AASLD2018[265]ALT水平与肝细胞癌的风险 白种人慢性癌中的癌（HC

StephenW

265
ALT Levels and Risk of Hepatocellular
Carcinoma (HCC) in Caucasian Chronic
Hepatitis B (CHB) Patients Under Long-Term
Therapy with Entecavir (ETV) or Tenofovir
Disoproxil Fumarate (TDF)
George V. Papatheodoridis1, George N. Dalekos2, Cihan
Yurdaydin3, Vana Sypsa4, Florian van Bömmel5, Maria
Buti6, Jose Luis Calleja7, Heng Chi8, Ioannis Goulis9,
Spilios Manolakopoulos10,11, Alessandro Loglio12, Spyros
Siakavellas11, Onur Keskin13, Rhea Veelken14, Marta Lopez-
Gomez15, Bettina E. Hansen8,16, Savvoula Savvidou17,
Anastasia Kourikou18, Ioannis Vlachogiannakos1, Kostas
Galanis19, Ramazan Idilman3, Rafael Esteban20, Harry L.
A. Janssen21, Thomas Berg22 and Pietro Lampertico23,
(1)Department of Gastroenterology, Medical School of
National & Kapodistrian University of Athens, Laiko General
Hospital, Athens, (2)Department of Medicine and Research
Laboratory of Internal Medicine, University of Thessaly,
(3)Gastroenterology, Ankara University, (4)Department of
Hygiene, Epidemiology & Medical Statistics, Medical School
of National and Kapodistrian University of Athens, (5)Clinic
for Gastroenterology and Rheumatology, University Clinic
Leipzig, (6)Hospital Universitari Vall d’Hebron, Barcelona,
Spain, (7)Hospital Universitario Puerta De Hierro, (8)
Department of Gastroenterology & Hepatology, Erasmus
MC, University Medical Center, (9)4th Department of
Internal Medicine, Hippokratio Hospital, Aristotle University
of Thessaloniki, (10)2nd Academic Department of Internal
Medicine, Medical School of National & Kapodistrian University
of Athens, Hippokratio General Hospital of Athens, (11)
Department of Gastroenterology, Medical School of National
and Kapodistrian University of Athens, Laiko General Hospital
of Athens, (12)Division of Gastroenterology and Hepatology,
Fondazione Irccs Cà Granda Ospedale Maggiore Policlinico,
Università Degli Studi Di Milano, Italy, (13)Department of
Gastroenterology, University of Ankara Medical School
(14)Section of Hepatology, Clinic for Gastroenterology and
Rheumatology, University Clinic Leipzig, (15)Hospital U
Puerta De Hierro, Idiphim Ciberehd, (16)Liver Clinic, Toronto
Western & General Hospital, University Health Network,
(17)4th Department of Internal Medicine, Αristotle University
of Thessaloniki Medical School, (18)2nd Department of
Internal Medicine, Medical School of National & Kapodistrian
University of Athens, Hippokratio General Hospital of Athens,
(19)Department of Internal Medicine, Thessalia University
Medical School, (20)Department of Internal Medicine/Liver
Unit, Vall D’hebron University Hospital, (21)Toronto Centre for
Liver Disease, University Health Network, (22)Department of
Gastroenterology and Rheumatology, Section of Hepatology,
University Hospital Leipzig, (23)CRC “AM e a Migliavacca”
Center for Liver Disease, Division of Gastrotnerology and
Hepatology, Fondazione Irccs Cà Granda Ospedale Maggiore
Policlinico, Università Degli Studi Di Milano
Background: Recent reports have suggested that ontherapy
ALT activity may be associated with the probability
of HCC in CHB patients who receive long-term oral antiviral
therapy. We evaluated whether ALT levels affect the incidence
of HCC in Caucasian CHB patients treated with long-term
ETV/TDF therapy in the multicenter, ongoing PAGE-B cohort
study. Methods: The PAGE-B cohort includes 1951 adult
Caucasians with CHB with or without compensated cirrhosis
(mean age 53±14 years, males:71%, HBeAg-positive:18%,
compensated cirrhosis:27%). Mean follow-up has been
6.9±2.8 (median:7.3) years from ETV/TDF onset. The
following upper normal limits (ULN) of ALT were considered:
30/19 IU/L for males/females (AASLD1-ULN), 35/25 IU/L for
males/females (AASLD2-ULN) and 40 IU/L for all patients
(EASL-ULN). The cumulative incidence rates of HCC derived
from Kaplan-Meier estimates. Results: HCC has been
diagnosed in 103 cases within the first 5 years and another
33 cases after year 5 (until year 13). ALT was >AASLD1-ULN,
>AASLD2-ULN and >EASL-ULN in 66.4%, 61.3% and 51.7%
of 1843 patients at baseline, 45.1%, 29.7% and 15.7% of 1688
patients at year 1 and 33.9%, 18.6% and 9.3% of 1341 patients
at year 5, respectively. In univariable analyses, elevated ALT
at baseline by any definition and ALT >EASL-ULN at year
1 were associated with subsequent HCC development, but
there was no association with ALT >AASLD1/2-ULN at year 1
or elevated ALT by any definition at year 5 or with ALT levels at
any time point. After adjustment for age, sex, platelet counts
and presence of cirrhosis, only ALT >EASL-ULN at year 1
was found to have an independent association with HCC
development after year 1 (HR:1.9, 95% CI:1.2-3.1; P=0.010).
ALT >EASL-ULN at year 1 was independently associated with
HCC development in patients with baseline cirrhosis (adjusted
HR:2.9, 95% CI:1.3-3.9; P=0.003), but not in non-cirrhotics
(P=0.913). In 465 cirrhotics, the 3-, 5-, 10-year HCC incidence
rates were 4%, 10%, 17% in 379 cases with ALT ≤EASL-ULN
and 10%, 17%, 22% in 86 cases with ALT >EASL-ULN at year
1. Conclusion: In ETV/TDF treated Caucasian CHB patients
a) maintenance of elevated ALT at 1 year of therapy increases
the subsequent HCC risk, particularly in patients with cirrhosis
at baseline; b) the ULN of ALT recommended by EASL (40
IU/L), but not those by AASLD, at year 1 of therapy appears
to offer independent clinically relevant predictability for HCC
development.

StephenW

265
ALT水平与肝细胞癌的风险
白种人慢性癌中的癌（HCC）
乙型肝炎（CHB）患者长期服用
恩替卡韦（ETV）或替诺福韦治疗
Disoproxil Fumarate（TDF）
George V. Papatheodoridis1，George N. Dalekos2，Cihan
Yurdaydin3，Vana Sypsa4，FlorianvanBömmel5，Maria
Buti6，Jose Luis Calleja7，Heng Chi8，Ioannis Goulis9，
Spilios Manolakopoulos10,11，Alessandro Loglio12，Spyros
Siakavellas11，Onur Keskin13，Rhea Veelken14，Marta Lopez-
Gomez15，Bettina E. Hansen8,16，Savvoula Savvidou17，
Anastasia Kourikou18，Ioannis Vlachogiannakos1，Kostas
Galanis19，Ramazan Idilman3，Rafael Esteban20，Harry L.
A. Janssen21，Thomas Berg22和Pietro Lampertico23，
（1）中华医学院消化内科
国家和Kapodistrian大学雅典，Laiko将军
医院，雅典，（2）医学和研究部
塞萨利大学内科实验室，
（3）安卡拉大学消化内科，（4）
卫生学，流行病学和医学统计学，医学院
雅典国立和卡波迪斯特拉大学，（5）诊所
大学诊所的胃肠病学和风湿病学
莱比锡，（6）巴塞罗那瓦尔德希伯伦大学医院，
西班牙，（7）Puerta De Hierro大学医院，（8）
伊拉斯谟的消化内科和肝病学系
MC，大学医学中心，（9）第四系
内科，亚里士多德大学Hippokratio医院
塞萨洛尼基，（10）内部第二学术部
医学，国立和Kapodistrian大学医学院
雅典，Hippokratio雅典总医院，（11）
国立医学院消化内科
和莱科总医院的雅典卡波迪斯特拉大学
雅典，（12）胃肠病学和肝病学，
FondazioneIrccsCàGrandaOspedale Maggiore Policlinico，
意大利米兰德意大利米兰大学（13）
安卡拉大学医学院消化内科
（14）肝病学，消化内科和门诊部
莱比锡大学诊所风湿病学，（15）U医院
Puerta De Hierro，Idiphim Ciberehd，（16）多伦多肝脏诊所
西部和总医院，大学健康网络，
（17）亚里士多德大学第四内科
塞萨洛尼基医学院，（18）第二系
内科，国立和Kapodistrian医学院
雅典大学，雅典Hippokratio综合医院，
（19）Thessalia大学内科
医学院，（20）内科/肝脏科
单位，Vall D'hebron大学医院，（21）多伦多中心
肝病，大学卫生网，（22）系
胃肠病学和风湿病学，肝病学科，
莱比锡大学医院，（23）CRC“AM e a Migliavacca”
肝病中心，胃肠病学和
Hepatology，FondazioneIrccsCàGrandaOspedale Maggiore
Policlinico，UniversitàDegliStudi Di Milano
背景：最近的报道提出了治疗方法
ALT活动可能与概率相关
HCC在接受长期口服抗病毒治疗的CHB患者中的应用
治疗。我们评估了ALT水平是否会影响发病率
高血压CHB患者长期接受HCC治疗的意义
多中心，正在进行的PAGE-B队列中的ETV / TDF治疗
研究。方法：PAGE-B队列包括1951年成人
伴有或不伴有代偿性肝硬化的CHB高加索人
（平均年龄53±14岁，男性：71％，HBeAg阳性：18％，
代偿性肝硬化：27％）。平均随访一直如此
ETV / TDF发病后6.9±2.8（中位数：7.3）年。该
遵循ALT的正常上限（ULN）：
男性/女性30/19 IU / L（AASLD1-ULN），35/25 IU / L
男性/女性（AASLD2-ULN）和所有患者的40 IU / L.
（EASL-ULN）。 HCC的累积发病率来源
来自Kaplan-Meier的估计。结果：HCC已经
在前5年内诊断出103例，另一例
第5年后33例（至第13年）。 ALT> AASLD1-ULN，
> AASLD2-ULN和> EASL-ULN分别为66.4％，61.3％和51.7％
基线时1843名患者，1688名患者中45.1％，29.7％和15.7％
第1年的患者和1341例患者的33.9％，18.6％和9.3％
分别在第5年。在单变量分析中，ALT升高
在任何定义的基线和年度的ALT> EASL-ULN
1与随后的HCC发展有关，但是
在第1年与ALT> AASLD1 / 2-ULN无关
或者在第5年通过任何定义或ALT水平升高ALT
任何时间点。调整年龄，性别，血小板计数
和肝硬化的存在，在第1年只有ALT> EASL-ULN
被发现与HCC有独立的关联
第1年后的发展（HR：1.9,95％CI：1.2-3.1; P = 0.010）。
ALT>第1年的EASL-ULN与其独立相关
HCC在基线肝硬化患者中的发展（调整后
HR：2.9,95％CI：1.3-3.9; P = 0.003），但不是非肝硬化
（P =0.913）。 在465例肝硬化患者中，3年，5年，10年的HCC发病率
ALT≤EASL-ULN 379例患者的发生率分别为4％，10％，17％
86例ALT> EASL-ULN患者中10％，17％，22％
结论：在ETV / TDF治疗的白种人CHB患者中
a）治疗1年时ALT升高的维持率增加
随后的HCC风险，尤其是肝硬化患者
在基线; b）EASL推荐的ALT ULN（40
IU / L），但不是AASLD的那些，在治疗的第1年出现
为HCC提供独立的临床相关可预测性
发展。