Prevalence o f M -proteins in Serum o f H ospitalized Patients

Transcription

1 ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 17, No. 3 Copyright 1987, Institute for Clinical Science, Inc. Prevalence o f M -proteins in Serum o f H ospitalized Patients Physicians Response to Finding M-proteins in Serum Protein Electrophoresis* ADRIAN O. VLADUTIU, M.D., Ph.D. Departments o f Pathology, Microbiology and Medicine, State University o f New York at Buffalo, The Buffalo General Hospital, Buffalo, NY ABSTRACT M -proteins (tall, narrow spikes) are the major finding in serum protein electrophoresis (SPE), and their presence could signify lymphoproliferative diseases. The physicians response to this finding in 73,630 patients in whom a SPE was perform ed as part of a routine screening at hospital admission was studied. Serum and urine im m unoelectrophoresis (IEP) were requested on the report of SPE in all patients who showed M -proteins on SPE. In 59 percent of these patients, neither serum nor urine IE P w ere ordered, and it was assum ed that the results of SPE w ere ignored by physicians. The frequency of M -proteins (1.1 percent) in the hospitalized patients was higher than that reported for norm al individuals. It is suggested that SPE should not be perform ed as a screening test in hospitals. Introduction The role of the laboratory in patient care has often been discussed, and with the introduction of prospective reim bursem ent, the need for particular laboratory tests has been reevaluated. O f particular im portance in this respect are the screening tests at admission to the hospital, i.e., the so-called adm ission profiles, which are still common in many hospitals. The clinical value, if any, of th ese screening tests was often ques * Address reprint requests to: Adrian O. Vladutiu, M.D., P h.d., The Buffalo General Hospital, 100 High Street, Buffalo, NY tio n e d.14 T he co m p o n en t tests of an admission profile are different in various hospitals; for exam ple, som e profiles include a thyroxine test, others a triglyce rid e assay, etc. A few h o sp ita ls,1017 including this in stitu tio n, p e rfo rm e d serum protein electrophoresis (SPE) in all newly adm itted patients. It has been reported that physicians often ignore abnorm al results from an admission profile or even from tests specifically ord ered d espite th e fact th at these abnormal results require prom pt action.4,13,29 In this institution, SPE was part of the adm ission profile for many years. To determ ine w hether or not this /87/ $00.90 Institute for Clinical Science, Inc.

2 158 VLADUTIU test, w hen perform ed routinely in all patients, has clinical value, the impact of an obvious abnorm al finding in SPE, namely, the presence of electrophoretogram tall spikes owing to M -proteins, was exam ined retrospectively. This finding can be associated with malignant diseases, and, in the m ind of many a physician, this could be a finding of grave significance for a patient. Indeed, m ultiple m yelom a and lym phom a, diseases often associated with M -proteins seen in SPE, can be clinically unsuspected at the tim e w hen serum protein abnormalities are found. Also reported here are the frequency of M -proteins in our hospitalized patients and the com parisons of these findings w ith those reported by others in different geographic areas. M aterial and M ethods From 1976 to 1981, all patients adm itted to this hospital w ere supposed to have an SPE perform ed. However, from comparing the num ber of electrophoreses p e rfo rm e d e a ch y e a r w ith th e n u m b e r o f h o s p ita l a d m issio n s, it appeared that only about 65 percent of th e adm itted patients had an SPE p e r formed. The reasons for this discrepancy are unknown. It was noted that patients a d m itte d th r o u g h th e E m e rg e n c y D epartm ent most often did not have an SPE perform ed at admission to the hospital. Serum p ro te in electro p h o resis was perform ed on agarose gel in sodium barbital buffer, ph 8.6.* The plates, stained w ith A m id o B lack, w e re v is u a lly inspected and w ere also scanned with a densitom eter (Model 720).* The densitom etric scans w ere pasted on an 8" x 11" standard size sheet and inserted in the p a tie n t charts. M ajor electrophoretic abnorm alities (e.g., decrease of gamma globulins, hypoalbum inem ia, etc.) w ere * Corning, Medfield, MA. recorded in the report in large capital le tte rs by m eans of ru b b e r stam ps. W hen an M -protein (tall, narrow spike) was observed on the graph, the report stated the electrophoretic location of this p ro te in ((3 or y) and, fu rth e rm o re, a request for additional serum and urine specimens for performing im m unoelectrophoresis (IEP) was stam ped on the report. It has been th e policy in this institution for m ore than 15 years that before any additional test is ordered after the finding of an M -protein in SPE, an IE P should be perform ed. Indeed, when a p h y sician re c e iv e d an SPE re p o rt showing a tall spike and he w anted to investigate this abnorm ality further, a serum IE P would be requested. T herefore, the absence of a serum IE P order was taken to signify that the physicians ignored the SPE report. To verify this assum ption, charts of random patients with M -proteins in the electrophoretograms but who did not have serum IE P perform ed were review ed for evidence of tests or notes w ritte n as a consequence of the finding of M -proteins. S ince SPE a n d IE P h av e d iffe re n t charges, and since IE P is an expensive lab o ra to ry te s t th a t re q u ire s e x p e rt interpretation, serum IE P was not p e r form ed by the laboratory unless specifically ordered. The results w ere reported one to two days after the patients adm ission to the hospital. All SPE reports for six consecutive years w ere retrospectively review ed, and those showing M -proteins w ere separated by year, from 1976 through If a patient had m ore than one SPE p erformed, only the first one was counted. F or each p a tie n t w ith M -p ro tein on SPE, a corresponding serum IE P was searched for in the yearly records of IE P, and the patients w ithout a corresponding IE P w ere considered to have the SPE report ignored by the physicians. Serum IE P was perform ed by a stan d ard m icro tech n iq u e w ith use of

3 M-PROTEINS IN SERUM OF HOSPITALIZED PATIENTS 1 59 agar gel in barbital buffer, ph M onospecific antibodies to heavy and light chains of the five immunoglobulins classes w ere used for IE P.t Results D uring the six years review ed in this study, 73,630 SPE s w ere perform ed and 881 (1.19 percent) of them show ed M- proteins. Of these latter, 74 (8.9 percent) w ere in the beta region only, 764 (91.1 percent) w ere in the gamma region, and 43 (4.8 percent) SPE s had two or three M -proteins. O f the 881 patients with M- proteins, 549 did not have a serum IEP perform ed and 33 patients had only a urine IE P perform ed. Therefore, it is assum ed that 59 percent of SPE reports that showed M -proteins w ere ignored by physicians (table I). Of the specimens with M -proteins on electrophoretogram s and w ith which a serum IE P was perform ed, 71 percent had a monoclonal IgG, 15.5 percent an IgA, 12.8 percent an IgM, and 0.8 percent had a monoclonal IgD. The ratio k / X for the monoclonal immunoglobulins was 1.6 for IgG, 1.5 for IgM, and 1.0 for IgA. t Cappel-Worthington, Malvern, PA. T A B L E I M-proteins in Serum Protein Electrophoresis (SPE) of Hospitalized Patients T o t a l SPE 7 3, S PE w i t h M - p r o t e i n s 8 81 (1-2)* M - p r o t e i n s w i t h o u t follow-'up (by s e r u m o r urine i m m u n o e l e c t r o p h o r e s i s ) 516 (59) L o c a t i o n of M - p r o t e i n $ r e g i o n 74 y r e g i o n 764 T w o spikes 41 T h r e e s p i k e s 2 S p e c i f i c i t y o f M - p r o t e i n s IgG 1 84 (71.3) in 258 s p e c i m e n s IgA 40 (15.5) I g M 33 (12.8) P e r c e n t a g e in p a r e n t h e s e s. IgD 2 ( 0.8) Discussion The term M -protein or M -com ponent seems to have been coined in to denote a tall and narrow peak in th e serum electrophoretogram. Later, these spikes, which represent in fact hom ogeneous proteins, w ere defined as having the height at least four times higher than th eir w idth at m id-point b etw een the base and the top.20 The M initially stood for m ultiple m yeloma, m acroglobulinem ia of W aldenstrom s, and m alignant lym phom a, i.e., diseases in w hich M- proteins w ere most often found. M -proteins (later thought to also m ean m onoclo n al) w e re also fo u n d in S P E of patients w ith various non-m alignant diseases as w ell as in serum of clinically normal individuals (the so-called benign monoclonal gam m opathies),28 b u t it is often thought that M -proteins found in an SPE of a hospitalized patient may signify a grave disease. In fact, the m ost im portant clinical indication for perform ing SPE is the detection of monoclonal im m unoglobulins, i.e., M -p ro tein s.17 O ther abnorm alities seen in SPE, for exam ple, th e d ecre a se of alb u m in or gam m a globulins and th e in crease of gamma globulins, are routinely detected by use of m ultiple param eter chem istry analyzers. It was assum ed by us that finding an M -protein in SPE required a follow-up action. Indeed, M -spikes in SPE are the m ost obvious and conceivably the most serious abnorm ality in this assay, such that ignoring an M -protein in an SPE is tantam ount to ignoring the whole SPE. How physicians respond to abnormal laboratory results is of im portance. P re viously, th e failure of a substantial prop o rtio n of physician s to re sp o n d to abnorm al la b o ra to ry te s ts has b e e n reported, e.g., low serum cobalam ine levels,4 abnorm al fasting blood sugar, low hem oglobin and abnorm al u rin aly sis.13,29 Perhaps these abnorm al param e

4 1 6 0 VLADUTIU ters are less likely to herald a poor prognosis th an are M -proteins in SPE of p a tie n ts w ith su sp ected lym phocytic malignancies. From our study, it appears that a large proportion of physicians also ignore abnorm al results of SPE. Several questions can be raised: Is the absence of ordering a follow-up serum IPE in a patient with M -protein in SPE a valid indication of physicians ignoring the results or SPE? If this were so, what is the explanation for their lack of action? The separate, large forms of SPE were n o t b u rie d am ong o th e r re su lts and c o u ld n o t h a v e b e e n ig n o re d. As observed from reviewing random charts, bone m arrow aspiration and/or X-ray bone survey w ere not perform ed on the basis of a single SPE showing M -protein. Still, th e re is no firm assurance th at other tests w ere not perform ed in some patients w ithout serum IE P because of th e finding of an M -p ro tein on SPE (since we did not review charts of all th ese p atien ts). T he existence of socalled b e n ig n m onoclonal gam m opathies,28 i.e., the presence of M -proteins in serum of asym ptom atic individuals, could explain w hy p hysicians m ight choose to ignore th e SPE findings in patien ts w ithout signs and sym ptom s suggestive of one of the malignant lymp h o p ro life ra tiv e d iseases com m only associated with M -proteins. This view is, how ever, to b e challenged since sym p to m s in a p a t i e n t w ith m u ltip l e m yeloma, for example, usually appear when the tum or burden reaches a mass of 1 Kg, w hereas w ith sensitive electrophoretic techniques an M -protein in the serum can be found w hen the tum or mass is only several hundred grams or as low as 100 g. The frequency of M -proteins in SPE was reported mainly for normal individuals (e.g., blood donors)3,5'8,9 18,21,22 25'27 and less for hospitalized patients or clinic p atients.1,10,16,19,23 In norm al subjects, the prevalence of M -proteins depends on the geographic factors3,25 as well as on the age; the frequency of M -proteins is higher in older individuals.3,712 In blood donors, who are presum ed to be healthy individuals, the frequency of M -proteins w as b e tw e e n a n d p e r cent.3,5,8,9,18,21,22,25 27 H igher frequencies of monoclonal proteins, sim ilar to our findings, have been reported in hospitalized p a tie n ts.1,10,16,19,23 24 It should be m entioned that the frequency of M-proteins is also dependent on the electrophoresis technique; it is h ig h er w hen agarose gel is used instead of cellulose acetate as the supporting m edium for electrophoresis. In a small num b er of hospitalized patients, the prevalence of small spikes in SPE was up to 65 percent w hen high resolution electrophoresis was used.15 Not all of these spikes were, however, m onoclonal proteins. T he distribution of M -proteins among the four classes of immunoglobulins was similar in our study w ith th at in o th e r stu d ies.2,6,19 Ratios of k/ \ above one w ere co n sisten tly re p o rte d for m onoclonal IgG, IgM, and IgA.2,6 In contrast, our findings showed a ratio of one for IgA, i.e., an increase of m onoclonal IgA -\. Similar findings w ere reported by Pick et al.24 Most of the patients with M -proteins w ere not followed after the discharge from th e hospital and th e ir final diagnosis and their outcome are not known. T herefore, it is not know n how m any patients w ith M -proteins in SPE developed lymphoid malignancies. From the present review of SPE perform ed during six years, it is concluded that SPE is not valuable for screening newly adm itted patients at least since the most im portant finding in this test, M -proteins, is often ignored by physicians. (The predictive value of SPE for certain diseases was not studied). For this reason, offering SPE as an admission screening test in our institution has been discontinued. The SPE is now specifically req u ested in certain

5 M-PROTEINS IN SERUM OF HOSPITALIZED PATIENTS 161 patients and the frequency of M -proteins is now about 10 percent of the total SPE perform ed. All sera showing M -proteins in S P E now h a v e a fo llo w -u p IE P ordered by physicians. Acknowledgm ents The invaluable help o f Jacqueline Teitz is highly appreciated. References 1. A d a m s, R. A., S m i t h, L., and P i c k e r i n g, P. G. C.: The incidence of monoclonal proteins during 7 years of screening in a District General Hospital. Immunology 541: , A m e i s, A. and P r u z a n s k i, W. : M -com ponents-a rev iew o f 1242 cases. Can. M ed. A ssoc. J. 114: , Ax e l s s o n, U., B a c h m a n n, R., and HÀLLEN, J.: Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med. Scand. 279: , C a r m e l, R. and K a r n a z e, D. S.: Physician response to low serum cobalamine levels. Ann. Intern. Med. 246: , C o o k e, K. B.: Essential paraproteinemia. Proc. Roy. Soc. 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