gemcitabine - induced hemolytic uremic syndrome ( hus ) is rare but can often be fatal .
early detection of hus is critical so that contributing chemotherapeutic agents , such as gemcitabine , can be discontinued . in clinical trials ,
hus is characterized by renal failure , microangiopathic hemolytic anemia ( maha ) , and thrombocytopenia.1 in addition , the onset of new and uncontrolled hypertension can be diagnostic for hus.2 while a few cases of gemcitabine - induced hus have been reported globally , but only a single korean case of hus in a lung cancer patient is known.3 with the increase in gemcitabine use in pancreatobiliary cancer , early detection of gemcitabine - induced hus is essential .
herein , we describe the first case of hus in a pancreatic cancer patient , associated with gemcitabine use in a korean hospital .
in june 2011 , a 56-year - old male visited a local hospital complaining of dyspepsia and back pain .
contrast - enhanced computed tomography ( ct ) revealed a 4.4 cm mass at the head of his pancreas ( fig .
he was referred to our hospital , where we found the mass had invaded the main portal vein , common hepatic artery , and stomach .
laboratory tests showed serum hemoglobin level of 14.9 g / dl , platelet count of 166,000/l , blood urea nitrogen of 21.3 mg / dl , and serum creatinine level of 1.28 mg / dl .
the carcinoembryonic antigen level was 2.34 ng / ml ( normal range , 0 to 5 ng / ml ) and carbohydrate antigen 19 - 9 was 798 u / ml ( normal range , 0 to 37 u / ml ) .
concurrent chemoradiotherapy ( ccrt ) with original gemcitabine weekly ( 1,000 mg / m per week , day 1 , 8 , 15 , 22 , and 29 ) and 25 radiation therapy ( total radiation dose , 4,500 cgy ) was performed from june 30 to august 3 , 2011 .
one month after ccrt , a repeat abdominal ct showed that the pancreatic mass had decreased from 4.4 to 3.0 cm but remained unresectable .
on october 21 , 2011 , gemcitabine therapy was administered weekly ( 1,000 mg / m per week , day 1 , 8 , and 15 ) for 3 out of 4 weeks .
a cumulative dose of gemcitabine from june 30 , 2011 was 26,250 mg . in february 2012 during week 2 of cycle 5 , the patient was admitted for generalized edema and general weakness .
he developed acute renal failure and had an elevated serum creatinine level of 2.08 mg / dl ( normal range , 0.5 to 1.40 mg / dl ) .
on physical examination , the patient had dyspnea on exertion , lower extremity pitting edema , and a blood pressure of 200/140 mm hg .
the patient 's hemoglobin level had decreased to 7.7 g / dl ( normal range , 13.0 to 17.0 g / dl ) and a platelet count of 87,000/l ( normal range , 150,000 to 400,000/l ) . the reticulocyte count was 11.69% ( normal range , 0.5% to 2.31% ) , with a corrected reticulocyte count of 6.6% and an elevated lactate dehydrogenase ( ldh ) level of 459 iu / l ( normal range , 110 to 247 iu / l ) .
a peripheral blood smear showed macrocytic hypochromic anemia with mild anisopoikilocytosis composed of schistocytes and acanthocytes ( fig .
2 ) . there was no evidence of proteinuria or hematuria , but the patient was positive for urine hemoglobin .
the patient 's total bilirubin , obtained from an indirect coombs test , was normal and the patient 's haptoglobin level was < 10 mg / dl .
the laboratory tests confirmed maha , thrombocytopenia , and acute renal failure - leading to a diagnosis of gemcitabine - induced hus .
after 19 plasmapheresis treatments , the patient 's creatinine level decreased to 2.02 mg / dl and he was able to maintain self - urine output .
he was transferred to a nursing home for hospice care and has continued with outpatient palliative therapy .
hus is characterized by renal failure , thrombocytopenia and maha characterized by a trio of classic symptoms - elevated ldh , low haptoglobin , and schistocytes on the peripheral blood smear .
five typical hus cases were first described by gasser et al . in a pediatric patient with hemorrhagic diarrhea and enterocolitis caused by verotoxin - producing escherichia coli.4 in 1979 , a gastric cancer patient developed chemotherapy - related hus associated with mitomycin c ( mmc ) and 5-fluorouracil.5 the causes of atypical hus include infectious diseases , malignancy , antineoplastic agents such as mmc , antiplatelet agents , pregnancy , hemolytic anemia , elevated liver enzymes , and low platelet syndrome ( hellp syndrome ) , malignant hypertension , systemic lupus erythematosus , and antiphospholipid syndrome .
the incidence of gemcitabine - induced hus is low ( 0.015% to 0.31% ) , but the mortality rate is as high as 50% in these patients .
there have been previous reported cases in patients with nonsmall cell lung cancer , ovarian cancer , and metastatic breast cancer.6 - 8 a review of the literature revealed only 15 patients of gemcitabine - induced hus in pancreatic cancer .
these 15 cases are summarized in table 1.1,2,9 - 15 our case is noteworthy because of the first reported case in korea .
the mechanism of gemcitabine - induced hus is unclear with hypotheses including microvascular endothelial damage or immunocomplex mediation.9 an increase of von willebrand factor levels in hus suggests a potential role in hus , but further investigation is needed.5 in the literature , the median duration of gemcibatine therapy was 5.8 months , with the majority of patients developing hus within 1 to 2 months of the last gemcitabine infusion.1 the median time between initiation of chemotherapy and onset of gemcitabine - induced hus was 7.4 months.16 gemcitabine - induced hus developed after an estimated median cumulative dose of 20,000 mg / m with a broad range from 2,450 to 48,000 mg / m with no clear dose - response relationship.11 our patient began developing symptoms of peripheral edema and hypertensive emergency after 7 months of therapy and a cumulative dose of 26,250 mg .
in patients treated with gemcitabine , hus must be considered when uncontrolled hypertension or worsening preexisting hypertension develops , and it is important to monitor blood pressure to detect any early indication of gemcitabine - induced hus . although there is currently no consensus as to the best treatment for gemcitabine - induced hus , immediate discontinuation of gemcitabine
is accepted as the initial step.17 other treatment modalities include corticosteroids , transfusion of fresh frozen plasma , plasmapheresis , or hemodialysis .
however , plasmapheresis reportedly had no direct therapeutic effect , which was attributed to discontinuing gemcitabine administration.18 to confirm a diagnosis of hus , a renal biopsy can be performed to show microvascular damage of arterioles and small arteries occluded by eosinophilic hyaline thrombi containing fibrin and platelet aggregates.1 generally , the histopathology of renal tissue in patients with hus shows characteristic thrombotic microangiopathy consisting of thrombi in blood vessels , glomerular mesangiolysis , and widening of the subendothelial space with detachment of endothelial cells from the glomerular basement membrane.4 a renal biopsy was scheduled for the patient in this case but he decided to cancel the procedure due to the high risk of bleeding .
it is possible that a diagnosis of hus may be delayed because anemia and thrombocytopenia can also be induced by myelotoxicity secondary to chemotherapy . in particular
, an elevated reticulocyte count could differentiate between anemia due to myelotoxicity of gemcitabine and gemcitabine induced - hus.19 furthermore , a sudden decrease in hemoglobin , sudden renal failure , uncontrolled hypertension , pulmonary congestion , peripheral edema , and thrombocytopenia should alert clinicians of the possibility of hus .
when hus is suspected , peripheral blood smears should be screened for the presence of fragmented red blood cells and elevated ldh level.20 in conclusion , few cases of gemcitabine - associated hus have been described . with the increase
is the use of gemcitabine therapy for pancreatic cancer , it is important to quickly and accurately diagnose gemcitabine - associated hus .
this case report demonstrates that a patient could overcome this life - threatening crisis with early clinical detection and immediate discontinuation of gemcitabine .
 hemolytic uremic syndrome ( hus ) is a rare thrombotic complication characterized by a triad of microangiopathic hemolytic anemia , thrombocytopenia , and acute renal failure . 
 hus may be caused by several different conditions , including infection , malignancy , and chemotherapeutic agents , such as mitomycin , cisplatin , and most recently , gemcitabine . 
 the outcome of gemcitabine - induced hus is poor , and the disease has a high mortality rate . 
 this study reports a case of gemcitabine - induced hus in a patient with pancreatic cancer in korea . 
INTRODUCTION
CASE REPORT
DISCUSSION