COVID-19-associated hepatic injury: Difference between revisions

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=== Medical Therapy ===
=== Medical Therapy ===
Currently there is no specific treatment for patient with [[COVID-19]] associated liver injury. The mainstay of medical therapy is to target the viral infection and control and prevent [[inflammation]].<ref name="TianYe2020">{{cite journal|last1=Tian|first1=Dandan|last2=Ye|first2=Qing|title=Hepatic complications of COVID‐19 and its treatment|journal=Journal of Medical Virology|year=2020|issn=0146-6615|doi=10.1002/jmv.26036}}</ref><ref name="pmid32345544">{{cite journal |vauthors=Su TH, Kao JH |title=The clinical manifestations and management of COVID-19-related liver injury |journal=J. Formos. Med. Assoc. |volume=119 |issue=6 |pages=1016–1018 |date=June 2020 |pmid=32345544 |pmc=7180368 |doi=10.1016/j.jfma.2020.04.020 |url=}}</ref>
Currently there is no specific [[treatment]]the  for patient with [[COVID-19]] associated liver injury. The mainstay of medical therapy is to target the viral infection and control and prevent [[inflammation]].<ref name="TianYe2020">{{cite journal|last1=Tian|first1=Dandan|last2=Ye|first2=Qing|title=Hepatic complications of COVID‐19 and its treatment|journal=Journal of Medical Virology|year=2020|issn=0146-6615|doi=10.1002/jmv.26036}}</ref><ref name="pmid32345544">{{cite journal |vauthors=Su TH, Kao JH |title=The clinical manifestations and management of COVID-19-related liver injury |journal=J. Formos. Med. Assoc. |volume=119 |issue=6 |pages=1016–1018 |date=June 2020 |pmid=32345544 |pmc=7180368 |doi=10.1016/j.jfma.2020.04.020 |url=}}</ref>
*In a [[SARS-Cov2]] patient with ''mild'' hepatic biochemical abnormalities, the mainstay of treatment is actively managing the primary infection. The use of hepatoprotective and [[enzyme]]‐lowering therapy is not recommended but supportive as well as specific antiviral therapy has to be given to halt [[viral replication]] and to reduce [[inflammation]].   
*''[[COVID-19]] associated mild hepatic injury'': In a [[SARS-Cov2]] patient with ''mild'' hepatic biochemical abnormalities, the mainstay of treatment is actively managing the primary infection. The use of hepatoprotective and [[enzyme]]‐lowering therapy is not recommended but supportive as well as specific antiviral therapy has to be given to halt [[viral replication]] and to reduce [[inflammation]].   
*In patients with ''severe'' [[COVID-19]] infection and liver injury, hyperinflammatory responses such as [[cytokine storms]] and tissue ischemia are usual causal factors. Treatment should focus on maintaining optimal blood [[oxygen saturation]]. This can be achieved either by [[oxygen therapy]] or the use of [[extracorporeal membrane oxygenation]]. The patient should be monitored closely with ongoing supportive and symptomatic treatment and correction of [[hypoproteinemia]] if required.   
*''[[COVID-19]] associated severe hepatic injury'': In patients with ''severe'' [[COVID-19]] infection and liver injury, hyperinflammatory responses such as [[Cytokine storm|cytokine storms]] and tissue [[ischemia]] are usual causal factors. Treatment should focus on maintaining optimal blood [[oxygen saturation]]. This can be achieved either by [[oxygen therapy]] or the use of [[extracorporeal membrane oxygenation]]. The patient should be monitored closely with ongoing supportive and symptomatic treatment and correction of [[hypoproteinemia]] if required.   
*In the case of [[acute liver failure]] in a [[COVID-19]] patient, after the cause of liver failure has been established, hepatoprotective and [[enzyme]]‐lowering drugs are administered. It is important to choose lower doses and fewer types of drugs (not more than 2, in general) with known [[mechanism of action]] and composition as the hepatic [[drug metabolism]] may pose a potential risk of harming the organ. The patient should be closely monitored with frequent [[Liver function tests|hepatic biochemical tests]] such as ([[AST]], [[ALT]], [[albumin]], [[total bilirubin]] and [[INR]]. [[Acute liver injury]] should be managed with close monitoring, supportive and symptomatic treatment, and correction of [[hypoproteinemia]].
*''[[COVID-19]] associated [[acute liver failure]]'': In the case of [[acute liver failure]] in a [[COVID-19]] patient, after the cause of liver failure has been established, hepatoprotective and [[enzyme]]‐lowering drugs are administered. It is important to choose lower doses and fewer types of drugs (not more than 2, in general) with known [[mechanism of action]] and composition as the hepatic [[drug metabolism]] may pose a potential risk of harming the organ. The patient should be closely monitored with frequent [[Liver function tests|hepatic biochemical tests]] such as ([[AST]], [[ALT]], [[albumin]], [[total bilirubin]] and [[INR]]. [[Acute liver injury]] should be managed with close monitoring, supportive and symptomatic treatment, and correction of [[hypoproteinemia]].
*In the cases of [[drug induced liver injury]], it is important to assess the degree of liver damage and identify the drug responsible and then adjust the treatment accordingly. If possible completely stop the drug, reduce the amount, or use an alternative drug. Anti‐inflammatory and hepatoprotective treatment should be provided. It is not recommended to discontinue [[Hepatitis B]] and [[Hepatitis C]] treatments but large doses of hormones are not to be used simultaneously.
*In the cases of [[drug induced liver injury]], it is important to assess the degree of liver damage and identify the drug responsible and then adjust the treatment accordingly. If possible completely stop the drug, reduce the amount, or use an alternative drug. Anti‐inflammatory and hepatoprotective treatment should be provided.  
* In patients with underlying [[chronic liver diseases]], target the coronavirus infection and maintain the original therapy for chronic liver diseases.
*The American Association for the Study of Liver Diseases (AASLD) does not recommend to discontinue [[Hepatitis B]] and [[Hepatitis C]] antiviral treatments but recommends that large doses of [[hormones]] are not to be used simultaneously. However, direct-acting antiviral therapy initiation for [[Hepatitis C]] [[patients]] may be delayed.
* In patients with underlying [[chronic liver diseases]], target the coronavirus infection and maintain the [[Chronic liver disease medical therapy|original therapy for chronic liver diseases]].
* [[Liver function tests]] can serve as indicators of disease progression.  
* [[Liver function tests]] can serve as indicators of disease progression.  
*Treatment and prevention of inflammation in the early stages of the disease will prevent severe disease.
*[[Treatment]] and prevention of [[inflammation]] in the early stages of the disease prevent severe [[disease]].
*To view medical treatment for [[COVID-19]], [[COVID-19 medical therapy|click here]].


=== Surgery ===
=== Surgery ===
*There is no surgical treatment associated with COVID-19-associated hepatic injury.
*Surgical intervention is not recommended for the management of [[COVID-19]]-associated hepatic injury.


=== Prevention ===
===Primary Prevention===
*The disease itself is associated with [[COVID-19]] infection so prevention of the [[infection]] itself is the most promising primary prevention strategy at the moment.
*There are no available vaccines against [[COVID-19]] at the moment. There have been rigorous efforts in order to develop a [[vaccine]] for [[COVID-10|novel coronavirus]] and several vaccines are in the later phases of trials.<ref name="urlNIH clinical trial of investigational vaccine for COVID-19 begins | National Institutes of Health (NIH)">{{cite web |url=https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins |title=NIH clinical trial of investigational vaccine for COVID-19 begins &#124; National Institutes of Health (NIH) |format= |work= |accessdate=}}</ref>
*The only prevention for [[COVID-19]] associated hepatic injury is the prevention and early diagnosis of the [[coronavirus-19]] infection itself. According to the [[CDC]], the measures include:<ref name="urlHow to Protect Yourself & Others | CDC">{{cite web |url=https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html |title=How to Protect Yourself & Others &#124; CDC |format= |work= |accessdate=}}</ref>
**Frequent handwashing with soap and water for at least 20 seconds or using a [[alcohol rub|alcohol based hand sanitizer]] with at least 60% alcohol.
**Staying at least 6 feet (about 2 arms’ length) from other people who do not live with you.
**Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs.
**Cleaning and [[Disinfectant|disinfecting]].
*At this time, the only effective measures for the primary prevention of COVID-19 related liver damage include prevention of itself [[COVID-19]]. [[Drug induced liver injury]] can be prevented by carefully selecting the drug with a known mechanism of action, not using more than two drugs, and avoiding large doses of hormones along with antiviral drugs.
*At this time, the only effective measures for the primary prevention of COVID-19 related liver damage include prevention of itself [[COVID-19]]. [[Drug induced liver injury]] can be prevented by carefully selecting the drug with a known mechanism of action, not using more than two drugs, and avoiding large doses of hormones along with antiviral drugs.
===Secondary prevention===
*Effective measures for the secondary prevention of contact tracing as it helps reduce the spread of the disease.<ref name="urlContact Tracing for COVID-19 | CDC">{{cite web |url=https://www.cdc.gov/coronavirus/2019-ncov/php/contact-tracing/contact-tracing-plan/contact-tracing.html |title=Contact Tracing for COVID-19 &#124; CDC |format= |work= |accessdate=}}</ref>
*In unexplained abnormal [[Liver function tests|hepatic biochemical tests]], [[CXR]], Chest [[CT scan]] or nasopharyngeal swab [[RT-PCR]] should be performed to diagnose the infection and treat it timely.


==References==
==References==

Revision as of 12:47, 14 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Tayyaba Ali, M.D.[2]

Overview

According to 12 clinical studies, 14.8%-53% of COVID-19 patients have liver impairment, suggesting COVID-19-associated hepatic injury, a common complication observed among COVID-19 patients. With the number of cases increasing, abnormal liver function test results have been observed in some patients with COVID-19, making this organ the most frequently damaged outside of the respiratory system.

Historical Perspective

Classification

There is no formal classification of liver damage associated with COVID-19 but, we attempt to divide the entity based on the etiology and mechanism of liver damage:[21][22][8][23][24][25][26][27]

To browse the classification of COVID-19, Click here.

Pathophysiology

The exact mechanism of liver injury is still unclear. There are several proposed mechanisms in an effort to understand the pathogenesis of hepatic injury but the hepatic complications in COVID-19 patients are described as multifactorial and heterogenous. A few of the proposed mechanisms include:

  • Antibody-mediated Hepatic Injury:

Clinical Features

Differentiating COVID-19-associated hepatic injury from other causes of hepatic injury

  • There are different etiologies of hepatic injury in general but a hepatic injury in a patient having COVID-19 infection itself can be due to different reasons. Although different etiologies of the liver disease show some difference in biochemistry, we lack sufficient data to suggest a specific biochemical factor characteristic, pathognomic of COVID-19 related liver injury. Abnormal liver biochemical markers at the time of diagnosis can give a clue of chronic liver disease in a patient.
  • Deteriorating liver function tests during the course of hospitalization may point towards drug induced liver injury or complication of COVID-19.

Epidemiology and Demographics

Liver test abnormalities from various COVID-19 studies[9]
Author Group Number of patients Alanine

aminotransferase (IU)

Aspartate

aminotransferase (IU)

Prothrombin

time (s)

Bilirubin (μmol/L) Elevated lactate

dehydrogenase, creatinine kinase, or myoglobin

Mortality (%)
Guan et al (2020)[19] ICU or death 67 Not known Not known Not known Not known Yes 22% (day 51)
Huang et al (2020)[18] ICU 13 49 (29–115) 44 (32–70) 12·2 (11·2–13·4) 14·0 (11·9–32·9) Yes 38% (day 37)
Chen et al (2020)[4] Hospitalised 99 39 (22–53) 34 (26–48) 11·3 (1·9) 15·1 (7·3) Yes 11% (day 24)
Wang et al (2020)[47] ICU 36 35 (19–57) 52 (30–70) 13·2 (12·3–14·5) 11·5 (9·6–18·6) Yes 17% (day 34)
Shi et al (2020)[48] Hospitalised 81 46 (30) 41 (18) 10·7 (0·9) 11·9 (3·6) Unclear 5% (day 50)
Xu et al (2020)[49] Hospitalised 62 22 (14–34) 26 (20–32) Not known Not known Unclear 0% (day 34)
Yang et al (2020)[3] ICU 52 Not known Not known 12·9 (2·9)* 19·5 (11·6)* Not described 62% (day 28)
Extracted from all

studies above

Chronic liver

disease

42 Not known Not known Not known Not known Not known 0–2%†



In addition, abnormal liver function test in cases of COVID-19 is often transient and often simultaneously combined with increased enzymes from muscle and heart; these laboratory changes can return to normal without liver-related morbidity and mortality.


Gender

Although is very limited data available, the incidence of liver injury associated with COVID-19 is reported to be higher in males.[42]

Risk Factors

  • Common risk factors in the development of hepatic complications include:[23][27]
    • Chronic liver disease
    • Hypoxemia
    • Hyper‐inflammatory reactions during COVID-19 infection
    • Critical COVID-19 infection - liver injury being more prevalent in patients with a critical disease (especially ICU admissions) rather mild cases, makes a severe coronavirus infection a risk factor.

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

Symptoms

Physical Examination

Laboratory Findings

  • Research has shown elevated ALT and AST levels in the blood of patients with liver injury on admission. AST elevation is more common than ALT, which reflects a possible source outside of liver.[26]
  • Serum albumin levels were found to get lower during the course of hospitalization. The tests is a measure of synthetic function of the liver.
  • ICU patients had higher levels of {ASLT]] and AST and a more reduced level of serum albumin indicating severe liver damage affecting its synthetic ability.
  • Total bilirubin and direct bilirubin: The data from limited studies show a higher incidence of hyperbilirubinemia in patients who required aggressive management during the course of their disease or died.[24]
  • LDH levels- a study reported the incidence of LDH levels to be highest followed by AST and ALT and suggested that LDH can be used as an early alarm tp prompt further analysis for COVID-19.[42]
  • Glycoprotein gamma-glutamyltransferase (GGT) may point towards hepatobiliary involvement.
  • PTA (INR) provides a good estimate of liver synthetic function.
  • Alkaline phosphatase (ALP) is higher in patients.[27]
  • Levels of IL‐2‐receptor (IL‐2R), IL‐4, IL‐6, IL‐18, IL‐10, TNF‐α were significantly increased IL‐6 in the serum of COVID‐19 patients are significantly increased and correlate with disease severity.

Imaging Findings

  • There are no imaging study findings associated with COVID-19-associated hepatic injury.

Other tests

Treatment

Medical Therapy

Currently there is no specific treatmentthe for patient with COVID-19 associated liver injury. The mainstay of medical therapy is to target the viral infection and control and prevent inflammation.[24][27]

Surgery

  • Surgical intervention is not recommended for the management of COVID-19-associated hepatic injury.

Primary Prevention

  • The disease itself is associated with COVID-19 infection so prevention of the infection itself is the most promising primary prevention strategy at the moment.
  • There are no available vaccines against COVID-19 at the moment. There have been rigorous efforts in order to develop a vaccine for novel coronavirus and several vaccines are in the later phases of trials.[52]
  • The only prevention for COVID-19 associated hepatic injury is the prevention and early diagnosis of the coronavirus-19 infection itself. According to the CDC, the measures include:[53]
    • Frequent handwashing with soap and water for at least 20 seconds or using a alcohol based hand sanitizer with at least 60% alcohol.
    • Staying at least 6 feet (about 2 arms’ length) from other people who do not live with you.
    • Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs.
    • Cleaning and disinfecting.
  • At this time, the only effective measures for the primary prevention of COVID-19 related liver damage include prevention of itself COVID-19. Drug induced liver injury can be prevented by carefully selecting the drug with a known mechanism of action, not using more than two drugs, and avoiding large doses of hormones along with antiviral drugs.

Secondary prevention

  • Effective measures for the secondary prevention of contact tracing as it helps reduce the spread of the disease.[54]
  • In unexplained abnormal hepatic biochemical tests, CXR, Chest CT scan or nasopharyngeal swab RT-PCR should be performed to diagnose the infection and treat it timely.

References

  1. ↑ Chau, Tai-Nin; Lee, Kam-Cheong; Yao, Hung; Tsang, Tak-Yin; Chow, Tat-Chong; Yeung, Yiu-Cheong; Choi, Kin-Wing; Tso, Yuk-Keung; Lau, Terence; Lai, Sik-To; Lai, Ching-Lung (2004). "SARS-associated viral hepatitis caused by a novel coronavirus: Report of three cases". Hepatology. 39 (2): 302–310. doi:10.1002/hep.20111. ISSN 0270-9139.
  2. ↑ Alsaad, Khaled O; Hajeer, Ali H; Al Balwi, Mohammed; Al Moaiqel, Mohammed; Al Oudah, Nourah; Al Ajlan, Abdulaziz; AlJohani, Sameera; Alsolamy, Sami; Gmati, Giamal E; Balkhy, Hanan; Al-Jahdali, Hamdan H; Baharoon, Salim A; Arabi, Yaseen M (2018). "Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection - clinicopathological and ultrastructural study". Histopathology. 72 (3): 516–524. doi:10.1111/his.13379. ISSN 0309-0167.
  3. ↑ 3.0 3.1 3.2 Yang, Xiaobo; Yu, Yuan; Xu, Jiqian; Shu, Huaqing; Xia, Jia'an; Liu, Hong; Wu, Yongran; Zhang, Lu; Yu, Zhui; Fang, Minghao; Yu, Ting; Wang, Yaxin; Pan, Shangwen; Zou, Xiaojing; Yuan, Shiying; Shang, You (2020). "Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study". The Lancet Respiratory Medicine. 8 (5): 475–481. doi:10.1016/S2213-2600(20)30079-5. ISSN 2213-2600.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Chen, Nanshan; Zhou, Min; Dong, Xuan; Qu, Jieming; Gong, Fengyun; Han, Yang; Qiu, Yang; Wang, Jingli; Liu, Ying; Wei, Yuan; Xia, Jia'an; Yu, Ting; Zhang, Xinxin; Zhang, Li (2020). "Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study". The Lancet. 395 (10223): 507–513. doi:10.1016/S0140-6736(20)30211-7. ISSN 0140-6736.
  5. ↑ Liu C, Jiang ZC, Shao CX, Zhang HG, Yue HM, Chen ZH; et al. (2020). "[Preliminary study of the relationship between novel coronavirus pneumonia and liver function damage: a multicenter study]". Zhonghua Gan Zang Bing Za Zhi. 28 (2): 107–111. doi:10.3760/cma.j.issn.1007-3418.2020.02.003. PMID 32077660 Check |pmid= value (help).
  6. ↑ Chen L, Liu HG, Liu W, Liu J, Liu K, Shang J; et al. (2020). "[Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia]". Zhonghua Jie He He Hu Xi Za Zhi. 43 (0): E005. doi:10.3760/cma.j.issn.1001-0939.2020.0005. PMID 32026671 Check |pmid= value (help).
  7. ↑ Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J; et al. (2020). "Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China". JAMA. doi:10.1001/jama.2020.1585. PMC 7042881 Check |pmc= value (help). PMID 32031570 Check |pmid= value (help).
  8. ↑ 8.0 8.1 8.2 Zhang C, Shi L, Wang FS (2020). "Liver injury in COVID-19: management and challenges". Lancet Gastroenterol Hepatol. 5 (5): 428–430. doi:10.1016/S2468-1253(20)30057-1. PMC 7129165 Check |pmc= value (help). PMID 32145190 Check |pmid= value (help).
  9. ↑ 9.0 9.1 Bangash MN, Patel J, Parekh D (2020). "COVID-19 and the liver: little cause for concern". Lancet Gastroenterol Hepatol. 5 (6): 529–530. doi:10.1016/S2468-1253(20)30084-4. PMC 7270582 Check |pmc= value (help). PMID 32203680 Check |pmid= value (help).
  10. ↑ Mao R, Liang J, Shen J, Ghosh S, Zhu LR, Yang H; et al. (2020). "Implications of COVID-19 for patients with pre-existing digestive diseases". Lancet Gastroenterol Hepatol. 5 (5): 425–427. doi:10.1016/S2468-1253(20)30076-5. PMC 7103943 Check |pmc= value (help). PMID 32171057 Check |pmid= value (help).
  11. ↑ Hu LL, Wang WJ, Zhu QJ, Yang L (2020). "[Novel coronavirus pneumonia-related liver injury: etiological analysis and treatment strategy]". Zhonghua Gan Zang Bing Za Zhi. 28 (2): 97–99. doi:10.3760/cma.j.issn.1007-3418.2020.02.001. PMID 32075364 Check |pmid= value (help).
  12. ↑ Ren LL, Wang YM, Wu ZQ, Xiang ZC, Guo L, Xu T; et al. (2020). "Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study". Chin Med J (Engl). 133 (9): 1015–1024. doi:10.1097/CM9.0000000000000722. PMC 7147275 Check |pmc= value (help). PMID 32004165 Check |pmid= value (help).
  13. ↑ Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J; et al. (2020). "Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study". Lancet Infect Dis. 20 (4): 425–434. doi:10.1016/S1473-3099(20)30086-4. PMC 7159053 Check |pmc= value (help). PMID 32105637 Check |pmid= value (help).
  14. ↑ Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL; et al. (2020). "Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series". BMJ. 368: m606. doi:10.1136/bmj.m606. PMC 7224340 Check |pmc= value (help). PMID 32075786 Check |pmid= value (help).
  15. ↑ Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y; et al. (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. PMC 7159299 Check |pmc= value (help). PMID 31986264.
  16. ↑ Yao N, Wang SN, Lian JQ, Sun YT, Zhang GF, Kang WZ; et al. (2020). "[Clinical characteristics and influencing factors of patients with novel coronavirus pneumonia combined with liver injury in Shaanxi region]". Zhonghua Gan Zang Bing Za Zhi. 28 (3): 234–239. doi:10.3760/cma.j.cn501113-20200226-00070. PMID 32153170 Check |pmid= value (help).
  17. ↑ Guan WJ, Zhong NS (2020). "Clinical Characteristics of Covid-19 in China. Reply". N Engl J Med. 382 (19): 1861–1862. doi:10.1056/NEJMc2005203. PMID 32220206 Check |pmid= value (help).
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 Huang, Chaolin; Wang, Yeming; Li, Xingwang; Ren, Lili; Zhao, Jianping; Hu, Yi; Zhang, Li; Fan, Guohui; Xu, Jiuyang; Gu, Xiaoying; Cheng, Zhenshun; Yu, Ting; Xia, Jiaan; Wei, Yuan; Wu, Wenjuan; Xie, Xuelei; Yin, Wen; Li, Hui; Liu, Min; Xiao, Yan; Gao, Hong; Guo, Li; Xie, Jungang; Wang, Guangfa; Jiang, Rongmeng; Gao, Zhancheng; Jin, Qi; Wang, Jianwei; Cao, Bin (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". The Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. ISSN 0140-6736.
  19. ↑ 19.0 19.1 Guan, Wei-jie; Ni, Zheng-yi; Hu, Yu; Liang, Wen-hua; Ou, Chun-quan; He, Jian-xing; Liu, Lei; Shan, Hong; Lei, Chun-liang; Hui, David SC; Du, Bin; Li, Lan-juan; Zeng, Guang; Yuen, Kowk-Yung; Chen, Ru-chong; Tang, Chun-li; Wang, Tao; Chen, Ping-yan; Xiang, Jie; Li, Shi-yue; Wang, Jin-lin; Liang, Zi-jing; Peng, Yi-xiang; Wei, Li; Liu, Yong; Hu, Ya-hua; Peng, Peng; Wang, Jian-ming; Liu, Ji-yang; Chen, Zhong; Li, Gang; Zheng, Zhi-jian; Qiu, Shao-qin; Luo, Jie; Ye, Chang-jiang; Zhu, Shao-yong; Zhong, Nan-shan (2020). doi:10.1101/2020.02.06.20020974. Missing or empty |title= (help)
  20. ↑ 20.0 20.1 Cai, Qingxian; Huang, Deliang; Ou, Pengcheng; Yu, Hong; Zhu, Zhibin; Xia, Zhang; Su, Yinan; Ma, Zhenghua; Zhang, Yiming; Li, Zhiwei; He, Qing; Fu, Yang; Liu, Lei; Chen, Jun (2020). doi:10.1101/2020.02.17.20024018. Missing or empty |title= (help)
  21. ↑ Lee IC, Huo TI, Huang YH (June 2020). "Gastrointestinal and liver manifestations in patients with COVID-19". J Chin Med Assoc. 83 (6): 521–523. doi:10.1097/JCMA.0000000000000319. PMC 7176263 Check |pmc= value (help). PMID 32243269 Check |pmid= value (help).
  22. ↑ Kumar, Pramod; Sharma, Mithun; Kulkarni, Anand; Rao, Padaki N. (2020). "Pathogenesis of Liver Injury in Coronavirus Disease 2019". Journal of Clinical and Experimental Hepatology. doi:10.1016/j.jceh.2020.05.006. ISSN 0973-6883.
  23. ↑ 23.0 23.1 Li, Yueying; Xiao, Shu‐Yuan (2020). "Hepatic involvement in COVID‐19 patients: Pathology, pathogenesis, and clinical implications". Journal of Medical Virology. doi:10.1002/jmv.25973. ISSN 0146-6615.
  24. ↑ 24.0 24.1 24.2 24.3 24.4 Tian, Dandan; Ye, Qing (2020). "Hepatic complications of COVID‐19 and its treatment". Journal of Medical Virology. doi:10.1002/jmv.26036. ISSN 0146-6615.
  25. ↑ Shehu, Amina I.; Lu, Jie; Wang, Pengcheng; Zhu, Junjie; Wang, Yue; Yang, Da; McMahon, Deborah; Xie, Wen; Gonzalez, Frank J.; Ma, Xiaochao (2019). "Pregnane X receptor activation potentiates ritonavir hepatotoxicity". Journal of Clinical Investigation. 129 (7): 2898–2903. doi:10.1172/JCI128274. ISSN 0021-9738.
  26. ↑ 26.0 26.1 Cai Q, Huang D, Yu H, Zhu Z, Xia Z, Su Y, Li Z, Zhou G, Gou J, Qu J, Sun Y, Liu Y, He Q, Chen J, Liu L, Xu L (April 2020). "COVID-19: Abnormal liver function tests". J. Hepatol. doi:10.1016/j.jhep.2020.04.006. PMC 7194951 Check |pmc= value (help). PMID 32298767 Check |pmid= value (help).
  27. ↑ 27.0 27.1 27.2 27.3 27.4 Su TH, Kao JH (June 2020). "The clinical manifestations and management of COVID-19-related liver injury". J. Formos. Med. Assoc. 119 (6): 1016–1018. doi:10.1016/j.jfma.2020.04.020. PMC 7180368 Check |pmc= value (help). PMID 32345544 Check |pmid= value (help).
  28. ↑ Xu X, Chen P, Wang J, Feng J, Zhou H, Li X; et al. (2020). "Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission". Sci China Life Sci. 63 (3): 457–460. doi:10.1007/s11427-020-1637-5. PMC 7089049 Check |pmc= value (help). PMID 32009228 Check |pmid= value (help).
  29. ↑ Letko M, Marzi A, Munster V (2020). "Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses". Nat Microbiol. 5 (4): 562–569. doi:10.1038/s41564-020-0688-y. PMC 7095430 Check |pmc= value (help). PMID 32094589 Check |pmid= value (help).
  30. ↑ Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C; et al. (2020). "Pathological findings of COVID-19 associated with acute respiratory distress syndrome". Lancet Respir Med. 8 (4): 420–422. doi:10.1016/S2213-2600(20)30076-X. PMC 7164771 Check |pmc= value (help). PMID 32085846 Check |pmid= value (help).
  31. ↑ Tian S, Xiong Y, Liu H, Niu L, Guo J, Liao M; et al. (2020). "Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies". Mod Pathol. 33 (6): 1007–1014. doi:10.1038/s41379-020-0536-x. PMC 7156231 Check |pmc= value (help). PMID 32291399 Check |pmid= value (help).
  32. ↑ Chai, Xiaoqiang; Hu, Longfei; Zhang, Yan; Han, Weiyu; Lu, Zhou; Ke, Aiwu; Zhou, Jian; Shi, Guoming; Fang, Nan; Fan, Jia; Cai, Jiabin; Fan, Jue; Lan, Fei (2020). doi:10.1101/2020.02.03.931766. Missing or empty |title= (help)
  33. ↑ Tirado, Sol M. Cancel; Yoon, Kyoung-Jin (2003). "Antibody-Dependent Enhancement of Virus Infection and Disease". Viral Immunology. 16 (1): 69–86. doi:10.1089/088282403763635465. ISSN 0882-8245.
  34. ↑ Wang, Sheng-Fan; Tseng, Sung-Pin; Yen, Chia-Hung; Yang, Jyh-Yuan; Tsao, Ching-Han; Shen, Chun-Wei; Chen, Kuan-Hsuan; Liu, Fu-Tong; Liu, Wu-Tse; Chen, Yi-Ming Arthur; Huang, Jason C. (2014). "Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins". Biochemical and Biophysical Research Communications. 451 (2): 208–214. doi:10.1016/j.bbrc.2014.07.090. ISSN 0006-291X.
  35. ↑ Wong, C. K.; Lam, C. W. K.; Wu, A. K. L.; Ip, W. K.; Lee, N. L. S.; Chan, I. H. S.; Lit, L. C. W.; Hui, D. S. C.; Chan, M. H. M.; Chung, S. S. C.; Sung, J. J. Y. (2004). "Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome". Clinical & Experimental Immunology. 136 (1): 95–103. doi:10.1111/j.1365-2249.2004.02415.x. ISSN 0009-9104.
  36. ↑ Channappanavar, Rudragouda; Perlman, Stanley (2017). "Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology". Seminars in Immunopathology. 39 (5): 529–539. doi:10.1007/s00281-017-0629-x. ISSN 1863-2297.
  37. ↑ Mahallawi, Waleed H.; Khabour, Omar F.; Zhang, Qibo; Makhdoum, Hatim M.; Suliman, Bandar A. (2018). "MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile". Cytokine. 104: 8–13. doi:10.1016/j.cyto.2018.01.025. ISSN 1043-4666.
  38. ↑ Liu, Yanli; Sun, Wenwu; Li, Jia; Chen, Liangkai; Wang, Yujun; Zhang, Lijuan; Yu, Li (2020). doi:10.1101/2020.02.17.20024166. Missing or empty |title= (help)
  39. ↑ Wan, Suxin; Yi, Qingjie; Fan, Shibing; Lv, Jinglong; Zhang, Xianxiang; Guo, Lian; Lang, Chunhui; Xiao, Qing; Xiao, Kaihu; Yi, Zhengjun; Qiang, Mao; Xiang, Jianglin; Zhang, Bangshuo; Chen, Yongping (2020). doi:10.1101/2020.02.10.20021832. Missing or empty |title= (help)
  40. ↑ Diao, Bo; Wang, Chenhui; Tan, Yingjun; Chen, Xiewan; Liu, Ying; Ning, Lifeng; Chen, Li; Li, Min; Liu, Yueping; Wang, Gang; Yuan, Zilin; Feng, Zeqing; Wu, Yuzhang; Chen, Yongwen (2020). doi:10.1101/2020.02.18.20024364. Missing or empty |title= (help)
  41. ↑ . doi:10.3969/j.issn.1672-5069.2020.02.001. Missing or empty |title= (help)
  42. ↑ 42.0 42.1 42.2 Fan, Zhenyu; Chen, Liping; Li, Jun; Tian, Cheng; Zhang, Yajun; Huang, Shaoping; Liu, Zhanju; Cheng, Jilin (2020). doi:10.1101/2020.02.26.20026971. Missing or empty |title= (help)
  43. ↑ Wang, Fu‐Sheng; Fan, Jian‐Gao; Zhang, Zheng; Gao, Bin; Wang, Hong‐Yang (2014). "The global burden of liver disease: The major impact of China". Hepatology. 60 (6): 2099–2108. doi:10.1002/hep.27406. ISSN 0270-9139.
  44. ↑ Lelubre, Christophe; Vincent, Jean-Louis (2018). "Mechanisms and treatment of organ failure in sepsis". Nature Reviews Nephrology. 14 (7): 417–427. doi:10.1038/s41581-018-0005-7. ISSN 1759-5061.
  45. ↑ Strnad, Pavel; Tacke, Frank; Koch, Alexander; Trautwein, Christian (2016). "Liver — guardian, modifier and target of sepsis". Nature Reviews Gastroenterology & Hepatology. 14 (1): 55–66. doi:10.1038/nrgastro.2016.168. ISSN 1759-5045.
  46. ↑ Li J, Li RJ, Lv GY, Liu HQ (2015). "The mechanisms and strategies to protect from hepatic ischemia-reperfusion injury". Eur Rev Med Pharmacol Sci. 19 (11): 2036–47. PMID 26125267.
  47. ↑ 47.0 47.1 47.2 Wang, Dawei; Hu, Bo; Hu, Chang; Zhu, Fangfang; Liu, Xing; Zhang, Jing; Wang, Binbin; Xiang, Hui; Cheng, Zhenshun; Xiong, Yong; Zhao, Yan; Li, Yirong; Wang, Xinghuan; Peng, Zhiyong (2020). "Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China". JAMA. 323 (11): 1061. doi:10.1001/jama.2020.1585. ISSN 0098-7484.
  48. ↑ Shi, Heshui; Han, Xiaoyu; Jiang, Nanchuan; Cao, Yukun; Alwalid, Osamah; Gu, Jin; Fan, Yanqing; Zheng, Chuansheng (2020). "Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study". The Lancet Infectious Diseases. 20 (4): 425–434. doi:10.1016/S1473-3099(20)30086-4. ISSN 1473-3099.
  49. ↑ Xu, Xiao-Wei; Wu, Xiao-Xin; Jiang, Xian-Gao; Xu, Kai-Jin; Ying, Ling-Jun; Ma, Chun-Lian; Li, Shi-Bo; Wang, Hua-Ying; Zhang, Sheng; Gao, Hai-Nv; Sheng, Ji-Fang; Cai, Hong-Liu; Qiu, Yun-Qing; Li, Lan-Juan (2020). "Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series". BMJ: m606. doi:10.1136/bmj.m606. ISSN 1756-1833.
  50. ↑ 50.0 50.1 Jothimani D, Venugopal R, Abedin MF, Kaliamoorthy I, Rela M (June 2020). "COVID-19 and Liver". J. Hepatol. doi:10.1016/j.jhep.2020.06.006. PMC 7295524 Check |pmc= value (help). PMID 32553666 Check |pmid= value (help).
  51. ↑ Li, Jie; Fan, Jian-Gao (2020). "Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease". Journal of Clinical and Translational Hepatology. 8 (1): 1–5. doi:10.14218/JCTH.2020.00019. ISSN 2225-0719.
  52. ↑ "NIH clinical trial of investigational vaccine for COVID-19 begins | National Institutes of Health (NIH)".
  53. ↑ "How to Protect Yourself & Others | CDC".
  54. ↑ "Contact Tracing for COVID-19 | CDC".

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