Budd-Chiari syndrome (BCS) is a clinical syndrome of portal and/or IVC hypertension caused by obstruction of the hepatic vein (HV) and/or the inferior vena cava (IVC) above its opening. Depending on the etiology, primary BCS can be classified into primary BCS due to endovascular occlusion of the IVC and/or HV, segmental obstruction and primary thrombosis, and secondary BCS due to extraluminal compression of the vein such as parasites, cysts and tumors; different causes of BCS have different clinical features.
The worldwide incidence of primary BCS is about 1 per million/year [4]. In Asian countries such as China and Japan, primary BCS due to IVC membranous occlusion above the opening of HV (IVC membranous occlusion BCS) is the most common, accounting for about 55% of all BCS patients, while primary BCS due to thrombosis within HV (HV thrombotic BCS) is the least common, accounting for only about 0.9% of all BCS patients.
Because HV thrombotic BCS is so rare, few studies have been reported on its clinical features. To improve the understanding of this type of BCS, we conducted a comprehensive retrospective analysis of the clinical data of 16 consecutive patients with HV thrombotic BCS admitted to our hospital from June 2010 to December 2012 and during the follow-up period, and conducted a comparative study with 132 patients with other types of primary BCS admitted during the same period.
Data and Methods
I. Study subjects
1. HV thrombotic group: Patients with new-onset HV thrombotic BCS admitted to our hospital from June 2010 to December 2012 were selected as the study subjects. Patients in this group were diagnosed with primary BCS by three imaging methods: magnetic resonance imaging, Doppler ultrasound, HV and IVC imaging, and confirmed thrombus formation in HV. Patients with HV thrombosis secondary to IVC and HV obstructive lesions were also excluded according to the imaging results after thrombolytic therapy with tube placement. Patients with hepatic sinusoidal occlusion syndrome (also known as hepatic small vein occlusion syndrome) were excluded in combination with medical history. There were 16 patients in this group, none of whom were lost to follow-up, and all of them were used as final study subjects.
2. Other types group: This group selected patients with new-onset other types of BCS admitted consecutively to our hospital during the same period as the study subjects. The patients in this group were diagnosed with primary BCS by three imaging methods: magnetic resonance imaging, Doppler ultrasound, HV and IVC imaging, and HV thrombotic BCS was excluded. 156 patients were included in this group, 24 patients were excluded, and the remaining 132 patients were used as the final study subjects.
II. Methods and criteria
1. study methods Retrospective analysis of medical history, clinical signs, laboratory and imaging findings, treatment course and follow-up results of all enrolled patients, combined with clinical data using the Rotterdam BCS prognostic index method [7] to assess the prognostic grading of each patient at the time of admission. All patients with BCS admitted to our hospital were routinely followed up once a month during the first 3 months after discharge and once every 3 months thereafter; the follow-up cut-off time for this study was June 2013, with a median follow-up time of 24 months (range: 6 months-36 months). Statistical analysis of the inter-group variability of the indicators between the two groups of patients.
2. Diagnostic criteria 1) BCS staging: patients with BCS-related symptoms lasting less than or equal to 6 months were considered to have acute BCS and more than 6 months were considered to have chronic BCS [4]. 2) Abdominal water volume: abdominal ultrasonography suggested that a more limited liquid dark area was seen under the diaphragm, liver, kidney, spleen, kidney or cysto-rectal space as a small amount of ascites; diffusely distributed anechoic areas in the abdominal cavity were seen in the middle and lower abdomen and lateral abdomen, between the intestinal tubes and around the parenchyma The flow with the change of position was moderate amount of ascites; the whole abdomen was detected in the anechoic area, and the intestinal tube was floating or fixed in which was large amount of ascites.
For patients in both groups, interventional opening treatment was performed first; if interventional opening treatment failed and the patient’s condition was severe, transjugular intrahepatic portosystemic shunt (THS) was used.
For patients with severe disease and failed interventional opening treatment, transjugular intrahepatic portosystemic shunt (TIPS) TIPS treatment was used to relieve the symptoms of portal hypertension. None of the cases were treated with surgical shunts or liver transplantation. Specific interventions were as follows: 1) Thrombolytic therapy [7]: a 5F thrombolytic catheter was first placed in HV via the jugular vein route for local thrombolytic therapy. Urokinase (100,000 U/dose, 4-6 times daily) was injected through the catheter for thrombolytic therapy; and low-molecular heparin sodium (5000 U/dose, twice daily) was injected subcutaneously for anticoagulation therapy. The catheter position was adjusted according to the dissolution of the thrombus, so that the lateral orifice segment of the catheter was located within the thrombus. When the thrombus is completely dissolved and there is no change in the thrombus on the second consecutive review, the HV is opened by interventional opening treatment, which includes balloon dilation and stent placement.
portosystemic shunt (TIPS) treatment: HV, IVC, and indirect portal venography are performed first, and if the primary HV cannot be visualized, the hepatic HV can be visualized by sub-HV or ultrasound-guided percutaneous hepatic HV. The puncture point for HV or IVC and the entry point for portal vein puncture will be selected according to the imaging results. 3)
Postoperative anticoagulation therapy: All patients were given oral warfarin (initial dose 5 mg) for 12 months after the intervention, and the coagulation function was reviewed regularly and the dosage of warfarin was adjusted according to the results. The prothrombin time was maintained at 20sec-25sec (normal value: 11.0
sec-15 sec), and the international normalized ratio of prothrombin was maintained at 2.0-3.0 (normal value: 0.8-1.5).
III. Statistical treatment
Qualitative data were expressed as percentages, and quantitative data were expressed as mean ± standard deviation (± s). For comparison between two groups of quantitative data, the Kolmogorov-Smimov method was first used to test the normality of quantitative data, and the independent sample t test was used if the data conformed to a normal distribution, and the Wilcoxon W rank sum test was used if the data did not conform to a normal distribution; for comparison between groups of hierarchical data, the Mann-Whitney U test; comparison of two sample rates by χ2 test or Fisher’s exact probability method; P<0.05 was considered statistically significant difference.
The Kaplan-Meier method was used to calculate the between-group variability of patient treatment survival. All statistical analyses were performed using PASW Statistics 18.0 statistical software.
Results
I. General information
There were 9 males and 7 females in the HV thrombotic group, aged (24.3±4.7) years, all with BCS-related symptoms lasting less than 3 months at diagnosis, all with acute BCS. 16 patients (16/16,100%) in the HV thrombotic BCS group had abdominal distension, including 3 patients with lower limb swelling. Patients with HV thrombotic BCS at admission Rotterdam
The prognostic rating of BCS: 9 patients (9/16,56.3%) were grade II and 7 patients (7/16,43.8%) were grade III. The length of hospital stay for the first intervention in the HV thrombosis group was (31.2±9.9) days. the age and duration of BCS-related symptoms in patients with HV thrombosis BCS were less than those in patients with other types of BCS, and the proportion of patients with abdominal distension, the length of hospital stay for intervention, and The proportion of patients with abdominal distension, length of interventional hospitalization, and prognostic rating of Rotterdam BCS were higher than those of patients with other types of BCS, and the differences between the above indicators were statistically significant (P<0.05), as detailed above in Table 1.
II. Laboratory test results
The serum alanine transaminase (ALT) was (386.3±165.3) U/L, the serum aspartate aminotransferase (AST) was (396.3±167.5) U/L, and the serum total bilirubin (TBIL) was (396.3±167.5) U/L. bilirubin (TBIL) was (75.3±25.5) umol/L and carbohydrate antigen-125 (CA-125) was (893.1±354.9) kmol/L. The serum albumin (ALB) was (30.0±4.2) g/L. .
The serum ALT, AST, and CA-125 were higher in HV thrombotic BCS patients than in other types of groups, and the differences between groups were statistically significant (P<0.05), and the above results are detailed in Table 2.
III. Imaging characteristics
All patients with HV thrombosis (16/16, 100%) were found to have HV thrombosis, and all patients had a compressive stenosis of the IVC lumen. HV thrombosis was shown to be hypoechoic with no flow signal on Doppler ultrasound, and high or mixed signal on T2WI images on MRI. In all patients (16/16, 100%), the peripheral zone of the liver (HV drainage area with thrombosis) was hyposignal on T1WI images, and the caudate lobe was relatively normal with higher signal.
On T2WI, the peripheral zone of the liver (T1WI low signal area) was slightly high signal, and the caudate lobe was normal and uniform with relatively low signal.
The incidence of ascites was higher in the HV thrombosis group than in the other types of groups; the mean maximum diameter of the spleen was smaller than in the other types of groups; the proportion of intra- and extra-hepatic traffic branches formed was lower than in the other types of groups, and the differences between the groups were statistically significant. The differences between the groups were statistically significant, as shown in Table 3.
IV. Treatment and prognosis
All 16 patients (16/16, 100%) with HV thrombotic BCS were treated with interventional recanalization by balloon dilatation plus HV placement thrombolysis, and the time of HV placement thrombolysis was (14.2±8.5) days. Transjugular intrahepatic
Portosystemic shunt (TIPS) was performed for shunt treatment. Three patients with HV thrombotic BCS died due to ineffective treatment, 12 days, 50 days and 64 days after the intervention, and the cause of death was liver failure. The technical success rate was 81.3%; 10 of these 13 patients reappeared with BCS-related symptoms during the follow-up period, of which 8 patients were successfully treated with interventional recanalization and 2 failed (1 of them was treated conservatively with oral diuretics and 1 died of upper gastrointestinal hemorrhage).
At the end of follow-up, the recurrence rate was higher in the HV thrombotic group than in the other types (86.0% vs. 9.0%, χ2=36.1, P<0.001), while the survival rate was lower than in the other types (72.7% vs. 98.2%, χ2=22.8, P<0.001), as shown in Figures 11-12.
Table 1 General information of patients with Bu-ga syndrome in both groups (cases)
Group
Number of cases
Gender
Abdominal swelling
Swelling of lower limbs
Varicose veins on body surface
Lower extremity hyperpigmentation
Staging
Male Female
Acute Chronic
Hepatic vein thrombosis group
16
9
7
16
3
2
1
16
0
Other type groups
132
69
63
35
73
64
61
8
124
χ2 value
P-value
0.91
0.763
34.12
0.000
7.63
0.006
7.47
0.006
9.22
0.002
-0.000
0.000
Group
Number of cases
Age (years)
Rotterdam BCS prognosis classification
Duration of symptoms (months)
Number of days in hospital
(days)
I
Ⅱ Ⅲ
Hepatic vein thrombosis type group
16
24.3±4.7
0
9
7
1.8±0.7
31.2±9.9
Other types of groups
132
44.6±13.5
65
51
16
84.7±87.4
11.0±5.1
Z-value
P-value
5.16
0.000
4.58
0.000
6.37
0.000
6.18
0.000
Note: -: no value
Table 2 General information of patients with Bu-ga syndrome in both groups (cases)
Group
Number of cases
Glutathione aminotransferase(U/L)
Glutathione aminotransferase(U/L)
Total bilirubin(umol/L)
Direct bilirubin(umol/L)
Albumin(g/L)
Hepatic vein thrombosis group
16
386.3±165.3
396.3±167.5
75.3±25.5
39.8±17.9
30.0±4.2
Other types of groups
132
30.7±25.0
41.6±33.7
48.1±78.9
20.5±41.5
36.7±7.6
Z-value
P-value
6.51
0.000
6.51
0.000
4.68
.000
4.88
0.000
3.72
0.000
Group
Number of cases
White blood cell count (×109/L)
Platelet count
(×1012/L)
Hemoglobin (g/L)
Alpha fetoprotein
(ug/L)
Glycoprotein antigen-125 (kmol/L)
Hepatic vein thrombosis group
16
5.85±1.3
147.1±37.9
128.4±23.8
3.0±2.5
893.1±354.9
Other types of groups
132
4.6±3.3
133.9±94.8
117.4±25.5
21.0±81.1
294.2±25.6
Z/ t-value
P-value
3.24
.001
2.35
.019
1.65*
0.101
3.42
.001
6.06
0.000
Note: * is t-value, the rest are Z-values
Table 3 Comparison of MRI features between two groups of patients with Bu-ga syndrome (cases)
Group
Number of cases
Intravascular T2WI high signal
ascites
Enlarged liver volume
caudate lobe enlargement
Intrahepatic nodules
Large amount Moderate Small amount
Hepatic vein thrombosis group
16
16
13
3
0
16
3
0
Other type groups
132
11
12
11
44
22
103
19
Z-value
P-value
P-value
0.000
6.08*.000
Z-value
0.000
-
0.001
0.000 – 0.001
0..226
Group
Number of cases
Spleen diameter (cm)
Lesion location
Intrahepatic communicating branch formation
Extrahepatic traffic branch formation
Parahepatic vein
A B
C
Hepatic vein thrombosis group
16
11.9±2.2
16
0
0
3
3
2
Other type groups
132
15.3±2.9
25
8
99
117
112
95
χ2/Z value
P-value
4.28*
0.000
46.54&
0.000
-0.000
0.000
-0.000
0.000
22.35&
0.000
Note: A: hepatic vein involvement alone, B: inferior vena cava involvement alone, C: combined involvement, *: is the Z value, &: is the χ2 value, -: no value
Figures 1 to 4
MR images of a 23-year-old female patient with acute Bu-ga syndrome Figure 1 shows the T1WI images, the
T2WI images, Figure 3 shows the dynamic enhanced venous phase axial images, and Figure 4 shows the dynamic enhanced venous phase coronal images, all images show the ischemic edema area in the peripheral zone of the liver, the white arrow marks the hepatic vein thrombosis, and the black arrow marks the compressed narrowed inferior vena cava.
Thrombolytic therapy in a 22-year-old female with hepatic vein thrombosis with Bu-plus syndrome Figure 5-6 On June 27, the image showed extensive thrombosis in the main hepatic vein, and the branch hepatic vein was not visualized, and a thrombolytic catheter was placed in the right hepatic vein for thrombolytic therapy. On July 15, a large amount of thrombus was still present in the right hepatic vein, and the branch hepatic veins were not visualized.
On July 25, the right hepatic vein still had a large amount of thrombus, and a small number of branch hepatic veins started to be visualized, so the catheter was retained for thrombolytic treatment. Figure 10 On August 29, the right hepatic vein and its surrounding branch vessels were clearly visualized and the blood flow was clear, so the thrombolytic catheter was withdrawn and the treatment was finished.
Comparison of survival and recurrence rates during the follow-up period between the two groups of patients with Buga synthesis : hepatic vein thrombosis group, : other types group, : hepatic vein thrombosis group censored values, : other types group censored values.
Discussion
HV and/or IVC membranous occlusion, segmental obstruction and primary thrombosis are the three main forms of lesions leading to primary BCS. HV thrombotic BCS is BCS caused by primary intravascular thrombosis and is mainly associated with hypercoagulability in vivo due to abnormalities in coagulation mechanisms such as myelodysplastic syndrome, coagulation factor V mutation, antiphospholipid antibody syndrome, and true deficiency of protein C and protein S. The cause of intimal occlusion is unknown, but there is no significant correlation with the hypercoagulable state of blood in the body;
Intravascular segmental obstruction may be the result of mechanization of old intravascular thrombus, but it is difficult to determine whether it originates from a primary intravascular thrombus or from a secondary thrombus formed after a membranous occlusion. We compared the least common HV thrombotic BCS with other types of BCS to investigate the unique clinical features of HV thrombotic BCS compared with other types of BCS by comparing and analyzing various clinical data of patients with different types of BCS.
The results of this study showed that all patients with HV thrombotic BCS were acute, and the age of onset and duration of symptoms were significantly lower than those of patients with other types of BCS, and the proportion of patients with symptoms related to portal hypertension such as abdominal distension, ascites and hepatomegaly was significantly higher than that of patients with other types of BCS. the differences in clinical manifestations of patients with different types of BCS were due to the differences in the characteristics of BCS lesions.
HV thrombotic BCS is an acute BCS caused by extensive thrombosis in the small hepatic vein to the main HV. Due to the short duration of the disease, no compensatory collateral circulation has yet formed around the involved vessels, resulting in heavy damage to their liver, and the clinical manifestations are dominated by symptoms related to portal hypertension.
In contrast, in other types of BCS, the disease is mostly chronic, and a large number of collateral circulation has been formed around the occluded vessels, so HV blood can be compensated through these collateral vessels, so the symptoms related to portal hypertension are relatively mild, and patients mostly visit the clinic for symptoms related to IVC hypertension, such as varicose veins on the body surface, swelling of lower limbs and persistent ulcers caused by long-term IVC chronic obstruction.
The serum levels of AST, ALT and CA-125 are higher in HV thrombotic BCS patients than in patients with other types of BCS, while the level of ALB is relatively low, mainly because of the heavy liver damage in HV thrombotic BCS patients and the increased release of AST and ALT into the blood after hepatocellular damage, as well as their reduced ability to synthesize ALB. CA-125 [12-13] has long been used as a one of the surveillance indicators for pelvic tract tumors such as ovarian cancer, but recent studies have shown that CA-125 also has an extremely high correlation with liver damage and ascites formation.
The higher serum levels of CA-125 in patients with HV thrombotic BCS also further suggest that patients with HV thrombotic BCS have relatively more liver damage.
Murad
SD et al [7] found that the survival rate of BCS patients was highly correlated with four independent factors, including hepatic encephalopathy, ascites, prothrombin time and TBIL, and established Rotterdam BCS prognostic ratings based on these four independent factors, with higher grades predicting a worse prognosis for the patients. The results of this study showed that the prognostic rating of Rotterdam BCS in patients with HV thrombotic BCS was significantly higher than that of other types of BCS; the follow-up results also showed that the survival rate and asymptomatic survival rate of patients with HV thrombotic BCS were lower, and the recurrence rate after interventional treatment was higher.
Patients with HV thrombotic BCS had lower success rates and longer hospital stays, lower postoperative symptom relief rates, lower survival rates and lower asymptomatic survival rates than patients with other types of BCS, and relatively higher recurrence rates during follow-up. In this study, all BCS patients in both groups were treated by the same doctors in our hospital, so the interference of medical technology level on the study results was excluded, so the study results were more reliable. This shows that HV thrombotic BCS is more difficult to treat and has a worse prognosis compared with other types of BCS.
The proportion of HV thrombotic BCS patients in Western countries is relatively high, and the overall survival rate of BCS is significantly lower than that of BCS patients in Asian countries, mainly using TIPS for shunt treatment or liver transplantation. Most Chinese BCS patients have IVC membranous occlusive BCS, and most of them are currently treated with interventional recanalization by angioplasty (including balloon dilation, stent placement and thrombolysis), and most of them have a good clinical prognosis. This shows that the choice of treatment for BCS patients with different lesion characteristics is different, and their clinical prognosis also varies greatly.
HV thrombotic BCS is an acute BCS caused by HV thrombosis, which has a short duration of BCS-related symptoms at the time of consultation, a young age of onset, heavy liver damage, and severe portal hypertension-related symptoms, making interventional treatment more difficult and with a poor prognosis. Therefore, sufficient attention should be paid to this type of BCS, and research on it should be strengthened in order to improve the diagnosis and treatment of BCS.