脂肪变性与乙型肝炎持续ALT增加有关

StephenW

Steatosis linked to persistent ALT increase in hepatitis B
Publish date: June 12, 2017
By:
    Amy Karon

FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY



About one in five patients with chronic hepatitis B virus (HBV) infection had persistently elevated alanine aminotransferase (ALT) levels despite long-term treatment with tenofovir disoproxil fumarate, according to data from two phase III trials reported in the July issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.01.032).

“Both host and viral factors, particularly hepatic steatosis and hepatitis B e antigen [HBeAg] seropositivity, are important contributors to this phenomenon,” Ira M. Jacobson, MD, of Mount Sinai Beth Israel Medical Center, New York, wrote with his associates. “Although serum ALT may indicate significant liver injury, this association is inconsistent, suggesting that relying on serum ALT alone is not sufficient to gauge either the extent of liver injury or the impact of antiviral therapy.”

Long-term treatment with newer antivirals such as tenofovir disoproxil fumarate (TDF) achieves complete viral suppression and improves liver histology in most cases of HBV infection. Transaminase levels are used to track long-term clinical response but sometimes remain elevated in the face of complete virologic response and regression of fibrosis. To explore predictors of this outcome, the researchers analyzed data from 471 chronic HBV patients receiving TDF 300 mg once daily for 5 years as part of two ongoing phase III trials (NCT00117676 and NCT00116805). At baseline, about 25% of patients were cirrhotic (Ishak fibrosis score greater than or equal to 5) and none had decompensated cirrhosis. A central laboratory analyzed ALT levels, which were up to 10 times the upper limit of normal in both HBeAg-positive and -negative patients and were at least twice the upper limit of normal in all HBeAg-positive patients.

After 5 years of TDF, ALT levels remained elevated in 87 (18%) of patients. Patients with at least 5% (grade 1) steatosis at baseline were significantly more likely to have persistent ALT elevation than were those with less or no steatosis (odds ratio, 2.2; 95% confidence interval, 1.03-4.9; P = .04). At least grade 1 steatosis at year 5 also was associated with persistent ALT elevation (OR, 3.4; 95% CI, 1.6-7.4; P =.002). Other significant correlates included HBeAg seropositivity (OR, 3.3; 95% CI, 1.7-6.6; P less than .001) and age 40 years or younger (OR, 2.1; 95% CI, 1.01-4.3; P = .046). Strikingly, half of HBeAg-positive patients with steatosis at baseline had elevated ALT at year 5, said the investigators.

Because many patients whose ALT values fall within commercial laboratory reference ranges have chronic active necroinflammation or fibrogenesis, the researchers performed a sensitivity analysis of patients who achieved a stricter definition of ALT normalization of no more than 30 U/L for men and 19 U/L for women that has been previously recommended (Ann Intern Med. 2002;137:1-10). In this analysis, 47% of patients had persistently elevated ALT despite effective virologic suppression, and the only significant predictor of persistent ALT elevation was grade 1 or more steatosis at year 5 (OR, 6.2; 95% CI, 2.3-16.4; P less than .001). Younger age and HBeAg positivity plus age were no longer significant.

Hepatic steatosis is common overall and in chronic HBV infection and often leads to increased serum transaminases, the researchers noted. Although past work has linked a PNPLA3 single nucleotide polymorphism to obesity, metabolic syndrome, and hepatic steatosis, the presence of this single nucleotide polymorphism was not significant in their study, possibly because many patients lacked genotype data, they added. “Larger longitudinal studies are warranted to further explore this factor and its potential effect on the biochemical response to antiviral treatment in [chronic HBV] patients,” they concluded.

Gilead Sciences sponsored the study. Dr. Jacobson disclosed consultancy, honoraria, and research ties to Gilead and several other pharmaceutical companies.

StephenW

脂肪变性与乙型肝炎持续ALT增加有关
发布日期：2017年6月12日
通过：
    艾米·卡伦

从临床胃肠病学和肝脏病学



根据七月号临床胃肠病学杂志报道的两项III期临床试验数据，大约有五分之一的慢性乙型肝炎病毒（HBV）感染患者仍然持续升高丙氨酸氨基转移酶（ALT）水平，尽管长期服用替诺福韦地索普利富马酸，肝病学（2017. doi：10.1016 / j.cgh.2017.01.032）。

纽约西奈贝斯以色列医学中心的艾拉·雅各布森博士和他的同事写道：“宿主和病毒因子，特别是肝脂肪变性和乙型肝炎e抗原[HBeAg]血清阳性是这一现象的重要贡献者。 。 “虽然血清ALT可能表明明显的肝损伤，但这种联系是不一致的，这表明依靠血清ALT单独不足以衡量肝损伤的程度或抗病毒治疗的影响。

使用较新的抗病毒药物如替诺福韦地索普肟富马酸盐（TDF）进行长期治疗可以完全病毒抑制，并改善大多数HBV感染病例的肝脏组织学。转氨酶水平用于跟踪长期临床反应，但有时在完全病毒学应答和纤维化消退的情况下保持升高。为了探索这一结果的预测因素，研究人员分析了471例慢性HBV患者的数据，其中接受TDF 300 mg，每日一次，持续5年，作为两项正在进行的III期试验（NCT00117676和NCT00116805）的一部分。在基线时，约25％的患者是肝硬化（Ishak纤维化评分大于或等于5），没有失代偿性肝硬化。一个中心实验室分析了ALT水平，高达HBeAg阳性和阴性患者正常上限的10倍，至少是所有HBeAg阳性患者正常上限的两倍。

在TDF 5年后，87例（18％）患者ALT水平升高。基线时至少5％（1级）脂肪变性的患者与脂肪肝较少或无脂肪变性的患者相比，具有持续性ALT升高的可能性更高（优势比为2.2; 95％置信区间，1.03-4.9; P = 0.04） 。在第5年，至少1级脂肪变性也与持续ALT升高（OR，3.4; 95％CI，1.6-7.4; P = .002）有关。其他显着相关性包括HBeAg血清阳性（OR，3.3; 95％CI，1.7-6.6; P小于0.001）和40岁以下（OR，2.1; 95％CI，1.01-4.3; P = 0.046）。研究人员指出，一半HBeAg阳性的基线脂肪变性患者在第5年时ALT升高。

由于许多ALT值落入商业实验室参考范围的患者都有慢性活动性坏死性炎症或纤维发生，研究人员进行了对男性ALT正常化不超过30 U / L更严格定义的患者的敏感性分析，以及19 U / L对于以前推荐的妇女（Ann Intern Med.2002; 137：1-10）。在这项分析中，尽管有效的病毒学抑制，47％的患者仍然持续升高ALT，而持续性ALT升高的唯一显着预测指标为5年级别的1级或更多脂肪变性（OR，6.2; 95％CI，2.3-16.4; P比.001）。年龄较小，HBeAg阳性加年龄不再显着。

研究人员指出，肝脏脂肪变性在全身和慢性HBV感染中是常见的，并且通常导致血清转氨酶升高。虽然过去的工作已经将PNPLA3单核苷酸多态性与肥胖，代谢综合征和肝脂肪变性相关联，但是这种单核苷酸多态性在其研究中的存在并不显着，可能是因为许多患者缺乏基因型数据。他们总结说：“需要进行更大的纵向研究，以进一步探索这一因素及其对慢性HBV患者抗病毒治疗生化反应的潜在影响。

吉利德科学赞助了这项研究。 Jacobson博士透露了与吉利德等几家制药公司的咨询，酬金和研究关系。