Key words
abdomen - MR functional imaging - MR imaging - SPECT - radionuclide imaging - laboratory
tests
Development of Imaging-Based Liver Function Tests
Development of Imaging-Based Liver Function Tests
The liver as the central metabolic organ assumes a wide range of functions in the
organism including synthesis of proteins and coagulation factors, storing of vitamins
and glycogens, elimination of bilirubin, medications, and bile salts, and immunological
functions via the Kupffer cells. There is a significant need to determine functional
capacity. It is relevant for risk assessment prior to liver resection, follow-up after
liver transplantation, and monitoring of chronic liver diseases. In correlation with
the plurality of subfunctions, clinical scores as well as a number of global liver
function tests were developed with the most well-known test being the indocyanine
green test including measurement of the ICG clearance rate [1]. However, a test that has been generally established in the clinical routine has
not yet been developed [1]
[2]
[3]. In addition to ease of use, a decisive criterion for such a test is significant
correlation with the clinical course or postoperative liver failure in cases of risk
assessment prior to liver resection.
The role of radiology was previously primarily liver resection planning with determination
of the total liver volume and the presumed postoperative liver volume (FLR – future
liver remnant) as a surrogate marker for liver function and enlargement of the FLR
via preoperative portal vein embolization (PVE) in patients with an insufficient liver
remnant. The risk of postoperative liver failure due to an insufficient functional
liver volume continues to be one of the greatest risks in modern liver surgery, particularly
in the case of extended right resection, in patients with a damaged liver parenchyma,
and in the case of preexisting liver cirrhosis [4]
[5]
[6]. As a result of the increasingly radical surgical methods, PVE has become standard
in patients with insufficient postoperative liver volume [7]
[8]. The challenges for radiology and surgery are selecting patients who profit from
PVE, monitoring the increase in function, and determining the optimal time point for
liver resection. Any delay of surgery due to PVE should be kept as minimal as possible
from an oncological perspective since tumor progression would be in direct conflict
with the planned curative approach by radical surgical therapy [9]. An alternative approach to enlarging the FLR is the in situ split technique [10]. In a two-step surgical approach, the FLR is first separated from the liver volume
to be resected to prevent collateralization and the right portal vein branch was ligated.
In a second step approximately two weeks later, definitive resection is performed.
However, the invasiveness and complication rate are significantly higher than in the
case of PVE.
At present, only the volume increase but not the functional capacity of the non-embolized
liver half is measured. For this purpose, CT or MRI examinations are performed before
and 4 – 6 weeks after portal vein embolization. If a sufficient increase in volume
is determined, definitive surgery is performed [8]
[11]. This approach assumes uniform distribution of liver function in the liver volume
that cannot be clearly identified as tumor. However, this can no longer be assumed
after portal vein embolization ([Fig. 1]). As systematically shown for the first time by de Graaf et al., the increase in
function exceeds the volume increase [12]. Global liver function tests such as the ICG test and clinical scores reach their
limit here since only the total functional capacity of the liver can be measured.
Fig. 1 Gd-EOB-enhanced MRI 4 weeks after right portal vein embolization, T1-VIBE sequence
after 20 minutes with flip angle of 30°. MRI with an increased excitation angle clearly
shows the different signal intensities of the embolized and the non-embolized liver
segments corresponding to a different function ratio.
Imaging-based liver function tests represent an alternative for determining liver
function with the possibility of measuring function in parts of the liver [13]
[14]. They are based on the intravenous application of pharmacological substances that
are absorbed by hepatocytes and are degraded or excreted in bile. Using nuclear medicine
or radiological methods, the drug concentration is measured via planar images (gamma
camera) or cross-sectional imaging (SPECT/CT or MRI). This can be performed at a fixed
point in time after application or dynamically to determine kinetics. Nuclear medicine
techniques followed by radiological methods will be discussed in the following.
Nuclear medicine techniques
Nuclear medicine techniques
In recent decades, different nuclear medicine tracers for determining liver function
have been developed. One of the first was 131I-rose bengal, which is currently no longer used due to the high β-radiation [15]. Current hepatobiliary tracers are based on 99 mtechnetium. 99 mTc-galactosyl (GSA) and 99 mTc-mebrofenin are used for imaging-based liver function measurement [14]
[16].
The asialoglycoprotein receptor is expressed exclusively on hepatocytes of mammals
and is specific for asialoglycoproteins. The receptor is expressed on the sinusoidal
surface of hepatocytes, known as the perisinusoidal space [17]. Asialoglycoproteins bind to the asialoglycoprotein receptor and are absorbed by
the hepatocytes via receptor-mediated endocytosis and are then broken down in the
lysosome [14]. In the case of chronic liver diseases, there is a significant decrease in the concentration
at the asialoglycoprotein receptors [18]
[19]. The synthetic 99 mTc-coupled asialoglycoprotein 99 mTc-GSA as a suitable tracer is currently only used in Japan [19].
IDA analogs for hepatobiliary scintigraphy were first described in 1976 by Lobert
et al. [20]. Today, mebrofenin is the most important substance in this group since it has the
highest specificity for hepatocytes [21]. All IDA analogs are bound to albumin and transported to the liver and then dissociate
again in the perisinusoidal space. They are then absorbed by the hepatocytes via organic
anion-transporting polypeptides (OATP) 1B1 and 1B3 and are eliminated in bile. This
occurs without prior biotransformation primarily as a result of multidrug resistance
protein (MRP) 2 [20]
[22]
[23]. The IDA analogs share their metabolic pathway with a number of endogenic and exogenic
substances, such as bilirubin, medications, toxins, and hormones [24].
99 mTc-GSA and 99 mTc-mebrofenin are highly liver-specific and have negligible renal elimination in the
case of normal serum bilirubin [18]
[25].
Nuclear medicine imaging can be performed using planar methods (single or dual head
gamma camera) or three-dimensionally via SPECT. SPECT acquisition allows 3 D distribution
analysis and the possibility to perform CT attenuation correction allows more exact
measurement [14]
[16]. However, it can only be used on a limited basis in the case of IDA analogs since
the temporal resolution is not sufficient for the determination of kinetics and thus
tracer clearance. A combination of dynamic planar imaging and an additional single
SPECT acquisition to resolve this problem has therefore been described [12]
[26]. The preferred parameters from the dynamic evaluation are blood-clearance rate and
hepatic uptake rate for GSA and hepatic uptake rate and extraction fraction for the
IDA analogs [16]
[27].
Due to the shared metabolic pathway, 99 mTc-mebrofenin scintigraphy correlates with the ICG tests and the postoperative liver
function [26]
[28]
[29]. Moreover, it can detect the function increase in the non-embolized liver segment
after portal vein embolization [12]
[30] and is also used to determine the function of an auxiliary liver transplant ([Fig. 2]). Successful liver function measurement with 99 mTc-GSA scinitigraphy has also been described. It was able to detect an increase in
function in the non-embolized liver segment after portal vein embolization and functional
differences between the two liver lobes [31]
[32]
[33]
[34]. For example, Sumiyoshi et al. were able to show significant regional functional
differences in patients with biliary drainage due to cholangiocarcinoma [34]. Prediction of the postoperative liver function and determination of the “functional
liver mass” are also possible [31]
[35]
[36].
Fig. 2 99 mTc-mebrofenin scintigraphy 1 week after auxiliary liver transplantation. The left
figure shows planar image after 45 minutes with 45° RAO detector rotation. The right
figure shows the two time activity curves of the first 10 minutes after tracer application.
MRI as imaging-based liver function test
MRI as imaging-based liver function test
Liver-specific MRI contrast agents were actually developed for improved detection
of focal liver lesions [37]
[38]. In addition to the still available superparamagnetic iron oxides (SPIO) which are
specific for the reticulo-endothelial system (RES), hepatocyte-specific contrast agents
are increasingly being evaluated with respect to their ability to be used for an imaging-based
liver function test [13].
Gadolinium ethoxybenzyl (Gd-EOB; Primovist®, Bayer AG, Berlin) and gadobenate-dimeglumine (Gd-BOPTA; MultiHance®, Bracco-Byk Gulden, Constance) are the two contrast agents with partial hepatocyte-mediated
elimination approved in Germany. 3 – 5 % of Gd-BOPTA is absorbed by the liver, while
up to approx. 50 % of Gd-EOB is absorbed in healthy subjects. The rest is eliminated
by the kidneys. Due to the low hepatic absorption, Gd-BOPTA has not been able to become
a relevant imaging-based liver function test [13]
[39].
Like mebrofenin, Gd-EOB is absorbed by the hepatocytes via organic anion-transporting
polypeptides (OATP) 1B1 and 1B3 and is then eliminated in bile via multidrug resistance
protein (MRP) 2 [39]
[40]
[41]
[42]. Therefore, its use as an imaging-based liver function test analogous to 99 mTc-mebrofenin scintigraphy is obvious, especially since MRI allows dynamic three-dimensional
measurement without ionizing radiation.
Two basic approaches have been described to date. The first approach measures the
biliary signal intensity, e. g. in the common bile duct, in the elimination phase.
This correlates with the biliary elimination rate of Gd-EOB and thus the liver function.
However, biliary outflow problems result in incorrect measurements [43]
[44]
[45].
The second approach is based on the measurement or evaluation of the parenchymal contrast
agent behavior over time. The relative enhancement of the liver parenchyma can be
determined by ROI analysis. A correlation with the function and prognosis of a liver
transplant could be shown for this simple approach. Wibmer et al. examined the relative
enhancement of the liver in Gd-EOB-enhanced MRI in 51 liver transplant patients. The
relative enhancement correlated directly with the retransplantation-free survival
rate [46]. Based on experiments in rats [47]
[48], Tajama et al. were one of the first to be able to show the connection between reduced
Gd-EOB enhancement and limited liver function in humans. Different lab values, the
Child-Pugh score and the ICG test were correlated with the SNR of the liver for this
purpose [49]. Various methods for optimizing this method were subsequently published including
a correction with the calculation of the liver-to-muscle enhancement ratio [50] and correction based on the liver volume and the enhancement of the spleen to determine
the "hepatocellular uptake index" (HUI) [50]. The HUI shows a significant correlation with the ICG clearance rate. Because of
its ease of use, this method is currently most widely used [13]. It is problematic to select the optimal MRI sequence.
Relaxometry makes it possible to measure absolute relaxation times and thus allows
better comparability between different equipment and sequence types. The T1 and T2*
relaxation times depend on the Gd-EOB concentration. Katsube et al. were able to correctly
determine the Child-Pugh stage with this technique [52]
[53]. Haimerl et al. showed a correlation with the MELD score. In total, 233 patients
were categorized in three groups according to MELD score. The percentage T1 reduction
rate was 59 % for a MELD score < 10, 44 % for a MELD score of 11 – 18, and 30 % for
a MELD score > 18 [54].
The use of dynamic MRI (DCE-MRI) analogously to scintigraphy is the most complicated
method since a signal intensity curve must be determined for every voxel of the liver
parenchyma with the highest possible temporal resolution. The hepatic extraction fraction
can then be calculated for every voxel [55]
[56]
[57]. This method provides excellent correlation with clinical and laboratory parameters
[58]
[59].
For dynamic data acquisition, sufficiently fast and highly resolved T1-weighted MRI
sequences are now available, e. g., the CAIPIRINHI-Dixon-TWIST sequence (controlled
aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) time-resolved
angiography with stochastic trajectories (TWIST) based on a 3 D gradient echo sequence
[60]. These 3 D gradient echo sequences allow quantification of the T1 relaxation rate
change and thus temporal recording of the local contrast agent concentration [61]. They form the technical foundation for hepatobiliary sequence MRI in analogy to
hepatobiliary sequence scintigraphy. Due to the high spatial resolution and the minimal
motion artifacts as a result of the high temporal resolution, the data can be used
for the usual visual evaluation of the signal behavior of focal liver lesions or liver
vessels as well as for the functional evaluation. Movement of the liver during individual
measurements is problematic for data analysis. With increasing temporal resolution,
movements become smaller, but motion correction is still necessary, particularly since
the higher temporal resolution allows data acquisition during free breathing. For
motion correction, there is currently primarily experience with renal perfusion measurement
in MRI [62]
[63]. However, motion correction has not yet been used clinically in Gd-EOB-based liver
function measurement. Two different motion correction methods are used for the liver:
local correction in which only the liver is selectively coregistered with a maximum
of 12 degrees of freedom (3x rotation, 3x translation, 3x scaling, 3x shear) or elastic
correction of the complete 3 D dataset [64]
[65].
In addition to the data acquisition obstacles still to be overcome, there are still
uncertainties regarding the optimum pharmacokinetic model and the most suitable parameters
for liver function measurement from this model. For evaluating signal-time curves,
Nilsson et al. used a model-free approach in which the tissue curve is a convolution
of the input curve via a residuum function [56]. The residuum function is calculated by singular value decomposition for which a
biexponential approach was selected. The fast exponential function represents the
sinusoidal flow in the vascular phase while the slow phase represents the contrast
agent retention by the hepatocytes. The use of an exponential residuum function implies
identical uptake and elimination rates, see [Fig. 3A]. Therefore, only the first 30 minutes of the measurement are evaluated. This method
has two disadvantages: only one input function, the arterial (AIF) or the portal venous
(PVIF), which differ greatly, can be taken into consideration; singular value decomposition
is very susceptible to noise. The validity of this approach in primary biliary cirrhosis,
liver cirrhosis, and primary sclerosing cholangitis was able to be shown [58]
[59]
[66]. The additional use of the keyhole technique as implemented in the TWIST sequence
allows inclusion of the AIF as a result of the higher temporal resolution [65]
[67]. Thus, a tissue model ([Fig. 3B]) with two input functions and two compartments can be used which significantly improves
the curve adjustment in the sinusoidal wash-in phase and also allows evaluation of
liver segments with portal vein embolization [67]. Sourbron et al. measure with high temporal resolution over a total of only 5 minutes
so that the contrast agent uptake rate but not the elimination rate can be determined.
If the contrast agent dynamics are measured for more than 30 minutes, additional parameters
can be determined on the basis of the additionally acquired information: hepatocyte
volume and the elimination rate from the hepatocytes, see [Fig. 3C], [4]. However, the increased temporal resolution associated with use of the keyhole technique
results in an enormous increase in the amount of data since the complete contrast
agent dynamics should be acquired with the same sequence parameters. To reduce the
amount of data, data acquisition should be interrupted multiple times after the initial
wash-in phase and measurements should be performed discontinuously [65].
Fig. 3 Published compartment model of A Nilsson et al. [56], B Sourbron et al. [67], and C Zylka et al. [65]. The parameters have the following meanings: FA: arterial flow, FPV: portal venous
flow, vs: sinusoidal volume; vH: Hepatocyte volume, Ki: Metabolic rate, Ke: Degradation
rate
Fig. 4 Spatially averaged curves of the time change of the T1 relaxation rate in a patient
with a liver segment with partial occlusion of the portal vein. The continuous lines
represent a curve adjustment with the model in [Fig. 3C]. The portal venous flow in a liver segment with occlusion of the portal vein was
set to zero.
In addition to the approach based on Gd-EOB for function measurement, techniques not
requiring contrast agent should also be mentioned for the determination of liver parenchyma
state. In light of the increasing incidence of non-alcoholic steatohepatitis (NASH),
measurement of the degree of fatty infiltration is becoming increasingly important
[68]. The quantification of iron content based on the R2 and R2* effects plays an important
role in hemochromatosis or hemosiderosis [69]. Fibrosis classification is also increasingly possible due to MR techniques, such
as T1 p imaging and MR elastography [70]
[71]
[72]
[73]
[74]
[75]
[76]. Diffusion-weighted imaging (DWI) has also already been used for this purpose with
advancing sequence technology and application of intravoxel incoherent motion MRI
[77]
[78]
[79]
[80]. All of these "parenchyma states" can result in cirrhosis and restricted liver function.
However, on their own they cannot be used for function measurement. Nonetheless, the
signal intensity of Gd-EOB-enhanced MRI is influenced, for example, by the degree
of fibrosis as a result of a changed distribution volume of the T1 contrast agent
and changed relaxivity in the extracellular space or by the fat or iron content. However,
these seem to be negligible due to fast gradient echo sequences with short echo times
and the use of relative enhancement [51].
Summary and comparison of the methods
Summary and comparison of the methods
A major advantage of Gd-EOB-based tests with respect to clinical workflow and cost
is the integration in existing preoperative imaging. The sequences necessary for function
measurement can be integrated in an existing MRI protocol with a moderate increase
of the examination time so that in addition to functional information practically
all data needed for surgical planning, such as tumor volume and distribution, liver
anatomy, vascular supply, and relevant extrahepatic findings, can be collected in
one examination and with a single dose of contrast agent [13].
In nuclear medicine methods, the measurement is performed via a planar gamma camera
or SPECT. Therefore, there are limitations with respect to either spatial or temporal
resolution. To achieve a temporal and spatial resolution comparable to that of MRI
with hepatobiliary sequence scintigraphy, the SPECT acquisition must be significantly
accelerated [81]. In contrast, MRI allows acquisition of a 3 D dataset of the entire liver within
2 – 3 seconds with good spatial resolution of 1.2 × 1.2 × 3 mm [60]. High spatial and temporal resolution is necessary for the use of a multi-compartment
model since the input function can only be determined from the portal vein and liver
artery in this way. A further disadvantage of nuclear medicine techniques is the necessary
and complicated attenuation correction and the resulting signal inhomogeneity [82]. An advantage of nuclear medicine techniques is the lack of a background signal.
A further advantage of radiological methods is the elimination of a radioactive tracer
and the resulting lack of radiation exposure as well as the simplified usage. According
to the guidelines of the Society of Nuclear Medicine (SNM), the effective whole body
dose for an applied activity of 175 MBq 99 mTc-mebrofenin is approx. 3 mSv. However, the local dose at the gallbladder can be
up to 19 Gy.
The end point for all methods is a correlation with the postoperative liver function
after liver resection, i. e., an exact as possible prediction of postoperative function
and postoperative liver failure from preoperative functional imaging. A correlation
with mortality and postoperative liver failure is currently only ensured for the laboratory
liver function test [5]
[83]. According to individual studies, postoperative function can also be predicted with
99 mTc-mebrofenin scinitigraphy [29]. If this requirement is met, Gd-EOB-enhanced MRI alone can generate all necessary
information prior to liver resection.
Outlook
A question that still needs to be clarified relates to the influence of the serum
bilirubin level. Bilirubin shares a metabolic pathway with Gd-EOB, IDA analogs, and
ICG. As a result, high serum concentrations can result in competitive inhibition causing
reduced uptake in the hepatocytes [84]. The influence of renal insufficiency also still needs to be clarified. In the case
of healthy renal function, the ratio of renal to hepatic elimination of Gd-EOB is
approx. 50:50. However, there is no data regarding the ratio in the case of restricted
renal function. Due to the different means of elimination, it remains to be determined
whether an imaging-based liver function test is suitable for determining absolute
liver function or whether it can only indicate relative function distribution and
must therefore be combined with a global test.
In addition to the described use in liver surgery, additional fields of application
for imaging-based liver function tests are conceivable. One possibility is dose determination
prior to radioembolization (Selective Internal Radiation Therapy, SIRT). Microspheres
loaded with yttrium-90 are applied via the liver artery [85]
[86]. Due to the predominantly arterial blood supply of liver neoplasias, the β-radiation
results in tumor cell reduction. However, restricted liver function due to irradiation
also of the healthy liver tissue is often a limitation and can result in postinterventional
liver failure [87]
[88]. Liver function is currently not included in dose determination. Only limit values
for typical lab values such as the serum bilirubin level are taken into consideration.
Moreover, to protect the healthy liver parenchyma, radioembolization is often performed
on one side, i. e., only in the region of the left or right liver artery [89]. A regional liver function measurement could therefore be included in dosimetry
particularly since Gd-EOB enhanced MRI is already often included in the routine protocol.
A further field of application is diffuse liver diseases, such as primary biliary
cirrhosis or primary sclerosing cholangitis, which primarily affect bile ducts but
can result in secondary (sub-)segmental restricted hepatic function [90]. An imaging-based liver function test could be used both for early detection and
for treatment monitoring. Global function is often not yet limited in the early stage.
However, zones of reduced function may be able to be detected by a regional liver
function test. Controlling of targeted biopsies from representative liver segments
or of segmental biliary decompression measures is conceivable. Initial results indicate
high sensitivity of Gd-EOB-enhanced MRI [58]
[59]
[91]
[92]. Detection of the most affected area could be beneficial for planning a diagnostic
liver biopsy.
Conclusion
Although it is a relatively new method – Gd-EOB as an MRI contrast agent was first
approved in 2004 in Germany – major advancements for using an imaging-based liver
function test have been made in recent years. The numerous advantages described here,
such as integration in routine diagnostics and the associated cost neutrality, will
open new application fields for functional Gd-EOB-enhanced MRI in both hepatology
and liver surgery.
