COVID-19: Gastrointestinal manifestations,liver injury and recommendations

Coronavirus disease 2019 (COVID-19) has caused a pandemic that affected all countries with nearly 270 million patients and 5 million deaths, as of as of December, 2021. The severe acute respiratory syndrome coronavirus 2 virus targets the receptor, angiotensin-converting enzyme 2, which is frequently found in human intestinal epithelial cells, bile duct epithelial cells, and liver cells, and all gastrointestinal system organs are affected by COVID-19 infection. The aim of this study is to review the gastrointestinal manifestations and liver damage of COVID-19 infection and investigate the severe COVID-19 infection risk in patients that have chronic gastrointestinal disease, along with current treatment guidelines. A literature search was conducted on electronic databases of PubMed, Scopus, and Cochran Library, consisting of COVID-19, liver injury, gastrointestinal system findings, and treatment. Liver and intestinal involvements are the most common manifestations. Diarrhea, anorexia, nausea/vomiting, abdominal pain are the most frequent symptoms seen in intestinal involvement. Mild hepatitis occurs with elevated levels of transaminases. Gastrointestinal involvement is associated with long hospital stay, severity of the disease, and intensive care unit necessity. Treatments and follow-up of patients with inflammatory bowel diseases, cirrhosis, hepatocellular carcinoma, or liver transplant have been negatively affected during the pandemic. Patients with cirrhosis, hepatocellular carcinoma, auto-immune diseases, or liver transplantation may have a greater risk for severe COVID-19. Diagnostic or therapeutic procedures should be restricted with specific conditions. Telemedicine should be used in non-urgent periodic patient follow up. COVID-19 treatment should not be delayed in patients at the risk group. COVID-19 vaccination should be prioritized in this group.     

COVID-19 related liver injuries in pregnancy

While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly spread across the globe, our understanding of its pathogenic mechanisms evolved. Importantly, coronavirus disease 2019 (COVID-19) is now considered a syndromic multisystem inflammatory disease involving not only the respiratory system but also the cardiovascular, excretory, nervous, musculoskeletal, and gastrointestinal systems. Moreover, a membrane-bound form of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2, is expressed on the surface of cholangiocytes and hepatocytes, suggesting the potential of COVID-19 to involve the liver. With the widespread distribution of SARS-CoV-2 throughout the population, infection during pregnancy is no longer a rare occurrence; however, little is known about the course of hepatic injuries and related outcomes in pregnant SARS-CoV-2-positive women. Thus, the understudied topic of COVID-related liver disease during pregnancy poses a great challenge for the consulting gynecologist and hepatologist. In this review, we aim to describe and summarize potential liver injuries in pregnant women with COVID-19.     

COVID-19 combined with liver injury: Current challenges and management

Coronavirus disease 2019 (COVID-19) combined with liver injury has become a very prominent clinical problem. Due to the lack of a clear definition of liver injury in patients with COVID-19, the different selection of evaluation parameters and statistical time points, there are the conflicting conclusions about the incidence rate in different studies. The mechanism of COVID-19 combined with liver injury is complicated, including the direct injury of liver cells caused by severe acute respiratory syndrome coronavirus 2 replication and liver injury caused by cytokines, ischemia and hypoxia, and drugs. In addition, underlying diseases, especially chronic liver disease, can aggravate COVID-19 liver injury. In the treatment of COVID-19 combined with liver injury, the primary and basic treatment is to treat the etiology and pathogenesis, followed by support, liver protection, and symptomatic treatment according to the clinical classification and severity of liver injury. This article evaluates the incidence, pathogenesis and prevention and treatment of COVID-19 combined with liver injury, and aims to provide countermeasures for the prevention and treatment of COVID-19 combined with liver injury.     

COVID-19 infection and liver injury: Clinical features,biomarkers, potential mechanisms,treatment, and management challenges

It is hypothesized that liver impairment caused by coronavirus disease 2019 (COVID-19) infection might play a central role in severe clinical presentations. Liver injury is closely associated with severe disease and, even with antiviral drugs, have a poor prognosis in COVID-19 patients. In addition to the common hepatobiliary disorders caused by COVID-19, patients with pre-existing liver diseases demand special considerations during the current pandemic. Thus, it is vital that upon clinical presentation, patients with concurrent pre-existing liver disease associated with metabolic dysfunction and COVID-19 be managed properly to prevent liver failure. Careful monitoring and early detection of liver damage through biomarkers after hospitalization for COVID-19 is underscored in all cases, particularly in those with pre-existing metabolic liver injury. The purpose of this study was to determine most recent evidence regarding causality, potential risk factors, and challenges, therapeutic options, and management of COVID-19 infection in vulnerable patients with pre-existing liver injury. This review aims to highlight the current frontier of COVID-19 infection and liver injury and the direction of liver injury in these patients.     

Gastroenterology and liver disease during COVID-19 and in anticipation of post-COVID-19 era: Current practice and future directions

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major threat to global public health. The virus causes the clinical syndrome known as coronavirus disease 2019 (COVID-19), in which multiple organs can get affected. Apart from manifestations of the respiratory system, which predominate, its clinical presentation is frequently accompanied by symptoms of the gastro-intestinal (GI) tract and liver abnormalities. The correlation of symptoms and abnormalities with disease severity is discussed, leading to ambiguous results from international literature. Moreover, the disease infects patients with co-existing liver and GI disorders affecting both their health status and the availability of healthcare services provided to them. The risk of transmission of the disease during aerosol-generating procedures has changed the diagnostic approach and follow-up algorithms for liver and GI diseases. For the safety of both doctors and patients, telemedicine and distant evaluation have become everyday practice, whereas several routines and emergency visits at outpatient and emergency departments have been postponed or delayed. Vaccination against SARS-CoV-2 is underway, providing hope to humanity and the expectation that the post-COVID-19 era is near. This review aims to update knowledge about the manifestations of COVID-19 related to liver and GI diseases and the effect of the pandemic on the diagnostic and therapeutic procedures for these diseases with a special focus on how current practices have changed and what changes will possibly remain in the future.     

Liver injury in COVID-19: Known and unknown

Since the first report of the coronavirus disease 2019 (COVID-19) in December 2019 in Wuhan, China, the outbreak of the disease is currently continuously evolving. Previous studies have shown varying degrees of liver damage in patients with COVID-19. However, the exact causes of liver injury and the relationship between COVID-19 and liver injury is unclear. This article describes liver injury induced by COVID-19, analyzes its causes, and discusses the treatment and prognosis of liver damage in patients with COVID-19.     

Remarkable gastrointestinal and liver manifestations of COVID-19: A clinical and radiologic overview

The coronavirus disease 2019 (COVID-19) raging around the world still has not been effectively controlled in most countries and regions. As a severe acute respiratory syndrome coronavirus, in addition to the most common infectious pneumonia, it can also cause digestive system disease such as diarrhea, nausea, vomiting, liver function damage, etc. In medical imaging, it manifests as thickening of the intestinal wall, intestinal perforation, pneumoperitoneum, ascites and decreased liver density. Angiotensin-converting enzyme 2 has great significance in COVID-19-related digestive tract diseases. In this review, we summarized the data on the clinical and imaging manifestations of gastrointestinal and liver injury caused by COVID-19 so far and explored its possible pathogenesis.     

Post COVID-19 infection: Long-term effects on liver and kidneys

Coronavirus disease 2019 is a pandemic, which has affected millions of people across the globe in the year 2020. This disease is caused by a virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that belongs to the family of coronaviruses and primarily affects the respiratory system. This infection has a wide spectrum of clinical manifestations ranging from asymptomatic form to mild, moderate and severe forms depending upon the age, comorbidity and immunity of an affected individual. Hyper-inflammatory response due to SARS-CoV-2 adversely affect several internal organs. Besides lung injury, which is the main outcome of SARS-CoV-2 infection, it has been reported to adversely impact other organs including the liver and kidneys. SARS-CoV-2 virus can also have a direct adverse impact on liver as well as kidneys due to systemic inflammatory response or drug toxicity, leading to elevated levels of liver injury markers and acute kidney injury. Clinical outcomes of SARS-CoV-2 infection could be worse in patients suffering from pre-existing liver and kidney disease. So far, there have been several reports on the mechanism of liver and kidney injury during SARS-CoV-2 viral attack. However, the long-term impact of this infection on these organs is yet to be understood. This review summarizes the possible causes and effects of SARS-CoV-2 on the liver and kidneys during the infection and post recovery based on available literature.     

Impact of COVID-19 on liver

The incidence of liver injury after coronavirus disease 2019 (COVID-19) infection ranged from 15%-53%. The mechanism includes direct viral cytopathic effect, cytokinesis, and treatment drug-induced liver injury. The symptoms include nausea, vomiting, diarrhea, and loss of appetite. The laboratory results include increased liver enzyme levels, decreased monocyte count, and longer prothrombin time. The most common imaging findings are hepatomegaly on ultrasound, ground-glass opacity on chest computed tomography (CT), and liver hypodensity and pericholecystic fat stranding on abdominal CT. Patients may also have different presentations and poor outcomes of different liver diseases concomitant with COVID-19 infection. Liver function test (LFT) results should be monitored, and all factors known to cause or predispose liver injury should be investigated while managing the patients. The risks of transfer to an intensive care unit, need for mechanical ventilator support, and acute kidney injury is higher in COVID-19 patients with than without abnormal LFTs. Increased mortality and length of hospital stay are both observed.     

Liver dysfunction-related COVID-19: A narrative review

The coronavirus 2019 disease (COVID-19) is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2. This disease was designated by the World Health Organization as a pandemic on March 11, 2020, which is not seen before. There are no classical features among the cases of the disease owing to the involvement of nearly all body tissues by the virus. Hepatic involvement is one of the characteristics of the COVID-19 course. There are six possible mechanisms of such involvement: Direct virus injury, drug-induced effect, inflammatory cytokine storm, hypoxia-ischemic destruction, abnormalities in liver function tests, and pre-existing chronic liver diseases. Liver abnormalities are seen commonly in the severe or critical stage of COVID-19. Therefore, these abnormalities determine the COVID-19 severity and carry a high rate of morbidity and mortality. The elderly and patients with comorbidities like diabetes mellitus and hypertension are more vulnerable to liver involvement. Another issue that needs to be disclosed is the liver manifestations following the COVID-19 vaccination, such as autoimmune hepatitis. Of note, complete vaccination with third and fourth booster doses is necessary for patients with previous chronic liver diseases or those who have been subjected to liver transplantation. This review aims to explore the various aspects of liver dysfunction during the COVID-19 course regarding the epidemiological features, predisposing factors, pathophysiological mechanisms, hepatic manifestations due to COVID-19 or following vaccination, role of liver function tests in the assessment of COVID-19 severity, adverse effects of the therapeutic agents for the disease, and prognosis.     

Autoimmunity as the comet tail of COVID-19 pandemic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can give rise to different clinical manifestations that are directly related to viral tissue damage or indirectly induced by the antiviral immune response. Hyper-activation of the immune system in an attempt to eradicate the infection may trigger autoimmunity. Several immune-mediated disorders have been described in SARS-CoV-2-infected individuals. These include cutaneous rashes and vasculitis, autoimmune cytopenia, anti-phospholipid syndrome, central or peripheral neuropathy, myositis and myocarditis. On the other hand, rheumatic patients were reported to have similar coronavirus disease 2019 (COVID-19) incidence, morbidity and mortality rates compared to general population. This opinion review will summarize the crucial immunologic steps which occur during SARS-CoV-2-infection that may link autoimmunity to COVID-19 and provides an opportunity for further discussion regarding this association.     

Living with liver disease in the era of COVID-19-the impact of the epidemic and the threat to high-risk populations

The cardinal symptoms of severe acute respiratory syndrome coronavirus 2 infection as the pandemic began in 2020 were cough, fever, and dyspnea, thus characterizing the virus as a predominantly pulmonary disease. While it is apparent that many patients presenting acutely to the hospital with coronavirus disease 2019 (COVID-19) infection have complaints of respiratory symptoms, other vital organs and systems are also being affected. In fact, almost half of COVID-19 hospitalized patients were found to have evidence of some degree of liver injury. Incidence and severity of liver injury in patients with underlying liver disease were even greater. According to the Centers of Disease Control and Prevention, from August 1, 2020 to May 31, 2022 there have been a total of 4745738 COVID-19 hospital admissions. Considering the gravity of the COVID-19 pandemic and the incidence of liver injury in COVID-19 patients, it is imperative that we as clinicians understand the effects of the virus on the liver and conversely, the effect of underlying hepatobiliary conditions on the severity of the viral course itself. In this article, we review the spectrum of novel studies regarding COVID-19 induced liver injury, compiling data on the effects of the virus in various age and high-risk groups, especially those with preexisting liver disease, in order to obtain a comprehensive understanding of this disease process. We also provide an update of the impact of the new Omicron variant and the changing nature of COVID-19 pathogenesis.     

Liver injury in COVID-19: Holds ferritinophagy-mediated ferroptosis accountable

Even in patients without a history of liver disease, liver injury caused by coronavirus disease 2019 (COVID-19) is gradually becoming more common. However, the precise pathophysiological mechanisms behind COVID-19's liver pathogenicity are still not fully understood. We hypothesize that inflammation may become worse by cytokine storms caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Elevated ferritin levels can initiate ferritinophagy mediated by nuclear receptor coactivator 4 (NCOA4), which leads to iron elevation, and ferroptosis. In COVID-19 patients, ferroptosis can be restricted to reduce disease severity and liver damage by targeting NCOA4-mediated ferritinophagy. To confirm the role of ferritinophagy-mediated ferroptosis in SARS-CoV-2 infection, further research is required.     

Beta receptor blocker therapy for the elderly in the COVID-19 era

When the coronavirus disease 2019 (COVID-19) pandemic spread globally from the Hubei region of China in December 2019, the impact on elderly people was particularly unfavorable. The mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was highest in older individuals, in whom frailty and comorbidities increased susceptibility to severe forms of COVID-19. Unfortunately, in older patients, the course of COVID-19 was often characterized by significant cardiovascular complications, such as heart failure decompensation, arrhythmias, pericarditis, and myopericarditis. Ensuring that the elderly have adequate therapeutic coverage against known cardiovascular diseases and risk factors is particularly important in the COVID-19 era. Beta blockers are widely used for the treatment and prevention of cardiovascular disease. The clinical benefits of beta blockers have been confirmed in elderly patients, and in addition to their negative chronotropic effect, sympathetic inhibition and anti-inflammatory activity are theoretically of great benefit for the treatment of COVID-19 infection. Beta blockers have not been clearly shown to prevent SARS-CoV-2 infection, but there is evidence from published studies including elderly patients that beta blockers are associated with a more favorable clinical course of COVID-19 and reduced mortality. In this minireview, we summarize the most important evidence available in the literature on the usefulness of beta blocker therapy for older patients in the context of the COVID-19 pandemic.     

Liver injury in COVID-19: A minireview

In December 2019, an outbreak of unexplained pneumonia was reported in Wuhan, China. The World Health Organization officially named this disease as novel coronavirus disease 2019 (COVID-19). Liver injury was observed in patients with COVID-19, and its severity varied depending on disease severity, geographical area, and patient age. Systemic inflammatory response, immune damage, ischemia-reperfusion injury, viral direct damage, drug induce, mechanical ventilation, and underlying diseases may contribute to liver injury. Although, in most cases, mild liver dysfunction is observed, which is usually temporary and does not require special treatment, the importance of monitoring liver injury should be emphasized for doctors. The risk of COVID-19 infection of liver transplantation recipients caused more and more concerns. In this article, we aimed to review the available literature on liver injury in COVID-19 to highlight the importance of monitoring and treating liver injury in COVID-19.     

Changes in liver enzymes and association with prognosis in patients with COVID-19: a retrospective case–control study

ObjectiveCOVID-19 has recently emerged as a serious threat to global health. This study examined the laboratory investigations of patients with COVID-19, with an emphasis on liver enzymes.MethodsThis retrospective, single-center study was performed on patients with COVID-19 who were admitted to Imam Reza Hospital, Iran from March 2020 to February 2021. Laboratory tests included a complete blood cell count, white blood cell (WBC) count, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio, and levels of aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase. Patient survival was among the outcome measures investigated in association with laboratory findings.ResultsWe enrolled 77 patients with COVID-19 and 63 healthy controls. In comparison with the control group, patients with COVID-19 showed COVID-19 increased ALT, WBC, neutrophils, NLR, and PLR, and decreased platelet counts and lymphocytes.ConclusionAlthough elevated levels of AST, NLR, PLR, and LMR were found in patients with COVID-19, they were not linked to mortality. Given the presence of AST in other tissues, the influence of SARS-CoV-2 on the liver should be interpreted with caution.