Clinical Chemistry 43: 1539-1545, 1997;
(Clinical Chemistry. 1997;43:1539-1545.)
© 1997 American Association for Clinical Chemistry, Inc.
Assessment of liver function: pre- and peritransplant evaluation
Abraham Shakeda,
Fredrick A. Nunes1,
Kim M. Olthoff and
Michael R. Lucey1
Departments of Surgery and
1
Medicine, University of Pennsylvania, Philadelphia, PA.
a Address correspondence to this author at: Hospital of the University of Pennsylvania, Department of Surgery, 3400 Spruce St., Philadelphia, PA 19104. Fax 215-662-2244; email shaked{at}mail.med.upenn.edu
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Abstract
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Liver transplantation has been demonstrated to be a successful
therapeutic modality for patients with end-stage liver disease. The
high rate of survival for an otherwise terminal condition has resulted
in significant expansion of the indications and diseases treated by
this procedure, and is hampered only by the limited numbers of organs
available for transplantation. Efforts in clinical and laboratory
medicine should be directed to identify candidates who would benefit
most from this procedure, to provide better means for accurate
assessment of liver reserve and the appropriate timing for
transplantation, to identify quality liver grafts that would have the
potential to tolerate cold preservation and reperfusion injury, and to
assist in accurate monitoring of graft function immediately after
transplantation. The aim of this manuscript is to describe the existing
pathways for clinical and laboratory assessment of pretransplant
residual liver function, the donor liver graft, and immediate
posttransplantation function.
Key Words: indexing terms: liver transplatation • end-stage liver disease • reperfusion injury • liver reserve
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Introduction
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Liver transplantation has become the treatment of choice in the
developed world for end-stage liver disease. The wider application is
limited by an inadequate supply of organ donors and by cost. Over 4000
liver transplants are performed in the US annually, as part of a
worldwide total of ~8000. The 1-year survival in many of the centers
is ~80%, after which there is a slight attenuation annually. This
significant initial mortality, and the relatively low numbers of organs
available, requires that the procedure be restricted to patients with
life-threatening disease. Under such circumstances, judging the
appropriate time for placement on the waiting list becomes a critical
issue, and is totally dependent on the clinical assessment of the
patient's condition, as well as laboratory evidence of residual liver
function. The relative shortage of organs for transplantation has
resulted in multiple attempts to utilize donors' organs that otherwise
would have been rejected for either medical reasons or on the basis of
donor social history. Obviously, the extended criteria to use organs
defined as marginal, i.e., those retrieved from older donors, unstable
donors, etc. are critical for expansion of the donor pool. The
inability of some of these grafts to withstand the injuries associated
with procurement, cold preservation, and reperfusion necessitates the
development of liver donor-specific assays that will assure that all
the grafts will be functioning after transplantation. The relatively
high rate of nonfunction of donor grafts (5–10%) judged to be
acceptable for transplantation indicates that clinical evaluation
coupled with a few basic biochemistry tests is not sufficient to
estimate whether immediate posttransplant graft function will recover.
The issue of residual liver function and reserve was addressed before
the days of liver transplantation, and continues to be studied by many
hepatology and transplant groups. There are numerous tests aimed toward
quantitative and qualitative analysis of liver reserve. The principle
of many of these assays is to define metabolic/energy-dependent
pathways that can be easily measured, and reflect the functioning
hepatic mass under normal circumstances and stress. This review will
concentrate on the current laboratory assays that are commonly used to
identify the status of the recipient liver reserve before
transplantation, the quality of the donor liver before procurement, and
the function of the graft immediately after reperfusion.
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pretransplant assessment of end-stage liver disease
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Determining the prognosis of liver disease and using this
information to time liver transplantation is difficult. Apart from
specific examples such as primary biliary cirrhosis, there are no
well-documented prognostic models for chronic liver disorders
(1)(2). The Child–Pugh scale is the easiest
prognostic instrument to use (3). It combines synthetic
function [serum bilirubin, prothrombin time (PT)], excretory function
(serum bilirubin), and clinical evidence of portal hypertension
(ascites, encephalopathy) (Table 1
).1
It is useful for segregating cirrhotics into high
and low risk strata, but it is not accurate in predicting prognosis
within these limits.
In addition to these global assessments, the decision to place a
patient on the waiting list is influenced by clinical events such as
episodes of variceal bleeding, spontaneous bacterial peritonitis,
intractable ascites, or poorly controlled encephalopathy
(4)(5)(6)(7). General systemic well-being as indicated by
fatigue and inability to work is also important. The current
indications for placement on the list are described in Table 2
. It is clear from these criteria that there is a desperate need
for better tools to assess residual liver function before
transplantation, and to determine who will benefit the most from the
procedure. Therefore, better utilization of existing liver-specific
tests, as well as new assays, must be developed to provide more
objective quantitative and qualitative assessment of liver reserve in
the cirrhotic patient.
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biochemical assessment of residual liver function and reserve
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Several quantitative tests have been proposed to measure residual
hepatic function. Different aspects of liver function may be measured
on the basis of the substrate selected. Substances that the liver
efficiently extracts from blood are chosen to measure hepatic blood
flow. The substance is administered and its rate of removal from the
blood is used to calculate clearance. A decrease in clearance for
substances with high extraction rates suggests decreased blood flow, as
occurs in cirrhosis. The rate of blood flow to the liver is
overestimated in patients with advanced liver disease because the
hepatic extraction of the administered substance falls. Substances used
to calculate flow include indocyanine green (ICG) (8),
which has a high hepatic extraction ratio of 70–96%. ICG is excreted
unchanged into the bile, and the liver appears to be the only site of
clearance. ICG is administered as a single intravenous infusion ranging
from 0.64 to 6.4 µmol/kg, and a blood concentration 20 min later is
determined (9).
Substances with a low hepatic extraction ratio have been used to
determine residual hepatic mass or metabolic ability. Changes in
hepatic blood flow do not alter clearance to a significant degree,
whereas changes in liver cells functionally able metabolize the
substance have a large effect on clearance. Substances are administered
and the loss of the substance from blood or the appearance of a
metabolic product in blood or expired air is determined.
The aminopyrine breath test has been investigated extensively as a
simple and reliable index of hepatic microsomal enzyme reserve
(10). [14C]Aminopyrine is administered
orally and the labeled carbon removed by hepatic microsomal enzyme
activity. Expired 14CO2 is collected 2 h
after oral administration and activity is determined. Marked decreased
isotope activity occurs in cirrhotic patients compared with controls
(11).
Galactose elimination capacity has been used as an index of residual
hepatic function (12). Galactose is administered
intravenously at a dose of 0.5 mg/kg and serial blood samples assayed
for galactose (13). The results are corrected for urinary
galactose excretion. The clearance of galactose is decreased in
individuals with chronic liver disease and cirrhosis compared with
healthy controls. Findings similar to the intravenous galactose test
have been obtained with a [14C]galactose breath test
(14).
Caffeine clearance tests have been used to estimate residual hepatic
function. Caffeine is well absorbed and almost completely metabolized
in the liver. The pharmacokinetics of caffeine in healthy humans is
well described, and clearance is delayed in individuals with cirrhosis.
A breath test analogous to the aminopyrine breath test has been
reported to represent a quantitative measure of hepatic microsomal
activity (15). Plasma clearance and salivary clearance
methods have been developed that eliminate the requirement for
radioactivity and breath collections (16). Smoking
increases caffeine clearance and can act as a confounding variable.
In the transplant setting, ICG, aminopyrine breath test, galactose
elimination capacity, and caffeine clearance tests are seldom used.
Their ability to distinguish and accurately determine the residual
liver reserve in the presence of an already obvious severe cirrhosis
and decompensated liver failure is limited. Once the patient becomes a
candidate for transplantation, surgery is performed on the basis of the
availability of a matched organ.
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assessment of donor graft function
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The limited time between determination of brain death and
procurement restrict the evaluation of the donor liver to the clinical
judgment of the transplant surgeon, and to the use of a limited set of
standard laboratory tests directed at liver synthetic function and
injury. These data are used to determine the capacity of the organ to
withstand the surgical insult during procurement, extended cold
ischemia, and reperfusion injury. Currently, most surgeons rely on the
donor's previous medical history, mechanism of death and its potential
effect on the liver, and the relative stability or instability of the
donor for initial assessment. Important laboratory tests include
liver-specific transaminases [aspartate aminotransferase (AST) and
alanine aminotransferase (ALT)], and synthetic function is reflected
by serum albumin and PT. Serology screening is used to indicate the
presence of acute or chronic liver diseases such as hepatitis B and C,
or other common types of viral infections.
Unfortunately, the accuracy of this assessment can be measured only by
outcome analysis of graft survival. Obviously, it is impossible and
unethical to demand that all available donor livers be transplanted for
the sole purpose of obtaining nonbiased data regarding the variables
affecting graft survival. In reality, all outcomes are correlated with
either immediate function or malfunction of the transplanted allograft,
excluding technical complications leading to posttransplant ischemic
damage.
Multivariate analysis of large numbers of recipients was used to
identify donor-related factors that have significant impact on graft
survival (17). In general, primary nonfunction (PNF) and
delayed nonfunction (DNF) of the graft were best correlated with the
age of the donor, mechanism of death, the development of significant
hemodynamic instability requiring treatment with multiple vasopressors,
and the length of cold ischemia time. In a limited number of studies,
donor liver function was analyzed by using liver-specific enzymatic
pathways, or assessment of mitochondrial viability.
A major variable affecting graft function is the donor age
(18)(19). Pattern of liver injury, synthetic
function, and graft survival in recipients receiving liver grafts from
donors older than age 50 years were compared with recipients
transplanted with grafts from donors ages 20–30. Ischemic/reperfusion
injury, reflected by AST and ALT, was more severe in older donors (Fig. 1
). PNF occurred at similar frequencies for all recipients (7%).
However, normal liver function was regained in only 76% of recipients
of older liver grafts vs 92% in recipients of younger grafts. DNF was
characterized by a rapid rise in bilirubin despite normalization of PT
and liver transaminases. There is no explanation for the relatively
similar number of PNF in both groups, and the more common development
of DNF in the older liver grafts. This phenomenon may relate to a
not-well-defined mutual relation between aging and liver function. The
question of whether aging of the liver affects outcome after exposure
to procurement-related injury, cold preservation, and reperfusion
injuries remains to be determined. In an experimental model of rat
liver transplantation, donor age was correlated with a histology
finding of biliary casts, and increased ALT concentrations were
significantly higher in recipients of old livers (20).
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Figure 1. Relation between donor age and probability of graft
failure.
The older donor population has higher rate of DNF.
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The length of cold ischemia has also been demonstrated to affect graft
function. Currently, livers can be successfully preserved in University
of Wisconsin (UW) preservation solution for 24 h. The UW solution
is effective because it has a number of agents (lactobionic acid,
raffinose, hydroxyethyl starch) that prevent cell swelling, as well as
glutathione and adenosine, which may stimulate recovery by augmenting
antioxidant capacity and high-energy phosphate generation
(21)
The findings that a selected number of older donor grafts exposed to
the same length of cold ischemia display more profound
ischemic/preservation injury as manifested by increased DNF and poorer
initial graft function indicate that specific biochemical/enzymatic
circuits are affected beyond recovery. Furthermore, preservation
methods and length of cold ischemia appear to contribute to graft
injury. Laboratory medicine must identify these pathways, provide rapid
tests to determine which livers of older donors will have acceptable
liver function early and late after transplantation, and correlate the
length of cold ischemia with graft function in these older donors.
Developing these tests may greatly encourage the use of many livers
that are currently discarded.
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biochemical analysis of the donor liver
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The relatively high rate of PNF of liver grafts seen in 5–10% of
the recipients after transplantation initiated the search for objective
indicators to identify the quality of the procured graft and predict
its capacity to withstand cold storage and reperfusion injuries.
Energy-dependent metabolic pathways.
Selecting
energy-sensitive metabolic processes that may reflect the integrity of
the various oxidative pathways within the hepatocyte was logical.
Previous studies have found that lidocaine disposition is a highly
sensitive indicator of hepatic dysfunction. Specifically, the kinetics
of the lidocaine metabolite monoethylglycinexylidide (MEGX) can be used
to assess hepatocyte injury (22)(23)(24). MEGX is formed from
lidocaine via oxidative N-deethylation by the hepatic cytochrome-P450
primarily by an enzyme identified as CYP34A. The product can be
measured in the blood within 15–30 min after administration, and the
metabolite can be detected via an automated immunoassay specially
designed for this test. Prospective studies have debated the efficacy
of this test in determining the donor liver graft survival after
transplantation (25)(26). However, there was a
high rate of false-positive results, as reflected by good graft
function after transplantation of liver grafts from donors with low
MEGX in almost 50% of the recipients (27). Furthermore,
the test was associated with some incidence of normal results at the
donor site, while the graft failed to function after transplantation,
indicating poor correlation with prognosis.
Function of endothelial cells.
The uptake of hyaluronate
by the vascular endothelium can serve as a marker for cell injury, and
may predict PNF of the graft secondary to reperfusion injury to the
microcirculation. The hyaluronate content of reperfusion effluent has
been found to inversely correlate with ultimate graft function. Because
hyaluronate uptake by the microvascular endothelial cell is
significantly greater than production, high concentrations in failing
livers reflect decreased uptake by the injured cells (28).
These assays serve as representatives of a large number of tests that
may be used to determine the quality of the donor liver before
procurement. They are limited by either low sensitivity and (or)
unrealistic application (since some are done immediately after
reperfusion). More sophisticated and clinically feasible methods will
be essential for more accurate assessment of the donor liver.
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assessment of posttransplant liver graft function
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Immediate and long-term function of the liver graft after
transplantation is directly correlated to the quality of the donor
liver, as well as multiple host-related variables that may affect the
intraoperative course and the initial posttransplant recovery period.
Previous studies have linked the pretransplant United Network for Organ
Sharing status with short-term graft and patient survival, indicating
that conditions reflecting the severity of the liver failure and (or)
the presence of other organ system failure(s) have a major impact on
the ability of the graft to function in the new surrounding
(29). Furthermore, the magnitude of the alloimmune
response may result in a severe destruction of the hepatic parenchyma,
leading to a significant decrease in hepatic reserve and subsequent
graft failure (30).
The main characteristics of a well-functioning graft are the relative
hemodynamic stability of the recipient immediately after reperfusion,
continuous urine output, and intact neurological function. PNF of the
graft can be defined as nonrecoverable hepatocellular function
necessitating emergency retransplantation within 72 h, whereas DNF
may be defined as initial marginal graft function necessitating
retransplantation within 1 month. PNF or DNF of the graft are usually
associated with persistent tachycardia, decreased urine output and
renal shutdown, and disturbances in mental status culminating in
hepatic coma. Production of bile appears to be one of the most useful
predictors of graft failure, and both quantity and quality of the bile
are correlated with the development of PNF and DNF of the graft.
Progressive increase in output, as well as a darker appearance, are
signs of recovery. Investigating better biochemical means to define the
quality of bile to more accurately determine the fate of the graft will
be important.
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biochemical assessment of posttransplant graft function
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Correction of acidosis.
Hemodynamic changes occurring
during the anhepatic stage, coupled with initial release of various
substances from the reperfused liver, result in the development of
metabolic acidosis. In the presence of a functioning graft, the
correction of the acidosis is possible with repeated injection of
sodium bicarbonate, and is further prevented by better tissue perfusion
and production of bicarbonate by the kidneys. Furthermore, the
conversion of the citrate (used as preservative in packed red blood
cells) to bicarbonate by the liver indicates the recovery of
hepatocellular function. In contrast, persistence of the metabolic
acidosis is an indicator of impaired liver graft function
(31)(32).
Serum markers and coagulation profile.
Liver-specific
transaminases are commonly used to determine the extent of
procurement/preservation/reperfusion injuries to the graft
(33). The serum concentrations of lactate dehydrogenase,
AST, and ALT are good markers of hepatocyte loss, and are present in
the systemic circulation within a short time after reperfusion.
Continuous increases of serum transaminases coupled with persistent
coagulopathy are signs of global injury and graft nonfunction, whereas
recovery of these biochemical indices indicates improvement in graft
function. Serial measurements of PT at different intervals within
24 h after reperfusion will indicate whether the new liver is
capable of producing factors that are necessary for maintenance of
normal coagulation. Typically, a trend toward normalization of the PT
will be seen within the first 24 h after surgery and may require a
few days for full recovery. In contrast, a nonfunctioning graft will
present with prolonged PT, which may be difficult to correct with
infusion of fresh frozen plasma.
Arterial ketone body ratio (AKBR).
Measurement of the
AKBR is the best demonstration of how the clinical laboratory can
assist in accurate determination of hepatic function and posttransplant
recovery of the graft. The oxidation–reduction theory is based on the
hypothesis that the energy charge of the liver is determined by the
liver mitochondria energy production, and is reflected by the ratio of
NAD+/NADH. The concept of an adenylate energy charge regards the
adenine nucleotide system as the energy currency of the cell, which is
a balance of energy-generating and energy-consuming reactions. Under
normal aerobic conditions, the energy charge of the cell is maintained
at a high and constant level. When energy-generating sequences are
insufficient, the energy charge decreases. Thus, the energy charge is a
convenient indicator by which to determine the intracellular energy
status as well as the organ energy charge at any given time and
condition.
The mitochondrial NAD+/NADH ratio was shown to correlate with the
concentration of the ketone bodies' acetoacetate and that of
ß-hydroxybutyrate (34). In the liver mitochondria,
acetoacetate is produced in the matrix compartment and undergoes
reduction to ß-hydroxybutyrate by ß-hydroxybutyrate dehydrogenase
localized in the mitochondrial inner membrane (35).
Because the ß-hydroxybutyrate dehydrogenase concentration is
exceptionally high in the liver (36), and these two
ketones penetrate cell membranes, the ketone body ratio in the hepatic
venous blood can reflect that in the liver mitochondria. Subsequent
studies proved that the changes in the ketone body ratio in the
arterial blood are consistent with the changes observed in the hepatic
veins (37). In contrast, venous blood sampling for ketone
body ratio will not reflect the actual energy status of the liver,
since the equation should consider the use of ketones in the peripheral
tissue.
Two possible mechanisms may explain the fall in AKBR after orthotopic
liver transplantation (OLT). The first is the inhibition of the
electron transport system, due to relative deprivation of blood supply
available to the liver mitochondria. The second is an enhancement of
ß-oxidation of fatty acids, since ß-oxidation reduces the
mitochondrial NAD+/NADH ratio. ß-oxidation is unlikely a contributing
factor in this system, since all the measurements were done under
glucose load. In contrast, ischemic damage is more likely to occur
after OLT, resulting in a decrease in AKBR as seen in the adult and
pediatric recipients with PNF and DNF of the graft. This was also
demonstrated in other systems where an acute decrease in arterial blood
flow to the liver after hepatic artery embolization, or warm ischemic
injury, resulted in falling AKBR (37)(38).
Laboratory and clinical studies have demonstrated the significance of
AKBR as a means to estimate liver functional reserve. Animal
experiments have shown that changes in AKBR reflect the energy charge
of the liver and the liver mitochondrial function during endotoxic
shock, jaundice, and after liver transplantation (39)(40)(41).
These experiments demonstrated that peripheral perfusion and acid–base
balance affect the residual liver function. Clinical studies confirmed
these observations, allowing a correlation between the residual hepatic
function and the outcome of patients undergoing liver resection or
transplantation, trauma, sepsis, and multisystem organ failure
(42)(43)(44). Recent studies by us and others have
demonstrated that the dynamic changes in the AKBR pattern are useful in
the diagnosis of PNF or DNF of adult liver recipients, and correlate
with short-term graft and patient survival (Fig. 2
). The assay requires 1 mL of heparinized arterial blood, and
results can be obtained within 40 min. AKBR was determined by the
enzymatic method of Williamson and Melanby
(45)(46), using a commercially available kit
(Ketorex Sanwa Kit; Sanwa Kagaku Kenkyusho Co., Kasugai, Japan).
Acetoacetate and ß-hydroxybutyrate are calculated by the decrease or
increase in absorbance at a wavelength of 340 nm in the adult
recipient. All measurements were done under glucose load [blood sugar
>6.66 mmol/L (120 mg/dL)], since ketosis occurring during
hypoglycemia was shown to affect the molar concentration of
acetoacetate and ß-hydroxybutyrate (47). Rapid recovery
was associated with 100% 1-month graft survival. In contrast, slow or
no recovery pattern resulted in the loss of 50% and 100% of the
grafts (48)(49)(50)(51)(52). These studies also demonstrated that the
synthetic function of the grafts, as reflected by the PT, correlated
with the AKBR, and predicted graft survival.
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Figure 2. AKBR reflects the ability of the graft to recover after
cold ischemia and reperfusion injury.
Rapid recovery with ratio >1 within 12 h is associated with
excellent graft function. In contrast, persistent low ratio of AKBR was
seen in PNF grafts.
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Peroxide and graft injury.
The formation of
prostacyclin, thromboxane, and lipid peroxide were postulated to
reflect the severity of hepatocyte damage and anoxia/reperfusion injury
to the microvasculature. Studies in human recipients demonstrated that
prostacyclin production correlated with early postoperative graft
function, whereas lipid peroxide production, as measured by
thiobarbituric acid-reacting substances, was indicative of significant
injury (53).
In summary, accurate assessment of residual liver function is based
on a set of clinical criteria as well as specific liver-related
laboratory tests. The current trend appears to be the development of
assays that can challenge energy-dependent metabolic pathways within
the hepatocyte, with an attempt to quantify the remaining hepatic mass
as well as to predict whether the liver can withstand a stress such as
procurement, cold-preservation, and reperfusion injuries. The most
promising approach appears to target the liver mitochondria and the
cytochrome-P450 system. The available assays such as the lidocaine test
are more accurate in the assessment of already established liver
disease, whereas the AKBR is more reliable in predicting recovery from
more acute injury such as the immediate posttransplant graft function.
The deficiencies of these methods are related to their inability to
identify more subtle changes in the liver, resulting in the failure to
differentiate mild from moderate disease in the patient with
progressive end-stage liver disease, or predict the function of the
procured graft before transplantation. More innovative approaches and
sophisticated assays need to be developed to better define liver
function and residual reserve.
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Footnotes
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1 Nonstandard abbreviations: PT, prothrombin time; ICG, indocyanine green; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PNF, primary nonfunction; DNF, delayed nonfunction; MEGX, monoethylglycinexylidide; OLT, orthotopic liver transplantation; and AKBR, arterial ketone body ratio. 
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Abstract
Introduction
