Chemokines CCL4, CCL5 may be associated with liver cancer in cirrhotic patients

Last Updated: 2015-08-20

By Joan Stephenson PhD

NEW YORK (Reuters Health) - High serum levels of the inflammatory chemokines CCL4 and CCL5 in patients with cirrhosis may be an indication of hepatocellular cancer (HCC), report researchers from Germany.

The researchers explained in their August 13 report online in the British Journal of Cancer that they sought to evaluate the value of cell death markers, growth factors, and inflammatory cytokines in serum for early detection of HCC in patients with cirrhosis.

American Association for the Study of Liver Diseases (AASLD) guidelines currently advise that surveillance for HCC "has to be based on ultrasound examination." Clinicians also sometimes use alpha-fetoprotein (AFP) as a screening test, which the AASLD says "lacks adequate sensitivity and specificity for effective surveillance."

The researchers collected serum samples from 139 patients with cirrhosis who underwent liver transplantation between January 2008 and April 2011, as well as from 39 healthy controls. HCC diagnosis was confirmed by pathology reports in 61 of the patients.

Of the 139 patients with cirrhosis, 40 had liver disease resulting from chronic viral hepatitis B and/or hepatitis C infection, 41 from alcohol abuse, and 58 from congenital or autoimmune diseases such as cryptogenic cirrhosis, biliary disease, metabolic liver disease, autoimmune hepatitis, and amyloidosis.

"One of the interesting findings was the similar immune responses in patients with different original liver diseases," senior author Dr. Arianeb Mehrabi, of the University of Heidelberg, told Reuters Health by email. "On the other hand, the immune responses in patients with HCC were significantly lower and inflammatory and necrotic markers were higher than in healthy individuals."

Mean serum levels of CCL4 were 170 pg/mL in the patients with HCC compared to 101 pg/mL in patients without HCC (p<0.0001). CCL5 mean serum levels were 3.6 ng/mL in patients with HCC compared to 2.0 ng/mL in patients without HCC (p<0.0001).

Sensitivity, specificity, positive predictive value, and negative predictive value were 66%, 74%, 67%, and 73% for CCL4, 71%, 68%, 62%, and 74% for CCL5, and 47%, 89%, 79%, and 64% for AFP, respectively.

"It can be postulated that high serum levels of CCL4 and CCL5 indicate the presence of HCC in patients with liver cirrhosis and along with other indicators can help in early detection of HCC," the researchers wrote.

"From the results of our study, we can speculate that CCL4 and CCL5 might be diagnostic markers," Dr. Mehrabi said, explaining that AFP could not diagnose HCC in more than half of the patients, while CCL4 and CCL5 were able to do so in two-thirds or more of cases.

The researchers proposed using CCL4 and CCL5 as confirmatory tests when imaging suggests the presence of HCC, but AFP level does not.

"We recommend a liver biopsy for patients with positive imaging and negative AFP, when CCL5 and/or CCL4 are positive," they wrote.

However, Dr. Mehrabi said, "Future large prospective trials may be needed to investigate the associations between these chemokines and HCC."

In a contrasting assessment of the study's findings, Dr. Myron Schwartz, clinical director of the liver cancer program at Mount Sinai Hospital in New York, told Reuters Health by email that CCL4 and CCL5 "are no more useful as indicators of the presence of HCC than AFP, which has been discarded as a screening test." CCL4 and CCL5 may be useful in stratifying patients into high- and low-risk groups for the purpose of screening/surveillance and for inclusion in clinical trials for HCC prevention, he said.

"The authors' suggestion that the markers be used to decide how to respond to imaging findings of a liver nodule is, in my view, flawed; imaging for HCC is considered the gold standard and is far more accurate than either AFP or the CCL4-5 tests in determining the nature of liver nodules," Dr. Schwartz said.

The authors reported no conflicts of interest.

SOURCE: http://bit.ly/1LjYZg2

Br J Cancer 2015