Case of nivolumab-induced sclerosing cholangitis: lessons from long-term follow-up

Abstract

Nivolumab is an immune checkpoint inhibitor used to treat multiple solid-organ malignancies. While many of its immune-related adverse events are well established, nivolumab-induced sclerosing cholangitis remains poorly characterised, with no defined diagnostic criteria. Moreover, data regarding long-term outcomes are particularly lacking. We present a biopsy-proven case of nivolumab-induced sclerosing cholangitis, which uniquely captures 18 months of follow-up post-treatment. Our case highlights key features of intrahepatic subtype sclerosing cholangitis and suggests durable response to corticosteroid therapy.

Long-term sequelae of drug-induced liver injury

“…44,45 However, recently a large number of cases presenting with clinical, biochemical and histological evidence of secondary sclerosing cholangitis have been reported. [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] In contrast with the most commonly reported hepatitis-like pattern, these patients have a cholestatic pattern of injury, with diffuse biliary duct dilatation and thickening of the bile ducts. [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Biliary tract dilatation without biliary obstruction is observed in almost 80% of cases according to a recent review.…”

“…[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] In contrast with the most commonly reported hepatitis-like pattern, these patients have a cholestatic pattern of injury, with diffuse biliary duct dilatation and thickening of the bile ducts. [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Biliary tract dilatation without biliary obstruction is observed in almost 80% of cases according to a recent review. 61 Furthermore, in 30% of patients, multiple strictures were seen intrahepatically and diffuse hypertrophy was found in the extrahepatic bile ducts in the vast majority of cases (>90%).…”

“…Endoscopic biopsies from the thickening bile ducts have shown lymphocytic infiltration with predominantly CD8+T-cytotoxic cells. 46,48,[51][52][53][54]59,60 Thus, accumulating literature on sclerosing cholangitis developing in patients treated with immune checkpoint inhibitors has increased our knowledge of this form of DILI considerably. For the first time since drug-induced secondary sclerosing cholangitis was reported, [28][29][30][31][32][33][34][35][36][37][38][39][40][41] biliary tract histology has been available and has almost invariably demonstrated infiltration of cytotoxic T CD8+ lymphocytes, suggesting that an alteration in the balance between effector and regulatory T cells is associated with immune-mediated hepatobiliary injury.…”

Immune-Related Uncommon Adverse Events in Patients with Cancer Treated with Immunotherapy

“…The time to onset oscillates from super acute presentations after first treatment administration to more than 11 months after initiation. As in non-ICI related disease, cholangitis can classically manifest with Charcot’s triad, as fever with chills, right upper abdominal pain, and jaundice, sometimes associated with hypotension and altered mental status (Reynold’s pentad) [ 192 , 193 , 194 , 195 , 196 ]. Rarely, routine blood analysis can evidence asymptomatic cases [ 197 ].…”

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…A majority of ILICI cases are hepatocellular, and histologically, anti-CTLA-4 agents have been associated with a form of granulomatous hepatitis and fibrin ring-type granulomas, along with central vein endotheliitis, while anti-PD-1 agents are associated with non-granulomatous forms of injury including zone 3 or panlobular inflammation and sinusoidal histiocytosis [106]. However, an increasing number of cases describing a form of immune-mediated SC have appeared [107][108][109][110]. Gudnason et al reviewed available magnetic resonance cholangiopancreatography imaging from 25 patients in an unselected Icelandic DILI cohort and found that ten (40%) of these patients had radiographic features of SC [111].…”