Liver & intrahepatic bile ducts
Viral hepatitis
COVID-19
Deputy Editors-in-Chief: Raul S. Gonzalez, M.D., Catherine E. Hagen, M.D.
Last author update: 21 July 2022
Last staff update: 21 July 2022
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PubMed Search: COVID-19 liver
See Also: COVID-19 associated colitis, COVID-19 associated kidney injury, COVID-19 convalescent plasma, COVID-19 lung pathology, COVID-19 placentitis, COVID-19 testing
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Pathophysiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Electron microscopy images | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: De Michele S, Lagana SM. COVID-19. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverCOVID19.html. Accessed December 22nd, 2024.
Definition / general
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily causes pulmonary disease but has been implicated in hepatic injury
- Coronavirus disease 2019 (COVID-19) viral hepatitis is defined by the clinical, laboratory and histopathological hepatic changes secondary to SARS-CoV-2 infection
Essential features
- Despite being primarily a pulmonary disease, SARS-CoV-2 infection has been shown to affect extrapulmonary sites, including the liver
- COVID-19 viral hepatitis is defined by the clinical, laboratory and histological liver abnormalities in the setting of real time reverse transcription polymerase chain reaction (RT PCR) proven SARS-CoV-2 infection
- Common laboratory findings include mild elevation of liver function tests: aspartate aminotransferase (AST) > alanine aminotransferase (ALT)
- Histologically, nonspecific findings include macrovesicular steatosis, lobular necroinflammation and portal inflammation
- Viral RNA can be detected in liver tissue by qRT PCR in approximately half of patients who die of COVID-19, although mainly at low levels
ICD coding
- ICD-10:
- ICD-11:
Epidemiology
- Liver injury is more common in severe cases (Lancet 2020;395:497)
- Incidence of elevated serum liver enzymes in hospitalized patients with COVID-19 ranges from 14% to 58% (AASLD: Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic [Accessed 25 May 2022])
- Characteristics of U.S. patients with SARS-CoV-2 and liver enzyme elevation (Hepatology 2020;72:807):
- Median age 65 years
- M > F
- Hispanic / Latino > White > Black
- 5% have underlying chronic liver disease
Pathophysiology
- Angiotensin converting enzyme receptor 2 (ACE2) is the main mode of entry for the virus into the cell
- ACE2 is found on cholangiocytes, endothelial cells and rarely in hepatocytes
- Several possible mechanisms of injury seem to be implicated in SARS-CoV-2 liver injury (Liver Int 2020;40:1278)
- Immune mediated damage secondary to the inflammatory / cytokine response to COVID-19 infection
- Direct cytotoxicity as a result of active viral replication in hepatic cells
- Hypoxic hepatitis
- Drug induced liver injury (DILI)
Diagrams / tables
Images hosted on other servers:
Liver injury in COVID-19
Clinical features
- Most commonly, respiratory symptoms and fever
- Digestive symptoms, including anorexia, nausea, vomiting and diarrhea in a subset of patients
- Liver involvement manifests as rising liver function tests or acute hepatitis or cholestasis in the setting of COVID-19 infection (Lancet Gastroenterol Hepatol 2020;5:776)
- Common comorbidities: hypertension and diabetes (Hepatology 2020;72:807)
Diagnosis
- RT PCR based SARS-CoV-2 RNA detection from respiratory samples
- Quantitative RT PCR of liver tissue can confirm viral presence in the liver
- SARS-CoV-2 RNA has been detected in the stool of patients with COVID-19 (J Chin Med Assoc 2020;83:521)
- Microscopic examination of liver tissue
Laboratory
- Liver injury:
- Primarily mild elevation of AST and ALT (1 - 2 times upper limit of normal) (Hepatology 2020;72:807, Mil Med Res 2020;7:28)
- AST > ALT > bilirubin > alkaline phosphatase (ALP)
- Gamma glutamyl transferase (GGT) has been reported to be elevated in up to 54% of patients with COVID-19 during hospitalization (Lancet Gastroenterol Hepatol 2020;5:428)
- Other markers (Int J Infect Dis 2020;95:304):
- Lymphopenia, thrombocytopenia, hypoalbuminemia
- Inflammatory markers: elevated D dimer, C reactive protein, IL6, lactate dehydrogenase, creatine kinase and ferritin
Radiology description
- Fatty liver by ultrasound in up to 46% of patients (Mil Med Res 2020;7:28)
Prognostic factors
- Overall risks include:
- Older age
- Underlying diseases
- Secondary infection (Intensive Care Med 2020;46:846)
- Liver specific risk associations include:
- Higher AST, ALT, ALP
- Hypoalbuminemia
- Elevated inflammatory markers (Hepatology 2020;72:807)
Case reports
- 6 month old girl with a history of biliary atresia, status post living donor liver allograft from a COVID-19 positive donor (Arch Pathol Lab Med 2020;144:929)
- 25 year old woman with intermittent fever, 34 year old woman with fever, cough and bilateral lung consolidations and 45 year old previously healthy woman with fever (Hepatology 2004;39:302)
- 25 year old man, 38 year old man and 40 year old woman who developed prolonged and severe cholestasis during recovery from critical cardiopulmonary COVID-19 (Am J Gastroenterol 2021;116:1077)
- 53 year old man, 75 year old woman and 87 year old man with preexisting decompensated cirrhosis (Hepatol Int 2020;14:478)
- 59 year old woman with a chief concern of dark urine (Am J Gastroenterol 2020;115:941)
Treatment
- Liver damage is often transient
- Supportive care
- Patients with abnormal liver function should be closely monitored when using off label lopinavir / ritonavir, chloroquine, hydroxychloroquine and tocilizumab (Lancet Gastroenterol Hepatol 2020;5:776)
- According to the FDA, liver biochemistries should be checked in all patients prior to starting and daily while receiving remdesivir
- Liver transplant might be necessary in the setting of progressive biliary injury and liver failure secondary to COVID-19 cholangiopathy (Am J Gastroenterol 2021;116:1414)
Gross description
- No specific gross pathology
- Varying degrees of steatosis
- Congestion and ischemia (likely perimortem pathology in autopsy cases)
Microscopic (histologic) description
- Steatosis (Liver Int 2020;40:2110, Hum Pathol 2021;109:59)
- Common (up to 75% of patients)
- Predominantly macrovesicular
- Usually mild (involving < 33% of the liver parenchyma) and often azonal
- Usually not associated with ballooning and Mallory-Denk bodies
- Acute hepatitis (lobular necroinflammation) (Liver Int 2020;40:2110)
- Present in up to 50% of cases
- Usually mild severity (80% of cases)
- Foci contain apoptotic hepatocytes plus lymphocytes and rare histiocytes without prominent plasma cells
- Lobular mitoses
- Portal inflammation (Liver Int 2020;40:2110)
- Up to half of cases
- Minimal to mildly increased portal mononuclear cells (lymphocytes and macrophages)
- Rarely interface hepatitis
- Biliary findings / COVID-19 cholangiopathy
- Mild and focal lobular cholestasis (up to 38% of cases) (Mod Pathol 2020;33:2147)
- Ductopenia, severe cholangiocyte injury, ductular reaction, variable portal inflammation, variable fibrosis (Am J Gastroenterol 2021;116:1077)
- Acute or chronic large duct obstruction without clear bile duct loss (Am J Gastroenterol 2021;116:1414)
- Vascular pathology
- Focal
- Phlebosclerosis (reminiscent of veno-occlusive disease), more often with involvement of portal venule (rarely of central vein)
- Abnormalities of portal arterioles:
- Arteriolar muscular hyperplasia
- Hyalinosis and rare fibrinoid necrosis with endothelial apoptosis
- Sinusoidal erythrocyte aggregation (up to 44%) and platelet microthrombi (up to 70%) (Hepatol Res 2021;51:1000, Hum Pathol 2021;109:59)
- Uncommon findings
- Thrombotic bodies: pale ovoid sinusoidal platelet rich inclusions seen in sinusoidal spaces (CD61+)
- Large megakaryocytes
- Perimortem pathology
- Congestion
- Centrilobular ischemic necrosis
- Reference: Mod Pathol 2020;33:2147
Microscopic (histologic) images
Contributed by Stephen M. Lagana, M.D.
Macrovesicular steatosis
Lobular necroinflammation
Apoptotic hepatocytes
Portal inflammation with interface hepatitis
Mild portal inflammation
Phlebosclerosis
Portal arteriolar hyalinosis
Lobular mitoses
Large megakaryocytes
Sinusoidal microthrombi
Positive stains
- IHC and ISH for SARS-CoV-2 can be used to detect virus in lung, particularly during the acute phase of diffuse alveolar damage and occasionally in other organs, such as placenta
- Needs validation in the liver
Electron microscopy images
Images hosted on other servers:
Electron microscopy
evidence of SARS-CoV-2
infection in liver cells
Molecular / cytogenetics description
- RT PCR of liver autopsy samples positive in up to 55% of COVID-19 deceased (Mod Pathol 2020;33:2147, Clin Gastroenterol Hepatol 2021;19:1726)
- Range from 10 copies to 9,254 copies/μl RNA
Videos
Liver histopathological findings in COVID-19 autopsies
Clinical insights: COVID-19 and the liver
Sample pathology report
- Liver, right lobe, core biopsy:
- Acute hepatitis and macrovesicular steatosis consistent with clinical history of SARS-CoV-2 infection
Differential diagnosis
- Reactivation of preexisting liver diseases:
- Correlate with clinical history
- Chronic hepatitis (commonly hepatitis C virus, hepatitis B virus, autoimmune hepatitis):
- Fibrosis implies chronicity, which would not be present in acute COVID-19; however, it has been described in subacute / chronic post COVID-19 biliary injury (Am J Gastroenterol 2021;116:1077, Am J Gastroenterol 2021;116:1414)
- Lymphoid aggregates are common in chronic hepatitis but are not typically encountered in COVID-19
- Preexisting fatty liver disease:
- Clinical risk factors
- Frank steatohepatitis does not seem to be a feature of COVID-19
- Chronic biliary tract disease:
- Features of primary sclerosing cholangitis / secondary sclerosing cholangitis have been reported in post COVID cholangiopathy (Am J Gastroenterol 2021;116:1414)
- Correlate with clinical history
- Drug induced liver injury (Surg Pathol Clin 2018;11:297):
- Clinical history of exposure to hepatotoxic drug
- May show prominent eosinophilia
- May show features reminiscent of autoimmune hepatitis
- Not always possible to distinguish from COVID-19 injury
Additional references
Board review style question #1
The liver sample shown above is from a patient with COVID-19. The histopathological process depicted in the image above is more often associated with which of the following conditions?
- Acetaminophen toxicity
- Autoimmune hepatitis
- COVID-19 associated hepatitis
- Primary biliary cholangitis
- Primary sclerosing cholangitis
Board review style answer #1
B. Autoimmune hepatitis. The finding of interface hepatitis is more common in autoimmune hepatitis but has been described in patients with COVID-19.
Comment Here
Reference: Viral hepatitis - COVID-19
Comment Here
Reference: Viral hepatitis - COVID-19
Board review style question #2
What is the most common histopathologic hepatic finding in patients dying of COVID-19?
- Apoptotic bodies
- Disseminated microthrombi
- Interface hepatitis
- Lobular necroinflammation
- Macrovesicular steatosis
Board review style answer #2
