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COVID-19: Issues related to liver disease in adults

COVID-19: Issues related to liver disease in adults
Authors:
Oren Fix, MD, MSc
K Rajender Reddy, MD
Section Editor:
Keith D Lindor, MD
Deputy Editors:
Kristen M Robson, MD, MBA, FACG
Shilpa Grover, MD, MPH, AGAF
Literature review current through: Feb 2022. | This topic last updated: Dec 20, 2021.

INTRODUCTION — At the end of 2019, SARS-CoV-2, a novel coronavirus, was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. Coronavirus disease 2019 (COVID-19) primarily manifests as a lung infection with symptoms ranging from those of a mild upper respiratory infection to severe pneumonia, acute respiratory distress syndrome (ARDS), and death. Medical professionals, including gastroenterology and hepatology clinicians, are tasked with adjusting their practice to curtail the spread of COVID-19, while providing care to their patients.

This topic will discuss COVID-19-related issues for patients with acute or chronic liver disease. As understanding of COVID-19 continues to evolve, the approach to diagnosis and management may require modification as well.

Other important aspects of COVID-19 infection are discussed in detail separately:

(See "COVID-19: Epidemiology, virology, and prevention".)

(See "COVID-19: Clinical features".)

(See "COVID-19: Diagnosis".)

(See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

(See "COVID-19: Management in hospitalized adults".)

(See "COVID-19: Outpatient evaluation and management of acute illness in adults".)

(See "COVID-19: Issues related to gastrointestinal disease in adults".)

LIVER-RELATED RISK FACTORS AND OUTCOMES

Risk of acquiring infection — Whether patients with chronic liver disease are more susceptible to COVID-19 is uncertain. Chronic liver disease in the absence of immunosuppressive therapy is not known to be associated with an increased risk of acquiring COVID-19 [1]. However, the liver may be susceptible to SARS-CoV-2 virus because of angiotensin-converting enzyme 2 (ACE2) receptors in the biliary and liver epithelial cells [2]. SARS-CoV-2 virus binds to the ACE2 receptor to gain entry and damage the target organ [3].

Risk of severe COVID-19 and mortality — Patients with chronic liver disease or who are immunocompromised may be at higher risk for severe illness from COVID-19 [4]:

Patients with chronic liver disease of any etiology – Data have suggested that pre-existing liver disease was associated with worse outcomes in patients with COVID-19 [5-14]. In a study of 2780 patients with COVID-19 (including 250 patients with chronic liver disease), patients with chronic liver disease had higher rates of mortality as compared with those without liver disease (12 versus 4 percent; risk ratio [RR] 2.8, 95% CI 1.9-4.0) [5]. Among patients with chronic liver disease, nonalcoholic liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) were the most common etiologies. In subgroup analyses, patients with cirrhosis had a higher risk of mortality compared with no liver disease (RR 4.6, 95% CI 2.6-8.3). The mortality risk was independent of age, race, nicotine use, body mass index, hypertension, and diabetes.

The severity of underlying liver disease has also been associated with an increased risk of mortality in patients with COVID-19 [6,12]. In a large database study of patients with chronic liver disease and COVID-19, cirrhosis was associated with higher risk of mortality compared with no cirrhosis, after adjusting for race, liver disease etiology, comorbidities and geographic region (30-day mortality rates: 8.9 versus 1.7 percent; adjusted hazard ratio [aHR] 3.31, 95% CI 2.91-3.77) [12]. In an earlier cohort study that included 152 patients with COVID-19 and chronic liver disease (including 103 patients with cirrhosis) from two international reporting registries, the mortality rate was 40 percent [6]. Deaths occurred in 12 percent of patients with chronic liver disease without cirrhosis. Among patients with Child-Pugh (CP) class A cirrhosis, CP class B cirrhosis, and CP class C cirrhosis, mortality rates were 24, 43, and 63 percent, respectively. CP class B or C cirrhosis were independent predictors of mortality (odds ratio [OR] 4.90, 95% CI 1.16-20.61 and OR 28.07, 95% CI 4.42-178.46, respectively). Mortality in patients with cirrhosis was most often attributed to pulmonary disease (79 percent), while liver-related causes were noted in 12 percent of patients. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Predictive models'.)

Patients on immunosuppressive therapy – Patients on maintenance immunosuppression (eg, liver transplant recipients) are characterized by the CDC as a population that is at risk for severe COVID-19 and its complications (eg, pneumonia) [4]. However, it is unclear if transplant recipients are at higher risk for severe COVID-19 than nontransplant patients. Several studies have reported high mortality rates in solid organ transplant recipients with COVID-19 [15-17], while other studies have suggested that transplantation was not a risk factor for mortality [18-21]. In a cohort study including 151 adult liver transplant recipients and 627 nontransplant patients with COVID-19, liver transplantation was not associated with an increased risk of death as compared with the nontransplant cohort (absolute risk difference 1.4 percent, 95% CI -7.7-10.4) [18]. For liver transplant recipients with COVID-19, risk factors for mortality included increased age (OR 1.06, 95% CI 1.01-1.11), presence of non-liver cancer (OR 18.30, 95% 1.96-170.75) and higher baseline serum creatinine (OR 1.57, 95% 1.05-2.36 per 1 mg/dL increase). Risk factors for mortality from COVID-19 in the general population are discussed separately. (See "COVID-19: Clinical features", section on 'Severity of symptomatic infection'.)

The effect of immunosuppressive medications on the systemic inflammatory response and acute respiratory distress syndrome (ARDS) is not well understood [22]. However, an overly intense inflammatory host immune response might contribute to disease severity, while it is also possible that low dose immunosuppression may be beneficial in patients with COVID-19 [23]. For example, immunosuppression in transplant recipients was not linked to worse outcomes during the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) outbreaks [24]. (See "COVID-19: Issues related to solid organ transplantation", section on 'Adjusting immunosuppression' and 'Liver transplantation' below.)

Patients with a disease flare – Whether patients with a flare of chronic liver disease such as hepatitis B virus (HBV) infection or autoimmune hepatitis (AIH) are at higher risk of severe illness from COVID-19 is uncertain. Indirect evidence from an epidemiologic study of patients with SARS suggested that HBV infection was a risk factor for progression to ARDS [25]. (See "Severe acute respiratory syndrome (SARS)", section on 'Epidemiology'.)

Factors that have not been associated with increased risk – Antiviral therapy for patients with HBV or hepatitis C virus (HCV) infection has not been associated with increased risk for severe COVID-19. (See 'Chronic viral hepatitis' below.)

Risk of prolonged viral shedding — Liver transplant recipients and other immunosuppressed patients who have COVID-19 may have a longer duration of viral shedding than nonimmunosuppressed patients. Thus, strategies for isolation and for testing for clearance may require modification to reduce the risk of spreading infection to others. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

LIVER-RELATED CLINICAL FEATURES

Laboratory findings — Patients with or without pre-existing liver disease may present with elevated aminotransferases in the setting of COVID-19 [5]. Elevated aminotransferase levels have been reported in 14 to 58 percent of hospitalized patients with COVID-19 [1,23,26-34]. The range of aspartate transaminase (AST) and alanine transaminase (ALT) elevations is usually mild (ie, <5 times the upper limit of normal); however, higher aminotransferase levels and severe acute hepatitis have also been reported [27,30,35-39]. The pattern of elevation is often AST greater than ALT, and this pattern has been associated with disease severity [23,31]. AST and ALT are more commonly elevated than bilirubin or alkaline phosphatase, although the angiotensin-converting enzyme 2 (ACE2) receptor is more frequently expressed on cholangiocytes than hepatocytes [2,32,40]. (See "COVID-19: Clinical features", section on 'Laboratory findings'.)

Low albumin has been associated with severe COVID-19 [29,32,41-43]. However, it is unclear if hypoalbuminemia is a risk factor for severe COVID-19 or if hypoalbuminemia is a result of severe COVID-19.

Liver histology — Liver histology in patients with COVID-19 is nonspecific, including moderate microvesicular steatosis with mild, mixed lobular and portal activity and focal necrosis [44,45]. In a series of 48 autopsies, pathologic liver findings included focal portal and lobular lymphocytic infiltrates and changes suggestive of hepatic vascular involvement [46].

DIAGNOSTIC TESTING — Considerations in diagnostic testing include when to test for COVID-19 in patients with elevated liver biochemical tests and how to evaluate liver biochemical tests in patients with COVID-19.

When to test for COVID-19 in patients with hepatitis — The diagnosis of COVID-19 is usually suspected in patients with new onset fever and/or respiratory tract symptoms (eg, cough, dyspnea) while other consistent symptoms include myalgias and aberrancy in sense of smell or taste (table 1). (See "COVID-19: Clinical features", section on 'Initial presentation'.)

Some patients with COVID-19 have elevated liver biochemistries and/or acute hepatitis, and we favor COVID-19 testing in the following cases (see 'Laboratory findings' above and "COVID-19: Diagnosis", section on 'Diagnostic approach'):

Hospitalized patients with elevated aminotransferases, even in the absence of respiratory symptoms or fever.

Outpatients with established liver disease who present with any of the following:

Elevated aminotransferases at least threefold above baseline values with or without jaundice

Symptoms such as fatigue, abdominal pain, or anorexia that are suggestive of a disease flare (eg, patients with autoimmune hepatitis [AIH] or hepatitis B virus [HBV] infection)

Features of decompensated liver disease (eg, hepatic encephalopathy)

Data from an international registry have suggested that up to 25 percent of patients with new hepatic decompensation and COVID-19 may have no respiratory symptoms at the time of COVID-19 diagnosis [6].

Evaluating abnormal liver biochemical tests in patients with COVID-19 — Although elevated liver biochemistries are commonly seen in hospitalized patients with COVID-19, it should not be assumed that these findings are a manifestation of COVID-19. For such patients, diagnostic evaluation to determine the etiology of elevated liver biochemistries includes (see "Approach to the patient with abnormal liver biochemical and function tests"):

Review the medication list, including outpatient therapies and new medications given during hospitalization, for drugs associated with drug-induced liver injury. (See "Drug-induced liver injury", section on 'Associated drugs'.)

Obtain serologies for hepatitis A virus (HAV) infection (immunoglobulin M [IgM] anti-HAV), HBV infection (HBsAg, antibody to HBsAg, anti-HBc) and hepatitis C virus (HCV) infection (anti-HCV antibody).

To reduce exposure and conserve resources (eg, personal protective equipment), we generally avoid imaging in patients with active COVID-19 unless biliary obstruction (eg, elevated alkaline phosphatase) or venous thrombosis (eg, patients with new onset ascites or acute decompensation of established liver disease) is suspected [47]. In addition, we obtain ultrasound with Doppler imaging or magnetic resonance (MR) venography for patients with suspected acute mesenteric venous thrombosis (eg, patients with colicky, periumbilical abdominal pain). (See "Mesenteric venous thrombosis in adults".)

MANAGEMENT PRINCIPLES

General strategies to reduce risk of infection — If community transmission of COVID-19 is present, measures to reduce exposure include (see "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'):

General preventive measures such as hand hygiene and social distancing.

Use of telemedicine visits for ongoing disease management.

Decreased frequency of routine laboratory and imaging surveillance when the associated risk is deemed to be low. For example, for patients in a surveillance program for hepatocellular carcinoma (HCC), the slow mean doubling time of HCC provides a rationale for this approach [48]. (See "Pathology of malignant liver tumors", section on 'Hepatocellular carcinoma' and "Surveillance for hepatocellular carcinoma in adults".)

Delay nonurgent endoscopic procedures (eg, colorectal cancer screening). (See "COVID-19: Issues related to gastrointestinal disease in adults", section on 'Implications for endoscopy'.)

For patients with stable disease and without known or suspected COVID-19, continue the established medication regimen to avoid a disease flare.

For patients on glucocorticoids, therapy should not be abruptly discontinued, but should be used at the lowest dose possible to control the underlying disease, regardless of COVID-19 exposure or infection status.

Cirrhosis — Patients with cirrhosis are advised to follow general preventive measures to avoid COVID-19, and these are discussed separately. (See 'General strategies to reduce risk of infection' above and "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

As hospitals and endoscopy centers resume nonurgent procedures, patients with cirrhosis and recent variceal bleeding and/or endoscopic variceal ligation are prioritized before consideration of patients scheduled for elective procedures (eg, upper endoscopy to screen for esophageal varices). (See "Endoscopic variceal ligation" and "COVID-19: Issues related to gastrointestinal disease in adults", section on 'Implications for endoscopy'.)

Autoimmune hepatitis

AIH without COVID-19 — For patients with autoimmune hepatitis (AIH) on maintenance immunosuppression who do not have COVID-19, we do not discontinue or adjust baseline immunosuppression. Patients with AIH are at risk for relapse when immunosuppression is reduced or discontinued, in addition to the potential challenges for inducing remission in the setting of a disease flare [49].

Patients without COVID-19 who have a flare of AIH are managed with escalating immunosuppression in a manner similar to the pre-COVID-19 era. For such patients, the risk of not treating a disease flare is likely greater than the risk of immunosuppression. Similarly, for patients with newly diagnosed AIH, immunosuppressive therapy can be initiated [50,51]. (See "Autoimmune hepatitis: Treatment".)

AIH with COVID-19 — For patients with AIH and COVID-19, our approach is individualized based on the severity of infection, patient comorbidities, severity of liver disease, and the existing medication regimen. The goal of medication adjustment is to reduce immunosuppression during active viral replication to lower the risk of COVID-19-related complications, while balancing the risk of disease flare [49]. The general strategy includes:

For patients with asymptomatic or mild COVID-19 (eg, outpatient status, no complications such as pneumonia), we typically do not adjust baseline immunosuppression.

For patients with moderate to severe COVID-19 (ie, patients with pneumonia, hospitalized patients), we assess the patient's prior history of disease relapse and risk for complications of a flare (eg, patients with cirrhosis may be at higher risk for hepatic decompensation). If the immunosuppressive medication (eg, azathioprine) is adjusted, the baseline dose may be reduced by 25 to 50 percent. We monitor the patient's symptoms and recheck liver biochemical tests daily for hospitalized patients. For patients who do not require hospitalization, we recheck liver biochemical tests in one to two weeks. If the patient's symptoms and liver biochemistries remain stable, the frequency of monitoring is decreased to every two to four weeks.

For patients with COVID-19-related neutropenia and/or lymphopenia (absolute lymphocyte count <1000 cells/microL for adults); we reduce the dose of azathioprine or mycophenolate and monitor laboratory studies (white blood cell count and differential) in one to two weeks.

Preliminary data have suggested that patients with AIH and COVID-19 were not at increased risk for severe illness and that pre-emptively reducing immunosuppression was not associated with improved outcomes. In a small case series of 10 patients with AIH on immunosuppression and COVID-19, six patients were hospitalized, including five patients with pneumonia and three requiring noninvasive ventilation [49]. Two patients with active AIH were receiving high-dose glucocorticoid therapy at the time of COVID-19 diagnosis and, for both patients, liver biochemistries improved during the hospital course. Nine patients recovered from COVID-19, while one patient with decompensated cirrhosis died.

The decision to continue immunosuppressive agents, including glucocorticoids, for patients with COVID-19 has been also informed by indirect data suggesting that low dose dexamethasone has a role in the management of severe COVID-19. The use of glucocorticoids for treating COVID-19 is discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids'.)

Chronic viral hepatitis — The strategy for patients with chronic viral hepatitis depends on presence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, COVID-19 status, and use of therapies to treat COVID-19. (See "Hepatitis B virus: Overview of management" and "Overview of the management of chronic hepatitis C virus infection".)

Patients without COVID-19 — Antiviral therapies for patients with HBV or HCV infection are not known to pose a greater risk of severe COVID-19, and there are no contraindications to initiating or continuing antiviral therapy in patients without COVID-19 during the pandemic [52].

Patients with COVID-19 — For patients with chronic viral hepatitis and COVID-19, antiviral treatment for HBV or HCV infection is not contraindicated. For patients with chronic HBV infection and COVID-19, HBV treatment may be indicated (eg, when initiating immunosuppressive therapy in patients with hepatitis B surface antigen or in those with a hepatitis B flare).

Reactivation of HBV infection has been observed in patients treated with glucocorticoids and tocilizumab, which have been used for treating COVID-19. Thus, HBV prophylaxis may be indicated when initiating these therapies [53-55]. Estimating the patient's risk of HBV reactivation and specific therapies to prevent HBV reactivation are discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Liver transplantation

Pretransplantation considerations — To minimize the risk of infection and to conserve resources (eg, intensive care unit [ICU] beds, personal protective equipment), elective transplantation (eg, living donor liver transplantation and nonurgent, deceased-donor liver transplants [DDLT]) has been deferred at transplant centers where the community prevalence of COVID-19 is high and/or resources are limited [56]. (See "COVID-19: Issues related to solid organ transplantation", section on 'Deferral of nonurgent transplantation'.)

Screening for COVID-19 in donors and potential recipients is discussed separately. (See "COVID-19: Issues related to solid organ transplantation", section on 'Pretransplantation screening'.)

Transplant recipients without COVID-19 — For liver transplant recipients without COVID-19, maintenance immunosuppression is continued without adjustment. While reducing immunosuppression may promote viral clearance, this strategy may also increase risk of developing acute rejection [57].

For patients with acute T cell mediated (cellular) rejection (TCMR) of the liver allograft, the approach to management, including high dose glucocorticoids for patients with moderate to severe rejection, has not been altered [51]. (See "Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft".)

Transplant recipients with COVID-19 — For liver transplant recipients with COVID-19, adjustments to immunosuppression are individualized based on COVID-19 severity, the specific regimen used, time posttransplant, and the risk of allograft rejection (see "COVID-19: Issues related to solid organ transplantation", section on 'Management'):

Mild COVID-19 – For patients with mild COVID-19 (eg, outpatient care, no complications), we do not routinely adjust immunosuppression.

Moderate to severe COVID-19 – For patients with moderate to severe COVID-19 (eg, inpatient care, complications such as pneumonia), general strategies for managing immunosuppression include [52]:

We generally lower the overall level of immunosuppression, particularly antimetabolite dosages (eg, azathioprine or mycophenolate) based on general principles for managing infections in transplant recipients and to decrease the risk of superinfection. However, for patients on glucocorticoids, the glucocorticoid dose is not routinely adjusted based on the presence of COVID-19. (See "Infection in the solid organ transplant recipient".)

For patients with COVID-19 related neutropenia and/or lymphopenia (absolute lymphocyte count <1000 cells/microL for adults), we reduce the dose of azathioprine or mycophenolate and monitor laboratory studies (white blood cell count and differential) in one to two weeks.

For patients on calcineurin inhibitors, we monitor drug levels one to two times a week or as outlined in transplant center-specific protocols because of the risk of acute kidney injury. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Acute kidney injury'.)

LIVER-RELATED CHRONIC COMPLICATIONS — Cholangiopathy has been reported as a late complication of severe COVID-19, and some patients have developed progressive biliary injury and liver failure [58-62]. In a study of 2047 patients who were hospitalized for COVID-19, 12 patients with severe COVID-19 developed a syndrome of cholangiopathy characterized by cholestasis and biliary tract abnormalities that were similar to those seen in critically ill patients with secondary sclerosing cholangitis [58,63]. The mean time from COVID-19 diagnosis to cholangiopathy was 118 days. Imaging findings included inflammation, beading, stricturing, and dilation of the biliary tree. Five patients (42 percent) were evaluated for liver transplantation because of persistent jaundice, hepatic insufficiency, and/or recurrent cholangitis. One patient underwent liver transplantation. Further studies are needed to understand the pathogenesis and to identify preventive and therapeutic measures for cholangiopathy related to COVID-19.

COVID-19 SPECIFIC THERAPY AND THE LIVER — Elevated liver biochemistries per se are not a contraindication to using therapy such as remdesivir or to enrolling patients with COVID-19 in trials for investigational agents. However, some patients (eg, those with alanine aminotransferase ≥5 times the upper limit of normal) may be excluded from a clinical trial based on the magnitude of the enzyme elevations. Elevated liver biochemistries have been commonly observed in clinical trials of remdesivir, but elevations have rarely been greater than 10 times the baseline values and have rarely led to treatment discontinuation [1,64,65].

Remdesivir is not recommended in patients with an alanine aminotransferase ≥5 times the upper limit of normal and should be discontinued if it rises above this level during treatment or if there are other signs of liver injury. Elevated liver biochemistries below this threshold (<5 times the upper limit of normal) should not be a contraindication to starting remdesivir. (See "COVID-19: Management in hospitalized adults", section on 'Remdesivir'.)

COVID-19 VACCINATION — Patients with chronic liver disease can receive the COVID-19 vaccine as soon as it is available to them [66]. The available SARS-CoV-2 vaccines, including messenger RNA (mRNA) vaccine and replication-incompetent adenovirus vector vaccine, are safe to administer to patients with chronic liver disease (table 2). Although the immunogenicity of vaccines is uncertain in this population, the potential for severe COVID-19 likely outweighs the uncertainties. Guidance regarding administration of COVID-19 vaccines is provided separately. (See "COVID-19: Vaccines".)

Because of increased mortality rates related to COVID-19 in adults with chronic liver disease [11], such patients should be prioritized to receive vaccination [67]. Administration of the COVID-19 vaccine does not require interrupting or delaying therapy for hepatitis B or C virus infection or for other liver diseases (eg, autoimmune hepatitis). When possible, candidates for liver transplantation should be vaccinated prior to transplant to ensure sufficient immune response. In addition, vaccination should be provided for individuals who are being evaluated for live liver donation.

Several COVID-19 vaccines are available, including mRNA vaccines by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) and an adenovirus-vectored vaccine by Johnson & Johnson/Janssen (Ad26.COV2.S) [68-70]. Other vaccines in development include DNA, protein subunits, and inactivated SARS-CoV-2 [66]. These vaccines do not contain live SARS-CoV-2 and cannot replicate, even in immunocompromised individuals. Although patients with chronic medical conditions were enrolled in vaccination trials, the safety and efficacy data for such patients are limited [68-70]:

In the Pfizer-BioNTech phase 2/3 trial, 20.5 percent of study participants had a comorbidity, which included liver disease (8030 participants with a comorbidity received BNT162b2 and 8029 participants received placebo). Vaccine efficacy was 95.3 percent in those with comorbidities and was similar to that seen in participants without comorbidities (94.7 percent). Among 214 participants with liver disease (0.6 percent), 124 participants received BNT162b2 and 90 participants received placebo, but safety and efficacy data in this subgroup have not been reported [66,71].

In the Moderna phase 3 trial, at least one high-risk condition was present in 22.3 percent of study participants. Among 196 participants with liver disease (0.6 percent), 100 participants received mRNA-1273 and 96 participants received placebo. No patients with liver disease developed COVID-19; thus, vaccine efficacy cannot be determined for this subgroup [72].

In the Janssen phase 3 trial, 40.8 percent of participants had one or more comorbidities, including liver disease [73]. Among 206 participants with liver disease (0.5 percent), 103 participants received Ad26.COV2.S and 103 participants received placebo. Among those with liver disease, one participant in the vaccine group and two participants in the placebo group developed moderate to severe COVID-19 at least 14 days after vaccination. Interpretation of these results is limited by the small sample size and low incidence of COVID-19.

Although the immunogenicity of SARS-CoV-2 vaccines in patients with chronic liver disease has not been fully described, data have suggested that vaccination was associated with lower risk of COVID-19 in patients with cirrhosis. In a cohort study including over 20,000 patients with cirrhosis, patients who received mRNA vaccine had lower rates of COVID-19 at 28 days after the first dose compared with unvaccinated patients who were matched for age, sex, race, and severity of liver disease (cumulative incidence of infection [day 28-onward] 0.69 versus 0.87 percent, vaccine efficacy 64.8 percent, 95% CI 10.9-86.1) [74]. No patients who received the second vaccine dose developed COVID-19 related hospitalization or death, compared with two hospitalizations and one death in the unvaccinated group.

Studies accounting for other factors such as racial and ethnic differences in disease prevalence are needed to address knowledge gaps about SARS-CoV-2 vaccination in patients with chronic liver disease [66,75,76].

Vaccination in solid organ transplant recipients is discussed separately. (See "COVID-19: Issues related to solid organ transplantation".)

The impact of other vaccine-preventable infections (viral hepatitis, pneumococcal disease, and influenza) in patients with chronic liver disease is discussed separately. (See "Immunizations for patients with chronic liver disease".)

DISEASE REGISTRIES — Data on patients with chronic liver disease who have been infected with SARS-CoV-2 virus are accumulating, and we encourage clinicians to report cases of COVID-19 to these registries:

SECURE-Liver – SECURE-Cirrhosis is an international registry that collects data for patients with chronic liver disease (ie, cirrhosis, liver transplantation recipients) and COVID-19 [77]. The SECURE-Liver registry is aimed to collect patient data from North America, South America, China, Japan, and Korea.

COVID-Hep – COVID-Hep is an international registry that collects data for patients with chronic liver disease (ie, cirrhosis or liver transplantation recipients) and COVID-19 [78]. The COVID-Hep registry is aimed to collect patient data outside of North America, South America, China, Japan, and Korea.

Liver transplantation data collection registry for pediatric patients (ages 0 to 21 years) – The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and Society of Pediatric Liver Transplantation (SPLIT-TTS) have created an online pediatric patient registry for patients infected with SARS-CoV-2 virus.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)

SUMMARY AND RECOMMENDATIONS

Whether patients with chronic liver disease are more susceptible to COVID-19 is uncertain. Chronic liver disease in the absence of immunosuppressive therapy is not known to be associated with an increased risk of acquiring COVID-19. However, the liver may be susceptible to SARS-CoV-2 virus because of angiotensin-converting enzyme 2 (ACE2) receptors in the biliary and liver epithelial cells. (See 'Risk of acquiring infection' above.)

Common laboratory findings among patients with COVID-19 include elevated aminotransferase levels, while the range of aspartate transaminase (AST) and alanine transaminase (ALT) elevations is usually mild (ie, <5 times the upper limit of normal). However, higher aminotransferase levels and severe acute hepatitis have also been reported. (See 'Liver-related clinical features' above.)

For hospitalized patients with COVID-19, elevated liver biochemistries are common, but these findings are not always a manifestation of COVID-19. For such patients, diagnostic evaluation to determine the etiology of elevated liver biochemistries includes (see "Approach to the patient with abnormal liver biochemical and function tests" and 'Diagnostic testing' above):

Review the medication list, including outpatient therapies and new medications given during hospitalization, for drugs associated with drug-induced liver injury.

Obtain serologies for hepatitis A virus infection (HAV; IgM anti-HAV), hepatitis B virus infection (HBV; HBsAg, antibody to HBsAg, anti-HBc) and hepatitis C virus infection (HCV; anti-HCV antibody).

To reduce exposure and conserve resources (eg, personal protective equipment), we generally avoid imaging in patients with active COVID-19 unless biliary obstruction (eg, elevated alkaline phosphatase) or venous thrombosis (eg, patients with new onset ascites) is suspected.

Patients with cirrhosis are advised to follow general preventive measures to avoid COVID-19 (eg, hand hygiene, social distancing), and these measures are discussed separately. (See 'General strategies to reduce risk of infection' above and "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

For patients with autoimmune hepatitis (AIH) on maintenance immunosuppression who do not have COVID-19, we do not discontinue or adjust baseline immunosuppression. Patients with AIH are at risk for relapse when immunosuppression is reduced or discontinued, in addition to the potential challenges for inducing remission in the setting of a disease flare. (See 'Autoimmune hepatitis' above.)

For liver transplant recipients without COVID-19, maintenance immunosuppression is continued without adjustment. For liver transplant recipients with COVID-19, adjustments to immunosuppression are individualized based on COVID-19 severity, the specific regimen used, time posttransplant, and the risk of allograft rejection. (See 'Liver transplantation' above and "COVID-19: Issues related to solid organ transplantation", section on 'Active COVID-19 in solid organ transplant recipients'.)

Patients with chronic liver disease can receive the COVID-19 vaccine as soon as it is available to them. Although the immunogenicity of vaccines has not been fully described in this population, vaccination has been associated with lower risk of COVID-19 in patients with cirrhosis. (See 'COVID-19 vaccination' above.)

Guidance regarding administration of COVID-19 vaccines is provided separately. (See "COVID-19: Vaccines".)

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  39. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395:1054.
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  43. Kovalic AJ, Huang G, Thuluvath PJ, Satapathy SK. Elevated Liver Biochemistries in Hospitalized Chinese Patients With Severe COVID-19: Systematic Review and Meta-analysis. Hepatology 2021; 73:1521.
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Topic 128410 Version 21.0

References

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2 : ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection

3 : Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.

4 : Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.

5 : Clinical Characteristics and Outcomes of Coronavirus Disease 2019 Among Patients With Preexisting Liver Disease in the United States: A Multicenter Research Network Study.

6 : High mortality rates for SARS-CoV-2 infection in patients with pre-existing chronic liver disease and cirrhosis: Preliminary results from an international registry.

7 : Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study.

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9 : Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center Study.

10 : High rates of 30-day mortality in patients with cirrhosis and COVID-19.

11 : Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study.

12 : Outcomes of SARS-CoV-2 Infection in Patients With Chronic Liver Disease and Cirrhosis: A National COVID Cohort Collaborative Study.

13 : Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort.

14 : Cirrhosis and Severe Acute Respiratory Syndrome Coronavirus 2 Infection in US Veterans: Risk of Infection, Hospitalization, Ventilation, and Mortality.

15 : COVID-19 in solid organ transplant recipients: Initial report from the US epicenter.

16 : COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy.

17 : Determining risk factors for mortality in liver transplant patients with COVID-19.

18 : Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.

19 : Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients.

20 : Outcomes of Coronavirus Disease 2019 in Living Donor Liver Transplant Recipients.

21 : Outcomes of critically ill solid organ transplant patients with COVID-19 in the United States.

22 : The Immunocompromised Transplant Recipient and SARS-CoV-2 Infection.

23 : Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.

24 : Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic.

25 : Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study.

26 : Clinical Characteristics of Coronavirus Disease 2019 in China.

27 : Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.

28 : Clinical Features of COVID-19-Related Liver Functional Abnormality.

29 : Liver injury during highly pathogenic human coronavirus infections.

30 : Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.

31 : Longitudinal Association Between Markers of Liver Injury and Mortality in COVID-19 in China.

32 : Liver involvement is not associated with mortality: results from a large cohort of SARS-CoV-2-positive patients.

33 : The association between markers of liver injury and clinical outcomes in patients with COVID-19 in Wuhan.

34 : Liver Enzyme Elevation in Coronavirus Disease 2019: A Multicenter, Retrospective, Cross-Sectional Study.

35 : Abnormal Liver Function Tests in Patients With COVID-19: Relevance and Potential Pathogenesis.

36 : Abnormal Liver Function Tests in Patients With COVID-19: Relevance and Potential Pathogenesis.

37 : Clinical Characteristics of Imported Cases of Coronavirus Disease 2019 (COVID-19) in Jiangsu Province: A Multicenter Descriptive Study.

38 : Clinical Features of 69 Cases With Coronavirus Disease 2019 in Wuhan, China.

39 : Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.

40 : COVID-19: Abnormal liver function tests.

41 : Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease.

42 : The association of low serum albumin level with severe COVID-19: a systematic review and meta-analysis.

43 : Elevated Liver Biochemistries in Hospitalized Chinese Patients With Severe COVID-19: Systematic Review and Meta-analysis.

44 : Pathological findings of COVID-19 associated with acute respiratory distress syndrome.

45 : [A pathological report of three COVID-19 cases by minimal invasive autopsies].

46 : Liver and COVID 19 infection: A very preliminary lesson learnt from histological post-mortem findings in 48 patients

47 : Liver and COVID 19 infection: A very preliminary lesson learnt from histological post-mortem findings in 48 patients

48 : Hepatocellular Carcinoma Demonstrates Heterogeneous Growth Patterns in a Multicenter Cohort of Patients With Cirrhosis.

49 : Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis: a lesson from immunosuppressed patients.

50 : Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases.

51 : Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.

52 : Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.

53 : American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.

54 : Short-course tocilizumab increases risk of hepatitis B virus reactivation in patients with rheumatoid arthritis: a prospective clinical observation.

55 : Hepatitis B Virus Reactivation: What Is the Issue, and How Should It Be Managed?

56 : Changes in Liver Transplant Center Practice in Response to Coronavirus Disease 2019: Unmasking Dramatic Center-Level Variability.

57 : Changes in Liver Transplant Center Practice in Response to Coronavirus Disease 2019: Unmasking Dramatic Center-Level Variability.

58 : Cholangiopathy After Severe COVID-19: Clinical Features and Prognostic Implications.

59 : Post-COVID-19 Cholangiopathy: A Novel Entity.

60 : Post-Covid-19 Cholangiopathy-A New Indication for Liver Transplantation: A Case Report.

61 : Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection.

62 : Secondary sclerosing cholangitis: an emerging complication in critically ill COVID-19 patients.

63 : Cholangiopathy in critically ill patients surviving beyond the intensive care period: a multicentre survey in liver units.

64 : Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

65 : Hepatic Disorders With the Use of Remdesivir for Coronavirus 2019.

66 : American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

67 : American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

68 : American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

69 : American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

70 : American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

71 : Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

72 : Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

73 : Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

74 : Association of BNT162b2 mRNA and mRNA-1273 Vaccines With COVID-19 Infection and Hospitalization Among Patients With Cirrhosis.

75 : Nonalcoholic Steatohepatitis: A Review.

76 : Hepatitis B and C in African Americans: current status and continued challenges.