Toxic Injury to Hepatic Sinusoids: Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease)

• ABSTRACT
• HISTORICAL PERSPECTIVES
• CLINICAL FEATURES OF SOS AFTER MYELOABLATIVE THERAPY
• Incidence
• Clinical Presentation and Diagnosis
• Laboratory Studies
• Ultrasonography, Computed Tomography, and Magnetic Resonance Imaging
• Liver Biopsy and Hepatic Venous Pressure Gradient
• Differential Diagnosis
• Clinical Course and Prognosis
• HISTOLOGIC FEATURES OF SOS: HUMAN STUDIES
• Early Histologic Abnormalities
• Later Histologic Finding: Stellate Cell Proliferation and Collagenization
• Correlation of Histologic Findings with Clinical Signs
• PATHOPHYSIOLOGY OF SINUSOIDAL INJURY: ANIMAL MODELS
• PATHOPHYSIOLOGY OF SINUSOIDAL INJURY: CLINICAL STUDIES
• Chemotherapy Drugs
• Total Body Irradiation
• Intrahepatic Coagulation
• Stellate Cells and Sinusoidal Fibrosis
• Vasoactive Mediators
• Renal Pathophysiology in SOS
• PREVENTION OF SOS IN PATIENTS RECEIVING MYELOABLATIVE THERAPY
• Alterations of Doses of Conditioning Therapy
• Anticoagulant or Antithrombin Infusions
• Other Medical Prophylaxis
• TREATMENT OF PATIENTS WITH SOS FOLLOWING MYELOABLATIVE THERAPY
• Thrombolytic Therapy
• Defibrotide
• Other Medical Therapies
• Transjugular Intrahepatic Portosystemic Shunt
• Surgical Approaches
• ACKNOWLEDGMENTS
• ABBREVIATIONS
• REFERENCES

ABSTRACT

The term veno-occlusive disease of the liver refers to a form of toxic liver injury characterized clinically by the development of hepatomegaly, ascites, and jaundice, and histologically by diffuse damage in the centrilobular zone of the liver. The cardinal histologic features of this injury are marked sinusoidal fibrosis, necrosis of pericentral hepatocytes, and narrowing and eventual fibrosis of central veins. Recent studies suggest that the primary site of the toxic injury is sinusoidal endothelial cells, followed by a series of biologic processes that lead to circulatory compromise of centrilobular hepatocytes, fibrosis, and obstruction of liver blood flow. Thus we propose a more appropriate name for this form of liver injury-sinusoidal obstruction syndrome. This review encompasses historical perspectives, clinical manifestations of sinusoidal obstruction syndrome in the setting of hematopoietic cell transplantation, histologic features of centrilobular injury, and a discussion of the pathophysiology of sinusoidal injury, based on both animal and clinical investigations.

HISTORICAL PERSPECTIVES

South Africa was the source of the first description of hepatic veno-occlusive disease (VOD) in humans[1] and the first recognition of the vascular origin of the disease.[2] Bras and colleagues in Jamaica coined the name hepatic veno-occlusive disease [3] to describe obliterative fibrosis within small hepatic venules, a feature readily observed by light microscopy. With the recognition that the injury is initiated by changes in the sinusoid[4] (see later section on pathophysiology) and that involvement of hepatic venules is not essential to development of clinical signs and symptoms,[5] we propose that the disease be renamed sinusoidal obstruction syndrome (SOS).

Until the advent of chemotherapy in the 1950s, the only recognized cause of SOS was the ingestion of herbal teas or food sources containing pyrrolizidine alkaloids, found in botanically unrelated plant species (Crotalaria, Heliotropium, Senecio, and, less frequently, Symphytum [comfrey]). Epidemics of SOS have occurred in underdeveloped nations due to consumption of bread made from inadequately winnowed wheat contaminated by seeds from Crotalaria, Heliotropium, and Senecio. [6] [7] There have been numerous reports of SOS related to long-term use of azathioprine for immunosuppression after renal and liver transplantation.[8] [9] [10] [11] [12] [13] Interestingly, there has often been coincident peliosis hepatis, nodular regenerative hyperplasia, or sinusoidal dilatation in the livers of patients with SOS due to azathioprine. Damage to sinusoidal endothelial cells and sometimes to hepatic venular endothelial cells seems to be the common link in these four types of liver injury.[11] [14] [15] [16] [17] [18] Chemotherapeutic agents associated with SOS at conventional doses include gemtuzumab ozogamicin, actinomycin D, dacarbazine, cytosine arabinoside, mithramycin, 6-thioguanine, urethane, indicine N-oxide (a pyrrolizidine alkaloid used as an experimental chemotherapeutic agent to treat leukemia), and chemotherapy combinations.[19] [20] [21] Combinations of irradiation and chemotherapy also may lead to SOS, for example, treatment of nephroblastoma (Wilms' tumor) with dactinomycin and abdominal irradiation.[22] [23] A variant of SOS, radiation-induced liver disease, is seen with radiation doses in excess of 30 to 35 Gy in adults.[24] Although radiation-induced liver disease shares some of the features of SOS, there are significant differences in the clinical presentation, histology, and time course. Recognition of SOS in marrow transplant patients came almost simultaneously from Australia, the United States, and South Africa.[25] [26] [27] Conditioning regimens used for marrow ablation are by far the most common cause of SOS, and will be the focus of this review.

CLINICAL FEATURES OF SOS AFTER MYELOABLATIVE THERAPY

Incidence

The incidence of SOS after stem cell transplantation varies from 0 to 50%, due largely to differences in conditioning regimens.[28] [29] [30] [31] [32] [33] There is no liver toxicity from newer, nonmyeloablative conditioning regimens, for example, fludarabine plus low-dose total body irradiation (TBI),[34] but regimens of cyclophosphamide and TBI of greater than 13.2 Gy may cause SOS in half of patients.[28] A major contributor to development of SOS after cyclophosphamide-based conditioning regimens is individual variability in drug metabolism.[35] Overall, the frequency and severity of SOS have fallen dramatically over the past few years, for several reasons: (a) transplantation physicians have retreated from the strategy of dose escalation of conditioning regimens in favor of nonmyeloablative regimens or regimens that do not contain cyclophosphamide; (b) a major risk factor for severe SOS, chronic hepatitis C,[36] has almost disappeared from populations of patients presenting for transplantation; (c) drugs that increase the risk of SOS (e.g., norethisterone[37]) have been removed from transplantation care protocols; and (d) patients are undergoing transplantation sooner after diagnosis of leukemia and arrive for transplantation in a healthier state.

Clinical Presentation and Diagnosis

Sinusoidal obstruction syndrome is defined by the clinical syndrome of tender hepatomegaly, fluid retention and weight gain, and elevated serum bilirubin that follows cytoreductive therapy, in the absence of other explanations for these signs and symptoms.[28] [31] The onset of SOS is heralded by an increase in liver size, right upper quadrant tenderness, renal sodium retention, and weight gain, occurring 10 to 20 days after the start of cyclophosphamide-based cytoreductive therapy[28] and later after other myeloablative regimens.[33] [38] [39] Patients then develop hyperbilirubinemia, usually before day 20.[28] Some researchers have described a syndrome of ``late VOD'' following conditioning with busulfan-containing regimens, where signs of liver disease are first recognized after day 30.[33] [39]

Laboratory Studies

Measurement of serum total serum bilirubin is a sensitive test for SOS but not a specific one, because there are many causes of jaundice after transplantation, for example, cholestasis from sepsis, acute graft-versus-host disease (GVHD), hemolysis, renal insufficiency, and cyclosporine therapy.[40] Elevations of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) can occur in the course of SOS and probably reflect ischemic hepatocyte necrosis, because peak levels are seen weeks after toxin exposure.[41] [42] A serum AST level over 750 U/L in patients with SOS is one marker of a poor prognosis.[41] [42] Several plasma proteins have been reported to be abnormally high in patients with SOS, including endothelial cell markers (hyaluronic acid, von Willebrand factor, plasminogen activator inhibitor-1 [PAI-1], tissue plasminogen activator), thrombopoietin, cytokines (tumor necrosis factor-α[TNF-α], transforming growth factor-β, interleukins-1, -2, -6, and -8, and soluble interleukin-2 [IL-2] receptor), and procollagen peptides.[43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] Some laboratory tests are abnormally low in patients with SOS, including the anticoagulant proteins protein C and antithrombin III[56] [57] and platelet counts.[28] [58] It is not clear whether any of these tests have diagnostic or prognostic utility beyond the clinical criteria of weight gain, jaundice, and hepatomegaly, although levels of PAI-1 and IL-8 have been proposed for this role.[53] [55] Serum levels of collagen peptides, however, appear to reflect the extent of sinusoidal fibrosis, probably the most important prognostic variable.[5]

Ultrasonography, Computed Tomography, and Magnetic Resonance Imaging

Imaging studies of the liver are useful for demonstrating hepatomegaly, ascites, and attenuated hepatic venous flow consistent with SOS,[59] [60] [61] as well as the absence of biliary dilation or infiltrative lesions in the liver and hepatic veins that might also explain hepatomegaly and jaundice.[62] Other ultrasonographic findings that have been reported more frequently in patients with SOS, compared with posttransplantation controls, include gallbladder wall thickening, splenomegaly, visualization of a paraumbilical vein, enlarged portal vein diameter, slow or reversed portal vein flow, high congestion index, portal vein thrombosis, and increased resistive index to hepatic artery flow.[60] [61] [63] [64] [65] [66] [67] Unfortunately, ultrasonographic findings very early in the course of SOS do not appear to add to the information provided by clinical criteria.[59] [68] Later in the course of SOS, especially in patients with severe disease, ultrasonographic evidence of altered liver blood flow, particularly reversal of portal flow and portal vein thrombosis,[66] [67] is more common. There may be value in following vascular parameters as indices of improvement in sinusoidal blood flow.

Liver Biopsy and Hepatic Venous Pressure Gradient

In cases where the diagnosis is unclear, a transvenous approach that allows both biopsy (using a Mansfield or Cordes forceps or a needle device) and hepatic venous pressure measurements is the most accurate diagnostic test.[69] [70] Percutaneous or laparoscopic needle biopsy are alternative methods of obtaining liver tissue but pose a high risk of bleeding in the thrombocytopenic patient,[71] whereas transvenous biopsy methods can be performed safely with platelet counts as low as 30,000/mm³. In hematopoietic cell transplant patients, a hepatic venous pressure gradient (using an occlusive balloon technique) of greater than 10 mm Hg is highly specific for SOS.[69] [70]

Differential Diagnosis

Other causes of posttransplantation jaundice seldom lead to renal sodium avidity, rapid weight gain, and hepatomegaly before the onset of jaundice.[40] [72] There are patients who present with jaundice and weight gain that can be confused with SOS.[62] [73] The most common combinations of illnesses that mimic SOS are (a) sepsis syndrome requiring large volumes of crystalloid, followed by renal insufficiency and sepsis-related cholestasis; (b) cholestatic liver disease, hemolysis, and congestive heart failure; and (3) hyperacute GVHD and sepsis syndrome. SOS also may coexist with these disease processes.

Clinical Course and Prognosis

The severity of SOS has been classified as mild (SOS that is clinically obvious, requires no treatment, and resolves completely), moderate (SOS that causes signs and symptoms requiring treatment such as diuretics or pain medications, but that resolves completely), or severe (SOS that requires treatment but that does not resolve before death or day 100).[28] [31] [32] [74] There is a range of clinical and laboratory findings that correspond to these operational definitions of disease severity (Table [1]).[28] Some patients have subclinical liver damage, evinced by histologic evidence of liver toxicity in the absence of clinical signs and symptoms.[41] Published case fatality rates for SOS after hematopoietic cell transplantation range from 0 to 67%.[28] [30] [31] [32] [33] [75] These figures are dependent on the definition of both SOS and what constitutes fatal SOS. Recovery from SOS was seen in over 70% of patients whose SOS followed cyclophosphamide-containing regimens and in 84% when SOS was caused by other alkylating agents.[28] [32] [38] Despite deep jaundice, patients with severe SOS seldom die of liver failure, but rather from renal and cardiopulmonary failure.[28] [31] [76] [77] A clinically useful model, derived from rates of increase of both bilirubin and weight in the first 2 weeks following transplantation, can predict the outcome of SOS after cyclophosphamide-based regimens.[78] In some patients, there is a bimodal presentation of SOS, that is, clinical signs of SOS appear shortly after transplantation, then wane, then reappear later; this pattern is associated with a worse prognosis.[38] In some cases, signs of SOS resolve, but ascites recurs following development of inflammatory liver disease (e.g., GVHD). A poor prognosis correlates with higher serum AST and ALT values, higher wedged hepatic venous pressure gradient, development of portal vein thrombosis, doubling of the baseline serum creatinine, and decreasing oxygen saturation.[42] [67] [69] [70] [79]

HISTOLOGIC FEATURES OF SOS: HUMAN STUDIES

Liver biopsy and autopsy specimens over an 80-day period reveal that the histology of injury to sinusoids, hepatocytes, and venules may be rapidly progressive (Fig. [1]). Trichrome connective tissue stains are critical in outlining venules, sinusoids, and hepatocyte cords. Other stains (e.g., Verhoeff-van Gieson and reticulin) are complementary. Serial sections are needed to identify characteristic histologic changes that may not be present in all levels.

Early Histologic Abnormalities

Histologic data do not elucidate the primary site of injury or molecular events that occur in the sinusoids before clinical signs of SOS appear. The first recognizable histologic change of liver toxicity, occurring 6 to 8 days after cytoreductive or myeloablative therapy, is widening of the subendothelial zone between the basement membrane and the adventitia of central veins and sublobular veins (Fig. [1]B and E).[5] [41] [80] [81] Within the edematous subendothelium are fragmented red cells and bits of cellular debris. Accompanying the venular changes are dilation and engorgement of sinusoids, extravasation of red cells through the space of Disse, and frank necrosis of perivenular hepatocytes-findings that often appear more widespread and severe than the extent of venular injury (Fig. [1]A, B, and E). This is reflected in tissue stained with anticytokeratin antibody (a marker of hepatocyte viability) that shows markedly diminished staining of centrizonal hepatocytes.[81] One morphologic consequence of sinusoidal obstruction, ischemia, elevated sinusoidal pressures, and fragmentation of hepatocyte cords is dislodgement of clusters of hepatocytes that may flow retrograde into portal veins or embolize through disrupted pores into lumina of damaged central veins (Fig. [1]C). Immunohistology studies demonstrate deposition of fibrinogen and Factor VIII/von Willebrand factor, but not platelet antigens, in the perivenular zone and in the widened subendothelial space of venules (but not within venular lumens), corresponding to clogging of pores that drain sinusoids into the venules (Fig. [1]D).[81] Electron microscopy studies show closure of fenestrae in sinusoidal endothelial cells and accumulation of extracellular material (collagen, possibly fibrin) in sinusoidal pores.[80]

Later Histologic Finding: Stellate Cell Proliferation and Collagenization

Within 2 weeks of the onset of clinical signs of SOS, curvilinear deposits of extracellular matrix can be seen in subendothelial spaces and in sinusoids (Fig. [1]C and E). Immunostaining for activated stellate cells with α smooth muscle actin antibodies demonstrates a marked increase in the number of stellate cells lining the sinusoids (Fig. [1]G)[82] [83] that are clogged by types I, III, and IV collagen.[81] We speculate that the bimodal pattern of clinical manifestations of SOS that is seen in some patients reflects early sinusoidal injury followed later by proliferation of stellate cells and deposition of matrix in sinusoids. The later stages of fatal SOS (i.e., beyond day 50 following cyclophosphamide-based regimens or earlier, following gemtuzumab ozogamicin infusions[19] [20]) are characterized by extensive collagenization of sinusoids and venules (Fig. [1]F and H). In some cases, there is coalescence of extinguished perivenular zones with fibrous bridging between central veins, simulating cardiac cirrhosis (Fig. [1]H).

Correlation of Histologic Findings with Clinical Signs

In retrospective autopsy studies, 20 to 30% of cases with occluded venules were without clinical symptoms.[31] [41] Furthermore, several perivenular lesions were reported to correlate with signs of SOS in the absence of venular occlusion.[41] A coded review of histologic features in a cohort of 76 consecutive necropsy patients found that the strongest statistical associations with clinically severe SOS were hepatocyte necrosis, sinusoidal fibrosis, eccentric localized thickening of the subendothelial zone of the venule, phlebosclerosis, and an estimate of venular narrowing.[5] Moreover, the number of such histologic changes present was proportional to the clinical severity of SOS.

PATHOPHYSIOLOGY OF SINUSOIDAL INJURY: ANIMAL MODELS

In vitro studies have shown that sinusoidal endothelial cells are more susceptible than hepatocytes to drugs that cause SOS.[17] [84] [85] This is consistent with in vivo studies conducted in the rat monocrotaline model. Monocrotaline, the pyrrolizidine alkaloid found in Crotalaria, is one of the best-studied toxins involved in SOS. The monocrotaline model of SOS has the same histologic characteristics as the human disease, as well as the same ``clinical features,'' i.e., hyperbilirubinemia, hepatomegaly, and ascites formation. In this model the first morphologic change noted by electron microscopy is loss of sinusoidal endothelial cell fenestration and the appearance of gaps in the sinusoidal endothelial cell barrier.[4] Studies with in vivo microscopy and confirmation by electron microscopy have shown that sinusoidal endothelial cells round up, and red blood cells begin to penetrate into the space of Disse beneath the rounded up endothelial cells and dissect off the sinusoidal lining. The sloughed sinusoidal lining cells (i.e., Kupffer cells, sinusoidal endothelial cells, and stellate cells) embolize downstream and obstruct sinusoidal flow.[86] By the time hepatocyte necrosis is observed, there is extensive denudation of the sinusoidal lining. Early on there is loss of Kupffer cells, but there is a significant influx of monocytes within the sinusoids, which exacerbates the obstruction of sinusoidal flow by the embolized sinusoidal lining cells. In summary, the major findings of these studies are that the initiating event of SOS is rounding up or swelling of sinusoidal endothelial cells and that this leads to dissection of the sinusoidal lining, which embolizes and blocks the microcirculation.

In addition to the morphologic changes described above, a number of biochemical changes have been observed in the experimental studies. Drugs and toxins that cause SOS profoundly deplete sinusoidal endothelial cell glutathione prior to cell death, and support of sinusoidal endothelial cell glutathione prevents cell death.[84] [85] [87] Continuous infusion of glutathione or N-acetylcysteine into the portal vein prevents the morphologic changes of SOS observed by light microscopy, electron microscopy, and in vivo microscopy, as well as the ``clinical features'' of SOS.[88] Infusion of glutathione 24 hours after treatment with monocrotaline attenuated, but did not prevent, SOS. Interestingly, discontinuation of the glutathione infusion several days after monocrotaline has been eliminated from the rat leads to accelerated development of full-blown SOS. Thus, initially glutathione may protect (partially) by preventing profound glutathione depletion. However another mechanism for protection must be invoked to explain glutathione protection several days after monocrotaline has been eliminated. Because full-blown SOS in this model normally takes 72 hours to develop, the development of SOS within 24 hours after discontinuation of glutathione indicates that glutathione is suppressing a persistent change in the sinusoid. The benefit of GSH described above is consistent with improved survival after administration of monocrotaline in rats treated with glutathione monoethyl ester.[89]

One possible explanation for the rounding up of sinusoidal endothelial cells may be increased activity of matrix metalloproteinases (MMPs). Because MMPs degrade extracellular matrix, increased MMP activity on the ablumenal side of the sinusoidal endothelial cell would allow the cells to let loose from the space of Disse. In the experimental model, de novo synthesis of MMP-9 (gelatinase B) and increased MMP-9 activity occur 12 hours after monocrotaline, which coincides with rounding up of the sinusoidal endothelial cells.[90] Inhibition of MMP activity completely prevents SOS. MMP expression and activity are regulated by redox status and can be suppressed by glutathione and N-acetylcysteine.[91] [92] [93] [94] Thus, the protective effect of glutathione and N-acetylcysteine may be (partially) due to inhibition of MMP activity.

In the in vivo model, hepatic vein nitric oxide decreases in parallel with the changes in sinusoidal flow.[95] Inhibition of nitric oxide elicits severe SOS due to a subtoxic dose of monocrotaline, whereas nitric oxide (NO) precursors prevent the morphologic changes and ``clinical features'' of SOS.[95] Interestingly, tonic release of NO by endothelial cells reduces MMP-9 expression, whereas inhibition of NO synthesis increases cytokine-stimulated MMP-9 expression.[96] Future studies will need to determine whether the contribution of decreased hepatic NO to SOS occurs through increased MMP-9 synthesis.

Although SOS is defined as a nonthrombotic obstruction of flow, the issue of clotting has been a recurring topic, based largely on plasma studies in patients with SOS.[97] However, electron microscopy of pyrrolizidine alkaloid-induced SOS in humans did not detect clotting.[98] Sequential observations during the development of SOS in the experimental model by in vivo microscopy and electron microscopy have not demonstrated any evidence of clotting.[4]

PATHOPHYSIOLOGY OF SINUSOIDAL INJURY: CLINICAL STUDIES

Pharmacokinetics of chemotherapy drugs and radiation dosimetry are the most important determinants of SOS after transplantation, but there are also events that follow toxic injury that appear to be prognostically important. In addition, some patients are at risk because of risk factors for fatal SOS, for example, hepatitis C, nonalcoholic steatohepatitis, and systemic bacterial or viral infection before the start of cytoreductive therapy.[28] [36] Previous radiation therapy that involved the liver and previous stem cell transplantation are also predisposing factors.[28] [37] [38] [99] Two observations about SOS in patients provide clues as to the mechanism of disease. First, unlike other intrinsic liver diseases, the signs and symptoms of portal hypertension precede evidence of parenchymal damage. In SOS, disruption of the liver circulation is the cause and not the consequence of the parenchymal disease. Second, involvement of the hepatic veins is not essential to the development of clinical signs: 45% of patients with mild or moderate disease and 25% of patients with severe SOS did not have occluded hepatic venules at autopsy.[5] Occlusion of central veins is associated with more severe disease and the development of ascites.[5] [100] This suggests that venular lesions exacerbate the circulatory impairment that occurs at the level of the sinusoid.

Chemotherapy Drugs

Cyclophosphamide is common to the transplantation conditioning regimens with the highest incidence of fatal SOS.[28] The metabolism of cyclophosphamide is highly variable; patients who generate a greater quantity of toxic metabolites are more likely to develop severe SOS following conditioning with cyclophosphamide and TBI.[35] [101] The liver toxin generated by cyclophosphamide metabolism is acrolein (a metabolite formed simultaneously along with the desired metabolite, phosphoramide mustard), via mechanisms dependent on glutathione.[84] [89] [102] [103] Busulfan is another component of regimens with a high frequency of SOS. A relationship between busulfan exposure (measured by the area under the curve or average steady-state concentration) following oral dosing and the toxicity of conditioning therapy has been reported.[104] [105] [106] [107] [108] However, in adults with chronic myeloid leukemia in chronic phase and children with acute leukemia, there is no relationship between busulfan exposure and SOS.[106] [109] [110] [111] Busulfan may contribute to liver injury by inducing oxidative stress, reducing glutathione levels in hepatocytes and sinusoidal endothelial cells,[112] and altering cyclophosphamide metabolism.[101] When cyclophosphamide is given before busulfan, a lower frequency of SOS results, suggesting that busulfan predisposes patients to cyclophosphamide toxicity.[113] Most transplantation centers now dose oral busulfan according to its metabolism or give intravenous doses of busulfan, with more predictable kinetics and less overall toxicity.[114] [115] SOS also has been described as dose limiting for regimens that contain high dose BCNU (1,3-bis(2-chbroethyl)-1-nitrosourea), carboplatin, or cytarabine.[75]

Total Body Irradiation

The doses of TBI given in the setting of hematopoietic cell transplantation are in the range of 10 to 16 Gy, far less that the dose of liver irradiation that causes radiation-induced liver disease.[24] [116] In combination with cyclophosphamide, however, there is a clear relationship between the total dose of TBI and the frequency of severe SOS.[28] [35] The relationship of irradiation technique to SOS is controversial, with one study showing such a relationship[117] and three studies showing no association.[28] [118] [119] The source of radiation for TBI also may be important, because the dose rate differs between radiation from opposing cobalt sources versus a linear accelerator.

Intrahepatic Coagulation

Some see SOS as a disease of disordered coagulation, in which damage to endothelium in the sinusoids and central veins leads to exposure of tissue factor and initiation of the coagulation cascade, a process abetted by low circulating levels of the natural anticoagulants protein C and antithrombin III, elaboration of cytokines that stimulate coagulation, high plasma levels of tissue plasminogen activator, and reduced fibrinolysis (reflected by elevated plasma levels of PAI-1).[53] [57] [120] [121] [122] [123] [124] However, heparin and antithrombin III infusions are ineffective in preventing SOS, and thrombolytic therapy effects improvement in only a minority of patients.[32] [79] [125] [126] [127] [128] [129] [130] [131] Genetic disorders predisposing to coagulation (Factor V Leiden and prothrombin gene 20210 G-A) have weak or no associations with SOS after transplantation.[132] [133] Disordered coagulation in SOS is probably an epiphenomenon secondary to widespread centrilobular damage, not a cause of damage.

Stellate Cells and Sinusoidal Fibrosis

Several series have documented the early appearance of a procollagen peptide in serum in patients who develop more severe SOS, along with inhibitors of fibrolysis,[47] [48] [52] [134] consistent with the intense fibrosis in centrilobular sinusoids and venular walls that is common in fatal SOS (Fig. [1]F and H).[5] [19] [20] The stimuli for stellate cell activation and proliferation in the transplantation setting have not been identified; candidates include centrilobular hypoxia, endotoxemia, Kupffer cell damage, loss of sinusoidal endothelial cells, and a melange of circulating growth factors and cytokines (platelet-derived growth factor, transforming growth factor-β, TNF-α, IL-8, and soluble IL-2 receptor).[44] [45] [54] [55] [135] [136] [137] Not all series have found cytokine levels to be elevated in patients with SOS.[50] [138]

Vasoactive Mediators

Serum levels of endothelin-1 are elevated in patients with SOS.[138] [139] Low plasma levels of nitrate are also seen during conditioning therapy.[138] [139] These data are consistent with the hypothesis that endothelin-1 is a mediator of hepatic sinusoidal constriction, unopposed by a vasorelaxant effect of endothelial nitric oxide.

Renal Pathophysiology in SOS

Decreasing fractional excretion of sodium occurs just before the clinical signs of SOS become apparent, reflecting both sinusoidal hypertension[69] [70] and renal tubular injury caused by metabolites of cyclophosphamide.[140] Plasma levels of nitrate increase sharply during fluid accumulation in patients who develop moderate to severe SOS.[139]

PREVENTION OF SOS IN PATIENTS RECEIVING MYELOABLATIVE THERAPY

The only certain way to prevent fatal SOS is to avoid giving hepatotoxic conditioning therapy to patients at high risk: (a) nonfatal SOS following previous chemotherapy or radiation therapy to the liver; (b) second transplants with myeloablative regimens[99]; (c) hepatic inflammation[28] [36]; and (d) extensive hepatic fibrosis or cirrhosis.[141] [142]

Alterations of Doses of Conditioning Therapy

The use of nonmyeloablative regimens that contain no liver toxins, followed by allogeneic transplantation, may be the only method of avoiding SOS in patients with underlying hepatic fibrosis.[34] Altering myeloablative conditioning regimens has been reported to lessen the risk of SOS, for example, adjusting oral doses of busulfan in individual patients based on busulfan disposition[104] [143] or giving busulfan as an intravenous preparation.[115] However, other studies of busulfan dosing based on steady-state concentrations have not shown benefit in preventing SOS.[109] [110] [111] [144] Giving intravenous busulfan along with cyclophosphamide does not eliminate fatal SOS, lending credence to cyclophosphamide as the more important liver toxin in this regimen.[115] Administering cyclophosphamide before busulfan[113] and giving irradiation doses of 10 Gy at 2 to 4 cGy/min may result in a lower incidence of SOS.[32] [145] [146] Fractionated doses of BCNU are associated with a lower incidence of SOS than are single doses.[147] Shielding the liver during TBI will lessen liver injury but leads to relapse of underlying hematologic disease.[148] Another approach for conditioning a patient who has risk factors for fatal SOS is to choose a regimen that does not contain cyclophosphamide.

Anticoagulant or Antithrombin Infusions

Anticoagulation with heparin can be given safely if the partial thromboplastin time is monitored carefully.[149] [150] Two randomized studies have reported a reduction in nonfatal SOS with heparin, but had little power to show a benefit in preventing severe SOS.[150] [151] Four additional studies of anticoagulation could find no benefit.[32] [146] [149] [152] Nonetheless, some centers routinely use heparin infusions or low-molecular-weight heparin subcutaneously.[153] [154] Prophylactic antithrombin III infusions effect no reduction in the frequency or severity of SOS despite restoring plasma antithrombin III levels to normal.[125]

Other Medical Prophylaxis

Ursodeoxycholic acid (ursodiol) has been reported to reduce the severity of posttransplantation SOS in two randomized trials,[155] [156] but was without effect in a large randomized Scandinavian study.[157] Two trials have administered prostaglandin E₁ by continuous infusion with no evidence that the frequency of fatal SOS was affected.[158] [159] Because some studies have reported elevated levels of cytokines (including TNF-α) in association with SOS,[44] anticytokine strategies have been studied. Several placebo-controlled, randomized trials have shown pentoxifylline, an inhibitor of TNF-α release, to be ineffective in preventing SOS.[160] [161]

TREATMENT OF PATIENTS WITH SOS FOLLOWING MYELOABLATIVE THERAPY

Because 70 to 85% of patients recover spontaneously, treatment of SOS involves management of sodium and water balance with diuretics and repeated paracenteses for ascites that is associated with discomfort or pulmonary compromise.[28] Renal and pulmonary failure in patients with severe SOS are managed with hemodialysis and mechanical ventilation, albeit with little impact on outcome.[28] [76] [77] [162] In severely ill hematopoietic stem cell transplant patients with SOS and organ failure, there are guidelines that have defined futility of treatment, allowing patients and their physicians to eschew life-support measures when appropriate, or to consider liver transplantation in special circumstances.[162] There is no completely satisfactory treatment for severe SOS, but the literature describes the following approaches.

Thrombolytic Therapy

Tissue plasminogen activator and heparin infusions show evidence of efficacy in less than a third of patients with severe SOS.[79] [126] [127] [128] [129] [130] [131] [163] In one large series, there were no responses when patients had either renal or pulmonary failure.[79] Thrombolytic therapy is further limited by the risk of fatal intracerebral and pulmonary bleeding.[79] [131] [164] [165] Thrombolytic therapy might be considered for treatment of patients with SOS whose prognostic indices[78] point to a greater than 20% estimated risk of fatality provided that renal and lung function are intact.

Defibrotide

Defibrotide, a single-stranded polydeoxyribonucleotide drug derived from animal tissue, has antithrombotic, antiischemic, and thrombolytic properties.[166] Uncontrolled trials with defibrotide in over 100 patients with moderate to severe SOS showed complete resolution in 35 to 55% of patients and no evidence of serious toxicity.[167] [168] Recovery of patients with severe SOS and multiorgan failure is unusual, lending credence to reports of complete recovery following defibrotide infusion.

Other Medical Therapies

Three patients with clinical evidence of moderate to severe SOS have been treated with intravenous N-acetylcysteine at 50 to 150 mg/kg/day for 2 to 4 weeks, during which serum bilirubin and inflammatory markers improved.[137] Patients with SOS have been treated with infusions of human antithrombin III concentrate or activated protein C[125] [169] [170] without clear evidence of efficacy. There are also anecdotal reports of improvement after therapy with prostaglandin E₁,[171] prednisone,[172] topical nitrate,[173] and vitamin E/glutamine therapy.[174]

Transjugular Intrahepatic Portosystemic Shunt

Transhepatic intrahepatic portosystemic shunts (TIPS) have been placed in patients with SOS after hematopoietic cell transplantation.[175] [176] [177] [178] TIPS placement reduces portal pressure and appears effective in mobilizing ascites, but does not have an effect on either serum bilirubin levels or patient outcomes.[177] [178] [179] In one case, TIPS led to acute respiratory distress syndrome that was fatal.[180]

Surgical Approaches

Two patients with SOS underwent successful portosystemic shunts for persistent ascites, but liver dysfunction had resolved long before these shunts were placed.[181] [182] Peritoneovenous shunts for intractable ascites have been unsuccessful. Eleven patients have received liver transplants for severe SOS,[165] [183] [184] [185] [186] [187] [188] [189] four of whom were midterm survivors.[183] [186] [188] [189] When severe SOS develops in a patient with a benign condition (a rare event) or in a patient with a favorable outcome posttransplantation (e.g., chronic myelogenous leukemia in chronic phase), liver transplantation should be considered.

ACKNOWLEDGMENTS

Dr. DeLeve is supported by the National Institutes of Health, NIDDK, Grant DK46357; Drs. McDonald and Shulman are supported by the National Institutes of Health, National Cancer Institute, Grants CA 15704 and CA 18029.

ABBREVIATIONS

ALT alanine aminotransferase

AST aspartate aminotransferase

GSH reduced glutathione

GVHD graft-versus-host disease

MMP matrix metalloproteinase

PAI-1 plasminogen activator inhibitor-1

SOS sinusoidal obstruction syndrome

TBI total body irradiation

TIPS transjugular intrahepatic portosystemic shunt

VOD veno-occlusive disease of the liver

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