Wrong biochemistry results
BMJ 2001; 323 doi: https://doi.org/10.1136/bmj.323.7315.705 (Published 29 September 2001) Cite this as: BMJ 2001;323:705All rapid responses
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Dear Sir,
Re: Wrong Biochemistry Results
We concur fully with the sentiments expressed by Ismail and Barth in
their editorial of 29th September 2001. Laboratories try to detect these
problems and provide an accurate, clinically relevant result. However,
the large numbers of assays has resulted in widespread reliance on
automation, particularly for hormones, and the one-size fit all approach
inherent in this makes the likelihood of inaccurate hormone results quite
high.
Clearly what is needed are fit-for-purpose assays on these automated
platforms. However we have experience of the difficulty of persuading a
company that the female testosterone values their machine produces are
analytically incorrect and may lead to inappropriate clinical action if
preceded by an Oestradiol assay (E2) (Table 1). That we elicited similar
findings from other centres through a computer mailbase and added this
weight of evidence to ours mattered not to them, nor worryingly to the
Medical Devices Agency.
Testosterone E2 + testosterone 1 3.9 [lead in sample, same sample as in 4] 2 2.6 6.8 3 2.7 6.0 4 3.9 7.0 5 3.6 5.7 6 1.7 4.0 7 1.9 3.8
Until companies recognise that in a Clinical Governance setting no
blame reporting is constructive criticism requiring positive action,
inappropriate interventions will continue to affect patients. More
critical oversight of analysis and its significant clinical implications
by the Medical Devices Agency is vital.
We all need confidence that if there is a problem it will be
addressed either co-operatively or by effective monitoring.
Yours faithfully,
Ian D. Watson
Consultant Biochemist
Mr. K. Lawton
Principal Biochemist
Competing interests: Testosterone E2 + testosterone1 3.9 [lead in sample, same sample as in 4]2 2.6 6.83 2.7 6.04 3.9 7.05 3.6 5.76 1.7 4.07 1.9 3.8
Sir
We agree with Drs Ismail and Barth, in their timely review, 1 that
interference in immunoassay may adversely affect patient care. We also
agree with the authors in their anticipation that analytical interference
will have an even greater impact in the future. Paradoxically, increased
degree of automation has led laboratory managers to believe that once
automated, assays no longer need supervision by professional competence in
immunoassay. Yet, a vital component of the immunochemical assay is one or
several antigen-antibody reactions, which may be influenced by a number of
factors including patient-specific interference!
We disagree, however, with their view that quality assurance schemes
can do little about this. During the past 5 years, the Swedish quality
assurance organisation EQUALIS (External quality as-surance in laborato-ry
medicine in Sweden) has distributed patient serum samples suspected of
containing interferents, such as heterophilic antibodies or antiligand
antibodies, as part of its Endocrinology survey. Participants are
presented with a brief history and are asked to provide results from
assays judged to be informative together with an evaluation of their data
in relation to the question at hand and suggestions for further work-up.
The data obtained can not only indicate whether generally available assay
methods are affected by patient-specific interferents and which diagnostic
companies are involved but also effectively alert participants to the
possibility that their results may be compromised by analytical
interference. Moreover, this scheme can provide a comprehensive laboratory
evaluation of problematical patient samples not necessarily affected by
interferents. Practical knowledge regarding the detection and elimination
of interferents is also highlighted at annual participants´ meetings,
which also give opportunities for discussing information from observations
made by doctors and individual laboratories. The main drawback is the
limited number of participating laboratories due to the limited amount of
serum that can be obtained from each patient.
The confusion created by false values may result in missed diagnosis,
unnecessary prolongation of the laboratory work-up or even incorrect
treatment.1 For instance, it was observed soon after the introduction of
an automated system for thyroid hormone measurements that total and free
triiodothyronine values were much too low in a number of patients.2 This
information, however, was withheld by the company and the evaluations of
the results were left to the doctors. Doctors, therefore, must be informed
of the risk of analytical interference in methods used for the laboratory
evaluation of their patients, e.g. through journals.3
Diagnostic kits vary in their sensitivity to analytical interference.
The Food and Drug Administration takes action against nonserious
diagnostic companies and prohibits sales of unreliable products in USA.4
In Europe, however, this problem has essentially been ignored. Hopefully,
however, future European Union directives on in-vitro diagnostic products
will improve the situation. The vigilance procedure5 implies that
information on incidents with consequences for a patient’s health should
be collected and evaluated centrally.
1. Ismail AAA, Barth JH. Wrong biochemistry results. Interference in
immunoassays is insidious and could adversely affect patient care. BMJ
2001;323:705-6.
2. Lindstedt G, Frändberg S. Unreliable immunoassays may threaten
patient safety and the quality of clinical research [Letter]. Lancet,
accepted for publication.
3. Aakvaag A, Leskinen E, Lindstedt G, Möller J, Nyberg A, Weber T.
Should evaluations of diagnostic reagent kits be published? Scand J Clin
Lab Invest 1986;46:495-6.
4. Center for Devices and Radiological Health (CDRH) Home Page. FDA
Home Page. Abbott Consent Decree Information.
http://www.fda.gov/cdrh/ocd/abbott.html
5. The European Parliament and The Council of the European Union.
Directive 98/79/EC of The European Parliament and of The Council of 27
October 1998 on in vitro diagnostic medical devices.
www.europa.eu.int/eur-lex/en/lif/dat/1998/en_398L0079.html
Göran Lindstedt
professor of clinical chemistry, head physician, Dpt of Clinical Chemistry
and Transfusion Medicine, Sahlgren Academy at Göteborg University
Rolf Ekman
professor of neurochemistry, Institute of Clinical Neuroscience, head
physician, Dpt of Clinical Chemistry and Transfusion Medicine, Sahlgren
Academy at Göteborg University
Anders Isaksson
associate professor, head physician, Dpt of Clinical Chemistry, Lund
University Hospital
Rosanne Forberg
top-grade biochemist, laboratory head, Clinical Chemistry Laboratory,
Västerås Hospital
Mats Stridsberg
associate professor, head physician, Dpt of Clinical Chemistry and
Pharmacology, Centre for Laboratory Medicine, University Hospital, Uppsala
Lena Hård
biomedical scientist, programme coordinator, EQUALIS AB, Uppsala
Gunnar Nordin
MD, managing director, EQUALIS AB, Uppsala
Ernst Nyström
professor, head physician, Section of Endocrinology, Dpt of Medicine,
Sahlgren Academy at Göteborg University
Competing interests: No competing interests
The enzyme CK is made of 2 sub-units which normally unite to form
either CK-MM (CK3, mainly found in the Muscles), or CK-MB (CK2, mainly
found in the Heart), or CK-BB (CK1, mainly found in the Brain).
Among the various analytical methods that can be used o measure CK-
MB, some methods consist of:
- using an anti-M sub-unit antibody in order to specifically inhibit M sub
-units enzymatic activity,
- then measuring the remaining CK enzymatic activity. Assuming that CK-BB
is normally absent from the serum, this measurement is supposed be that of
CK-MB.
It is therefore clear that if CK-BB, or macro-CKs (i.e. CK associated
with immunoglobuline, macro-CK1, or mitochondrial/autoaggregated CK, macro
-CK2), are present in a patient’ serum, this analytical method can be
responsible of falsely elevated levels of measured CK-MB. In some cases,
this measured “CK-MB” can even be higher than total CK activity.
The solutions in this case can be the following:
- to measure myoglobin and troponin levels,
- and/or to use another analytical method to measure CK-MB.
In some cases, it can also be useful to measure CK-BB, or even macro-
CKs, because CK-BB as well as macro-CKs have their own diagnoctic
utilities. In particular, CK-BB and macro-CK2 are tumour markers.
Competing interests: No competing interests
our lab experiences the strange phenomenon of obtaining elevated CKMB
values whilst the CPK is normal. this are on specimens from the casualty
deprtment and have been confirmed by second laboratories as well on
successive repetions.Do any of you experinced similar situations? Have you
reached a conclusion?
Thank you
Areti Zarvou
Competing interests: No competing interests
Ismail and Barth remind us of the possibility of interferences in
biochemistry results that can affect patients outcomes, and they propose
solutions to fight against the problem [1].
First, we would like to insist on the fact that such pre-analytical
and analytical problems are not at all limited to biochemistry results,
but can affect all sorts of laboratory results, leading for example to
erroneous blood cell counts [2-6], erroneous bacterial or viral
identifications, or antibiograms [7-11], erroneous toxicology results [12-
15], etc.
Among the best ways to fight against these problems, Ismail and Barth
are certainly right to mention the need for the clinicians to alert (the
laboratory doctors) to the mismatch of clinical and biochemical data. We
would like to insist on the fact they (clinicians and laboratory doctors)
should also systematically report all these cases in the biomedical
literature. This would be most useful for all their colleagues.
References:
1) Ismail AAA, Barth JH. Wrong biochemistry results. BMJ 2001;323:705
-6 [http://www.bmj.com/cgi/content/full/323/7315/705].
2) Lesesve JF, Goupil JJ, Latger V, Buisine J, Lecompte T.
Artefactual elevation of the automated white cell count in the context of
a bone marrow aspirate analysis. Clin Lab Haematol 2000;22:56-7 (Comment
on: Clin Lab Haematol. 1999;21:65-8).
3) Thomson S, Sheridan B. Erroneous automated eosinophil counts in
HIV-infected individuals. Br J Biomed Sci 1995;52:165-6.
4) Van Acker J, Wilmes P, Philippe J. Erroneous monocyte and
neutrophil counts with the Sysmex NE-1500 in patients recovering from bone
marrow aplasia. Clin Chem Lab Med 1998;36:107-9.
5) Villamor N, Kirsch A, Huhn D, Vives-Corrons JL, Serke S.
Interference of blood leucocytes in the measurements of immature red cells
(reticulocytes) by two different (semi-) automated flow-cytometry
technologies. Clin Lab Haematol 1996;18:89-94 (Comment in: Clin Lab
Haematol 1997;19:83).
6) Whiteway AJ, Bain BJ. Artefactual elevation of an automated white
cell count following femoral vein puncture. Clin Lab Haematol 1999;21:65-8
(Comment in: Clin Lab Haematol 2000;22:56-7).
7) Kochman M, Lawrynowicz M, Fordymacki P, Kaluzewski S. [Evaluation
of external laboratory test results for the correct identification and
determination of chemotherapeutic sensitivity of staphylococci in
bacteriologic provincial laboratories of sanitary-epidemiologic stations
in 1995]. Med Dosw Mikrobiol 1996;48:131-40 [Article in Polish].
8) Springer B, Stockman L, Teschner K, Roberts GD, Bottger EC. Two-
laboratory collaborative study on identification of mycobacteria:
molecular versus phenotypic methods. J Clin Microbiol 1996;34:296-303.
9) Vedel G, Peyret M, Gayral JP, Millot P. Evaluation of an expert
system linked to a rapid antibiotic susceptibility testing system for the
detection of beta-lactam resistance phenotypes. Res Microbiol 1996;147:297
-309.
10) Watine J, Martorell J, Bruna T, Gineston JL, Poirier JL, Lamblin
G. In vivo pefloxacin-resistant Campylobacter fetus responsible for gastro
-intestinal infection and bacteremia associated with arthritis of the hip.
Yonsei Med J 1995;36:202-5.
11) Zaaijer HL, Cuypers HT, Reesink HW, Winkel IN, Gerken G, Lelie
PN. Reliability of polymerase chain reaction for detection of hepatitis C
virus. Lancet 1993;341:722-4.
12) Ali AA, Ali GS, Steinke JM, Shepherd AP. Co-oximetry interference
by hemoglobin-based blood substitutes. Anesth Analg 2001;92:863-9.
13) Morris RG, Frewin DB, Saccoia NC, Goldsworthy WL, Jeffries WS,
McPhee AJ. Interference from digoxin-like immunoreactive substances(s) in
commercial digoxin kit assay methods. Eur J Clin Pharmacol 1990;39:359-63.
14) Steimer W, Müller C, Eber B, Emmanuilidis K. Intoxication due to
negative canrenone interference in digoxin drug monitoring. Lancet
1999;354:1176-7.
15) Watine J. Carbon Monoxide Poisoning: How About More Precise
Analytic and Preanalytic Techniques ? Ann Emerg Med 2000;35:629-30.
Competing interests: No competing interests
Clinicians need to be aware of pitfalls
Editor, interference with immunoassay, as Ismail and Barth highlight,
are uncommon, but may have serious implications (1. We would like to share
the details of two patients with suspected thyroid disease who, as a
consequence of such interference, were investigated and treated
unnecessarily.
Patient (1)
In December 1994, a 33-year-old man with a personality disorder was
admitted to the mental health unit. He was anxious, thin, had tremor and
sinus tachycardia. He had no goitre or eye signs of hyperthyroidism. He
had not been on any medication. Free thyroxine (f+ree T4) 41 pmol/l
(reference range 10-25), thyroid stimulating hormone (TSH) 6.99 mU/l (0.15
-3.5) and total triiodothyronine (TT3) was 3.3 nmol/l (1.2-2.7). These
results were produced using the Amerlite chemiluminescent immunometric
assays (Kodak Clinical Diagnostics, Amersham, UK). They were confirmed on
repeat analysis. The initial working diagnosis was a TSH- producing
pituitary tumour. However an isotope thyroid scan and a computerised
tomography scan of the pituitary were normal. A thyrotrophin releasing
hormone (TRH) test produced two-fold increase of basal TSH level. A repeat
of his thyroid test at another laboratory produced a TSH of 3.2 (0.1-
5.0), free T4 21.5 nmol/l (10-30) and a free T3 of 8.1 pmol/l (3.5-7.5).
He was treated for his mental illness and discharged home a fortnight
later. He was seen in the clinic in May 1995, with no change in his
clinical features. Thyroid tests were repeated using a heterophilic
antibody-blocking agent (Bionotics Ltd, Milton Keynes, UK). This
produced normal results with free T4 18 pmol/l, TSH 2.55 mU/l and TT3 2.6
nmol/l.
Patient (2)
In August of 1998 a 45-year-old lady reported some symptoms of possible
thyroid over-activity (mainly heat intolerance) while attending the
Diabetic Clinic. There were no clinical signs of thyroid dysfunction.
Serum TSH was reported as 11.2 mU/l (0.5-5.0). A repeat test a few weeks
later showed TSH 8.29 mU/l, free T4 13 pmol/l (8-30). A diagnosis of
compensated thyroid failure [subclinical hypothyroidism] was made and she
was started on treatment with thyroxine. Thyroid antibodies were
negative. The dose of thyroxine was gradually increased over subsequent
months as repeated measurements of TSH showed levels greater than 20 mU/l;
the patient, however, assured us that she was taking her tablets as
prescribed. By July 2001 TSH was 19.3 mU/l with a free T4 level of 39
pmol/l and total T3 3.5 nmol/l (1.5-2.6); by this stage the patient was on
200mcg thyroxine daily and was symptomatic of hyperthyroidism, with
anxiety, tearfulness, marked heat intolerance, sweaty palms and tremor.
The patient was advised to stop thyroxine forthwith.
All the in-house tests have been carried out using the Vitrous Eci
immunodiagnostic system (Ortho Clinical Diagnostics, Rochester NY). Re-
evaluation of thyroid hormone levels in another laboratory showed a TSH
level of 0.02 mU/l (0.1-5.0) with free T4 of 43 pmol/l (10-30) and free
T3 of 8.6 pmol/l (3.5-7.3), in keeping with hyperthyroidism.
As the authors correctly point out, clinicians treating such patients
need to be aware of the pitfalls. Equally as important these clinicians
need to communicate any discrepancy between the clinical picture and the
result of investigation to laboratory clinicians to ensure that such
discrepancies are further investigated. Ideally this interaction should be
prior to subjecting the patients to further unnecessary investigations.
The most practical way to investigate a possible interference is to
measure the hormone using a different method. This however, does indicate
which is the correct result, but reviewing results in conjunction with the
clinical picture should make it easier to clarify the picture.
Interference in thyroid two site immunometric assays could result in
plausible results that would only called into question if the remainder of
thyroid tests do not conform to a pattern. There have been, however,
reports of grossly abnormal TSH results using IRMAs (2,3)
References:
1. Ismail AAA, Barth JH. Wrong biochemistry results. BMJ 2001;323:705-706
2. Cusick CF, Mistry K, Addisson GM. Interference in a two-site
immunoradiometric assay for thyrotropin in a child. Clin Chem 1985;31:348-
349
3. Marstein S. Caution against spuriously increased thyrotropin values as
determined by two-site immunoradiometric assays. Clin Chem 1987;33: 1290-
1291
A Waise, R A Fisken.
Endocrine Clinic, Friarge Hospital,
Northallerton, North Yorkshire DL6 1JG. UK
Funding: none. Competing interests: none
Editorial note
Both patients have given their signed informed consent to publication of their cases.
Competing interests: No competing interests