Liver disease in the Era of Coronavirus Disease 19 (COVID-19) pandemic

A novel strain of virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identi ied in Wuhan, China following outbreak of pneumonia in December 2019. Despite efforts at containment, this virus has now spread rapidly across most, if not all, of the world and has caused the worst world-wide pandemic since that of Spanish lu of 19181919. It has resulted in signi icant morbidity and mortality worldwide stretching already overburdened healthcare systems throughout the world.


Introduction
Coronavirus infections have caused outbreaks in humans: SARS-COV ((Severe Acute Respiratory Syndrome) and MERS-CoV (Middle East Respiratory Syndrome) resulting in signi icant mortality and morbidity.
A novel strain of virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identi ied in Wuhan, China following outbreak of pneumonia in December 2019. Despite efforts at containment, this virus has now spread rapidly across most, if not all, of the world and has caused the worst world-wide pandemic since that of Spanish lu of 1918-1919. It has resulted in signi icant morbidity and mortality worldwide stretching already overburdened healthcare systems throughout the world.
53% of patients hospitalized with COVID-19 disease [8][9][10]. In patients with fatal COVID-19 the incidence of liver injury is signi icantly higher (58% -78%) [11,12]. The elevations in liver tests are mild [1-2 times upper limit of normal (ULN)] at the time of admission in 90% of patients but often become more pronounced during hospitalization [13]. The elevations of the liver enzymes show improvement with effective treatment and acute hepatitis occurs more commonly in severe COVID-19 [9,10].
Gamma glutamyl transferase (GGT) levels are increased in severe cases but serum alkaline phosphatase (AKP) levels usually remain normal in both mild and severe cases. Abnormal liver tests could be the result of virus induced cytotoxicity or due to in lammatory response to immune mediated liver injury [14,15]. Liver biopsy indings are nonspeci ic and show micro vesicular steatosis, mixed lobular and portal round-cell in lammatory activity, and focal hepatocyte necrosis. Liver biopsy indings suggest overactivation of T cell immune mediated liver injury rather than direct cytopathic damage from virus-speci ic effector cells seen in other viral respiratory infections [16]. Abnormalities in liver tests in patients without underlying liver disease could also be secondary to ischemia/hypotension, positive pressure ventilation resulting in hepatic congestion, hepatotoxic effects of drugs used to treat COVID-19 (e.g., Hydroxy Chloroquine, Tocilizumab, Baricitinib) or myositis. Thus, it is dif icult to differentiate whether increases in liver biochemistries are due to SARS-CoV-2 infection or due to other causes [11,17]. Pneumonia-associated hypoxia might also contribute to liver injury or even develop into liver failure in patients with COVID-19 who are critically ill [10]. Some of the investigational therapeutic drugs like Tocilizumab, Chloroquine, Hydroxychloroquine, and Remdesivir are not contraindicated in patients with abnormal liver tests, although serum Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) levels >5x ULN may exclude patients from inclusion in trials of some investigational agents. Patients with abnormal liver chemistries can be evaluated by excluding drugs as a cause for abnormal liver chemistries, investigating to determine viral hepatitis, ischemia and congestion.
As with abnormal liver tests in most acute infectious illnesses, if ALT/AST are elevated but stable in COVID-19 patients, monitor closely; consider liver biopsy if ALT/AST > 5X ULN, if serum total bilirubin is increased and rising, or if there is evidence of developing acute liver failure with hepatic encephalopathy and INR > 1.5. Patients with higher AST compared to ALT are at higher risk of severe COVID-19 infection and mortality.
However, even then, liver biopsy may not be wise unless results of the biopsy would be likely to affect overall management, e.g.: patients with severe pneumonia or multiorgan 'cytokine storm syndrome' are not candidates for liver transplantation. Patients with abnormal liver tests at presentation, and particularly those with hepatocellular or mixed patterns (OR=9.04, 95% CI 3.19-25.6, p < 0.001) are at greater risk of progression to severe COVID-19 disease compared to those with normal liver tests [13].

Viral hepatitis
Chronic viral hepatitis (Hepatitis B &C) does not seem to affect the course or outcome of COVID-19 patients with the information available unlike SARS-CoV [18]. Patients with chronic hepatitis B and hepatitis C already on treatment should continue antivirals. Initiation of evaluation and treatment for chronic hepatitis C in patients with COVID-19 should be postponed to a later time.

Autoimmune liver disease
Patients on immunosuppression do not seem to be at increased risk of SARS-CoV-2 infection and COVID-19 disease based on data available from past and present Corona virus outbreaks.
Routine reductions in the dose of immunosuppressants is not recommended in patients with SARS-CoV-2 infection. Medication-induced lymphopenia, or bacterial/fungal superinfection are indications for immunosuppressant dose reduction with specialist supervision. In patients with Pr imary Biliary Cholangitis (PBC) on Ursodiol should continue medication without any change in dosing. Liver biopsy should be performed prior to diagnosing lare and making signi icant changes to autoimmune hepatitis treatment in COVID-19 patients [19,20].

No n-Alcoholic Fatty Liver Disease (NAFLD)/Non-Alcoholic Steatohepatitis (NASH)
Diabetes, hypertension and obesity are known risk factors for severe COVID 19. They are also commonly associated in patients with NAFLD/NASH. A recent observational study by Dong Ji etal analyzed the implication of NAFLD in COVID 19 patients at a single center in China [21]. Liver injury was observed in 75.2% patients and liver test abnormalities were predominantly hepatocellular. Th ere was higher risk of disease progression, likelihood of abnormal liver function from admission to discharge and longer viral shedding time when compared with non-NAFLD subjects [22].
Patients with NAFLD and obesity are known to produce increased pro-in lammatory cytokines like TNF-α by adipose cells and Kupffer cells. This associated with possible derailment of functional balance between in lammationpromoting M1 macrophages and in lammation-suppressing M2 macrophages is thought to cause progression of COVID-19 in NAFLD/NASH patients [19].

He patocellular Cancer (HCC)
Patient with newly diagnosed HCC should be informed about the diagnosis and treatment plan using virtual media (telephone/Video) reducing risk of exposure to SARS-CoV-2 virus. There is divergence of views between Eu ropean Association of Study of Liver disease (EASL) and American Association of Liver Disease (AASLD) regarding locoregional treatments [19,20]. AASLD recommends proceeding with HCC treatments while EASL prefers postponement of therapy whenever possible. Immune checkpoint inhibitor treatment should be withdrawn and decision to continue tyrosine kinase inhibitor should be individualized [23]. Recommend early hospitalization in patients with HCC who develop COVID -19.

Compensated and decompensated cirrhosis
There is limited information regarding effects of SARS-CoV-2 on cirrhotic patients.
A recent multi center retrospective study of patients with SARS-COV-2 infection from 37 healthcare organizations (HCOs) found increased risk of mortality in cirrhotic patients (cirrhosis (RR 4.6, 95% CI 2.6-8.3, p -value < 0.001 [24]. There is no evidence to suggest increased risk of decompensation or development of acu te-on-chronic liver failure (ACLF), as has been shown for in luenza infection [23]. Conversely cirrhotic patients who develop acute decompensation or ACLF should be tested for SARS-CoV-2 infection.
Routine follow-up appointments should be done using telemedicine. Spontaneous bacterial peritonitis and hepatic encephalopathy prophylaxis guidelines should be closely followed to avoid hospitalization. All cirrhotic patients should be vaccinated against Streptococcus pneumoniae [Pneumovax, Prevnar] and In luenza.
Routine screening for HCC and esophageal varices should be postponed to a later date to avoid inadvertent exposure to SARS-CoV-2. Esophageal varices screening can be offered to high risk patients in accordance with Baveno VI criteria. All cirrhotic patients, including those listed for liver transplant, should avoid in-person dietitian, social work assessments, liver transplant education, inancial counseling and support meetings (Alcoholics Anonymous). Alternatively, telephone or video consultations should be encouraged.

Pre-liver transplant/listed patients
Routine inpatient liver transplant evaluations should be avoided to reduce risk of exposure to virus.
Only patients with poor short-term prognosis like those with high MELD scores, risk of decompensation, or tumor progression should be considered for work up for liver transplantation. Cen ters for Medicare and Medicaid Services (CMS) categorize transplant surgery as Tier 3b ("do not postpone").
Donor and recipients should be evaluated for COVID-19 symptoms in addition to testing for SARS-CoV-2 prior to liver transplantation since there is signi icant false negative rates. Liver transplantation is not recommended if the donor or the recipient tests positive for SARS-CoV-2, has close contact with con irmed COVID-19 case or has traveled to high risk area within last 14 days [20].
Chest computerized tomography is done in many centers to exclude viral pneumonitis prior to liver transplantation. Potential liver transplant recipients should be informed about risk of nosocomial COVID-19 infection and restriction/ prohibition of visitor access during hospital stay. Living donor transplants should be avoided whenever possible. Exposure to SARS COV-2 can be minimized by having backup recipients wait at home and accepting graft with low risk of delayed function.
Transplant surgeons and staff are at increased risk of contracting infection and they should limit travel for organ retrieval and utilize courier services for organ transport. Surgeons and staff should avoid being in the room when patient is either being intubated or extubated whenever possible to reduce risk of contracting the virus [19,20].

Post-liver iransplant patients
Gown/face protection, frequent handwashing, maintaining social distancing should be followed and drainage luids should be considered contaminated in immediate post-transplant patients. Outpatient in person follow up should be avoided by effective use of telemedicine.
Post-transplant patients should be advised against travel during the pandemic and to work from home whenever possible. Patients and their care givers should be provided with documentation for leave of absence if necessary [25].

Information available so far does not show increased risk of mortality like other corona virus epidemics (SARS/MERS).
Post-transplant patients with COVID-19 have prolonged viral shedding, high viral titers hence likely more infectious [25,26].
Immunosuppression should not be changed or stopped for asymptomatic post-transplant patients without SARS-COV-2 infection. Antimetabolites (mycophenolic acid, mycophenolate mofetil) should be stopped or reduced and calcineurin inhibitor (Cyclosporin, Tacrolimus) can be maintained in post-liver transplant patients with COVID-19 with specialist guidance [27].
Risks of nosocomial infection and mortality should be considered prior to pursuing imaging or procedures (liver biopsy, endoscopic retrograde pancreatography). Several treatment options are being used for management of COVID-19 drug interactions should be considered before treatment initiation. Lopinavir/ritonavir and mam malian target of rapamycin (m-Tor) inhibitors should not be used concurrently because of drug-drug interactions and cyclosporine, tacrolimus levels should be closely monitored.

Impact of SARS-2-COV-2 infection on long term management of hepatology patients
SARS-2-COV-2 pandemic has caused serious disruption in Table 1: Impact of SARS-2-COV-2 infection on Liver.

Liver Tests (LT)
Aff ects 14 Routine screening for HCC and esophageal varices is being deferred. Delaying screening, elective liver resection, locoregional therapies for HCC is safe in majority of patients but may lead to diagnosis of aggressive HCC at a later stage in about 25% of patients [28].
Living donor transplants are being cancelled and deceased donor liver transplants are being offered to limited number of patients because of application of stringent prioritization criteria due to possible risk with nosocomial SARS-2-COV2, concern regarding availability of ventilators, blood products, renal replacement therapy etc. This can lead to increased wait list mortality. Angelico R etal. reported 25 % reduction in donor procurement during the irst 4 weeks of the pandemic in Italy [29].
Chronic liver disease patients are at increased risk of physical deconditioning, frailty, decompensation and malnutrition because of reduction in mobility due to social distancing policies, reduced access to mental health care providers, support groups and meal delivery. Relatively easier availability of processed foods and alcohol increase risk of further decompensation. The framework that had been developed for managing patients with chronic liver disease has been disrupted during this pandemic because of issues with routine follow up, screening and missed diagnosis.
The COVID-19 pandemic is expected to result in long term disruption of world economy which may have implications regarding insurance coverage for signi icant section of the population. Healthcare systems may make up for the inancial losses by freezing new hires, postponing new investments, making cuts in staff etc. Adverse patient outcomes because of delayed follow up, postponement of routine screening and treatment procedures along with inancial challenges can add serious psychological stress to already overburdened health care providers. (Table 1), but it is unclear if it can cause further worsening in patients with previously existing liver disease. However, it has long term implications for patients with liver disease (Table 2) resulting in signi icant morbidity and mortality.