Post-COVID-19 cholangiopathy: Systematic review

Abstract

BACKGROUND

The coronavirus disease 2019 (COVID-19) pandemic has had a profound impact on global health, primarily characterized by severe respiratory illness. However, emerging evidence suggests that COVID-19 can also lead to secondary sclerosing cholangitis (SC), referred to as post-COVID-19 cholangiopathy.

AIM

To synthesize currently reported cases to assess the current state of knowledge on post-COVID-19 cholangiopathy.

METHODS

Medical Subject Headings and Health Sciences Descriptors were used to retrieve relevant studies, which were combined using Boolean operators. Searches were conducted on electronic databases including Scopus, Web of Science, and MEDLINE (PubMed). Studies published in English, Spanish, or Portuguese were included, with no restrictions on the publication date. Additionally, the reference lists of retrieved studies were manually searched. Simple descriptive analyses were used to summarize the results. Then the data were extracted and assessed based on Reference Citation Analysis (https://www.referencecitationanalysis.com/).

RESULTS

The initial search yielded a total of 192 articles. After screening, 85 articles were excluded due to duplication, leaving 107 articles for further review. Of these, 63 full-length articles met the inclusion criteria and were included in the analyses. Most of the patients were male and exhibited elevated liver function tests (93.8%). Magnetic resonance imaging revealed duct thickening with contrast enhancement (47.7%), as well as beading of the intrahepatic ducts (45.7%) with peribiliary contrast enhancement on diffusion (28.7%). Liver biopsy results confirmed SC in most cases (74.4%). Sixteen patients underwent liver transplantation, with three experiencing successful outcomes.

CONCLUSION

Post-COVID-19 cholangiopathy is a serious condition that is expected to become increasingly concerning in the coming years, particularly considering long COVID syndromes. Although liver transplantation has been proposed as a potential treatment option, more research is necessary to establish its efficacy and explore other potential treatments.

Key Words: Coronavirus disease 2019; Severe acute respiratory syndrome coronavirus 2; Cholangiopathy; Liver function tests; Liver transplantation

Core Tip: Post-coronavirus disease 2019 (COVID-19) cholangiopathy is a rare but serious complication that can occur after contracting COVID-19. It is characterized by inflammation and damage to the bile ducts. To better understand this condition and its treatment, we conducted a systematic review of post-COVID-19 cholangiopathy cases. Sixty-three articles met the inclusion criteria, representing 540 patients. Males over 50-years-old were more prone to this condition, which is often accompanied by elevated liver function, bile duct thickening, and kidney failure after prolonged use of mechanical ventilation. Further research is needed to confirm the effectiveness of liver transplantation in treating post-COVID-19 cholangiopathy.

INTRODUCTION

On March 2020, the World Health Organization declared a global health pandemic after the first case was recognized on December 2019 in Wuhan City, China, of what was called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[1]. This led to catastrophic events in the world resulting in more than 6 million deaths globally. The pandemic has led to a great financial and humanitarian loss due to prolonged lockdowns, which have had a tragic effect on the global economy[2].

Also, coronavirus disease 2019 (COVID-19) keeps enduring second and third waves of outbreaks in many countries, probably caused by mutant new variants of the virus[2]. Despite the accelerated speed of vaccine development for the prevention of COVID-19 to control the disease and robust mass vaccination worldwide including booster doses, these new SARS-CoV-2 variants threaten the progress made so far with the purpose of controlling the spread of the disease[2,3].

Respiratory symptoms are the most common manifestation of the disease, which range from mild to severe and may include fever, dry cough, shortness of breath, anosmia, ageusia, and fatigue[4]. It may lead to viral pneumonia with severe complications such as acute respiratory failure, acute respiratory distress syndrome requiring intubation, mechanical ventilation (MV), and intensive care management[5,6].

In addition to respiratory symptoms, COVID-19 might also cause a range of extrapulmonary manifestations including cardiovascular, neurological, and renal complications[7]. Gastrointestinal symptoms, including diarrhea, nausea, and vomiting, are also commonly reported[8]. Post-COVID-19, derangement of liver enzymes is a potential complication observed in admitted COVID-19 patients, with a prevalence ranging from 14% to 83%[9]. Other liver-related conditions such as autoimmune hepatitis, vascular thrombosis, and hemophagocytic lymphohistiocytosis have also been associated with the post-COVID-19 period[9,10].

However, one emerging complication of COVID-19 is post-COVID-19 cholangiopathy (PCC), a novel clinical entity characterized by inflammation and damage to the bile ducts in individuals who have recovered from COVID-19 infection[11]. The clinical presentation of PCC can vary, but common symptoms may include abdominal pain, fever, and jaundice[12]. PCC has been observed in patients without a history of prior liver disease. This condition can manifest in various clinical settings, such as in individuals with severe COVID-19 infection requiring MV, as well as in those experiencing milder forms of the disease[5,13]. The prevalence of PCC is not well understood, and it is not clear if it is more common in certain patient populations. Some researchers have suggested a potential association between certain drugs, including immunomodulator agents, ketamine, and antiviral medications, and the development of PCC. However, the available evidence regarding these drugs causing cholangiopathy remains insufficient[9].

This systematic review comprehensively analyzes and synthesizes the existing evidence pertaining to PCC. The primary objective is to explore the clinical presentation and management approaches documented in the available cases reported in the literature. By conducting this review, we provide a comprehensive overview of the current understanding and knowledge gaps surrounding PCC, which can contribute to the development of effective strategies for diagnosis and treatment in clinical practice.

MATERIALS AND METHODS

Study design

This study was conducted in accordance with the guidelines for preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocol guidelines[14].

Data sources

The studies included in this review were identified using the search strategy: in ("COVID-19" OR "SARS-COV-2") AND ("cholangiopathy" OR "cholangitis" OR "liver transplantation"). This search command was run on the electronic databases Scopus, Web of Science, and Medline (PubMed). Languages were restricted to English, Spanish, and Portuguese. There was no date of publication restrictions. The reference lists of the retrieved studies were also manually searched. The databases were searched in March 2023. Reference Citation Analysis (https://www.referencecitationanalysis.com/) was used to supplement the search.

Inclusion and exclusion criteria

Inclusion criteria were clinical case reports or case series of post-COVID cholangiopathy. Studies needed to include detailed information about the clinical presentation, diagnosis, management, and outcomes. Articles unrelated to the topic were excluded as were those that did not provide sufficient detail about the cases. If there was more than one study published using the same case, the variables were complemented with both articles. Studies published only as abstracts were included, as long as the available data made data collection possible.

Study selection and data extraction

A comprehensive search of various databases was conducted using the search terms listed in the COVID-19, cholangitis, and liver transplantation ("COVID-19" OR "SARS-COV-2") AND ("cholangiopathy" OR "cholangitis" OR "liver transplantation"). The initial screening process involved reviewing titles and abstracts to identify potentially relevant studies. These studies were then analyzed in full, and some were excluded due to a lack of clinical information. Two reviewers independently extracted data from eligible studies using a standardized form and assessed the characteristics of the subjects and outcomes measured. Any discrepancies in study selection or data extraction were resolved by a third party.

Data collection

Variables included were age, sex, clinical presentation, liver function tests, renal function test, imaging findings, histopathology, whether or not the patient had undergone orthotopic liver transplantation (OLT), and outcome.

Data processing and analysis

Data were analyzed and summarized using descriptive techniques such as frequency, means, and median. The analyses were performed using Microsoft Excel 2010.

RESULTS

The search strategy retrieved 192 articles; 85 articles were excluded because they were duplicates and 107 articles were screened in the review. A total of 88 full-length articles were included and retrieved, of which 63 were included in the review. The PRISMA flowchart illustrating the search strategy is shown in Figure 1. Studies reviewed were either a case report or a case series.

Figure 1 The preferred reporting items for systematic reviews and meta-analyses flowchart for the systematic review.

This systematic review included a total of 540 patients, of whom 69 (12.7%) were male, 26 (4.8%) were female, and 445 (82.5%) did not note their sex. The majority of patients (66, 12.2%) were over 50-years-old. Almost all patients (93.8%) had elevated liver enzymes in the acute phase, with an increase of these levels in the chronic phase. Total bilirubin was elevated in 343 patients (63.5%), while only 80 (14.8%) had levels lower than 1.2 mg/dL. Data on bilirubin levels were not reported for 19 cases. Levels of alkaline phosphatase were high among 488 patients (90.3%) and gamma-glutamyl transferase were consistently elevated, often surpassing 1000 U/L.

In this study, based on imaging findings, 225 of 540 (41.6%) patients had biliary ductal dilatation with fibrosis on ultrasound, while 50 (9.2%) patients did not show any alteration. Furthermore, according to magnetic resonance imaging (MRI) results, 258 (47.7%) patients had bile duct thickening with contrast enhancement, 247 (45.7%) had beading of the intrahepatic ducts, and 155 (28.7%) had peribiliary enhancement on diffusion.

Moreover, 223 (41.3%) patients with PCC had respiratory failure type 2, which was characterized by acute respiratory distress syndrome (ARDS). Some of these patients underwent bilateral lung transplantation, but unfortunately 1 patient died. Additionally, 355 patients (65.7%) had acute renal injury that required either dialysis or renal transplantation after OLT. Data on renal function were not reported for 16 patients. According to liver biopsy results, 402 patients (74.4%) had sclerosing cholangitis (SC). Moreover, 16 patients (2.96%) with post-COVID-19 cholangitis underwent OLT. Of these, 15 patients experienced successful outcomes, with an improvement in liver enzyme levels post-transplantation.

DISCUSSION

After the first of case of SARS-CoV-2 disease in 2019[1], a novel clinical entity emerged. This condition has been reported in a small number of patients who have recovered from the virus and is characterized by elevated liver enzymes, biliary ductal dilatation on imaging, and histopathological findings of secondary SC (SSC)[11]. This systematic review examined the clinical presentations and outcomes of 540 patients with PCC, a rare complication of COVID-19 that affects the biliary system.

It is important to consider the differential diagnosis, as other diseases may present with a similar presentation[15]. Ketamine-induced cholangiopathy can lead to fusiform dilatation of the common bile ducts, without evidence of extrinsic or intrinsic obstruction[16]. The severity depends on the duration of using ketamine, and it is reversible in abstinent patients. Another difference is ischemic cholangitis, which occurs as a consequence of deficient blood flow to the bile duct wall[17]. This can affect the bile ducts leading to segmental strictures and cholangiectasis, resulting in mechanical restriction of bile acid flow.

SC is a medical condition characterized by the destruction of bile ducts due to inflammation and fibrosis and severe progressive stenosis of the bile tracts including three types: primary SC (PSC); immunoglobulin G-related SC (IgG-SC); and secondary cholangitis such as bacterial cholangitis, viral cholangitis (cytomegalovirus), postoperative biliary stenosis, and choledocholithiasis. Usually the patients present with similar cholestatic features such as itching and jaundice, and blood tests reveal high cholestatic enzymes[18,19]. Although the clinical presentation of PSC and IgG4-SC are nearly the same, they differ in treatment response, outcomes and comorbidities, and how to differentiate it from cholangiocarcinoma[18,19]. The difference between them is that IgG4-SC patients respond actively to prednisolone and steroid therapy, whereas PSC has no standard treatment approved; only ursodeoxycholic acid can be used in some patients, but it does not improve the overall prognosis[18-21].

Distinguishing and differentiating between PSC-high IgG and IgG-SC is challenging. A promising study that calculated serum IgG4:IgG1 ratios showed excellent specificity in distinguishing IgG4-SC from PSC-high IgG4[18,19]. The most common diagnostic test for PSC is cholangiography, which shows a pruned tree appearance, beaded ducts, and band-like stricture; thus, endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography is highly recommended. PSC is also highly associated with inflammatory bowel disease (ulcerative colitis more than Crohn’s disease); thus, a colonoscopy is recommended for the diagnosis, which increases the risk of cholangiocarcinoma and gallbladder carcinoma[18,19]. Therefore, more studies are required on the diagnostic procedures of PSC, IgG4-SC, and cholangiocarcinoma and their treatment and management[18,19].

The present results on PCC showed that most patients are male (12.7%) older than 50-years-old, consistent with the previous literature[9]. Every patient had elevated liver enzymes in the acute phase, and their levels increased in chronic phase if left untreated.

Also, ultrasound findings showed that 225 patients (41.6%) presented with biliary ductal dilatation. The MRI findings in this systematic review showed that only a small number of patients (28.7%) had peribiliary enhancement on diffusion, while a larger number of patients (47.7%) had bile duct thickening and enhancement, and 247 patients (45.7%) had beading of the intrahepatic ducts. By contrast, a previous retrospective study by Faruqui et al[13] showed that a higher proportion of patients (11/12, 92%) had beading of the intrahepatic ducts, 7/12 (58%) had bile duct wall thickening with enhancement, and 10/12 (83%) had peribiliary diffusion high signal[11]. Details can be found in Table 1 and Table 2.

Table 1 Baseline features in 540 patients with post-COVID-19 cholangiopathy, n (%).

Variable	Patients, n = 540 (100)
Sex
Male	69 (12.7)
Female	26 (4.8)
Age > 50 year	66 (12.2)
Liver enzymes
High (> 45)	507 (93.8)
Total bilirubin
High (> 1.2 mg/dL)	343 (63.5)
Alkaline phosphatase
High (> 147 IU/L)	488 (90.3)
Ultrasound findings
Biliary ductal dilatation with fibrosis	225 (41.6)
MRI Findings
Bile duct thickening and enhancement	258 (47.7)
Beading of intrahepatic ducts	247 (45.7)
Peribiliary diffusion	155 (28.7)
Histopathology with secondary sclerosing cholangitis	402 (74.4)
Orthotopic liver transplantation	16 (2.96)

COVID-19: Coronavirus disease 2019; MRI: Magnetic resonance imaging.

Table 2 Summary of systemically reviewed clinical cases.

Ref.	Age, yr	Sex	Clinical presentation	Elevated liver enzyme	U/S findings	MRI findings	Respiratory failure	Renal failure	Histopathology	OLT	Outcome
Roth et al[28], 2021	38	Male	Post-COVID-19 cholangiopathy	Yes	Intrahepatic bile ducts beading, with sub-segmental strictures and dilatation	Beading of intrahepatic ducts	Yes, required MV; On supplemental oxygen, then off on day 63 and decannulated	Yes, recovered	Portal tract findings; Mild duct paucity, moderate bile duct swelling & reaction; Mild portal tract inflammation; Endothelial hepatic artery swelling; Portal veins with focal endo phlebitis	Not done	Recovered
	25	Male	Post-COVID-19 cholangiopathy	Yes	Hepatomegaly, extrahepatic bile duct dilatation, intrahepatic bile duct dilatation	Beading of intrahepatic ducts	Yes, required MV; On supplemental oxygen, then off on day 112 and decannulated	Yes, recovered	Portal tract findings; Moderate duct paucity, moderate bile duct swelling & reaction. Moderate portal tract inflammation; Endothelial hepatic artery swelling; Portal veins with focal endo phlebitis	Not done	Recovered
	40	Female	Post-COVID-19 cholangiopathy	Yes	Hepatomegaly, no dilatation	Peribiliary diffusion, moderate portal and periportal fibrosis	Yes, remains with tracheostomy & MV, and then off MV on day 63	Yes, recovered	Portal tract findings; Moderate duct paucity, moderate bile duct swelling & reaction; Severe portal tract inflammation; Endothelial hepatic artery swelling; Portal veins with focal endo phlebitis	Not done	Death, cardiac arrest
Faruqui et al[13], 2021	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	U/S showed; extrahepatic bile duct dilatation and intrahepatic bile duct dilatation and periportal diffusion	MRI showed, beading of intrahepatic ducts (11/12, 92%); Peribiliary diffusion (10/12, 83%); Bile duct wall thickening (7/12, 58%)	Patients required MV	Yes, recovered	Large duct obstruction without clear bile duct loss	Done OLT	Had t successful recovery and rapid clinical improvement
	Mean age 58	Female	Post-COVID-19 cholangiopathy	Yes	Experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis	Beading of intrahepatic ducts; Peribiliary diffusion; Bile duct wall thickening	Patients required MV	Yes, recovered	Large duct obstruction without clear bile duct loss	Highly recommended for OLT. Patient on transplantation waiting list, still not done OLT at time of study	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis	Beading of intrahepatic ducts; Peribiliary diffusion; Bile duct wall thickening	Patients required MV	Yes, recovered	Large duct obstruction without clear bile duct loss	Highly recommended for OLT. Patient on transplantation waiting list, still not done OLT at time of study	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis	Beading of intrahepatic ducts; Peribiliary diffusion; Bile duct wall thickening	Patients required MV	Yes, recovered	Large duct obstruction without clear bile duct loss	Highly recommended for OLT. Patient on transplantation waiting list, still not done OLT at time of study	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis	Beading of intrahepatic ducts; Peribiliary diffusion; Bile duct wall thickening	Patients required MV	Yes, recovered	Secondary sclerosing cholangitis	Highly recommended for OLT, patient on transplantation waiting list, still not done OLT at time of study	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Intrahepatic bile duct dilatation and periportal diffusion	Beading of intrahepatic ducts; Peribiliary diffusion; Bile duct wall thickening	Patients required MV	Yes, recovered	Secondary sclerosing cholangitis	OLT Not done	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Intrahepatic bile duct dilatation and periportal diffusion	Beading of intrahepatic ducts; Peribiliary diffusion; Bile duct wall thickening	Patients required MV	Yes, recovered	Secondary sclerosing cholangitis	OLT Not done	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Intrahepatic bile duct dilatation and periportal diffusion	Beading of intrahepatic ducts; Peribiliary diffusion	Patients required MV	Yes, recovered	Secondary sclerosing cholangitis	OLT Not done	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Intrahepatic bile duct dilatation and periportal diffusion	Beading of intrahepatic ducts; Peribiliary diffusion	Patients required MV	Yes, recovered	Secondary sclerosing cholangitis	OLT Not done	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Intrahepatic bile duct dilatation and periportal diffusion	Beading of intrahepatic ducts; Peribiliary diffusion	Patients required MV	Yes, recovered	Secondary sclerosing cholangitis	OLT Not done	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Intrahepatic bile duct dilatation and periportal diffusion	Beading of intrahepatic ducts	Patients required MV	Yes, recovered	Secondary sclerosing cholangitis	OLT Not done	Recovery with long-term liability and comorbidity
	Mean age 58	Male	Post-COVID-19 cholangiopathy	Yes	Intrahepatic bile duct dilatation and periportal diffusion	MRI not available	Patients required MV	Yes, recovered	Secondary sclerosing cholangitis	OLT Not done	Recovery with long-term liability and comorbidity
Li et al[29], 2022	N/A	Two sample mendelian randomization	The autoimmune diseases showed not associated with COVID-19 infection	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Hunyady et al[30], 2023	N/A	24 Patients	Post-COVID-19 cholangiopathy developed after a median of 91 d	Yes	N/A	N/A	Patients required MV, the median was 48 d among all patients	N/A	COVID-SSC and CIP-SSC share the same clinical phenotype	N/A	UDCA showed great improvement in patients without liver cirrhosis and reduced severity in patients with liver cirrhosis, while OLT showed significant improvement in patient with liver cirrhosis
Weaver et al[31], 2021	63	Male	Post-COVID-19 cholangiopathy	Yes	Sludge in the gallbladder, no biliary ductal dilation, and patent vasculature	N/A	Patients required MV	N/A	Filling defects in the common bile duct as well as an irregular and beaded appearance of the intrahepatic ducts	Not done	Recovered, after ERCP sphincterotomy followed by balloon sweep of the biliary ducts and removal of thick stone
Hartl et al[32], 2022	N/A	N/A	Post-COVID-19 cholangiopathy (65 patients with CLD of 496 patients included in the study, around 24.6% non-ACLD vs ACLD 10.6% associated with COVID	Yes. Alkaline phosphatase showed (pre: 91.0 vs T1: 121.0 vs last: 175.0 U/L) and gamma glutamyl transferase GGT (pre: 95.0 vs T1: 135.0 vs last: 202.0 U/L)	N/A	N/A	N/A	N/A	20% of patients with CLD developed progressive cholestasis post-COVID-19 cholangiopathy, and patients with NASH/NAFLD also have a risk of developing cholestatic liver failure and secondary sclerosing cholangitis post-COVID-19	N/A	N/A
Duengelhoef et al[33], 2022	N/A	N/A	Post-COVID-19 cholangiopathy, associated more with Autoimmune hepatitis AIH as well as post COVID vaccine than PBC and PSC patients	Yes	N/A	N/A	N/A	N/A	N/A	N/A	N/A
John et al[34], 2023	N/A	N/A	Post-COVID -19 cholangiopathy study included 1607 patients with liver cirrhosis used UDCA	Yes	N/A	N/A	N/A	N/A	N/A	N/A	UDCA showed great improvement in patients with liver cirrhosis, by decreased symptoms and decreased COVID-19 infection
Heucke et al[35], 2022	N/A	48	Post-COVID-19 cholangiopathy 13% from 496 patients developed CLD; 23% of patients with CLD developed cholestasis/cholangiopathy	Yes (ALT & AST were elevated in 50 patients less than 5 times upper limit of normal. While in late-stage alkaline phosphatase and GGT were highly progressively elevated	N/A	N/A	Yes, require oxygen supply & some patients MV	Yes, some patients required dialysis for renal failure	The histopathology reported SARS-CoV-2 RNA and/or proteins in human liver tissue and bile samples, this SARS-CoV-2 RNA may lead to provoke a strong proinflammatory cytokine response (TNF, IL‐1, IL‐6) with hypercoagulation, endothelial damage, consecutive venous and arterial embolism, as well as secondary parenchymal damage	9 patients listed for OLT and 6 patients done OLT with good recovery	16 patients died, and 24 patients were treated with ketamine during the acute phase of COVID-19 and around 28 patients with SSC from 48 were reduced after using UDCA treatment
Bazerbachi et al[36], 2022	56	Female	Post-COVID-19 cholangiopathy	Yes alkaline phosphatase 1574U/L, total bilirubin 11 mg/dL, ALT 88 U/L, AST 101 U/L	EUS showed a left hepatic duct stricture and heterogenous, non-shadowing cylindric objects in the main bile duct	N/A	Yes, require tracheostomy & MV	Yes, developed renal failure and required hemodialysis	LHD stricture with upstream dilation of the left ducts, and obliteration of right intrahepatic with secondary sclerosing changes	Not done	Improved, casts were swept and removed, and left lobe was stented with a 10 Fr 20 cm plastic stent improving bilirubin level to a baseline of 3 mg/dL
Cho et al[37], 2022	47	Female	Post-COVID-19 cholangiopathy	Yes, highly elevated ALP-positive ANA, anti-mitochondrial highly positive	N/A	N/A	N/A	N/A	N/A	N/A	Post-COVID-19 cholangiopathy may be due to direct cytotoxicity from SARS-CoV-2 active replication, hypoxia induced respiratory failure, drug induced liver injury, vascular coagulopathy, immune mediated liver damage
	57	Male	Post-COVID-19 cholangiopathy	Yes, hypogammaglobinemia, high GGT, elevated AST/ALT, positive anti-mitochondrial antibody, anti-smooth muscle antibodies, and anti-double stranded DNA antibodies	N/A	N/A	N/A	N/A	N/A	OLT Considered for some patients
	N/A	N/A	Post-COVID-19 cholangiopathy	Yes, ALP > three times	N/A	MRCP showed dilatation of hepatic ducts with stenosis and beading of intrahepatic ducts	N/A	N/A	N/A
	N/A	24 Patients	Post COVID-19 Cholangiopathy	Yes	N/A	N/A	N/A	N/A	N/A
Yu et al[38], 2022	N/A	N/A	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	N/A	N/A	N/A	N/A	The patients are not only related to liver disease, but also cholangitis may be due to viral cholangitis, systemic inflammation response, and hypoxic liver injury
Sanders et al[39], 2021	57	Male	Post-COVID-19 cholangiopathy	Yes	Dilated CBD with a distal CBD stone	N/A	Yes, required MV. (Tracheostomy & gastrostomy)	Renal impairment required fluid resuscitation	N/A	N/A	Improved, biliary cast removed by ERCP, and bile duct stent and patient referred for cholecystectomy
López Romero-Salazar et al[40], 2022	76	Male	Post-COVID-19 cholangiopathy	Yes, elevated ALT & AST developed AIH and complicated to liver cirrhosis secondary to primary biliary cholangitis (PBC) igg positive, ANA	U/S showed hepatic fibrotic inflammation, dilated lobes, and biliary ducts	N/A	N/A	N/A	Biopsy showed lobular hepatitis, with intense interface, centrilobular necrosis with lymphoplasmacytic inflammation	N/A	The patient has poor prognosis due to liver cirrhosis, the study emphasizes the hypothesis that AIH induced due to or post COVID-19 vaccination. Patient given UDCA and obeticholic acid
Wall et al[41], 2022	N/A	N/A	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	N/A	N/A	N/A	N/A	The study showed to avoid using SARS-CoV-2-positive donors for liver transplantation unless there is a justifying indicator such as recipient illness severity
Ghafoor et al[42], 2022	Mean Age 60.5	15 Male patients	Post-COVID-19 cholangiopathy	Yes	N/A	All patients had intrahepatic bile duct strictures and 10 patients had associated upstream dilatation. Fourteen patients showed intrahepatic bile duct beading. One patient had extrahepatic bile duct structuring; 9 patients showed high signal on T2 and diffusion weighted images & 7 patients showed patchy arterial phase hyperenhancement; 2 patients showed biliary casts. Vascular complication, and periportal lymphadenopathy were not seen on MRI/MRCP	N/A	N/A	N/A	N/A	The post-COVID-19 cholangiopathy patients showed on MRI/MRCP multiple intrahepatic bile duct strictures with intrahepatic bile duct beading
Singh et al[43], 2021	57	Male	Post-COVID-19 cholangiopathy	Yes, elevated ALT, AST, GGT, hypergammaglobulinemia and anti-mitochondrial antibody, anti-smooth muscle antibody and anti-double stranded DNA antibodies	N/A	N/A	N/A	N/A	N/A	N/A	The patient diagnosed with auto immune hepatitis with primary biliary cholangitis overlap syndrome triggered by COVID-19
Seifert et al[44], 2023	N/A	7 patients (3 males & 4 females)	Post-COVID-19 cholangiopathy among 7 patients of 544 patients with cholangitis. 4 patients had SSC due to other reasons	Yes, elevated GGT, Alkaline phosphatase ALP among 7 patients more than 4 patients non COVID-19	N/A	N/A	N/A	N/A	N/A	N/A	The 7 patients with post-COVID-19 cholangiopathy showed more hepatitis and cholangitis than other group non-COVID cholangitis most probably due to direct cytopathologic effect of COVID virus
Lee et al[45], 2021	64	Male	Post-COVID-19 cholangiopathy	Yes	U/S intrahepatic bile ducts loss	MRI not available	Required MV	Yes, Recovered	Diffuse hepatic injury, onion skinning of the bile ducts and bile duct loss in scattered portal tracts	OLT not done; patient need to be stable for the operation	Not recovered
Cunha-Silva et al[46], 2023	45	Male	Post-COVID-19 cholangiopathy	Yes, elevated in the first 2-wk AST, ALT, GGT, Alkaline phosphatase post SARS-CoV-2 infection: ANA and anti-smooth muscle-positive. Negative viral hepatitis & anti-mitochondrial antibodies	N/A	No dilatation of biliary ducts	N/A	AKI after recovering 2 wk from COVID-19	Numerous foci of lobular necrosis but with no ductopenia or portal biliary reaction. After 2 mo: Biopsy showed: extensive areas of confluent necrosis, hepatocytes regenerating into pseudorosettes and numerous plasma cells, non-suppurative cholangitis all these features diagnosed by PARIS Criteria as AIH-PBC-OS	N/A	The patient is given prednisolone in the first phase, then after 2 mo added azathioprine and UDCA to management and showed great response and recovery
Hamid et al[47], 2021	N/A	N/A	Post-COVID-19 cholangiopathy	Yes, elevated AST, ALT, low albumin, and low platelet	N/A	N/A	N/A	N/A	Endoscopy and ERCP are recommended by WGO	N/A	OLT is advised to be postposed till SARS-CoV-2 infection treated and patient recovered
Kroepfl et al[48]	N/A	2 patients	Post-COVID-19; cholangiopathy	Yes	N/A	N/A	N/A	N/A	ERCP biopsy showed severely destructed biliary mucosa with ischemia and epithelial roughness	N/A	N/A, early cholangioscopy can confirm the diagnosis
Mayorquín-Aguilar et al[24]	3 Cases		Post-COVID-19 cholangiopathy	Yes	Not available	Mild intrahepatic; Biliary ductal; Dilatation with; Multifocal strictures or; Beading without; Extrahepatic biliary; Dilatation	Yes, required MV	Yes, recovered	SSC-CIP beading of intrahepatic ducts, bile duct wall thickening with enhancement, and peribiliary diffusion high signal	2 Done OLT, 1 Not done	2 males death; 1 female recovered
	45	Male
	52	Male
	46	Female
Graciolli et al[49]	63	Male	Post-COVID-19 cholangiopathy	Yes	Not available	Dilations with intercalated stenotic segments in intra and extrahepatic bile ducts and edema of the bile ducts corresponding to inflammation of the adjacent parenchyma	Yes	Not available	Intrahepatocellular cholestasis	Not done	Death, infected ulcer, palliative care
Keta-Cov research group[50]	Median Age 59 (35-65)	Male	Post-COVID-19 cholangiopathy	Yes, elevated AST, ALTGGT, ALP, total bilirubin all elevated	N/A	Aspects of sclerosing cholangitis, with strictures and dilatations of intrahepatic bile ducts, peribiliary cysts and multiple biliary casts	All patients required M/V	All patients developed acute kidney injury required renal replacement therapy	ERCP showed filling defects in the common bile duct and rarefication of the intrahepatic biliary tract and biopsy showed biliary obstructions, including cholangiolar proliferation, biliary plugs, portal inflammation with neutrophil infiltrates, extensive biliary fibrosis and cirrhosis	N/A	Intravenous ketamine is dose dependant and used for maintenance sedation of patients required M/V for acute respiratory distress syndrome ARDS, and showed associated with biliary obstructions, cholestatic liver injury, biliary cirrhosis, and end-stage liver disease, that’s the reason the new guidelines is not recommend ketamine especially if prolonged or at higher dose
		Male
		Male
		Female
		Female
Zdanowicz et al[51], 2022	Paediatric patient	Male	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	N/A	N/A	N/A	N/A	Patient developed autoimmune hepatobiliary diseases, autoimmune sclerosing cholangitis ASC which required long-term liver function monitoring
Schwarz et al[52], 2022	N/A	15 patients	Post-COVID-19 cholangiopathy	Yes, GGT is elevated in 15 patients with SSC-CIP after lung transplantation out of 40 patients in the study. ALP is elevated after lung transplant	N/A	N/A	15 patients out of 40 developed SSC-CIP underwent lung transplant	N/A	N/A	N/A	GGT showed to be a sensitive parameter to predict severity in SSC-CIP
Keskin et al[53], 2022	N/A	32 patients	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	N/A	N/A	N/A	N/A	Technical problems with ECRP were more common in biliary patients with delay group than in those without delay, while 7 pancreatic patients showed no difference in ERCP with or without delay of intervention. Technical issues considered such as abundant stone sludge in bile duct, stent migration, etc
Bartoli et al[54], 2021	44	Female	Post-COVID-19 cholangiopathy	Yes, AST, ALT elevated and GGT, ALP elevated more ANA positive, anti-mitochondrial-positive, anti-smooth muscle negative	U/S showed slightly enlarged liver with moderate steatosis and a mildly enlarged spleen	N/A	Yes, required intubation and MV	N/A	Florid ductal lesions, moderate peri-portal fibrosis, portal chronic inflammatory infiltrate	Not done	Patient treated with UDCA and discharged and breathing normally, also treated from Guillain barre syndrome GBS by intravenous immunoglobulin
Ferreira et al[55], 2022	N/A	4 cases	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	N/A	N/A	ERCP showed beaded appearance of intrahepatic bile ducts and bile casts	N/A	One patient undergone stone removal, and one patient complicate with liver cirrhosis, the other two progressed to advanced chronic liver disease
Bütikofer et al[56], 2021	N/A	20 Cases	Post-COVID-19 cholangiopathy	Yes 9 patients with severe cholestasis 11 patients with mild cholestasis	N/A	N/A	N/A	N/A	Ischemic changes to the perihilar bile ducts	N/A	SSC is more common and severe in critically COVID-19 patients, with prolonged ICU period
Zafar et al[57], 2022	N/A	2 Cases	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	N/A	N/A	N/A	N/A	Both patients developed SSC post-COVID-19 vaccination, which lead to hepatitis and eventually cholangitis
Otani et al[58], 2022	N/A	N/A	Post-COVID-19 cholangiopathy in some cases of 166 cases	Yes	N/A	N/A	N/A	N/A	N/A	N/A	166 cases for endoscopic procedures for causes; Cholangitis, GI bleeding, Obstructive jaundice, neoplasia, COVID-19 led to delay in endoscopic procedures which led to delayed diagnosis of cholangitis, cancers, etc.
Cesar Machado et al[59], 2022	66	Male	Post-COVID-19 cholangiopathy	Yes	Ultrasound showed slight hepatomegaly and no bile duct dilatation	MRI showed biliary cast, also revealed. Diffuse irregularity of intra- and extrahepatic bile ducts, with multiple focal strictures alternating with mild focal dilations of the biliary tree, suggesting a sclerosing cholangiopathy	Yes, required MV	Yes, required haemodialysis	Biopsy showed a prominent bile ductular reaction, cholangiocyte injury, inflammatory infiltrate rich in neutrophils, biliary infarctions, marked cholestasis, and portal fibrosis	Not done OLT, due to poor clinical condition	Slight recovery, under observation & follow-up
Steiner et al[60], 2022	33	Female	Post-COVID-19 cholangiopathy	Yes, elevated liver enzymes AST, ALT, marked elevated GGT, ALP	N/A	MRCP done showed cholangiopathy	Yes hypoxia required intubation and MV, patient developed respiratory distress syndrome in which she was given veno-venous extracorporeal membrane oxygenation	Yes renal failure, and went through haemodialysis frequently	ERCP done showed cholangiopathy	OLT not done	Patient passed away, her clinical condition deteriorated, with severe hypoxia, renal failure, and multi-organ failure
Gourjault et al[61], 2021	55	Male	Post-COVID-19 cholangiopathy	Yes, elevated AST, ALT high GGT, ALP, elevated bilirubin, LDH	N/A	Periportal hypersignal without hepatic biliary dilatation	Yes, Required intubation& MV for 20 d with four sessions prone position	N/A	Interlobular biliary lesions with cholestasis	Waiting list for OLT	Discharged home, he had sphincterotomy and stone removal, planned for OLT
	45	Male			Hepatic steatosis without hepatomegaly or biliary dilatation	Diffuse intra-hepatic dilatation and liver steatosis without any focal obstructing lesion	MV for 26 d and sedated with ketamine for 24 d then he was on ECMO for 18 d	Fifteen sessions of hemodialysis			Discharged home, improved, not done OLT
	30	Male			US normal	Progressive irregular intrahepatic ductal dilatation	MV for 12 d with ketamine sedation, then replaced by ECMO for 29 d with 6 sessions of prone position	30 sessions of hemodialysis	Biopsy showed cholestatic hepatitis, bile ducts dystrophy	OLT done 11 mo after his admission	Developed liver failure with ascites, prolonged prothrombin, OLT done
Tafreshi et al[62], 2021	38	Male	Post-COVID-19 cholangiopathy	Yes, mildly elevated AST, ALT and GGT mild bilirubin level	Intrahepatic biliary ductal irregularity and a markedly thickened common bile duct	Diffuse mild intrahepatic biliary distention, marked beading and irregularity& mild irregularity of the extra hepatic common bile duct	Required intubation & MV	N/A	Biopsy showed cholestatic hepatitis with cholangiocyte injury, bile ductular proliferation, canalicular cholestasis	Waiting list for OLT	Improved by treatment, waiting list for OLT
Leonhardt et al[63], 2023	N/A	N/A	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	Yes. Intubated on MV	N/A	N/A	N/A	One patient developed SSC-CIP in every 43 invasive ventilated COVID-19 patients (total 1082 patients)
Zengarini et al[64], 2022	30	Female	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	N/A	N/A	N/A	N/A	Patient developed subacute cutaneous lupus erythematosus post COVID-19 vaccination in patient with PBC
Wendel-Garcia et al[65], 2022	N/A	N/A	Post-COVID-19 cholangiopathy	Yes. High total bilirubin	N/A	N/A	N/A	N/A	N/A	N/A	The study showed 243 patients; 170 Patients infused with ketamine developed post-COVID-19 cholangiopathy while other patients received propofol, fentanyl were not associated with cholestatic liver injury
Morão et al[66], 2022	46	Female	Post-COVID-19 cholangiopathy	Yes	N/A	MRCP; liver abscesses, intrahepatic bile duct dilation with multiple strictures and some linear repletion defects at the bifurcation of the common hepatic duct	Intubation with MV 12 d	N/A	ERCP Showed; biliary casts	N/A	N/A
Lee et al[67], 2022	56	Female	Post-COVID-19 cholangiopathy	Yes, hepatitis C, AST, 243, ALT 630, ALP 449, GGT 2765	N/A	N/A	N/A	N/A	Granulomatous cholangitis, nonsuppurative with destruction and proliferation of bile ducts with PBC Also immune infiltrations of CD3 T-cells, CD8 T-cells	N/A	Patient improved and discharged after high dose UDCA treatment, liver enzymes become normal
Nikoupour et al[68], 2020	35	Male	Post-COVID-19 cholangiopathy	Yes	N/A	N/A	N/A	N/A	N/A	OLT done before 3 yr from COVID-19 infection	Two identical twins had COVID-19 infection, both developed PSC, one of them who had OLT showed improvement with mild symptoms, while the other twin had more severe symptoms
	35	Male								Did not have OLT
Arnstadt et al[69], 2021	62	N/A	Post-COVID-19 cholangiopathy	Yes	Echogenic intraductal longitudinal structures characteristic for intraductal casts and for SSC-CIP	MRCP showed irregular intrahepatic bile ducts	Yes, need long-term ventilation	N/A	Necrotic bile ducts	N/A	N/A
Meersseman et al[70], 2021	Mean age 48-68	Male	Post-COVID-19 cholangiopathy	Yes, elevated GGT, ALP, AST, ALT	N/A	MRCP showed focal strictures in intrahepatic bile ducts with intraluminal sludge and casts	Yes, intubated & MV then VV- ECMO	Yes, required renal support	ERCP: Patient 1 diffuse beading of the intrahepatic biliary system, patient 2 & 3 diffuse beading of the intrahepatic biliary ducts, patient 4 focal strictures on the right hepatic duct	OLT done for patient 1 and 2patient 3 & 4 did not undergo OLT	Patient 1 is doing well, patient 2 died due to septic shock and pneumonia, patient 3 have mild SSC-CIP, patient 4 died due to lethal liver hemorrhage
Durazo et al[5], 2021	47	Male	Post-COVID cholangiopathy	Yes	Cholelithiasis without evidence of acute cholecystitis	Mild intrahepatic biliary ductal dilatation with multifocal strictures and beading with intra hepatic dilatation but without extrahepatic biliary dilatation	Yes, off MV on day 29	Yes, recovered	Liver abscess; Bile collection associated with bile duct dilatation with vacuolization and neutrophilia. Endothelial hepatic arteries swelling. Severe portal tract inflammation with Obliterative venopathy	OLT done	Recovered
Raes et al[71], 2022	64	Male	Post-COVID-19 cholangitis	Yes	N/A	N/A	Yes, MV then venovenous ECMO VV-ECMO	N/A	N/A	N/A	Passed away; patient having CAHA, progressive liver failure, secondary to ischemic cholangitis
Fajardo et al[72], 2021	24	Female	Post-COVID-19 cholangitis	Yes, GGT, ALP, AST, ALT, bilirubin	US: thickening of the gallbladder without stones	MRI: showed normal biliary tree and wall oedema of the gallbladder	N/A	N/A	Cholangitis of the small bile ducts consisting of a mixed inflammatory infiltrate with lymphocytes, plasma cells and neutrophils, accompanied by eosinophils, localized around and within the bile ducts	Not done OLT	Improved, patient discharged after laparoscopic cholecystectomy and liver biopsy
Pizarro Vega et al[73], 2023	63	Male	Post-COVID-19 cholangiopathy	Yes, GGT high in all patients especially in patient NO. 3 to 143 U/L then reached to 1130 U/L and patient 4 reached 3550 U/L. AST is high and higher in patient 4 to 82 U/L and patient 5 to 85 U/L then reached maximum 250 and 148, respectively. And patient 1 reached 1520 U/L. High tot. Bilirubin, ALT, ALP	N/A	MRI showed intrahepatic duct dilatations, stenosis without lithiasis, no extrahepatic duct alteration	Yes, required intubation, MV. Pronosupination	Yes, impaired renal function, required vasoactive drugs	No liver biopsy	One patient planned for OLT	All patients treated with UDCA and discharge. 3 patients re-admitted due to complication, patient 4 had pleural empyema. Patient 5 had cholecystectomy, patient 6 readmitted for acute cholangitis without lithiasis, no patients died during follow up
	66	Female
	60	Male
	65	Male
	44	Female
	68	Male
Knooihuizen et al[74], 2021	54	Female	Post-COVID-19 cholangiopathy KISC	Yes, ALP peaked 2239 U/L, GGT 773 U/L, AST 1260 U/L, ALT 1729 U/L	N/A	MRI showed intrahepatic biliary dilatation with a beaded appearance & dilated common bile duct with distal narrowing	Yes	Yes	Liver biopsy showed minimal infiltration of neutrophils in the portal tract and lobule without cholestasis, also showed portal tract with bile duct injury	Not done	Patient have KISC during intensive sedation, then ceased the KISC is transient, patient for repeat MRCP
Zhou et al[75], 2022	36	Female	Post-COVID-19 vaccination leading autoimmune hepatitis	Yes, AST 581, ALT 588 elevated, GGT, ALP slight elevation, bilirubin 1.4	N/A	N/A	N/A	N/A	Liver biopsy showed interface hepatitis with portal infiltration and discrete presence of rosette formation and apoptotic hepatocytes	Not done	Patients have Autoimmune hepatitis AIH post vaccination (Moderna mRNA), treatment given after 2nd dose vaccine with prednisolone PSC treated with UDCA and ERCP
Muehlenberg et al[76], 2021	80	Female	Post-COVID-19 cholangiopathy	Yes, AST 100 U/L, ALT 113 U/L, bilirubin 12 mg/dL	US of liver and bile duct were normal	N/A	Yes, intubation and MV with antibiotics and catecholamine treatment	N/A	N/A	N/A	Patient done ERCP with papillotomy and foreign body extraction
Soldera and Salgado[77], 2021	62	Male	Post-COVID-19 cholangiopathy	Yes	Not Available	Diffuse irregularity of the intrahepatic bile ducts associated with sacular dilations suspicious for cholangiolithic abscesses	Yes	Not available	Intense cytoplasmic vacuolization of cholangiocytes and microvascular alterations	OLT done	Recovery
Rojas et al[78], 2021	29	Female	Post-COVID-19 cholangiopathy	Yes	Resemble SSC (secondary sclerosing cholangitis) but no portal inflammation, dilatation, or fibrosis)	MRI is negative	Yes, off MV on day 30	Yes, recovered	Low periportal inflammatory infiltrate without necrosis but with a severe obstructive cholestatic pattern	Not done	Not recovered
Dhaliwal et al[23], 2022	42	Female	Post-COVID-19 cholangiopathy	Yes	Not Available	Mild intrahepatic biliary ductal dilation. With subtle central biliary enhancement concerning for. Cholangitis along with hypodense material hin extrahepatic. Biliary system likely representing transiting gallbladder. Sludge	Not required MV	No	Filling defects secondary to multiple large biliary casts (Biliary case syndrome)	OLT Done	Recovery with long-term liability and comorbidity
Caballero-Alvarado et al[79], 2023	7 cases	7 cases	Post-COVID-19 cholangiopathy	Yes	Not available	Not available	Not available	Yes, recovered	Secondary sclerosing cholangitis	1 done OLT 6 send for consideration of OLT	One recovered, 6 no data available
Soldera et al l[26], 2023	50	One male	Post-COVID-19 cholangiopathy	Yes	Not available	MRI showed intra-hepatic sclerosing cholangitis and a dilated chilidium, with no signs of lithiasis (11 mm)	Yes, required MV	Yes, required haemodialysis	ERCP which showed a cast in the format of the external biliary tract, which was removed	Not done OLT	Recovered post cast removal
Franzini et al[80], 2022	65	Male	Post-COVID-19 cholangiopathy	Yes	U/S showed no abnormalities	MRI Not available	Yes, required MV; under Fentanyl, Midazolam, and Ketamine sedation	Yes, required haemodialysis	ERCP revealed rarefaction of intrahepatic bile ducts, and removal of biliary casts	OLT Not done	No improvement
Roda et al[81], 2022	63	Male	Post-COVID-19 cholangiopathy	Yes	Ultrasound results was inconclusive	MRI not done	Yes, required MV, and veno-venous extracorporeal membrane oxygenation support (VV-ECMO). And eventually done bilateral lung transplant	Acute renal failure (AKI III); chronic illness neuropathy; several episodes of bacterial superinfections and lastly, PLS, characterized by severe haemolysis	Transjugular hepatic biopsy was performed with histopathological evidence of portal and periportal fibrosis, and intraparenchymal cholestasis with cholangiopathy and vasculopathy	OLT not done, patient did bilateral lung transplant	Not recovered, patient passed away due to Multiorgan failure MOF due to septic shock
Tebar et al[82], 2022	43	Male	Post-COVID-19 cholangiopathy	Yes	Ultrasound Not available	MRI not done	Yes, required MV	Not available	ERCP, MRCP Showed: Bile cholestatic, toxic. Cause necrosis of cholangiocytes and stenosis, determining persistent and irreversible biliary obstruction, with rapid progression to liver cirrhosis	Not available	Not available
Santisteban Arenas et al[83], 2022	6 cases		Post-COVID-19 cholangiopathy	Yes	Ultrasound not available	Destruction and curling of the pathway, beading of the intrahepatic bile duct	Yes, all 6 cases required MV	1 male not having renal failure or haemodialysis. All other 5 cases have renal failure; 2 females not required haemodialysis; 2 males required haemodialysis; 1 male have renal failure but not required haemodialysis	MRCP/ERCP showed destruction of biliary tract. In three of the six patients underwent liver biopsy, the most frequent findings were the presence of a reaction. Ductular, proliferation of cholangioles, infiltrate. Inflammatory associated with the biliary epithelium with component. Lymphoplasmocyte and polymorphonuclear neutrophils	Not available	1 patient died, 5 other survived with severe comorbidities such as pneumonia, tracheal stenosis, pressure ulcers etc.
	55	Male
	54	Male
	62	Male
	56	Female
	73	Female
	34	Male

ACLD: Advanced chronic liver disease; AIH: Autoimmune hepatitis; AIH-PBC-OS: Auto-immune hepatitis-primary biliary cholangitis overlap syndrome; AKI: Acute kidney injury; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; ANA: Antinuclear antibodies; AST: Aspartate aminotransferase; CAHA: Cold agglutinin hemolytic anemia; CBD: Common bile duct; CBD: Common bile duct; CIP: Critically ill patients; CLD: Chronic liver disease; COVID-19: Coronavirus disease 2019; EUS: Endoscopic ultrasound; ECMO: Extracorporeal membrane oxygenation; ERCP: Endoscopic retrograde cholangiopancreatography; GI: Gastrointestinal; GGT: Gamma-glutamyl transpeptidase; IL: Interleukin; KISC: Ketamine-induced sclerosing cholangitis; MRI: Magnetic resonance imaging; MRCP: Magnetic resonance cholangiopancreatography; MV: Mechanical ventilation; N/A: Not applicable; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; OLT: Orthotopic liver transplantation; PBC: Primary biliary cirrhosis; PLS: Passenger lymphocyte syndrome; PSC: Primary sclerosing cholangitis; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; SSC: Secondary sclerosing cholangitis; TNF: Tumor necrosis factor; U/S: Ultrasound; UDCA: Ursodeoxycholic acid; WGO: World Gastroenterology Organization.

PCC appears to have different histologic characteristics compared to SSC in critically ill patients caused by other factors. Biopsy samples from patients with PCC show extensive degeneration and injury of cholangiocytes, as well as unique microvascular features such as swelling of hepatic artery endothelial cells, phlebitis in the portal vein, and sinusoidal obstruction syndrome[5]. Several studies have suggested that COVID-19 cholangiopathy is the result of progressive paucity of bile ducts; however, the exact pathophysiology is not well known[11]. Our histopathology biopsy results showed SSC in 402 patients (74.4%).

On the other hand, PCC presentation is difficult to treat, and sometimes requires OLT[5,6,21]. Almost all patients presented with respiratory failure type 2 as they had ARDS, and 1 patient had bilateral lung transplant and unfortunately died. Every patient presented with acute kidney injury, which required either dialysis or renal transplantation post OLT. As described in the literature, PCC is often accompanied by respiratory failure and acute renal injury[22-25]. Also, some cases of biliary casts have been described, removed via ERCP. The diagnosis and management of post-COVID 19 cholangiopathy requires an ERCP, especially in the presence of a dilated choledocus in imaging studies[9,26].

Also, 16 patients (2.96%) underwent OLT, which can be a viable treatment option for this condition[5,27]. One of these cases was reported by Durazo et al[5], which comprised SSC in a 47-year-old patient who was recovering from severe acute respiratory distress syndrome caused by COVID-19 infection. He was admitted to the intensive care unit for prolonged MV (29 d) and was listed for liver transplantation with a model for end-stage hepatic disease score of 37. On day 108 from his presentation, the patient underwent successful OLT with a whole liver allograft from a deceased donor.

CONCLUSION

In conclusion, this paper presents an extensive review of post-COVID-19 cholangiopathy published in medical journals. Our analysis indicates that post-COVID-19 cholangiopathy is a serious systemic illness that can affect the liver in addition to the lungs. Most cases were found in males over 50-years-old, and patients with cholangiopathy exhibited elevated liver enzymes particularly alkaline phosphatase and gamma-glutamyl transpeptidase, and signs of liver dysfunction. Radiology showed bile duct thickening and enhancement, beading of the intrahepatic ducts, and peribiliary enhancement on diffusion. Additionally, every patient had severe respiratory distress syndrome and kidney failure reported as complications. Liver transplantation has been suggested as a potential management option for PCC, although its efficacy as a curative treatment requires further validation. Not all PCC patients require liver transplantation, as some may recover without undergoing this procedure. Studies have demonstrated that liver enzymes, especially alkaline phosphatase, total bilirubin, and gamma-glutamyl transferase, decrease after medical treatment of PCC. While liver transplantation is not suitable for all PCC patients, it remains the most effective option for select cases. Further research, clinical studies, and international collaborations are needed to gain a better understanding of this novel disease and explore potential treatment avenues.

ARTICLE HIGHLIGHTS

Research background

The coronavirus disease 2019 (COVID-19) pandemic, declared by the World Health Organization in March 2020, has had devastating global impacts, resulting in millions of deaths and significant economic and humanitarian losses. Despite vaccination efforts, new variants of the virus continue to pose a threat, hindering control measures. While respiratory symptoms are common in COVID-19, extrapulmonary manifestations and derangement of liver enzymes have been observed. One emerging complication is post-COVID-19 cholangiopathy (PCC), characterized by bile duct inflammation and damage in recovered individuals. PCC presents with symptoms such as abdominal pain, fever, and jaundice, affecting both severe and milder cases. The prevalence and potential drug associations with PCC remain uncertain.

Research motivation

Understanding post-COVID-19 cholangiopathy is crucial due to its novelty and potential impact on recovered patients. Exploring the clinical presentation and management of PCC can provide valuable insights into its diagnosis and treatment. By addressing the knowledge gaps surrounding this condition, future research can develop effective strategies for patient care and improve outcomes in clinical practice. The significance of solving these problems lies in advancing our understanding of this novel disease and facilitating evidence-based approaches to manage post-COVID-19 cholangiopathy.

Research objectives

The primary objectives of this systematic review were to comprehensively analyze and synthesize existing evidence on post-COVID-19 cholangiopathy, focusing on the clinical presentation and management approaches documented in reported cases. By realizing these objectives, we provide a comprehensive overview of the current understanding of post-COVID-19 cholangiopathy, identify knowledge gaps, and contribute to the development of effective diagnostic and therapeutic strategies for this condition. The findings from this study can guide future research endeavors, leading to improved patient care and outcomes in the field of post-COVID-19 cholangiopathy.

Research methods

The research methods employed in this study adhered to the guidelines for preferred reporting items for systematic reviews and meta-analyses protocols. A comprehensive search was conducted in electronic databases (Scopus, Web of Science, and Medline/PubMed) using specified search terms. The search was limited to English, Spanish, and Portuguese language publications without any date restrictions. In addition to database searches, the reference lists of identified studies were manually searched. The inclusion criteria encompassed clinical case reports or case series focusing on post-COVID cholangiopathy, with detailed information on clinical presentation, diagnosis, management, and outcomes. Studies that lacked relevant clinical information or were unrelated to the topic were excluded. Two independent reviewers performed data extraction using a standardized form, and any discrepancies were resolved through discussion or consultation with a third reviewer. The extracted data included variables such as age, sex, clinical presentation, liver and renal function tests, imaging findings, histopathology, liver transplantation status, and outcomes. Data analysis involved descriptive techniques, including frequencies, means, and medians.

Research results

This systematic review identified a total of 540 patients with post-COVID-19 cholangiopathy, predominantly male (12.7%) and over 50-years-old (12.2%). Elevated liver enzymes were observed in nearly all patients during the acute phase (93.8), persisting in the chronic phase. Total bilirubin levels were elevated in 63.5% of cases, while alkaline phosphatase was 488 (90.3%) and gamma-glutamyl transferase levels consistently exceeded 1000 U/L. Imaging findings revealed biliary ductal dilatation with fibrosis on ultrasound in 41.6% of patients and bile duct thickening with contrast enhancement on MRI in 47.7% of patients. Respiratory failure type 2, associated with acute respiratory distress syndrome, was observed in 41.3% of patients, with 1 patient undergoing lung transplantation. Acute renal injury requiring dialysis or renal transplantation was present in 65.7% of cases. Liver biopsy showed sclerosing cholangitis in 74.4% of patients. Sixteen patients (2.96%) underwent orthotopic liver transplantation, with successful outcomes observed in 93.75% of these cases. These findings provide important insights into the clinical characteristics and complications of post-COVID-19 cholangiopathy, highlighting the need for further research to elucidate its pathogenesis and optimal management strategies.

Research conclusions

This study proposes several new theories and methods in the field PCC. First, the study suggests that PCC is a serious systemic illness that affects not only the lungs but also the liver. It provides evidence that PCC is characterized by elevated liver enzymes, biliary ductal dilatation, and histopathological findings of secondary sclerosing cholangitis. The study highlights the importance of considering the differential diagnosis, as other diseases may present with similar symptoms, such as ketamine-induced cholangiopathy and ischemic cholangitis. The study emphasizes the diagnostic procedures for PCC. It recommends the use of cholangiography, endoscopic retrograde cholangiopancreatography, or magnetic resonance cholangiopancreatography to visualize the biliary system and identify characteristic features of PCC, such as pruned tree appearance, beaded ducts, and band-like strictures.

Research perspectives

The future research in the field of PCC should focus on understanding its pathophysiology, including the mechanisms of bile duct paucity and unique microvascular features. Improving diagnostic procedures through novel imaging techniques and biomarkers is essential for early and accurate detection. Comparative studies with other cholangiopathies can enhance treatment approaches. Additionally, investigating the management and treatment of PCC, including the efficacy of liver transplantation, is crucial. Identifying predictive factors for transplantation and determining long-term prognosis are valuable areas of research. Overall, future studies should deepen our understanding, develop improved diagnostics, and explore effective treatments to enhance patient outcomes. Collaboration among researchers and international efforts will play a vital role in advancing knowledge and management of this disease.

ACKNOWLEDGEMENTS

We would like to extend our sincere appreciation to the Acute Medicine MSc program at the University of South Wales for their invaluable assistance in our work. We acknowledge and commend the University of South Wales for their commitment to providing advanced problem-solving skills and life-long learning opportunities for healthcare professionals.