What Is Known
- Primary Budd-Chiari syndrome in children is a rare entity reported mostly from the Indian subcontinent; data are scarce from the West.
- Prothrombotic states are present in two-thirds of these children.
- Radiological interventions are technically feasible with good long-term outcome.
What Is New
- Genetic prothrombotic states leading to Budd-Chiari syndrome are manageable medically (venesection, pegylated-interferon, Janus kinase 2 [JAK2] inhibitor or stem cell transplantation).
- Liver transplantation is required in a small proportion of children with Budd-Chiari syndrome presenting either with acute liver failure or complications related to portal hypertension.
- Multidisciplinary management is required for a good long-term outcome.
Budd-Chiari syndrome (BCS) is characterised by obstruction to the hepatic venous outflow at any level from the hepatic veins (HVs) to the atrio-caval junction regardless of the cause of obstruction. This excludes veno-occlusive disease where the obstruction is at the level of the sinusoids and terminal hepatic venules and also cardiac conditions such as constrictive pericarditis and right-sided heart failure. BCS can be primary or secondary. Primary BCS is defined as obstruction in the lumen of the veins or venules resulting from thrombus, webs, or endophlebitis. Secondary BCS results from an extra-luminal lesion such as tumour, abscess, or cyst, which can invade the lumen or cause extrinsic compression (1).
Children usually have a chronic presentation and in the past, the majority were labelled idiopathic, but in a recent series a prothrombotic state could be identified in a significant proportion of the children (2–5). We report a single-centre experience of the evolution of diagnosis and management of this rare condition.
We retrospectively reviewed the medical records of all children under 18 years of age who presented to King's College Hospital, London from January 2001 to November 2015 with a clinical diagnosis of primary BCS. The diagnosis of BCS was made on the basis of demonstration of occlusion of all 3 HVs with or without occlusion of inferior vena cava (6) on colour Doppler. In cases with a high index of suspicion and a non-contributory Doppler study, contrast-enhanced computerised tomography or magnetic resonance venography scan (Fig. 1) was done. Depending on the mode of presentation, the illness was classified as type I (acute), type II (chronic), or type III (acute on chronic) (7).
Seven children with BCS were identified. Their demographics can be seen in Table 1. Four were Caucasian, 2 were of mixed race and 1 of Indian origin. None of them were born to consanguineous parents. The father of 1 child had died at 27 years of age from thromboembolic disease (patient 4), and a mother of another child had died of cryptogenic cirrhosis (patient 5).
The commonest symptoms at diagnosis were abdominal distension, lethargy, and anorexia. Abdominal pain was present in 2 of them. On clinical examination, all had hepatomegaly with a palpable left lobe and ascites, whereas 5 of them also had a palpable spleen. The abdominal veins were prominent in 4 and pedal oedema was present in 2 children. At presentation, there was a mild to moderate elevation of transaminases in 3 children, and marked elevation in one child. Only 3 children had a serum bilirubin above 20 mmol/L. One child (patient 6) had severe anaemia necessitating blood transfusion. Hypoalbuminemia was present in 3 (43%) and coagulopathy was present in 2 children. All children had 1 or more identifiable prothrombotic risk factors as seen in Table 1.
Patients 1 and 2 had a myeloproliferative disorder; polycythaemia rubra vera (PRV). They were managed with venesection and pegylated—interferon alpha 2a. Patient 1 had to be changed to hydroxyurea and ruxolitinib (a JAK2 inhibitor), because of a relapse 3 years later, whereas patient 2 remained on the interferon, but also required a transjugular intrahepatic portosystemic shunt (TIPSS).
Patient 3 did well with a middle HV stent insertion, whereas patient 5 who had all the HVs blocked, had a meso-caval shunt. Aside an episode of encephalopathy, which was managed with anti-ammonia measures, this patient remains well. Patient 7 was managed with endoscopic banding sessions, but eventually required a liver transplant. The other child requiring a liver transplant, was the one who presented acutely, patient 4. This child died 3 years after liver transplantation because of a subarachnoid haemorrhage while on warfarin.
Patient 6 was diagnosed with paroxysmal nocturnal haemoglobinuria with severe episodic intravascular haemolysis requiring blood transfusion support and serial partial red cell exchange transfusions. He developed seizures secondary to sagittal sinus thrombosis. He also had antiphospholipid syndrome. A decision to insert a TIPSS resulted in a dramatic improvement of the symptoms related to portal hypertension. Subsequently, he underwent reduced intensity matched-unrelated donor allogeneic bone marrow transplant 4 months after his initial presentation, following anti-thymocyte globulin, melphalan, and fludarabine conditioning with full donor engraftment and eradication of the paroxysmal nocturnal haemoglobinuria clone. He remains well after 9 years of follow-up.
BCS is a rare disease in children, described most frequently in the Indian subcontinent. In India the prevalence of BCS as a cause of paediatric chronic liver disease is estimated as 7.4% (4). In our centre studying approximately 500 new liver cases per year, it is 0.093%, or approximately 1 new case of BCS every 2 years. Other paediatric series have described, similar to us, a male preponderance with a wide age range of presentation (9 months to 17 years) (2–5,8,9).
Prothrombotic predisposition has been described in paediatric BCS but most of the studies lack detailed etiological workup (2,3,8). Two studies described presence of protein-C deficiency, protein-S deficiency, methylene tetrahydrofolate reductase mutation, and anti-thrombin-III deficiency as common hypercoagulable states. The presence of a single prothrombotic factor is seen in 67% to 77% of paediatric BCS with >1 factor in 62% to 70% of cases (3,4). The significance of this is uncertain as the reduced activity of protein-C and anti-thrombin-III, could also be due to the liver dysfunction or recent thrombus formation and consumption.
Focal lesions are commonly seen in livers of patients with BCS, with an incidence of 43% over a median follow-up period of 5 years in adults. Most of these nodules are histologically benign—nodular regenerative hyperplasia or focal nodular hyperplasia—, but up to 25% can be malignant (10). Hepatocellular carcinoma has been reported in a 14-year-old adolescent with BCS (11). In our series, benign regenerative nodules were present in 3 children.
The management decision in BCS depends on various factors including local expertise, acuity of presentation, site of block and structural anatomy of liver. In the present era, most of the BCS patients are managed with radiological intervention. A step-wise management has been described recently (12). A recent meta-analysis on radiological intervention for BCS in adults has shown a successful intervention in 94%, restenosis in 6.5% and 1- and 5-year survival rates of 92% and 76%, respectively (13). In an older French study, 17 children were subjected to shunt surgery—5 died postoperatively and 6 developed complications in the form of secondary inferior vena cava thrombosis or stenosis of shunt (8). A more recent paediatric series from India, reports complications in up to one-third of cases in the form of stent block, encephalopathy, haemoperitoneum, and neck haematoma (3–5). Successful liver transplant has been reported in paediatric case reports (14). Our patients also experienced adverse events following radiological interventions (Table 1), but we would like to highlight the fact that in 3 of our children liver transplantation was averted with successful medical therapy (Patient 1) and TIPSS (Patients 2 and 6). The long-term patency of the radiological stents and the surgical shunt was good in the longest follow-up described in this paediatric BCS series.
Children with BCS despite the high morbidity can have a good long-term outcome with a multidisciplinary approach. Prothrombotic states need to be worked up carefully. The decision to intervene radiologically depends on the anatomy of the block and expertise.
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