Abstract
Introduction
Postoperative vascular complications in patients after liver transplantation are a quite common problem in clinical routine [2]. Initial B-mode and colour-Doppler ultrasound is the most widespread imaging approach for the detection of vascular complications [5, 10]. Most commonly described are portal vein thromboses or stenoses, thromboses or stenoses of the hepatic artery, occlusion of the hepatic artery or narrowing of the anastomosis of the hepatic veins [6, 25–27]. Clinical signs and symptoms of vascular complications show a broad spectrum and initial imaging is most critical for patient care. Basic ultrasound with colour-Doppler is most commonly used as the initial imaging method of choice and shows a good sensitivity of 92% in the detection of vascular complications [7, 9, 17]. Big disadvantages of colour-Doppler examinations are misdiagnoses or inconclusive diagnoses due to aliasing or overwriting artifacts or other limiting factors using conventional ultrasound. With contrast-enhanced ultrasound (CEUS) an imaging modality has been established into clinical routine, which can overcome these limitations due to the specific way CEUS images are generated [5, 11–13, 20]. In patients with an initial suspicion for a vascular complication mostly additional imaging modalities such as magnetic resonance imaging (MRI), contrast enhanced computed tomography (CE-CT) or angiography is performed to confirm initial ultrasound findings [19]. Disadvantages of these methods are the use of ionizing radiation and/or of nephrotoxic contrast media, as well as high costs and a high effort to examine critical ill patients from intensive care units. CEUS offers a cheap and easy way for bed-side examinations of these patients making it a viable alternative to other imaging modalities. Ultrasound contrast agents can be used in patients with chronic renal failure or a known allergy to contrast agents containing iodine because of their independence from thyroid and renal function. Ultrasound contrast agents show a low incidence rate of allergic reactions, which are described in the literature to occur only in 1 of 10.000 cases [18, 23].
This retrospective analysis study was performed to evaluate the sensitivity and specificity of CEUS in the diagnosis of vascular complications compared to CT as the gold standard.
Materials and methods
Between July 2005 and November 2015 a total of 60 patients with elevated liver function tests after liver transplantation were retrospectively analysed. CEUS was compared with CT in diagnostic accuracy of vascular complications. From all patients we could retrieve additional CT imaging studies from our department. The local ethics committee approved this study. All study data were collected in compliance with the principles of the Helsinki/Edinburgh Declaration of 2002. The authors followed the ethical guidelines for publication in Clinical Hemorheology and Microcirculation [3]. Oral and written informed consent of all patients was obtained prior to each CEUS and CTexamination.
The additional imaging studies consisted of CE-CT scans performed on the basis of imaging protocols and with scanners used at the time the scans were conducted.
The 60 patients had their liver transplantation between 1990 and 2015. Mean age at the time of the CEUS examination was 52 years (Min. 19; Max 75; SD±12.8 years).
Mean time between initial liver transplantation and CEUS examination were 30.4 months (SD±62.6 months).
Mean time between CT and CEUS examination were 2.6 weeks (SD±220 weeks).
The CEUS examinations were performed with high-end ultrasound systems with up-to-date CEUS specific examination protocols available at the time of the examination (Siemens Acuson Sequoia and Siemens S2000, EPIQ 7, Philips Ultrasound). Used ultrasound probes consisted of the C4-1 and C6-1 HD probes for the Siemens ultrasound system and C9-2 probe for the Philips system. All CEUS examinations were performed and interpreted by one board certified radiologist with more than 15 years of experience in CEUS. To avoid unintended destructions of microbubbles a low mechanical index (always <02) was used for each examination.
A second-generation blood pool contrast agent (SonoVue®, Bracco, Milan, Italy) was used in all examinations and was administered through a peripheral 20–22 G needle as a bolus injection followed by a flush of 5 to 10 ml of 0.9% NaCl. 1.4 to 2.0 ml of contrast agent was administered in most cases with a maximum of 4.8 ml and minimum of 1.0 ml. In most cases a single dose of contrast agent was given. After the injection of the contrast agent cine loops were acquired and archived in the picture archiving and communication system (PACS) of our department. Mean examination time was 3–5 minutes for the whole examination. If additional imaging was necessary a total of up to three injections of contrast agent was given.
From the patients record files we retrospectively obtained the results of the CEUS and CT examinations.
Out of the 60 patients, 28 patients showed vascular complications in CT including portal vein thrombosis (Figs. 1–3), narrowing of the portal vein or narrowing of the hepatic artery, occlusion of the hepatic artery, narrowing of the anastomosis of the hepatic veins (Figs. 4–6) or reperfusion injury (Figs. 7–10). In 25 out 28 of cases the complication could also be detected using CEUS. For statistical analysis diagnostic accuracy of CEUS was tested using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and compared to CT as the goldstandard.
Results
CEUS images could be acquired successfully in a satisfactory image quality in all 60 patients. CT images in diagnostic image quality could be obtained from our PACS-system in all cases. No examination had to be excluded due to lack of image quality or missing image series.
No critical adverse reaction of administration of SonoVue® could be observed in all 60 patients. In almost all cases 1.4 to 2.0 ml of SonoVue® given as one single dose was sufficient for the characterization of the vascular pathologies. Doses given ranged from 1.0 ml to 4.8 ml. If necessary for diagnostic purposes additional doses of SonoVue® were given up to three times.
Liver transplantations were necessary in 26 patients (43.3%) because of alcohol use disorder, in 17 patients (28.3%) after infection with hepatitis and in 17 patients (28.3%) because of immunological liver disorders.
CEUS showed a sensitivity of 89.3%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 91,4% compared to CT as the gold standard. Out of the 60 patients 28 patients showed vascular complications in CT, which could also be detected in 25 out 28 of cases using CEUS. In 3 cases CT showed a vascular complication, whereas the CEUS examination was reported as normal. Concordant, CEUS and CT excluded a vascular complication in 32 cases.
Discussion
Vascular complications are one of the major complications after liver transplantation that occur in about 9% of all liver transplant patients [17]. By far the most significant complication after liver transplantation is the occlusion of the hepatic artery due to thrombosis with an estimated incidence of 4–12% in adults and 42% in children described in literature [17, 27]. Hepatic artery thrombosis can lead to hepatic necrosis with severe hepatic failure [1, 24]. Using conventional colour-Doppler there are several reasons described in literature for false positive or false negative results in evaluating vascular complications, e.g. because of collateralization of the hepatic artery, vascular spasms after transplantation or drug induced vasospasms using catecholamines on intensive care unit [8, 21]. Usually, suspicion of a vascular complication after liver transplantation leads to additional examinations using CE-CT, MRI or angiography. Our study suggests that with CEUS an imaging modality exists that shows comparable specificity and PPV to CE-CT scans without the necessity to use ionizing radiation or nephrotoxic contrast agents. Nevertheless, CEUS still has its limitations in the use for the detection of vascular complications. Severe obesity as well as bowel gas are limitations that cannot be overcome using CEUS as well as a limited field of view compared to CE-CT. As all ultrasound examinations, CEUS examinations do heavily rely on the experience of the sonographer and are dependant on skills and training of the examiner.
For patients with chronic renal impairment, known hyperthyroidism or allergies to iodine contrast agents CEUS is a practicable method for the evaluation of vascular complications after liver transplantation. Additionally, using CEUS adds the benefit of using a non-ionizing radiation approach compared to CT and is much more cost-effective than using CT. As a dynamic examination method without any interference to renal, thyroid or hepatic function CEUS can be performed repetitively (26). The high PPV and NPV of CEUS could reduce the number of necessary postoperative CT examinations and the associated radiation doses as well as the use of nephrotoxic contrast agents.
This study showed several additional limitations regarding study design. First of all this was a retrospectively conducted mono-center study with only one radiologists evaluating the vascular complications using CEUS. Different ultrasound systems were used and contrast agent doses varied among patients depending on the CEUS techniques used at the time of the examination. The CT protocols and imaging series also varied among these patients also depending on the scanning-protocols and CT-scanners available at the time of the examination.
Conclusion
CEUS is a fast, non-ionizing imaging modality for the initial exclusion of vascular complications after liver transplantation. CEUS shows a high specificity and PPV in the detection of vascular complications. In unclear cases CT still is considered as the gold standard.