COVID-19 is a risk factor for severe liver damage for patients with intrahepatic cholestasis of pregnancy: a case report

Background: Patients with intrahepatic cholestasis of pregnancy (ICP) may present with slight liver damage. In the global outbreak, the number of pregnant women infected with coronavirus disease 2019 (COVID-19) is increasing. For the pregnant patients with ICP, COVID-19 may cause severe liver damage. Case presentation: A 31-year-old pregnant woman was admitted with fever and respiratory symptoms to Tongji Hospital in Wuhan amid the outbreak of COVID-19. Her chest CT scan showed an infection with viral pneumonia as multiple ground glass opacities in both lungs were spotted. Laboratory tests revealed increased white blood cell (WBC) count and decreased lymphocyte count. The levels of serum total bile acid (TBA) were highly elvated. So were the indices of liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (AKP), -glutamyltranspeptidase (-GT), and lactate dehydrogenase (LDH). The patient was later diagnosed of COVID-19 with comorbid ICP, presenting severe liver damage. Through timely termination of pregnancy and effective treatments, the prognoses of the patient and the fetus were well improved. Conclusions: This case highlights that COVID-19 may be a risk factor of severe liver damage for patients with ICP.Timely termination of pregnancy and effective symptomatic treatments are helpful to improve the progonosis.

presentation. The fetal heart rate (FHR) was 145bpm and fetal heart monitoring showed no abnormality.
Laboratory tests on admission showed increased white blood cell (WBC) count (9.86×10 9 /L), increased neutrophil percentage (86.8%), decreased lymphocyte count (1.07×10 9  Under the consultation from a MDT, an emergent cesarean section was performed successfully under spinal anesthesia in a designated negative pressure operating room. All personnel involved wore protective equipment according to the third level prevention of infectious diseases, and the patient wore an N95 mask as well. A female infant was delivered with Apgar scores of 8 and 9 at 1 and 5minutes, and was transferred to neonatology department 10 minutes after birth for close observation and the paitent was transferred to the fever ward under 24-hour ECG monitoring and 5L/min oxygen through nasal cannula. On the first postoperative day (POD), the result of SARS-CoV-2 detection in oropharyngeal swab specimen of the patient was positive, while the detection of the neonate was negative. Laboratory tests were detected again and blood-routine test showed obviously increased WBC count, increased neutrophil count and normal lymphocyte count (Table 1). The levels of ALT and AST were slightly lower compared with the day before, but still obviously higher than the baseline (Table 1). The other indexes of liver function were still highly increased, including AKP, -GT, LDH, and TBA (Table 1).
Diagnosed as a general case of confirmed COVID-19 with comorbid severe ICP [3], this patient presented severe liver damage. Accordingly, bicyclol (50 mg administered orally every 8 hours) and ursodeoxycholic acid (250mg administered orally every 12 hours) for liver protection and cholagogic, and mucosolvan (90mg administered intravenously every day) for expectorant were given symptomatically. Ganciclovir (0.25g administered intravenously every 12 hours) for anti-virus was given. Meropenem (1g administered intravenously every 8 hours) and micafungin sodium (0.1g administered intravenously every day) were given for anti-bacterial infection empirically. (Fig.2) After the operation, the patient's vital signs were stable with SpO 2 ≥98% under 5-8L/min oxygen inhalation through nasal cannula. She had intermittent fever on POD 1 and POD 2, with the highest temperature up to 38.5°C, and loxoprofen sodium (30mg administered orally) was given for antipyretic. On POD 3, her body temperature returned to normal, and pruritus disappeared. On POD 7, her cough and expectoration were alleviated. On POD 12, her chest tightness disappeared as well. On POD 12, the patient was tested negative for SARS-CoV-2( Fig.2), and the repeated test on POD 14 remained negative. On POD 12, blood routine tests and inflammatory-related tests returned normal (Table 1). On POD 12, except LDH, most of liver function indexes returned to normal (Table 1). In addition, the test of classification of peripheral blood lymphocytes was normal. Renal function and coagulation tests remained normal as well.
On POD 7 (25/1/2020), chest CT scan was repeated, and showed ground glass opacities in both lungs, indicating viral pneumonia with improvement (Fig.1B). On POD 12 (30/1/2020), the third chest CT scan showed that the shadows were absorbed and well improved, leaving a small amount of pleural effusion (Fig.1C).
On POD 15, the patient was discharged and sent to the quarantine area for further isolation.

Discussion And Conclusion
The most sensitive and specific marker for ICP is the elevated level of serum TBA. Patients may present with or without slight liver impairment. Usually, levels of transaminase are slightly elevated, ranging from two folds to 30-fold of the baseline. And levels of -GT and LDH are commonly normal.
In addition, limited reports about COVID-19 infection during pregnancy show that the clinical characteristics in pregnant women with confirmed COVID-19 were similar to those for non-pregnant COVID-19 patients in the general population [4,5]. Mild cases and general cases of COVID-19 presented with unobvious liver damage. Among ICU cases, levels of liver function indexes were not significantly increased. In addition, jaundice was rare, only appearing in a few deadly cases [6,7]. In comparison, the patient reported in this case experienced highly increased levels of ALT, AST, AKP, -GT and LDH, indicating that COVID-19 may be a risk factor of severe liver injuries ICP patients.
Based on the literature and clinical experience, the pathophysiological mechanisms of the patient reported in the case were speculated as follows. First, in addition to alveolar type 2 cells, cholangiocytes also expressed angiotensin converting enzyme2 (ACE2) [8], and could be targeted by SARS-CoV-2 to cause damage to cholangiocytes and hepatocytes. Second, SARS-CoV-2 activated lymphocytes to proliferate and secrete large amounts of pro-inflammatory cytokines, called "cytokine storm", which could attack the tissue cells to cause liver damage, myocardial injury and kidney failure [9]. Third, excessive serum bile acid and toxins caused by ICP in this patient, could accumulate in the liver and helped activate immune cells to magnify "cytokine storm", which accelerated hepatocyte damage [10]. Fourth, contraction of placental blood vessels caused by excessive acid in circulation, could cause damages to the morphology and function of placentas, and induce various oxidative stress responses; hypoxia in hepatocytes was worsened, and the increase of ROS and its peroxides might lead to the release of a variety of pro-inflammatory factors and aggravate ischemia-reperfusion injury (IRI) in liver [11][12][13].
Delivery decision was made based on both the severity of COVID-19 of the maternal and the gestational age of the fetus. Termination of pregnancy after gestation of 32-34 weeks might be helpful to the follow-up treatment and prognosis improvement [5]. Monitoring of FHR was important before the delivery, because changes in FHR pattern might serve as an early indicator of maternal respiratory deterioration [14]. In the presented case, considering the great risk to the patient and the fetus, an emergent cesarean section was performed immediately on her admission. After removal of the placenta, hormone levels would return to normal, which might help alleviate the immune imbalance. On the other hand, hypoxia and oxidative stress metabolites produced by contraction of placental blood vessels in ICP could be reduced, and hence, the cytokine storm triggered by SARS-CoV-2 could be alleviated.
At present, antiviral treatment has been routinely used to treat COVID-19 infection in China, but there was little evidence to support the effectiveness of specific antiviral drug. Nebulized -interferon inhalation together with one or two kinds of antiviral drug is recommended in the Chinese guideline.
Reduction of pulmonary inflammatory exudation caused by bacterial infection could help alleviate "cytokine storm" and organ injuries. In our case, WBC count and neutrophil count were highly elevated on POD 1, meropenem and micafungin sodium were used. Micafungin sodium was empirically used for six days to prevent secondary fungal infection. In case of antibiotic resistance, cefoperazone sulbactam sodium was used to replace eight days treatment of meropenem. Use of corticosteroids in the treatment of COVID-19 pneumonia was not recommended because it might delay the virus clearance. However, methylprednisolone could be used in cases with rapid disease progression or severe illness to improve patients' condition [15].
Bicyclol, a traditional Chinese medicine, has been widely used as a liver protectant when treating with viral hepatitis, fatty liver disease (FLD) and drug induced liver injury(DILI). Bicyclol could maintain hepatocyte membrane stability, alleviate mitochondria injury, decrease nuclear DNA damage and increase the produce of heat shock proteins (HSPs) to stop the progressing of hepatocyte apoptosis [16]. In addition, ursodeoxycholic acid could reduce the concentration of harmful bile acid in the circulation, promote the secretion of bile acid and improve the state of cholestasis. Combined treatment of bicyclol and ursodeoxycholic acid has achieved ideal effects when treating hepatocyte damage complicated with cholestasis.
In our case, the infant was tested negative for SARS-CoV-2 after delivery. This result bears importance regarding the possible maternal-fetus transmission of COVID-19. There have been two cases of COVID-19 infection reported by recent literature. One case was confirmed with close contact history. And the other case was confirmed at 36 hours after birth, and close contact could not be ruled out [14]. Despite there is no solid evidence for maternal-fetus transmission, it is recommended that newborns shall be separated from the mother in a timely fashion, and close observation ensue.
Although it is rare, COVID-19 could be a risk factor of severe liver damage for patient with comorbid ICP. Both the patient and the fetus are of great risk of poor outcomes. Early diagnosis, timely termination of pregnancy and appropriate treatments may help improve their prognoses.  Ground glass opacities in both lungs, indicating viral pneumonia with improvement. C: Two transverse thin-section chest CT scan on POD 12 (30/1/2020). The shadows were absorbed and well improved, leaving a small amount of pleural effusion.

Figure 2
Clinical course of treatments, symptoms and outcomes of the Patient