The hallmark of HVOD is the appearance of ascites and hepatomegaly that leads to weight gain accompanied by hyperbilirubinemia. The onset of symptoms is approximately 10-20 days after introduction of drugs such as cyclophosphamide into the system, but a longer period between initiation of therapy and disease onset have been reported [8]. Symptoms may last for a prolonged period of time, especially in the setting of continuous unknown ingestion of remedies containing pyrrolizidine alkaloids, whereas a rapidly progressive course of the disease is characteristic of patients in whom HVOD is associated with HSCT [8].

To make the diagnosis of HVOD, it is necessary to obtain a full patient history that will include previous interventions such as organ transplantation or recent use of toxic drugs, as well as the timing and onset of symptoms. A thorough physical examination is equally important in the workup, in order to exclude other potential causes of ascites and hyperbilirubinemia. Because the diagnosis may mimic numerous conditions (graft vs. host disease, cholestasis, viral hepatitis, heart failure, renal failure or malignant disease), two sets of criteria have been proposed in patients [8]. The Seattle criteria mandate two of the following: jaundice, hepatomegaly together with pain in the right upper quadrant and either ascites and/or unexplained weight gain, whereas the Baltimore criteria comprise hyperbilirubinemia and two out of three signs - hepatomegaly, more than 5% increase in body weight or ascites [6]. To facilitate the diagnostic process, ultrasonography and MRI are useful imaging studies that may show narrowing of the hepatic vein, thickening of the gallbladder wall and patchy enhancement of the liver, but most importantly, sinusoidal congestion [6] [8]. Certain studies have shown that serum antigen levels of plasminogen activator inhibitor-1 may serve as a helpful tool in excluding HVOD in HSCT patients [5] [18]. Finally, liver biopsy and evaluation of hepatic vein pressure through the transjugular route may be performed and are effective, but highly risky procedures that may confirm the diagnosis after subsequent histological examination [7] [8]. Thickening of the subintimal zone of central and sublobular venules, marked sinusoidal fibrosis and necrosis of pericentral hepatocytes are main histopathological features of HVOD [19].

Fortunately, between 70-85% of cases resolve spontaneously after discontinuation of the drug or remedy and only supportive therapy in the form of sodium restriction, diuretics and paracentesis for dyspnea and shortness of breath is sufficient for either mild or moderate disease forms [8]. The use of defibrotide [10], a single-stranded phosphodiester oligonucleotide that binds to adenosine receptors and evidently possesses antithrombotic, thrombolytic, anti-inflammatory and anti-ischemic properties through an incompletely understood mechanism, has been evaluated in patients suffering from severe forms of the disease and promising results were obtained in the setting of an early initiation [20]. Due to its superior efficacy over other potential candidates for treatment, it is recommended as first-line therapy in both adults and children [9]. In fact, this drug has shown great results in the treatment of severe forms of infection with multi-organ failure [10]. Methylprednisolone is also considered as a viable adjunctive option in therapy, but it must be cautiously introduced due to a significant risk for infection, whereas tissue plasminogen activator and N-acetylcysteine are avoided because of their increased risk for bleeding and lack of efficacy, respectively [9]. If the condition persists despite therapy, intrahepatic portosystemic shunting through the transjugular approach or liver transplantation may be performed [9].

The disease may be classified into three stages based on its severity - mild (clinically evident, but spontaneously resolving disease), moderate (pharmacologic agents are necessary for treatment) or severe (inability to resolve symptoms after 100 days, which may end in multi-organ failure or death) [15]. Pretransplant elevations of transaminases, use of cytoreductive therapy and presence of fever have been determined as predictors of severe disease, while a frequent association between HVOD and cardiac and renal failure has been reported [16]. Mortality rates range from 0-70% across numerous reports, whereas 100-day mortality for patients with severe disease is over 80% [3] [17]. The use of cyclophosphamide in therapy has especially shown to be a predictor of high mortality, indicating that its role in therapy should be either attenuated or completely ceased [8].

Various causes of HVOD have been described in the literature. In the United States and Western Europe, high-dose chemotherapy, when used for recipients of hematopoietic stem cells, is the principal cause of this condition [6], due to the extensive toxicity of these drugs on the liver architecture. Initial reports have also determined that ionizing radiation leads to extensive injury of the endothelial cells of central veins, resulting in massive fibrin deposition and vessel occlusion [11]. On the other hand, ingestion of herbal remedies containing pyrrolizidine alkaloids, which are severely toxic for hepatic tissue, are the principal cause of disease in many countries over the world [6].

HVOD has been reported all over the world and in countries such as India, Egypt, Israel and several other, HVOD has been strongly associated with consumption of traditional herbal remedies and wheat that contain pyrrolizidine alkaloids, which possess deleterious effects on the hepatic circulation and parenchyma [8]. In South Africa, approximately 60-80% of the population rely on these remedies and HVOD has been reported and confirmed in such instances in this country, but also in Afghanistan and Spain [2] [6]. On the other hand, numerous chemotherapeutic agents, including cyclosporine, methotrexate, azathioprine, dacarbazine, tioguanine, terbinafine, actinomycin D, urethane and several other are known inducers of HVOD in solid organ recipients and hematologic cancer patients [8]. Other factors that have shown to be important in the pathogenesis of HVOD are alcohol, use of oral contraceptives and radiation injury [6]. Earlier epidemiologic studies have shown incidence rates range between 5-70% in HSCT patients [7] [12], but the reduction of cyclophosphamide use, decrease in chronic hepatitis C virus infection in transplant candidates and increasing use of non-myeloablative regimens have substantially decreased the overall number of HVOD cases [8].

The pathogenesis of HVOD is thought to include several pathophysiological mechanisms [7] [8] [11]:

• Depletion of glutathione in sinusoidal endothelial cells (SECs) - In vitro studies have confirmed that toxic effects of drugs and their metabolites deplete the levels of glutathione, one of the most important intracellular antioxidants. As a result, reduced capacity for mediation of free radical damage leads to extensive hepatic cell death.
• Depletion of nitric oxide (NO) - NO is known for its vasodilatative effects in the circulatory system and in the setting of iatrogenic hepatotoxicity, its reduced levels lead to vasoconstriction and reduced blood flow.
• Increased activity of matrix metalloproteinases - MMPs are involved in many catabolic functions and degradation of many extracellular components and in the setting of HVOD, studies have shown higher concentrations of these enzymes.

Additionally, intracellular changes in hepatocytes such as megalocytosis, cytoplasmic vacuolization, inhibition of protein and nucleic acid synthesis, as well as increased numbers of abnormal mitoses have been documented as well [2]. The most important event in the pathogenesis of this disease, however, is the initiation of the coagulation cascade as a result of endothelial injury of the sinusoid epithelium, leading to abundant deposition of fibrous tissue in the sinusoids and impediment of hepatic blood flow [13]. Specifically, transforming growth factor beta (TGF-β) secreted from activated platelets was shown to impair hemostasis in sinusoids through overexpression of tissue factor and plasminogen activator inhibitor-1 (PAI-1) [14].

Although it may be difficult to prevent HVOD in high-risk patients, such as those undergoing HSCT or receiving aggressive chemotherapy [8], prophylaxis with heparin has not shown positive results [4], and is even contraindicated because of increased risk for bleeding episodes [9]. Preventive use of defibrotide, however, seems to reduce the risk for HVOD in this group, indicating that it should be used whenever at-risk patients are identified [21]. Screening methods for detection of pyrrolizidine alkaloids have been proposed in certain studies [2].

Hepatic veno-occlusive disease (HVOD), initially described almost 100 years ago [1], is a rare but life-threatening condition arising due to endothelial and hepatocellular injury. Either high-dose chemotherapy or ingestion of herbal remedies containing pyrrolizidine alkaloids, both exerting potent hepatotoxic effects, initiate the pathological cascade of events in the liver [2] [3]. This condition is now known as hepatic sinusoidal obstruction syndrome (HSOS) because it primary involves sinusoids with the relative absence of venular damage in initial stages. By far, the most significant risk factor for HVOD is previous hematopoietic stem cell transplantation (HSCT) and the use of drugs for prevention of graft-versus-host diseases, such as cyclosporine or methotrexate, indicating that this condition is most likely encountered among SCT recipients [4]. Regardless of the type of toxic substance, the pathogenesis includes endothelial cell injury, activation of the coagulation cascade, thrombosis of hepatic venous vessels and finally, extensive fibrosis of sinusoidal vessels [5]. The clinical presentation encompasses painful hepatomegaly, ascites, weight gain and hyperbilirubinemia [6]. To make the diagnosis, it is important to obtain a full patient history, perform a thorough physical examination and determine whether patients fulfill some of the proposed criteria. Specifically, Seattle and Baltimore clinical criteria based on signs and symptoms are used for confirmation of HVOD [6], while ultrasonography and magnetic resonance imaging (MRI) may provide significant benefit by excluding other conditions that have a similar presentation [6] [7]. A biopsy may be performed in cases when the diagnosis is inconclusive, but the procedure carries a great risk [7]. Fortunately, most patients (75-80%) resolve spontaneously without the need for therapy, but a small subset develops a systemic and life-threatening condition characterized by multi-organ failure [8]. But because high mortality rates are observed in severe cases who are not recognized on time (> 80%) [3], the importance of an early diagnosis must be emphasized in all cases so that appropriate therapeutic measures can be taken [4]. Defibrotide, a drug possessing a poorly understood anti-thrombotic and anti-inflammatory effect, is the cornerstone of treatment for both adults and children and it is given to patients regardless of disease severity [9] [10]. Defibrotide has also been proposed in long-term prophylaxis of high-risk patients due to its efficacy, while certain reports suggest relatively easy tests to screen for pyrrolizidine alkaloid ingestion [2].

Hepatic veno-occlusive disease (HVOD) is a rare but life-threatening condition that is characterized by extensive damage to blood vessels in the liver and subsequent scarring accompanied with impaired blood flow through this organ. In the developed world, this condition is most commonly seen among individuals who are undergoing hematologic stem-cell transplantation (HSCT) and receive drugs such as cyclophosphamide and methotrexate for immunosuppression, whereas ingestion of various natural remedies containing pyrrolizidine alkaloids is the main mechanism of disease in other parts of the globe. Regardless of the cause, specific sites of the liver become damaged through various mechanisms that result in cell death and deposition of fibrous tissue, eventually causing cell death and blood flow obstruction. Consequently, abdominal pain, liver enlargement, accumulation of fluids in the abdomen (ascites) and increased body levels of bilirubin (hyperbilirubinemia) are most prominent symptoms of HVOD, usually occurring a few weeks after introduction of the harmful substance into the body. The diagnosis may be difficult to attain, as the condition mimics various liver diseases (viral hepatitis, gall-bladder obstruction, abdominal cancer and several other diseases) which is why a detailed patient history is necessary in order to assess for previous procedures and therapy. Abdominal ultrasonography and magnetic resonance imaging (MRI) are useful imaging studies to distinguishing HVOD from other diseases through visualizing characteristic changes such as marked thickening of the gall bladder and congestion of specific blood vessels in the liver - sinusoids (for this reason, the condition is now more commonly known as hepatic sinusoidal obstruction syndrome - HSOS). In almost 80% of cases, cessation of drug or substance use will lead to spontaneous resolution of symptoms, but in a small group of patients, a severe and often fatal condition resulting in failure of multiple organs will ensue, in which case aggressive treatment should be attempted. Defibrotide is a drug that has shown good results in overall management, even in those with most severe forms of the disease, whereas liver transplantation and use of highly invasive procedures to allow normal circulation (portosystemic shunting) may be performed, but these procedures carry a very high risk of adverse effects. Because of the fact that mortality rates in patients who are critically ill are over 80%, it is imperative to make an early diagnosis in order to reduce the burden of this disease among high-risk patient groups. Moreover, preventive use of defibrotide has been advocated by several studies and its prophylactic use in HSCT patients should be considered.

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