Liver & intrahepatic bile ducts

Viral hepatitis

COVID-19


Deputy Editors-in-Chief: Raul S. Gonzalez, M.D., Catherine E. Hagen, M.D.
Simona De Michele, M.D.
Stephen M. Lagana, M.D.

Last author update: 21 July 2022
Last staff update: 21 July 2022

Copyright: 2020-2023, PathologyOutlines.com, Inc.

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

Simona De Michele, M.D.
Stephen M. Lagana, M.D.
Page views in 2022: 1,054
Page views in 2023 to date: 62
Cite this page: De Michele S, Lagana SM. COVID-19. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverCOVID19.html. Accessed February 8th, 2023.
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:
    • U07.1 - COVID-19
    • B34.2 - coronavirus infection, unspecified
    • B97.2 - coronavirus as the cause of disease classified elsewhere
    • B17.9 - acute viral hepatitis, unspecified
    • B17.8 - other specified acute viral hepatitis
    • K76.0 - fatty (change of) liver, not elsewhere classified
  • ICD-11:
    • RA01.0 - COVID-19, virus identified
    • RA01.1 - COVID-19, virus not identified
Epidemiology
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:
  • 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
Prognostic factors
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
  • 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

Macrovesicular steatosis

Lobular necroinflammation

Lobular necroinflammation

Apoptotic hepatocytes

Apoptotic hepatocytes

Portal inflammation with interface hepatitis

Portal inflammation with interface hepatitis

Mild portal inflammation

Mild portal inflammation


Phlebosclerosis

Phlebosclerosis

Portal arteriolar hyalinosis

Portal arteriolar hyalinosis

Lobular mitoses

Lobular mitoses

Large megakaryocytes

Large megakaryocytes

Sinusoidal microthrombi

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
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
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?

  1. Acetaminophen toxicity
  2. Autoimmune hepatitis
  3. COVID-19 associated hepatitis
  4. Primary biliary cholangitis
  5. 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
Board review style question #2
What is the most common histopathologic hepatic finding in patients dying of COVID-19?

  1. Apoptotic bodies
  2. Disseminated microthrombi
  3. Interface hepatitis
  4. Lobular necroinflammation
  5. Macrovesicular steatosis
Board review style answer #2
E. Macrovesicular steatosis

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Reference: Viral hepatitis - COVID-19
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