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Hepatology - 2009 - Jalan - Alterations in The Functional Capacity of Albumin in Patients With Decompensated Cirrhosis Is
Hepatology - 2009 - Jalan - Alterations in The Functional Capacity of Albumin in Patients With Decompensated Cirrhosis Is
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LIVER FAILURE/CIRRHOSIS/PORTAL HYPERTENSION
A
lbumin is the major plasma protein and consti-
See Editorial on Page 355
tutes around 50% of the cell free protein in
healthy individuals. It is produced exclusively in
the liver, and therefore its concentration is reduced during
Abbreviations: ACLF, acute-on-chronic liver failure; AUROC, area under the hepatic dysfunction.1 Following the Cochrane meta-anal-
receiver operating curve; EPR, electron paramagnetic resonance; IMA, ischemia-
modified albumin; IMAR, IMA/albumin ratio; MARS, Molecular Adsorbents Re- ysis describing potential harmfully effect of albumin in-
circulating System; MELD, model of end-stage liver disease. fusion in critically ill patients, there has been a re-
From the 1Liver Failure Group, Institute of Hepatology, University College examination of the use of albumin infusions for volume
London, London, United Kingdom; 2MedInnovation GmbH, Wildau, Germany;
and the 3Institute of Transfusion Medicine, University Hospital Leipzig, Leipzig, replacement. However, the results of the recently pub-
Germany. lished SAFE study have provided new data confirming the
Received October 28, 2008; accepted February 9, 2009.
safety of albumin infusion in critically ill patients.2,3
Supported by The Seigmund Warburg Benevolent fund and by an unrestricted
grant from CSL Behring Grifols; and Talecirs; and BPL (for supplying Human Liver failure results in multiple organ dysfunction, and
Serum Albumin); coordinated by the Plasma Proteins Therapeutic Association. This mortality rates without liver transplantation remain un-
work was undertaken at UCLH/UCL, who received a proportion of funding from
the Department of Health’s NIHR Biomedical Research Centres funding scheme.
acceptably high.4 However, recovery is associated with
The views expressed in this work are those of the authors and not necessarily those complete reversal of multiorgan dysfunction. At present,
of the Department of Health. in patients with cirrhosis, albumin is used mainly to re-
Address reprint requests to: Nathan Davies, Liver Failure Group, Institute of Hepa-
tology, 69-75 Chenies Mews, University College London, London WC1E 6HX, United
plenish the circulating volume. With increasing severity
Kingdom. E-mail: nathan.davies@ucl.ac.uk; fax: (44)-2073800405. of cirrhosis, there is a progressive increase in cardiac out-
Copyright © 2009 by the American Association for the Study of Liver Diseases. put, which is associated with a progressive reduction in
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22913 individual organ blood flow. This peculiar circulatory dis-
Potential conflict of interest: Nothing to report. turbance is thought to occur as a result of splanchnic
555
15273350, 2009, 2, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.22913 by Cochrane Mexico, Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
556 JALAN ET AL. HEPATOLOGY, August 2009
and 48 hours after initiation of specific therapy to treat the Merck KG, Germany), increasing aliquots of which were
precipitating event, and this group served as disease con- added to the labeled plasma samples, which were then
trols. The other 22 patients were included on the day they incubated at 37°C for 10 minutes before the EPR spectra
were admitted to the intensive care unit with a diagnosis were recorded (MMS, MedInnovation GmbH, Ger-
of ACLF, which was defined as acute deterioration in liver many). Analysis of the recorded spectra, using MMS soft-
function over a period of 2 to 4 weeks, associated with a ware, provided information on albumin conformation
precipitating event, leading to severe deterioration in clin- and binding properties. Two different situations were
ical status, with jaundice and hepatic encephalopathy considered: (1) in vitro conditions, which included non-
(grade 2 or more) and/or hepatorenal syndrome, with a competitive examination of fatty acid adsorption, trans-
sequential organ failure assessment score of 8 or more. Of port capacity, and fatty acid unloading; and (2) a
these 22 patients, 12 were treated with the molecular ad- competitive test that simulated in vivo conditions in
sorbents recirculating system and 10 with standard sup- which albumin loading, transport and unloading were
portive medical therapy. The selection for treatment with studied for the functional parameters of albumin quality
MARS or standard of care was decided randomly as a part as transport drug in competitive situations. Using EPR
of other clinical studies (unpublished data). Samples from spectroscopy, albumin conformational modifications can
patients with cirrhosis without organ failure were col- be determined from its interaction with other ligands.
lected from patients within 48 hours of admission, after The EPR spectra-based parameters (KB1, binding coeffi-
initiation of therapy for their precipitating event. cient, and N1, capacity of high-affinity sites; KB2, binding
coefficient, and N2, capacity of secondary binding sites;
Study Design RTE, real transport efficiency; DTE, detoxification effi-
Peripheral venous blood was aseptically collected into ciency) allow conclusions to be made as to the extent of
pyrogen-free tubes (BD Vacutainer Lithium-Heparin [60 maintained transport of fatty acids, drugs, bilirubin, me-
U per tube]; BD, Plymouth, UK) at the time of inclusion tabolites, biomarkers, and so forth. In addition, it is pos-
into the study and used for routine biochemistry, markers sible to assess the detoxification function of measured
of oxidative stress, and albumin functional capacity. For albumin.16,17
harvesting plasma, blood was placed immediately on ice. Ischemia-Modified Albumin. Ischemia-modified al-
After centrifugation, plasma was aliquoted into cryotubes bumin (IMA) is identified using an assay to determine the
(Corning Inc., Corning B.V., Netherlands) and stored at ability of the protein to chelate cobalt. There are several
⫺80°C until further analysis. Bilirubin, albumin, liver sites on the protein that have the ability to bind metals,
function tests, coagulation parameters, full blood count, though most interest to date has focused on the N-termi-
and c-reactive protein were routinely performed. model of nal region.13,18 IMA was determined according to the co-
end-stage liver disease (MELD)14 and Pugh score15 were balt-binding assay method of Bhagavan et al.13 Briefly,
calculated. The patients were followed prospectively over plasma was incubated with a cobalt chloride (1 g/L, 10
a period of 90 days. In the patients that developed ACLF, minutes) and dithiothreitol (1.5 g/L, 2 minutes) before
plasma samples were collected again 7 days after inclu- dilution in saline prior to measurement at 470 nm in a
sion. spectrophotometer (Agilent 8453 Diode Array, Agilent,
UK). IMA was calculated from the difference between
Measurement of Albumin Function samples measured with and without dithiothreitol.
The functional characteristics of albumin were mea- Plasma albumin concentration was determined using an
sured using two techniques. The molecular structure is automated COBAS Integra biochemical analyzer (Roche
shown in Fig. 1 which also depicts the binding sites stud- Diagnostics, UK).
ied.
Electron Paramagnetic Resonance. The functional Markers of Oxidative Stress
capacity of the albumin binding sites were measured using Malondialdehyde. Malondialdehyde (MDA) was de-
a spin label and electron paramagnetic resonance spec- termined using a modified thiobarbituric acid reactive
troscopy as described.16,17 There are six well-known bind- substances assay described by Lapenna et al.19 wherein the
ing sites for fatty acids on the albumin molecule, three major interfering/oxidizable component in the plasma is
with high and three with lower affinity, that were exam- inhibited by addition of sodium sulphate.
ined in this study. The spin label used for albumin 16- F2 Isoprostanes. F2 isoprostanes (free 8-isoprostane
doxyl stearic acid (Sigma-Aldrich GmbH, Germany) was F2␣) was assayed with a commercial EIA kit (Cayman
added to plasma samples in defined concentrations. Eth- Chemical, Ann Arbor, MI) according to the manufactur-
anol was used as a polar reagent (99% puriss, USPXXII, er’s instructions and as described.20 Briefly, 200 L
15273350, 2009, 2, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.22913 by Cochrane Mexico, Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
558 JALAN ET AL. HEPATOLOGY, August 2009
plasma was deproteinized with 600 L ethanol contain- Table 1. Patient Characteristics
ing 3H-prostaglandin E2 as an internal standard to ac- Cirrhosis, No Organ ACLF Treated ACLF Treated
count for losses. After centrifugation, the supernatant was Dysfunction with MARS with SMT
(n ⴝ 12) (n ⴝ 12) (n ⴝ 10)
reduced to near dryness, and 2 mL acetic acid was added
Age 47 ⫾ 3.4 47 ⫾ 4.4 48 (2.9)
and applied to a preconditioned C18 SPE cartridge (Wa-
Sex 10 M, 2 F 9 M, 3 F 8 M, 2 F
ters, Milford, MA). The column was washed with water, MELD score 9.3 ⫾ 2* 19.7 ⫾ 3 20 ⫾ 3
dried with nitrogen, and eluted with high-performance Child-Pugh score 7.9 ⫾ 1.3† 11.4 ⫾ 1.5 12.2 ⫾ 1.4
liquid chromatography– grade hexane. The prostanoid SOFA score 5.5 ⫾ 1.2† 9.3 ⫾ 2.5 9.4 ⫾ 1.7
Albumin (g/L) 37 ⫾ 4† 26 ⫾ 1.7 25 ⫾ 1.3
fraction was eluted with 5 mL ethylacetate containing 1% Bilirubin (mol/L) 83 ⫾ 9‡ 428 ⫾ 57 323 ⫾ 47
methanol, eluant reduced to dryness and reconstituted in INR 1.2 ⫾ 0.2‡ 1.8 ⫾ 0.2 1.8 ⫾ 0.1
450 L of EIA buffer, 100 L being used to determine Creatinine (mol/L) 73 ⫾ 8‡ 146 ⫾ 41 179 ⫾ 67
MDA (mol/L) 3.3 ⫾ 2.1† 7.4 ⫾ 1.9 7.7 ⫾ 2.3
recovery of 3H-PGE2 and 50 L added to the EIA plate F2-Isoprostanes (pg/mL) 267 ⫾ 32† 423 ⫾ 39 489 ⫾ 28
with isoprostane tracer and antibody. Isoprostane levels In-hospital mortality None 8 patients 7 patients
were determined by reference to authentic standards and
Data are expressed as the mean ⫾ standard error.
corrected for losses. Abbreviations: F, female; INR, international normalized ratio; M, male; SMT,
standard medical therapy; SOFA, sequential organ failure assessment.
Statistical Analysis *P ⬍ 0.05, †P ⬍ 0.01, ‡P ⬍ 0.001 for the cirrhosis, no organ dysfunction
group versus the ACLF groups.
All the data were described as mean and standard error.
Differences between groups were calculated using an in-
dependent samples t test for the normally distributed data parameters: Albumin functionality is characterized by
and the Mann-Whitney test for data not normally distrib- three groups of EPR spectrum parameters: (1) capacity of
uted. Correlations between variables were calculated us- binding sites and strength of fatty acid holding; (2) global
ing linear regression. Survival analysis was performed parameters of albumin transport (transport, loading, and
using the Kaplan-Meier method and the log-rank test was unloading of fatty acids); and (3) functional parameters of
used to test statistical significance. albumin quality in regard to its ability to uptake and hold
toxic substances produced via metabolism. The EPR data
Results of the healthy subjects were used as reference values. All
Patients healthy volunteers showed normal albumin conformation
The main causes leading up to acute decompensation and transport functionality. Examination of the data ob-
in the patients were infection (n ⫽ 18), superimposed tained from the 80 control subjects showed no significant
alcoholic hepatitis (n ⫽ 11), and variceal bleeding (n ⫽ differences in any measured value for either age or sex
5). Twenty-two patients proceeded to deterioration in (Fig. 2). For each parameter measured, patients with both
their clinical condition requiring prolonged hospital ad- stable cirrhosis and those with ACLF were significantly
mission and supportive care in a high-dependency/inten- worse compared with the healthy volunteers.
sive care unit and were considered to have ACLF. Of Transport Efficiency. Albumin transport function
these, 12 were treated with MARS and the rest with stan- parameters were evaluated following the model of a three-
dard of care. No clinical or biochemical differences were step transport process for fatty acids. This incorporates
observed between the patients treated with MARS com- substrate sorption and binding parameters in which albu-
pared with the group treated with standard medical care. min from healthy subjects demonstrate high binding con-
In the MARS-treated patients, there was a reduction in stants for substrate uptake. The second phase is transfer of
bilirubin (P ⬍ 0.01) and creatinine (P ⬍ 0.05) concen- the bound substrates into the circulatory system. Finally,
trations at day 7, which resulted in a reduction in MELD the albumin should be able to demonstrate the ability to
score. However, although this would suggest an improve- release the substrate to target objects. Substrate delivery
ment in outcome, survival remained unaffected, with from albumin requires albumin receptor or albumin sur-
eight of the 12 patients dying in the MARS group and 7 of face interaction with the cell membrane; in this process,
the 10 patients dying in the group treated with standard the albumin substrate binding constant is controlled by
of care (Table 1). The cause of death was multiorgan hydrophobic interactions at the target binding site. In the
failure in both groups. EPR studies, the local albumin membrane delivery oper-
ations were simulated using ethanol for modification of
Albumin Function these hydrophobic interactions. Overall, the albumin
Electron Paramagnetic Resonance. Albumin func- transport efficiency in ACLF patients was found to be
tionality is characterized by four groups of EPR spectrum only about 10% of the normal functional ability of albu-
15273350, 2009, 2, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.22913 by Cochrane Mexico, Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HEPATOLOGY, Vol. 50, No. 2, 2009 JALAN ET AL. 559
EPR spectroscopy
Binding coefficient (high-
affinity KB1) 97.4 (15.6) 27.5 (5.6)* 17.9 (3.5)*
min from healthy volunteers (Table 2). These values were Number of labels (high-
found to be significantly lower in cirrhotic patients com- affinity site, N1) 3.1 (0.1) 2.4 (0.1) 2.5 (0.9)
pared with healthy controls (P ⬍ 0.001 in each case) and Binding coefficient (low-
affinity KB2) 58.3 (11) 20.1 (3.1)* 14.1 (1.8)*,†
were further reduced in ACLF subjects. Transport effi- Number of labels (low-
ciency was significantly lower in nonsurvivors compared affinity site, N2) 2.9 (0.2) 3.1 (0.1) 2.6 (0.1)*,†
with survivors (P ⬍ 0.05). Calculated real transport
efficiency 75 (6.9) 27.5 (5.1)* 14.3 (1.9)*,†
Detoxification Efficiency. Albumin screening pa- Calculated detoxification
rameters were evaluated using concentration parameters efficiency 120 (33) 28.2 (5.3)* 11.6 (2.6)*,‡
of free fatty acid and 16-DS bound to albumin. The mea- Effective albumin 50.26 (3.02) 25.6 (3.1)* 20.98 (2.2)*
IMA 0.69 (0.034) 0.64 (0.022) 0.64 (0.017)
sured binding capacity was significantly reduced in sub- IMAR 0.010 (0.001) 0.021 (0.001) 0.03 (0.002)*,‡
jects with liver disease compared with healthy controls
(P ⬍ 0.05). This finding demonstrates that the three- Data are expressed as the mean (standard error). See text for explanations
regarding the description of the various binding sites.
dimensional protein structure of the albumin is affected *P ⬍ 0.001 compared with healthy volunteers; †P ⬍ 0.05, ‡P ⬍ 0.01
in patients with liver disease. compared with cirrhosis, no organ dysfunction group.
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560 JALAN ET AL. HEPATOLOGY, August 2009
Table 3. Characteristics of Survivors versus NonSurvivors during the study period, this difference was not statisti-
Survivors Nonsurvivors cally significant.
Factor (n ⴝ 19) (n ⴝ 15) P Value AUROC
already evidence to suggest that the plasma antioxidant apy for hepatorenal syndrome.7 According to the clas-
status of cirrhotic patients is reduced compared with sical hypothesis, the benefit of albumin in these
healthy controls.9,23 Because albumin is the dominant situations is thought to be due to expansion of the
plasma protein and is known to exhibit antioxidant prop- circulating plasma volume, thereby ensuring adequate
erties, this lack of functional ability to both remove toxins renal perfusion. The results of this study indicate that it
and prevent oxidant stress damage suggests that further is likely that additional benefit may have been con-
decompensation may occur more readily. ferred by the enhancement of the transport and detox-
It is interesting to note that the initial results from ification function of albumin contributing to the
the IMA studies failed to show any differences between improved outcome in these patients.1
groups. However, once the IMA values were normal- Though the exact mechanism/stress mediator lead-
ized to the plasma albumin concentration, a clear dis- ing to the formation of IMA could be varied, in the
tinction between the patients with ACLF compared laboratory the effect can be consistently repeated via
with those who did not have organ failure became ap- exposure of albumin to hydroxyl radicals.18 The signif-
parent. In the currently licensed use of this assay, as a icance of this assay in determining periods of ischemia
rule-out test for cardiac ischemia, most patients would is evident in that it has recently been licensed by the
be expected to have normal albumin levels. This is not U.S. Food and Drug Administration as a rule-out test
true for patients with liver disease in whom a progres- for cardiac ischemia.25 Though the presence of IMA is
sive decrease in albumin concentration is associated not diagnostic of a cardiac infarct, as any regional isch-
with reduced hepatic function, which may be reduced emia has the potential to generate IMA, its absence
further with bleeding or sepsis.24 A reduced albumin indicates that it is most unlikely and patients with a low
level will immediately result in a lower capacity to bind IMA score can be discharged. The loss of metal chela-
cobalt, yielding an artificially high false positive IMA tion function, as evidenced by increasing IMA, would
score; however, this provides no information to the contribute to an environment of continued oxidative
degree of albumin damage or oxidative stress load. stress. As proteins become damaged and release metal
Hence, a normalbuminemic subject with significant ions into the system, where they become redox active,
albumin damage would have a similarly high IMA they contribute to radical formation by Fenton chem-
score compared with a hypoalbuminemic individual, istry processes.26,27 Albumin ordinarily provides a first-
even if the albumin present was functioning normally line defense against these reactions by binding and
(e.g., following venesection). It is only by expressing removing metal ions from the plasma, an ability that
the IMA per unit albumin that an understanding of the appears to be deficient in this patient cohort.
amount of albumin dysfunction can be determined. By Of further interest is the observed relationship be-
normalizing the measured IMA score to the plasma tween the calculated binding constant (KB) of binding
albumin concentration in this way, a relative indicator sites 1 and 2 and the IMAR score. Previous research
of albumin damage, and hence the environment of into the areas of albumin affected to result in increased
oxidative stress, can be obtained. We would therefore IMA have focused on the metal binding region at the N
suggest that IMA should be expressed relative to the terminus of the protein. However, a recent study28 has
albumin concentration (IMAR) to minimize the inter- suggested that although cobalt may bind at this site
ference from reduced albumin level. Using this ratio- transiently, its electronic configuration is better suited
nale, our studies revealed that IMAR levels predicted to binding at the fatty acid binding sites. We observed
mortality of patients with acute decompensation of cir- a significant relationship between the IMAR and the
rhosis accurately with an AUROC of 0.8. Though it is functionality of these sites, supporting the hypothesis
likely that a patient with liver disease is likely to have that this is the binding location (Fig. 3). This finding
reduced albumin levels, our study indicates that when suggests that IMAR may be a more useful indicator of
this is coupled with ongoing albumin damage and ex- albumin function than previously thought, providing
pressed as a ratio, the prognostic indication is less fa- insight into the normal functional capacity of this im-
vorable. This observation must be taken in light of the portant, ubiquitous protein.
fact that it is a relatively small study and would require MARS is an extracorporeal albumin dialysis device
confirmation in larger studies. These observations do, that has been shown to be of value as a detoxification
however, indicate alternative mechanisms to explain tool with evidence that it can effectively remove pro-
the proven value of albumin infusion in patients with tein-bound substances from the circulation and has
cirrhosis with spontaneous bacterial peritonitis6 and been shown to be useful for the treatment of hepatic
also where albumin formed part of a combination ther- encephalopathy and in patients with severe cholestasis
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HEPATOLOGY, Vol. 50, No. 2, 2009 JALAN ET AL. 563
to possibly improve survival.4,10-12 Current hypotheses for dialysis with improved transport and detoxification
suggest that the removal of excess protein-bound toxins capacity. Furthermore, these findings argue for further
in the extracorporeal circuit is likely to regenerate the studies of albumin biology in cirrhosis, giving consid-
native albumin, thereby enhancing its functional ca- eration to the use of albumin infusion not for fluid
pacity so that it may be able to transport and detoxify replacement, but as an agent to increase detoxification
more toxins. Contrary to this existing hypothesis, al- capacity.
bumin dialysis using MARS did not improve the mea-
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