COVID-19 related biliary injury: A review of recent literature.

Since its emergence in 2019, it has become apparent that coronavirus 2019 (COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests (LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However, severe biliary tract injury progressing to liver failure has been reported in patients requiring prolonged intensive care unit stay or mechanical ventilation. Due to the timing of its presentation, this form of progressive cholestatic injury has been referred to as COVID-19 cholangiopathy or post-COVID-19 cholangiopathy, and can result in devastating consequences for patients. COVID-19 cholangiopathy is recognized by dramatic elevation in serum alkaline phosphatase and bilirubin and radiologic evidence of bile duct injury. Cholangiopathy in COVID-19 occurs weeks to months after the initial infection and during the recovery phase. Imaging findings and pathology often resemble bile duct injury associated with primary or secondary sclerosing cholangitis. Etiology of COVID-19 cholangiopathy is unclear. Several mechanisms have been proposed, including direct cholangiocyte injury, vascular compromise, and cytokine release syndromes. This review summarizes existing data on COVID-19 cholangiopathy, including reported cases in the literature, proposed pathophysiology, diagnostic testing, and long-term implications.

COVID-19-associated secondary sclerosing cholangitis - A case series of 4 patients.

We report a case series of four patients diagnosed with COVID-19-associated secondary sclerosing cholangitis (SSC), a recently described rare late complication of severe COVID-19. Following prolonged stays in the intensive care unit, these patients developed marked sustained cholestasis and jaundice despite clinical improvement. Cholangiography showed beaded appearance of intra-hepatic bile ducts and bile casts were removed in one patient. None of the patients reached normalization of liver enzymes and at least one progressed to liver cirrhosis (follow-up time of 11 to 16 months). COVID-19-associated SSC has a dismal prognosis with rapid progression to advanced chronic liver disease.

Secondary sclerosing cholangitis after COVID-19 pneumonia: a report of two cases and review of the literature.

Secondary sclerosing cholangitis in critically ill patients (SC-CIP) is a rare disease characterized by chronic cholestasis. The underlying pathophysiology of SC-CIP is not fully understood, and prognosis in severe cases remains poor with liver transplantation remaining the only curative treatment option. There is a growing amount of literature describing patients with chronic cholangiopathy after COVID-19 infection. The vast majority of the patients described in these reports were male and had a poor outcome. While the exact percentage of patients with COVID-19-related SC-CIP cannot be estimated accurately due to a lack of larger studies, an increase in patients with long-term complications of chronic cholestatic liver disease after severe COVID19-pneumonia can be expected in the upcoming years. Treatment options remain limited and further research is needed to improve the dismal prognosis of SC-CIP. Here, we present the cases of two patients who developed SC-CIP after prolonged intensive care unit stay due to severe COVID-19 pneumonia. Both patients required invasive ventilation for 31 and 141 days, respectively, as well as extra-corporal membrane oxygenation for 23 and 87 days. The patients suffered from jaundice and severe pruritus, and typical features of SC-CIP were present by MRCP and ERC. Repeated removal of biliary casts resulted in some alleviation of their clinical symptoms, but cholestasis parameters remain elevated. Furthermore, an increased liver stiffness was indicative of advanced fibrosis in both patients. In addition to these two case reports, we provide a concise review of the literature of SC-CIP after COVID-19 infection and discuss risk factors, treatment options and prognosis.

Post-COVID-19 Secondary Sclerosing Cholangitis: A Rare but Severe Condition with no Treatment Besides Liver Transplantation.

BACKGROUND The incidence of abnormal liver function, mainly aspartate aminotransferase and alanine aminotransferase elevations, in patients with COVID-19 is not uncommon, but persistent liver damage after the acute phase of the disease is uncommon and has been recently recognized as a new entity named post-COVID-19 cholangiopathy. CASE REPORT We report a clinical case with progressive cholestatic disease following severe COVID-19. AST and ALT peaked at hospital admission and while its serum concentration went down, bilirubin and cholestatic liver enzymes started to increase, reaching the maximum at day 122. Magnetic resonance imaging (MRI) revealed a 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. A transjugular liver biopsy showed a prominent bile ductular reaction, cholangiocyte injury, inflammatory infiltrate rich in neutrophils, biliary infarctions, marked cholestasis, and portal fibrosis, suggesting the diagnosis of post-Covid-19 secondary sclerosing cholangitis. The patient evolved with a continuous deterioration of liver functions, but liver transplantation was not performed due to his poor clinical condition. CONCLUSIONS Post-COVID-19 SSC is a severe disease with no effective clinical treatment and has liver transplantation as the only treatment for a few selected patients.

Gamma-glutamyltransferase is a strong predictor of secondary sclerosing cholangitis after lung transplantation for COVID-19 ARDS.

BACKGROUND: Lung transplantation (LTx) can be considered for selected patients suffering from COVID-19 acute respiratory distress syndrome (ARDS). Secondary sclerosing cholangitis in critically ill (SSC-CIP) patients has been described as a late complication in COVID-19 ARDS survivors, however, rates of SSC-CIP after LTx and factors predicting this detrimental sequela are unknown. METHODS: This retrospective analysis included all LTx performed for post-COVID ARDS at 8 European LTx centers between May 2020 and January 2022. Clinical risk factors for SSC-CIP were analyzed over time. Prediction of SSC-CIP was assessed by ROC-analysis. RESULTS: A total of 40 patients were included in the analysis. Fifteen patients (37.5%) developed SSC-CIP. GGT at the time of listing was significantly higher in patients who developed SSC-CIP (median 661 (IQR 324-871) vs 186 (109-346); p = 0.001). Moreover, higher peak values for GGT (585 vs 128.4; p < 0.001) and ALP (325 vs 160.2; p = 0.015) were found in the 'SSC' group during the waiting period. Both, GGT at the time of listing and peak GGT during the waiting time, could predict SSC-CIP with an AUC of 0.797 (95% CI: 0.647-0.947) and 0.851 (95% CI: 0.707-0.995). Survival of 'SSC' patients was severely impaired compared to 'no SSC' patients (1-year: 46.7% vs 90.2%, log-rank p = 0.004). CONCLUSIONS: SSC-CIP is a severe late complication after LTx for COVID-19 ARDS leading to significant morbidity and mortality. GGT appears to be a sensitive parameter able to predict SSC-CIP even at the time of listing.

A pilot study of vidofludimus calcium for treatment of primary sclerosing cholangitis.

The purpose of this pilot study was to explore the efficacy, safety, and tolerability of vidofludimus calcium (VC) in the treatment of primary sclerosing cholangitis (PSC). This was a single-arm open-label pilot study with a cohort of 18 patients with PSC. Study patients received VC for a period of 6 months. The study was undertaken at two sites, Mayo Clinic, Rochester, MN, and Mayo Clinic, Phoenix, AZ. The primary endpoint of the study was improvement of serum alkaline phosphatase (ALP) at the end of the study. Secondary endpoints included assessment of other liver biomarkers (bilirubin, alanine aminotransferase, and aspartate aminotransferase). Of 18 patients enrolled, 11 completed the 6 months of study treatment. Patients who completed treatment versus those who did not were similar other than a significantly higher direct bilirubin at baseline in the group that completed treatment (mean ± SD, 0.4 ± 0.3 versus 0.1 ± 0.1, p = 0.04). By intent to treat analysis, the primary outcome was met in 16.7% (3/18) of patients. By per-protocol analysis, including only patients who completed treatment, normalization of ALP occurred in 27.7% (3/11) at week 24 (95% confidence interval, 6.0% to 61.0%). VC was well tolerated with no drug-related serious adverse events. Conclusion: This proof of concept study provides support for further exploration of VC in patients with PSC.

Persistent Cholestatic Injury and Secondary Sclerosing Cholangitis in COVID-19 Patients.

CONTEXT.­: COVID-19 has been associated with liver injury, and a small subset of patients recovering from severe disease have shown persistent markedly elevated liver biochemistries for months after infection. OBJECTIVE.­: To characterize persistent biliary injury after COVID-19. DESIGN.­: A search of the pathology archives identified 7 post-COVID-19 patients with persistent biliary injury, and the clinical, radiologic, and pathologic features were assessed. RESULTS.­: All patients in this cohort presented with respiratory symptoms and had a complicated clinical course with acute elevation of liver biochemistries. Alkaline phosphatase (ALP) was markedly and persistently elevated after discharge (median peak ALP, 1498 IU/L, at a median of 84 days from diagnosis). Magnetic resonance cholangiopancreatography showed 3 patients with irregularity, stricturing, and dilatation of intrahepatic ducts; no radiographic abnormalities were identified in the remaining 4 patients. Liver biopsies showed mild portal changes with features of cholestatic injury in 4 patients (bile duct injury and canalicular cholestasis) and marked biliary obstruction in 2 patients (profound cholestasis, ductular reaction, and bile infarcts), but no SARS-CoV-2 RNA was identified on in situ hybridization. On follow-up, most patients had minimal intervention and showed marked improvement of liver biochemistries but with mild persistent elevation of ALP. CONCLUSIONS.­: A subset of critically ill COVID-19 patients demonstrates marked and persistent cholestatic injury, with radiographic and histologic evidence of secondary sclerosing cholangitis, suggesting that cholestatic liver disease and secondary sclerosing cholangitis may be long-term sequelae of COVID-19 acute illness as a longstanding manifestation of critical illness.

Progressive cholestasis and associated sclerosing cholangitis are frequent complications of COVID-19 in patients with chronic liver disease.

BACKGROUND AND AIMS: Cholestasis is associated with disease severity and worse outcome in COVID-19. Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described. APPROACH AND RESULTS: Hospitalized patients with COVID-19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non-advanced CLD (non-ACLD), or (iii) advanced CLD (ACLD). Patients with CLD and non-COVID-19 pneumonia were matched to patients with CLD and COVID-19 as a control cohort. Liver chemistries before (Pre) and at first, second, and third blood withdrawal after SARS-CoV-2 infection (T1-T3) and at last available time point (last) were recorded. A total of 496 patients were included. In total, 13.1% (n = 65) had CLD (non-ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was NAFLD/NASH (60.0%). COVID-19-related liver injury was more common among patients with CLD (24.6% vs. 10.6%; p = 0.001). After SARS-CoV-2 infection, patients with CLD exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (Pre: 91.0 vs. T1: 121.0 vs. last: 175.0 U/L; p < 0.001) and gamma-glutamyl transferase (Pre: 95.0 vs. T1: 135.0 vs. last: 202.0 U/L; p = 0.001). A total of 23.1% of patients with CLD (n = 15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6 mg/dl) during COVID-19, and 15.4% of patients (n = 10/65) developed SSC. SSC was significantly more frequent among patients with CLD and COVID-19 than in patients with CLD and non-COVID-19 pneumonia (p = 0.040). COVID-19-associated SSC occurred predominantly in patients with NAFLD/NASH and metabolic risk factors. A total of 26.3% (n = 5/19) of patients with ACLD experienced hepatic decompensation after SARS-CoV-2 infection. CONCLUSIONS: About 20% of patients with CLD develop progressive cholestasis after SARS-CoV-2 infection. Patients with NAFLD/NASH and metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID-19.

SARS-CoV-2 vaccination response in patients with autoimmune hepatitis and autoimmune cholestatic liver disease.

BACKGROUND/AIMS: In this observational study, we explored the humoral and cellular immune response to SARS-CoV-2 vaccination in patients with autoimmune hepatitis (AIH) and patients with cholestatic autoimmune liver disease (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). METHODS: Anti-SARS-CoV-2 antibody titers were determined using the DiaSorin LIAISON and Roche immunoassays in 103 AIH, 64 PSC, and 61 PBC patients and 95 healthy controls >14 days after the second COVID-19 vaccination. The spike-specific T-cell response was assessed using an activation-induced marker assay (AIM) in a subset of individuals. RESULTS: Previous SARS-CoV-2 infection was frequently detected in AIH but not in PBC/PSC (10/112 (9%), versus 4/144 (2.7%), p = 0.03). In the remaining patients, seroconversion was measurable in 97% of AIH and 99% of PBC/PSC patients, respectively. However, in 13/94 AIH patients antibody levels were lower than in any healthy control, which contributed to lower antibody levels of the total AIH cohort when compared to PBC/PSC or controls (641 vs. 1020 vs. 1200 BAU/ml, respectively). Notably, antibody levels were comparably low in AIH patients with (n = 85) and without immunosuppression (n = 9). Also, antibody titers significantly declined within 7 months after the second vaccination. In the AIM assay of 20 AIH patients, a spike-specific T-cell response was undetectable in 45% despite a positive serology, while 87% (13/15) of the PBC/PSC demonstrated a spike-specific T-cell response. CONCLUSION: Patients with AIH show an increased SARS-CoV-2 infection rate as well as an impaired B- and T-cell response to SARS-CoV-2 vaccine compared to PBC and PSC patients, even in the absence of immunosuppression. Thus, antibody responses to vaccination in AIH patients need to be monitored and early booster immunizations considered in low responders.

Severe acute respiratory syndrome coronavirus-2-associated cholangiopathies.

PURPOSE OF REVIEW: SARS-CoV2 is a ß-coronavirus, isolated for the first time in Wuhan in December 2019. Bilateral interstitial pneumonia is the hallmark of this disease. Liver is the second viral target for frequency and AST and ALT elevation is a common finding. From February 2020, two different cholangiopathies have been reported in COVID-19 patients. The aim of this article is to review the cases so far described in order to share information and awareness about these new clinical entities. RECENT FINDINGS: SARS-CoV2 seems to trigger autoimmunity and two cases of primary biliary cholangitis (PBC) have been developed after viral infection while more than 30 patients have showed a rapidly progressing cholangiopathy with features of secondary sclerosing cholangitis (SSC). For what concerns SSC pathogenesis, a theory combining multiple hits is the most recognized. SUMMARY: Two different cholangiopathies have been reported in patients after severe-COVID-19. Attention should be paid to the development of cholestasis in ICU setting but above all after discharge and liver function tests should be, therefore, periodically performed. No treatment strategies are available and liver transplantation remains the last option in individuals with liver failure because of SSC. Other efforts are necessary to better understand the pathogenesis and to expand therapeutic options.

Corona again? SSC after a severe COVID-disease.

Secondary sclerosing cholangitis (SSC) is a severe complication of intensive care treatment in critically ill patients. It is characterized by rapid onset and severe chlolestasis with elevation of gGT. In contrast to primary sclerosing cholangitis, SSC-CIP has a distinct and timely well defined trigger and can have a rapid progress to cirrhosis and liver failure. In context of the COVID-19-pandemic, there are reports about patients, who developed SSC after a severe COVID-infection and intensive care treatment.We report on a 62-year old patient without any relevant pre-existing illnesses, who suffered from severe COVID-19 pneumonia with the need for long term ventilation. In the course of the disease he developed a critical-illness-polyneuropathy a pronounced cholestasis. After recovery from COVID-pneumonia, the PNP regressed but the cholestasis progressed. MRCP showed only irregular intrahepatic bile ducts, while EUS showed echogenic intraductal longitudinal structures characteristic for intraductal casts and for SSC-CIP. This was confirmed with ERC, where the complete necrotic bile ducts could be extracted and retrieved for histological and molecular analysis.The patient was included in a scheduled ERC-program to prevent a progress of SSC and the concomitant cirrhosis.SSC is an often missed diagnosis, which obviously can also occur in COVID-patients. In case of elevated liver function tests with cholestasis, EUS might be the key diagnostic method to characterize intraductal casts and identify those patients who should undergo ERC.

Effective use of switching biologics for ulcerative colitis complicated with pyoderma gangrenosum and primary sclerosing cholangitis.

Although prednisolone, granulocyte/monocyte apheresis, calcineurin inhibitor and anti-tumour necrosis factor (TNF) therapy are generally used, no treatment strategy for inflammatory bowel disease complicated with pyoderma gangrenosum (PG) has been established yet. Herein, we present the case of a 29-year-old man with ulcerative colitis (UC) complicated with primary sclerosing cholangitis. When UC relapsed and PG developed, prednisolone and granulocyte/monocyte apheresis were used; however, their therapeutic effects were deemed insufficient. After 2 weeks, adalimumab (ADA) induced remission; however, his UC and PG relapsed 20 weeks later. As a result of switching to infliximab, since a loss of response to ADA was deemed to have occurred, remission was reintroduced and subsequently maintained for 40 weeks. We conclude that anti-TNF-α antibodies might be selected as the first choice when PG and UC are refractory to treatment, and a switch to anti-TNFs should be considered when the effect is still insufficient.

Liver transplantation for post-COVID-19 sclerosing cholangitis.

Since identified in December 2019, COVID-19 has remained a pandemic across the globe. Although primarily a respiratory illness, the impact of COVID-19 on other end organs has been increasingly identified. The effect of COVID-19 on the liver has yet to be completely understood. We describe a case of COVID-19 leading to end-stage cholangiopathy and deceased donor liver transplantation (LT). A 64-year-old man with no underlying respiratory or liver disease presented with acute respiratory distress secondary to COVID-19 pneumonia requiring intubation. Several months after resolution of his respiratory symptoms, he developed transaminitis, worsening jaundice, abdominal pain and dark-coloured urine. Hepatic function remained severely impaired warranting LT 259 days following his initial COVID-19 diagnosis. Explant pathology demonstrated diffuse hepatic injury, onion skinning of the bile ducts and bile duct loss in scattered portal tracts. As more patients develop COVID-19-related complications, we suggest LT as an option for COVID-19-related end-stage liver disease.

A case of secondary sclerosing cholangitis due to COVID-19.

COVID-19 was first recognized by the World Health Organization (WHO) in December 2019 and declared a global pandemic in March 2020. Although COVID-19 primarily results in pulmonary symptoms, it is becoming apparent that it can lead to multisystemic manifestations. Liver damage with elevated AST and ALT is seen in patients with COVID-19. Although the etiology of liver damage is still debated, biliary damage is rarely seen. This case demonstrates a potential complication of COVID-19 in a previously healthy patient. The patient contracted COVID-19 in March 2020 and endured a complicated course including intubation, multiple readmissions, and chronic abdominal pain. He is now awaiting a liver transplant. Our case portrays biliary damage as an additional possible complication of COVID-19 and the importance of imaging in its diagnosis.

Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.

BACKGROUND & AIMS: Little is known about cholestasis, including its most severe variant secondary sclerosing cholangitis (SSC), in critically ill patients with coronavirus disease 19 (COVID-19). In this study, we analysed the occurrence of cholestatic liver injury and SSC, including clinical, serological, radiological and histopathological findings. METHODS: We conducted a retrospective single-centre analysis of all consecutive patients admitted to the intensive care unit (ICU) as a result of severe COVID-19 at the University Hospital Zurich to describe cholestatic injury in these patients. The findings were compared to a retrospective cohort of patients with severe influenza A. RESULTS: A total of 34 patients with severe COVID-19 admitted to the ICU were included. Of these, 14 patients (41%) had no cholestasis (group 0), 11 patients (32%, group 1) developed mild and 9 patients (27%, group 2) severe cholestasis. Patients in group 2 had a more complicated disease course indicated by significantly longer ICU stay (median 51 days, IQR 25-86.5) than the other groups (group 0: median 9.5 days, IQR 3.8-18.3, P = .001; and group 1: median 16 days, IQR 8-30, P < .05 respectively). Four patients in group 2 developed SSC compared to none in the influenza A cohort. The available histopathological findings suggest an ischaemic damage to the perihilar bile ducts. CONCLUSIONS: The development of SSC represents an important complication of critically ill COVID-19 patients and needs to be considered in the diagnostic work up in prolonged cholestasis. The occurrence of SSC is of interest in the ongoing pandemic since it is associated with considerable morbidity and mortality.