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REVIEW ARTICLE Table of Contents   
Year : 2009  |  Volume : 52  |  Issue : 3  |  Page : 297-303
Approach to diagnosis of auto-immune hepatitis


1 Department of Pathology, Lawrence General Hospital, Lawrence, USA
2 Tufts University School of Medicine, Department of Anatomic Pathology, Lahey Clinic Medical Center, Burlington, USA

Click here for correspondence address and email

Date of Web Publication12-Aug-2009
 

   Abstract 

Auto-immune hepatitis (AIH) is one of the chronic liver diseases, seen predominantly in women, resulting from dysregulated immune mechanisms not yet clearly defined. Based on a combination of clinical and laboratory parameters with both positive and negative weights, the International AIH Group devised a scoring system in 1993. The system was modified in 1999 and has proven useful for both diagnostic and research purposes. This review deliberates on the clinical, immunological and histological features of this entity.

Keywords: Auto-antibodies, auto-immune diseases, chronic liver disease, hepatitis, liver biopsy

How to cite this article:
Joshi M, Khettry U. Approach to diagnosis of auto-immune hepatitis. Indian J Pathol Microbiol 2009;52:297-303

How to cite this URL:
Joshi M, Khettry U. Approach to diagnosis of auto-immune hepatitis. Indian J Pathol Microbiol [serial online] 2009 [cited 2020 Sep 20];52:297-303. Available from: http://www.ijpmonline.org/text.asp?2009/52/3/297/54979



   Brief Summary and Objectives Top


Auto-immune hepatitis (AIH) is one of the chronic liver diseases resulting from dysregulated immune mechanisms which are not yet clearly defined. The diagnosis is based on a constellation of clinical, serological, and histopathological findings. Clinically, it is more often encountered in women than men and may be seen in both adult and pediatric populations. Seropositivity for auto-antibodies is found in most cases. Histologically, the typical findings consist of periportal, portal, and lobular chronic inflammation with prominent plasma cells. Most AIH patients respond to immunosuppressive therapy. Liver transplantation is a valid treatment option for end-stage liver disease resulting from AIH as, in a transplanted liver, AIH may recur.

The objectives of this review are to:

  • delineate the typical clinico-pathological findings of AIH
  • define the subtypes of AIH
  • identify the differential diagnostic issues
  • describe the role of liver biopsy in the management of AIH patients
  • emphasize the importance of a "correct" diagnosis
  • discuss recurrence in transplanted liver
Overview

Auto-immune hepatitis is a chronic liver disorder seen predominantly in women and is associated with polyclonal hyper-gammaglobulinemia, and serologically demonstrable autoantibodies. [1],[2],[3] A characteristic immunogenetic phenotype consisting of HLA A1, B8, DR3 or DR4 is noted in a majority of cases. The establishment of the diagnosis of AIH mandates exclusion of other causes of chronic liver disease such as viral, alcohol, or drug-related hepatic injury. A favorable response to immunosuppressive therapy is usually seen and considered a "confirmatory clinical test."

Based on a combination of clinical and laboratory parameters with both positive and negative weights, the International Auto-immune Hepatitis Group devised a scoring system in 1993 [Table 1]. [4] The sum of the numerical scores given to each of these parameters is useful in predicting the definite or possible diagnosis of AIH in a given patient. The system was modified in 1999 [Table 2] and has proven useful for both diagnostic and research purposes.[5] It is highly sensitive for the diagnosis of AIH with a diagnostic accuracy close to 90%. The negative scores given to biliary markers/findings help in excluding AIH in patients with biliary diseases who may have some overlapping features.

Similar to other autoimmune disorders, AIH is also a manifestation of dysregulated immune reaction possibly of the suppressor T-cells. [6] Exact pathogenic mechanisms have, however, not yet been delineated. It is postulated that perhaps a peripheral break of tolerance against antigens expressed in the liver may induce an autoimmune response possibly in a genetically susceptible individual. [7] Auto-antibodies seen in patients with AIH do have an immense diagnostic importance, but their role, if any, in the pathogenesis of the disease, is not clear. However, it must be noted that some of the auto-antibodies seen in AIH patients may act against hepatocytic surface antigens or may be directed against molecules present on the myriads of enzyme systems present within the hepatocytes.


   Clinical Data Top


Clinical presentation of AIH patients is variable. [8],[9],[10],[11] Elevated liver enzymes may be found on screening asymptomatic patients or those who seek medical attention for other conditions such as arthralgias, thyroid disease, and other disorders of putative autoimmune etiology.[12],[13] A few patients may have fulminant hepatic failure or rapidly progressive hepatitic disorder of recent onset. [14],[15] Majority of the patients present with a chronic disease with lethargy or low-grade flu-like symptoms or even liver decompensation due to cirrhosis. [16]

Most cases of AIH are seen among Caucasian and Japanese population. [17] However, it is now being reported from other regions of the world, including India, due to increasing awareness and recognition of characteristic findings. [18],[19],[20] AIH is almost eight-fold more common in women as compared to men and is seen in pediatric population as well. The disease seen in children is often more rapidly progressive than that encountered in adult population. Although often not performed, testing for HLA phenotypes associated with AIH i.e., A1, B8, DR3 or DR4, provides important laboratory support for the diagnosis of AIH. [21]

Liver function tests in AIH are usually more ''hepatitic'' than ''cholestatic'' and reflected biochemically as elevation of transaminases rather than alkaline phosphatase or bilirubin. However, a completely normal profile may be seen during the quiescent periods interrupted by a severe hepatitic profile during the disease "flare-ups". Disease progression with the development of cirrhosis may be biochemically associated with elevated bilirubin and evidence of synthetic dysfunction.

Hypergammaglobulinemia with disproportionately increased IgG and serologic positivity for autoantibodies are the important defining features of AIH. [22],[23],[24] Auto-antibodies are not specific for AIH. However, their presence in the serum is of diagnostic importance and further help in categorizing the various subtypes of AIH. As a rule, auto-antibodies should not be used to monitor therapy, predict AIH activity or outcome. [22] Anti-nuclear antibodies (ANA) are encountered in about 80% of AIH patients in titers greater than 1:40 and anti-smooth muscle antibodies (ASMA) in titers greater than 1:40 are seen in approximately 70%. The ANA associated with AIH usually give a homogeneous pattern, due to reactivity against histones and DNA, but other patterns may be seen as well. [25],[26] ASMA are directed against several cytoskeletal elements. [27] Both ANA and ASMA, in low titers, may be seen in other chronic liver diseases such as hepatitis C (HCV), Wilson disease, alcohol-related liver disease, or nonalcoholic steatohepatitis. [28],[29],[30],[31] A case of acute hepatitis E with serum ANA and ASMA positivity has also been reported. [32] Other auto-antibodies that may be seen in AIH include anti-liver kidney microsomal (anti-LKM), anti-soluble liver antigen (anti-SLA), anti-liver pancreas (anti-LP), anti-asialoglycoprotein (anti-ASGPR) antibodies, and also pANCA. [33],[34],[35],[36] The target protein for anti-LKM1 antibody is P450(CYP)2D6 and is seen in patients with DRB1*0701 allele.

Based on clinical and serological parameters, AIH cases have been categorized into three subtypes [37] Type I, Type II and Type III.

Type I is the most common form of the disease. Seen mostly in adult women serologically, it is characterized by the presence of high-titer ANA and/or ASMA; Typ e II, seen more frequently in the pediatric population, is often associated with severe clinical disease and positive anti-LKM in the serum and these patients are usually negative for ANA or ASMA. Type II AIH was earlier sub-classified into Type IIa that included patients with characteristics described before, and Type IIb representing HCV patients with low-titer anti-LKM in their sera. The latter category is now considered clinically irrelevant and these cases, with both anti-HCV and anti-LKM positivity, are viewed as essentially chronic hepatitis C with perhaps some autoimmune features. AIH patients with other autoantibodies, like anti-SLA, anti-LP, or anti-ASGPR, are categorized as Type III , but clinically, this group does not seem to have any particular distinctive characteristics. A case of IgG4-associated AIH with elevated serum IgG4 and IgG4-bearing plasma cells in the liver has been recently reported. [38]

Most patients with AIH respond to corticosteroids with or without azathioprine. [39] AIH-related cirrhosis [Figure 9] may develop despite proper therapy or when treatment is delayed for any reason. These patients presenting with late-stage disease may require liver transplantation. Recurrence of AIH in the allograft has been reported. [40],[41]


   Pathology Top


A pathological diagnosis of AIH is usually made by observing compatible histopathological findings on a liver specimen. [42] A detailed knowledge of all available clinical and serologic findings is imperative for the pathologist interpreting these specimens. In addition to evaluating liver biopsies during the diagnostic work- up of AIH patients, pathologists' role in the management of AIH patients has expanded in recent years and now, also involves examination of explanted liver specimens from these patients undergoing liver transplantation (LT) and post-LT biopsies. [40],[41]

The gross findings present in explants from AIH patients are not very distinctive and mirror those seen in other chronic liver disorders. However, the gross characteristics do correlate with the clinical presentation and may range from being normal in early stages to obvious cirrhosis in long-standing progressive cases. Submassive and massive hepatic necrosis with parenchymal collapse is seen in patients who present with rapidly progressive or fulminant hepatic failure. Although hepato-cellular carcinoma can develop in any cirrhotic liver, their occurrence in AIH cirrhosis is highly unlikely.

Histologically, portal and periportal chronic inflammation [Figure 1] with prominent plasma cells [Figure 2] is typically seen on liver biopsies from patients with AIH. The amount of inflammation and number of plasma cells can be quite variable [Figure 5]. In clinically severe cases the periportal lymphoplasmacytic activity (interface hepatitis or piece-meal necrosis) may be very pronounced [Figure 3]. [43] Presence of portal plasma cells in liver biopsies, from patients under therapy-induced remission, was found to be a predictor of relapse following treatment withdrawal. The necro-inflammatory process may involve the lobules too with scattered lymphoplasmacytic aggregates with single cell hepatocytic necrosis resulting in acidophil bodies may be present [Figure 4]. While pericentral chronic inflammation with prominent plasma cells is fairly frequently observed in cases with high grade of activity, this may be the only feature present in some cases that lack portal and periportal inflammation. It is possible that pericentral plasma cell rich chronic inflammation may be the earliest finding in some cases of AIH [Figure 6]. [44],[45],[46],[47] Severe lymphoplasmacytic necro-inflammation with bridging collapse is often seen in cases presenting clinically with a rapid onset course [Figure 7]. In severe or progressive cases, the hepatocytic regenerative changes following lobular injury may alter the cord pattern and foci of hepatocytic acinar transformation may be seen [Figure 8].

Since AIH is a chronic liver disease, all biopsy reports must include the grade of inflammation and stage of fibrosis. Many different validated scoring systems have been published and are available for use by pathologists involved in interpreting liver biopsies. [48],[49],[50] However, consistency in the grading and staging of chronic hepatitis at any given institution is highly recommended and the choice of system can be made following a joint consultation between the pathologist and clinicians.

Although, the earliest Knodell scoring system was being extensively used for numerous studies, the inclusion of the fibrosis score in the overall hepatitis activity index (HAI) seemed to be a drawback of that system. As a result, the severity of necro-inflammation and extent of fibrosis could not be distinctly delineated. This flaw of the system was corrected in Ishak's modification of the original HAI system by reporting separately the numerical scores for grading of necro-inflammation and staging of fibrosis. A much simpler, yet, quite useful schema was proposed by Batts and Ludwig. In their system, both the necro-inflammation and fibrosis are individually scored semiquantitatively on a scale of 0-4. The French METAVIR system is similar and grades necro-inflammation on a scale of 0-3 and stages fibrosis as 0-4. [51]


   Overlap Syndromes Top


Some AIH patients may present with features that do not fit within the established criteria and in addition, have features of another putative immune mediated liver disorder such as, primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). These patients can not be assigned to a single disease category and the term overlap syndrome is used to characterize them. [52],[53],[54],[55],[56],[57],[58] Clinical and histologic evidence of both disorders may be present simultaneously or may appear sequentially. In rare patients there may be a switch from one disease to the other. Although standardized diagnostic criteria have not yet been defined, the diagnosis of overlap syndrome mandates definite evidence of both a hepatitic and biliary disease complemented with complete evaluation of clinical, biochemical, immunologic, radiological and pathological findings. The diagnosis is of importance from a therapeutic standpoint, because both components of the syndrome must be considered before an optimal treatment can be tailored for each patient. PBC/AIH overlap syndrome is more common than PSC/AIH.


   Differential Diagnostic Issues Top


Auto-antibody negative patients - Some AIH patients at their initial presentation may be negative for serum autoantibodies that are typically associated with that diagnosis. The establishment of the correct diagnosis of AIH may pose difficulties and is usually made on the basis of "hepatitic" serum biochemical abnormalities, characteristic microscopic findings, and HLA phenotypes. In addition, they may have other serum auto-antibodies such as p-ANCA or just elevated IgG levels. There may be other patients who persistently remain auto-antibody-negative and carry the diagnosis of cryptogenic hepatitis or cirrhosis. The possible autoimmune pathogenesis in some patients with cryptogenic liver disease is of therapeutic importance because they might benefit from immunosuppressive therapy. [59],[60] Furthermore, if transplanted, the disease may recur in the liver allograft with features of AIH, causing significant differential diagnostic problems. [59]

Viral hepatitis - Low titer auto-antibodies may be seen in HBV or HCV patients. Viral markers are usually helpful in clarifying the diagnostic dilemma in most cases. However, a small percentage of HCV patients may indeed have concomitant AIH and pose considerable problems in devising a therapeutic strategy for them. While steroids may increase viral replication, interferon therapy for HCV may be associated with a strong autoimmune type inflammatory response. [61] Since pANCA is rare in chronic viral hepatitis it may be of use in such clinical circumstances to diagnose concomitant AIH.

Drug induced or toxic hepatitis - Some drugs or toxins may elicit an autoimmune reaction or mimic liver biopsy findings seen in AIH. [62],[63],[64] As with any drug or toxin, withdrawal of the particular agent ("drug holiday") should, in most cases, resolve the hepatic disorder.

Importance of liver biopsy

Liver biopsy plays an important role in management of AIH patients. It provides the clinicians with information regarding the following four issues - Pathological findings compatible with AIH diagnosis Grade of necro-inflammatory activity Stage of fibrosis Response to therapy

Diagnostic approach to AIH

The following factors must be taken into consideration by both the clinician and pathologist during the evaluation of patients with the possible diagnosis of AIH.

  • Consider as a cause of liver disease in both adult and pediatric population
  • Consider as a cause of liver disease regardless of clinical presentation: fulminant, rapid-onset, or chronic
  • Consider some of the demographic findings: female gender, both in pediatric and adult population Obtain serologic studies for auto-antibodies
  • Exclude other causes of liver disease by history (including "drug holiday"), biochemical, radiologic, serologic, and molecular studies.
  • Consider the confounding issues in HCV patients.
  • Correlate with liver biopsy findings: a) portal and periportal inflammation with prominent plasma cells, b) grade and stage.
  • If available, correlate with the HLA subtypes.
  • Response to steroids or other immunosuppressive therapy.
  • Consider overlap syndrome in atypical cases.
Recurrence in transplanted liver

AIH can recur following liver transplantation and may pose significant differential diagnostic problems. The scoring system devised by the International AIH Study Group is generally of limited value in a transplant setting, given the multitude of other causes of graft dysfunction with overlapping features. A diagnosis of recurrent AIH mandates optimal clinicopathological and serological correlation and expert review of biopsies.

A syndrome of de novo AIH is seen in liver transplant recipients who receive hepatic allograft for diseases other than AIH. [65],[66] A correct diagnosis, albeit difficult, is of utmost clinical importance for optimal therapeutic strategy.


   Summary and Conclusions Top


AIH is an a priori chronic liver disease and is diagnosed based on a combination of clinical, serologic and histological findings.

AIH patients respond favorably to immunosuppressive therapy.

Exclusion of other forms of hepatitis is important for therapeutic reasons.

 
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65.Rodriguez-Diaz Y, Reyes-Rodriguez R, Dorta-Francisco MC, Aguilera I, Perera-Molinero A, Moneva-Arce E, et al . De novo autoimmune hepatitis following liver transplantation for primary biliary cirrhosis. Transplant Proc 2006;38:1467-70.  Back to cited text no. 65    
66.Kerkar N, Hadzic N, Davies ET, Portmann B, Donaldson PT, Rela M, et al . De-novo autoimmune hepatitis after liver transplantation. Lancet 1998;351:409-13.  Back to cited text no. 66    

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Correspondence Address:
Megha Joshi
Lawerence General Hospital, Lawrence, MA 01842
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.54979

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