Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5767_Библиотеки_им_академика_М_И_Перельмана.pdf
4 Liver
79
The greatest difculties are caused by a hepatocellular adenoma, which exhibits arterial phase
hyperenhancement and can demonstrate mild late
washout in the late phase. Quantitative analysis
revealed that HCA has the smallest gures of the
half-time of washout (DT/2) in the group of
benign liver tumors. This parameter is also signicantly different from HCC, the latter having
the reliably lower DT/2 (Table4.1, Fig.4.24).
Experimental data obtained in some studies
suggest the diagnostic potential of quantitative
analysis of CEUS data in the differential diagnostics of FLL.It supplies more objective and reproducible data, quantitatively evaluates tumor
perfusion, which is successfully used in the
assessment of the response to therapy. Some
authors report the possible application of quantitative analysis for the prediction of the tumor
response. Although the quantitative analysis of
CEUS is not included in ofcial guidelines and
recommendations, the literature data created the
background for further research and standardization of the protocols.
4.4 Diuse Liver Disorders
Chronic diffuse liver diseases along with FLL
are reported to benet from CEUS. Depending
on the stage, some of them are associated with
characteristic changes in hepatic blood ow.
Hemodynamic disturbances were assessed with
Doppler imaging, studied in early publications
with Levovist [95], and may be veried with
quantitative analysis of CEUS.
Liver cirrhosis may be accompanied by the
increased cardiac output, reduced peripheral vascular resistance, pulmonary arteriovenous shunts,
portosystemic venous shunts, intrahepatic shunts
between hepatic artery, portal, or hepatic veins,
and arterialization of the hepatic capillary bed. It
leads to the earlier arrival of the UCA bolus introduced into a peripheral vein [96].
In clinical practice, for the non-invasive diagnosis of liver cirrhosis, the denition of the time
necessary for the UCA to arrive in hepatic veins
(HVAT, Hepatic Vein Arrival Time) is most
widely used. The study is typically conducted
after night starvation with the position of the
abdominal convex probe in the right intercostal
spaces to visualize the right or middle hepatic
vein. The original image of the hepatic vein is
recorded for 10 s, then 2.4 mL of SonoVue® is
introduced into the peripheral vein followed by
5mL saline ush. The cine loop of the hepatic
vein is recorded for 60s after the UCA injection.
In 5 s after UCA administration, the patient is
asked to exhale and hold the breath for 20s. To
obtain the necessary TICs, position ROI in the
hepatic vein of the rst or second generation at
the distance of 3–5 cm from the inferior vena
cava (IVC). The highest TIC value during the
rst 10 s before the introduction of UCA is
accepted for the original intensity. The HVAT is
dened as the interval between the UCA administration and the moment of a 10% increase in the
intensity on the TIC [97, 98].
Kim et al. [99] published the data of metaanalysis of 12 studies with 844 patients. They
compared HVAT with the histopathology of the
liver biopsy and reported the total sensitivity of
HVAT for the diagnosis of liver cirrhosis of 0.83
(95%CI 0.77–0.89), specicity—0.75 (95%CI
0.69–0.79), PPV—3.45 (95%CI 1.60–7.43), and
NPV—0.28 (95%CI 0.10–0.74). Additionally,
they revealed a signicant decrease in the HVAT
(p < 0.05) in patients with liver brosis
(Mean ± SD—25.01 ± 5.46 s) and cirrhosis
(17.62 ± 3.57 s) compared with the group of
healthy persons (34.63 ± 10.27 s). However, it
should be noted that the studies in meta-analysis
used different techniques (Doppler and contrastspecic) and different UCAs (Levovist and
SonoVue®). The study [100] revealed the decrease
in HVAT in patients with chronic hepatitis C that
corresponded with the severity of liver brosis in
both Levovist and SonoVue®. Mean HVTTs with
SonoVue® in control, mild hepatitis, moderate or
severe hepatitis, and cirrhosis groups were 38.3s,
47.5 s, 29.5 s, and 17.6 s, respectively, with
Levovist and 29.4s, 27.4 s, 22.9 s, and 16.4 s,
respectively. There was no signicant difference
in HVTT between mild and moderate hepatitis
groups with SonoVue®; however, there were sig-
80
E. I. Peniaeva and Y. R. Kamalov
a
b
Fig. 4.24 Quantitative analysis of CEUS TICs.
(a)Normal liver parenchyma, all ROIs. (b) FNH, ROI 1.
(c) HCC, ROI 1. (d) Liver metastasis. (e) Liver cyst, ROI
1. (f) Hemangioma, ROI 1. In all images ROI 2, 3, and 4
correspond to the surrounding normal liver parenchyma
4 Liver
c
81
d
Fig. 4.24 (continued)
82
E. I. Peniaeva and Y. R. Kamalov
e
f
Fig. 4.24 (continued)
4 Liver
Table 4.2 HVAT values at various stages of liver brosis in different studies
Author, study UCA No brosis Mild or moderate brosis Cirrhosis
Abbattista etal. (2008) [102] SonoVue 24.9±4.4 21.7±3.5 14.0±2.5
Albrecht etal. (1999) [95] Levovist 49.8±22.6 35.8±9.9 18.3±3.0
Lim etal. (2006) [100] Levovist 38.3±2.4 47.5±6.5/29.5±10.8 17.6±5.0
Lim etal. (2011) [103] Levovist 33.8±3.8 29.7±2.2 15.8±0.9
Lim etal. (2006) [100] SonoVue 29.4±6.9 27.4±9.3/25.2±7.0 16.4±4.9
Ridol etal. (2007) [101] SonoVue 24.8±4.4 22.1±3.4 14.3±2.1
83
nicant differences in HVTT between all patient
groups with Levovist.
The values of HVAT≤17s were reported to
correspond to liver cirrhosis, while healthy individuals and patients with chronic liver diseases
without cirrhosis exhibit HVAT>18s [101]. In
the group of patients with chronic hepatitis C, the
severity of liver brosis (METAVIR brosis stage
0–3) and necrotic/inammatory changes did not
signicantly affect the HVAT. The authors suggest that HVAT can be a simple and reliable
method to exclude liver cirrhosis with portal
hypertension, but is not capable to assess the
severity of liver brosis.
Table 4.2 confers the data of some publications, which demonstrate that HVAT values below
14–17s were specic for liver cirrhosis [99].
Several studies demonstrated that HVAT
increases in patients with liver metastases. This
fact limits the use of HVAT for the specication
of liver cirrhosis due to similar hemodynamic
changes [104, 105].
Attempts were also made to use the intensity
of contrast enhancement of the liver parenchyma
to diagnose the liver cirrhosis based on the theory
of degradation of Kupffer cells function in cirrhotic liver. However, these studies utilized
Levovist, which is capable of interacting with the
reticuloendothelial system.
The study [106] compared the intensity of
contrast enhancement of the liver parenchyma
and the right kidney in patients with alcohol and
other diffuse liver diseases on the 20th, 90th seconds, and fth minute after the introduction of
Levovist and specied the following three types
of contrast enhancement:
• Type A—on the 20th second, the contrast
enhancement is observed only in the kidney,
on the 90th—in the kidney and liver, on the
fth minute—only in the liver.
• Type B—on the 20th and 90th seconds contrasting enhancement is registered in the liver
and kidney, but on the fth minute—only in
the liver.
• Type C—on the 20th and 90th seconds contrasting enhancement is registered in the liver
and kidney, on the fth minute—a low contrast enhancement of both organs.
Type A has been revealed in 83% of healthy
people, type B—in 60–80% of patients with
chronic diffuse liver diseases, and type C—in
almost all patients with alcoholic liver disease.
The authors associate the low contrast enhancement of the liver parenchyma in type C with the
Kupffer cells dysfunction in cirrhotic liver, which
causes the slow clearance of UCA [106].
A signicant decrease in the liver parenchyma
enhancement in the late phase (7 min after the
administration of Levovist) in patients with liver
cirrhosis stage A (p<0.05) and C (p<0.001) as
compared to healthy people was reported [107].
Besides, the statistically signicant (p < 0.01)
decrease in the intensity of the contrast enhancement was determined in patients with liver cirrhosis stage C as compared to stage A. The
authors explained it with the decrease in UCA
absorption by the reticuloendothelial system
resulted from the impaired functionality of the
Kupffer cells due to portosystemic shunts
(Figs.4.25 and 4.26).
The study [108] with Levovist and inversed
tissue harmonic revealed a signicant reverse
correlation between the brightness of the image
of the liver parenchyma in the shades of gray and
the brosis index (r = −0.809, p < 0.01). The
average signal intensity was 144.5 in normal
84
E. I. Peniaeva and Y. R. Kamalov
a
b
Fig. 4.25 Liver brosis. Reduced vascularization of the liver parenchyma. CEUS images. (a) Early portal venous
phase. (b) The beginning of the late phase
4 Liver
a
85
b
Fig. 4.26 Micronodular liver cirrhosis. CEUS images. Irregular non-intensive contrast enhancement of the liver parenchyma. (a) Arterial phase. (b) Portal venous phase. (c) Late phase. (d) Quantitative analysis
86
E. I. Peniaeva and Y. R. Kamalov
c
d
Fig. 4.26 (continued)
4 Liver
Table 4.3 Histopathological, hemodynamic, and clinical stages of liver brosis [112]
Classication Stages
METAVIR F1–F3 F4 F4 F4 F4
HVPG (mmHg) >6 >10 >12 >16
>20
Clinical class No
cirrhosis
1-year mortality
(%)
Stage 1 Stage 2 Stage 3 Stage 4
Compensated Compensated Decompensated Decompensated
Varices Variceal bleeding Variceal bleeding
Ascites Ascites
Encephalopathy Encephalopathy
Bacterial infection
Hepatorenal
syndrome
1 3 10–30 60–100
87
liver, 133.6—in chronic hepatitis, and 102.6—in
cirrhotic liver with reliable difference between
the groups of the normal and cirrhotic liver
(p<0.01). They suggested that the extent of the
bubble destruction in the late phase with Levovist
can correspond to the degree of liver brosis.
There are almost no publications on the diagnosis of chronic diffuse liver diseases with CEUS in
recent years. This fact shows the decrease in the
interest to this CEUS application. This is probably
the result of the implementation of ultrasound elastometry, which has better diagnostic value for staging liver brosis and cirrhosis. Currently, CEUS is
used to detect the liver cirrhosis complications,
such as portal vein thrombosis and the development of HCC, as well as for the assessment of the
transjugular intrahepatic portosystemic shunt.
Portal hypertension is a clinical syndrome,
which results from the increase in hepatic venous
pressure gradient (HVPG) >5mmHg, due to high
hepatic resistance [109]. Portal hypertension
develops in patients with liver brosis and is one
cause of serious complications of liver cirrhosis
(esophageal or gastric variceal bleeding, ascites,
peritonitis, and hepatic encephalopathy), which
are associated with high mortality [110].
HVPG is usually measured by cannulation of
the liver vein with a balloon catheter. It is dened
as the difference between the wedged and free
hepatic venous pressures. It is assumed that serial
HVPG measurements contribute to the determination of the liver brosis stage and liver cirrhosis
regardless of their etiology [111, 112]. HVPG
measurement is also used for risk stratication,
preoperative screening before liver resection,
monitoring the response to drug therapy, and specication of the prognosis of liver cirrhosis [113].
A new classication of liver cirrhosis, which
combines histopathological, clinical, hemodynamic, and prognostic signs was proposed
[112] (Table4.3). This system classies liver
brosis depending on compensation or decompensation, which are determined by clinical
manifestations [114].
Endoscopic examination is the “gold standard” for the identication and staging of esophageal and gastric varices. However, both the
denition of HVPG and endoscopic examination
are invasive techniques with some possible complications. Therefore, new alternative tests for
non-invasive diagnosis, including CEUS, are
developing in recent years [115].
The correlation between the regional liver perfusion, HVPG (r = 0.279, p = 0.041), and the
hyperdynamic syndrome markers was demonstrated by the study [116] with SonoVue® and a
disruption-replenishment protocol described in
Sect. 3.2. Regional hepatic perfusion was calculated as microbubbles velocity multiplied by their
concentration.
Compared to healthy people, in patients with
liver cirrhosis, regional hepatic perfusion
88
E. I. Peniaeva and Y. R. Kamalov
increases (3.4±0.7 and 5.1±3.7, respectively)
and correlates with the model of the terminal
stage of the disease. The inverse correlation of
the quantitative TIC parameters with portal
venous pressure with a bolus administration of
SonoVue® is reported [117]. Portal venous pressure was inversely correlated with the area under
the portal vein/hepatic artery time-intensity curve
ratio (Qp/Qa), portal vein/hepatic artery strength
ratio (Ip/Ia), and portal vein/hepatic artery washin
perfusion slope ratio (βp/βa), with correlation
coefcients of −0.701, −0.625, and −0.494,
respectively. The specied values in patients with
portal hypertension and normal liver are presented in Table4.4.
In a later experiment on dogs, the following
results were obtained: with the threshold of
≥18cmH2O for Qp/Qa AUC—0.866, the sensi-
tivity was 76%, specicity—84%; for Ip/Ia
AUC—0.895, the sensitivity was 85% and specicity—89% [118].
Table 4.5 shows the data regarding the diagnostic value of HVAT and intrahepatic transit
time (ITT, i.e. the difference between the time
Table 4.4 The TIC ratios in the diagnosis of portal
hypertension [117]
Ratio Portal hypertension Normal liver p
Qp/Qa 2.57±1.20 4.93±2.0 0.001
Ip/Ia 0.35±0.18 1.91±0.75 0.001
βp/βa
0.23±0.21 0.63±0.53 0.006
of the UCA arrival in the hepatic vein and
hepatic artery).
Shimada et al. [121] suggested using not
hepatic, but splenic hemodynamics to assess
HVPG, determining the difference between the
arrival time of Sonazoid in the splenic artery and
the peak intensity time in the splenic vein. They
reported a positive correlation of this parameter
with HVPG.At HVPG≥10mmHg and the thresh-
old of 13.5s, it had AUC—0.76, sensitivity—71%,
and specicity—68%; at HVPG≥12mmHg and
the threshold of 14.5s it had AUC—0.76, sensitivity—60%, and specicity—80%, which indicate
the relatively satisfactory capabilities of this technique to determine HVPG.
Eisenbrey etal. [122] based on the fact that the
pressure of the uid surrounding microbubbles
can be evaluated when determining the subharmonic amplitude (subharmonic-aided pressure
estimation—SHAPE) with the appropriate mathematical modeling, demonstrated that SHAPE
gradient between the portal and hepatic veins has
a good correlation with HVPG (r=0.82). They
report the SHAPE sensitivity of 89% and the
specicity of 88% in the detection of
HVPG≥10mmHg; and the sensitivity and specicity of 100% and 81%, respectively, in
HVPG≥12mmHg.
Amat-Roldan etal. [22] showed that the clustering coefcient of the vascular connectome,
created with computer graphic analysis of ultra-
Table 4.5 Diagnostic values of HVAT and ITT in the determination of HVPG with SonoVue
Number of
Study
Kim etal. (2013)
[119]
Jeong etal.
(2015) [120]
Se/Sp/PPV/NPV/Ac/PLR/NLR/—sensitivity/specicity/positive predictive value/negative predictive value/diagnostic
accuracy/positive likelihood ratio/negative likelihood ratio
R1 researcher 1, R2 researcher 2
patients
71 HVAT (14s) Clinically signicant
53 HVAT (19s) Pronounced
Parameter
(threshold)
ITT (6s) Pronounced
Severity of portal
hypertension
(HVPG≥10mmHg)
(HVPG≥12mmHg)
(HVPG≥12mmHg)
Se/Sp/PPV/NPV/Ac/PLR/
NLR AUC
93/87/91/90/–/6.95/0.08 0.973
56/89/95/35/63/–/– 0.72
R1
50/89/94/32/58/–/– 0.71
R2
91/89/97/73/91/–/– 0.94
R1
85/78/94/58/84/–/– 0.90
R2
®