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chronic hepatitis c virus ( hcv ) infection affects an estimated 130150 million people worldwide , and is a substantial global health problem .
however , treatment regimens containing pegylated interferon have been problematic for patients with cirrhosis because of reduced response rates and more frequent and severe adverse events [ 2 , 3 , 4 , 5 ] .
direct - acting antivirals ( daas ) have been developed as alternative treatments due to their efficacy and safety .
the oral combination of daclatasvir ( dcv ) and asunaprevir ( asv ) is an interferon - free regimen consisting of daas , and shows high efficacy and safety even in patients with compensated cirrhosis [ 6 , 7 ] .
this dcv+asv regimen was first available as interferon - free treatment for hcv infection in daily practice in japan , earlier than in other countries .
the main adverse event of dcv+asv treatment is transaminitis , and elevation of alanine aminotransferase ( alt ) and aspartate aminotransferase ( ast ) levels were reported in 17.6% and 14.1% of cases in phase 2 and phase 3 trials conducted in japan , respectively .
however , severe hyperbilirubinemia over grade 3 was reported in only 0.8% of cases , and hyperbilirubinemia followed transaminitis in these cases .
we encountered a patient exhibiting hyperbilirubinemia > 10 mg / dl without transaminitis during combined dcv+asv therapy .
the clinical course and results of histopathological analysis suggested dysfunction of hepatocytic transporters causing severe bilirubinemia and liver failure .
we report this case , which highlights the need for caution in use of daas for patients with compensated cirrhosis who may have hepatocytic transporter hypofunction .
a japanese woman had been found to have liver dysfunction and was diagnosed with chronic hepatitis c in her 40s .
as she had paroxysmal atrial fibrillation and showed arterial thrombosis in her lower leg , she had been treated with warfarin since 75 years old . at
78 years old , she was found to have hepatocellular carcinoma ( hcc ) , and was treated with radiofrequency ablation ( rfa ) .
although she was 79 years old , administration of daas was considered suitable to preserve liver function and suppress the recurrence of hcc .
although liver biopsy had not been done , the laboratory data suggested that she had liver cirrhosis , and child - pugh score was 6 .
her hcv genotype was ib and serum hcv - rna was 6.5 log copies / ml .
ns5a resistance - associated variants ( at positions l31 or y93 ) were not detected .
therefore , dcv ( 60 mg once daily ) and asv ( 100 mg twice daily ) were introduced .
there were no significant changes in laboratory data at 14 days after commencement of dcv+asv treatment .
her hcv - rna level was markedly decreased to 1.76 log copies / ml at 14 days after commencement of dcv+asv administration . at 18 days , she developed fever > 38c .
the fever did not abate , and she was admitted to our hospital at 21 days after introduction of dcv+asv .
alt and ast were not elevated , but bilirubin , predominantly direct bilirubin , showed marked elevation .
prothrombin time was prolonged from 83% before to < 10% after introduction of combined daa treatment .
in addition , inflammatory markers , such as white blood cell counts and c - reactive protein , were elevated .
although physical findings suggesting hepatic encephalopathy were not observed , abdominal ultrasound showed mild ascites , which was not recognized before introduction of daas treatment .
on computed tomography ( ct ) examination , no obvious obstruction in the biliary tract was found , but infiltrative shadow and pleural fluid in the left lung were recognized ( fig .
although we performed blood and sputum culture on admission , the causative agent could not be detected .
however , inflammatory responses in laboratory data and findings from ct suggested bacterial pneumonia accompanying daas treatment .
the absence of obvious obstruction in the biliary tract and transaminitis suggested that jaundice was caused by dysfunction of hepatocytes .
as jaundice occurred after the introduction of dcv+asv treatment , it was most likely induced by daas ; therefore , we decided to stop administration and observe the process .
treatment for pneumonia was begun with ampicillin / sulbactam ( ampc / sbt ) at 6 g / day .
was elevated to 15 mg / dl , peaked at 3 days after admission , and subsequently decreased .
fever and inflammatory responses in laboratory data also improved , and administration of ampc / sbt was ended at 8 days after admission .
eosinophilia was also recognized on admission , and the eosinophil count increased to 860/l , peaking at 4 days after admission .
the drug - induced lymphocyte stimulation test ( d - lst ) was also performed at 3 days after admission . as a result ,
stimulation index of dcv and asv were 261 and 240% respectively whereas control stimulation index was 170% , which showed both drugs were positive for d - lst .
these results , such as eosinophilia and positive for d - lst , suggested that daas - induced hypersensitivity might be found . to assess the causes of hyperbilirubinemia and histopathological changes in the liver
3 ) . chronic moderate to severe interface hepatitis and fibrosis with bridging pattern were observed , compatible with hcv - induced cirrhosis .
bile ducts in the portal area were preserved , and chronic nonsuppurative destructive cholangitis was not observed .
these findings suggested that temporary drug - induced cholestatic liver injury was accompanied with hcv - cirrhosis and hyperbilirubinemia was induced .
although dcv and asv were not administered after cessation of treatment , hcv - rna became negative at 4 weeks after the introduction of daas ( at 7 days after admission ) .
then the sustained virological response at 12 weeks ( svr12 ) was confirmed ( table 1 ) .
the all - oral combination of dcv and asv is an interferon - free regimen consisting of daas , and shows high efficacy and safety even in patients with compensated cirrhosis [ 6 , 7 ] .
although one advantage of the combination of these two drugs is applicability in patients with compensated cirrhosis , we encountered a patient turning from compensated to decompensated cirrhosis exhibiting severe hyperbilirubinemia during combined therapy .
the most common adverse events ( 10% ) were reported to be nasopharyngitis , increased alt and ast , headache , and pyrexia headache , in japanese phase 3 study , and fatigue , diarrhoea , nausea , and asthenia in multinational phase 3 study . on the other hand ,
alt and ast elevations were the most frequent adverse events over grade 3 and were the most frequent cause of discontinuation in both trials [ 6 , 7 ] .
although hyperbilirubinemia has been reported , hyperbilirubinemia over grade 3 was rare [ 6 , 7 ] .
in addition , hyperbilirubinemia over grade 3 reported in these trials accompanied transaminitis . thus , grade 3 hyperbilirubinemia without transaminitis has not been reported previously .
the clinical course in this case strongly suggested that combined dcv+asv therapy caused aggravation of liver function with severe jaundice .
the first was allergy - induced hyperbilirubinemia , which was suggested by the temporary increase in number of eosinophils in the blood and the result of d - lst .
however , the discrepancy of severity between hyperbilirubinemia and eosinophilia and atypical histology for allergic liver injury indicated that an allergic mechanism can explain only part of this pathology .
daas , including dcv and asv , are metabolized via hepatocyte transporters , such as organic anion - transporting polypeptide ( oatp ) and p - glycoprotein ( p - gp ) .
especially , dcv and asv are known to be substrates and inhibitors of p - gp expressed in hepatocytes , which is involved in bilirubin transport .
the expression of p - gp was reported to decrease with progression of liver fibrosis in chronic hepatitis c patients [ 9 , 10 ] .
moreover , cholestasis often occurs through inhibition of canalicular excretion of conjugated bilirubin by proinflammatory cytokines in cases of systemic infection , such as pneumonia .
indeed , jaundice was observed in 325% of patients with pneumococcal pneumonia . in this case , cholestasis could occur because the function of p - gp , expression of which was originally decreased with the progression of chronic hepatitis , was impaired by administration of daas and the onset of pneumonia .
the elevated concentrations of dcv and asv caused temporary dysfunction of hepatocytes , and the function recovered with gradual decreases in concentration .
the svr12 with administration of daas for only 3 weeks may have been related to the high concentrations of daas used in this case .
although there was discrepancy between serum hcv - rna level and liver histology , previous studies found no correlation between histology and the extent of replicative activity of hcv .
considered with the absence of new parenchymal inflammation and bile duct obstruction , there was a high possibility that temporary dysfunction of hepatocytes had been occurred .
the treatment of hcv infection with daas is highly effective , and these regimens will likely be widely adopted over the next 20 years , which would result in hcv infection becoming a rare disease . on the other hand , severe adverse events may occur in patients with compensated cirrhosis like this case .
although the examination of hepatic function once every two weeks is encouraged during first 12 weeks from administration , more frequent examinations are desirable for high - risk cases in terms of the prevention of severe side effects . in conclusion , we encountered a patient exhibiting severe hyperbilirubinemia without transaminitis during combined dcv+asv therapy .
daclatasvir ( dcv ) and asunaprevir ( asv ) are direct - acting antivirals ( daas ) used in the treatment of chronic hepatitis c virus ( hcv ) infection . 
 combined therapy with dcv and asv shows high efficacy and safety even in patients with cirrhosis . 
 we encountered a patient exhibiting severe hyperbilirubinemia during combined therapy , which is an unreported side effect of dcv and asv . a 78-year - old woman with cirrhosis developed hyperbilirubinemia > 10 mg / dl without transaminitis 3 weeks after starting combined therapy . 
 we suspected daas - induced liver disorder and discontinued treatment , which resulted in the improvement of hyperbilirubinemia . 
 caution is required in the use of daas for patients with advanced cirrhosis .