Skip to main content
SpringerLink
Log in

Budd-Chiari Syndrome: The Western Perspective

  • Chapter
  • First Online:
Diagnostic Methods for Cirrhosis and Portal Hypertension

  • 1039 Accesses

Abstract

Primary Budd-Chiari syndrome (BCS) is defined as hepatic venous outflow obstruction from small hepatic veins to the inferior vena cava (IVC), due to thrombosis or fibrous stenosis of these veins. In Western countries, one or multiple prothombotic diseases are usually identified, mainly myeloproliferative neoplasms. New noninvasive diagnostic tools facilitate the diagnosis of these causes which may be difficult to detect in the presence of portal hypertension (PH) or liver failure.

The spectrum of symptoms ranges from an absence of signs to fulminant hepatic failure. Specific and sensitive criteria for the diagnosis of BCS have been described with Doppler ultrasound or contrast imaging (CT or MRI) so that liver biopsy is not necessary in most situations.

A minimally invasive therapeutic strategy is currently proposed for BCS patients in the West. The first step includes anticoagulant therapy and treatment of the identified cause when appropriate, to avoid the recurrence or extension of thrombosis, and nonspecific management of the complications of PH. The second step includes an attempt to recanalize and reestablish physiological venous outflow, with angioplasty/stenting. When symptoms are not resolved by this approach, the disease is managed by TIPS. If TIPS fail, or in patients with HCC, liver transplantation is performed. Long-term management must focus on close follow-up of the cause and nodules to prevent recurrent thrombosis, the complications of treatment and a misdiagnosis of HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 89.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 119.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

APLS:

Antiphospholipid syndrome

BCS:

BUDD Chiari Syndrome

BMB:

Bone marrow biopsy

BMI:

Body mass index

HCC:

Hepatocellular carcinoma

HV:

Hepatic vein

IVC:

Inferior vena cava

MPN:

Myeloproliferative neoplasm

OLT:

Orthotopic liver transplantation

OP:

Oestro-progestative

PH:

Portal hypertension

PMI:

Per million inhabitants

PNH:

Paroxysomal noctural haemoglobinuria

TIPS:

Transjugular porto systemic shunt

References

  1. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu. EASL clinical practice guidelines: vascular diseases of the liver. J Hepatol. 2016;64(1):179–202.

    Article  Google Scholar 

  2. DeLeve LD, Valla D-C, Garcia-Tsao G, American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology. 2009;49(5):1729–64.

    Article  CAS  PubMed  Google Scholar 

  3. Allaire M, Ollivier-Hourmand I, Morello R, Chagneau-Derrode C, Dumortier J, Goria O, et al. P1288: Budd chiari syndrome (BCS) in France from a large national cohort. J Hepatol. 2015;62:S842.

    Article  Google Scholar 

  4. Ki M, Choi HY, Kim K-A, Kim BH, Jang ES, Jeong S-H. Incidence, prevalence and complications of Budd-Chiari syndrome in South Korea: a nationwide, population-based study. Liver Int. 2016;36(7):1067–73.

    Article  PubMed  Google Scholar 

  5. Zhang W, Qi X, Zhang X, Su H, Zhong H, Shi J, et al. Budd-Chiari syndrome in China: a systematic analysis of epidemiological features based on the Chinese literature survey. Gastroenterol Res Pract. 2015;2015:738548.

    PubMed  PubMed Central  Google Scholar 

  6. Smalberg JH, Arends LR, Valla DC, Kiladjian J-J, Janssen HLA, Leebeek FWG. Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood. 2012;120(25):4921–8.

    Article  CAS  PubMed  Google Scholar 

  7. Kiladjian J-J, Cervantes F, Leebeek FWG, Marzac C, Cassinat B, Chevret S, et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood. 2008;111(10):4922–9.

    Article  CAS  PubMed  Google Scholar 

  8. Poisson J, Plessier A, Kiladjian J-J, Turon F, Cassinat B, Andreoli A, et al. Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: a prospective cohort study. J Hepatol. Epub 2017 May 5

    Google Scholar 

  9. Hayek G, Ronot M, Plessier A, Sibert A, Abdel-Rehim M, Zappa M, et al. Long-term outcome and analysis of dysfunction of transjugular intrahepatic portosystemic shunt placement in chronic primary Budd-Chiari syndrome. Radiology. 2017;283(1):280–92. Epub 2016 Oct 31

    Article  PubMed  Google Scholar 

  10. De Stefano V, Qi X, Betti S, Rossi E. Splanchnic vein thrombosis and myeloproliferative neoplasms: molecular-driven diagnosis and long-term treatment. Thromb Haemost. 2016;115(2):240–9.

    Article  PubMed  Google Scholar 

  11. Pieri L, Paoli C, Arena U, Marra F, Mori F, Zucchini M, et al. Safety and efficacy of ruxolitinib in splanchnic vein thrombosis associated with myeloproliferative neoplasms. Am J Hematol. 2017;92(2):187–95.

    Article  CAS  PubMed  Google Scholar 

  12. Janssen HL, Meinardi JR, Vleggaar FP, van Uum SH, Haagsma EB, van Der Meer FJ, et al. Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study. Blood. 2000;96(7):2364–8.

    CAS  PubMed  Google Scholar 

  13. Zhang P, Ma H, Min Q, Zu M, Lu Z. CALR mutations in Chinese Budd-Chiari syndrome patients. Eur J Gastroenterol Hepatol. 2016;28(3):361–2.

    Article  PubMed  Google Scholar 

  14. Austin SK, Lambert JR. The JAK2 V617F mutation and thrombosis. Br J Haematol. 2008;143(3):307–20.

    Article  CAS  PubMed  Google Scholar 

  15. Teofili L, Martini M, Iachininoto MG, Capodimonti S, Nuzzolo ER, Torti L, et al. Endothelial progenitor cells are clonal and exhibit the JAK2(V617F) mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms. Blood. 2011;117(9):2700–7.

    Article  CAS  PubMed  Google Scholar 

  16. Helman R, Pereira W de O, Marti LC, Campregher PV, Puga RD, Hamerschlak N, et al. Granulocyte whole exome sequencing and endothelial JAK2V617F in patients with JAK2V617F positive Budd-Chiari syndrome without myeloproliferative neoplasm. Br J Haematol. Epub 2016 Sep 21.

    Google Scholar 

  17. Seijo S, Plessier A, Hoekstra J, Dell’era A, Mandair D, Rifai K, et al. Good long-term outcome of Budd-Chiari syndrome with a step-wise management. Hepatology. 2013;57(5):1962–8.

    Article  PubMed  Google Scholar 

  18. Darwish Murad S, Plessier A, Hernandez-Guerra M, Fabris F, Eapen CE, Bahr MJ, et al. Etiology, management, and outcome of the Budd-Chiari syndrome. Ann Intern Med. 2009;151(3):167–75.

    Article  PubMed  Google Scholar 

  19. De Stefano V, Za T, Ciminello A, Betti S, Rossi E. Causes of adult splanchnic vein thrombosis in the mediterranean area. Mediterr J Hematol Infect Dis. 2011;3(1):e2011063.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jadallah KA, Sarsak EW, Khazaleh YM, Barakat RMK. Budd-Chiari syndrome associated with coeliac disease: case report and literature review. Gastroenterol Rep. Epub 2016 Sep 7.

    Google Scholar 

  21. Ben Ghorbel I, Ennaifer R, Lamloum M, Khanfir M, Miled M, Houman MH. Budd-Chiari syndrome associated with Behçet’s disease. Gastroenterol Clin Biol. 2008;32(3):316–20.

    Article  CAS  PubMed  Google Scholar 

  22. Seyahi E, Caglar E, Ugurlu S, Kantarci F, Hamuryudan V, Sonsuz A, et al. An outcome survey of 43 patients with Budd-Chiari syndrome due to Behçet’s syndrome followed up at a single, dedicated center. Semin Arthritis Rheum. 2015;44(5):602–9.

    Article  PubMed  Google Scholar 

  23. Bissonnette J, Durand F, de Raucourt E, Ceccaldi P-F, Plessier A, Valla D, et al. Pregnancy and vascular liver disease. J Clin Exp Hepatol. 2015;5(1):41–50.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Valla D, Le MG, Poynard T, Zucman N, Rueff B, Benhamou JP. Risk of hepatic vein thrombosis in relation to recent use of oral contraceptives. A case-control study. Gastroenterology. 1986;90(4):807–11.

    Article  CAS  PubMed  Google Scholar 

  25. Faraoun SA, Boudjella MEA, Debzi N, Benidir N, Afredj N, Guerrache Y, et al. Budd-Chiari syndrome: an update on imaging features. Clin Imaging. 2016;40(4):637–46.

    Article  PubMed  Google Scholar 

  26. Pariente D, Franchi-Abella S. Paediatric chronic liver diseases: how to investigate and follow up? Role of imaging in the diagnosis of fibrosis. Pediatr Radiol. 2010;40(6):906–19.

    Article  PubMed  Google Scholar 

  27. Cazals-Hatem D, Vilgrain V, Genin P, Denninger M-H, Durand F, Belghiti J, et al. Arterial and portal circulation and parenchymal changes in Budd-Chiari syndrome: a study in 17 explanted livers. Hepatology. 2003;37(3):510–9.

    Article  PubMed  Google Scholar 

  28. Moucari R, Rautou P-E, Cazals-Hatem D, Geara A, Bureau C, Consigny Y, et al. Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors. Gut. 2008;57(6):828–35.

    Article  CAS  PubMed  Google Scholar 

  29. Raza SA, Jang H-J, Kim TK. Differentiating malignant from benign thrombosis in hepatocellular carcinoma: contrast-enhanced ultrasound. Abdom Imaging. 2014;39(1):153–61.

    Article  PubMed  Google Scholar 

  30. Mukund A, Pargewar SS, Desai SN, Rajesh S, Sarin SK. Changes in liver congestion in patients with Budd-Chiari syndrome following endovascular interventions: assessment with transient elastography. J Vasc Interv Radiol. Epub 2017 Jan 30.

    Google Scholar 

  31. Faraoun SA, Boudjella MEA, Debzi N, Afredj N, Guerrache Y, Benidir N, et al. Budd-Chiari syndrome: a prospective analysis of hepatic vein obstruction on ultrasonography, multidetector-row computed tomography and MR imaging. Abdom Imaging. 2015;40(6):1500–9.

    Article  PubMed  Google Scholar 

  32. Martens P, Maleux GA, Devos T, Monbaliu D, Heye S, Verslype C, et al. Budd-Chiari syndrome: reassessment of a step-wise treatment strategy. Acta Gastro-Enterol Belg. 2015;78(3):299–305.

    CAS  Google Scholar 

  33. Sempoux C, Paradis V, Komuta M, Wee A, Calderaro J, Balabaud C, et al. Hepatocellular nodules expressing markers of hepatocellular adenomas in Budd-Chiari syndrome and other rare hepatic vascular disorders. J Hepatol. 2015;63(5):1173–80.

    Article  CAS  PubMed  Google Scholar 

  34. Garcia-Pagán JC, Heydtmann M, Raffa S, Plessier A, Murad S, Fabris F, et al. TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients. Gastroenterology. 2008;135(3):808–15.

    Article  PubMed  Google Scholar 

  35. Plessier A, Sibert A, Consigny Y, Hakime A, Zappa M, Denninger M-H, et al. Aiming at minimal invasiveness as a therapeutic strategy for Budd-Chiari syndrome. Hepatology. 2006;44(5):1308–16.

    Article  PubMed  Google Scholar 

  36. Langlet P, Escolano S, Valla D, Coste-Zeitoun D, Denie C, Mallet A, et al. Clinicopathological forms and prognostic index in Budd-Chiari syndrome. J Hepatol. 2003;39(4):496–501.

    Article  PubMed  Google Scholar 

  37. Rautou P-E, Moucari R, Cazals-Hatem D, Escolano S, Denié C, Douarin L, et al. Levels and initial course of serum alanine aminotransferase can predict outcome of patients with Budd-Chiari syndrome. Clin Gastroenterol Hepatol. 2009;7(11):1230–5.

    Article  CAS  PubMed  Google Scholar 

  38. Rautou P-E, Moucari R, Escolano S, Cazals-Hatem D, Denié C, Chagneau-Derrode C, et al. Prognostic indices for Budd-Chiari syndrome: valid for clinical studies but insufficient for individual management. Am J Gastroenterol. 2009;104(5):1140–6.

    Article  PubMed  Google Scholar 

  39. Darwish Murad S, Kim WR, de Groen PC, Kamath PS, Malinchoc M, Valla D-C, et al. Can the model for end-stage liver disease be used to predict the prognosis in patients with Budd-Chiari syndrome? Liver Transpl. 2007;13(6):867–74.

    Article  PubMed  Google Scholar 

  40. Min AD, Atillasoy EO, Schwartz ME, Thiim M, Miller CM, Bodenheimer HC. Reassessing the role of medical therapy in the management of hepatic vein thrombosis. Liver Transpl Surg. 1997;3(4):423–9.

    Article  CAS  PubMed  Google Scholar 

  41. Zeitoun G, Escolano S, Hadengue A, Azar N, El Younsi M, Mallet A, et al. Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting. Hepatology. 1999;30(1):84–9.

    Article  CAS  PubMed  Google Scholar 

  42. Ouwendijk RJ, Koster JC, Wilson JH, Stibbe J, Lameris JS, Visser W, et al. Budd-Chiari syndrome in a young patient with anticardiolipin antibodies: need for prolonged anticoagulant treatment. Gut. 1994;35(7):1004–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Plessier A, Darwish-Murad S, Hernandez-Guerra M, Consigny Y, Fabris F, Trebicka J, et al. Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study. Hepatology. 2010;51(1):210–8.

    Article  PubMed  Google Scholar 

  44. Plessier A, Rautou P-E, Valla D-C. Management of hepatic vascular diseases. J Hepatol. 2012;56(Suppl 1):S25–38.

    Article  CAS  PubMed  Google Scholar 

  45. Zaman S, Wiebe S, Bernal W, Wendon J, Czuprynska J, Auzinger G. Increased prevalence of heparin-induced thrombocytopenia in patients with Budd-Chiari syndrome: a retrospective analysis. Eur J Gastroenterol Hepatol. 2016;28(8):967–71.

    Article  CAS  PubMed  Google Scholar 

  46. Rautou P-E, Douarin L, Denninger M-H, Escolano S, Lebrec D, Moreau R, et al. Bleeding in patients with Budd-Chiari syndrome. J Hepatol. 2011;54(1):56–63.

    Article  PubMed  Google Scholar 

  47. Chagneau-Derrode C, Roy L, Guilhot J, Gloria O, Ollivier-Hourmand I, Bureau C, et al. Impact of cytoreductive therapy on the outcome of patients with myeloproliferative neoplasms and hepatosplanchnic vein thrombosis. 58th ed; 2013. p. 857A.

    Google Scholar 

  48. Desbois AC, Rautou PE, Biard L, Belmatoug N, Wechsler B, Resche-Rigon M, et al. Behcet’s disease in Budd-Chiari syndrome. Orphanet J Rare Dis. 2014;9:104.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tripathi D, Sunderraj L, Vemala V, Mehrzad H, Zia Z, Mangat K, et al. Long-term outcomes following percutaneous hepatic vein recanalization for Budd-Chiari syndrome. Liver Int. 2017;37(1):111–20.

    Article  PubMed  Google Scholar 

  50. Zhang QQ, Xu H, Zu MH, Gu YM, Shen B, Wei N, et al. Strategy and long-term outcomes of endovascular treatment for Budd-Chiari syndrome complicated by inferior vena caval thrombosis. Eur J Vasc Endovasc Surg. 2014;47(5):550–7.

    Article  CAS  PubMed  Google Scholar 

  51. Huang Q, Shen B, Zhang Q, Xu H, Zu M, Gu Y, et al. Comparison of long-term outcomes of endovascular management for membranous and segmental inferior vena cava obstruction in patients with primary Budd-Chiari syndrome. Circ Cardiovasc Interv. 2016;9(3):e003104.

    Article  PubMed  Google Scholar 

  52. Qi X, Guo X, Fan D. Difference in Budd-Chiari syndrome between the West and China. Hepatology. 2015;62(2):656.

    Article  PubMed  Google Scholar 

  53. Fu Y-F, Li Y, Cui Y-F, Wei N, Li D-C, Xu H. Percutaneous recanalization for combined-type Budd-Chiari syndrome: strategy and long-term outcome. Abdom Imaging. 2015;40(8):3240–7.

    Article  PubMed  Google Scholar 

  54. Ding P-X, Zhang S-J, Li Z, Fu M-T, Hua Z-H, Zhang W-G. Long-term safety and outcome of percutaneous transhepatic venous balloon angioplasty for Budd-Chiari syndrome. J Gastroenterol Hepatol. 2016;31(1):222–8.

    Article  PubMed  Google Scholar 

  55. Fan X, Liu K, Che Y, Wang S, Wu X, Cao J, et al. Good clinical outcomes in Budd-Chiari syndrome with hepatic vein occlusion. Dig Dis Sci. 2016;61(10):3054–60.

    Article  CAS  PubMed  Google Scholar 

  56. Sharma VK, Ranade PR, Marar S, Nabi F, Nagral A. Long-term clinical outcome of Budd-Chiari syndrome in children after radiological intervention. Eur J Gastroenterol Hepatol. 2016;28(5):567–75.

    Article  PubMed  Google Scholar 

  57. Shalimar, Kumar A, Kedia S, Sharma H, Gamanagatti SR, Gulati GS, et al. Hepatic venous outflow tract obstruction: treatment outcomes and development of a new prognostic score. Aliment Pharmacol Ther. 2016;43(11):1154–67.

    Article  CAS  PubMed  Google Scholar 

  58. Tripathi D, Macnicholas R, Kothari C, Sunderraj L, Al-Hilou H, Rangarajan B, et al. Good clinical outcomes following transjugular intrahepatic portosystemic stent-shunts in Budd-Chiari syndrome. Aliment Pharmacol Ther. 2014;39(8):864–72.

    Article  CAS  PubMed  Google Scholar 

  59. Mentha G, Giostra E, Majno PE, Bechstein WO, Neuhaus P, O’Grady J, et al. Liver transplantation for Budd-Chiari syndrome: a European study on 248 patients from 51 centres. J Hepatol. 2006;44(3):520–8.

    Article  PubMed  Google Scholar 

  60. Potthoff A, Attia D, Pischke S, Mederacke I, Beutel G, Rifai K, et al. Long-term outcome of liver transplant patients with Budd-Chiari syndrome secondary to myeloproliferative neoplasms. Liver Int. 2015;35(8):2042–9.

    Article  PubMed  Google Scholar 

  61. Westbrook RH, Lea NC, Mohamedali AM, Smith AE, Orr DW, Roberts LN, et al. Prevalence and clinical outcomes of the 46/1 haplotype, Janus kinase 2 mutations, and ten-eleven translocation 2 mutations in Budd-Chiari syndrome and their impact on thrombotic complications post liver transplantation. Liver Transpl. 2012;18(7):819–27.

    Article  PubMed  Google Scholar 

  62. Okuda H, Yamagata H, Obata H, Iwata H, Sasaki R, Imai F, et al. Epidemiological and clinical features of Budd-Chiari syndrome in Japan. J Hepatol. 1995;22(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  63. Almdal TP, Sørensen TI. Incidence of parenchymal liver diseases in Denmark, 1981 to 1985: analysis of hospitalization registry data. The Danish Association for the Study of the Liver. Hepatology. 1991;13(4):650–5.

    Article  CAS  PubMed  Google Scholar 

  64. Rajani R, Melin T, Björnsson E, Broomé U, Sangfelt P, Danielsson A, et al. Budd-Chiari syndrome in Sweden: epidemiology, clinical characteristics and survival – an 18-year experience. Liver Int. 2009;29(2):253–9.

    Article  PubMed  Google Scholar 

  65. Ageno W, Dentali F, Pomero F, Fenoglio L, Squizzato A, Pagani G, et al. Incidence rates and case fatality rates of portal vein thrombosis and Budd-Chiari syndrome. Thromb Haemost. Epub 2017 Feb 9.

    Google Scholar 

  66. Cheng D, Xu H, Lu Z-J, Hua R, Qiu H, Du H, et al. Clinical features and etiology of Budd-Chiari syndrome in Chinese patients: a single-center study. J Gastroenterol Hepatol. 2013;28(6):1061–7.

    Article  CAS  PubMed  Google Scholar 

  67. Han G, Qi X, Zhang W, He C, Yin Z, Wang J, et al. Percutaneous recanalization for Budd-Chiari syndrome: an 11-year retrospective study on patency and survival in 177 Chinese patients from a single center. Radiology. 2013;266(2):657–67.

    Article  PubMed  Google Scholar 

  68. Qi X, Wu F, Fan D, Han G. Prevalence of thrombotic risk factors in Chinese Budd-Chiari syndrome patients: results of a prospective validation study. Eur J Gastroenterol Hepatol. 2014;26(5):576–7.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. DHU Unity, Pole des Maladies de l’Appareil Digestif, Service d’Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, HUPNVS, APHP, Clichy, France

    Aurélie Plessier, Audrey Payancé & Dominique Valla

Authors
  1. Aurélie Plessier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Audrey Payancé
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dominique Valla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aurélie Plessier .

Editor information

Editors and Affiliations

  1. Inselspital, University of Bern, UVCM, DMLL, Hepatology Inselspital, University of Bern, Berne, Switzerland

    Annalisa Berzigotti

  2. Hospital Clinic, Hepatic Hemodynamic Laboratory Hospital Clinic, Barcelona, Spain

    Jaime Bosch

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Plessier, A., Payancé, A., Valla, D. (2018). Budd-Chiari Syndrome: The Western Perspective. In: Berzigotti, A., Bosch, J. (eds) Diagnostic Methods for Cirrhosis and Portal Hypertension. Springer, Cham. https://doi.org/10.1007/978-3-319-72628-1_16

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-72628-1_16

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-72627-4

  • Online ISBN: 978-3-319-72628-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation