Pembrolizumab-induced large duct cholangiopathy: Diagnosis and follow.up imaging.

Immune-checkpoint inhibitor mediated hepatobiliary injury is an emerging concern in cancer treatment. Most of these adverse reactions are attributed to nivolumab and are characterized by panlobular hepatitis. Large duct cholangiopathy related to these drugs is extremely rare. We present a case of adenocarcinoma of lung treated with pembrolizumab who developed biochemical and imaging features consistent with cholangiopathy characterized by common bile duct dilatation, wall enhancement, and gallbladder wall edema. On follow-up in the fourth month, the imaging features persisted despite the normalization of liver enzymes. To the best of our knowledge, this is the first description of diagnosis and follow-up imaging of pembrolizumab-related cholangiopathy in imaging literature.

Introduction

Immune-checkpoint inhibitors are known to be associated with hepatobiliary injury. However, most of these adverse reactions are attributed to nivolumab and are characterized by panlobular hepatitis. Large duct cholangiopathy related to these drugs is extremely rare. We present a case of adenocarcinoma of lung treated with pembrolizumab who developed biochemical and imaging features consistent with cholangiopathy characterized by common bile duct dilatation, wall enhancement, and gallbladder edema.

Case Report

A 66-year-old man presented with cough, hoarseness of voice, and right shoulder pain for 1 month. He was a known diabetic and hypothyroid on oral medication. No personal or family history of cancer or liver disease was present. A chest radiograph done in October 2019 showed left hilar mass and a PET-CT showed left lung mass with bone metastases which explained the shoulder pain. No abdominal metastasis was detected. The liver was mildly enlarged without any other abnormalities. Bile ducts were normal [Figure 1a]. Biopsy done on late November 2019 from the lung mass showed adenocarcinoma that was negative for anaplastic lymphoma kinase (ALK) rearrangement and endothelial growth factor receptor (EGFR) mutation. Liver function test was normal. Systemic chemotherapy with palliative intent was initiated with pemetrexed, carboplatin, and pembrolizumab in December 2019. The patient tolerated the first cycle of chemotherapy well. Following the second cycle of chemotherapy, mild to moderate elevation of liver enzymes was noted as followed - serum alkaline phosphatase [ALP] [232 U/L; normal range 38-126 U/L], gamma-glutamyl transferase [GGT] [981 U/L; normal range 15-73 U/L], alanine aminotransferase [ALT] [85 U/L; normal range 17-59 U/L], and aspartate aminotransferase [AST] [174 U/L; normal range 0-50 U/L. He was observed at this point. In January 2020, before the initiation of the third cycle, he had marked elevation of serum ALP [1843 U/L] and GGT [2097 U/L] with mild to moderate elevation of ALT [165 U/L] and AST [238 U/L]. His bilirubin and albumin levels were normal. A contrast-enhanced computed tomography [CECT] scan of thorax and abdomen showed a stable neoplastic disease process. The liver was of pre-therapy size without any focal or diffuse parenchymal change. Marked diffuse dilatation of common bile duct was noted associated with enhancement of duct walls and smooth distal tapering [Figure 1b]. Gallbladder showed wall edema. No calculus was detected on screening ultrasound. Central intrahepatic biliary radicles (maximum diameter 3 mm) were mildly prominent [Figure 1c]. The total leukocyte count was normal. Hepatitis viral serology was negative. An upper gastrointestinal endoscopy ruled out ampullary obstruction. Since there was no clinical feature of obstructive jaundice or cholangitis, we suspected immune-mediated liver injury secondary to chemotherapy. Liver biopsy was not done considering the presence of acute liver injury and potential non-contributory biopsy findings. Transmainitis [Grade 2 as per Common Terminology Criteria for Adverse Events (CTACE) version 5.0] along with bile duct dilatation was attributed to pembrolizumab as the same has not been reported with pemetrexed and carboplatin. Pembrolizumab was withheld and tablet ursodeoxycholic acid [UDCA] [150 mg twice daily] was started. Liver enzymes were serially monitored [Figure 2]. In late February, near-normalization of enzymes [ALP 292 U/L; GGT 357 U/L; ALT 40 U/L and AST 14 U/L] was observed. Upper abdominal ultrasound showed persistent dilatation of common bile duct but decreased gallbladder wall edema. Pembrolizumab was restarted in view of near normal ALT & AST [Figure 2]. Liver enzymes, repeated in late April 2020, were normal. CT chest and abdomen done at this time showed stable cancer with persistent dilatation of common bile duct and wall enhancement [Figure 1d]. A final diagnosis of pembrolizumab-induced large duct cholangiopathy was made. The patient is currently on pembrolizumab (completed 9 cycles) and pemetrexed maintenance and his disease is under control.

Figure 1

Serial coronal reformatted contrast-enhanced CT through upper abdomen. (a) Pre-treatment image shows mildly enlarged liver and normal common bile duct (diameter 7 mm) (arrow). (b and c) CT done immediately before discontinuation of pembrolizumab shows dilated common bile duct (15 mm) (solid arrow in b) with wall enhancement. Gallbladder shows wall edema (open arrow). Central intrahepatic bile ducts are also dilated (arrow in c). (d) CT done approximately four months later shows persistent dilatation of common bile duct (arrow)

Figure 2

Graph showing serial trend of liver enzymes with clinical events marked by solid yellow arrows. (UDCA = ursodeoxycholic acid; CT = computed tomography). Notice normalization of liver enzymes to pre-treatment level at the end of observation period. X – axis represents time since Pembrolizumab was started

Discussion

Anti-PD-1 antibody [nivolumab, pembrolizumab] and anti-PD-L1 antibody [atezolizumab, durvalumab] are increasingly being used in cancer treatment. Hepatic immune-related adverse reactions [irAE] related to these drugs are most attributed to nivolumab and are characterized by panlobular hepatitis.[1] Cholangiopathy related to nivolumab is rare and characterized by extrahepatic bile duct dilation with thickening of bile duct wall and disproportionate increase of ALP and GGT relative to ALT and AST.[2] These features were present in our patient. Pathological features include sclerosing cholangiopathy associated with CD8+ predominant lymphocytic infiltration.[1] Only isolated case reports of pembrolizumab-related cholangiopathy are available in the literature.[34] Case reports have shown a similarity between nivolumab- and pembrolizumab-related cholangiopathy, both in clinical features and histopathology.[134] Typically, these patients do not respond well to corticosteroid therapy but may benefit from UDCA therapy.[3] Only one case report has indicated that imaging features of cholangiopathy may persist even after one year; however, in that particular case, the liver functions also remained deranged.[3] In our case, the imaging features persisted even after enzymes normalized. We diagnosed pembrolizumab-related cholangiopathy because of acute biliary dilatation with disproportionate ALP and GGT elevation and normalization of enzymes following discontinuation of pembrolizumab with UDCA therapy. Pemetrexed and carboplatin are not known to cause similar cholangiopathy. The patient did not have a previous history of liver disease or clinical-endoscopic evidence of duct obstruction or cholangitis. We did not perform a biopsy as it was deemed non-contributory with a high risk-benefit ratio. According to the modified Naranjo algorithm, the ADR probability score was 6 [Table 1], which makes cholangiopathy as a “probable” adverse effect of pembrolizumab in our case.[5] The severity of the transaminitis was grade 2 as per CTCAE criteria [version 5.0]. We could not asses the severity of cholangiopathy as it is not a recognised adverse event as per CTCAE criteria.

Table 1

Drug ADR probability score* according to the modified Naranjo algorithm in our case

Conclusion

Pembrolizumab may cause cholangiopathy that presents with acute biliary dilatation and elevated ALP and GGT. Biliary dilatation may persist for months even after liver enzymes are normalized. In patients receiving pembrolizumab with acute elevation of ALP and biliary dilatation, this adverse reaction should be considered after other possible hepatotoxic agents and obstructive biliopathy are ruled out.

Declaration of patient consent

The authors certify that appropriate patient consent was obtained.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.