Liver enzyme a marker of disease progression in primary biliary cholangitis

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.