Imaging of autoimmune hepatitis and overlap syndromes. Neera Malik & Sudhakar K. Venkatesh. Abdominal Radiology. ISSN X Volume 42 Number 1

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1 Imaging of autoimmune hepatitis and overlap syndromes Neera Malik & Sudhakar K. Venkatesh Abdominal Radiology ISSN X Volume 42 Number 1 Abdom Radiol (2017) 42:19-27 DOI /s x 1 23

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3 Abdominal Radiology Author's personal copy ª Springer Science+Business Media New York 2016 Published online: 20 December 2016 Abdom Radiol (2017) 42:19 27 DOI: /s x Imaging of autoimmune hepatitis and overlap syndromes 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, chronic inflammatory, and relapsing liver disease of unknown origin that may lead to liver cirrhosis, hepatocellular carcinoma, liver transplantation, or death. AIH occurs in all age groups and races but can frequently manifest as acute fulminant hepatitis. Clinical presentation of AIH can have features similar to primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC), and these diseases may coexist leading to overlap syndromes. Although histological diagnosis is necessary, imaging features often can demonstrate characteristics that may be helpful to distinguish these diseases. Imaging features of AIH are those of chronic liver disease, and imaging plays important role in detection of complications and ruling out other possible causes of chronic liver disease. Emerging techniques such as elastography provide noninvasive options for diagnosis of significant fibrosis and cirrhosis during clinical follow-up as well as assessment of response to treatment. In this study, we will describe imaging findings in AIH and overlap syndromes. Key words: Autoimmune hepatitis Cirrhosis Primary sclerosing cholangitis Primary biliary cirrhosis MR elastography Correspondence to: Sudhakar K. Venkatesh; venkatesh.sud Autoimmune liver disease is an uncommon cause of chronic liver disease but accounts for 24% of liver transplants [1]. The spectrum of autoimmune liver diseases includes primary autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC), each with characteristic clinical, laboratory, histology, and imaging findings [2 5]. The spectrum also includes overlap syndromes and transplant-related autoimmunity which share similar immunologic mechanisms of disease and tissue injury [6]. Occasionally these individual entities overlap with common causes of chronic liver diseases such as chronic hepatitis C, alcoholic hepatitis, and non-alcoholic fatty liver disease (NAFLD). Involvement of the biliary tract is characteristically absent or minimal in AIH, and the presence of clinical or histological features of cholestasis should lead to evaluation of overlap syndromes. Overlap syndromes comprise a variant form of autoimmune liver disease characterized by classic features of AIH with additional findings of PSC or PBC an important distinction with implications for management and prognosis. However, controversies exist whether these should be considered as distinct entities or treated as predominant disease with overlapping features of a second disease either at imaging or serology or histology [7]. The diagnosis of AIH and overlap syndromes is largely clinical and based on detection of autoimmune antibodies and elevated liver enzymes. Liver biopsy is still considered the reference standard as the only test that can reliably diagnose the presence of necroinflammation, lymphocytic infiltration, and early fibrosis. However, liver biopsy is an imperfect standard with sampling and interpretative errors in addition to being an invasive technique that reduces compliance among patients and carries a non-negligible risk of complications. Noninvasive imaging methods play a more significant and complementary role in the diagnosis and management of these diseases. Magnetic resonance cholangiography (MRC) is increasingly being recommended in patients with AIH and cholestasis to detect concurrent overlap syndromes, particularly PSC. Elastography techniques are also proving beneficial as non-invasive methods of detecting and quantifying advanced fibrosis and cirrhosis in patients with chronic liver disease regardless of etiology [8 12]. Screening with imaging is also performed for detection of HCCs in patients with cirrhosis.

4 20 N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes Autoimmune hepatitis Autoimmune hepatitis is a chronic, relapsing autoimmune liver disease. AIH is characterized by interface hepatitis (piecemeal necrosis) at histology, increased serum transaminases levels, presence of autoantibodies in serum, and elevated serum immunoglobulin (IgG) levels [13]. The etiology of AIH is still unknown and both environmental agents and genetic factors have possible roles in the pathogenesis. The environmental agents include drugs, herbs, microbes, and immunization [14 16]. AIH has been strongly associated with genes that encode the class II DRB1 alleles. These alleles have also been linked to clinical manifestations, response to treatment, and prognosis (see Table 1). It is hypothesized that with increased genetic susceptibility to AIH, an exposure to a trigger such as a viral infection, antibodies such as nitrofurantoin, minocycline, statins and anti-tnf agents would initiate an immune response and an autoimmune attack against the liver continues through molecular mimicry [17 19]. The pathological hallmark of AIH is interface hepatitis with lymphoplasmocytic infiltrates and varying degrees of lobular inflammation and damage. Acute onset AIH is characterized by pan acinar hepatitis with or without centrilobular perivenulitis and with or without interface activity. Interestingly, 36% of patients with AIH have cirrhosis at presentation [20]. Clinical manifestations vary from asymptomatic to severe or rare presentation of fulminant acute hepatitis. AIH should be considered as an etiology of chronic liver disease after ruling out viral, metabolic, genetic, and toxic etiologies. Diagnosis of autoimmune hepatitis is based on the criteria of the International Autoimmune Hepatitis Group (IAHG). The criteria is based on a numeric scoring system [21] that relies on identifying characteristic clinical, biochemical, immunological, and histopathological features. Although originally described as a disease affecting predominantly young Caucasian females, the diagnosis has expanded considerably and now includes male and female patients of all ages and diverse ethnicities. While most patients have an acute presentation, 1/4 to 1/2 of patients have an indolent presentation characterized by mildly elevated liver function tests [22]. The progression to fibrosis and cirrhosis is similar between asymptomatic and symptomatic presentations [22]. Approximately one quarter to one-third of patients with AIH have liver cirrhosis at presentation [23, 24]. Liver biopsy is essential for confirming a diagnosis of AIH. The characteristic histopathological change includes interphase hepatis, but this is not exclusive for AIH. Generally inflammation spares the biliary system. Histology is useful for grading and staging of the disease for prognosis, however, the necroinflammatory activity and severity does not always correlate with biochemical activity of the disease [25]. AIH is divided into types 1 and 2 based on autoantibody expression. Characteristics of the two types are summarized in Table 1. Type 1 AIH accounts for 80% of AIH cases and is characterized by antinuclear autoantibodies (ANA) and/or smooth muscle autoantibodies (SMA), it typically occurs in older adults and tends to be associated with treatment failure, relapse, and the need for long-term treatment. In Type 2 AIH, specific antiliver/kidney microsomal (anti-lkm) antibodies and/or anti-liver cytosol type 1 antigen (anti-lc1) are detected and are commonly found in children and young adults. It can have a severe or acute course with advanced changes in histology at presentation. About 40% of patients have a family history of autoimmune disease, and 20% have concomitant autoimmune disease or development during the course of the disease [21, 26]. Concomitant autoimmune disorders include autoimmune thyroiditis, Sjogren s syndrome, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, vitiligo, diabetes mellitus type-1, and celiac disease [27]. Standard treatment is a combination of corticosteroids and azathioprine, with budesonide, mycophenolate mofetil, and calcineurin inhibitors as salvage therapies. Treatment is continued until normal laboratory tests are achieved, which occurs within two years in greater than two-thirds of patients [28]. Incomplete response 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 adults Auto 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 acute Likely to present with advanced histological stages or cirrhosis Treatment and prognosis Compiled from references [19, 25, 56 58] Good response to steroids. Frequently relapses after stopping treatment. Need long-term treatment Progression to cirrhosis under treatment Failure to respond often but with sustained response. Need long-term treatment

5 N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes 21 failure occurs in 7% of patients [30]. Overlap with other etiologies should be considered in cases of treatment failure. Liver transplantation may be indicated in those patients with liver failure, and carries a 10 year survival rate exceeding 70% [31]. Recurrence of AIH in transplants occurs in about 16% to 43% of patients who receive transplant for AIHrelated cirrhosis [32]. De novo autoimmune hepatitis in transplants is also known but has been termed differently as post-lt AIH-like hepatitis, post-transplant immune hepatitis, etc. [33]. No characteristic imaging appearance of AIH has been described. Although imaging is not required for initial diagnosis of AIH, CT, and MRI are useful for detection of cirrhosis and its complications. About 1 9% of cirrhotic AIH develop HCC [34] meriting surveillance imaging every 6 months similar to other chronic liver diseases. Non-invasive methods for detection and staging of liver fibrosis would be useful for management of AIH initially as well as during clinical follow-up. Ultrasound (US) in AIH The sonographic features of AIH vary with the severity of disease, ranging from normal appearance to findings of chronic parenchymal disease such as coarsening of hepatic echotexture (Figs. 1, 2), surface nodularity, and volume redistribution. Doppler is useful for assessment of hepatic and portal vein patency and direction of flow in the portal venous system. Ultrasound-based transient elastography (TE) for detection of fibrosis may be of utility in determining the extent of fibrosis, and has shown promise in two studies examining extent of fibrosis in patients with AIH [35, 36]. Ultrasound has a central role in HCC surveillance in patients with AIH, with the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Disease (EASL) both recommending semiannual ultrasound surveillance among high-risk patients. Ultrasound is a non-invasive, radiation-free, and cost-effective imaging modality that is well accepted for this indication. Ultrasound for HCC surveillance has a sensitivity of 40% to 81% and specificity of 80% to 100% [37]. More recently, contrast-enhanced ultrasound (CEUS) using microbubble contrast agents has garnered attention for its utility in characterizing liver nodules. CEUS can be used as a problem-solving method for newly detected liver nodules measuring greater than 1 cm during ultrasound surveillance, or for characterization of indeterminate nodules on CT or MRI. Advantages of CEUS over CT and MRI include no renal excretion of contrast, no exposure to ionizing radiation as with CT, real-time imaging capability, low cost, and tolerability in claustrophobic patients [38]. CT in AIH The main role of CT is for characterization of liver nodules detected by US and for detection of the com- Fig. 1. Acute hepatitis due to AIH. A 65-year-old male presenting with painless jaundice and markedly raised serum liver enzyme levels. Ultrasound (A) showing mild coarsening of parenchyma echoes and contrast-enhanced CT (B) showing no morphological changes in the liver. Axial T2 (C), DWI (D), and post contrast-enhanced T1-weighted MR image (E)do notrevealany significant abnormality. MR Elastography (F) shows markedly elevated liver stiffness with a mean value of 8.6 kpa. Liver biopsy revealed moderate to severe (grade 3 4 of 4)active chronic hepatitis with cholestasis and periportal fibrosis (stage 2 of 4).

6 22 N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes Fig. 2. Advanced fibrosis in AIH in morphologically normal appearing liver. A 27-year-old male with recently diagnosed AIH. US (A) and T2-weighted MR image (B) are both normal with no findings of cirrhosis. MRE demonstrates increased liver stiffness of 3.6 kpa compatible with stage 2 3 fibrosis, subsequently confirmed on biopsy which demonstrated stage 3 (advanced) fibrosis. Elevated liver stiffness may be the earliest indication of fibrosis even in the absence of morphological features. plications of cirrhosis. For these indications, a triplephase CT protocol with dynamic imaging during the late arterial, portal venous, and delayed phases is recommended. In a study characterizing CT findings of AIH in 22 patients [39], the most common features were surface nodularity (50%), intrahepatic biliary dilatation (18%), varices (18%), and ascites (32%). 22% had porta hepatic lymphadenopathy with a short axis mean dimension of 15.4 mm, and 27% had portocaval lymph nodes with short axis mean dimension of 14.3 mm. Almost one quarter of patients had a normal imaging appearance of the liver. No patients demonstrated findings of portal vein thrombosis or hepatic steatosis. Benign hypervascular nodules may be found in AIH. In a retrospective series of seven patients, five patients had between two and four hyperenhancing liver lesions, some with delayed washout. All patients had tissue sampling and/or follow-up consistent with benign regenerative nodules [40]. With regard to HCC surveillance, although triplephase CT has a higher sensitivity (85% to 90%) and similar specificity (80% to 96%) in comparison to ultrasound [37], it is not recommended for routine surveillance due to ionizing radiation exposure and increased cost. MRI in AIH In acute AIH, there may be no morphological features to suggest underlying chronic liver disease (Fig. 1). Studies examining the morphological features of AIH on MRI have shown that the most common feature is surface nodularity (Figs. 3, 4, 5), present in 62% of cases, which is frequently associated with moderate to severe fibrosis [3]. Fibrosis tends to occur most commonly in a reticular pattern (94%) [39] and less frequently as confluent fibrosis (19%) (Fig. 4) [3]. Patchy early enhancement is commonly seen (31%), and may reflect hepatocellular damage [3]. Volumetric changes occur in AIH with global atrophy being the most common pattern [3], in contradistinction to PSC, where central lobe enlargement with left lateral hypertrophy predominates. Lymphadenopathy was not a prominent or consistent finding in patients with AIH occurring in 12% to 27% of patients [3, 39], in comparison to patients with viral hepatitis, PSC, and PBC in which the incidence may be as high as 67% [41]. Hypervascular nodules were seen in 22% of patients and were thought to represent dysplastic nodules [3]. 12% of patients demonstrated intrahepatic biliary ductal dilatation. Hepatic steatosis is a rare finding, occurring in up to 3% of cases [3]. Fig. 3. Chronic AIH on treatment with progression. A 19-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 cirrhosis. Note splenomegaly. MR Elastography shows elevated liver stiffness with a mean of 6.2 kpa consistent with cirrhosis that was confirmed with liver biopsy.

7 N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes 23 Fig. 4. Seronegative AIH with confluent fibrosis. A 62-year-old male patient with AIH. MRI demonstrates lobulated liver contour with right hepatic lobe atrophy. Axial T2 (A), T1 (B) and post contrast T1 images showing T2 hyperintense confluent, enhancing fibrosis in the right lobe (arrow). While MRI has excellent sensitivity and specificity for detection of HCC approaching 90% [37], its high cost and lower availability as compared to CT may preclude its use in routine surveillance in resource-limited contexts. MRCP may be useful for evaluation of the biliary tree when cholestasis is suspected to rule out overlap syndrome with PSC. MR elastography in AIH Histologic evaluation is the current gold standard for assessing hepatic fibrosis in patients with AIH, but is suboptimal for monitoring disease progression due to its invasive nature, sampling error, and inter-observer variability [21, 42]. Magnetic resonance elastography (MRE) may have an important role for non-invasive assessment of liver stiffness, and has shown value in predicting the stage of fibrosis in patients with chronic liver diseases [43]. A recent study has shown a statistically significant correlation between liver stiffness and stage of fibrosis when controlling for inflammation grade and BMI [43]. MRE is useful to detect fibrosis in unsuspected or morphologically normal appearing liver (Fig. 1). In our preliminary experience with 36 patients (Wang et al. manuscript in press [44]), MRE had superior accuracy compared to conventional MRI findings and laboratory marker assessment in detecting advanced fibrosis and cirrhosis in patients with AIH. A liver stiffness threshold of >4.1 kpa predicted advanced (i.e., greater than stage 3) fibrosis with 89.5% sensitivity and 100% specificity, and a threshold of >4.5 kpa predicted cirrhosis with 92% sensitivity and 96% specificity. As such, MRE shows promise as a non-invasive surrogate for staging liver fibrosis, although this remains to be validated prospectively. In this study, MRE had similar accuracy for detection of advanced fibrosis in both treatment naı ve and treated patients (Figs. 1,2, 3). MRI combined with MRE may be useful for detection of advanced fibrosis and for follow-up assessment for treatment response. AIH and overlap syndromes Overlap syndromes are characterized by predominant features of AIH with concurrent clinical and/or biochemical features of cholestasis. Overlap syndromes occur in approximately 10% of patients with otherwise classical features of AIH [45] having additional features of PSC (cholangiography demonstration of multifocal biliary stricturing) or PBC (positive antimitochondrial antibody 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 the absence of PBC, and large duct PSC in 5% to 11% [45]. This distinction between overlap syndromes is clinically important with implications for management and prognosis. The major clinical consequence of overlap syndromes is a variable response to conventional treatment regimens [51]. Corticosteroids in combination with low-dose ursodeoxycholic acid is a common empiric management strategy that has been advocated despite weak clinical evidence [52]. AIH PBC overlap patients respond well to corticosteroid therapy and achieve higher rates of remission in comparison to patients with AIH PSC overlap. Conversely, patients with AIH PSC overlap die more frequently of liver failure and more frequently require liver transplantation [51]. Overlap syndromes must be considered in all patients with AIH who do not respond to conventional corticosteroid therapy, and have concurrent cholestatic features or inflammatory bowel disease [11]. AIH PSC overlap Cholangiographic (endoscopic cholangiography or magnetic resonance cholangiography) changes showing strictures and segmental dilatations of the biliary tree characteristic of PSC in patients with AIH (Fig. 6) defines the AIH PSC overlap syndrome. Concurrent inflammatory bowel disease is common in this overlap syndrome but may not be present [46, 53, 54]. Up to 41% of adults with AIH and chronic ulcerative colitis may

8 24 N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes have cholangiography features of PSC [54]. In one study examining MRI features in AIH PSC overlap syndrome [55], MRI findings included central macroregenerative nodules, peripheral atrophy, biliary ductal obstruction, and biliary ductal beading. The presence of macroregenerative nodules, peripheral atrophy, and biliary ductal irregularity, alone or in combination, had 100% specificity for PSC-type overlap syndrome. Based on these findings, the authors suggest that MRCP should be considered in patients with chronic autoimmune liver disease to improve the detection of a PSC-type overlap syndrome. This had been disputed by Lewin et al. who found mild MRCP abnormalities in 25% of patients that were secondary to architecture distortion from hepatic fibrosis, rather than concurrent PSC overlap [11]. Lewin et al. recommend MRCP in adult-onset AIH only in cases of cholestasis or poor response to corticosteroid treatment. Nonetheless, a low threshold for raising the possibility of PSC overlap in patients with AIH is suggested due to the increased risk of cholangiocarcinoma and noncirrhotic portal hypertension which may prompt screening for these complications [55]. AIH PBC overlap The minimum diagnostic criterion for the AIH PBC overlap syndrome is the presence of antimitochondrial antibody and histological findings of bile duct injury or loss in a background of a classical picture of AIH. There is limited imaging literature on this entity of overlap. In a series of 3 patients [55], no distinctive imaging features were identified. Rather, imaging features were consistent with either isolated PBC or AIH. These included reticular or confluent fibrosis with minimal early enhancement that progresses on delayed images. No patients demonstrated central macroregeneration, peripheral atrophy, or beading of the biliary system. Liver morphology was relatively normal without atrophy [55]. The periportal halo sign (Fig. 7) referring to T1-weighted and 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 post contrast-enhanced arterial phase (C) and portal venous phase (D) T1-weighted images showing a T1 hyperintense nodule (arrow) in the left lobe that demonstrates arterial phase hyperenhancement. Note the lesion is not visible on T2 W and in portal venous phase images. The lesion remained stable on subsequent follow-up MRI studies and disappeared at 2 years follow-up consistent with benign hypervascular lesion.

9 N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes 25 Fig. 6. AIH + PSC overlap syndrome. A 50-year-old male patient with AIH PSCoverlap complicated by HCC. CECT (A, B) andmri(c, E, F) demonstrate cirrhotic liver morphology and biliary ductal stricturing and dilatation on MRCP (D) consistent with PSC overlap. An arterially (A, E) hyperenhancing mass (arrows) in the left hepatic lobe shows washout in the portal venous phase (B, F) and is compatible with HCC. Fig. 7. AIH PBC overlap syndrome in a 43-year-old female patient. T2-weighted (A) and T1-weighted (B) images showing periportal T1 hypointensity or T1 halo sign (arrows) of PBC.

10 26 N. Malik, S. K. Venkatesh: Imaging of autoimmune hepatitis and overlap syndromes 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 of chronic liver disease, and may include surface nodularity, fibrosis, and global atrophy with macroregenerative nodules. Associated irregularity of the bile ducts and caudate/left lateral lobe hypertrophy may raise concern for overlap with PSC. Overlap with PBC may present with imaging features of isolated AIH or PBC. MRE is an emerging technology that correlates well with advanced fibrosis/cirrhosis in patients with AIH and the overlap syndromes, and may be helpful for non-invasive monitoring of disease progression. Compliance with ethical standards Funding Conflict of interest interest. No funding was received for this study. 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