Misleading biochemical laboratory test results

will examine some of the conditions bility increases with each additional AMIN A. NANJI, MB, CH B, FRCP[C] under which commonly performed test, as shown in Table I. Interpre- laboratory tests may give misleading tation of the table is subject to the results. caveat that the probability of all This article reviews the general and A few general principles may be tests giving results within the nor- specific factors that interfere with helpful. The great progress that has mal limits is slightly increased by the performance of common bio- been made in recent years in the the fact that low values for some chemical laboratory tests and the quality of laboratory tests means tests do not indicate an abnormality. interpretation of their results. The that most errors are now due to Indeed, several authors have warned clinical status of the patient, drug nonanalytic factors;' primarily these against pursuing a marginally ab- interactions, and in-vivo and in-vitro include the steps involved in request- normal test result.4-6 biochemical interactions and changes ing the test, in preparing the patient, Other factors can also alter test may alter the results obtained from and in storing and processing the results. These include the patient's biochemical analysis of con- specimens. Drugs can also alter lab- sex, diet, physical activity and smok- stituents. Failure to recognize invalid oratory test results, either by affect- ing habits; these factors have been laboratory test results may lead to ing a physiologic process or by inter- discussed in detail elsewhere.78 injudicious and dangerous manage- fering with the laboratory analysis.2 Table II presents a concept out- ment of patients. All laboratories publish the line of the major sources of poten- ranges of normal values for the tially misleading laboratory test re- Cet article passe en revue les fac- results of the tests they perform. sults. In the following discussion, teurs generaux et specifiques qui Limits of normal are set to include however, it will be easier for you to genent la realisation de tests de labo- the central 95% of the population, review each laboratory test com- ratoire biochimiques courants ainsi excluding the 2.5% in each tail of pletely while referring to the general que l'interpretation de leurs resul- the normal curve. In other words, by principles set out in the table. The tats. L'etat clinique du malade, les definition the probability of an ab- three categories of headings in the interactions medicamenteuses et les normal result of any given test in a following discussion represent the interactions ou changements biochi- normal individual is 0.05; the proba- main area of testing, the specific miques in vivo et in vitro peuvent fausser les resultats des analyses biochimiques des constituants san- Table I-Predicted probability that the results of at least one test will exceed guins. Le fait de ne savoir identifier laboratory limits des resultats non valables de tests de Probability* laboratoire peut conduire a un traite- ment inapproprie et dangereux pour That results of all That results of one le malade. tests will be or more tests within limits* will exceed limits Laboratory results that do not corre- No. of tests (p) (1 - p) late with the patient's clinical status 1 0.95 0.05 or with the disease process may lead 6 0.74 0.26 to an incorrect diagnosis and injudi- 8 0.66 0.34 cious management. In this paper I 12 0.54 0.46 14 0.49 0.51 From the division of clinical chemistry, Van- 17 0.42 0.58 couver General Hospital and the department 20 0.36 0.64 of pathology, University of British Columbia, 100 0.006 0.99 Vancouver = = = Reprint requests to: Dr. Amin A. Nanji, *p sw, where p the statistical probability, s the probability (usually 95%) Director of clinical biochemistry, Ottawa that a normal person will have values within the normal range for each test, and General Hospital, 501 Smyth Rd., Ottawa, n = the number of tests performed. Ont. KIG 8L5 CAN MED ASSOC J, VOL. 130, JUNE 1, 1984 1435 component being tested and the type instrument and hyperproteinemia. monoclonal protein in the plasma of error or the condition leading to In a study of 11 patients with vari- causing a decrease of 0.7 mmol/L in error. ous degrees of hyperviscosity Blank the sodium level.'8 and Ill found that the measurements Presence of cationic paraproteins obtained with direct potentiometry in the blood: Bloth and coworkers" were accurate, whereas those ob- described three asymptomatic pa- sodium tained with flame photometry and tients with whose indirect potentiometry were artifi- serum sodium levels were reported Sampling: One of the commonest cially low. No correction factor can to be around 110 mmol/L. Cationic causes of a falsely low value for the be applied to measurements ob- paraproteins may displace other cat- concentration of sodium in the tained with flame photometry; how- ions, especially sodium. serum occurs when the venous sam- ever, for the results determined by Presence of osmotically active ple is taken downstream from an indirect potentiometry each centi- particles in the blood: is ah intravenous infusion of hypotonic stoke increase in the serum viscosity osmotically active substance that fluid, such as 5% dextrose in water. accounted for a 2-mmol/L decrease can cause water to move from the I attempted to determine the cause in the serum sodium level. Serum intracellular to the extracellular of in 87 patients with viscosity. is temperature-dependent.'6 fluid space and thus dilute the sodi- reported serum sodium levels of less Blank and I'` found that the differ- um ions in the extracellular fluid. In than 125 mmol/L and found that in ences in the viscosity of hyperviscous patients with diabetic ketoacidosis 10 patients the blood sample had serum at 20°C and 37°C caused or with hyperglycemic, hyperosmo- been diluted by the intravenous flu- differences in the measured sodium lar, nonketotic diabetic coma the id. This type of error can usually be levels. high concentration of plasma glu- identified by the high glucose level : The cose causes a dilution of sodium ions in the sample. reduced water content in the plasma in the plasma. In this case the low Hyperlipemia: With some analy- of patients with monoclonal gam- values for the serum sodium level tic techniques the reported sodium mopathy without hyperviscosity can result from renal loss of sodium and levels in serum samples from pa- result in falsely low reported serum the shift of water into the extracel- tients with hyperlipemia may be sodium levels, each gram per litre of lular fluid space. Katz20 suggested, falsely low because of the decrease in the proportion of water in the Table II-Major sources of misleading results of biochemical laboratory tests plasma secondary to the large amount of lipid present.9'0 Ladenson Use of a specimen that is not representative as a result of one of the following: and colleagues" showed that errors Biochemical change or interaction in the measurement of serum sodi- In vitro um concentrations in hyperlipemic Hemolysis/lysis of cells, with leakage of cellular constituents (e.g., lactate patients were related to the method dehydrogenase or potassium) Storage, leading to alkalinization of serum, with subsequent increase in of measurement. If the serum sam- activity ple is diluted, as it is when analysed Evaporation-induced errors (e.g., concentration of electrolytes) by indirect potentiometry, the re- Artefactual in the presence of large numbers of cells (i.e., sulting values will be falsely low; erythrocytes, leukocytes or platelets) however, with direct potentiometry In vivo the results will be valid because the Interference by endogenous metabolites or drugs (e.g., cephalosporins or concentration of sodium ions is acetoacetate, which falsely elevate the serum level) being measured in the aqueous Cell rupture, with release of cellular constituents (e.g., platelet acid phospha- phase. Frier and associates'2 des- tase, which spuriously increases the prostatic acid phosphatase level) cribed a patient with hyperlipemia, Sampling error Contamination of specimen (e.g., by residual detergent, which spuriously hemiplegia and convulsions who was increases the phosphate level) treated with normal saline because Venous stasis, which leads to increases in the lactate, potassium and the serum sodium level was reported levels to be 116 mmol/L. When the level Upright posture, which leads to hemoconcentration and an increase in the total was corrected for the hyperlipemia, serum protein level however, it became 222 mmol/L. As Blood drawn downstream from an intravenous line, which leads to spurious a rule, every increase of 11.3 hyponatremia and mmol/L in the serum The patient's not being in the basal state level results in an apparent decrease After exercise, which increases the serum level of 1.5 mmol/L in the serum sodium During diet, which increases the serum triglyceride levels After ethanol consumption, which increases the y-glutamyl transpeptidase level level.'" Laboratory error in one of the following areas: Hyperviscosity: Serum samples Analysis from patients with hyperviscosity Interference by , turbidity or chemicals yield falsely low values for the sodi- Poor quality control um level when analysed by flame Reporting of results with identification error photometry'4 because of problems in Normal variation sample aspiration, dilution by the 1436 CAN MED ASSOC J, VOL. 130, JUNE 1, 1984 and I have verified clinically,2' that as a cause of reported decrease by an average of 4 for every 5.6-mmol/L increase in the in patients with myeloproliferative mmol/L. A serum sample with a plasma glucose level there is a disorders, lest treatment of the ap- higher Pco2 will have a proportion- 1.6-mmol/L decrease in the sodium parent hyperkalemia lead to serious ately greater loss in total CO2 con- level. Similarly, the administration hypokalemia.36 tent if it is exposed to air.45"' Such of mannitol may cause dilution of Familial pseudohyperkalemia: exposure causes a loss of water as the sodium ions because of the This extremely rare cause of appar- well as of CO2, which leads to movement of water into the extra- ent hyperkalemia is characterized overestimates of the serum sodium, cellular space.22 by a normal in-vivo potassium level potassium and chloride levels and in the blood but in-vitro leakage of underestimates of the total CO2 con- Serum potassium potassium from the blood cells due tent.47 Thus, the clinically useful to an autosomal dominant trait.3` calculation of the ([Na+] Falsely low values for the serum + [K+] - [Cl-] - [HCO3-])48may concentration of potassium are rare, Serum chloride yield an overestimate.49 The size of occurring only when the blood sam- error induced by exposure of the ple is grossly lipemic. Falsely elevat- A falsely elevated value for the sample to air may be enough to ed values are more common. serum chloride concentration is a suggest a diagnosis of significant Release ofpotassium from plate- useful indication of the presence of metabolic acidosis. Air bubbles in lets and blood cells: Probably the other halide ions, such as bro- samples to be used for blood gas most common cause of falsely ele- mide.3839 While there are a number analysis can cause a substantial er- vated values for the serum potassi- of methods for measuring the con- ror:50'51 an air bubble occupying 10% um level is the release of potassium centration of chloride ions, bromide of the blood space causes an in- from the platelets during clotting, interferes with chloride determina- crease in the partial pressure of the potassium level in the serum tions done with colorimetric and oxygen (Po2) of approximately 11 being an average of 0.4 mmol/L ion-selective electrode techniques,' mm Hg. greater than that in the plasma.23 more so with the latter. Since mini- Consumption of oxygen by blood Technical error: In-vitro hemoly- mal interference occurs with chlori- cells: In patients with extreme leu- sis - caused by, say, the expression dimetry, this procedure is useful in kocytosis and thrombocytosis the of blood from a syringe through the identifying possible interference by leukocytes and platelets may con- needle or prolonged contact of plas- halides if significantly increased sume enough oxygen to lead to an ma with cells - may also result in serum chloride levels are found with incorrect diagnosis of hypoxemia.52 falsely elevated values for the serum colorimetric and ion-selective tech- Therefore, samples for blood gas potassium level.24 Prolonged contact niques. analysis should be put on ice imme- of serum with the wooden applicator diately after they are drawn and sticks that are used to remove fibrin Acid-base balance and blood gases should be stored at 2°C until the from blood samples may cause an analysis is done.53 increase in the potassium level of up In most clinical laboratories the Presence of heparin in the blood: to 0.5 mmol/L.25 In addition, exer- pH and the partial pressure of car- Dilution of arterial blood with hepa- cising of the arm when the tourni- bon dioxide (Pco2) in the blood are rin can significantly decrease the quet is applied may increase the measured, while the serum bicar- Pco2, by up to 25%,14 and therefore level by up to 3 mmol/L.21 bonate (HCO3 ) level is calculated can lead to miscalculation of the Myeloproliferative disorders: from the Henderson-Hasselbalch serum level. Falsely high values for the serum equation, as follows: potassium level in patients with Serum calcium myeloproliferative disorders are well pH = pK' + log([HCO3j/aPCO2) recognized and are associated with Falsely elevated values for the thronibocytosis27'29 and leukocyto- While it is generally agreed that serum calcium concentration occur sis.3-3 Thrombocytosis causes a re- changes in pK occur with changes in in various situations, as follows. lease of potassium ions from the pH and temperature,4' the changes Venous stasis: During venous sta- platelets during coagulation.28 True are not enough to cause errors in sis the protein-bound, nondiffusible results can be determined by analy- most clinical work.42 However, the calcium becomes more concentrated, sing blood collected in ethylenedia- calculated concentration of bicar- which results in an increase in the minetetra-acetic acid (EDTA) or bonate may not be valid in acutely total serum calcium level of up to heparin. It has been postulated that ill patients with a rapidly changing 0.2 mmol/L.55 increased leukocyte fragility, which condition.43 Contamination of blood samples: may be related to antileukemic che- Exposure of sample to air: A Contamination of a sample that is motherapy,33`34 and liberation of po- partial explanation for the discrep- kept in a cork-stoppered tube can tassium from the leukocytes during ancies in the calculated serum bicar- lead to a false diagnosis of hypercal- coagulation account for the in- bonate level and the measured total cemia.` creased serum potassium level asso- CO2 content is faulty handling of Multiple myeloma: Hypercal- ciated with leukocytosis.35 It is very the sample." If the sample is ex- cemia develops in 20% to 30% of important that in-vitro leakage of posed to air for approximately 1 patients with multiple myeloma.'7 potassium from the cells be excluded hour the total CO2 content will Rarely this is due to an abnormally CAN MED ASSOC J, VOL. 130, JUNE 1, 1984 1437 high degree of binding of calcium alosporins: The effects of cephalo- tions in enzyme activity are often ions to the paraprotein.5859 Falsely sporins are particularly interesting. subjected to numerous additional in- low values for the serum calcium On the one hand, these antibiotics vestigations because the clinician level in patients undergoing hemodi- react like creatinine in the Jaffe does not recognize that the cause of alysis were first reported by Coburn procedure for measuring the serum the elevation is a large protein- and collaborators,'" who observed creatinine level,75 cefoxitin causing enzyme complex that, because of its values up to 60% less than the true the most pronounced effect;76 on the size, is cleared slowly from the levels. This is probably because hep- other hand, some are nephrotoxic," blood. Such complexes have been arin activates lipoprotein , necessitating careful monitoring of described for creatine kinase (CK),88 which then hydrolyzes renal function. With the Jaffe meth- ,89 ,' to glycerol and free fatty acids, the od an infusion of 2 g of cefoxitin alkaline phosphatase,9' alanine dehy- latter binding with calcium to form causes an increase in the serum drogenase91 and aspartate amino- calcium soaps.6' creatinine level of about 180 transferase.93 Also, hemolysis invali- Exposure of sample to EDTA: ,umol/L.78 This false increase in the dates the results for serum enzymes The serum calcium level can also be creatinine level could easily be mis- such as lactate dehydrogenase.24 falsely low when the blood is collect- taken as a sign of renal insufficiency ed in tubes containing EDTA, which caused by cefoxitin. Therefore, Creatine kinase chelates calcium. blood samples for determining the creatinine level should not be drawn Creatine kinase has three isoen- Metabolic for at least 4 hours following infu- zymes: muscle form (MM), brain components of the serum sion of cephalosporins and for at form (BB) and hybrid form (MB). Creatinine least 8 hours in patients with com- The MB isoenzyme is fairly specific promised renal function. for myocardial tissue, and a high Analytic interference by a high serum concentration of MB indi- Ingestion of beef: It has been level of bilirubin: High levels of cates myocardial damage.94 The suggested that the serum creatinine serum bilirubin interfere with esti- serum level of CK-MB is commonly level may increase after meals.6263 mates of the serum creatinine level79 measured by a specific immunoin- Jacobsen and colleagues' found that by lowering the level, the degree hibition method.95 However, when in six healthy young adults who depending on the method of mea- CK-BB dimers are present, as they ingested 300 g of boiled beef the surement, thus masking increases in are in various conditions other than serum creatinine level increased the creatinine level or falsely sug- myocardial damage (such as malig- from about 90 to 160,umol/L; how- gesting an improvement in renal nant disease, dermatomyositis and ever, others have been unable to function.80 The clinical implications cerebrovascular accident), the lab- confirm this observation.65 of this interference have not been oratory results can be misleading.96 Analytic interference by acetoace- emphasized enough.8' Changes in Macro-CK, which is a complex tate: That acetoacetate interferes the serum creatinine level in the between immunoglobulin G and with the measurement of the serum presence of severe hyperbilirubin- CK-BB, can also be misinterpreted as creatinine level has been known for emia should thus be interpreted with CK-MB by some routine methods a long time66 but has only recently caution. that are used to identify CK-MB.97 been brought to the attention of With the use of the new, double- clinicians.6'68 In diabetic ketoacido- Glucose techniques, the interfer- sis the serum creatinine level thus ence by CK-BB will become less of appears to be elevated out of propor- Catabolism of glucose by blood a problem.88 tion to the urea nitrogen level. Acet- cells and bacteria in vitro will lead Over the past few years, tech- oacetate interferes more with the to abnormally low estimates of the niques for measuring the serum level end-point method of measuring the blood glucose level. This has been of CK-MB have been made more creatinine level than with the kinetic noted especially in patients with sensitive. It has been demonstrated (rate) methods.69 This interference chronic myelogenous leukemia (even that CK-MB is not entirely specific may result in miscalculation of the when fluoride has been added to for myocardial tissue and may be amylase:creatinine clearance ratio, prevent the breakdown of glu- elevated in many other conditions, which has been reported to be ele- cose),82'84 overwhelming sepsis85 or such as muscle trauma, polymyositis vated in diabetic ketoacidosis.'7' polycythemia," as well as in normal and muscular dystrophies.98 This error is especially evident when blood after prolonged storage.87 To- Low and normal serum levels of the end-point method of measuring doacetate seems to be more effective total CK have been reported in the creatinine level is used.72 Be- than fluoride in preventing the patients with connective tissue disor- cause of the large amount of keto- breakdown of glucose in vitro,23 but ders even in the presence of active acids spilling into the urine'3 the a combination of iodoacetate and myositis,99 and it is believed that reported level of creatinine in the fluoride is more effective than either steroids are responsible for lowering urine of patients with poorly con- agent alone. the CK activity. Thus, a normal CK trolled diabetes may also be falsely level should not dissuade one from high, resulting in overestimates of Serum enzymes considering myositis, especially the creatinine clearance.74 when the patient is receiving steroid Analytic interference by ceph- Patients with unexplained eleva- therapy. 1438 CAN MED ASSOC J, VOL. 130, JUNE 1, 1984 Amylase Although the belief that the 5. SACKETT DL: The usefulness of labora- serum acid phosphatase level rises tory tests in health-screening programs. Interpretation of serum amylase after prostatic massage has been Clin Chem 1973; 19: 366-372 levels may be in mac- disproved;'08 the myth had persisted 6. WERNER M, MARSH WL: Normal val- complicated ues: theoretical and practical aspects. roamylasemia, which is character- among 70% of physicians recently CRC Crit Rev Clin Lab Sci 1976; 6: ized by a macromolecular complex surveyed.'` 81-100 (in most cases an immunoglobulin- Serum acid phosphatase levels 7. STATLAND BE: Fundamental issues in enzyme conmbination) with amylase may fluctuate dramatically in pa- clinical chemistry. Am J Pathol 1979; activity that is too large to be ex- tients with prostatic cancer"0 and 95: 243-272 creted by the kidneys.'°° Thus, cer- thus may cause errors in interpreta- 8. HARRIS EK: Effects of intra- and in- tain abdominal conditions may be tion when they are measured serially terindividual variation on the appropri- misdiagnosed, and failure of the either to follow a patient's progress ate use of normal ranges. Clin Chem serum amylase level to return to or to determine a tumour's response 1974; 20: 1535-1542 normal may result in erroneous to therapy. 9. ALBRINK MJ, HALD PM, MAN EB, PETERS JP: The displacement of serum management. water by the lipids of hyperlipemic In contrast, for reasons unknown, Hormones serum. New method for rapid determi- normal serum amylase levels are nation of serum water. J Clin Invest sometimes seen in association with It is important to be aware of the 1955; 34: 1483-1488 hyperlipidemia secondary to pan- interference of with the 10. BELL JA, HILTON PJ, WALKER G: creatitis.'°' measurement of such hormones as Severe hyponatraemia in hyperlipaemic insulin,"' thyroxine,"2 triiodothyro- diabetic ketosis. Br Med J 1972; 4: Alkaline phosphatase nine,"' thyrotropin,"'4 gonado- 709-710 11. LADENSON JH, APPLE FS, KOCH DD: tropins,"5 growth hormone"6 and Misleading hyponatremia due to hyper- Refrigerated storage of serum for thyroglobulin."' A detailed discus- lipemia: a method-dependent error. Ann 12 to 24 hours causes a spurious sion of this problem has been pub- Intern Med 1981; 95: 707-708 increase in the serum alkaline phos- lished elsewhere."8 12. FRIER BM, STEER CR, BAIRD JD, phatase level.'02 Patients receiving BLOOMFIELD S: Misleading plasma elec- intravenous therapy with albumin Summary trolytes in diabetic children with severe may have elevated levels of serum hyperlipidaemia. Arch Dis Child 1980; alkaline phosphatase'03 because some In conclusion, with improved 55: 771-775 pharmaceutical companies it is 13. STEFFES MW, FREIER EF: A simple and market techniques becoming increasing- precise method of determining true so- albumin that has been extracted ly evident that invalid laboratory dium, potassium, and chloride concen- from human placentas, which have results may be generated for a vari- trations in hyperlipemia. J Lab Clin high alkaline phosphatase levels. ety of reasons (e.g., the basic condi- Med 1976; 88: 683-688 In some normal individuals whose tion of the patient, improper prepa- 14. TARAIL R, BUCHWALD KW, HOLLAND blood group is B or 0 the alkaline ration of the patient, and improper JF, SELAWRY OS: Misleading reduc- phosphatase level will increase after taking and handling of blood speci- tions in serum sodium and chloride associated with hyperproteinemia in pa- a fatty meal because of the release mens), many of which are drug- tients with multiple myeloma. Proc Soc of an intestinal isoenzyme.`'0 related. Physicians must be sensitive Exp Biol Med 1962; 110: 145-153 Less commonly, alkaline phos- to the causes of invalid biochemical 15. NANII AA, BLANK DW: Pseudohypona- phatase-immunoglobulin complexes values in order to avoid making tremia and hyperviscosity [C]. J Clin will cause a two- or threefold in- erroneous diagnoses and subjecting Pathol 1983; 36: 834-835 crease above the upper normal level the patient to unnecessary, indeed 16. STUART J, KENNY MW: Blood rheolo- of alkaline phosphatase activity.'05 A often dangerous, management. gy. J Clin Pathol 1980; 33: 417-429 familial condition, without underly- 17. NANJI AA, BLANK D: Effect of temper- ing disease, in which the alkaline ature and methodology on spurious hy- phosphatase activity is 10 times the References ponatremia due to serum hyperviscosity upper limit of normal has been de- [C]. Clin Chem 1983; 29: 595 scribed.`'0 1. 18. NANII AA, HALSTEAD AC: Changes in STATLAND BE, WINKEL P: Sources of serum anion gap and sodium level in Clinicians should remember that variation in laboratory measurements. monoclonal gammopathies. Can Med the normal range of alkaline phos- In HENRY JB (ed): Clinical Diagnosis Assoc J 1982; 127: 32-35 phate levels is and Management, Saunders, Philadel- higher in children. phia, 1979: 3-28 19. BLOTH B, CHRISTENSSON T, MELLSTEDT H: Extreme hyponatremia in patients Acid phosphatase 2. YOUNG DS, PESTANER LC, GIBBERMAN with myelomatosis: an effect of cationic V: Effects of drugs on clinical laborato- paraproteins. 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