key: cord-0899049-b5fhqc9y
authors: Garrido, Isabel; Liberal, Rodrigo; Macedo, Guilherme
title: Review article: COVID‐19 and liver disease—what we know on 1st May 2020
date: 2020-06-02
journal: Aliment Pharmacol Ther
DOI: 10.1111/apt.15813
sha: a7b3d9ce56ac2679aa29941dd0c14596decc5688
doc_id: 899049
cord_uid: b5fhqc9y

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative pathogen of coronavirus disease 2019 (COVID‐19), became a global threat to human health. Liver impairment has been frequently reported as a common manifestation, although its clinical significance is still unclear, particularly in patients with underlying chronic liver disease (CLD). AIMS: To summarise the changes in liver function tests during SARS‐CoV‐2 infection and the impact of COVID‐19 in patients with underlying CLD. METHODS: A literature review using online database PubMed was done using the search terms “SARS‐CoV‐2”, “COVID‐19”, “liver”, “cirrhosis” and “liver transplantation”. RESULTS: COVID‐19 is frequently associated with different degrees of abnormal liver function tests, most notably transaminases, which are usually transitory and of mild degree. Available evidence suggests that liver injury may result from direct pathogenic effect by the virus, systemic inflammation or toxicity from commonly used drugs in this subset of patients. SARS‐CoV‐2 infection in children is associated with minimal or no increase in liver enzymes, thus the presence of abnormal liver function tests should trigger evaluation for underlying liver diseases. Although it seems that patients with CLD are not at greater risk for acquiring the infection, those with cirrhosis, hepatocellular carcinoma, non‐alcoholic fatty liver disease, autoimmune liver diseases or liver transplant may have a greater risk for severe COVID‐19. CONCLUSIONS: Abnormal liver function tests during the course of COVID‐19 are common, though clinically significant liver injury is rare. Further research is needed focusing on the effect of existing liver‐related comorbidities on treatment and outcome of COVID‐19.

Coronavirus disease 2019 is caused by the recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially reported in Wuhan, China, but that rapidly spread around the world and caused a serious threat to global public health. 1 Similar to SARS-CoV, SARS-CoV-2 mainly affects the respiratory system, with fever, cough and dyspnoea being the most frequently reported symptoms. 2 In severe cases, patients may develop pneumonia and associated complications, such as severe acute respiratory distress syndrome, septic shock and, eventually, death. 3 Liver impairment has also been reported as a common manifestation, although its clinical significance is still unclear. Moreover it is important to define if chronic liver disease (CLD) should be considered a risk factor for severe disease course. Thereby, we aimed to review the changes in liver function caused by SARS-CoV-2, in both adults and children, and the impact of COVID-19 in patients with CLD. In addition, we overview some of the therapies for COVID -19 under investigation and their risk of drug-induced hepatotoxicity.

Several studies have shown different degrees of elevated serum liver biochemistries in COVID-19 patients, mainly indicated by abnormal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels accompanied by slightly elevated total bilirubin (TB) levels. 2, In fact, the incidence of elevated ALT and AST ranged from 2.5%-50.0% to 2.5%-61.1% respectively. 2, With regard to TB, studies have reported increased levels in 0%-35.3% of cases. 2, Relevant elevations of alkaline phosphatase (AKP) and gammaglutamyl transferase (GGT) levels have not been reported in most studies (Table 1) . 2, However, Ji et al examined 202 patients with confirmed COVID-19, 37.6% of which with non-alcoholic fatty liver disease (NAFLD), and showed that elevated GGT levels portend a more severe course of the disease. 26 It remains unclear whether these laboratory test alterations are associated with a worse prognosis. In Furthermore, Wang and colleagues analysed 339 elderly COVID-19 patients and reported that there were no evident differences in ALT levels between survival and death. 6 In addition, cases of severe acute liver injury have rarely been described. 27 Thereby, most recent studies argue that the COVID-19-related liver injuries are usually transitory and mild degree, with small clinical significance. 19 Hence, it is recommended close monitoring and no specific treatment is required.

It remains unclear whether liver injury is caused by the virus itself or reflects a severe inflammatory response with liver damage. 28 SARS-CoV-2 may directly infect liver cells as the receptor of the virus, angiotensin-converting enzyme 2 (ACE2), is expressed by liver and bile duct cells. 29 Data from two independent cohorts revealed ACE2 expression in 2.6% of hepatocytes and 59.7% of cholangiocytes, suggesting that SARS-CoV-2 might directly bind to ACE2-positive cholangiocytes to dysregulate liver function. 30 Moreover liver biopsies in patients with SARS-associated coronavirus infection showed a significant increase in mitotic cells and ballooned hepatocytes, suggesting that it may induce apoptosis of liver cells. 31 Additionally, although viral load was relatively low, virus was detected in liver tissue.

Tan et al have also demonstrated that SARS-CoV-specific protein 7a induces apoptosis via a caspase-dependent pathway in cell lines of different organs, including the liver, further confirming the possibility that SARS-CoV directly affects liver tissue. 32 However, this hypothesis has been contested by some authors since the derangement of liver function is usually mild and there is no evidence that late-onset symptoms are associated with greater liver function damage. 33 Some systemic viral infections, such as Epstein-Barr virus, cytomegalovirus, herpes simplex virus, parvovirus and adenovirus, are associated with similar elevations of liver function biomarkers which reflect immune activation and inflammation caused by circulating cytokines. 34 Furthermore, few studies reported higher serum pro-inflammatory cytokines and chemokines levels in patients with abnormal liver function compared to those with normal liver function. 16, 35 Hence, these data point to a relationship between liver damage and the inflammatory responses induced by SARS-CoV-2 infection. Lastly, some authors suggest that drug-induced liver injury is also a possible contributing factor to laboratory test abnormalities. 33, 36 Liver injury may occur after the use of multiple drugs, such as antivirals, antibiotics, traditional Chinese medicine, antipyretics and analgesics. 7, 10 Although liver histology is poorly accessible in COVID-19, few studies have already reported pathological findings on autopsies performed on SARS-CoV-2 infected patients. Xu et al observed microvesicular steatosis and mild lobular and portal activity. 37 Zhang et al reported mild sinusoidal dilatation and minimal lymphocytic infiltration. 13 These changes are nonspecific and may be caused by either SARS-CoV-2 infection, hypoxemia or drug-induced liver injury.

However, it is important to note that in none of these samples intranuclear or intracytoplasmic viral inclusions were identified.

Patients with CLD, particularly those with autoimmune liver dis- 44 In what concerns to COVID-19, the Hospital Papa Giovanni XXIII in Bergamo hosts one of the largest European centers for pediatric liver transplantation and is located in the "red zone" for the Italian outbreak.

They reported that, among around two hundred transplant recipients, including ten current inpatients, none of them have developed clinical pulmonary disease, despite three tested positive for SARS-CoV-2. 45 Thus, immunosuppressed patients may not have an increased risk of severe complications by COVID-19 when compared to the general population. Nevertheless, the effects of immunosuppression on COVID-19 are not well established and it is urgent that clinics share their experience with immunocompromised patients. 46 The incidence reported in the literature of CLD in patients with COVID-19 is 0.6%-37.6%. 2,4-26 However, the exact cause of pre-existing liver conditions has not been outlined in many of these case studies, which makes it difficult to analyse the impact of COVID-19 on the different aetiologies of CLD (Table 1) .

Patients with liver cirrhosis may develop acute-on-chronic liver failure because of overwhelming inflammatory responses. 47 In fact, liver cirrhosis patients have a significantly higher risk of secondary bacterial infection and a more severe course of influenza, including the development of organ failures, secondary infections and death. 40 In a study of 111 decompensated cirrhotics in Wuhan, none of these patients had clinical symptoms suggestive of SARS-CoV-2 infection when a precautionary approach was implemented, namely protective measures for outpatients, hospital staff training, new processes for diagnosis and treatment and emergency plans. 48 Abbreviations: AKP, alkaline phosphatase; ALD, alcoholic fatty liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHB, chronic hepatitis B; CHC, chronic hepatitis C; GGT, gamma-glutamyl transferase; ICU, intensive care unit; NA, not available; NAFLD, non-alcoholic fatty liver disease; TB, total bilirubin. autoimmune hepatitis. EASL-ESCMID currently advises against reducing immunosuppressive therapy in patients with autoimmune liver disease and recommends that reductions should only be considered in case of severe COVID-19 under special circumstances (eg drug-induced lymphopenia or bacterial/fungal superinfection). 49 The World

Health Organization (WHO) suggests minimising high-dose prednisone but to maintenance small doses to avoid adrenal insufficiency. 53 Post-transplant management is complex: insufficient immunosuppression results in graft loss due to rejection, whereas excessive immunosuppression may lead to severe infections. 54 

People of all ages are susceptible to SARS-CoV-2 infection.

However, infected children appear to have a milder disease course and a better prognosis than adults. 59 In fact, children have a special Tocilizumab, an interleukin-6 inhibitor, frequently causes mild serum elevations of aminotransferase and bilirubin levels, which are usually short lived and asymptomatic. 70 Tocilizumab has been used safety and without worsening of disease in patients with concurrent CHC. 71 Importantly, Tocilizumab may increase the risk of HBV reactivation; HBV screening is mandatory and when needed antiviral prophylaxis should follow international guidelines. [72] [73] [74] Ivermectin, an anti-parasitic agent, has been associated with minor, self-limiting serum aminotransferase elevations and very rare instances of clinically apparent liver injury. 75 Dose adjustments are not necessary in patients with hepatic impairment.

Remdesivir is a novel nucleotide analog, currently under investigation, and with no experience in liver cirrhosis. Elevations of transaminase levels have been reported in up to 22.6% of patients. 76 Similarly, there is no data available in patients with CLD about Favipiravir, an RNA polymerase inhibitor that may also cause liver cytolysis. 77 

The COVID-19 epidemic has spread globally and raised many ques- 

Declaration of funding interests: None.

Guarantor of the article: Isabel Garrido. 

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Review article: COVID-19 and liver disease-what we know on 1st