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Articles |
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Abteilung Klinische Chemie und Zentrallaboratorium, Baldingerstr.;
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Medizinisches Zentrum für Nervenheilkunde, Funktionsbereich Neurochemie, Rudolf-Bultmannstr. 8;
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Abteilung Nephrologie, Baldingerstr., Philipps-Universität Marburg, D-35033 Marburg, Germany.
a address for correspondence: bioscientia, Institut für Laboruntersuchungen Ingelheim GmbH, Hamburger Str. 1, D-55218 Ingelheim, Germany. Fax 49-6132-781-214; e-mail bioscientia{at}t-online.de
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Key Words: indexing terms: alcoholism • isoelectric focusing • isotransferrins • sialic acid-deficient transferrins
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Increased concentrations of sialic acid-deficient
Fe2-isotransferrins (a-, mono-, and
disialo-Fe2-Tf) with pI values 
5.7 are detected in serum
of alcoholics (7). Analysis of these isotransferrins,
collectively referred to as carbohydrate-deficient transferrin (CDT),
is widely used for detection and follow-up of chronic alcohol abuse
(7)(8)(9)(10)(11)(12)(13)(14)(15).
In contrast to earlier reports (7)(16)(17)(18),
several recently published studies
(9)(10)(15)(19)(20)(21)
indicate a diagnostic sensitivity of CDT that is not superior to those
of other commonly used markers of alcohol abuse, e.g.,
-glutamyltransferase (-GT; EC 2.3.2.2) and mean corpuscular
volume of erythrocytes (MCV), especially in female populations. In
comparison with -GT and MCV, however, CDT shows the overall best
diagnostic specificity: >90%
(7)(9)(10). Some cases of
increased cCDT in the absence of alcohol abuse have been reported in
patients with heart, pancreas, or lung disorders, malignancy, or
hypertension
(13)(19)(20)(22). The
majority of falsely positive results with regard to chronic alcohol
abuse are seen in patients with the rare carbohydrate-deficient
glycoprotein syndrome (7)(23)(24)(25) or with
primary biliary cirrhosis
(7)(20)(26)(27) and in
healthy persons with genetic Tf-D variants
(6)(7). Excluding these subjects, CDT
measurements are now used for clinical decisions in forensic and
employment medicine and alcohol-related problems in traffic, and for
screening for alcohol abuse as an exclusion criterion in patients with
liver cirrhosis and undergoing liver transplantation
(14)(28)(29)(30).
Within the scope of clinical evaluation of cCDT at our institute, we repeatedly found abnormal cCDT values despite a lack of alcohol overconsumption in patients who had undergone combined pancreas and kidney transplantation. Our aim in the present study was to investigate this clinical condition, kidney transplantation alone, and the corresponding immunosuppression as potential causes of abnormal cCDT values. Furthermore, we sought new insights into the pathomechanism of CDT increase, in addition to the increased sialidase activity and diminished activities of glycosyltransferases found by Xin et al. (31) in alcohol-treated rats and alcohol-abusing patients.
Here, we report for the first time above-normal cCDT and CDT/Tf ratios seen in male and female patients with combined pancreas and kidney transplantation despite no abnormal alcohol consumption. In contrast, patients with kidney transplantation alone or diabetics with end-stage nephropathy did not show increased cCDT or CDT/Tf ratios.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subjects
All procedures were in accordance with the Helsinki Declaration of
1975, as revised in 1983. The reference subjects were 36 nonpregnant
women (29 ± 10 years; mean ± SD), and 30 men (28 ± 9
years), all healthy subjects with an alcohol (ethanol) consumption of
<20 g/day, who were recruited from the staff of our laboratory and
from the medical student population at the University of Marburg
(Marburg, Germany). Persons taking medication (other than oral
contraceptives) were excluded from the study. Frequency, approximate
daily total, and time of last alcohol intake were assessed by
subjects' responses to a structured questionnaire
(8)(32).
Six outpatients (three men and three women) with combined pancreas and kidney transplantation were studied, all with type I diabetes with end-stage nephropathy. The kidney and pancreas were transplanted simultaneously from the same donor. A whole vascularized pancreas along with a segment of duodenum was implanted intraperitoneally, arterial blood being supplied from one iliac artery and venous drainage being directed into the ipsilateral iliac vein (33)(34). The exocrine secretion from the graft was drained into the bladder (by means of pancreatico-duodeno-cystostomy). All patients had functioning pancreas and kidney grafts at the time of investigation, as checked regularly by routine clinical and laboratory analysis. None of them received insulin after transplantation. There were no clinical or laboratory signs of inflammation or sepsis, as indicated, e.g., by normal concentrations of C-reactive protein and neopterin in serum and physiological neopterin excretion in urine.
To assess possible effects of immunosuppression on cCDT, we also studied 16 patients with only kidney transplantation and functioning kidney grafts.
All transplanted patients had received a cadaveric allograft (pancreas and kidney or kidney alone) at the University of Marburg between 1991 and 1994. Characteristics of both groups of transplant patients, including immunosuppressive protocol and laboratory data, are given in Tables 1 and 2.
serum samples
To avoid additional blood drawing for the transplant patients, we
used only surplus serum volumes obtained for routine investigations.
For all subjects, blood was drawn after an overnight fast into sterile
gel-tubes (Sarstedt, Nümbrecht, Germany). After the samples
clotted at room temperature for 30 min, serum was obtained by
centrifugation (2000g, 10 min, 4 °C). To avoid
contaminating a sample with microorganisms, we removed the surplus
sample volume with disposable pipettes and transferred it into a
sterile, leakproof, 1.2-mL plastic container (Nalgene Cryotubes System
100; Nalge Co., Rochester, NY). Samples were immediately stored at
-70 °C and were thawed only once for assaying. By this regimen,
cCDT in the serum was stable for at least 6 months, as proved by
additional use of these samples for analytical evaluation of the CDTect
assay.
methods
Assay of serum CDT.
Serum CDT was determined by
CDTect-RIA (Pharmacia, Freiburg, Germany). After in vitro iron
saturation of serum Tf and adsorption of isotransferrins with pI <5.7
on anion-exchange microcolumns, isotransferrins with pI >5.7 (CDT)
were determined in the efflux by a competitive double-antibody RIA. CDT
in the efflux competes with a fixed amount of 125I-labeled
Tf for the binding sites of the anti-Tf antibodies. Bound and free Tf
were separated by addition of a second antibody as immunoadsorbent and
centrifugation. The radioactivity in the pellet is inversely
proportional to cCDT in the sample. Precision and accuracy of the assay
were assessed by analysis of a serum pool and a quantitative control
sample (delivered with the test kit) with cCDT values near the upper
reference limits for men and women in each run, according to the
recommendations in the Guidelines of the Federal German Medical
Association. Intra- and interassay variations were 10% and 17%,
respectively. No external quantitative control sample was available.
All measurements were done in duplicate and the mean was calculated.
The 95th percentile for cCDT and CDT/Tf ratio in 36 female and 30 male nondrinking or moderately drinking subjects was taken as the decision limit: 28 U/L and 1.0% in women, and 18 U/L and 0.6% in men. (The corresponding CDT values cited by the manufacturer are 26 and 20 U/L, respectively).
IEF.
For qualitative confirmation of the CDTect results,
we performed IEF according to Hackler et al. (4), using
the PhastSystemTM (Pharmacia/LKB). The pH 5–6
polyacrylamide gels [total acrylamide content (T) = 5%, cross-linker
content (C) = 3%; Pharmalytes 5–6® diluted 16-fold], adhering
to a 43 x 50 x 0.45 mm plastic support film (Gel
BondTM PAG film; Biozym-Diagnostik, Hameln, Germany), were
prepared in the laboratory with a capillary casting mold similar to
that described by Esen (35). To reduce the number of Tf
bands within the gel, we incubated the serum samples with ferric
citrate solution, which yielded only Fe2- but no
Fe1- and Fe0-Tfs (4). Also, we
diluted the serum samples to equal Tf concentrations, to allow
comparison of the intensity of the Tf bands in different lanes. Gels
were placed on the cooling plate of the PhastSystem and prefocused for
75 Vh. We pipetted 1 µL of iron-saturated sample per lane (8 lanes
available) onto the Sample ApplicatorTM 8/1
(Pharmacia/LKB), which was inserted into the sample applicator arm
immediately after the "extra alarm." After the automated sample
application, IEF was continued for a total of 200 Vh.
Immunofixation.
Immunofixation was carried out as
described by Hackler et al. (36)(37) with
minor modifications. After removing the IEF gels from the cooling
plate, we covered each gel with 150 µL of anti-Tf polyclonal
antibodies [diluted threefold with 150 mmol/L NaCl solution (isotonic
saline)]. The specificity of the Tf antibodies was tested as described
by Hackler et al. (4). To achieve even distribution of the
antibody solution, we covered the gel with a plastic foil the same size
as the gel; after antibody incubation for 40 min at room temperature in
a moist chamber, the foil was removed. Unprecipitated proteins were
removed by washing the gel in isotonic saline with vigorous agitation
at room temperature (20 °C). In all, 15–20 h of washing was
required to thoroughly remove unprecipitated proteins; this was
conveniently done overnight.
Band visualization.
Silver staining of the
isotransferrin bands was carried out in the PhastSystem Development
UnitTM according to Hackler et al. (37). The
Tf bands were identified by comparison in each gel with identically
treated isotransferrin standard preparations (4), or by
parallel analysis of a cerebrospinal fluid sample, showing asialo- to
hexasialo-Fe2-Tf bands (lane CSF in Fig. 1
). Gels were air-dried and stored for documentation. In
adjusting the sensitivity of the IEF for detection of CDTs
(physiological concentration range usually 10–30 mg/L), we accepted an
overload of the tetrasialo-Fe2-Tf band as the main fraction
(usually >2000 mg/L) (Fig. 1
). Because the intensity of the
tetrasialo-Fe2-Tf band thus does not correlate with the
amount of this isotransferrin present, measurement of the CDT/Tf ratio
in the IEF gel is not possible.
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Other assays.
Serum -GT activity was measured at
25 °C with -glutamyl-4-nitroanilide as a substrate; serum
creatinine was determined kinetically, without prior precipitation of
proteins, by use of the Jaffe method; and serum glucose was analyzed by
the hexokinase method, all with a Hitachi 747 analyzer and reagents
from Boehringer Mannheim (Mannheim, Germany). Serum Tf concentration
was determined immunonephelometrically with a Behring Nephelometer
Analyzer (BNA; Behring, Marburg, Germany) and with reagents from the
manufacturer. MCV was assessed with a MAXM-Hematology Analyzer
(Coulter, Krefeld, Germany).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Despite no
excessive alcohol consumption, cCDT was above the pertinent upper
reference limit in patient 4 once and in the other patients repeatedly.
Concentrations as great as 45 U/L were found in patients 3 and 4 (both
women). A more than double increase of cCDT (42 U/L) was measured in
patient 6 (a man). Abnormal CDT/Tf ratios between 0.7% and 1.1% for
men and between 1.2 and 1.6% for women were found in 12 of 15 samples
with increased cCDT. Owing to a reduced Tf concentration, an abnormal
CDT/Tf ratio despite normal cCDT was found in one
sample from patient 5. Increased serum Tf
concentrations as a possible cause of the increase in cCDT were not
seen in these patients (Table 1
).
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Except for patient 6, all patients with combined pancreas and kidney
transplantation showed at least once an abnormal result for -GT or
MCV, analytes often used as additional indicators of alcohol abuse.
Both markers were above normal, however, only in patients 1 and 4, the
latter showing only a slightly increased -GT activity. Increased
-GT activities but normal MCV values were found in patients 2 and 5,
the latter showing fluctuations of -GT between normal and abnormal
values that did not correlate with cCDT. Increased MCV but normal
-GT was measured in patient 3. We found no correlation between cCDT,
CDT/Tf ratio, and -GT or MCV.
In contrast, none of the patients with kidney transplantation alone had
an abnormal cCDT or CDT/Tf ratio or abnormal MCV (Table 2
).
Above-normal -GT activities were measured in only 3 of 16 patients.
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In 20 poorly controlled diabetic patients (HbA1c >8%) with end-stage nephropathy who were admitted to the outpatient clinics for hemodialysis, no cCDT or CDT/Tf values were abnormal (data not shown).
To exclude as causes of abnormal cCDT specific analytical errors, e.g.,
abnormal chromatographic behavior of the isotransferrins of patients
with combined pancreas and kidney transplantation or interassay
variations of the CDTect assay, we analyzed all serum samples for CDT
by a second, independent method: qualitative IEF (Fig. 1
). Lane CSF of
Fig. 1
shows a typical isotransferrin pattern of cerebrospinal fluid,
which we used to identify the isotransferrin bands in lanes A-F. From
anode to cathode, the fractions are a-, mono-, di-, tri-, tetra- (main
fraction), penta-, and hexasialo-Fe2-Tf. The
isotransferrin pattern in lane F (from anode to cathode: di-, tri-,
tetra-, penta-, and hexasialo-Fe2-Tf) is typical of healthy
Caucasians with normal alcohol consumption. We ran with each gel an
aliquot of this typical serum, which allowed us to identify altered
isotransferrin patterns. Lanes A-E of Fig. 1
represent isotransferrin
band patterns found in patients with combined pancreas and kidney
transplantation. The isotransferrin patterns within lanes A-C and E are
similar to those of patients with chronic alcohol abuse, i.e., intense
disialo- and additional mono- and asialo-Fe2-Tf bands
(4). The corresponding cCDT values obtained by CDTect-RIA
were also increased, whereas serum of lane D had a normal cCDT value
and a normal isotransferrin band pattern. The double bands in lane D
reflect the genetic Tf-C polymorphism (C1–C2
phenotype).
Other patients—diabetics or patients with kidney transplantation
alone—did not show isotransferrin patterns similar to those in lanes
A-C and E. This confirms the normal cCDT values found in these patients
(Table 2
).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The reason for increased cCDT and CDT/Tf ratios as well as for
individual fluctuations of these markers remains unclear, given the
absence of any change in transplant function, clinical background,
medication, or alcohol intake. Although all samples from controls,
diabetics, and transplant patients were collected and treated in the
same way, increased cCDT was observed only in patients with combined
pancreas and kidney transplantation. Some of these samples were
reanalyzed after 6 months and some after repeated thawing, but the cCDT
results remained the same. Contamination of the serum samples, e.g.,
with sialidase-producing microorganisms, is therefore unlikely as a
cause for increased cCDT. A microbial infection of the transplant
patients is also improbable: Regular measurements of serum C-reactive
protein as an immediate and sensitive indicator of inflammation
(38) and regular assays of neopterin in serum and urine as
very early and sensitive markers for most forms of infection in
transplant patients (39) yielded normal results.
Analytical errors could be excluded as causes for increased cCDT in
each case because the corresponding IEF isotransferrin band pattern
showed distinct bands of sialic acid-deficient transferrins similar to
those seen in alcoholics (Fig. 1
). The interassay CV of 17% for cCDT
could not account for the cCDT fluctuations shown here between
consecutive measurements, which were always done in duplicate.
Sorvajarvi et al. (40) recently reported a marked decrease
of the diagnostic specificity of cCDT in patients with increased serum
concentrations of Tf; however, this specificity could be improved by
use of %CDT values. For the patients with combined pancreas and kidney
transplantation, no increased serum Tf concentration was measured, thus
excluding this condition as a cause of increased cCDT. Furthermore,
when we calculated the CDT/Tf ratios of 15 samples with increased cCDT,
12 samples showed above-normal values, 1 had normal values, and 2 had
the ratio at the upper reference limit. Moreover, one patient had an
increased CDT/Tf ratio despite having a normal value for cCDT. Thus,
using the CDT/Tf ratio did not improve the diagnostic specificity in
the transplant patients.
In view of history, close surveillance, and self-reports stating a
daily ethanol consumption of <20 g, chronic alcohol abuse is unlikely
as a cause of increased cCDT in each of the transplant patients.
However, -GT activity and MCV as potential indicators of alcohol
abuse were increased in several of these patients' samples (Table 1
).
Hepatotoxic effects of cyclosporine and of azathioprine are well
documented (41). The latter, metabolized to
6-mercaptopurine (which acts as a purine antagonist), inhibits DNA
synthesis and thus the proliferation of fast-growing cells, such as
granulocytes, erythrocytes, and platelets
(41)(42). Given this mechanism, and with
normal erythropoietin synthesis in kidney transplant recipients,
macrocytemia may occur as a side effect of azathioprine therapy, a fact
that is often used for monitoring patients' compliance
(42). A deficiency in thiopurine
S-methyltransferase (EC 2.1.1.67; an enzyme involved in
6-mercaptopurine metabolization that exhibits a wide range of activity
in the normal population (43)) must also be taken into
account as a cause of increased MCV. It is, however, unlikely that all
patients with combined pancreas and kidney transplantation would have
this disorder. Summing up, abnormal MCV and increased -GT activities
most probably result from the medication rather than increased alcohol
intake.
Initially, we assumed that the increase in cCDT was a side effect of
the immunosuppressive medication, so we measured cCDT in 16 patients
after kidney transplantation alone and treatment with similar basic
immunosuppressive regimens (Table 2
). None showed an increased cCDT or
CDT/Tf ratio (Table 2
). Medication could therefore hardly cause
increased cCDT in patients with combined pancreas and kidney
transplantation. Interestingly, above-normal MCV was not observed in
patients with kidney transplantation alone, even though six of them
received azathioprine. This could result from: (a) a
statistical effect related to the small number of patients,
(b) the different hormonal situation in the two groups of
patients (see below), and (or) (c) the different metabolic
situation, e.g., hyperglycemia in patients with kidney transplantation
alone vs normoglycemia in patients with combined pancreas and kidney
transplantation. To our knowledge, whether these factors exacerbate or
mitigate the azathioprine side effects is unknown.
A causal role by the underlying disease of type I diabetes mellitus for
increased cCDT is also unlikely. On the one hand, the metabolic
situation was effectively treated in all of the patients with combined
pancreas and kidney transplantation, as indicated by, e.g., generally
normal serum glucose concentrations (Table 1
). On the other hand, 20
sera from poorly controlled diabetic outpatients on hemodialysis
(HbA1c >8%) did not show increased cCDT or abnormal
CDT/Tf ratios. To our knowledge, increased cCDT in diabetics has not
been reported. A correlation between cCDT and renal function, i.e., as
expressed by the serum creatinine concentration (Tables 1
and 2
), was
not observed in either transplant patient group.
The implantation of the pancreas allograft remains the main difference
between the patient groups. According to present knowledge, the
pancreas itself does not play any important role in the metabolism and
turnover of transferrin and CDT. Successful pancreas transplantation
results in a carbohydrate metabolism similar to that in nondiabetic
subjects (44)(45). However, the drainage of
the pancreatic venous effluent into the systemic venous system instead
of the portal venous system inevitably induces systemic
hyperinsulinemia (46)(47), owing to reduced
insulin clearance by the liver (46). This hyperinsulinemia
is exacerbated by the steroid (e.g., prednisolone)-induced peripheral
insulin resistance (48), and we can speculate that these
conditions may alter Tf and CDT turnover. The peripheral insulin
resistance should develop within the duration of systemic
hyperinsulinemia (46)(48). This may explain
why 20 serum samples drawn from patient 4 within the first 60 days
after simultaneous pancreas and kidney transplantation showed normal
cCDT values (preliminary results), whereas ~2 years after
transplantation her cCDT had increased to 45 U/L (Table 1
). In this
context, the findings of Fagerberg et al. (49) concerning
a relation between insulin sensitivity and cCDT need further
investigation. Besides hyperinsulinemia and normoglycemia, patients
with combined pancreas and kidney transplantation differ from patients
with kidney transplantation alone by having improved lipid metabolism
(50). Which factor or hormone–substrate interaction is
responsible for increased cCDT in patients with combined pancreas and
kidney transplantation remains unclear.
In conclusion, combined pancreas and kidney transplantation must be considered as a new cause of above-normal cCDT and CDT/Tf ratios despite normal alcohol consumption. Owing to the increasing number of studies reporting pathological cCDT values despite normal alcohol intake in various diseases (7)(13)(19)(20)(22), a synopsis of clinical data and of suitable laboratory markers is a prerequisite for diagnosis of alcohol abuse.
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Acknowledgments |
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Footnotes |
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-GT, -glutamyltransferase; HbA1c, glycosylated hemoglobin A; IEF, isoelectric focusing; MCV, mean corpuscular volume of erythrocytes; and Tf(s), transferrin(s). 
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-glutamyltransferase as markers of heavy alcohol consumption: gender differences. Alcohol Clin Exp Res 1994;18:747-754.
[Web of Science][Medline]
[Order article via Infotrieve]
-GT, methanol, isopropanol and ethanol in forensic blood samples for assessment of chronic alcohol abuse. Lab Med 1994;18:143-153.
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