docMalattie autoimmuni del fegato e farmaci
download 
Report Transcription
Malattie autoimmuni del fegato e farmaci
Malattie autoimmuni del fegato e farmaci Marco Lenzi Dipartimento di Medicina Clinica Università di Bologna Putative pathogeneticpathwaysof AIH Drugs, Chemicals , Viruses Manns, 2010 Patientsdiagnosedwith AIH during the follow‐up after DILI diagnosis Björnsson E, 2009 Drugs and Cytochromes P450 Bioactivationofdrugsbycytochromes P450 and hypothesisforinductionofautoimmunity in drug‐inducedhepatitis Hepatology, 1997 LKM1‐positive sera reactwith CYP2D6 exposed on the outersurfaceofisolatedhepatocytes Anti‐CYP2D6 autoreactivity may be involved in the pathogenesis of liver damage Muratori L, Gut 2000 Indirectimmunofluorescence on snap‐ frozenratliver and kidneysections LKM homogeneously stains the cytoplasm of the liver lobule and the distal portion (P3) of the proximal renal tubules Autoantibodiestomicrosomal antigens in autoimmune and druginducedhepatitis Antibody Kd Targetantigen LKM‐1 50 CYP450 2D6 Autoimmune hepatitistype2 HCV LKM‐2 50 CYP450 2C9 Tienilic acid inducedhepatitis Anticonvulsivanthepatitis LKM‐3 55 family 1UGTs family 2UGTs Autoimmunehepatitistype2 HDV 52 CYP 450 1A2 Dihydralazineinducedhepatitis Autoimmune polyendocrinesyndrome1 54 Hydroxyethylate CYP450 2E1 Alcoholichepatitis CYP450 2E1 Halothanehepatitis LM 52 Rat CYP450 3A Diseaseassociation Anticovulsivantinducedhepatitis Tielinic acid Prototypicexampleofdrug‐induced autoimmune hepatitis ;Uricosuricdiuretic ;340 casesreported in US ;Developmentof anti‐LKM2 antibodiesdirectedagainstcytochrome P4502C9 ;Symptoms: malaise, fatigue and jaundice ;Promptrecurrenceofinjury in patientswhowerere‐challenged ;In patientswithhepatocellularjaundice 10% mortalityisreported ;Complete recoverywasseen in a 3monthperiod Autoimmunityagainstcytochrome P450 in immune mediatedliverdisease HCV autoimmune hepatitis 2D6 HDV Addison disease adrenalfail ure in APS1 UGT1 hepatitis in APS1 dihidralazinehe patitis 1A2 P450s c21 2C9 tienilic acid hepatitis halotane hepatitis 2E1 3A alcoholic liverdisease anticonvulsivant hepatitis Autoimmune Hepatitis: an unresolving inflammation of the liver of unknown cause 1. interface hepatitis 2. hypergammaglobulinemia 3. non organ‐specific autoantibodies Diagnosis: International scoring system Gender ALP/AST (ALT) γ-globulin ANA/SMA AMA Viralmarkers Drugs Alcohol Female +2 >3 -2 1.5-3.0 0 >2 +2 >2.0 +3 1.5-2.0 +1 >1:80 +3 1:80 +2 1:40 +1 <1:40 0 Positive -4 Positive -3 Negative +3 Yes -4 No +1 <25g/day +2 >60g/day -2 HLA Immune disease Othermarkers Histology Treatment response ≥10 pts: probable AIH >15 pts: definite AIH ≥12 pts: probable AIH >17 pts: definite AIH DR3/DR4 +1 Thyroiditis/colit is +2 Anti-SLA/LP, actin; LC1, pANCA +2 Interface hepatitis +3 Plasmacytic +1 Rosettes +1 None of the above -5 Biliary changes -3 Other features -3 Complete +2 Relapse +3 Pre‐ ‐treatment Pre Pre‐treatment Post‐ ‐treatment Post Post‐treatment Typesofliverinjury in DILI Spectrumof DILI Associateddrugs Acute livernecrosis Isoniazid, disulfiran, paracetamol Chronichepatitis Phenytoin,isoniazid Drug‐induced AIH Minocycline, nitrofurantoin Granulomatoushepatitis Carbamazepine,quinidine Steatohepatitis Amiodarone, valproate Cholestatichepatitis Flucloxacillin, amoxicillin/clavulate Blandcholestasis Estrogen, nimesulide Ductopenia Amoxicillin,trimethoprin‐sulpha Fibrosis Methotrexate Nodularregenerativehyperplasi a Azathioprine, 6‐thioguanine Drug‐inducedchronichepatitis Type Type I Syndromeresembling autoimmune hepatitistype1 (AIH‐1) Type II Syndromeresembling autoimmune hepatitistype2 (AIH‐2) Type III Syndromewithhistologyofchroniche patitis, but no serologicalmarkers Causative drugs Serology Oxyphenisatin ANA (67%), ASMA(67%) Methyldopa ANAS (16%) ASMA (35%) Minocycline ANA, anti‐DNA Nitrofurantoin ANA (80%), ASMA (72%) Germander ANA, ASMA Ectasy ANA Clometacine ASMA, anti‐DNA Statins ASMA Fenofibrate ANA Dihydralazine Anti‐Cyp1A2 Tienilic acid Anti‐Cyp2C9 Halotane Anti‐carboxylesterase, anti‐ proyeindisulfideisomerase Iproniazide AMA6 Etrinate ‐ Lisinopril ‐ Sulphonamide ‐ Trazadone ‐ Characteristicsofdrug‐induced AIH Duration ofdrugintake Female predominance Clinical Biochemical 2‐24 months or more >80% Fatigue ,anorexia, weight loss, jaundice, portalhypertension, hepatomegaly AST, ALT:5‐50xUNL. Increased γ‐gobulin level Serology Histology ANA, SMA, ASMA (anti‐actin) Activenecroinflammatorylesion, periportalnecrosis, withprominent plasma cells infiltrate, zone 3necrosis Course Resolution on withdrawalofdrug. Progression or deathifdrugcontinued 261 well‐characterized AIH casesfullfillingsemplifiedcriteria 24/261 (9.2%) suspectedtohavedrug‐induced AIH Minocycline 11 cases Nitrofurantoin 11 cases Cephalexin1 case Prometrium1 case Autoimmune hepatitis (AIH) vs Drug‐inducedliverinjury (DIAIH): comparisonofclinical and laboratoryfeatures at presentation AIH (n=237) DIAH (n=24) Pvalue Age 52(37‐62) 53(24‐61) NS Sex, female% 184(78%) 20(90%) NS ANA 165/237(70%) 20/24 (83%) NS SMA 106/237 (45%) 12/24(50%) NS Both ANA/SMA 69/237 (29%) 9/24(38%) NS AIH score Probable/definite 181/237 (94%) 19/24(90.5%) NS 18/52 (35%) 14/14(100%) <0.0001 Immunosuppressivetherapy (%) 222/237 (94%) 21/21 (88%) NS Steroids and Azathioprine (%) 191/222 (94%) 12/21 (57%) 0.0024 Steroids alone (%) 31/222 (14%) 9/21 (43%) 0.0024 ALT (<48UI/L) 480 (185‐1141) 728(255‐1141) NS ALP (<115UI/L) 241(138‐350) 376(229‐514) NS TB (<1mg/dL) 2.0 (1.0‐8.0) 4.0 (1.0‐12.0) NS 110/237 (46%) 12/24 (50%) NS Trial in discontinuationoftherapysuccessful (%) Jaundice at presentation Björnsson E, 2010 Nitrofurantoin‐induced vs Minocycline‐induced AIH: Comparisonofclinical and laboratoryfeatures at presentation Nitrofurantoin DIAIH Minocycline DIAIH Pvalue Age 61 (54‐66) 24 (18‐38) 0.0019 Sex,female% 11(100%) 10 (91%) NS ANA 8/11 (73%) 10/11 (91%) NS SMA 6/11 (55%) 5/11 (45%) NS Both ANA/SMA 4/11 (36%) 4/11 (36%) NS AIH score Probable/definite 7/9 (78%) 10/10 8100%) NS 9/9 (100%) 5/5 (100%) NS 11/11 (100%) 9/11 (82%) NS Steroids and Azathioprine (%) 3/11 (27%) 8/9 (89%) 0.0098 Steroids alone (%) 8/11 (73%) 1/11 (11%) 0.0098 ALT (<48UI/L) 778 (448‐1159) 380 (213‐871) 0.0235 ALP (<115UI/L) 426 (314‐503) 188 (110‐1081) NS TB (<1mg/dL) 7 (2.7‐21.0) 1.5 (0.8‐7.5) NS Jaundice at presentation 8/11 (73%) 3/11 (27%) NS Björnsson E, 2010 Trial in discontinuationoftherapysuccessf ul (%) Immunosuppressivetherapy (%) Nitrofurantoin ;Usedasantisepticfor the treatment and preventionofurinaryinfections ;Female sex 90% ;Incidence1:3000 case in USA ;The spectrumofinjuryincludes acute hepatocellular, cholestatic or chronichepatitis (augmented in chronicuse) ;In more than 90% ofcaseschronichepatitisisassociatedwithexposurelongerthan6months ;Symptoms: malaise, jaundice, hepatomegaly ;LiverBiopsy: portal and periportalinflammationwithmononuclear and plasma cells infiltrate withoccasionaleosinophils. ;Antinuclearantibodiespresent in 80% ofcases and SMA in 72%. ;Prognosisgenerallygood, providedthat the drugiswithdrawanbeforeadvancedliverdiseasedevelopment ;Autoantibodylevelsdeclineafterdrugwithdrawal Minocyclin ;Semisynthetictetracyclineused in treatment of acne ;Prevalentlyseen in female under the ageof 30 ;Latencyofdrugexposurerangesfrom4weeksto 104 weeks ;Clinical presentation include hypersensitivityhepatitis, fulminanthepaticfailure and chronichepatitiswith autoimmune features ;Histologyusuallytypicalfor autoimmune hepatitis (55% necrosis zone 3) ;Low rate ofprogressiontocirrhosis ;Developmentofanti‐nuclear antibody withtitrerangeof1:40 to1:1280, withhomogeneous pattern (rarelyanti‐dsDNA), withoutanycorrelationwith ALT peak ;SLE syndromewithouthepaticinjuryhasbeendescribed ;Promptrecurrenceofinjury in patientswhowerere‐challenged ;Resolution withoutrecurrenceafterdrugwithdrawal or short courseofimmunosuppressive treatment. Statins ;InhibitorsofHMG‐CoAreductase ;Asymtomaticelevations in serumtransaminases are common ;Sporadicreportsofstatintriggering autoimmune disease (LES, dermatomyositis, lichenplanus) ;Sporadicreportsofstatin‐induced autoimmune hepatitis ;ANA, SMA and hypergammagobulinemia are present in mostcases ;Liverbiopsyiscompatiblewith AIH ;Responsetoimmunosuppressivetherapy ;Severalmoleculshavebeenimplicated: Fluvastatin, Atorvastatin, Pravastatin, Simvastatin Anti‐TNF‐α agents ;Induce immunomediatedliverinjurythatresembles AIH ;Associatedwith ANA, SMA, anti dsDNA ;Prevalent in females (82%) ;Infliximab, adalizumab, certolizumabpegol and etanercept are allimplicated ;Signsofliverinjurytendtoappearwithin the fourthinfliximabinfusion and rarelylater ;ALT range 175 to 2250 U/L ;Histologyconsistentwih AIH withmarkedinflammatory infiltrate of the portaltractwithlymphocytes, plasma cells and piecemealnecrosis and rare lobularspottynecrosis ;Positive responsetosteroids in mostcases (10/11) ;No deaths are reported ;Fullyrecoveryisgenerallyobtainedwithin6weeks FinalComment Whetherdrugs and herbsunmaskor induce autoimmune hepatitis or simply cause a druginducedhepatitiswitha ccompanying autoimmune featuresisunclear Krawitt EL 2006 Case Report G.M. 46 year-oldfemale BMI 28.3 family history: positive forbreastcancer (mother and granmother) Drug and alcoholhistory: assumptionof Herbalife® for1year. December 2009: admittedto the local hospital for nausea, vomiting, abdominalpainwith dark urine and hypocholicstool. AST 31 xUNL, ALT 49 xUNL, total bilirubin 5.10 mg/dl (conjugated 3.31mg/dl). Case Report Testsperformedduringhospitalization: Viralmarkers negative, iron and coppermetabolism, alfa1-antitripsin: normal. All the other blood tests (including γ-globulin): normal Autoantibodies (ANA, SMA, LKM1, AMA, tTG): negative liver ultrasound: negative. Herbalife® was stopped followed by normalization of transaminases and bilirubin. Case Report February 2010: referredtoourUnitfor nausea, vomiting, jaundice. AST 1246 (< 32 U/L), ALT 1684 (< 54 U/L), ALP 486 (98-280 U/L), γGT 88 (5-36 U/L), total bilirubin 9.05 mg/dl (conjugated 8.68 mg/dl), INR 1.34. Albumina 3.7 g/l, IgG 1007 (700-1600 mg/dl), IgM 139 (40-230), TSH 1.62 (0.27-4.2 µU/ml). Shewasagainassuming Herbalife ANA: 1/1280, SMA: 1/320. LKM1, AMA, pANCAsearchedbyimmuno-fluorescence (serumdilution1:40): Negative Celiacdiseasemarkers (EmA, tTG, DGP) IgA and IgG: Negative Liver ultrasound: no signsofchronicliverdisease LiverBiopsy Case Report Liverbiopsy: ⇒Hepaticnecrosiswithmarkedlymphoplasmacytic and granulocytic infiltrate (neutrophil and eosinophil). ⇒Ductularproliferation. ⇒Presenceofportal and periportalfibrosis. Case Report First hypothesis: Herbalife®hepatotoxicity …but, despite Herbalife® withdrawal… Case Report •Sex Female +2 •ALP:AST (or ALT) ratio <1.5 +2 1.5-3.0 0 >3.0 -2 •Serumglobulins or IgGabovenormal >2.0 +3 1.5-2.0+2 1.0-1.5 +1 <1.0 0 • ANA, SMA, or LKM-1 >1:80+3 1:80 +2 1:40 +1 <1:40 0 •AMA-positive -4 •Hepatitisviralmarkers Positive -3 Negative +3 •Drughistory Positive-4 Negative +1 •Average alcohol intake <25 g/day +2 >60 g/day -2 •HLA DR3 or DR4 +1 • Immune disease: thyroiditis, colitis, other +2 • Other Markers: SLA, LC1, pANCA +2 • Liver histology Interface hepatitis +3 Predominantly lymphoplasm. infiltrate +1 Rosetting of liver cells +1 None of the above -5 Biliary changes-3 Atypical features -3 Pre-treatment Revised AIH score = 11 ⇒ probable AIH Case Report •ANA or SMA 1:40 +1 ANA or SMA ≥1:80 +2 LKM ≥1:40 +2 SLA positive +2 •IgGlevel>UNL +1 >1.1 x UNL +2 •LiverhistologyCompatiblewith AIH +1 Typicalof AIH +2 •AbsenceofViralHepatitis No 0 Yes+2 Simplified AIH score =6 ⇒ Probable AIH Case Report March 2010: corticosteroid treatment wasstarted metilprednisolone 0.5 mg/Kg/d Case Report May 2010: relapseduringcorticosteroidtapering(Metilprednisolone 24 mg/d). AST 10 xUNL, ALT 20xUNL, total bilirubin 0.97 mg/dl. The patienthasoccasionallyreassumed Herbalife® (sheexperienced a 10 Kg weightgainwhiletakingsteroids) → Dosage of steroids was increased (32 mg/d) and Azathioprine (50 mg) was associated. October 2010: AST 22 (<32 U/L), ALT 31 (<54U/L). Drugsassociatedwithhepatiticim mune‐mediatedreactions 9Dyhidralazine 9Halotane 9Methyldopa 9Minocycline 9Nitrofurantoin 9Phenytoin 9Tienilic acid 9Germander Drugsassociatedwithhepatiticim mune‐mediatedreactions 9Dyhidralazine 9Halotane 9Methyldopa 9Minocycline 9Nitrofurantoin 9Phenytoin 9Tienilic acid 9Germander FinalComment
