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Abdominal Radiology ISSN 2366-004XVolume 42Number 1 Abdom Radiol (2017) 42:19-27DOI 10.1007/s00261-016-1019-x

Imaging of autoimmune hepatitis andoverlap syndromes

Neera Malik & Sudhakar K. Venkatesh

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Imaging of autoimmune hepatitis and overlapsyndromes

Neera Malik, Sudhakar K. Venkatesh

Division of Abdominal Imaging, Department of Radiology, Mayo Clinic, 200, First Street SW, Rochester, MN 55905, USA

Abstract

Autoimmune hepatitis (AIH) is an uncommon, chronicinflammatory, and relapsing liver disease of unknownorigin that may lead to liver cirrhosis, hepatocellularcarcinoma, liver transplantation, or death. AIH occurs inall age groups and races but can frequently manifest asacute fulminant hepatitis. Clinical presentation of AIHcan have features similar to primary sclerosing cholan-gitis (PSC) and primary biliary cirrhosis (PBC), and thesediseases may coexist leading to overlap syndromes. Al-though histological diagnosis is necessary, imaging fea-tures often can demonstrate characteristics that may behelpful to distinguish these diseases. Imaging features ofAIH are those of chronic liver disease, and imaging playsimportant role in detection of complications and rulingout other possible causes of chronic liver disease.Emerging techniques such as elastography provide non-invasive options for diagnosis of significant fibrosis andcirrhosis during clinical follow-up as well as assessmentof response to treatment. In this study, we will describeimaging findings in AIH and overlap syndromes.

Key words: Autoimmune hepatitis—Cirrhosis—Primarysclerosing cholangitis—Primary biliary cirrhosis—MRelastography

Autoimmune liver disease is an uncommon cause ofchronic liver disease but accounts for 24% of liver trans-plants [1]. The spectrum of autoimmune liver diseases in-cludes primary autoimmune hepatitis (AIH), primarysclerosing cholangitis (PSC), and primary biliary cirrhosis(PBC), each with characteristic clinical, laboratory, his-tology, and imaging findings [2–5]. The spectrum also in-

cludes overlap syndromes and transplant-relatedautoimmunity which share similar immunologic mecha-nisms of disease and tissue injury [6]. Occasionally theseindividual entities overlap with common causes of chronicliver diseases such as chronic hepatitis C, alcoholic hep-atitis, and non-alcoholic fatty liver disease (NAFLD).

Involvement of the biliary tract is characteristicallyabsent or minimal in AIH, and the presence of clinical orhistological features of cholestasis should lead to evalu-ation of overlap syndromes. Overlap syndromes com-prise a variant form of autoimmune liver diseasecharacterized by classic features of AIH with additionalfindings of PSC or PBC—an important distinction withimplications for management and prognosis. However,controversies exist whether these should be considered asdistinct entities or treated as predominant disease withoverlapping features of a second disease either at imagingor serology or histology [7].

The diagnosis of AIH and overlap syndromes is lar-gely clinical and based on detection of autoimmuneantibodies and elevated liver enzymes. Liver biopsy isstill considered the reference standard as the only testthat can reliably diagnose the presence of necroinflam-mation, lymphocytic infiltration, and early fibrosis.However, liver biopsy is an imperfect standard withsampling and interpretative errors in addition to being aninvasive technique that reduces compliance among pa-tients and carries a non-negligible risk of complications.Noninvasive imaging methods play a more significantand complementary role in the diagnosis and manage-ment of these diseases. Magnetic resonance cholangiog-raphy (MRC) is increasingly being recommended inpatients with AIH and cholestasis to detect concurrentoverlap syndromes, particularly PSC. Elastographytechniques are also proving beneficial as non-invasivemethods of detecting and quantifying advanced fibrosisand cirrhosis in patients with chronic liver diseaseregardless of etiology [8–12]. Screening with imaging isalso performed for detection of HCCs in patients withcirrhosis.Correspondence to: Sudhakar K. Venkatesh; email: venkatesh.sud

[email protected]

ª Springer Science+Business Media New York 2016

Published online: 20 December 2016AbdominalRadiology

Abdom Radiol (2017) 42:19–27

DOI: 10.1007/s00261-016-1019-x

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Autoimmune hepatitis

Autoimmune hepatitis is a chronic, relapsing autoimmuneliver disease. AIH is characterized by interface hepatitis(piecemeal necrosis) at histology, increased serumtransaminases levels, presence of autoantibodies in serum,and elevated serum immunoglobulin (IgG) levels [13].

The etiology of AIH is still unknown and both envi-ronmental agents and genetic factors have possible rolesin the pathogenesis. The environmental agents includedrugs, herbs, microbes, and immunization [14–16]. AIHhas been strongly associated with genes that encode theclass II DRB1 alleles. These alleles have also been linkedto clinical manifestations, response to treatment, andprognosis (see Table 1). It is hypothesized that with in-creased genetic susceptibility to AIH, an exposure to atrigger such as a viral infection, antibodies such asnitrofurantoin, minocycline, statins and anti-TNF agentswould initiate an immune response and an autoimmuneattack against the liver continues through molecularmimicry [17–19]. The pathological hallmark of AIH isinterface hepatitis with lymphoplasmocytic infiltratesand varying degrees of lobular inflammation and dam-age. Acute onset AIH is characterized by pan acinarhepatitis with or without centrilobular perivenulitis andwith or without interface activity. Interestingly, 36% ofpatients with AIH have cirrhosis at presentation [20].

Clinical manifestations vary from asymptomatic tosevere or rare presentation of fulminant acute hepatitis.AIH should be considered as an etiology of chronic liverdisease after ruling out viral, metabolic, genetic, andtoxic etiologies. Diagnosis of autoimmune hepatitis isbased on the criteria of the International AutoimmuneHepatitis Group (IAHG). The criteria is based on anumeric scoring system [21] that relies on identifyingcharacteristic clinical, biochemical, immunological, andhistopathological features. Although originally describedas a disease affecting predominantly young Caucasianfemales, the diagnosis has expanded considerably andnow includes male and female patients of all ages anddiverse ethnicities. While most patients have an acutepresentation, 1/4 to 1/2 of patients have an indolent

presentation characterized by mildly elevated liver func-tion tests [22]. The progression to fibrosis and cirrhosis issimilar between asymptomatic and symptomatic presen-tations [22]. Approximately one quarter to one-third ofpatients with AIH have liver cirrhosis at presentation [23,24].

Liver biopsy is essential for confirming a diagnosis ofAIH. The characteristic histopathological change in-cludes interphase hepatis, but this is not exclusive forAIH. Generally inflammation spares the biliary system.Histology is useful for grading and staging of the diseasefor prognosis, however, the necroinflammatory activityand severity does not always correlate with biochemicalactivity of the disease [25].

AIH is divided into types 1 and 2 based on autoan-tibody expression. Characteristics of the two types aresummarized in Table 1. Type 1 AIH accounts for 80% ofAIH cases and is characterized by antinuclear autoanti-bodies (ANA) and/or smooth muscle autoantibodies(SMA), it typically occurs in older adults and tends to beassociated with treatment failure, relapse, and the needfor long-term treatment. In Type 2 AIH, specific anti-liver/kidney microsomal (anti-LKM) antibodies and/oranti-liver cytosol type 1 antigen (anti-LC1) are detectedand are commonly found in children and young adults. Itcan have a severe or acute course with advanced changesin histology at presentation.

About 40% of patients have a family history ofautoimmune disease, and 20% have concomitantautoimmune disease or development during the course ofthe disease [21, 26]. Concomitant autoimmune disordersinclude autoimmune thyroiditis, Sjogren’s syndrome,systemic lupus erythematosus, rheumatoid arthritis,vasculitis, vitiligo, diabetes mellitus type-1, and celiacdisease [27].

Standard treatment is a combination of corticos-teroids and azathioprine, with budesonide, mycopheno-late mofetil, and calcineurin inhibitors as salvagetherapies. Treatment is continued until normal labora-tory tests are achieved, which occurs within two years ingreater than two-thirds of patients [28]. Incomplete re-sponse occurs in 14% of patients [29] and treatment

Table 1. AIH types according to antibody profile

Characteristic AIH type 1 AIH type 2

Prevalence 80% 10% to 15%Age Children and older adults Children and young adultsAuto antibodies Antinuclear antibody (ANA)

Smooth muscle autoantibody (SMA)Anti-liver/kidney microsomal (anti-LKM)Anti-liver cytosol type 1 antigen (anti-LC1)

Presentation Indolent Severe or acuteLikely to present with advanced histological

stages or cirrhosisTreatment and prognosis Good response to steroids. Frequently

relapses after stopping treatment. Needlong-term treatment

Progression to cirrhosis under treatment

Failure to respond often but with sustained response.Need long-term treatment

Compiled from references [19, 25, 56–58]

20 N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes


failure occurs in 7% of patients [30]. Overlap with otheretiologies should be considered in cases of treatmentfailure. Liver transplantation may be indicated in thosepatients with liver failure, and carries a 10 year survivalrate exceeding 70% [31].

Recurrence of AIH in transplants occurs in about16% to 43% of patients who receive transplant for AIH-related cirrhosis [32]. De novo autoimmune hepatitis intransplants is also known but has been termed differentlyas post-LT AIH-like hepatitis, post-transplant immunehepatitis, etc. [33].

No characteristic imaging appearance of AIH hasbeen described. Although imaging is not required forinitial diagnosis of AIH, CT, and MRI are useful fordetection of cirrhosis and its complications. About 1–9%of cirrhotic AIH develop HCC [34] meriting surveillanceimaging every 6 months similar to other chronic liverdiseases. Non-invasive methods for detection and stagingof liver fibrosis would be useful for management of AIHinitially as well as during clinical follow-up.

Ultrasound (US) in AIH

The sonographic features of AIH vary with the severityof disease, ranging from normal appearance to findingsof chronic parenchymal disease such as coarsening ofhepatic echotexture (Figs. 1, 2), surface nodularity, andvolume redistribution. Doppler is useful for assessmentof hepatic and portal vein patency and direction of flowin the portal venous system. Ultrasound-based transient

elastography (TE) for detection of fibrosis may be ofutility in determining the extent of fibrosis, and hasshown promise in two studies examining extent offibrosis in patients with AIH [35, 36].

Ultrasound has a central role in HCC surveillance inpatients with AIH, with the American Association forthe Study of Liver Diseases (AASLD) and EuropeanAssociation for the Study of Liver Disease (EASL) bothrecommending semiannual ultrasound surveillanceamong high-risk patients. Ultrasound is a non-invasive,radiation-free, and cost-effective imaging modality thatis well accepted for this indication. Ultrasound for HCCsurveillance has a sensitivity of 40% to 81% and speci-ficity of 80% to 100% [37].

More recently, contrast-enhanced ultrasound (CEUS)using microbubble contrast agents has garnered atten-tion for its utility in characterizing liver nodules. CEUScan be used as a problem-solving method for newly de-tected liver nodules measuring greater than 1 cm duringultrasound surveillance, or for characterization of inde-terminate nodules on CT or MRI. Advantages of CEUSover CT and MRI include no renal excretion of contrast,no exposure to ionizing radiation as with CT, real-timeimaging capability, low cost, and tolerability in claus-trophobic patients [38].

CT in AIH

The main role of CT is for characterization of livernodules detected by US and for detection of the com-

Fig. 1. Acute hepatitis due to AIH. A 65-year-old male pre-senting with painless jaundice and markedly raised serum liverenzyme levels. Ultrasound (A) showing mild coarsening of par-enchyma echoes and contrast-enhanced CT (B) showing nomorphological changes in the liver.Axial T2 (C),DWI (D), andpost

contrast-enhanced T1-weighted MR image (E) do not reveal anysignificant abnormality. MR Elastography (F) shows markedlyelevated liver stiffness with a mean value of 8.6 kPa. Liver biopsyrevealed moderate to severe (grade 3–4 of 4) active chronichepatitis with cholestasis and periportal fibrosis (stage 2 of 4).

N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes 21


plications of cirrhosis. For these indications, a triple-phase CT protocol with dynamic imaging during the latearterial, portal venous, and delayed phases is recom-mended.

In a study characterizing CT findings of AIH in 22patients [39], the most common features were surfacenodularity (50%), intrahepatic biliary dilatation (18%),varices (18%), and ascites (32%). 22% had porta hepaticlymphadenopathy with a short axis mean dimension of15.4 mm, and 27% had portocaval lymph nodes withshort axis mean dimension of 14.3 mm. Almost onequarter of patients had a normal imaging appearance ofthe liver. No patients demonstrated findings of portalvein thrombosis or hepatic steatosis.

Benign hypervascular nodules may be found in AIH.In a retrospective series of seven patients, five patientshad between two and four hyperenhancing liver lesions,some with delayed washout. All patients had tissuesampling and/or follow-up consistent with benignregenerative nodules [40].

With regard to HCC surveillance, although triple-phase CT has a higher sensitivity (85% to 90%) andsimilar specificity (80% to 96%) in comparison to ultra-sound [37], it is not recommended for routine surveil-lance due to ionizing radiation exposure and increasedcost.

MRI in AIH

In acute AIH, there may be no morphological features tosuggest underlying chronic liver disease (Fig. 1). Studiesexamining the morphological features of AIH on MRIhave shown that the most common feature is surfacenodularity (Figs. 3, 4, 5), present in 62% of cases, whichis frequently associated with moderate to severe fibrosis[3]. Fibrosis tends to occur most commonly in a reticularpattern (94%) [39] and less frequently as confluentfibrosis (19%) (Fig. 4) [3]. Patchy early enhancement iscommonly seen (31%), and may reflect hepatocellulardamage [3].

Volumetric changes occur in AIH with global atrophybeing the most common pattern [3], in contradistinctionto PSC, where central lobe enlargement with left lateralhypertrophy predominates. Lymphadenopathy was not aprominent or consistent finding in patients with AIHoccurring in 12% to 27% of patients [3, 39], in compar-ison to patients with viral hepatitis, PSC, and PBC inwhich the incidence may be as high as 67% [41].Hypervascular nodules were seen in 22% of patients andwere thought to represent dysplastic nodules [3]. 12% ofpatients demonstrated intrahepatic biliary ductal dilata-tion. Hepatic steatosis is a rare finding, occurring in upto 3% of cases [3].

Fig. 2. Advanced fibrosis in AIH in morphologically normalappearing liver. A 27-year-oldmalewith recently diagnosedAIH.US (A) and T2-weighted MR image (B) are both normal with nofindings of cirrhosis.MREdemonstrates increased liver stiffness

of 3.6 kPa compatible with stage 2–3 fibrosis, subsequentlyconfirmed on biopsy which demonstrated stage 3 (advanced)fibrosis. Elevated liver stiffness may be the earliest indication offibrosis even in the absence of morphological features.

Fig. 3. Chronic AIH on treatment with progression. A19-year-old male with 10-year history of AIH. Axial T2-weighted image (A), post contrast T1-weighted image(B) showing nodular outline of the liver consistent with cir-

rhosis. Note splenomegaly. MR Elastography shows elevatedliver stiffness with a mean of 6.2 kPa consistent with cirrhosisthat was confirmed with liver biopsy.



While MRI has excellent sensitivity and specificity fordetection of HCC approaching 90% [37], its high costand lower availability as compared to CT may precludeits use in routine surveillance in resource-limited con-texts. MRCP may be useful for evaluation of the biliarytree when cholestasis is suspected to rule out overlapsyndrome with PSC.

MR elastography in AIH

Histologic evaluation is the current gold standard forassessing hepatic fibrosis in patients with AIH, but issuboptimal for monitoring disease progression due to itsinvasive nature, sampling error, and inter-observervariability [21, 42]. Magnetic resonance elastography(MRE) may have an important role for non-invasiveassessment of liver stiffness, and has shown value inpredicting the stage of fibrosis in patients with chronicliver diseases [43]. A recent study has shown a statisti-cally significant correlation between liver stiffness andstage of fibrosis when controlling for inflammation gradeand BMI [43]. MRE is useful to detect fibrosis inunsuspected or morphologically normal appearing liver(Fig. 1).

In our preliminary experience with 36 patients (Wanget al. manuscript in press [44]), MRE had superioraccuracy compared to conventional MRI findings andlaboratory marker assessment in detecting advancedfibrosis and cirrhosis in patients with AIH. A liverstiffness threshold of >4.1 kPa predicted advanced (i.e.,greater than stage 3) fibrosis with 89.5% sensitivity and100% specificity, and a threshold of >4.5 kPa predictedcirrhosis with 92% sensitivity and 96% specificity. Assuch, MRE shows promise as a non-invasive surrogatefor staging liver fibrosis, although this remains to bevalidated prospectively. In this study, MRE had similaraccuracy for detection of advanced fibrosis in bothtreatment naı̈ve and treated patients (Figs. 1,2, 3).

MRI combined with MRE may be useful for detec-tion of advanced fibrosis and for follow-up assessmentfor treatment response.

AIH and overlap syndromes

Overlap syndromes are characterized by predominantfeatures of AIH with concurrent clinical and/or bio-chemical features of cholestasis. Overlap syndromes oc-cur in approximately 10% of patients with otherwiseclassical features of AIH [45] having additional featuresof PSC (cholangiography demonstration of multifocalbiliary stricturing) or PBC (positive antimitochondrialantibody and elevated serum alkaline phosphatase).Overlap of PSC occurs in 6% to 11% of cases, PBC in 6%to 11% of cases [46–51] and cholestatic syndrome in theabsence of PBC, and large duct PSC in 5% to 11% [45].

This distinction between overlap syndromes is clini-cally important with implications for management andprognosis. The major clinical consequence of overlapsyndromes is a variable response to conventional treat-ment regimens [51]. Corticosteroids in combination withlow-dose ursodeoxycholic acid is a common empiricmanagement strategy that has been advocated despiteweak clinical evidence [52]. AIH–PBC overlap patientsrespond well to corticosteroid therapy and achieve higherrates of remission in comparison to patients with AIH–PSC overlap. Conversely, patients with AIH–PSC over-lap die more frequently of liver failure and more fre-quently require liver transplantation [51]. Overlapsyndromes must be considered in all patients with AIHwho do not respond to conventional corticosteroidtherapy, and have concurrent cholestatic features orinflammatory bowel disease [11].

AIH–PSC overlap

Cholangiographic (endoscopic cholangiography ormagnetic resonance cholangiography) changes showingstrictures and segmental dilatations of the biliary treecharacteristic of PSC in patients with AIH (Fig. 6) de-fines the AIH–PSC overlap syndrome. Concurrentinflammatory bowel disease is common in this overlapsyndrome but may not be present [46, 53, 54]. Up to 41%of adults with AIH and chronic ulcerative colitis may

Fig. 4. Seronegative AIH with confluent fibrosis. A62-year-old male patient with AIH. MRI demonstrates lob-ulated liver contour with right hepatic lobe atrophy. Axial T2

(A), T1 (B) and post contrast T1� images showing T2hyperintense confluent, enhancing fibrosis in the right lobe(arrow).



have cholangiography features of PSC [54]. In one studyexamining MRI features in AIH–PSC overlap syndrome[55], MRI findings included central macroregenerativenodules, peripheral atrophy, biliary ductal obstruction,and biliary ductal beading. The presence of macrore-generative nodules, peripheral atrophy, and biliary duc-tal irregularity, alone or in combination, had 100%specificity for PSC-type overlap syndrome. Based onthese findings, the authors suggest that MRCP should beconsidered in patients with chronic autoimmune liverdisease to improve the detection of a PSC-type overlapsyndrome. This had been disputed by Lewin et al. whofound mild MRCP abnormalities in 25% of patients thatwere secondary to architecture distortion from hepaticfibrosis, rather than concurrent PSC overlap [11]. Lewinet al. recommend MRCP in adult-onset AIH only incases of cholestasis or poor response to corticosteroidtreatment. Nonetheless, a low threshold for raising thepossibility of PSC overlap in patients with AIH is sug-gested due to the increased risk of cholangiocarcinoma

and noncirrhotic portal hypertension which may promptscreening for these complications [55].

AIH–PBC overlap

The minimum diagnostic criterion for the AIH–PBCoverlap syndrome is the presence of antimitochondrialantibody and histological findings of bile duct injury orloss in a background of a classical picture of AIH. Thereis limited imaging literature on this entity of overlap. In aseries of 3 patients [55], no distinctive imaging featureswere identified. Rather, imaging features were consistentwith either isolated PBC or AIH. These included retic-ular or confluent fibrosis with minimal early enhance-ment that progresses on delayed images. No patientsdemonstrated central macroregeneration, peripheralatrophy, or beading of the biliary system. Liver mor-phology was relatively normal without atrophy [55]. The‘periportal halo sign’ (Fig. 7) referring to T1-weightedand T2-weighted hypointensities surrounding portal ve-

Fig. 5. A 29-year-old woman with autoimmune hepatitis.Axial T2 weighted (A), pre contrast T1-weighted (B), and postcontrast-enhanced arterial phase (C) and portal venousphase (D) T1-weighted images showing a T1 hyperintensenodule (arrow) in the left lobe that demonstrates arterial

phase hyperenhancement. Note the lesion is not visible onT2 W and in portal venous phase images. The lesion re-mained stable on subsequent follow-up MRI studies anddisappeared at 2 years follow-up consistent with benignhypervascular lesion.



Fig. 6. AIH + PSC overlap syndrome. A 50-year-old malepatient with AIH–PSCoverlap complicated by HCC. CECT(A, B) and MRI (C, E, F) demonstrate cirrhotic liver mor-phology and biliary ductal stricturing and dilatation on MRCP

(D) consistent with PSC overlap. An arterially (A, E) hyper-enhancing mass (arrows) in the left hepatic lobe showswashout in the portal venous phase (B, F) and is compatiblewith HCC.

Fig. 7. AIH–PBC overlapsyndrome in a 43-year-oldfemale patient. T2-weighted(A) and T1-weighted(B) images showingperiportal T1 hypointensityor ‘‘T1 halo sign’’ (arrows) ofPBC.



nous branches found in 43% of patients with PBC [5]may sometimes be seen in AIH–PBC overlap.

Conclusion

In conclusion, the imaging features of AIH are those ofchronic liver disease, and may include surface nodularity,fibrosis, and global atrophy with macroregenerativenodules. Associated irregularity of the bile ducts andcaudate/left lateral lobe hypertrophy may raise concernfor overlap with PSC. Overlap with PBC may presentwith imaging features of isolated AIH or PBC. MRE isan emerging technology that correlates well with ad-vanced fibrosis/cirrhosis in patients with AIH and theoverlap syndromes, and may be helpful for non-invasivemonitoring of disease progression.

Compliance with ethical standards

Funding No funding was received for this study.

Conflict of interest The authors declare that they have no conflict ofinterest.

Ethical approval This article does not contain any studies with humanparticipants or animals performed by any of the authors.

Informed consent Statement of informed consent was not applicablesince the manuscript does not contain any patient data.

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