Abstract
Background
The characteristics and prevalence of Budd–Chiari syndrome in China remain unclear. This study aimed to analyze the clinical features of Budd–Chiari syndrome in Chinese patients in the Hubei area.
Methods
One-hundred and thirty patients with Budd–Chiari syndrome, admitted to Union Hospital from January 2002 to January 2011, were included in this retrospective study. Clinical features, laboratory data, imaging characteristics, and cumulative patency rates were analyzed.
Results
Of the 130 patients with Budd–Chiari syndrome, 77 were men (59.2%) and 53 women (40.8%). Budd–Chiari syndrome was more commonly associated with inferior vena cava block (56.9%, 74/130) than hepatic vein block (19.2%, 25/130) and combined inferior vena cava/hepatic vein block (23.9%, 31/130). The clinical features of Budd–Chiari syndrome varied based on the location of the obstruction. The incidence of bilirubin abnormality, elevated alkaline phosphatase, and γ-glutamyl peptide transferase levels was common in patients with Budd–Chiari syndrome. Liver injury was more severe in cases with combined inferior vena cava/hepatic vein block than in the other two types of Budd–Chiari syndrome. Color Doppler ultrasound imaging was better for the diagnosis of hepatic vein obstruction, while computed tomography and magnetic resonance imaging were superior in diagnosing inferior vena cava obstruction. The cumulative 1-, 5-, and 10-year patency rates were 97%, 69%, and 59%, respectively. Univariate analysis indicated that liver cirrhosis was an independent risk factor of recurrence.
Conclusion
The most prevalent type of Budd–Chiari syndrome is inferior vena cava obstruction in Chinese patients in the Hubei area. Different types of Budd–Chiari syndrome have diverse clinical and biochemical features, which may assist clinicians in diagnosing Budd–Chiari syndrome. Liver cirrhosis was found as an independent risk factor of recurrence.
Introduction
Budd–Chiari syndrome (BCS) is a rare vascular disorder characterized by hepatic venous outflow tract obstruction and is potentially life threatening. 1 BCS may occur at different ages and the incidence rate is approximately 1 in 100,000 in the general population. 2 The prevalence of BCS greatly varies according to geographical location. In certain Asian countries, BCS is a common cause of liver disease, while in Western countries, BCS is a rare disease with an incidence of 1 in 2.5 million per person-year. 3 Its rarity commonly leads to misdiagnosis.
Obstruction of the hepatic venous outflow may result from the small hepatic veins (HVs) to the junction of the inferior vena cava (IVC) with the right atrium. 4 BCS is classified in three types according to the location of obstruction: HV block (HV type), IVC block (IVC type), and IVC/HV combination block (IVC/HV type).4,5 In China, the widely used classification is dependent on the position of obstruction.6,7 In Western countries, the main types of BCS is pure HV block, while IVC or IVC/HV combined blockage are more common in Asia. 7 The clinical manifestations of BCS may vary from hepatomegaly and portal hypertension to liver dysfunction or even liver failure, 2 which further complicates the diagnosis.
Data from parts of China show that the IVC/HV combination block type seems to be the most common type in the Chinese population.8,9 However, the exact prevalence and clinical features in the Chinese population are unknown. There have been only a few reports describing the prevalence of each type of BCS in some areas of China. 4 As BCS is heterogeneous and varies by location, which may easily lead to misdiagnosis in clinical practice, it is urgent to survey the characteristics of BCS in other districts of China. In the Hubei area, which is located in the middle and lower reaches of the Yangtze, the blockage type and clinical characteristics of BCS remain unknown. Here, we retrospectively investigated the clinical features, laboratory data, imaging characteristics, and treatment of 130 patients with BCS in the Hubei area in China, aiming to further the understanding of this disease in the Chinese population.
Methods
Patients
One-hundred and thirty consecutive patients from the Hubei area with primary BCS diagnosed at Wuhan Union Hospital from 2004 to 2011 were retrospectively analyzed. The date of diagnosis of BCS was the date of the first imaging procedure showing an obstructed venous outflow tract, according to the guidelines of American Association for the Study of Liver Diseases. 10 Patients with hepatic outflow obstruction due to heart failure, sinusoidal obstruction syndrome, cancer, or liver transplantation were excluded. All data including general characteristics, signs and symptoms, laboratory tests, radiological data, and mode of treatment, such as use of hepatinica, diuretics, transjugular portosystemic shunt (TIPS), percutaneous transluminal angioplasty (PTA), and endovascular stent (ES) were recorded. Patients were followed up until the cutoff date (31 December 2014) or the date of recurrence. The date of recurrence was defined using color Doppler ultrasound (CDUS), computed tomography (CT), or magnetic resonance imaging (MRI), when the HVs and/or IVC were reoccluded. The study’s flowchart is shown in Figure 1.
The study flowchart.
Ethical aspects
This study was based on hospital databases and patient medical histories. All procedures were performed in accordance with the principles stated in the Declaration of Helsinki.
Statistical analysis
All results were analyzed using the SPSS 17.0 statistical software. Data regarding counts were analyzed using the chi-square test for categorical variables. Measured data were shown as means. The significance of the differences between the groups was analyzed using one-way analysis of variance. Cumulative patency rates were analyzed using the Kaplan–Meier method. The log-rank test was used to assess the differences between risk factors. P < 0.05 was considered as the statistically significant threshold.
Results
General characteristics and features of signs and symptoms of the patients with BCS in the Hubei area
A total of 130 patients, including 77 male patients (59.2%) and 53 female patients (40.8%) were included in the analysis. Seventy-four patients (74/130, 56.9%) with 39 men (39/74, 52.7%) and 35 women (35/74, 47.3%) had IVC obstruction. Twenty-five patients (25/130, 19.2%) had hepatic venous obstruction (HV) and the male patients accounted for 68.0% (17/25) of these patients. Thirty-one patients (31/130, 23.9%) with 21 men (21/31, 68.2%) and 10 women (10/31, 31.8%) had a combination of both conditions. The age of the patients with BCS ranged from 12 to 72 years and the average age was 40.3 ± 12.5 years. The duration of disease was 70 days to 20 years, and the median duration was 5 years. The general conditions of the three different types of BCS are shown in Figure 2(a)–(c). The main complaints and significant signs of the patients are shown in Figure 2(d). The prominent clinical features of the IVC type were leg edema in 40 patients (54.1%), abdominal wall distended veins in 35 patients (47.3%), and distension of the abdomen in 34 patients (45.9%). The most common clinical features in HV occlusion were splenomegaly in 12 patients (48.0%), followed by distension of the abdomen in nine patients (36.0%). In IVC/HV type, the most frequent signs were ascites (18/31, 58.1%), leg edema (14/31, 45.2%), and hepatomegaly (13/31, 41.9%). Fatigue was the additional typical symptom in the IVC/HV-type group (P = 0.002). Compared to the IVC and IVC/HV type, abdominal wall distended veins were rare and gastrointestinal bleeding was common in HV type. These data indicated that the different types of BCS manifested with different signs and symptoms, which may provide clues for diagnosis.
General characteristics of signs and symptoms of Budd–Chiari syndrome patients in Hubei area. (a) The proportion of different types of Budd–Chiari syndrome in Hubei area were shown. (b) The sex ratio of different types of Budd-Chiari syndrome patients (white bar means female, black bar means male). (c) The average age of different types of Budd-Chiari syndrome in Hubei area. (d) The signs and symptoms different types of Budd–Chiari syndrome (white bar means IVC type, gray bar means HV type, black bar means IVC/HV type). *P < 0.05, compared to HV type; #P < 0.05, compared to IVC/HV type.
The characters of laboratory tests and evaluation of severity of liver dysfunction of BCS in the Hubei area
We also analyzed laboratory test results of patients with BCS. The findings of the laboratory biochemical tests are shown in Figure 3(a)–(d). Overall, the most frequent abnormality was bilirubin metabolic disorder (including total bilirubin (TBIL) and direct bilirubin (DBIL)). The elevation of serum alanine aminotransferase and aspartate aminotransferase levels was not prevalent in the Hubei area, especially in the HV type. The average of TBIL in the three types was beyond the upper limit of normal and the IVC/HV type showed much higher levels of TBIL and DBIL (P < 0.01). The level of γ-glutamyl peptide transferase (γ-GT) and alkaline phosphatase (ALP) in patients with IVC/HV type BCS were also significantly increased compared to those in patients having the other two types (P < 0.001). Delayed prothrombin time occurred in the IVC/HV type, but there was no statistic difference compared to the other two types in this study. Additionally, we used the Child-Pugh classification to assess the severity of liver dysfunction of the different BCS types. The proportion of patients with Child-Pugh A, B, and C grades in the three types of BCS are shown in Figure 3(e). The IVC/HV type was characterized by a much higher proportion of patients with Child-Pugh grade B and C (P < 0.01). These data indicated that liver dysfunction in the IVC/HV type is more severe than in the other two BCS types.
The laboratory data and grade of Child-Pugh of three different types of Budd–Chiari syndrome. (a–d) Serum index of Liver function of different types of Budd-Chiari syndrome. (e) The coagulation of three different types of Budd-Chiari syndrome. (f) The comparison of grade of Child-Pugh among the three different types of Budd–Chiari syndrome. (White bar means IVC type, grey bar means HV type, black bar means IVC/HV type). *P < 0.05; **P < 0.01; ***P < 0.001.
Accuracy rate of CDUS, CT, and MRI in diagnosing BCS in the Hubei area
CDUS, which widely used in clinical practice, was employed in this study; CT and MRI were taken as secondary diagnostic measures. All 130 patients underwent digital subtraction angiography (DSA) to confirm the location of obstruction associated with the BCS. All 130 patients were examined using CDUS, and 64 with CT; MRI was performed on 45 patients. Ten cases with complications were tested using a combination of CDUS and CT, and another seven patients using CDUS and MRI. One case of the IVC/HV type was examined using all three methods. The accuracy rate of each method for the different types of BCS is as shown in Figure 4. CDUS seemed to be more sensitive to diagnose HV obstruction and the accuracy rate reached 84%. Using CT and MRI, IVC obstructions were easily revealed and the accuracy rate was above 80%. The combination of CDUS with CT or MRI increased the accuracy rate of diagnosis, which reached 100%.
The accuracy rate of different radiological examination in diagnosis of different types of Budd–Chiari syndrome. (CDUS bar means CDUS, gray bar means CT, black bar means MRI).IVC: inferior vena cava; HV: hepatic vein; CDUS: color Doppler ultrasound; CT: computed tomography; MRI: magnetic resonance imaging. *P<0.05.
IVC occlusion and IVC collateral circulation drainage are more common of BCS in the Hubei area
We also analyzed the radiological vascular features of BCS in the Hubei area. All DSA features of the 130 patients with BCS are shown in Figure 5. Among the 130 patients with BCS, the radiological images showed that IVC occlusion and IVC collateral circulation drainage were more common compared to IVC stenosis (Figure 5(b)). Stenosis often occurred in the right HV, but once the middle HV was blocked, the collateral circulation drainage occurred in sequence. The frequency of left HV stenosis or occlusion was low in this study.
The general radiology data of 130 Budd–Chiari syndrome. (a) Location of the outflow obstruction in the different types of Budd–Chiari syndrome with CT scan. (a′) HV obstruction (the white arrow). (b′) The occlusion of IVC (the white arrow). (c′) The combination of HV and IVC obstruction (the white arrows). (b) The obstruction condition and collateral circulation drainage among the different vein obstruction.IVC: inferior vena cava; HV: hepatic vein. *P < 0.05.
Treatment and outcomes of BCS in the Hubei area
PTA, ES, and TIPS were the main therapeutic interventions for BCS, which were applied according to the type and characteristics of obstruction in patients with BCS. Hepatinica, diuretics, and propranolol were administered if liver dysfunction, portal hypertension, or ascites were present. Anticoagulants were administrated to all patients after intervention therapy. In this study, 107 patients (82.3%) received interventional treatment and 23 (17.7%) were treated with medicine, such as hepatinica and propranolol. Among the 107 patients, 103 (96.3%) received a successful intervention treatment. Four patients (3.7%) failed to be treated with interventional methods due to the long-segment occlusion in the target vein. In these 107 patients, 52 (48.6%) were treated with percutaneous recanalization alone and 17 (15.8%) received balloon catheters, 11 (10.3%) treated with solo ES treatment, and 21 (19.6%) with PTA and ES. Additionally, patients received TIPS, which had a notable effect on controlling ascites and improving hepatic function. PTA was applied to treat BCS successfully, as shown in Figure 6(a).
The intervention therapy of different type of Budd–Chiari syndrome and cumulative rates of patency in follow-up group of Budd-Chiari syndrome. (a) (a′–c′), Different type of Budd–Chiari syndrome; (a′) HV obstruction, (b′) IVC obstruction, and (c′) blockage at both IVC and HV. (a) (d′–f′), The related interventional therapy; (d′) angioplasty, (e′) angioplasty and stent, and (f′) angioplasty. (b) Cumulative patency rate and life table in Budd–Chiari syndrome patients. (c) Cumulative patency rate and numbers at risk in Budd-Chiari syndrome patients with and without liver cirrhosis (P < 0.01). (The dotted line presents the patients with liver cirrhosis, the solid means the group without liver cirrhosis)
Recurrence of BCS in the Hubei area
Among the 130 patients, 30 (23.08%) completed follow-up. The demographic data and clinical features of the follow-up group and the general group (130 patients) are presented in Table 1. There was no significant difference between the demographic data and clinical features of the two groups (P > 0.05). Therefore, the follow-up group was included into this patency analysis. Twelve patients suffered recurrence during follow-up. The cumulative 1-, 5-, and 10-year patency rates were 97%, 69%, and 59%, respectively (Figure 6(b)). Each individual factor’s influence on the patency of the patients with BCS is shown in Table 2. The univariate analysis showed that there was no significant impact of sex, age at onset, abdominal distension, abdominal wall distended veins, splenomegaly, hepatomegaly, leg edema, ascites, smoking, or alcohol consumption for recurrence in patients with BCS; in contrast liver cirrhosis was an independent risk factor of recurrence (P < 0.01, Figure 6(c)).
Comparison of demographic data and clinical features between the two groups (n).
Each single factor’s influence on the patency of Budd–Chiari syndrome patients (months).
Discussion
In this retrospective study, we found that the number of male patients with BCS was larger than the number of female patients with BCS, which indicates that men were more susceptible to BCS in this single-center study. The average age of patients with BCS in this study was 40.3 ± 12.5 years, the majority of patients with BCS featured with long and chronic duration, which is the same as in other region in China (such as Xuzhou, Jiangsu, China), 8 but shorter than in Western countries. 7
A previous study indicated that pure HV blockage appeared to be the main type of BCS in Western countries and IVC or combined blockage were more common in Asia. 7 IVC/HV involvement was the predominant type in China according to some reports from the regions along the Yellow and Huaihe Rivers.8,9 However, in the Hubei area, which is located in the middle and lower reaches of the Yangtze River, sole IVC was the most frequent type of BCS, followed by the IVC/HV type, the proportion of pure of HV seemed to be the smallest, which was different from previous recent reports in China. For example, Cheng et al. 8 and Zhou et al., 9 respectively, reported that 63% and 84.3% of cases had both IVC and HV obstruction, while in the Hubei area only 23.8% of cases had this type of blockage. These findings confirmed that the predominant type of BCS may vary from region to region, even in different areas of the same country. However, whether environmental factors are involved in the occurrence of BCS remains unknown and multicenter studies are needed in the future. In this study, we also found that the characteristics of symptoms and signs of BCS in the Hubei area were different from that of other areas in China. The most frequent symptom of BCS in the Hubei area was leg edema, similar to the Huanghuai region. 8 Different types of BCS had their own clinical signs and symptoms based on their intrinsic mechanism. In the Huanghuai region, edema, leg pigmentation, and leg ulcer were prevalent in the IVC type of BCS, while ascites, distension of the abdomen, and abdominal pain were the most prevalent clinical features in the HV type of BCS. However, according to the analysis of clinical symptoms and signs, the predominant clinical features were leg edema, abdominal wall distended veins, and ascites in patients with the IVC type; in the HV type, splenomegaly, distension of the abdomen, and abdominal pain were more common; while in the HV/IVC type of BCS, the prevalent signs were ascites, leg edema, and hepatomegaly. These findings confirmed that the clinical features of BCS could vary from region to region and the different types of BCS have diverse characteristics.
The laboratory findings showed that the incidence rates of bilirubin metabolism abnormality, ALP, and abnormal γ-GT were more common in BCS in the Wuhan area, which was consistent with the Xuzhou area. 8 Bilirubin metabolism abnormality, higher level of ALP, abnormal γ-GT, and lower level of albumin occurred more frequently in the HV/IVC type than in the other two types of BCS. In patients with BCS who had apparently high TBIL, DBIL, ALP, and abnormal γ-GT, it is necessary to ascertain whether both HV and IVC are blocked. These laboratory findings may be indicative of obstruction in two or more veins, and more attention should be paid.
Multiple imaging methods were employed for BCS diagnosis, such as CDUS, CT, MRI, and DSA. CDUS was the most frequently used method in diagnosing BCS for its low expenditure and high sensitivity. 11 CDUS also provides indexes of real-time hepatic artery and vein changes. All of the patients in this study received CDUS and the positive rate was 77.7%, which was similar to previous reports,11–13 and it was more sensitive to obstruction of HV than IVC according to this study. CT and MRI were used second line of investigation for its better anatomic orientation. 14 Our data showed that CT and MRI had similar accuracy rates to CDUS for BCS diagnosis, but CT and MRI were more accurate in identifying IVC blockage. Combination of CDUS, CT, and MRI could increase the accuracy rate to 100% in this study and were useful for choosing proper intervention therapy. Hepatic venography and inferior venocavography were the gold standards for diagnosing BCS. It could clearly show the location and range of the obstruction as well as the condition of collateral circulation. It is recommended even in the absence of typical findings in other imaging modalities. 15 Therefore, this test is required for all patients who are due to receive interventional treatment. These findings provide the most important evidence for the clinical decision to choose angioplasty, stent, or balloon catheter as interventional therapy for patients with BCS.
The treatment of BCS mainly included medical therapy, radiological interventions, and liver transplantation. Anticoagulation was the fundamental therapy and thrombolysis was usually used in acute thrombosed veins. Liver transplantation was applied to the final stage of BCS in which overall actuarial survival was 76% at 1 year, 71% at 5 years, and 68% at 10 years. 10 With the rapid advances in radiological interventions, TIPS, ES, and PTA are widely chosen as the conventional treatment for their less harmful and more effective outcomes.16,17 In this study, the 107 patients received different interventional treatment according to the location of the hepatic venous outflow. For example, percutaneous recanalization was referred to post-hepatic IVC membranous-type obstruction. Stent and balloon catheter were recommended to patients with stenosis in veins or with segmental IVC obstruction, which is consistent with previous reports. 18 In some cases, these three therapies could be combined according to the condition of the obstruction in patients. TIPS is effective for controlling patients with BCS’ clinical signs and symptoms such as ascites and abdominal distention, and it provides patients an opportunity to wait for liver transplantation. This study was based on the hospital databases and the superiority of each method for BCS is difficult to evaluate. Moreover, the number of patients who received TIPS intervention was limited; therefore, it is challenging to assess its long-term therapeutic effect.
The main limitation of the follow-up is that our study was retrospective. Although we tried our best to contact all patients by telephone or mail, only a few patients could be contacted. It is because most patients with BCS in Hubei area live in rural area with poor transportation and had no mobile phones to easy contact. In our study, the cumulative 1-, 5-, and 10-year patency rates were 97%, 69%, and 59%, respectively, of the patients with BCS in the Hubei area. The patency of these patients seemed to be comparable to other areas of China.19,20 There are various risk factors of recurrence in Chinese patients with BCS. Research has shown that age ≤ 30 years, HV type, combined type, increased LDH levels, and the Child-Pugh class B/C were independent predictors of BCS recurrence. 21 However, our study showed that age at onset was not an independent risk factor of recurrence. More studies are needed with longer follow-up. We found liver cirrhosis was an independent risk factor of recurrence. In theory, the coagulation and anticoagulation system is abnormal in patients with liver cirrhosis, who develop vein thrombosis more easily. Therefore, patients with BCS with liver cirrhosis should shorten follow-up time and pay more attention to coagulation function.
In summary, our study showed that patients with BCS in the Hubei area had different features from those of other districts of China. The causes of this inconsistence need to be elucidated in the future. The role of diet, genetic factors, or environment factors in the pathogenesis of BCS remains unknown. This heterogeneity also confirmed that BCS is complicated and the clinical features are variable, which further complicates the diagnosis. CDUS, as the simplest and most economic diagnostic method, is the first choice for evaluating the location of BCS. Although the outcomes of the interventional treatments were presented in this study, the superiority of different interventional methods remains uncertain. Therefore, it is imperative to conduct a multicenter study in China.
Footnotes
Acknowledgments
We appreciate the patients involved in this study and also thank our colleagues who contribute to the medical care of all the patients.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by National Natural Science Foundation of China (nos 81570530, 81370550, 30500658) and Wuhan Science and Technology Bureau (no. 2014060101010050).