Patients with liver diseases, especially those with cirrhosis, have an increased mortality risk when infected by SARS-CoV-2 and therefore anti-SARS-CoV-2 vaccine has been recommended by leading Scientific Associations for all patients with chronic liver diseases. However, previous reports have shown a reduced antibody response following the full course of vaccination in immunosuppressed patients, including liver transplant recipients and several rheumatic diseases.This document, drafted by an expert panel of hepatologists appointed by the Italian Association for the Study of the Liver (AISF), aims to present the updated scientific data on the safety and efficacy of anti-SARS-CoV-2 mRNA vaccines in patients with autoimmune hepatitis (AIH). Furthermore, given the recent reports of sporadic cases of AIH-like cases following anti-SARS-CoV-2 mRNA vaccines, we summarize available data. Finally, we provide experts recommendations based on the limited data available.
1. 2022 AISF recommendation on anti-SARS-CoV-2 vaccines for patients with known autoimmune hepatitis
Patients with chronic liver diseases (CLD), especially those with cirrhosis, have an increased mortality risk when infected by SARS-CoV-2 []. One of the largest international studies currently available, showed an observed mortality of 32% in patients with cirrhosis compared to 8% in those without []. Therefore, the European Association for the Study of the Liver (EASL) has recommended vaccination against SARS-CoV-2 for all patients with CLD []. Although contrasting data have been published, patients with AIH with or without cirrhosis under immunosuppressive therapy represent an at-risk category of developing severe COVID-19 when infected [,]. Therefore, based on the data available, the benefit of anti-SARS-CoV-2 vaccination outweighs the potential risk for disease exacerbation in AIH.Although the registration trials of mRNA vaccines enrolled patients with CLD (217 patients in Pfizer trial and 196 patients in Moderna trial), subjects under immunosuppressive therapy were excluded. A recent study by Thuluvath and colleagues found that 75% of patients with CLD without cirrhosis and 77% of patients with cirrhosis had adequate antibody response to anti-SARS-CoV2 vaccines []. The authors included 233 patients with CLD with 61 being affected by immune mediated liver diseases, including AIH, primary biliary cholangitis, and primary sclerosing cholangitis. Also 62 patients were liver transplant (LT) recipients, 79 had cirrhosis, and 92 had CLD without cirrhosis. Antibody levels were undetectable in 11 patients who had LT, 3 with cirrhosis, and 4 without liver cirrhosis. LT and treatment with two or more immunosuppressive drugs were associated with poor antibody responses. However, only 3 patients out of 18 with undetectable antibody were AIH patients on immunosuppression (2 on prednisone plus mycophenolate mofetil (MMF) and 1 on prednisone plus azathioprine).Reports have shown a reduced antibody response following the full course of vaccination in liver transplant recipients []. It has also been formerly demonstrated that specific drugs (i.e. methotrexate, abatacept, and rituximab) reduced the immune response to influenza or pneumococcal vaccines in a number of different rheumatic diseases [8, 9, 10]. The efficacy of anti-SARS-CoV-2 vaccination in preventing COVID-19 in patients with AIH on immunosuppressive therapies [,], as well as the risk of disease reactivation after anti-SARS-CoV-2 vaccination, have been poorly investigated. Similarly, cellular immunity to SARS-CoV-2 in AIH patients has not been studied.The American College of Rheumatology (ACR) has recently proposed a guidance [] suggesting a short-term withdrawal of methotrexate, JAK inhibitors, abatacept, and MMF, and deferral of rituximab and cyclophosphamide infusion if possible before anti SARS-Cov-2 vaccination, according to rheumatic disease activity. However, there is no solid evidence as to whether it is appropriate or not to suspend or reduce the dose of immunosuppressive drugs immediately before or following the administration of the vaccine in AIH patients. Importantly, this strategy may be potentially associated with an increased risk of AIH reactivation particularly dangerous in patients with cirrhosis. Of interest, high doses of MMF and rituximab remain independent predictors of failure to develop an antibody response after vaccination in rheumatic diseases []; however, no data are available in AIH. At the present time, the available data do not justify withdraw or reduction of immunosuppression before or immediately after vaccination in patients with AIH.Finally, no clear evidence of reactivation of AIH after anti-SARS-CoV-2 vaccination has been reported in the literature. Interestingly, the presence of significant fibrosis at the liver histology of a small number of newly diagnosed AIH following anti-SARS-CoV-2 vaccination might suggest the possibility of disease reactivation [15, 16, 17]. However, until new multicenter studies are available there is no current indication for routine testing of transaminases levels in AIH patients after vaccination.
2. 2022 aisf recommendation on autoimmune hepatitis like onset following anti-SARS-CoV-2 vaccination
The COVID-19 pandemics has necessitated the development and registration of several vaccines in record time. The monitoring for safety, side effect and efficacy is ongoing in the post-marketing surveillance. Recent reports inform on the possible occurrence of immune mediated hepatitis or AIH-like disease in predisposed individuals. Autoimmunity is widely accepted to develop in genetically predisposed individuals and some polymorphisms have been identified in AIH []; unfortunately, they are not yet of clinical use and cannot be of help to identify individuals at risk.Considering that 58% of the world population has received at least one dose of anti-SARS-CoV-2 vaccine, with 9.2 billion doses been administered globally, it is unclear whether this is a pure coincidence rather than a causality.The fact that someone developed immune-mediated acute hepatitis after vaccination does not necessarily mean that this was caused by the vaccine.The European Medicine Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC) has recently started an assessment following the very small number of cases reported after vaccination with SpikevaxⓇ and ComirnatyⓇ (known as Moderna and Pfizer vaccines, respectively) in the medical literature and EudraVigilance (www.ema.europa.eu). Further data and analyses have been requested from the marketing authorization holder to support the ongoing assessment by PRAC. Given the small number of cases currently reported, the issue seems to be rare; however, specific studies should be performed to define the number and severity of cases.At the time these recommendations are drafted, 17 reports have been published in the medical literature that overall include 31 cases of suspected AIH-like triggered by the vaccine (Table 1). Patients were more often women (F:M 21:10), age ranging from 32 to 89 years old (median 58 years). In eleven cases a pre-existent autoimmune condition (i.e., seven Hashimoto thyroiditis, one primary biliary cholangitis, two rheumatoid arthritis, one systemic lupus erythematosus) is reported. Two patients had experienced COVID-19 infection before the vaccine. All except four presented with an acute onset of AIH-like with jaundice. All patients underwent liver biopsy and in six of them fibrosis was already present, which might suggest that they had a previous liver disease, possibly an undiagnosed AIH. All were treated with steroid therapy, and all improved the liver function tests (LFTs), although details on the biochemical response are not thoroughly reported.Table 1Cases of suspected AIH triggered by the vaccine reported in the literature.
Adverse effects of the vaccine are possible, and abnormal liver function tests following vaccination represent an important clinical issue. AIH is a relatively rare, chronic immune-mediated liver disease, which develops in genetically predisposed individuals following environmental triggers; viral infections and drug exposures have been suggested to trigger the disease, but not definitive evidence is available [,]. AIH-like onset after vaccination – other than anti-SARS-CoV-2 – has been also previously reported []. However, even if it can be speculated that the vaccines can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells, it might be hard to definitively state that AIH is induced by a vaccine. Considering the reported AIH-like cases following SARS-CoV-2 vaccination, timing of occurrence of acute hepatitis from vaccination in some of them is very short (less than 7 days), suggesting that a dysregulation of immune system has already occurred before vaccination in those cases. So far, given the availability of only observational literature without a structured collection of AIH-like cases after anti-SARS-CoV-2 vaccines, no definitive conclusions can be drawn. There is a need for population-based studies to gather data on the incidence, severity, and clinical features of anti-SARS-Cov-2 vaccination-induced AIH under the umbrella of the national and European Scientific Societies.In the meantime, while intensive vaccination against SARS-CoV-2 continues, healthcare providers should include the diagnosis of AIH triggered by vaccines in the differential diagnosis in cases of acute hepatitis of unexplained etiology and manage them as drug-induced AIH or AIH-like liver injury as recommended by current guidelines [].
*These recommendations will be reviewed periodically as further information becomes available.
•AIH patients should receive anti-SARS-CoV-2 vaccination consistent with the age restriction of the local approval. In Italy, as recommended by the Italian Ministry of Health for all immunosuppressed patients, mRNA vaccines should be used. Based on the data for the mRNA vaccines available, there is no preference for one vaccine over another.
•Patients with AIH are suggested to undergo vaccination when the disease activity is controlled by immunosuppressive therapy. To date there are no data available to establish variations on the interval between doses of anti-SARS-Cov2 vaccine.
•There is no current evidence to recommend suspension or reduction of immunosuppressive drugs in AIH patients before or immediately after anti-SARS-CoV-2 vaccination.
•The risk of AIH flare or disease worsening following anti-SARS-Cov-2 vaccination has not been assessed to date and specific studies are required before defining a line of recommendation. Based on available data routine testing of transaminases levels in AIH patients after vaccination could be suggested in selected patients although the timing needs to be defined.
•Testing of antibody levels for IgM and/or IgG to spike or nucleocapsid proteins to assess immunity to SARS-Cov2 after vaccination in AIH patients is not recommended, nor to assess the need for vaccination in an unvaccinated AIH patients.
•Patients with new acute onset of liver injury following anti-SARS-Cov-2 vaccine should be managed as suggested by current guidelines and known clinical algorithms, including the indication to liver biopsy. Considering the lack of evidence currently available to exclude drug induced AIH in this setting, immunosuppressive therapy should be carefully considered and used if AIH diagnosis is confirmed; long-term immunosuppressive therapy needs to be assessed on a patient-by-patient basis.
•Patients with newly diagnosed AIH or AIH flare after anti-SARS-Cov-2 vaccine should be consider for vaccine booster; however, the timing of the booster could be personalised based on the disease activity and ongoing therapy and discussed case-by-case with an expert center in autoimmune liver diseases.
•Given the limited number of cases compared to the number of vaccinated subjects, extended testing of transaminases level after vaccination in the general population is not sustainable nor suggested.
•EMA’s PRAC encourages all healthcare professionals and patients to report any cases of autoimmune hepatitis and other adverse events in people after vaccination.
The coronavirus disease 2019 (COVID-19) has led to a global health crisis. Its clinical manifestations are well-documented, and severe complications among patients who survived the infection are being continuously reported. Several vaccines with well-established efficacies and excellent safety profiles have also been approved. To date, few side effects of vaccines have been reported. Drug-induced hepatotoxicity is an extremely rare side effect of these vaccines, with few reported instances. In this case report, we describe a patient who experienced hepatotoxicity after receiving the COVID-19 vaccine from Pfizer BioNTech.
The coronavirus disease 2019 (COVID-19) has caused an unprecedented global health crisis. Its most common symptoms include fever, cough, fatigue, and myalgia. Rarely, patients may develop an acute respiratory distress syndrome or multiple organ failure . Other conditions, such as liver injury, may occur. Various factors can lead to liver injury, including severe inflammatory responses, severe hypoxia, drug-induced liver injury (DILI), and worsening of pre-existing metabolic conditions . The manifestations of liver injury vary from elevated serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin to hepatic dysfunction in severe cases . In May 2020, the Pfizer‐BioNTech COVID‐19 vaccine received emergency authorization for use among adolescents aged 12-15 years . Clinical trials have demonstrated that its efficacy in this age group may be as high as 100%. The vaccine’s side effects are typically mild and non-life-threatening, including headache, fatigue, myalgias, and chills . However, there have been reports on extremely rare yet life-threatening side effects, such as anaphylactic shock, deep venous thromboembolism, and pulmonary embolism [1,6].
A 14-year-old female, not known to have any chronic illnesses, presented to the emergency department with epigastric pain, diarrhea, nausea, and vomiting for the past four days. Three days prior to her current presentation, the patient received the second dose of the Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine. The patient denied the use of any pharmaceutical, herbal, or recreational drugs. Upon arrival to the emergency room, the patient had a temperature of 36.9°C, a pulse rate of 128 bpm, a blood pressure of 90/63 mmHg, a respiratory rate of 18 rpm, and oxygen saturation of 97% on room air. On physical examination, the patient was conscious, oriented, and had a Glasgow coma scale (GCS) score of 15/15. In addition, she had mild epigastric tenderness and jaundice. No signs of chronic liver disease were evident.
On the first day of admission, vital signs returned to normal after resuscitation with intravenous fluids. The patient’s urine was dark as observed after urinary catheter insertion. The hematology panel showed Leukopenia, neutropenia, and lymphopenia among others as seen in Table 1. Biochemical and coagulation profile workups are shown in Table 2. Abdominal ultrasound was unremarkable except for a minimal rim of free fluid in the pelvic cavity. Along with conservative treatment, the patient was started on N-acetylcysteine, lactulose, and Vitamin K. In addition, ceftriaxone was given as an empirical antibiotic. On the second day, the results of AST, ALT, and alkaline phosphatase decreased, yet remained abnormally high (Figures 1, 2).
White blood cells
Table 1: Trend of the complete blood counts and bilirubin
Normal ranges: White blood cells: 4-10 x 109/L, Neutrophils: 2-7×103/µL (40%-75%), Lymphocytes: 1-3.5×103/µL (20%-45%), Platelets: 150-400×103/µL, Total bilirubin: 0-21 µmol/L, Direct bilirubin: 0-3.4 µmol/L
international normalized ratio
Table 2: Trends of the chemical and coagulation profiles
Abbreviations: APTT: Activated Partial prothrombin time, INR: international normalized ratio
Normal ranges: AST – Aspartate transaminase (0-40 U/L), ALT – Alanine transaminase (0-41 U/L)
Figure 2: Alkaline phosphatase and albumin trends
Normal ranges: Albumin: 39.7-49.4 mmol/L, Alkaline phosphate: 35-104 mmol/L
On the fourth day, the patient became agitated and non-responsive, when assessed, her GCS score dropped to 8/15. Consequently, she was transferred to the intensive care unit, where she was intubated. Consultations from gastroenterology, infectious disease, neurology, and hematology departments were requested. Following this, a wide range of infectious, immunological, and toxicological tests were ordered (Tables 3,4). Nevertheless, all the results were unremarkable. To rule out structural brain pathologies, a brain computed tomography without contrast was performed. A suspicious hypodense lesion in the right temporal lobe was identified. However, the findings from the brain magnetic resonance imaging were unremarkable.
Blood culture and sensitivity
Cytomegalovirus immune globulin M (CMV IgM)
Indirect Coombs test
Direct Coombs test
Hepatitis A virus immune globulin M (HAV IgM)
Hepatitis C virus antibodies (enzyme immunoassays)
Hepatitis B surface antigen (HBsAg)
Urine culture and sensitivity
human immunodeficiency virus serology (HIV)
Stool Culture and sensitivity
Alkhurma virus PCR
Dengue virus PCR
Dengue virus serotype
Dengue virus IgG
Dengue virus nonstructural protein 1 (NS1)
Dengue virus IgM
Rift valley fever PCR
Anti-Smooth Muscle Antibody (ASMA)
Antinuclear Antibodies (ANA)
Anti-Liver-Kidney Microsomal Antibody (LKM)
Table 3: Immunologic and infectious work-up for liver disease
The patient’s level of consciousness returned to normal by the seventh day, her liver enzyme levels continued to decline, and her symptoms have resolved. Afterward, she was transferred to a liver transplant center for further investigation and management.
DILI is the most common cause of acute liver injury in developed countries . Its presentation ranges from an incidental elevation of liver enzymes to outright acute liver failure . There are two types of DILI: idiosyncratic and intrinsic. The most common type of which is the intrinsic type that has a short latency period and is dose-dependent. An example of an offending agent in this type is acetaminophen. Contrarily, the idiosyncratic type is less common and has a longer latency. A few examples of idiosyncratic drugs are amoxicillin, nonsteroidal anti-inflammatory drugs, and isoniazid . In our case, we hypothesized the type of DILI to be idiosyncratic, due to the short latency period.
The diagnosis of DILI is made by identifying a relationship between drug exposure and the onset of liver disease. It is important to exclude any infectious, autoimmune, or other forms of liver disease. A thorough medical history and a high clinical suspicion are the basis for a correct diagnosis. A recovery following withdrawal from an offending agent may indicate DILI . A diagnostic criterion that can be utilized in diagnosing DILI is the Rousse Uclaf Causality Assessment Method of the Council of International Organization of Medical Science (RUCAM/CIOMS) . This criterion was applied to our patient’s case, and a total of 6 was calculated, indicating that DILI is probable.
Currently, there is no effective treatment for DILI other than discontinuing the offending drug and providing patients with supportive measures until their condition improves . The exception is acetaminophen intoxication in which an antidote can be used in management, namely N-acetylcysteine. Early transfer of patients with idiosyncratic DILI to tertiary liver centers is important. Liver transplantation increases overall survival from 27.8% to 66.2% . Withholding the transplantation can result in infection, brain damage, organ failure, and even death .
There have been three reports of patients having hepatic failure, with one case being acute, after receiving the Pfizer/BioNTech BNT162b2 mRNA vaccine in the United Kingdom between September 12, 2020 and September 4, 2021. Moreover, there have been 17 reported cases of liver injury, with two cases being drug-induced . The possible side effects of the COVID-19 vaccines on the liver are not limited to one type. Two case reports suggested that the ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca) may trigger acute autoimmune hepatitis . Mann et al. reported a case of a 61-year-old female who developed generalized weakness and low-grade fever after receiving the second dose of Pfizer/BioNTech BNT162b2 mRNA vaccine. The patient had an ALP of 207 µ/L, total bilirubin of 6.2 mg/dL, direct bilirubin of 3.9 mg/dL, a WBC of 17 x 109, and AST of 37 U/L. All laboratory workup and imaging to investigate possible etiologies were unremarkable. As compared to our case, there were significant differences in age group, initial presentation, and degree of liver injury .
Prior to her recent presentation, our patient had no chronic illnesses. Given that her history, physical examination, and laboratory workups were unremarkable, the patient’s clinical picture was attributed to hepatotoxicity secondary to the Pfizer/BioNTech BNT162b2 mRNA vaccine, the only pharmacological agent that she was exposed to before her current presentation.
This is a case of hepatotoxicity in a 14-year-old patient that occurred after receiving the second dose of the Pfizer/BioNTech BNT162b2 mRNA vaccine. The exhaustive clinical and laboratory evaluation failed to establish any other plausible etiology besides the vaccine. The purpose of this report is to raise awareness of this uncommon but potentially life-threatening side effect.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported to trigger several autoimmune diseases. There are also recent reports of autoimmune diseases that develop after SARS-CoV-2 vaccines. Autoimmune hepatitis is a polygenic multifactorial disease, which is diagnosed using a scoring system. A 61-year-old woman presented with malaise, fatigue, loss of appetite, nausea and yellow eyes. She had a Pfizer/BioNTech BNT162b2 mRNA vaccine a month ago. Her physical examination revealed jaundice all over the body, especially in the sclera. The laboratory tests showed elevated liver enzymes and bilirubin levels. Antinuclear antibody and anti-smooth muscle antibody were positive and immunoglobulin G was markedly elevated. The liver biopsy revealed histopathological findings consistent with autoimmune hepatitis (AIH). The patient was diagnosed with AIH and initiated on steroid therapy. She rapidly responded to steroid therapy. A few cases of AIH have been reported after the COVID-19 vaccine so far. Although the exact cause of autoimmune reactions is unknown, an abnormal immune response and bystander activation induced by molecular mimicry is considered a potential mechanism, especially in susceptible individuals. As intensive vaccination against SARS-CoV-2 continues, we would like to emphasize that clinicians should be cautious and consider AIH in patients presenting with similar signs and symptoms.
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Autoimmune diseases result from a breach of immunological self-tolerance and tissue damage by autoreactive T lymphocytes. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is characterized by an inflammatory dysregulation that has been associated with the development of autoimmune processes .
Molecular mimicry has been suggested as a potential mechanism for these associations as well as ‘bystander activation’ where the infection may lead to activation of antigen presenting cells that may activate autoreactive T-cells, with the production of pro-inflammatory mediators and tissue damage .
There is a potential antigenic cross-reactivity between SARS-CoV-2 and human tissue possibly linked to an increase in autoimmune diseases. A recent study showed that antibodies against the spike protein S1 of SARS-CoV-2 had high affinity against some human tissue proteins such as transglutaminase 2 and 3, or myelin basic protein, among others .
As both mRNA vaccine (Comirnaty BioNTech BNT162b2 and Spikevax ARNm-1273) and vectorial vaccine (ChAdOx1nCoV-19 Vaxzevria/Covishield) give rise to the production of protein S, the antibodies produced against this protein after vaccination may also trigger autoimmune conditions in predisposed individuals.
Thirteen case reports (including 16 patients) have recently reported an association between COVID-19 vaccines and acute hepatitis development [3–15].
Here we report two new cases of liver injury possibly related to COVID-19 vaccination.
A 77-year-old woman developed intense malaise, vomiting and disorientation 2 days after receiving the second dose of Comirnaty vaccine and was hospitalized the following day. She did not have a history of autoimmune disorders. She denied alcohol drinking and was on long-term therapy with bromazepam, losartan, and omeprazole. Her previous liver tests back in 2020 were normal.
Physical examination was normal except for scleral icterus. Liver test showed acute hepatocellular injury: total bilirubin (TB) 3.1 mg/dL (reference, <1 mg/dL), aspartate aminotransferase (AST) 474 U/L (reference, <40 UI/L), alanine aminotransferase (ALT) 552 U/L (reference, <40 U/L), and alkaline phosphatase (ALP) 159 U/L (reference, <117 U/L). Immunoglobulin G levels were within normal ranges (reference, 800–1,600 mg/dL), while anti-nuclear antibody and anti-mitochondrial antibody M2 were detected with 1/160 and 1/40 titre, respectively. Human leukocyte antigen (HLA) testing was positive for HLA-DR4. All the other possible aetiologies were ruled out.
The patient was discharged and closely monitored. Due to increased transaminase levels, she underwent a liver biopsy (Supplementary Figure 1.1), which showed findings compatible with autoimmune hepatitis (AIH).
Prednisone 60 mg/day on tapering dose was initiated and 3 weeks later liver test had markedly improved. Azathioprine was added 2 months later, but it had to be withdrawn due to rash. Prednisone was then replaced by budesonide 9 mg/day. Five months after onset, transaminases were within the normal range; however, the subject was hospitalized with neurologic symptoms in relation to brain lesions in both hemispheres of probable infectious origin and died 1 month later.
A 23-year-old man presented with mononucleosis syndrome-like symptoms and jaundice at the emergency room, 10 days after receiving the second dose of Spikevax vaccine. He did not suffer from previous autoimmune disorders. He denied having taken any conventional drug treatments as well as alcohol consumption.
Physical examination was unremarkable except for scleral icterus. Liver tests showed acute hepatocellular injury: TB 2.3 mg/dL, AST 702 U/L, ALT 587 U/L, and ALP 202 U/L. Immunoglobulin G levels were minimally elevated (1,647 mg/dL), while autoantibodies resulted as negative. HLA testing was positive for HLA-DR3. Serology ruled out viral causes and abdominal ultrasonography was normal. After admission to the hospital, a thoracic-abdominal scan was performed and revealed generalized lymphadenopathy.
Prednisone 60 mg/day on tapering dose was initiated and 1 month later lymphadenopathies were undetectable and liver test had significantly improved. Three months after onset, transaminases were within the normal range and he is still on low-dose prednisone 10 mg/day.
These new cases of liver injury compatible with AIH, which developed post COVID-19 vaccination, along with 13 prior published case reports (16 patients) reinforce that this association could be more than coincidental. In the previously published case reports, all the patients, except three, were females and their age ranged from 35 to 80 years [3–15]. Twelve of these patients received one of the mRNA vaccines [3, 5–12, 14, 15], while four patients received vectorial vaccines [4, 12, 13]. In 6 of the 16 patients, liver biopsy revealed infiltration with eosinophils [3, 4, 7, 9, 14] and IgG levels were increased in 12 cases [4–12, 15].
Fourteen reported patients were successfully treated with prednisolone whereas two died due to acute liver failure [4, 12] (Table 1).
Characteristics of patients with liver injury after SARS-CoV-2 vaccine (published cases and two new cases)
The patient died due to an extrahepatic cause (brain lesions in both hemispheres of probable infectious origin).Open in new tab
In both cases of the present study, a number of laboratory (including HLA testing) and histological features supported the autoimmune nature of the liver injury. In our first case, the short period elapsed after vaccine administration, the laboratory and histopathological findings (showing moderate liver fibrosis), the positive HLA-DR4, and the response to therapy suggest unmasking of AIH by the vaccine. However, in our second case, the medical history negative for liver and autoimmune diseases, the short time interval after vaccination, the typical onset of symptoms to which was added generalized lymphadenopathy, the elevated immunoglobulin G levels, the positive HLA-DR3, histopathological findings with absence of liver fibrosis, and the response to therapy reinforce the hypothesis of SARS-CoV-2 vaccine as a trigger of an autoimmune liver injury debut. We realize that there are no pathognomonic (laboratory or histological) features of AIH, but the appropriate exclusion of viral and metabolic causes of liver injury makes the autoimmune mechanisms the more likely explanation for both cases.
Taking into account the large number of vaccinated subjects worldwide, the suspicion of vaccine-related AIH carries important clinical implications. It is unknown whether prolonged immunosuppression would be required in these cases or whether re-exposure to a new dose of COVID-19 vaccine might trigger fulminant liver injury. Nevertheless, the risk of receiving another dose must be balanced against the risk of contracting SARS-CoV-2 infection. In addition, it remains unclear whether patients who have developed liver injury after vaccination with one type of vaccine can receive other COVID-19 vaccine with a different mechanism of action.
Post COVID-19 vaccination, AIH has been rarely reported so far [3–15], which might be due to either minimal awareness of this disease or because patients without jaundice often do not seek medical attention. However, given the growing number of cases compatible with AIH reported after SARS-CoV-2 vaccination, regulators should consider the inclusion of this potential adverse event in the label of COVID-19 vaccines.
In conclusion, clinicians should be aware of the potential association between the vaccines and the onset of immune mediated disorders such as AIH. However, this rare complication should not discourage people from getting vaccinated.
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In response to the COVID-19 pandemic, two novel mRNA-based vaccinations against the SARS-CoV-2 virus have been manufactured and distributed in an unprecedented fashion. In light of their rapid uptake, providers must remain vigilant in their monitoring of new adverse events. In early 2021, multiple providers, communicating on AST LICOP and AASLD online forums, shared strikingly similar experiences with patients who presented with liver injury following COVID-19 vaccination with no other clear precipitants. Given the pattern, we report herein on a multicenter cohort of patients with liver injury following COVID-19 vaccination. No personally identifiable information or protected health information was collected for any patient. The series was reviewed by the Northwestern University IRB and deemed not to be human subjects research.
Our cohort includes 16 total patients (Table 1 ) aged 25 to 74, who presented between 5 to 46 days following their first vaccine dose (Pfizer: 12, Moderna: 4). Notably, 75% of patients (12/16) presented after their second vaccine dose.
Liver disease history
Timing of presentation (days)a
Pattern of injury
Peak lab values
Relevant work-up (medications, labs, imaging)
Inflammation severityd, location
Cellular pattern of inflammation
Cholestasisd and bile duct features
NAFLD, prior DILI (due to amoxicillin)
ASMA 1:40 Other autoimmune and viral serologies negative ERCP with new severe sclerosing cholangitis
+ Portal No interface hepatitis
+ Mild ductular proliferation
Focal portal and peri-portal
Endoscopic biliary dilation
Received nitrofurantoin 3 months prior ASMA 1:160, other autoimmune and viral serologies negative
+ Portal and lobular No interface hepatitis
Lymphocytes and plasma cells
None Normal bile ducts
Ibuprofen x 3 days Autoimmune and viral serologies negative
+ Portal and lobular No interface hepatitis
None Normal bile ducts
HCV (treated); Compensated cirrhosis
No biopsy performed
Extramedullary hematopoiesis of unknown significance on prior liver biopsy
ANA 1:640, other autoimmune serologies negative Viral serologies negative
No biopsy performed
No biopsy performed
Ibuprofen x 2 days ANA 1:640, ASMA 1:20; viral studies negative
No biopsy performed
ANA 1:320, other autoimmune serologies negative EBV viral load 78, VZV IgM+/IgG+ Hepatic steatosis on imaging
++/+++ Portal No interface hepatitis
None Neutrophilic peri-cholangitis
Autoimmune and viral serologies negative
No biopsy performed
AIH (treated)b Compensated cirrhosis
+/++ Portal and lobular with interface hepatitis
Lymphocytes and plasma cells
None Normal bile ducts
AIH (treated)b Compensated cirrhosis
Imaging with new diagnosis of solitary HCC
++ Portal and lobular with interface hepatitis
Mixed with plasma cells
None Normal bile ducts
Prior biliary stricture after cholecystectomy
No biopsy performed
Received shingles vaccine 3 months earlier Viral serologies negative
+++ Portal and lobular with interface hepatitis and central perivenulitis
None Normal bile ducts
Autoimmune and viral serologies negative E. Coli UTI treated with ceftriaxone (after ALI onset)
+++ Portal and lobular Interface hepatitis not reported
None Severe bile ductular reaction
IV steroids, NAC infusion
Tylenol several days per week for preceding year ANA 1:640, IgG 1,750 other autoimmune serologies negative EBV VCA IgM+, IgG+ Other viral markers negative
+++ Portal and lobular No interface hepatitis
None Ductular reaction
Taking Tylenol/Norco for 4 days prior to presentation due to recent knee surgery ANA 1:1,240, ASMA 1:40, IgG normal Viral serologies negative
AIH, autoimmune hepatitis; ALI, acute liver injury; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, anti-nuclear antibodies; ASMA, anti-smooth muscle antibodies; Bili, bilirubin; DILI, drug-induced liver injury; EBV, Epstein-Barr virus; HCC, hepatocellular carcinoma; INR, international normalized ratio; NAC, N-acetylcysteine; NAFLD, non-alcoholic fatty liver disease; UTI, urinary tract infection; VCA, viral capsid antigen.aIn relation to first dose of vaccine.bNo medication changes for over 6 months with normal preceding labs.cBiopsy findings are reported based on each institution’s written report. Biopsies were not independently reviewed.dSeverity of inflammatory infiltrate and cholestasis graded as follows: +, minimal or mild; ++, moderate; +++, severe/extensive.
Six patients had a history of chronic liver disease, including 4 (#6, 10, 11, 13) with autoimmune hepatitis (AIH) in treated remission (i.e., no medication changes or abnormal labs for a minimum of 6 months). Three patients had cirrhosis: 2 patients with AIH (#10 and 11) and 1 with previously treated HCV (#4).
The majority (13/16) of cases demonstrated a hepatocellular pattern of liver injury (peak alanine aminotransferase: 96 to >5,000 U/L). Of the remaining 3 cases, 1 (#4) was cholestatic and 2 (#12, 16) were mixed. Acute liver injury (ALI, defined as international normalized ratio [INR] >1.5) occurred in 3 patients (#9, 14, and 15; INR range 2.2 to 5.5); no patients developed acute liver failure.
Patient #1 was diagnosed with “new” sclerosing cholangitis via endoscopic retrograde cholangiopancreatography on this presentation; however, on chart review, he presented with drug-induced liver injury (DILI) (amoxicillin) two years earlier, at which time a magnetic resonance cholangiopancreatography showed subtle non-diagnostic biliary findings, raising the possibility of undiagnosed primary sclerosing cholangitis. At the time of presentation, the DILI was long-since resolved, and the current presentation appears to represent an ALI event in a patient with pre-existing cholangitis. Patient #2 had been prescribed a 3-day course of nitrofurantoin approximately 90 days prior to presentation. The scenario was deemed atypical for nitrofurantoin toxicity (particularly the short exposure and clinical presentation). Patients #3 and #7 used ibuprofen immediately following the second vaccine dose (2 to 3 days total, unknown total doses); patient #15 reported chronic acetaminophen use (3-4 grams for several days per week over the preceding year); and patient #16 had knee surgery 3 days prior to presentation and used alternating acetaminophen and acetaminophen-hydrocodone for a total of 4 days. None of these were deemed likely to be causative given the time frame and short exposures. No patient displayed laboratory evidence of viral hepatitis, and all patients tested negative for COVID-19 infection. While 7 of the 12 patients without previously known AIH had at least 1 positive autoimmune marker at the time of presentation, only 1 (#15) met IAIHG simplified criteria for “probable” AIH (anti-nuclear antibody 1:640, elevated IgG to 1,750 mg/dl, and biopsy “compatible” with AIH).1
Out of 16 patients, 10 underwent liver biopsy (Table 1). All exhibited portal inflammation (60% graded as moderate or severe). Five cases demonstrated a significant plasma cell component (of whom #10, 11, and 13 had pre-existing AIH and displayed interface activity), all of whom received prednisone. Cholestasis and bile duct reaction, though variably present, were only prominent in 1 case (#16) with severe cholestasis and minimal inflammation. Excluding patients with known cirrhosis (n = 3), significant fibrosis was not seen in any patient.
Out of 16 patients, 10 required hospitalization. In total, 6 of 16 patients required no treatment. Of the 10 who received treatment, 2 (#9, 14; both with ALI) received N-acetylcysteine infusions, and 8 (see Table 1) received steroids. Patient #1, newly diagnosed with sclerosing cholangitis, underwent biliary dilatation. Importantly, all patients recovered or were recovering from the acute event at the time of assembling our cohort.
We acknowledge that our series of patients with hepatic injury following mRNA-based COVID-19 vaccination contains retrospective and observational data without adjudication. Thus, our report is not structured to evaluate potential causality. In our patients with prior drug exposure (amoxicillin; nitrofurantoin; non-steroidal anti-inflammatory drugs, acetaminophen), the exposures were either too short or the presentations highly atypical (by laboratory data or histopathology) to be attributed solely to the medication. Thus, DILI is not readily implicated in this patient series, although it cannot be wholly excluded. We also consider unlikely direct hepatotoxicity from SARS-CoV-2 mRNA vaccines, noting the strong safety profile for delivery of lipid nanoparticle mRNA vaccines to human tissues.2 Rather, vaccine-induced immune-mediated hepatitis is a known phenomenon,3,4 and other autoimmune events (e.g., AIH, ITP) have been reported following COVID-19 vaccination.5,6 It is plausible that a similar mechanism is occurring here, whereby the host immune response directed against the COVID-19 spike protein triggers an aberrant, autoimmune-like hepatic condition in predisposed individuals. Many questions still remain. In particular, should patients at higher risk of hepatic autoimmunity (e.g., existing AIH, post-liver transplant) undergo pre-emptive laboratory monitoring post-vaccination? Will there be safety concerns for these patients if booster doses are recommended in the future?
We emphasize that our intent is not to promote vaccine hesitancy. The overwhelming benefits of these and other highly efficacious vaccines in the setting of a global pandemic greatly surpass any potential risk of liver injury that may exist. We simply aim to share a clinical scenario that has been observed independently by multiple providers at various institutions, with the hope that as vaccine uptake continues to increase, our shared experience can help in early recognition, further study, and management of potential adverse events.Go to:
L.V.W. is supported by the National Heart, Lung and Blood Institute grant K23HL136891.Go to:
Hersh Shroff (conceptualization, methodology, visualization, writing original draft, writing review and editing). Sanjaya K. Satapathy (visualization, resources, writing review and editing). James M. Crawford (visualization, resources, writing review and editing). Nancy J. Todd (resources, writing review and editing). Lisa B. VanWagner (conceptualization, methodology, resources, supervision, visualization, writing review and editing).Go to:
Data availability statement
Data and study materials will not be made available to other researchers.Go to:
Conflict of interest
The authors disclose no conflicts of interest.
Please refer to the accompanying ICMJE disclosure forms for further details.Go to:
We acknowledge the following individuals for assistance in contributing cases and reviewing the manuscript: Juan Pablo Arab (Pontificia Universidad Católica de Chile); Timea Csak (Northwell Health), Winston Dunn and Beth Floyd (University of Kansas); R. Todd Frederick (California Pacific Medical Center); Alexander Lemmer (Piedmont Healthcare); Benedict Maliakkal (Ascension Medical Group); Atoosa Rabiee (Washington DC VA Medical Center); and Priyanka Singh (Northwell Health).Go to:
Author names in bold designate shared co-first authorship
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Background & aims: We aimed to assess the safety and immunogenicity of inactivated whole-virion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with chronic liver diseases (CLD) in this study.
Methods: This was a prospective, multi-center, open-label study. Participants aged over 18 years with confirmed CLD and healthy volunteers were enrolled. All participants received 2 doses of inactivated whole-virion SARS-CoV-2 vaccines. Adverse reactions were recorded within 14 days after any dose of SARS-CoV-2 vaccine, laboratory testing results were collected after the second dose, and serum samples of enrolled subjects were collected and tested for SARS-CoV-2 neutralizing antibodies at least 14 days after the second dose.
Results: A total of 581 participants (437 patients with CLD and 144 healthy volunteers) were enrolled from 15 sites in China. Most adverse reactions were mild and transient, and injection site pain (n = 36; 8.2%) was the most frequently reported adverse event. Three participants had grade 3 aminopherase elevation (defined as alanine aminopherase >5 upper limits of normal) after the second dose of inactivated whole-virion SARS-CoV-2 vaccination, and only 1 of them was judged as severe adverse event potentially related to SARS-CoV-2 vaccination. The positive rates of SARS-CoV-2 neutralizing antibodies were 76.8% in the noncirrhotic CLD group, 78.9% in the compensated cirrhotic group, 76.7% in the decompensated cirrhotic group (P = .894 among CLD subgroups), and 90.3% in healthy controls (P = .008 vs CLD group).
Conclusion: Inactivated whole-virion SARS-CoV-2 vaccines are safe in patients with CLD. Patients with CLD had lower immunologic response to SARS-CoV-2 vaccines than healthy population. The immunogenicity is similarly low in noncirrhotic CLD, compensated cirrhosis, and decompensated cirrhosis.
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The U.S. Centers for Disease Control and Prevention (CDC) is investigating more than 100 cases of a mysterious form of hepatitis in children, saying that five have died so far.
Dr. Jay Butler, the CDC’s deputy director of infectious diseases, said during a briefing said the agency is investigating 109 cases of acute hepatitis, or liver inflammation, in 24 U.S. states and Puerto Rico. The cause of the outbreak is not yet clear, he stressed, adding that about half of the children had adenovirus infections, although Butler said the CDC doesn’t know yet if adenovirus is the actual cause.
Approximately 90 percent of the children required hospitalization, Butler said. Five have died so far, and more have required liver transplants, he added in the briefing.
Last month, the CDC issued a nationwide alert after nine acute hepatitis cases were discovered among children in Georgia. Since then, a number of state agencies have reported cases and several deaths.
Several days ago, the CDC issued a report saying that it found no evidence that COVID-19 vaccines caused the outbreak of hepatitis among children. None of the initial children in Alabama, the agency said, received the vaccine.
Meanwhile, other countries have reported similar outbreaks of hepatitis among children. On Friday, the UK Health Security Agency reported that (pdf) the country’s case count had risen to 163, dating back to early January, adding that 11 children have received liver transplants so far.
“Adenovirus remains the most frequently detected potential pathogen. Amongst 163 UK cases, 126 have been tested for adenovirus of which 91 had adenovirus detected,” said the agency.
“Amongst cases the adenovirus has primarily been detected in blood.”
UK officials also ruled out the COVID-19 vaccine as a potential cause.
“There are fewer than five older case-patients recorded as having had a COVID-19 vaccination prior to hepatitis onset,” the report said, adding that most of the impacted children are too young to receive the shot.
“There is no evidence of a link between COVID-19 vaccination and the acute hepatic syndrome.”
Earlier this week, the World Health Organization (WHO) told news outlets that there were at least 228 probable cases of hepatitis worldwide in at least 20 countries. That statement came before the CDC’s latest announcement Friday.
Hepatitis is an inflammation of the liver that can be caused by a viral infection, alcohol, prescription drugs, over-the-counter medications acetaminophen, high doses of certain herbal supplements, toxins, and various medical conditions. Hepatitis viruses, which spread via bodily fluids, can also cause liver inflammation. The hepatitis A, hepatitis B, and hepatitis C viruses are also well known to target the liver.
Symptoms include abdominal pain—namely in the upper right part of the abdomen right below the ribs—dark-colored urine, light-colored stools, and jaundice, which is the yellowing of the skin and whites of the eyes.
Japan has detected its first probable case of a mysterious liver disease that has so far affected over 170 children, largely in Britain.
Health experts are exploring its possible links to Covid-19 or a common virus known as adenovirus.
Of those infected, one child has died and 17 have required liver transplants.
Japan has detected its first probable case of a mysterious liver disease that has so far affected over 170 children, largely in Britain, as health experts explore its possible links to Covid-19.
Japan’s Health Ministry said Tuesday that a child had been hospitalized with an unidentified type of severe acute hepatitis — or liver inflammation — in what is thought to be the first reported case in Asia.
As of April 23, at least 169 cases of the disease have been detected in 11 countries globally, according to the World Health Organization. The vast majority of those have been in the U.K. (114), followed by Spain (13), Israel (12) and the U.S. (9). The addition of Japan marks the 12th country to identify a case.
Of those infected, one child has died and 17 have required liver transplants.
The WHO said it is “very likely more cases will be detected before the cause can be confirmed.”
Health experts explore Covid links
Children aged five years old or younger have so far been the most widely affected by the disease, though cases have been detected in children aged one month to 16 years.
Common symptoms including gastroenteritis — diarrhea and nausea — followed by jaundice or yellowing of the skin and eyes.
Health experts are now investigating the likely cause of the outbreak, which was first reported in the U.K. in January 2022, and whether it bears any connection to the coronavirus.
Specifically, they are exploring if a lack of prior exposure to common viruses known as adenoviruses during coronavirus restrictions, or a previous infection with Covid-19, may be related. Alternatively, the genetic make-up of hepatitis may have mutated, resulting in an easier triggering of liver inflammation.
Crucially, experts say there is no known link to the Covid-19 vaccine.
A strain of adenovirus called F41 is so far looking like the most probable cause, according to the U.K. Health Security Agency.
Adenovirus was the most common pathogen detected in 40 of 53 (75%) of confirmed cases tested in the U.K. Globally, that number was 74.
Covid (SARS-CoV-2) was identified in 20 cases of those tested globally. Adenovirus and Covid-19 co-infection was detected in 19 cases.
The new case from Japan tested negative for adenovirus and the coronavirus, though officials have not revealed other details.
What are the symptoms and how worried should we be?
Typically, children gain exposure — and immunity — to adenoviruses and other common illnesses during their early childhood years. However, pandemic restrictions largely limited that early exposure, leading to more serious immune responses in some.
Adenoviruses, which present cold-like symptoms such as fever and sore throat, are generally mild. However, some strains can display liver tropism, or a favoring of liver tissue, which can lead to more serious consequences like liver damage.
Just how serious this latest outbreak will be is not yet clear and will depend largely on how much it spreads over the coming months, according Dr. Amy Edwards, an assistant professor of pediatrics at the Case Western Reserve School of Medicine.
“Adenovirus is a ubiquitous virus and it’s not seasonal. If this is a more severe form of adenovirus that causes liver disease in children, that’s very concerning. But right now it’s isolated enough and few enough cases not to jump to conclusions,” she told CNBC.
Edwards said health authorities had been placed on alert and would be monitoring the situation.
In the meantime, parents and guardians should be alert to common signs of hepatitis, including jaundice, dark urine, itchy skin and stomach pain, and contact a health care professional if they are concerned.
“Normal hygiene measures such as thorough handwashing (including supervising children) and good thorough respiratory hygiene, help to reduce the spread of many common infections, including adenovirus,” UKHSA’s Chand said.
“Children experiencing symptoms of a gastrointestinal infection including vomiting and diarrhea should stay at home and not return to school or nursery until 48 hours after the symptoms have stopped,” she added.
A novel strain of coronoviridae (SARS-CoV-2) was reported in Wuhan China in December 2019. Initially, infection presented with a broad spectrum of symptoms which typically included muscle aches, fever, dry cough, and shortness of breath. SARS-CoV-2 enters cells via ACE2 receptors which are abundant throughout the respiratory tract. However, there is evidence that these receptors are abundant throughout the body, and just as abundant in cholangiocytes as alveolar cells, posing the question of possible direct liver injury. While liver enzymes and function tests do seem to be deranged in some patients, it is questionable if the injury is due to direct viral damage, drug-induced liver injury, hypoxia, or microthromboses. Likely, the injury is multifactorial, and management of infected patients with pre-existing liver disease should be taken into consideration. Ultimately, a vaccine is needed to aid in reducing cases of SARS-CoV-2 and providing immunity to the general population. However, while considering the types of vaccines available, safety concerns, particularly of RNA- or DNA-based vaccines, need to be addressed.
A novel strain of coronaviridae (SARS-CoV-2) was first reported in the Wuhan province of China in December 2019. As of 8 May 2020, it has spread to 215 countries with 265,961 deaths worldwide . On 11 March 2020, the World Health Organisation categorised the outbreak as a pandemic [2,3].
The SARS-CoV-2 virus is a single stranded RNA, enveloped, beta coronavirus characterised by spikes protruding from the surface . Normally found in mammals, birds, and reptiles, this strain has not previously been identified in humans . Previous strains of coronavirus outbreaks in humans include Middle East Respiratory Syndrome (MERS) in 2012 and Severe Acute Respiratory Syndrome (SARS) in 2003 [5,6].
Similar to SARS, SARS-CoV-2 is primarily transmitted by respiratory droplets produced by infected persons when they sneeze, cough, or are deposited on surfaces, where they are transmitted through contact. However, as SARS-CoV-2 has been detected in the gastrointestinal tract, urine and saliva, other routes of transmission have been considered [7,8].
COVID-19 disease refers to infection with the SARS-CoV-2 virus. Incubation time is within 14 days following exposure, with a median of four days [7,9]. Although often asymptomatic (with frequency estimated between 17% and 88% of cases) [10,11,12,13,14], infection initially presents with a broad spectrum of symptoms that typically includes general malaise, fever (commonly over 37 °C), dry cough, shortness of breath, anosmia/dysgueusia, headaches, and muscle aches [7,11,15,16,17]. Some other viral related symptoms, albeit less common, can also be seen—sore throat, chest pain, nausea, vomiting, diarrhoea, skin rashes, and vasculitic manifestations. Severe infection seems to present a biphasic pattern [18,19,20,21]. A first phase (‘viremia’), corresponding to viral invasion of the body, causes symptoms as described above. This phase is followed by an ‘inflammatory’ phase, corresponding to excessive host inflammatory response (‘cytokine storm’), responsible for severe cardiopulmonary manifestations, sometimes leading to acute respiratory distress syndrome, shock, and death [18,19,20,21]. Respiratory symptoms, in particular hypoxia, have been the main indication for hospitalisation.
It has been reported that 14.8–53% of SARS-CoV-2 patients had liver injury indicated by abnormal liver function tests—mainly elevated alanine aminotransferase (ALT), hypoalbuminemia, and elevated gamma-glutamyl transferase (GGT) [22,23,24]. These abnormalities seem to occur during either the viremia or inflammatory phase. Reduced albumin can be due to inflammatory response while raised levels of GGT and bilirubin are associated with biliary damage. This is confirmed in recent reports that SARS-CoV-2 has a much greater affinity for biliary cells (cholangiocytes), which have higher expression of ACE2 receptors compared with hepatocytes [7,22,25]. Significant liver injury with raised levels of ALT, Bilirubin, variable levels of alkaline phosphatase and GGT has been reported in 58–78% of patients with severe clinical manifestations of COVID-19 disease, being a surrogate marker for adverse outcome [4,7,15,22,25] (Table 1).
Liver enzyme abnormalities in COVID-19 disease vary and reflect the degree of inflammatory response, direct biliary injury by the virus, the presence or absence of ischemia/microthromboses, and possible drug-induced liver injury. Hypoalbuminaemia and high transaminases levels are associated with poor prognosis.
Severe liver injury from inflammatory response (cytokine storm)
This review summarises the up to date knowledge on liver injury in the context COVID-19 disease in patients with or without pre-existing liver disease. We also discuss possible mechanisms of liver injury and the current advice regarding management of liver disease patients including liver transplant recipients.Go to:
2. Viral Entry and Effect on Liver
SARS-CoV-2 enters the host via the Angiotensin-converting enzyme 2 (ACE2) receptor. It has been suggested that SARS-CoV-2 binds ACE2 receptors more efficiently than previous COVID viruses, allowing for its extensive transmission .
ACE2 is found in a variety of tissues (heart, liver, lung, bladder, kidney, and pancreas); however, it is known to be abundant in alveolar cells accounting for the viral injury to lungs of infected patients . While there is conflicting evidence of ACE2 receptor density in the liver, current reports using single-cell RNA sequencing have confirmed that cholangiocytes have the highest levels of ACE2 receptors [7,22,25,27]. Hu et al. used in silico and in vitro techniques to sample hepatocytes, cholangiocytes, Kupffer cells and other components of fresh liver samples . They found that 59.7% of cholangiocytes had ACE2 receptors in comparison to only 2.6% of hepatocytes. This data suggests that cholangiocytes have the same percentage of ACE2 receptors as aveolar type 2 cells . Further, it has been suggested that infection of cholangiocytes may be the source of the virus found in faeces . While the presence of a receptor is needed for the virus to gain entry into the host, it is still unclear if other conditions are also needed or could possibly aid the virus.Go to:
3. Possible Causes of Elevated Liver Enzymes
Emerging data for abnormal liver enzymes seen in SARS-CoV-2-infected patients raises several questions. Are these abnormalities due to direct viral damage, drug-induced liver injury (DILI), unknown pre-existing liver disease, or indirect consequence of viral damage to other systems (cardiopulmonary, haemostasis)? Liver samples from infected patients were examined, and moderate microvascular steatosis with mild lobular and portal activity were reported . It does seem likely that damage that may affect liver function could principally be due to hypoxia and shock, although a direct effect of SARS-CoV-2 to the liver or DILI can also be contributing factors [29,30].
3.1. Direct Viral Damage
While mechanisms of direct damage to the liver remain unclear, concerns about viral damage have already been raised, e.g., with a case of SARS-CoV-2 infection concurrent with liver failure, without other apparent cause, recently described in Germany .
However, direct viral damage has been contested by some, and other explanations have been offered, which will be discussed below  (Figure 1).
Liver injury in SARS-CoV-2. There are multiple reports of increased liver enzymes and liver dysfunction in SARS-CoV-2 patients presenting with elevated alanine transaminase (ALT), gamma-glutamyl transferase (GGT), bilirubin, and monocyte chemoattractant protein 1 (MCP1). Taken together with lower levels of albumin, this points to liver damage with possible injury to biliary cells. Liver injury is most likely multifactorial and seen mainly in patients at the severe end of the disease spectrum.
3.2. Drug-Induced Liver Injury
A study by Fan et al.  has raised the question of DILI as a possible cause of liver injury seen in COVID-19 patients. They show that patients given lopinavir or ritonavir after admission presented higher incidence of liver injury and required longer stay in hospital. It is also possible that these patients were given antivirals because they had a more severe presentation that might have affected their liver in the first place. Though recent evidence suggests lopinavir and ritonavir had no clinical effect on SARS-CoV-2, perhaps future application of antiviral drugs should also take into account their effects on the liver .
Many infected with SARS-CoV-2 regularly use paracetamol as it is the recommended antipyretic medication. Unintentional overdose with paracetamol contributing to raised ALT cannot be excluded in patients’ non-remitting pyrexia, as paracetamol is a well-recognised cause of fulminant hepatic failure . This also needs to be taken into consideration when evaluating liver injury in these patients.
Several drugs have been trialled on SARS-CoV-2 patients such as hydroxychloroquine and azithromycin with ambiguous results on the virus but possibly exacerbating liver injury . This ambiguity leads to many questions involving the management of SARS-CoV-2 and pre-existing liver disease.
3.3. Hypoxic Liver
Sepsis complicating severe COVID-19 illness and hypoxia can also be significant contributing factors . Hypoxic liver injury can be characterised by an increase in transaminases due to an imbalance of oxygen supply . This typically occurs in the elderly with right side congestive heart failure . Though the median age of patients contracting SARS-CoV-2 is 47 years of age, the elderly have proven to be particularly vulnerable, with increasing age an indicator of mortality [7,27]. In the elderly population, it is likely that a rise in liver enzymes, particularly transaminases, is due to pre-existing conditions.
SARS-CoV-2 has been shown to lead to a hypercoagulable state, therefore increasing thromboembolism risk [36,37,38]. It has recently been reported that in certain patient groups, often younger patients, micro vascular thromboses can cause end stage organ damage and may potentially affect the liver. It is also notable that high levels of alkaline phosphatase have been used as a prognostic value for ischemic stroke patients and in identifying high risk haemorrhagic transformation and are also shown to be high in COVID-19 patients suffered thrombotic events, although in other cases, alkaline phosphatase levels have been normal or very mildly raised [39,40,41].
Results of autopsies from Wuhan province, China, have also shown infiltration of lymphocytes and monocytes in the portal area with microthrombosis and congestion of hepatic sinuses . The liver was described as having hepatocyte degeneration accompanied by lobular focal necrosis and neutrophil infiltration. Though histological features of liver failure and bile duct injuries were not observed in these cases .
3.5. SARS-CoV-2 in Patients with Pre-Existing Liver Disease
Patients with pre-existing conditions have shown increased susceptibility to SARS-CoV-2. At present, it is unclear to what extent pre-existing liver disease contributes to liver injury seen in SARS-CoV-2 patients. A very recent study conducted in the UK on more than 17 million people has identified pre-existing liver disease as an independent risk factor of death in SARS-CoV-2 infections .
For instance, it has been shown that patients with SARS-CoV-2 show an increase of monocyte chemoattractant protein 1 (MCAP1), which is a chemokine known to exacerbate steatohepatitis . A recent short communication describes possible implications for patients with non-alcoholic fatty liver disease (NAFLD) . NAFLD patients, alongside those with metabolic syndrome and type 2 diabetes, are often treated with ACE inhibitors, which have anti-inflammatory and anti-obesity effects. While there has not been a reported effect on mortality of ACE inhibitor drug use, it has been speculated that ACE inhibitors up-regulate the ACE2 receptor and therefore can increase viral load in patients taking these medications [43,44]. NAFLD patients often exhibit increased cytokine levels due to their chronic inflammatory stage. Prins and Olinga suggest that this predisposition, in patients infected with SARS-CoV-2, could expedite the progression of NAFLD to a more aggressive non-alcoholic steatohepatitis .
There is suggestion that derangement of liver function should be taken into consideration alongside other physiological values [11,30]. Patients with SARS-CoV-2 have exhibited increased levels of creatine kinase, lactate dehydrogenase, ferritin, C-reactive protein, and myoglobin alongside liver dysfunction, and it has been suggested that liver damage is collateral, caused by induced cytotoxic T cells and the induction of the innate immune response rather than direct injury from the virus itself, as observed with other respiratory viruses [11,16,30,45].
Regardless of the source of injury, it is clear that managing those with pre-existing liver disease needs to be thought out carefully during this pandemic and in future outbreaks of coronavirus infection. These patients are at higher risk of being infected and of more severe COVID-19 disease and should be practising strict social distancing or shielding if they take steroids or immunosuppressive therapies . The British Liver Trust has recently called on the UK government to classify those with extreme liver disease as ‘extremely vulnerable’ . Recent reports suggest that more than 1/3 of cirrhotic patients who developed SARS-CoV-2 died . A new international registry developed between the University of Oxford and the University of North Carolina has shown that those with decompensated cirrhosis are at most risk and are calling on hospitals to routinely test patients with deranged liver function/enzyme results for SARS-CoV-2 so early observation and treatment may prevent further deterioration. The British Liver Trust also suggests that all patients with decompensated cirrhosis practice social shielding, a step up from social distancing, even though it is not yet part of the formal guidance .
Boettler et al. have published comprehensive recommendations for management and surveillance of patients with liver disease throughout the SARS-CoV-2 outbreak . This paper now forms the official position of the European Association for the Study of Liver and the European Society of Clinical Microbiology and Infectious Disease . They suggest prioritization of outpatient clinics, inpatient admission depending on presence of certain risk factors, reducing exposure through social distancing (remodelling waiting areas, reduction of waiting times, reduction of face to face contact through telemedicine), and carefully considering the benefits of patient care weighed against the risk of infection.Go to:
4. Disease Severity in the Immunocompromised and Transplant Patients
Under ordinary conditions, organ transplant recipients and those on immunosuppressants are at high risk of infection due in particular to the suppression of T cell response, making their susceptibility to SARS-CoV-2 and prognosis, if infected, unclear. On one hand, it has been postulated that reduction of systemic inflammation by immunosuppressants could improve outcome for COVID-19 patients as the severity of inflammatory response can be an indicator of prognosis . However, it is also a case that immunosuppressed individuals tend to have a higher viral load, take longer to shed the virus, and may show more severe clinical symptoms with a poorer prognosis .
Zhu et al. reported on 10 SARS-CoV-2-positive renal transplant recipients in Wuhan, China . All were admitted to hospital with significant progressive pneumonia. The severity of pneumonia in this group was recorded as greater than their infected family members and others in the local population. In accordance with Influenza A/HINI guidance, calcineurin inhibitors were stopped in seven patients for nine days and in one patient for 12 days [51,52]. Within this group, there was no acute renal graft rejection, and all patients eventually recovered from COVID-19, though it took longer for them to become SARS-CoV-2-negative than their infected family members . They attributed the length of infection but eventual recovery to the hypothesis that long-term immunosuppression might delay viral clearance and prolong the course of disease but avoid fatal pneumonia caused by a hyperimmune response .
Another study of 90 SARS-CoV-2-positive transplant patients in New York City also described reducing antimetabolites, steroids, and/or calcineurin inhibitors in 55 patients . Pereira et al. categorized patients as mild (outpatient care only), moderate (admission as general inpatient), or severe (mechanical ventilation, admission to intensive care unit, or death) . Within this group, 24% presented with mild disease, 46% moderate, and 30% severe. As with other studies, advanced age and comorbidities were associated with disease severity [7,27,39,40,41]. Type of transplant and time of viral infection after transplant were not statistically significant factors . Laboratory values were similar between moderate and severe cases, though albumin was lower in the severe group .
At present there is little data regarding the use of immunomodulatory agents such as tocilizumab or sarilumab when trying to suppress the ‘cytokine storm’ in these patients . Pereira et al. noted that 14 patients receiving 1–3 doses each of tocilizumab and 16 patients receiving bolus steroids showed no adverse outcomes at the time of their publication . They also noted that while all biomarkers of inflammation were elevated, procalcitonin was the only marker which differed between moderate and severe disease and suggested that the chronically immunosuppressed may undergo a uniquely dysfunctional inflammatory response to SARS-CoV-2. This was further supported by Lippi et al., who showed that high levels of procalcitonin can be a predictor of severe COVID-19 syndrome and potentially related to secondary bacterial infection . From this study there were no confirmed cases of thromboembolic complications or organ rejection .
Many epidemiological reports regarding treatment and prognosis of COVID-19 syndrome are based on the general population who would have had healthy immunity before viral infection, thus overlooking important data for immunocompromised patients . Many such patients present with atypical signs and symptoms leading to missed diagnosis, late presentation, and worse prognosis . At the time of this publication, no significant conclusions have been drawn regarding the outcome of COVID-19 in patients in receipt of immunosuppressive therapy. More research into cytokine activation, T cell signalling and migration, and viral clearance are needed . The postulated anti-inflammatory benefits of immunosuppression should be balanced against the possibility of inhibiting anti-viral immunity by delaying viral shedding and possible organ rejection for those patients having undergone transplant .Go to:
5. Vaccination for SARS-CoV-2
Ultimately, a vaccine against SARS-CoV-2 will be key in preventing spread of virus and loosening social restrictions, but many factors need to be considered in the development of a vaccine so as not to increase innate immune response, increase likelihood of autoimmune diseases, or further DILI.
Vaccinations are costly and usually take years to complete stringent animal and human trials before being made available to the public. However, in an epidemic or pandemic situation, the scientific community faces increasing pressure to rapidly respond with an effective vaccine. In previous epidemics such as Ebola, H1N1, SARS, and MERS, vaccine development was never completed due to the epidemic ending and funds being reallocated .
In the context of this review, it is important to highlight that one possible side effect of vaccinations could result in liver damage. Vaccines with the greatest potential, in pandemic situations, are RNA- or DNA-based vaccines . These vaccines do not need to be cultured or require fermentation, they avoid risks of working with live pathogens, and can specifically encode key antigens without also coding for other toxins, but they are not without risks [55,56].
There are no approved RNA vaccines to date, as toxicity cannot always be predicted from animal studies due to species differences between human and animals . Some effects seen in previous RNA-based vaccinations have been pancreatitis, lactic acidosis, liver steatosis, nerve damage, and death . Liver toxicity was reported in preclinical studies using RNA therapy for Crigler–Nayjor syndrome, and in an RNA-based rabies vaccination trial, an increased and deleterious inflammatory response ended the trial . This is possibly due to type 1 interferon induction by RNA, which is known to induce autoimmune diseases . DNA-based vaccines have also been implicated in inducing an innate immune response through toll-like receptor (TLR) 9 and non-TLR activation .Go to:
SARS-CoV-2 is a novel coronavirus known to cause respiratory infections with severity ranging from mild cold- and flu-like symptoms to fatal pneumonia. While respiratory based, if severe, it can cause dysfunction of other organs such as the kidneys and liver. It is likely that the liver injury seen in SARS-CoV-2-positive patients is multifactorial and the result of a combination of inflammatory response, sepsis, hypoxia, microthrombotic events, DILI, and viral damage. Pre-existent liver disease is an independent risk factor of death in SARS-CoV-2 related infection, and severity of liver damage most likely correlates with COVID-19 disease severity. Nevertheless, abnormalities in the liver function tests of these patients, without pre-existing liver disease, may have prognostic significance and predict adverse outcomes. Patients with chronic liver disease and in particular those on immunosuppressive therapies including liver transplant recipients should be particularly careful and managed according to internationally accepted guidelines regarding strict social distancing or shielding.
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In a recent study posted to the medRxiv* preprint server, researchers assessed the prevalence of organ impairment in long coronavirus disease 2019 (COVID-19) six months and a year post-COVID-19 at London and Oxford.
Multi-organ impairment associated with long COVID-19 is a significant health burden. Standardized multi-organ evaluation is deficient, especially in non-hospitalized patients. Although the symptoms of long COVID-19, also known as post-acute sequelae of COVID-19 (PASC), are well-established, the natural history is poorly classified by symptoms, organ impairment, and function.
About the study
In the present prospective study, researchers assessed organ impairment in long COVID-19 patients six months and a year after the onset of early symptoms and correlated them to their clinical presentation.
The participants were recruited based on specialist referral or the response to advertisements in sites such as Mayo Clinic Healthcare, Perspectum, and Oxford from April 2020 to August 2021, based on their COVID-19 history.
The study was conducted on COVID-19 patients who recovered from the acute phase of the infection. Their health status, symptoms, and organ impairment were assessed. The symptoms assessed comprised cardiopulmonary, severe dyspnoea, and cognitive dysfunction. Biochemical and physiological parameters were analyzed at baseline and post-organ impairment. The radiological investigation comprised multi-organ magnetic resonance imaging (MRI) performed in the long COVID-19 patients and healthy controls.
Over a year, the team prospectively investigated the symptoms, organ impairment, and function, especially dyspnea, cognitive dysfunction, and health-related quality of life (HRQoL). They also evaluated the association between organ impairment and clinical symptoms.
Patients with symptoms of active pulmonary infections (body temperature >37.8°C or ≥3 coughing episodes in a day) and hospital discharges in the previous week or >4 months were excluded from the study. Asymptomatic patients and those with MRI contraindications such as defibrillators, pacemakers, devices with metal implants, and claustrophobia were removed.
Participants with impaired organs, as diagnosed by blood investigations, incidental findings, or MRI, were included in the follow-up assessments. Every visit comprised blood investigations, MRI scanning, and online questionnaire surveys, which were to be filled out beforehand. In addition, a sensitivity analysis was performed that excluded patients at risk of metabolic disorders (including body mass index (BMI) ≥30 kg/m2, diabetes, and hypertension)
Out of 536 participants, the majority were middle-aged (mean age 45 years), female (73%), White (89%), and healthcare workers (32%). About 13% of the COVID-19 patients hospitalized during the acute phase of the infection completed the baseline evaluation. A total of 331 patients (62%) had incidental findings, organ impairment, or reduction in the symptoms from the baseline at both the time points.
Cognitive dysfunction (50% and 38%), poor HRQoL (EuroQOL <0.7 in 55% and 45%), and severe dyspnea (36% and 30%) were observed at six months and one year, respectively. On follow-up, the symptoms were reduced, especially cardiopulmonary and systemic symptoms, whereas fatigue, dyspnea, and cognitive dysfunction were consistently present. The greatest impact on quality of life was related to pain and difficulties performing routine activities. Almost every patient took time off work due to COVID-19. The symptoms were largely associated with obese women, young age, and impairment of a single organ.
At baseline, fibrous inflammation was observed in the pancreas (9%), heart (9%), liver (11%), and kidney (15%). Additionally, increased volumes of the spleen (8%), kidney (9%), and liver (7%) were observed. Moreover, reduced lung capacity (2%), excess adipose deposits in pancreatic tissues (15%) and liver (25%) were observed. High liver fibro-inflammation was associated with cognitive dysfunction at follow-up in 19% and 12% of patients with and without cognitive dysfunction, respectively. Low liver fat was more likely in those without severe dyspnoea at both time points. Increased liver volumes at follow-up were associated with lower HRQoL scores.
The prevalence of multi and single-organ impairment was 23% and 59% at baseline, respectively, and persisted in 27% and 59% of the participants on follow-up assessments. Most of the organ impairments were mild. However, they did not improve substantially between visits. Notably, participants without organ impairment had the lowest symptom burden.
Most biochemical parameters were normal except creatinine kinase (8% and 13%), lactate dehydrogenase (16% and 22%), mean cell hemoglobin concentration (21% and 15%), and cholesterol (46% and 48%), at six months and a year post-COVID-19, respectively. These biochemical markers increased from the baseline on follow-up assessments.
To summarize, organ impairment was detected in 59% of the patients at six months post-COVID-19 and persisted in 59% at one-year follow-up. This has significant implications on the quality of life, symptoms, and long-term health of the patients. These observations highlight the requirement for enhanced preventive measures and integrated patient care to decrease the long COVID-19 burden.