other compounds has been examined

( 3,4 ,6,9). Sensitivity of tests in detecting im, paired function: Ideally, a quantitariw liver funct ion tes t o ught w determine the severity of hepatic impairment in all forms of chronic liver disease. Most of the available data have been obta ined in patients with alcoholic c irrhosis, with few da ta availahlc for other diseases such as chrome active hepatll 1s, primary bi liary cirrhosis or sc lcrnsing c holangitb (3,4 ). With isolated exccptiom (57,58), quan tita tive tests of hepatic function genernlly appear normal until the disea,e is at an advanced stage a nd dccompensaced c irrhosb is present ( 59-64).

S tudies with test compounds suc h as antipyrine (45,62,65-69 ), ammopyrine (61,62), caffeine (54,70), indocyanme green (23,45,62) and galacro,e (45) show impa irment of hepa tic (uncriun only in patients with advanced c irrhosis. A comp I ic.iting factor is, however, that even in advanced c irrhos is e limination of some drugs i, normal, cg, those metabo lized by glucuronidation

CAN J GASTROENTEROL V o l 5 No 2 MARCI I/APRIi. 199 l

Quantitative liver function tests

(55,7 1,72). An exception is theophylline, the elimination of which is impaired in apparently well compensated c irrhosis (64). Accuracy of test s in measuring hepatic function: A I though there is a broad correlation among results from various markers in patient, with c irrhosis, there is a great deal of va riation int he degree of impairment of elim ination with different marke rs in the samc pat icnt. Even for marke rs that are eliminated by similar pathways, cg, hy oxidat ive metabolism, the re is still a disparity in test results (62,63,66,68,69,73). S tudies with multiple markers in the , amc patient indicate th at correlatio ns among results with individual marker, may nor he suffic iently strong to a llow the rl'sult with a n y one marker to

predict th e resul t o f the o th e rs (45,62,64,73).

It is a lso of interest to compare res ult s o btain ed with exoge nous marker, to tho~e obtained with endogenous markers. In some studies, results with caffei ne , thcophylline and indocyanine green have rnrrclatcd well with those of tests such as scrum a lhumin, scrum bilirubin, prothrombin time and C hild-Pugh criteria (23,74, 75). However, these correlations arc aga in not suffic iently ~crong t.o he of predictive value. There arc also studies in which result s w1rh th eophyllinc, l1docaine (64), antipyrinc (73), galacw~e (74) and £1uxotenc (76) did nor correlate with tests with endogenou, ma rkers or c linical criteria. Funherm,1re , a study evaluating the a minopyrinc bremh test in cirrhotics found tha t the test added no predic tive abili ty above that of the C hild-Turcotte clas~ificmion (77).

CONCLUSION T he pn:~ent evidence suggc~t~ that it

b unrealistic to expect one simple te~t to predic t the course and outcome of all chronic live r dbcase. Nevertheless It

may turn out rhat antipyrinc clearance, for example , will prove to be very helpful in predicting the course of ch ronic I ivc r d isease of one or perhaps all types, despite intuition and the ahovc ,irgumcnts. The onus is on the advocates of the vr1rious tests lll establish their use-

M()Rt,'\N er al

fulness l'mprncnlly, as has hl'en dune f<lr 1hc varinus md1ccs employing clinical cr iteria and n\nvenrional liver lunct ion lCs(,.

Arc pa1 icnts coming to tran~planrntinn, hcpal it resection or splcntirl·nal

shunt ,urgcry wirhnul t he hcnefi1 nt regular assessment with quantitative

liver function test~ d1sadv,1ntaged 111

some mc.isurahlc way? Establishing the

usdulnl'ss of a q u:m1i1 :11ive liver func tinn test will require Sllll1C form of \1hJl'CI I\ l' assessment of o utcome wh ic h

shows that patil'nts whose management 1s h,1sed lln rhe results of the reM arc

helter off than those in whom the test 1s not used. As yet such an exercise has not been 11ndl'rwkcn.

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4 t Branch RA. Janws _IA, Read AE. Tht· dc,1ranu· of ant1pyrmc and mdnq ,m 111c grct•n m nnrm,11 ,uh1et ts and 111 p:ll1cn1, w1rh chrun1c liver d1,ca,e ( 'Im Pharmacnl Thcr 1976;20:h 1-9.

44. Vt•scll E.."i. Thl' a1111pynnc t,·st m d 1111c.1l pharmacnlngy: Cnnccprinn, and 1111,u>1Kcpt1nns. Clm Ph,irtnacol Thcr I 979;26:275 ·86.

45. Kawa,al..1 S, Sugiyama Y, lg,1 T, t'l al. 1 kp,nu.: dearatKt' l>f an11pynn,•, 111dncyanmc grel'n, ,md gaLKtose 111 11unn,1I suhicct, .md 111 p,ll 1t·nrs w11 h chrome ltn·r dist•a,c. ( ·1111 Pharma,,,! Tlwr I 9H8;44:2 l 7 24.

46. 1 kpn,·1 ( ,W, V,•,c ll E!:>. 1\ ,,es.,11w111 , ,r ,1111111,ipvnnt' nwr.,hult,m m man h1 hrc·,1th .111.1ly,1, ,1h,·r oral adm1n1,1ra11nn ,11 1\~-.1m11H>pyn11,·. N Engl) 1'.hl 1974;291 I 11N-8.

47 ~hne1,kr JF, B,11..cr AL. I Lune, NW. A11111111pynne N-ck111c1hyla11on: A prngn,1,tK test of 11\cr fun,tHm 111 p,1t1ent, w11h .1lu1h,1ltc liverd1sea,e. ( ~a,rrucnterolngy 1980;79: 1145-50.

4.~. Rt·nner r, W1c1h,,h: H, l lugucn111 P. Arnaud Ml. Pre1s1g R. Caffeine: ,\ mudl'l n>mpound fur measurmg 11\t'r lu111:1um I kpa1<1lugy 1W'i4;4:3H,46

49. Breen KJ, Bury RW, Cal,b I. A (( ')-pht·n,1cct1n hrc,1th r,•,t 10 111t•;1,ur,· hepat tl funcrinn 111 man. I lepar,ilogy 1%4;4:47-52.

50. I kpner t ,W, Ve,rll ES, l.1p1on A. l )i,p,1S1l l1 ll1 of ,1m1nop) r111c, ,111r1 pyr111e. d1a:cpam ,md 111doqan111t· green 111 patient, 1111h l1vl'rd1,c,ht' nron ·1nr1u 1n1 ul,ant I lwrapy: L )1a:cpam hreath tt'st and cmrehirn>11 111 drug ,·l1111111.t1Hm.J LahClin Med I 977;90:44L1-56.

51 B1rcht·r _J, Kupkr A, C,11..alm I, Prt·i,ii.: R. Am1nupyrtnt• demerhyl.111nn measured hy hreath an,1ly,1s 111 urrhn,1,. Clm Ph,1rmacnl Ther l 976;20:484-92.

52. W1e1hnlt· 11, Vm•gcl,n M, Amaud MJ. Mea,urcmcnc ,if cytochrome P-448 depl'nde111 I 1vcr cn:ymc sy,rem hy ,I Laffoim• hremh rt•,t. Eur J ( ' tin Ph,irm,1wl 198 I ;21·53-9

5 3. Uuengt·nd1 Fr. Polymllrplw,111 of cytochrome P450 in hum,1rn,. Trl·nd, Ph,irm.m 11 Su 1989; I 0: I 07 9

54. ~()tr NR, Sramhul.. L). Ch.1kr.1h"rry J. Marb V. Morgan MY. Caffeine

clearance and h1orr.111,form,H1lln 111 p,tt1enr, 11 uh Lhn>ntl ltl'er ,11'-·,1,,·. Cl111 Sc, 1988;74:177 94.

55. Ghahr,al 11. l),.,m,ui.l PV, \X ,1ts11n K_JR, ct al. The cflt·..:1, llf .\L!l' ,tnd chrnnK ltl't'r ,lt,east· 1111 rlw el11111natllll1 for tun.1:cp,1111 1:ur ( ·1111 Ph.1r111ac, ,I 1986; 10:9 3-7.

56. Mutl..low J( •. En\'1rnnmcm,tl faLt,,r, ,1fh:u mg drug me1;1h. ,lt,m. l'h.1rmacol Ther 1988; 16: I 05 I 7

57. B1rn1e GG, McCnll KFL. Thompi,on (~(,. Mtlore MR. (~,,klhc·ri.: t\, Rrlldt,· MJ. Ant1pyn11e llll'lahlllt,111111 .1u11,· llt'palll pllrphyn,1 1n rt·lap'<' and r,·m1"111n Br Clm l'harm;1c"I 191'7;21:15H.61.

58. Wa11 U. Wh1rc NJ, 1'.1dre L. i.:t .ii. Pr.1~1qu,tn1 t·l pharn1.1,, ,k 111t't It' .111,I , 1de l'fku, 111 Sch1,ro,"111l1 J<1/>rn11c11m mkcrcd pa11t·n1, w11h iil'l'r d1sc•.1sc. l11fe<..t D1, 19Sh;l57 5W-5.

59. William, RI , Rla,chke TF, 1'-lcttm Pl, lvlt·lmon KL. Rowland M. lnflui.:nu· Ill viral hcparm, ,,n tht· d1spn,11um nf 1w,, C1llllJ1\lUl1ds \\ II h high hep,tl I( cle.trann·: I .1dnc111w ,tnd mdnLyanmt• green Cl,n l'h,1rn1.lt',1l Tht·r 1976;20· 29L1, 9.

60. Pt·";tyre I), Lchrec I), l)c,t.11u1ri.: V, l't·ti.:nllu, M, Benh.1mnu JP Mt•th,1111,111 t,,r rc,hK,·d drug ,lc.1r,111tt· 111 p,nient, 1\ 1th, 1rrhn,1,. (;,1,tn1,·n1,·n,l,1gy 197S;74:'i66, 71.

61 1'101m'k' r. l\.iker 1\, i(rai.:t·r I'. Sthllt·llcr !), Klem I'. The ;1111111llpyrtm· hrea1h rc,1 (ABT) pr,·dKts h1,tlll<>g\ and corrcl,u,·, 111th u,ur": m p,lltcnts wnh chronic hcp.11111, (Cl I). G1,1n1t·111en,lng1 1980; 78: l 114. (:\h,1)

62 \ 1llt-m•u1·,· JI'. Thtlht'lult 1'1J, Ampd.1, M, ,·r al. l)rui.:di,p1"1t1nn 111 p,111cm, 1111h I lh, Ag-pmtt l\'l' tlml111l lt1·cr ,l1sc'<1'l'. D1i.: Dis Su 19:--7.32 710-4

61. [\me,hmcnd TK, I l,,111e1d.1 M, Ka)t' (. 'M, Elamin AA, Rnht·m ('_I(' [)tsp11'1r1011 ,if llral 111t·tro111d,1~lllc 111

hepat 1c c1rrhmi, ,md 111 hepa1,isple111t ,lh1,tosn111t.1s1,. Gut 1982;2 3:807-11.

(14 C.dlt A, Run.mn(,, (\1cc1lll,, 1'1, Parra\ tetnl R, Scalrr111n G. [)1,p11Strltlll nf ,1 fl1m ltnlllcd drug (11cl<K,11nc) and ,1 merahnlK c.1paut,-l11111rcd drug (rlwnphyll111d 111 lil'l~r c1rrho,1,. Cl111 Ph.irmacnl Ther I 988;44:642 9.

(15. Kirch W, Ohnh.,u, f· E. P.1h,1 J. Sr,>rsii.:111 [ . l11g1t\lx111 111 patt,·111, 1\ 11h hL'J',llllrenal 111suff1t tl'tK y atr,·1 r,·p,·,11c,l .1cl111111i,;1r,1tu111. Eur I k,irr J 1989; I 0:4Ll 7

66. McQumn RI. Pen11k,11nen l'J. Chang

Quantitative liver function tests

"iF, Clln,1rd t, l'harnl,Klll..1nettl, ,,t tlec.11111lk 1n p,lftt•nt, 1111h .:1rrhost, 111 thl' lt \'l'r. t '1111 l'h.irm.1u 1l Tlw1 1%8;44-566 72

(:, 7. Nkhi.1 MU, \ ,·11k.1r,1ram,m.111 R. Burl...m t ,J, ct .ii. At111py1111,· l..111,·110 m ltH·r d1'e.1,e and lt\'l'r rn111.,pl.111tat1n11. ( '1111 l'h,1r111.1u1I l'ht·r 1986; N· l72 7

6~ Pent 1b111i.:n Pi, I lll·tak, 1rp1 ...,, I l.1l111c11 MO, Lampmen LM C1rrh,1s1, of rh1: liver 111,trkedly impair, tlw cl11n111.11 1lln ni mextlec111c htr Cl111 l'harm.iLnl I %6; 10:8 l-8.

69 Pent1k,11nc11 PJ. Val1sal1111 L. I l1111h<:rg IJ, Crt•1·rn,1er l' Ph.1rm,1n,l..1m·110 nf n11daml.11n fnll1m mg 1111r,11·cnllu, .md llntl ad111111i-1r,111,m 1n p,llii.:nts 1111h d1r,1111c lt1·cr ,ltse,1se .111,l 111 lw.1lth1 ,uhi,·t t,. Cl111 Pharm,Klll I 989;29:272-7.

70. "ic,m NR, Stamhuk [), Ch.1kr.1hony J. Marb \, M,irgan MY. Thl' pharn1au,k111c110 ,if cafkine .111d 11, d1111erhyh.1111h111e mctah,,ltre, 111 par1cnr, 1\ 1th d1mnK l11·er d1,,•,1,,•. Br<. '1111 Ph,11111,,u,I I 989;27:205 11.

71 Och, I IR, t,recnhlau DJ, V<'rhurgOch, B, M,nlis R. Tema~cram 1.kar,,nte unaltered 111 urrho,1,. ( ,a,rrornrerol, 1g) 1986;1' l :80-4

7 2 Cn>tt\ ll, W.1r-,m KJR. De,mond PV, rr al. I kpa11c t'Xtrauum uf m11rph1nc 1, 1111pa1red ,n urrhm" fur Cltn l'h,1rm,Knl 1989, 16:'>l~ I 6

7 l. Mm:li,khmt AJ, B1mtl' ti(,, Cnllk A, t'l al l'h,1rm;icnl..111eu,, ,md pharm.1ul(.lyn.11nK, ,it 1111 ral'en,111, n11d.1~ul.1m 111 pat1e111, wnh ,<·1·ere .tlrnlwltc urrlw,1,. (;ur 1986;27 190-5

74 I llll,1,•gi.: A, ~1a1ger M, I I.1,1g [), (,mil.. W. ( \,rrelanon uf caffeine eltm1natton and Child\ tl,1"1f1c,IIH>11111 ltn•r urrh"'''· Kim Wllch,•nschr 1989;67:6-l 5.

75 Kra.111 J, Jonl..rmn JI IC,, Koercr Ul 1. et ,11 The pharmacnktnt'tKs of the,1phyll111e ,md ,·npr,1fyll1ne 111 p,1ril·nt, wi1h li ver c1rrhow, and 111 p,1ttent, 1111h chronic rt•n,11 dtsea,e l::.ur J l 'I 111 Pharmacol 1988; 3 5· 15 7 -62.

76 Sch,·11ker S, Bergstrom RI-, Wolen RL, Lemht·rger L. Huoxet111e d1,pllst111 m .mcl el11rnn,111on 111 c1rrhm1,. Clm Pharm,Kol T her 1988;44: '35 '3-9.

77 Villeneuve JP, lnt.intt' Rivard C, Amrela, M, Pom1cr-L1yrcrgue, (,, I luet l'M, Marlcau D. Pn1i.:n,1,11c value of rh,· .,mmllpyrtnc hrt•,11h cc,r 111 urrho11c p,1t1ent,. I le-pawing) l 986;6:928- '31

81

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Quantitative liver function tests: A realizable goal?