COVID-19-associated hepatic injury: Difference between revisions

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Revision as of 06:54, 16 July 2020

For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here

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]

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]

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

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.

History and Symptoms

The majority of patients (14.5%) with COVID-19 associated hepatic injury have a fever, which may be related to the immune response after viral infection.^[18]^[47]^[42]
Other COVID-19 associated symptoms reported in patients with COVID-19 include:^[27]^[42]
- Cough (dry or productive)
- Diarrhea
- Nausea and vomiting
- Pharyngitis
- Abdominal pain
- Anosmia (partial or complete loss of smell)
- Anorexia (Loss of appetite)
- Ageusia (Loss of smell)
- Fatigue
The patient history and symptom associated with COVID-19 can be viewed by clicking here.

Physical Examination

The most common physical examination finding of patients with COVID-19 associated hepatic injury includes fever (normal temperature is not uncommon).^[42]
The presence of hepatomegaly on deep palpation in patients with COVID-19-associated hepatic injury is a forethought of organomegaly.^[51]
The physical exam findings associated with COVID-19 can be viewed by clicking here.

Laboratory Findings

Laboratory findings consistent with the diagnosis of COVID-19-associated hepatic injury include abnormal Liver function tests specially raised AST.^[52]
ALT and AST: The level of both enzymes is elevated in the blood of patients (reported in one-third of patients in a few studies) with liver injury on admission. AST elevation is more common than ALT, reflecting a possible source outside of liver. ICU patients have higher levels of ALT and AST and reduced levels of serum albumin indicating severe liver damage affecting the liver's synthetic ability.^[26]^[52]
LDH: Following AST and ALT, LDH] rise has the highest incidence. Some studies suggest that LDH can be used as an early alarm to prompt further analysis for COVID-19 but the data is insufficient to be conclusive.^[42]
Alkaline phosphatase (ALP): The levels are raised.^[27]
Serum albumin: The levels are found to decrease during the course of hospitalization. The tests are a measure of the synthetic function of the liver.
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]
C-reactive protein (CRP), ESR and specially procalcitonin levels are found to be higher in patients and can give a fair idea of infection.^[18]^[47]^[42]
Glycoprotein gamma-glutamyltransferase (GGT): A rise in the level of GGT points towards cholestasis and thus hepatobiliary involvement.
PTA (INR): It provides a good estimate of liver synthetic function.
Interleukins: Levels of IL‐2‐receptor (IL‐2R), IL‐4, IL‐6, IL‐18, IL‐10, TNF‐α are significantly increased. Specially IL‐6 in the serum of COVID‐19 patients are significantly increased and correlates with disease severity.^[53]
Abnormal liver biochemistries are uncommon in children.^[27]
CBC: Leukocytosis indicates infection and lymphocytosis indicating possible viral infection.^[42]

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

The most common ultrasound findings associated with COVID-19-associated hepatic injury was fatty liver on the right upper quadrant abdominal ultrasound. Abnormal liver laboratory findings as indicated in Lab finding sections served as an indication to perform the abdominal ultrasound. Distended sludge-filled gallbladder suggestive of cholestasis has been reported in half of the patients studied. Portal venous gas has also been identified in a few patients. ^[54]
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

Portal venous gas on abdominal CT has been reported.^[54]
A non-peer-reviewed retrospective cohort study mentions upper abdominal CT findings in 115 COVID-19 patients in China. The study reports liver hypodensity (more common) and pericholecystic fat stranding. The study claims the correlation betwen CT signs and disease severity grading.^[55]
Chest CT scan is helpful in suggesting lung 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 is one liver MRI with gadolinium on a 3T MRI reported to have been performed in a patient with COVID-19-associated hepatic injury and abnormal liver biochemical tests.No specific findings have been reported.^[54]
The MRI findings in COVID-19 can be viewed by clicking here.

Other Imaging Findings

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

Other Diagnostic Studies

There are no other diagnostic studies associated with COVID-19-associated hepatic injury.

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.^[56]
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:^[57]
- 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.^[58]
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

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↑ 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.
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↑ 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.
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↑ 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)
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↑ ^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.
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[ChauLee2004-1] 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.

[AlsaadHajeer2018-2] 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.

[YangYu2020-3] 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.

[ChenZhou2020-4] 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.

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[pmid32031570-7] 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).

[pmid32145190-8] 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).

[pmid32203680-9] 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).

[pmid32171057-10] 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).

[pmid32075364-11] 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).

[pmid32004165-12] 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).

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[pmid32075786-14] 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).

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[pmid32153170-16] 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).

[pmid32220206-17] 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).

[HuangWang2020-18] 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.

[GuanNi2020-19] 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)

[CaiHuang2020-20] 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)

[pmid32243269-21] 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).

[KumarSharma2020-22] 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.

[LiXiao2020-23] 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.

[TianYe2020-24] 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.

[ShehuLu2019-25] 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.

[pmid32298767-26] 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).

[pmid32345544-27] 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).

[pmid32009228-28] 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).

[pmid32094589-29] 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).

[pmid32085846-30] 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).

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[ChaiHu2020-32] 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)

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@@ Line 189: / Line 189: @@
 == Diagnosis ==
 ===Diagnostic Study of Choice===
-*The [[diagnosis]] of [[COVID-19]]-associated hepatic injury is based on the abnormal [[Liver function tests|liver biochemical]] and function tests. The key lies in suspecting liver damage in a [[COVID-19|SARS-CoV2]] patient and testing [[Liver function tests|liver biochemical]] and function tests such as [[LDH]], [[albumin]], [[ALT]], [[AST]], [[Bilirubin#Bilirubin blood tests|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 function tests|liver biochemistries]] are uncommon in children.<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>
+*The diagnosis of [[COVID-19]]-associated hepatic injury is based on the abnormal [[Liver function tests|liver biochemical]] and function tests. The key lies in suspecting liver damage in a [[COVID-19|SARS-CoV2]] patient and testing [[Liver function tests|liver biochemical]] and function tests such as [[LDH]], [[albumin]], [[ALT]], [[AST]], [[Bilirubin#Bilirubin blood tests|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.
 ===History and Symptoms===
-*The majority of patients with [[Liver function test|abnormal liver function]] have a [[fever]], which may be related to the [[immune response]] after viral infection.<ref name="HuangWang2020">{{cite journal|last1=Huang|first1=Chaolin|last2=Wang|first2=Yeming|last3=Li|first3=Xingwang|last4=Ren|first4=Lili|last5=Zhao|first5=Jianping|last6=Hu|first6=Yi|last7=Zhang|first7=Li|last8=Fan|first8=Guohui|last9=Xu|first9=Jiuyang|last10=Gu|first10=Xiaoying|last11=Cheng|first11=Zhenshun|last12=Yu|first12=Ting|last13=Xia|first13=Jiaan|last14=Wei|first14=Yuan|last15=Wu|first15=Wenjuan|last16=Xie|first16=Xuelei|last17=Yin|first17=Wen|last18=Li|first18=Hui|last19=Liu|first19=Min|last20=Xiao|first20=Yan|last21=Gao|first21=Hong|last22=Guo|first22=Li|last23=Xie|first23=Jungang|last24=Wang|first24=Guangfa|last25=Jiang|first25=Rongmeng|last26=Gao|first26=Zhancheng|last27=Jin|first27=Qi|last28=Wang|first28=Jianwei|last29=Cao|first29=Bin|title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China|journal=The Lancet|volume=395|issue=10223|year=2020|pages=497–506|issn=01406736|doi=10.1016/S0140-6736(20)30183-5}}</ref><ref name="WangHu2020">{{cite journal|last1=Wang|first1=Dawei|last2=Hu|first2=Bo|last3=Hu|first3=Chang|last4=Zhu|first4=Fangfang|last5=Liu|first5=Xing|last6=Zhang|first6=Jing|last7=Wang|first7=Binbin|last8=Xiang|first8=Hui|last9=Cheng|first9=Zhenshun|last10=Xiong|first10=Yong|last11=Zhao|first11=Yan|last12=Li|first12=Yirong|last13=Wang|first13=Xinghuan|last14=Peng|first14=Zhiyong|title=Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China|journal=JAMA|volume=323|issue=11|year=2020|pages=1061|issn=0098-7484|doi=10.1001/jama.2020.1585}}</ref>
+*The majority of patients (14.5%) with [[COVID-19]] associated hepatic injury have a [[fever]], which may be related to the [[immune response]] after viral infection.<ref name="HuangWang2020">{{cite journal|last1=Huang|first1=Chaolin|last2=Wang|first2=Yeming|last3=Li|first3=Xingwang|last4=Ren|first4=Lili|last5=Zhao|first5=Jianping|last6=Hu|first6=Yi|last7=Zhang|first7=Li|last8=Fan|first8=Guohui|last9=Xu|first9=Jiuyang|last10=Gu|first10=Xiaoying|last11=Cheng|first11=Zhenshun|last12=Yu|first12=Ting|last13=Xia|first13=Jiaan|last14=Wei|first14=Yuan|last15=Wu|first15=Wenjuan|last16=Xie|first16=Xuelei|last17=Yin|first17=Wen|last18=Li|first18=Hui|last19=Liu|first19=Min|last20=Xiao|first20=Yan|last21=Gao|first21=Hong|last22=Guo|first22=Li|last23=Xie|first23=Jungang|last24=Wang|first24=Guangfa|last25=Jiang|first25=Rongmeng|last26=Gao|first26=Zhancheng|last27=Jin|first27=Qi|last28=Wang|first28=Jianwei|last29=Cao|first29=Bin|title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China|journal=The Lancet|volume=395|issue=10223|year=2020|pages=497–506|issn=01406736|doi=10.1016/S0140-6736(20)30183-5}}</ref><ref name="WangHu2020">{{cite journal|last1=Wang|first1=Dawei|last2=Hu|first2=Bo|last3=Hu|first3=Chang|last4=Zhu|first4=Fangfang|last5=Liu|first5=Xing|last6=Zhang|first6=Jing|last7=Wang|first7=Binbin|last8=Xiang|first8=Hui|last9=Cheng|first9=Zhenshun|last10=Xiong|first10=Yong|last11=Zhao|first11=Yan|last12=Li|first12=Yirong|last13=Wang|first13=Xinghuan|last14=Peng|first14=Zhiyong|title=Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China|journal=JAMA|volume=323|issue=11|year=2020|pages=1061|issn=0098-7484|doi=10.1001/jama.2020.1585}}</ref><ref name="FanChen2020">{{cite journal|last1=Fan|first1=Zhenyu|last2=Chen|first2=Liping|last3=Li|first3=Jun|last4=Cheng|first4=Xin|last5=Yang|first5=Jingmao|last6=Tian|first6=Cheng|last7=Zhang|first7=Yajun|last8=Huang|first8=Shaoping|last9=Liu|first9=Zhanju|last10=Cheng|first10=Jilin|title=Clinical Features of COVID-19-Related Liver Functional Abnormality|journal=Clinical Gastroenterology and Hepatology|volume=18|issue=7|year=2020|pages=1561–1566|issn=15423565|doi=10.1016/j.cgh.2020.04.002}}</ref>
-*Other [[COVID-19]] associated symptoms reported in patients with [[COVID-19]] include:<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>
+*Other [[COVID-19]] associated symptoms reported in patients with [[COVID-19]] include:<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><ref name="FanChen2020">{{cite journal|last1=Fan|first1=Zhenyu|last2=Chen|first2=Liping|last3=Li|first3=Jun|last4=Cheng|first4=Xin|last5=Yang|first5=Jingmao|last6=Tian|first6=Cheng|last7=Zhang|first7=Yajun|last8=Huang|first8=Shaoping|last9=Liu|first9=Zhanju|last10=Cheng|first10=Jilin|title=Clinical Features of COVID-19-Related Liver Functional Abnormality|journal=Clinical Gastroenterology and Hepatology|volume=18|issue=7|year=2020|pages=1561–1566|issn=15423565|doi=10.1016/j.cgh.2020.04.002}}</ref>
-**[[Cough]]
+**[[Cough]] (dry or productive)
-**Sorethroat
+**[[COVID-19-associated diarrhea|Diarrhea]]
-**[[Diarrhea]]
+**[[COVID-19-associated nausea and vomiting|Nausea and vomiting]]
-**[[Abdominal pain]]
+**[[Pharyngitis]]
-**[[COVID-19-associated anosmia|Anosmia]]
+**[[COVID-19-associated abdominal pain|Abdominal pain]]
-*[[Ageusia]]
+**[[COVID-19-associated anosmia|Anosmia]] (partial or complete loss of smell)
-* To browse the symptoms of COVID-19, [[COVID-19 natural history, complications and prognosis|Click here]].
+**[[COVID-19-associated anorexia|Anorexia]] (Loss of appetite)
+**[[Ageusia]] (Loss of smell)
+**[[Fatigue]]
+*The patient history and symptom associated with [[COVID-19]] can be viewed by [[COVID-19 physical examination|clicking here]].
 ===Physical Examination===
-* The presence of [[hepatomegaly]] in patients with COVID-19-associated hepatic injury may be aforethought of [[organomegaly]].<ref name="LiFan2020">{{cite journal|last1=Li|first1=Jie|last2=Fan|first2=Jian-Gao|title=Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease|journal=Journal of Clinical and Translational Hepatology|volume=8|issue=1|year=2020|pages=1–5|issn=2225-0719|doi=10.14218/JCTH.2020.00019}}</ref>
+*The most common physical examination finding of patients with [[COVID-19]] associated hepatic injury includes [[fever]] (normal temperature is not uncommon).<ref name="FanChen2020">{{cite journal|last1=Fan|first1=Zhenyu|last2=Chen|first2=Liping|last3=Li|first3=Jun|last4=Cheng|first4=Xin|last5=Yang|first5=Jingmao|last6=Tian|first6=Cheng|last7=Zhang|first7=Yajun|last8=Huang|first8=Shaoping|last9=Liu|first9=Zhanju|last10=Cheng|first10=Jilin|title=Clinical Features of COVID-19-Related Liver Functional Abnormality|journal=Clinical Gastroenterology and Hepatology|volume=18|issue=7|year=2020|pages=1561–1566|issn=15423565|doi=10.1016/j.cgh.2020.04.002}}</ref>
-* To browse the physical exam findings associated with [[COVID-19]], [[COVID-19 physical examination|Click here]].
+*The presence of [[hepatomegaly]] on deep [[palpation]] in patients with COVID-19-associated hepatic injury is a forethought of [[organomegaly]].<ref name="LiFan2020">{{cite journal|last1=Li|first1=Jie|last2=Fan|first2=Jian-Gao|title=Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease|journal=Journal of Clinical and Translational Hepatology|volume=8|issue=1|year=2020|pages=1–5|issn=2225-0719|doi=10.14218/JCTH.2020.00019}}</ref>
+* The physical exam findings associated with [[COVID-19]] can be viewed by [[COVID-19 history and symptoms|clicking here]].
 ===Laboratory Findings===
-*Laboratory findings consistent with the diagnosis of [[COVID-19]]-associated hepatic injury include abnormal [[Liver function tests]] specially raised [[AST]].
+*Laboratory findings consistent with the diagnosis of [[COVID-19]]-associated hepatic injury include abnormal [[Liver function tests]] specially raised [[AST]].<ref name="AlqahtaniSchattenberg2020">{{cite journal|last1=Alqahtani|first1=Saleh A|last2=Schattenberg|first2=Jörn M|title=Liver injury in COVID-19:  The current evidence|journal=United European Gastroenterology Journal|volume=8|issue=5|year=2020|pages=509–519|issn=2050-6406|doi=10.1177/2050640620924157}}</ref>
-*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.<ref name="pmid32298767">{{cite journal |vauthors=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 |title=COVID-19: Abnormal liver function tests |journal=J. Hepatol. |volume= |issue= |pages= |date=April 2020 |pmid=32298767 |pmc=7194951 |doi=10.1016/j.jhep.2020.04.006 |url=}}</ref>
+*''[[ALT]] and [[AST]]'': The level of both enzymes is elevated in the blood of patients (reported in one-third of patients in a few studies) with liver injury on admission. [[AST]] elevation is more common than [[ALT]], reflecting a possible source outside of liver. [[ICU]] patients have higher levels of [[ALT]] and [[AST]] and reduced levels of [[serum albumin]] indicating severe liver damage affecting the liver's synthetic ability.<ref name="pmid32298767">{{cite journal |vauthors=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 |title=COVID-19: Abnormal liver function tests |journal=J. Hepatol. |volume= |issue= |pages= |date=April 2020 |pmid=32298767 |pmc=7194951 |doi=10.1016/j.jhep.2020.04.006 |url=}}</ref><ref name="AlqahtaniSchattenberg2020">{{cite journal|last1=Alqahtani|first1=Saleh A|last2=Schattenberg|first2=Jörn M|title=Liver injury in COVID-19:  The current evidence|journal=United European Gastroenterology Journal|volume=8|issue=5|year=2020|pages=509–519|issn=2050-6406|doi=10.1177/2050640620924157}}</ref>
-*Serum [[albumin]] levels were found to get lower during the course of hospitalization. The tests is a measure of synthetic function of the liver.
+*''[[LDH]]'': Following [[AST]] and [[ALT]], [[LDH]]] rise has the highest [[incidence]]. Some studies suggest that LDH can be used as an early alarm to prompt further analysis for [[COVID-19]] but the data is insufficient to be conclusive.<ref name="FanChen2020">{{cite journal|last1=Fan|first1=Zhenyu|last2=Chen|first2=Liping|last3=Li|first3=Jun|last4=Cheng|first4=Xin|last5=Yang|first5=Jingmao|last6=Tian|first6=Cheng|last7=Zhang|first7=Yajun|last8=Huang|first8=Shaoping|last9=Liu|first9=Zhanju|last10=Cheng|first10=Jilin|title=Clinical Features of COVID-19-Related Liver Functional Abnormality|journal=Clinical Gastroenterology and Hepatology|volume=18|issue=7|year=2020|pages=1561–1566|issn=15423565|doi=10.1016/j.cgh.2020.04.002}}</ref>
-*[[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.
+*''[[Alkaline phosphatase]] (ALP)'': The levels are raised.<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>
-*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.<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>
+*''[[Serum albumin]]'': The levels are found to decrease during the course of hospitalization. The tests are a measure of the synthetic function of the liver.
-*[[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]].<ref name="FanChen2020">{{cite journal|last1=Fan|first1=Zhenyu|last2=Chen|first2=Liping|last3=Li|first3=Jun|last4=Cheng|first4=Xin|last5=Yang|first5=Jingmao|last6=Tian|first6=Cheng|last7=Zhang|first7=Yajun|last8=Huang|first8=Shaoping|last9=Liu|first9=Zhanju|last10=Cheng|first10=Jilin|title=Clinical Features of COVID-19-Related Liver Functional Abnormality|journal=Clinical Gastroenterology and Hepatology|volume=18|issue=7|year=2020|pages=1561–1566|issn=15423565|doi=10.1016/j.cgh.2020.04.002}}</ref>
+*''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.<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>
-* Glycoprotein [[gamma-glutamyltransferase]] (GGT) may point towards [[hepatobiliary]] involvement.
+*[[C-reactive protein]] (CRP), [[ESR]] and specially [[procalcitonin]] levels are found to be higher in patients and can give a fair idea of [[infection]].<ref name="HuangWang2020">{{cite journal|last1=Huang|first1=Chaolin|last2=Wang|first2=Yeming|last3=Li|first3=Xingwang|last4=Ren|first4=Lili|last5=Zhao|first5=Jianping|last6=Hu|first6=Yi|last7=Zhang|first7=Li|last8=Fan|first8=Guohui|last9=Xu|first9=Jiuyang|last10=Gu|first10=Xiaoying|last11=Cheng|first11=Zhenshun|last12=Yu|first12=Ting|last13=Xia|first13=Jiaan|last14=Wei|first14=Yuan|last15=Wu|first15=Wenjuan|last16=Xie|first16=Xuelei|last17=Yin|first17=Wen|last18=Li|first18=Hui|last19=Liu|first19=Min|last20=Xiao|first20=Yan|last21=Gao|first21=Hong|last22=Guo|first22=Li|last23=Xie|first23=Jungang|last24=Wang|first24=Guangfa|last25=Jiang|first25=Rongmeng|last26=Gao|first26=Zhancheng|last27=Jin|first27=Qi|last28=Wang|first28=Jianwei|last29=Cao|first29=Bin|title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China|journal=The Lancet|volume=395|issue=10223|year=2020|pages=497–506|issn=01406736|doi=10.1016/S0140-6736(20)30183-5}}</ref><ref name="WangHu2020">{{cite journal|last1=Wang|first1=Dawei|last2=Hu|first2=Bo|last3=Hu|first3=Chang|last4=Zhu|first4=Fangfang|last5=Liu|first5=Xing|last6=Zhang|first6=Jing|last7=Wang|first7=Binbin|last8=Xiang|first8=Hui|last9=Cheng|first9=Zhenshun|last10=Xiong|first10=Yong|last11=Zhao|first11=Yan|last12=Li|first12=Yirong|last13=Wang|first13=Xinghuan|last14=Peng|first14=Zhiyong|title=Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China|journal=JAMA|volume=323|issue=11|year=2020|pages=1061|issn=0098-7484|doi=10.1001/jama.2020.1585}}</ref><ref name="FanChen2020">{{cite journal|last1=Fan|first1=Zhenyu|last2=Chen|first2=Liping|last3=Li|first3=Jun|last4=Cheng|first4=Xin|last5=Yang|first5=Jingmao|last6=Tian|first6=Cheng|last7=Zhang|first7=Yajun|last8=Huang|first8=Shaoping|last9=Liu|first9=Zhanju|last10=Cheng|first10=Jilin|title=Clinical Features of COVID-19-Related Liver Functional Abnormality|journal=Clinical Gastroenterology and Hepatology|volume=18|issue=7|year=2020|pages=1561–1566|issn=15423565|doi=10.1016/j.cgh.2020.04.002}}</ref>
-*[[PTA]] (INR) provides a good estimate of liver synthetic function.
+* ''Glycoprotein [[gamma-glutamyltransferase]] (GGT)'': A rise in the level of GGT points towards [[cholestasis]] and thus [[Biliary|hepatobiliary]] involvement.
-*[[Alkaline phosphatase]] (ALP) is higher in patients.<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>
+*[[PTA]] (INR): It provides a good estimate of liver synthetic function.
-*Levels of [[Interleukin|IL]]‐2‐receptor (IL‐2R), IL‐4, IL‐6, IL‐18, IL‐10, [[Tumour necrosis factor|TNF‐α]] were significantly increased IL‐6 in the serum of [[COVID‐19]] patients are significantly increased and correlate with disease severity.<ref name="AliHossain2020">{{cite journal|last1=Ali|first1=Nurshad|last2=Hossain|first2=Khaled|title=Liver injury in severe COVID-19 infection: current insights and challenges|journal=Expert Review of Gastroenterology & Hepatology|year=2020|issn=1747-4124|doi=10.1080/17474124.2020.1794812}}</ref>
+*''[[Interleukins]]'': Levels of [[Interleukin|IL]]‐2‐receptor (IL‐2R), IL‐4, IL‐6, IL‐18, IL‐10, [[Tumour necrosis factor|TNF‐α]] are significantly increased. Specially IL‐6 in the serum of [[COVID‐19]] patients are significantly increased and correlates with disease severity.<ref name="AliHossain2020">{{cite journal|last1=Ali|first1=Nurshad|last2=Hossain|first2=Khaled|title=Liver injury in severe COVID-19 infection: current insights and challenges|journal=Expert Review of Gastroenterology & Hepatology|year=2020|issn=1747-4124|doi=10.1080/17474124.2020.1794812}}</ref>
+*Abnormal [[Liver function tests|liver biochemistries]] are uncommon in children.<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>
+*''[[CBC]]'': [[Leukocytosis]] indicates infection and [[lymphocytosis]] indicating possible viral infection.<ref name="FanChen2020">{{cite journal|last1=Fan|first1=Zhenyu|last2=Chen|first2=Liping|last3=Li|first3=Jun|last4=Cheng|first4=Xin|last5=Yang|first5=Jingmao|last6=Tian|first6=Cheng|last7=Zhang|first7=Yajun|last8=Huang|first8=Shaoping|last9=Liu|first9=Zhanju|last10=Cheng|first10=Jilin|title=Clinical Features of COVID-19-Related Liver Functional Abnormality|journal=Clinical Gastroenterology and Hepatology|volume=18|issue=7|year=2020|pages=1561–1566|issn=15423565|doi=10.1016/j.cgh.2020.04.002}}</ref>
 ===Electrocardiogram===
@@ Line 224: / Line 230: @@
 ===X-ray===
-*There are no [[X-ray]] findings associated with [[COVID-19]]-associated hepatic injury.
+*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.
+*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 [[COVID-19 x ray|clicking here]].
+*The x-ray finidings on [[COVID-19]] can be viewed by [[COVID-19 x ray|clicking here]].
 ===Echocardiography or Ultrasound===
-*There are no echocardiography/ultrasound findings associated with [[COVID-19]]-associated hepatic injury.
+*The most common ultrasound findings associated with [[COVID-19]]-associated hepatic injury was fatty liver on the right upper quadrant abdominal ultrasound. Abnormal liver laboratory findings as indicated in Lab finding sections served as an indication to perform the abdominal ultrasound. Distended sludge-filled gallbladder suggestive of cholestasis has been reported in half of the patients studied. Portal venous gas has also been identified in a few patients. <ref name="BhayanaSom2020">{{cite journal|last1=Bhayana|first1=Rajesh|last2=Som|first2=Avik|last3=Li|first3=Matthew D|last4=Carey|first4=Denston E|last5=Anderson|first5=Mark A|last6=Blake|first6=Michael A|last7=Catalano|first7=Onofrio|last8=Gee|first8=Michael S|last9=Hahn|first9=Peter F|last10=Harisinghani|first10=Mukesh|last11=Kilcoyne|first11=Aoife|last12=Lee|first12=Susanna I|last13=Mojtahed|first13=Amirkasra|last14=Pandharipande|first14=Pari V|last15=Pierce|first15=Theodore T|last16=Rosman|first16=David A|last17=Saini|first17=Sanjay|last18=Samir|first18=Anthony E|last19=Simeone|first19=Joseph F|last20=Gervais|first20=Debra A|last21=Velmahos|first21=George|last22=Misdraji|first22=Joseph|last23=Kambadakone|first23=Avinash|title=Abdominal Imaging Findings in COVID-19: Preliminary                     Observations|journal=Radiology|year=2020|pages=201908|issn=0033-8419|doi=10.1148/radiol.2020201908}}</ref>
-*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]].
+*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 [[COVID-19 echocardiography and ultrasound|clicking here]].<br />
 ===CT scan===
-*There are no [[CT scan]] findings associated with [[COVID-19]]-associated hepatic injury.
+*Portal venous gas on abdominal CT has been reported.<ref name="BhayanaSom2020">{{cite journal|last1=Bhayana|first1=Rajesh|last2=Som|first2=Avik|last3=Li|first3=Matthew D|last4=Carey|first4=Denston E|last5=Anderson|first5=Mark A|last6=Blake|first6=Michael A|last7=Catalano|first7=Onofrio|last8=Gee|first8=Michael S|last9=Hahn|first9=Peter F|last10=Harisinghani|first10=Mukesh|last11=Kilcoyne|first11=Aoife|last12=Lee|first12=Susanna I|last13=Mojtahed|first13=Amirkasra|last14=Pandharipande|first14=Pari V|last15=Pierce|first15=Theodore T|last16=Rosman|first16=David A|last17=Saini|first17=Sanjay|last18=Samir|first18=Anthony E|last19=Simeone|first19=Joseph F|last20=Gervais|first20=Debra A|last21=Velmahos|first21=George|last22=Misdraji|first22=Joseph|last23=Kambadakone|first23=Avinash|title=Abdominal Imaging Findings in COVID-19: Preliminary                     Observations|journal=Radiology|year=2020|pages=201908|issn=0033-8419|doi=10.1148/radiol.2020201908}}</ref>
-*Chest [[CT scan]] may be helpful in suggesting other organ involvement in the [[COVID-19]] which is a multi-organ [[disease]].
+*A non-peer-reviewed retrospective cohort study mentions upper abdominal CT findings in 115 [[COVID-19]] patients in China. The study reports liver hypodensity (more common) and pericholecystic fat stranding. The study claims the correlation betwen CT signs and disease severity grading.<ref name="LeiZhang2020">{{cite journal|last1=Lei|first1=Ping|last2=Zhang|first2=Lan|last3=Han|first3=Ping|last4=Zheng|first4=Chuansheng|last5=Tong|first5=Qiaoxia|last6=Shang|first6=Haitao|last7=Yang|first7=Fan|last8=Hu|first8=Yu|last9=Li|first9=Xin|last10=Song|first10=Yuhu|year=2020|doi=10.21203/rs.3.rs-28692/v1}}</ref>
-*The [[CT scan]] findings in [[COVID-19]] can be viewed by [[COVID-19 CT scan|clicking here]]
+*Chest CT scan is helpful in suggesting lung involvement in the [[COVID-19]] which is a multi-organ [[disease]].
+*The CT scan findings in [[COVID-19]] can be viewed by [[COVID-19 CT scan|clicking here]].
 ===MRI===
-*There are no [[MRI]] findings associated with [[COVID-19]]-associated hepatic injury.
+*There is one liver MRI with gadolinium on a 3T MRI reported to have been performed in a patient with [[COVID-19]]-associated hepatic injury and abnormal liver biochemical tests.No specific findings have been reported.<ref name="BhayanaSom2020">{{cite journal|last1=Bhayana|first1=Rajesh|last2=Som|first2=Avik|last3=Li|first3=Matthew D|last4=Carey|first4=Denston E|last5=Anderson|first5=Mark A|last6=Blake|first6=Michael A|last7=Catalano|first7=Onofrio|last8=Gee|first8=Michael S|last9=Hahn|first9=Peter F|last10=Harisinghani|first10=Mukesh|last11=Kilcoyne|first11=Aoife|last12=Lee|first12=Susanna I|last13=Mojtahed|first13=Amirkasra|last14=Pandharipande|first14=Pari V|last15=Pierce|first15=Theodore T|last16=Rosman|first16=David A|last17=Saini|first17=Sanjay|last18=Samir|first18=Anthony E|last19=Simeone|first19=Joseph F|last20=Gervais|first20=Debra A|last21=Velmahos|first21=George|last22=Misdraji|first22=Joseph|last23=Kambadakone|first23=Avinash|title=Abdominal Imaging Findings in COVID-19: Preliminary                     Observations|journal=Radiology|year=2020|pages=201908|issn=0033-8419|doi=10.1148/radiol.2020201908}}</ref>
+*The MRI findings in [[COVID-19]] can be viewed by [[COVID-19 MRI|clicking here]].
 ===Other Imaging Findings===
@@ Line 245: / Line 253: @@
 ===Other Diagnostic Studies===
-*[[Procalcitonin]] and [[C-reactive protein]] is found to be higher in patients and can give a fair idea of [[infection]].<ref name="HuangWang2020">{{cite journal|last1=Huang|first1=Chaolin|last2=Wang|first2=Yeming|last3=Li|first3=Xingwang|last4=Ren|first4=Lili|last5=Zhao|first5=Jianping|last6=Hu|first6=Yi|last7=Zhang|first7=Li|last8=Fan|first8=Guohui|last9=Xu|first9=Jiuyang|last10=Gu|first10=Xiaoying|last11=Cheng|first11=Zhenshun|last12=Yu|first12=Ting|last13=Xia|first13=Jiaan|last14=Wei|first14=Yuan|last15=Wu|first15=Wenjuan|last16=Xie|first16=Xuelei|last17=Yin|first17=Wen|last18=Li|first18=Hui|last19=Liu|first19=Min|last20=Xiao|first20=Yan|last21=Gao|first21=Hong|last22=Guo|first22=Li|last23=Xie|first23=Jungang|last24=Wang|first24=Guangfa|last25=Jiang|first25=Rongmeng|last26=Gao|first26=Zhancheng|last27=Jin|first27=Qi|last28=Wang|first28=Jianwei|last29=Cao|first29=Bin|title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China|journal=The Lancet|volume=395|issue=10223|year=2020|pages=497–506|issn=01406736|doi=10.1016/S0140-6736(20)30183-5}}</ref><ref name="WangHu2020">{{cite journal|last1=Wang|first1=Dawei|last2=Hu|first2=Bo|last3=Hu|first3=Chang|last4=Zhu|first4=Fangfang|last5=Liu|first5=Xing|last6=Zhang|first6=Jing|last7=Wang|first7=Binbin|last8=Xiang|first8=Hui|last9=Cheng|first9=Zhenshun|last10=Xiong|first10=Yong|last11=Zhao|first11=Yan|last12=Li|first12=Yirong|last13=Wang|first13=Xinghuan|last14=Peng|first14=Zhiyong|title=Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China|journal=JAMA|volume=323|issue=11|year=2020|pages=1061|issn=0098-7484|doi=10.1001/jama.2020.1585}}</ref>
+*There are no other diagnostic studies associated with [[COVID-19]]-associated hepatic injury.
 == Treatment ==