The gut microbiota has recently been recognized to play a role in the pathogenesis of autoimmune liver disease (AILD), mainly primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). This study aimed to analyze and compare the composition of the oral microbiota of 56 patients with AILD and 15 healthy controls (HCs) and to evaluate its association with salivary immunological biomarkers and gut microbiota. The subjects included 39 patients with PBC and 17 patients with AIH diagnosed at our hospital. The control population comprised 15 matched HCs. Salivary and fecal samples were collected for analysis of the microbiome by terminal restriction fragment length polymorphism of 16S rDNA. Correlations between immunological biomarkers measured by Bio-Plex assay (Bio-Rad) and the oral microbiomes of patients with PBC and AIH were assessed. Patients with AIH showed a significant increase in Veillonella with a concurrent decrease in Streptococcus in the oral microbiota compared with the HCs. Patients with PBC showed significant increases in Eubacterium and Veillonella and a significant decrease in Fusobacterium in the oral microbiota compared with the HCs. Immunological biomarker analysis showed elevated levels of inflammatory cytokines (IL-1β, IFN-γ, TNF-α, IL-8) and immunoglobulin A in the saliva of patients with AILD. The relative abundance of Veillonella was positively correlated with the levels of IL-1β, IL-8 and immunoglobulin A in saliva and the relative abundance of Lactobacillales in feces. Dysbiosis of the oral microbiota is associated with inflammatory responses and reflects changes in the gut microbiota of patients with AILD. Dysbiosis may play an important role in the pathogenesis of AILD.

The present study aimed to investigate the incidence of hepatocellular carcinoma (HCC) and factors related to HCC occurrence after direct-acting antiviral (DAA) treatment in the Fukushima Liver Academic Group (FLAG). We conducted a multicenter retrospective cohort study of 1068 patients without cirrhosis (NC) or with compensated liver cirrhosis (LC) who achieved a sustained virologic response (SVR). First, we compared the cumulative HCC incidence and survival rates in NC (n = 880) and LC (n = 188) patients without a history of HCC treatment. Second, we performed multivariate analysis of factors related to HCC occurrence after DAA treatment. Overall, the average age was 65 years, and the male/female ratio was 511/557. Thirty-nine (4%) patients developed HCC. The cumulative 4-year HCC incidence and survival rates were 3.0% and 99.8% in NC patients and 11.5% and 98.5% in LC patients, respectively. The independent factors affecting HCC occurrence identified by multivariate analysis were the serum albumin (ALB) level before SVR for NC patients and the ALBI score, platelet count, and diabetes before SVR for LC patients. The factors related to HCC occurrence differed between NC and LC patients. Careful surveillance of post-SVR patients with these risk factors is needed.

Recently, the number of follicular helper T (Tfh) cells expressing interleukin (IL)-21 was found to increase in peripheral blood of human and murine models of autoimmune hepatitis (AIH). IL-21, the most recently discovered member of the type-I cytokine family, exerts various effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. We aimed to assess the relationship of serum IL-21 levels in patients with type I AIH with clinical and laboratory parameters and histology. Ninety-two Japanese patients with liver disease (22 AIH, 20 primary biliary cholangitis, 19 drug-induced liver injury, 8 acute hepatitis B, 8 chronic hepatitis C, 10 non-alcoholic steatohepatitis, 5 viral hepatitis) and 10 healthy volunteers were recruited. Serum IL-21 levels were detected by enzyme-linked immunosorbent assay. Real-time polymerase chain reaction measured mRNA levels of Bcl-6, IL-21, and CXCR5 (Tfh-related factors) in peripheral mononuclear cells. Mean age at diagnosis of AIH was 58.6 years, male-to-female ratio was 4:18, 18.2 % of participants had cirrhosis, and 22.7 % had severe disease. IL-21 levels were significantly increased in the serum of patients with AIH compared to those with other liver diseases and controls (p < 0.0001). Particularly, serum IL-21 levels were significantly increased in severe AIH cases compared to non-severe cases (p < 0.05). Serum IL-21 levels correlated positively with total serum bilirubin levels (r = 0.46, p < 0.05), grading of necroinflammatory activity (r = 0.68, p < 0.005) and negatively with serum albumin levels in patients with AIH (r = −0.49, p < 0.05). In patients with biochemical remission of AIH, serum IL-21 levels remained elevated and correlated positively with serum IgG levels (r = 0.84, p < 0.01). Expression of Tfh-related factors, such as Bcl-6 and IL-21, in peripheral blood mononuclear cells of patients with AIH was significantly higher than that in healthy volunteers. IL-21 may play an important role in the pathogenesis and severity of AIH, and may present a promising target for AIH therapy.

To compare clinicopathological features of acute presentation of type 1 autoimmune hepatitis (AIH) with or without centrilobular necrosis (CN). Our study comprised 41 patients with biopsy-proven acute presentation (acute exacerbation phase 36, acute hepatitis phase 5) of type 1 AIH at our hospital from 1975 to 2009. Elevated serum alanine aminotransferase (ALT) (> 5x upper limit of normal) identified acute presentation of the disease. We compared clinicopathological features of these AIH patients with or without CN. The data used for analysis included patient background (age, sex, type of disease, presence of complications with other autoimmune diseases, human leukocyte antigen, and International Autoimmune Hepatitis Group score), clinical parameters at presentation (ALT, alkaline phosphatase, IgG, anti-nuclear antibodies, and anti-smooth muscle antibodies), histology and therapy. CN was found in 13 (31.7%) patients with acute presentation (acute exacerbation phase 10, acute hepatitis phase 3) of AIH. Serum IgG levels of patients with CN were significantly lower than those of patients without CN (mean: 2307 mg/dL vs 3126 mg/dL, P < 0.05), while antinuclear antibody-negative rates were significantly higher (30.7% vs 3.5%, P < 0.05). However, other clinical features were similar between the two groups. The frequency of advanced fibrosis in patients with CN was significantly lower than in patients without CN (F0-2: 84.6% vs 35.7%, F3-4: 15.4% vs 64.3%, P < 0.05). Other histological features were similar between the two groups. Although there was no significant difference between groups when evaluated using the revised original score (12 vs 14), the simplified AIH score of patients with CN was significantly lower (6 vs 7, P < 0.05). Frequency of DR4 was similar between patients with and without CN. CN is observed in both Japanese patients with acute hepatitis phase and acute exacerbation phase of type 1 AIH, although AIH with CN often shows clinical features of the genuine acute form.

The gut microbiota plays a key role in the development of chronic inflammatory liver disease. The gut-liver axis involves inflammatory cells, cytokines, and other molecules that cause liver deterioration. Dysbiosis is important in understanding several liver diseases, especially in relation to the development of autoimmune liver disease. The aim of this review is to provide a current overview of alterations in the gut and oral microbiota associated with autoimmune liver diseases.