key: cord-356195-5pcaxpp9
authors: Jothimani, Dinesh; Venugopal, Radhika; Abedin, Mohammed Forhad; Kaliamoorthy, Ilankumaran; Rela, Mohamed
title: COVID-19 and Liver.
date: 2020-06-15
journal: J Hepatol
DOI: 10.1016/j.jhep.2020.06.006
sha: 
doc_id: 356195
cord_uid: 5pcaxpp9

The current pandemic coronavirus labelled as Severe Acute Respiratory Distress Syndrome Coronavirus -2 (SARS -CoV-2) is a significant public health threat over for past few weeks. Overall case fatality rates range between 2-6%; however, the rates are higher in patients with severe disease, advanced age and underlying comorbidities like diabetes, hypertension and heart disease. Recent reports showed about 2-11% of patients with COVID-19 had underlying chronic liver disease. Experience from previous SARS epidemic suggest that 60% of patients developed various degrees of liver damage. In the current pandemic, hepatic dysfunction was seen in 14-53% of patients with COVID-19, particularly in those with severe disease. Cases of acute liver injury have been reported, associated with higher mortality. Hepatic involvement in COVID-19 could be multifactorial related to any of direct cytopathic effect of the virus, uncontrolled immune reaction, sepsis or drug induced liver injury. The postulated mechanism of viral entry is through the host ACE2 receptors that are abundantly present in type 2 alveolar cells. Interestingly, the expression of ACE2 receptors were identified in the gastrointestinal tract, vascular endothelium and cholangiocytes of the liver. Liver transplant recipients with COVID-19 have been reported recently. Effects of COVID-19 on underlying chronic liver disease requires a detailed evaluation and currently data is lacking and further research is warranted in this area. With lack of definitive therapy, patient education, hand hygiene and social distancing appears to be the cornerstone in minimising the disease spread.

The current pandemic coronavirus labelled as Severe Acute Respiratory Distress Syndrome Coronavirus -2 (SARS -CoV-2) is a significant public health threat over for past few weeks. Overall case fatality rates range between 2-6%; however, the rates are higher in patients with severe disease, advanced age and underlying comorbidities like diabetes, hypertension and heart disease. Recent reports showed about 2-11% of patients with COVID-19 had underlying chronic liver disease. Experience from previous SARS epidemic suggest that 60% of patients developed various degrees of liver damage. In the current pandemic, hepatic dysfunction was seen in 14-53% of patients with COVID-19, particularly in those with severe disease. Cases of acute liver injury have been reported, associated with higher mortality. Hepatic involvement in COVID-19 could be multifactorial related to any of direct cytopathic effect of the virus, uncontrolled immune reaction, sepsis or drug induced liver injury. The postulated mechanism of viral entry is through the host ACE2 receptors that are abundantly present in type 2 alveolar cells. Interestingly, the expression of ACE2 receptors were identified in the gastrointestinal tract, vascular endothelium and cholangiocytes of the liver. Liver transplant recipients with COVID-19 have been reported recently. Effects of COVID-19 on underlying chronic liver disease requires a detailed evaluation and currently data is lacking and further research is warranted in this area. With lack of definitive therapy, patient education, hand hygiene and social distancing appears to be the cornerstone in minimising the disease spread.

Coronavirus is an enveloped single stranded RNA virus, belonging to the Coronaviridae family and Previously with the SARS epidemic, around 60% of patients developed various degrees of liver damage. Due to phylogenetic resemblance it is possible that SARS-CoV-2 also causes liver injury.

Several cases of severe unexplained pneumonia were reported from Wuhan 6 . These data indicate the rapid spread of the disease around the world, with a doubling rate of 7.2 days.

Similar to SARS Co-V, Angiotensin Converting Enzyme2 (ACE2) appears to be the susceptible receptor for COVID-19 and is expressed in more than 80% of alveolar cells in the lungs. Invitro Studies from SARS CoV epidemic identified ACE2 as the host receptor for viral entry 7 .Immunohistochemistry studies from human tissues during SARS pandemic showed, higher expression of ACE2 receptor protein in vascular endothelium of small and large arteries and veins. In the lungs, type 2 alveolar cells highly expressed ACE2. Interestingly, fibrotic lungs had much higher staining for ACE2; whereas bronchial epithelial cells showed weaker expression.

Interestingly, a latest study showed SARS Co-V-2 possessed 10-20-fold higher receptor binding affinity 8 . In addition to respiratory system, ACE2 receptors are expressed in the gastrointestinal tract. Nasal, oral and nasopharyngeal mucosa highly express ACE2 in the basal layer of the squamous epithelium. Smooth muscles of gastric, intestinal colonic mucosa also express ACE2. In addition, brush borders of enterocytes of duodenum, jejunum and ileum abundantly express ACE2 9 .

Hepatic expression of ACE2 is peculiar. It is highly expressed in the endothelial layer of small blood vessels.

Interestingly sinusoidal endothelium does not express ACE2. A latest study by Chai and colleagues 10 found a higher expression of ACE2 cell surface receptor in cholangiocytes (59.7%) than hepatocytes (2.6%).

Interestingly, the level of ACE2 expression in cholangiocytes was similar to type 2 alveolar cells of the lungs, indicating that the liver could be a potential target for SARS-CoV-2. Immunohistochemistry stains were negative on Kupffer cells, T and B lymphocytes.

A recent study from Wuhan showed Asian men had higher expression of ACE2, indicating the possibility of higher susceptibility for COVID-19 in this population 11, 12 .

SARS CoV-2 started as a zoonotic infection; however, the disease spread rapidly from person to person through coughing and sneezing, particularly amongst close contacts. SARS CoV-2 is resilient and can remain viable for 2 hours to 14 days depending on the fomite and the weather condition 13 .

The transmission potential of an infection in the community is based on its basic reproduction rate which is usually denoted as disease transmission ratio (R0). This represents the number of secondary cases occurred from an index case in a susceptible population. The (R0 -R naught) of COVID-19 is 2.2 14 .

Previous studies showed 19.6% to 73% of patients with SARS presented with gastrointestinal symptoms [15] [16] [17] .

Active replication of SARS Co-V was detected in the enterocytes of small intestine 15 . Moreover, SARS Co-V RNA was detected in patients stool samples during the SARS pandemic [15] [16] [17] , which lead to the possibility of faeco-oral transmission Similar pattern was observed with SARS Co-V-2; between 3% and 79% of patients with 

Initial reports from China showed incubation period of SARS-CoV-2 was between 3 to 7 days and occasionally 2 weeks. The longest incubation period identified was 12.5 days 14 .

Large studies from Chinese population reported fever (≥ 38 0 C), dry cough, fatigue, myalgia, leukopenia and raised liver enzymes as presenting clinical features of COVID-19, as shown in (Table 1) . Nausea, vomiting and diarrhoea was seen in 2-10% of patients with COVID-19.

In the latest case series from Wuhan by Wang and colleagues 22 and hypersensitive cardiac troponin (11 vs 5.1, P=0.004). All 138 patients showed bilateral pneumonia in the thoracic scan. Analysis between the survivors and non-survivors showed higher white blood cell count with severe progressive lymphopenia in the non-survivors. With disease progression, these patients required organ support with progressive deterioration in renal function before death.

In the largest database analysis of 1099 confirmed COVID-19 patients from China, by Guan and colleagues 23 

It is intriguing to know the pattern of liver injury in COVID 19. Hepatic involvement in COVID-19 could be multifactorial related to the direct cytopathic effect of the virus, uncontrolled immune reaction, sepsis or drug induced liver injury. Given the higher expression of ACE2 receptors in cholangiocytes, the liver is a potential target for SARS CoV-2. Moreover, COVID-19 may cause worsening of underlying chronic liver disease leading to hepatic decompensation and Acute on Chronic liver failure leading to mortality.

Summary of recently published studies are in described in Table 2 With the knowledge of current evidence, it is clear that elevated liver enzymes are observed predominantly severe and critical cases of COVID-19 compared to mild infection. Raised AST was noted in 8/13 (62%) patients in ICU compared to 7/28 (25%) in the non-ICU setting 24 . The peak ALT and AST levels noted were 7590 U/L and 1445 U/l in severe COVID-19 illness, resepectively 27 . Interestingly, a higher proportion of enzyme elevation was noted in patients receiving Lopinavir/Ritonavir therapy (56.1% vs 25 %). 28 . It is unclear whether the elevated liver enzymes were due to the disease per se or drug induced liver injury. Apart from direct effects, the liver can also be involved in Systemic Inflammatory Response syndrome (SIRS) due to COVID-19

and from the adverse effects of drugs used for viral illness.

Interestingly, despite the presence of ACE2 in cholangiocytes, more patients developed raised transaminases.

However, an unpublished data from Wuhan China, by Xu et al showed an increased GGT in severe cases of COVID-19 30 . However, whether COVID_19 aggravates cholestasis in patients with PBC and PSC need further analysis in this subgroup 31 . Larger data is required to ascertain the pattern and the degree of liver injury in patients affected with COVID-19. Figure 1 ., illustrates the distribution of comorbidities in deceased patients. In the largest case series by Wu and colleagues 59 , the overall mortality was 2.3%; however, in patients with critical disease the mortality was 49%. In a recent report from Italy by Remuzzi and colleagues 60 , mortality related to COVID-19 was 6% (827 patients) with Male: Female ratio 4:1 and a mean age 81 years. More than 60% of these patients had comorbidities. The median time from presentation to death was 14 days. 4, 22 . Age adjusted mortality in these two large series is shown in Figure 2 .

Mortality of COVID-19 is higher in patients with underlying comorbidities. According to a metanalysis of eight studies with 46248 patients in total, which analysed the prevalence of co morbidities in COVID-19, the most common is hypertension with a prevalence of 14-22%, followed by diabetes 6-11%, cardiovascular diseases 4-7% and respiratory disease 1-3 % 61 . The mortality rate was higher in patients with hypertension 48%, followed by 21% in diabetics, 14% in patients with cardiovascular illness, 10 % in chronic Lung disease, 4% each for malignancy, chronic kidney disease and cerebro vascular diseases 26 . However, the mortality in patients with underlying Chronic Liver disease was 0-2 % 62 . In this analysis, HT (48% vs 24%, diabetes (21% vs 14%), and Cardiovascular disease (14% vs 4%) were more common in the deceased patients. Fatty liver is likely seen in this group patient as part of metabolic syndrome which can complicate the issue. Diagnosis of COVID-19 was based on Real time reverse transcription polymerase chain reaction (RT-PCR). In the case series described by Wang and colleagues 22 centrifuged throat swab samples were used for testing. The total viral RNA was extracted within 2 hours using an RNA isolation kit. RT-PCR of the suspension was performed and amplification of Open reading frame (ORIF) and nucleocapsid protein were carried out using respective forward, reverse primers and the probe. Diagnosis were also obtained using nasal swabs, oral and rectal swabs. Interestingly, Xiao and colleagues 20 showed patients with SARS CoV-2 related respiratory illness can continue to shed virus in stool even after a negative respiratory sample.

Although the evidence is less clear, the current treatment recommendations include anti-viral drugs, antibiotics, intravenous fluids and corticosteroids. Oseltamivir was utilized in 89.9% of patients in the Wuhan series this current pandemic situation. Remdisivir has shown good results with COVID-19 63 . Being an RNA virus, one would expect broad spectrum Ribavirin to work; unfortunately, during SARS outbreak ribavirin was associated with significant toxicity including severe haemolysis. Interestingly, Omrani and colleagues 64 19 . In this study, 20.5% and 41% of patients had elevated AST and ALT prior to randomisation, respectively; however, presence of cirrhosis, ALT or AST >5 times upper limit normal were exclusion criteria in this trial.

Increased bilirubin and elevated AST were noted in 3.2% and 2.1%, respectively in the treatment group 66 . Usage of this drug Inhibition of CYP450 will increase the trough levels of CNI, the most commonly used immunosuppression in solid organ transplant recipients. This can lead to potential drug toxicity.

Antibiotics such as fluoroquinolones, third generation cephalosporins were used to reduce secondary infection.

Corticosteroids was used in 44.9% of COVID-19 patients to curtail inflammation 22 They also had and poorer outcomes as against those without cancer 68 . Most patients with HCC have underlying chronic liver disease and therefore, they fall under this high-risk category and likely to have worse outcome.

AASLD currently recommends to possibly delay HCC surveillance by 2 months; however, HCC related treatments should be carried out without much delay 31 . EASL recommends to avoid HCC surveillance in COVID 19 positive patients, also to postpone locoregional therapy and to temporarily withhold immune check point inhibitor theray 69 .

There has been a significant decline in cadaveric organ donation during COVID-19 pandemic 69 . This can affect patients awaiting liver or other solid organ transplantation leading to death. There has been a recent debate on harvesting organs from SARS-Co-V-2 positive donors, similar to the utility of HCV positive donors 70 .

However, the risk of disease transmission to the transplant team remains a major concern 71 . This may be an interesting option in future following effective vaccination.

COVID 19 leaves no stone unturned, including liver transplant recipients. A recent case report from Wuhan described a 37-year-old gentleman with Hepatitis B and HCC, who developed fever on 3 rd day post Trans arterial chemoembolization. He was treated initially with antibiotics and subsequently liver transplantation on day 7. His fever continued on day 9, and a CT chest showed hypostatic changes in both lung fields. A repeat CT chest on the third week showed bilateral ground glass appearance. His nasopharyngeal swab confirmed COVID-19. His tacrolimus was dose reduced to maintain under 10 ng/ml. His liver enzymes increased by 4 th week but settled gradually. His PCR remained positive for nearly 2 months and subsequently cleared 72 Literature from SARS-CoV and MERS show that post liver transplant patients on immunosuppression were not at risk for high mortality. The data for the same with SARS-CoV-2 is very limited. 78 The rapid clinical deterioration in COVID-19 is due to cytokine storm associated with elevated interleukins IL-6, IL-8 and TNF alpha levels. The effects of SARS-CoV-2 infection in immunosuppression is not well established. However, stopping immunosuppressive medications in transplant patients may lead to rejection. In COVID patients on high dose steroids the dose needs to be brought down and maintained at 10 mg/day. When there is lymphopenia, fever and worsening lung condition, azathioprine and Mycophenolate and Calcineurin inhibitors dose needs to be reduced but not stopped. Caution needs to be exercised when considering initiation of steroids or other immunosuppressive therapy in liver disease patients e.g.; Severe alcoholic hepatitis, Auto immune hepatitis etc 31 . Patients on immunosuppression may be more infectious as they have higher viral titres. 79 .

The American Society of Transplantation has provided few recommendations for COVID-19 specifically for those awaiting liver transplantation and transplant recipients. The recommendations include patient education, hand hygiene and social distancing, provision for patients to contact the transplant centre via telephone if they develop fever, cough or flu like symptoms. Each hospital should provide layout protocols for managing these high-risk patients. Careful monitoring of allograft function and drug interactions should be excised in transplant recipients with COVID-19, because Ritonavir can potentially inhibit CYP34A enzyme leading to increasing trough levels of mTOR and calcineurin inhibitors, and drug toxicity. In addition, they have recommended postponing elective surgeries including living donor transplantation and non-urgent deceased donor transplantations in areas of high COVID-19. In addition, potential deceased donors should be adequately tested for SARS-CoV-2 with nucleic acid assay 79 .

With limited therapeutic options, prevention by social distancing appears to be the corner stone of to minimise COVID-19 spread. Virus transmission can be reduced in various methods described in the WHO protocol 6 . This includes, maintaining safe social distance, regular hand washing for 20 seconds, using 60% alcohol hand rub, not to touch face, nostrils or mouth, avoiding crowded places and public events. Countries have taken different measures to reduce viral transmission and most of the countries in the world have gone into 'Lockdown' in order to stop viral transmission. Being a large virus particle, a surgical face mask should provide adequate protection against viral inhalation. N-95 masks should be reserved to the treating team. Personal Protective Equipment (PPE) should be worn according to the institutional policy. All patients with a history of travel to affected regions should be screened for SARS-CoV-2 even if they are asymptomatic. People with high temperature, dry cough, profound tiredness, diarrhoea or other unusual symptoms with recent travel history should be tested for COVID-19. Nations need to make and modify their prevention, testing and treatment strategies time to time based on Guidelines issued by WHO.

COVID-19 caused by SARS-CoV-2 is currently a pandemic. Overall mortality is 2-6% but higher in patients with advanced age and comorbidities. COVID-19 causes pneumonia, but hepatic dysfunction can occur in severe cases and were associated with fatal outcome. Cases of severe acute liver injury has been reported with higher mortality Larger studies with long term follow up are required to characterize the extent of liver damage in COVID-19. Effects of COVID-19 on underlying chronic liver disease requires a detailed evaluation and currently data is lacking and further research is warranted in this area. Critical Disease (reported in 5% cases) Respiratory failure, septic shock and/or multiple organ dysfunction or failure. 

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