Sinusoidal obstruction syndrome (hepatic veno-occlusive disease)

Abstract

Hepatic sinusoidal obstruction syndrome (SOS) is an obliterative venulitis of the terminal hepatic venules, which in its more severe forms imparts a high risk of mortality. SOS, also known as veno-occlusive disease (VOD), occurs as a result of cytoreductive therapy prior to hematopoietic stem cell transplantation (HSCT), following oxaliplatin-containing adjuvant or neoadjuvant chemotherapy for colorectal carcinoma metastatic to the liver and treated by partial hepatectomy, in patients taking pyrrolizidine alkaloid-containing herbal remedies, and in other particular settings such as the autosomal recessive condition of veno-occlusive disease with immunodeficiency (VODI). A central pathogenic event is toxic destruction of hepatic sinusoidal endothelial cells (SEC), with sloughing and downstream occlusion of terminal hepatic venules. Contributing factors are SEC glutathione depletion, nitric oxide depletion, increased intrahepatic expression of matrix metalloproteinases and vascular endothelial growth factor (VEGF), and activation of clotting factors. The clinical presentation of SOS includes jaundice, development of right upper-quadrant pain and tender hepatomegaly, ascites, and unexplained weight gain. Owing to the potentially critical condition of these patients, transjugular biopsy may be the preferred route for liver biopsy to exclude other potential causes of liver dysfunction and to establish a diagnosis of SOS. Treatment includes rigorous fluid management so as to avoid excessive fluid overload while avoiding too rapid diuresis or pericentesis, potential use of pharmaceutics such as defibrotide, coagulolytic agents, or methylprednisolone, and liver transplantation. Proposed strategies for prevention and prophylaxis include reduced-intensity conditioning radiation for HSCT, treatment with ursodeoxycholic acid, and inclusion of bevacizumab with oxaliplatin-based chemotherapeutic regimes. While significant progress has been made in understanding the pathogenesis of SOS and in mitigating against its adverse outcomes, this condition remains a serious complication of a selective group of medical treatments.

Keywords: AML, acute myeloid leukemia; APRI, aspartate aminotransferase to platelet ratio; AST, aspartate aminotransferase; Bmab, bevacizumab; Colorectal cancer; DF, defibrotide; FOLFOX, chemotherapy regimen containing Folinic acid, 5-Fluorouracil, and Oxaliplatin; GO, gemtuzumab ozogamicin; GSTM1, glutathione S-transferase M1; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; Hematopoietic stem cell transplantation; Herbal remedies; Liver; MOF, multi-organ failure; Oxaliplatin; PML, promyelocytic leukemia protein; RIC-HSCT, reduced-intensity conditioning hematopoietic stem cell transplantation; RILD, radiation-induced liver disease; RT, radiation therapy; SEC, sinusoidal endothelial cells; SOS, sinusoidal obstruction syndrome; TBI, total body irradiation; TIPS, transjugular intrahepatic porto-systemic shunt; UPLC-MS, ultra-performance liquid chromatography-mass spectrometry; V-PYRRO/NO, O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; VOD, veno-occlusive disease; VODI, veno-occlusive disease with immunodeficiency; l-NAME, N(G)-nitro-l-arginine methyl ester; s-ICAM-1, soluble intercellular adhesion molecular-1; t-PA, tissue plasminogen activator; v-WF, von Willebrand factor.

Figure 1

Early histology changes of sinusoidal obstruction syndrome. (A) Post-mortem liver: low power image showing massive pericentral congestion and hemorrhagic necrosis. Masson Trichrome, 4X. (B) Liver biopsy: high power image of pericentral region, showing subtotal occlusion of terminal hepatic venule, with entrapped erythrocytes. Hematoxylin & eosin, 400X. (C) Liver biopsy: high power image showing dilatation of sinusoids and necrosis of hepatocytes. Terminal hepatic vein is occluded, but collagen deposition has not yet occurred. Masson trichrome, 400X.

Figure 2

Sinusoidal obstruction syndrome of longer duration, post-mortem livers. (A) Medium power image showing deposition of loose fibrous tissue in pericentral region, with early formation of fibrous bridges to adjacent centrilobular areas. Masson trichrome, 40X. (B) Medium power image of terminal hepatic vein, showing complete loss of pericentral hepatocytes with sharp demarcation zone from viable hepatocytes in the middle of the lobule. The lumen of the terminal hepatic vein is completely occluded, and there is extravasation of erythrocytes in the pericentral space. Masson trichrome, 100X. (C) Higher power image of terminal hepatic vein, showing intraluminal deposition of extracellular matrix, with residual lumen. Reticulin stain, 200X. (D) Low power image of post-mortem liver with SOS of longer duration, with extensive destruction of the parenchyma and central-to-central fibrous bridging. Masson trichrome, 4X.

Figure 3

Liver biopsies. (A) Biopsy from patient with acute SOS, demonstrating extensive dilatation and congestion of sinusoids, and lack of evident terminal hepatic veins. Hematoxylin and eosin, 100X. (B) Same liver biopsy, showing terminal hepatic vein with narrowed lumen, intraluminal deposition of extracellular matrix with entrapped erythrocytes. Masson trichrome, 100X. (C) Biopsy from patient with chronic consumption of herbal teas, showing extensive destruction of pericentral parenchyma with deposition of fibrous tissue, inflammation, and partial obliteration of the terminal hepatic vein lumen. Hematoxylin and eosin, 100X. (D) Liver biopsy from a different patient, also consuming herbal teas, showing inapparent terminal hepatic vein, extensive extravasation of erythrocytes into pericentral parenchyma, and diffuse pericentral fibrosis. Masson trichrome, 100X.