The liver is responsible for filtering blood, metabolizing nutrients, and detoxifying chemicals. Although the SARS-CoV-2 virus primarily causes respiratory illness, COVID-19 frequently involves other major organ systems. Liver function abnormalities are common, with a significant percentage of hospitalized patients showing some degree of liver involvement. This distress is recognized through changes in specific blood markers, signaling that the infection’s systemic effects extend beyond the lungs.
How the SARS-CoV-2 Virus Affects Liver Cells
The mechanisms of COVID-19 liver injury fall into three categories: direct viral attack, severe systemic inflammation, and oxygen deprivation. The virus initiates its attack by binding to the Angiotensin-Converting Enzyme 2 (ACE2) receptor, present on cells throughout the body. In the liver, ACE2 expression is high on the cells lining the bile ducts, known as cholangiocytes, often exceeding the expression found on the main liver cells, or hepatocytes.
The high concentration of ACE2 on cholangiocytes suggests the virus can directly infect and damage the bile ducts. Damage to these cells disrupts bile flow, leading to a buildup of toxic substances that can injure surrounding hepatocytes. While hepatocytes express lower levels of ACE2, post-mortem biopsies show signs of direct cell damage, including mild necrosis and fatty changes (steatosis).
A second cause of liver injury stems from the body’s overzealous immune reaction, often called a “cytokine storm.” In severe COVID-19, the immune system releases massive amounts of pro-inflammatory signaling proteins (cytokines), causing widespread systemic inflammation. This hyper-inflammatory state overwhelms the liver, leading to rapid cell damage and dysfunction. The inflammatory cascade can also induce microthrombosis, or tiny blood clots, within the liver’s small vessels.
The third mechanism involves hypoxic injury, a consequence of severe respiratory failure. When the lungs are compromised, the body cannot deliver enough oxygen to the tissues, creating systemic hypoxia. The liver is susceptible to this lack of oxygen, resulting in “shock liver” or hypoxic hepatitis. This oxygen deprivation leads to cell death and a rapid release of liver enzymes into the bloodstream.
Clinical Signs of Liver Distress During Infection
Liver involvement during COVID-19 is identified through routine blood tests measuring specific proteins and enzymes. The most frequently observed indicator is the elevation of liver transaminases: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST). These enzymes are released into the bloodstream when hepatocytes are damaged. Elevations are typically mild, but significant increases (such as ALT exceeding five times the normal limit) are associated with a more severe disease course and poorer outcomes.
Markers of bile duct injury are also monitored, including Alkaline Phosphatase (ALP), Gamma-Glutamyl Transferase (GGT), and bilirubin. Elevated GGT and bilirubin levels suggest a problem with bile flow, supporting the observation that the virus targets bile duct cells. In mild cases, patients usually do not experience physical symptoms related to the liver injury. Severe injury may cause non-specific symptoms like profound fatigue. Jaundice, a yellowing of the skin and eyes caused by bilirubin buildup, is a rare symptom occurring in acute, severe hepatitis.
Vulnerability in Patients with Pre-existing Liver Conditions
Individuals with compromised liver function face a significantly higher risk for severe illness and mortality if they contract COVID-19. Patients with Chronic Liver Disease (CLD) have a two to three times greater chance of developing severe COVID-19 and a higher risk of death. The severity of the underlying liver condition is the most important predictor of a poor outcome.
Cirrhosis
Patients with cirrhosis, or advanced scarring of the liver, are particularly vulnerable to life-threatening complications. SARS-CoV-2 infection can trigger hepatic decompensation, a sudden worsening of liver function. This may progress to Acute-on-Chronic Liver Failure (ACLF), a condition with high mortality. The risk of death is directly correlated with the severity of the cirrhosis, often measured by scoring systems like the MELD score.
Fatty Liver Disease
Non-Alcoholic Fatty Liver Disease (NAFLD), also known as Metabolic-Associated Steatotic Liver Disease (MASLD), also heightens the risk for severe COVID-19. This is due to the chronic low-grade inflammation already present in the fatty liver tissue. When the systemic inflammation of COVID-19 occurs, the underlying liver inflammation is exacerbated, intensifying the “cytokine storm” and contributing to a worse prognosis.
Drug Interactions and Treatment-Related Liver Injury
The management of COVID-19 often requires multiple medications, creating a risk of Drug-Induced Liver Injury (DILI). The liver is the body’s primary metabolic hub, and many antiviral and anti-inflammatory drugs used to treat moderate to severe COVID-19 are processed there. Antiviral agents like remdesivir, lopinavir/ritonavir, and favipiravir are known to cause transient elevations in liver enzymes.
Remdesivir, for instance, can cause mild to moderate, temporary elevations in ALT and AST levels. Immunosuppressive agents used to quell the cytokine storm, such as tocilizumab, are also associated with liver enzyme increases. Even common medications used for symptom relief, such as high doses of acetaminophen, can become hepatotoxic, especially in patients with pre-existing liver conditions.
A persistent challenge for clinicians is determining the exact cause of elevated liver enzymes in a hospitalized patient. It is often unclear whether the injury is due to the direct effects of the virus, widespread inflammation and hypoxia, or the toxicity of the administered drugs. The cumulative prevalence of acute liver injury in treated patients has been reported to be around 23.7%. Due to this uncertainty, close monitoring of liver function tests is a standard component of care for individuals undergoing COVID-19 treatment.