The identification of a potentially reversible etiology of ALF, such as AI-ALF, is a primary goal in management. However, the absence of a formal classification system based upon morphology remains a major obstacle. A broad range of terms has been used to describe the MHN of ALF, including “map-like” (18
), “zonal,” or “panlobular” (19
), changes interpreted as non-specific. Therefore, this study focused on characterizing specific patterns of MHN as well as other specific histological features which favor an autoimmune pathogenesis.
In contrast to classical AIH, there are no consensus guidelines to distinguish AI-ALF from other etiologies of ALF. Moreover, adequate numbers of patients with ALF and liver histology are not available to prospectively test our observations, even within a large research consortium devoted to the study of ALF. Consequently, we analyzed our observations in terms of their ability to identify a classical autoimmune phenotype assuming the phenotype for patients with AIH is similar to patients with AI-ALF. We found that the 4 histological features proposed to represent AI-ALF are common in patients with ALF of indeterminate etiology, and that the features usually occur concurrently in the same liver specimen (). Although certain histological features of autoimmunity are associated with clinical features suggestive of AIH (), an overall histological impression of AI-ALF is associated with a decidedly autoimmune phenotype (subacute clinical course, higher globulins, higher prevalence of autoantibodies; ). Furthermore, the addition of ANA±ASMA to a histological diagnosis of probable AI-ALF appears to strengthen this autoimmune phenotype to include a predominantly female population with a higher incidence of hepatitis in long-term follow-up (). The SDC for AIH, which identified 24% of patients with non-acetaminophen ALF as having possible or probable AIH in a recent study (20
), did not appear to improve the identification of patients with an autoimmune phenotype over concordance for final histological diagnosis of AI-ALF and the presence of ANA±ASMA.
Classical histological features of non-fulminant AIH include a portal tract-based necroinflammatory process with interface hepatitis, often with lobular (zone 2 and 3) involvement (1
); centrilobular predominance is distinctly unusual. A centrilobular variant of AIH first proposed by Pratt, et al.
) was followed by several other case reports and small series (7
), suggesting that the centrilobular variant represents an early, severe or acute presentation of AIH, which may either evolve into the classical portal-based hepatitis or remain centrilobular (11
). In the largest series to date, 20 of 114 (18%) of liver biopsies from classical AIH patients (none with ALF) had predominantly centrilobular necroinflammation, 4 of whom had exclusive centrilobular disease (11
). Patients with the centrilobular variant more often presented as an acute hepatitis, had higher hepatic activity indices, and had less fibrosis than did the classical portal-based variants; centrilobular hemorrhage resembling hepatic venous outflow obstruction (MHN4 in the present work) has also been noted (12
). Although these reports described patients with acute AIH without ALF, a few subsequent cases of ALF considered likely autoimmune feature central perivenulitis as the histological hallmark of severe, immune-mediated liver injury (8
The individual histological features of autoimmunity are not entirely specific to AI-ALF. Although the 16 liver specimens from patients with “defined” etiology exhibited fewer features of autoimmunity, those from all 5 patients with HBV-ALF and 2/9 from APAP-ALF were characterized by at least some autoimmune features. Several explanations are plausible, including more than one etiology, misdiagnosis, similar immunopathogenesis, or evolution from an early metabolite-mediated necrosis to a lymphocyte-plasma cell mediated injury following exposure of autoantigens. A similar immunopathogenesis between AI-ALF and HBV-induced ALF seems likely, as overwhelming viral infections are known to activate B-lymphocytes to differentiate into plasma cells secreting IgM and IgG against the hepatitis B core antigen (23
). Moreover, despite the classical description of APAP-induced hepatotoxicity as bland centrilobular necrosis, the innate immune system also participates in liver injury (25
). It should be emphasized that the aim of the current study was to identify AI-ALF among subjects with indeterminate etiology, and no single test, including liver histology, is capable of cinching the diagnosis; AI-ALF remains a diagnosis based on exclusion of viral and drug etiologies first, but also requires histological and serological evaluation. Although liver biopsies are not performed routinely in ALF due to bleeding risk, our observations suggest that the information provided by histology may be worth the risk in indeterminate cases.
It remains unclear whether the centrilobular variant of AIH represents the same or a different disease as the classical portal-based variant. Perivenulitis and centrilobular necrosis are also features of atypical liver allograft rejection, which appears to be distinct from classical, portal-based rejection in that it resists immunosuppression and may presage chronic rejection (13
). Liver allografts with centrilobular acute rejection can also evolve into a state of veno-occlusive congestion similar to the hemorrhagic MHN4 lesion noted in many patients herein with AI-ALF (13
). These histological and clinical features are distinct from classical descriptions of acute allograft rejection (28
). Hepatotoxicity due to certain drugs can also target the centrilobular region (29
); halothane hepatitis, the best defined, results from metabolic idiosyncrasy and autoantibody formation toward antigens located within pericentral hepatocytes (30
). Therefore, it seems plausible that specific antigens, whether environmental, drug-derived, or expressed on non-self hepatocytes, may trigger an immune-mediated injury to the centrilobular region by targeting antigens preferentially expressed by zone 3 hepatocytes.
The fact that no true gold standard exists for the diagnosis of AIH represents a limitation of our observations. Accordingly, we reasoned that patients with bona fide AI-ALF would more often develop chronic hepatitis in their native livers (in spontaneous survivors) or allografts (in transplant recipients) than those with indeterminate ALF. After 1-4 years follow-up, we found a high (44%) incidence of hepatitis in the study population, and those with histologically proven hepatitis were more frequently those with positive ANA ± ASMA who were given a final histological diagnosis of probable AI-ALF. These data seem further supported by the fact that none of these markers of autoimmunity before transplant were associated with allograft rejection (data not shown).
The clinical relevance of non-organ specific autoantibodies in ALF remains uncertain. A recent screen of ANA, ASMA, AMA, and LKM autoantibodies in patients with ALF revealed a prevalence of 25% in patients with non-acetaminophen drug reactions and hepatotrophic viral infections, but in none of patients with acetaminophen-induced ALF (31
), suggesting that their presence may non-specifically accompany overwhelming immune activation. Our observations suggest that the presence of autoantibodies correlate with histological diagnosis of AI-ALF. Specifically, patients with AI-ALF more frequently had ANA and/or ASMA, and anti-LKM, anti-SLA, and anti-tTG were exclusively detected in patients with histological AI-ALF (data not shown). Moreover, the addition of ANA ± ASMA to a histological diagnosis of AI-ALF appeared to improve the detection of histology alone to identify an autoimmune phenotype.
In conclusion, we propose that 4 histological features of autoimmune liver disease can be interpreted as probable AI-ALF. Patients with probable AI-ALF on histology have a distinctly autoimmune clinical phenotype, and the presence of ANA and/or ASMA may improve the distinction of AI-ALF from other cases of indeterminate ALF. Similar to aggressive, refractory cases of acute cellular allograft rejection, centrilobular necroinflammatory features appear to be a hallmark of AI-ALF.