COVID-19-associated hepatic injury

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Liver injury is relatively common among COVID‐19 patients.

Historical Perspective

• Deranged ALT and AST levels in patients infected with COVID-19 were first reported by Nanshan Chen et al. from Wuhan Jinyintan Hospital in a January 30th, 2020 publication. 43.4% (n=43) of the patients infected with the COVID-19 virus had elevated AST and ALT with one patient having an extremely high level of the enzymes, measuring in thousands.

Classification

There is no formal classification of liver damage associated with COVID-19 but, we attempt to divide the entity based on the etiology and mechanism of liver damage:

• Direct viral damage to hepatocytes
• Drug induced liver injury
• Overactive immune response
• Ischemia and reperfusion injury
• Aggravation/ Recurrence of existing liver disease- According to the data available, 2% to 11% of COVID-19 patients had pre-existing chronic liver disease.

Pathophysiology

• The exact mechanism of liver injury is still unclear. There are several proposed mechanisms in an effort to understand the pathogenesis of hepatic injury but the hepatic complications in COVID-19 patients are described as multifactorial and heterogenous. A few of the proposed mechanisms include:
  • Hepatocyte injury: Liver cell injury can be due to direct viral damage. The detection of SARS-CoV-2 RNA in stool gives a notion of viral exposure of the liver cells, directly causing the damage. The studies have not explained the specific mechanisms of hepatocyte injury as it contains minimal ACE2 receptor.
  • Chalangiocyte damage: Angiotensin-converting enzyme 2 (ACE2) receptor expression is enriched in cholangiocytes and not in hepatocytes, indicating that SARS-CoV-2 might directly bind to ACE2-positive cholangiocytes to dysregulate liver function. The studies have not yet answered about the specific mechanisms of cholangiocytes injury, and how hepatocyte injury occurs as it lacks the ACE2 receptor.
  • Immune causes: Overactivated immune reaction causing cytokine storm and chemokine release (e.g; TNF‐α, interferon‐γ, and interleukins) leads to systemic inflammatory response syndrome (SIRS) and cellular necrosis due to ischemia.
  • Drug induced liver injury: Of the drugs known to cause liver damage include antimalarial drugs, antibiotics and acetaminophen overdose. They are all used in the treatment of patients with COVID-19. Ritonavir and antiviral drug use in the treatment has been reported to cause liver damage via CYP3A metabolic pathways via ROS to cause membrane lipid peroxidation and organelle damage. Increasing the drug types used further increase the incidence of liver damage. The combined use of lopinavir and ritonavir was also found to lead to an increase in the chances of liver injury.
  • Sepsis
  • Reperfusion injury: COVID‐19 being primarily a respiratory disease explains the hypoxemia but some systemic complications such as ARDS, SIRS or MODS can further increase the chances of hypoxia. Cellular hypoxia causing ischemia leads to adenosine triphosphate (ATP) depletion and eventually hepatocyte death.
  • Hypoxia can also cause an increase in the level of reactive oxygen species (ROS) due to oxidative stress. Thus, certain oxidation sensitive transcription factors are activated and cause the release of certain pro‐inflammatory factors and induce liver damage.
  • Others: There can be other possible causes, such as positive pressure ventilation related liver congestion and myositis but there is no literature discussing the possibilities.
• On microscopic pathology, the main pathologic finding is hepatic sinusoidal dilatation and mild lymphocytic infiltration. Mild- moderate microvascular steatosis and multifocal hepatic necrosis have also been reported in some cases.

Differentiating [COVID-19] associated hepatic injury from other causes of hepatic injury

• There are different etiologies of hepatic injury in general but a hepatic injury in a patient having COVID-19 infection itself can be due to different reasons. Although different etiologies of the liver disease show some difference in biochemistry, we lack sufficient data to suggest a specific biochemical factor characteristic, pathognomic of COVID-19 related liver injury. Abnormal liver biochemical markers at the time of diagnosis can give a clue of chronic liver disease in a patient.
• Deteriorating liver function tests during the course of hospitalization may point towards drug induced liver injury or complication of COVID-19.

Epidemiology and Demographics

• Collectively, the data from 12 clinical studies, reports that 14.8-53% COVID-19 positive patients have liver injury.

Gender

Although is very limited data available, the incidence of liver injury associated with COVID-19 is reported to be higher in males.

Race

• There is no racial predilection for [disease name].

Risk Factors

• Common risk factors in the development of hepatic complications include:
  • Chronic liver disease
  • Hypoxemia
  • Hyper‐inflammatory reactions during COVID-19 infection
  • Critical COVID-19 infection - liver injury being more prevalent in patients with a critical disease (especially ICU admissions) rather mild cases, makes a severe coronavirus infection a risk factor.

Natural History, Complications and Prognosis

• According to the data available to date, mild liver injury can occur in patients with moderate-severe illness but the incidence of hepatic dysfunction higher among patients with severe or critical COVID-19 illness.
• The association of acute liver injury with higher mortality has also been reported. Research is underway and few studies describe the correlation of liver biochemical indicators and severity of COVID-19. The impairment of hepatic function (guaged via biochemical markers of hepatic function) may become a predictor of the exacerbation and deterioration in patients with COVID‐19.

• The majority of patients with [disease name] remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications
• The prognosis of COVID-19 patients with mild liver injury (shown by mild elevation in liver function tests) is good and they usually recover without treatment. Patients with decompensated liver cirrhosis have an increased risk of mortality from COVID-19.

Diagnosis

Diagnostic Criteria

• The key lies in suspecting liver damage in a SARS-CoV2 patient and testing liver biochemical and function tests such as LDH, albumin, ALT, AST, total bilirubin, and INR. A COVID-19 patient with acute liver failure should be investigated and effort has to be made to find the cause liver injury. Abnormal liver biochemistries are uncommon in children.

Symptoms

• Symptoms of [disease name] may include the following:

• [symptom 1]

Physical Examination

• Patients with [disease name] usually appear
• Physical examination may be remarkable for:

• [finding 1]

Laboratory Findings

• Research has shown elevated ALT and AST levels in the blood of patients with liver injury on admission. AST elevation is more common than ALT, which reflects a possible source outside of liver.
• Serum albumin levels were found to get lower during the course of hospitalization. The tests is a measure of synthetic function of the liver.
• ICU patients had higher levels of {ASLT]] and AST and a more reduced level of serum albumin indicating severe liver damage affecting its synthetic ability.
• Total bilirubin and direct bilirubin: The data from limited studies show a higher incidence of hyperbilirubinemia in patients who required aggressive management during the course of their disease or died.
• LDH levels- a study reported the incidence of LDH levels to be highest followed by AST and ALT and suggested that LDH can be used as an early alarm tp prompt further analysis for COVID-19.
• Glycoprotein gamma-glutamyltransferase (GGT) may point towards hepatobiliary involvement.
• PTA (INR) provide a good estimate of liver synthetic function.
• Alkaline phosphatase (ALP) is higher in patients.
• Levels of IL‐2‐receptor (IL‐2R), IL‐4, IL‐6, IL‐18, IL‐10, TNF‐α were significantly increased IL‐6 in the serum of COVID‐19 patients are significantly increased and correlate with disease severity.

Imaging Findings

• There are no [imaging study] findings associated with [disease name].

Other tests

• Procalcitonin is found to be higher in patients and can give a fair idea of infection.

Treatment

Medical Therapy

Currently there is no specific treatment for patient with COVID-19 associated liver injury. The mainstay of medical therapy is to target the viral infection and control and prevent inflammation.

• In a SARS-Cov2 patient with mild hepatic biochemical abnormalities, the mainstay of treatment is actively managing the primary infection. The use of hepatoprotective and enzyme‐lowering therapy is not recommended but supportive as well as specific antiviral therapy has to be given to halt viral replication and to reduce inflammation.
• In patients with severe COVID-19 infection and liver injury, hyperinflammatory responses such as cytokine storms and tissue ischemia are usual causal factors. Treatment should focus on maintaining optimal blood oxygen saturation. This can be achieved either by oxygen therapy or the use of extracorporeal membrane oxygenation. The patient should be monitored closely with ongoing supportive and symptomatic treatment and correction of hypoproteinemia if required.
• In the case of acute liver failure in a COVID-19 patient, after the cause of liver failure has been established, hepatoprotective and enzyme‐lowering drugs are administered. It is important to choose lower doses and fewer types of drugs (not more than 2, in general) with known mechanism of action and composition as the hepatic drug metabolism may pose a potential risk of harming the organ. The patient should be closely monitored with frequent hepatic biochemical tests such as (AST, ALT, albumin, total bilirubin and INR. Acute liver injury should be managed with close monitoring, supportive and symptomatic treatment, and correction of hypoproteinemia.
• In the cases of drug induced liver injury, it is important to assess the degree of liver damage and identify the drug responsible and then adjust the treatment accordingly. If possible completely stop the drug, reduce the amount, or use an alternative drug. Anti‐inflammatory and hepatoprotective treatment should be provided. It is not recommended to discontinue Hepatitis B and Hepatitis C treatments but large doses of hormones are not to be used simultaneously.
• In patients with underlying chronic liver diseases, target the coronavirus infection and maintain the original therapy for the chronic liver diseases.
• Liver function tests can serve as indicators of disease progression.
• Treatment and prevention of inflammation in the early stages of the disease will prevent severe disease.

Surgery

Hepatic transplant patients have been identified but no research is published on a case of liver transplant in a patient with COVID-19 related liver damage.

Prevention

• At this time, the only effective measures for the primary prevention of COVID-19 related liver damage include prevention of itself COVID-19. Drug induced liver injury can be prevented by carefully selecting the drug with a known mechanism of action, not using more than two drugs, and avoiding large doses of hormones along with antiviral drugs.