Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease)

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. 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. Obliterative endophlebitis in the terminal hepatic veins of the human liver lobule was first reported by a pathologist from Prague in 1905, with the only etiologic suggestion being syphilis.1Hess J. Fatal obliterative endophlebitis of the hepatic vein.Am J Med Sci. 1905; 130: 986-1001Crossref Google Scholar In 1954, terminal vein lesions were described in Jamaican drinkers of bush tea, characterized by obliteration of hepatic vein radicals by varying amounts of subendothelial swelling and fine reticulated tissue.2Bras G. Jelliffe D.B. Stuart K.I. Veno-occlusive disease of liver with nonportal type of cirrhosis, occurring in Jamaica.Arch Pathol Lab Med. 1954; 57: 285-300Google Scholar At later stages, a fibrous pericentral scar developed. In the early 1960's, studies of the effects of ionizing radiation on mammalian tissues documented that the hepatic vasculature could be damaged by this mechanism,3Hahn P.F. Jackson M.A. Goldi H. Liver cirrhosis with ascites, induced in dogs by chronic massive hepatic irradiation with radioactive colloidal gold.Science. 1951; 114: 303-305Crossref PubMed Google Scholar in the absence of antecedent vascular thrombosis.4Stirling G.A. Bras G. Urquhart A.E. The early lesions in veno-occlusive disease of the liver.Arch Dis Child. 1962; 37: 535-538Crossref PubMed Scopus (1) Google Scholar, 5Bras G. McLean E. Toxic factors in veno-occlusive disease.in: Sterling J.A. Fetal and Infant Liver Function and Structure. Ann N Y Acad Sci. Vol. 111. 1963: 392-398Google Scholar The most striking example of an obliterative venous lesion induced by irradiation was documented in humans with lung tumors receiving radiation treatment; both the lung vasculature and that of the dome of the liver that was included in the radiation field developed vascular obliteration, but not the remainder of the unexposed liver.6Ogata K. Hizawa K. Yoshida M. et al.Hepatic injury following irradiation – a morphologic study.Tokushima J Exp Med. 1963; 9: 240-251Google Scholar Shortly thereafter, induction of obliterative venopathy following heavy irradiation directly of the human liver for metastatic disease was reported in 12 patients receiving upper abdominal irradiation by the Stanford Linear Accelerator.7Reed G.B. Cox Jr., A.J. The human liver after radiation injury: a form of veno-occlusive disease.Am J Pathol. 1966; 48: 597-611PubMed Google Scholar Thus, by the mid-1960s, the concept of hepatic veno-occlusive disease was well-established, induced by either chemical or radiation toxicity, and as a lesion separate from Budd-Chiari syndrome and Banti syndrome.8Gibson J.B. Chiari's disease and the Budd-Chiari syndrome.J Path Bact. 1960; 79: 381-401Crossref PubMed Google Scholar, 9Shillam D.S. Congestive splenomegaly (Banti's syndrome) due to portal stenosis.Calif Med. 1947; 67: 379-381PubMed Google Scholar In the late 1970's, similar histologic lesions were reported from outbreaks in India and Israel, attributed to contamination of wheat and traditional herbal remedies with plant toxins.10Tandon B.N. Tandon H.D. Tandon R.K. Narmdranathan M. Joshi Y.K. An epidemic of hepatic veno-occlusive disease in central India.Lancet. 1976; ii: 271Abstract Scopus (100) Google Scholar, 11Ghanem J. Hershko C. Veno-occlusive disease and primary hepatic vein thrombosis in Israeli Arabs.Isr J Med Sci. 1981; 17: 339-347PubMed Google Scholar The histological lesions resembled previously described hepatic veno-occlusive lesions described in rats poisoned with Senecio plant extracts12Selzer G. Parker R.G.F. Sapeika N. An experimental study of Senecio poisoning in rats.Br J Exp Path. 1951; 32: 14-20PubMed Google Scholar or Crotolaria.13McLean E. Bras G. György P. Veno-occlusive lesions in livers of rats fed Crotolaria fulva.Br J Exp Path. 1964; 45: 242-247PubMed Google Scholar This form of liver toxicity was ultimately attributed to hepatic exposure to plant pyrrolizidine alkaloids,14McLean E.K. The toxic actions of pyrrolizidine (Senecio) alkaloids.Pharmacol Rev. 1970; 22: 429-483PubMed Google Scholar establishing these plant toxins as the cause of veno-occlusive disease in users of herbal teas. Bone marrow transplantation for humans with leukemias became a therapeutic option during the 1960s. Initial challenges to this new therapy were preservation of harvested marrow, and achieving successful marrow engraftment.15Thomas E.D. Epstein R.B. Bone marrow transplantation in acute leukemia.Cancer Res. 1965; 25: 1521-1524PubMed Google Scholar Reports of hepatic veno-occlusive disease in patients undergoing bone marrow transplantation emerged in the 1970's,16Jacobs P. Miller J.L. Uys C.J. Dietrich B.E. Fatal veno-occlusive disease of the liver after chemotherapy, whole-body irradiation and bone marrow transplantation for refractory anemia.S Afr Med J. 1979; 55: 5-10PubMed Google Scholar followed by numerous reports which established the following apparent risk factors: bone marrow transplantation for malignancy, involving intense chemotherapeutic and radiation conditioning regimens; patient age over 15 years; and in particular, abnormal pretransplant serum levels of liver enzymes.17Shulman H.M. McDonald G.B. Matthews D. et al.An analysis of hepatic veno-occlusive disease and centrilobular hepatic degeneration following bone marrow transplantation.Gastroenterology. 1980; 79: 1178-1191PubMed Google Scholar, 18Woods W.G. Dehner L.P. Nesbit M.E. et al.Fatal veno-occlusive disease of the liver following high dose chemotherapy, irradiation and bone marrow transplantation.Am J Med. 1980; 68: 285-290Abstract Full Text PDF PubMed Scopus (24) Google Scholar, 19McDonald G.B. Sharma P. Matthews D.E. Shulman H.M. Thomas E.D. Veno-occlusive disease of the liver after bone marrow transplantation: diagnosis, incidence and predisposing factors.Hepatology. 1984; 4: 116-122Crossref PubMed Google Scholar The presence of metastatic liver disease in patients undergoing bone marrow transplantation for solid tumors and lymphomas also predisposed to veno-occlusive disease.20Ayash L.J. Hunt M. Antman K. et al.Hepatic veno-occlusive disease in autologous bone marrow transplantation of solid tumors and lymphomas.J Clin Oncol. 1990; 8: 1699-1706Crossref PubMed Google Scholar, 21Shibayama Y. Hashimoto K. Nakata K. Focal veno-occlusive lesions following metastasis of cancer in the liver with special reference to obstruction of lymphatics in hepatic veins.Virchows Arch [A]. 1991; 418: 169-174Crossref Google Scholar In these initial years after recognition of veno-occlusive disease as a complication of induction regimes prior to bone marrow transplantation, the incidence of veno-occlusive disease varied from 21% to 25% in allogeneic graft recipients,19McDonald G.B. Sharma P. Matthews D.E. Shulman H.M. Thomas E.D. Veno-occlusive disease of the liver after bone marrow transplantation: diagnosis, incidence and predisposing factors.Hepatology. 1984; 4: 116-122Crossref PubMed Google Scholar, 21Shibayama Y. Hashimoto K. Nakata K. Focal veno-occlusive lesions following metastasis of cancer in the liver with special reference to obstruction of lymphatics in hepatic veins.Virchows Arch [A]. 1991; 418: 169-174Crossref Google Scholar, 22Jones R.J. Lee K.S. Beschorner W.E. et al.Veno-occlussive disease of the liver following bone marrow transplantation.Transplantation. 1987; 44: 778-783Crossref PubMed Google Scholar to 5% in recipients of autologous marrow.20Ayash L.J. Hunt M. Antman K. et al.Hepatic veno-occlusive disease in autologous bone marrow transplantation of solid tumors and lymphomas.J Clin Oncol. 1990; 8: 1699-1706Crossref PubMed Google Scholar, 23Dulley F.L. Kanfer E.J. Appelbaum R.F. et al.Veno-occlusive disease of the liver after chemoradiotherapy and autologous bone marrow transplantation.Transplantation. 1987; 43: 870-873Crossref PubMed Google Scholar, 24Brugieres L. Hartman O. Benhamou E. et al.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.Bone Marrow Transplant. 1988; 3: 53-58PubMed Google Scholar In the four decades since routine use of bone marrow transplantation for solid malignancies, lymphomas and leukemias, induction regimes and therapies have helped improve, but not eliminate, the incidence of this condition in the transplant population. Its incidence now is primarily in the setting of hematopoietic stem cell transplantation, but SOS may occur in other settings as well (Table 1).Table 1Causes of Sinusoidal Obstruction Syndrome (SOS).Hematopoietic stem cell transplantation (HSCT)Adjuvant or neoadjuvant chemotherapy with hepatectomy for metastatic liver diseaseRadiation-induced liver diseaseChemotherapy for acute myeloid leukemia (AML)Liver transplantationUse of herbal remediesVeno-occlusive disease with immunodeficiency (VODI) Open table in a new tab Initial experimental efforts to induce veno-occlusive disease in animals focused on irradiation. Although the non-human primate liver is relatively resistant to radiation-induced veno-occlusive disease,25Stephens L.C. Peters L.J. Ang K.K. Tolerance of rhesus monkey liver to ionizing radiation.Radiat Oncol Invest. 1994; 1: 279-284Crossref Google Scholar veno-occlusive lesions could be induced in primates26Allen J.R. Carstens L.A. Katagiri G.J. Hepatic veins of monkeys with veno-occlusive disease. Sequential ultrastructural changes.Arch Pathol. 1969; 87: 279-289PubMed Google Scholar and in non-primates27Shulman H.M. Luk K. Deeg H.J. Shuman W.B. Storb R. Induction of hepatic veno-occlusive disease in dogs.Am J Pathol. 1987; 126: 114-125PubMed Google Scholar by exposure to chronic irradiation regimes. However, the underlying pathogenesis of this condition was not elucidated with these early experimental models. Careful ultrastructural examination of human tissues suggested that the initial morphologic change in hepatic veno-occlusive disease was obstruction at the level of hepatic sinusoids, followed by obliteration of the terminal hepatic veins.28Shulman H.M. Fisher L.B. Schoch H.G. Henne K.W. McDonald G.B. Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms.Hepatology. 1994; 19: 1171-1181Crossref PubMed Google Scholar This observation was confirmed with the report in 1999 of a more economical and reproducible rodent model of veno-occlusive disease.29DeLeve L.D. McCuskey R.S. Wang X. et al.Characterization of a reproducible rat model of hepatic veno-occlusive disease.Hepatology. 1999; 29: 1779-1791Crossref PubMed Scopus (135) Google Scholar In rats gavaged with the pyrrolizidine alkaloid monocrotaline and killed between days 1–10 after exposure, the earliest documented change was damage to the hepatic sinusoids; fibrosis and obliteration of the terminal hepatic veins occurred as a subsequent lesion. This articulation that toxic injury to the hepatic sinusoids was the fundamental lesion of hepatic veno-occlusive disease led to its being renamed sinusoidal obstruction syndrome (SOS).30DeLeve L.D. Shulman H.M. McDonald G.B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (venoocclusive disease).Semin Liver Dis. 2002; 22: 623-638Crossref Google Scholar The rat model of SOS may be summarized as follows.29DeLeve L.D. McCuskey R.S. Wang X. et al.Characterization of a reproducible rat model of hepatic veno-occlusive disease.Hepatology. 1999; 29: 1779-1791Crossref PubMed Scopus (135) Google Scholar, 31DeLeve L.D. Ito Y. Bethea N.W. McCusky M.K. Wang X. McCuskey R.S. Embolization by sinusoidal lining cells obstructs the microcirculation in rat sinusoidal obstruction syndrome.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G1045-G1052PubMed Google Scholar Following a single gavage with monocrotaline, within 24 h–48 h there is ultrastructural evidence of damage to hepatic sinusoidal endothelial cells (SEC), but little clinical or histological evidence of hepatic toxicity. By days 3–5 (early SOS), manifestations of sinusoidal obstruction are severe, with severe centrilobular necrosis and hemorrhage, damage to endothelial cells of the terminal hepatic veins, subendothelial hemorrhage, and ultrastructural evidence of extensive destruction of the sinusoidal wall. The clinical manifestations are hepatomegaly, ascites, and hyperbilirubinemia. By days 6–7 (late SOS), the characteristic subendothelial and adventitial fibrosis of terminal hepatic veins becomes evident. There is continued sinusoidal and subendothelial hemorrhage, but gradual resolution of the ultrastructural evidence of damage to the sinusoidal endothelial cells. By days 8–10, SOS has resolved completely in some animals, or persisted as a severe pattern of hepatic damage in others. Detailed study of the first hours after monocrotaline exposure31DeLeve L.D. Ito Y. Bethea N.W. McCusky M.K. Wang X. McCuskey R.S. Embolization by sinusoidal lining cells obstructs the microcirculation in rat sinusoidal obstruction syndrome.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G1045-G1052PubMed Google Scholar reveal that SECs become swollen, with increased adhesion of leukocytes to the endothelium. Red blood cells dissect beneath the endothelial cells and into the space of Disse, separating the endothelial cells from the underlying hepatocytes and permitting free access of blood to the parenchymal space. In contrast, blood flow in the restricted sinusoidal channel becomes sluggish. The sinusoid is eventually obstructed by an embolism of aggregated sinusoidal lining cells, red blood cells, and adherent monocytes. Kupffer cells are lost along the sinusoidal lining, and are replaced with an influx of circulating phagocytic monocytes which accumulate in the injured centrilobular area. The specific toxicity of monocrotaline is that of its reactive metabolite, monocrotaline pyrrole, which binds covalently to the actin microfilaments of endothelial cells.10Tandon B.N. Tandon H.D. Tandon R.K. Narmdranathan M. Joshi Y.K. An epidemic of hepatic veno-occlusive disease in central India.Lancet. 1976; ii: 271Abstract Scopus (100) Google Scholar The F-actin depolymerizes leading to disassembly of the actin cytoskeleton and rounding up of the endothelial cells. Increased expression and release of matrix metalloproteinase-9 into the extracellular space leads to breakdown of the extracellular matrix in the space of Disse, permitting further dehiscence of the endothelial cells.31DeLeve L.D. Ito Y. Bethea N.W. McCusky M.K. Wang X. McCuskey R.S. Embolization by sinusoidal lining cells obstructs the microcirculation in rat sinusoidal obstruction syndrome.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G1045-G1052PubMed Google Scholar These experiments gave rise to the premise that SECs are more susceptible to toxic injury than hepatocytes. Key pathogenic factors include SEC glutathione depletion, nitric oxide depletion, increased expression of matrix metalloproteinases and vascular endothelial growth factor (VEGF), and activation of clotting factors.32Helmy A. Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome.Aliment Pharmacol Ther. 2006; 23: 11-25Crossref PubMed Scopus (50) Google Scholar In the first instance, drugs leading to SOS are metabolized exclusively by the hepatocellular cytochrome P450 systems, for which glutathione is an antioxidant recovery mechanism. Hepatic exposure to these drugs leads to depletion of glutathione. Severe depletion of glutathione levels in SECs renders them susceptible to cell death; prophylactic infusion of glutathione or N-acetyl cysteine prevents the development of SOS in the monocrotaline-treated rat model31DeLeve L.D. Ito Y. Bethea N.W. McCusky M.K. Wang X. McCuskey R.S. Embolization by sinusoidal lining cells obstructs the microcirculation in rat sinusoidal obstruction syndrome.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G1045-G1052PubMed Google Scholar; post-hoc administration of glutathione reduces the degree of sinusoidal injury, but does not prevent it. Additional evidence in favor of the central role of glutathione depletion includes the predisposition to SOS in humans with a glutathione S-transferase M1 (GSTM1) null genotype who are undergoing bone marrow transplantation33Srivastava A. Poonkuzhali B. Shaji R.V. et al.Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation.Blood. 2004; 104: 1574-1577Crossref PubMed Scopus (81) Google Scholar or receiving oxaliplatin for metastatic colon cancer.34Vreuls C.P.H. Olde Damink S.W.M. Koek G.H. et al.Glutathione S-transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer.Br J Cancer. 2013; 108: 676-680Crossref PubMed Scopus (4) Google Scholar In the second instance, nitric oxide levels in the hepatic vein of rats decrease during induction of SOS,35DeLeve L.D. Wang X. Decrease in nitric oxide production contributes to hepatic venoocclusive disease.Hepatology. 1999; 30: 218AGoogle Scholar and induction of SOS can either be exacerbated by administration of N(G)-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide synthase, or be mitigated by infusion of V-YRRO/NO, a liver-selective nitric oxide donor prodrug,36DeLeve L.D. Wang X. Kanel G.C. et al.Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome.Hepatology. 2003; 38: 900-908Crossref PubMed Google Scholar Beyond providing evidence for nitric oxide depletion in the pathogenesis of SOS,35DeLeve L.D. Wang X. Decrease in nitric oxide production contributes to hepatic venoocclusive disease.Hepatology. 1999; 30: 218AGoogle Scholar a role for vasoconstriction also is implicated, since adequate nitric oxide levels inhibit vasoconstriction of hepatic stellate cells, which invest the hepatic sinusoidal from within the space of Disse.37Ueno T. Bioulac-Sage P. Balabaud C. Rosenbaum J. Innervation of the sinusoidal wall: regulation of the sinusoidal diameter.Anat Rec A Discov Mol Cell Evol Biol. 2004; 280: 868-873Crossref PubMed Scopus (18) Google Scholar Matrix metalloproteinase-9 expression increases early in the rat monocrotaline-induced SOS model; later there is a lower magnitude increase in matrix metalloproteinase-2. SECs are the major source of both basal and monocrotaline-induced enzyme expression and release. Administration of matrix metalloproteinase inhibitors prevents the development of experimental SOS.38DeLeve D.L. Wang X. Tsai J. Kanel G. Strasberg S. Tokes Z.A. Sinusoidal obstruction syndrome (veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition.Gastroenterology. 2003; 125: 882-890Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar This implicates degradation of the extracellular matrix within the space of Disse as contributing to loss of endothelial cell adhesion. Using the rat model of monocrotaline-induced SOS, DeLeve and associates also have demonstrated that constituitive bone marrow stem cell repair of sinusoidal endothelial cells (SEC) is critical to maintenance of the sinusoidal architecture.39Harb R. Xie G. Lutzko C. et al.Bone marrow progenitor cells repair hepatic sinusoidal endothelial cells after liver injury.Gastroenterology. 2009; 137: 704-712Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Bone marrow suppression by irradiation, by impairing this SEC repair mechanism, may contribute to the pathogenesis of SOS. The role of VEGF as an angiogenic factor is less clearcut. Iguchi et al observed increased serum levels of VEGF during development of SOS in human patients,40Iguchi A. Kobayashi R. Yoshida M. et al.Vascular endothelial growth factor (VEGF) is one of the cytokines causative and predictive of hepatic veno-occlusive disease (VOD) in stem cell transplantation.Bone Marrow Transplant. 2001; 27: 1173-1180Crossref PubMed Scopus (35) Google Scholar leaving open the question of whether VEGF-induced acceleration of vasopermeability, neovascularization, and/or expression of coagulopathic tissue factors on circulating mononuclear cells may play a role in SOS pathogenesis.32Helmy A. Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome.Aliment Pharmacol Ther. 2006; 23: 11-25Crossref PubMed Scopus (50) Google Scholar Nakamura et al41Nakamura K. Hatano E. Narita M. et al.Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9.J Hepatol. 2012; 57: 1037-1043Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar hypothesized that antiangiogenic agents may protect against SOS, and chose to use sorafenib to test this hypothesis. Sorafenib is a multiple receptor tyrosine kinase inhibitor that inhibits multiple tyrosine kinases including the VEGF receptor-2 (VEGFR-2) and -3 (VEGFR-3). Its primary use is as standard treatment for hepatocellular carcinoma and renal cell carcinoma, but it may also have an antifibrotic effect in the liver and prevent the development of portal hypertension.42Mejias M. Garcia-Pras E. Tiani C. Miquel R. Bosch J. Fernandez M. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats.Hepatology. 2008; 49: 1245-1256Crossref Scopus (111) Google Scholar, 43Wang Y. Gao J. Zhang D. Ma J. Jiang H. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis.J Hepatol. 2010; 53: 132-144Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Nakamura treated rats with sorafenib before induction of SOS by monocrotaline prior to partial hepatectomy, and demonstrated significant suppression of the morphological features of SOS, with significant improvement in post-hepatectomy survival.41Nakamura K. Hatano E. Narita M. et al.Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9.J Hepatol. 2012; 57: 1037-1043Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar While loss of endothelial cells was not completely blocked, it did suppress degradation of extracellular matrix in the space of Disse and uplift of the endothelial cells. Hence, although the link to VEGF is not proven owing to the broad inhibitory action of sorafenib on tyrosine kinases, remodeling of the extracellular matrix in the space of Disse is demonstrated to be a contributing factor to the dehiscence of sinusoidal endothelial cells in the development of SOS. Recent technological advances in radiation therapy have sparked renewed interest in understanding radiation-induced liver disease (RILD)44Yannam G.R. Han B. Setoyama K. et al.A nonhuman primate model of human radiation-induced venoocclusive liver disease and hepatocyte injury.Int J Radiat Oncol Biol Phys. 2013; (Accessed 1.01.14)https://doi.org/10.1016/j.ijrobp.2013.10.037Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Although whole-liver irradiation has generally been restricted to 30–35 Gy in standard daily fractions of 1.8–2.0 Gy owing to risk of lethal RILD above these levels, intensity-modulated radiation therapy, 3-dimensional conformal radiation treatment planning, and organ and tumor motion tracking enable treatment of liver cancer with fewer but larger dose fractions.45Rusthoven K.E. Kavanagh B.D. Cardenes H. et al.Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases.J Clin Oncol. 2009; 27: 1572-1578Crossref PubMed Scopus (219) Google Scholar This innovation is called “hypofractionated stereotactic body RT”. Returning to the original Cynomolgus monkey model of RILD,26Allen J.R. Carstens L.A. Katagiri G.J. Hepatic veins of monkeys with veno-occlusive disease. Sequential ultrastructural changes.Arch Pathol. 1969; 87: 279-289PubMed Google Scholar Yannam et al44Yannam G.R. Han B. Setoyama K. et al.A nonhuman primate model of human radiation-induced venoocclusive liver disease and hepatocyte injury.Int J Radiat Oncol Biol Phys. 2013; (Accessed 1.01.14)https://doi.org/10.1016/j.ijrobp.2013.10.037Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar recently conducted an escalated dose study to examine the effect of newer hypofractionated regimes on the liver. The authors demonstrated a higher tolerance for hypofractionated radiation, but that the characteristic histological lesions of SOS still developed at radiation doses above 40 Gy. However, a key additional finding was that metabolic stress on the liver, such as glucose loading or administration of total parenteral nutrition, produced substantial additional hepatic injury and generated hepatic failure. This points towards radiation-induced hepatocellular injury as a key component of RILD. Although this injury may be secondary to inadequate blood supply to perivenous hepatocytes per se, a broader level of injury to the parenchyma may also be operative owing to upstream impairment of sinusoidal blood flow. In separate work, a new rodent model for oxaliplatin-induced SOS has been developed,46Robinson S.M. Mann J. Vasilaki A. et al.Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model.J Hepatol. 2013; 59: 318-326Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar owing to the importance of this form of chemotherapy for advanced colorectal cancer (vide infra). The model consisted of intra-peritoneal administration of FOLFOX (folinic aci