Management of liver diseases during the pandemic of coronavirus disease-19



# Introduction
Coronavirus disease-19 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is spreading rapidly all over the world, including Korea, which was firstly reported from Wuhan, China.Even in this pandemonium, the treatment of patients with chronic liver disease, hepatocellular carcinoma (HCC), and management associated with liver transplantation should be elegantly continued. Precautions to be undertaken with knowledge of COVID-19 are summarized in this document.

## Details and recommendations

## Effect of sars-cov-2 virus on the liver
1) SARS-CoV-2 binds to cells through angiotensin-converting enzyme 2 (ACE2). ACE2 is highly expressed in hepatocytes and bile duct epithelial cells. Thus, hepatocytes and bile duct epithelial cells can become target cells for viral infection.However, there is no evidence of viral inclusion within liver tissue.Liver function test (LFT) abnormalities. (1) Incidence: 14-53%.Rare cases of acute liver damage have been reported in COVID-19 patients.(2) Presented as: elevated serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase, and bilirubin. LFT abnormalities can be caused by immune-cytopathic damage following direct cytotoxicity and inflammatory response of SARS-CoV-2.It is difficult to distinguish whether liver dysfunction is due to SARS-CoV-2 itself, its complications, or side effects caused by therapeutic drugs.
(3) SARS-CoV-2 can influence the disease course of chronic liver disease due to its direct toxicity to the liver, reactivation of preexisting chronic hepatitis virus, and liver damage from medications targeting the SARS-CoV-2. Experimental drugs such as remdesivir, chloroquine, hydroxychloroquine, tocilizumab, and statins used as therapeutic agents for COVID-19, along with antibiotics and antifungal agents used as treatments for accompanying bacterial and fungal pneumonia may induce liver toxicity. In a Chinese randomized controlled trial of remdesivir, serum bilirubin was elevated in approximately 10% of subjects in the remdesivir group, which was not significantly higher than that (9%) in the placebo group. AST elevation was also reported in 5% of subjects in the remdesivir group, which was not significantly different from the placebo group (12%).In another randomized controlled trial of remdesivir vs. placebo, the elevation of AST and ALT was not significantly more frequent in the remdesivir group than that in the placebo group. 10 (4) LFT abnormalities are more common in patients with severe COVID-19 than in patients with mild cases. 6 (5) Hypoalbuminemia at hospitalization reflects the severity of COVID-19. 7 (6) Hepatic dysfunction is generally transient and does not require special treatment.Data on liver histology of patients with COVID-19 are limited and its characteristics are mainly nonspecific. 11

## Management of outpatients with stable liver disease
1) Interindividual transmission of SARS-CoV-2 may occur even from asymptomatic patients to both immunocompromised and immunocompetent groups.In children, severe or fatal COVID-19 is uncommon and increases in ALT and AST are usually mild. However, transmission of the virus is still possible.About 0.6% of COVID-19 patients had chronic liver disease according to report from Centers for Disease Control and Prevention (CDC) of the USA. 14 Approximately 2-11% of Chinese COV-ID-19 patients accompanied chronic liver disease.Approximately 1% of COVID-19 patients were reported to have a history of cancer. They had a higher risk of intensive care unit care or death.The incidence of COVID-19 or the risk of death associated with SARS-CoV-2 in HCC patients are unknown.
5) The median tumor doubling time of 4-6 months in HCC could be the rationale for a brief delay of radiological surveillance. 17

## [considerations]
1. Postponing an appointment or considering a non-visit, nonface-to-face interview is necessary in the management of patients with stable liver disease. considering the lack of capacity in medical services amid COVID-19 pandemic according to each institution and patients' personal circumstances. (It is necessary to discuss benefits and risks caused by a delay in cancer monitoring with the patient and a documentation of the explanation is recommended.) 6. Treatment of HCCs should be continued regardless of the COVID-19 pandemic.

## Management of patients with decompensated cirrhosis or waiting for a liver transplant
1) The effects of SARS-CoV-2 infection on patients with chronic liver disease, decompensated cirrhosis, and awaiting liver transplantation are not clearly understood.
2) Based on previous experience with SARS-CoV, patients with chronic liver disease (chronic hepatitis B and C) are expected to be more vulnerable to COVID-19 infection, 7 but some studies have reported that patients with chronic liver disease do not have worse prognosis.Therefore, it is too early to make a conclusion with the evidence that we have so far.
3) A nationwide study in the USA showed that cirrhosis hospitalizations declined during the COVID-19 pandemic and model for end-stage liver disease (MELD) score at admission was higher in the late-COVID era compared to the previous period.This finding suggests that the COVID-19 pandemic delayed admission of cirrhotic patients possibly due to limited medical resources. Such indirect secondary effect of COVID-19 on cirrhotic patients needs to be considered.

## Liver transplantation and post-transplantation care
There is no evidence that the severity of COVID-19 infection increases in patients after liver transplantation. (1) According to data reported up to date, pulmonary injury is increased due to innate immune response to SARS-CoV-2 and immunosuppression might have a protective role.(2) In cases of severe acute respiratory syndrome and Middle East respiratory syndrome (MERS; from 2012), immunosuppression after liver transplantation did not increase the risk of mortality.(3) According to a case report, a patient who was tested positive for COV-ID-19 immediately after liver transplantation became negative for COVID-19 after treatment but returned to positive after increasing the dosage of immunosuppressants. 22

## [considerations]
1. SARS-CoV-2 positive patients are limited as candidates for organ donation. A. Deceased donors: All deceased donors should be tested for SARS-CoV-2 before donation. They should be confirmed as negative for SARS-CoV-2 before performing an organ harvesting surgery.Treatment of HCC patientsAs the COVID-19 pandemic state is prolonged, shortage of medical devices and health care providers may occur.
2) A multidisciplinary team approach is recommended to plan treatment method and appropriate time for HCC patients while considering the risk of in-hospital infection.
3) Treatment of HCC can be undertaken at the public relief hospitals. 4) HCC patients should minimize visits to hospitals in order to decrease the risk of infection. Invasive treatments should be considered for patients with low possibility of decompensation and minimal risk for developing severe COVID-19.

## [considerations]
1. There is no need to delay necessary treatment unless there is a shortage of medical devices or health care providers. 2. For patients with a high risk of developing severe COVID-19, treatment should be decided after evaluating risks and benefits. 3. Treatment response evaluation can be extended temporarily according to COVID-19 pandemic status. 4. When a patient is on a clinical trial, rearrangement of hospital visits, treatment schedule and treatment site can be considered. 5. If it is difficult to apply the first recommended treatment modality, optimal alternative therapy or intensive imaging examinations should be performed. 6. Liver transplantation can be delayed in order to protect the donor and the recipient. In such a case, the patient should be fully informed about the possibility of cancer progression and deterioration of liver function. 7. While waiting for liver transplantation, bridging therapies could be considered.The use of immunosuppressantsEffects of immunosuppression on the development of COV-ID-19 have not been established yet.
2) Rapid exacerbation of respiratory symptoms has been reported to be systemic and respiratory inflammatory reactions related to increased levels of serum interleukin (IL)-6, IL-8, and tumor necrosis factor-.Potential benefits of corticosteroids in preventing the progression of symptoms in mild COVID-19 patients have not been well understood yet. However, the use of steroids in SARS and MERS patients was not advantageous in a meta-analysis.In patients with autoimmune liver disease or patients with acute rejection after liver transplantation, rapid reduction or discontinuation of immunosuppressive agents can exacerbate the course of the disease.
[Considerations]

## Use of immunosuppressants in covid-19-negative patients
A. djustment of the dose of immunosuppressants in advance due to the COVID-19 pandemic is not necessary.

## Use of immunosuppressants in covid-19-positive patients
A. Steroids or immunosuppressants can be used when potential benefits are greater than the risk. B. Consider minimizing the dosage of high-dose steroids, but maintain a sufficient dose to avoid adrenal insufficiency or aggravation of underlying liver disease that has been controlled by steroids. C. In cases of pneumonia aggravation, lymphopenia and persisting fever, the daily dose of azathioprine or mycophenolate can be reduced or discontinuation of the drug can be considered according to the discretion of the clinician's judgement. D. In cases of pneumonia aggravation, lymphopenia, and persisting fever, the daily dose of calcineurin inhibitors may be reduced. However, such inhibitors should not be discontinued since calcineurin inhibitors as cornerstones

## Inpatient care and inpatient/outpatient procedures
1) The possibility of fecal-to-oral transmission of SARS-CoV-2 has been suggestedand the virus has been identified in saliva.The stability of SARS-CoV-2 in aerosols has been confirmed,suggesting the possibility of virus transmission via aerosols. 31

## [considerations]
1. Before admission, check travel history to prevalent areas, fever, and respiratory symptoms. Delaying hospitalization should be considered for symptomatic patients. If the emergency patient with pneumonia of unknown origin is recommended to be admitted to an isolated unit, COVID-19 infection should be tested. 2. All visitors should be checked for their travel history and symptoms such as fever, cough, and sore throat when they visit the hospital. Their access should be recorded and visits other than one guardian are strictly restricted. 3. In patients with liver disease diagnosed with COVID-19, non-emergency procedures such as elective endoscopy, liver biopsy, and etc. should be postponed as much as possible. However, urgent or emergent procedures (e.g., liver biopsy to confirm graft rejection in transplant patients, therapeutic paracentesis, transjugular intrahepatic portosystemic shunt, endoscopy for treatment of variceal bleeding, and pancreatobiliary procedures) should be performed promptly. 4. During all medical procedures, healthcare workers should comply with standard precautionary guidelines. They should wear goggles or face shields and gloves when an exposure to secretions is expected and apply KF94 or N95 masks when aerosol spread of the virus is concerned.5. After all procedures, follow appropriate disinfection guidelines for each procedure. Follow the Korean CDC instructions after performing procedures for confirmed or suspected COVID-19 patients.Medication management and potential drug-drug interactions in COVID-19 patients 1) US Food and Drug Administration granted emergency use authorization for investigational antiviral remdesivir to treat COV-ID-19.
2) Remdesivir, a nucleotide analogue, is currently undergoing multiple randomized controlled studies on its effectiveness as a treatment for SARS-CoV-2 treatment.(ClinicalTrials.gov ID: NCT04292899, NCT04292730, NCT04257656, NCT04252664, and NCT04280705). (1) This drug has been demonstrated to inhibit SARS-CoV and MERS-CoV in vitro and in vivo experiments.(2) Data from compassionate use of remdesivir showed that 68% of severe COVID-19 patients showed clinical improvement.(3) The first randomized controlled trial conducted at Hubei province of China showed that remdesivir was not associated with statistically significant clinical benefits including shortened time to clinical improvement.However, preliminary data from another randomized controlled trial in the USA, Korea, and other countries showed that remdesivir could shorten the time to recovery in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection.In randomized, open-label clinical trials comparing lopinavir/ ritonavir with conservative treatment in patients with COVID-19, there was no clinical benefit of lopinavir/ritonavir and the trial was discontinued prematurely due to adverse drug reactions.In addition to negative results of the clinical trial, unfavorable pharmacodynamics of lopinavir/ritonavir and reported hepatotoxicity limits its use for treating COVID-19. (1) Lopinavir/ritonavir, a potent inhibitor of CYP3A4, can affect the metabolism of calcineurin inhibitors, sirolimus, and everolimus. (2) When using lopinavir/ritonavir, the dose of tacrolimus should be reduced by 1/20-1/50 folds. 4) Tocilizumab, a drug that targets the IL-6 receptor, is being tested only in hospitalized patients with moderate to severe COV-ID-19.Hydroxychloroquine was confirmed to have an inhibitory effect on SARS-CoV-2 in vitro experiments.However, only nonrandomized studies have been conducted in clinical trials with 248 http://www.e-cmh.org https://doi.org/10.3350/cmh.2020.0111 Volume_26 Number_3 July 2020 conflicting results.Further studies with well-designed clinical trials are needed to confirm the antiviral effect of hydroxychloroquine against COVID-19. (1) A combination therapy with hydroxychloroquine and azithromycin did not result in clinical improvement or viral clearance and several patients presented with prolonged QT intervals.Several promising case reports of convalescent plasma transfusion have been reported in critically ill patients with COVID-19.Niclosamide, an anti-helminthic drug, exhibited antiviral properties against SARS-CoV, MERS-CoV, and more recently SARS-CoV-2. Although niclosamide suffers a pharmacokinetic flaw of low adsorption, further development of its drug formulation could enable an effective delivery of this drug to the target tissue.
8) Clevudine, a nucleoside analogue developed in Korea that can inhibit the replication of hepatitis B virus, has recently demonstrated antiviral activity against SARS-CoV-2 and further clinical research is to be initiated.Attention to reversible myopathy, which has been reported in treated chronic hepatitis B patients due to the depletion of mitochondrial DNA leading to mitochondrial myopathy, is warranted.ACE inhibitors and angiotensin receptor inhibitors (ARBs) can theoretically promote SARS-CoV-2 infection as they can increase the expression of ACE2, the target for the virus to enter cells.However, there has been insufficient evidence to limit ACEI/ARB treatment in COVID-19 patients because reports have shown that ACEI/ARB have cardio-pulmonary protective effects and increased expression of ACE2 can reduce acute lung injury. 50

## [considerations]