Prolonged Heterogeneous Liver Enhancement on Contrast-Enhanced Ultrasound

Abstract

Introduction: Prolonged heterogeneous liver enhancement (PHLE) is a rare phenomenon that is similar to the ultrasound findings of portal venous gas. The purpose of this report is to describe the phenomenon of PHLE after the injection of the ultrasound contrast agent SonoVue^®.

Patients and Methods: From 2000 to 2013, 13 patients with PHLE (“cloudy”, “wool-like”) after bolus injection of SonoVue^® were observed. The height, weight, and body mass index (BMI) of the patients, and the number of injections were analyzed. In addition, the literature was reviewed.

Results: The phenomenon occurred as early as 2 minutes after bolus contrast administration and lasted up to 5 hours on both B-mode and contrast-specific ultrasound. 8/13 (62 %) patients received two or more boluses. None of the patients experienced SonoVue^®-related side effects or health problems. The phenomenon was not reproducible in 3 patients who received a second SonoVue^® injection 24 hours after receiving the first.

Conclusion: This phenomenon is more likely to occur in patients who receive high-dose (or multiple) injections of UCA. It may occur as early as 2 minutes after contrast administration, and therefore, may affect the evaluation of focal liver lesions in the late phase. This phenomenon should not be misdiagnosed as a pathological finding of the liver.

Zusammenfassung

Einleitung: Die langanhaltende heterogene Leberanreicherung (PHLE) entspricht einem seltenen Phänomen portalvenöser Gaseinlagerung durch Kontrastmittelsonografie. Die vorliegende Studie beschreibt das Phänomen nach Injektion des Ultraschallkontrastmittels SonoVue^® und diskutiert mögliche zugrundeliegende Hypothesen.

Patienten und Methode: Von 2000 bis 2013 wurden 13 Patienten mit einer heterogenen (wolkigen) Leberanreicherung nach Bolusinjektion von SonoVue^® beobachtet. Die Größe, das Gewicht und der Body Mass Index (BMI) der Patienten und die Anzahl der Injektionen wurden erfasst. Zusätzlich wurde eine Literaturrecherche zum Thema durchgeführt.

Ergebnis: Das Phänomen wurde frühestens zirka 2 Minuten nach Kontrastmittelinjektion beobachtet und war bis zu 5 Stunden im B-Bild und kontrastspezifischer Einstellung nachweisbar. Das Phänomen wurde gehäuft (aber nicht ausschließlich) bei jungen untergewichtigen Frauen beobachtet. 8 von 13 Patienten (62 %) erhielten 2 und mehr Kontrastmittelinjektionen. Keiner der beobachteten Patienten zeigte Nebenwirkungen oder gesundheitliche Probleme. Das Phänomen konnte bei 3 von 13 Patienten nicht reproduziert werden.

Zusammenfassung: Das an sich harmlose Phänomen kann gehäuft bei jungen untergewichtigen Frauen nach mehrfacher Kontrastinjektion beobachtet werden. Es entwickelt sich nach ca. 2 Minuten und kann somit die Beurteilung der späteren Kontrastphasen beeinflussen und sollte nicht als Leberpathologie fehl diagnostiziert werden.

Key words

ultrasound - microbubbles - liver - heterogeneous enhancement

Introduction

The ultrasound contrast agents (UCA) currently used in diagnostic ultrasound (US) imaging of the liver are microbubbles of gas stabilized by a shell [1]. Three UCAs are approved and marketed for liver evaluation: SonoVue^® (sulfur hexafluoride within a phospholipid shell; Bracco SpA, Milan, Italy), Definity^®/Luminity^® (perflutren lipid microsphere; Lantheus Medical Imaging, Billerica, Massachusetts, United States), and Sonazoid^® (perfluorobutane microbubbles; GE Healthcare, Oslo, Norway). SonoVue^® is the most common UCA used in Europe.

Because of the dual blood supply to the liver, the vascular phase on contrast-enhanced ultrasound (CEUS) after the bolus injection of SonoVue^® can be divided into three phases – the arterial phase, the portal-venous phase, and the late phase [1]. The late phase lasts until the UCA is completely cleared from the circulation. Typically, significant enhancement of the liver occurs for approximately 6 minutes after the bolus injection of SonoVue^® although more prolonged enhancement (up to 10 minutes) may occur in some cases [2]. It has been widely accepted that prolonged duration of contrast enhancement can be achieved only by means of infusion injection or with the use of post-vascular phase agents such as Sonazoid^®.

However, we have observed prolonged liver enhancement over the past decade after the bolus injection of SonoVue^®. It appears as heterogeneous enhancement in the liver within 2 minutes to 5 hours after contrast injection in both B-mode and contrast-specific mode. Meanwhile, the enhanced signals can also be observed in the portal and superior mesenteric veins [3] [4], rather than in the systemic circulation (i. e., inferior vena cava, hepatic vein, abdominal aorta). This is very similar to US findings of portal venous gas that have been observed in end-stage oncological (e. g., gastrointestinal and urological) diseases within the last hours to days before death and also in severe enterocolitis in newborns and adults as well as in some asymptomatic patients.

Thus far only two publications have reported this rare phenomenon with the use of Levovist^®, EchoGen^® [5], and SonoVue^® [6] in a total of 12 cases (Levovist^® = 5, EchoGen^® = 1, SonoVue^® = 6). We have also observed this phenomenon in patients examined with EchoGen^® [7] and Levovist^® [8]. The mechanism of the phenomenon is still not clear. However, a few hypotheses have been described.

Here we describe our patients with prolonged heterogeneous liver enhancement (PHLE) after bolus injections of SonoVue^® to enrich the discussion of this phenomenon.

Patients and methods

From 2000 to 2013, a total of > 10,000 patients underwent CEUS for various indications with a bolus intravascular injection of SonoVue^®. In almost all patients the blood pressure and heart rate were monitored. The following ultrasound systems were used: Hitachi (6500, 8500, HV 900, Preirus, Ascendus), Siemens (Acuson Sequoia 512, S2000), GE Logiq E9 and Toshiba Aplio. B-mode and color Doppler ultrasound were performed to scan the organ and to prepare CEUS for various indications including the liver [9] [10] [11] [12] [13] [14] [15], pancreas [16] [17], spleen [18], kidney [19] [20], adrenals [21], and for other techniques [22] [23] and organ imaging [www.efsumb.org. case of the month].

Before 2004, bolus injections of 4.8 mL SonoVue^® were used followed by a flush of 10 mL saline; thereafter, bolus injections of 2.4 mL were used. Most patients received only one bolus injection. However, depending on the indication (e. g., focal lesions in multiple organs), some patients (about 10 – 20 %) received multiple bolus injections of SonoVue^®. For patients with PHLE, vital signs (heart rate, blood pressure, and respiratory rate) were monitored with a standard monitoring system. The liver enhancement was scanned at intervals until the PHLE enhancement vanished. Three patients underwent a second CEUS examination 24 hours after the first examination using the same ultrasound system.

In addition, patient height, weight, body mass index (BMI) and the number of injections were analyzed. Finally, the data from the 12 patients (6 in each case) in the two papers that referred to PHLE in humans [5] [6] were combined with our data of 13 patients in order to assess PHLE in terms of gender, age, and concomitant diseases of the patients.

Results

13 patients (5 males, 8 females; approx 0.13 % (13/10,000)) with PHLE on both fundamental B-mode imaging and contrast-specific imaging were observed ([Table 1]). The mean age was 42 ± 18 (range, 18 – 72) years. PHLE (“cloudy”, “wool-like”) began to appear within 2 – 6 minutes after the intravenous injection of SonoVue^® and lasted between 40 minutes to 5 hours. Thereafter, the phenomenon gradually disappeared ([Fig. 1], [2], [3]). Contrast enhancement dissipated in the systemic circulation (inferior vena cava, hepatic vein, heart, abdominal aorta) within 5 – 15 minutes after SonoVue^® injection ([Fig. 1], [2]). However, enhancement in the portal vein and superior mesenteric vein lasted for more than 5 hours in some cases ([Fig. 2]). Splenic clearance was steady and the contrast signals disappeared within 6 – 15 minutes after injection. Prolonged enhancement was not observed in the spleen and splenic vein ([Fig. 2]).

Table 1 Characteristics of 13 patients with PHLE.

no.	sex	age	weight (kg)	height (m)	BMI	injections	indication for CEUS
1	F	38	45	1.54	18.97	3	renal cell carcinoma
2[1]	F	24	50	1.68	17.72	2	hemangioma
3	F	28	52	1.67	18.65	1	FNH
4	M	44	61	1.84	18.02	3	colorectal carcinoma, T2, N0, M0
5	F	18	44	1.73	14.70	2	FNH
61	F	38	46	1.68	1630	3	breast carcinoma with liver metastases
7	F	25	56	1.72	18.93	2	hemangioma
8	F	67	47	1.67	16.85	2	colon carcinoma, liver metastasis
9	M	59	68	1.80	20.99	1	bladder carcinoma, T1, N0, M0
10	M	60	75	1.80	23.15	1	hemangioma (2 nodules)
11	M	29	80	1.83	23.89	2	liver metastases in gastric carcinoma
11	F	49	56	1.66	20.32	1	cholangiocarcinoma
131	M	72	63	1.70	21.78	1	adenocarcinoma of prostate, liver cirrhosis

¹ Received second CEUS examination 24 hours after the first CEUS examination.

Fig. 1 A 38-year-old female patient with renal cell carcinoma. 27 minutes after the injection of SonoVue^®, CEUS showed prolonged heterogeneous contrast enhancement in the liver a, and no enhancement in the right hepatic vein (RHV) and inferior vena cava (IVC) b. 10 days later, the liver was homogeneous c.

Abb. 1 38-jährige Patientin mit Zufallsbefund eines Nierenzellkarzinoms. 27 min nach der Injektion von SonoVue zeigt sich eine heterogene Kontrastmittelanreicherung der Leber a. Es fand sich kein Kontrastmittel in den Lebervenen (RHV) und der Vena cava inferior (IVC) b. 10 Tage später unauffälliger Leberparenchymbefund c.

Fig. 2 A 25-year-old female patient with a hemangioma. The prolonged heterogeneous enhancement was shown in B-mode a and in contrast-specific mode b; the spleen was homogeneous c. Enhancement (bubbles movement) in the portal vein (d, arrows) and superior mesenteric vein (e, arrows) was revealed in the overlay mode. However, no bubbles were found in the splenic vein (f, arrows).

Abb. 2 25-jährige Patientient zur Abklärung eines Lebertumors (Hämangiom). Eine andauernde Kontrastmittelanreicherung der Leber fand sich im B-Bild a und im leberspezifischen Modus b. Es zeigte sich eine homogene Kontrastmittelanreicherung der Milz c. Eine andauernde Kontrastmitteldarstellung einzelner Gasbläschen fand sich in der Pfortader (d, Pfeile) und A. mesenterica superior (e, Pfeile) mittels Überlagerungsmodus. In der Milzvene fanden sich dagegen keine Mikrobläschen (f, Pfeile).

Fig. 3 A 72-year-old male patient with adenocarcinoma of the prostate and liver cirrhosis. 20 minutes after the injection, heterogeneous enhancement of the liver was seen on B-mode US a and CEUS (overlay mode) b; 48 hours later, a second CEUS was performed c. The liver was homogeneous 30 min after the injection d.

Abb. 3 72-jähriger Patient mit Adenokarzinom der Prostata und Leberzirrhose. 20 min nach Injektion fand sich eine andauernde Kontrastmittelanreicherung der Leber im B-Bild a und im (überlagerten) leberspezifischen Modus b. 48 Std. später erfolgte eine zweite SonoVue-Injektion c. die Leber zeigte ein homogenes Echomuster nach 30 min d.

Conventional B-mode US revealed homogeneous liver parenchyma in the following days ([Fig. 1], [3]). The phenomenon could not be reproduced in 3 patients who underwent a second CEUS examination at least 24 hours after the first examination using the same ultrasound system ([Fig. 3]).

None of the patients experienced deleterious effects related to SonoVue^® administration or had health problems, and no changes of vital signs were observed. Only one patient complained of pain at the injection site, which was probably related to the puncture (determined to be without clinical relevance).

Combining our patients with the 12 cases from 2 previously published studies [5] [6] ([Table 2]) gave a total of 25 patients (9 male, 16 female; mean age 47 ± 18 [range, 18 – 78] years). 7 patients were ≤ 30 years old (y/o), 11 patients were between 30 and 60 y/o, and 7 patients were > 60 y/o. The other two papers [5] [6] did not provide information on patient weight and height. The mean height, weight, and BMI of the male patients from our center were 69 ± 9 (range, 60 – 80) kg, 179 ± 6 (range, 170 – 184) cm, and 22 ± 2.3 [range, 18 – 24] kg/m², respectively, while the mean height, weight, and BMI of the female patients from our center were 50 ± 4.8 (range, 44 – 56) kg, 167 ± 6 (range, 154 – 173) cm, and 18 ± 1.8 (range, 15 – 18) kg/m², respectively. According to the BMI criteria for German adults [24] [25], the male patients were within normal BMI ranges, but the female patients were underweight. In addition, 8/13 (62 %) patients received two or more bolus injections on SonoVue^®. Together with data from the two previously published studies, UCA was utilized for the following indications: 4 cases of liver hemangioma, 4 cases of focal nodular hyperplasia (FNH), 4 metastases of colorectal carcinoma, 3 metastases of breast carcinoma, 2 metastases of gastric carcinoma, 1 metastasis of bladder carcinoma, 1 metastasis of prostate carcinoma, 2 cholangiocellular carcinomas (CCC), 1 patient with chronic virus hepatitis C, 1 patient with gastric outlet obstruction, 1 patient with renal cell carcinoma, and 1 ultimately healthy subject.

Table 2 Characteristics of 12 patients with PHLE in the other two previous studies.

patient	age	gender	disease	reference
1[1]	23	F	FNH, hemochromatosis	[5]
21	47	F	cholangiocarcinoma	[5]
31	75	F	gastric outlet obstruction, healthy liver	[5]
41	30	M	healthy volunteer	[5]
51	78	F	colorectal carcinoma + liver metastases	[5]
6[2]	35	F	breast carcinoma, healthy liver	[5]
7[3]	73	M	liver metastasis in gastric carcinoma	[6]
83	43	F	FNH	[6]
93	45	F	multiple hepatic hemangioma	[6]
103	63	M	chronic hepatitis C	[6]
113	54	F	liver metastasis in breast carcinoma	[6]
123	62	M	liver metastasis in colon carcinoma	[6]

¹ With Levovist^®.

² With EchoGen^®.

³ With SonoVue^®.

Discussion

PHLE is a rare phenomenon that can occur as early as at the end of the portal venous phase (2 min after injection), and thus influence the evaluation of the late phase for the characterization of focal liver lesions.

The incidence reported in the cited case study is approximately 0.35 % [6]. However, only a few CEUS patients are monitored beyond five minutes, and thus this percentage is possibly an underestimation. The typical patients that experience this phenomenon are young or middle-aged women who may also be underweight.

In accordance with our personal experience, three UCAs (Levovist^®, EchoGen^® and SonoVue^®) have been reported to produce this phenomenon [5] [6]. The mechanism of the phenomenon is not yet clear, but a few hypotheses are discussed below.

Hypothesis 1: gas bubble fusion

It is common knowledge that US microbubbles are destroyed under a high mechanical index (MI). This is also the rationale behind using UCAs as carriers for targeted drug therapy [26] [27]. However, the PHLE phenomenon can last for several hours even on conventional B-mode US using high MI US.

It may be hypothesized that in PHLE the shell of microbubbles is destroyed initially but the microbubbles then immediately fuse together to form large gas bubble conglomerates that are more stable. The higher the dosage, the larger the resulting gas bubbles. This hypothesis implies that gas bubbles responsible for PHLE are not normal microbubbles with a shell. These gas bubble conglomerates cannot cross the hepatic sinusoids and thus are trapped in the liver parenchyma, particularly along the branches of the portal vein.

Referring to the origins of these large bubbles, Okada et al. [5] suggested that they are a result of bubble growth or fusion in vivo. This hypothesis was also supported by Caruso et al. [6] who noted that these fusional gas bubbles have different insonation properties (including size) compared to UCA microbubbles. Caruso et al. [6] also noted that a higher dose of SonoVue^® (4.8 mL) was used for all patients. In the study by Okada, some patients (< 5 %) received infusion of the respective UCA. In our case study, 8 (62 %) of our patients received multiple bolus injections of SonoVue^®, which is higher than the typical usage.

All these findings support the hypothesis that larger bubbles may be caused by the fusion of microbubbles after the destruction of the shell. However, the limitation of this hypothesis is that it cannot explain the rarity of this phenomenon. In addition, it does not explain the massive PHLE that can occur in patients who receive only one UCA injection. Finally, an explanation for the long lasting perfusion of the mesenteric and portal vein is missing.

Hypothesis 2: gas emboli originating in the intestinal microcirculation and transported to the liver via enteroportal circulation

Another hypothesis has also been described in which gas emboli originating in the intestinal microcirculation are transported to the liver via the enteroportal circulation [6]. Studies in mice and rats have shown that rapid intravascular growth of microbubbles can produce these emboli as they enter the intestinal microcirculation [28]. This implies that PHLE may be related to the formation of large intravascular gas bubbles in the cecal and colonic wall. However, this hypothesis cannot explain why contrast signals can still be detected in the superior mesenteric and portal vein up to 5 hours after UCA administration when the microbubble should have disappeared from the circulation.

Hypothesis 3: pooling of UCA in the capillary bed of the small intestine

Both of the above-mentioned hypotheses cannot completely explain PHLE. One other possible explanation is pooling of UCA in the capillary bed of the small intestine. According to this hypothesis, these microbubbles are not destroyed or absorbed and gradually flow to the liver via the portal venous system. In our patients, since the splenic clearance was steady and the contrast signals disappeared within 6 – 15 minutes after contrast injection, it can be concluded that there is no pooling of SonoVue^® in the sinus of the spleen.

Disease-related hepatic portal venous gas, a similar finding

PHLE is similar to the US findings of portal venous gas caused by a variety of intestinal [5] [6] and systemic diseases [29] [30] [31] [32]. Hepatic portal venous gas (HPVG) has been reported with increasing frequency in medical, sonographic, and radiologic literature, and usually accompanies severe or lethal conditions.

The diagnosis of HPVG is usually made by US, color Doppler flow imaging, plain abdominal radiography or computed tomography [33] [34]. Further distinction of different patterns (e. g., dot-like pattern; streak-like pattern and fruit-pulp-like pattern) has been proposed but this does not play a role in routine diagnosis [35].

Limitations

One limitation is that this study was not a prospective study, since the phenomenon is rarely observed. All cases with prolonged heterogeneous liver enhancement were found by chance and, therefore, the exact incidence could be larger than 0.13 %.

Conclusion

In conclusion, PHLE is a rare phenomenon that is similar to the US findings of portal venous gas. It is still not clear why this phenomenon is not reproducible, but it is more likely to occur in patients with high dose (or multiple) injections of UCA. Nevertheless, the understanding of its mechanism requires further study. This phenomenon itself should not be misdiagnosed as a pathological finding of the liver during the CEUS examination. Gastrointestinal diseases with changes of permeability and parameters of gas pressure might be explanatory pathophysiological features.

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