hepatic sinusoidal obstruction syndrome ( sos ) , also known as veno - occlusive disease ( vod ) , is a serious , life - threatening complication that is sometimes observed after hematopoietic - stem cell transplantation ( hsct ) ( 1,2 ) . pathophysiologically , sos results from the activation of the sinusoidal endothelial cells ( secs ) , leading to the damage of these cells and the obstruction of the hepatic sinusoids in the acinar zone 3 ( 3 ) . secs are activated by chemotherapy and radiotherapy , resulting in the sustained and intense production of cytokines , which induces endothelial damage and sinusoidal endothelial swelling ( 3 ) . the progression of sos involves the depletion of glutathione and nitric oxide from the secs , the increased expression of intrahepatic matrix metalloproteinases and vascular endothelial growth factor , and the activation of clotting factors ( 4 ) . these alterations induce the egress of red blood cells , leucocytes and cellular debris into the space of disse , leading to the obstruction of the sinusoid ( 1 ) . for example , patients with metastatic colorectal cancer who receive oxaliplatin - based neo - adjuvant chemotherapy frequently experience sos , resulting from toxic injury to the secs ( 5 ) . moreover , a significant correlation was observed between the administration of oxaliplatin and the development of sos , suggesting the importance of the functional liver reserve in patients undergoing major hepatectomy for colorectal metastasis ( 6 ) . these reports suggested that chemotherapies that are toxic to endothelial cells may induce sos , especially in patients with liver damage . we herein describe the case of a patient who developed hepatic sos after non - hsct chemotherapy for non - hodgkin lymphoma . the patient was a 58-year - old japanese man who had previously undergone splenectomy with red blood cell transfusion for autoimmune hemolytic anemia . prior to his presentation at our hospital , he had experienced a fever of 38c , night sweats , and fatigue for several days . at admission , he had systemic lymphadenopathy . the laboratory data showed a white blood cell count of 9,100 /l with normal fractions , hemoglobin , 10.7 g / dl , lactate dehydrogenase ( ldh ) the patient 's liver enzyme levels were within normal limits , and he was negative for hepatitis b surface antigen , anti - hepatitis c virus ( hcv ) antibody , and anti - human immunodeficiency virus antibody . serum antibodies to epstein - barr virus ( ebv ) demonstrated a past infection pattern . an esophagogastroduodenal endoscopy showed an irregular ulcer in the body of the stomach and multiple flat - elevated lesions in the duodenum ( fig . computed tomography ( ct ) showed multiple adenopathy of the lymph nodes of the neck , axilla , mesentery , and paraaorta ( fig . 1c - e ) , with the uptake of fluorodeoxyglucose . following a cervical lymph node biopsy , biopsies were performed from < 1-<2 and < 4-<6 , and all of the samples revealed diffuse large b - cell lymphoma . c ) a ct image showing the enlargement of multiple lymph nodes from the neck . e ) a ct image showing the ascites on the surface of the liver . a cytological analysis of the ascites revealed class v. the patient was started on treatment for dlbcl , which consisted of rituximab , cyclophosphamide ( cpa ) , doxorubicin ( dxr ) , vincristine ( vcr ) and prednisolone ( r - chop ) . however , fluorescence in situ hybridization revealed that his lymphoma tissue was positive for both myc and bcl2 rearrangements . thus , he was re - diagnosed with double - hit lymphoma ( dhl ) , an aggressive disease that is associated with poor clinical outcomes ( 7 ) . although r - chop has been associated with inferior outcomes in patients with dhl ( 7 ) , at the present time , there is no standard treatment for dhl . data from retrospective studies suggest that more intensive chemotherapy , such as r - codox - m / ivac , which consists of rituximab , cpa , vcr , dxr and methotrexate ( r - codox - m ) alternated by ifosfamide , etposide and high - dose cytarabine ( ivac ) , may achieve better outcomes in patients with dhl ( 8) . after 2 cycles of r - chop , he was started on r - codox - m / ivac . after the first cycle of r - codox - m , the patient 's hepatobiliary enzyme levels were transiently elevated , dropping to normal levels in the absence of treatment . his hepatobiliary enzyme levels were elevated again after the second cycle of r - codox - m / ivac ( fig . 2a ) ; for example , the concentrations of aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) were 516 iu / l and 288 iu / l , respectively , and the concentrations of total and direct bilirubin were 5.5 mg / dl and 3.9 mg / dl , respectively . a blood test revealed a white blood cell count of 800 /l , a hemoglobin level of 6.3 g / dl and a platelet count of 3,000 /l because of the myelosuppressive effect of the chemotherapy . a physical examination showed body weight gain ( + 2 kg / week ) , jaundice , lower leg edema and abdominal distention . serum antibodies to herpes simplex virus , cytomegalovirus ( cmv ) and ebv indicated their past infection . although the serum transaminase concentration was slightly decreased without any specific treatment , the serum bilirubin concentration gradually increased . abdominal ultrasonography showed a normal hepatobiliary tract with hepatomegaly and mild ascites on the surface of the liver . these findings were suggestive of severe drug - induced liver injury ; thus , all possibly causative drugs , including the antibiotics that were initiated after admission , were discontinued . nevertheless , the serum concentrations of liver enzymes remained high . the bilirubin level to rise until it peaked at 34.4 mg / dl ( fig . ct showed hepatomegaly with a geographic low density area at the posterior segment of the liver ( fig . a liver biopsy specimen showed bile congestion of the bile capillaries and hepatocytes , as well as sinusoidal dilatation , but the structure of the bile duct was preserved and there was no evidence of central vein stenosis or obstruction ( fig . the patient was therefore diagnosed with severe cholestatic - type drug - induced liver injury . he was treated with nafamostat mesilate in addition to glycyrrhizic acid and ursodeoxycholic acid and was observed carefully . however , his severe jaundice persisted and his liver function did not recover . follow - up ct showed progressive atrophy of the liver and an increase in ascites ( fig . 2c - e ) , followed by cmv pneumonia . despite being admitted to the intensive care unit and receiving ventilator support , there was an exacerbation of the patient 's pneumonia and he died of respiratory failure . a ) the clinical course of the present patient , including the timing of ct ( as shown as b - e ) . b ) a contrast - enhanced ct image shows hepatomegaly and geographic low density area at the posterior segment of the liver . c)-e ) ct images showing the increase of ascites and the progression of liver atrophy . e ) h&e staining ( 200 ) the arrowhead shows dilatation of the sinusoid and congestion caused by erythrocytes . his liver weighted 1,175 g , and its surface division resembled nutmeg liver ( fig . 4a ) . microscopically , torn hepatic cords were visible , along with fibrosis of the sinusoids , bile congestion , and stenosis of the central vein . 4b - f ) . inflammatory cell infiltration was less apparent , and there was no evidence of thrombosis . we also observed congestion of the central vein due to the occlusion of venules , ischemic necrosis of the hepatocytes , the growth of connective tissue under secs by the dilatation of the sinusoids , along with the narrowing and occlusion of the sinusoids ( fig . the autopsy also revealed that there were no identifiable lymphoma cells in any of the organs or lymph nodes . b ) h&e staining ( 400 ) showing the dilation of the sinusoid due to erythrocytes ( arrowhead ) and a bile plug ( arrow ) . c ) azan staining ( 400 ) showing the growth of connective tissue under the sinusoidal endothelial cells ( arrowhead ) . e ) h&e staining ( 400 ) showing stenosis of the central vein ( arrowhead ) and ischemic necrosis of the hepatocytes . f ) azan staining ( 400 ) showing the deposition of connective tissue around the central vein , which caused stenosis of the central vein ( arrowhead ) . hepatic sos is a life - threatening complication that is usually observed after hsct ; however , some patients experience hepatic sos outside the transplantation setting ( 4 ) . clinical diagnostic criteria have been proposed for the diagnosis of hepatic sos ( 9,10 ) . these are based on the presence of the following clinical findings within the first three weeks after hsct : 1 ) jaundice ( bilirubin > 2 mg / dl ) ; 2 ) hepatomegaly or right upper quadrant pain ; and 3 ) weight gain ( 11 ) . in hepatic sos , non - thrombotic fibrous occlusion of the terminal hepatic vein is a characteristic finding of hepatic sos ( 4 ) . in this case , sos had been suspected due to jaundice , ascites and body weight gain ; however , the diagnosis of sos was not confirmed by liver biopsy findings . liver biopsies are almost never obtained during the acute phase of hepatic sos and the failure to recognize the centrilobular venopathy may lead to the misinterpretation of the histologic findings ( 4 ) . thus , clinicians should carefully consider the possibility of hepatic sos if clinical manifestations indicating hepatic sos are observed after chemotherapy . the risk factors for sos include older age , female gender , specific types of conditioning regimen ( e.g. myeloablative ) , preexisting liver diseases , atiii defects , and thalassemia ( 4 ) . in particular , patients with a serum transaminase level of > 2.5 times the upper limit of normal ( uln ) , a serum bilirubin level of > 1.5 times the uln , liver cirrhosis , hepatic irradiation , and active viral hepatitis are considered to be at risk of sos ( 12,13 ) . this patient experienced a serum transaminase concentration of 10 times the uln after the first cycle of r - codox , suggesting that this treatment regimen may have been responsible for the induction of hepatic sos . the drugs administered to our patient may have also influenced liver dysfunction leading to hepatic sos . the intensity of the transplant conditioning regimen has been reported to be the greatest risk factor for sos ( 14 ) . in r - codox - m / for example , in r - chop for dlbcl , the dose of cpa is 750 mg / m ( 15 ) . in contrast , in r - codox - m / ivac for dhl , the dose of cpa is 1,600 mg / m ( 8) , or approximately two - fold higher . cpa metabolites have been shown to deplete hepatic glutathione levels , inducing oxidative stress and hepatotoxicity ( 16 ) , which may lead to sos . genetic polymorphisms of glutathione s - transferase ( gst ) m1 , which are associated with glutathione depletion have recently been shown to be a risk factor for the development of sos in patients undergoing hsct and those receiving oxaliplatin - based chemotherapy ( 17,18 ) . although we could not investigate the presence of possible genetic polymorphisms of gst m1 in our patient , caution should be exercised in treating patients with high - dose cpa or chemotherapy regimens that contain agents that are toxic to the secs . despite our best efforts , we did not reach the diagnosis of sos while the patient was alive . although we performed a liver biopsy to assess the cause of liver injury , the liver parenchyma showed only sinusoidal dilatation and congestion . the absence of sinusoidal obstruction or central vein stenosis in the biopsy specimen prevented us from reaching a diagnosis of hepatic sos while the patient was alive . a liver biopsy is essential in diagnosing liver injury ; however biopsy samples are limited , as they only evaluate 0.002% of the area of the liver ( 19 ) . ct findings , such as hepatomegaly , abdominal effusion and geographic low density changes , have been recently reported as characteristics of hepatic sos ( 20 ) . although additional patients with hepatic sos should be assessed by ct , hepatic sos should be considered when ct shows hepatomegaly , abdominal effusion and a geographic low density area or when a liver biopsy shows sinusoidal dilatation and congestion after the administration of a chemotherapy regimen that is toxic to the secs . there are no established therapies for this condition other than for defibrotide ( df ) , a polydisperse mixture of single - stranded oligonucleotides with antithrombotic and fibrinolytic effects ( 2,14 ) . df has been shown to be effective both in the treatment of severe sos accompanied by multiple organ failure ( 21,22 ) , and in preventing the development of sos ( 23 ) . although the patient of the present study may have benefited from df , this agent has not yet been approved in japan . hepatic sos occurs in patients after hsct and in those receiving chemotherapy regimens that are especially toxic to the secs . identifying patients who are at risk of developing sos , and the awareness of the possibility of sos in patients who experience refractory liver injury after chemotherapy are important . ct findings , such as hepatomegaly , abdominal effusion and geographic low density changes , and liver biopsy findings , such as sinusoidal dilatation and congestion , that occur after chemotherapy should be considered to be highly suggestive of hepatic sos .