COVID-19-associated hepatic injury
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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] Javaria Anwer M.D.[3]
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
- Severe acute respiratory syndrome (SARS) has shown manifestations of liver impairment in up to 60% of patients.[1]
- Liver impairment has also been reported in patients infected with MERS-CoV.[2]
- 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. COVID-19-associated hepatic injury is mainly indicated by abnormal ALT/AST levels accompanied by slightly elevated bilirubin levels. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]
- In severe cases, albumin is seen to be diminished and the level of albumin is around 26.3-30.9 g/l.[4]
- Patients with severe COVID-19 symptoms showed a high percentage of liver injury than that of mild patients.[18][19][20]
- According to one study, serum ALT and AST levels increased up to 7590 U/L and 1445 U/L, respectively, in a severe COVID-19 patient.[4]
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]
- Direct viral damage to hepatocytes
- Drug induced liver injury
- Overactive immune response
- Ischemia and reperfusion injury
- Aggravation/ Recurrence of existing liver disease- According to the data available, 2% to 11% of COVID-19 patients had pre-existing chronic liver disease.
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:
Hepatic Injury through ACE2 receptors
- S protein facilitates SARS-CoV-2 to enter host cells through binding to ACE2 receptors. ACE2 is the primary receptors that enable the entry of SARS-CoV into different target tissues, including hepatic cells.[28][29]
- According to a biopsy performed in a COVID-19 patient after death, moderate microvascular steatosis, and mild portal and lobular activity in liver tissue were observed.[30]
- Another four autopsies were performed on COVID-19 patients. In 2 cases, mild zone 3 sinusoidal dilatation, patchy hepatic necrosis, minimal increase in sinusoidal lymphocytes were observed in hepatocytes. In one case, RT-PCR showed direct evidence of the SARS-CoV-2 RNA sequence in the liver cells.[31]
- The expression of ACE2 receptors in liver tissue is only 0.31%. The expression of ACE2 receptors is 20 times higher in bile duct epithelial cells as compared to hepatocytes.[32] Because of the low number of ACE2 expression in the liver, further research is needed to investigate direct damage of liver tissue by SARS-CoV-2.
Antibody-mediated Hepatic Injury
- Antibody-mediated liver injury may occur in patients with SARS.[33] It involves the binding of a virus-specific antibody to Fc receptors (FcR) and complement receptor (CR) that enables the virus to enter immune cells such as granulocytes, monocytes, and macrophages. The virus can damage the liver by constant replication in these immune cells.[34] Further investigation is required to understand whether SARS-CoV-2 causes liver injury through this pathway.
Cytokine-mediated Hepatic Injury
- Historical data on SARS-CoV and MERS-CoV suggest that cytokine storm including interleukin (IL), tumor necrosis factor (TNF), and endotoxin and systemic inflammatory response syndrome played a major role in liver impairment among infected patients.[35][36][37]
- A high serum levels of interleukin-2, interleukin-6, interleukin-7, interleukin-10, tumor necrosis factor-α, granulocyte-colony stimulating factor, interferon-inducible protein-10, monocyte chemotactic protein 1, macrophage inflammatory protein 1 alpha, Th17, and CD8 T cells are observed in severe cases of COVID-19.[18][20][38][39][40]
COVID-19 medical therapy-induced Hepatic Injury
- COVID-19 medical therapy includes antibiotics, antivirals, and steroids similar to the treatment for SARS infection. These medications are on the whole likely reasons for liver injury during COVID‐19, however not yet being obvious.[3]
- Most antipyretic medications contain paracetamol, which is commonly perceived as a typical explanation behind liver injury.[41]
- According to a study by Fan et al., the liver injury observed in COVID‐19 patients might be caused by lopinavir/ritonavir, which is used as antivirals for the treatment of COVID-19.[42]
- In this way, if variation from the norm of liver enzymes happens in the wake of utilizing a hepatotoxic medication, the drug-induced hepatic injury should initially be affirmed or precluded. China has a high prevalence of chronic liver diseases such as nonalcoholic fatty liver disease, chronic hepatitis B, and liver cirrhosis. Immune reactions as a result of COVID-19 infection may be viewed as a "second hit" to already existing liver disease and can actuate liver injury and steatohepatitis.[43]
Sepsis-induced COVID-19-associated Hepatic Injury
- Sepsis can also be considered as a contributing factor to COVID-19-associated hepatic injury and can impair the prognosis of COVID-19. Sepsis is a dysregulated immune response to an infection that leads to psychological stress and multiple organ dysfunction.[44]
- The pathophysiology of sepsis-related liver injury incorporates hypoxic liver injury because of ischemia and shock, cholestasis because of altered bile metabolism, hepatocellular injury because of drug toxicity, or overwhelming inflammation.[45]
Ischemia-reperfusion-induced Hepatic Injury
- Ischemia and hypoxia as a result of COVID-19 infection can result in metabolic acidosis, calcium overloading, and changes in mitochondrial membrane permeability. These factors have impacted hepatic injury manifested as very high aminotransferase concentrations in serum.[46]
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
- In a cohort of 41 COVID-19 patients, levels of aspartate aminotransferase increased by 15 (37%) patients. Among these 15 patients, eight (62%) of 13 ICU patients and seven (25%) of 28 non-ICU patients.[18]
- According to a single-center study of 99 COVID-19 patients. A wide range of liver function abnormality was observed among 43 patients, with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above the normal range. A severe liver function abnormality was observed in one patient (ALT 7590 U/L, AST 1445 U/L).[4]
| 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
- Out of 148 COVID-19 patients, ninety-two (62.2%) patients were released from the hospital as of February 19, 2020, that includes 34 cases with abnormal liver function before admission, 24 cases with abnormal liver function during hospitalization, and 34 cases with normal liver function during the stay in hospital. Of note, we found that baseline abnormal liver function was associated with a prolonged hospital stay. Whereas, abnormal liver function observed during admission had little impact on the length of hospital stay.
- According to the data available to date, mild liver injury can occur in patients with moderate-severe illness but the incidence of hepatic dysfunction higher among patients with severe or critical COVID-19 illness. [8][50][24]
- The association of acute liver injury with higher mortality has also been reported.[50] Research is underway and few studies describe the correlation of liver biochemical indicators and severity of COVID-19. The impairment of hepatic function (guaged via biochemical markers of hepatic function) may become a predictor of the exacerbation and deterioration in patients with COVID‐19.[24]
Diagnosis
Diagnostic Study of Choice
- The diagnosis of COVID-19-associated hepatic injury is based on the abnormal liver biochemical and function tests. The key lies in suspecting liver damage in a SARS-CoV2 patient and testing liver biochemical and function tests such as LDH, albumin, ALT, AST, total bilirubin, and INR. A COVID-19 patient with acute liver failure should be investigated and effort has to be made to find the cause liver injury. Abnormal liver biochemistries are uncommon in children.[27]
History and Symptoms
- The majority of patients with abnormal liver function have a fever, which may be related to the immune response after viral infection.[18][47]
- Other COVID-19 associated symptoms reported in patients with COVID-19 include:[27]
- Cough
- Sorethroat
- Diarrhea
- Abdominal pain
- Anosmia
- Ageusia
- To browse the symptoms of COVID-19, Click here.
Physical Examination
- The presence of hepatomegaly in patients with COVID-19-associated hepatic injury may be aforethought of organomegaly.[51]
- To browse the physical exam findings associated with COVID-19, Click here.
Laboratory Findings
- Laboratory findings consistent with the diagnosis of COVID-19-associated hepatic injury include abnormal Liver function tests specially raised AST.
- 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 ALT 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.[52]
Electrocardiogram
- There are no ECG findings associated with COVID-19-associated hepatic injury.
- ECG shows significant findings in other manifestations or complications of COVID-19 infection such as COVID-19-associated myocardial injury, COVID-19-associated myocardial infarction, COVID-19-associated arrhythmia and conduction system disease, or COVID-19-associated pericarditis.
- The electrocardiogram findings on COVID-19 can be viewed by clicking here.
X-ray
- There are no x-ray findings associated with COVID-19-associated hepatic injury.
- However, an x-ray may be helpful in the diagnosis of complications of COVID-19 such as COVID-19-associated pneumonia which is the most common finding associated with COVID-19 infection.
- The x-ray finidings on COVID-19 can be viewed by clicking here.
Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with COVID-19-associated hepatic injury.
- However, echocardiography may be helpful in the diagnosis of cardiac complications of COVID-19 which include COVID-19-associated heart failure, or COVID-19-associated pericarditis. An abdominal ultrasound may be helpful in the case of COVID-19-associated abdominal pain.
- The echocardiographic findings on COVID-19 can be viewed by clicking here.
CT scan
- There are no CT scan findings associated with COVID-19-associated hepatic injury.
- Chest CT scan may be helpful in suggesting other organ involvement in the COVID-19 which is a multi-organ disease.
- The CT scan findings in COVID-19 can be viewed by clicking here
MRI
- There are no MRI findings associated with COVID-19-associated hepatic injury.
Other Imaging Findings
- There are no other imaging findings associated with COVID-19-associated hepatic injury.
Other Diagnostic Studies
- Procalcitonin and C-reactive protein is found to be higher in patients and can give a fair idea of infection.[18][47]
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]
- 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.
- COVID-19 associated severe hepatic injury: 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 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 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.
- 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 original therapy for chronic liver diseases.
- Liver function tests can serve as indicators of disease progression.
- Treatment and prevention of inflammation in the early stages of the disease prevent severe disease.
- To view medical treatment for COVID-19, click here.
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.[53]
- 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:[54]
- 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.[55]
- 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
- ↑ 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.
- ↑ 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.
- ↑ 3.0 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.
- ↑ 4.0 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.
- ↑ 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). - ↑ 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). - ↑ 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). - ↑ 8.0 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). - ↑ 9.0 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). - ↑ 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). - ↑ 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). - ↑ 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). - ↑ 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). - ↑ 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). - ↑ 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. - ↑ 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). - ↑ 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). - ↑ 18.0 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.
- ↑ 19.0 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) - ↑ 20.0 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) - ↑ 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). - ↑ 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.
- ↑ 23.0 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.
- ↑ 24.0 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.
- ↑ 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.
- ↑ 26.0 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). - ↑ 27.0 27.1 27.2 27.3 27.4 27.5 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). - ↑ 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). - ↑ 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). - ↑ 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). - ↑ 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). - ↑ 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) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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) - ↑ 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) - ↑ 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) - ↑ . doi:10.3969/j.issn.1672-5069.2020.02.001. Missing or empty
|title=(help) - ↑ 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) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 47.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 50.0 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). - ↑ 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.
- ↑ Ali, Nurshad; Hossain, Khaled (2020). "Liver injury in severe COVID-19 infection: current insights and challenges". Expert Review of Gastroenterology & Hepatology. doi:10.1080/17474124.2020.1794812. ISSN 1747-4124.
- ↑ "NIH clinical trial of investigational vaccine for COVID-19 begins | National Institutes of Health (NIH)".
- ↑ "How to Protect Yourself & Others | CDC".
- ↑ "Contact Tracing for COVID-19 | CDC".