COVID-19-associated hepatic injury

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Tayyaba Ali, M.D.[2] Javaria Anwer M.D.[3]

Overview

According to 12 clinical studies, 14.8%-53% of COVID-19 patients have liver impairment, suggesting COVID-19-associated hepatic injury, a common complication observed among COVID-19 patients. With the number of cases increasing, abnormal liver function test results have been observed in some patients with COVID-19, making this organ the most frequently damaged outside of the respiratory system.

Historical Perspective

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:[21][22][8][23][24][25][26][27]

To browse the classification of COVID-19, Click here.

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:

Hepatic Injury through ACE2 receptors

Antibody-mediated Hepatic Injury

Cytokine-mediated Hepatic Injury

COVID-19 medical therapy-induced Hepatic Injury

Sepsis-induced COVID-19-associated Hepatic Injury

Ischemia-reperfusion-induced Hepatic Injury

Clinical Features

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

Liver test abnormalities from various COVID-19 studies[9]
Author Group Number of patients Alanine

aminotransferase (IU)

Aspartate

aminotransferase (IU)

Prothrombin

time (s)

Bilirubin (μmol/L) Elevated lactate

dehydrogenase, creatinine kinase, or myoglobin

Mortality (%)
Guan et al (2020)[19] ICU or death 67 Not known Not known Not known Not known Yes 22% (day 51)
Huang et al (2020)[18] ICU 13 49 (29–115) 44 (32–70) 12·2 (11·2–13·4) 14·0 (11·9–32·9) Yes 38% (day 37)
Chen et al (2020)[4] Hospitalised 99 39 (22–53) 34 (26–48) 11·3 (1·9) 15·1 (7·3) Yes 11% (day 24)
Wang et al (2020)[47] ICU 36 35 (19–57) 52 (30–70) 13·2 (12·3–14·5) 11·5 (9·6–18·6) Yes 17% (day 34)
Shi et al (2020)[48] Hospitalised 81 46 (30) 41 (18) 10·7 (0·9) 11·9 (3·6) Unclear 5% (day 50)
Xu et al (2020)[49] Hospitalised 62 22 (14–34) 26 (20–32) Not known Not known Unclear 0% (day 34)
Yang et al (2020)[3] ICU 52 Not known Not known 12·9 (2·9)* 19·5 (11·6)* Not described 62% (day 28)
Extracted from all

studies above

Chronic liver

disease

42 Not known Not known Not known Not known Not known 0–2%†


In addition, abnormal liver function test in cases of COVID-19 is often transient and often simultaneously combined with increased enzymes from muscle and heart; these laboratory changes can return to normal without liver-related morbidity and mortality.

Gender

Although is very limited data available, the incidence of liver injury associated with COVID-19 is reported to be higher in males.[42]

Risk Factors

  • Common risk factors in the development of hepatic complications include:[23][27]
    • 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

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

  • Laboratory findings consistent with the diagnosis of COVID-19-associated hepatic injury include abnormal Liver function tests specially raised AST.
  • 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.[26]
  • 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 ALT 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.[24]
  • 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.[42]
  • Glycoprotein gamma-glutamyltransferase (GGT) may point towards hepatobiliary involvement.
  • PTA (INR) provides a good estimate of liver synthetic function.
  • Alkaline phosphatase (ALP) is higher in patients.[27]
  • 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.[52]

Electrocardiogram

X-ray

Echocardiography or Ultrasound

CT scan

  • There are no CT scan findings associated with COVID-19-associated hepatic injury.
  • Chest CT scan may be helpful in suggesting other organ involvement in the COVID-19 which is a multi-organ disease.
  • The CT scan findings in COVID-19 can be viewed by clicking here

MRI

  • There are no MRI findings associated with COVID-19-associated hepatic injury.

Other Imaging Findings

  • There are no other imaging findings associated with COVID-19-associated hepatic injury.

Other Diagnostic Studies

Treatment

Medical Therapy

Currently there is no specific treatmentthe for patient with COVID-19 associated liver injury. The mainstay of medical therapy is to target the viral infection and control and prevent inflammation.[24][27]

Surgery

  • Surgical intervention is not recommended for the management of COVID-19-associated hepatic injury.

Primary Prevention

  • The disease itself is associated with COVID-19 infection so prevention of the infection itself is the most promising primary prevention strategy at the moment.
  • There are no available vaccines against COVID-19 at the moment. There have been rigorous efforts in order to develop a vaccine for novel coronavirus and several vaccines are in the later phases of trials.[53]
  • The only prevention for COVID-19 associated hepatic injury is the prevention and early diagnosis of the coronavirus-19 infection itself. According to the CDC, the measures include:[54]
    • Frequent handwashing with soap and water for at least 20 seconds or using a alcohol based hand sanitizer with at least 60% alcohol.
    • Staying at least 6 feet (about 2 arms’ length) from other people who do not live with you.
    • Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs.
    • Cleaning and disinfecting.
  • 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.

Secondary prevention

  • Effective measures for the secondary prevention of contact tracing as it helps reduce the spread of the disease.[55]
  • In unexplained abnormal hepatic biochemical tests, CXR, Chest CT scan or nasopharyngeal swab RT-PCR should be performed to diagnose the infection and treat it timely.

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