Severe acute respiratory syndrome coronavirus 2 may cause liver injury via Na+/H+ exchanger

Abstract

The liver has many significant functions, such as detoxification, the urea cycle, gluconeogenesis, and protein synthesis. Systemic diseases, hypoxia, infections, drugs, and toxins can easily affect the liver, which is extremely sensitive to injury. Systemic infection of severe acute respiratory syndrome coronavirus 2 can cause liver damage. The primary regulator of intracellular pH in the liver is the Na⁺/H⁺ exchanger (NHE). Physiologically, NHE protects hepatocytes from apoptosis by making the intracellular pH alkaline. Severe acute respiratory syndrome coronavirus 2 increases local angiotensin II levels by binding to angiotensin-converting enzyme 2. In severe cases of coronavirus disease 2019, high angi-otensin II levels may cause NHE overstimulation and lipid accumulation in the liver. NHE overstimulation can lead to hepatocyte death. NHE overstimulation may trigger a cytokine storm by increasing proinflammatory cytokines in the liver. Since the release of proinflammatory cytokines such as interleukin-6 increases with NHE activation, the virus may indirectly cause an increase in fibrinogen and D-dimer levels. NHE overstimulation may cause thrombotic events and systemic damage by increasing fibrinogen levels and cytokine release. Also, NHE overstimulation causes an increase in the urea cycle while inhibiting vitamin D synthesis and gluconeogenesis in the liver. Increasing NHE3 activity leads to Na⁺ loading, which impairs the containment and fluidity of bile acid. NHE overstimulation can change the gut microbiota composition by disrupting the structure and fluidity of bile acid, thus triggering systemic damage. Unlike other tissues, tumor necrosis factor-alpha and angiotensin II decrease NHE3 activity in the intestine. Thus, increased luminal Na⁺ leads to diarrhea and cytokine release. Severe acute respiratory syndrome coronavirus 2-induced local and systemic damage can be improved by preventing virus-induced NHE overstimulation in the liver.

Keywords: Liver; Hepatocyte; Severe acute respiratory syndrome coronavirus 2; COVID-19; Na⁺/H⁺ exchanger; Sodium-proton pump

Core Tip: Severe acute respiratory syndrome coronavirus 2 readily infects the liver by angiotensin-converting enzyme 2. Increased angiotensin II causes Na⁺/H⁺ exchanger (NHE) overstimulation allowing the accumulation of Na⁺ and Ca²⁺ in hepatocytes. Thus, hepatocytes are damaged and eventually die. Increased cytokine release increases fibrinogen levels, enhancing thrombotic events. Cytokine storms can be triggered by NHE overstimulation. Severe acute respiratory syndrome coronavirus 2-induced NHE overstimulation can change bile acid structure, which disrupts gut microbiota and can trigger cytokine storms. Liver damage from the virus can be considered the most important cause of disease progression and mortality.