Post-COVID-19 cholangiopathy: Current understanding and management options

Table 1 A summary of reported cases of post-coronavirus disease 2019 cholangiopathy in the literature

Ref.	Number of patients	Age, median (range)	Sex	Time interval between COVID-19 diagnosis and presentation with features of PCC	Peak bilirubin (mg/dL)	Peak ALP (U/L)	MRCP	Biopsy	Treatment	Outcome reported
Edwards et al[21], 2020	1	59	Male	Time to elevation of bilirubin: 15 d. Peak at 79 d	14.6	4000	Beading of intrahepatic ducts	Not reported	ERCP for sludge clearance	Alive (planning biopsy to decide on liver transplantation)
Roth et al[13], 2021	3	34 (25-40)	2 males, 1 female	Around 6 mo	Patient 1-7 gm/dL, patient 2-24 and patient 3-15	16 × ULN	Two of three: Hepatomegaly. One of three: Extrahepatic bile ducts dilatation and one of three: Intrahepatic bile ducts strictures and dilatations with beaded aspect or solely dilatation	Two of three: Mild and moderate bile ducts paucity. Three of three moderate ductular reaction, cholangiocytes swelling and regenerative changes with portal tract inflammation, hepatic artery endothelial swelling, hepatic veins endophlebitis and periportal fibrosis	Conservative	Two patients discharged home, one still hospitalized
Faruqui et al[22], 2021	12	58 (38-73)	Male: 92%; female: 8%	Mean interval-118 d	Range: 2-35	Range: 965-2544	Eleven of twelve patents showed beaded images of intrahepatic bile ducts, seven of twelve patients showed bile ducts thickening and hyperenhancement, ten of twelve patients showed peribiliary diffusion high signal	Performed in four of twelve pts. Acute or chronic large bile ducts obstruction, mild fibrosis of some portal tracts, Keratin 7 immunostain positivity	UDCA. UDCA slightly improved some lab tests (AST and ALT) but GGT and ALP remained elevated	Four of twelve died for complications consequent to sclerosing cholangiopathy, 2/12 listed for transplantation, 5/12 continuing conservative management
Durazo et al[27], 2021	1	47	Male	Around 2 mo	19	1644	Mild intrahepatic bile ducts dilatation with focal strictures and beaded aspect, no dilatation of CBD	Inflammatory mononuclear infiltrates of bile ducts walls with increased collagen deposition, liver abscesses and bile lakes associated with bile duct injury with vacuolization and neutrophilia. Endothelial cell swelling, lumen obliteration of arterial vessels and obliterative portal venopathy	Liver transplantation	Alive with normal LFT at 7 mo after liver transplantation
Tafreshi et al[42], 2021	1	38	Male	Cholestasis at a few months after initial hospital admission	9.8	3665	Mild dilatation of intrahepatic bile ducts with beaded aspect, dilatation of CBD and periportal oedema	Cholangiocytes injury, ductular proliferation, canalicular cholestasis, a bile lake and focal bridging fibrosis	Under evaluation for liver transplantation	Under evaluation for liver transplantation
Lee et al[38], 2021	1	64	Male	51 d	7.8	1600	Mild intrahepatic biliary ductal dilatation and mild patchy T2 hyperintensity within the right hemiliver, concerning for cholangitis	Explant pathology: Bridging fibrosis, severe bile duct injury, ductular reaction and leucocytes and plasma cells infiltrate	Liver transplantation	Alive at 8 mo and returned to work
Klindt et al[43], 2021	1	47	Male	Around 50 d	18	1700	Alterations of medium and small intrahepatic bile ducts	Enlarged portal tracts with phlogistic infiltrate, ductular reaction with degenerative alterations of bile duct epithelium; focal biliary metaplasia of periportal hepatocytes. A few bile infarcts and perivenular canalicular cholestasis	Liver transplantation	Alive
Rojas et al[44], 2021	1	29	Female	Around 2 mo	19	6000	Only a cystic lesion in liver segment V	Low periportal phlogistic infiltrate without necrosis but with a severe obstructive cholestatic pattern	UDCA and cholestyramine	Slight improvement at the time of reporting
Bütikofer et al[28], 2021	4	59 (54-67)	Male: 3, female: 1	70-153 d	3.81-26.05	(12.85-21.26) × ULN	Diffuse irregularities of the bile ducts with dilatations and strictures	Portal inflammation with pericellular fibrosis	UDCA	2 patients: Deceased. 1 patient: Listed for liver transplantation (MELD-17). 1 patient: Persistently marked increased ALP and GGT at 9 mo of follow up
Rela et al[16], 2022	1	50	Male	4 wk	42.4	248	Mild prominence of central intrahepatic, common hepatic, and common bile ducts with minimal beading of the right posterior sectoral and segment 2 ducts	Mild portal tract inflammation with lymphocytes, histiocytes and few eosinophils, with loss of interlobular bile ducts	Auxiliary partial orthotopic liver transplantation	Asymptomatic at 6 mo follow-up with good graft function and recovering function in native liver remnant
Kulkarni et al[17], 2022	15	Unvaccinated: 59 (24-67). Vaccinated: 52 (29-67)	Unvaccinated: Male (8/8, 100%). Vaccinated: Male (5/7, 71.4%)	The median time to the development of cholestasis was 35 (19-44) d and in vaccinated group and 39.5 (27-57) in the unvaccinated group	Unvaccinated group: 22.95 (4.2-48.5), vaccinated group 17 (8.3-32.4)	312 (239-517) U/L in the vaccinated group and 571.5 (368-1058) U/L in the unvaccinated group	Normal in all patients	Architectural distortion, fibrosis, cholestasis, and ductular reaction with duct openia in unvaccinated group. Cholestasis and inflammation and no fibrosis in vaccinated group	UDCA. Plasma exchange: 5. Oral steroids: 4	2-died. 2-liver transplantation. 2-listed for liver transplantation. 1-declined liver transplantation. 2-recovered. All 7 in vaccinated group recovered
Mayorquín-Aguilar et al[45], 2022	3	46 (45-52)	Male	12-14 wk in two patients and 20 d in another patient	17.32 (5.8-22.7)	1328 (705-1695)	Irregular morphology of intrahepatic and extrahepatic bile ducts. Multiple areas of stenosis in the distal intrahepatic bile ducts	Intracanalicular cholestasis, portal inflammation, ductular reaction, and moderate portal fibrosis	UDCA, cholestyramine, and sertraline	Persisitent cholestasis in one patient and disease progressed to cirrhosis in another patient. Third patient expired due to unrelated cause
Hunyady et al[37], 2023	24	57 (19-73)	Out of 24 patients, 20 were male, 4 females	91 d (IQR: 64-154 d)	Peak bilirubin 24.3 mg/dL. Median bilirubin 11.9 mg/dL (6.0-24.3)	Peak ALP 1100 U/L. Median ALP 925 U/L. (555-1100)	Strictures or dilatation of biliary system, rarefication of biliary tree including contrast filling defects or detection of biliary casts	-	UDCA in 16 (66.7%) patients, ERCP with sphincterotomy done in 20 (83.3%) patients. Cast extraction done in 11 (45.8% patients). 3 patients underwent liver transplantation	3 patients underwent liver transplantation. 2 patients had transplant free survival

ULN: Upper limit of normal; UDCA: Ursodeoxycholic acid; COVID-19: Coronavirus disease 2019; ALP: Alkaline phosphatase; PCC: Post-coronavirus disease 2019 cholangiopathy; IQR: Interquartile range; ERCP: Endoscopic retrograde cholangiopancreatography; GGT: Gamma glutamyl transpeptidase; MELD: Model for end-stage liver disease; CBD: Cannabidiol; LFT: Liver function test; MRCP: Magnetic resonance cholangiopancreatography; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Table 2 A summary of authors’ experience with post coronavirus disease 2019 cholangiopathy

Case	Age/sex	ICU admission for COVID	Mechanical ventilation for COVID	Medications received for COVID	LFT at initial admission for COVID	LFT (peak values)	Time interval1	MRCP	Biopsy	Treatment	Outcome
1	67/male	Yes (hypoxia-high flow oxygen)	No	Remdesivir, methylprednisolone	Bilirubin 0.84 mg/dL, AST 54 U/L, ALT 32 U/L, ALP 127 U/L, GGT 78 U/L and albumin 4.1 mg/dL	Bilirubin 12.7 mg/dL, AST 322 U/L, ALT 527 U/L, ALP 474 U/L and GGT 1318 U/L, albumin 3.2 g/dL, INR 0.98	4 wk	Normal except for cholelithiasis	Mild portal fibrous expansion with diffuse loss of interlobular bile ducts	Prednisolone, ursodeoxycholic acid	Hyperbilirubinemia continued to worsen. Expired of pneumonia
2	50/male	Yes	Yes	Methylprednisolone, Remdesivir, antibiotics and thromboprophylaxis	Bilirubin 0.5 mg/dL, AST 43 U/L, ALT 57 U/L, ALP 60 U/L, GGT 64 U/L, albumin 2.8 mg/dL	Bilirubin 31.3 mg/dL, ALP 248 U/L, GGT 355 U/L, AST 176 U/L and ALT 200 U/L	6 wk	Mild prominence of central intrahepatic, common hepatic, and common bile ducts with minimal beading of the right posterior sectoral and segment 2 ducts	Mild portal tract inflammation with lymphocytes, histiocytes and few eosinophils, with loss of interlobular bile ducts	Auxiliary partial orthotopic liver transplantation	Asymptomatic at 6 mo follow-up with good graft function and recovering function in native liver remnant
3	58/male	No	No	Doxycycline, ivermectin, methylprednisolone. Remdesivir, paracetamol along with zinc and other vitamin supplements	Bilirubin 1.99 mg/dL, AST 145 U/L, ALT 140 U/L, ALP 70 U/L, GGT 65 U/L and albumin 4.1 g/dL	Bilirubin 10 mg/dL, AST 167 U/L, ALT 181 U/L, ALP 532 U/L and GGT 728 U/L	6 wk	Normal	Bile duct degenerative changes in majority of portal tracts along with prominent centrilobular hepatocanalicular bilirubinostasis	Aspirin, clopidogrel, prednisolone, ursodeoxycholic acid	Improved, LFT at 18 mo of follow up. Bilirubin 1.3 mg/dL, AST 101 U/L, ALT 101 U/L, ALP 309 U/L
4	52/male	Yes	Yes	Amoxycillin, remedesivir, IV methyl prednisolone	Bilirubin 1 mg/dL, albumin 4.2 g/dL, ALT 25 U/L, AST 49 U/L, ALP 110 U/L, GGT 62 U/L	Bilirubin 33.9 mg/dL ALP 390 U/L, ALT 41 U/L, GGT 94 U/L, AST 58 U/L	6 wk	Normal	Bile ducts showed mild injury, lobular bilrubinostasis	Therapeutic plasma exchange, aspirin, clopidogrel, prednisolone, ursodeoxycholic acid	Improved, LFT at 6 mo of follow up. Bilirubin 1.1 mg/dL, ALP 101 U/L, AST 23 U/L, ALT 32 U/L

¹Time interval between coronavirus disease 2019 (COVID-19) diagnosis and presentation with features of post-COVID-19 cholangiopathy.

COVID: Coronavirus disease; ALP: Alkaline phosphatase; GGT: Gamma glutamyl transpeptidase; MELD: Model for end-stage liver disease; LFT: Liver function test; MRCP: Magnetic resonance cholangiopancreatography; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ICU: Intensive care unit; INR: International normalized ratio.