Overlap designations, therefore, have a tendency to be arbitrary and imprecise, and the clinical phenotypes of patients with the same overlap designation exhibit considerable heterogeneity. cirrhosis (PBC), main sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) are much more varied in their presentation and end result, than three disease labels does credit for. Table 1 Features of AIH, PBC, and PSC thead valign=”bottom” th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Feature /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ AIH /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ PBC /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ PSC /th /thead SexFemales: 60%\75%Females: 90%Females: 30%\35%AgeAll age groups; median age 45 yearsTypically 30\65 years; not diagnosed in childrenTypically 30\50 years, but all age groupsAminotransferasesMarkedly elevated, often 3\ to 10\fold, but may Xdh be normal or only minimally elevatedNormal or slightly elevatedNormal or slightly elevatedALPElevated levels may be seenModerately to markedly elevatedModerately to markedly Miglitol (Glyset) elevated (typically at least 3 ULN; but variable levels, may even be normal)BilirubinVariable increaseVariable increase, but normal in majority at diagnosisVariable increase, but normal in majority at diagnosisImmunoglobulinsHyper\gammaglobulinemia, especially elevated IgG (generally elevated 1.2\3.0 ULN)IgM increased in most patientsIgG increased in up to 61%; IgM increased in up to 45%AutoantibodiesANA, SMASignificant titers (1:40) of ANA and/or SMA in 70%\80%ANA in 30% (anti\gp210 and anti\Sp100 highly specific); SMA may be presentANA in 8%\77%; SMA in 0%\83%Anti\LKMAnti\LKM in 3%\4%Anti\SLA/LPAnti\SLA/LP in 10%\30%Anti\SLA/LP Miglitol (Glyset) may be detectedAnti\SLA/LP may be detectedpANCApANCA in 50%\96% (often atypical, pANNA); standard autoantibodies not detected in up to 10%pANCA in 26%\94%AMAAMA in low titer occasionally seen (AMA antiCPDC\E2 pattern rarely detected)AMA in 90%\95% (AMA antiCPDC\E2 pattern highly specific)AMA occasionally positiveLiver biopsyInterface hepatitisTypical findinga In a proportion of casesb In a variable quantity of casesc Portal inflammationPortal plasma cell infiltratePortal lymphocytic infiltratePortal lymphocytic infiltrateBiliary changesIn a proportion of casesTypicalTypicalGranulomasAtypicalSuggestive of PBC, but invariably presentAtypical, but may be observedCholangiographyNormal or indicators of liver cirrhosisNormal or indicators of liver cirrhosisCharacteristic findings, diagnostic of PSC; normal cholangiography in small duct PSCIrritable bowel diseaseRarely associated with AIH; PSC should be excludedRarely associated with PBCPresent in up to 80% Open in a separate windows Abbreviations: IgG, immunoglobulin G; IgM, immunoglobulin M; pANCA, perinuclear anti\neutrophil cytoplasmic antibodies; pANNA, anti\neutrophil nuclear antibody; PDC\E2, pyruvate dehydrogenase complex\E2; LKM, Liver Kidney Microsomal; SLA/LP, soluble liver antigen/liver\pancreas. aA diagnosis of definite AIH should not be concluded without a liver biopsy. bA liver biopsy is not required in AMA\positive cases. In early disease, characteristic features are uncommon. cA liver biopsy is not necessary for the diagnosis of large duct PSC but is required for the diagnosis of small duct PSC. Based on Trivedi and Hirschfield.2 Adapted from Reference 2. The often slow natural history of Miglitol (Glyset) autoimmune liver disease, the absence of disease\specific markers, and the invasive nature and sampling error of liver biopsy result in a clinical reliance on surrogates of disease activity. The way in which one applies surrogates of treatment efficacy must be critically appraised when faced with overlap presentations. The ability of changes to alkaline phosphatase levels in PBC to predict outcome3 is not comparable in PSC, where the same treatment has been trialed,4 and similarly the efficacy of corticosteroids in AIH5 does not imply that steroid treatment Miglitol (Glyset) for a significant transaminitis associated with interface hepatitis in PBC is usually equally beneficial to Miglitol (Glyset) patients.6 Underlying Concepts Overlap autoimmune liver syndromes are best not considered as distinct entities, but more the reflection of an inherent distribution of clinical features across patient populations presenting with autoimmune liver disease. The more extreme the distribution, the more distinct the apparent overlap, and the greater the likelihood that treatment based on the classic autoimmune liver disease distinctions will be of value. Clinically, overlap should be considered in the differential when a patient deviates from the normal clinical course and expected response to therapy, but it is usually not necessary to overdiagnose, nor is it necessary at presentation of a predominant disease process to consider overlap a means of justifying nonstandard therapy. The prevalence.