Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus

Abstract

Liver disease (LD), defined as ≥2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment.

Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus‐Prone Mice

“…In summary, the model of lupus pathogenesis proposed herein involves mTORC1-controlled mitochondrial dysfunction in the liver, with related generation of aPL and increased hepatocarcinogenesis in SLE (29). In support of this model, liver disease, which was defined as a $2-fold elevation in the levels of aspartate aminotransferase or alanine aminotransferase, was associated with the production of aPL in our SLE cohort (16) as well as in previous meta-analyses (17,18). Along these lines, HCC develops in the liver following chronic inflammation, which is driven by mitochondrial oxidative stress (19,36) and responds to treatment with rapamycin (48).…”

“…Interestingly, the prevalence of HCC is increased in patients with SLE (29). Recently, liver disease was found to be associated with APS in our lupus cohort (16), a finding consistent with that in metaanalyses of liver involvement in patients with APS (17,18). TAL is overexpressed in the T cells of SLE patients, which may be related to protection against oxidative stress (3).…”

“…This finding is consistent with the data reported in meta-analyses of liver involvement in patients with APS (17,18). Interestingly, treatment with rapamycin, which blocks the activation of mTORC1, prevented liver disease in our cohort of lupus patients (16). We therefore undertook the present study to examine the role of the liver in mTOR activation and its association with APS in mice that spontaneously develop SLE.…”

Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years

“…Liver disease, defined as a >2-fold elevation of AST or ALT, was present in 20.7 % of SLE patients independent of hepatotoxic medications [47]. Both NAC and rapamycin, but not azathioprine, cyclosporine, or cyclophosphamide, were successful in preventing liver disease [47].…”

“…Both NAC and rapamycin, but not azathioprine, cyclosporine, or cyclophosphamide, were successful in preventing liver disease [47]. Furthermore, liver disease correlated to higher SLE disease activity index (SLEDAI) scores in patients and thus is an important organ system to monitor [47]. …”