Autoimmune hepatitis triggered by nitrofurantoin: a case series

<p>Abstract</p> <p>Introduction</p> <p>Drugs can occasionally trigger the onset of autoimmune liver disease.</p> <p>Case presentation</p> <p>Three Caucasian women (aged 65, 42 and 74 years old) who were receiving long-term nitrofurantoin as prophylaxis against recurrent urinary tract infections developed hepatitic liver disease. Serological auto-antibody profiles and liver histology appearances were consistent with autoimmune hepatitis. Two of the patients presented with jaundice, and one required a prolonged hospital admission for liver failure. In all three patients nitrofurantoin was withdrawn, and long-term immunosuppressive therapy with prednisolone and azathioprine or mycophenolate was given. The patients responded well, with liver biochemistry returning to normal within a few months.</p> <p>Conclusions</p> <p>Although nitrofurantoin rarely causes autoimmune hepatitis, this antimicrobial is increasingly used as long-term prophylaxis against recurrent urinary tract infection. General practitioners and urologists who prescribe long-term nitrofurantoin therapy should be aware of this adverse effect.</p

Maternal obesity programs offspring non-alcoholic fatty liver disease via innate immune dysfunction in mice

The global prevalence of obesity-induced liver disease (nonalcoholic fatty liver disease; NAFLD) is rising. Suggested causes include a role for in utero influences of maternal obesity compounded by the availability of energy-dense foods throughout postnatal life. Using a physiologically relevant model, we investigated the role of the innate immune system in liver injury induced by maternal obesity followed by a postnatal obesogenic diet. Female C57BL/6J mice were fed a standard or obesogenic diet before and throughout pregnancy and during lactation. Female offspring were weaned onto a standard or obesogenic diet at 3 weeks postpartum. Biochemical and histological indicators of dysmetabolism, NAFLD and fibrosis, analysis of profibrotic pathways, liver innate immune cells, and reactive oxygen species (ROS) were investigated at 3, 6, and 12 months. Female offspring exposed to a postweaning obesogenic diet (OffCon-OD) demonstrated evidence of liver injury, which was exacerbated by previous exposure to maternal obesity (OffOb-OD), as demonstrated by raised alanine aminotransferase, hepatic triglycerides, and hepatic expression of interleukin (IL)-6, tumor necrosis factor alpha, transforming growth factor beta, alpha smooth muscle actin, and collagen (P < 0.01). Histological evidence of hepatosteatosis and a more-robust NAFLD phenotype with hepatic fibrosis was observed at 12 months in OffOb-OD. A role for the innate immune system was indicated by increased Kupffer cell numbers with impaired phagocytic function and raised ROS synthesis (P < 0.01), together with reduced natural killer T cells and raised interleukin (IL)-12 and IL-18. Conclusion: Maternal obesity in the context of a postnatal hypercalorific obesogenic diet aggressively programs offspring NAFLD associated with innate immune dysfunction, resulting in a comprehensive phenotype that accurately reflects the human disease. © 2013 American Association for the Study of Liver Diseases

Two-Way ANOVA results when comparing the influence of gender and group on the overall variance seen between offspring.

<p>Two-Way ANOVA results when comparing the influence of gender and group on the overall variance seen between offspring.</p

Anthropometric Data: Con_Con, Con_Ob, Ob_Con, Ob_Ob.

<p>A = Offspring Body Weights; B = Offspring Pancreas Weights; C = Pancreatic Triglyceride Concentrations; D = Macrovesicular Fat Infiltration; E = Oral Glucose Tolerance Test. * = p<.05; ** = p<.001; *** = p<.0001 (n = 4–5/group). ANOVA with Tukey post hoc test.</p

Primer sequences were obtained for the relevant genes of interest from GenBank (except for the primers for the circadian study arm).

<p>The primer sequences were analyzed for optimum primers using Primer 3 Software. Ready-to-use Quantitect Primer Assays (Qiagen) were purchased for the circadian arm of the study. Each assay contains forward and reverse primers that are generated from the NCBI Reference Sequence database, optimised and bioinformatically validated.</p

Cosinor Analysis of Circadian Genes: Con_Con, Con_Ob, Ob_Con, Ob_Ob.

<p>A = Clock; B = Bmal-1; C = Per-1; D = Per-2; E = REV-ERB-α. (% = Con_Con versus Con_Ob; * = Con_Con versus Ob_Ob; § = Ob_Con versus Ob_Ob) (n = 4–5/group).</p

mRNA Expression of markers of Pancreatic Injury: Con_Con, Con_Ob, Ob_Con, Ob_Ob.

<p>A = IL-6; B = TNF-α; C = α-SMA; D = Collagen; E = TGF- β. * = p<.05; ** = p<.001; *** = p<.0001 (n = 4–5/group). ANOVA with Tukey post hoc test.</p

mRNA Expression of Circadian Genes: Con_Con, Con_Ob, Ob_Con, Ob_Ob.

<p>A = Clock; B = Per-2; C = BMAL-1; D = Per-1; E = REV-ERB-α. %%% = p<.0001; ∞∞∞ = p<.0001; * = p<.05; ** = p<.001; *** = p<.0001; ## = p<.001; § = p<.05. (% = Con_Con versus Con_Ob; ∞ = Con_Con versus Ob_Con; * = Con_Con versus Ob_Ob; # = Con_Ob versus Ob_Ob; § = Ob_Con versus Ob_Ob) (n = 4–5/group). ANOVA with Tukey post hoc test.</p