EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Budd-Chiari syndrome can lead to fulminant hepatic failure and cirrhosis. The treatment depends on the severity of disease. Liver transplant is a successful treatment option for those with advanced-stage disease.

Material and Methods: In this retrospective study, we analyzed all liver transplants conducted for Budd-Chiari syndrome at the organ transplant unit of Shiraz University of Medical Sciences, Iran, from 1993 to January 2016. Overall, 3201 liver transplant procedures were performed. Among these, 68 presented with Budd-Chiari syndrome.

Results: The median age was 31 years among 27 male and 41 female patients. Five patients received pretransplant interventions, with 2 treated with inferior vena cava stenting and 3 having transjugular intrahepatic portosystemic shunts. Sixty-five patients with Budd-Chiari syndrome received deceased-donor grafts and 3 received living-donor grafts. Among the Budd-Chiari transplant patients, 6 patients died. Five deaths occurred in the early posttransplant period, and 1 patient retransplanted after 2 years for recurrence of disease died due to graft failure. The five-year survival rate was 89% among patients with Budd-Chiari syndrome.

Conclusions: Liver transplant along with posttransplant anticoagulation therapy can improve the survival of patients with advanced-stage Budd-Chiari syndrome.

Key words : Deceased donor, Hepatic failure, Living donor

Budd-Chiari syndrome is a rare disease of the liver caused by hepatic venous outflow obstruction. The site of the outflow obstruction can vary from the small intrahepatic vein up to the junction of inferior vena cava (IVC) with the right atrium.¹ This disease does not affect liver parenchyma directly; however, liver disease results from the long-term exposure of increased hepatic sinusoidal pressure. The resulting venous congestion and portal hypertension cause centrilobular necrosis and fibrosis. In some cases, it can lead to liver cirrhosis and fulminant hepatic failure.²

Budd-Chiari syndrome is postulated to be multifactorial. The causes vary among western and eastern countries. Studies from Japan, India, and China have suggested that it is often caused by membranous obstruction of IVC.^3-5 The other common factors are congenital webs and presence of infections. In western countries, hypercoagulable states (congenital and acquired) are thought to be responsible for Budd-Chiari syndrome.^6,7

The clinical presentation of Budd-Chiari syndrome can be acute, subacute, or chronic. However, some patients remain asymptomatic and a small number present as fulminant hepatic failure.⁸ The presentation depends on the rapidity of hepatic vein occlusion and formation of collateral circulation.⁹

The clinical presentation is usually in the form of a triad of symptoms, ie, abdominal pain, ascites, and hepatomegaly. Fever, pedal edema, esophageal bleeding, and hepatic encephalopathy are less common clinical features.¹⁰

Budd-Chiari syndrome diagnosis depends on the demonstration of hepatic venous outflow obstruction. The noninvasive methods of diagnosis include Doppler ultrasonography,¹¹ contrast-enhanced computed tomography (CT), and magnetic resonance imaging.¹² According to present guidelines, invasive methods like venography and liver biopsy are not recommended for diagnosis. However, for therapeutic purposes, these interventions can be considered.¹³

The management of Budd-Chiari syndrome depends on the severity of disease. A stepwise approach has been advised¹⁴ and has shown better prognosis. Initially, after the confirmation of diagnosis, anticoagulation should be started to keep the international normalized ratio (INR) between 2 and 2.5.¹⁵ For acute cases of Budd-Chiari syndrome, percutaneous or transhepatic angioplasty should be considered in combination with anticoagulation.¹⁶ For recurrent occlusion or inadequate response to angioplasty, stenting is considered more effective. Transjugular intrahepatic portosystemic shunt (TIPS) is considered as the next step of treatment when these methods fail or venous occlusion is chronic.¹⁷ It is a common treatment method in Europe and is associated with lower mortality and morbidity.¹⁸ For the established cases of cirrhosis and fulminant hepatic failure, the only treatment of choice is orthotopic liver transplant. It is the most promising treatment for this disease, and the 5-year survival rates are very encouraging. Ten-year survival rates of 68% to 83.5% have been reported among various retrospective studies.^19,20

In this study, we report a series of patients who underwent orthotopic liver transplant for Budd-Chiari syndrome. Here, we focused on disease characteristics and long-term outcomes. We also compared the posttransplant survival of patients with Budd-Chiari syndrome versus patients having other liver diseases.

Materials and Methods

Study population and follow-up
Between May 1993 and January 2016, 3201 liver transplants were performed in the organ transplant center at the Shiraz University of Medical Sciences, Iran. Among these patients, the frequency of Budd-Chiari syndrome was 2.1% (n = 68). The patients were scheduled for transplant procedures because of the severity of their disease and the continuous deterioration of their condition. We collected and evaluated data retrospectively from computerized data records and hospital charts. Demographic, laboratory, and clinical characteristics, including age at the time of transplant, sex, Child-Turcotte-Pugh classification, presence of portal vein thrombosis, blood group, graft type, and histopathologic findings, were collected. Postoperative complications and mortality were also recorded.

Detailed history, physical examination, and laboratory investigations were recorded, which included color Doppler ultrasonography and CT scans of the abdomen at diagnosis. All patients had received a hematologic evaluation from a hematologist. Venography was not performed. Most of the liver transplants were done without use of venovenous bypass. The standard technique was used for hepatectomy in all patients.

Postoperatively, all patients received heparin and warfarin. The immunosuppressant regimen had included induction with methylprednisolone for 3 days and then administration of prednisolone. From the first postoperative day, calcineurin inhibitors and mycophenolate mofetil were added to the immunosuppression regimen.

Statistical analyses
Mean (standard deviation) or median (range) was estimated for continuous variables, such as age and follow-up time. Frequency (%) was calculated for categorical variables such as sex, Child-Pugh classification, and type of graft. Patient survival after liver transplant was evaluated using Kaplan-Meier curves, and differences between groups were determined by log-rank test. A P value of < .05 was considered as significant. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 18, IBM Corporation, Armonk, NY, USA).

A total of 3201 liver transplants were done at our center. Of these, 68 patients (2.1%) had Budd-Chiari syndrome, for which 70 transplants were done. The median follow-up was 26 months (range, 1-96 mo). There were 41 female (60 %) and 27 male patients (40%). Patient age ranged from 3 to 48 years, with median of 31 years (Table 1).

Most patients in the Budd-Chiari group had Child-Pugh classification B (36/68; 53%), whereas 30 patients (44%) had C classification and 2 patients (3%) had A classification. Among the patients with Budd-Chiari syndrome, 2 had portal vein thrombosis and 10 (15%) had myeloproliferative disease. Four patients (6%) had protein C deficiency. Antithrombin III deficiency, a hepatic venous web, and antiphospholipid antibody positivity were reported in one patient each.

Pretransplant transjugular intrahepatic portosystemic shunt was performed in 3 patients, and in 2 other patients IVC stenting was done. The most common histopathologic findings in explanted liver were cirrhosis in 46 patients (67%), followed by fibrosis and congestion in 9 patients (13 %) each, and necrosis in 4 patients (6%).

Only 3 patients with Budd-Chiari syndrome underwent living-donor liver transplant. Among these, 2 received right lobes and 1 received a left lateral liver segment. Of the 68 patients with Budd-Chiari syndrome, 65 patients (96%) received deceased-donor liver transplants, with 5 done using split in situ technique. The remaining patients received whole organ transplants.

The most common postoperative complication was bleeding for which exploratory laparotomy was done in 7 patients (Table 2). Two other patients had postoperative portal vein thrombosis and hepatic artery thrombosis each; however, in regard to immediately posttransplant, all grafts and patients had survived. Thrombectomy with revision of anastomosis was done in all transplant procedures.

Only 3 patients needed temporary renal replacement therapy postoperatively. There were 6 deaths in patients with Budd-Chiari syndrome (Table 2), with 5 deaths within the first month of transplant. Among these, 1 patient underwent retransplant for primary nonfunctioning graft but died due to cardiac arrest. The sixth patient was retransplanted after 2.83 years for disease recurrence but died postoperatively due to primary nonfunctioning graft.

The Kaplan-Meier patient survival curve for Budd-Chiari syndrome is shown in Figure 1. The survival rates at 1 and 5 years were 92% and 89%, with similar rates at 10-year follow-up. In contrast, the Kaplan-Meier survival rates at 1-, 5-, and 10-years posttransplant in patients with other liver diseases were 85%, 80%, and 73% (Figure 2). Overall, patients with Budd-Chiari syndrome showed better survival results. Log-rank test analyses showed no statistically significant results.

Budd-Chiari syndrome results from obstruction of hepatic veins occurring anywhere from their origin to the junction of IVC with right atrium of heart. This excludes the venous congestion resulting from cardiac diseases.¹ About 90% of Budd-Chiari syndrome patients die within 3 years if not treated by medical, radiologic, or surgical interventions.²¹ Anticoagulation therapy is required for patients who are asymptomatic and have mild disease but with preserved liver function.²² In others, shown in up to 70% of patients, symptoms may be relieved by angioplasty if there is localized narrowing of the hepatic vein or the IVC.^23,24 Inferior vena cava stents have shown good results in improving patient symptoms,1 and the rate of patency is good when covered stents are used.²⁵ Transjugular intrahepatic portosystemic shunt is more common than open surgical shunting and has shown less morbidity and mortality.²⁶ In cases when all of the above measures fail and the patient deteriorates or presents with fulminant disease, then orthotopic liver transplant is indicated.¹⁴

In this retrospective study, we analyzed the data from a single center from May 1993 to January 2016. Of 3210 liver transplants, 68 recipients had Budd-Chiari syndrome. Our findings showing 53% of these patients with Child-Pugh classification B and 44% with Child-Pugh classification C are comparable with Ulrich and associates,¹⁹ who reported rates of 57% and 31%. In our study, 3 patients had history of transjugular intrahepatic portosystemic shunt before liver transplant, shown in previous study to not affect posttransplant outcomes.²⁷

Most Asian studies have reported membranous obstruction of IVC as the leading cause of Budd-Chiari syndrome; however, we found a high frequency of membranoproliferative disease and other thrombotic conditions among our patients. Another Iranian study by Nozari and associates also stated congenital and acquired thrombophilia as main causes of Budd-Chiari syndrome.²⁸ This trend has been reported in western studies, where myeloproliferative disease or other acquired hypercoagulable conditions were reported in 30% to 50% cases of Budd-Chiari syndrome.²⁹

The rate of recurrence of disease in our study was very low (1.47%) compared with other studies, where recurrence of disease ranged from 2.4% to 27%.^20,30 Mackiewicz and associates, however, found no recurrence in their cohort study.²

The prevalence of hepatocellular carcinoma among patients with Budd-Chiari syndrome varies from 2% to 51.6% in previous studies,^31,32 but we did not find a single case of hepatocellular carcinoma in explanted liver.

Since the first successful liver transplant for Budd-Chiari syndrome conducted in 1976,³³ many series have reported liver transplants in patients with Budd-Chiari syndrome using both living- and deceased-donor grafts. The earlier series mentioned less favorable survival, with 5-year posttransplant survival rate of less than 50%.³⁴ Later studies showed better survival rates. In our study, the 1- and 5-year posttransplant survival rates were 92% and 89%. Srinivasan and associates reported an outstanding survival rate of 95%.³⁵ These improvements may be due to persistent use of anticoagulation therapy postoperatively. This approach has also been supported in the literature.^20,36

For the management of Budd-Chiari syndrome, the stepwise approach has shown better outcomes. Liver transplant improves survival of patients with severe Budd-Chiari syndrome when combined with anticoagulation therapy after transplant. Despite worse baseline characteristics, survival is better in cases of Budd-Chiari syndrome receiving liver transplant compared with liver transplant for other indications.

Volume: 16 Issue: 2 April 2018

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