Epidemiology of chronic autoimmune liver disease: A histopathological study in third-level hospital in Mexico City

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1 ORIGINAL Vldivi-Corre ARTICLE B, et l. Epidemiology of chronic utoimmune liver disese: A histopthologicl study in third-level hospitl in Mexico City Bárbr Vldivi-Corre,* Fredy Chblé-Montero,** Misel Uribe,* Nhum Méndez-Sánchez* * Deprtment of Heptology nd Gstroenterology, ** Deprtment of Pthology. Medic Sur Clinic nd Foundtion. Mexico City. Mexico. RESUMEN Introducción. Ls enfermeddes hepátics utoinmunes (EHAI) comprenden un grupo heterogéneo. Ls frecuencis reltivs de ls EHAI no se hn estudido decudmente. Los estudios epidemiológicos en México son limitdos. Objetivo. El objetivo es determinr l prevlenci de histoptologí comptible con EHAI en un grupo de pcientes mexicnos. Mteril y métodos. Se exminron retrospectivmente 785 biopsis hepátics. Se nlizron los expedientes clínicos pr l recolección de dtos. Result- dos. Sesent y siete pcientes mostrron crcterístics comptibles con EHAI; 56 mujeres (83.6%) y 11 hombres (16.4%). Los resultdos mostrron que l prevlenci de EHAI durnte este periodo fue de 8.5%. L comorbilidd frecuentemente socid fueron otrs enfermeddes utoinmunes (20.89%). L principl cus de cirrosis en el grupo de mujeres fue heptitis utoinmune (100%) y en el grupo de hombres fue colngitis bilir primri (42%). Con- clusiones. Este estudio muestr un probble tendenci en umento de l prevlenci de EHAI; sin embrgo, es importnte recolectr más informción epidemiológic pr determinr l verdder prevlenci. Plbrs clve. Heptitis utoinmune. Colngitis. Esclerosnte. Biopsis. Hígdo. Prevlenci. ABSTRACT Bckground. Autoimmune liver diseses (AILD) comprise heterogeneous group. The reltive frequencies of AILD hve not been studied properly. Epidemiologicl studies in Mexico re limited. Objective. The im ws to determine the prevlence of AILD histopthology in group of Mexicn ptients. Mteril nd methods. We retrospectively exmined 785 liver biopsy specimens. Medicl records were nlyzed in order to recollect dt. Results. Sixty-seven ptients showed comptible chrcteristics with AILD; 56 were women (83.6%) nd 11 men (16.4%). The results showed tht the prevlence of AILD during this period ws 8.5%. The most frequent ssocited comorbidity ws other utoimmune diseses (20.89%). The min cuse of cirrhosis in the femle group ws AIH (100%), nd in the mle group PBC (42%). Conclu- sions. This study shows probble incresing tendency in the prevlence of AILD, however, it is importnt to collect more epidemiologicl informtion in order to truly define the prevlence. Key words. Heptitis. Autoimmune. Cholngitis. Sclerosing. Liver. Biopsy. Prevlence. INTRODUCTION The group of utoimmune liver diseses (AILD) comprises utoimmune heptitis (AIH), primry biliry cirrhosis (PBC), primry sclerosing cholngitis (PSC) nd recently discovered entity, n immunoglobulin G4-ssocited cholngitis (IAC). These, in turn, re clssified depending on the trget cell ffected: heptocyte or biliry epithelium. The heptocellulr dmge chrcterizes the AIH; on the contrry, cholngiopthies in- clude PBC nd PSC. There re proportion of ptients exhibiting fetures of two different AILD, designted s n overlp syndrome (OS), subdivided into 3 types: AIH- PBC, AIH-PSC nd PBC-PSC. 1 The precise pthogenesis of AILD is poorly understood nd includes n ssocition of environmentl, genetic nd immunologicl fctors. All types of AILD re chrcterized by vrying degree of immune-medited liver injury nd by strong ssocition with humn leukocyte ntigen (HLA). Despite shring common utoimmune pthogenesis, the Correspondence: Prof. Nhum Méndez-Sánchez, M.D., MSc, Ph.D., FACG, AGAF Liver Reserch Unit. Medic Sur Clinic & Foundtion Puente de Piedr, No. 150, Toriello Guerr, Z.P Mexico City. Tel.: (+5255) Ext Fx: (+5255) E-mil: nmendez@medicsur.org.mx Mnuscript received: Jnury 02, Mnuscript ccepted: Jnury 30, Rev Invest Rev Med Invest Sur Med Mex, Sur Jnury-Mrch Mex, 2016; ; (1): (1):

2 Autoimmune liver disese AILD re chrcterized by firly distinct demogrphic ptterns of disese. 2 The reltive frequencies of AILD hve not been studied properly. Epidemiologicl studies in Mexico re limited nd scrce. A recent study projected the trends in liver disese prevlence to 2,050 bsed on mortlity dt; lcohol etiology will be ccounting for 996,225 cses in 2050; no dt regrding AILD ppered to be significnt. 3 A multicenter study with ntionl smple of 1,486 liver cirrhosis ptients confirmed tht lcohol nd heptitis C were the min cuses; PBC first ppered s secondry cuse with 5.7%. 4 Frequently dt from other countries is extrpolted to popultion with different demogrphic chrcteristics, not truly reflecting the prevlence of the disese. Globlly, the vst mjority of studies hve focused on PBC; perhps s result of these, it is the subtype with the most vrition in incidence rtes. Jepsen, et l. 5 systemticlly reviewed 55 studies on the incidence of AILD in generl popultion, only 14 (25%) of them used stndrd popultion. 5 Specificlly, studies of PBC covering the yers before 1985 tend to find incidence rtes round 1 per 100,000 nnully minly in Europen popultions. Since then, studies from North Englnd hve found even higher incidence rtes, 4.33 per 100,000 per yer in New Cstle, Englnd. 6 No studies hve found higher incidence rtes of PBC thn in the ones conducted in Englnd. Menwhile, 17 studies described the popultion incidence of AIH. The process of identifying AIH ptients is more complex nd the dignostic criteri re uncler in the mjority of studies. The highest incidence 3 per 100,000 person-yers ws found in West Suffolk, Englnd. 7 Finlly, 14 studies identified PSC popultion. The highest incidence, 2 per 100,000 person-yers in ws found in West Suffolk, 7 nd t the other end of the spectrum, none of 100,000 Alsk ntives were dignosed during 1984 to No studies exmined the popultion incidence of IAC. Most of the epidemiologicl studies hve been conducted very differently, nd therefore, it is difficult to determine whether incidence vries becuse of differences in methods or becuse of different risk fctors ssocited. 5 Further, there ws not single Ltin Americn epidemiologicl study ddressing these issues, nd only few in the United Sttes popultion. The dignosis of AILD requires the exclusion of other cuses of liver dmge, s well s creful evlution of clinicl, biochemicl, histopthologicl, nd cholngiogrphic chrcteristics specific to ech of the mjor AILD entities. Although few of these disese fetures re individully dignosed, prticulr combintions re needed for high sensitivity nd specificity criteri, re in which further development is needed. 9 Moreover, liver biopsy hs been the gold stndrd for dignosing liver disese; however with the development of dignostic testing, novel utontibodies nd noninvsive ssessment of liver fibrosis existing indictions re limited. According to the AASLD, liver biopsy currently hs three mjor roles: 1) dignosis, 2) ssessment of prognosis (disese stging), nd/or 3) ssistnce in mking therpeutic mngement decisions. 10 Liver histology is commonly used in disese monitoring of ptients with AIH, minly becuse of the different histologicl presenttions. Predominnt or exclusive centrilobulr injury is now recognized in the histologicl spectrum of AIH nd my represent n erly stge of the disese. 11 There is evidence tht ptients with PBC nd dvnced fibrosis on biopsy t dignosis my respond less well to ursodeoxycholic cid thn do ptients with miniml o mild fibrosis, thus plcing them t risk of more rpid disese progression nd premture deth/requirement for liver trnsplnttion. 12 Furthermore, in ptients with chronic liver disese, liver biopsy ws required in 7.2%, but in 31.2% of cses, it cn chnge the dignosis. 13 The im of this study ws to determine the prevlence of positive utoimmune liver disese histopthology in group of Mexicn ptients. The second im ws to chrcterize the clinicopthologicl fetures nd describe the spectrum of morphologicl findings of AILD. MATERIAL AND METHODS A retrospective study ws conducted. We used the pthology records of seven hundred eighty-five liver biopsy specimens between the yers 2008 nd Of these, sixty-seven ptients showed comptible histopthologicl chrcteristics with AILD. Liver biopsies were performed on n outptient bsis or by direct ultrsound guided biopsy. The choice of method ws left to the ttending physicin. Formlin-fixed prffin-embedded sections were stined with H/E, periodic cid-schiff, nd Msson s trichome stin. A semi-quntittive 4-grde system (bsent, miniml, moderte, nd severe) ws used to ssess histologic prmeters such s portl inflmmtion, lymphocytic ggregtes in portl trcts, piecemel necrosis, nd spotty lobulr necrosis. Fibrosis ws grded s portl, bridging, or cirrhosis. Two pthologists who were blinded to the clinicl nd serologic dt performed the histologic evlution. We reviewed the medicl records of ll 67 ptients who hd histopthologicl chrcteristics comptible with AILD. Dt on demogrphics such s ge, sex, nd plce of birth were obtined; s well s clinicl dt such s lcohol nd cigrette consumption. Finlly, biochemicl 44 Rev Invest Med Sur Mex, 2016; 23 (1): 43-48

3 Vldivi-Corre B, et l. nd immunologicl dt ws sought. Liver utontibodies including ntinucler ntibodies (ANA), smooth muscle ntibody (SMA), liver kidney microsoml ntibody type 1 (LKM1), nd ntimitochondril ntibodies (AMA). AIH ws suspected when immunoglobulin type G (IgG) ws elevted nd/or when utontibodies ANA, SMA, LKM1 were present. PBC ws suspected in the presence of cholesttic enzyme pttern nd positive AMA. PSC ws suspected in the presence of cholesttic enzyme pttern, negtive AMA nd bile duct bnormlities with multifocl strictures nd segmentl dilttions in mgnetic resonnce cholngiopncretogrphy or endoscopic cholngiopncretogrphy. We clculted the prevlence in the period of 6 yers, nd then the point prevlence for ech yer of biopsies nlysis. RESULTS Of the seven hundred eighty-five (n = 785) liver biopsy specimens, only sixty-seven ptients (n = 67) hd positive histopthology comptible with AILD by the following dignosis: AIH (n = 38), PBC (n = 17), PSC (n = 1), OS (n = 11) (Figure 1); 56 were women (83.6%) nd 11 men (16.4%). The verge ge in the femle group ws 49.5 yers (19-73 yers), nd in the mle group, 52 yers (28-72 yers). The results showed tht the prevlence of positive histopthology of AILD in liver biopsies during the period of six yers ws 8.5% (Figure 2). The distribution of plce of birth ws s follow: 32 ptients were born in Mexico City (47.76%), 16 ptients in Estdo de México (23.88%) the rest were distributed mong different sttes. In 8 ptients no dt could be obtined from lcohol nd cigrette consumption; from the rest, 28 ptients (41.79%) hd positive cigrette consumption nd 31 (46.26%) hd negtive consumption; 26 (38.80%) ptients consumed lcohol (< 40 g/dy), nd 41 (61.19%) hd never consumed it. Only 46 of 67 ptients (68.65%) disply complete biochemicl lbortories. Ptients with PBC exhibit predominnt cholesttic pttern, chrcterized by higher levels of lkline phosphtse nd gmm glutmil trnspeptidse (Tble 1). Concerning histopthologicl findings, portl inflmmtion ws present in ll the ptients (100%), regrdless AILD subtype. Grnuloms were present in 1 (2.6%), 1 (9.1%), nd 2 (11.8%) of AIH, OS nd PBC liver biopsy specimens, respectively. Biliry lesions nd duct loss were more prominent in PBC nd OS thn in AIH, relevnt to this, cholestsis ws lso chrcteristic feture in PBC (41.2%). Fetures of heptocellulr dmge such s focl or spotty necrosis were seen frequently in AIH nd OS; none of the ptients presented confluent necrosis. Interfce heptitis (piecemel necrosis) ws predominntly in OS (90.9%) while AIH nd PBC hd similr presenttion, 16 (42.1%) nd 7 (41.2%) respectively. PBC showed consistent low-grde portl fibrosis (F1-2), while cirrhosis ws more prominent in the OS group (36.4%). AILD cses showed low-grde level of stetosis, minly grde 1 o less. Min histopthologicl findings re summrized in tble 2. The most frequent ssocited comorbidity were other utoimmune diseses (20.89%), minly systemic lupus erythemtosus, nkylosing spondylitis nd Sjogren syndrome. Smoking ws present in 28 ptients (41.79%) nd lcohol consumption in 32 (47.7%) (Tble 3). The min cuse of cirrhosis in the femle group with the estblished 2% Primry sclerosing cholngitis (n = 1/67) 16% Overlp syndrome (n = 11/67) Prevlence (%) % Primry biliry cirrhosis (n = 17/67) 57% Autoimmune heptitis (n = 38/67) Prevlence ( ) 0.51%* 0.63%* 1.39%* 1.40%* 2.51%* 2.04%* 8.50%* Figure 1. Distribution of subtypes of utoimmune liver diseses. Figure 2. Point prevlence* distribution of utoimmune liver diseses. Rev Invest Med Sur Mex, 2016; 23 (1):

4 Autoimmune liver disese Tble 1. Min lbortory prmeters in the different dignostic groups (medin nd rnge re given). Histopthol. N Hb Pl Glob ALT AST BT Alk. P γ-gt Alb dig. (g/dl) (mill/mm 3 ) (g/dl) (UI/L) (UI/L) (mg/dl) (UI/L) (UI/L) (g/dl) AIH (n = 38) ( ) (57-395) ( ) ( ) ( ) ( ) (11-537) (11-625) (1.86-5) PBC (n = 17) ( ) ( ) ( ) (21-160) (30-168) (.7-5) ( ) ( ) (2-4.9) OS (n = 11) ( ) ( ) ( ) (39-208) (40-142) ( ) (41-641) ( ) ( ) Histopthol. dig.: Histopthologicl dignosis N: number of ptients with complete lbortory findings. Hb: hemoglobin. Pl: pltelets. Glob: globulins. ALT: lnine minotrnsferse. AST: sprtte minotrnsferse. BT: totl bilirubin. Alk P: lkline phosphtse. γ-gt: gmm glutmil trnspeptidse. Alb: lbumin. dignosis of utoimmune liver disese ws AIH (100%); nd in the mle group PBC (42%). In this series, there were no mjor complictions ssocited with the liver biopsy procedure. DISCUSSION In the present retrospective study, the prevlence of positive AILD histopthology in the period of six yers ws 8.5%. A tendency in incresing prevlence is observed throughout the yers, confirming similr results round the world. Between , prevlence rtes in the United Kingdon incresed significntly from 14.9 to 25.1 cses per 100,000 popultion (p < ). 14 In the cse of AIH, it is noteworthy the incresing incidence in Dnish popultion with bout 0.3 to 0.4 cses per 100,000 popultion higher between the yers , lthough the popultion ws not stndrdized. 15 It is importnt not to ignore possible regionl vrition tht could explin the incresing trend. Other findings such s femle predominnce nd n verge ge of presenttion between 49.5 nd 52 yers old re consistent with the literture. There re few studies exmining using liver biopsy s determinnt key in its dignosis. A similr study published by Terrcino, et l., 16 exmined 42 liver biopsies from ptients with histologicl criteri of ALD. The distribution of the entities ws significntly different: 10 cses of OS, 10 of IAC, 10 of PBC nd 9 of AIH. 16 Similr to our study, the minority of cses or even none of PSC cses were dignosed by histopthology chrcteristics, emphsizing the fct tht dignosis of PBC is mde with bile duct chnges seen on n imging study long with cholesttic pttern. The high number of ptients tht underwent liver biopsy s n outptient mnner could explin the minimum shortge of utontibodies. Moreover, specific serology hs proved to be minsty of dignostic testing in AIH nd PBC, but disese-relevnt rectnt hs not been identified in PSC. 9 Autontibody titres usully vry during the course of the disese. Hence, seronegtivity, low or high utontibody titres on single test cnnot exclude the dignosis of AILD0 9 when pproching ptient with AILD complete biochemicl, serologicl, clinicl nd/or histologicl chrcteristics re required. The vst mjorities of epidemiologicl studies of ALD re mrked with heterogeneity in the study design, nd lck informtion to determine n ccurte dignosis. To improve the stndrdiztion nd ccurcy of future epidemiologicl studies of AILD, Metclf nd Jmes 6 proposed set of specific guidelines to be followed: Stringent cse inclusion criteri. Cler definition of dte of disese onset. Well defined study period, re nd popultion. Multiple cse-finding methods. Rigorous trcing of ll vilble informtion nd possible cses. 6 More work is needed to be done to regulte the use of more dt sources such s serches of liver biopsy, immunology, lbortory or even utopsy dtbses to identify ptients. The benefits of epidemiologicl dt re well studied; the dvnces mde in the understnding of the definition nd pthogenesis of these complex diseses is the most significnt contribution. These studies provide informtion tht is importnt not only to our ptients, but lso to helthcre dministrtors who must dimension our outptient clinics nd even to phrmceuticl compnies who pln experimentl studies. 5 Finlly, the informtion given by this type of studies my enble to estimte the number of liver trnsplnttions required due to AILD. The specific vlue of isolted liver biopsy in AILD remins unnswered. Histology is often considered to be 46 Rev Invest Med Sur Mex, 2016; 23 (1): 43-48

5 Vldivi-Corre B, et l. Tble 2. Histologicl findings.* Tble 3. Disese ssocitions of utoimmune liver disese. AIH (n = 38) OS (n = 11) PBC (n = 17) PSC (n = 1) 1. Portl inflmmtion 38 (100%) 11 (100%) 17 (100%) 1 (100%) 2. Bile duct lesions 9 (23.7%) 9 (81.8%) 15 (88.2%) 1 (100%) 3. Bile duct loss 2 (5.3%) 2 (18.2%) 3 (17.6%) 0 (0%) 4. Nodulr lymphocytic ggregtes or germinl centers 0 (0%) 0 (0%) 2 (11.8%) 0 (0%) 5. Focl or spotty lobulr necrosis 6 (15.8%) 2 (18.2%) 1 (5.9%) 0 (0%) 6. Confluent necrosis 0 (0%) 0 (0%) 0 (0%) 0 (0%) 7. Piecemel necrosis (interfce heptitis) 16 (42.1%) 10 (90.9%) 7 (41.2%) 0 (0%) 8. Portl fibrosis (F1-2) 6 (15.8%) 4 (36.4%) 6 (35.3%) 0 (0%) 9. Bridging fibrosis (F3) 5 (13.2%) 0 0 (0%) 1 (100%) 10. Cirrhosis (F4) 9 (23.7%) 4 (36.4%) 5 (29.4%) 0 (0%) 11. Grnuloms 1 (2.6%) 1 (9.1) 2 (11.8%) 1 (100%) 12. Stetosis (grdes 1-3)** 7 (18.4%) 2 (18.2%) 9 (52.9%) 0 (0%) 13. Cholestsis 2 (5.3%) 2 (18.2%) 7 (41.2%) 1 (100%) AIH: utoimmune heptitis. OS: overlp syndrome. PBC: primry biliry cholngitis. PSC: primry sclerosing cholngitis. * Dt re given s number (%) of biopsy specimens with moderte or severe findings. ** Stetosis ws minly grde 1 o less. Primry biliry cirrhosis (n = 17) Autoimmune heptitis (n = 38) Overlp syndrome (n = 11) Systemic lupus erythemtosus Rheumtoid rthritis Sjögren s syndrome Sjögren s syndrome Ulcertive colitis Rheumtoid rthritis Ankylosing spondylitis Liquen plnus Systemtic lupus erythemtosus Grves disese Lymphocytic colitis gold stndrd in mny spects of the dignosis. However, there is n cknowledgment tht dignostic errors cn occur, nd tht intr-nd inter-observer vrition my be considerble; 17 the yield is prticulrly high in mrker negtive ptients. 18 In recent study of histopthologicl dignosis of 1,265 liver biopsies, differences in histopthologicl interprettion were present in 59% biopsies nd 67% were predicted t the time to impct on ptient mngement; dignostic differences occurred in 70% of biliry disese, utoimmune heptitis, nd vsculr chnges. 17 The differentil dignosis between ALD remins chllenging problem, so this study could suggest tht biopsies in AILD should be reviewed not only by the pthologist but lso by liver specilist to reduce misunderstnding in the dignosis. To emphsize this point, it is well known tht the key histologic fetures of AIH re chronic heptitis pttern of injury with portl nd periportl lymphoplsmcytic infiltrtes, interfce heptitis, not prominent bile destruction nd severity of necro-inflmmtory ctivity quite vrible. Our dt confirms these observtions nd others regrding tht this histologic pttern of injury my be indistinguishble from PBC. The PBC cses in our study demonstrte mild bile duct injuries nd low bile duct loss. Recent studies hve shown tht the dignostic ccurcy of PBC cses depends on the bile duct injury; in cses with severe bile duct injuries the ccurcy is very high (over 80%), while the ccurcy in mild bile duct injuries lowers to 50% or less. 19 Another problem in PBC cses is tht the differentil dignosis depends on the stge of the disese. The high number of cses with interfce heptitis nd cholestsis in our PBC group could be explined by the fct tht these cses were detected in dvnced stges 2 or 3 of the disese, coupled with the presence of portl fibrosis in this group. The vlue of histologic stging in ssessing prognosis in erlystge PBC is debtble, given the lck of uniformity of duct loss in the liver disese. 20 These dt confirm recent observtions showing the lck of substntil histologic differences between AIH nd PBC, so other dignostic tools like clinicl nd serologicl mrkers should be used. In cses of PSC, liver biopsy is undertken to rule other cuses but not s dignostic tool, demonstrted by the low prevlence of this subtype in our study. The OS ws first described in 1997, is n uncommon chronic liver disese with morphologic, serologic nd clinicl fetures of both PBC nd AIH. 16 While moderte nd severe bile duct Rev Invest Med Sur Mex, 2016; 23 (1):

6 Autoimmune liver disese lesions were present in 80%, bile loss ws only present in less thn 20%, grnuloms were seen in 2 ptients (20%) nd the typicl heptitis fetures such s lobulr necrosis, piecemel necrosis were found in 5.9 nd 41.2% respectively. These dt suggest tht the histologic fetures of OS re closer to AIH thn to PBC. The present study hs some limittions. First, this ws retrospective observtionl study. Second, smpling error nd histopthologicl nlysis done only by one pthologist re fctors tht limit dignostic ccurcy. Finlly, lthough our biopsy smple ws lrge, we cnnot overlook the fct tht more thn hlf of the ptients (68.65%) lck complete biochemicl lbortories nd only 6 of 67 (8.95%) hd specific utontibodies. In conclusion, the group of AILD is complex nd vried group of entities. When mnging ptient with AILD, long term nd strtified pproch to cre must be dopted; focus on clinicl, serologicl, nd histopthologicl chrcteristics is essentil in determining with ccurcy definitive dignosis. Nowdys, there is lrge shortfll of epidemiologicl studies in certin popultions, including Mexico. Thus, further rigorous studies re needed to truly define the incidence, prevlence, fmilil risk nd disese ssocitions in this entity. REFERENCES 1. Bunchorntvkl C, Reddy KR. Dignosis nd mngement of Overlp Syndromes. Clin Liver Dis 2015; 19: [PubMed: ]. 2. Krlsen TH, Chung BK. Genetic risk nd the development of utoimmune liver disese. Dig Dis 2015; 33: [PubMed: ]. 3. Méndez Sánchez N, Vill AR, Chávez Tpi NC, Poncino Rodríguez G, Almed Vldés P, González D, Uribe M. Trends in liver disese prevlence in Mexico from 2005 to 2050 through mortlity dt. Ann Heptol 2005; 4: [PubMed: ]. 4. Méndez Sánchez N, Aguilr Rmírez JR, Reyes A, Dehes M, Juárez A, Cstñed B, Sánchez Ávil F, et l. Etiology of liver cirrhosis in Mexico. Ann of Heptol 2004; 3: [PubMed: ]. 5. Jepsen P, Gronbek L, Vilstrup H. Worldwide incidence of utoimmune liver disese. Dig Dis 2015; 33: 2-12 [PubMed: ]. 6. Metclf J, Jmes O. The Geoepidemiology of Primry Biliry Cirrhosis. Semin Liver Dis 1997; 17: [PubMed: ]. 7. Whlley S, Puvnchndr P, Desi A, Kennedy H. Heptology outptient service provision in secondry cre: study of liver disese incidence nd resource costs. Clin Med (Lond) 2007; 7: [PubMed: ]. 8. Hurlburt KJ, McMhon BJ, Deubner H, Hsu Trwinski B, Willims JL, Kowdley KV. Prevlence of utoimmune liver disese in Alsk ntives. Am J Gstroenterol 2002; 97: [PubMed: ]. 9. Invernizzi P, Lleo A, Podd M. Interpreting serologicl tests in dignosing utoimmune liver diseses. Semin Liver Dis 2007; 27: [PubMed: ]. 10. Rockey DC, Cldwell SH, Goodmn ZD, Nelson RC, Smith AD, Americn Assocition for the Study of Liver Diseses. Liver Biopsy. Heptology 2009; 49: [PubMed: ]. 11. Tinikos DG, Brin JG, Bury YA. Role of histopthology in utoimmune heptitis. Dig Dis 2015; 33: [PubMed: ]. 12. Corpechot C, Crrt F, Bhr A, Chrétien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic cid therpy on the nturl course of primry biliry cirrhosis. Gstroenterology 2005; 128: [PubMed: ]. 13. Amrpurkr D, Amrpurkr A. Indictions of liver biopsy in the er of noninvsive ssessment of liver fibrosis. J Clin Exp Heptol 2015; 5: [PubMed: ]. 14. Jmes OF, Bhopl R, Howel D, Gry J, Burt AD, Metclf JV. Primry biliry cirrhosis once rre, now common in the United Kingdom? Heptology 1999; 30: [PubMed: ]. 15. Gronbek L, Vilstrup H, Jepsen P. Autoimmune heptitis in Denmrk: incidence, prevlence, prognosis nd cuses of deth. A ntionwide registry-bsed cohort study. J Heptol 2014; 60: [PubMed: ]. 16. Terrcino LM, Ptzin RA, Lehmn FS, Tornillo L, Cthoms G, Mhwech P, Vecchione R, et l. A spectrum of histopthologic findings in utoimmune liver disese. Am J Clin Pthol 2000; 114: [PubMed: ]. 17. Ptterson AL, Allison ME, Bris R, Dvies SE. Any vlue in specilist review of liver biopsies? Conclusions of four-yer review. Histopthology 2016, 69: [PubMed: ]. 18. Spycher C, Zimmermnn A, Reichen J. The dignostic vlue of liver biopsy. BMC Gstroenterol 2001; 1: 1-6 [PubMed: ]. 19. Zen Y, Hrd K, Sski M, Tsuneym K, Mtsui K, Hrtke J, Skisk S, et l. Are bile duct lesions of primry biliry cirrhosis distinguishble from those of utoimmune heptitis nd chronic virl heptitis? Interobserver histologicl greement on trimmed bile ducts. J Gstroenterol 2005, 40: [PubMed: ]. 20. Wshington MK. Autoimmune liver disese: overlp nd outliers. Mod Pthol 2007; 20: S15-S30 [PubMed: ]. Revist de Investigción Órgno de Difusión de l Sociedd de Médicos 48 Rev Invest Med Sur Mex, 2016; 23 (1): 43-48