Ultrasound in Med. & Biol., Vol. 41, No. 4, pp. 952–959, 2015 Copyright Ó 2015 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2014.12.001
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Original Contribution CONTRAST-ENHANCED ULTRASOUND IN DIFFERENT STAGES OF PYOGENIC LIVER ABSCESS OHLER* GEORG KUNZE,* MARTIN STARITZ,y and MICHAEL K€
* Department for Internal Medicine and Gastroenterology, Schwarzwald-Baar Klinikum Villingen-Schwenningen, Villingen-Schwenningen, Germany; and y Kreisspital Surses, Savognin, Switzerland (Received 23 July 2014; revised 20 October 2014; in final form 2 December 2014)
Abstract—To enable sonographic classification of different stages of pyogenic liver abscesses, sonographic findings in 86 patients with 113 pyogenic liver abscesses were retrospectively analyzed and compared with established pathomorphologic descriptions of the disease. The typical findings in contrast-enhanced ultrasound were sub-segmental hyperemia (93/113, 82%) and necrosis with a hyperemic margin (109/113, 96%) in the arterial phase and a washout of liver tissue surrounding necrosis in the late phase (101/113, 89%). Four different sonomorphologic stages of pyogenic liver abscess were identified. Stage I was defined by focal inflammation without necrosis (n 5 2); stage II by focal clusters of micro-abscesses appearing to coalesce (n 5 41); and stage III by a single cavity with or without capsule (n 5 64). Stage IV was defined as numerous small abscesses scattered all over the liver (n 5 6). The results indicate that contrast-enhanced ultrasound is suitable for classifying different stages of pyogenic liver abscesses. Knowledge of the described morphologic patterns influences therapeutic decisions and helps distinguish abscesses from other liver masses. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Pyogenic liver abscess, Contrast media, Sulfur hexafluoride, Microbubbles.
internal septa, perifocal edema, transient arterial phase hypervascularity and portal phase hypovascularity around abscesses (Catalano et al. 2004; Federle and Anne 2004; Gabata et al. 2001; Liu et al. 2008; Mathieu et al. 1985; Mendez et al. 1994; Mortele et al. 2004). However, these varying morphologic manifestations of liver abscess have not been aligned with the corresponding pathologic stages on the basis of a larger number of cases. The purpose of the present study was to compare sonographic findings in patients with pyogenic liver abscess with established and well-known pathomorphologic descriptions of the disease to enable the classification of different stages of liver abscess on the basis of native ultrasound and CEUS.
INTRODUCTION Although the pathogenesis of pyogenic liver abscess was described 150 y ago (Budd 1857; Frerichs 1861a, 1861b), only a few publications have discussed the medical imaging patterns of different stages of the disease (Dewbury et al. 1980; Freeny 1980; Jeffrey et al. 1988; Philips 1994; Wermke 2006). Descriptions of the appearance of liver abscesses in medical imaging have been concerned primarily with advanced stages in which liquid necrosis is surrounded by a wall corresponding histologically to a fibrous capsule (Albrecht 2005; Alobaidi and Shirkhoda 2004; Claudon et al. 2013). On contrast-enhanced ultrasound (CEUS), this capsule exhibits enhanced arterial perfusion (Albrecht 2005; Claudon et al. 2013; Wermke 2006; Wermke and Gaßmann 1998). On the basis of computed tomography, magnetic resonance imaging, and CEUS, additional criteria have been described for liver abscess, including
METHODS The institutional review board approved this retrospective study and required neither patient approval nor informed consent for the review of patient images and records. Between December 2005 and December 2013, 86 patients with 113 pyogenic liver abscesses were examined in our ultrasound laboratory by both gray-scale ultrasound and CEUS.
Address correspondence to: Georg Kunze, Department for Internal Medicine and Gastroenterology, Schwarzwald-Baar Klinikum Villingen-Schwenningen, Klinikstrasse 11, D-78052 VillingenSchwenningen, Germany. E-mail: [email protected] 952
CEUS in different stages of pyogenic liver abscess d G. KUNZE et al.
After conventional ultrasound examination with a convex multifrequency abdominal probe on a Siemens device (4–1 MHz, Acuson Sequoia 512, Siemens Healthcare, Erlangen, Germany) or a Philips device (5–2 MHz, HDI 5000, Philips Healthcare, Hamburg, Germany), CEUS was performed using a low-mechanical-index imaging technique after the injection of sulfur hexafluoride (Sonovue, Lumason) in contrast pulse sequencing mode (Siemens Acuson Sequoia 512, injection of 0.8–1.2 mL sulfur hexafluoride) or in pulse-inversion mode (Philips HDI 5000, injection of 2.4 mL sulfur hexafluoride). Digital records of all examinations were analyzed retrospectively by the same physician with more than 10 y of experience in CEUS to evaluate the gray-scale patterns and behavior in the arterial phase (5–25 s), portal venous phase (25–90 s) and late phase (90–240 s). These findings were compared with the descriptions of different pathologic stages of liver abscess formation, which are: focal infection and inflammation, liquefaction and suppuration, coalescence of clusters of small abscesses to one single cavity and, finally, abscess walled-off by a capsule (Frerichs 1861a; Kaufmann 1907; Rokitansky 1861). Accordingly, four sonographic stages were defined, and each abscess was allocated to one of these stages. The diagnosis ‘‘liver abscess’’ was confirmed by fineneedle aspiration or by core-needle biopsy. In 14 patients with liver abscess caused by penetrating gangrenous cholecystitis, the diagnosis was confirmed by the surgeon performing cholecystectomy and surgical drainage of the abscess in the same procedure. When fine-needle aspiration was not successful, refused by the patient or assessed as hazardous, the diagnosis was made clinically. In all but two of those patients, over the course of the disease, healing from liver abscess was documented by contrastenhanced computed tomography or by CEUS. RESULTS Demographic and microbiologic data Liver abscesses occurred more often in men than in women (n 5 61 vs. n 5 25). Biliary obstruction was the most frequent cause, followed by cryptogenic etiology. Microbiologic specimens (blood cultures or smear tests of abscess aspirate) were collected from 75 patients (87%) and were sterile in 16 of these cases (21%), most likely because of antibiotic pre-treatment. Liver abscesses were monomicrobial in 38 patients (51%) and polymicrobial in 21 patients (28%). Overall, 28 different germs were isolated. The demographic and microbiologic data for all patients is summarized in Table 1. Classification of different stages of liver abscess Except in the case of mature walled-off abscesses, gray-scale ultrasound alone was not able to distinguish
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Table 1. Demographic and microbiological data Demographic data Mean age (n 5 86) Sex Mean diameter (n 5 113) Etiology (n = 86) Cryptogenic Biliary obstruction Gastrointestinal Immunosuppression Concomitant disease Foreign bodies/post-operative Acute cholecystitis Microbiological data (n = 86) No analysis Sterile Monomicrobial infection Polymicrobial infection Escherichia coli Streptococcus species Klebsiella pneumoniae Enterococcus species E. faecium E. faecalis Vancomycin-resistant Enterococcus Anaerobes Fusobactium nucleatum Enterobacter cloacae Parvimonas micra Clostridium perfringens Enterococcus avium Morganella morganii Proteus mirabilis Eubacterium lentum Bacteroides thetaiotaomicron Veillonella species Proteus vulgaris Enterobacter aerogenes Bacteroides fragilis Other aerobes Klebsiella oxytoca Citrobacter freundii Raoultella ornithinolytica Pseudomonas aeroginosa Methicillin-resistant Staphylococcus aureus Citrobacter koseri Citrobacter brakii
67 (18–87) y 25 female 61 male 47 (10–120) mm 17 27 8 5 2 13 14 11 16 (21%) 38 (51%) 21 (28%) 25 21 9 12 7 4 1 23 4 3 2 2 2 2 2 1 1 1 1 1 1 15 3 3 2 2 2 2 1
between different stages of the disease. With the use of CEUS, three different sonomorphologic manifestations of liver abscess were identified: focal inflammation without necrosis (stage I, n 5 2), focal clusters of microabscesses appearing to coalesce (‘‘early’’ stage II, n 5 41) and a single cavity with or without capsule (‘‘advanced’’ stage III, n 5 64). Corresponding to Frerichs’ (1861a), Rokitansky’s (1861) and Kaufmann’s (1907) descriptions, stages II and III were further classified into subgroups reflecting the pathogenesis from infection to suppuration and liquefaction (Wermke 2006). Antibiotic treatment was initiated as soon as a diagnosis of pyogenic liver abscess was assumed and was followed by fine-needle aspiration or interventional
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Fig. 1. Sixty-one-year-old man with pyogenic liver abscess. On ultrasound, the morphology changes over 2 wk from stage IIb (a–c) to stage IIIc (d–f) as a result of occluded drainage. Arterial phase hyperemia (b, e) and late phase washout (c, f) are less striking in the walled-off abscess or limited to the capsule respectively.
drainage in most cases. Therefore, we could not document the entire course of the disease from infection to mature walled-off abscess in any single patient. However, in one patient with liver abscess caused by biliary obstruction, the interventional drainage became occluded. In this case, the abscess advanced from stage IIb to stage IIIc within 2 wk (Fig. 1a–f). Six patients whose abscesses could not be assigned to one of the three stages had numerous (.10) small abscesses (,2 cm) spread all over the liver. Four of these patients were treated by myelo-ablative chemotherapy, and two patients suffered from liver cirrhosis because of continued alcohol abuse. Because of the special presentation and small size, they were assigned stage IV, although these abscesses almost surely ran through all stages of liver abscess. The pathomorphologic and sonographic presentations of all stages are illustrated in Figure 2. Characteristic patterns in CEUS The following were identified as characteristic patterns of liver abscess in CEUS: subsegmental or segmental hyperemia (93/113, 82%) and necrosis with a hyperemic margin (109/113, 96%) in the arterial phase, and a washout of the liver tissue surrounding necrosis in the late phase (101/113, 89%) (Fig. 3). In addition, in 38 of the 113 abscesses (34%) a small halo of delayed contrast enhancement surrounding the hyperemic margin was observed in the early arterial phase. This phenomenon vanished within a few seconds. According to findings in magnetic resonance imaging and computed tomography (Mathieu et al. 1985; Mendez et al. 1994; Mortele
et al. 2004), this was interpreted as perifocal edema (Fig. 4). In the early stage, areas and bridges of vital liver tissue were found between areas of necrosis, and most of these washed out in the late phase. In some cases, vital liver tissue was detected between necroses, even in the late phase (Fig. 5). In mature walled-off abscesses characterized by a hyperemic multilayer capsule, both the hyperemia in the arterial phase and washout in the late phase seemed to be less striking or limited to the capsule, respectively (Fig. 1a–f). Findings on gray-scale ultrasound and CEUS are summarized in Table 2. DISCUSSION In recent years, CEUS using microbubbles in lowmechanical-index mode has become a reliable imaging procedure for the characterization of focal liver masses (Burns and Wilson 2007; Claudon et al. 2013; Quaia 2011, 2012; Quaia et al. 2014; Strobel et al. 2008; Tranquart et al. 2008; Wermke 2006; Wilson et al. 2009). Though mature pyogenic liver abscesses can be diagnosed easily in gray-scale ultrasound, at early stages of liver abscess it is difficult to distinguish necrosis from vital parenchyma, which is crucial for adequate microbiologic diagnosis and treatment. Knowledge of the pathogenesis of pyogenic liver abscess (Fig. 6) is essential to understanding the changing presentation of liver abscesses at different stages and the varying patterns in medical imaging. Infection may ascend from the bile duct, transfer
CEUS in different stages of pyogenic liver abscess d G. KUNZE et al.
Fig. 2. Sonographic classification of different stages of pyogenic liver abscess reflecting the pathogenesis from inflammation to suppuration and liquefaction based on pathology, native ultrasound and contrast-enhanced ultrasound (n 5 number of cases in study).
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Fig. 3. Seventy-eight-year-old man with mixed echo-poor and echoic liver abscess (stage IIa) on gray-scale ultrasound (a). In the arterial phase, contrast-enhanced ultrasound reveals segmental hyperemia and small contiguous necroses (b). In the late phase, washout of the perinecrotic liver tissue reveals pylephlebitis (c).
from the gastrointestinal tract via the portal vein, penetrate from neighboring infections, such as cholecystitis, or occur hematogenously via the hepatic artery. Inflammation caused by bacterial infection causes thrombosis of small hepatic and portal veins, with portal vein involvement being known as pylephlebitis (stage I). Despite inflammatory arterial hyperemia, absence of portal perfusion leads to critical ischemia and subsequent necrosis in liver tissue (stage IIa). Necrosis is an excellent nutrient medium for further bacterial growth. Ongoing inflammation and neutrophil invasion lead to suppuration
and liquefaction; small abscess cavities coalesce (stage IIb). As a result of the loss of bridges of vital liver tissue, a single necrotic cavity with an uneven wall is formed (stage IIIa) and becomes more and more round (stage IIIb). To separate the inflammatory process, a capsule rich in capillaries is formed around the necrotic cavity, and finally, the abscess presents as a mature walled-off abscess (stage IIIc) (Fig. 2). Arterial segmental and perifocal hyperemia and washout around necrosis in the late phase are characteristic of liver abscess in CEUS at all stages. Hyperemia is
Fig. 4. Eighteen-year-old man presenting with a liver abscess 4 wk after appendectomy. T2-Weighted magnetic resonance image (a) reveals pronounced edema (D) that can be assumed (*) in gray-scale ultrasound (b). With contrastenhanced ultrasound, edema presents as a halo with delayed contrast enhancement (**) in the early arterial phase (c) that vanishes within a few seconds (d). The edema needs to be distinguished from washout caused by pylephlebitis in the late phase (e).
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of the disease, the liver tissue in these regions will perish, as arterial perfusion alone is not sufficient to provide the blood supply required for abscess healing. The clinical importance of this loss of liver tissue depends on the capability of the liver to regenerate. In the last few years, the role of Klebsiella pneumoniae in causing liver abscesses has been emphasized, especially in Asian populations (Law and Kong Li 2013; Liu et al. 2013; Wang et al. 1998, Wang et al. 2013). In medical imaging, liver abscesses caused by this germ rarely present as single necrotic cavity, but often as a solid mass or multiloculated clusters of small microabscesses with internal septa (Alsaif et al. 2011; Hui et al. 2007; Kim et al. 2007; Lee et al. 2011). Because of phagocytosis-resistant serotypes, the liquefaction of K. pneumoniae liver abscesses develops more slowly than in abscesses caused by other organisms. As patients with K. pneumoniae infection exhibit signs of severe septicemia more often than patients infected with other organisms (Liu et al. 2013; Shon et al. 2013), their liver abscesses may present at an earlier stage. In line with the data from other Western countries (Cerwenka 2010;
Fig. 5. Fifty-four-year-old man with severe sepsis caused by early-stage pyogenic liver abscess (stage IIa). In the late phase (3 min 35 s), vital liver parenchyma is detected between necroses.
caused by inflammatory cytokines and increased arterial perfusion resulting from thrombosis of small portal and hepatic veins. In the portal and late phase, thrombosis of these small portal and hepatic veins leads to a washout of the inflamed parenchyma (Figs. 1–4). Over the course
Table 2. Findings on ultrasound Stage I
Gray-scale ultrasound Echogenicity (n 5 113) Invisible Hypo-echoic Anechoic Hypo-echoic 1 anechoic Hypo-echoic 1 echogenic Gas (n 5 113) Yes No Capsule (n 5 113) Complete Incomplete No Shape (n 5 109, 4 invisible) Well defined Blurred C ontrast-enhanced ultrasound Arterial phase (n 5 113) Necrosis with surrounding hyperemic rim Hyperemia without necrosis Edema (Sub-)segmental hyperemia Portal venous phase* (n 5 113) Hyper-echoic Iso-echoic Hypo-echoic Late phase* (n 5 113) Iso-echoic Hypo-echoic Blurred rim
Stage II
Stage III
Stage IV
Overall (n 5 113) (100%)
(n 5 2)
a (n 5 18)
b (n 5 23)
a (n 5 24)
b (n 5 23)
c (n 5 17)
(n 5 6)
4 (3) 32 (28) 21 (19) 41 (36) 15 (13)
1 1 0 0 0
1 8 2 4 3
0 4 0 12 7
0 8 5 10 1
1 5 7 9 1
0 2 7 5 3
1 4 0 1 0
16 (14) 97 (86)
0 2
2 16
4 19
5 19
0 23
5 12
0 6
12 (11) 39 (34) 62 (55)
0 0 2
0 2 16
0 15 8
1 8 15
0 8 15
11 6 0
0 0 6
24 (21) 85 (79)
0 1
0 17
4 19
5 19
5 17
10 7
0 5
109 (96)
0
18
23
24
23
15
6
2 (2) 38 (34) 93 (82)
2 0 2
0 3 18
0 8 20
0 8 20
0 12 15
0 7 14
0 0 4
21 (19) 52 (46) 40 (37)
1 0 1
6 4 8
6 11 6
2 11 11
1 14 8
3 12 2
2 0 4
12 (11) 101 (89) 107 (95)
0 2 2
0 18 18
0 23 23
3 21 23
3 20 21
5 12 14
1 5 6
* Behavior of liver tissue around necrosis.
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Fig. 6. Pathogenesis of abscess formation in the liver.
Mohsen et al. 2002; Petri et al. 2002), only nine abscesses in this study were caused by K. pneumoniae. This germ was found in both early-stage and mature abscesses. Because of the small number of cases, this study is not able to describe the specific morphologic patterns of liver abscesses caused by K. pneumoniae. A miliary spreading of small abscesses on the liver occurs primarily in immunocompromised patients and was described previously as a typical pattern of fungal or mixed fungal/bacterial abscesses (Callen et al. 1980; G€ org et al. 1994, 2010; Lipsett et al. 1997; Thaler et al. 1988). We examined six patients with such a manifestation of liver abscess. Even though gram-positive coccoid bacteria could be isolated from only one of the two patients with cirrhosis, healing was achieved by antibiotic therapy without antimycotic therapy. The other four patients with miliary liver abscesses had septicemia over the course of myelo-ablative chemotherapy for acute leukemia. Liver abscesses in patients with agranulocytosis are hardly detectable in medical imaging (G€ org et al. 1994; Thaler et al. 1988). Therefore, these patients were treated with both antibiotic and antimycotic drugs immediately after the clinical signs of infection appeared, and CEUS was performed several days later. None of these abscesses presented as ‘‘bull’s eye’’ or ‘‘target’’ lesions, which are described as being characteristic of mycotic abscesses (Callen et al. 1980; Thaler et al. 1988), and none of these patients had splenic abscesses. Core-needle biopsy was performed in all four patients in order to rule out leukemic infiltration. Yeasts and hyphae were not found, but in one case gram-positive coccoid bacteria were proven histologically. Therefore, we cannot exclude that three of these six abscesses were mycotic abscesses. Nevertheless, a miliary spreading of bacterial liver abscesses has been described in 11 other patients in the past (Lipsett et al. 1997; Mathieu et al. 1985; Ryan et al. 2001). Naturally, also small scattered abscesses run through all liver abscess stages. The specific appearance of these abscesses warrants separate classification.
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Treatment with antibiotics for several weeks (Bamberger 1996; Liu et al. 2013) is the most effective means of achieving healing of liver abscesses. Fineneedle aspiration is crucial for identifying causative bacteria and leads to decompression of the purulent cavity. In the course of the disease, sometimes serial aspiration is necessary. If required at all, interventional drainage is appropriate when the cavity is larger than 5 cm (Giorgio et al. 1995, 2006; Zerem and Hadzic 2007). As CEUS is safe for distinguishing necrosis from ischemic liver tissue, even in small abscesses, we recommend it before fine-needle aspiration in cases of earlystage liver abscess. In addition, CEUS can be repeated easily, making it a valuable tool for assessing the course of the disease and deciding whether further interventions are needed. Our study has some limitations. First, antibiotic treatment started immediately when the diagnosis of pyogenic liver abscess was assumed, so we could not document all stages in any single patient. Second, this was a retrospective study; all exams were analyzed by the same physician, who was not blinded to patient history and other findings concerning the patient. However, the criteria described for CEUS in different stages of pyogenic liver abscess are distinct and comprehensible and agree with the pathologic descriptions of the disease (Frerichs 1861a; Kaufmann 1907; Wermke 2006). The results indicate that CEUS is suitable for classifying different stages of liver abscess. Knowledge of the described morphologic patterns helps distinguish them from other liver masses, especially malignancies. Acknowledgments—We thank Professor Wolfram Wermke, Charite Berlin, for the longlasting and inspiring discussion on the subject of this article. Furthermore, we are grateful to Dr. Frank Schmid and Professor Ulrich Fink from our Institute for Clinical Radiology for the magnetic resonance image in Figure 4 and the explanation of computed tomography and magnetic resonance imaging scans. This work would not have been possible without the untiring and friendly assistance of Brigitte Quattl€ander in the ultrasound laboratory and support by all colleagues from our Department for Internal Medicine and Gastroenterology.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2014.12.001
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Original Contribution CONTRAST-ENHANCED ULTRASOUND IN DIFFERENT STAGES OF PYOGENIC LIVER ABSCESS OHLER* GEORG KUNZE,* MARTIN STARITZ,y and MICHAEL K€
* Department for Internal Medicine and Gastroenterology, Schwarzwald-Baar Klinikum Villingen-Schwenningen, Villingen-Schwenningen, Germany; and y Kreisspital Surses, Savognin, Switzerland (Received 23 July 2014; revised 20 October 2014; in final form 2 December 2014)
Abstract—To enable sonographic classification of different stages of pyogenic liver abscesses, sonographic findings in 86 patients with 113 pyogenic liver abscesses were retrospectively analyzed and compared with established pathomorphologic descriptions of the disease. The typical findings in contrast-enhanced ultrasound were sub-segmental hyperemia (93/113, 82%) and necrosis with a hyperemic margin (109/113, 96%) in the arterial phase and a washout of liver tissue surrounding necrosis in the late phase (101/113, 89%). Four different sonomorphologic stages of pyogenic liver abscess were identified. Stage I was defined by focal inflammation without necrosis (n 5 2); stage II by focal clusters of micro-abscesses appearing to coalesce (n 5 41); and stage III by a single cavity with or without capsule (n 5 64). Stage IV was defined as numerous small abscesses scattered all over the liver (n 5 6). The results indicate that contrast-enhanced ultrasound is suitable for classifying different stages of pyogenic liver abscesses. Knowledge of the described morphologic patterns influences therapeutic decisions and helps distinguish abscesses from other liver masses. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Pyogenic liver abscess, Contrast media, Sulfur hexafluoride, Microbubbles.
internal septa, perifocal edema, transient arterial phase hypervascularity and portal phase hypovascularity around abscesses (Catalano et al. 2004; Federle and Anne 2004; Gabata et al. 2001; Liu et al. 2008; Mathieu et al. 1985; Mendez et al. 1994; Mortele et al. 2004). However, these varying morphologic manifestations of liver abscess have not been aligned with the corresponding pathologic stages on the basis of a larger number of cases. The purpose of the present study was to compare sonographic findings in patients with pyogenic liver abscess with established and well-known pathomorphologic descriptions of the disease to enable the classification of different stages of liver abscess on the basis of native ultrasound and CEUS.
INTRODUCTION Although the pathogenesis of pyogenic liver abscess was described 150 y ago (Budd 1857; Frerichs 1861a, 1861b), only a few publications have discussed the medical imaging patterns of different stages of the disease (Dewbury et al. 1980; Freeny 1980; Jeffrey et al. 1988; Philips 1994; Wermke 2006). Descriptions of the appearance of liver abscesses in medical imaging have been concerned primarily with advanced stages in which liquid necrosis is surrounded by a wall corresponding histologically to a fibrous capsule (Albrecht 2005; Alobaidi and Shirkhoda 2004; Claudon et al. 2013). On contrast-enhanced ultrasound (CEUS), this capsule exhibits enhanced arterial perfusion (Albrecht 2005; Claudon et al. 2013; Wermke 2006; Wermke and Gaßmann 1998). On the basis of computed tomography, magnetic resonance imaging, and CEUS, additional criteria have been described for liver abscess, including
METHODS The institutional review board approved this retrospective study and required neither patient approval nor informed consent for the review of patient images and records. Between December 2005 and December 2013, 86 patients with 113 pyogenic liver abscesses were examined in our ultrasound laboratory by both gray-scale ultrasound and CEUS.
Address correspondence to: Georg Kunze, Department for Internal Medicine and Gastroenterology, Schwarzwald-Baar Klinikum Villingen-Schwenningen, Klinikstrasse 11, D-78052 VillingenSchwenningen, Germany. E-mail: [email protected] 952
CEUS in different stages of pyogenic liver abscess d G. KUNZE et al.
After conventional ultrasound examination with a convex multifrequency abdominal probe on a Siemens device (4–1 MHz, Acuson Sequoia 512, Siemens Healthcare, Erlangen, Germany) or a Philips device (5–2 MHz, HDI 5000, Philips Healthcare, Hamburg, Germany), CEUS was performed using a low-mechanical-index imaging technique after the injection of sulfur hexafluoride (Sonovue, Lumason) in contrast pulse sequencing mode (Siemens Acuson Sequoia 512, injection of 0.8–1.2 mL sulfur hexafluoride) or in pulse-inversion mode (Philips HDI 5000, injection of 2.4 mL sulfur hexafluoride). Digital records of all examinations were analyzed retrospectively by the same physician with more than 10 y of experience in CEUS to evaluate the gray-scale patterns and behavior in the arterial phase (5–25 s), portal venous phase (25–90 s) and late phase (90–240 s). These findings were compared with the descriptions of different pathologic stages of liver abscess formation, which are: focal infection and inflammation, liquefaction and suppuration, coalescence of clusters of small abscesses to one single cavity and, finally, abscess walled-off by a capsule (Frerichs 1861a; Kaufmann 1907; Rokitansky 1861). Accordingly, four sonographic stages were defined, and each abscess was allocated to one of these stages. The diagnosis ‘‘liver abscess’’ was confirmed by fineneedle aspiration or by core-needle biopsy. In 14 patients with liver abscess caused by penetrating gangrenous cholecystitis, the diagnosis was confirmed by the surgeon performing cholecystectomy and surgical drainage of the abscess in the same procedure. When fine-needle aspiration was not successful, refused by the patient or assessed as hazardous, the diagnosis was made clinically. In all but two of those patients, over the course of the disease, healing from liver abscess was documented by contrastenhanced computed tomography or by CEUS. RESULTS Demographic and microbiologic data Liver abscesses occurred more often in men than in women (n 5 61 vs. n 5 25). Biliary obstruction was the most frequent cause, followed by cryptogenic etiology. Microbiologic specimens (blood cultures or smear tests of abscess aspirate) were collected from 75 patients (87%) and were sterile in 16 of these cases (21%), most likely because of antibiotic pre-treatment. Liver abscesses were monomicrobial in 38 patients (51%) and polymicrobial in 21 patients (28%). Overall, 28 different germs were isolated. The demographic and microbiologic data for all patients is summarized in Table 1. Classification of different stages of liver abscess Except in the case of mature walled-off abscesses, gray-scale ultrasound alone was not able to distinguish
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Table 1. Demographic and microbiological data Demographic data Mean age (n 5 86) Sex Mean diameter (n 5 113) Etiology (n = 86) Cryptogenic Biliary obstruction Gastrointestinal Immunosuppression Concomitant disease Foreign bodies/post-operative Acute cholecystitis Microbiological data (n = 86) No analysis Sterile Monomicrobial infection Polymicrobial infection Escherichia coli Streptococcus species Klebsiella pneumoniae Enterococcus species E. faecium E. faecalis Vancomycin-resistant Enterococcus Anaerobes Fusobactium nucleatum Enterobacter cloacae Parvimonas micra Clostridium perfringens Enterococcus avium Morganella morganii Proteus mirabilis Eubacterium lentum Bacteroides thetaiotaomicron Veillonella species Proteus vulgaris Enterobacter aerogenes Bacteroides fragilis Other aerobes Klebsiella oxytoca Citrobacter freundii Raoultella ornithinolytica Pseudomonas aeroginosa Methicillin-resistant Staphylococcus aureus Citrobacter koseri Citrobacter brakii
67 (18–87) y 25 female 61 male 47 (10–120) mm 17 27 8 5 2 13 14 11 16 (21%) 38 (51%) 21 (28%) 25 21 9 12 7 4 1 23 4 3 2 2 2 2 2 1 1 1 1 1 1 15 3 3 2 2 2 2 1
between different stages of the disease. With the use of CEUS, three different sonomorphologic manifestations of liver abscess were identified: focal inflammation without necrosis (stage I, n 5 2), focal clusters of microabscesses appearing to coalesce (‘‘early’’ stage II, n 5 41) and a single cavity with or without capsule (‘‘advanced’’ stage III, n 5 64). Corresponding to Frerichs’ (1861a), Rokitansky’s (1861) and Kaufmann’s (1907) descriptions, stages II and III were further classified into subgroups reflecting the pathogenesis from infection to suppuration and liquefaction (Wermke 2006). Antibiotic treatment was initiated as soon as a diagnosis of pyogenic liver abscess was assumed and was followed by fine-needle aspiration or interventional
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Fig. 1. Sixty-one-year-old man with pyogenic liver abscess. On ultrasound, the morphology changes over 2 wk from stage IIb (a–c) to stage IIIc (d–f) as a result of occluded drainage. Arterial phase hyperemia (b, e) and late phase washout (c, f) are less striking in the walled-off abscess or limited to the capsule respectively.
drainage in most cases. Therefore, we could not document the entire course of the disease from infection to mature walled-off abscess in any single patient. However, in one patient with liver abscess caused by biliary obstruction, the interventional drainage became occluded. In this case, the abscess advanced from stage IIb to stage IIIc within 2 wk (Fig. 1a–f). Six patients whose abscesses could not be assigned to one of the three stages had numerous (.10) small abscesses (,2 cm) spread all over the liver. Four of these patients were treated by myelo-ablative chemotherapy, and two patients suffered from liver cirrhosis because of continued alcohol abuse. Because of the special presentation and small size, they were assigned stage IV, although these abscesses almost surely ran through all stages of liver abscess. The pathomorphologic and sonographic presentations of all stages are illustrated in Figure 2. Characteristic patterns in CEUS The following were identified as characteristic patterns of liver abscess in CEUS: subsegmental or segmental hyperemia (93/113, 82%) and necrosis with a hyperemic margin (109/113, 96%) in the arterial phase, and a washout of the liver tissue surrounding necrosis in the late phase (101/113, 89%) (Fig. 3). In addition, in 38 of the 113 abscesses (34%) a small halo of delayed contrast enhancement surrounding the hyperemic margin was observed in the early arterial phase. This phenomenon vanished within a few seconds. According to findings in magnetic resonance imaging and computed tomography (Mathieu et al. 1985; Mendez et al. 1994; Mortele
et al. 2004), this was interpreted as perifocal edema (Fig. 4). In the early stage, areas and bridges of vital liver tissue were found between areas of necrosis, and most of these washed out in the late phase. In some cases, vital liver tissue was detected between necroses, even in the late phase (Fig. 5). In mature walled-off abscesses characterized by a hyperemic multilayer capsule, both the hyperemia in the arterial phase and washout in the late phase seemed to be less striking or limited to the capsule, respectively (Fig. 1a–f). Findings on gray-scale ultrasound and CEUS are summarized in Table 2. DISCUSSION In recent years, CEUS using microbubbles in lowmechanical-index mode has become a reliable imaging procedure for the characterization of focal liver masses (Burns and Wilson 2007; Claudon et al. 2013; Quaia 2011, 2012; Quaia et al. 2014; Strobel et al. 2008; Tranquart et al. 2008; Wermke 2006; Wilson et al. 2009). Though mature pyogenic liver abscesses can be diagnosed easily in gray-scale ultrasound, at early stages of liver abscess it is difficult to distinguish necrosis from vital parenchyma, which is crucial for adequate microbiologic diagnosis and treatment. Knowledge of the pathogenesis of pyogenic liver abscess (Fig. 6) is essential to understanding the changing presentation of liver abscesses at different stages and the varying patterns in medical imaging. Infection may ascend from the bile duct, transfer
CEUS in different stages of pyogenic liver abscess d G. KUNZE et al.
Fig. 2. Sonographic classification of different stages of pyogenic liver abscess reflecting the pathogenesis from inflammation to suppuration and liquefaction based on pathology, native ultrasound and contrast-enhanced ultrasound (n 5 number of cases in study).
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Fig. 3. Seventy-eight-year-old man with mixed echo-poor and echoic liver abscess (stage IIa) on gray-scale ultrasound (a). In the arterial phase, contrast-enhanced ultrasound reveals segmental hyperemia and small contiguous necroses (b). In the late phase, washout of the perinecrotic liver tissue reveals pylephlebitis (c).
from the gastrointestinal tract via the portal vein, penetrate from neighboring infections, such as cholecystitis, or occur hematogenously via the hepatic artery. Inflammation caused by bacterial infection causes thrombosis of small hepatic and portal veins, with portal vein involvement being known as pylephlebitis (stage I). Despite inflammatory arterial hyperemia, absence of portal perfusion leads to critical ischemia and subsequent necrosis in liver tissue (stage IIa). Necrosis is an excellent nutrient medium for further bacterial growth. Ongoing inflammation and neutrophil invasion lead to suppuration
and liquefaction; small abscess cavities coalesce (stage IIb). As a result of the loss of bridges of vital liver tissue, a single necrotic cavity with an uneven wall is formed (stage IIIa) and becomes more and more round (stage IIIb). To separate the inflammatory process, a capsule rich in capillaries is formed around the necrotic cavity, and finally, the abscess presents as a mature walled-off abscess (stage IIIc) (Fig. 2). Arterial segmental and perifocal hyperemia and washout around necrosis in the late phase are characteristic of liver abscess in CEUS at all stages. Hyperemia is
Fig. 4. Eighteen-year-old man presenting with a liver abscess 4 wk after appendectomy. T2-Weighted magnetic resonance image (a) reveals pronounced edema (D) that can be assumed (*) in gray-scale ultrasound (b). With contrastenhanced ultrasound, edema presents as a halo with delayed contrast enhancement (**) in the early arterial phase (c) that vanishes within a few seconds (d). The edema needs to be distinguished from washout caused by pylephlebitis in the late phase (e).
CEUS in different stages of pyogenic liver abscess d G. KUNZE et al.
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of the disease, the liver tissue in these regions will perish, as arterial perfusion alone is not sufficient to provide the blood supply required for abscess healing. The clinical importance of this loss of liver tissue depends on the capability of the liver to regenerate. In the last few years, the role of Klebsiella pneumoniae in causing liver abscesses has been emphasized, especially in Asian populations (Law and Kong Li 2013; Liu et al. 2013; Wang et al. 1998, Wang et al. 2013). In medical imaging, liver abscesses caused by this germ rarely present as single necrotic cavity, but often as a solid mass or multiloculated clusters of small microabscesses with internal septa (Alsaif et al. 2011; Hui et al. 2007; Kim et al. 2007; Lee et al. 2011). Because of phagocytosis-resistant serotypes, the liquefaction of K. pneumoniae liver abscesses develops more slowly than in abscesses caused by other organisms. As patients with K. pneumoniae infection exhibit signs of severe septicemia more often than patients infected with other organisms (Liu et al. 2013; Shon et al. 2013), their liver abscesses may present at an earlier stage. In line with the data from other Western countries (Cerwenka 2010;
Fig. 5. Fifty-four-year-old man with severe sepsis caused by early-stage pyogenic liver abscess (stage IIa). In the late phase (3 min 35 s), vital liver parenchyma is detected between necroses.
caused by inflammatory cytokines and increased arterial perfusion resulting from thrombosis of small portal and hepatic veins. In the portal and late phase, thrombosis of these small portal and hepatic veins leads to a washout of the inflamed parenchyma (Figs. 1–4). Over the course
Table 2. Findings on ultrasound Stage I
Gray-scale ultrasound Echogenicity (n 5 113) Invisible Hypo-echoic Anechoic Hypo-echoic 1 anechoic Hypo-echoic 1 echogenic Gas (n 5 113) Yes No Capsule (n 5 113) Complete Incomplete No Shape (n 5 109, 4 invisible) Well defined Blurred C ontrast-enhanced ultrasound Arterial phase (n 5 113) Necrosis with surrounding hyperemic rim Hyperemia without necrosis Edema (Sub-)segmental hyperemia Portal venous phase* (n 5 113) Hyper-echoic Iso-echoic Hypo-echoic Late phase* (n 5 113) Iso-echoic Hypo-echoic Blurred rim
Stage II
Stage III
Stage IV
Overall (n 5 113) (100%)
(n 5 2)
a (n 5 18)
b (n 5 23)
a (n 5 24)
b (n 5 23)
c (n 5 17)
(n 5 6)
4 (3) 32 (28) 21 (19) 41 (36) 15 (13)
1 1 0 0 0
1 8 2 4 3
0 4 0 12 7
0 8 5 10 1
1 5 7 9 1
0 2 7 5 3
1 4 0 1 0
16 (14) 97 (86)
0 2
2 16
4 19
5 19
0 23
5 12
0 6
12 (11) 39 (34) 62 (55)
0 0 2
0 2 16
0 15 8
1 8 15
0 8 15
11 6 0
0 0 6
24 (21) 85 (79)
0 1
0 17
4 19
5 19
5 17
10 7
0 5
109 (96)
0
18
23
24
23
15
6
2 (2) 38 (34) 93 (82)
2 0 2
0 3 18
0 8 20
0 8 20
0 12 15
0 7 14
0 0 4
21 (19) 52 (46) 40 (37)
1 0 1
6 4 8
6 11 6
2 11 11
1 14 8
3 12 2
2 0 4
12 (11) 101 (89) 107 (95)
0 2 2
0 18 18
0 23 23
3 21 23
3 20 21
5 12 14
1 5 6
* Behavior of liver tissue around necrosis.
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Fig. 6. Pathogenesis of abscess formation in the liver.
Mohsen et al. 2002; Petri et al. 2002), only nine abscesses in this study were caused by K. pneumoniae. This germ was found in both early-stage and mature abscesses. Because of the small number of cases, this study is not able to describe the specific morphologic patterns of liver abscesses caused by K. pneumoniae. A miliary spreading of small abscesses on the liver occurs primarily in immunocompromised patients and was described previously as a typical pattern of fungal or mixed fungal/bacterial abscesses (Callen et al. 1980; G€ org et al. 1994, 2010; Lipsett et al. 1997; Thaler et al. 1988). We examined six patients with such a manifestation of liver abscess. Even though gram-positive coccoid bacteria could be isolated from only one of the two patients with cirrhosis, healing was achieved by antibiotic therapy without antimycotic therapy. The other four patients with miliary liver abscesses had septicemia over the course of myelo-ablative chemotherapy for acute leukemia. Liver abscesses in patients with agranulocytosis are hardly detectable in medical imaging (G€ org et al. 1994; Thaler et al. 1988). Therefore, these patients were treated with both antibiotic and antimycotic drugs immediately after the clinical signs of infection appeared, and CEUS was performed several days later. None of these abscesses presented as ‘‘bull’s eye’’ or ‘‘target’’ lesions, which are described as being characteristic of mycotic abscesses (Callen et al. 1980; Thaler et al. 1988), and none of these patients had splenic abscesses. Core-needle biopsy was performed in all four patients in order to rule out leukemic infiltration. Yeasts and hyphae were not found, but in one case gram-positive coccoid bacteria were proven histologically. Therefore, we cannot exclude that three of these six abscesses were mycotic abscesses. Nevertheless, a miliary spreading of bacterial liver abscesses has been described in 11 other patients in the past (Lipsett et al. 1997; Mathieu et al. 1985; Ryan et al. 2001). Naturally, also small scattered abscesses run through all liver abscess stages. The specific appearance of these abscesses warrants separate classification.
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Treatment with antibiotics for several weeks (Bamberger 1996; Liu et al. 2013) is the most effective means of achieving healing of liver abscesses. Fineneedle aspiration is crucial for identifying causative bacteria and leads to decompression of the purulent cavity. In the course of the disease, sometimes serial aspiration is necessary. If required at all, interventional drainage is appropriate when the cavity is larger than 5 cm (Giorgio et al. 1995, 2006; Zerem and Hadzic 2007). As CEUS is safe for distinguishing necrosis from ischemic liver tissue, even in small abscesses, we recommend it before fine-needle aspiration in cases of earlystage liver abscess. In addition, CEUS can be repeated easily, making it a valuable tool for assessing the course of the disease and deciding whether further interventions are needed. Our study has some limitations. First, antibiotic treatment started immediately when the diagnosis of pyogenic liver abscess was assumed, so we could not document all stages in any single patient. Second, this was a retrospective study; all exams were analyzed by the same physician, who was not blinded to patient history and other findings concerning the patient. However, the criteria described for CEUS in different stages of pyogenic liver abscess are distinct and comprehensible and agree with the pathologic descriptions of the disease (Frerichs 1861a; Kaufmann 1907; Wermke 2006). The results indicate that CEUS is suitable for classifying different stages of liver abscess. Knowledge of the described morphologic patterns helps distinguish them from other liver masses, especially malignancies. Acknowledgments—We thank Professor Wolfram Wermke, Charite Berlin, for the longlasting and inspiring discussion on the subject of this article. Furthermore, we are grateful to Dr. Frank Schmid and Professor Ulrich Fink from our Institute for Clinical Radiology for the magnetic resonance image in Figure 4 and the explanation of computed tomography and magnetic resonance imaging scans. This work would not have been possible without the untiring and friendly assistance of Brigitte Quattl€ander in the ultrasound laboratory and support by all colleagues from our Department for Internal Medicine and Gastroenterology.
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