—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 3 - Probable Seronegative Autoimmune Hepatitis, Severe Activity

Maha Guindi
University of Toronto
Toronto Ontario, Canada




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Clinical History
This is a previously healthy young man with a presumptive diagnosis of Ehlers Danlos syndrome - this was made on the basis of physical findings, and strong family history. He developed a biochemical hepatitis with icterus following a cruise holiday to Honduras, Grand Canyon, Mexico in March 2008. Two months later he developed a fluctuating illness characterized by nausea, pruritus, dark urine. No significant pain. No obvious drug precipitants. US- small hemangioma. MRCP normal. Viral hepatitis screen negative for A, B, C and EBV. Autoantibody screen and immunoglbulins normal. Normal ceruloplasmin.

Biochemically and symptomatically whilst initially settling he began to relapse.

Laboratory tests:
TBili AST ALT ALP Albumin INR
May 2008 72 909 2220 136 45
June 2008 37 678 1552 137 43 0.89
July 2008 12 258 752 76 44 1.93
August 2008 53 1141 2482 105 42 0.96



Case 3 - Figure 1
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Diagnosis
Probable seronegative autoimmune hepatitis, severe activity

Follow Up
After discussion with the patient, including the risks and the benefits, a trial of Prednisone 20mg once daily was elected in the 4th month of illness.

Liver copper concentration performed on the paraffin embedded biopsy tissue was normal. HCV RNA was negative. Hep E was negative x 2. The patient responded very well to Prednisone.

October 2008 post prednisone labs: Bili 13, AST 36, ALT 85, ALP 40, INR 0.92, platelets 202

November 2008 latest labs: Bili 9, AST 33, ALT 52, ALP 31, Alb 45, INR 0.92, platelets 223, IgG 10.5.

The Many Faces of Autoimmune Hepatitis in Liver Biopsies/Explants

Autoimmune hepatitis does not have a pathognomonic feature, and its laboratory, serological, and histological manifestations are found in acute and chronic liver disease of diverse causes [1, 2]. Consequently, the diagnosis of autoimmune hepatitis requires confident exclusion of other causative factors. Difficulties in distinguishing toxic, drug-related, virus-induced, and autoimmune causes of severe acute liver injury can result in misclassification [3].

Histologically, autoimmune hepatitis has many faces depending on the course of the disease, the form of its initial presentation, its evolution, and effects of treatment. The pattern that the pathologist encounters depends on the stage of disease in a given patient at the time of obtaining material for histologic examination, diagnosis or follow up.

1. Acute AIH
Long-standing but indolent autoimmune hepatitis may have a spontaneous exacerbation that can be mistaken for de novo severe acute or fulminant disease [4, 5]. In these patients, the chronic nature of the illness may be overlooked, and the failure to institute corticosteroid therapy may jeopardize survival [3].

Acute and fulminant forms of autoimmune hepatitis were recognized by the International Autoimmune Hepatitis Group in 1992 when it codified diagnostic criteria and waived the requirement for 6 months of disease activity to establish the diagnosis [6].

Liver histology in patients with recent-onset autoimmune hepatitis shows evidence of chronic liver disease in many patients despite the lack of correlating clinical chronicity. The histologic evidence of chronicity includes septal fibrosis, and overt cirrhosis [5].

Superimposed on this are features of brisk recent ongoing immune-mediated hepatitic activity. There is portal inflammation and diffuse lobular necroinflammation. Hepatitis activity may show zone 3 accentuation or predominance. Bridging necrosis may occur. Evidence of hepatocellular injury and necrosis - ballooning degeneration, spotty hepatocyte necrosis, and apoptotic bodies are common but not specific. Lobular dis array is present. Interface hepatitis may be extensive. Plasma cells typically predominate at the interface and throughout the lobules and portal areas. Injury may be followed by regeneration in the form of thickened hepatic plates and hepatic rosette formation.

Most of these patients probably have a lobular "flare" in disease activity, which likely precipitated the clinical presentation as an acute hepatitis. Few patients may not have evidence of underlying fibrosis or present with a truly acute hepatitis as a first presentation of what is to become chronic disease. Thus, autoimmune hepatitis is by definition a chronic disease and the term "chronic" is as such redundant and may be eliminated from autoimmune hepatitis lexicon.

Variations on the Histologic Theme:

a) Zone 3 necrosis with or without portal inflammation
This can also occur in viral and drug induced hepatitis. Zone 3 necrosis has not been formally included in the histological spectrum of AIH. Many of the patients who were described in the initial reports of AIH as showing this histologic finding lacked autoantibodies and hypergammaglobulinemia, and the true autoimmune nature of their disease remains suspect [7].

b) Sparsity or absence of plasma cells in the inflammatory infiltrate
Predominance of plasma cell infiltration is not specific for AIH, and does not occur in all patients with the disease. Its presence supports the diagnosis, and the finding is more common in this condition (66%) than in chronic hepatitis B (40%) or chronic hepatitis C (21%) [8, 9].

c) Giant syncytial multinucleated hepatocytes
Giant syncytial multinucleated hepatocytes may be a dominant feature in autoimmune hepatitis (''syncytial giant cell hepatitis''); however, they are also associated with drug toxicity and viral infection, especially with the paramyxovirus [10, 11]. Other etiologies should be sought before concluding that they represent an autoimmune process.

d) Duct injury in AIH
Although bile duct destruction is generally not prominent in AIH, up to 12% of biopsies may show duct destruction, and an additional 12% show lymphocytic infiltration of bile duct epithelium without ductopenia [12].

Variations on the Serologic Theme

a) Seronegative AIH
Approximately 10-15% of autoimmune hepatitis is marker negative [13, 14].

b) AMA-M2 positive AIH
AMA can be found in AIH, for example, and the significance of this requires further study. Some patients with overt AIH who test positive for AMA at initial presentation and are treated with corticosteroid therapy have shown no clinical or histologic evidence of PBC despite the continued detection of AMA over a follow-up of up to 27 years [15].

2. Fulminant AIH
Fulminant autoimmune hepatitis was recognized by the International Autoimmune Hepatitis Group in 1992, as mentioned above. Numerous clinical descriptions of severe acute /fulminant autoimmune hepatitis have emerged from small retrospective analyses within single institutions before and after that decision. These limited experiences have attested mainly to the uncommon nature of fulminant presentation of AIH and the difficulty in developing a confident management algorithm for this manifestation. The features are similar to but more severe than acute AIH. In addition to lobular necrosis, some patients with AIH exhibit bridging, zonal and multilobular necrosis. Massive hepatocyte necrosis and drop out, parenchymal extinction and stromal collapse may be present [16, 17].

Regenerative foci of hepatocytes may be present mimicking parenchymal nodules of established cirrhosis.

3. Chronic "Grumbling" Hepatitis
AIH can assume a chronic hepatitis pattern of injury, with portal and periportal lymphoplasmacytic infiltrates and interface hepatitis. Plasma cells are often but not always prominent, and are sometimes seen singly and in clusters in the lobule. The severity of necroinflammatory activity is quite variable. . Ballooning degeneration, spotty hepatocyte necrosis, and apoptotic bodies are common but not specific [18]. Hepatocytes may form regenerating rosette-like structures

4. AIH Post Treatment (Inactive chronic liver disease/chronic hepatitis with residual activity):
The findings are those of chronic liver disease with fibrosis, without or with mild lobular, portal or interface necroinflammatory activity or a combination of these. This scenario is typically seen on biopsies of AIH post treatment. However, they may be encountered in the setting of subclinical AIH where elevated transaminases are incidentally discovered at a time when underlying AIH may be inactive or minimally active. In this scenario, it may be difficult to determine that AIH is the cause of liver disease given the lack of specificity of findings. In biopsies obtained after therapy, there is reduction in all parameters of hepatitic activity [19, 20, 21, 22, 23].

After treatment, the pathologist is key in evaluation of treatment response. The histologic interpretation may affect treatment duration. The goals of corticosteroid therapy are to resolve symptoms, normalize laboratory tests, and improve histologic findings to normal, to quiescent portal hepatitis, or to inactive cirrhosis

Liver biopsy is the only means of confirming remission, and it should be performed before drug withdrawal. Histologic improvement lags behind clinical and laboratory improvement by 3 to 6 months, and in 55% of instances, liver biopsy examination at the time of clinical and laboratory normality discloses residual interface hepatitis [19].

What is the pathologist's approach in this setting?

The key issue is not diagnosis of disease but rather assessment of response. Histologic findings that predict a high (>50%) probability of relapse after drug withdrawal must be documented so that premature withdrawal of medication can be averted [20, 24].

The degree and nature of residual inflammation and whether there has been progression to cirrhosis are important as they predict the likelihood of relapse after drug withdrawal and define the next step in management. Restoration of normal hepatic architecture during treatment is associated with a 20% frequency of relapse after drug withdrawal; the presence of portal hepatitis is associated with a 50% frequency of relapse; and the presence of interface hepatitis of any degree or progression to cirrhosis is associated with an 87% to 100% frequency of relapse [19, 20, 21, 25, 26, 27, 28].

5. Cryptogenic Chronic Hepatitis
The histologic features are of chronic hepatitis in a patient with clinical, and laboratory findings of AIH but with no detectable autoantibodies [9, 13, 19, 29]. It is a diagnosis of exclusion. Interface hepatitis and/or panacinar hepatitis are present.

6. Cryptogenic Cirrhosis, Regressed or Otherwise
There is inactive cirrhosis of a nondiscriminative nature in a patient awaiting liver transplantation [30]. Obvious causes of cirrhosis have been excluded by a combination of laboratory tests and absence of characteristic histologic features e.g. biliary disease, alpha-1-antitrypsin deficiency, iron overload. Remaining possibilities include burnt out processes without specific laboratory findings, and absent disease activity to allow characterization of the process. Burnt out autoimmune hepatitis and steatohepatitis are usually at the top of the list. Rojkind and Dunn, Wanless, Cotler et al, and Czaja and Carpenter [31, 32, 33, 34] reported fibrosis/cirrhosis regression in patients with AIH subjected to immunosuppressive treatment.

In addition to regression of cirrhosis, immunosuppressive treatment improved the fibrosis scores in children, with an arrest in its progression and no development into cirrhosis. Fibrosis control is mainly associated with regression of necroinflammatory activity [35].

7. AIH as Part of an Overlap Syndrome

A) AIH/PBC overlap
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that is characterized by gradual destruction of the interlobular bile ducts that leads to damage of the hepatocytes. Approximately 10% of patients who have all the features of PBC - positive antimitochondrial antibodies and cholestatic biochemical findings - present with additional features of AIH. These features include other autoantibodies such as smooth muscle antibodies, hypergammaglobulinemia with a fivefold elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), or a 10-fold elevation of the AST. Histologically, these patients may have lymphoplasmacytic interface hepatitis in addition to the typical florid duct lesions present in PBC. In addition to AIH-PBC overlap that is present at the time of diagnosis, a 'sequential' overlap syndrome of AIH with PBC can occur. There are several reports of cases where AIH occurred during the course of PBC. In AIH-PBC overlap the histologic features includes a variable combination of inflammatory lymphoplasmacytic infiltrates directed at biliary epithelium and hepatocytes producing duct injury, interface hepatitis and parenchymal necroinflammation. The latter is associated with hepatocyte swelling and acidophilic bodies. Stage 2 PBC is characterized by portal lymphoplasmacytic inflammation and interface hepatitis, and it may be impossible to distinguish from AIH (AIH as the main disease process or as an overlapping component) if diffuse lobular hepatitis is not present. Distinction requires correlation with other clinical and laboratory parameters [17, 18, 36, 37].

What does the surgical pathologist need to be careful about when embarking on a diagnosis of AIH-PBC overlap?

- Overlap syndromes are a clinical pathological diagnosis

- ANA can be found in high rates in PBC patients, this autoantibody is not considered a helpful marker of overlap syndrome.

- Classification of these patients may change with time depending on the prevalent disease and transitioning from one component to the other e.g. cholestatic to hepatitic enzymes

- An AIH overlap should not be applied to otherwise typical cases of PBC with prominent interface hepatitis.

B) AIH/PSC overlap
AIH–PSC overlap is not uncommon in young patients with autoimmune liver disease and may comprise 6% of patients with AIH and 8% of PSC patients. Similarly in adults with PSC, an overlap with AIH may be seen. In the Kings cohort of pediatric AIH, "autoimmune sclerosing cholangitis", as they called it, and AIH were even more prevalent in childhood (~50%).

Histology can reflect features of both conditions synchronously or sequentially. Histologic examination may show duct lesions of PSC; fibrous obliteration of bile ducts (fibrous knots) and/or concentric periductal fibrosis. However, the characteristic duct lesions of PSC are uncommon in biopsies in general and rare in biopsies from children. Biopsies may show portal inflammation with piecemeal necrosis resembling AIH. There may be loss of interlobular bile ducts. Variation in the intensity of the ductal lesions and variability between affected portal tracts are noted in PSC. Because biliary epithelium is not easily identified in the inflammatory infiltrate, immunohistochemistry for keratins 7 and 19 can be useful. The inflammatory infiltrate is variable both in intensity and composition, and ranges from a mixture of lymphocytes and polymorphonuclear cells to a lymphoplasmacytic infiltrate as is usually observed in patients who have AIH. Discordance between clinical, laboratory, and radiologic findings resulting from sampling limitations and errors are frequently reported, in part because the bile duct injury is not homogenously distributed in the liver [38, 39].

In our own center, a study published shows that using dedicated liver magnetic resonance imaging (MRI) and liver histology, 12% of adult patients with AIH will have detectable subtle biliary changes. Two patients with a normal MRC had distinct bile duct changes suggestive of the concentric periductal onion-skin fibrosis seen in PSC raising the possibility of small duct PSC in these two patients [40]. The presence of SC detected by MRC and from liver histology in adult patients with AIH may not be clinically overt, and thus the prevalence of this AIH/SC overlap may be higher than previously recognized. Our data suggest that routine radiological evaluation of the biliary tree should be performed in adults given a diagnosis of AIH

Take Home Messages
- Communication between the pathologist and the clinician is crucial in autoimmune hepatitis, beginning with a proper clinical history accompanying the biopsy and a clinical pathological correlation discussion upon review of the biopsy.

- The histologic findings are limited by the overlap between AIH, viral-related, drug-induced immune-mediated liver injury, and often do not otherwise discriminate between them.

- Atypical morphologic features must sought because they may indicate an overlap syndrome or explain an unexpected clinical behavior or treatment response

- The classification of an autoimmune liver disease in the setting of an overlap syndrome may change over time as enzymes, clinical features and histology transition from one pattern to another.

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