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.

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Historical Perspective

• Severe acute respiratory syndrome (SARS) has shown manifestations of liver impairment in up to 60% of patients.
• Liver impairment has also been reported in patients infected with MERS-CoV.
• 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. COVID-19-associated hepatic injury is mainly indicated by abnormal ALT/AST levels accompanied by slightly elevated bilirubin levels.
• In severe cases, albumin is seen to be diminished and the level of albumin is around 26.3-30.9 g/l.
• Patients with severe COVID-19 symptoms showed a high percentage of liver injury than that of mild patients.
• According to one study, serum ALT and AST levels increased up to 7590 U/L and 1445 U/L, respectively, in a severe COVID-19 patient.

To browse the historical perspectives of COVID-19, Click here.

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.

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 heterogeneous. A few of the proposed mechanisms include:

Hepatic Injury through ACE2 receptors

• S protein facilitates SARS-CoV-2 to enter host cells through binding to ACE2 receptors. ACE2 is the primary receptors that enable the entry of SARS-CoV into different target tissues, including hepatic cells.
• According to a biopsy performed in a COVID-19 patient after death, moderate microvascular steatosis, and mild portal and lobular activity in liver tissue were observed.
• Another four autopsies were performed on COVID-19 patients. In 2 cases, mild zone 3 sinusoidal dilatation, patchy hepatic necrosis, minimal increase in sinusoidal lymphocytes were observed in hepatocytes. In one case, RT-PCR showed direct evidence of the SARS-CoV-2 RNA sequence in the liver cells.
• The expression of ACE2 receptors in liver tissue is only 0.31%. The expression of ACE2 receptors is 20 times higher in bile duct epithelial cells as compared to hepatocytes. Because of the low number of ACE2 expression in the liver, further research is needed to investigate direct damage of liver tissue by SARS-CoV-2.

Antibody-mediated Hepatic Injury

• Antibody-mediated liver injury may occur in patients with SARS. It involves the binding of a virus-specific antibody to Fc receptors (FcR) and complement receptor (CR) that enables the virus to enter immune cells such as granulocytes, monocytes, and macrophages. The virus can damage the liver by constant replication in these immune cells. Further investigation is required to understand whether SARS-CoV-2 causes liver injury through this pathway.

Cytokine-mediated Hepatic Injury

• Historical data on SARS-CoV and MERS-CoV suggest that cytokine storm including interleukin (IL), tumor necrosis factor (TNF), and endotoxin and systemic inflammatory response syndrome played a major role in liver impairment among infected patients.
• A high serum levels of interleukin-2, interleukin-6, interleukin-7, interleukin-10, tumor necrosis factor-α, granulocyte-colony stimulating factor, interferon-inducible protein-10, monocyte chemotactic protein 1, macrophage inflammatory protein 1 alpha, Th17, and CD8 T cells are observed in severe cases of COVID-19.

COVID-19 medical therapy-induced Hepatic Injury

• COVID-19 medical therapy includes antibiotics, antivirals, and steroids similar to the treatment for SARS infection. These medications are on the whole likely reasons for liver injury during COVID‐19, however not yet being obvious.
• Most antipyretic medications contain paracetamol, which is commonly perceived as a typical explanation behind liver injury.
• According to a study by Fan et al., the liver injury observed in COVID‐19 patients might be caused by lopinavir/ritonavir, which is used as antivirals for the treatment of COVID-19.
• In this way, if variation from the norm of liver enzymes happens in the wake of utilizing a hepatotoxic medication, the drug-induced hepatic injury should initially be affirmed or precluded. China has a high prevalence of chronic liver diseases such as nonalcoholic fatty liver disease, chronic hepatitis B, and liver cirrhosis. Immune reactions as a result of COVID-19 infection may be viewed as a "second hit" to already existing liver disease and can actuate liver injury and steatohepatitis.

Sepsis-induced COVID-19-associated Hepatic Injury

• Sepsis can also be considered as a contributing factor to COVID-19-associated hepatic injury and can impair the prognosis of COVID-19. Sepsis is a dysregulated immune response to an infection that leads to psychological stress and multiple organ dysfunction.
• The pathophysiology of sepsis-related liver injury incorporates hypoxic liver injury because of ischemia and shock, cholestasis because of altered bile metabolism, hepatocellular injury because of drug toxicity, or overwhelming inflammation.

Ischemia-reperfusion-induced Hepatic Injury

• Ischemia and hypoxia as a result of COVID-19 infection can result in metabolic acidosis, calcium overloading, and changes in mitochondrial membrane permeability. These factors have impacted hepatic injury manifested as very high aminotransferase concentrations in serum.

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

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.

To browse the differential diagnosis of COVID-19, Click here.

Epidemiology and Demographics

• In a cohort of 41 COVID-19 patients, levels of aspartate aminotransferase increased by 15 (37%) patients. Among these 15 patients, eight (62%) of 13 ICU patients and seven (25%) of 28 non-ICU patients.
• According to a single-center study of 99 COVID-19 patients. A wide range of liver function abnormality was observed among 43 patients, with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above the normal range. A severe liver function abnormality was observed in one patient (ALT 7590 U/L, AST 1445 U/L).

Liver test abnormalities from various COVID-19 studies

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)	ICU or death	67	Not known	Not known	Not known	Not known	Yes	22% (day 51)
Huang et al (2020)	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)	Hospitalised	99	39 (22–53)	34 (26–48)	11·3 (1·9)	15·1 (7·3)	Yes	11% (day 24)
Wang et al (2020)	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)	Hospitalised	81	46 (30)	41 (18)	10·7 (0·9)	11·9 (3·6)	Unclear	5% (day 50)
Xu et al (2020)	Hospitalised	62	22 (14–34)	26 (20–32)	Not known	Not known	Unclear	0% (day 34)
Yang et al (2020)	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.

To browse the epidemiology and demographics of COVID-19, Click here.

Risk Factors

• Common risk factors in the development of COVID-19 associated hepatic injury complications include:
  • Critical/ severe COVID-19 infection, especially ICU admissions.
  • Prexisting Chronic liver disease. Also patients with decompensated liver cirrhosis have higher mortality due to COVID-19.
  • Old age
  • Severe hypoxemia
  • Hyper‐inflammatory reactions during COVID-19 infection
  • Drugs causing hepatotoxicity. This may include drugs used for the treatment of COVID-19 itself such as interferon beta , lopinavir, ritonavir and imatinib.

To browse the risk factors of COVID-19 clicking here.

Natural History, Complications and Prognosis

• Out of 148 COVID-19 patients, ninety-two (62.2%) patients were released from the hospital as of February 19, 2020, that includes 34 cases with abnormal liver function before admission, 24 cases with abnormal liver function during hospitalization, and 34 cases with normal liver function during the stay in hospital. Of note, we found that baseline abnormal liver function was associated with a prolonged hospital stay. Whereas, abnormal liver function observed during admission had little impact on the length of hospital stay.
• 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.

To browse the natural history, complications, and prognosis of COVID-19, Click here.

Diagnosis

Diagnostic Study of Choice

• The diagnosis of COVID-19-associated hepatic injury is based on the abnormal liver biochemical and function tests. 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.

History and Symptoms

• The majority of patients (14.5%) with COVID-19 associated hepatic injury have a fever, which may be related to the immune response after viral infection.
• Other COVID-19 associated symptoms reported in patients with COVID-19 include:
  • Cough (dry or productive)
  • Diarrhea
  • Nausea and vomiting
  • Pharyngitis
  • Abdominal pain
  • Anosmia (partial or complete loss of smell)
  • Anorexia (Loss of appetite)
  • Ageusia (Loss of smell)
  • Fatigue
  • Pruritis
  • Chills
  • Skin rash
• The patient history and symptom associated with COVID-19 can be viewed by clicking here.

Physical Examination

• Patients with COVID-19 associated hepatic injury may appear lethargic or confused due to hepatic encephalopathy. Jaundice, rash and bruises (signs of liver's deranged synthetic function) are more common in patients with chronic liver disease.
• Vital signs:
  • The most common physical examination finding reported in patients with COVID-19 associated hepatic injury includes fever (normal temperature is not uncommon).
  • Tachycardia
  • Hypotension is common in patients with chronic liver disease
  • Tachypnea maybe due to fever, respiratory involvement due to COVID-19 infection or massive ascites.
• On Abdominal exam:
  • Inspection: Jaundice, Ascites, abdominal distension or bulging flanks.
  • Auscultation: Accompanyinggastrointestinal infection may present as Increased bowel sounds due to enteritis.
  • Palpation: Tenderness on superficial palpation. The presence of hepatomegaly on deep palpation in patients with COVID-19-associated hepatic injury is a forethought of organomegaly.
  • Percussion: Shifting dullness
• The physical exam findings associated with COVID-19 can be viewed by clicking here.

Laboratory Findings

• Laboratory findings consistent with the diagnosis of COVID-19-associated hepatic injury include abnormal Liver function tests specially raised AST.
• ALT and AST: The level of both enzymes is elevated in the blood of patients (reported in one-third of patients in a few studies) with liver injury on admission. AST elevation is more common than ALT, reflecting a possible source outside of liver. The enzyme levels may rise above three times the normal level. ICU patients have higher levels of ALT and AST and reduced levels of serum albumin indicating severe liver damage affecting the liver's synthetic ability.
• LDH: Following AST and ALT, LDH] rise has the highest incidence. Some studies suggest that LDH can be used as an early alarm to prompt further analysis for COVID-19 but the data is insufficient to be conclusive.
• Alkaline phosphatase (ALP): The levels are raised.
• Serum albumin: The levels are found to decrease during the course of hospitalization. The tests are a measure of the synthetic function of the liver.
• 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.
• C-reactive protein (CRP), ESR and specially procalcitonin levels are found to be higher in patients and can give a fair idea of infection.
• Glycoprotein gamma-glutamyltransferase (GGT): A rise in the level of GGT points towards cholestasis and thus hepatobiliary involvement.
• PTA (INR): It provides a good estimate of liver synthetic function.
• Interleukins: Levels of IL‐2‐receptor (IL‐2R), IL‐4, IL‐6, IL‐18, IL‐10, TNF‐α are significantly increased. Specially IL‐6 in the serum of COVID‐19 patients are significantly increased and correlates with disease severity.
• Abnormal liver biochemistries are uncommon in children.
• CBC: Leukocytosis indicates infection and lymphocytosis indicating possible viral infection.

Electrocardiogram

• There are no ECG findings associated with COVID-19-associated hepatic injury.
• ECG shows significant findings in other manifestations or complications of COVID-19 infection such as COVID-19-associated myocardial injury, COVID-19-associated myocardial infarction, COVID-19-associated arrhythmia and conduction system disease, or COVID-19-associated pericarditis.
• The electrocardiogram findings on COVID-19 can be viewed by clicking here.

X-ray

• There are no x-ray findings associated with COVID-19-associated hepatic injury.
• However, an x-ray may be helpful in the diagnosis of complications of COVID-19 such as COVID-19-associated pneumonia which is the most common finding associated with COVID-19 infection.
• The x-ray finidings on COVID-19 can be viewed by clicking here.

Echocardiography or Ultrasound

• The most common ultrasound findings associated with COVID-19-associated hepatic injury was fatty liver on the right upper quadrant abdominal ultrasound. Abnormal liver laboratory findings as indicated in Lab finding sections served as an indication to perform the abdominal ultrasound. Distended sludge-filled gallbladder suggestive of cholestasis has been reported in half of the patients studied (fig 1). Portal venous gas has also been identified in a few patients.
• However, echocardiography may be helpful in the diagnosis of cardiac complications of COVID-19 which include COVID-19-associated heart failure, or COVID-19-associated pericarditis. An abdominal ultrasound may be helpful in the case of COVID-19-associated abdominal pain.
• The echocardiographic findings on COVID-19 can be viewed by clicking here.

  

  Fig 1 Upper abdominal ultrasound in an 83-year-old patient with raised enzymes on liver function tests and sepsis is suggestive of cholestasis. A distended gallbladder is marked by arrows and sludge by a (*) -

CT scan

• Portal venous gas on abdominal CT has been reported.
• Fig 2: A non-peer-reviewed retrospective cohort study mentions upper abdominal CT findings in 115 COVID-19 patients in China. The study reports homogeneous or heterogeneous hepatic hypodensity as the most common CT finding (26% patients) and pericholecystic fat stranding (21.3% cases). The study claims the correlation betwen CT signs and disease severity grading.
• Chest CT scan is helpful in suggesting lung involvement in the COVID-19 which is a multi-organ disease.
• The CT scan findings in COVID-19 can be viewed by clicking here.

  

  Fig 2 Transverse upper abdomen non-contrast CT scan film showing:
  A and B: Lung consolidation with air bronchograms, ground-glass opacity, interlobular septal thickening, Crazy paving sign, and pleura effusion are visible in both lungs
  C: Liver hypodensity
  D: Pericholecystic fat stranding marked by yellow arrows -

MRI

• There is one liver MRI with gadolinium on a 3T MRI reported to have been performed in a patient with COVID-19-associated hepatic injury and abnormal liver biochemical tests.No specific findings have been reported.
• The MRI findings in COVID-19 can be viewed by clicking here.

Other Imaging Findings

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

Other Diagnostic Studies

• There are no other diagnostic studies associated with COVID-19-associated hepatic injury.

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 using antivirals such as remdesivir, lopinavir/ritonavir and darunavir/cobicistat, control and prevent inflammation and symptomatic treatment. The recommended medical therapy is based upon expert opinion rather than randomized control trials is as follows:

Mild hepatic injury

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.

Severe hepatic injury

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. The Chinese Pharmaceutical Association recommends the use of jaundice-reducing, hepatoprotective and anti-inflammatory agents such as phosphatidylcholine, glycyrrhizin, bicyclol, and vitamin E. Maximum of one to two hepatoprotective or anti-viral drugs should be used to minimize drug interactions and possible liver damage.

Acute liver failure

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.

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.

Underlying chronic liver disease

Target the coronavirus infection and maintain the original therapy for chronic liver diseases.The American Association for the Study of Liver Diseases (AASLD) does not recommend to discontinue Hepatitis B and Hepatitis C antiviral treatments but recommends that large doses of hormones are not to be used simultaneously. However, direct-acting antiviral therapy initiation for Hepatitis C patients may be delayed.

Liver transplant patients

Specific COVID-19 therapy used in patients includes steroids (the study does not specify the type), hydroxychloroquine, antivirals (such as lopinavir/ritonavir, darunavir/cobicistat, and remdesivir). Some patients were administered antibiotics such as azithromycin and immunomodulatory therapies such as rituximab and tocilizumab. Immunosuppression has been reduced in most patients and discontinued in some. It is also advised at some places to keep the immunosuppression to the minimal possible dosage.

Monitoring

Liver function tests can serve as indicators of disease progression. Treatment and prevention of inflammation in the early stages of the disease prevent severe disease.
To view medical treatment for COVID-19, click here.

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.
• 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.
• 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:
  • Frequent handwashing with soap and water for at least 20 seconds or using a alcohol based hand sanitizer with at least 60% ethyl alcohol. It is essential to be sure that the hand sanitizer is free of methanol (wood alcohol) as FDA recently warns that ma=ethanol is harmful to human skin.
  • 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.

Secondary prevention

• Effective measures for the secondary prevention of contact tracing as it helps reduce the spread of the disease.
• 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.