Acute-on-Chronic Liver Failure: Possibly the Main Culprit of Increased Mortality in COVID-19 Patients with Liver Disease

Dear Editors:

We read with great interest the article “Clinical Characteristics and Outcomes of COVID-19 Among Patients with Pre-Existing Liver Disease in the United States: A Multi-Center Research Network Study” by Singh et al.¹ The study is one of the first to describe the impact of coronavirus disease 2019 (COVID-19) in patients with preexisting liver disease. The mechanism of increased mortality in this population is not well defined and is possibly multifactorial. We want to report a case to highlight that one of the possible explanations of higher mortality is the development of acute-on-chronic liver failure (ACLF) in liver disease patients with COVID-19.

A 38-year-old man with cryptogenic liver cirrhosis (Child B9, Model for End-stage Liver Disease score of 20) and history of variceal bleeding and on the national transplant list presented with a 3-day history of fever and dry cough. He was febrile but otherwise stable vitally. Clinically, he was jaundiced with stigmata of chronic liver disease. His initial labs showed pancytopenia, an international normalized ratio of 1.9, bilirubin of 3.74 mg/dL, albumin of 2.4 g/dL, alkaline phosphatase of 335 IU/L, alanine aminotransferase of 40 IU/L, and aspartate aminotransferase of 64 IU/L. A chest radiograph on admission revealed bilateral infiltrates. A nasopharyngeal and throat swab was positive for COVID-19 polymerase chain reaction.

During the hospitalization, he developed grade II encephalopathy and was started on lactulose. On day 3 of the hospitalization, owing to progressive respiratory failure, the patient was intubated and mechanical ventilation was initiated. During his intensive care unit stay, he received broad-spectrum antibiotics and convalescent plasma of a recovered COVID patient. The patient developed ACLF with a bilirubin reaching 56.4 mg/dL and an international normalized ratio of 3.5. He developed refractory metabolic acidosis requiring continuous renal replacement therapy. His European Association for the study of Liver - Chronic Liver Failure organ failure score was 17, ACLF grade 3 with 5 organs involved. Unfortunately, on day 14 of hospitalization patient expired because of multiorgan failure.

ACLF is a syndrome characterized by acute hepatic decompensation (the development of ascites, encephalopathy, gastrointestinal hemorrhage, and/or bacterial infections), organ failure (liver, kidney, brain, coagulation, respiration, and circulation) as defined by the Chronic Liver Failure organ failure score, and 28-day mortality exceeding 15%, resulting from different types of insults to the liver.^{2 , 3} The prevalence of ACLF ranges from 24% to 40% of patients with liver cirrhosis who are hospitalized. ACLF may develop in patients with previously compensated or decompensated cirrhosis, and in patients with the underlying chronic liver disease without cirrhosis.³ Hepatitis B and alcohol are the most common underlying etiologies of chronic liver disease in patients with ACLF⁴; however, nonalcoholic fatty liver disease–related liver disease is expected to take the lead in coming years.³ Bacterial infections, active alcoholism, and exacerbation of hepatitis B are the most common triggers of ACLF, but in 20%–45% of cases, the trigger remains unknown.^{3 , 5}

The hallmark of ACLF is excessive systemic inflammation, and patients with ACLF have higher levels of inflammatory markers and proinflammatory cytokines—IL-6, IL-1β, and IL-8. The inducers of systemic inflammation can be exogenous or endogenous and viruses have been described previously to trigger inflammation.³ Immunopathology resulting from uncontrolled activation of the immune system and excessive production of proinflammatory cytokines has been proposed as a mechanism of tissue injury in ACLF, as these patients have a higher degree of systemic inflammation and the degree of inflammatory markers is linearly associated with the number of organ failures.² In patients with COVID-19, a cytokine storm has been reported characterized by increased IL-2, IL-7, granulocyte-colony stimulating factor, and tumor necrosis factor-α.⁶ We believe the excessive inflammatory response associated with COVID-19 can serve as a trigger of ACLF in patients with underlying chronic liver disease and potentially explains the increased mortality in patients with liver disease observed in the study. Previously, it has been reported that cirrhotic patients who develop influenza have a high risk of severe disease, organ failure, and death.⁷ In addition to excessive systemic inflammation, other mechanisms may also contribute to the development of ACLF. Direct tissue damaged caused by infectious agents and failed tolerance to inflammatory response at the tissue level can also contribute to the ongoing tissue damage.^{2 , 3}

It would be interesting to know the incidence of acute on chronic liver disease in patients with preexisting liver disease who had mortality in the study by Singh et al.¹ Further research is warranted to elucidate the mechanisms of increased mortality in patients with liver disease who develops COVID-19. Furthermore, physicians should be alerted to the possibility of the development of ACLF in this population.