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A serious complication of Paroxysmal Nocturnal Hemoglobinuria (PNH) is hepatic venous thrombosis leading to Budd-Chiari Syndrome (BCS). Mortality due to untreated BCS is high despite aggressive treatment. Liver Transplantation in PNH is riddled with the risk of intraoperative and postoperative thrombotic complications, which can cause recurrent BCS and graft dysfunction. We report the case of a 33 year male with PNH who developed BCS and successfully underwent Transjugular Intrahepatic Porto-Systemic Shunt (TIPSS) placement, which led to rapid clinical recovery.

A 33-year-old male presented with a history of progressive jaundice over nine months. He also complained of painless progressive ascites for four months. Three months ago, he had a bout of hematemesis for which he underwent endoscopic variceal ligation (EVL).

In the past, he was investigated for refractory anemia. He had an episode of intravascular hemolysis six years ago, and the diagnosis of PNH was made based on flow cytometry analysis and positive anti-membrane inhibitor of reactive lysis (MIRL) and anti-decay-accelerating factor (DAF) antibodies. He received Anti-thymocyte globulin and oral danazol therapy.

He was admitted presently with deep jaundice and ascites. Routine laboratory evaluation revealed hemoglobin of 7g/dl, total leucocyte count 1,630 cells/cumm, and platelet count 76000/cumm. The international normalized ratio was 1.39. Serum Bilirubin was 38.6 mg/dl, aspartate aminotransferase 271 U/L, alanine aminotransferase 44 U/L, alkaline phosphatase 144 U/L and gamma-glutamyl transferase 67 U/L. Serum total proteins were 6.1 g/dl, and serum albumin was 2.9 g/dl. His renal parameters were normal. His HBsAg and anti-HCV tests were negative. Serology for Hepatitis A and E and autoimmune markers were negative. The serum ceruloplasmin and ferritin were normal.

The ascitic fluid analysis revealed a high serum ascites-albumin gradient (SAAG). There was no evidence of spontaneous bacterial peritonitis. Upper Gastrointestinal endoscopy revealed esophageal candidiasis, small residual esophageal varices, and post EVL ulcers. Serology for cytomegalovirus and Epstein Barr virus was negative. An ultrasound examination of the abdomen with Doppler revealed hepatosplenomegaly and sluggish hepatopetal flow. Middle and left hepatic veins were not visualized.

With high suspicion of Budd Chiari Syndrome, he underwent a dynamic Magnetic Resonance Imaging (MRI) of the liver, which revealed an enlarged liver with nodular margins, hypertrophy of central segments, and a significantly enlarged caudate lobe. Discrete hepatic veins were not visualized, and the intrahepatic Inferior Vena Cava (IVC) was significantly chinked and barely visualized as a slit for a small focal length. Multiple small omental, anterior abdominal wall, perisplenic, mesenteric, and surface perihepatic collaterals were noted along with multiple comma-shaped intrahepatic collaterals. Moderate ascites, splenomegaly, and bowel wall edema were also noted. The renal cortex and medulla showed altered signal intensity classically seen in PNH with repeated hemolysis (Figures 1-4).

A diagnosis of decompensated cirrhosis of liver secondary to Budd Chiari Syndrome with PNH was made. His Child-Turcotte-Pugh score was 10/C; Model for End-Stage Liver Disease-Sodium (MELD-Na) score was 15.

Given underlying cirrhosis, liver transplantation was thought of as definitive treatment but was not performed as liver transplantation is considered relatively contraindicated in PNH, especially when done without administration of Eculizumab. The patient successfully underwent a Transjugular Intrahepatic Porto-Systemic Shunt (TIPSS) placement using a Polytetrafluoroethylene stent. His ascites and jaundice resolved, and two months later, at follow-up, he is healthy and maintaining a therapeutic INR on oral anticoagulation.

PNH is a unique clinical syndrome characterized by hemolytic anemia, pancytopenia, and thrombosis. PNH occurs due to a genetic mutation that leads to an inability to synthesize a glycosylphosphatidylinositol (GPI) anchor that binds surface proteins on the red blood cell membranes. The critical proteins include the decay-accelerating factor (DAF), or CD55, homologous restriction factor (HRF), or C8 binding protein, and membrane inhibitor of reactive lysis (MIRL), or CD59. These proteins regulate complement factors (C3b and C4b). As a result of absent GPI anchor, an uncontrolled amplification of the complement system occurs leading to intravascular destruction of the RBC membrane.¹

Thrombosis accounts for the most common causes of death. Four out of ten deaths in PNH patients are attributed to venous thrombosis. Most frequently, thrombosis involves hepatic veins, pulmonary veins, the deep venous system of the lower limbs, cerebral veins, dermal veins, and the inferior vena cava. Hepatic vein thrombosis manifests as Budd-Chiari syndrome (BCS). PNH is responsible for approximately 6-8% of cases of BCS.²

Allogenic stem cell transplantation is possibly the only potentially curative treatment for PNH. However, it carries high morbidity and mortality risks. It has been reported that stem cell transplantation for PNH can correct even long-standing thrombosis.³ For BCS secondary to PNH, TIPSS is considered as an effective therapy. In one study, seven patients with PNH underwent TIPSS procedure with a success rate of 86%.² It is vital to start anticoagulation immediately after TIPSS to prevent stent thrombosis.

Most centers consider PNH as a contraindication to liver transplantation. This is because of the high risk of thrombotic complications, both intraoperative and perioperative. The primary reason is that liver transplantation does not cure the inability to produce the GPI anchor. Hence, the tendency for thrombosis persists even after liver transplantation. Recurrent thrombosis of the hepatic veins can result in recurrence of BCS post liver transplantation.⁴ This results in a loss of graft and clinical worsening.

Eculizumab is a humanized monoclonal antibody that inhibits the activation of the terminal complement at C5. By doing so, it pauses the production of the anaphylatoxin C5a and the membrane attack complex C5b-9. Based on the results of multicenter phase III clinical trials, Eculizumab was approved by the Food and Drug Administration for the treatment of PNH in March 2007. Eculizumab reduces intravascular hemolysis and, thus, the requirement for red cell transfusions. It significantly reduces the risk of thrombosis and results in rapid improvement in hepatic function. Furthermore, long term treatment with Eculizumab is safe and improves the quality of life in patients with PNH. Eculizumab has also been used to prevent recurrent BCS and hepatic artery and portal vein thromboses in the post liver transplant setting.⁵ The monoclonal antibody thus offers a new arena of treatment to patients with end-stage liver disease secondary to PNH-induced BCS.

The major limitation to the use of Eculizumab in the Indian setting is the high cost. Our patient underwent TIPS with a successful outcome. In the forthcoming years, innovative inhibitors of the alternative complement pathway and complement inhibitors with prolonged half-lives are expected to further improve the survival of PNH patients.