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    • Because serum ATX activity and plasma LPA are

    2023-12-29

    Because serum ATX activity and Risedronate LPA are well correlated with liver fibrosis stage histologically, both of these parameters merit consideration as novel markers of fibrosis. However, serum ATX activity may be a more useful test from a clinical laboratory perspective. First, LPA can increase markedly after sample preparation unless temperature is strictly controlled [32]. This finding may result from the presence of synthetic ATX and its substrate lysophosphatidyl choline that can lead to abundant production of LPA in plasma [32]. Second, LPA is released from platelets, among other sources, and LPA should be measured in plasma to evaluate its clinical significance [33]. On the other hand, ATX activity can be measured in serum and is temperature stable [32]. Furthermore, using an immunoenzymetric system, a high-throughput test for ATX mass measurement has been developed [34]. This approach provides results much more quickly than traditional ATX activity assays. Using this system, serum ATX concentration has been assessed as a marker for liver fibrosis [35] accounting for gender bias [36]. As expected, serum ATX was correlated to liver fibrotic stage in chronic hepatitis C patients. When compared to serum hyaluronate and aminotransferase/platelet ratio, ie, two established markers for liver fibrosis [31], serum ATX concentration was the best parameter for predicting cirrhosis in both men and women [35]. Although the mechanism of uptake from the circulation may be similar for ATX and hyaluronate, both did not behave similarly as liver fibrosis markers. For example, ATX, but not hyaluronate, exhibited gender difference. Thus, the origin and fate of serum ATX must be further elucidated and serum ATX should be evaluated as a possible liver fibrosis marker in not only patients with chronic hepatitis C, but also patients with liver fibrosis in general. Increased serum ATX activity and/or concentration has been reported in pregnancy [37], [38], follicular lymphoma [39], and pancreatic cancer [40].
    ATX association with pruritus and hepatocellular carcinoma Recently, Kremer et al. [41], proposed a new role for LPA/ATX in the pathophysiology of liver fibrosis by suggesting that LPA might be a potential mediator of cholestatic pruritus. They showed that blood LPA and ATX activity were increased in cholestatic patients with pruritus and that serum ATX activity was correlated with the intensity of pruritus. They also reported increased serum ATX activity in chronic hepatitis C patients, in agreement with a previous report. Thus, this finding raised the possibility that increased serum ATX and plasma LPA may directly contribute to the pathogenesis of pruritus as a complication of liver fibrosis. A potential ATX inhibitor is now available [42]. This inhibitor merits consideration as a therapeutic agent for pruritus in patients with liver fibrosis. Hepatocellular carcinoma often develops in patients with chronic liver injury as a major complication of liver fibrosis [43]. Considering the high levels of LPA and ATX in the blood of patients with liver fibrosis, hepatocellular carcinoma cells are likely exposed to an abundance of these molecules. In fact, a stimulatory effect of LPA on the motility of hepatocellular carcinoma-derived cells has been reported [44], [45], [46], suggesting a potential role in metastasis. ATX is highly expressed in malignancy including Hodgkin lymphoma [47], glioblastoma [48], [49], non-small cell lung cancer [50], renal cell carcinoma [51], breast cancer [52], thyroid carcinoma [53], and hepatocellular carcinoma [54]. Unfortunately, the exact role of increased ATX expression in hepatocellular carcinoma is unclear. Recent evidence, however, suggests that LPA (due to increased ATX) may accelerate tumor progression via peritumoral fibroblasts [55]. Increased blood LPA was found in these patients with metastasis vs those without metastasis. Conflicting results on LPA in the blood of patients with hepatocellular carcinoma has also been reported [56]. This study found no correlation between plasma LPA and tumor burden in hepatocellular carcinoma. Clearly, the role of ATX and LPA in hepatocellular carcinoma requires further examination.