Budd–Chiari syndrome versus Pyrrolizidine alkaloids-induced hepatic sinusoidal obstructive syndrome: A multi-center study

doi:10.21203/rs.3.rs-1730035/v1

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Budd–Chiari syndrome versus Pyrrolizidine alkaloids-induced hepatic sinusoidal obstructive syndrome: A multi-center study

https://doi.org/10.21203/rs.3.rs-1730035/v1

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Background

Budd-Chiari syndrome (BCS), especially BCS-hepatic vein occlusion type (BCS-HV), and Pyrrolizidine alkaloids-induced hepatic sinusoidal obstructive syndrome (PA-HSOS) share many clinical characteristics. In this study, we comprehensively compare the two diseases to identify key characteristics.

Methods

139 patients with BCS-HV and 257 PA-HSOS patients admitted to six hospitals between January 2014 and October 2021 were retrospectively analyzed. The two groups were then comprehensively compared and analyzed clinically.

Results

Among the 139 BCS-HV and 257 PA-HSOS patients, the mean age and the median time from symptom onset to the first visit have a statistical difference. 257 PA-HSOS patients all had a history of taking PA-containing plants, while no patients in the BCS-HV group were exposed to PA-containing plants (p < 0.05). BCS-HV and PA-HSOS were found in abdominal distension, abdominal pain, ascites, abdominal wall varicose veins and jaundice were significantly different (p < 0.05). The prevalence of local stenosis or occlusion of the hepatic vein in BCS-HV group was higher than that in the PA-HSOS group (P < 0.05). On the three characteristics of hepatic vein traffic branches, enlarged caudate lobe of the liver and early liver enhancement nodules, the prevalence in BCS-HV was 73.90%, 47.70%, and 8.50%, while those of the PA-HSOS group were zero (P < 0.05).

Conclusion

The history of PA intake, local stenosis or occlusion of the hepatic vein, a communicating branch of the hepatic vein, and caudate lobe hypertrophy are the key factors to distinguish the two diseases.

Budd-Chiari syndrome

Hepatic sinusoidal obstructive syndrome

Anticoagulation

Transjugular intrahepatic portosystemic shunt

Although liver vascular diseases affect less than 5 in 10,000 patients, they collectively cause many rare but important conditions in the field of liver disease¹. Budd-Chiari syndrome (BCS), especially BCS-hepatic vein obstruction type (BCS-HV), and hepatic sinus obstruction syndrome induced by pyrrolizidine alkaloids (PA-HSOS) are uncommon and difficult to distinguish^{2, 3}due to similar clinical and imaging characteristics, such as abdominal distension, hepatomegaly, ascites, mild to moderate abnormal liver function, and uneven enhancement of the liver on enhanced CT andMRI⁴. However, according to the current classification of vascular liver disease, BCS-HV and HSOS are considered to be different diseases due to differing etiologies, pathologies, and their natural clinical course ^{1, 5}. To date, few studies have directly compared these diseases, and unfortunately, misdiagnosis is common. In this study, we aimed to comprehensively compare the etiologies,, clinical manifestations, and imaging features of BCS-HV and PA-HSOS to identify the key differential characteristics of the two diseases. The clinical outcomes of anticoagulation-interventional therapy in two diseases were also reviewed.

2.1 Patients

A total of 150 BCS-HV patients and 306 PA-HSOS patients from multiple centers were retrospectively enrolled in our study between January 2014 and November 2021. The participating hospitals included theAffiliated Drum Tower Hospital of Nanjing University Medical School; theShandong Provincial Hospital Affiliated to Shandong First Medical University; theFirst Affiliated Hospital of Zhengzhou University,Nanfang Hospital, Southern Medical University; The First Affiliated Hospital of Wenzhou Medical University; and the Beijing Friendship Hospital Affiliated to Capital Medical University. We included patients aged 12–80 years with a diagnosis of BCS-HV or PA-HSOS according to the disease diagnostic criteria⁶. The exclusion criteria included: malignancy,severe cardiopulmonary disease,previous history of cirrhosis or liver diseases with other causes, ora large amount of missingclinicaldata.

2.2Anticoagulation therapy

Anticoagulation therapy in patients with BCS-HV or PA-HSOS included low molecular weight heparin (LMWH) or warfarin alone, LMWHcombined withwarfarintherapy, or LMWH sequential warfarin treatment⁷.The criteria for non-response to anticoagulant therapy are based on guidelines⁸.

2.3 TIPS therapy

All TIPS procedures were performed by experienced interventional radiologists or hepatologists trained in interventional technology.The TIPS procedure was the same as that used in the treatment of patients with liver cirrhosis and portal hypertension complications. We note that some patients with BCS-HV underwent portal vein branch puncture from the inferior vena cava due to complete occlusion of the hepatic vein; a 6–8mm diameter stent-graft (Viatorr, Gore; or Fluency combined with Luminexx, Bard) was used in all cases^{9, 10}.

2.4 Statistics

GraphPad Prism 5.0 was used for statistical analysis (GraphPad Software, San Diego, CA, USA). Qualitative variables were expressed as numbers, percentages, or frequencies, whereas continuous variables were expressed as mean ± standard deviation.Fisher's exact test and χ2 test were used to compare the differences between the two groups. Survival data were analyzed using Kaplan-Meier estimates and the log-rank test. A Pvalue of < 0.05 was regarded as statistically significant. SPSS 26.0 software (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.

2.5 Ethical approval

This study was approved by the ethics committees of the Nanjing Drum Tower Hospital and conformed to the principles of the World Medical Association Declaration of Helsinki, as revised in 2013.

3.1 Clinical presentation

139 BCS-HV and 257 PA-HSOS patients (Figure 1) met all study criteria and were included in our analyses.The demographic and clinical characteristics of the cohort are summarized in Table 1. The mean BCS-HV patient age was 43.00 ± 13.08 years and 62.75 ± 9.68for PA-HSOS (p < 0.05).Patients with PA-HSOS had a shorter duration of illness (median of 1 month with96.90% ≤ 6 months) than those with HCS-HV (p < 0.05). Mild ascites was defined as ascites detectable only by abdominal ultrasound or with a maximum ultrasound depth of less than 3 cm, whereas moderate-to-severe ascites was defined otherwise¹¹.Jaundice was defined as yellowing of the sclera or yellowing of the skin or TB≥34.2umol/L¹².Except for lower limb edema, there was a significant difference in the incidence of clinical symptoms between the two groups, including abdominal distension, abdominal pain, ascites, abdominal wall varices, and jaundice.

3.2 Risk factors

Hepatic sinusoidal obstruction syndrome wasinduced by plants containing pyrrolizidine alkaloids in all cases. A total of 43 BCS-HV patients had well-defined risk factors.If the length of hepatic vein obstruction was≤1 cm, we defined it as membranous obstructive BCS (MOBCS-HV).Otherwise, it was defined as segmental obstructive BCS (SOBCS-HV)¹³. A total of 10 patients with MOBCS-HV and 65 patients with SOBCS-HV were screened for at least one risk factor.Among them, 1 of the 6 MOBCS-HV patients (16.67%) and 11 of the 38 SOBCS-HV(28.95%) patients screened for protein C deficiency was positive;1 of the 6 MOBCS-HV patients (16.67%) and 8 of the 38 SOBCS-HV(21.05%) patients screened for protein Sdeficiency was positive;1 of the 6 MOBCS-HV patients (16.67%) and 13 of the 38 SOBCS-HV (34.21%) patients screened for antithrombin III deficiency was positive; 1 of the 2 MOBCS-HV patients (50.00%) and 1 of the 5 SOBCS-HV (20.00%) patients screened for paroxysmal nocturnal hemoglobinuria (PNH) was positive; 2 of the 8 MOBCS-HV patients (25.00%) and 11 of the 56 SOBCS-HV (9.64%) patients screened for hyperhomocysteinemiawas positive; 1 of the 7 MOBCS-HV patients (14.29%) and 6 of the 18 SOBCS-HV (33.33%) patients screened for connective tissue disease positive. For SOBCS-HV patients, other risk factors were also screened. Among them,1(14.29%)of the 7 patients screened for thalassemia was positive;1 (20.00%) of the 5 patients screened for primary thrombocythemia was positive; 1 (20.00%) of the 5 patients screened for true erythrocytosis was positive; 1(20.00%) of the 5 patients screened for a JAK2 V617F gene mutation was positive; 2(28.57%) of the 7 patients screened for antiphospholipid antibody syndrome werepositive;1 (0.93%) of the 107 patients screened for inflammatory bowel disease werepositive; and 1 (2.22%) of the 45patients screened for recent oral contraceptive use was positive. Moreover, 2 patientswith MOBCS-HV and 14 patients with SOBCS-HV had two risk factors, and 3 patients with SOBCS-HV had three risk factors. Table 2 shows the risk factors and their proportions in patients with different types of BCS-HV.

3.2 Laboratory tests

The results of laboratorytests are providedin Table 3. In this study, it was observed that patients with BCS-HV hadsignificantlylower white blood count (WBC) andhemoglobin (Hb)than patients with PA-HSOS (p< 0.05).The median levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) and total bilirubin in the BCS-HV patients were within the normal ranges and significantly lower than those in the PA-HSOS group. Although there was some impairment in the hepatic synthetic capacities in both groups, that seen in BCS-HV was less severe, with higher albumin levels (36.45 ± 5.64) compared to PA-HSOS patients (32.70± 3.52) (p < 0.05). Coagulation function was also poorer in PA-HSOS patients with significantly prolongedprothrombin time(PT) and activated partial thromboplastin time (APTT) (p< 0.05). Child-Pugh scores were significantly lower in BCS-HV than in PA-HSOS patients. Finally, serum creatinine was significantly higher inPA-HSOS than in the BCS-HV group (p < 0.05).

3.3 Imaging findings

Table 4 illustrates the radiological signs found withDoppler ultrasound, computed tomography(CT), magnetic resonance imaging (MRI), and digital subtraction angiography (DSA) in the cohort. Hepatomegaly with heterogeneous density can be seen on all imaging examinations in the two diseases. However, we found major differences in the imaging presentation between the two groups ofpatients.

Portal vein thrombosis was confirmed in 6 BCS-HV (4.4%, 6/136) patients, four of whom had concomitant cirrhosis; this was significantly higher in PA-HSOSwith 30 cases (11.7%, 30/257) (p=0.018), of which one(3.33%) was complicated byhepatic venous thrombosis. The proportion of patients with cirrhosis in the BCS-HV group was 47.10% (65/138) and2.00% (5/256)in PA-HSOS (p=0.000).

The main imaging features of BCS-HV includedhepatic venous traffic branches (73.90%), esophageal varicose veins (64.00%), splenomegaly (63.80%), hepatomegaly (56.20%), stenosis of the hepatic segmental inferior vena cava (55.20%), and caudate lobe enlargement (47.70%). The main imaging features of PA-HSOS were hepatomegaly (67.10%)and stenosis of the hepatic segmental inferior vena cava (44.20%). It is notable that, unlike BCS-HV, PA-HSOS patients rarely showedhepatic venous traffic communications, caudate lobe enlargement, esophageal varicose veins, and splenomegaly. The diameters of the hepatic veins, the portal vein, and the splenic vein were significantly larger in the BCS-HV group than those in the PA-HSOS group. Peak flow velocities in the portal and splenic veins were significantly slower in the PA-HSOS group than those in BCS-HV patients. Figure 2 shows theultrasound and CT findings typical of the two diseases.

3.4 Treatments and Prognosis

3.4.1 Treatments and outcomes

Anticoagulation and interventional therapy are the mainstays of treatment for BCS-HV and PA-HSOS¹. The results of anticoagulant and TIPStreatmentare shown in Figure 3. Patients with BCS-HV and 248 patients with PA-HSOS received admission anticoagulation. For BCS-HV patients, the effective rate of anticoagulation was 42.11% (8/19), with failure in 11 patients; 2 died of liver failure or multiple organ dysfunction syndrome (MODS), 2 transitioned to PTA treatment, and 4 transitioned to TIPS. For PA-HSOS patients, the effective rate of anticoagulation was 48.39% (120/248). There was no difference intheanticoagulation response rate between the two groups (p=0.279). Of the remaining non-responders of the 128 PA-HSOS patients, 118 were transformed to TIPS treatment. The remaining 10 patients who refused or could not be converted to TIPS treatment continued with medication. Among them, 7 patients died of liver failure or MODS, 1 died of septic shock, and 2 died of esophagogastric variceal bleeding (EGVB). (Figure 3.A.)

Patients with either disease can be treated with TIPS. In our cohort, 25 BCS-HV patients received TIPS; among these, 4 were converted from ineffective anticoagulation, and 21 received TIPS directly. 127 PA-HSOS patients received TIPS; 118 were converted from ineffective anticoagulation and 9 received TIPS directly. One case was excluded due totechnical failure during surgery. Survival rate after surgery was 88.00% (22/25) for BCS-HV patients with3 deaths due to liver failure or MODSand86.51% (109/126) for PA-HSOS patientswith8 deaths due toliver failure or MODS, 3 from septic shock, 3 from EGVB, 2 from hepatic encephalopathy (HE), and 1 frombiliary hemorrhage (Figure 3. B). The TIPS survival rate was slightly higher in BCS-HV than in PA-HSOS (p=0.040). It is important to note that we have quantified disease-related death, including liver failure, multiple organ failure, septic shock, EGVB, hepatic encephalopathy, and iatrogenic biliary hemorrhage^{10, 13}. Other causes of death (accidental, related to malignancy, cardiovascular, and cerebrovascular diseases) were excluded.

3.4.2 Prognosis of survival

Overall survival and disease-related survival were analyzed for both groups (Figure 5). The median follow-up time was comparable:35.27 months inBCS-HV and 36.07 months inPA-HSOS (p=0.200). There was no significant differencein overall survivalbetween the two groups (p=0.079)(Figure 4.A.). It should be mentioned that the cumulative 6-month survival rates, 1-year cumulative survival rates, and 5-year cumulative survival rates for the BCS-HV and PA-HSOS groups were 98.60% vs 88.30%, 96.20% vs 88.30%, and 85.00% vs 77.10%, respectively. There was also no statistically significant difference in disease-related survival for either BCS-HV or PA-HSOS (p=0.090), with median follow-up times of 34.90 and 37.67 months, respectively (p=0.431)(Figure 4.B.).

BCS is characterized by the obstruction of hepatic venous outflow anywhere from the small hepatic veins to the junction of the inferior vena cava (IVC) and the right atrium^{1, 3}. According to the location of the obstruction, BCS is classified as an inferior vena cava obstruction(BCS-IVC), hepatic venous obstruction(BCS-HV), or mixed obstruction¹⁴. The differential diagnosis of BCS-IVC or mixed type with HSOS is not difficult because the former involves the inferior vena cava, leading to disturbed IVC blood flow and the establishment of collateral circulation, especially the expansion of the azygos and hemiazygos veins¹⁵. The diagnosis of HSOS related to hematopoietic stem cell transplantation (HSCT-HSOS)¹⁶is also relatively straight forward because it occurs only in high-risk patients with myeloablative treatment before hematopoietic stem cell transplantation. Therefore, these were excluded from our study.

PA-HSOS is likely to be missed or misdiagnosed due to its sporadic nature and because exposure to PA is often not easily detected or dismissed. In 2019, an expert consensus on the diagnosis and treatment of PA-HSOS was published, proposing the "Nanjing Criteria" for the diagnosis of PA-HSOS⁶. In 2021, we further demonstrated that the "Nanjing Criteria" displaysatisfactory sensitivity and specificity for diagnosing PA-HSOS. It was in this validation study that we reported that PA-HSOS andBCS, especially BCS-HV, were most likely to be confused among patients whose history of PA exposure could not be established ². Both PA-HSOS and BCS-HV are rare vascular diseases of the liver with overlapping clinical features and are thus difficult to distinguish. As such, there is a critical need to identify criteria that will help to differentiate the two diseases.

To our knowledge, we present the largest cohort study with an extensive and in-depth comparison of BCS-HV and PA-HSOS. Although one earlier study compared these conditions, it was primarily focused on HSOS induced by HSCT, with little description of HSOS caused by PA and generalized to all types of BCS to identify the two diseases^{3, 17}.While comparing PA-HSOS and BCS, the other two trials did not undertake specific typing for BCS and lacked a prognostic evaluation of the various treatment options targeted at the cause^{17, 18}.

Our study shows that the age of onset ofBCS-HV is younger than of PA-HSOS. In China, older people are more likely to receive plant-based drugs than young adults for health care or the management of chronic pain disease. On the other hand, it is recognized that BCS-HV is often complicated by thrombophilia, the main cause of which are underlying hereditary and acquired hematological disorders ^{19, 20}. Given the younger age of onset in patients with hematologic diseases, this may partly explain why BCS-HV patients are generally younger on average. This is consistent with our findings that half the patients in the BCS-HV group with MOBCS-HV and 58.46% of patients with SOBCS-HV had risk factors for thrombophilia. These estimates may be inexact as many patients in our cohort were not screened for risk factors for thrombophilia.

In addition, patients in the PA-HSOS group had a more rapid onset with a median time from symptom onset to presentation of one month; this was significantly shorter than in the BCS-HV group. This time frame parallels that which is seen in drug-induced liver disease^{21, 22}. Conversely, most splanchnic vein thromboses progress relatively slowly, resulting in insidious symptoms, and a difficult and prolonged diagnosis. A small number of patients in both groups developed abdominal wall varices and lower extremity edema, which were mainly associated with compression of the inferior vena cava by an enlarged liver.

Although BCS-HV and PA-HSOS present with abdominal pain, abdominal distention, ascites, jaundice, and lower limb edema, as reported in previous studies¹³, these symptoms were usually more severe or pronounced in patients with PA-HSOS in this study. Similarly, in patients with PA-HSOS, laboratory tests such as liver, renal, and coagulation function were also worse than in BCS-HV patients. BCS patients may have a lower white blood cell count, serum hemoglobin concentration, and platelet count due to compensation that occurs with chronic disease²³. We were unable to establish why platelet counts were lower in PA-HSOS than in BCS-HVpatients. The increased hemoglobin in PA-HSOS patients could stem from haemoconcentration due to frequent large-volume paracentesis or the administration ofdiuretic drugs^{24, 25}.

Both BCS-HV and PA-HSOS can manifest ascites, hepatomegaly, heterogeneous density, and plaque-like or map-like enhancements on CT or MRI imaging. Although there was a significant difference between the two groups in these characteristics, we cannot recommend them as specific distinguishing features without extensive validation work. We also found a significant difference between the two groups in the prevalence of venous thrombosis. Patients with BCS-HV showed a high incidence of mainly hepatic venous thrombosis, which is consistent with the BCS risk factors identified in our study. Conversely, the percentage of portal vein thrombosis in PA-HSOS patients was higher than in BCS-HV. This may be related to the significantly slower portal blood flow velocity in patients with PA-HSOS compared to that in BCS-HV; some studies have found that slower portal vein blood flow is more conducive to the formation of portal vein thrombosis²⁶. Notably, only BCS-HVpatients had signs of hepatic venous traffic(73.9% vs 0), caudate lobar enlargement of the liver (47.7% vs 0), and early enhancement nodules (8.5% vs 0). Therefore, we believe that these three indicators play an important role in differentiating the two diseases. We also found that the prevalence of gastroesophageal varices was significantly higher in BCS-HVpatients than in PA-HSOS (64% vs 21.2%). This may be related to the more prolonged disease course of BCS-HV compared to PA-HSOS, the former being more likely to develop cirrhosis and produce compensatory varicose veins.

Relevant guidelines and recommendations have been establishedfor the treatment of BCS-HV and PA-HSOS. Barring contraindications, patients should receive anticoagulation therapy¹. Failing this,patientsshould be converted to interventional therapy, PTA, or TIPS. Studies have demonstrated that TIPS therapy is effective in patients with BCS and PA-HSOS^{10, 27}. Both groups of patients in our cohort benefitted from anticoagulation therapy. The response rate to anticoagulation therapy was 48.39% for PA-HSOS patients and 42.11% for BCS-HV patients. In addition, TIPS treatment showed efficacy inboth diseases, with TIPS response rates of 86.51% inPA-HSOS patients and 88.00% inBCS-HV patients, which is consistent withpreviously published studies^{7, 17}. The 1- and 5-year survival rates inBCS-HV were 96.20% and 85.00% respectively and that in PA-HSOSpatientswere 88.30% and 77.10%, respectively, highlighting that anticoagulation-TIPS treatment can result in greater benefit.

The main advantages of the present study are that it is a multi-center, large sample-size study and that we have comprehensively and systematically compared two rare liver vascular diseases using real-world clinical data. Limitations include its retrospective nature which can attract selection bias and while improving generalizability we identified heterogeneity in etiological screening and treatment stemming from the enrolment of multiple medical centers. Furthermore, as patients with PA-HSOS or BCS-HV are always associated with massive ascites and hepatomegaly , which leading the high risk of a routine liver biopsy, therefore, the liver biopsy is rarely done in the actual work, we did not compare the similarities and differences in the pathological findings between the two patient groups. .

We identified differences between twoimportant hepaticdiseases in terms of clinical presentation, laboratory examination, and imaging characteristics; most critically this includedahistory of PA exposure, existence of hepatic venous thrombosis, inter-hepatic venous traffic branch, and hepatic caudate lobe enlargement which were of important differential diagnostic value. Although the BCS-HV patients in this study appeared to havesome advantages in long-term survival based on the anticoagulation-TIPS strategy, there wasno statistically significant difference.

Conflict of interest

The authors have no conflicts of interest related to this publication.

Author contributions

Conception and design of the study (YZZG, GCW, XPD); generation, collection, and assembly of data (YRT, MZ, ZXQ, WW, JJC, FLH, XFZ, FZ, BZ, WZ, QY); analysis and/or interpretation of data (YRT, MZ, TSL); drafting or revision of the manuscript (YRT, MZ, YZZG).

Data sharing statement

All data are available upon request.

1. European Association for the Study of the Liver. Electronic address eee. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol. 2016;64(1):179-202. Epub 2015/10/31.

2. Zhang W, Liu L, Zhang M, et al. Validation of the Nanjing Criteria for Diagnosing Pyrrolizidine Alkaloids-induced Hepatic Sinusoidal Obstruction Syndrome. J Clin Transl Hepatol. 2021;9(3):345-52. Epub 2021/07/06.

3. Bayraktar UD, Seren S, Bayraktar Y. Hepatic venous outflow obstruction: three similar syndromes. World J Gastroenterol. 2007;13(13):1912-27. Epub 2007/04/28.

4. Plessier A, Rautou PE, Valla DC. Management of hepatic vascular diseases. J Hepatol. 2012;56 Suppl 1:S25-38. Epub 2012/02/04.

5. Northup PG, Garcia-Pagan JC, Garcia-Tsao G, et al. Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;73(1):366-413. Epub 2020/11/22.

6. Zhuge YZ, Wang Y, Zhang F, et al. Clinical characteristics and treatment of pyrrolizidine alkaloid-related hepatic vein occlusive disease. Liver Int. 2018;38(10):1867-74. Epub 2018/01/04.

7. Xiao J, Tu J, Zhang H, et al. Risk factors of poor prognosis in patients with pyrrolidine alkaloid-induced hepatic sinusoidal obstruction syndrome after transjugular intrahepatic portosystemic shunt. Hepatol Int. 2021;15(3):720-9. Epub 2021/01/29.

8. Wang X, Zhang W, Zhang M, et al. Development of a Drum Tower Severity Scoring (DTSS) system for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome. Hepatol Int. 2022. Epub 2022/01/14.

9. Zhou CZ, Wang RF, Lv WF, et al. Transjugular intrahepatic portosystemic shunt for pyrrolizidine alkaloid-related hepatic sinusoidal obstruction syndrome. World J Gastroenterol. 2020;26(24):3472-83. Epub 2020/07/14.

10. Inchingolo R, Posa A, Mariappan M, et al. Transjugular intrahepatic portosystemic shunt for Budd-Chiari syndrome: A comprehensive review. World J Gastroenterol. 2020;26(34):5060-73. Epub 2020/09/29.

11. Aithal GP, Palaniyappan N, China L, et al. Guidelines on the management of ascites in cirrhosis. Gut. 2021;70(1):9-29. Epub 2020/10/18.

12. Fargo MV, Grogan SP, Saguil A. Evaluation of Jaundice in Adults. Am Fam Physician. 2017;95(3):164-8. Epub 2017/02/02.

13. Shukla A, Shreshtha A, Mukund A, et al. Budd-Chiari syndrome: consensus guidance of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int. 2021;15(3):531-67. Epub 2021/07/10.

14. Coilly A, Potier P, Broue P, et al. Budd-Chiari syndrome. Clin Res Hepatol Gastroenterol. 2020;44(4):420-5. Epub 2020/04/07.

15. Yang XQ, Ye J, Li X, et al. Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: Pathogenesis, clinical manifestations, diagnosis, treatment, and outcomes. World J Gastroenterol. 2019;25(28):3753-63. Epub 2019/08/09.

16. Zhang Y, Jiang HY, Wei Y, et al. Sinusoidal obstruction syndrome: A systematic review of etiologies, clinical symptoms, and magnetic resonance imaging features. World J Clin Cases. 2019;7(18):2746-59. Epub 2019/10/17.

17. Liu F, Rong X, Guo H, et al. Clinical characteristics, CT signs, and pathological findings of Pyrrolizidine alkaloids-induced sinusoidal obstructive syndrome: a retrospective study. BMC Gastroenterol. 2020;20(1):30. Epub 2020/02/06.

18. Dai F, Qiao W, Kang Z, et al. Clinical Features and CT Imaging Analysis of Hepatic Sinuscase-Syndrome and Budd-Chiari Syndrome. Int J Gen Med. 2022;15:2389-96. Epub 2022/03/11.

19. Qi X, Wu F, Ren W, et al. Thrombotic risk factors in Chinese Budd-Chiari syndrome patients. An observational study with a systematic review of the literature. Thromb Haemost. 2013;109(5):878-84. Epub 2013/03/01.

20. Denninger MH, Chaït Y, Casadevall N, et al. Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology. 2000;31(3):587-91. Epub 2000/03/08.

21. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019;70(6):1222-61. Epub 2019/03/31.

22. Larrey D, Meunier L, Valla D, et al. Drug induced liver injury and vascular liver disease. Clin Res Hepatol Gastroenterol. 2020;44(4):471-9. Epub 2020/05/07.

23. Aydinli M, Bayraktar Y. Budd-Chiari syndrome: etiology, pathogenesis and diagnosis. World J Gastroenterol. 2007;13(19):2693-6. Epub 2007/06/15.

24. Zhuge Y, Liu Y, Xie W, et al. Expert consensus on the clinical management of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome. J Gastroenterol Hepatol. 2019;34(4):634-42. Epub 2019/01/23.

25. Xu ZM, Zhuge YZ, Xu TS. Raise the recognition of hepatic veno- occlusive disease induced by chrysanthemum-like groundsel. Chin. J. . Gastroenterol 2009;14: 577–9 (in Chinese).

26. Senzolo M, Garcia-Tsao G, García-Pagán JC. Current knowledge and management of portal vein thrombosis in cirrhosis. J Hepatol. 2021;75(2):442-53. Epub 2021/05/01.

27. Magaz M, García-Pagán JC. Risk factors of poor prognosis in patients with pyrrolidine alkaloids induced hepatic sinusoidal obstruction syndrome after transjugular intrahepatic portosystemic shunt : Transjugular intrahepatic portosystemic shunt in patients with sinusoidal obstruction syndrome, etiology matters. Hepatol Int. 2021;15(3):568-70. Epub 2021/03/19.

Table 1 The epidemiology and clinical manifestations of the patients.

Variables	BCS-HV (n = 139)	PA-HSOS (n = 257)	*P value*
Age, years	43.00 ± 13.08	62.75 ± 9.68	*0.000*
Male, n(%)	67 (48.20)	132 (51.40）	0.549
Course of disease,(months)	3 (1.00-24.00)	1.00 (0.67-2.00)	*0.000*
≤6 month, n(%)	85 (61.20)	249 (96.90)	*0.000*
Abdominal distension, n(%)	89 (64.00)	257 (100）	*0.000*
Abdominal pain, n(%)	24 (17.30)	68 (26.10)	*0.047*
Ascites	97 (69.78)	256 (99.60）	*0.000*
None, n(%)	43 (31.20)	1 (0.40）	*0.000*
Mild, n(%)	37 (26.80)	11 (4.30）	*0.000*
Moderate to severe, n(%)	58 (42.00)	245 (95.30）	*0.000*
Varices of abdominal wall, n(%)	13 (9.40)	11 (4.30）	*0.044*
Jaundice, n(%)	37 (26.60)	115 (44.70）	*0.000*
Lower extremity edema, n(%)	28 (20.10)	66 (25.70)	0.217
History of PA intake, n(%)	0	257(100.00)	*0.000*

Table1.Cohort epidemiology and clinical symptoms. Disease course: Time from symptom onset to first presentation. Significant differences are indicated in bold throughout the article.

Table 2 Risk factors for the patients with BCS-HV.

Risk factors of BCS-HV	MOBCS-HV % (n/N)	SOBCS-HV % (n/N)
Inherited thrombophilia
l Thalassemia	0	14.29% (1/7)
l Protein C deficiency	16.67% (1/6)	28.95% (11/38)
l Protein S deficiency	16.67% (1/6)	21.05% (8/38)
l Antithrombin Ⅲ deficiency	16.67% (1/6)	34.21% (13/38)
Acquired thrombotic states
l Polycythemia vera	0	20.00% (1/5)
l Essential thrombocythemia	0	20.00% (1/5)
l PNH(Paroxysmal nocturnal hemoglobinuria)	50.00% (1/2)	20.00% (1/5)
l JAK2 V617F gene mutation	0	25.00% (1/4)
l Antiphospholipid antibody syndrome	0	28.57% (2/7)
l Hyperhomocysteinemia	25.00% (2/8)	19.64% ( 11/56)
Systemic factors
l Connective tissue disease	14.29% (1/7)	33.33% (6/18)
l Inflammatory bowel disease	0	0.93% (1/107)
l Oral contraceptive therapy	0	2.22% (1/45)

Table2. Risk factors for patients with BCS-HV. N: the total number of patients screened for related factors; n: number of people diagnosed with related risk factors; Percentage (%): n/N

Table 3 Baseline characteristics of the laboratory tests.

Variables	BCS-HV (n = 139)	PA-HSOS (n = 257)	*P value*
WBC count(×10⁹/L)	4.70 (3.20–6.32)	6.00 (4.80–7.90)	0.000
HB(g/L)	120.14 ± 29.92	143.78 ± 20.13	0.000
PLT count(×10¹²/L)	117.00 (78.00–185.00)	101.00 (72.00–134.50)	0.001
ALT(U/L)	23.00 (16.00–32.00)	48.80 (25.15–101.85)	0.000
AST(U/L)	28.00 (21.00–40.00)	64.10 (40.00–107.45)	0.000
ALP(U/L)	111.00 (78.00–149.00)	128.80 (97.40–174.05)	0.001
Albumin(g/L)	36.45 ± 5.64	32.70 ± 3.52	0.000
TBil (μmoI/L)	26.20 (16.06–45.33)	37.60 (25.40–55.65)	0.000
SCr (μmoI/L)	57.00 (50.50–68.60)	72.00 (59.00–88.50)	0.000
PT(s)	13.90 (12.50–15.90)	15.20 (13.70–17.55)	0.000
APTT(s)	38.70 (31.50–62.00)	35.00 (30.15–43.95)	0.001
INR	1.21 (1.09–1.37)	1.31 (1.19–1.52)	0.000
Fib,g/L	2.42 (2.00–2.86)	2.10 (1.70–2.70)	0.000
Child-Pugh scores	7.43 ± 1.98	9.15 ± 1.48	0.000
Child-Pugh class
A, n(%)	51 (36.70%)	2 (0.80%)
B, n(%)	65 (46.80%)	152 (59.10%)
C, n(%)	23 (16.50%)	103 (40.10%)

Table3. WBC, white blood cell; Hb, hemoglobin; PLT, platelet count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TBil, total bilirubin; Scr, serum creatinine; PT, prothrombin time; aPTT, activated partial thromboplastin time; Fib, fibrinogen; INR, international normalized ratio.

Table 4 Imaging features of patients with BCS-HV and PA-HSOS.

Variables	BCS-HV	PA-HSOS	*P value*
Portal vein thrombosis, %(n/N)	4.4% (6/136)	11.70%(30/257)	0.018
Localized stenosis or occlusion of the hepatic veins, %(n/N)	100.00% (130/130)	1.20% (3/256)	0.000
Liver cirrhosis, %(n/N)	47.10% (65/138)	2.00% (5/256)	0.000
Hepatomegaly, %(n/N)	56.20% (73/130)	67.10% (163/243)	0.037
Splenomegaly, %(n/N)	63.80% (78/130)	16.10% (39/242)	0.000
Traffic branch, %(n/N)	73.90% (99/134)	0	0.000
Diameter of left hepatic vein, (cm), n/N	0.70 (0.50~1.09) (78/139)	0.39 (0.30~0.45) (156/257)	0.000
Diameter of middle hepatic vein, (cm), n/N	0.70 (0.50~1.10) (70/139)	0.42 (0.35~0.49) (160/257)	0.000
Diameter of right hepatic vein, (cm), n/N	0.80 (0.50~1.10) (54/139)	0.42 (0.36~0.49) (159/257)	0.000
Diameter of portal vein, (cm), n/N	1.19 ± 0.27 (112/139)	1.00 ± 0.16 (243/257)	0.000
Portal vein blood flow velocity, cm/s, n/N	21.84 ± 9.22 (54/139)	15.74 ± 7.99 (238/257)	0.000
Diameter of splenic vein,(cm), n/N	0.89 ± 0.29 (72/139)	0.60 ± 0.12 (230/257)	0.002
Splenic vein blood flow velocity, cm/s, n/N	18.78 ± 9.42 (30/139)	13.47 ± 6.26 (230/257)	0.001
Enlarged caudate lobe of the liver, n/N(%)	47.70% (62/130)	0	0.000
Early strengthening nodules in the liver, n/N(%)	8.50% (11/129)	0	0.000
Narrowed inferior vena cava, n/N(%)	55.20% (69/125)	44.20% (80/177)	0.087
Esophageal Varicose Veins, n/N(%)	64.00% (80/125)	21.20% (38/179)	0.000

Table 4. N: the total number of patients screened by related indicators; n: the number of individuals with positive indicators or screening results; Percentage (%): n/N.

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Budd–Chiari syndrome versus Pyrrolizidine alkaloids-induced hepatic sinusoidal obstructive syndrome: A multi-center study

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