the incidence of hepatocellular carcinoma ( hcc ) is increasing in the united states , europe , and worldwide , and has become a serious problem in many countries .
patients with chronic liver disease related to hepatitis b or c virus infection are at high risk for developing hcc , and the risk of hcc development becomes higher as fibrosis of the liver advances .
indeed , it is reported that the risk of hcc development in cirrhotic patients with hepatitis c virus ( hcv ) infection is as high as 7% per year in japan . interferon ( ifn )
has a potent antiviral effect and has been widely used for the treatment of chronic hcv infection .
ifn therapy improves inflammation and fibrosis in the liver of the patients and reduces the risk of hcc development , particularly when it results in sustained virological response . on the other hand ,
there are several reports that describe hcc development long after the clearance of hcv by successful ifn therapy .
therefore , it is still uncertain how long the patients hold the risk of hcc development after the resolution of chronic hcv infection . in the current report , we describe a patient who developed hcc 11 and a half years after the clearance of hcv .
a 41-year - old japanese man was found to be seropositive for anti - hcv antibody ( dainabot , tokyo , japan ) with abnormal liver function tests at a health check - up in 1994 .
he had no history of blood transfusion or drug abuse , but had been consuming approximately 25 g / day of alcohol for 20 years .
serum hepatitis b surface antigen ( hbsag ) and antibody to hbsag ( anti - hbs ) were negative .
a liver biopsy specimen was consistent with the feature of chronic hepatitis showing moderate fibrosis and mild necroinflammatory reaction , diagnosed later as f2/a1 according to the classification by desmet et al . .
he was diagnosed to have chronic hepatitis c ( ch - c ) and received ifn monotherapy with natural ifn alpha ( human lymphoblastoid ifn ; sumitomo pharmaceutical co. , osaka , japan ) , 6 million units ( mu ) , every day for the first 2 weeks and three times a week for the following 22 weeks .
hcv rna became negative during therapy , and the negativity of hcv rna continued during 6 months of follow - up after discontinuation of therapy .
he abstained from alcohol during and after the ifn therapy , but his body weight showed a gradual increase with slight elevation of serum aminotransferase levels .
he was diagnosed to have fatty liver and diabetes mellitus , but treatment was not introduced . in january 2006 , he was found to have a hepatic nodule 4.0 cm in diameter at liver s4/8 region by plain abdominal ct at an annual follow - up examination .
he was admitted to our hospital ( department of gastroenterology , aichi medical university hospital , aichi , japan ) in february 2006 . on admission ,
physical examination was unremarkable ; the liver and spleen were not palpable , and jaundice , ascites , peripheral edema and other signs of chronic liver disease were not observed .
complete blood counts ( cbc ) were normal ( white blood cell count 6,900/l , hemoglobin 14.4 g / dl , and platelet count 253,000/l ) .
liver function tests were normal ; serum levels of transaminases and total bilirubin were within normal range ( ast 22 iu / l , alt 23 iu / l , and total bilirubin 0.9 mg / dl ) . other laboratory tests , including liver fibrosis markers such as type iv collagen 7s , type iii procollagen - n - peptide and hyaluronic acid , were also within normal range .
however , fasting blood sugar ( 128 mg / dl ) and hba1c ( 6.8% ) were slightly elevated ( table 1 ) .
serum tumor makers of hcc were within normal range , prothrombin induced by vitamin k absence - ii ( pivka - ii ) level was 18 mau / ml ( normal range < 40 mau / ml ) , and a - fetoprotein level was 4.4 ng / ml ( normal range < 10 ng / ml ) .
he was seropositive for anti - hcv by a second - generation enzyme immunoassay ( dainabot , tokyo , japan ) and seronegative for hcv rna by amplicore hcv test ( roche diagnostic inc . , tokyo , japan ) .
on dynamic ct , the nodule on liver s8 area revealed a tumor staining of 4.0 cm in diameter in the early arterial phase and modest washout density in the post - vascular phase ( fig .
on contrast - enhanced us scan , blood inflow into the same nodule was detected in the early arterial phase , and the nodule became hypoechoic compared to the liver parenchyma in the post - vascular phase .
celiac angiography revealed a hypervascular tumor with proliferation of fine tumor vessels ( which also showed nodular and mosaic features ) at the s4/8 region of the liver , just below the dome of right the diaphragm ( fig .
percutaneous liver biopsy was performed at the noncancerous lesion , and the specimen showed fibrosis of stage f2 and mild inflammation of grade a1 with mild steatosis ( fig .
the tumor was curatively resected without any complication , and the histological study of the resected specimen revealed that the tumor was a moderately differentiated hcc ( fig .
in the present study we describe a patient with hcc who developed hcc 11 and a half years after the eradication of hcv .
there are many reports aimed to elucidate the risk factors for liver carcinogenesis , and some of them have tried to examine the incidence of hcc in patients with ch - c after ifn therapy .
examined the risk of hcc development in ch - c patients treated by ifn and showed that the cumulative incidence of hcc in relapsers ( transient responders ) to ifn therapy was almost equal to that in sustained responders , and that it was significantly higher in nonresponders than in sustained and transient responders .
the seventh - year cumulative incidence rates of hcc in sustained responders , relapsers , and nonresponders were estimated to be 4.3 , 4.7 , and 26.1% , respectively .
they suggested that patients in the high - risk group of hcc after ifn therapy were those who showed no response , those who were older , or males .
sustained responders to ifn therapy usually show normal alt levels continuously . in relapsers , alt values usually become normal when hcv rna becomes seronegative during therapy .
thus , the reduction in the necroinflammatory activity in the liver appears to be an important factor to prevent the development of hcc even when the eradication of hcv is not achieved .
another report indicated that the group at high risk for developing hcc in sustained responders to ifn therapy were older , more often male , and had more advanced histological disease stages .
in addition , kasahara et al . showed that the risk of death from liver - related diseases in sustained and nonsustained virological responders was significantly lower compared with that in untreated patients .
furthermore , sustained and transient biochemical responders were shown to have a reduced risk of liver - related death compared to biochemical nonresponders .
thus , it is likely that ifn treatment prevents liver - related death and improves survival of ch - c patients with virological as well as biochemical response . in the present case ,
the liver biopsy specimen at the time of operation ( before operation ) revealed liver damage of f2/a1 .
this finding was almost the same compared with that at the start of ifn therapy 12 years earlier .
we considered the possibility that the presence of nonalcoholic fatty liver disease ( nafld ) might contribute , at least in part , to the development of hcc .
nafld is a clinicopathological term that encompasses a disease spectrum ranging from simple triglyceride accumulation in hepatocyte ( hepatic steatosis ) to hepatic steatosis with inflammation ( steatohepatitis ) , fibrosis , and cirrhosis .
judging from the clinicopathological features in the current case , we could not exclude the influence of nafld for the development of hcc , while the pathological role of nafld might be limited . although it has been reported that hcc rarely develops long after eradication of hcv , all patients with chronic hcv infection should be followed as long as possible for the potential development of hcc , even sustained virological responders to ifn therapy .
more careful follow - up is recommended , particularly when patients have complications such as nafld .
 a 41-year - old japanese man had received successful interferon ( ifn ) therapy against chronic hepatitis c in 1994 . since then , serum hepatitis c virus ( hcv ) rna had been negative , and aminotransferase levels had been continuously normal . 
 he had abstained from alcohol . however , his serum aminotransferase levels showed slight elevation as his body weight increased gradually . 
 he was diagnosed as having fatty liver and diabetes mellitus . in january 2006 , 11 and a half years after the resolution of hcv infection , he was found to have a hepatic nodule 4.0 cm in diameter at liver s4/8 region by plain abdominal ct at an annual follow - up examination . 
 he was diagnosed as having hepatocellular carcinoma ( hcc ) by angiography . 
 the tumor was curatively resected and its histological diagnosis was moderately differentiated hcc . 
 noncancerous lesion of the liver revealed fibrosis of stage f2 and mild inflammation of grade a1 with mild steatosis . 
 this case suggests that all patients with chronic hcv infection should be followed as long as possible for the potential development of hcc even after clearance of the virus . 
Introduction
Case Report
Discussion