adalimumab ( humira nr ) is a fully humanized monoclonal antibody whose biologic target is tumor necrosis factor alpha ( tnf - alpha ) . the label indications are nowadays rheumatoid arthritis , psoriatic arthritis , ankylosing spondylitis , psoriasis , and crohn 's disease . clinical studies have demonstrated that the most frequent adverse drug reactions ( adrs ) to this drug are the injection site reactions that occur in more than 10% of treated patients , and the most serious adr is tuberculosis reactivation . other serious systemic infections , which occur very rarely , are drug - induced systemic lupus erythematosus , lymphoma or demyelinating disease [ 14 ] . these same studies demonstrate that hepatotoxicity is a rare condition that occurs in less than 5% of treated patients , and asymptomatic elevation of liver enzymes is the most common manifestation of liver toxicity . a 35-year - old male patient with a medical history of chronic hepatitis c virus ( genotype 1a ) since 1999 and rheumatoid arthritis ( ra ) treated with hydroxychloroquine was examined in the hepatology unit of our hospital . he showed a liver biopsy done in 2001 with an a1 f0 metavir score   and was treated with interferon alfa 2b ( ifn ) , but this treatment was suspended at the sixth month because of reactivation of ra symptoms . liver function tests after treatment with ifn were similar to the previous ones , showing a minimal cholestatic pattern : alanine amino transferases ( alt ) slightly elevated ( 1.5 times the upper normal limit ) , alkaline phosphatase ( ap ) 1.6 times the upper normal limit , and gamma - glutamyl - traspeptidase ( ggt ) 9 times the upper normal limit . the patient did not receive any treatment for his hcv and only received chloroquine ( 400  mg / d ) for ra .   in 2008 methotrexate ( mtx ) was prescribed , because of ra reactivation and a rise of ggt , and pruritus appeared , and the drug was withdrawn at the third month of onset . the viral load was 4,070,000  ui / ml , log(6.6 ) and a liver biopsy showed an a2 f1 metavir score . adalimumab was started in april 2010 , and at the third month liver function tests showed a rise of ggt ( 23 times the upper normal limit ) , ap ( 2.5 times the upper limit ) and ast , alt with no change ( 1.5  nv ) , and pruritus . a liver biopsy was then performed with an a1 f2 pattern , portal dystrophy , portal inflammation with eosinophils , lobular hepatitis , and microabscesses ( figures 1 and 2 ) . antiliver kidney microsomal ( anti - lkm ) antibodies , antinuclear antibodies ( anas ) , antimitochondrial antibodies ( amas ) , and anti - smooth muscle antibodies ( asmas ) were negative . adalimumab was stopped and liver function tests improved but remained altered ( slightly elevated ) six months later ( ap  1,5  nv , ggt  3  nv ) . we report a case of adalimumab - induced cholestasis ( pruritus , increase of cholestatic enzymes with elevated ast and alt ) in a patient with ra and chronic hepatitis c infection . drug - induced liver injury ( dili ) is one of the most common adrs and the main cause of drugs withdrawal . in the last few years , several drugs have had to be withdrawn from the market because they were linked to severe liver toxicity . more than 50% of all acute liver failures and near 10% of all acute hepatitis cases are due to drugs nowadays . there are two main types of liver toxicity : the one caused by an immune response triggered by the drug or the one produced by direct toxicity of the drug . the first one is generally dose independent , and it is impossible to recognize who will suffer from this adr before the drug was administered . the cholestatic pattern is the most frequent in this type of toxicity , and the withdrawal of the drug does not guarantee the solution to the problem , as sometimes the dili persists long after the drug withdrawal , and in rare cases chronic liver injury may occur owing to a self - perpetuating injury ( this is the characteristic of the patient presented here ) . this toxicity can be induced by penicillin , estrogens , oral contraceptives , macrolides , and so forth , [ 612 ] . direct toxicity is a dose - dependant adr ; its incidence is proportional to the dose of the drug , and when the drug is withdrawn , the pathologic findings are usually resolved , except for the serious cases with severe liver failure that may need liver transplant . examples of drugs that have frequently induced direct toxicity are methotrexate , statins , and acetaminophen . some chemotherapeutic drugs can alter specifically some transporting pumps and increase mainly total bilirubin without altering other biochemical tests . adalimumab - related dili seems to be idiosyncratic , dose independent , and caused by an immune - mediated response with infiltration of the liver by eosinophils . the response to drug withdrawal is uncertain and the exact evolution is only known with a strict followup of the patient . rechallenge is not recommended since a recurrent injury may be more severe than the first insult . most of the patients with liver function test alterations during adalimumab treatment usually experience a reactivation of occult viral hepatitis ( mainly hepatitis b virus ) [ 1320 ] or dili because of other drugs such as mtx that are with some doubts linked to liver toxicity . in the case that we present , liver toxicity was temporally associated with symptoms , and liver function tests alterations improved when adalimumab was withdrawn . the pattern was cholestatic as few other case reports of adalimumab - induced hepatotoxicity [ 21 , 22 ] . this patient can present doubts about the origin of the biochemical alterations either because of hcv infection or adalimumab toxicity . generally the changes in the liver function tests due to hcv virus show a predominant rise in transaminases , and it is not very common for a cholestatic pattern to appear . besides , it is not common at all to find portal infiltration with eosinophils in the liver biopsy of an hcv patient . to assess the likelihood of a causal association between adalimumab exposure and the liver toxicity , the drug - induced liver injury diagnostic scales were used . the degree of association between the implicated drug and the cholestatic damage was graded as  highly probable  using the roussel uclaf causality assessment method ( rucam ) scale [ 23 , 24 ] ( score of 10 ) and  probable  using the maria and victorino   ( score of 14 ) scales . those are the reasons why we think that adalimumab was responsible for the liver toxicity in this patient . in the case reported , adalimumab appears to be responsible for the liver injury because of the temporal relationship between the administration of the drug and the onset of pruritus and liver function tests alterations , the liver biopsy findings , other clinical conditions being discarded , and the improvement of clinical symptoms and biochemical abnormalities when adalimumab was suspended .
the most serious adverse drug reaction of adalimumab ( adr ) is tuberculosis reactivation . 
 we describe a case of a 35-year - old man , with rheumatoid arthritis ( ra ) and hepatitis c virus genotype 1a with a liver biopsy in 2001 with a metavir score pattern a1 f0 ; he received interferon alpha 2b for six months , but treatment was suspended because of reactivation of ra . 
 liver function tests after treatment were similar to previous ones showing a minimal cholestatic pattern . in 2008 , 
 methotrexate was prescribed , but the drug was withdrawn at the third month because of the appearance of pruritus and ggt rise . 
 viral load at that moment was 9300000  ui / ml , log 6,9 . 
 the liver biopsy showed a metavir score a2 f1 . 
 adalimumab was started in 2010 , and at the third month of treatment , ggt showed a rise of 23 times normal value ( nv ) , alkaline phosphatase 2,5 times nv with ast and alt with no change . 
 a new liver biopsy showed portal inflammation with eosinophils and a metavir a1 f2 . we think that adalimumab appears to be responsible for the liver injury , because of temporal relationship , liver biopsy findings 
 , other clinical conditions being discarded , and the improvement of clinical symptoms and biochemical abnormalities when adalimumab was suspended .