Patel Kalyani R, Harpavat Sanjiv, Finegold Milton, Eldin Karen, Hicks John, Firan Mihail, Keitel Verena, Kubitz Ralf, Wu Hao
*Department of Pathology and Immunology†Department of Pediatrics (Section of Hepatology), Baylor College of Medicine and Texas Children's Hospital, TX‡Department of Gastroenterology, Heinrich-Heine-University of Düsseldorf, Düsseldorf, Germany.
J Pediatr Gastroenterol Nutr. 2017 Oct;65(4):364-369. doi: 10.1097/MPG.0000000000001653.
Recurrent bile salt export pump (rBSEP) disease has been reported in progressive familial intrahepatic cholestasis type 2 (PFIC2) patients following liver transplantation (LT) and is often refractory to standard anti-cellular rejection immunosuppressants. The mechanism of rBSEP disease is proposed to be a form of type II hypersensitivity reaction with de novo anti-BSEP antibodies blocking the function of allograft BSEP. Utilization of C4d has not been evaluated in rBSEP. We describe a girl with 3 episodes of rBSEP with severe pruritus at 8.9, 10.3, and 11.0 years post-LT, respectively. Patient's serum reacted with normal liver canaliculi by indirect immunofluorescence (IF), whereas patient's liver showed canalicular immunoglobulin G deposition. The histologic features of all 3 liver biopsies recapitulate PFIC2 with cholestatic giant cell hepatitis. Canalicular BSEP expression was not detected in areas of feathery degeneration by immunohistochemistry, but was retained in morphologically normal liver. By direct IF, C4d showed diffuse sinusoidal staining in the third biopsy. Patient responded well to rituximab with or without intravenous immunoglobulin with subsiding symptoms and normalization of serum bile acid levels. In conclusion, rBSEP disease should be considered in the differential diagnosis when evaluating for rejection in a PFIC2 patient post-LT presenting with pruritus. A portion of liver core may be snap frozen in OCT medium for possible direct IF for C4d, that can serve as a surrogate marker for complement activation and antibody-mediated graft dysfunction.
复发性胆盐输出泵（rBSEP）疾病已在2型进行性家族性肝内胆汁淤积症（PFIC2）患者肝移植（LT）后被报道，且通常对标准的抗细胞排斥免疫抑制剂难治。rBSEP疾病的机制被认为是一种II型超敏反应，即新生抗BSEP抗体阻断同种异体移植BSEP的功能。C4d在rBSEP中的应用尚未得到评估。我们描述了一名女孩，在肝移植后分别于8.9岁、10.3岁和11.0岁出现3次严重瘙痒的rBSEP发作。患者血清通过间接免疫荧光（IF）与正常肝小管反应，而患者肝脏显示肝小管免疫球蛋白G沉积。所有3次肝活检的组织学特征均重现了伴有胆汁淤积性巨细胞肝炎的PFIC2。免疫组化在羽毛状变性区域未检测到肝小管BSEP表达，但在形态学正常的肝脏中保留。通过直接IF，C4d在第三次活检中显示弥漫性窦状染色。患者对利妥昔单抗联合或不联合静脉注射免疫球蛋白反应良好，症状减轻，血清胆汁酸水平恢复正常。总之，在评估LT后出现瘙痒的PFIC2患者的排斥反应时，鉴别诊断应考虑rBSEP疾病。一部分肝组织芯可在OCT介质中速冻，以便可能直接进行C4d的IF检测，C4d可作为补体激活和抗体介导的移植物功能障碍的替代标志物。
