Historical Perspective.

The concept of a ‘chronic hepatitis’ resulting in cirrhosis developed during the 20th century, with many proposed triggers including infections, alcohol, toxins or nutritional disease. A seemingly clinically distinct variant of chronic active hepatitis was recognized as affecting mostly women and children.

Appreciation for an autoimmune aetiology emerged in the 1940s as Waldenström [1] recognized the relevance of hypergammaglobulinaemia in chronic hepatitis, and Kunkel [2] described a persistent liver disease predominantly in young females with hypergammaglobulinaemia, alongside extrahepatic symptoms including rash, arthralgias, fever and amenorrhoea.

Serological testing in the 1950s supported an autoimmune aetiology for a proportion with chronic hepatitis. The lupus erythematous (LE) test was initially a diagnostic test for systemic lupus erythematosus (SLE), that later proved to be neither sensitive nor specific. Patients with active chronic liver disease and hypergammaglobulinaemia were found to have LE cells. The factor responsible for the phenomenon, noted when incubating the peripheral blood of a patient with LE cell factor, found in the bone marrow of patients with SLE, is a family of antinuclear antibodies (ANA) [3].

The laboratory findings suggestive of an immune-mediated disease prompted treatment with cortisone, and a marked symptomatic improvement was noted, suggesting an important inflammatory component to this disease. Prolonged immunosuppressive therapy with prednisolone and azathioprine, offered to patients from the 1960s onward, proved effective and remains standard therapy [4–6].

This presumed autoimmune liver disease was originally named lupoid hepatitis, a misleading label still occasionally used. Eventually, the term autoimmune hepatitis (AIH) was applied in 1965 by Cowling and Mackay, and endorsed globally in 1993.

Disease Overview

Clinical Manifestations.

There is a broad spectrum of clinical manifestations, ranging from asymptomatic to fulminant hepatic failure with approaching 10% of patients presenting with acute liver failure. Although most patients present for medical attention at the onset of symptoms (fatigue, arthralgia, anorexia, jaundice), others are only found to have the disease incidentally. Whether all asymptomatic AIH progresses to symptomatic disease is not known, nor is there consensus on the significance in terms of outcome of the presence or absence of symptoms.

Clinical presentation and outcome varies between racial groups and geographical regions. Cirrhosis at presentation is more frequent in black North American patients with AIH than in white North Americans [7]. They are also younger at presentation, similar to patients from Brazil and Argentina. Africans, Asians and Arabs similarly have an earlier disease onset than patients from Northern Europe. Along with Alaskan natives, they additionally appear to have a higher frequency of cholestatic laboratory findings and of acute icteric disease.

The hepatitis may be chronic or present as intermittent episodes of apparently acute hepatitis.

Serology.

Serological patterns of autoreactivity permit two major classifications of disease: type 1 is characterized by antinuclear (ANA) and/or antismooth muscle (SMA) antibodies; type 2 by antiliver kidney microsomal type 1 (anti-LKM-1) antibodies. The identification of the antigen in type 2 disease, human cytochrome P450 2D6, has driven immunological dissection of the disease. Type 1 AIH lacks the same specificity, suggesting it comprises a number of different insults to the liver [8].

Epidemiology.

Patients of all ages, both genders (female preponderance, with a ratio of about 4 : 1 for type 1 AIH, as compared to 9 : 1 for type 2 AIH) and all races may develop AIH. The prevalence of AIH is crudely estimated at 1.0–12 cases per 1 000 000 Caucasian Western European/ North Americans; it appears to be markedly less common in Japan, whilst contemporary population-based estimates from Northern Europe (Sweden) estimates the annual incidence as 8.5 per 1 000 000 with a point prevalence of 107 per 1 000 000.

Natural History.

Sherlock’s follow-up study of 44 patients diagnosed between 1963 and 1967, who were randomly allocated into control and treatment (prednisolone) groups, provides stark natural history data for those with severe disease. Ten-year survival data demonstrated a significantly improved survival in the treatment group, where 63% of patients were alive at 10 years (median survival 12.2 years) compared with only 27% (median survival 3.3 years) in the control group (Fig. 23.2). Untreated patients with mild hepatitis are said to have an approximately 1 in 5 chance of developing cirrhosis within 5 years and patients with mild-to-moderate laboratory disturbances have about a 50% chance of cirrhosis within 15 years but a 10-year survival of 90% [9–11,12].

Fig. 23.2. Later results of the Royal Free Hospital trial of prednisolone in chronic autoimmune hepatitis. Note the improved survival in the treated group. (From [12].)

Biological Determinants of Disease

Hepatic immunological tolerance is maintained in a number of ways, which include antigen priming in the liver, sinusoidal tolerance induction, induction of regulatory T cells and hepatic stellate cell-induced T-cell apoptosis. Loss of tolerance is precipitated as a result of a number of different events, which collectively culminate in a common final pathway towards liver injury. An interaction of host genetics and environmental triggers (infections, drugs, toxins) remains most probable. In animal studies the specific loss of tolerance to a known target autoantigen can be modelled by infection with hepatic adenovirus Ad5 expressing human cytochrome P450 2D6 [13].

Immunology.

Data as a whole demonstrates a genetic predisposition, particularly associated with the HLA locus, systemic immunoregulatory changes notably affecting T regulatory (Treg) cell function and immune restricted responses to target antigens. Microscopic evaluation of the liver demonstrates lymphocytes, macrophages, and plasma cells forming a portal mononuclear cell infiltrate that involves surrounding parenchyma to a varying degree (interface hepatitis). An antigen restricted immune-mediated injury is driven through a combination of cellular and antibody-dependent cytotoxicity. Patients have reduced numbers of peripheral Tregs, with decreased proliferative activity in response to stimulation. In patients with type 2 AIH, LKM antibody titres correlate with Treg numbers. Monocyte activation alongside this, also contributes to loss of tolerance and promotes chronicity [14].

Th1, Th2 and Th17 lymphocyte cell populations interact to generate disease; Th1 cells enhance expression of HLA class I and induce expression of HLA class II molecules on hepatocytes, Th2 cells favour autoantibody production by B lymphocytes and Th17 cells play a role in organ-specific autoimmune inflammation.

HLA Loci and AIH.

In European and North American Caucasians HLA-A1-B8, HLA-DRB1*0301 and HLA-DRB1*0401 are susceptibility loci. The alleles DRB1*0301 and DRB1*0401 encode a six-amino acid sequence at positions 67–72 in the DRβ polypeptide chain of the class II molecules of MHC. The amino acid lysine at position DRβ71 appears key [15]. Those over 60 years of age are more likely to have the HLA DRB1*04 allele, whilst the HLA A1-B8-DR3 haplotype is over-represented in men with AIH. The presence of HLA DRB1*03 has been shown as one of the characteristics associated with failure to respond to therapy [16].

As expected, HLA associations vary around the globe and may explain some of the differences in disease presentation; for example in Japan and Argentina, HLA-DRB1*0405 is associated with AIH, in Brazil, HLA-DRB1*1301 and DRB3*01 associate with disease whilst among Mestizo Mexicans, HLA-DRB1*0404 is predominant.

Non-HLA Loci and AIH.

Confident identification of non-HLA susceptibility loci will follow on from genomic analyses of large, well-characterized populations, studied in parallel to carefully chosen controls. The finding of other autoimmune diseases in patients and their relatives supports a genetic contribution to disease. Future studies may confirm already proposed candidate gene associations that are shared across autoimmune diseases such as type 1 diabetes, thyroid disease and primary biliary cirrhosis, for example the T-cell immunoregulatory receptor CTLA-4 [17].

Other immunoregulatory genes are probably based on the monogenetic association of AIH in the autoimmune polyglandular syndrome type 1 (APS1), which is a result of defects in a single gene, the autoimmune regulator type 1 (AIRE-1). This transcription factor regulates clonal deletion of autoreactive T cells. Patients with APS1 suffer from mucocutaneous candidiasis and a number of organ-specific autoimmune diseases, including AIH [18].

Environmental and Drug Triggers.

Environmental factors may include nutritional supplements/ herbal chemical compounds, drugs and viral infections. Drugs can induce both immunologically mediated hepatocellular and cholestatic liver disease.

Generally, liver injury results from the bioactivation of drugs to reactive metabolites, which may interact with cellular macromolecules, disrupt cellular signalling and lead to mitochondrial dysfunction. Phase 1 and 2 drug metabolism can induce immunological responses against haptens and autoepitopes of self-carrier proteins. Such injury occurs when enzyme–drug adducts migrate to the cell surface and form neoantigens, which become cytotoxic T-cell targets. The detection of antibodies that recognize drug-modified hepatic proteins in sera supports this, for example antibodies that recognize trifluoroacetate-altered hepatic proteins in the sera of patients with halothane-induced hepatitis [19]. Such drug-specific antibodies or autoantibodies that recognize native liver proteins have also been found in patients with liver injury caused by other drugs, including tienilic acid, dihydralazine and diclofenac [20].

In immunogenetically susceptible individuals, apoptosis of hepatocytes containing concentrated complexes of drug hapten-cytochrome P450, – UDP glucuronosyl transferase and/or other self-proteins facilitates effective presentation of autoantigens and loss of tolerance.

The p-i concept (pharmacological interaction of drugs/ chemicals with immune receptors) is also relevant and suggests certain drugs are able to bind to T-cell receptors, mimicking ligand–receptor interaction, so generating MHC-dependent T-cell activation. In patients who developed drug-induced hepatitis, drug-specific T cells have been detected and, in some cases, T-cell clones are generated (e.g. carbamazepine and halothane) [21].

Viral Triggers.

Viruses have repeatedly been shown to trigger autoimmune hepatitis, the best descriptions being following hepatitis A [22]. Careful history taking from patients can reveal viraemic symptoms prior to development of hepatitis. Sequence similarities between viral and self-proteins could trigger autoimmunity and the simultaneous presence of inflammatory cytokines during virus infection may add to the risk of developing self-perpetuating autoimmunity.

Disease Presentation

General Features.

Since AIH presents at all ages, across men and women and in all races it needs to be considered in the differential of any hepatitis (Table 23.1).

Table 23.1. Differential diagnosis for transaminitis

Type 2 disease presents more acutely, at a younger age and immunoglobulin A deficiency is often noted, whereas symptoms, signs, family history, associated autoimmune diseases and treatment response are similar for both serological groups (Table 23.2) [23].

Table 23.2. Clinical differences between serological classifications of autoimmune hepatitis

ANA, antinuclear antibodies; LKM-1, antiliver kidney microsomal type 1; SMA, antismooth muscle antibodies.

In childhood, sclerosing cholangitis with marked autoimmune features (called autoimmune sclerosing cholangitis by some), including interface hepatitis and serological features identical to type 1 AIH, is as common as AIH, but it affects boys and girls equally [24]. Differentiation relies on cholangiographic studies. It is not yet clear if these overlap cases have a worse outcome than AIH alone.

The fact that 30% of patients have cirrhosis at presentation, suggests clinically silent chronic hepatitis was probably present prior to diagnosis. Pathologists must be careful, however, not to mistake the acute collapse and architectural change of acute severe AIH (bridging necrosis) for cirrhosis.

Patterns of Presentation.

In a community study from California, approximately one-third had an acute onset of symptoms simulating acute viral hepatitis, half had chronic symptoms of greater than 6 months’ duration, and the remaining patients were asymptomatic [25]. In an Italian study of just under 100 patients, two-thirds presented with a chronic pattern, one-quarter with an acute pattern, and a minority (1 in 20) were asymptomatic. All three groups though had a similar prevalence of moderate/ severe (versus mild) histological findings and liver cirrhosis [26].

The elderly may have an indolent progressive disease that is asymptomatic or masked by other concurrent conditions. There response to treatment is, however, the same.

Symptoms.

When symptomatic, patients frequently note clinical jaundice, fatigue, arthralgias, arthritis, acne and amenorrhea. Acute presentations are often indistinguishable from a viral illness, and hepatic discomfort, anorexia and nausea may be evident. Clinical features can range from firm hepatomegaly, splenomegaly (in which case a small liver is usually found) to other features of chronic liver disease including palmar erythema and telangiectasia.

Associated Autoimmune Diseases.

Clinicians need to be aware of the possible association with other autoimmune disease that may be evident in as many as one in three patients: Sjörgen’s syndrome, autoimmune thyroid disease, autoimmune haemolysis, rheumatoid arthritis, ulcerative colitis and idiopathic thrombocytopenic purpura stand out. Coeliac disease can be coexistent, but care needs to be taken to ensure liver abnormalities are not secondary to coeliac disease itself.

Presentation After Liver Transplant.

Autoimmune hepatitis can occur de novo after liver transplant (so called alloimmune hepatitis) or reoccur in those transplanted for AIH. Recurrences of autoimmune hepatitis, the development of an alloimmune phenomenon, or allograft dysfunction mimicking autoimmune hepatitis, are difficult to differentiate based on histological findings. Alloimmune hepatitis does not differ from recurrence of classic AIH based on serology, and they are treated similarly.

Laboratory Features

Liver Biochemistry and Immunoglobulins.

Elevated immunoglobulin G values (Fig. 23.3), commonly 1.2–3.0 times the upper limit, usually accompany a transaminitis, from minor elevations to levels in the thousands. In over 200 patients at one centre, aspartate aminotransferase levels at presentation were less than 2 times upper limit in just over 10%, 2 to 10 times upper limit in one-third and greater than 10 times the upper limit in just over half [27]. Elevated alkaline phosphatase values can be seen, but if greater than threefold, should prompt additional biliary investigation. Jaundice, coagulopathy and hypoalbuminaemia may be noted in very acute presentations. Haemolysis is a feature that should prompt exclusion of Wilson’s disease.

Fig. 23.3. Electrophoresis of the serum proteins. Note the very high γ-globulin.

Serology.

Antinuclear antibodies and antismooth muscle antibodies categorize type 1 autoimmune hepatitis, whilst antibodies to liver and kidney microsome, mark the rarer, typically childhood-onset, type 2 autoimmune hepatitis (Table 23.3). Usual titres of serum autoantibodies are at or above 1 in 40–80, but found in isolation they have low positive predictive values since the prevalence of autoantibodies in healthy individuals exceeds the burden of disease; their presence also increases with age. Lower titres, at or above 1 in 20, are of significance only in children. Seronegative disease may also occur (Fig. 23.4).

Table 23.3. Autoantibodies commonly associated with chronic liver disease

* Cannot be measured outside research setting.

AIH, autoimmune hepatitis; ANA, antinuclear antibodies; AMA, antimitochrondial antibodies; SMA, antismooth muscle antibodies; LKM-1, antiliver kidney microsomal type 1; pANCA, perinuclear antineutrophil cytoplasmic antibody; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SLA/LP, soluble liver and pancreas antigen.

Fig. 23.4. Use of serology to distinguish patterns of autoimmune liver disease. ANA, antinuclear antibodies; AMA, antimitochrondial antibodies; ELISA, enzyme-linked immunosorbent assay; LKM-1, antiliver kidney microsomal type 1; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SMA, antismooth muscle antibodies.

Antinuclear Antibodies.

ANA are present alone (approximately 10%) or with SMA (approximately 50%) in two-thirds of patients. ANA comprises antibodies with reactivity directed against nuclear membranes and DNA, although the target antigens are heterogeneous and incompletely defined, for example centromeres, ribonucleoproteins and cyclin A. Nuclear reactivity can be assessed by indirect immunofluorescence on Hep-2 cell lines or by enzyme-linked immunosorbent assay (ELISA) with recombinant or highly purified antigens. Classic AIH is associated with homogenous, speckled and nucleolar patterns. ANAs in AIH are not specific, unlike in primary biliary cirrhosis (PBC), and therefore assessment by immunofluorescence is preferable to use of ELISA-based automated assays.

Smooth Muscle Antibodies.

SMA are directed against actin and non-actin components, including tubulin, vimentin, desmin and skeletin. SMA are present in approximately 90% of patients with AIH, either as the sole marker of the disease (approximately one-third) or in conjunction with ANA (approximately half). However SMA is very non-specific, and low titre antibody results are frequent in healthy individuals, particularly in those over 60 years of age, as well as those with an assortment of viral, autoimmune or malignant disease. Anti-F-actin antibodies, determined by ELISA, are more specific for type 1 AIH but assays are not universally available [28].

ANA and SMA levels fluctuate during the course of AIH and may disappear with corticosteroid therapy. Neither their titre at diagnosis nor their fluctuation during the course of illness predicts outcome in adult patients, and thus they are only of diagnostic value.

Microsomal Antibodies.

Different targeted autoantigens produce distinct microsomal immunofluorescence patterns leading to four subclassifications of LKM-1. LKM-1 (associated with type 2 AIH) reacts with the mitochondrial enzyme cytochrome P450 2D6 subtype (CYP2D6), inhibiting its activity in vivo [29]. CYP2D6 metabolizes several known medications, including antihypertensives and benzodiazepines, and is genetically polymorphic. LKM-2 reacts with CYP450 2C9 and has been associated with the hepatitis caused by the medication ticrynafen (tienilic acid), taken off the US market in 1982. LKM-3, which has affinity to uridine diphosphate glucuronosyl transferase, was previously associated with chronic hepatitis D, and LKM-4, which recognizes CYP1A2 and CYP2A6 (with an immunofluorescence pattern indistinguishable from LKM-1), has been described in patients with AIH associated with autoimmune polyendocrinopathy–candiasis–ectodermal dystrophy.

In practice, it is possible to misinterpret LKM-1 staining for antimitochrondial antibody (AMA), and recourse to an ELISA-based LKM-1 assay may be required. Antibodies to LKM-1 are rare in the USA, occurring in only 4% of adults with AIH. They have been described mainly in paediatric patients in Europe, but 20% of patients with anti-LKM-1 in France and Germany are adults. Anti-LKM-1 and anti-LC-1 (liver cytosol) can occur alone or together in type 2 AIH. Anti-LC-1 recognizes formiminotransferase cyclodeaminase, a liver-specific 58-kDa metabolic enzyme [30].

Soluble Liver and Pancreas Antigen.

A third subtype of AIH (type 3) is occasionally described, based serologically on the presence of autoantibodies against soluble liver and pancreas antigen (SLA/LP). The two autoantibodies target the same antigen. Initially, individuals who were SLA/LP positive were classified as type 3 AIH, since it was observed first among patients negative for ANA, SMA and LKM. However three-quarters of patients with so-called type 3 AIH are also ANA and/or SMA positive, and clinically these individuals are indistinct from those with type 1 disease; conversely 10–30% of patients with type 1 AIH when tested are SLA/LP positive.

Anti-SLA/LP is a better marker of AIH than ANA or SMA, since normal individuals and those with non-hepatic disorders are invariably anti-LP negative. SLA/LP autoantibodies target a UGA-suppressor tRNA-associated protein, demonstrated to function as a selenocysteinyl-transfer RNA synthase [31].

Mitochondrial Antibodies.

Antimitochondrial antibodies may be found in AIH in as many as 20% of patients. They are usually lower in titre (≤1 : 40) and in some represent false positives misinterpreted by indirect immunofluorescence. The presence of AMA must not be directly taken to imply an AIH–PBC overlap syndrome. Long-term study of patients with AIH who are persistently AMA positive shows these individuals to have the same laboratory, histological and clinical features, as well as the same treatment outcomes compared to individuals who are AMA negative [32].

New markers remain to be identified and the advent of powerful tools such as proteomics has potential in this regard, for example the identification of phosphoglycerate mutase isozyme B as a putative target of autoantibodies in autoimmune hepatitis [33].

Imaging

Imaging is unlikely to help in the diagnosis of AIH but it is of use in excluding important differential diagnoses, in particular acute Budd–Chiari, infiltrative disease and unsuspected biliary processes. Doppler ultrasound is the initial investigation of choice as no radiation exposure is involved. In those with an acute/ subacute presentation of autoimmune hepatitis there is often marked histological architectural collapse. Radiologically, this may give a pseudocirrhotic appearance in the absence of true cirrhosis. Furthermore, in those with subacute liver failure, splenomegaly and ascites can be present without true chronic liver disease.

Biliary overlap is variably reported, more commonly in those presenting in childhood, suggesting that MR cholangiography should be routinely considered for those with AIH [34,35]. Careful interpretation is needed, as those with a cirrhotic liver may have peripheral secondary biliary changes consequent on architectural distortion, which resemble those of sclerosing cholangitis.

Periportal lymphadenopathy is a common finding in those with autoimmune liver disease and is rarely lymphoma, despite it commonly being raised by radiologists in the differential diagnosis. In those with a marked hepatitis, non-specific gallbladder wall thickening should not be mistaken for cholecystitis.

Cirrhosis regardless of aetiology is a risk factor for hepatocellular carcinoma [36], and those with biopsy proven cirrhosis or imaging highly suggestive after initial presentation may be considered for hepatocellular carcinoma surveillance programmes. However, hepatocellular carcinoma is generally considered uncommon in those with cirrhosis due to AIH (perhaps because patients are predominantly female and their disease is treated) and there are no data to demonstrate surveillance must be performed; individualized decisions remain reasonable.

Additionally, on treatment, imaging periodically is appropriate; historic data suggests 30% of patients progress histologically despite therapy [37]. A change in spleen size, alongside thrombocytopenia, is a useful parameter to evaluate when determining the need for variceal surveillance.

Liver Biopsy and Histological Features

Few would be confident to diagnose and manage autoimmune hepatitis in the absence of histology.

Occasionally, there are scenarios where a presumptive diagnosis is made without a liver biopsy such as when overt contraindications to percutaneous biopsy exist or transjugular biopsy is not available. Generally, however, a liver biopsy should always be performed to identify features suggestive of AIH, to exclude alternative liver disease (in particular viral inclusions, vascular disease, steatohepatitis, alcoholic hepatitis, infiltration by lymphoma or adenocarcinoma, and for the potential to determine liver copper content), as well as to estimate fibrosis.

Those with access to laparoscopic biopsy have become aware that the disease is not necessarily homogenous. To minimize sampling error, care to obtain adequately sized liver specimens (≥2.5 cm) is essential as both parenchymal and biliary evaluation are important. Pretreatment histological findings may help predict outcomes [38] whilst liver biopsy is also used to confirm resolution of histological activity before stopping therapy with steroids. Histological activity commonly lags behind biochemical response by 3–6 months [6]. Portal plasma cell infiltrates, whilst on immunosuppressant therapy, are associated with relapse upon stopping treatment. However, an inactive biopsy does not equate with an absent risk of relapse.

Histological Features.

These include lymphoplasmacytic interface hepatitis (mononuclear cell infiltrate invading the limiting plate, i.e. the sharply demarcated hepatocyte boundary surrounding the portal triad), lobular hepatitis and centrilobular necrosis but the appearance of autoimmune hepatitis remains the same as that of chronic hepatitis, and although certain changes are common, no findings are specific (Figs 23.5–23.7). It is therefore usual for reports to conclude that the features are consistent with AIH, but viral and drug-induced liver injury cannot be excluded. Clinicians need to ensure that their pathologists pay close attention to biliary features, as it is not infrequent for patients with PBC to have interface activity and be initially reported as having autoimmune hepatitis.

Fig. 23.5. Gross histological features of autoimmune hepatitis. (H & E, ×50.) Image provided by Dr Oyedele Adeyi, Staff Pathologist, Ass. Professor, Department of Laboratory Medicine & Pathobiology, University of Toronto.

Fig. 23.6. Plasma-cell-rich hepatitis in acute autoimmune hepatitis. (H & E, ×100.) Image provided by Dr Oyedele Adeyi, Staff Pathologist, Ass. Professor, Department of Laboratory Medicine & Pathobiology, University of Toronto.

Fig. 23.7. Interface hepatitis, a characteristic lesion in autoimmune hepatitis. (H & E, ×200.) Image provided by Dr Oyedele Adeyi, Staff Pathologist, Ass. Professor, Department of Laboratory Medicine & Pathobiology, University of Toronto.

Simplified Grading.

In a new, simplified scoring system, histology was graded atypical, compatible with AIH and typical. Interface hepatitis, lymphocytic/ lymphoplasmocytic infiltrates in portal tracts and extending into the lobule, emperipolesis (active penetration by one cell into and through a larger cell) and hepatic rosette formation were regarded as typical for the diagnosis of AIH. To be considered typical, each of the three features of classic AIH histology had to be present. Compatible features are a chronic hepatitis with lymphocytic infiltration without all the features considered usual. Histology was considered atypical when showing signs of another diagnosis, such as steatohepatitis, a condition that will increasingly coexist with AIH and confound evaluation [39].

Biliary Lesions.

The portal lesion generally spares the biliary tree but up to approximately 10% of biopsies may show duct destruction (not associated with detectable mitochondrial antibodies), and an additional approximately 10% show lymphocytic infiltration of bile duct epithelium without ductopenia [40]. The histological pattern of injury may be indistinguishable from PBC. Just as the presence of antimitochondrial antibody does not mean the patient has PBC, nor are biliary changes synonymous with a diagnosis of an AIH–PBC overlap syndrome. All features need to be considered in the context of the presentation of the particular patient, including the severity of the underlying liver disease (Figs 23.8, 23.9).

Fig. 23.8. Trichrome staining demonstrating marked interface hepatitis in acute autoimmune hepatitis, with plasma cell infiltration and incidental duct injury. (×200.) Image provided by Dr Oyedele Adeyi, Staff Pathologist, Ass. Professor, Department of Laboratory Medicine & Pathobiology, University of Toronto.

Fig. 23.9. Cytokeratin 7 stain demonstrating bile duct injury in acute-onset autoimmune hepatitis. Image provided by Dr Oyedele Adeyi, Staff Pathologist, Ass. Professor, Department of Laboratory Medicine & Pathobiology, University of Toronto.

Fibrosis and Necroinflammatory Activity.

Some degree of fibrosis is almost always present. With disease progression, periportal fibrosis with formation of portal–portal and portal–central bridges and nodular regeneration results in cirrhosis. The severity of necroinflammatory activity is variable, ranging from mildly active hepatitis to bridging necrosis to massive hepatic necrosis (which should not be mistaken for cirrhosis). The degree of hepatocyte necrosis is not sufficiently reliable to determine prognosis, as sampling variation is common in those with an acute liver injury.

Ballooning degeneration, spotty hepatocyte necrosis, and apoptotic bodies are common but not specific. Syncytial multinucleated hepatocyte giant cells are seen in some, and giant cell hepatitis, seen more in children, is frequently, but not always, a variant of AIH. Giant cell hepatitis is also noted in atypical viral infections (reportedly paramyxoviral infection and human herpesvirus 6) as well as occasionally in PBC and drug-induced liver injury.

Surrogate Markers of Fibrosis.

Non-invasive markers of liver fibrosis may have potential in the future. However validation will, be necessary and it will be important to evaluate the effects of active inflammation on any derived score. It should not be assumed that performance characteristics of non-invasive markers will be the same across diseases, genders and clinical scenarios. Liver stiffness is known to increase during hepatitic illnesses suggesting transient elastography during active hepatitis would potentially overestimate fibrosis stage at diagnosis in many patients.

Differential Diagnosis

In the absence of a marker equivalent to a viral load, AIH is still a diagnosis of exclusion, and one traditionally confirmed by adequate response to treatment. Relapse off treatment can also be seen as confirmation of a correct diagnosis.

When evaluating the patient the clinician must remain vigilant for viral, drug and metabolic (e.g. Wilson’s disease) presentations that can mimic AIH. The natural history of such insults can make it appear that the processes are steroid responsive if treatment is started on the assumption the disease is AIH. Re-evaluation of patients that do not respond to therapy as expected, is also important, although more often than not this is related to compliance rather than an alternative diagnosis.

Drug Injury.

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