SOS results from occlusion of the sinusoids by necrotic cells (hepatocytes, red blood cells, sinusoidal epithelial cells, and lymphocytes). The initial toxic injury to the sinusoidal epithelial cells extends to involve the adjacent hepatocytes. These necrotic cells initially fill the spaces of Disse, but they then spill into the sinusoids and eventually block the sinusoidal outflow channel. Occasionally, sinusoidal obstruction may be complicated by thrombosis extending into the hepatic venules. This observation was at the origin of the old name "hepatic veno-occlusive disease." However, venule thrombosis is not a constant finding in this disease, thus SOS is a more accurate designation. Pyrrolizidine alkaloids, found in certain types of plants including certain bush teas, contributed the major cause of SOS until chemotherapeutic and immunosuppressive agents started being used. A list of the major causes is shown in Table 118-3. Liver irradiation, chronic hepatitis C, and concomitant administration of norethisterone can potentiate the toxic effect of these agents.
The presentation of SOS can be identical to that of acute Budd-Chiari, sepsis-related cholestatic liver disease, right-sided heart failure, and graft-versus-host disease (GVHD), and includes tender hepatomegaly, ascites, weight gain, and signs of portal hypertension. Though biopsy is the only effective method that allows discrimination of these entities, the appearance of the above symptoms 10 to 30 days after cytoreductive or myeloablative treatment with the drugs listed in Table 118-3 should raise the suspicion of SOS.
Laboratory tests, though sensitive, are nonspecific and do not distinguish between SOS, Budd-Chiari, cholestatic disease, and GVHD. In addition, predisposing factors (such as liver transplantation, cancer chemotherapy, immunosuppression)
TABLE 118-3. Medications Implicated as Causative Agents for Sinusoidal Obstructive Syndrome
* Chemotherapeutic agents. f Immunosuppressive.
predispose patients to more than one of the above to a certain extent. Imaging studies including ultrasound, MRI and CT, are nonspecific and include early changes, such as hepatomegaly, ascites and attenuated liver venous flow, or late changes, such as reversal of portal venous flow, PVT, gas-troesophageal varices, splenomegaly, and formation of spontaneous portosystemic shunts. Hepatic venograms may be normal or show hepatic venule thrombosis as a consequence of sinusoidal obstruction, which may erroneously point to Budd-Chiari. As mentioned earlier transjugular or percutaneous liver biopsy is the only definitive diagnostic test. In addition, the transjugular approach allows pressure measurements. Early biopsy specimens (1 to 2 weeks postinjury) reveal edematous changes in the subendothelial layers of the central veins, sinusoidal engorgement, adjacent hepatocellu-lar injury, and necrotic red cells lodging in the spaces of Disse. Later changes (> 2 weeks postinjury) include perisunsinu-soidal collagenization that may lead to fibrosis, and necrotic debris filling the sinusoids that eventually become obstructed.
SOS is classified as mild (clinical symptoms, no treatment, complete resolution), moderate (clinical symptoms, requires treatment, complete resolution), and severe (death or clinical symptoms that persist for more than 100 days despite optimum treatment). With appropriate treatment, most patients (60 to 75%) eventually recover. Paradoxically, those who die, die not from liver failure, but rather from cardiac or renal failure. Both unimodal and bimodal forms of the disease have been identified. In unimodal disease, the symptoms appear and progress or resolve as described above. In bimodal disease, initial symptoms abate only to reappear at a later time. Prognosis is worse in bimodal disease. Prevention should be optimized by (1) avoiding SOS causing chemotherapeutic agents if possible and (2) eliminating modulating factors (liver shielding during total body irradiation and adequate treatment of sepsis). Empiric anticoagulation, usually with heparin or low molecular weight heparin, has met with limited success, attenuating the frequency of nonsevere SOS only. Once SOS has been diagnosed, treatment depends on severity. In cases with limited symptoms and no evidence of liver malfunction or significant portal hypertension/thrombosis, treatment should be supportive. Electrolyte correction (a frequent abnormality in SOS), diuretics and paracentesis for ascites may be adequate.
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