Serum autotaxin is a prognostic indicator of liver-related events in patients with non-alcoholic fatty liver disease.

BACKGROUND: Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. METHODS: This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. RESULTS: During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22-4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10-30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. CONCLUSIONS: Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

In non-alcoholic fatty liver disease (NAFLD), fat accumulates and can cause damage within the liver. The disease is becoming increasingly common worldwide. It is therefore important to identify individuals with NAFLD who are at higher risk of developing severe liver complications. In this study, we found that NAFLD patients with elevated levels of a substance called autotaxin (ATX) in their blood were more prone to liver-related issues. Thus, it is crucial for doctors to give special attention to NAFLD patients exhibiting high ATX levels. Through close ATX monitoring and appropriate treatment, doctors can potentially enhance their health outcomes and prevent the onset of more severe liver complications.

Long-term prediction of hepatocellular carcinoma using serum autotaxin levels after antiviral therapy for hepatitis C.

INTRODUCTION AND OBJECTIVES: Continuous monitoring for hepatocellular carcinoma is necessary following treatment with direct-acting antivirals in patients with hepatitis C virus infection. We investigated whether the long-term follow-up of serum autotaxin levels could predict the development of hepatocellular carcinoma. PATIENTS AND METHODS: This prospective observational study enrolled adult patients with chronic hepatitis C virus infection who presented to the study center from January 2016 to March 2021. Among the patients who achieved a sustained viral response, the relationship between the development of hepatocellular carcinoma and serum autotaxin levels was assessed before treatment with direct-acting antivirals; at the end of therapy; at 12 and 24 weeks; and at 12, 24, 36, and 48 months after treatment. RESULTS: Data were analyzed for 139 patients. Thirteen patients developed hepatocellular carcinoma 48 months after treatment. The cut-off serum autotaxin values that predicted hepatocellular carcinoma after 24 weeks were 1.22 (men) and 1.92 (women) mg/L. The area under the curve for serum autotaxin was 0.83 (95% confidence interval [CI]:0.71-0.95) in men and 0.90 (95% CI: 0.82-0.99) in women. The positive predictive value of serum autotaxin was 0.208 (95% CI: 0.139-0.248), and the negative predictive value was 0.971 (95% CI: 0.939-0.990). The cumulative incidence of hepatocellular carcinoma was significantly higher when serum autotaxin levels were above the cut-off value after 24 weeks (p < 0.0001). CONCLUSIONS: Serum autotaxin is a candidate biomarker for predicting hepatocellular carcinoma during the long-term follow-up of patients with a sustained viral response following treatment with direct-acting antivirals.

Autotaxin and soluble IL-2 receptor concentrations in cerebrospinal fluids are useful for the diagnosis of central nervous system invasion caused by haematological malignancies.

BACKGROUND: Invasion of the central nervous system by haematological malignancies is diagnosed by cytological analyses of cerebrospinal fluid or diagnostic imaging, while quantitative biomarkers for central nervous system invasion are not available and needed to be developed. METHODS: In this study, we measured the concentrations of autotaxin and soluble IL-2 receptor in cerebrospinal fluid and evaluated their usefulness as biomarkers for central nervous system invasion. RESULTS: We observed that both the autotaxin and soluble IL-2 receptor concentrations in cerebrospinal fluid were higher in subjects with central nervous system invasion than in those without, and the cerebrospinal fluid concentrations were independent from the serum concentrations of these biomarkers. ROC analyses revealed that the soluble IL-2 receptor concentration in cerebrospinal fluid was a strong discriminator of central nervous system invasion in subjects with haematological malignancies, while the autotaxin concentration in cerebrospinal fluid also had a strong ability to discriminate central nervous system invasion when the subjects were limited to those with lymphoma. The combined measurement of autotaxin and soluble IL-2 receptor in cerebrospinal fluid improved the sensitivity without notably reducing the specificity for central nervous system invasion in subjects with lymphoma when central nervous system invasion was diagnosed in cases where either value was beyond the respective cut-off value. CONCLUSION: These results suggest the possible usefulness of soluble IL-2 receptor and autotaxin concentrations in cerebrospinal fluid for the diagnosis of central nervous system invasion.

Association between serum autotaxin or phosphatidylserine-specific phospholipase A1 levels and melanoma.

Autotaxin (ATX), a producing enzyme for lysophosphatidic acids, was first identified from the medium of a melanoma cell line and has been considered to be one of the candidate targets to treat melanoma; however, the association between serum ATX and melanoma in human subjects has not been elucidated. Along with ATX, phosphatidylserine-specific phospholipase A1 (PS-PLA1 ) is a producing enzyme for lysophosphatidylserine, a similar glycero-lysophospholipid mediator to lysophosphatidic acids. In the present study, we aimed to investigate the association between serum ATX or PS-PLA1 levels and melanoma. We measured the serum levels of ATX, ATX isoforms and PS-PLA1 in subjects with melanoma (n = 57) and healthy subjects (n = 58). We further investigated the existence of trends according to the clinical stages of melanoma. We observed that serum total ATX and classical ATX levels were significant higher and serum novel ATX levels tended to be higher in male subjects with melanoma, while no significant difference was observed between the two groups in female subjects. The trend test revealed that the serum total ATX and ATX isoforms were significantly associated with the clinical stages of female subjects with melanoma. Regarding PS-PLA1 , serum PS-PLA1 levels were significantly higher in the melanoma subjects and associated with the clinical stages. The present study is the first study which revealed the association between ATX or PS-PLA1 and melanoma, suggesting the possible involvement of ATX/lysophosphatidic acids or PS-PLA1 /lysophosphatidylserine axis in the pathogenesis of melanoma.

Performance of autotaxin as a serum marker for liver fibrosis.

Background Because autotaxin reportedly has a better performance than hyaluronic acid as a marker for liver fibrosis for the prediction of cirrhosis caused by hepatitis C, we aimed to further evaluate the role of autotaxin in liver fibrosis of other aetiologies. Methods Autotaxin antigen was measured in serum samples from 108 patients with chronic hepatitis B and 128 patients with non-alcoholic fatty liver disease who had undergone a liver biopsy as well as healthy subjects and patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis and cardiac dysfunction. Results When evaluated using receiver operator characteristics curves, the performance of autotaxin for the prediction of significant fibrosis (F2-F4) in chronic hepatitis B patients was better than that of hyaluronic acid or type IV collagen 7S. In non-alcoholic fatty liver disease patients, however, the performance of autotaxin for the prediction of significant fibrosis was poorer than that of hyaluronic acid or type IV collagen 7S. The increase in the serum autotaxin concentrations was less notable than that of hyaluronic acid or type IV collagen in patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis or cardiac dysfunction. Food intake did not affect the serum autotaxin concentrations. Conclusions Autotaxin is useful as a serum marker for liver fibrosis caused by not only chronic viral hepatitis C but also by hepatitis B, although it was less useful in patients with non-alcoholic fatty liver disease. The increase in serum autotaxin concentrations is fairly specific for liver fibrosis, and the serum autotaxin concentrations can be analysed without consideration of food intake before blood collection.

A New Enzyme Immunoassay for the Quantitative Determination of Classical Autotaxins (ATXα, ATXß, and ATXγ) and Novel Autotaxins (ATXδ and ATXε).

BACKGROUND: Autotaxin (ATX) is a secreted enzyme that converts lysophosphatidylcholine to lysophosphatidic acid, a potent bioactive lipid mediator, through its lysophospholipase D activity. Although five alternative splicing isoforms of ATX have been identified as ATXα, ATXß, ATXγ, ATXδ, and ATXε and the expression patterns of each isoform differ among several tissues, the clinical significance of each isoform remains to be elucidated. METHODS: Anti-ATXß and anti-ATXδ monoclonal antibodies were produced by immunization with recombinant human ATXß and ATXδ expressed using a baculovirus system, respectively. We then developed enzyme immunoassays to measure the serum concentrations of "classical ATX" (ATXα, ATXß, and ATXγ) and "novel ATX" (ATXδ and ATXε) antigens and evaluated the usefulness of these assays using human serum samples. RESULTS: The with-run and between-run precision, interference, detection limit, and linearity studies for the present assay were well validated. In healthy subjects, the serum concentrations of classical ATX and novel ATX were significantly (P < 0.01) higher in women than in men, while the ratios of classical ATX or novel ATX to total ATX were not different between women and men. The concentrations of both classical ATX and novel ATX in normal pregnant subjects and patients with chronic liver diseases or follicular lymphoma were significantly higher than those in healthy subjects, while the ratio of both ATX isoforms to total ATX did not vary among these groups. CONCLUSIONS: We have developed a new enzyme immunoassay to determine the concentrations of classical ATX and novel ATX in human serum. These assays may be helpful for elucidating the distinct functional roles of each ATX isoform, which are largely unknown at present.