CGHE合成：COVID-19与肝病

StephenW

CGHE Synthesis: COVID-19 and Liver Disease
Coronavirus
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CGHE Synthesis- COVID-19 and Liver Disease-vf.pdf
01 Apr 2020
Dr. John W Ward, The Coalition for Global Hepatitis Elimination

In December 2019, a novel coronavirus was identified as the cause of severe pneumonia, respiratory failure and mortality in Wuhan China (1). The virus was found to have 82% genetic homology with SARS-CoV, a virus identified in 2002 as the cause of Severe Acute Respiratory Syndrome and 50% homology with MERS-CoV identified in 2012 as the cause of Middle Eastern Respiratory Syndrome. In February 2020, WHO named the virus SARS-CoV-2 and the related disease Coronavirus Disease 2019 (COVID-19) [*]. Epidemiologic studies revealed SARS- CoV-2 readily transmitted through exposures to respiratory droplets of infected persons (2,3). SARS-CoV-2 spread rapidly in China and progressively and quickly to other countries globally. On March 11, 2020, WHO declared COVID-19 a pandemic. As of March 28, 2020, a total of 571,678 confirmed COVID-19 cases and 26,494 deaths have been reported worldwide (4). In the absence of a vaccine or licensed therapies, countries are implementing public health measures to prevent transmission and marshalling clinical care capacity for those with severe COVID-19 disease.

The emergence of SARS-CoV-2 as a major pathogen raises the question of the interrelationship between this infection and liver disease (13,14).  Reports from China identified older age, immunocompromised states, and underlying health conditions as risks for severe COVID-19 disease (2,3,5-11). Chronic liver disease (CLD) is considered an underlying disease placing COVID-19  patients at risk (4).  In case series published to date, only a small proportion (3-11%) of COVID-19 patients had CLD at diagnosis (4, 8,10).  A recent CDC study found persons with underlying health conditions were more likely to be hospitalized (27-%-30%) and to require intensive care (13%-14%) than others with COVD-19, (7%–8%) and (2%), respectively. Diabetes mellitus (11%), chronic lung disease (9%), and cardiovascular disease (9%) were the most frequently reported conditions.   CLD was reported for less than 1% of the study population.  Additional case series can add experience to the management of COVID-19 patients with CLD.  

Liver injury is relatively common during the course of COVID-19 disease.  Available data suggest ~15% - 45% of patients with COVID-19 have some evidence of liver injury during the course of disease. Alanine aminotransferase (ALT) levels are typically mildly elevated and often accompanied by elevations of enzymes on other liver function tests (LFTs) including alkaline phosphatase, aspartate aminotransferase (AST), and lactate dehydrogenase. Some studies find increases in LFTs (ALT, AST) correlate with severity of disease requiring longer hospitalizations and intensive care (5, 8, 10). A study of the clinical course of deceased COVID-19 patients found elevations in ALT and AST associated with shorter survival after hospitalization; however, liver failure was not listed as a cause of death for any patient (9). A study of 52 COVID-19 patients requiring intensive care found 15 (29%) with liver dysfunction; there was no difference in hepatitis impairment among survivors versus non-survivors (11). In the United States, the first patient reported with COVID-19 had progressive increases in ALT exceeding four times the upper limit of normal (ULN) by the 9th hospital day. However, by that time, the patient’s clinical course was improving and was soon discharged (12). Evidence regarding SARS-CoV-2/ HBV and SARS-CoV-2/HCV coinfections is needed.

The observations in previous years regarding liver impairment among persons with SARS is instructive (12-16). Elevations in LFTs are common (22%-56%). Increases in ALT tend to be modest with a median ALT levels on admission and during hospitalization of 0.55 and 1.53 times the ULN, respectively (15). For most patients, LFT elevations are transient; in one study of SARS patients with abnormal ALT, ~70% had normal values by hospital discharge.  Large increases (>5 X ULN) in ALT are associated with poor outcomes from SARS.  However, in this series, HBV co-infection was not associated with high peak ALT level, ICU admission, or mortality. Another study of SARS patients revealed chronic HBV infection as a significant risk for acute respiratory distress and intensive care; however liver damage was not greater for these severely ill patients (17).

The liver damage observed among patients with COVID-19 is probably related to several factors. Viral infection of liver cells could play a role.  SARS-CoV has been isolated from liver tissue although not in large quantities; isolation of SARS- CoV-2 has yet to be reported. For cell entry, both SARS-CoV and SARS-CoV-2 bind to the receptor angiotensin converting enzyme 2 (ACE2); ACE2 is found on hepatocytes and in greater quantities cholangiocytes providing a site for direct viral binding and impairment of hepatitis function (18). Interestingly, cholestatic liver disease is not a common feature of COVID-19 disease (13). Other etiologies can have a role. Certain medications cause hepatotoxicity.  One study found the elevation in LFTs in COVID-19 patients significantly associated with administration of lopinavir/ritonavir (5). Postmortem biopsies of patients with COVID‐19 show findings- moderate microvascular steatosis, mild lobular and portal activity- indicative of injuries from either SARS‐CoV‐2 infection or medications (7,19). Clinical trials can look for hepatotoxicity among promising therapeutic agents for COVID-19 (20).  Liver damage can also result from immune mediated inflammation. (9,10). This is observed for other viral infections. Elevation in ALT can be accompanied by increases in LDH and creatinine kinase suggesting extra-hepatic origins of these enzyme elevations.

In summary, SARS-CoV-2 infection is the cause of an ongoing and growing pandemic. The understanding of the relationship between this infection, COVID-19 disease and liver disease continues to evolve. The cause of liver injury among patients with COVID-19 appears multifactorial. The liver injury is often mild with but can be severe for patients with advanced COVID-19 disease. There is scant evidence regarding SARS-CoV-2 infection among persons with current HBV or HCV infection. Based on current evidence, persons with viral hepatitis and chronic liver disease should continue to be regarded as populations at increased risk for co-morbid complications during the course of COVID-19 disease.

CGHE will update this resource as data become available from trusted sources and local investigators (21-24). CGHE encourages partners to submit reports for inclusion in the series.  

StephenW

CGHE合成：COVID-19与肝病
新冠病毒
文件资料
pdf格式
686.8 KB
CGHE合成-COVID-19和肝病-vf.pdf
2020年4月1日
John W Ward博士，全球消除肝炎联盟

2019年12月，在中国武汉发现了一种新型冠状病毒，该病毒是导致严重肺炎，呼吸衰竭和死亡的原因（1）。该病毒与SARS-CoV具有82％的遗传同源性，SARS-CoV在2002年被鉴定为严重急性呼吸系统综合症的病因，而与MERS-CoV在2012年被鉴定为中东呼吸系统综合症的病因具有50％的同源性。 2020年2月，WHO将病毒命名为SARS-CoV-2病毒和相关疾病冠状病毒病2019（COVID-19）[*]。流行病学研究表明，SARS-CoV-2容易通过暴露于感染者的呼吸道飞沫而传播（2,3）。 SARS-CoV-2在中国迅速传播，并逐步向全球其他国家迅速传播。 2020年3月11日，世卫组织宣布COVID-19大流行。截至2020年3月28日，全世界共报告了571,678例确诊的COVID-19病例和26,494例死亡（4）。在没有疫苗或未获许可的疗法的情况下，各国正在实施公共卫生措施，以防止严重COVID-19疾病患者的传播和集结临床护理能力。

SARS-CoV-2作为主要病原体的出现提出了这种感染与肝病之间相互关系的问题（13,14）。中国的报告指出，老年人，免疫功能低下的国家和潜在的健康状况是严重COVID-19疾病的风险（2,3,5-11）。慢性肝病（CLD）被认为是使COVID-19患者处于危险之中的潜在疾病（4）。在迄今为止发表的病例系列中，只有一小部分（3-11％）的COVID-19患者在诊断时患有CLD（4、8、10）。 CDC最近的一项研究发现，与COVD-19的其他人（7％–8％）相比，具有潜在健康状况的人更有可能住院（27 %%-30％）和需要重症监护（13％-14％）和（2％）。糖尿病（11％），慢性肺部疾病（9％）和心血管疾病（9％）是最常报告的疾病。据报道，CLD的研究人群不到1％。其他案例系列可以为处理COVID-19的CLD患者增加经验。

在COVID-19疾病过程中，肝损伤相对常见。现有数据表明，约15％-45％的COVID-19患者在病程中有肝损伤的证据。丙氨酸氨基转移酶（ALT）的水平通常会轻度升高，并经常伴随其他肝功能检查（LFT）酶的升高，包括碱性磷酸酶，天冬氨酸氨基转移酶（AST）和乳酸脱氢酶。一些研究发现，LFT（ALT，AST）的升高与疾病的严重程度相关，需要住院和重症监护时间更长（5、8、10）。一项针对已故COVID-19患者的临床病程的研究发现，ALT和AST升高与住院后的较短生存期相关；但是，肝衰竭并未被列为导致任何患者死亡的原因（9）。对52位需要重症监护的COVID-19患者进行的研究发现，有15位（29％）患有肝功能异常；幸存者和非幸存者在肝炎损害方面没有差异（11）。在美国，第一个报告有COVID-19的患者到第9天住院时，ALT的进行性增加超过正常上限（ULN）的四倍。但是，到那时，患者的临床病情正在改善，很快就康复了（12）。需要有关SARS-CoV-2 / HBV和SARS-CoV-2 / HCV合并感染的证据。

过去几年中有关SARS患者肝功能损害的观察具有指导意义（12-16）。 LFT的升高很常见（22％-56％）。入院时和住院期间ALT的中位数分别为ULN的0.55和1.53倍，ALT的升高趋于适度（15）。对于大多数患者来说，LFT升高是短暂的。在一项ALT异常的SARS患者的研究中，出院时约有70％的患者具有正常值。 ALT的大幅增加（> 5 X ULN）与SARS的不良预后相关。但是，在本系列中，HBV合并感染与高峰值ALT水平，ICU入院率或死亡率无关。另一项关于SARS患者的研究表明，慢性HBV感染是急性呼吸窘迫和重症监护的重大风险。然而，对于这些重症患者来说，肝损害并不严重（17）。
在COVID-19患者中观察到的肝损害可能与多种因素有关。肝细胞的病毒感染可能起作用。从肝脏组织中分离出SARS-CoV，尽管数量不多。尚未报道SARS-CoV-2的分离。对于细胞进入，SARS-CoV和SARS-CoV-2均与受体血管紧张素转换酶2（ACE2）结合； ACE2存在于肝细胞上，并且大量胆管细胞为直接病毒结合和肝炎功能受损提供了位点（18）。有趣的是，胆汁淤积性肝病并不是COVID-19疾病的共同特征（13）。其他病因也可能起作用。某些药物会引起肝毒性。一项研究发现COVID-19患者的LFT升高与洛匹那韦/利托那韦的给药显着相关（5）。 COVID-19患者的尸检结果显示-中度微血管脂肪变性，轻度小叶和门静脉活动-表明是SARS-CoV-2感染或药物引起的损伤（7,19）。临床试验可以在有希望的COVID-19治疗剂中寻找肝毒性（20）。肝损伤也可能由免疫介导的炎症引起。 （9,10）。对于其他病毒感染，可以观察到这一点。 ALT升高可伴有LDH和肌酸酐激酶的升高，提示这些酶升高的肝外起源。

总而言之，SARS-CoV-2感染是持续大流行的原因。对这种感染，COVID-19病和肝病之间关系的理解仍在不断发展。 COVID-19患者中肝损伤的原因似乎是多因素的。肝损伤通常是轻度的，但对于晚期COVID-19疾病的患者可能更为严重。在目前的HBV或HCV感染者中，很少有证据表明SARS-CoV-2感染。根据目前的证据，病毒性肝炎和慢性肝病患者应继续被视为在COVID-19疾病过程中发生合并症并发症风险增加的人群。

随着可信赖来源和本地调查人员获得数据，CGHE将更新此资源（21-24）。 CGHE鼓励合作伙伴提交报告以纳入该系列。

StephenW

https://www.globalhep.org/news/c ... 9-and-liver-disease

https://www.worldhepatitisallian ... nd-viral-hepatitis-