Paraproteins Are a Common Cause of Interferences With
Automated Chemistry Methods
Yusong Yang, MD, PhD; Peter J. Howanitz, MD; Joan H. Howanitz, MD; Helen Gorfajn, MS; Keung Wong, MS
● Context.—Previous studies have shown that paraproteins
caused spurious results on individual analytes including to-
tal bilirubin (TBIL), direct bilirubin (DBIL), or HDL-choles-
terol (HDL-C). Studies demonstrating paraprotein interfer-
ences with multiple analytes measured by different analyz-
ers have not been reported.
Objective.—To systemically investigate interferences of
paraproteins on TBIL, DBIL, and HDL-C measured by the
Roche MODULAR and the Olympus AU2700.
Design.—Eighty-eight serum specimens with monoclo-
nal gammopathies were analyzed using the Roche MOD-
ULAR and the Olympus AU2700. Paraprotein interferences
with the MODULAR and AU2700 were identified by ab-
normal absorbance curves and confirmed by results from
the Ortho Vitros 950 or inconsistent laboratory informa-
tion.
Results.—Spurious results occurred in 89 of 528 mea-
surements; 29 specimens did not demonstrate any inter-
ferences whereas 26 specimens gave spurious results in 2
M onoclonal immunoglobulins, also known as parapro-
teins, have been reported to interfere with a num-
ber of routine chemistry methods including analyses for
creatinine,1,2 C-reactive protein,3 glucose,4 iron,5,6 inorganic
phosphate,7–9 and uric acid.10 Recent studies have shown
that paraproteins caused false-positive results for total bil-
irubin (TBIL)11–13 and direct bilirubin (DBIL)14 and false-
negative results for HDL-cholesterol (HDL-C).12,15–19 The
frequency of paraprotein interferences with these analytes
on automated chemistry analyzers was reported to be very
rare,12–14 and comparative studies of paraprotein interfer-
ences with TBIL, DBIL, and HDL-C have not been report-
ed with major automated chemistry analyzers. These in-
terferences may cause incorrect diagnoses, inappropriate
treatments, longer hospital stays, and increased morbidity
in patients who already may be gravely ill. We systemi-
cally investigated the potential interference of parapro-
teins on measurements of TBIL, DBIL, and HDL-C using
Accepted for publication October 12, 2007.
From the Department of Pathology, State University of New York
Downstate Medical Center, Brooklyn, NY (Drs Yang, P. J. Howanitz,
and J. H. Howanitz, and Ms Gorfajn); and Institute of Pathology, Clin-
ical Chemistry Laboratory, Kings County Hospital Center, Brooklyn, NY
(Mr Wong).
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Yusong Yang, MD, PhD, Department of Pathology, Box 24,
State University of New York Downstate Medical Center, 450 Clarkson
Ave, Brooklyn, NY 11203 (e-mail: yusong.yang@downstate.edu).
Arch Pathol Lab Med—Vol 132, February 2008
to 4 of the 6 assays. Paraprotein interferences caused spu-
riously high levels of TBIL in 4 sera measured by the MOD-
ULAR. In contrast, paraprotein interferences on DBIL were
observed by at least 1 method in 44% (39/88) of sera as-
sayed, occurring almost exclusively with the AU2700. Para-
protein interferences with HDL-C results were present in
35% of specimens assayed with the MODULAR and 16%
of specimens assayed with the AU2700. In specimens with
interferences, spuriously low AU2700 DBIL, MODULAR
HDL-C, and AU2700 HDL-C results occurred with 28%,
90%, and 91% of specimens, respectively.
Conclusions.—We demonstrated that paraprotein inter-
ferences with TBIL, DBIL, and HDL-C are relatively com-
mon and provided explanations why these interferences
occurred. Although it is difficult to predict which speci-
mens cause interferences, spurious results appeared meth-
od and concentration dependent.
(Arch Pathol Lab Med. 2008;132:217–223)
88 serum specimens collected from patients with mono-
clonal gammopathies and measured using 2 commonly
used automated chemistry analyzers.
MATERIALS AND METHODS
This study was conducted as part of a laboratory performance
improvement program for patient result reporting. Serum spec-
imens were collected from patients with monoclonal gammopa-
thies determined by serum protein electrophoretic and immu-
nofixation studies during a 1-year period. The sera were free of
hemolysis, icterus, and lipemia by routine index checks on au-
tomated analyzers. None of the specimens were duplicates or
triplicates; if they were from the same patients, they were ob-
tained at different times.
Serum protein electrophoretic and immunofixation studies
were performed using the SPIFE 3000 (Helena Laboratories,
Beaumont, Tex), and serum total protein concentrations were de-
termined with the Roche P800 MODULAR (Roche Diagnostics,
Indianapolis, Ind). Paraprotein concentrations were quantitated
by the Quickscan 2000 (Helena Laboratories).
Serum levels of TBIL, DBIL, and HDL-C were measured in-
dependently using the Roche P800 MODULAR, Olympus
AU2700 (Olympus Diagnostics, Melville, NY), and Vitros 950 (Or-
tho-Clinical Diagnostics, Rochester, NY) automated chemistry an-
alyzers.
Paraprotein interferences with the Roche MODULAR and
Olympus AU2700 were identified by an abnormal reaction ab-
sorbance curve obtained directly from the reaction monitor in-
tegrated into the automated analyzers and confirmed by at least
1 additional finding. Absorbance curve data from the Olympus
AU2700 printouts were plotted manually, whereas similar data
Paraprotein Interferences With Automated Methods—Yang et al 217
Figure 1. Scatter plot of total bilirubin (TBIL)
concentrations measured by 2 automated
chemistry analyzers. 䢇, Specimens without
interferences by paraproteins; 䉭, specimens
displaying interferences by paraproteins mea-
sured by the Roche MODULAR. * To convert
to SI units in micromoles per liter, multiply
values in milligrams per deciliter by 17.104.
from the Roche MODULAR were used directly. Because it had
been shown that the Vitros 950 did not provide spurious results
for DBIL and TBIL, it was used for confirmation of interferenc-
es.12,14,16 The Ektachem slide method used in the Vitros 950 was
interference free because the specimens had to penetrate through
several layers before reaching the reaction layer, and the interfer-
ing compounds were probably filtered out.20 Therefore, when po-
tential interferences were identified and an adequate specimen
remained, confirmation of the spurious results was made by ad-
ditional measurements using the Vitros 950, except for HDL-C,
as our instrument did not have this method included in its test
menu. Paraprotein interferences also were confirmed by speci-
mens with negative DBIL or negative HDL-C results, specimens
with abnormally high TBIL levels from nonicteric patients with-
out evidence of liver diseases and hemolysis, or specimens with
DBIL levels higher than TBIL levels.
The Roche MODULAR TBIL assay is a chromogenic 2-point
end point assay modified from the diazo method21 that is per-
formed in 1 cuvette. First the patient’s serum is incubated with
reagent 1 (R1), which contains surfactant to accelerate the reac-
tion and to solubilize protein. Then, reagent 2 (R2) containing a
diazonium salt and HCl is added to produce azobilirubin, which
is red under acidic conditions. Before R1 is added, the serum
specimen should not be turbid. In contrast, the Olympus AU2700
TBIL assay is a 2-cuvette, 1-point end point assay that uses sim-
ilar reagents. Both the reaction cuvette and the blank cuvette
contain surfactant, whereas the chromogen is not added to the
blank cuvette.
The Roche MODULAR and Olympus AU2700 DBIL assays re-
semble their manufacturers’ TBIL assays, other than that a solu-
bilizing agent such as surfactant is not added. When paraprotein
interferences with DBIL initially were suspected in the specimens
with either negative DBIL values or DBIL concentrations higher
than TBIL concentrations, they subsequently were confirmed by
abnormal reaction absorbance curves.
The Roche HDL-C Plus second-generation assay and the Olym-
pus HDL-C assay are 2-reagent homogenous systems for the se-
lective measurement of serum HDL-C in the presence of other
lipoprotein particles. Reagent 1 (R1) selectively forms colorless
water-soluble complexes with non-HDL lipoprotein, which is pro-
tected from subsequent enzymatic reactions. The HDL-C is then
determined enzymatically by the addition of R2 containing cho-
lesterol esterase, cholesterol oxidase, and a chromogen system
into the reaction mixture. The HDL-C concentration is deter-
218 Arch Pathol Lab Med—Vol 132, February 2008
mined by the absorbance after the addition of R2 subtracted from
the baseline absorbance in the presence of R1.
RESULTS
The present study included 88 serum specimens from
52 patients with monoclonal gammopathies treated at a
major municipal hospital or a university hospital. The
paraprotein concentrations of these specimens ranged
from 0.5 to 8.9 g/dL with a mean of 3.67 g/dL. The ma-
jority (60%) of the paraproteins were immunoglobulin (Ig)
G ␬, 18% were IgG ␭, 11% were IgA ␭, and 7% were IgM
␬. Specimens with paraprotein concentrations less than 3.0
g/dL had spurious results in 7.2% of assays; when para-
protein concentrations were 3.0 to 5.0 g/dL, spurious re-
sults were seen in 22.4% of assays, and when paraprotein
concentrations were greater than 5.0 g/dL, spurious re-
sults were seen in 31.3% of assays.
Spurious results occurred in 89 of 528 measurements;
29 specimens did not demonstrate any interferences,
whereas 26 specimens gave spurious results in 2 to 4 of
the 6 assays. Of 88 serum specimens, 4 specimens (4.3%)
from 3 patients with monoclonal gammopathies displayed
spuriously high Roche MODULAR TBIL concentrations.
The interferences in 3 specimens initially were suggested
by nonicteric sera with abnormally high TBIL values of
greater than 25 mg/dL (428 ␮mol/L), (Figure 1) and sub-
sequently were identified and confirmed along with a
fourth specimen by abnormal reaction absorbance curves
(Figure 2, C and D) compared with those obtained from
normal control serum (Figure 2, A), measurements by the
Vitros 950, and icteric serum without measurable para-
proteins (Figure 2, B). In our study, the interferences were
found exclusively in specimens from patients with IgG ␬
or IgG ␭ monoclonal gammopathies, and in these 4 spec-
imens, the paraprotein concentrations (mean, 5.45 g/dL)
were higher than the overall mean of the 88 monoclonal
proteins studied.
When we manually performed the Roche MODULAR
TBIL assay in test tubes according to manufacturer’s sug-
gested protocol using a specimen with the suspected in-
Paraprotein Interferences With Automated Methods—Yang et al

terference, the specimen was slightly turbid visually be-
fore adding R1 but became clear after the addition of R1.
However, the addition of R2 caused the reaction mixture
to become clear instead of the red translucent appearance
observed with the control patient’s specimens. When the
TBIL concentrations of these sera were measured indepen-
dently by the Olympus AU2700 and Vitros 950 automated
chemistry analyzers, no interferences were identified with
these 2 instruments.
Using the criteria we established for interference, 39
(44%) of 88 specimens were found to display interferences
with DBIL on the Olympus AU2700 (Figure 3). However,
only 1 specimen was found to have interferences with
Arch Pathol Lab Med—Vol 132, February 2008
Figure 2. Reaction absorbance curves of the
Roche MODULAR total bilirubin (TBIL) assay
monitored. A, Normal control serum. B, An
icteric patient serum without paraprotein. C
and D, Nonicteric, nonhemolytic serum spec-
imens containing paraproteins. The gray ver-
tical bars indicate the points at which mea-
surements are taken to calculate results. IgG
indicates immunoglobulin G.
DBIL when measured by the Roche MODULAR, and this
result was confirmed as spurious by the Vitros 950.
We found that these interferences occurred when the
reaction absorbance curve of the blank cuvette (DBIL-B)
did not parallel the absorbance curve of the reaction cu-
vette (DBIL-C) (Figure 4). The Olympus instrument was
programmed to subtract the absorbance of the blank cu-
vette from the absorbance of the reaction cuvette at the
end point, then tally the difference and convert this dif-
ference into a numerical result. If the absorbance of the
blank cuvette was lower than the end point absorbance of
the reaction cuvette, the instrument reported a positive
value (Figure 4, A); in contrast, if the absorbance of the
Paraprotein Interferences With Automated Methods—Yang et al 219
Figure 3. Scatter plot of direct bilirubin
(DBIL) measurements made by 2 automated
chemistry analyzers. 䢇, Specimens without
evidence of paraprotein interferences; 䉭,
specimens displaying interferences by para-
proteins measured by the Olympus AU2700;
䡵, specimens displaying interferences by
paraproteins measured by the Olympus
AU2700 and the Roche MODULAR. * For SI
units in micromoles per liter, multiply results
in milligrams per deciliter by 17.104.

blank cuvette was higher than the end point absorbance

of the reaction cuvette, the instrument reported a negative
value (Figure 4, B).
Among the 39 specimens with Olympus AU2700 DBIL
interferences, 14 specimens had spuriously high values
and 25 specimens had spuriously low values. However, the
specimens displaying interferences with the Olympus
AU2700 DBIL method tended to give irreproducible DBIL
values, as demonstrated by a specimen that varied from
falsely positive (13.0 mg/dL [222 ␮mol/L]) to falsely neg-
ative (⫺17.3 mg/dL [296 ␮mol/L]) values when measured
repeatedly (data not shown).
Figure 5 depicts 31 (35%) of 88 specimens that demon-
strated HDL-C interferences with the Roche MODULAR,
and of these, 90% were spuriously low. In contrast, 14
(16%) of 88 specimens demonstrated HDL-C interferences
when measured by the Olympus AU2700. Of these inter-
fering sera, 7 demonstrated interferences with both meth-
ods.
Examples of absorbance curves demonstrating interfer-
ences with HDL-C as identified by abnormal reaction ab-
sorbance curves compared with those from control spec-
imens and confirmed by negative HDL-C values are
shown in Figure 6. In Figure 6, B and C, the Roche MOD-
ULAR absorbance values of the blank obtained just before
the addition of R2 were higher than after the addition of
R2, thereby giving spurious results.
There was a much higher baseline absorbance before the
addition of R2 in the specimens displaying interferences
with the Olympus AU2700 HDL-C method compared

←
Figure 4. Absorbance curves from the Olympus AU2700 direct bili-
rubin (DBIL) assay. A and B, Abnormal reaction absorbance curves of
the Olympus AU2700 DBIL assay from 2 patient specimens containing
paraproteins. The DBIL assay is a 2-cuvette, end point assay utilizing
a sample blank; the sample blank cuvette (DBIL-B) absorbance is sub-
tracted from the color cuvette (DBIL-C) absorbance to determine the
net reaction absorbance. The arrows indicate reaction end point.

220 Arch Pathol Lab Med—Vol 132, February 2008 Paraprotein Interferences With Automated Methods—Yang et al

with that in the control specimens; after the addition of
R2, absorbance values did not increase as much as ex-
pected (Figure 6, D), thereby accounting for the spuriously
low values of HDL-C. Visually checking cuvettes contain-
ing specimens with the interference also demonstrated
white precipitates that were formed after the addition of
R1.
The paraprotein interferences appear to be concentra-
tion dependent, as dilution of patient sera and treatment
of the patient by therapeutic plasmapheresis or chemo-
therapeutic agents causing decreasing monoclonal pro-
teins minimized paraprotein interferences (data not
shown).
COMMENT
Our studies demonstrate that the interferences with
TBIL, DBIL, and HDL-C are relatively common in the
presence of paraproteins. Comparing results among dif-
ferent analyzers and monitoring absorbance curves led us
to conclude that paraprotein interferences are more prev-
alent than previously reported. Pantanowitz and cowork-
ers11 found that artifactual TBIL occurred in 2 (1.2%) of
115 patient sera, whereas Nauti et al14 reported that para-
protein interferences with the Olympus AU2700 DBIL
were observed in only 3 (1.5%) of 200 serum specimens.
Spuriously low levels of HDL-C on the Roche 917 analyzer
caused by paraprotein were found in 2 (13%) of 15 spec-
imens at a major medical center.12 To our knowledge, para-
protein interferences with HDL-C measured by the Olym-
pus automated chemistry analyzers have not been report-
ed. Our study revealed that the incidence of paraprotein
interference with the Olympus AU2700 and Roche MOD-
ULAR DBIL assays was 16% and 35%, respectively, in 88
serum specimens. We also found that paraproteins inter-
fere with Olympus AU2700 HDL-C, although the frequen-
cy (16%) was not as high as that on the Roche MODULAR
(35%). Specimens that gave spurious results in one assay
had a high likelihood of yielding a spurious result in other
assays.
Arch Pathol Lab Med—Vol 132, February 2008
Figure 5. Scatter plot of high-density lipo-
protein cholesterol (HDL-C) measurements
made by 2 automated chemistry analyzers.
䢇, Specimens without evidence of parapro-
tein interferences; 䉱, specimens displaying
interferences by paraproteins measured by
the Roche MODULAR; 䡵, specimens dis-
playing interferences by paraproteins mea-
sured by the Olympus AU2700; #, speci-
mens displaying interferences by paraproteins
measured by the Roche MODULAR and the
Olympus AU2700. * For SI units in millimoles
per liter, multiply results in milligrams per
deciliter by 0.0259.
A recent study showed that paraprotein caused only
spuriously high levels with Olympus AU2700 DBIL mea-
surements.14 However, in contrast, our study demonstrat-
ed that most DBIL interferences (64%) were spuriously
low when measured by the Olympus AU2700 DBIL. Be-
cause the Olympus DBIL assay gave exceedingly variable
repetitive results ranging from a markedly positive to
markedly negative interferences in specimens containing
a monoclonal protein, we believe that describing an inter-
ference as negative or positive is unsatisfactory.
The paraprotein interferences with TBIL, DBIL, and
HDL-C appeared to be method dependent. The interfer-
ences with TBIL and HDL-C mainly were observed with
the Roche MODULAR, while DBIL interferences occurred
most frequently with the Olympus AU2700.
The Roche TBIL assay is a 1-cuvette, 2-point end point
assay. Because the addition of R2 to the reaction mixture
changed the assay conditions to more acidic (pH 1–2),
paraproteins could form insoluble complexes with R2,
which cause the interferences. On the other hand, the
Olympus TBIL assay is a 2-cuvette end point assay. Both
cuvettes, the sample blank cuvette and the reaction cu-
vette, contain the same reagents, except the chromogen is
only in the reaction cuvette. Therefore, the condition in the
assay is not changed as there is no addition of R2.
The chromogenic reaction of the DBIL assay occurs at a
very low pH (⬍1). A ‘‘protein stabilizing agent’’ is includ-
ed to avoid protein precipitation. It appears that the sol-
ubilization capacity of the Olympus AU2700 protein sta-
bilizing agent is not sufficient to prevent the proteins in
solution from precipitating at such an acidic pH, which
may cause more interferences with DBIL on the Olympus
AU2700.
As mentioned in the ‘‘Results,’’ spuriously low HDL-C
results observed in the patients with monoclonal gam-
mopathies on the Roche MODULAR and the Olympus
AU2700 may be due to the high baseline absorbance in
the presence of R1 reagent. The R1 reagent contains a
buffer system to selectively form a water-soluble complex
Paraprotein Interferences With Automated Methods—Yang et al 221
Figure 6. Comparison of high-density lipo-
protein cholesterol (HDL-C) measurements
made by 2 automated chemistry analyzers;
the Roche MODULAR (A through C) and the
Olympus AU2700 (D) HDL-C assay absor-
bance curves. A, A control patient serum. B
and C, Serum specimens containing parapro-
teins. The gray vertical bars indicate the
points at which measurements were taken to
calculate results. D, Reaction absorbance
curve of the Olympus AU2700 HDL-C assay.
The arrows indicate photometric points at
which R1 (point 0) and R2 (point 10) reagents
were added. The reaction stops at photomet-
ric point 27. IgG indicates immunoglobu-
lin G.

with low-density lipoprotein, very low-density lipopro-
tein, and chylomicrons. It may be that the differences of
the components or concentrations of the components of
the buffer system in the Roche MODULAR and Olympus
AU2700 HDL-C assays caused more interferences with
HDL-C to be observed on the Roche MODULAR.
Our studies demonstrate that paraprotein interferences
with DBIL and HDL-C are relatively common, and spu-
rious results of TBIL, DBIL, and HDL-C appear to be
methodology and concentration dependent. In a few pa-
tients followed for a period of time, treatment that de-
222 Arch Pathol Lab Med—Vol 132, February 2008
creased paraprotein concentrations caused interferences to
disappear, while disease progression and increasing
monoclonal protein concentrations caused interferences to
increase. It is important to appreciate the occurrence of
these interferences to avoid misinterpretation of the re-
sults, especially because low HDL-C (⬍40 mg/dL [684
␮mol/L]) is considered to be an independent risk factor
for coronary heart disease.22 To automatically detect the
interference, Smogorzewska et al12 suggested manually
programming the analyzer to trigger a flag when the dif-
ference of absorbance between certain points was above a
Paraprotein Interferences With Automated Methods—Yang et al
preset value for the Roche MODULAR TBIL assay or the
absorbance immediately before the addition of the R2
agent was above a designated value for the Roche AU2700
HDL-C assay. This may help when the abnormal absor-
bance reaction curves follow a similar kinetic pattern.
However, our studies showed that the abnormal reaction
curves of the Roche MODULAR TBIL assay and the Olym-
pus AU2700 DBIL assay have different patterns (Figures 2
and 4), which may lead to missing some interferences if a
programmable rule is used. An approach that we favor for
bilirubin assays is to program the analyzer to automati-
cally flag results for confirmation when specimens have
TBIL results greater than 20 mg/dL (342 ␮mol/L) and the
icteric flag is not markedly positive.13 To prevent results
preceded by a negative sign from being reported, we rec-
ommend programming the laboratory information system
to reject patient DBIL and HDL-C results that are preced-
ed by a minus sign.
In conclusion, we found that paraprotein interferences
with clinical laboratory measurements are far more fre-
quent than previously reported. If an interference occurs
with one assay, it is likely that other assays also will be
affected. These types of interferences appear in part to be
concentration dependent. Specimens with paraproteins
cause spurious results by causing precipitation in TBIL,
DBIL, and HDL-C assays.
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