1. Update of liver cirrhotic nodules imaging by contrast enhanced ultrasound
Dr Kamal Jabre
French Board MD
Consultant Radiologist
Dr Ruba AlKurd
MD.PBR

2. Introduction
Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide
hepatitis B virus and hepatitis C virus infection.
 alcohol and nonalcoholic fatty liver  disease.
 A well-defined risk group for HCC defines the screening population.
Surveillance imaging aimed to detect small nodules at a time when potentially curative treatments can be offered.

3. -

4. CEUS of Cirrhotic Liver
Accurate diagnosis of benign and malignant nodules.
Real-time assessment.
High contrast sensitivity:
1 to 10 microns in size .
systemic ultrasound enhancement.
Intravascular.
Contrast-enhanced ultrasound (CEUS) represents a recent revolutiب42يon in the field of ultrasonography and it has become increasingly important in the detection and evaluation of FLLs. 
Real-time evaluation allow detection of suspicious nodules immediately after surveillance saving time , reducing pt.'s anxiety and emit the need for further evaluation.
Ultrasound contrast agents are 1 to 10 microns in size (equal to or smaller than red blood cells) and permit visualization of both the macrovasculature and the microvasculature. The minute bubbles survive transpulmonary passage and recirculate, producing systemic ultrasound enhancement. This is an advantage over larger molecules that are retained in vascular beds .Most ultrasound contrast agents are confined to the vascular space. By contrast, most of the contrast agents used for computed tomography or magnetic resonance imaging (MRI) are rapidly cleared from the blood pool into the extravascular space .Because ultrasound contrast agents remain within the vascular space, only a small amount of contrast agent is required
CEUS permits real-time visualization of contrast-enhancement patterns during all vascular phases (arterial, portal-venous, and late).This results in higher temporal resolution than can be achieved with other imaging modalities.

5. Technique
The 1.2-mL bottle of Definity is shaken in a vial shaker, activating the contrast agent and increasing the volume of bubbles to 1.8 mL. Intravenous access in an antecubital vein is obtained and a three-way stopcock arrangement is used.
Successful technique includes proper injection of the microbubbles, as the entire syringe of fragile bubbles can be destroyed if the bubbles are mishandled during their withdrawal from the vial or if pressure is applied against a closed stopcock.
The contrast agent is injected intravenously by using established doses to a maximum of 10 uL/kg followed immediately by a saline flush.
Generally, a liver study for focal mass evaluation might include two to four injections of 0.2 mL per injection. These are separated by an interval of several minutes for clearance of the bubbles from the field of view
-Dual-screen imaging is used for gray-scale anatomic guidance alongside the contrast-only image.
- Specialized US software uses a subtraction technique called pulse inversion imaging to make the preinjection liver appear black. 

6. Technique Arterial phase
The UCA reaches the liver first via the hepatic artery and provides information on the degree and pattern of vascularity. Tumors with substantial arterial blood supply show hyper-enhancement during this phase. This phase is usually defined as the period from 0 to 30 s after UCA injection.
Portal vein phase
After the arterial phase, the UCA has passed through the circulation and spreads through the liver via the portal branches. This phase is usually defined as the period from 31 to 120 s after UCA injection.
Late or parenchymal phase
. Both the portal and late phases provide information regarding the washout of contrast agent from the lesion compared with normal liver tissue. In the case of hemangiomas, a progressive filling can be observed during these phases. The portal and late phase enhancement can provide important information regarding the character of the lesions. Most malignant lesions are hypo-enhanced, while the majority of solid benign lesions are iso- or hyper-enhanced. This phase is usually defined as the period from 121 to 360 s after UCA injection.
Post-vascular or Kupffer phase
This is an extra phase when Sonazoid is used. Kupffer imaging in the post-vascular phase is stable for at least 60 min post-injection and tolerable for multiple scanning. This can be obtained with low acoustic power, because Sonazoid microbubbles are phagocytosed by Kupffer cells

7. Technique
Hepatocellular carcinoma. A: Gray-scale sonogram shows an isoechogenic nodule (arrows); B: Contrast-enhanced ultrasound (CEUS) scan at arterial phase shows homogeneous hyper-enhancement (arrows); C: CEUS scan at portal phase shows iso-enhancement in comparison with adjacent-liver tissue (arrows); D: CEUS scan at late phase shows hypo-enhancement in comparison with adjacent-liver tissue (arrows); E: Computed tomography (CT) scan shows hyper-attenuation of the nodule (arrows) during the arterial phase; F: CT scan during the portal phase shows hypo-attenuation (arrows).

8. Contrast Advantages
Safe, with an extremely low incidence of side effects .
The incidence of severe hypersensitivity events is lower than with CT contrast agents.
Life-treating reactions have been seen, with a rate of 0.001% and no deaths reported in the literature .
Microbubbles are eliminated partly by means of metabolization in the liver (stabilizing shells) and partly by the patient breathing out of the lungs (gas filling) in approximately 10–15 minutes [20], with no risk of nephrotoxicity.
-Ultrasound contrast agents are safe, with an extremely low incidence of side effects [19]. There are no cardio-, hepato-, or nephrotoxic effects. Thus, it is not necessary to perform liver or kidney function blood tests before contrast medium administration. The incidence of severe hypersensitivity events is lower than with CT contrast agents. Life-treating reactions have been seen, with a rate of 0.001% and no deaths reported in the literature [19]. -

9. Advantages of CEUS Avoidance of Misregistration of Nodules.
patients with innumerable nodules.
CT and MR Imaging Occult Nodules.
Nodule in a Nodule.
Indeterminate masses on CT and MR images.
Pseudolesions.
Post treatment Surveillance.
-If a nodule cannot be confirmed as benign at contrast-enhanced US, further work-up with CT or MR imaging is indicated. On the other hand, if a nodule is characteristically malignant at initial contrast-enhanced US examination, then MR imaging and CT can be expedited for staging and treatment planning.
-Low price of the procedure, large accessibility and lack of the radiation, are among the most prominent advantages of CEUS that should be taken into consideration. Real time information and clinical character are among them also. These characteristics make CEUS a good and reliable procedure for the detection of liver tumors and follow–up under treatment. -

10. CT and MR Imaging Occult Nodules
An occult lesion on CT and MR images is shown in a 56-year-old man with hepatitis B virus. (a) Surveillance US image shows a 1.6-cm nodule in the tip of the right lobe of the liver. Contrast-enhanced US images of the nodule demonstrate classic enhancement characteristics of HCC with (b) arterial hypervascularity (arrow) and (c) portal venous washout (arrow). (d) The patient underwent two subsequent gadolinium-enhanced MR examinations (arterial phase images shown) and one CT scan showing no nodule. At 6 months, MR imaging with a hepatobiliary contrast agent (gadoxetate disodium) was performed at our suggestion. This examination showed no nodule on precontrast images or arterial or portal venous phase postcontrast images. (e) The nodule only becomes apparent on the hepatobiliary phase (arrow). At liver resection, the nodule is moderately differentiated HCC.

15. Nodule in a Nodule
Classically, the nodule-in-a-nodule appearance is arterial phase hypervascularity and portal venous washout of the central nodule representing HCC, while the outer dysplastic nodule or well-differentiated HCC shows arterial hypovascularity and portal venous isovascularity.
Overall size of the mass is important in treatment planning, and in these cases, it would be prudent to treat both the HCC and the high-grade dysplastic nodule.
-Nodule-in-a-nodule lesion in a 66-year-old man with hepatitis C virus. (a) Gray-scale US image shows a nodule-in-a-nodule appearance of an echogenic nodule within a larger hypoechoic nodule, overall measuring 4.2 cm. (b) Contrast-enhanced US image shows arterial phase hypervascularity of the central echogenic nodule and hypovascularity of the surrounding nodule. (c) Portal venous phase image shows washout of the central echogenic nodule (arrowhead) and isovascularity of the outer nodule (arrow), consistent with HCC within a dysplastic nodule. (d, e) CT scans show (d) a fat-containing nodule only measuring 2.7 cm with arterial phase hypervascularity (arrow) and (e) portal venous phase washout (arrow). CT images do not show the surrounding dysplastic nodule resulting in size discordance.

21. Inactive, solid, organized hydatid cyst of the liver (Gharbi classification, 1981). b. Organized hydatid cyst. CEUS exam demonstrates the lack of vascularity within the tumor and thus contributes to the decisive exclusion of a malignant liver tumor.

22. Pseudo lesions Arterioportal venous shunts.
Absence of Arterial Phase Hyper vascularity.
Absence of Portal Venous Phase Washout
 On CT and MR images, nontumorous arterioportal venous shunts manifest as transient focal areas of arterial hypervascularity with no washout in the portal venous phase . As a result, the small subset of HCCs that do not show washout can be misinterpreted as vascular shunts.
small vascular shunts are not well seen at contrast-enhanced US due to its high contrast agent sensitivity resulting in very rapid visualization of the contrast agent–filled arterial branches in the wash-in phase followed by early homogeneous parenchymal enhancement.

23. : Mistiming of arterial phase CT scanning in a 49-year-old man with hepatitis C virus cirrhosis with mass found at surveillance US. (a) Arterial phase CT image with fixed time delay at 35 seconds shows the majority of contrast within the abdominal aorta and celiac axis. No mass is identified in the arterial phase. (b) On the portal venous phase image, there is faint washout of a mass (arrow) measuring 2 cm, resulting in an indeterminate CT. There is a corresponding mass at baseline US, not shown. (c) Contrast-enhanced US shows homogeneous arterial enhancement on image obtained at 20 seconds and washout at 3.5 minutes (not shown). This confirms HCC and demonstrates the advantage of the real-time scanning technique. The mass is biopsy-proven well-differentiated HCC.

26. Questionable pseudolesion in a 64-year-old man with hepatitis B virus
 Questionable pseudolesion in a 64-year-old man with hepatitis B virus. (a) MR image shows no nodule on precontrast T1- and T2-weighted images and a small focus of enhancement in the arterial phase (arrow). (b) No corresponding washout is identified in the portal venous or delayed (shown) phases. This was reported as indeterminate but favored to represent a vascular shunt. (c) Gray-scale US image shows a baseline nodule, essentially excluding the possibility of vascular shunt. (d,e) Contrast-enhanced US images show (d) arterial phase hypervascularity of the nodule and (e) washout, beginning at 3.5 minutes and remaining weak until 6 minutes, confirming that the MR-indeterminate nodule represents HCC.

31. Liver hemangioma. a. CEUS performed during the arterial phase (18 seconds since contrast media injection) shows a well defined “ring” around the nodule. b. The appearance of the contrast “buds” suggests the centripetal character of CA progression. c. At the end of the arterial phase there is complete enhancement of the lesion with contrast agent.

32. Post treatment Surveillance
Assess for tumor recurrence or new tumor development .
MR imaging and contrast-enhanced US are then alternated every 3 months so that patients are screened with each modality every 6 months for the first 2 years.

33. 50% of tumor recurrence following surgical resection occurs within the first 2 years.
After the first 2 years, we alternate the scans every 6 months, until the 5-year mark when, if patients remain recurrence free, they are returned to US surveillance every 6 months. 

34. Pitfalls of Contrast-enhanced US
 Obese and very large patients as well as penetration problems in those with fatty livers and deep lesions at greater than 10 cm depth from the transducer crystal.
The sub diaphragmatic liver is a recognized potential blind area.
Patients with very cirrhotic heterogeneous livers on gray-scale US studies can be challenging to evaluate.

35. Hemodynamic changes in cirrhotic patients with hyper dynamic circulation and shunting.
Inability to evaluate the extra hepatic extension of HCC or other malignant diseases.
-Hemodynamic changes in cirrhotic patients with hyper dynamic circulation and shunting, the parenchyma enhancement in the late phase may appear heterogeneous and less intense than in normal livers, making evaluation difficult.

36. Thank You