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Lejia Sun, Huanhuan Yin, Meixi Liu, Gang Xu, Xiaoxiang Zhou, Penglei Ge,
Huayu Yang & Yilei Mao
To cite this article: Lejia Sun, Huanhuan Yin, Meixi Liu, Gang Xu, Xiaoxiang Zhou, Penglei Ge,
Huayu Yang & Yilei Mao (2019): Impaired albumin function: A novel potential indicator for liver
function damage?, Annals of Medicine, DOI: 10.1080/07853890.2019.1693056
Lejia Sun1*, Huanhuan Yin2*,Meixi Liu2*, Gang Xu1 , Xiaoxiang Zhou2, Penglei
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Medical Sciences, Beijing, 100730, China.
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3 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of
Zhengzhou University, Zhengzhou, 450052, China.
E-mail: pumch-liver@hotmail.com
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Phone: 8600-010-69156042
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Authors’ contributions
Yilei Mao proposed the study. Lejia Sun, Yin Huanhuan and Meixi Liu wrote the first
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manuscript. Meixi Liu and Gang Xu made charts and illustrations. Xiaoxiang Zhou,
Penglei Ge and Huayu Yang collected the literature and revised the manuscript. All
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authors contributed to the design and interpretation of the study and to further drafts.
* These authors contributed equally to this article.
Abstract
Albumin is the most abundant plasma protein and albumin infusion is commonly used.
Conventionally, the biologic and therapeutic effects of albumin have been thought to
be due to its oncotic properties. However, albumin has a variety of biologic functions,
including molecular transport, anti-oxidation, anti-inflammation, endothelial
stabilization, anti-thrombotic effects, and the adjustment of capillary permeability.
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Despite this, the functions of albumin have not been thoroughly investigated. Recent
studies have shown non-alcoholic fatty liver disease (NAFLD), viral hepatitis,
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cirrhosis, and liver failure to be associated with impairments in albumin function,
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which are associated with impairments in liver function and disease prognosis.
Post-translational modifications of albumin cause structural modifications that affect
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protein function. Recently, the concentration of albumin associated with normal
function, the “efficient albumin concentration”, has been attracting more interest. In
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diseases, the predictive values are unsatisfactory. However, clinical evidence has
suggested that albumin function may represent a novel biomarker of early impairment
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in liver function. In this review, we summarize the factors affecting albumin function
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1. The importance of albumin depends not only on its concentration, but also on its
various physiological functions.
2.Impaired albumin function has been reported in a variety of liver diseases, and is
associated with disease severity and prognosis, thereby proposing the concept of
“effective albumin concentration”.
3. Albumin dysfunction occurs earlier than other conventional indicators, and albumin
dysfunction may be a new biomarker of early impairment in liver function.
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4. Many exogenous and endogenous factors lead to post-translational modifications of
albumin, which alters the three-dimensional structure of albumin, resulting in a
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decrease in its biological activity.
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Introduction
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capillary permeability. It has been shown that albumin infusion can improve the
prognosis of patients with spontaneous peritonitis [8, 9]or hepatorenal syndrome[10,
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11], not only via plasma volume expansion, but also because of its non-colloid
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osmotic function. However, the clinical significance of the non-oncotic functions of
HSA have not been investigated in detail. It is likely that albumin function is altered
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during liver dysfunction, and recent studies[12, 13] have shown that the
three-dimensional structure of albumin is modified, along with its function, in liver
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diseases, and that these modifications are related to the specific clinical features and
severity of the disease, and the prognosis.
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the main methods of assessing albumin function, and discuss the changes in albumin
function associated with specific liver diseases and their potential mechanisms.
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negative charge[18] of HSA are responsible for this best-known property. Indeed,
HSA accounts for >50% of the total plasma protein[15], and it therefore has a direct
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osmotic effect, which is the main mechanism underlying its role in oncotic pressure.
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The negative charge of HSA is the result of a large percentage of its constituent amino
acids being acidic. As a result of this, HSA draws sodium ions, and consequently
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water, into the intravascular compartment.
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ability, which can increase the solubility of a variety of endogenous and exogenous
substances in plasma, and permits their transportation or detoxification. The ability of
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number of α-helices and three homologous domains (I–III) (Fig. 1), each of which
comprise two subdomains (A and B) [21]. The specific structure is stable but flexible:
the conformation is easily modified[22], which enables the molecule to accommodate
many compounds with protein-binding affinity. Furthermore, some molecules
compete for HSA binding sites and alter the three-dimensional structure of the
macromolecule, which in turn affects its function.
Such binding can occur at numerous different sites in HSA[22], but sites I and II
(Fig.1) predominate. Binding to albumin affects the distribution, biologic activity, and
clearance of endogenous compounds, including bile acids, long-chain fatty acids, and
bilirubin, and of exogenous compounds, including non-steroidal anti-inflammatory
drugs, warfarin, antibiotics, and furosemide. In particular, the HSA-binding properties
of drugs are important for both their pharmacodynamics and pharmacokinetics. In
addition, the N-terminus of HSA can bind metals, such as copper, nickel, cobalt, and
iron, and HSA can also bind lipopolysaccharide (LPS), reactive oxygen species, and
nitric oxide (NO) [15], which explains its anti-inflammatory and antioxidant roles.
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Antioxidant function
Albumin can effectively scavenge reactive oxygen species using reduced
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sulfhydryl (-SH) moieties, and the antioxidant activity of albumin is mainly
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determined by the 34th cysteine residue (Cys-34, Fig.1)[23]. HSA represents the
largest plasma reservoir of -SH (80%)[2, 24, 25], because it contains 35 cysteine
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residues, 34 of which form 17 disulfide bonds. However, Cys-34 is not linked to
another local residue by a disulfide bond, and can therefore be responsible for the
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addition, the binding of the N-terminal site of albumin to certain reduced metal ions,
such as Cu(II) and Fe(II)[27-29], also contributes to the antioxidant capacity of HSA.
Anti-inflammatory effects
HSA can bind a variety of inflammatory mediators, such as LPS[15, 22, 30]and
other bacterial antigens, and is responsible for regulation of the immune response
through an interaction with toll-like receptor 4 in systemic inflammation and sepsis.
In vitro experiments have shown that HSA can reduce endothelial inflammation by
inhibiting the adhesion of inflammatory cells to the endothelium[21]. Furthermore, an
infusion of albumin can reduce the levels of LPS and other pro-inflammatory factors
in patients with cirrhosis[21], and HSA can inhibit the respiratory burst of neutrophils
in critically ill patients.
There is increasing evidence that HSA can regulate adaptive immunity rather than
an immune-inert protein. Interestingly, HSA may behave differently under different
pathological or physiological conditions. In vitro experiments [31] have shown that
albumin can inhibit T cell adhesion. Graner et al. [32]found that albumin expressed in
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mouse tumors can inhibit T cell activation and response in vivo and in vitro,
promoting tumor progression. They speculated that immunosuppression may be
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related to the transport capacity of albumin, and the albumin ship more
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immunosuppressive molecules to the tumor microenvironment, allowing tumor cells
to achieve immune escape.The albumin extracted from the plasma of cancer patients
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shows similar immunosuppressive ability. However, it has also been reported [33] that
HSA can bind to glycerol monolaurate (GML) and reduce the immunosuppressive
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effect of GML.
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Antithrombotic effects
Cys-34 residues can also bind NO, forming S-nitroso albumin, which may be
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responsible for the antithrombotic effect of HSA, because this prolongs the biologic
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Endothelial stabilization
The antioxidant and anti-inflammatory properties of HSA protect the endothelium
from pro-inflammatory factors and reduce endothelial oxidative stress[21, 35]. For
example, the oxidation of HSA increases the risk of cardiovascular disease in the
elderly by promoting endothelial aging and injury. This was illustrated by Anraku et
al. [36], who used a vascular endothelial cell model to demonstrate that Cys-34 can
mediate a reduction in vascular endothelial oxidative stress and protect the vascular
endothelium from damage. Furthermore, clinical studies have confirmed that HSA can
improve systemic hemodynamics in patients with spontaneous bacterial peritonitis by
reducing endothelial cell activation[37]. Finally, animal studies have also shown that
HSA concentration is associated with endothelial dysfunction[38]. Thus, the binding
of NO by HSA provides a possible mechanism for its involvement in hemodynamic
regulation.
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which affects the permeability of capillaries to macromolecules. And albumin can also
bind to arachidonic acid, which increases capillary permeability[14]. Animal studies
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have shown that albumin administration can reduce the permeability of the mesenteric
capillary bed in endotoxemia[14].
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Methods of assessing albumin function
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acid-binding sites on an albumin molecule, of which three have high affinity and the
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other four have lower affinity. First, 16-Hexyl stearic acid is used as a spin label and
is added to plasma samples at a specific concentration, then ethanol is added as a
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polar reagent and the mixture is incubated for 10 min. When the albumin structure is
broken down, the free spin label increases and can be detected and recorded using
EPR spectroscopy. “H” and “L” are used to represent the affinity of the high and low
affinity fatty acid binding sites, respectively, and the ratio H/L reflects conformational
changes in the albumin molecule[40].
Dansylsarcosine-binding capacity
Albumin contains two major binding sites: site I, where the major heterocyclic
complexes and dicarboxylic acids (such as arachidic acid, warfarin, and bilirubin)
bind, and site II, which binds aromatic acids, such as diazepam, tryptophan, and
guanidine. The binding properties of site II can be assessed using dansylsarcosine (DS)
as a ligand, and Klammt et al. [41]have described a method for determining DS
binding. Samples and a standard preparation of albumin as control are first reacted
with the binding site II-specific fluorescent label (DS), then unbound DS molecules
are removed by ultrafiltration. The same volume and concentration of albumin
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solution is added as a fluorescence amplifier, and the albumin-binding capacity
(ABiC)[41, 42] is determined using a spectrophotometer. ABiC (%) = fluorescence in
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the filtrate of the reference / fluorescence in the filtrate of the sample × 100%. Similar
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measurements can also be made using a high-performance liquid chromatography
(HPLC) system[13].
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Metal ion-binding capacity
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The metal ion-binding ability of the N-terminal metal ion binding site can be
assessed using cobalt, and this is a method of determining the proportion of ischemic
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IMA has been found to be associated with liver diseases, including acute liver injury,
hepatitis, cirrhosis, and liver failure. Bar-Or et al. [43] have described a method for
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determining IMA using the metal-binding ability of albumin. Normal albumin binds
cobalt and dithiothreitol is added to allow it to react with free cobalt in the solution,
then the free cobalt concentration is quantified by spectrophotometry. The free cobalt
concentration is directly proportional to the IMA concentration, and therefore the IMA
can be calculated on the basis of the difference between the samples to which
dithiothreitol has or has not been added. Thus, the higher the absorbance, the larger
the amount of cobalt that is not bound to albumin, and the lower the metal-binding
ability of the albumin in the sample.
Antioxidant capacity
According to the oxidation state of Cys-34, HSA can be divided into three
categories: HMA, HNA1, and HNA2. Increases in HNA1 and HNA2 have been
documented in liver disease and are associated with the progression of liver disease,
which imply a reduction in the antioxidant capacity of albumin. HMA, HNA1, and
HNA2 can be separated and quantified using HPLC[13] and fluorescence detection.
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Isoforms of HSA
Post-translational modification (PTM) generates multiple isoforms of albumin
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that have diverse structures and play different roles in liver diseases. PTM is primarily
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studied using mass spectrometry methods[44], such as matrix-assisted laser
desorption/ionization tandem mass spectrometry (MALDI-MS/MS) and liquid
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chromatography/mass spectrometry (LC/MS)[26]. A change in the chemical group of
an amino acid side chain alters the molecular weight of the protein and this can be
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consequent poor prognosis. Recent studies have shown that the function of albumin is
impaired in a number of ways and that this is associated with the clinical features of
cirrhosis. In a study of 34 patients with cirrhosis[12], the transport efficiency,
detoxification efficiency, and metal-chelating ability of albumin were all lower in
cirrhosis. The metal-chelating ability of patients with cirrhosis was half that of healthy
individuals, and the transport efficiency of patients with cirrhosis was approximately
one third of that of healthy individuals. Furthermore, the detoxification efficiency of
patients with cirrhosis was 75% lower than in healthy individuals. After molecular
adsorption recirculation system (MARS) treatment, albumin function did not change
significantly, which suggests that functional impairments in albumin may be
irreversible. In addition, an impairment in the binding function of site II was
identified using dansylsarcosine studies in decompensated liver cirrhosis[13]. In
particular, the binding capacity of albumin was independently associated with the
bilirubin concentration and international normalized ratio (INR). There are multiple
sites on the albumin molecule that can bind bilirubin, which may partially explain this
phenomenon, but this association does not exist in patients with sepsis.
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A reduction in the binding ability of albumin implies that higher concentrations of
harmful substances that require metabolism remain in the blood, which may further
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aggravate the pathology. Indeed, such alterations in binding are associated with
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impairment in liver function, the severity of liver injury, and the prognosis. For
instance, positive correlations have been identified between IMAR and serum
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bilirubin, INR, end-stage liver disease (MELD) score, and total antioxidant capacity
(TAC)[46]. Albumin treatment improve bilirubin and MELD scores in patients but
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does not correct IMA and IMAR. Furthermore, IMAR is significantly associated with
oxidative stress markers[12], meaning that there is an impairment in the plasma
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antioxidant status of patients with cirrhosis. Moreover, patients with higher IMAR
have higher MELD scores, which implies a link between high IMAR and a poor
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prognosis. It has been reported that IMA is associated with bacterial infection in
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stages of cirrhosis, the albumin concentration is not usually lower than normal.
Therefore, it is difficult to assess the severity of the disease using albumin
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concentration or other related indicators. However, albumin function can be altered at
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an earlier stage of the disease. We have shown[40] that the fatty acid-binding capacity
and metal chelating-ability of albumin are much lower in cirrhosis. In addition, IMAR
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is higher in livers with advanced fibrosis than in those with mild fibrosis; therefore, it
may have potential as a marker of the severity of fibrosis[48, 49]. However, there are
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no clear differences in these parameters between early cirrhosis and hepatitis. This
may be accounted for by the substantial functional reserve of the liver with respect to
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Effects of liver failure on albumin function
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Acute-on-chronic liver failure (ACLF) syndrome is the cause of death in most
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patients with cirrhosis. Using the EASL‐ Chronic Liver Failure (EASL-CLIF)
Alliance definition, the reported global ACLF mortality is between 30 and 50%[52].
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In China[53], the 28-day mortality rate for patients with ACLF varies from 23.6% to
60.2%, depending on its severity. However, there is a lack of suitable early predictors
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of ACLF, making the early diagnosis and assessment of disease severity difficult.
Oettl et al. [13]have studied oxidative albumin damage in patients with chronic liver
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failure and found that the oxidation state of albumin and the binding capacity of site II
in patients with liver failure is significantly impaired. The percentage of oxidized
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proportion of HNA2 is directly related to their prognosis, and the 90-day mortality is
significantly higher in patients with a proportion of HNA2 >12%. These researchers
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also compared the accuracy with which HNA2 and MELD could be used to predict
survival, and found that HNA2 is more effective at predicting short-term (30-day)
survival than MELD. Fortunately, although the oxidation of HNA2 is irreversible, the
albumin in these patients is still mainly in the form of reduced HMA and
reversibly-oxidized HNA1. Jalan et al. [12] have also shown evidence of impaired
albumin function in patients with liver failure. They evaluated 34 patients with
cirrhosis, including 20 patients with ACLF, and found that the fatty acid-binding
capacity of albumin is significantly lower in those patients, whereas IMA is higher.
In vitro liver support systems, such as MARS, remove toxins, including bile
acids and bilirubin, from patients with liver failure[54, 55], but do not provide a
significant survival benefit in patients with ACLF[12]. MARS can “regenerate”
albumin, but does not remove damaged albumin (permanently oxidized HNA2), and
subsequent studies should pay more attention to the severity of the oxidative damage
to albumin.
Artificial liver is an effective method for treating liver failure. The ability to
synthesize and secrete albumin is a vital indicator for testing the function of artificial
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liver[56-59], but researchers only detect the concentration of albumin. Whether
albumin synthesized by the artificial liver exhibits the same biological properties as
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albumin in physiological state is unknown. Albumin function may become an
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effective indicator for the biological characteristics of the in vitro liver tissue model.
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Effects of non-alcoholic fatty liver disease on albumin function
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The prevalence of NAFLD is continuing to increase, such that it is now one of the
most common chronic liver diseases worldwide. NAFLD is a progressive disease,
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with various diseases such as cardiovascular disease [61, 62]. Therefore, early
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the early stage of NAFLD, making it impossible for clinicians to detect early liver
damage using non-invasive methods. We previously studied 23 patients with
NAFLD[40] and found that the binding capacity of albumin, including for metals and
fatty acids, decreases before the total plasma albumin or bilirubin concentration, or
the prothrombin time show abnormalities. In addition, the H/L ratio was used to
characterize conformational changes in HSA, and showed that indeed the albumin
conformation in NAFLD patients does change. Interestingly, however, we found no
correlation between the metal-binding capacity of albumin and its ability to bind fatty
acids, suggesting that there are differences in the modifications to the binding sites of
albumin during the progression of liver disease. Non-invasive clinical assessment of
NAFLD is needed for its diagnosis[63]. Thus, albumin binding function may be used
as an indicator of early liver injury, but whether this is superior to other indicators for
the diagnosis of NAFLD requires further investigation, given the rising prevalence of
NAFLD.
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Viral hepatitis is an important risk factor for cirrhosis and liver cancer, and it’s
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one of the leading causes of human death and is becoming an increasingly serious
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problem of world health. But just like NAFLD, conventional non-invasive
measurements cannot detect injury caused by early hepatitis. Impairments in metal-
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and fatty acid-binding by albumin are found in patients with hepatitis B and C, and
these occur before other routine parameters become abnormal[40]. Furthermore, these
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changes are more severe than in NAFLD patients. A study[49] of 74 patients with
chronic hepatitis B and 25 patients with HBV-induced cirrhosis found that serum IMA
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concentration and IMAR was higher in these patients than healthy controls, and both
groups demonstrated liver fibrosis. Therefore, the authors proposed the use of IMA
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and IMAR as non-invasive markers of liver fibrosis in HBV patients. Similar results
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have also been reported for children with chronic liver disease[48].
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Liver resection may have a substantial effect on liver function and postoperative
liver failure can endanger the lives of patients[64]. Therefore, the preoperative
evaluation of liver functional reserve is very important for patients due to undergo
hepatectomy. Preoperative albumin concentration can be used as an indicator to
predict surgical outcomes [65], but there are few studies on albumin function in
perioperative patients. We have previously[66] studied 42 patients with hepatocellular
carcinoma and 17 patients with hepatic cavernous hemangioma who underwent
surgical resection, and found that hepatectomy has a significant impact on albumin
concentration and function, but that the changes in albumin function do not parallel
perioperative changes in albumin concentrations. The metal ion- and fatty
acid-binding capacity of patients with cirrhosis reached a nadir on postoperative day 3,
and then increased gradually to near-preoperative levels by postoperative day 7.
However, the albumin concentration was still lower than the preoperative level on
postoperative day 7, implying that albumin function is more sensitive to surgery than
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concentration. However, further research is needed to confirm the usefulness of
evaluating perioperative liver function.
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The potential mechanisms of impairments in albumin function
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Changes in albumin function result from structural changes, the most important
cause of which is PTM, which leads to the formation of multiple HSA isoforms[67].
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Previous studies have focused on the protein expression of HSA, but changes in
protein expression do not accurately reflect the changes in complex biologic systems
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various functions of HSA[68, 69]. There are hundreds of known PTMs[70], including
phosphorylation, ubiquitination, acetylation, and glycosylation[44], which are
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was significantly lower, whereas the proportion of isoforms with structural changes
was significantly higher. Furthermore, these changes were associated with disease
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severity, the incidence of clinical complications, and survival rate.
albumin with normal function, which reflects the importance of the biological
function of albumin. Based on last research reports, it is speculated that effective
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albumin concentration is decreased in many kinds of liver disease, though there is still
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disorders, surgical trauma and oxidative stress have deleterious effects on liver
function, and some of these are associated with PTMs of albumin, which can cause
three-dimensional structural changes and consequent dysfunction. Studies of
impairments in albumin function have shed new light on the diagnosis, evaluation and
treatment of patients with liver diseases, especially those in the early stage of liver
diseases, such as viral hepatitis and NAFLD.
However, it is unclear whether impairments in albumin function are a component
of the pathogenesis or are a consequence of liver disease, and the specific mechanisms
involved remain to be established. In part, this has been because the number of
patients included in previous studies has been relatively small; therefore, larger
studies are required. Moreover, albumin function has not been studied in many liver
diseases, such as liver cancer, liver transplantation, autoimmune hepatitis,
drug-induced liver damage, and hereditary metabolic liver disease. Thus, more
high-quality research is urgently needed in this field.
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Acknowledgments:
This study was supported by grants from the CAMS Innovation Fund for Medical
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Sciences (CIFMS) (No.2016-I2M-1–001) and the National High-tech Research and
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Development Projects (863) (No.2015AA020303).
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Declaration of interest:
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subdomains (A and B). Binding site I and binding site II, and Cys34 are indicated by
arrows.
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Ac
Figure.2 The alterations of albumin function in liver diseases
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Many factors including hepatitis virus, alcohol intake, metabolic disorders, surgical
trauma and oxidative stress result in the PTMs of albumin. The impaired
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three-dimensional structure will cause decreased albumin function in maintaining
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plasma oncotic pressure, dissolving, binding and transporting endogenous and
exogenous molecules, antioxidant, anti-inflammatory, hemostatic effects, endothelial
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stabilization and adjusting capillary permeability, which has an impact on a variety of
liver diseases.
M
Antioxidant The largest plasma reservoir Cys-34 and chelating metal ions
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of SH (80%) [Cu(II) and Fe(II)]
Anti-inflammatory One of the mechanisms of Bind to bacterial antigens and
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immune regulation endotoxin, and inhibit the