Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3273-3281 Budd-Chiari syndrome: current perspectives and controversies L. LIU 1, X.-S. QI 1,2 , Y. ZHAO 1, H. CHEN 1, X.-C. MENG 1, G.-H. HAN 1 1Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China 2Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China Lei Liu, Xingshun Qi, Yan Zhao, Hui Chen and Xiangchen Meng contributed equally to this work Abstract. – Budd-Chiari syndrome (BCS) is a jury of the sinusoidal wall 4. Given that BCS can rare disorder caused by hepatic venous outflow lead to potentially life-threatening liver failure obstruction with a wide spectrum of etiologies. and portal hypertension-related complications 1-4 , Clinical manifestations are so heterogeneous early diagnosis and treatment should be worth - that the diagnosis should be considered in any patients with acute or chronic liver disease. while. In the recent years, the number of publica - Therapeutic modalities for BCS have improved tions regarding BCS has been remarkably in - dramatically during the last few years. The con - creased 5. This paper aims to review the advances cept of a step-wise treatment strategy has been in the classification, etiology, diagnosis and treat - established, including anticoagulation, thrombol - ment of primary BCS. BCS secondary to malig - ysis, percutaneous recanalization, transjugular nant tumors, especially hepatocellular carcinoma, intrahepatic portosystemic shunt, surgery and liver transplantation. However, this strategy is is not considered as primary BCS. Their mecha - primarily based on experts’ opinions and retro - nisms should be mainly tumor invasion. spective case series, rather than prospective randomized trials. Furthermore, an earlier use of TIPS has been proposed in selected cases be - Classifications cause of a relatively high mortality from BCS pa - According to the potential causes, BCS can be tients who underwent medical therapy alone. classified as two groups: primary and secondary. Herein, we review the advances in the classifica - tion, etiology, clinical presentation, diagnosis BCS is considered primary when obstruction of and treatment of BCS. the hepatic venous outflow tract is the result of an endoluminal venous lesion (i.e., thrombus or Key Words: web). BCS is considered secondary when hepatic Budd-Chiari syndrome, Etiology, Diagnosis, Treat - venous outflow obstruction originates from a le - ment; review . sion outside the venous system (tumor, abscess, cysts). The lesions can obstruct outflow by invad - ing the lumen or by extrinsic compression. According to the clinical manifestations, BCS Introduction can be divided into two groups: asymptomatic and symptomatic. BCS is considered asympto - Budd-Chiari syndrome (BCS) is defined as he - matic when there are no remarkable signs 6. patic venous outflow obstruction at any levels About 15%-20% of BCS patients are asympto - from the small hepatic veins (HV) to the junction matic. The major compensation mechanism of the inferior vena cava (IVC) and the right atri - should be the spontaneous development of large um, regardless of the cause of obstruction 1-3 . intra- or extra-hepatic and portosystemic collater - However, hepatic venous outflow obstructions als 7. By comparison, most of BCS patients are caused by hepatic veno-occlusive disease/sinu - symptomatic. They include abdominal pain, as - soidal obstruction syndrome and cardiac disor - cites, jaundice, hepatomegaly, edema, en - ders should be excluded from this definition. cephalopathy and/or gastrointestinal bleeding. This is because veno-occlusive disease/sinusoidal According to the location of obstruction, BCS obstruction syndrome refers to the obstruction of is briefly classified as three types: pure obstruc - sinusoids or central hepatic veins due to toxic in - tion of HVs, pure obstruction of IVC, and com - Corresponding Author: Guohong Han, MD; e-mail: [email protected] 3273 L. Liu, X.-S. Qi, Y. Zhao, H. Chen, X.-C. Meng, G.-H. Han bined obstruction of HVs and IVC 8. Pure IVC or ditional acquired risk factors should be clearly combined IVC/HV obstruction is common in recognized, such as oral contraceptive use and Asian countries 9, whereas pure HV obstruction is pregnancy 35-38 . frequent in Western countries. Given the nature Factor V Leiden mutation and prothrombin of obstruction, BCS is further classified as two G20210A gene mutation are considered as the major groups: (1) HV and/or IVC obstruction or most common inherited prothrombotic factors in thrombosis; and (2) HV and/or IVC webs. BCS patients 39-42 . However, a recent systematic review and meta-analysis suggests that the factor Etiology V Leiden mutation is associated with an in - One or more underlying prothrombotic condi - creased risk of BCS, but not the prothrombin tions are observed in at least 75% of patients G20210A mutation 43,44 . Thus, routine screening with primary BCS 10,11 . The systemic prothrom - for prothrombin G20210A mutation in BCS pa - botic conditions are divided into acquired and in - tients is questioned. Additionally, both gene mu - herited types. Acquired causes primarily include tations were hardly observed in Chinese patients myeloproliferative neoplasms (MPNs), hyperho - with BCS. To our knowledge, only few patients mocysteinemia, paroxysmal nocturnal hemoglo - with familial BCS presented with factor V Lei - binuria (PNH) and Behçet’s syndrome, etc. In - den mutation 45 . herited causes primarily include factor V Leiden Inherited protein C, protein S, and antithrom - mutation, G20210A prothrombin gene mutation bin deficiencies are also considered as the major and inherited protein C, protein S, and antithrom - risk factors for BCS. However, their roles are bin deficiencies. ambiguous, because chronic liver diseases often BCR-ABL negative MPNs, including poly - obscure the recognition of these deficiencies. cythemia vera, essential thrombocythemia, and Recently, a systematic review and meta-analysis idiopathic myelofibrosis, are the most common confirms that inherited protein C, protein S, or acquired causes of primary BCS 12,13 . The preva - antithrombin deficiencies should significantly lence of MPNs is about 50% in BCS patients 14 . increase the risk of BCS 46 Accordingly, the Because JAK2 V617F mutation is found in about measurement of protein C, protein S, or an - 80% of patients with polycythemia vera and 50% tithrombin concentrations should be regularly of patients with essential thrombocythemia or id - performed in BCS patients and their first-degree iopathic myelofibrosis, routine screening for JAK relatives. V617F mutation is very valuable to establish an Besides, the coagulation and fibrinolysis ab - early diagnosis of MPNs in BCS patients. Nu - normalities are found. In our recent study, the pa - merous observational studies and meta-analyses tients with BCS had significantly higher factor confirm that the JAK2 V617F mutation can be VIII levels and significantly lower factor V, VII, detected in 30-50% of BCS patients 15-19 . Howev - IX, X, XI, XII, protein C and antithrombin levels er, it should be noted that MPNs are rare in Chi - than healthy controls. This finding suggests an nese patients with BCS 20-24 . These findings sug - imbalance of pro- and anti-coagulation factors in gest that MPNs may not be a major etiology of BCS patients 47 . Additionally, a slightly increased BCS in China. fibrinolytic potential was observed in BCS pa - By comparison, hyperhomocysteinemia, PNH , tients 48 . and Behçet’s syndrome appear to be relatively rare etiologies of BCS. However, several impor - Diagnosis tant points should be clearly recognized. First, a A diagnosis of BCS should be considered in systematic review and meta-analysis suggests all patients with acute or chronic liver disease, that hyperhomocysteinemia with homozygous especially when common causes for liver disease MTHFR mutation may be associated with the oc - have been ruled out. In other words, the patency currence of BCS 25 . However, the relevant evi - of HV and IVC may be considered as a part of dence originates from very limited data. Second, routine evaluation of liver diseases. PNH is an extremely rare condition 26-28 . Howev - Imaging tests play a crucial role in the early er, the presence of hepatic vein thrombosis is ex - diagnosis of BCS and assessment of location of traordinarily high in patients with PNH 29 . Third, obstruction 49-51 . There are various imaging Behçet’s syndrome is a well-recognized cause of modalities for the investigation of hepatic vascu - BCS 30,31 . However, this is frequently observed in lar patency, such as Doppler ultrasound, MRI and Turkey 32-33 , but not in other countries 34 . Some ad - computed tomography. Doppler ultrasound has a 3274 Budd-Chiari syndrome: current perspectives and controversies diagnostic sensitivity of over 85% and should be and location of outflow obstruction and measure - the first choice of imaging investigation 52,53 . The ment of HVs pressure. Liver biopsy is also useful major signs of BCS include no blood flow signal for the exclusion of veno-occlusive disease 57 . in the hepatic veins, intra- or extra-hepatic collat - eral circulation, a spider-web appearance located Treatment adjacently to the hepatic vein ostia and stagnant, Currently, a step-wise treatment strategy has and reversed or turbulent blood flow 54,55 . Com - been proposed and widely adopted