Autoimmune acute liver failure: proposed clinical and histological criteria

Abstract

Identifying autoimmune hepatitis as the etiology of acute liver failure (ALF) is potentially important, because administering corticosteroids might avoid the need for liver transplantation. However, clinical and histological criteria of autoimmune ALF (AI-ALF) have not been defined. Liver sections (biopsies and explants) from a 72-patient subset of the ALF Study Group Registry with indeterminate ALF were reviewed by a pathologist blinded to all clinical data and were diagnosed with probable AI-ALF based on four features suggestive of an autoimmune pathogenesis: distinctive patterns of massive hepatic necrosis (present in 42% of sections), presence of lymphoid follicles (32%), a plasma cell-enriched inflammatory infiltrate (63%), and central perivenulitis (65%). Forty-two sections (58%) were considered probable for AI-ALF; this group demonstrated higher serum globulins (3.7 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P = 0.037) and a higher prevalence of antinuclear and/or anti-smooth muscle antibodies (73% versus 48%; P = 0.034) compared to those without histology suggestive of probable AI-ALF. Thirty patients concordant for autoantibodies and probable AI-ALF upon histological analysis were more likely to have the classical autoimmune hepatitis phenotype (female predominance [72% versus 48%; P < 0.05], higher globulins [3.9 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P < 0.005], and higher incidence of chronic hepatitis in long-term follow-up [67% versus 17%, P = 0.019]) compared to the population without concordant AI-ALF histology and autoantibodies.

Conclusion: Patients with indeterminate ALF often have features of autoimmune disease by histological analysis, serological testing, and clinical recurrence during follow-up. In contrast to classical autoimmune hepatitis, histological features of AI-ALF predominate in the centrilobular zone.

Figure 1. Diagrammatic depiction of five patterns of massive hepatic necrosis (MHN)

Normal hepatic architecture is depicted in the upper left diagram for comparison. Areas of hatched blue represent necrotic hepatocytes and areas in light blue represent portal tracts.

Figure 2. Histological variants of massive hepatic necrosis (MHN)

A. MHN type 1: “typical” MHN with panlobular necrosis and neocholangiolar proliferation (ductular reaction) (arrows) emerging from parenchyma near portal tracts (PT). B. MHN type 2: there is confluent necrosis in the field left of the hatched line, with early regenerative nodules (N), a pattern also referred to as ‘submassive necrosis’. C. MHN type 3: acute hepatitis with lobular disarray, inflammation and liver-cell damage is seen at bottom and is separated by the hatched line from more severe confluent necrosis above. D. MHN type 4: centrilobular hemorrhagic necrosis superimposed on the general features of massive necrosis is prominent at low power. Inset: one centrilobular region (arrow) shows lymphocytes and plasma cells around, infiltrating, and within the lumen of a central vein (‘central perivenulitis’), in association with hemorrhage and hepatocyte loss. E. MHN type 5: confluent necrosis is present superimposed on features of an underlying chronic hepatitis, including portal lymphoid aggregates (LA) and interface hepatitis (IH). Note confluent bridging hepatic necrosis (blue arrows) extending between central vein (CV) and portal tract at upper right. Multilobular necrosis is also present at the left of the field. (A-E: Hematoxylin and eosin stain, × 40. Inset to D: Hematoxylin and eosin stain, × 200.)

Figure 3. Central perivenulitits

This section from an explanted liver shows severe hepatitis with extensive inflammation extending from the portal tract (PT) into the lobule, with marked loss of hepatocytes. Note the prominent hepatocyte loss and inflammation around the central vein (CV), “central perivenulitis.” Inset: Higher magnification of central perivenulitis highlighted by plasma cells surrounding and infiltrating the vein wall, associated with marked hepatocyte destruction. (Hematoxylin and eosin stain).