New Ultrasound Techniques Challenge the Diagnosis of Sinusoidal Obstruction Syndrome

ARTICLE IN PRESS Ultrasound in Med. & Biol., Vol. 00, No. 00, pp. 112, 2018 Copyright © 2018 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Printed in the USA. All rights reserved. 0301-5629/$ - see front matter

https://doi.org/10.1016/j.ultrasmedbio.2018.06.002


Review TAGEDH1NEW ULTRASOUND TECHNIQUES CHALLENGE THE DIAGNOSIS OF SINUSOIDAL OBSTRUCTION SYNDROMETAGEDN € ,D8X{X TAGEDPD1X XCHRISTOPH F. DIETRICH,D2X X*,y D3X XCORINNA TRENKER,D4XzX D5X XTERESA FONTANILLA,Dx6X X D7X XCHRISTIAN GORG ║ # yy D9X XANDREAS HAUSMANN,D10X X D1X XSTEFAN KLEIN,D12X X D13X XNATHALIE LASSAU,D14X X** D15X XROSA MIQUEL,D16X X D17X XDAGMAR SCHREIBER-DIETRICH,D18XzzX and D19X XYI DONGD20xx X X AGEDNTE

* Department of Internal Medicine 2, Caritas Krankenhaus, Bad Mergentheim, Germany; y Ultrasound Department, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; z Department of Haematology, Oncology and Immunology, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany; x Radiology Department, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; { Interdisciplinary Center of Ultrasound, University Hospital Giessen and Marburg, unchner Leuk€amielabor GmbH, M€ unchen, Germany; # Department of Philipps University Marburg, Marburg, Germany; ║ MLL M€ Hematology and Oncology, University Clinic Mannheim, Mannheim, Germany; ** Gustave Roussy Imaging Department, CNRS Universite Paris-Sud, Paris, France; yy Liver Histopathology, Institute of Liver Studies, King’s College Hospital, London, United Kingdom; zz Pediatric Department, Caritas Krankenhaus, Bad Mergentheim, Germany; and xx Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China (Received 16 March 2018; revised 14 May 2018; in final from 4 June 2018)

Abstract—Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation. Clinically, SOS/VOD is characterized by hepatomegaly, right upper quadrant pain, jaundice and ascites, most often occurring within the first 3 wk after hematopoietic cell transplantation. Early therapeutic intervention is pivotal for survival in SOS/ VOD. Thus, a rapid and reliable diagnosis has to be made. Diagnosis of SOS/VOD is based on clinical criteria, such as the Seattle, Baltimore or recently issued European Society for Blood and Marrow Transplantation criteria, to which hemodynamic and/or ultrasound evidence of SOS were added for the first time. However, to rule out major differential diagnoses and to verify the diagnosis, a reliable imaging method is needed. Ultrasound techniques have been proposed in SOS/VOD. Nevertheless, the sensitivity and specificity of transabdominal ultrasound and Doppler techniques need to be improved. Innovative ultrasound methods such as a combination of Doppler ultrasound with shear wave elastography and contrast-enhanced ultrasound techniques should be evaluated for diagnosis and follow-up of SOS/VOD. The goals of this review are to discuss currently available ultrasound techniques and to identify areas for future studies in SOS/VOD. (E-mail: Christoph.dietrich@ckbm. de) © 2018 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Key Words: Sinusoidal obstruction syndrome, Diagnosis, Ultrasound, Elastography, Guideline.

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Although SOS/VOD progressively resolves within a few weeks in some patients, the most severe forms (grade III) result in multi-organ dysfunction and are associated with a high mortality rate (>80%) (Mohty et al. 2015, 2016). Accurate and early diagnosis of SOS/VOD is clinically important to reduce the reported high fatality rate (Jones et al. 1987; McDonald et al. 1984). Jones et al. (1987) reported that only 1 of 25 patients with SOS/VOD and a serum bilirubin level >15 mg/dL survived, and Zager et al. (1989) reported that only 14% of SOS/VOD patients who required hemodialysis survived. Most patients with distinct SOS/VOD die of multi-organ failure within the second month after the transplant. Therefore, careful attention must be paid to allow early detection of

Sinusoidal obstruction syndrome, also known as venoocclusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation (HCT) and classically presents in the early post-transplantation period and, with a potentially late-onset SOS/VOD, after certain medications (e.g., gemtuzumab ozogamicin or inotuzumab ozogamicin). The average incidence of SOS/VOD is approximately 10% in adults and 20% in children (Corbacioglu et al. 2018). Address correspondence to: Christoph F. Dietrich, Department of Internal Medicine 2, Caritas Krankenhaus, D-97980 Bad Mergentheim, Germany. E-mail: [email protected]

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SOS/VOD (or prevention), particularly because defibrotide has proven to be effective and is licensed for its treatment (Braden et al. 2002, Ignee et al. 2016; Imran et al. 2006; Mohty et al. 2016). The mortality could potentially be reduced (Richardson et al. 2016) by early diagnosis and treatment and, in high-risk pediatric patients, by a prophylactic approach. Here we describe the current and potential value of ultrasound techniques to diagnose SOS/ VOD. All cited studies have obtained informed consent from each study participant and protocol approval by an ethics committee andinstitutional review board TAGEDH1SYMPTOMS AND CLINICAL EVALUATIONTAGEDN Sinusoidal obstruction syndrome/veno-occlusive disease is characterized by a marked, otherwise unexplained sudden increase in weight >2% (Seattle criteria) (McDonald et al. 1984) and 5% (Jones et al. 1987), respectively, resulting from fluid retention (>2% [5%] of the initial weight caused by hypotonic hyperhydration), right upper quadrant pain caused mainly by painful hepatomegaly (“capsule pain”), ascites (Baltimore criteria) (peripheral edema) and jaundice (increase in serum bilirubin >2 mg/dL caused by ductal plate injury). Patients with a severe course of the disease often appear confused (hepatic encephalopathy), have spontaneous hemorrhages and develop hepatorenal syndrome (50%80%). About 25% of patients with renal insufficiency will require hemodialysis (Corbacioglu et al. 2016; Mohty et al. 2015). Heart failure (
60%) has been reported as well. Not all clinical features may be present, and the severity of signs and symptoms can vary (Corbacioglu et al. 2012; Mahgerefteh et al. 2011). Most patients develop symptoms within the first 3 wk after HCT (Carreras 2015; Richardson and Guinan 1999), although later presentations have been reported (Bearman 1995; McDonald et al. 1993; Pai et al. 2012; Platzbecker et al. 2009; Richardson and Guinan 1999; Richardson et al. 2017). SOS/VOD has also been described after the use of chemotherapeutic agents in nontransplant settings (e.g., oxaliplatin), ingestion of alkaloid toxins, after high-dose radiation therapy and after liver transplantation (Coppell et al. 2010). Very late onset SOS/ VOD has been reported after use of the new toxin-linked antibody inotuzumab-ozogamizin (Kantarjian et al. 2016). The sensitivity of the reported symptoms is good, but the specificity is relatively low because a large number of patients with pre-existing hepatic diseases could worsen under HCT, and its accompanying therapy must be taken into account. In addition, other conditions such as infections and graft versus host disease (GVHD) may cause similar symptoms. A system of subdividing SOS/VOD patients according to symptoms has been proposed: patients with minor

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symptoms (frequency of occurrence 10%20%, no symptomatic therapy necessary); patients with moderate symptoms (50%70%, symptomatic therapy necessary) and patients with a severe clinical picture (approximately 25%) that is detectable more than 100 d after HCT or a lethal outcome within the first 100 d after HCT (Mohty et al. 2016). Icterus occurs slightly later than the weight increase and hepatomegaly. On the sixth day, the average bilirubin level is 2 mg/dL and gradually increases to a maximum level between 12 and 18 mg/dL (Essell et al. 1992). The revised European Society for Blood and Marrow Transplantation (EBMT)) criteria divide VOD into four severity classes, which are explained in detail. TAGEDH1DIAGNOSISTAGEDN In general, SOS/VOD is diagnosed clinically. Daily clinical examination and weight monitoring are the easiest and most important tools used to diagnose SOS (Mohty et al. 2015). Baltimore and Seattle criteria Until recently, two slightly different definitions of SOS/VOD co-existed: that based on the Seattle criteria, reported by McDonald et al. (1984), and that based on the Baltimore criteria, reported by Jones et al. (1987). With minor clarifications and modifications (Corbacioglu et al. 2012; McDonald et al. 1993), the modified Seattle and the Baltimore criteria have been used in clinical practice, as well as in research studies and trials, in the past three decades. According to a recent meta-analysis, the incidence of SOS/VOD 2XD1 Xvaries, XD according to the criteria used, between 17.3% (Seattle) and 9.6% (Baltimore) (Coppell et al. 2010). One of the major difficulties is that, unlike some other transplant-related complications, SOS/VOD is very dynamic in its manifestations, and the exact definition is hard to establish (Table 1). Before their diagnosis, the severe forms require overt clinical manifestations and serious organ damage, such as severe pulmonary or renal dysfunction and encephalopathy (Mohty et al. 2016). Revised EBMT criteria for diagnosis of SOS/VOD As indicated earlier, the Seattle and Baltimore criteria have been published and used since the 1980s. However, the HCT landscape has changed significantly over the past 30 y. Briefly, modern imaging techniques; the use of unrelated, mismatch or haploidentical donors; reduced-intensity conditioning; and the observation of late-onset SOS/VOD (beyond day 21) led the EBMT to reconsider and to consent to a revision of the diagnosis criteria for SOS/VOD. The updated EBMT criteria for diagnosis of SOS/VOD in adult patients includes the changes described below.

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Table 1. Diagnostic criteria for SOS/VOD diagnosis in adults Classical SOS/VOD (within 21 d after HSCT) Modified Seattle criteria (McDonald et al. 1984) Baltimore criteria (Jones et al. 1987) New EBMT criteria (Mohty et al. 2015)

Late-onset SOS/VOD (>21 d after HSCT)

Bilirubin 2 mg/dL Painful hepatomegaly Weight gain >5% Bilirubin 2 mg/dL and 2 of the following criteria: Hepatomegaly Ascites Weight gain >5% from pre-HCT weight Bilirubin 2 mg/dL and 2 of the following criteria: Painful hepatomegaly Weight gain >5% Ascites

Classic VOD/SOS beyond day 21 or Histologically proven VOD/SOS or 2 of the following criteria: Bilirubin 2 mg/dL Painful hepatomegaly Weight gain >5 % Ascites and Hemodynamical or/and ultrasound evidence of SOS/VOD

EBMT = European Society for Blood and Marrow Transplantation; SOS = sinusoidal obstruction syndrome; VOD = veno-occlusive disease.

Symptoms of SOS/VOD are typically observed within the first week after HCT, and both the modified Seattle (McDonald et al. 1993) and Baltimore (Jones et al. 1987) criteria require that patients present within 21 d after HCT to be diagnosed with this complication. However, late-onset SOS/VOD beyond day 21 has been reported (Carreras et al. 2007). The investigators thus recommend including late-onset SOS/VOD (beyond day 21) in these clinical criteria (Table 2). Obviously, there are many other causes of liver dysfunction after HCT, such as hepatic GVHD, viral infection, iron overload, sepsis and drug toxicity. Patient history, concomitant symptoms and laboratory testing allow exclusion of these differential diagnoses.

Table 2. New EBMT criteria for SOS/VOD diagnosis in adults Classical SOS/VOD (within 21 d after HSCT)

Late onset SOS/VOD (>21 d after HSCT)

Bilirubin 2 mg/dL and 2 of Classic VOD/SOS beyond day 21 the following criteria: or Painful hepatomegaly Histologically proven VOD/SOS Weight gain >5 % or Ascites 2 of the following criteria: Bilirubin 2 mg/dL (or 34 mmol/L) Painful hepatomegaly Weight gain >5% Ascites and Hemodynamical or/and ultrasound evidence of SOS/VOD EBMT = European Society for Blood and Marrow Transplantation; SOS = sinusoidal obstruction syndrome; VOD = veno-occlusive disease.

However, it must be kept in mind that SOS/VOD may co-exist with other conditions presenting with common symptoms. Peripheral thrombocytopenia with rapid consumption of transfused platelets was not retained as a criterion for SOS/VOD diagnosis in adults. Its importance for pediatric patients will play a crucial role in the new EBMT criteria for children, which are currently under discussion (Corbacioglu et al. 2018). Laboratory data Liver biochemical tests usually reveal an elevation in serum aminotransferases, alkaline phosphatase and hyperbilirubinemia (mostly conjugated). Thrombocytopenia refractory to platelet transfusion is common and may precede other signs of disease (Rio et al. 1986). Plasma levels of antithrombin III and protein C are decreased, as are consumption of factor VII and plasma levels of plasminogen activator inhibitor I (PAI-I), although the results of different studies are conflicting. An increase in factor VIII-associated antigen has also been detected (pro-coagulatory stage) (Iguchi et al. 2010; Tabbara et al. 1996). At present, no validated VOD-defining laboratory tests are available. TAGEDH1DIFFERENTIAL DIAGNOSISTAGEDN Differential diagnosis should take into consideration cholangitis lenta, cyclosporine cholestasis, acute GVHD, sludge in the ductus hepatocholedochus, mycotic infections of the liver and acute fulminant viral hepatitis (cytomegalovirus, EpsteinBarr virus, hepatitis

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virus B or C), especially within the first 3 mo after the transplant (referred to in the order of their probable occurrence) and acute heart failure. In the case of allogeneic HCT recipients, differential diagnosis of SOS/VOD and other causes of liver dysfunction, particularly GVHD, may be difficult because such entities may be associated with similar biochemical abnormalities (Matsumoto et al. 2009). The disease resembles BuddChiari syndrome (BCS) clinically; however, hepatic venous outflow obstruction in SOS/ VOD is due to intrahepatic microscopic endothelial damage leading to occlusion of hepatic sinusoids and terminal hepatic venules, rather than large hepatic veins and inferior vena cava obliteration (McDonald et al. 1984; Shulman et al. 1987). Combined occurrence with BCS and portal vein thrombosis is possible. Ultrasound imaging At present, the role of imaging in SOS/VOD is often limited to ultrasound to assist in the exclusion of differential diagnoses (Mohty et al. 2016). However, as clinical signs are non-specific, ultrasound findings can aid in a timely diagnosis and in dubious or in late-onset cases. The EBMT states that early detection of SOS/ VOD should be a priority and includes, as mandatory for late-onset SOS/VOD diagnosis, hemodynamic and/or ultrasound evidence of SOS/VOD in addition to other clinical criteria (Lassau et al. 1997; Mohty et al. 2015, 2016). Also the American Association for the Study of Liver Diseases recommends the use of ultrasound to aid in the diagnosis of this condition (Kumar et al. 2003). Review of the literature Two prospective studies with 100 and 71 patients, respectively, described the role of ultrasound for the diagnosis and the severity of VOD. Seven B-mode criteria and seven Doppler criteria linked to portal hypertension were studied. The seven B-mode criteria examined were hepatomegaly, portal diameter >12 mm, gallbladder wall thickening >6 mm (Fig. 1), hepatic vein diameter <3 mm (observed in any vein), splenomegaly, ascites and visualization of para-umbilical veins. The seven Doppler criteria examined were portal vein flow demodulation, decrease in spectral density, portal vein flow <10 cm/s, congestion index <0.1, hepatic artery resistive index >0.75, monophasic flow in the hepatic veins and detectable flow in the paraumbilical vein. To date, these criteria have been widely used routinely in several countries, but consecutive published studies are lacking. In the first study, 100 patients receiving total body irradiation or busulfan therapy as intensive treatment before hematopoietic stem cell transplantation were studied prospectively. Each patient underwent B-mode

Fig. 1. Gallbladder thickening. B-Mode ultrasound image reveals stratified thickening (>6 mm) of the gallbladder wall day 23 after hematopoietic cell transplantation for myelodysplastic syndrome in a 53-y-old man diagnosed with sinusoidal obstruction syndrome/veno-occlusive disease by imaging and clinical criteria.

and Doppler US examinations before transplantation and weekly thereafter while hospitalized (about four examinations per patient). A total of 400 Doppler ultrasound examinations were performed at the bedside. The aforementioned criteria were studied, yielding three individual scores: B-mode US, Doppler and total scores. Twenty-five patients developed hepatic VOD. A score >6 was linked to the diagnosis of VOD. The ultrasound findings differed significantly between patients with VOD and those with GVHD of the liver (p = 0.0001) (Lassau et al. 1997). In the second study, the prognostic value of Doppler ultrasound was studied in 71 children who developed VOD after intensive myeloablative therapy with busulfan before hematopoietic stem cell transplantation. All patients had post-transplantation US and Doppler examinations at the time of the clinical and biological diagnoses of VOD. The same seven US morphologic criteria and seven Doppler criteria were studied, and the three scores described were calculated. All patients with an US Doppler score >9 developed grade 2 or 3 VOD (Lassau et al. 2002). Ultrasound of the portal and hepatic veins revealed typical changes, although single criteria had relatively low sensitivity and specificity. At first, portal venous flow is spared, but as hepatic involvement worsens, portal flow demodulation occurs; then portal velocity diminishes (Lassau et al. 1997). In severe cases, retrograde flow can be observed in the portal vein (Herbetko et al. 1992; Teefey et al. 1995) (Fig. 2). Additional important signs include loss of the normally triphasic hepatic venous outflow and narrowed

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Fig. 2. Day 18 after allogenic stem cell transplantation in a patient with acute myeloid leukemia with retrograde flow in the portal vein (marked in blue), high resistive index in the hepatic artery (a) and low and monophasic flow in the right liver vein (b). GB = gallbladder. PV = portal vein; HA = hepatic artery; RLV = right liver vein; K = right kidney.

but patent hepatic veins with reduced monophasic flow toward the heart (Fontanilla et al. 2011), explained by loss of hepatic compliance caused by hepatic congestion. The third observation includes an increase in the resistive D1X X index of the hepatic artery (RI) >0.75 (Sharafuddin et al. 1997). Brown et al. (1990) reported that reversed portal venous flow represents one of the late and severe changes in patients with clinically evident VOD. Hashiguchi et al. (2005) reported that 6 of 9 patients did not fulfill the diagnostic criteria when the reversed portal venous flow was first detected. Color Doppler ultrasound is also helpful in diagnosing or excluding BuddChiari syndrome. The arterial resistive index typically increases as well, but has been less frequently examined, and its value is controversial (Lassau et al. 1997; Teefey et al. 1995). It is of interest that the evaluation of all Doppler criteria via the intercostal approach is possible in almost all patients (Braden et al. 2002; Dietrich et al. 1998, 2001; Hirche et al. 2007; Hocke et al. 2007; Ignee et al. 2002, 2016; Klein et al. 2001). The ultrasound features mentioned vary with the degree of hepatic congestion and extent of portal hypertension. Intra- and interobserver variability must be taken into account as well (Fontanilla et al. 2011; Ignee et al. 2016).

Doppler ultrasound and recommendations The portal vein should be evaluated from an intercostal approach and not from a subcostal approach (Ignee et al. 2016). The reasons for this are the much better insonation angle using the intercostal approach, with only 6% non-adequate examinations at angles >60˚

compared with 56% inadequate examinations using the subcostal approach (average angle of 46 § 14˚ [14˚ 82˚] using the intercostal approach versus 61 § 9˚ [42˚ 81˚]), and the inability to examine the confluens region of the portal vein in a midrespiratory position from subcostal approach. Doppler changes of the hepatic veins can be observed with a reduced and monophasic flow pattern. The identical position of the transducer using intercostal evaluation of the right hepatic vein about 10 cm from the confluens to the inferior vena cava is recommended because evaluation of the left hepatic vein is influenced by heart movements with artifacts and the middle hepatic vein can often be examined only in deep inspiration. We refer to the validating studies (Dietrich et al. 1998; Ignee et al. 2002). In more severe forms of SOS/VOD, the flow pattern of the hepatic artery is influenced mainly by a higher resistive index. Other parameters are less reliable (Ignee et al. 2016). In addition, special care should be taken for concomitant portal vein thrombosis and BuddChiari syndrome. Other minor Doppler criteria include the less practical congestion index (with measurement of the cross-sectional area of the portal vein and parameters of the blood flow). The measurement of blood flow is less reliable because of higher intra- and inter-observer variability (Dietrich et al. 2001; Hirche et al. 2007; Ignee et al. 2016).

Follow-up Because ultrasound is a non-invasive, repeatable method, there have been a few reports of its use for monitoring the course of SOS/VOD- (Brown et al. 1990; Hommeyer et al. 1992; Lassau et al. 1997; Mahgerefteh

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et al. 2011). Bearman (1995) reported that in patients with SOS/VOD, hepatomegaly and fluid retention were followed by hyperbilirubinemia. Ultrasound revealed improvements in reversed portal venous flow before the peak in serum bilirubin level and coagulopathy. This analysis was useful for both early diagnosis and clinical follow-up of SOS/VOD (Matsumoto et al. 2009). Ultrasound is often abnormal in patients undergoing HCT in the absence of SOS/VOD. In one prospective study, the prevalence of hepatobiliary abnormalities was determined in 21 patients undergoing HCT. Baseline scans were abnormal in 62% of patients. Findings on serial examinations could not discriminate patients with SOS/VOD from those without the syndrome (Hommeyer et al. 1992). The detection of ascites, gallbladder wall thickening and reversed portal venous flow is valid for the diagnosis of SOS/VOD (Kriegshauser et al. 1988; Lassau et al. 1997). However, these were found to be non-specific or not necessarily associated with SOS/VOD (Herbetko et al. 1992; Hommeyer et al. 1992; Teefey et al. 1995). The introduction of mandatory baseline and serial ultrasound evaluation may be useful for early detection of signs suggestive of SOS/VOD and exclusion of preexisting ultrasound findings, but studies are lacking. Baseline ultrasound imaging might become mandatory, at least for children, with the new pediatric EBMT criteria, which are currently under discussion. The combination of hepatomegaly, ascites, reduced flow in the portal vein measured in the intrahepatic portal vein (threshold 10 cm/s), elevated resistive index in the hepatic artery (>0.8) and reduced but monophasic flow in the right liver vein (measured >80 mm from the inferior vena cava) has not been evaluated so far, but these seem to be the most promising imaging features eventually in combination with elastographic techniques and contrast enhanced ultrasound techniques.

Shear wave elastography and contrast-enhanced ultrasound Fontanilla et al. (2011) reported quantitative liver acoustic radiation force impulse (ARFI) elastographic and contrast-enhanced ultrasound (CEUS) findings in two patients with SOS/VOD. ARFI revealed median high shear wave velocities (case 1: 2.75 m/s, case 2: 2.58 m/s) that normalized after specific treatment. ARFI elastography provided quantitative information that helped diagnose SOS/VOD, as well as monitor the response to treatment. CEUS revealed patchy enhancement during all phases, with a geographic morphologic pattern best depicted during the portal phase. The less enhanced areas corresponded to the areas with the highest shear wave velocities on ARFI elastography.

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Ultrasound elastography uses ultrasonic echoes to observe tissue displacement as a function of time and space after applying a force that is D1X X dynamic (e.g., by thumping or vibrating) or varying so slowly that it is considered “quasi-static” (e.g., by probe palpation). The displacement measurements may be represented in an elasticity image (elastogram) or as a local measurement in one of three ways: (i) Tissue displacement may be displayed directly, as in ARFI imaging; (ii) tissue strain may be calculated from the spatial gradient of displacement and displayed, producing what is termed strain elastography; or (iii) when the force is dynamic only, the time-varying displacement data may be used to record at various positions the arrival times of propagating shear waves. These are used to calculate regional values of shear wave speed (without making images). Shear wave elastography comprises several tissue strain imaging techniques that use sound waves to interrogate the mechanical stiffness properties of tissues and provide quantitative information on shear wave propagation (Shiina et al. 2015). Recently, different shear wave technologies have been described in detail, including transient elastography (TE, so-called Fibroscan), point shear wave elastography and 2-D (or 3-D) shear wave elastography (Sidhu et al. 2017). This information is related to the elasticity/stiffness of the tissues. In the liver, shear wave velocity is increased and elasticity is diminished because of fibrosis, inflammation, congestion, portal hypertension and cholestasis. Even though the information is non-specific, shear wave velocity has been proven to have high performance in diagnosing and staging liver fibrosis in chronic hepatitis and is useful in non-alcoholic fatty liver disease (Ferraioli et al. 2015) among other conditions. Liver stiffness has been reported to improve in parallel to the clinical improvement, presumably related to liver congestion improvement. Because of the quantitative information it provides and the ease of the technique, which can be performed bedside, shear wave elastography might have a potential role in the follow-up of SOS/VOD, especially if pre-transplantation values are evaluated. Liver stiffness is increased with hepatic inflammation (often, but not exclusively assessed with an elevated transaminase level) (Arena et al. 2008; Coco et al. 2007; Sagir et al. 2008; Vigano et al. 2010), obstructive cholestasis (Millonig et al. 2008) and hepatic congestion (Colli et al. 2010, Millonig et al. 2010). In addition, acute toxic hepatitis (phenprocoumon-induced liver failure) increases measurements (Karlas et al. 2011). For patients with falsely elevated liver stiffness measurements as a result of alcoholic hepatitis, liver stiffness decreases after 14 wk of abstinence (Bardou-Jacquet et al. 2013; Mueller et al. 2010; Trabut et al. 2012). Other diseases that increase liver stiffness, independent

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of liver fibrosis, include amyloidosis, lymphomas and extramedullary hemopoiesis. At present, whether hepatic steatosis modulates liver stiffness (Macaluso et al. 2014; Petta et al. 2015) or not (Sidhu et al. 2017; Wong et al. 2010; Yoneda et al. 2008) remains uncertain. Liver biopsy and histologic examination In general, invasive diagnostic measures are not required or justified for the diagnosis of SOS/VOD (Carreras et al. 1993a, 1993b; Mohty et al. 2016), and liver biopsy is seldom performed for the diagnosis of SOS/ VOD in the first day after transplantation. On a few occasions, histologic examination of hepatic tissue may be important mainly for differential diagnosis, to avoid underestimation of co-morbidities and false-positive diagnosis (Carreras et al. 1993a, 1993b; Shulman et al. 1995). If a liver biopsy is indicated early post-transplantation, transjugular liver biopsy is the recommended approach rather than percutaneous liver biopsy because with the former procedure, it is possible to perform multiple passes to obtain quality samples, minimizing the risk of complications related to the procedure in general (Kalambokis et al. 2007). The combination of hemodynamic venous gradient pressure determination (>10 mm Hg) and histopathology provides high specificity for the diagnosis (Carreras et al. 1993a, 1993b; Shulman et al. 1995), but the riskbenefit balance must be carefully measured on a case-by-case basis before the decision is made to obtain a biopsy sample. Most of the information available on the role, risk and clinical impact of liver biopsy in SOS/VOD comes from early series (Carreras et al. 1993a, 1993b; Shulman et al. 1995) with very scant recent information available (Chahal et al. 2008). At later stages after transplantation, percutaneous liver biopsy may be indicated, especially in patients who develop late-onset SOS/VOD without the typical clinical picture of the early stage (Jamali et al. 2015; Pai et al. 2012). One study reported hemorrhage in 11 of 60 patients, which ended lethally for 3 patients. Within the framework of this study, it was also possible to illustrate that the gradient between the occlusion pressure of the hepatic vein (which corresponds to the approximate sinusoidal and portal venous pressure in patients with hepatic cirrhosis) and the free pressure of the hepatic vein >10 mm Hg corresponds to a diagnosis of SOS/ VOD with a specificity of 91% and a positive predictive value of 86% (Dignan et al. 2013). Liver biopsy is more frequently performed at later stages after transplantation. In this case, coagulation is more stable and the percutaneous approach should be preferred (Sidhu et al. 2015a, 2015b). The initial structural hepatic changes taking place in sinusoidal endothelial cells, which show morphologic changes and detachment leading to disruption of the

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sinusoidal integrity and producing micro-embolization and blockage of the sinusoidal microcirculation, have been described in experimental animal and human electron microscopy studies (DeLeve 2015; DeLeve et al. 1999; Vreuls et al. 2016). Histologic evaluation of early changes reveals dilation and congestion of sinusoids by erythrocytes (McDonald et al. 1984; Shulman et al. 1987, 1994). Non-thrombotic fibrous occlusion of sinusoids and small hepatic venules may be observed, with variable degree of zonal liver plate disruption and secondary centrilobular ischemic-type hepatocyte necrosis. Later pathologic changes include perisinusoidal collagen deposition, sclerosis of central hepatic venule walls and fibro-obliteration (Figs. 3 and 4). Nodular regenerative hyperplasia has also been described. Of note is the patchy nature of these lesions, a fact that may have to be considered at the time of evaluation of imaging studies. Complications or consequences over time in patients who recover are not well defined, and although likely unusual, persistence of damage and development of significant fibrosis and/or portal hypertension may occur, as has been reported in the context of oxaliplatin-based SOS/VOD cases, in which progression of fibrosis or increase in late portal hypertension have been reported (Rubbia-Brandt et al. 2004; Slade et al. 2009) (Figs. 57). TAGEDH1SUGGESTIONSTAGEDN The first ultrasound examination is B-mode imaging for topographic orientation. The major B-mode signs are painful swelling of the liver (hepatomegaly) and newly developed ascites. Sensitive but less specific stratified and hypo-echoic gallbladder thickening >6 mm

Fig. 3. Acute sinusoidal obstruction syndrome after bone marrow transplant. Marked perivenular congestion (red blood cell accumulation) and sinusoidal dilation are appreciated at lowpower magnification. Hematoxylin and eosin, £ 40.

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Fig. 4. Acute sinusoidal obstruction syndrome after bone marrow transplant (same case as in Fig. 3). Sinusoidal dilation and acute congestion with red blood cells filling dilated sinusoidal spaces. Hematoxylin and eosin, £ 200 .

Fig. 6. Histologic changes associated with sinusoidal obstruction syndrome secondary to oxaliplatin therapy in a hepatic resection for colorectal liver metastasis. Perivenular parenchymal atrophy around a terminal hepatic venule with fibro-obliterative lesion and nodular regenerative hyperplasia as representative lesions found later in sinusoidal obstruction syndrome. Reticulin stain, £ 100.

can reliably be observed (Fig. 1). This sign is also common in the important differential diagnosis including hepatitis and GVHD. Because of the often underlying severe diseases with splenomegaly as a common sign, changes in splenic size are less helpful than the other two signs of portal hypertension. The acute development of collaterals (including para-umbilical veins) is a sign of severe portal hypertension. Reduced diameter of the hepatic veins can be observed as minor B-mode criteria.

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Fig. 5. Fibro-obliterative lesion of the wall of a terminal hepatic venule with significant narrowing of the lumen. Acute congestion with sinusoidal dilation is also observed. Masson’s trichrome, £ 200.

Fig. 7. Histologic changes associated to sinusoidal obstruction syndrome secondary to oxaliplatin therapy in a hepatic resection for colorectal liver metastasis. Fibro-obliterative lesion of a terminal hepatic venule and perisinusoidal fibrosis.

As the second ultrasound technique we recommend Doppler evaluation of hepatic vessels as described above mainly because of the level of published evidence. The earliest Doppler changes in portal hypertension can be observed in the portal venous system as changes in the flow pattern. This fact can be explained by the primary sinusoidal endothelial lesion with obstruction and consecutive congestion in the portal vein system. Third, shear wave elastography might be helpful because objective values can be obtained (kPa or m/ s) (Bamber et al. 2013; Cosgrove et al. 2013; Cui et al. 2014; Dietrich and Dong 2016; Ferraioli et al. 2015; Fontanilla et al. 2011; Shiina et al. 2015; Sidhu

ARTICLE IN PRESS New Ultrasound Techniques Challenge the Diagnosis of Sinusoidal Obstruction Synd
C. F. DIETRICH et al.

et al. 2017). Knowledge of pretransplantation shear wavelasticity and /or velocity values D1X X before hematopoietic stem cell transplantation are mandatory when SWE techniques are used. We conclude that the increase in shear wave speed reflecting the stiffness of parenchyma might be more sensitive than the described Doppler criteria of larger hepatic vessels for early diagnosis of SOS/VOD. It would helpful to have such techniques in the current randomized prevention study of VOD. The fourth ultrasound technique is contrastenhanced ultrasound, the findings of which might coincide with those described for magnetic resonance imaging and computed tomography (but more sensitive and without radiation exposure) and reflect the hepatic hemodynamic changes and the state of congestion. We observed all stages of parenchymal enhancement of the liver from missing portal venous enhancement, the most severe sign of SOS/VOD, to patchy enhancement in intermediate stages (Fontanilla et al. 2011) and homogenous enhancement as a sign of normalization (Trenker et al. 2018). As the only imaging method with a strict intravascular contrast agent, contrast-enhanced ultrasound might best reflect pathophysiological changes of the disease (Chiorean et al. 2016; Claudon et al. 2013a, 2013b; Cui et al. 2013, 2014; Dietrich and Greis 2016; Dietrich et al. 2014; Piscaglia et al. 2012; Sidhu et al. 2017; Strobel et al. 2008). Timeintensity curve analysis may provide a more objective approach to the early diagnosis of SOS/VOD (Dietrich et al. 2012a, 2012b, 2012c). The fifth suggestion is that future multimodality ultrasound imaging studies should focus specifically on the pre-existing findings, comorbidity and differential diagnosis before conditioning the patient. This statement is valid for all ultrasound examination techniques mentioned. Although difficult, liver biopsy remains the gold standard for diagnosis. TAGEDH1CONCLUSIONSTAGEDN The sensitivity and specificity of transabdominal ultrasound and Doppler techniques need to be improved. Innovative ultrasound methods such as a combination of quantitative Doppler ultrasound with contrast-enhanced ultrasound techniques and shear wave elastography are promising and should be further evaluated for diagnosis and follow up of SOS/VOD. TAGEDH1REFERENCESTAGEDN Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, Moscarella S, Boddi V, Petrarca A, Laffi G, Marra F, Pinzani M. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008;47:380–384.

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