Hepatic veno-occlusive disease (VOD) with complete occlusion of liver venules after tandem autologous stem cell transplantation – successful treatment with high-dose methylprednisolone and defibrotide

Veno-occlusive disease (VOD) is a life-threatening complication following allogeneic or autologous stem cell transplantation. We report on a patient with a high grade B-cell lymphoma who presented 28 days after the second autologous stem cell transplantation with weight gain, ascites, hyperbilirubinemia, and liver venules occlusion as demonstrated by sonography. Starting with high-dose methylprednisolone treatment followed by defibrotide maintenance therapy the patient showed dramatic complete response of VOD, resulting in a normal sonography of the liver and normalization of laboratory values. The response of the occlusion of nearly all liver venules underlines the value of anti-inflammatory treatment combined with new thrombolytic medication such as defibrotide for the treatment of severe VOD.     

Veno-occlusive disease of the liver after hemopoietic cell transplantation

The clinical syndrome of veno-occlusive disease (VOD) after hemopoietic cell transplantation is characterised by jaundice, painful liver enlargement, and fluid retention with weight gain. Cytoreductive therapy is presumably the primary cause of VOD, but several other agents (and a special susceptibility of the liver) can also play a role in its genesis. The risk of VOD can be predicted before BMT by analysing the presence or absence of the main risk factors. For the diagnosis of VOD most teams worldwide apply the clinical criteria developed by both the Seattle and Baltimore teams. Transjugular liver studies and some biological markers can help establish a correct differential diagnosis. In most cases clinical manifestations improve after several days, but 20-25% of patients could die of VOD. Data regarding whether or not pharmacological prophylactic measures are effective are contradictory. There a few therapeutical approaches directed towards the improvement of venular occlusion; recombinant tissue plasminogen activator and defibrotide can solve some cases of severe VOD.     

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation

Hepatic veno-occlusive disease (VOD) is a serious complication of stem cell transplantation in children. VOD is characterized by rapid weight gain, hepatomegaly, hyperbilirubinemia and ascites. The pathogenesis of VOD is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. These processes lead to concomitant progressive hepatocellular dysfunction and subsequent fluid retention and renal impairment. Severe VOD is typically associated with multiorgan failure and high mortality. A number of possible strategies for the prevention and/or treatment of VOD in children have been investigated. The most promising agent to date is defibrotide, a novel polydeoxyribonucleotide with fibrinolytic properties but no major bleeding risk. Numerous studies, including Phase II/III trials, have shown clinical benefit in pediatric patients with the use of defibrotide treatment and prophylaxis. This review discusses VOD in children and focuses on therapeutic options, including defibrotide, in this patient population.     

Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation

Introduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a complication that is typically associated with conditioning for hematopoietic stem cell transplantation (HSCT). In patients with concomitant multi-organ dysfunction, mortality may be >80%. Recently, the European Society for Blood and Marrow Transplantation established separate criteria for diagnosis and severity of VOD/SOS for adults and children, to better reflect current understanding of the disease.

Areas covered: This review provides an overview of post-HSCT hepatic VOD/SOS and defibrotide, including its pharmacological, clinical, and regulatory profile. In children and adults following HSCT, defibrotide is approved for the treatment of hepatic VOD/SOS with concomitant renal or pulmonary dysfunction in the United States and for the treatment of severe hepatic VOD/SOS in the European Union. Day +100 survival rates with defibrotide are superior to those of historical controls receiving best supportive care only, and safety profiles are similar.

Expert commentary: Defibrotide appears to act through multiple mechanisms to restore thrombo-fibrinolytic balance and protect endothelial cells, and there are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT. An ongoing randomized controlled trial in children and adults will better assess the clinical value of defibrotide as a preventive medication.     

A comparison of clinical criteria for the diagnosis of veno-occlusive disease of the liver after bone marrow transplantation.

Two major studies have established clinical criteria for the diagnosis of veno-occlusive disease of the liver (VOD) after bone marrow transplantation (BMT). McDonald and co-workers defined VOD as the onset of two of the following occurring before day 30 post-BMT: (a) jaundice (bilirubin > 27 mmol/l), (b) tender hepatomegaly, and (c) ascites or weight gain. In contrast, Jones and co-workers defined VOD as the onset, before day 21 post-BMT, of hyperbilirubinemia (bilirubin > 34 mmol/l) as well as two of the following: (a) hepatomegaly, (b) ascites, and (c) weight gain. We retrospectively reviewed the occurrence of VOD in 101 patients transplanted primarily for hematologic malignancies between 1979 and 1990, applying both sets of criteria. Of the 101 patients, eight (7.9%) fulfilled the Jones criteria whereas 32 (31.7%) had VOD according to the McDonald criteria (p < 0.001). Early mortality (prior to 50 days post-BMT) was 75% (6/8) in patients who fulfilled the Jones criteria but only 28.1% (9/32) in the McDonald group (p < 0.005). Overall, mortality in each group was 75% (6/8) and 65.6% (21/32), respectively. All of the six patients with VOD according to the Jones criteria who died had evidence of hepatic failure. Of the 32 patients who fulfilled the McDonald criteria, eight have also fulfilled the Jones criteria and are described above. Of the remaining 24 patients, 22 had complete resolution of VOD as defined by these criteria within 50 days of BMT, none developed hepatic failure, and 15 died.(ABSTRACT TRUNCATED AT 250 WORDS)     

Radiation Veno-Occlusive Liver Disease

Abstract: Two fatal cases of veno-occlusive disease (VOD) of the liver following whole-abdominal irradiation for malignant lymphoma are described. This occurred despite a radiotherapy programme designed to reduce the toxic effect of irradiation to the liver. The clinical picture of rapid weight gain, progressive ascites, jaundice, raised alkaline phos-phatase and thrombocytopenia following abdominal radiotherapy should alert the clinician to the possibility of irradiation induced VOD .     

Veno-occlusive disease of the liver following high-dose chemotherapy and autologous bone marrow transplantation in children with solid tumors: incidence, clinical course and outcome

Two hundred and thirty-six consecutive courses of high-dose chemotherapy with autologous bone marrow transplantation in children with solid tumors were reviewed in order to assess the incidence, clinical presentation and outcome of veno-occlusive disease (VOD) of the liver. Patients conditioned with total body irradiation were excluded from this study. Eleven patients (4.6%) met the diagnostic criteria for VOD. The clinical course included sudden weight gain, jaundice, hepatomegaly and ascites. Renal dysfunction and refractoriness to platelet transfusions occurred in the most severe forms. Seven patients recovered within 7-29 days of onset and four patients died, all with renal failure and fluid overload. The time of onset appeared to determine two patterns of outcome: mild forms with early onset (before day 11) and more severe forms with onset after day 17. Analysis of pretransplant factors revealed no significant association with an increased risk of VOD. However, all the patients with severe VOD had received a conditioning regimen containing cyclophosphamide which might be involved in the pathogenesis of VOD.     

Veno occlusive disease： Update on clinical management

Hepatic veno-occlusive disease is a clinical syndrome characterized by hepatomegaly, ascites, weight gain and jaundice, due to sinusoidal congestion which can be caused by alkaloid ingestion, but the most frequent cause is haematopoietic stem cell transplantation （STC） and is also seen after solid organ transplantation. The incidence of veno occlusive disease （VOD） after STC ranges from 0 to 70%, but is decreasing. Survival is good when VOD is a mild form, but when it is severe and associated with an increase of hepatic venous pressure gradient 〉 20 mmHg, and mortality is about 90%. Prevention remains the best therapeutic strategy, by using non-myeloablative conditioning regimens before STC. Prophylactic administration of ursodeoxycholic add, being an antioxidant and antiapoptotic agent, can have some benefit in reducing overall mortality. Defibrotide, which has pro-fibrinolytic and antithrombotic properties, is the most effective therapy; decompression of the sinusoids by a b-ansjugular intrahepatic portosystemic shunt （TIPS） can be tried, especially to treat VOD after liver transplantation and when multiorgan failure （HOF） is not present. Liver transplantation can be the last option, but can not be considered a standard rescue therapy, because usually the concomitant presence of multiorgan failure contraindicates this procedure.     

Veno-occlusive disease of the liver during induction therapy for acute lymphoblastic leukemia

Veno-occlusive disease (VOD) of the liver, also termed as sinusoidal obstruction syndrome, constitutes a well-known complication of high-dose cytoreductive chemotherapy prior to allogeneic or autologous bone marrow transplantation and is associated with the intensity of treatment [1]. On the contrary, there is only one report of VOD during induction therapy for acute lymphoblastic leukemia in a patient with Marfan syndrome, who was successfully treated with defibrotide [2]. In this article, we present the first fatal case of VOD during induction therapy for acute lymphoblastic leukemia.     

Low,fixed dose defibrotide in management of hepatic veno-occlusive disease post stem cell transplantation

Objective/background

Hepatic veno-occlusive disease (VOD) is well recognized potentially serious regimen-related toxicity seen after stem cell transplantation. Severe VOD is associated with poor long-term outcomes with very high mortality. Besides supportive care, only defibrotide has been found to be effective in the management of VOD. The recommended dose of defibrotide is 25 mg/kg/d but there has been no classical dose finding study done for this drug. A higher dose of defibrotide is associated with increased risk of bleeding and this drug is prohibitively expensive. We report our experience of using fixed low dose of defibrotide in patients with VOD.

Transient infantile hypertriglyceridemia with jaundice: A case report

Rationale:Transient infantile hypertriglyceridemia (HTGTI) is a rare autosomal recessive inherited disease caused by inactivating mutations in the glycerol-3-phosphate dehydrogenase 1 gene. To date, only a few patients have been reported worldwide. The symptoms of the affected individuals present a certain degree of transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis in early infancy. However, the clinical characteristics and pathogenesis of this disease are remain unclear.Patient concerns:A one month and twenty-five days old girl was admitted to hospital because of persisted jaundice and hepatomegaly for fifty days.Diagnose:The girl was diagnosed with HTGTI coincident with a noval mutation in glycerol-3-phosphate dehydrogenase 1.Intervention:She was advised to take low-fat diet and supplement of medium-chain fatty acids.Outcomes:Her jaundice was gradually normal at the age of 4 months without any treatment, and hypertriglyceridemia were normal at the age of 13 months, but still had elevated transaminases and hepatic steatosis.Lessons:Jaundice may be a novel phenotype in HTGTI. The report contributes to the expansion of HTGTI''s gene mutation spectrum and its clinical manifestations.     

Pazopanib-induced severe acute liver injury: A case report

Rationale:Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United States. Painkillers and fever antipyretics are the most common cause of DILI. Hepatic injury can be provoked by DILI as hepatocellular or cholestatic type.Patient concerns:A 48-year-old woman presented jaundice accompanied by nausea and vomiting. The patient was an inactive hepatitis B carrier with low viral titer and was diagnosed renal cell carcinoma (RCC) with hepatic metastasis requiring pazopanib treatment. Prior to administration of pazopanib, tenofovir administration was started to prevent exacerbation of hepatitis B. The patient was referred to clinic of gastroenterology department due to sudden elevation of bilirubin after 5 weeks of pazopanib treatment.Diagnoses:Abdominal ultrasound and computed tomography showed non-specific finding other than metastatic nodule in the liver and liver cirrhosis. After then, the patient was performed liver biopsy, and the biopsy result was acute cholestatic hepatitis with centrilobular area necrosis and portal inflammation. Therefore, considering the clinical history and biopsy results, the patient was diagnosed as DILI due to pazopanib.Interventions:After the biopsy, empirical steroid therapy was initiated and after 7 weeks of pazopanib discontinuation.Outcomes:The total bilirubin level returned to normal from peak level of 24.61 to 1.52 mg/dL.Lessons:In patients with renal cell carcinoma, pazopanib treatment requires clinical caution as it causes rare complications such as severe jaundice and acute cholestatic hepatitis.     

Earlier defibrotide initiation post‐diagnosis of veno‐occlusive disease/sinusoidal obstruction syndrome improves Day +100 survival following haematopoietic stem cell transplantation

Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant (HSCT). The VOD/SOS pathophysiological cascade involves endothelial‐cell activation and damage, and a prothrombotic‐hypofibrinolytic state. Severe VOD/SOS (typically characterized by multi‐organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/SOS post‐HSCT in the European Union, and for hepatic VOD/SOS with renal or pulmonary dysfunction post‐HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded‐access treatment protocol for patients with VOD/SOS. Data from this study were examined post‐hoc to determine if the timing of defibrotide initiation post‐VOD/SOS diagnosis affected Day +100 survival post‐HSCT. Among 573 patients, defibrotide was started on the day of VOD/SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post‐diagnosis showed superior survival when treatment was initiated closer to VOD/SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation (P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/SOS.     

Compressive stenosis of the inferior vena cava due to localized ascites after living-donor liver transplantation

A 54-year-old woman was admitted to our hospital following the diagnosis of decompensated liver cirrhosis with hepatitis C. She underwent living-donor liver transplantation, performed using the left hepatic lobe with the middle hepatic vein donated by her husband. After the transplantation, the patient suffered from massive ascites with liver dysfunction. Computed tomography demonstrated stenosis of the suprahepatic inferior vena cava (IVC) with focal collection of fluid. A second laparotomy was performed 19 days after the transplantation. When the encapsulated localized ascites on both sides of the IVC was opened, the ascites was flushed away. Subsequently, the grafted liver was easily mobilized and it was placed in the natural position without any tension, and the pressure gradient of the IVC was improved. Herein, we report a very rare case of compression stenosis of the IVC resulting in Budd-Chiari syndrome caused by localized encapsulated ascites.     

Use of prostaglandin E1 for prevention of liver veno-occlusive disease in leukaemic patients treated by allogeneic bone marrow transplantation

Prostaglandin E1 (PGE₁) was used to prevent veno-occlusive disease (VOD) of the liver after allogeneic bone marrow transplantation (BMT) for leukaemia. It was given in continuous i.v. infusion from day – 8 to day 30 after BMT at a dose of 0.3 μg/kg/h. The patients were studied according to the risk factors for VOD: diagnosis, intensification of the conditioning and previous liver abnormalities. The diagnosis of VOD was made on at least two of the following factors: weight gain, hepatomegaly, jaundice, ascitis, pain of the right upper quadrant, increased platelet consumption. 109 patients were studied, 50 were treated by PGE₁ and 59 did not receive it. The actuarial incidence of VOD was 12.2% in the PGE₁ group and 25.5% in the non PGE₁ group ( P =0.05). In acute leukaemia, the incidence was 39.1% in the non-treated group and 12.8% in the PGE₁ treated group (P=0.02). Patients with previous hepatitis had an incidence of 62.5% in the non treated group and 15.5% in the treated group ( P =0.05). A positive cytomegalovirus (CMV) serology seemed to increase the risk of VOD: the incidence of VOD was 31.4% in non-treated patients and 22% in PGE₁ treated patients. The multivariate analysis of the risk factors for VOD shows that unfavourable factors were: recipient positive CMV serology ( P =0.06), hepatic disease prior to transplant ( P =0.02) and the absence of PGE₁ treatment ( P =0.02). This study suggests that prophylactic PGE₁ treatment may decrease the incidence of VOD in patients treated for leukaemia by allogeneic bone marrow transplantation.     

Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome

Veno-occlusive disease (VOD) is the most common regimen-related toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost uniformly fatal. Preliminary experience with defibrotide (DF), a single-stranded polydeoxyribonucleotide with fibrinolytic, antithrombotic, and anti-ischemic properties, in the treatment for severe VOD has suggested safety and activity. Eighty-eight patients who developed severe VOD after SCT were treated with DF under a defined treatment plan. At diagnosis, median bilirubin was 76.95 microM (4.5 mg/dL), median weight gain was 7%, ascites was present in 84%, and abnormal hepatic portal venous flow was present in 35%. At DF initiation, median bilirubin had increased to 215.46 microM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported. Complete resolution of VOD was seen in 36%, with 35% survival at day +100. Predictors of survival included younger age, autologous SCT, and abnormal portal flow, whereas busulfan-based conditioning and encephalopathy predicted worse outcome. Decreases in mean creatinine and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy predicted better survival. The complete response rate, survival to day +100, and absence of significant DF-associated toxicity in this largest patient cohort reported to date confirm the results of earlier studies. Certain features associated with successful outcome may correlate with DF-related treatment effects, and prospective evaluation of DF therapy for severe VOD should allow better definition of predictors of response or failure.     

Acute-onset autoimmune hepatitis treated with living donor-liver transplantation

A 50-year-old woman was diagnosed with acute-onset autoimmune hepatitis. She did not respond to steroid therapy including pulse therapy, and was subsequently treated with living donor-liver transplantation 36 days after the beginning of steroid therapy. Except for a period of transient mild acute rejection, her liver function tests remained within a normal range for 2.5 years after the operation. The courses of autoimmune hepatitis patients treated with living-donor liver transplantation have not been previously documented to our knowledge. Living donor-liver transplantation is thought to be one of the therapy options for severe autoimmune hepatitis.     

Clinical severe hepatic venoocclusive disease during induction treatment of acute monoblastic leukemia managed with defibrotide

Hepatic venoocclusive disease (VOD) is the most common complication of cytoreductive therapy used for stem cell transplantation, but it is rarely encountered during induction treatment of acute leukemia. We describe a patient in whom severe clinical VOD developed shortly after induction treatment for acute monoblastic leukemia. Administration of intravenous defibrotide for 19 days induced complete resolution of the VOD. Further consolidation treatment was resumed including high-dose cytosine arabinoside without further complications.     

Acute respiratory distress syndrome associated with macrophage activation syndrome in systemic lupus erythematosus: A case report and literature review

Rationale:Previous treatment for macrophage activation syndrome (MAS) includes high-dose intravenous methylprednisolone along with intravenous immunoglobulin G. If MAS worsened, second-line therapy consisted of anakinra; if the disease remained refractory, third-line therapy with etoposide was considered. In addition, cyclosporine A plays a role in early MAS and in preventing recurrence. Some studies have reported the use of cytokine-targeting agents other than anakinra, such as canakinumab, tocilizumab, abatacept, and tofacitinib.Patient concerns:The patient with systemic lupus erythematosus (SLE) had an uncommon combination of intermittent fever, hyperferritinemia, hypertriglyceridemia, jaundice, and significantly abnormal liver function test results. The patient reported a history of daily fever of 38 to 39°C, painful oral ulcer, anorexia, abdominal bloating, diarrhea, and malar rash progression for 2 weeks, and jaundice, tea-colored urine, and clay-colored stool for 1 week preceding hospital admission.Diagnosis:SLE flareups in the patient were initially suspected. However, the final diagnosis was acute respiratory distress syndrome (ARDS) associated with MAS.Interventions:The treatment included disease-modifying antirheumatic drugs (DMARDs), such as azathioprine, and titrated steroid doses of methylprednisolone (40 mg q8 h) and dexamethasone (15 mg q8 h), after the patient had ARDS and was intubated.Dose-adjusted monotherapy with dexamethasone was found to be effective; this may be attributed to some DMARDs being unsuitable for cytokine storms, that is, some DMARDs may cause complications in cytokine storms.Outcomes:After dexamethasone 15 mg q8 h treatment, the patient''s fever subsided within 2 days, and liver function became normal within 3 weeks. The patient regularly attended scheduled outpatient follow-up visits after discharge. After 2 years, the patient reported no symptoms or signs of SLE with 2 mg/d oral dexamethasone.Lessons:Early diagnosis of MAS and dexamethasone treatment for MAS with ARDS appear to be crucial for these patients.     

Recombinant tissue plasminogen activator (rt-PA) for veno-occlusive liver disease in pediatric autologous bone marrow transplant patients

The pathogenesis of veno-occlusive disease (VOD) of the liver appears to be secondary to endothelial damage of terminal hepatic venules, which leads to activation of the coagulation cascade, fibrin deposition, and eventual fibrous obliteration of the hepatic venules. Patients with VOD usually present with jaundice, hepatomegaly, weight gain, and ascites. This complication is usually associated with a high mortality rate. We report here the frequency and treatment of VOD in our autologous bone marrow transplant (BMT) patient population. Three of 15 (20%) children (median age 9 years) developed VOD and were treated with recombinant tissue plasminogen activator (rt-PA). Two of these three patients were prepared for BMT with busulfan (16 mg/kg) and cyclophosphamide (Cytoxan, 200 mg/kg), while the other child received cytosine arabinoside (ARA-C 18 g/m²), Cytoxan (3,600 mg/m²) and total body irradiation (TBI, 1,400 r). VOD developed between days 7–24 posttransplant. Clotting studies obtained pretransplant and during VOD included prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrin-degradation product (FDP), proteins C and S, and platelet count. There was no correlation between the incidence of VOD and coagulation status. All patients had normal pretransplant clotting studies. However, protein C levels were noted to be consistently low for those patients at the time of VOD. All three patients received rt-PA at a dose of 0.25–0.5 mg/kg for 4 days. This dose produced increased levels of FDP but did not significantly prolong PT nor PTT. Two of the patients had dramatic responses and had complete resolution of VOD within 6–12 days from the start of therapy. The other patient died of fulminant hepatic failure. It seems that rt-PA is effective in VOD of the liver, which may be associated with low protein C level. © 1994 Wiley-Liss, Inc.