Introduction

Liver dysfunction in cardiogenic shock (CS) is common and is associated with increased mortality.¹ In critically ill patients, hypoxic hepatitis must be differentiated from cholestatic liver injury due to ischemic cholangiopathy, termed ‘secondary sclerosing cholangitis in critically ill patients’ (SSC-CIP), a rare progressive syndrome of rapid bile duct destruction and subsequent liver failure. SSC-CIP has primarily been recognized in critically ill populations experiencing trauma, burns, or acute respiratory distress syndrome, yet the underlying pathogenesis remains unclear.^2-5 As opposed to hepatocytes, which receive dual blood supply from the portal vein and hepatic artery, biliary epithelium uniquely relies solely on perfusion from the peribiliary plexus of hepatic artery branches.^{5, 6} In SSC-CIP, low perfusion states and biliary ischaemia are hypothesized to contribute to bile necrosis and development of typical biliary casts, identified mainly through endoscopic retrograde cholangiopancreatography (ERCP) and less commonly magnetic resonance cholangiopancreatography (MRCP).⁷ Evidence supporting this hypothesis of ischaemia to vulnerable intrahepatic biliary epithelium is lacking. Potential risk factors for the development of SSC-CIP such as high-dose vasopressors, positive pressure mechanical ventilation, ketamine use, toxic bile composition, or biliary infections have been discussed.⁵ Prognosis of SSC-CIP is poor, and liver transplantation often represents the only long-term treatment option.^{2, 3} Further, CS patients suffer from severe organ hypoperfusion,⁸ yet the incidence of SSC-CIP in this critically ill population is poorly described. Given the limited evidence and severity of this syndrome, we aimed to further investigate SSC-CIP in the context of CS.

Methods

24 251 total CS patients admitted between 1 January 2010 and 31 December 2023 were retrospectively screened for the diagnosis of SSC-CIP across nine German tertiary care centers. Patients in which SSC-CIP was suspected though not confirmed were excluded from analysis following a critical internal review of individual cases. Following identification of CS patients with a diagnosis of SSC-CIP, chart review of baseline characteristics, laboratory values, SSC-specific imaging, diagnostics, and outcomes as per pre-selected variables was performed.

Results

Discussion

This is the first study to report on the incidence of SSC-CIP in the context of CS. SSC-CIP was a rare but serious complication with a prevalence of 0.14% in a cohort of 24 251 CS patients. True prevalence of SSC-CIP in the critically ill is unclear, as case numbers often reported from liver transplant centers are subject to selection bias.^{9, 10} Further, the observed in-hospital mortality was higher than reported in most CS cohorts, though rates were consistent with findings from previously reported SSC-CIP studies.^{3, 4} Despite extensive length of stay in the ICU, most SSC-CIP diagnoses were made after 1 month using ERCP, reflecting the difficulties of establishing the diagnosis. While liver values rise quickly in CS and development of hypoxic hepatitis is common,¹¹ early clinical suspicion of SSC-CIP in patients with increased cholestatic laboratory values should prompt timely consultation with gastroenterology. Leonhardt et al. found a cholestatic injury on laboratory analysis after a median of 7 days in a cohort of 16 SSC-CIP patients with a median ICU stay of 31 days.⁹ Confirmation of SSC-CIP diagnosis has been reported in cohorts following a median of 44⁴ and 89 days² in the ICU. This delay in diagnosis may be explained by reluctance to perform invasive diagnostic imaging in haemodynamically unstable patients, and frequent re-evaluation of optimal ERCP timing should follow interdisciplinary discussion. Further, high ERCP utilization indicates this may be the diagnostic tool of choice, though interventional treatment with bile cast removal has not shown to improve prognosis. Removal of bile casts and stent implantation with ERCP in nearly half of SSC-CIP cases proved a safe procedure, with only 5.7% developing cholangiosepsis in our cohort. Though reports of improved biliary drainage and drop in cholestatic laboratory values following ERCP intervention suggest short-term relief,^{6, 12} progressive biliary destruction leading to cirrhosis does not seem to be halted. Liver transplantation is the only viable treatment option should SSC-CIP progress to biliary cirrhosis, and early evaluation of transplant candidacy is essential. Only two patients (5.7%) in our cohort underwent successful liver transplantation for SSC-CIP and were alive after 3 years, making comparison with other cohorts difficult. Observed low liver transplantation rates and high mortality in CS reflect poor transplant candidacy and lack of feasible treatment options in these patients. CS patients may be particularly vulnerable to a rapid and severe course of SSC-CIP, especially in the context of low-perfusion states and the need for mechanical circulatory support. SSC-CIP patients lack prior history of liver disease or biliary obstruction, and rapid development of biliary cirrhosis and liver failure in relatively young and previously healthy individuals calls for further research into risk factors and treatment options to improve exorbitantly high mortality rates.

Conclusions

Long duration of ICU stay and high in-hospital mortality in SSC-CIP should encourage early suspicion of disease in patients suffering CS and cholestatic liver injury, triggering a timely diagnostic workup to identify potential transplant candidates prior to development of biliary cirrhosis. Future studies should aim to improve understanding of triggering factors und management of SSC-CIP to improve outcomes.

Conflict of interest

The authors declare no conflict of interest.

Funding

There was no funding for this study.