Keywords
COVID-19 - pregnancy - hepatic manifestations - liver - transaminitis - viral injury
- hepatocellular damage
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2), started in December 2019 in Wuhan, China and spread rapidly around
the world, becoming a substantial threat to public health globally. Certain vulnerable
populations such as the elderly[1] and those with medical comorbidities[2]
[3]
[4] have been found to be at greater risk of severe disease, and there is speculation
that pregnancy may be another vulnerable population.[5]
[6] COVID-19 primarily impacts the lungs, causing acute respiratory distress syndrome;
however, other organs have been found to be affected as well, including the kidneys,[3] heart,[7] gastrointestinal tract, bile ducts, and liver.[8]
[9] The virus has been found to cause liver function abnormalities of varying degrees
from mild transaminitis to severe liver injury,[9]
[10] but the exact mechanism of liver injury in these cases is unknown. Here, we describe
a case of a pregnant woman with COVID-19 who developed significant transaminitis and
had a liver biopsy performed.
Case
A 30-year-old gravida 3 para 1101 with diet-controlled gestational diabetes, obesity
with body mass index (BMI) 45, fatty liver found on ultrasound 7 years prior, history
of laparoscopic cholecystectomy, and a history of preterm delivery had sore throat,
cough, and fever and was found to have a positive COVID-19 test 2 days later. Six
days after her positive COVID-19 test (285/7 weeks), she presented with worsening cough, new shortness of breath, and persistent
fever up to 101.7. She had taken a limited amount of acetaminophen (less than 3 g/24 hours)
at home prior to admission. She was admitted to the hospital for observation and supportive
care.
On the day of admission, her temperature was 100.2, heart rate 114, and peripheral
capillary oxygen saturation (SpO2) 91 to 94% on room air. She was started on supplemental
oxygen by nasal cannula (1–3 L per minute throughout her hospitalization). Medications
included dexamethasone 6 mg by mouth daily, a therapeutic heparin drip, and a vitamin
regimen (melatonin, thiamine, zinc, ascorbic acid) per hospital COVID-19 protocol.
Additional medications included prenatal vitamin, famotidine, calcium carbonate, and
acetaminophen pro re nata.
Her acetaminophen quantity throughout the hospitalization was 1,000 mg on hospital
day (HD) 1, 1,650 mg on HD 2, and 650 mg on two other occasions (HD 6, HD 10). She
received her weekly 17-hydroxyprogesterone injection (for history of preterm delivery)
on HD 5; however, this was subsequently discontinued.
Throughout her hospitalization she continued to symptomatically improve. While her
cough was persistent, hypoxia was mostly isolated to nighttime during sleeping, requiring
between 1 and 3 L per minute supplemental oxygen by nasal cannula at night. Fetal
monitoring was reassuring.
On HD 5, despite symptom improvement, her liver function tests were noted to have
increased, with aspartate aminotransferase (AST) of 172 and alanine aminotransferase
(ALT) of 209 ([Table 1]). Notably, baseline liver function tests prior to and at the beginning of pregnancy
were within normal limits. She felt well subjectively and denied any symptoms suggestive
of preeclampsia. Blood pressure remained normal. She appeared well on physical exam
without hyperreflexia or abdominal discomfort.
Table 1
Pertinent laboratory values throughout hospital admission
|
HD 1
|
HD 5
|
HD 6
|
HD 7
|
HD 8
|
HD 9
|
HD 10
|
HD 11
|
HD 12
|
HD 13
|
11 days discharge
|
|
Total bilirubin, mg/dL
|
1.6
|
1.3
|
1.0
|
1.1
|
1.0
|
1.3
|
1.2
|
1.2
|
0.5
|
0.9
|
0.4
|
|
Aspartate aminotransferase (AST), U/L
|
30
|
172
|
212
|
284
|
441
|
501
|
500
|
415
|
321
|
269
|
47
|
|
Alanine aminotransferase (ALT), U/L
|
30
|
209
|
337
|
524
|
846
|
1,115
|
1,313
|
1,336
|
1,093
|
981
|
105
|
|
Alkaline phosphatase, U/L
|
100
|
118
|
120
|
117
|
121
|
121
|
124
|
114
|
102
|
100
|
71
|
|
International normalized ratio (INR)
|
0.9
|
|
|
1.2
|
1.0
|
1.1
|
1.0
|
1.0
|
1.0
|
1.0
|
|
|
Platelets
|
197
|
385
|
396
|
470
|
495
|
529
|
550
|
489
|
365
|
362
|
190
|
|
Fibrinogen, mg/dL
|
750
|
1,043
|
886
|
934
|
912
|
966
|
980
|
8,766
|
817
|
821
|
|
|
Ferritin, ng/mL
|
178
|
623
|
683
|
568
|
1,036
|
1,159
|
979
|
757
|
463
|
366
|
|
|
Lactate dehydrogenase (LDH), IU/L
|
198
|
400
|
342
|
346
|
380
|
433
|
406
|
295
|
257
|
323
|
|
Abbreviation: HD, hospital day.
Other notable negative laboratories included hepatitis A, B, C, and E serologies,
Epstein–Barr virus, cytomegalovirus immunoglobulin M (IgM), herpes simplex virus IgM,
antimitochondrial and anti-smooth muscle antibodies, antinuclear antibody, and antineutrophil
cytoplasmic antibody. She had a negative immunoglobulin panel and ammonia levels within
normal limits.
Her urine protein to creatinine ratio was 0.22 with a 24-hour urine protein of 319.
Her creatinine, platelets, international normalized ratio, and haptoglobin remained
normal.
An abdominal ultrasound suggested hepatomegaly (craniocaudal diameter 21.27 cm). Liver
echogenicity was slightly increased, and liver echotexture was coarse. The gallbladder
was surgically absent, and the abdominal vasculature was normal.
While her 24-hour urine protein was suggestive of mild proteinuria, the absence of
elevate blood pressures or symptoms of preeclampsia made both preeclampsia and acute
fatty liver disease of pregnancy unlikely.
On HD 10, a liver biopsy was performed given concern for persistently increasing transaminases,
with AST max of 501 and ALT max of 1,313.
The liver biopsy showed reactive changes consistent with medication effect—prescription
or over-the-counter supplement—as well as mild steatosis ([Figs. 1] and [2]). Trichrome and reticulin stains were performed. There was no significant fibrosis.
Iron stains were negative as was the periodic acid-Schiff with and without diastase
stain for α-1 antitrypsin granules.
Fig. 1 Hematoxylin-eosin-stained liver biopsy showing portal tract with normal bile duct
(arrow) (magnification ×100).
Fig. 2 Hematoxylin-eosin-stained liver biopsy showing reactive changes (magnification ×80).
Following the biopsy, her transaminases stabilized and as she had appeared well for
several days therefore was discharged home with follow-up. Eleven days following her
hospitalization her transaminases had declined and she continued to feel well.
Discussion
COVID-19 has become a global health crisis and there remain many unknowns regarding
which populations are the most vulnerable and how the virus impacts different organ
systems of the body.
Prior pandemics such as that from H1N1 influenza suggest higher morbidity and mortality
among affected pregnant women[11]; however, current evidence is mixed regarding the relationship between pregnancy
and the severity of COVID-19. Reports from early in the pandemic from China, the epicenter
of the outbreak, suggested that pregnant women are not more severely affected by COVID-19.[12]
[13] And a study from March to April 2020 in New York City did not find higher rates
of intensive care unit admission in pregnant compared with nonpregnant women.[6] However, more recently there have been several case reports demonstrating severe
maternal morbidity secondary to COVID-19 in pregnancy,[5]
[14]
[15]
[16]
[17]
[18] and subsequent studies have suggested that pregnant women may be a more vulnerable
population.[19]
While the lung is the primary organ affected by the virus in both pregnant and nonpregnant
individuals, other organs including the liver have been found to be impacted as well,
especially in more severe cases. Guan et al report incidence of elevated AST levels
to be 18.2 and 39.4% of patients with nonsevere and severe disease, respectively,
and incidence of elevated ALT levels to be 19.8 and 28.1% of patients with nonsevere
and severe disease, respectively.[20] Data from large U.S. studies show elevated ALT is observed in approximately 39%
of patients with COVID-19 infection, mostly below 80 U/L.[21]
[22] It is not currently known if SARS-CoV-2 causes direct liver injury or if liver injury
in the setting of COVID-19 is secondary to other factors. Other proposed mechanisms
of secondary liver injury as a result of COVID-19 include simultaneous use of hepatotoxic
drugs, systemic inflammatory response, respiratory distress syndrome-induced hypoxia,
and multiple organ failure.[8] Hepatotoxic drugs that may be administered in the setting of COVID-19 include antiviral
medications, investigational drugs, or more commonly used medications such as acetaminophen.
In our case, the patient had taken limited amount of acetaminophen prior to hospital
admission (< 3 g/24 h) and then 1,000 mg on HD 1, 1,650 mg on HD 2, and 650 mg on
two other occasions. In addition, she had received her scheduled dose of 17-hydroxyprogesterone.
There have been some reports of liver biopsies among patients with liver injury in
the setting of COVID-19. One case report from a patient with severe acute respiratory
distress who died from COVID-19 in China reported a liver biopsy showing moderate
microvesicular steatosis and mild lobular and portal activity, consistent with either
viral injury or drug-induced liver injury.[23] Other cases report liver pathologic findings of mild sinusoidal lymphocytic infiltration
and sinusoidal dilatation, with some reports of multifocal hepatic necrosis as well.[10] Our case reports a liver biopsy with reactive changes consistent with medication
effect as well as mild steatosis.
Some have suggested that obesity and nonalcoholic fatty liver disease (NAFLD) may
be a risk factor in the development of drug-induced hepatotoxicity,[24] including acetaminophen-induced liver injury.[25] The patient presenting in our case had morbid obesity with a BMI of 45 with known
radiologic evidence suggesting fatty liver on ultrasound, therefore it is possible
that underlying obesity and mild NAFLD may have contributed to the acute liver injury
during her COVID-19 course.
There has also been data to suggest that certain viruses such as human immunodeficiency
virus and hepatitis C may increase susceptibility for drug-induced liver disease such
as secondary to acetaminophen toxicity.[26]
[27]
[28] It is possible that SARS-CoV-2 has a similar effect of potentiating hepatotoxic
drug effects on the liver.
There remain many unknowns both about the effect of COVID-19 on pregnancy and on acute
liver injury. In our case, it is likely that the liver injury with an unusual elevation
of ALT above 1,000 U/L in the setting of COVID-19 is multifactorial with contribution
from the virus itself, and medications with liver metabolism (acetaminophen and 17-hydroxyprogesterone)
on a liver potentially already affected by preexisting fatty liver disease. This case
also demonstrates the significant transaminitis that can occur in such cases. Further
investigation regarding the impact of COVID-19 on the liver as well as the mechanism
of action of these effects is warranted.
