COVID-19 associated liver injury: A general review with special consideration of pregnancy and obstetric outcomes

Table 1 Clinical characteristics and management of COVID-19 and perinatal liver diseases

	COVID-19	PEC/severe PEC	HELLP	ICHP	AFLP
Epidemiology	-	5.0%-7.5%	1%	0.3%-5.6%	0.005%-0.010%
Symptoms	Respiratory +/- GI symptoms	Variable: Headache, swelling, vision changes (or none)	Variable: Headache, nausea, vomiting, RUQ pain (or none)	Pruritis; starting at palms + soles (can be diffuse)	Nausea, vomiting, abdominal pain
Pathophysiology of liver disease	SARS-CoV-2 infection and systemic inflammation	Inflammation and imbalanced endothelial activity	Thrombotic micro-angiopathy	Hormonal cholangiopathy	Mitochondrial dysfunction + fatty acid accumulation in hepatocytes
Increased transaminases	13%-42%, 2-5 × ULN	Approximately 50%, > 2 × ULN	Typical, > 2 × ULN	Typical, > 2 × ULN	Always, < 10 × ULN
Jaundice	Rare (unclear%)	Rare	Rare (< 5%)	Uncommon (< 25%)	Mostly (> 70%)
Other findings	Radiographic lung disease	HTN, ↑ sFLT-1/PIGF	↓ PLC; ↓ haptoglobin; ↑ LDH ↑ D-dimer	↑ ALP; ↑ bile acids	Coagulopathy; hypoglycemia
Diagnosis	Viral antigen PCR or Nucleic acid amplification test (NAAT)	HTN ≥ 140/90 + organ dysfunction (proteinuria not required)	Tennessee or Mississippi classification	Bile acids (BA); > 10 umol/L	Swansea criteria; biopsy if unclear
Management	Anti-virals +/- Steroids Mono-clonal antibodies	HTN control; delivery if > 37 wk GA or > 34 wk if severe	Delivery after 34 wk GA	Ursodiol; delivery at 36 wk GA if BA > 100 or 36-39 wk if BA < 100	Prompt delivery
Complications	↑ Risk of post-partum hemorrhage; ↑ multi-systemic organ failure	↑ Complications; mortality: 1%-5%; ↑ Neonatal respiratory distress + mortality	↑ Complications Mortality: 1%-3%	↑ Neonatal complications	↑ Maternal + neonatal complications; morality: 20% (mother); 6%-77% (neonate)

Comparison of the clinical presentation and management of Coronavirus disease 2019 (COVID-19) complicated by COVID-19 associated liver injury (COVALI) in pregnant compared to liver diseases specific to pregnancy[105-107,134-138]. Many of the diseases present along a spectrum however, they each have features that can help narrow the differential diagnosis. Importantly, management of perinatal liver diseases includes early delivery in most cases based on American College of Obstetrics and Gynecology recommendations, whereas management of COVALI does not involve decisions about pregnancy delivery. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; PEC: Pre-ec clampsia; HELLP: Hemolysis, elevated liver enzymes, low platelets; Ahellp: atypical HELLP; AFLP: Acute fatty liver of pregnancy; ICHP: Intrahepatic cholestasis of pregnancy/obstetric cholestasis; LDH: Lactate dehydrogenase; PLC: Platelet count.

Table 2 Summary of case reports

Ref.	Patient	Case information	Laboratory data		Clinical course
Improved without delivery
Anness and Siddiqui[114], 2020	35 y/o G2P1, GA 285w, PMH: IHCP	CC: Progressive dyspnea and cough; vitals: HR 133, RR 42, O2 96%; chest CT: Patchy peri-hilar inflammatory changes; differential: ICHP vs ICHP + COVID-19 vs COVID-19	AST		Normal bile acids @ GA 20
			ALT	571	↑ Bile acids and NO itch
			Bilirubin	0.76	Conservative management
			PLC	135	LFTs resolved with COVID-10
			CRP	60	Discharged home
			LDH	194	Healthy delivery at GA 391
			Ferritin
Azimi et al[115], 2021	27 y/o G2P1, GA 30 wk	CC: Headache and lower limb pain; vitals: BP 100/70, HR 90-100; chest CT: Peripheral GGO’s + consolidation; differential: HELLP vs systemic lupus vs COVID-19	AST	126	No delivery
			ALT	89	LFTs resolved with COVID-19
			Bilirubin	2.3	Discharged at GA 33
			PLC	220	Healthy delivery at GA 39
			CRP	114
			LDH	1036
			Ferritin	1360
Naeh et al[116], 2022	39 y/o G5P1, GA 264 wk	CC: Dry cough and dyspnea; vitals: BP 152/132, HR 141, RR 20, SpO2 96%; chest CT: Patchy multi-focal GGO’s; differential: PEC with severe features vs COVID-19	AST	1154	Evaluated for PEC with PIGF
			ALT	864	PIGF 158 (high)→No delivery
			Bilirubin		LFTs resolving with COVID-10
			PLC	WNL	Discharged HD13; AST 331
			CRP		Healthy delivery at GA 392
			LDH	1018
			Ferritin
Improved with delivery
Ronnje et al[117], 2020	26 y/o, G2P1, GA 321 wk	CC: Cough, fever. Dyspnea, abdominal pain; vitals: BP 116/71, HR 113, RR 22, SpO2 95; chest CT bilateral diffuse GGO; differential: aHELLP vs COVID-19	AST	1687	5 d earlier normal labs
			ALT	348	Delivery on HD2 @ GA 326
			Bilirubin	1.23	LFTs trend down after delivery
			PLC	122
			CRP	136
			LDH	2039
			Ferritin	875
Arslan et al[118], 2022	30 y/o G3P2, GA 32 wk	CC: 6 d of chills, cough, dyspnea; vitals: RR 26, SpO2 84%; chest CT bilateral GGO’s + peripheral thickening; differential: HELLP vs PEC vs AFLP vs SLE vs COVID-19	AST	146	HD 2: BP 185/120, + proteinuria, intubated, IV nitroprusside
			ALT	102	HD 3: Cardiac injury, ↓ PLC, ↑ fetal distress→ Cesarean section
			Bilirubin	2.54	HD4: LFTs improved
			PLC	59	Patient + child died
			CRP	215
			LDH	697
			Ferritin
Delivery without improvement in 24-72 h of delivery (or other)
Madaan et al[119], 2022	26 y/o G1P0, GA 39w	CC: RUQ pain and headache; vitals: BP 160/100, HR 98, SpO2 95%; chest CT: Bilateral diffuse GGO’s; differential: Not given	AST	589	Suspicion of HELLP→ Cesarean section
			ALT	300	Improved over hospitalization and LFTs trended down (no timeline given)
			Bilirubin	9.4
			PLC	90
			CRP	78.5
			LDH	3100
			Ferritin	734
Choudhary et al[120], 2021	27 y/o G1P0, GA 35 wk, di-di twins	CC: Cough, fever, abdominal pain; vitals: BP 142/94, HR 88, RR 20. SpO2 98%; chest X-ray: Bilateral basal opacities; differential: aHELLP vs PEC vs AFLP vs COVID 19	AST	728.5	Suspicion of aHELLP→Cesarean-section
			ALT	473.2	POD 0: Hypo-glycemia, altered mentation, ↑ bilirubin→AFLP
			Bilirubin	4.9	Transfer to ICU + IV labetalol
			PLC	162	POD 8 discharged, normal LFT’s
			CRP	22
			LDH	96.9
			Ferritin	120

Gestational age is noted as week^d. Vitals reported as: BP: Blood pressure (mmHg); HR: Heart rate (beats per minute); RR: Respiratory rate (breaths per minute); Spo2: Oxygen saturation (%). Laboratory values are reported with the following standardized units: AST: Aspartate aminotransaminase (U/L); ALT: Alanine aminotransaminase (U/L); bilirubin (mg/dL); PLC: Platelet count (× 10³/ mm); CRP: C-reactive protein (mg/dL); LDH: Lactate dehydrogenase (u/L); ferritin (ng/dL). PEC: Pre-ec clampsia; HELLP: Hemolysis, elevated liver enzymes, low platelets; Ahellp: Atypical HELLP; AFLP: Acute fatty liver of pregnancy; ICHP: Intrahepatic cholestasis of pregnancy/obstetric cholestasis; CT: Computed tomography; GGO: Ground glass opacities; GA: Gestational age; WNL: Within normal limits; LFTs: Liver function tests; HD: Hospital day; C-section: Cesarean section; POD: Post-operative day; ICU: Intensive care unit.