《临床胃肠病学与肝病学》杂志4月刊发表的一项研究显示，血清α-甲胎蛋白(AFP)水平随时间改变与丙型肝炎患者发生肝细胞癌(HCC)之间存在关联(doi:10.1016/j.cgh.2012.11.029)。

　　主要研究者、密歇根大学的Elliot Lee博士指出：“假如能在今后的研究中得到证实，那么我们的发现将有助于开发针对丙型肝炎患者的个体化风险评估工具。”

　　在这项被称为“首个显示出AFP随时间改变的模式与发生HCC独立相关的大规模研究”中，Lee博士及其同事对参与HALT-C试验的患者进行了观察。在这项试验中，对此前抗病毒治疗无应答的丙型肝炎患者被随机分组，接受Peg干扰素或安慰剂维持治疗。根据试验方案，患者在头3.5年内每3个月接受1次筛查，此后在自愿的基础上每6个月筛查1次，筛查方法是检测血清AFP水平。

　　研究者将发生HCC的患者与随访时间相同、未发生HCC的对照者按1:3比例配对，“以排除随访时间较长者的HCC累计发生几率更大并且AFP检测值更多所造成的偏倚”。967例丙型肝炎患者中有82例在研究期间发生HCC，AFP检测的中位次数为18次(范围：5~22次)。随后，研究者分析了发生HCC与3种AFP变化模式之间的关联。

　　研究者首先评估了AFP上升率，定义为[患者在研究结束前或发生HCC前(以先到达者为准)最后1次AFP检测值+AFP基线值(入组时检测)]/90天。仅校正基线危险因素的简单logistic回归分析结果显示，AFP上升率与发生HCC的比值比(OR)为1.178有关(P＜0.001)，受试者工作特征(AUROC)曲线下面积为0.69。

　　然后，研究者计算了AFP标准差，定义为每例患者的所有AFP检测值的标准差。结果在同样的简单logistic回归分析中，AFP标准差每增加1个单位，发生HCC的OR值为1.026(P＜0.001)，AUROC曲线下面积为0.76。

　　第三步，Lee博士等人观察了最近的AFP检测值。结果显示，发生HCC的OR值为1.012(P＜0.001)，AUROC曲线下面积也是0.76。

　　最后，研究者合并分析了标准差和AFP上升率，并结合基线年龄、血小板计数和吸烟史，建立了一个“历史”模型，其AUROC为0.81，从而成为了更好的HCC预测因素。

　　研究者称：“AFP上升率与发生HCC之间的关系一目了然，但是应该如何解释标准差与HCC的关联呢？其生物学基础尚不明确，我们猜测AFP波动可能反映了肝内损伤和再生的循环，而参与再生的多种生长因子可刺激肝癌发生。”

　　研究者承认该研究存在一些局限性：“从临床实践的角度看，这些指标只有在患者接受至少2年随访的情况下才有用，因为需要较长时间才能显示出变化模式。此外，该研究仅纳入丙型肝炎患者，而我们并不清楚上述相关性是否也存在于其他慢性肝病中。”

　　研究者报告称无相关利益冲突，披露从国家科学基金会研究生奖学金获得了拨款支持。

　　By: DENISE NAPOLI, Clinical Endocrinology News Digital Network

　　Changes in serum alpha-fetoprotein levels over time correlated with the development of hepatocellular carcinoma in hepatitis C patients, wrote Dr. Elliot Lee and his colleagues in the April 1 issue of Clinical Gastroenterology and Hepatology News.

　　"If confirmed in future studies, these findings could be used to develop individualized risk assessments for clinical use, which could then influence the frequency and type of further testing" in this population, added the researchers (doi:10.1016/j.cgh.2012.11.029).

　　In what he called "the first large study to demonstrate that patterns of AFP [alpha-fetoprotein] over time are independently associated with HCC [hepatocellular carcinoma] development," Dr. Lee of the University of Michigan, Ann Arbor, looked at patients enrolled in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial, in which hepatitis C patients who were nonresponders to prior antiviral therapy were randomized to receive maintenance pegylated interferon or placebo.

　　According to the trial protocol, patients were screened every 3 months for the first 3.5 years, then every 6 months thereafter on a voluntary basis, with levels of serum alpha-fetoprotein measured at each visit.

　　Patients who developed hepatocellular carcinoma were matched to controls without HCC in a 1:3 ratio according to the length of follow-up "in order to exclude bias caused by subjects with longer follow-up time having higher cumulative probability of HCC development, as well as more AFP values available," wrote the authors.

　　Overall, among 967 subjects with hepatitis C, 82 developed HCC during the study period, with a median of 18 (range, 5-22) AFP tests performed.

　　Dr. Lee then analyzed the association between the development of HCC and three AFP patterns.

　　First, the researchers assessed the rate of rise, defined as the patient’s final alpha-fetoprotein level (before study conclusion or HCC development, whichever came first) minus the AFP baseline value (on study entry), all over the follow-up duration divided by 90 days.

　　He found that this metric was associated with an odds ratio for developing HCC of 1.178 (P less than .001) in a simple logistic regression analysis that accounted for baseline risk factors only, with an area under the receiver-operating characteristic (AUROC) of 0.69.

　　Next, Dr. Lee calculated the standard deviation of AFP, defined as the standard deviation of all AFP values recorded within each patient.

　　In the same simple logistic regression, the standard deviation calculation was associated with an odds ratio of 1.026 for HCC per unit increase in standard deviation (P less than .001) and an AUROC of 0.76.

　　Third, Dr. Lee looked at the most recent AFP value on record. In this case, the odds ratio for developing HCC was 1.012 (also with P less than .001) and an AUROC of 0.76.

　　Finally, the researchers incorporated both standard deviation and rate of rise of AFP along with baseline age, platelet count, and smoking history to create a "history" model, which had an AUROC of 0.81 – an even better predictor than the models that looked only at one of those factors.

　　In an attempt to explain their findings, the researchers wrote, "it is intuitively evident why the rate of rise of AFP might be associated with risk of HCC development, but what might explain the association with standard deviation?"

　　They added, "The biologic basis is unknown, but we theorize that fluctuations in AFP may reflect cycles of damage and regeneration within the liver, and that growth factors involved in regeneration could stimulate hepatocarcinogenesis."

　　The authors acknowledged that the study had several limitations. "From a practical perspective, these metrics will only be useful once a patient has been followed for at least 2 years in order for the patterns to emerge," they wrote.

　　Additionally, "this study included only patients with hepatitis C; it is unknown whether these associations would be present among patients with other chronic liver diseases."

　　The authors said they had no relevant financial disclosures. They disclosed grant support from the National Science Foundation Graduate Research Fellowship.