Management of Difficult Cases of Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a complex autoimmune disease characterized by immune-mediated destruction of hepatic parenchyma which can result in cirrhosis, liver failure, and death. Current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver (EASL) guidelines recommend corticosteroids alone or in combination with azathioprine as first-line treatment strategies. However, a significant proportion of patients may not be able to tolerate or achieve complete biochemical response with these options. In this article, we discuss approaches to these patients and other challenging AIH patient groups such as the asymptomatic, pregnant, elderly, and liver transplant recipients

Automatic quantification of lobular inflammation and hepatocyte ballooning in NAFLD liver biopsies

Automatic quantification of cardinal histologic features of nonalcoholic fatty liver disease (NAFLD) may reduce human variability and allow continuous rather than semiquantitative assessment of injury. We recently developed an automated classifier that can detect and quantify macrosteatosis with greater than or equal to 95% precision and recall (sensitivity). Here, we report our early results on the classifier's performance in detecting lobular inflammation and hepatocellular ballooning. Automatic quantification of lobular inflammation and ballooning was performed on digital images of hematoxylin and eosin–stained slides of liver biopsy samples from 59 individuals with normal liver histology and varying severity of NAFLD. Two expert hepatopathologists scored liver biopsies according the nonalcoholic steatohepatitis clinical research network scoring system and provided annotations of lobular inflammation and hepatocyte ballooning on the digital images. The classifier had precision and recall of 70% and 49% for lobular inflammation, and 91% and 54% for hepatocyte ballooning. In addition, the classifier had an area under the curve of 95% for lobular inflammation and 98% for hepatocyte ballooning. The Spearman rank correlation coefficient for comparison with pathologist grades was 45.2% for lobular inflammation and 46% for hepatocyte ballooning. Our novel observations demonstrate that automatic quantification of cardinal NAFLD histologic lesions is feasible and offer promise for further development of automatic quantification as a potential aid to pathologists evaluating NAFLD biopsies in clinical practice and clinical trials

Vitamin E Improves Transplant‐free Survival and Hepatic Decompensation among Patients with NASH and Advanced Fibrosis

Vitamin E improves liver histology in non‐diabetic adults with nonalcoholic steatohepatitis (NASH), but its impact on long‐term patient outcomes is unknown. We evaluated whether vitamin E treatment improves clinical outcomes of NASH patients with bridging fibrosis or cirrhosis. Two hundred and thirty‐six patients with biopsy‐proven NASH and bridging fibrosis or cirrhosis seen at Indiana University Medical Center between October 2004, and January 2016 were included. Ninety of them took 800 IU/day of vitamin E for ≥ 2 years (vitamin E users) and were propensity matched to 90 adults who did not take vitamin E (controls) after adjusting for fibrosis severity, age, gender, body mass index, comorbidities and their treatment, LDL cholesterol, liver biochemistries and length of follow‐up on vitamin E. Covariate‐adjusted cox and competing risk regression models were assessed to evaluate association between vitamin E treatment and patient outcomes. The median follow‐up was 5.62 (IQR: 4.3‐7.5) and 5.6 (IQR: 4‐6.9) years for vitamin E users and controls respectively. Vitamin E users had higher adjusted transplant‐free survival (78% vs. 49%, P<.01) and lower rates of hepatic decompensation (37% vs. 62%, P=.04) than controls. After controlling for severity of fibrosis, calendar year of patient enrollment and other potential confounders, vitamin E treatment decreased the risk of death or transplant (adj. HR: 0.30, 95% CI: 0.12‐0.74, P<.01) and hepatic decompensation (adj. sHR: 0.52, 95% CI: 0.28‐0.96, P=.036). These benefits were evident in both diabetics as well as non‐diabetics. Adjusted 10‐year cumulative probability of HCC, vascular events and non‐hepatic cancers were not different between vitamin E exposed and controls

Clinical Characteristics and Outcomes of Mild to Moderate Alcoholic Hepatitis

Introduction & Aim Much is known about alcoholic hepatitis (AH) that is severe enough to require hospitalisation. The characteristics of individuals with alcoholic hepatitis presenting with mild to moderate severity are not well understood. In this study, we investigated the risk factors, characteristics and outcomes of mild to moderate AH (M‐AH). Methods A total of 255 individuals with AH enrolled into a multicenter, prospective, observational study between 12/2014 and 4/2018 was included. Participants were seen at enrollment, 6 and 12 months. M‐AH was defined as MELD ≤20 at presentation, whereas severe AH as MELD ≥21. Results In total, 100 individuals had M‐AH, whereas 155 had severe AH. Individuals with M‐AH were older (49 vs 44 years, P = 0.01), had lower BMI (27 vs 31 kg/m2, P = 0.0007) and more likely to be male (68% vs 55%, P = 0.046) compared to the severe AH group. A higher proportion in the M‐AH group consumed coffee in the last 5 years compared to the severe AH group (29% vs 18%, P = 0.03), and fewer had PNPLA3 risk allele G (P = 0.019) compared to the severe AH group. Average drinks per drinking day (12.9 vs 10.7, P = 0.13) and total number of drinks in last 30‐day period (331 vs 280, P = 0.14) were not different between two groups. Compared to severe AH, patients with M‐AH had significantly lower mortality at 30 days (2% vs 13.6%), 90 days (3% vs 22.6%) and 12 months (10.4% vs 31.4%) (P < 0.001 for all). Conclusions Individuals with M‐AH were older, less obese, drank coffee more often and carried more favourable PNPLA3 genotype compared to severe AH, despite similar alcohol consumption. M‐AH had substantial mortality with one in ten dying by 12 months

Function of inhibitor of Bruton's tyrosine kinase isoform α (IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response

Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the α isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR

Older Age and Disease Duration Are Highly Associated with Hepatocellular Carcinoma in Patients with Autoimmune Hepatitis

Background: Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood. Aims: To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design. Methods: Over a 14.5-year period, medical records of all patients with HCC were reviewed. Cases are AIH patients identified from the cohort, and controls are patients with AIH without HCC. Three controls were randomly chosen from the Genetic Repository of Autoimmune Liver Disease and Coexisting Exposures database for each eligible case. Results: Out of 1250 eligible patients, 20 were linked to AIH (1.6%). Their median age was 64 years, 40% men and 100% Caucasian. Ten percent of AIH patients did not have evidence of cirrhosis at HCC diagnosis. The proportion of HCCs due to AIH decreased during the time intervals of the study. Compared to controls, cases were more likely men (40.0% vs. 18%, p = 0.049), with longer AIH duration (median 16 years vs. 5 years, p = 0.004). Prolonged AIH duration (OR 1.68, p = 0.006) and older age (OR 1.15, p = 0.049) were risk factors for HCC. Conclusions: AIH is a rare cause (1.6%) for HCC in Midwestern USA with a decreasing trend over 14.5 years. Ten percent of AIH-HCC patients did not have cirrhosis at time of HCC diagnosis. Patients with prolonged duration of the disease and older age are at high risk to develop HCC

Integrative omics analysis identifies macrophage migration inhibitory factor signaling pathways underlying human hepatic fibrogenesis and fibrosis

The genetic basis underlying liver fibrosis remains largely unknown. We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers. By accepting a liberal significance level of P<1e-4, we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin (α-SMA) levels (fibrogenesis) and total collagen content (fibrosis). The top genetic loci associated with the two markers were BAZA1 and NOL10 for α-SMA expression and FAM46A for total collagen content (P<1e-6). We further investigated the relationship between the candidate loci and the nearby gene transcription levels (cis-expression quantitative trait loci) in the same liver samples. We found that 44 candidate loci for α-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes (P<0.05). Pathway analyses of these genes indicated that macrophage migration inhibitory factor (MIF) related pathway is significantly associated with fibrogenesis and fibrosis, though different genes were enriched for each marker. The association between the single nucleotide polymorphisms, MIF and α-SMA showed that decreased MIF expression is correlated with increased α-SMA expression, suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression. In summary, our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers. Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis, thus further investigation for the role of the MIF pathway in liver fibrosis is warranted. The study was reviewed and approved by the Institutional Review Board (IRB) of Wayne State University (approval No. 201842) on May 17, 2018