Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease

Autoimmune reactions are often associated with alcoholic liver disease; however, the mechanisms responsible are largely unknown. This study investigates the potential role of the immune response against hydroxyethyl free radical (HER)-derived antigens and of polymorphisms in immunoregulatory genes in the development of anti-cytochrome P4502E1 (CYP2E1) autoantibodies in alcohol abusers. Immunoglobulin G (IgG) recognizing human CYP2E1 and HER-derived epitopes were measured by microplate immunosorbent assay in the sera of 90 patients with alcoholic fibrosis/cirrhosis (ALD), 37 heavy drinkers without liver disease or steatosis only (HD), and 59 healthy subjects. Single nucleotide polymorphisms in the interleukin 10 (IL-10) promoter and in exon 1 of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The titers and frequency of anti-CYP2E1 autoantibodies were significantly higher in ALD than in HD subjects or controls. ALD patients with anti-HER IgG had higher titers and a 4-fold increased risk (OR: 4.4 [1.8-10.9]) of developing anti-CYP2E1 autoantibodies than subjects without anti-HER antibodies. The mutant CTLA-4 G allele, but not the IL-10 polymorphism, was associated with an enhanced risk of developing anti-CYP2E1 IgG (OR: 3.8 [1.4-10.3]). CTLA-4 polymorphism did not influence antibody formation toward HER-antigens. ALD patients with concomitant anti-HER IgG and the CTLA-4 G allele had a 22-fold higher (OR: 22.9 [4.2-125.6]) risk of developing anti-CYP2E1 autoreactivity than subjects negative for these factors. In conclusion, antigenic stimulation by HER-modified CYP2E1 combined with an impaired control of T-cell proliferation by CTLA-4 mutation promotes the development of anti-CYP2E1 autoantibodies that might contribute to alcohol-induced liver injury.     

Multiple small bowel perforations due to invasive aspergillosis in a patient with acute myeloid leukemia: case report and a systematic review of the literature

Purpose

Invasive aspergillosis (IA) represents a major cause of morbidity and mortality in immunocompromised patients. Involvement of the gastrointestinal tract by Aspergillus is mostly reported as part of a disseminated infection from a primary pulmonary site and only rarely as an isolated organ infection.

Methods

We report a case of small bowel perforation due to IA in a patient with acute leukemia under chemotherapy and pulmonary aspergillosis. We performed a systematic review of the literature as well.

Results

A 43-year-old man with acute myeloid leukemia under chemotherapy developed severe neutropenia and pulmonary aspergillosis due to Aspergillus flavus. He developed melena and hemodynamic failure and a contrast-enhanced ultrasound scan suggested active intestinal bleeding. During emergency laparotomy we found multiple intestinal abscesses, several perforations of intestinal loop and Aspergillus flavus was isolated from the abscesses. Resection of the jejunum was performed. The patient received voriconazole and finally recovered. The patient is now alive and in complete disease remission. From literature review we found 35 intestinal IA previously published in single case reports or small case series as well.

Conclusion

Clinical manifestations of gastrointestinal aspergillosis are nonspecific, such as abdominal pain, and only occasionally it presents as an acute abdomen. Antemortem detection of bowel involvement is rarely achieved and, only in cases of complicated gastrointestinal aspergillosis, the diagnosis is achieved thanks to the findings during surgery. Gastrointestinal aspergillosis should be suspected in patients with severe and prolonged neutropenia with or without pulmonary involvement in order to consider the right therapy and prompt surgery.