REVIEWS Imaging in clinical decision-making for portal vein thrombosis Annalisa Berzigotti, Ángeles García-Criado, Anna Darnell and Juan-Carlos García-Pagán Abstract | Thrombosis of the portal venous system is a frequent and potentially life-threatening condition that can take place in a number of different clinical settings including liver cirrhosis, hepatocellular carcinoma, other solid tumours, abdominal septic foci, acute pancreatitis, haematological malignancies and congenital or acquired prothrombotic disorders. Clinical decision-making in patients with thrombosis of the portal venous system is a particularly complex process owing to the heterogeneity of the population affected by this condition and the lack of high-quality evidence from randomized controlled trials for the use of anticoagulation therapy in these patients. This Review discusses the available data regarding how imaging can provide assistance to physicians involved in this decision-making process in different clinical settings. A flowchart illustrating how to use imaging in this setting, based on current evidence and on the experience of the Vascular Liver Diseases Group of the Hospital Clinic in Barcelona, is also presented. Berzigotti, A. et al. Nat. Rev. Gastroenterol. Hepatol. 11, 308–316 (2014); published online 14 January 2014: doi:10.1038/nrgastro.2013.258
Introduction
Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, CIBERehd (A. Berzigotti, J.-C. García-Pagán), Centre Diagnostic per la Imatge (A. García‑Criado, A. Darnell), Hospital Clinic c/Villarroel 170, 08036 Barcelona, Spain.
Portal vein thrombosis (PVT) indicates the presence of a clot in the portal vein lumen or a permanent obliter ation of the portal vein as a result of prior thrombosis with replacement by numerous tortuous venous chan nels (termed cavernoma). PVT can be located in the intrahepatic and/or the extrahepatic venous tracts and can extend to the splenic and superior mesenteric veins; thrombosis can also be restricted to the splenic vein and/ or the superior mesenteric vein and altogether these con ditions are known as ‘thrombosis of the portal venous system’. Multiple classifications regarding PVT extension exist, but none is generally accepted in clinical practice; the most commonly used classification in clinical studies is the one proposed by Yerdel et al.1 (Box 1). The prevalence of PVT in unselected necropsy studies is ~1%,2 being rare in the general population and much more frequent in the presence of pre-existing cirrhosis or neoplastic diseases, particularly hepatocellular carcin oma (HCC). More than 60% of cases of noncirrhotic, nonmalignant PVT are associated with congenital or acquired thrombophilic disorders (also named hyper coagulable states or prothrombotic diseases),3–5 and in 30% of cases an additional known risk factor (namely, a local factor, such as a septic focus) can be identified.6–8 PVT prevalence in cirrhosis ranges from 10–25%,9 the highest figure relates to patients who have advanced decompensated cirrhosis. Risk factors for PVT in patients with cirrhosis are only partially known, and are the result of a complex interaction between the three factors of the Virchow’s triad—stasis, hypercoagulability and endothelial dysfunction.10,11
Correspondence to: A. Berzigotti [email protected]
Competing interests The authors declare no competing interests.
308 | MAY 2014 | VOLUME 11
PVT clinical presentation is extremely variable and ranges from asymptomatic cases identified during imaging for an alternative reason, to devastating episodes complicated by intestinal infarction. Acute PVT is often asymptomatic or paucisymptomatic in patients without underlying liver diseases, but can present as an acute process characterized by abdominal pain, fever and/or features of intestinal venous ischaemia. In up to 30% of acute PVT cases, splenomegaly and minimal ascites are already present.4 The effect of PVT on the clinical outcome of patients with cirrhosis is controversial, but it has been shown that, at least in some patients, it can result in worsening of pre-existing portal hypertension with development of ascites or variceal bleeding.12,13 In addi tion, PVT is an independent negative prognostic factor for post-transplantation survival in patients who are on a waiting list for liver transplantation.14 Furthermore, in patients with cirrhosis and HCC, the onset of malignant PVT indicates an advanced stage of the disease in which locoregional therapy is no longer indicated.15 Data from the past 10 years have revealed the follow ing: anticoagulant therapy is effective for obtaining reca nalization in a fair proportion (~40%) of patients with acute PVT;4 anticoagulant therapy is safe both in patients with a healthy liver and in patients with cirrhosis;16 and neoplastic PVT holds a strong prognostic importance in patients with HCC.15 A prompt and accurate diagnosis of this thrombotic disease is always required. Most patients with PVT, however, present with complications of portal hypertension (including oesophageal varices, variceal bleeding and hypersplenism), which are a direct con sequence of long-lasting, chronic thrombosis.3 In these patients, surgical treatment or transjugular intrahepatic portosystemic shunts are often needed; meticulous
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Doppler ultrasonography is the first imaging technique to be used for portal vein thrombosis (PVT) diagnosis; it is well-tolerated, accurate and a negative examination performed by a trained operator is sufficient to rule out thrombosis ■■ Following PVT diagnosis, imaging techniques should guide clinicians about the presence or absence of prothrombotic conditions such as cirrhosis, solid tumours and septic foci, and signs suggestive of malignant thrombosis ■■ CT or MRI is needed to assess the number of vessels involved in thrombosis, the severity of thrombotic stenoses and to map collateral circulation, all of which have prognostic importance ■■ Imaging should determine signs of chronicity to determine the age of the thrombus; existence of a portal vein remnant should also be investigated ■■ Magnetic resonance cholangiography is the technique of choice to assess portal cholangiopathy in patients with PVT; grade 3 portal cholangiopathy is associated with an increased risk of biliary complications ■■ Imaging should be repeated 3–6 months after the first diagnosis and every 6 months thereafter, to inform about thrombosis improvement, stability and progression; symptoms suggesting re-thrombosis should be reassessed by CT or MRI
Box 1 | Classification in PVT PVT extension1 ■■ Grade I: Minimal or partial thrombosis of portal vein (thrombosis 50% thrombosis of portal vein, including complete thrombosis, with or without minimal extension into the SMV ■■ Grade III: Complete thrombosis of both portal vein and proximal SMV; patent distal SMV ■■ Grade IV: Complete thrombosis of the portal vein and SMV (proximal and distal) Severity of biliary tree abnormalities60 ■■ Absent: No abnormalities ■■ Grade 1: Minimal irregularities or angulation of the biliary tree ■■ Grade 2: Indentations or strictures without dilation of the biliary tree ■■ Grade 3: Strictures with dilation (intrahepatic duct ≥4 mm or extrahepatic duct ≥7 mm) Abbreviations: MRC, magnetic resonance cholangiography; PVT, portal vein thrombosis; SMV, superior mesenteric vein.
evaluation by clinicians is needed to assess the feasibility of these approaches. This Review is aimed at providing updated information on how imaging can assist physi cians involved in the decision-making process of patients with PVT in different clinical settings.
How to diagnose PVT by imaging Imaging examination to diagnose or rule-out PVT is indicated in patients with clinical symptoms or signs (such as abdominal pain and variceal bleeding) that could suggest the presence of PVT, in particular in patients with a known increased risk of this disorder (such as those who have cirrhosis or history of HCC). Ultrasonography is the first-line approach for the study of the portal venous system. Indeed, for the detec tion of thrombi in the portal vein, it has an accuracy of 88–98% (sensitivity and specificity are 80–100% in most studies).17–22 The high specificity of this method suggests that once PVT is visualized by ultrasonography,
other imaging techniques are not required to confirm the diagnosis. 2D grey-scale ultrasonography displays benign throm bosis as isoechoic or hypoechoic material filling the vessel (Figure 1a), either involving a part of the lumen (partial or mural thrombosis), or the entire lumen (complete thrombosis). Alternatively, cavernomatous transform ation can be found as multiple tortuous small vessels replacing a normal portal vein. Specific signs that characterize malignant (neoplastic) PVT include expan sive aspect (enlargement of the portal vein owing to mass-forming thrombus), disruption of the vessel’s walls and intra-thrombus arterial neovascularization. The use of colour Doppler ultrasonography (CDUS) and spectral Doppler (pulsed wave ultrasonography, PWUS) improves the characterization of thrombosis,23 enabling confirm ation of the absence of flow in complete PVT. Similarly, CDUS is useful for the assessment of portal cavernoma as the presence of venous flow within the small vessels can be verified with this method. In patients with extremely low portal vein velocity (below the measurable range), CDUS cannot reliably exclude PVT. Contrast-enhanced ultrasonography (CEUS) should be used in such cases,24 as it is superior to grey-scale ultrasonography and CDUS for assessing the presence or absence of flow.25 It should be underlined that the reliability of ultrasonography improves as a function of know-how,26 so that suspected PVT should be evaluated by experienced physicians whenever possible. Drawbacks of ultrasonography involve: reduced visualization in patients with abundant bowel gas or obesity; reduced accuracy for the detec tion of thrombi in the splenic and superior mesenteric vein;18,27 and the impossibility of correctly assessing bowel ischaemia, which can arise as a consequence of acute mesenteric vein thrombosis. When ultrasonography cannot be performed (owing to lack of availability or lack of experienced operators), or when its results are considered incomplete owing to the above mentioned limits, contrast-enhanced CT (CECT) or contrast-enhanced MRI (CEMRI) should be performed to complete the diagnostic assessment (Figure 1b and 1c). Unenhanced CT can display fresh thrombi (that is those 80% of patients with portal cavernoma. However, after being diagnosed, few patients develop symptoms at follow-up, and laboratory tests are not useful to predict the risk of symptomatic disease.58 Magnetic resonance cholangio graphy (MRC) is the reference noninvasive procedure for the study of the biliary duct and is currently the investi gation method of choice for this disorder.59 In a study published in 2011, we showed that MRC enables portal cholangiopathy to be accurately identified in patients with PVT.60 By evaluating patients who are experiencing acute PVT, the appearance of portal cholangiopathy was found to be an early event in the natural history of PVT and, once abnormalities of the biliary tree have appeared, they do not progress. Moreover, according to the results of this study, MRC findings correlate with the risk of developing clinical symptoms, and these symptoms are limited to patients showing dilatation of the biliary tree (grade 3 portal cholangiopathy) (Figure 3a). The simple radiological classification used to stratify the patients’ risk is shown in Box 1.60 Although these results require validation in inde pendent series, it is accepted at our institution that MRC should be performed at the time of diagnosis in all patients with chronic PVT and after 9–12 months of acute PVT if anticoagulant therapy does not achieve recanalization so as to assess the presence of portal chol angiopathy at risk of later complications. In the latter case, if grade 3 portal cholangiopathy has not devel oped at the 12 month follow-up, no further MRC exam ination is needed, as no progression is expected to occur thereafter.60 Radiologists and clinicians should be aware of the importance of correctly diagnosing the cause of biliary tree dilatation in patients with cavernomatosis, as imaging findings of portal cholangiopathy might be confused with hilar cholangiocarcinoma.61
How to follow-up PVT by imaging? Current recommendations suggest that acute PVT episodes should be treated with anticoagulant therapy (such as warfarin), and that anticoagulation treatment should be maintained life-long in patients with congeni tal thrombophilic conditions or haematological malig nancies.62 However, no consensus exists on how long anticoagulant agents should be maintained in patients
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
VOLUME 11 | MAY 2014 | 313
REVIEWS Box 2 | Details required for imaging reports Liver and abdominal cavity ■■ Presence or absence of signs of cirrhosis, focal lesions, solid tumours, septic foci and ascites Portal vein right branch, left branch and main trunk ■■ Patency and/or degree of thrombosis including diameter (normal, enlarged or reduced); calcifications; aspects suggesting malignant nature of thrombosis (expansive; thrombus neovascularization); flow direction (ultrasonography) Splenic vein and superior mesenteric vein ■■ Patency; diameter (normal, enlarged or reduced); calcifications; flow direction (ultrasonography) Collateral vessels ■■ Presence or absence of collateral vessels with hepatopetal flow ■■ Presence or absence of portosystemic collateral vessels and specify site Spleen ■■ Diameter and area Hepatic veins and inferior vena cava ■■ Patency and/or thrombosis Comparison with previous imaging ■■ Specify if thrombosis is stable, improved or worsened
Clinical suspicion of PVT Diagnose PVT using ultrasonography, CDUS and PWUS (CEUS if needed) No
PVT? Unreliable or sepsis
Evaluate ■ Signs of cirrhosis ■ Malignancies ■ Ascites
Yes
Stop investigation for PVT
Assess PVT extent (protocol)
CT or MRI Confirms PVT?
No
Evaluate ■ PVT extension ■ Cofactors
Yes Cavernoma?
No
Yes Assess portal cholangiopathy by MRC No
Follow-up every 6 months
Portal cholangiopathy?
CDUS if good visualization, CT or MRI if not
Yes Stratify the risk of bilary complications Grade 3 portal cholangiopathy?
Yes
STOP The patient has a high risk of biliary complications
No MRC after 12 months If no grade 3 portal cholangiopathy then stop, the patient has a low risk of biliary complications
Figure 4 | Flowchart summarizing how the different imaging methods are used for diagnosing and follow-up of patients with PVT according to the consensus of the Vascular Liver Diseases Group at the Hospital Clinic in Barcelona. Abbreviations: CDUS, colour Doppler ultrasonography; MRC, magnetic resonance cholangiopathy; PVT, portal vein thrombosis; PWUS, pulsed wave ultrasonography.
314 | MAY 2014 | VOLUME 11
without cirrhosis and with no established thrombophilia as the risk of re-thrombosis is low.63 Anticoagulation therapy should also be considered in patients with PVT and cirrhosis, but again there is no consensus on if this therapy should be routinely used or not, and, if used, for how long.64 The natural history of PVT is not completely known. It is clear that PVT can progress in patients with overt thrombophilic disorders, leading to complete thrombosis of the whole portal venous system (Figure 3b,c); the aim of anticoagulant therapy in these patients is not only to attempt recanalization, but also to prevent progression and re-thrombosis episodes62 (Figure 3d,e). On the other hand, it was reported in 2012 that benign partial PVT in 42 patients with cirrhosis spontaneously improved in ~50% cases.65 In this complex scenario, the ideal roles of imaging are stratifying the probability of successful recanalization with anticoagulant therapy before start ing treatment and showing the effects of anticoagulant therapy and its discontinuation in the portal venous system on follow-up. As for imaging surrogates of achieving recanalization with anticoagulant therapy, the extent and age of the thrombus are of help. In addition, a study published in 2012 suggested that intra-thrombus enhancement during pre-treatment CEUS in patients with acute PVT (using perflubutane, such as Sonazoid®GE Healthcare, Oslo, Norway, as a contrast medium) is predictive of anti coagulant therapy success.66 These results, obtained in a very small number of cases, have not been confirmed and require validation before translating into clinical practice. By contrast, imaging follow-up is a useful tool to identify which patients recanalize during anticoagulant therapy (Figure 3f), and if recanalization is maintained after stopping therapy. No consensus exists on which technique should be preferred, the best interval to be used for follow-up, or how long imaging follow-up should be maintained. Our view is that follow-up should be individualized: the technique and interval used need to be set on a case-by-case basis depending on individual risk of re-thrombosis, hospital expertise and risks related to repeated imaging studies (such as irradiation and contrast agents). Hence, we propose that the first imaging control should be performed 3–6 months after starting anticoagulant therapy (or wait-and-see decision) by the same technique used to depict thrombosis extent at baseline (either CT or MRI). CDUS should also be performed at this time point to evaluate whether characterization of PVT by ultrasonography correlates well with that obtained by CT or MRI. Imaging findings should be carefully compared with those obtained at first observation, and the report should inform about improvement, stability and pro gression of PVT in all vessels of the portal venous system (Box 2). Subsequent measurements should be repeated every 6 months thereafter; CDUS should be used when ever possible owing to its safety. If CDUS cannot be used (because of lack of expertise or lack of complete visual ization of the site of thrombosis), CECT or CEMRI can be used, depending on the experience and availability of
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS the centre. These imaging techniques can be alternated to reduce the risks associated with repeated ionizing radiation30,67 and the use of contrast medium.68 Patients presenting with new symptoms or signs suggestive of re‑thrombosis should undergo a new assessment directly by a second-line technique (either CECT or CEMRI). Figure 4 summarizes the protocol used to ev aluate patients with PVT at the Hospital Clinic in Barcelona.
Conclusions In summary, as shown in detail in this Review, ultra sonography, CT and MRI have a complementary role in the assessment of PVT and are of central importance to guide the clinical management of these complex patients who require a multidisciplinary approach. Owing to the large number of factors that need to be evaluated in patients with PVT, we believe that it is important both for 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Yerdel, M. A. et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 69, 1873–1881 (2000). Rajani, R. et al. The epidemiology and clinical features of portal vein thrombosis: a multicentre study. Aliment. Pharmacol. Ther. 32, 1154–1162 (2010). Garcia-Pagan, J. C., Hernandez-Guerra, M. & Bosch, J. Extrahepatic portal vein thrombosis. Semin. Liver Dis. 28, 282–292 (2008). Plessier, A. et al. Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study. Hepatology 51, 210–218 (2010). Valla, D. et al. Etiology of portal vein thrombosis in adults. A prospective evaluation of primary myeloproliferative disorders. Gastroenterology 94, 1063–1069 (1988). Denninger, M. H. et al. Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology 31, 587–591 (2000). Primignani, M. et al. Risk factors for thrombophilia in extrahepatic portal vein obstruction. Hepatology 41, 603–608 (2007). Turnes, J. et al. Portal hypertension-related complications after acute portal vein thrombosis: impact of early anticoagulation. Clin. Gastroenterol. Hepatol 6, 1412–1417 (2008). Nonami, T., Yokoyama, I., Iwatsuki, S. & Starzl, T. E. The incidence of portal vein thrombosis at liver transplantation. Hepatology 16, 1195–1198 (1992). Tripodi, A., Anstee, Q. M., Sogaard, K. K., Primignani, M. & Valla, D. C. Hypercoagulability in cirrhosis: causes and consequences. J. Thromb. Haemost. 9, 1713–1723 (2011). Tripodi, A. & Mannucci, P. M. The coagulopathy of chronic liver disease. N. Engl. J. Med. 365, 147–156 (2011). Amitrano, L. et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J. Hepatol. 40, 736–741 (2004). Francoz, C. et al. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 54, 691–697 (2005). Englesbe, M. J. et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl. 16, 83–90 (2010).
clinicians and radiologists to follow a consensus protocol for the systematic exploration, reporting and interpret ation of the imaging results in this population, enabling changes to be tracked over time. Review criteria The PubMed database was searched in April 2013 for publications in English that contained the terms “portal vein thrombosis”, “splenic vein thrombosis” or “mesenteric vein thrombosis”; the same terms were then used in combination with the terms “ultrasound”, “Doppler ultrasound”, “computerized tomography”, “magnetic resonance” or “imaging”. Additional papers were found by cross-checking the reference lists of those previously identified. No date restriction was applied. The full text of the identified references was obtained and relevant data were used for the current review.
15. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 56, 908–943 (2012). 16. Delgado, M. G. et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin. Gastroenterol. Hepatol. 10, 776–783 (2012). 17. Tessler, F. N. et al. Diagnosis of portal vein thrombosis: value of color Doppler imaging. AJR Am. J. Roentgenol. 157, 293–296 (1991). 18. Bach, A. M. et al. Portal vein evaluation with US: comparison to angiography combined with CT arterial portography. Radiology 201, 149–154 (1996). 19. Chawla, Y. & Kumar, S. Portal venous flow in Budd-Chiari syndrome [letter]. Indian J. Gastroenterol. 17, 37 (1998). 20. Gertsch, P., Matthews, J., Lerut, J., Luder, P. & Blumgart, L. H. Acute thrombosis of the splanchnic veins. Arch. Surg. 128, 341–345 (1993). 21. Berzigotti, A., Zoli, M., Bru, C. & Gilabert, R. in Portal Hypertension V: Proceedings of the Fifth Baveno International Consensus Workshop (ed. de Franchis, R.) 28–36 (Wiley Blackwell, 2010). 22. Berzigotti, A. & Piscaglia, F. Ultrasound in portal hypertension—part 2—and EFSUMB recommendations for the performance and reporting of ultrasound examinations in portal hypertension. Ultraschall. Med. 33, 8–32 (2012). 23. Grant, E. G., Tessler, F. N. & Perrella, R. R. Clinical Doppler imaging. AJR Am. J. Roentgenol. 152, 707–717 (1989). 24. Claudon, M. et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver—update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultraschall. Med. 34, 11–29 (2013). 25. Rossi, S. et al. Contrast-enhanced versus conventional and color Doppler sonography for the detection of thrombosis of the portal and hepatic venous systems. AJR Am. J. Roentgenol. 186, 763–773 (2006). 26. Sabba, C. et al. Interobserver and interequipment variability of echo-Doppler examination of the portal vein: effect of a cooperative training program. Hepatology 21, 428–433 (1995). 27. Kuszyk, B. S. et al. Portal venous system thrombosis: helical CT angiography before transjugular intrahepatic portosystemic shunt creation. Radiology 206, 179–186 (1998).
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
28. Mori, H. et al. High-attenuation recent thrombus of the portal vein: CT demonstration and clinical significance. Radiology 163, 353–356 (1987). 29. DeLeve, L. D., Valla, D. C. & Garcia-Tsao, G. Vascular disorders of the liver. Hepatology 49, 1729–1764 (2009). 30. Sodickson, A. et al. Recurrent CT, cumulative radiation exposure, and associated radiationinduced cancer risks from CT of adults. Radiology 251, 175–184 (2009). 31. American College of Radiology. Manual on Contrast Media version 8, 33–42 (2012). 32. Shimada, K. et al. Non‑contrast‑enhanced MR portography with time-spatial labeling inversion pulses: comparison of imaging with threedimensional half-fourier fast spin-echo and true steady-state free-precession sequences. J. Magn. Reson. Imaging 29, 1140–1146 (2009). 33. Berzigotti, A. et al. Ultrasonographic evaluation of liver surface and transient elastography in clinically doubtful cirrhosis. J. Hepatol. 52, 846–853 (2010). 34. Colli, A. et al. Severe liver fibrosis or cirrhosis: accuracy of US for detection—analysis of 300 cases. Radiology 227, 89–94 (2003). 35. Vilgrain, V. et al. Atrophy-hypertrophy complex in patients with cavernous transformation of the portal vein: CT evaluation. Radiology 241, 149–155 (2006). 36. Hillaire, S. et al. Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients. Gut 51, 275–280 (2002). 37. Seijo, S. et al. Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension. Dig. Liver Dis. 44, 855–860 (2012). 38. Sharma, P., Mishra, S. R., Kumar, M., Sharma, B. C. & Sarin, S. K. Liver and spleen stiffness in patients with extrahepatic portal vein obstruction. Radiology 263, 893–899 (2012). 39. Friedrich-Rust, M. et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 252, 595–604 (2009). 40. Ferraioli, G. et al. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 56, 2125–2133 (2012). 41. Harris, S., Nadkarni, N. A., Naina, H. V. & Vege, S. S. Splanchnic vein thrombosis in acute pancreatitis: a single-center experience. Pancreas 42, 1251–1254 (2013).
VOLUME 11 | MAY 2014 | 315
REVIEWS 42. Calvet, X. et al. Natural history of hepatocellular carcinoma in Spain. Five year’s experience in 249 cases. J. Hepatol. 10, 311–317 (1990). 43. Stuart, K. E., Anand, A. J. & Jenkins, R. L. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer 77, 2217–2222 (1996). 44. Rossi, S. et al. Contrast-enhanced ultrasonography and spiral computed tomography in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma. Eur. Radiol. 18, 1749–1756 (2008). 45. Raab, B. W. The thread and streak sign. Radiology 236, 284–285 (2005). 46. Catalano, O. A., Choy, G., Zhu, A., Hahn, P. F. & Sahani, D. V. Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: application of diffusion-weighted MR imaging. Radiology 254, 154–162 (2010). 47. Qian, L. J. et al. Differentiation of neoplastic from bland macroscopic portal vein thrombi using dual-energy spectral CT imaging: a pilot study. Eur. Radiol. 22, 2178–2185 (2012). 48. Piscaglia, F. et al. Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation. Liver Transpl. 16, 658–667 (2010). 49. de Ville de Goyet, J. et al. Direct bypassing of extrahepatic portal venous obstruction in children: a new technique for combined hepatic portal revascularization and treatment of extrahepatic portal hypertension. J. Pediatr. Surg. 33, 597–601 (1998). 50. Hanbidge, A. E., Lynch, D. & Wilson, S. R. US of the peritoneum. Radiographics 23, 663–684 (2003). 51. de Ville de Goyet, J. et al. Meso-Rex bypass as an alternative technique for portal vein reconstruction at or after liver transplantation in children: review and perspectives. Pediatr. Transplant. 17, 19–26 (2013). 52. Chaves, I. J. et al. Pre- and postoperative imaging and interventions for the meso-Rex bypass in children and young adults. Pediatr. Radiol. 42, 220–232 (2012).
316 | MAY 2014 | VOLUME 11
53. Cakmak, O. et al. Role of contrast-enhanced 3D magnetic resonance portography in evaluating portal venous system compared with color Doppler ultrasonography. Abdom. Imaging 33, 65–71 (2008). 54. Seeger, M. et al. Chronic portal vein thrombosis: transcapsular hepatic collateral vessels and communicating ectopic varices. Radiology 257, 568–578 (2010). 55. Miyamoto, A. et al. Living-related liver transplantation with renoportal anastomosis for a patient with large spontaneous splenorenal collateral. Transplantation 75, 1596–1598 (2003). 56. Brancatelli, G., Federle, M. P., Pealer, K. & Geller, D. A. Portal venous thrombosis or sclerosis in liver transplantation candidates: preoperative CT findings and correlation with surgical procedure. Radiology 220, 321–328 (2001). 57. Luca, A. et al. Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis. Gut 60, 846–852 (2011). 58. Dhiman, R. K., Behera, A., Chawla, Y. K., Dilawari, J. B. & Suri, S. Portal hypertensive biliopathy. Gut 56, 1001–1008 (2007). 59. Condat, B. et al. Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study. Hepatology 37, 1302–1308 (2003). 60. Llop, E. et al. Portal cholangiopathy: radiological classification and natural history. Gut 60, 853–860 (2011). 61. Galati, G. et al. A mocking finding: portal cavernoma mimicking neoplastic mass. First sign of myeloproliferative disorder in a patient with Janus kinase2 V617F mutation. Eur. J. Gastroenterol. Hepatol. 21, 233–236 (2009). 62. Plessier, A., Rautou, P. E. & Valla, D. C. Management of hepatic vascular diseases. J. Hepatol. 56 (Suppl. 1), S25–S38 (2012). 63. Spaander, M. C. et al. Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding. J. Thromb. Haemost. 11, 452–459 (2013).
64. Francoz, C., Valla, D. & Durand, F. Portal vein thrombosis, cirrhosis, and liver transplantation. J. Hepatol. 57, 203–212 (2012). 65. Luca, A. et al. Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis. Radiology 265, 124–132 (2012). 66. Maruyama, H. et al. Prediction of the therapeutic effects of anticoagulation for recent portal vein thrombosis: a novel approach with contrastenhanced ultrasound. Abdom. Imaging 37, 431–438 (2012). 67. Brenner, D. J. & Hall, E. J. Computed tomography —an increasing source of radiation exposure. N. Engl. J. Med. 357, 2277–2284 (2007). 68. Reiter, T. et al. Minimizing risk of nephrogenic systemic fibrosis in cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 14, 31 (2012). 69. Berzigotti, A., Piscaglia, F. & EFSUMB Education and Professional Standard Committee. Clinical recommendations for the performance and reporting of ultrasound examination for portal hypertension European Federation of Societies for Ultrasound in Medicine and Biology [online], http://www.efsumb-portal.org/ep/ article.php?id=108 (2011). Acknowledgements The authors are members of the Vascular Liver Diseases Group of the Hospital Clinic in Barcelona, and would like to express their gratitude to all the colleagues (clinicians, radiologists, anaesthesiologists and surgeons) that participate in the work of this multidisciplinary team. The authors thank the nursing and technical staff of the Hepatic Hemodynamic Laboratory and of the CDIC, and Ms C. Esteva for expert secretarial support. CIBERehd is funded by the Instituto de Salud Carlos III. Author contributions A. Berzigotti contributed to all aspects in the generation of this article. Á. García-Criado and A. Darnell contributed equally to researching data for the article, discussion of content and reviewing/ editing the manuscript before submission. J.-C. García-Pagán substantially contributed to the discussion of content and reviewed/edited the manuscript before submission.
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
Introduction
Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, CIBERehd (A. Berzigotti, J.-C. García-Pagán), Centre Diagnostic per la Imatge (A. García‑Criado, A. Darnell), Hospital Clinic c/Villarroel 170, 08036 Barcelona, Spain.
Portal vein thrombosis (PVT) indicates the presence of a clot in the portal vein lumen or a permanent obliter ation of the portal vein as a result of prior thrombosis with replacement by numerous tortuous venous chan nels (termed cavernoma). PVT can be located in the intrahepatic and/or the extrahepatic venous tracts and can extend to the splenic and superior mesenteric veins; thrombosis can also be restricted to the splenic vein and/ or the superior mesenteric vein and altogether these con ditions are known as ‘thrombosis of the portal venous system’. Multiple classifications regarding PVT extension exist, but none is generally accepted in clinical practice; the most commonly used classification in clinical studies is the one proposed by Yerdel et al.1 (Box 1). The prevalence of PVT in unselected necropsy studies is ~1%,2 being rare in the general population and much more frequent in the presence of pre-existing cirrhosis or neoplastic diseases, particularly hepatocellular carcin oma (HCC). More than 60% of cases of noncirrhotic, nonmalignant PVT are associated with congenital or acquired thrombophilic disorders (also named hyper coagulable states or prothrombotic diseases),3–5 and in 30% of cases an additional known risk factor (namely, a local factor, such as a septic focus) can be identified.6–8 PVT prevalence in cirrhosis ranges from 10–25%,9 the highest figure relates to patients who have advanced decompensated cirrhosis. Risk factors for PVT in patients with cirrhosis are only partially known, and are the result of a complex interaction between the three factors of the Virchow’s triad—stasis, hypercoagulability and endothelial dysfunction.10,11
Correspondence to: A. Berzigotti [email protected]
Competing interests The authors declare no competing interests.
308 | MAY 2014 | VOLUME 11
PVT clinical presentation is extremely variable and ranges from asymptomatic cases identified during imaging for an alternative reason, to devastating episodes complicated by intestinal infarction. Acute PVT is often asymptomatic or paucisymptomatic in patients without underlying liver diseases, but can present as an acute process characterized by abdominal pain, fever and/or features of intestinal venous ischaemia. In up to 30% of acute PVT cases, splenomegaly and minimal ascites are already present.4 The effect of PVT on the clinical outcome of patients with cirrhosis is controversial, but it has been shown that, at least in some patients, it can result in worsening of pre-existing portal hypertension with development of ascites or variceal bleeding.12,13 In addi tion, PVT is an independent negative prognostic factor for post-transplantation survival in patients who are on a waiting list for liver transplantation.14 Furthermore, in patients with cirrhosis and HCC, the onset of malignant PVT indicates an advanced stage of the disease in which locoregional therapy is no longer indicated.15 Data from the past 10 years have revealed the follow ing: anticoagulant therapy is effective for obtaining reca nalization in a fair proportion (~40%) of patients with acute PVT;4 anticoagulant therapy is safe both in patients with a healthy liver and in patients with cirrhosis;16 and neoplastic PVT holds a strong prognostic importance in patients with HCC.15 A prompt and accurate diagnosis of this thrombotic disease is always required. Most patients with PVT, however, present with complications of portal hypertension (including oesophageal varices, variceal bleeding and hypersplenism), which are a direct con sequence of long-lasting, chronic thrombosis.3 In these patients, surgical treatment or transjugular intrahepatic portosystemic shunts are often needed; meticulous
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Doppler ultrasonography is the first imaging technique to be used for portal vein thrombosis (PVT) diagnosis; it is well-tolerated, accurate and a negative examination performed by a trained operator is sufficient to rule out thrombosis ■■ Following PVT diagnosis, imaging techniques should guide clinicians about the presence or absence of prothrombotic conditions such as cirrhosis, solid tumours and septic foci, and signs suggestive of malignant thrombosis ■■ CT or MRI is needed to assess the number of vessels involved in thrombosis, the severity of thrombotic stenoses and to map collateral circulation, all of which have prognostic importance ■■ Imaging should determine signs of chronicity to determine the age of the thrombus; existence of a portal vein remnant should also be investigated ■■ Magnetic resonance cholangiography is the technique of choice to assess portal cholangiopathy in patients with PVT; grade 3 portal cholangiopathy is associated with an increased risk of biliary complications ■■ Imaging should be repeated 3–6 months after the first diagnosis and every 6 months thereafter, to inform about thrombosis improvement, stability and progression; symptoms suggesting re-thrombosis should be reassessed by CT or MRI
Box 1 | Classification in PVT PVT extension1 ■■ Grade I: Minimal or partial thrombosis of portal vein (thrombosis 50% thrombosis of portal vein, including complete thrombosis, with or without minimal extension into the SMV ■■ Grade III: Complete thrombosis of both portal vein and proximal SMV; patent distal SMV ■■ Grade IV: Complete thrombosis of the portal vein and SMV (proximal and distal) Severity of biliary tree abnormalities60 ■■ Absent: No abnormalities ■■ Grade 1: Minimal irregularities or angulation of the biliary tree ■■ Grade 2: Indentations or strictures without dilation of the biliary tree ■■ Grade 3: Strictures with dilation (intrahepatic duct ≥4 mm or extrahepatic duct ≥7 mm) Abbreviations: MRC, magnetic resonance cholangiography; PVT, portal vein thrombosis; SMV, superior mesenteric vein.
evaluation by clinicians is needed to assess the feasibility of these approaches. This Review is aimed at providing updated information on how imaging can assist physi cians involved in the decision-making process of patients with PVT in different clinical settings.
How to diagnose PVT by imaging Imaging examination to diagnose or rule-out PVT is indicated in patients with clinical symptoms or signs (such as abdominal pain and variceal bleeding) that could suggest the presence of PVT, in particular in patients with a known increased risk of this disorder (such as those who have cirrhosis or history of HCC). Ultrasonography is the first-line approach for the study of the portal venous system. Indeed, for the detec tion of thrombi in the portal vein, it has an accuracy of 88–98% (sensitivity and specificity are 80–100% in most studies).17–22 The high specificity of this method suggests that once PVT is visualized by ultrasonography,
other imaging techniques are not required to confirm the diagnosis. 2D grey-scale ultrasonography displays benign throm bosis as isoechoic or hypoechoic material filling the vessel (Figure 1a), either involving a part of the lumen (partial or mural thrombosis), or the entire lumen (complete thrombosis). Alternatively, cavernomatous transform ation can be found as multiple tortuous small vessels replacing a normal portal vein. Specific signs that characterize malignant (neoplastic) PVT include expan sive aspect (enlargement of the portal vein owing to mass-forming thrombus), disruption of the vessel’s walls and intra-thrombus arterial neovascularization. The use of colour Doppler ultrasonography (CDUS) and spectral Doppler (pulsed wave ultrasonography, PWUS) improves the characterization of thrombosis,23 enabling confirm ation of the absence of flow in complete PVT. Similarly, CDUS is useful for the assessment of portal cavernoma as the presence of venous flow within the small vessels can be verified with this method. In patients with extremely low portal vein velocity (below the measurable range), CDUS cannot reliably exclude PVT. Contrast-enhanced ultrasonography (CEUS) should be used in such cases,24 as it is superior to grey-scale ultrasonography and CDUS for assessing the presence or absence of flow.25 It should be underlined that the reliability of ultrasonography improves as a function of know-how,26 so that suspected PVT should be evaluated by experienced physicians whenever possible. Drawbacks of ultrasonography involve: reduced visualization in patients with abundant bowel gas or obesity; reduced accuracy for the detec tion of thrombi in the splenic and superior mesenteric vein;18,27 and the impossibility of correctly assessing bowel ischaemia, which can arise as a consequence of acute mesenteric vein thrombosis. When ultrasonography cannot be performed (owing to lack of availability or lack of experienced operators), or when its results are considered incomplete owing to the above mentioned limits, contrast-enhanced CT (CECT) or contrast-enhanced MRI (CEMRI) should be performed to complete the diagnostic assessment (Figure 1b and 1c). Unenhanced CT can display fresh thrombi (that is those 80% of patients with portal cavernoma. However, after being diagnosed, few patients develop symptoms at follow-up, and laboratory tests are not useful to predict the risk of symptomatic disease.58 Magnetic resonance cholangio graphy (MRC) is the reference noninvasive procedure for the study of the biliary duct and is currently the investi gation method of choice for this disorder.59 In a study published in 2011, we showed that MRC enables portal cholangiopathy to be accurately identified in patients with PVT.60 By evaluating patients who are experiencing acute PVT, the appearance of portal cholangiopathy was found to be an early event in the natural history of PVT and, once abnormalities of the biliary tree have appeared, they do not progress. Moreover, according to the results of this study, MRC findings correlate with the risk of developing clinical symptoms, and these symptoms are limited to patients showing dilatation of the biliary tree (grade 3 portal cholangiopathy) (Figure 3a). The simple radiological classification used to stratify the patients’ risk is shown in Box 1.60 Although these results require validation in inde pendent series, it is accepted at our institution that MRC should be performed at the time of diagnosis in all patients with chronic PVT and after 9–12 months of acute PVT if anticoagulant therapy does not achieve recanalization so as to assess the presence of portal chol angiopathy at risk of later complications. In the latter case, if grade 3 portal cholangiopathy has not devel oped at the 12 month follow-up, no further MRC exam ination is needed, as no progression is expected to occur thereafter.60 Radiologists and clinicians should be aware of the importance of correctly diagnosing the cause of biliary tree dilatation in patients with cavernomatosis, as imaging findings of portal cholangiopathy might be confused with hilar cholangiocarcinoma.61
How to follow-up PVT by imaging? Current recommendations suggest that acute PVT episodes should be treated with anticoagulant therapy (such as warfarin), and that anticoagulation treatment should be maintained life-long in patients with congeni tal thrombophilic conditions or haematological malig nancies.62 However, no consensus exists on how long anticoagulant agents should be maintained in patients
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
VOLUME 11 | MAY 2014 | 313
REVIEWS Box 2 | Details required for imaging reports Liver and abdominal cavity ■■ Presence or absence of signs of cirrhosis, focal lesions, solid tumours, septic foci and ascites Portal vein right branch, left branch and main trunk ■■ Patency and/or degree of thrombosis including diameter (normal, enlarged or reduced); calcifications; aspects suggesting malignant nature of thrombosis (expansive; thrombus neovascularization); flow direction (ultrasonography) Splenic vein and superior mesenteric vein ■■ Patency; diameter (normal, enlarged or reduced); calcifications; flow direction (ultrasonography) Collateral vessels ■■ Presence or absence of collateral vessels with hepatopetal flow ■■ Presence or absence of portosystemic collateral vessels and specify site Spleen ■■ Diameter and area Hepatic veins and inferior vena cava ■■ Patency and/or thrombosis Comparison with previous imaging ■■ Specify if thrombosis is stable, improved or worsened
Clinical suspicion of PVT Diagnose PVT using ultrasonography, CDUS and PWUS (CEUS if needed) No
PVT? Unreliable or sepsis
Evaluate ■ Signs of cirrhosis ■ Malignancies ■ Ascites
Yes
Stop investigation for PVT
Assess PVT extent (protocol)
CT or MRI Confirms PVT?
No
Evaluate ■ PVT extension ■ Cofactors
Yes Cavernoma?
No
Yes Assess portal cholangiopathy by MRC No
Follow-up every 6 months
Portal cholangiopathy?
CDUS if good visualization, CT or MRI if not
Yes Stratify the risk of bilary complications Grade 3 portal cholangiopathy?
Yes
STOP The patient has a high risk of biliary complications
No MRC after 12 months If no grade 3 portal cholangiopathy then stop, the patient has a low risk of biliary complications
Figure 4 | Flowchart summarizing how the different imaging methods are used for diagnosing and follow-up of patients with PVT according to the consensus of the Vascular Liver Diseases Group at the Hospital Clinic in Barcelona. Abbreviations: CDUS, colour Doppler ultrasonography; MRC, magnetic resonance cholangiopathy; PVT, portal vein thrombosis; PWUS, pulsed wave ultrasonography.
314 | MAY 2014 | VOLUME 11
without cirrhosis and with no established thrombophilia as the risk of re-thrombosis is low.63 Anticoagulation therapy should also be considered in patients with PVT and cirrhosis, but again there is no consensus on if this therapy should be routinely used or not, and, if used, for how long.64 The natural history of PVT is not completely known. It is clear that PVT can progress in patients with overt thrombophilic disorders, leading to complete thrombosis of the whole portal venous system (Figure 3b,c); the aim of anticoagulant therapy in these patients is not only to attempt recanalization, but also to prevent progression and re-thrombosis episodes62 (Figure 3d,e). On the other hand, it was reported in 2012 that benign partial PVT in 42 patients with cirrhosis spontaneously improved in ~50% cases.65 In this complex scenario, the ideal roles of imaging are stratifying the probability of successful recanalization with anticoagulant therapy before start ing treatment and showing the effects of anticoagulant therapy and its discontinuation in the portal venous system on follow-up. As for imaging surrogates of achieving recanalization with anticoagulant therapy, the extent and age of the thrombus are of help. In addition, a study published in 2012 suggested that intra-thrombus enhancement during pre-treatment CEUS in patients with acute PVT (using perflubutane, such as Sonazoid®GE Healthcare, Oslo, Norway, as a contrast medium) is predictive of anti coagulant therapy success.66 These results, obtained in a very small number of cases, have not been confirmed and require validation before translating into clinical practice. By contrast, imaging follow-up is a useful tool to identify which patients recanalize during anticoagulant therapy (Figure 3f), and if recanalization is maintained after stopping therapy. No consensus exists on which technique should be preferred, the best interval to be used for follow-up, or how long imaging follow-up should be maintained. Our view is that follow-up should be individualized: the technique and interval used need to be set on a case-by-case basis depending on individual risk of re-thrombosis, hospital expertise and risks related to repeated imaging studies (such as irradiation and contrast agents). Hence, we propose that the first imaging control should be performed 3–6 months after starting anticoagulant therapy (or wait-and-see decision) by the same technique used to depict thrombosis extent at baseline (either CT or MRI). CDUS should also be performed at this time point to evaluate whether characterization of PVT by ultrasonography correlates well with that obtained by CT or MRI. Imaging findings should be carefully compared with those obtained at first observation, and the report should inform about improvement, stability and pro gression of PVT in all vessels of the portal venous system (Box 2). Subsequent measurements should be repeated every 6 months thereafter; CDUS should be used when ever possible owing to its safety. If CDUS cannot be used (because of lack of expertise or lack of complete visual ization of the site of thrombosis), CECT or CEMRI can be used, depending on the experience and availability of
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS the centre. These imaging techniques can be alternated to reduce the risks associated with repeated ionizing radiation30,67 and the use of contrast medium.68 Patients presenting with new symptoms or signs suggestive of re‑thrombosis should undergo a new assessment directly by a second-line technique (either CECT or CEMRI). Figure 4 summarizes the protocol used to ev aluate patients with PVT at the Hospital Clinic in Barcelona.
Conclusions In summary, as shown in detail in this Review, ultra sonography, CT and MRI have a complementary role in the assessment of PVT and are of central importance to guide the clinical management of these complex patients who require a multidisciplinary approach. Owing to the large number of factors that need to be evaluated in patients with PVT, we believe that it is important both for 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Yerdel, M. A. et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 69, 1873–1881 (2000). Rajani, R. et al. The epidemiology and clinical features of portal vein thrombosis: a multicentre study. Aliment. Pharmacol. Ther. 32, 1154–1162 (2010). Garcia-Pagan, J. C., Hernandez-Guerra, M. & Bosch, J. Extrahepatic portal vein thrombosis. Semin. Liver Dis. 28, 282–292 (2008). Plessier, A. et al. Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study. Hepatology 51, 210–218 (2010). Valla, D. et al. Etiology of portal vein thrombosis in adults. A prospective evaluation of primary myeloproliferative disorders. Gastroenterology 94, 1063–1069 (1988). Denninger, M. H. et al. Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology 31, 587–591 (2000). Primignani, M. et al. Risk factors for thrombophilia in extrahepatic portal vein obstruction. Hepatology 41, 603–608 (2007). Turnes, J. et al. Portal hypertension-related complications after acute portal vein thrombosis: impact of early anticoagulation. Clin. Gastroenterol. Hepatol 6, 1412–1417 (2008). Nonami, T., Yokoyama, I., Iwatsuki, S. & Starzl, T. E. The incidence of portal vein thrombosis at liver transplantation. Hepatology 16, 1195–1198 (1992). Tripodi, A., Anstee, Q. M., Sogaard, K. K., Primignani, M. & Valla, D. C. Hypercoagulability in cirrhosis: causes and consequences. J. Thromb. Haemost. 9, 1713–1723 (2011). Tripodi, A. & Mannucci, P. M. The coagulopathy of chronic liver disease. N. Engl. J. Med. 365, 147–156 (2011). Amitrano, L. et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J. Hepatol. 40, 736–741 (2004). Francoz, C. et al. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 54, 691–697 (2005). Englesbe, M. J. et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl. 16, 83–90 (2010).
clinicians and radiologists to follow a consensus protocol for the systematic exploration, reporting and interpret ation of the imaging results in this population, enabling changes to be tracked over time. Review criteria The PubMed database was searched in April 2013 for publications in English that contained the terms “portal vein thrombosis”, “splenic vein thrombosis” or “mesenteric vein thrombosis”; the same terms were then used in combination with the terms “ultrasound”, “Doppler ultrasound”, “computerized tomography”, “magnetic resonance” or “imaging”. Additional papers were found by cross-checking the reference lists of those previously identified. No date restriction was applied. The full text of the identified references was obtained and relevant data were used for the current review.
15. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 56, 908–943 (2012). 16. Delgado, M. G. et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin. Gastroenterol. Hepatol. 10, 776–783 (2012). 17. Tessler, F. N. et al. Diagnosis of portal vein thrombosis: value of color Doppler imaging. AJR Am. J. Roentgenol. 157, 293–296 (1991). 18. Bach, A. M. et al. Portal vein evaluation with US: comparison to angiography combined with CT arterial portography. Radiology 201, 149–154 (1996). 19. Chawla, Y. & Kumar, S. Portal venous flow in Budd-Chiari syndrome [letter]. Indian J. Gastroenterol. 17, 37 (1998). 20. Gertsch, P., Matthews, J., Lerut, J., Luder, P. & Blumgart, L. H. Acute thrombosis of the splanchnic veins. Arch. Surg. 128, 341–345 (1993). 21. Berzigotti, A., Zoli, M., Bru, C. & Gilabert, R. in Portal Hypertension V: Proceedings of the Fifth Baveno International Consensus Workshop (ed. de Franchis, R.) 28–36 (Wiley Blackwell, 2010). 22. Berzigotti, A. & Piscaglia, F. Ultrasound in portal hypertension—part 2—and EFSUMB recommendations for the performance and reporting of ultrasound examinations in portal hypertension. Ultraschall. Med. 33, 8–32 (2012). 23. Grant, E. G., Tessler, F. N. & Perrella, R. R. Clinical Doppler imaging. AJR Am. J. Roentgenol. 152, 707–717 (1989). 24. Claudon, M. et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver—update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultraschall. Med. 34, 11–29 (2013). 25. Rossi, S. et al. Contrast-enhanced versus conventional and color Doppler sonography for the detection of thrombosis of the portal and hepatic venous systems. AJR Am. J. Roentgenol. 186, 763–773 (2006). 26. Sabba, C. et al. Interobserver and interequipment variability of echo-Doppler examination of the portal vein: effect of a cooperative training program. Hepatology 21, 428–433 (1995). 27. Kuszyk, B. S. et al. Portal venous system thrombosis: helical CT angiography before transjugular intrahepatic portosystemic shunt creation. Radiology 206, 179–186 (1998).
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
28. Mori, H. et al. High-attenuation recent thrombus of the portal vein: CT demonstration and clinical significance. Radiology 163, 353–356 (1987). 29. DeLeve, L. D., Valla, D. C. & Garcia-Tsao, G. Vascular disorders of the liver. Hepatology 49, 1729–1764 (2009). 30. Sodickson, A. et al. Recurrent CT, cumulative radiation exposure, and associated radiationinduced cancer risks from CT of adults. Radiology 251, 175–184 (2009). 31. American College of Radiology. Manual on Contrast Media version 8, 33–42 (2012). 32. Shimada, K. et al. Non‑contrast‑enhanced MR portography with time-spatial labeling inversion pulses: comparison of imaging with threedimensional half-fourier fast spin-echo and true steady-state free-precession sequences. J. Magn. Reson. Imaging 29, 1140–1146 (2009). 33. Berzigotti, A. et al. Ultrasonographic evaluation of liver surface and transient elastography in clinically doubtful cirrhosis. J. Hepatol. 52, 846–853 (2010). 34. Colli, A. et al. Severe liver fibrosis or cirrhosis: accuracy of US for detection—analysis of 300 cases. Radiology 227, 89–94 (2003). 35. Vilgrain, V. et al. Atrophy-hypertrophy complex in patients with cavernous transformation of the portal vein: CT evaluation. Radiology 241, 149–155 (2006). 36. Hillaire, S. et al. Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients. Gut 51, 275–280 (2002). 37. Seijo, S. et al. Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension. Dig. Liver Dis. 44, 855–860 (2012). 38. Sharma, P., Mishra, S. R., Kumar, M., Sharma, B. C. & Sarin, S. K. Liver and spleen stiffness in patients with extrahepatic portal vein obstruction. Radiology 263, 893–899 (2012). 39. Friedrich-Rust, M. et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 252, 595–604 (2009). 40. Ferraioli, G. et al. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 56, 2125–2133 (2012). 41. Harris, S., Nadkarni, N. A., Naina, H. V. & Vege, S. S. Splanchnic vein thrombosis in acute pancreatitis: a single-center experience. Pancreas 42, 1251–1254 (2013).
VOLUME 11 | MAY 2014 | 315
REVIEWS 42. Calvet, X. et al. Natural history of hepatocellular carcinoma in Spain. Five year’s experience in 249 cases. J. Hepatol. 10, 311–317 (1990). 43. Stuart, K. E., Anand, A. J. & Jenkins, R. L. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer 77, 2217–2222 (1996). 44. Rossi, S. et al. Contrast-enhanced ultrasonography and spiral computed tomography in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma. Eur. Radiol. 18, 1749–1756 (2008). 45. Raab, B. W. The thread and streak sign. Radiology 236, 284–285 (2005). 46. Catalano, O. A., Choy, G., Zhu, A., Hahn, P. F. & Sahani, D. V. Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: application of diffusion-weighted MR imaging. Radiology 254, 154–162 (2010). 47. Qian, L. J. et al. Differentiation of neoplastic from bland macroscopic portal vein thrombi using dual-energy spectral CT imaging: a pilot study. Eur. Radiol. 22, 2178–2185 (2012). 48. Piscaglia, F. et al. Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation. Liver Transpl. 16, 658–667 (2010). 49. de Ville de Goyet, J. et al. Direct bypassing of extrahepatic portal venous obstruction in children: a new technique for combined hepatic portal revascularization and treatment of extrahepatic portal hypertension. J. Pediatr. Surg. 33, 597–601 (1998). 50. Hanbidge, A. E., Lynch, D. & Wilson, S. R. US of the peritoneum. Radiographics 23, 663–684 (2003). 51. de Ville de Goyet, J. et al. Meso-Rex bypass as an alternative technique for portal vein reconstruction at or after liver transplantation in children: review and perspectives. Pediatr. Transplant. 17, 19–26 (2013). 52. Chaves, I. J. et al. Pre- and postoperative imaging and interventions for the meso-Rex bypass in children and young adults. Pediatr. Radiol. 42, 220–232 (2012).
316 | MAY 2014 | VOLUME 11
53. Cakmak, O. et al. Role of contrast-enhanced 3D magnetic resonance portography in evaluating portal venous system compared with color Doppler ultrasonography. Abdom. Imaging 33, 65–71 (2008). 54. Seeger, M. et al. Chronic portal vein thrombosis: transcapsular hepatic collateral vessels and communicating ectopic varices. Radiology 257, 568–578 (2010). 55. Miyamoto, A. et al. Living-related liver transplantation with renoportal anastomosis for a patient with large spontaneous splenorenal collateral. Transplantation 75, 1596–1598 (2003). 56. Brancatelli, G., Federle, M. P., Pealer, K. & Geller, D. A. Portal venous thrombosis or sclerosis in liver transplantation candidates: preoperative CT findings and correlation with surgical procedure. Radiology 220, 321–328 (2001). 57. Luca, A. et al. Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis. Gut 60, 846–852 (2011). 58. Dhiman, R. K., Behera, A., Chawla, Y. K., Dilawari, J. B. & Suri, S. Portal hypertensive biliopathy. Gut 56, 1001–1008 (2007). 59. Condat, B. et al. Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study. Hepatology 37, 1302–1308 (2003). 60. Llop, E. et al. Portal cholangiopathy: radiological classification and natural history. Gut 60, 853–860 (2011). 61. Galati, G. et al. A mocking finding: portal cavernoma mimicking neoplastic mass. First sign of myeloproliferative disorder in a patient with Janus kinase2 V617F mutation. Eur. J. Gastroenterol. Hepatol. 21, 233–236 (2009). 62. Plessier, A., Rautou, P. E. & Valla, D. C. Management of hepatic vascular diseases. J. Hepatol. 56 (Suppl. 1), S25–S38 (2012). 63. Spaander, M. C. et al. Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding. J. Thromb. Haemost. 11, 452–459 (2013).
64. Francoz, C., Valla, D. & Durand, F. Portal vein thrombosis, cirrhosis, and liver transplantation. J. Hepatol. 57, 203–212 (2012). 65. Luca, A. et al. Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis. Radiology 265, 124–132 (2012). 66. Maruyama, H. et al. Prediction of the therapeutic effects of anticoagulation for recent portal vein thrombosis: a novel approach with contrastenhanced ultrasound. Abdom. Imaging 37, 431–438 (2012). 67. Brenner, D. J. & Hall, E. J. Computed tomography —an increasing source of radiation exposure. N. Engl. J. Med. 357, 2277–2284 (2007). 68. Reiter, T. et al. Minimizing risk of nephrogenic systemic fibrosis in cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 14, 31 (2012). 69. Berzigotti, A., Piscaglia, F. & EFSUMB Education and Professional Standard Committee. Clinical recommendations for the performance and reporting of ultrasound examination for portal hypertension European Federation of Societies for Ultrasound in Medicine and Biology [online], http://www.efsumb-portal.org/ep/ article.php?id=108 (2011). Acknowledgements The authors are members of the Vascular Liver Diseases Group of the Hospital Clinic in Barcelona, and would like to express their gratitude to all the colleagues (clinicians, radiologists, anaesthesiologists and surgeons) that participate in the work of this multidisciplinary team. The authors thank the nursing and technical staff of the Hepatic Hemodynamic Laboratory and of the CDIC, and Ms C. Esteva for expert secretarial support. CIBERehd is funded by the Instituto de Salud Carlos III. Author contributions A. Berzigotti contributed to all aspects in the generation of this article. Á. García-Criado and A. Darnell contributed equally to researching data for the article, discussion of content and reviewing/ editing the manuscript before submission. J.-C. García-Pagán substantially contributed to the discussion of content and reviewed/edited the manuscript before submission.
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
